Synthesis and evaluation of 4-amino-3,4-dihydro-2H-naphthalen-1-one derivatives as mast cell stabilising and anti-inflammatory compounds

Article abstract of DOI:10.1016/j.ejmech.2008.02.009

A novel series of amine and amide derivatives of 4-amino-3,4-dihydro-2H-naphthalen-1-one were synthesised. The amine derivatives were evaluated for mast cell stabilising activity in rodent mast cell preparations against the reference compound disodium cromoglycate and found to possess significant activity in vitro. The amide compounds were evaluated in an in vivo murine model for anti-inflammatory activity.

Full text of DOI:10.1016/j.ejmech.2008.02.009

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European Journal of Medicinal Chemistry 43 (2008) 2891e2900
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Short communication
Synthesis and evaluation of 4-amino-3,4-dihydro-2H-naphthalen-1-one
derivatives as mast cell stabilising and anti-inflammatory compounds
*
James W. Barlow, John J. Walsh
Department of Pharmacognosy, School of Pharmacy, University of Dublin, Trinity College, Dublin 2, Ireland
Received 17 September 2007; received in revised form 1 February 2008; accepted 8 February 2008
Available online 29 February 2008
Abstract
A novel series of amine and amide derivatives of 4-amino-3,4-dihydro-2H-naphthalen-1-one were synthesised. The amine derivatives were
evaluated for mast cell stabilising activity in rodent mast cell preparations against the reference compound disodium cromoglycate and found to
possess significant activity in vitro. The amide compounds were evaluated in an in vivo murine model for anti-inflammatory activity.
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: 4-Amino-3,4-dihydro-2H-naphthalen-1-one; Mast cell stabilising; Anti-inflammatory
1. Introduction
generation antihistamines and immunomodulating molecules,
both for topical and systemic application [4,5]. In addition,
the newer class of leukotriene antagonists represents an ad-
vance in the adjunctive treatment of asthma [6]. Novel immu-
nological therapies, such as the use of the anti-IgE therapy
Omalizumab [7] are undoubtedly exciting developments, yet
the associated costs with biotechnological therapies can be
prohibitive. Thus the development of novel small molecules
for the treatment of allergic disease remains an important
area of research.
In traditional medicine systems, members of the Pterida-
ceae have been utilised as smooth muscle relaxants. Activity
has been ascribed to the presence of indane sesquiterpenes
[8]. Synthetic indane derivatives based on the indanone
pterosin Z, found in Pityrogramma and Pteris species were
then investigated for their activities as smooth muscle relax-
ants [9,10]. Further research into the development of synthetic
indane and aminoindane analogues of these molecules has
resulted in the discovery of several active molecules [11,12],
including aminoindanone 1 (Fig. 1). Interestingly, these
molecules exhibited a pharmacological profile encompassing
not only smooth muscle relaxant, but also marked anti-
inflammatory and mast cell stabilising activities. In light of
these discoveries, the present study describes the synthesis
and preliminary pharmacological screening of a series of tetra-
lone derivatives, to investigate the effect of ring expansion of
The classical role of the mast cell as the origin of mediators
involved in allergic disease and the response to parasitic infes-
tation has been significantly expanded in the recent past, and
new potential roles continue to be elucidated for this heteroge-
neous cell type and its circulating counterpart, the basophil.
For instance, important contributory roles in autoimmune dis-
eases such as multiple sclerosis and rheumatoid arthritis have
been ascertained [1], and also in biological processes includ-
ing wound healing and angiogenesis [2]. Increased prolifera-
tion and activation of mast cells occur in conditions such as
irritable bowel syndrome [3]. Potential therapeutic interven-
tion during both developmental and maturational stages of
mast cell development may provide future therapies, while es-
tablished agents including cromoglycate and nedocromil target
the activation and degranulation of these cells. Indeed, the
search for more potent and efficacious small molecule thera-
pies for the treatment of allergic and inflammatory disease
has in recent years seen the development of several new
Abbreviations: AA, arachidonic acid; ACN, 1,10-azobis(cyclohexanecarbo-
nitrile); DCM, dichloromethane; DMAP, 4-(dimethylamino)pyridine; DSCG,
disodium cromoglycate; NBS, N-bromosuccinimide; RPMC, rat peritoneal
mast cell.
* Corresponding author. Tel.: þ353 1 8962806; fax: þ353 1 8962804.
E-mail address: jjwalsh@tcd.ie (J.J. Walsh).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.02.009

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J.W. Barlow, J.J. Walsh / European Journal of Medicinal Chemistry 43 (2008) 2891e2900
cyclopentylamino ring was achieved by substitution of 4
with cyclopentylamine in basic media. Acyl hydrolysis using
K2CO3 in methanol followed by oxidation with Cr(VI) (Jones
reagent) in acetone [14] yielded ketone 6 in acceptable yield.
Alkylation (7aeh) or acylation (7i and j) was accomplished
using standard N-alkylation or N-acylation conditions [15].
Some of the amides of Scheme 2 11a, b and e have already
been reported in the patent literature [16], where they have
been utilized as intermediates in the synthesis of 1,2,3,4-
tetrahydro-4-oxo-1-naphthylureas and thioureas, developed
for use as animal growth promoters. Their preparation in-
volved the benzylic oxidation of tetrahydro-1-naphthylamines
using one of a variety of oxidants. In contrast, our synthesis of
amide derivatives 11aee, as depicted in Scheme 2, involved
benzylic bromination of a-tetralone and reaction with a strong
nucleophile, azide. Reductive coupling of azide 10 under
hydrogenation conditions (H2/Pd/C/EtOAc/EtOH) using either
anhydride for 11a and b or pentafluorophenyl esters for 11cee
of the parent acids afforded good yields of the required
amides. To investigate the importance of the intact ring struc-
ture in derivatives of 6, molecules 12 and 14 were synthesized,
as shown in Schemes 3 and 4. Benzylic bromination of a-
tetralone and substitution with N-benzylmethylamine afforded
compound 12, while compound 14 was obtained via bromina-
tion of 20-methylacetophenone, and reaction with N-benzylme-
thylamine [17].
Fig. 1. Aminoindanone 1.
the core indanone skeleton on pharmacological activity, con-
centrating on their protective effects in models of inflamma-
tion and immunological phenomena.
2. Chemistry
Two primary synthetic routes to the novel tetralone deriva-
tives were employed; that for the tertiary amine and amide
derivatives is shown in Scheme 1 and that for secondary
amides is shown in Scheme 2. Direct bromination and substi-
tution of a-tetralone, akin to the methodology used by Walsh
and co-workers [12] in their synthesis of indanone 1 was
precluded due to the formation of unacceptable quantities of
aromatised product (1-naphthol) upon substitution with amine
nucleophiles. Therefore, the selected starting material was
alcohol 2. WohleZiegler bromination [13] of the protected al-
cohol 3 afforded the bromo acetate 4. Incorporation of the
3. Pharmacology
3.1. 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 [11]. Cell populations
Scheme 1. Synthetic methods for the preparation of 4-(cyclopentylamino)-1,2,3,4-tetrahydro-1-naphthalenone derivatives 7aej.

J.W. Barlow, J.J. Walsh / European Journal of Medicinal Chemistry 43 (2008) 2891e2900
2893
Scheme 2. Synthetic methods for the preparation of secondary amides 11aee.
were of >90% viability and mast cells comprised 1.4% of the
total cell count. The results are shown in Table 1. Compound
7c was also evaluated in more detail using three elicitors of
histamine release in the same cell population; in addition to
doseeresponse studies using Compound 48/80, these studies
were additionally performed using the degranulating agents cal-
cium ionophore A23187 and the lectin Concanavalin A. The
IC50 values using each of these elicitors are shown in Table 2.
compounds retained significant activity (67% and 65% inhibi-
tion, respectively). Conversely, substitution of the benzyl
group by electron-donating trimethoxy groups (7g) resulted
in abolition of mast cell stabilising activity. Finally, a large
planar 20-naphthalenyl substituent on the amino group (7h)
did not greatly reduce activity as compared to the benzyl
group, affording 77% protection against degranulation. The
doseeresponse studies undertaken with the most active
compound tested, 7c, exhibited in all cases dose-dependent
inhibition of histamine release, with IC50 values of 2.4 mM,
0.28 mM and 7.2 mM against Compound 48/80, ionophore
and concanavalin A, respectively, as shown in Table 2. Amide
compounds 7i and j and 11aee were not tested for mast cell
stabilising activity and although acetamide 7i did not affect
oedema induced by arachidonic acid, phenylacetamide 7j
significantly reduced the oedema (Table 3). Within the second-
ary amide series 11aee, compound 11b showed mild (11%)
inhibition of arachidonic acid-induced oedema.
3.2. Inhibition of murine ear oedema
Inflammation of murine ears was achieved by topical appli-
cation of arachidonic acid (AA) using a previously reported
method [18]. Test compounds were evaluated for ability to
inhibit oedema and compared to the standard inhibitor
indomethacin. Compounds showing activity in this study are
shown in Table 3.
4. Results
5. Discussion
Several of the novel amine derivatives of a-tetralone (7a, c,
d, f and h) displayed strong in vitro inhibitory effects against
secretagogue-induced degranulation of rat peritoneal mast
cells, as illustrated in Table 1. The methylated derivative 7a
was capable of inhibiting histamine release from rat peritoneal
cells by 43%, whereas allylation to yield 7b actually had the
opposite effect within this series of molecules. Introduction
of a bulky planar benzyl 7c had a profound effect on activity,
resulting in complete inhibition of histamine release at
the concentration tested. Activity was reduced slightly by the
presence of electron-withdrawing para-substituents on the
benzyl ring such as nitrile (7d) or nitro (7f), although both
Five of the novel amines tested as described above were
better than the reference compound disodium cromoglycate
(DSCG), which inhibited histamine release by 10% in the
mast cell stabilising assay. In addition, within the analogous
indanone series, both N-methyl and N-allyl derivatives
exhibited mast cell stabilising activity, the reported inhibitory
effect of 1 being 90%, albeit using slightly different challenge
conditions [12]. In the same work, the benzylated indanone
analogue of 7c inhibited release by 83% whereas the indanone
amides were wholly ineffective; therefore amides 7i and j
were not evaluated in the present study for mast cell stabilising
activity. The requirement for the core skeletal structure of the
Scheme 3. Synthetic method for the preparation of 12.
Scheme 4. Synthetic method for the preparation of 14.

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J.W. Barlow, J.J. Walsh / European Journal of Medicinal Chemistry 43 (2008) 2891e2900
Table 1
Mast cell stabilising activity of synthesised compounds and the reference com-
pound disodium cromoglycate in RPMC stimulated by Compound 48/80
Table 3
Inhibition of arachidonic acid-induced mouse ear oedema
Compound
% Inhibition
P
Compound
NeR (7aeh)
% Inhibition
7i
2
53
11
74
NS
7a
7b
7c
CH3
CH2]CHCH2
43 (17)
NI
7j
11b
<0.05
NS
<0.0001
Indomethacin
99 (1)
67 (5)
Values are the mean of at least 5 animals; test compounds and indomethacin
administered at a dose of 300 mg earꢁ1; arachidonic acid administered at
a dose of 1 mg earꢁ1; NS, not significant.
7d
7e
caused by antigen, in an energy-dependent process [19]. How-
ever, mast cells from all species do not respond equally to
Compound 48/80. Therefore, we employed degranulating
agents operating through different mechanisms. Unlike
Compound 48/80, concanavalin A induces the cross-linking
of IgE molecules on the mast cell membrane, leading to the
activation of the adenylate cyclase system, and subsequent
histamine release [20]. The intracellular [Ca2þ] is known to
increase following antigeneantibody interactions, and selec-
tive ionophores such as A23187 have an important role in
mechanistic studies [21]. It is interesting to note that 7c
inhibited histamine release induced by all three elicitors
employed in the study.
The results of the anti-inflammatory assay contrast with
those observed for the indanone congeners. In this study, 7i
did not prevent arachidonic acid-induced oedema, whereas
in previous work the indanone analogue of 7i afforded almost
complete protection from arachidonic acid provocation, albeit
at less than half the challenge dose of elicitor [12].
NT
7f
65 (7)
NI
7g
7h
77 (4)
12
14
NI
NI
DSCG
10 (3)
Values are mean of at least five experiments, standard error in parentheses; test
compounds and DSCGat a concentration of 2 ꢀ 10ꢁ5 M; challenge with
Compound 48/80 at a concentration of 0.2mg mlꢁ1 for 5 min; NI, no
inhibition at concentration tested; NT, not tested.
6. Conclusions
most active compounds, as typified by 7c, was seen from the
fact that neither compound 12 nor compound 14 possessed
any ability to prevent Compound 48/80-induced mast cell
degranulation. Neither of these molecules possessed any
mast cell stabilising activity, emphasising the need for the
core ring system. The doseeresponse studies undertaken
with 7c revealed interesting results. Compound 7c prevented
release by all three elicitors in a dose-dependent fashion. As
these releasing agents act through different pathways to induce
histamine release, it is difficult to speculate on the manner by
which the compounds are stabilising the RPMCs. Compound
48/80 is a hypotensive polymer amine which induces hista-
mine release with similar kinetic characteristics to those
Of the novel amine derivatives of 4-amino-3,4-dihydro-2H-
naphthalen-1-one tested, the benzylated derivative 7c showed
the best ability to inhibit degranulation of Compound 48/80-
induced rat peritoneal mast cell degranulation. The abolition
of activity seen with compounds 12 and 14 demonstrates the
need for both the tetralone nucleus and the aminocyclopentyl
substituent. Further studies to ascertain whether compound 7c
possesses ability to prevent degranulation caused by other
secretagogues are envisaged. However, it has been ascertained
that the expansion of the indanone ring, as contained in the pat-
ented compounds referenced above [12], is permissible without
loss of mast cell stabilising activity. The amide derivatives
tested in the murine oedema assay, however, displayed less
anti-inflammatory activity than their indanone congeners,
only the N-phenylacetamide (7j) showing significant inhibition.
Table 2
Protective activity of 7c against degranulation of RPMC induced by various
elicitors
Elicitor
IC50 (mM)
7. Experimental protocols
Compound 48/80
Calcium ionophore A23187
Concanavalin A
2.4
0.28
7.2
7.1. Chemistry
Best-fit values were obtained from a mean of four experiments; calcium
ionophore and Concanavalin A used at concentrations of 1 and 20 mg mlꢁ1
Melting points were obtained using an Electrothermal appa-
ratus, and are uncorrected. Infrared spectroscopy (IR) of test
samples was performed on a Perkin Elmer Paragon 1000
,
respectively; buffer system used with both elicitors was mast cell medium
(MCM).

J.W. Barlow, J.J. Walsh / European Journal of Medicinal Chemistry 43 (2008) 2891e2900
2895
FT-IR. Nuclear magnetic resonance (NMR) spectroscopy was
performed using a Bruker DPX-400 instrument, at 400.13
MHz for proton (1H) magnetic resonance and 100.61 MHz
for carbon (13C) spectra. Gas chromatographic-mass spectral
data (GCMS) were obtained using a Saturn GC/MS 2000
[CP-3800 Gas Chromatograph]. High resolution mass spectros-
copy (HRMS) was performed using a Micromass LCT instru-
ment, operating in ESþ mode. Flash column chromatography
was performed using Silica Gel, Grade 9385, 230e400 mesh,
OCH ), 7.20e7.30 (m, 3H, 3 ꢀ Ar-H ), 7.38, 7.55 (each d, J ¼
7.5 Hz, 1H, Ar-H8); 13C NMR dppm ¼ 20.9 (CH3), 23.4,
23.5 ꢀ 2, 23.8, 24.4, 25.4, 25.6 (4 ꢀ CH2), 32.8, 33.8, 33.9
(2 ꢀ CH2), 52.9 and 53.4 (NCH), 56.7 and 56.9 (NCHAr),
69.3 and 69.9 (OCHAr), 126.5 and 126.7 (tert. C), 127.7,
127.9, 128.2, 128.5, 128.8 (3 ꢀ tert. C), 134.1 and 134.4,
140.2 and 140.7 (2 ꢀ quat. C), 170.1 and 170.2 (C]O);
MS, m/z, (RI) 274 (M þ 1, 25), 213 (100), 185 (5), 129 (13),
86 (14).
˚
60 A (Merck Laboratories). For thin layer chromatographic
(TLC) procedures, aluminium foil plates pre-coated with Silica
Gel 60 F254 were used (Merck Laboratories). TLC plates were
visualised under ultraviolet light at 254 nm.
7.1.3. 4-(Cyclopentylamino)-1,2,3,4-tetrahydro-1-
naphthalenone (6)
To a solution of 5 (0.25 g, 0.92 mmol) in methanol/water
(10 ml, 1:1) was added excess potassium carbonate (0.25 g,
1.83 mmol). The reaction was heated under reflux for 1 h,
monitored by GCMS. On completion, the reaction mixture
was filtered and the solvent removed in vacuo, using toluene
to azeotropically distil any residual water. To the residue
was added acetone (10 ml) and Jones reagent (1.4 ml), the
latter was added drop-wise over 30 min to the ice-cooled re-
action. On appearance of the green Cr2(SO4)3, anhydrous
sodium sulphate (0.30 g, 2.12 mmol) was added. After 2 h,
the solvent was evaporated, and the reaction separated using
ether/water. After three washings with ether (3 ꢀ 20 ml), the
combined organic extracts were filtered and the solvent re-
moved in vacuo. The residue was purified by flash column
chromatography on silica gel (eluant: pet ether/ethyl acetate,
1:1) to yield the amine as a brown oil, which crystallised
slowly on standing (83 mg, 60%): IR (CCl4, n) 2955,
7.1.1. 4-Bromo-1,2,3,4-tetrahydro-1-naphthalenyl
acetate (4)
To a stirred solution of 3 (1 g, 5.26 mmol) in carbon
tetrachloride (30 ml) was added N-bromosuccinimide (g, 7.89
mmol) and a catalytic amount of 1,10-azobis(cyclohexanecar-
bonitrile) (ACN). The reaction mixture was heated under
reflux, and upon reaching reflux, the heat source was removed
and replaced by two 240 W lamps, the light from these
focused on the reaction, stirring vigorously all the time. On
completion of the reaction a colour change from deep orange
to clear was observed. The reaction mixture was then filtered
to remove the insoluble N-hydrosuccinimide, and the solvent
was removed in vacuo, using the lowest temperature possible.
The residue was purified by flash column chromatography on
silica gel (eluant: pet ether/ethyl acetate, 10:1) to yield the
benzylic bromide as a stereoisomeric mixture (0.83 g, 59%).
The bromide was isolated as oil, with the following physical
properties: IR (CCl4, n) 2960, 1732, 1438, 1370, 1236, 1025,
2868, 1689, 1600, 1453, 1284 cmꢁ1 1H NMR (CDCl3,
;
400 MHz): dppm ¼ 1.35 (m, 2H, CH2), 1.53 (m, 2H, CH2),
1.69 (m, 2H, CH2), 1.84 (m, 2H, CH2), 2.04e2.24 (m,
2H, COCH2CH2), 2.49 (dd, J ¼ 7, 4.5 Hz, 1H, CH2CO),
2.93 (dd, J ¼ 10, 4.5 Hz, 1H, CH2CO), 3.25 (quintet,
J ¼ 6.5 Hz, 1H, CH2CHCH2), 3.91 (dd, J ¼ 6.0, 3.5 Hz,
1H, CHCH2CH2CO), 7.29 (m, 1H, Ar-H), 7.47 (m, 2H,
2 ꢀ Ar-H), 7.95 (d, J ¼ 7.5 Hz, 1H, COAr-H); 13C NMR
dppm ¼ 23.4, 23.5, 28.2, 32.9, 33.6, 34.5 (5 ꢀ CH2), 53.5,
56.9 (2 ꢀ CH), 126.6, 127.0, 127.6 (3 ꢀ tert. C), 131.4
(quat. C), 133.0 (tert. C), 146.1 (quat. C), 197.6 (C]O);
MS, m/z, (RI) 230 (M þ 1, 100), 229 (Mþ, 44), 115 (4);
HRMS (M þ H)þ 230.1561, C15H20NO requires 230.1545.
964 cmꢁ1
;
1H NMR (CDCl3, 400 MHz) dppm ¼ 2.05, 2.18
(each s, 3H, CH3), 2.03e2.12 (m, 2H, CH2), 2.29 (m, 1H,
CH2), 2.47 (m, 1H, CH2), 5.50, 5.61 (each bm, 1H,
BrCHCH2), 6.07 (m, 1H, OCHCH2), 7.25e7.35 (m, 3H,
3 ꢀ Ar-H ), 7.42 (m, 1H, Ar-H ); 13C NMR dppm ¼ 20.9 ꢀ 2
(CH3), 24.4 and 25.2 (CH2), 27.9 and 30.7 (CH2), 49.4 and
49.8 (BrCHCH2), 67.7 and 69.7 (OCHCH2), 127.3, 127.8,
128.3, 128.5, 128.6, 130.1, 130.1, 130.2 (4 ꢀ tert. C), 132.8,
134.2 (quat. C), 137.0, 137.1 (quat. C), 169.8 and 170.4
(C]O).
7.1.2. 4-(Cyclopentylamino)-1,2,3,4-tetrahydro-1-
naphthalenyl acetate (5)
To a solution of 4 (0.83 g, 3.08 mmol) in DCM (10 ml) was
added cyclopentylamine (0.60 ml, 6.16 mmol) and triethyl-
amine (0.86 ml, 6.16 mmol). The reaction was refluxed for
9 h, the solvent removed in vacuo, and the residue purified
by flash column chromatography on silica gel (eluant: pet
ether/ethyl acetate, 2:1) to yield the amine as a stereoisomeric
mixture (0.25 g, 30%) a brown oil, with the following physical
properties: IR (CCl4, n) 2954, 2867, 1733, 1452, 1371, 1240
7.1.4. General procedure for the preparation
of tertiary amines (7aeh)
Mixtures of 4-(Cyclopentylamino)-1,2,3,4-tetrahydro-1-
naphthalenone (1 mmol), appropriate alkyl halide, namely
methyl iodide, allyl iodide, benzyl bromide, 4-(bromomethyl)-
benzonitrile, 4-methylbenzyl bromide, 4-nitrobenzyl bromide,
3,4,5-trimethoxybenzyl bromide or 2-(bromomethyl)naphtha-
lene (1 mmol) and anhydrous potassium carbonate (3 mmol)
were stirred at room temperature for 7 days in acetone (10
ml). The reaction mixture was filtered, the solvent removed
in vacuo, and the residue purified by flash column chromatog-
raphy on silica gel (eluant: pet ether/ethyl acetate, 10:1) to
cmꢁ1
;
1H NMR (CDCl3, 400 MHz) dppm ¼ 1.27e2.12 (m,
12H, 6 ꢀ CH2), 2.07, 2.09 (each s, 3H, CH3), 3.29, 3.35
(each quintet, J w 6.4 Hz, 1H, NCH ), 3.75, 3.86 (each t, J ¼
5.3 Hz, 1H, NCHAr), 5.95, 6.02 (each t, J ¼ 5.0 Hz, 1H,

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yield the pure amines pure 7aeh which were routinely
converted to their hydrochloride salts.
127.9 (8 ꢀ tert. C), 132.6 (quat. C), 133.2 (tert. C), 140.5,
146.9 (2 ꢀ quat. C), 197.3 (C]O); MS, m/z, (RI) 320 (M þ
1, 42), 319 (Mþ, 27), 290 (29), 228 (36), 177 (100); HRMS
(M þ H)þ 320.1997, C22H26NO requires 320.2014.
7.1.4.1. 4-[Cyclopentyl(methyl)amino]-1,2,3,4-tetrahydro-1-
naphthalenone (7a). Yield: 94%; IR (CCl4, n) 2958, 2873,
1
2791, 1691, 1598, 1453, 1285 cmꢁ1; H NMR (CDCl3, 400
7.1.4.4. 4-[Cyclopentyl(4-oxo-1,2,3,4-tetrahydro-1-naphthale-
MHz) dppm ¼ 1.56 (m, 4H, CH2CH2), 1.74 (m, 2H, CH2),
1.89 (m, 2H, CH2), 2.02 (m, 1H, CH2CH2CO), 2.15 (s, 3H,
CH3), 2.27 (m, 1H, CH2CH2CO), 2.54 (m, 1H, CH2CO),
2.86 (2 ꢀ dd, J ¼ 16.1, 3.6 Hz, 1H, CH2CO), 3.06 (quintet, J
¼ 7.5 Hz, 1H, CH2CHCH2), 4.21 (dd, J ¼ 11.4, 4.0 Hz, 1H,
ArCHN), 7.33 (dd, J ¼ 8.2, 7.5 Hz, 1H, Ar-C(7)H ), 7.56 (dd, J
¼ 8.0, 7.5 Hz, 1H, Ar-C(6)H ), 7.90 (d, J ¼ 8.0 Hz, 1H, Ar-
C(5)H ), 8.02 (d, J ¼ 8.0 Hz, 1H, Ar-C(8)H ); 13C NMR
dppm ¼ 21.8, 23.8, 23.9, 30.8, 31.7, 34.6 (CH3), 38.1
(CH2CO), 60.1 (CH), 63.0 (CH), 126.3, 126.6, 127.1 (3 ꢀ tert.
C), 132.4 (quat. C), 133.1 (tert. C), 146.3 (quat. C), 197.5
(C]O); MS, m/z, (RI) 244 (M þ 1, 100), 243 (Mþ, 61), 214
(45), 186 (11), 146 (18), 100 (49); HRMS (M þ H)þ
244.1682, C16H22NO requires 244.1701.
nyl)amino]methylbenzonitrile (7d). Yield: 78%; m.p. 186e
188 ꢂC; IR (KBr, n); 2947, 2865, 2227, 1686, 1596 cmꢁ1
;
1H NMR (CDCl3, 400 MHz) dppm ¼ 1.38 (m, 1H, CH2),
1.49e1.66 (m, 6H, CH2), 1.93 (m, 1H, CH2), 2.02 (m, 1H,
CH2CH2CO), 2.45 (m, 2H, CH2CH2CO), 2.87 (m, 1H,
CH2CO), 3.19 (quintet, J ¼ 7.9 Hz, 1H, CH2CHCH2), 3.84,
3.95 (each d, J ¼ 15 Hz, 2H, NCH2), 3.94 (dd, 1H,
CHCH2CH2CO, signal overlap), 7.35 (dd, J ¼ 8.3, 7.5 Hz,
1H, Ar-H ), 7.58e7.63 (m, 5 ꢀ Ar-H ), 7.92 (d, J ¼ 8.0 Hz,
1H, Ar-H ), 8.01 (dd, J ¼ 7.8, 1 Hz, 1H, Ar-H ); 13C NMR
dppm ¼ 23.2, 24.6, 24.7, 27.6, 31.7 (5 ꢀ CH2), 38.0
(CH2CO), 49.7 (NCH2), 58.3 (CH), 59.2 (CH), 110.2
(CChN), 118.5 (ChN), 126.4, 126.7, 127.0 (3 ꢀ tert. C),
128.3, 131.8 (4 ꢀ tert. C), 132.6 (quat. C), 133.3 (tert. C),
145.9, 146.6 (2 ꢀ quat. C), 196.9 (C]O); MS, m/z, (RI) 344
(Mþ, 20), 315 (29), 228 (36), 199 (86), 171 (100), 145 (47),
116 (91), 89 (51); HRMS (M þ H)þ 345.1986, C23H25N2O re-
quires 345.1967.
7.1.4.2. 4-[Allyl(cyclopentyl)amino]-1,2,3,4-tetrahydro-1-
naphthalenone (7b). Yield: 60%; IR (CCl4, n) 2957, 2869,
1
1692, 1598, 1550, 1452, 1284 cmꢁ1; H NMR (CDCl3, 400
MHz) dppm ¼ 1.34e1.89 (m, 8H, CH2CH2CH2CH2), 1.98
(m, 1H, CH2CH2CO), 2.34 (m, 1H, CH2CH2CO), 2.54 (m,
1H, CH2CO), 2.86 (2 ꢀ dd, J ¼ 16.1, 3.5 Hz, 1H, CH2CO),
3.13 (quintet, J ¼ 7.9 Hz, 1H, CH2CHCH2), 3.22 (dd, J ¼
15.2, 7.9 Hz, 1H, CH2N), 3.35 (m, J ¼ 15.2 Hz, 1H, CH2N),
4.21 (dd, J ¼ 11.6, 3 Hz, 1H, COCH2CH2CH ), 5.07 (d, J ¼
10.4 Hz, 1H, CH2]CH), 5.22 (d, J ¼ 17.3 Hz, 1H,
CH2]CH), 5.92 (1H, m, CH2]CH ), 7.34 (dd, J ¼ 8.0, 7.5
Hz, 1H, Ar-C(7)H ), 7.58 (dd, J ¼ 8.2, 7.5 Hz, 1H, Ar-C(6)H ),
7.94 (d, J ¼ 8.0 Hz, 1H, Ar-C(5)H ), 8.03 (d, J ¼ 8.0 Hz, 1H,
Ar-C(8)H ); 13C NMR dppm ¼ 23.2, 24.2 (2 ꢀ cyclopentyl
CH2), 25.0 (CH2 tetralin), 28.3, 31.5 (2 ꢀ cyclopentyl CH2),
38.2 (CH2CO), 49.3 (CH2N), 58.1 (CHCH2CH2CO), 59.7
(CH2CHCH2), 115.3 (CH2]CH), 126.3 (Ar-C(7)H), 126.7
(Ar-C(8)H), 126.9 (Ar-C(5)H), 132.6 (quat. C), 133.1 (Ar-
7.1.4.5. 4-[Cyclopentyl(4-methylbenzyl)amino]-1,2,3,4-tetra-
hydro-1-naphthalenone (7e). Yield: 80%; IR (HCl salt, KBr,
n); 3422, 2960, 1691, 1590, 1452, 1421 cmꢁ1 1H NMR
;
(CDCl3, 400 MHz) dppm ¼ 1.36 (m, 1H, CH2), 1.54e1.73
(m, 6H, CH2), 1.91e2.04 (m, 2H, CH2), 2.35 (s, 3H, CH3),
2.42e2.51 (m, 2H, CH2CH2CO), 2.87 (m, 1H, CH2CO),
3.18 (quintet, J ¼ 8 Hz, 1H, CH2CHCH2), 3.84 (each d,
J ¼ 14.2 Hz, 2H, NCH2), 4.03 (dd, J ¼ 3.5 Hz, 1H,
CHCH2CH2CO), 7.16 (m, 2H, 2 ꢀ Ar-H ), 7.32e7.39 (m,
3H, 3 ꢀ Ar-H ), 7.60 (dd, J1 ¼ 8.5, 7.5 Hz, 1H, Ar-H ), 8.01
(m, 2H, 2 ꢀ Ar-H ); 13C NMR dppm ¼ 20.6 (CH3), 23.3, 24.7,
24.8, 27.4, 31.6 (5 ꢀ CH2), 38.2 (CH2CO), 49.2 (NCH2),
57.6 (CH), 58.9 (CH), 126.3, 126.7, 126.8 (3 ꢀ tert. C),
127.8 (2 ꢀ tert. C), 128.6 (2 ꢀ tert. C), 132.6 (quat. C),
133.1 (tert. C), 136.0, 137.3, 147.0 (3 ꢀ quat. C), 197.3
(C]O); MS, m/z, (RI) 333 (Mþ, 18), 304 (15), 276 (8), 229
(30), 190 (100), 105 (46); HRMS (M þ H)þ 334.2144,
C23H28NO requires 334.2171.
C(6)H), 138.1 (CH2]CH), 147.1 (quat. C), 197.3 (C]O);
MS, m/z, (RI) 270 (M þ 1, 25), 269 (Mþ, 34), 227 (67), 126
(100); HRMS (M þ H)þ 270.1866, C18H24NO requires
270.1858.
7.1.4.3.
4-[Benzyl(cyclopentyl)amino]-1,2,3,4-tetrahydro-1-
7.1.4.6. 4-[Cyclopentyl(4-nitrobenzyl)amino]- 1,2,3,4-tetrahy-
dro-1-naphthalenone (7f). Yield: 53%; IR (CCl4, n) 2959,
naphthalenone (7c). Yield: 55%; IR (CCl4, n) 2956, 2869,
1691, 1597, 1452, 1284 cmꢁ1; H NMR (CDCl3, 400 MHz)
1
1
2871, 1692, 1526, 1346 cmꢁ1; H NMR (CDCl3, 400 MHz)
dppm ¼ 1.39 (m, 1H, CH2), 1.55e1.73 (m, 6H, CH2), 1.93e
2.06 (m, 2H, CH2), 2.47 (m, 2H, CH2CH2CO), 2.88 (m, 1H,
CH2CO), 3.20 (quintet, J w 7 Hz, 1H, CH2CHCH2), 3.80,
3.97 (each d, J ¼ 14.5 Hz, 2H, NCH2), 4.03 (1H, dd, J ¼ 12,
3.5 Hz, CHCH2CH2CO), 7.26 (1H, dd, J ¼ 8.1, 7.5 Hz,
Ar-CH ), 7.33e7.37 (3H, m, 3 ꢀ Ar-H ), 7.51 (2H, m, 2 ꢀ
Ar-H ), 7.62 (1H, dd, J ¼ 8.5, 8 Hz, Ar-CH ), 8.03 (2H, m,
2 ꢀ Ar-H ); 13C NMR dppm ¼ 23.7, 25.1, 25.3, 27.8, 32.1 (4 ꢀ
CH2 cyclopentyl and CH2CH2CO), 38.6 (CH2CO), 49.9
(NCH2), 58.1, 59.2 (2 ꢀ CH), 126.4, 126.5, 126.8, 127.9,
dppm ¼ 1.41 (m, 1H of CH2), 1.52e1.70 (m, 6H, 3 ꢀ CH2
cyclopentyl), 1.94 (m, 1H, CH2), 2.05 (m, 1H, CH2CH2CO),
2.42e2.51 (m, 2H, CH2CH2CO), 2.88 (m, 1H, CH2CO),
3.23 (quintet, J ¼ 7.8 Hz, 1H, CH2CHCH2), 3.90, 3.99 (each
d, J ¼ 15.6 Hz, 2H, NCH2), 3.99 (dd, 1H, CHCH2CH2CO, sig-
nal overlap), 7.36 (dd, J ¼ 8.2, 7.5 Hz, 1H, Ar-H ), 7.59e7.65
(m, 3H, 3 ꢀ Ar-H ), 7.93 (d, J ¼ 8.0 Hz, 1H, Ar-H ), 8.02 (dd,
J ¼ 7.8, 1 Hz, 1H, Ar-H ), 8.19 (m, 2H, 2 ꢀ Ar-H ); 13C NMR
dppm ¼ 23.1, 24.5, 24.8, 27.8, 31.7 (5 ꢀ CH2), 37.9 (CH2CO),
49.7 (NCH2), 58.5 (CH), 59.5 (CH), 123.2 (2C), 126.4, 126.7,

J.W. Barlow, J.J. Walsh / European Journal of Medicinal Chemistry 43 (2008) 2891e2900
2897
127.0, 128.2 (2C) (7 ꢀ tert. C), 132.6 (quat. C), 133.2 (tert. C),
(KBr, n) 2946, 2869, 1688, 1644, 1597, 1434, 1285 cmꢁ1
;
145.7 (quat. C), 148.7 (quat. C), 151.4 (quat. C), 196.7
(C]O); MS, m/z, (RI) 364 (Mþ, 17), 335 (22), 307 (13),
228 (28), 221 (100), 191 (52), 145 (27), 117 (45), 89 (24);
HRMS (M þ H)þ 365.1837, C22H25N2O3 requires 365.1865.
1H NMR (CDCl3, 400 MHz) dppm ¼ 1.45e2.48 (br. m), 2.21
(s, 3H, COCH3), 2.57e2.75 (m), 2.78e2.91 (m), 3.07 (br. s,
CH ), 5.15 (br. s, CH ), 7.21 (m, 1H, 1 ꢀ Ar-H ), 7.38 (m,
1H, 1 ꢀ Ar-H ), 7.53 (m, 1H, 1 ꢀ Ar-H ), 8.05 (dd, J ¼
8.0 Hz, 1H, Ar-H ); 13C NMR dppm ¼ 23.0 (CH3), 23.3 (br.),
23.4 (br.), 25.0 (br.), 25.3 (br.), 28.0, 28.8 (br.), 29.2 (br.),
30.2 (br.), 37.6 (br.), 38.2 (CH2CO), 53.2 (CH), 57.6 (br.),
58.3 (br.), 126.3 (br.), 127.1, 127.4, 127.5, 133.0 (4 ꢀ tert.
C), 133.5 (br.), 195.4, 196.2 (C]O); MS, m/z, (RI) 272 (M þ
1, 100), 271 (Mþ, 15), 160 (12), 115 (13), 84 (9); HRMS
(þHþ) 272.1646, C17H22NO2 requires 272.1651; (M þ Na)þ
294.1454, C17H21NO2Na requires 294.1470.
7.1.4.7. 4-Cyclopentyl[3,4-dimethoxy-5-(methoxymethyl)benzy-
l]amino-1,2,3,4-tetrahydro-1-naphthalenone
70%; IR (CCl4, n) 2957, 2870, 1692, 1593, 1508, 1465,
(7g). Yield:
1
1228, 1133 cmꢁ1; H NMR (CDCl3, 400 MHz) dppm ¼ 1.37
(m, 1H, CH2), 1.54e1.64 (m, 6H, CH2), 1.91e2.05 (2H, m,
CH2), 2.44e2.51 (m, 2H, CH2CH2CO), 2.86 (m, 1H,
CH2CO), 3.20 (1H, quintet, J ¼ 7 Hz, CH2CHCH2), 3.75 (d, J
¼ 14.6 Hz, 1H, NCH2), 3.83e3.93 (m, 10H, 3 ꢀ Ar-OCH3, 1H
of NCH2, signal overlap), 4.04 (m, 1H, CHCH2CH2CO), 6.73
(s, 2H, 2 ꢀ (CH3O)3Ar-H ), 7.34 (dd, J ¼ 8.5, 7.5 Hz, 1H,
Ar-H ), 7.59 (1H, dd, J ¼ 8.5, 7.5 Hz, Ar-H ), 8.01 (m, 2H,
2 ꢀ Ar-H ); 13C NMR dppm ¼ 23.3, 24.8, 24.8, 27.5, 31.6 (5 ꢀ
CH2), 38.1 (CH2CO), 49.7 (NCH2), 55.6, 55.7, 57.9 (3 ꢀ Ar-
OCH3), 58.8, 60.3 (2 ꢀ CH), 104.3 (2 ꢀ (CH3O)3Ar-CH), 126.4
(2C), 126.9 (3 ꢀ tert. C), 132.7 (quat. C), 133.0 (tert. C), 136.2,
146.7 (2 ꢀ quat. C), 152.3 (2 ꢀ quat. C), 197.1 (C]O), one
quat. signal obscured due to peak overlapping; MS, m/z, (RI)
409 (Mþ, 1), 264 (9), 229 (51), 181 (100), 117 (12); HRMS
(M þ Na)þ 432.2114, C25H31NO4Na requires 432.2151.
7.1.5.2. N1-Cyclopentyl-N1-(4-oxo-1,2,3,4-tetrahydro-1-naph-
thalenyl)-2-phenylacetamide (7j). Yield: 68%; IR (CCl4, n)
1
2956, 1694, 1646, 1599, 1456, 1284, 1140 cmꢁ1; H NMR
(CDCl3, 400 MHz) dppm ¼ 1.39, 1.58, 1.71, 1.95 (4 ꢀ br m,
8H, 4 ꢀ CH2), 2.19 (m, 1H, CH2), 2.40 (m, 1H, CH2), 2.77
(m, 2H, CH2), 3.06 (CH ), 3.83 (m, 3H, CH and CH2, peaks
overlapping), 7.25e7.48 (m, 7H, 7 ꢀ Ar-H ), 7.56 (dd, J ¼
8.5, 7.5 Hz, 1H, Ar-H ), 8.07 (1H, COAr-H ); 13C NMR
dppm ¼ 25.2, 25.5, 28.8, 29.1, 30.1 (5 ꢀ CH2), 37.4, 43.4 (2 ꢀ
CH2CO), 57.8 (2C, 2 ꢀ CH), 126.2, 126.6, 127.4, 127.5,
127.9, 128.2, 128.3, 128.5 (8 ꢀ tert. C), 132.9 (quat. C),
133.3 (tert. C), 134.7 (quat. C), 169.9 (NC]O), 195.4
(C]O), one quat. signal obscured due to peak overlapping;
MS, m/z, (RI) 348 (M þ 1, 100), 347 (Mþ, 7), 115 (11);
HRMS (M þ H)þ 348.1950, C23H26NO2 requires 348.1964.
7.1.4.8. 4-[Cyclopentyl(2-naphthylmethyl)amino]-1,2,3,4-
tetrahydro-1-naphthalenone (7h). Yield: 27%; IR (CCl4, n)
1
2957, 2869, 1692, 1550, 1284 cmꢁ1; H NMR (CDCl3, 400
MHz) dppm ¼ 1.41 (m, 1H, CH2), 1.58e1.76 (m, 6H, CH2),
1.97e2.08 (m, 2H of CH2), 2.41e2.53 (m, 2H, CH2CH2CO),
2.88 (m, 1H, CH2CO), 3.23 (quintet, J ¼ 7.5 Hz, 1H,
CH2CHCH2), 3.97, 4.10 (each d, J ¼ 14 Hz, 2H, NCH2), 4.08
(m, 1H, CHCH2CH2CO), 7.33 (dd, J ¼ 8.5 Hz, 1H, Ar-H ),
7.47 (m, 2H, 2 ꢀ Ar-H ), 7.61 (d, J ¼ 9 Hz, 1H, Ar-H ), 7.70
(d, J ¼ 8 Hz, 1H, Ar-H ), 7.85 (m, 4H, 4 ꢀ Ar-H ), 8.03 (m,
2H, 2 ꢀ Ar-H ); 13C NMR dppm ¼ 23.3, 24.8, 24.8, 27.5, 31.7,
38.2 (6 ꢀ CH2), 49.8 (CH2Ar), 57.6, 59.0 (2 ꢀ CH), 125.1,
125.5, 126.3 (2C), 126.4, 126.7, 126.8, 127.1, 127.2, 127.7
(10 ꢀ tert. C), 132.4, 132.6, 132.9 (3 ꢀ quat. C), 133.1 (tert.
C), 138.0, 146.8 (2 ꢀ quat. C), 197.1 (C]O); MS, m/z, (RI)
370 (M þ 1, 5), 340 (12), 228 (100), 141 (30), 115 (20);
HRMS (M þ H)þ 370.2194, C26H28NO requires 370.2171.
7.1.6. 4-Azido-3,4-dihydro-2H-naphthalen-1-one (10)
Benzylic bromination of a-tetralone (8) yielded (9). To
a solution of (9) (3 g, 13.3 mmol) in DMF (20 ml) was added
sodium azide (8.6 g, 133 mmol). The resultant slurry was
heated on an oil bath for 2 h at 50 ꢂC, and then partitioned
between water and ether. The aqueous layer was washed twice
with ether (2 ꢀ 20 ml portions) and the combined ethereal
layers dried over sodium sulphate and concentrated in vacuo.
The residue was purified by flash column chromatography
on silica gel (eluant: pet ether/ethyl acetate, 20:1) to yield
azide (10) as a yellow oil (2.73 g, 89%), with the following
physical properties: IR (CCl4, n) 2944, 2100, 1686, 1600,
1
1455, 1283 cmꢁ1; H NMR (CDCl3, 400 MHz) dppm ¼ 2.24
(m, 1H, CH2), 2.38 (m, 1H, CH2), 2.60 (dd, J ¼ 7, 4.5 Hz,
1H, COCH2), 2.89 (dd, J ¼ 10, 4.5 Hz, 1H, COCH2), 4.75
(dd, J ¼ 6.3, 3.8 Hz, 1H, CHN3), 7.41e7.46 (m, 2H, 2 ꢀ Ar-
H ), 7.58 (m, 1H, Ar-H ), 8.04 (dd, J ¼ 8.04, 1 Hz, 1H, Ar-
H ); 13C NMR dppm ¼ 28.1 (CH2CHN3), 34.0 (CH2CO), 58.4
(CHN3), 127.2, 127.6, 128.7, 133.5 (4 ꢀ tert. C), 131.1,
139.6 (2 ꢀ quat. C), 195.7 (C]O).
7.1.5. General procedures for the preparation
of amides (7i and j)
Amides 7i and j were prepared by adding to a solution of 6 in
pyridine (5 ml) 5 mol equivalents of anhydride and a catalytic
amount of DMAP. The reaction was stirred at room temperature
for 3 h. The pyridine was removed by washing the organic phase
(diluted with 20 ml DCM) three times with 2 M HCl (3 ꢀ 20 ml);
the organic layer was then concentrated in vacuo, and the residue
purified by flash column chromatography on silica gel (eluant: pet
ether/ethyl acetate, 5:1) to yield amides 7i and j.
7.1.7. General procedures for the
preparation of amides (11aee)
For amides 11a and b, mixtures of 4-azido-3,4-dihydro-2H-
naphthalen-1-one (1 mmol), appropriate anhydride, namely ace-
tic or propionic (1 mmol) and a catalytic amount of 10% Pd/C
were stirred at room temperature overnight in EtOH/EtOAc
7.1.5.1. N1-Cyclopentyl-N1-(4-oxo-1,2,3,4-tetrahydro-1-naph-
thalenyl)acetamide (7i). Yield: 57%; m.p. 131e132 ꢂC; IR

2898
J.W. Barlow, J.J. Walsh / European Journal of Medicinal Chemistry 43 (2008) 2891e2900
(10 ml, 1:1) under an atmosphere of hydrogen, filtered, and the
solvent was removed in vacuo. The residue was purified by flash
column chromatography on silica gel (eluant: pet ether/ethyl
acetate, 10:1) to yield amides 11a and b.
40), 115 (16), 89(15); HRMS (M þ Na)þ 302.1143,
C18H17NO2Na requires 302.1157.
7.1.7.4. N1-(4-Oxo-1,2,3,4-tetrahydro-1-naphthalenyl)-3-phe-
For amides 11cee, mixtures of 4-azido-3,4-dihydro-2H-
naphthalen-1-one (1 mmol), appropriate pentafluorophenyl
ester, namely phenylacetic acid [22], 3-phenylpropionic
acid [23] or 3,4-dichlorobenzoic acid (1 mmol) and a cata-
lytic amount of 10% Pd/C were stirred at room temperature
overnight in EtOH/EtOAc (10 ml, 1:1) under an atmosphere
of hydrogen, filtered, and the solvent was removed in vacuo.
The residue was purified by flash column chromatography
on silica gel (eluant: pet ether/ethyl acetate, 10:1) to yield
amides 11cee.
nylpropanamide (11d). Yield: 69%; m.p. 110e112 ꢂC; IR
(CCl4, n) 3279, 2929, 1689, 1633, 1542 cmꢁ1 1H NMR
;
(CDCl3, 400 MHz) dppm ¼ 1.97 (m, 1H, CH2), 2.24 (m, 1H,
CH2), 2.51e2.66 (m, 4H, ArCH2 and CH2CO, signal overlap),
3.02 (ddd, J ¼ 8.5, 7.4, 2.3 Hz, 2H, CH2CO), 5.30 (dt, J ¼ 8.6,
4.5 Hz, 1H, CH ), 6.05 (NH ), 7.04 (d, J ¼ 8 Hz, 1H, Ar-H ),
7.21e7.34 (m, 6H, 6 ꢀ Ar-H ), 7.44 (dd, J ¼ 8.5, 7.5 Hz, 1H,
Ar-H ), 7.93 (d, J ¼ 7.5 Hz, 1H, COAr-H ); 13C NMR
dppm ¼ 29.2 (CH2), 31.3 (CH2), 35.7 (CH2CO), 38.1
(CH2CO), 46.8 (CH), 125.9 (tert. C), 126.7 (tert. C), 126.8
(tert. C), 127.5 (tert. C), 128.0 (2 ꢀ tert. C), 128.1 (2 ꢀ tert.
C), 131.4 (quat. C), 133.5 (tert. C), 140.0 (quat. C), 142.8
(quat. C), 171.4 (NHC]O), 196.5 (C]O); MS, m/z, (RI)
294 (M þ 1, 100), 293 (Mþ, 43), 249 (23), 218 (27), 249
(23), 160 (20), 128 (25); HRMS (M þ Na)þ 316.1307,
C19H19NO2Na requires 316.1313.
7.1.7.1. N1-(4-Oxo-1,2,3,4-tetrahydro-1-naphthalenyl)aceta-
mide (11a). Yield: 50%; m.p. 138e139 ꢂC; IR (CCl4, n)
1
3252, 2929, 1689, 1637, 1543 cmꢁ1; H NMR (CDCl3, 400
MHz) dppm ¼ 2.05 (s, 3H, CH3), 2.10 (m, 1H, CH2), 2.32
(m, 1H, CH2), 2.62 (m, 1H, CH2CO), 2.75 (m, 1H, CH2CO),
5.32 (1H, CH ), 6.43 (NH ), 7.35 (m, 2H, 2 ꢀ Ar-H ), 7.54
(m, 1H, Ar-H ), 7.94 (m, 1H, Ar-H ); 13C NMR dppm ¼ 22.8
(CH3), 29.2 (CH2), 35.7 (CH2CO), 46.9 (CH), 126.8 (tert.
C), 126.9 (tert. C), 127.6 (tert. C), 131.5 (quat. C), 133.6
(tert. C), 142.9 (quat. C), 169.5 (NHC]O), 196.5 (C]O);
MS, m/z, (RI) 204 (M þ 1, 100), 203 (Mþ, 21), 144 (70),
115 (25); HRMS (M þ Na)þ 226.0839, C12H13NO2Na re-
quires 226.0844.
7.1.7.5.
dichlorobenzamide (11e). Yield: 81%; m.p. 165e167 ꢂC; IR
(CCl4, n) 3252, 2929, 1689, 1637, 1543 cmꢁ1 1H NMR
N1-(4-Oxo-1,2,3,4-tetrahydro-1-naphthalenyl)-3,4-
;
(CDCl3, 400 MHz) dppm ¼ 2.25 (m, 1H, CH2), 2.45 (m, 1H,
CH2), 2.70 (m, 1H, CH2CO), 2.83 (m, 1H, CH2CO), 5.55
(m, 1H, CH ), 6.94 (NH ), 7.40 (m, 2H, 2 ꢀ Ar-H ), 7.48e
7.59 (m, 2H, 2 ꢀ Ar-H ), 7.67 (m, 1H, Ar-H ), 7.97 (m, 2H,
2 ꢀ Ar-H ); 13C NMR dppm ¼ 29.2 (CH2), 35.7 (CH2CO),
47.7 (CH), 125.9, 126.8, 127.0, 127.9, 128.8, 130.2 (6 ꢀ tert.
C), 131.6, 132.7, 133.3 (3 ꢀ quat. C), 133.8 (tert. C), 135.9,
142.4 (2 ꢀ quat. C), 164.7 (NHC]O), 196.3 (C]O); MS,
m/z, (RI) 334 (M þ 1, 15), 333 (Mþ, 10), 144 (100), 115 (25).
7.1.7.2. N1-(4-Oxo-1,2,3,4-tetrahydro-1-naphthalenyl)propa-
namide (11b). Yield: 40%; m.p. 142e143 ꢂC; IR (CCl4, n)
1
3274, 1692, 1645, 1541 cmꢁ1; H NMR (CDCl3, 400 MHz)
dppm ¼ 1.24 (t, J ¼ 7.5 Hz, 3H, CH3), 2.13 (m, 1H, CHCH2),
2.33 (q, J ¼ 7.5 Hz, 2H, CH2CH3), 2.38 (m, 1H, CHCH2),
2.76 (m, 2H, CH2CO), 5.41 (br. s, 1H, CH ), 5.92 (NH ),
7.38 (m, 2H, 2 ꢀ Ar-H ), 7.57 (dd, J ¼ 9.4, 7.5 Hz, 1H, Ar-
H ), 8.03 (br. s, COAr-H ); 13C NMR dppm ¼ 9.4 (CH3), 29.4
(2C, 2 ꢀ CH2), 35.8 (CH2CO), 46.8 (CH), 126.7 (tert. C),
126.9 (tert. C), 127.7 (tert. C), 131.6 (quat. C), 133.6 (tert.
C), 143.0 (quat. C), 173.1 (NHC]O), 196.3 (C]O); MS,
m/z, (RI) 218 (M þ 1, 100), 217 (Mþ, 18), 144 (16), 115
(17); HRMS (M þ Na)þ 240.1012, C13H15NO2Na requires
240.1000.
7.1.8. 4-[Benzyl(methyl)amino]-1,2,3,4-tetrahydro-1-
naphthalenone (12)
To compound 9 (obtained from 1 g a-tetralone), was imme-
diately added acetone (10 ml), N-benzylmethylamine (1.76 ml,
13.7 mmol) and anhydrous K2CO3 (4.7 g, 34.2 mmol). The
reaction was stirred overnight at room temperature, and
separated by sequential acid (2 M HCl) and base (2 M
NaOH) washings, extracting the organic phase three times in
each case with ether (3 ꢀ 20 ml). The combined organic
extracts were dried over anhydrous sodium sulphate and the
solvent was removed in vacuo. The residue was purified by flash
column chromatography on silica gel (eluant: pet ether/ethyl
acetate, 10:1) to yield the tertiary amine, a colourless oil that
solidified on standing (0.45 g, 25%): IR (CCl4, n) 2647, 2797,
7.1.7.3. N1-(4-Oxo-1,2,3,4-tetrahydro-1-naphthalenyl)-2-phe-
nylacetamide (11c). Yield: 64%; IR (CCl4, n) 3267, 2929,
1690, 1640, 1542 cmꢁ1
;
1H NMR (CDCl3, 400 MHz)
dppm ¼ 1.97 (m, 1H, CH2CH2CO), 2.28 (m, 1H, CH2CH2CO),
2.58 (m, 1H, CH2CO), 2.68 (m, 1H, CH2CO), 3.63 (s, 2H,
PhCH2CO), 5.32 (1H, m, NHCH ), 6.24 (br. s, 1H, NH ),
7.21 (1H, d, J ¼ 7.7 Hz, Ar-H ), 7.26e7.36 (6H, m, 6 ꢀ Ar-
H ), 7.48 (dd, J ¼ 8.5, 7.5 Hz, 1H, Ar-H ), 7.94 (d, J ¼ 8 Hz,
1H, Ar-H ); 13C NMR dppm ¼ 29.3 (CH2CH2CO), 35.9
(CH2CO), 43.3 (CH2CO), 47.0 (CH), 126.4, 126.9, 127.0,
127.5, 128.6 (2C), 128.7 (2C) (8 ꢀ tert. C), 131.5 (quat. C),
133.5 (tert. C), 134.3, 142.9 (2 ꢀ quat. C), 170.5 (NHC]O),
196.3 (C]O); MS, m/z, (RI) 280 (M þ 1, 100), 279 (Mþ,
1
1693, 1599, 1545, 1285, 1026 cmꢁ1; H NMR (CDCl3, 400
MHz) dppm ¼ 2.18 (m, 1H, CH2CH), 2.26 (s, 3H, CH3), 2.36
(m, 1H, CH2CH), 2.55 (m, 1H, CH2CO), 2.93 (m, 1H,
CH2CO), 3.73 (dd, J ¼ 13.8 Hz, 2H, NCH2Ar), 4.08 (dd,
J ¼ 10.9, 3.2 Hz, 1H, CH ), 7.26e7.44 (m, 6H, 6 ꢀ Ar-H ),
7.60 (dd, J ¼ 8.3, 7.4 Hz, 1H, Ar-H ), 7.96 (d, J ¼ 8.0 Hz, 1H,
Ar-H ), 8.05 (d, J ¼ 8.0 Hz, 1H, Ar-H ); 13C NMR dppm ¼ 21.3
(CHCH2), 37.0 (COCH2), 37.0 (CH3), 57.7 (NCH2Ar), 60.8
(CH), 126.6, 126.7, 126.8, 127.2, 127.9 (2C), 128.0 (2C) (9 ꢀ

J.W. Barlow, J.J. Walsh / European Journal of Medicinal Chemistry 43 (2008) 2891e2900
2899
tert. C), 132.5, 139.2, 145.3 (3 ꢀ quat. C); MS, m/z, (RI) 265
(Mþ, 15), 146 (100), 120 (86), 91 (30); HRMS (M þ H)þ
266.1527, C18H20NO requires 266.1545.
compounds, the control (indomethacin), and arachidonic acid
(AA) were dissolved in acetone. All individual applications
to an ear consisted of a 20 mL volume, 10 mL of which was ap-
plied evenly to each ear surface. The amount of arachidonic
acid to be applied was determined from a standard curve.
One hour after application of arachidonic acid, the animals
were sacrificed by cervical dislocation. Using a 5 mm surgical
punch, tissue sections were removed from both ears of each
animal, and carefully weighed. The weights of the left ears
were subtracted from those of the right, and a mean value
obtained for the difference in weights in each group. The
reduction in swelling was obtained by comparison of the
weight differences in the positive control group (AA only),
with those in the indomethacin and test groups.
7.1.9. 1-(2-{[Benzyl(methyl)amino]methyl}
phenyl)1-ethanone (14)
To a solution of 20-methylacetophenone 13 (1.5 g, 11.2
mmol) in CCl4 (30 ml) was added NBS (2.99 g, 16.8 mmol)
and a catalytic amount of ACN. The reaction mixture was
heated under reflux, and upon reaching reflux conditions the
heat source was removed and replaced by two 240 W lamps,
the light from these focussed on the reaction, stirring
vigorously all the time. On completion of the reaction a colour
change from deep orange to clear was observed. The reaction
mixture was then filtered to remove the insoluble N-hydrosuc-
cinimide, and the solvent removed in vacuo. To the residue
were added N-benzylmethylamine (2.9 ml, 22.4 mmol), ace-
tone (10 ml) and anhydrous K2CO3 (3.09 g, 22.3 mmol). The
reaction was stirred overnight at room temperature, filtered
and purified by flash column chromatography on silica gel (el-
uant: pet ether/ethyl acetate, 10:1) to yield the tertiary amine,
7.4. Statistical analysis
Statistical analysis was performed using GraphPAD Prism
software Version 3.02 (GraphPAD, San Diego, CA, USA).
The RPMC experiments were repeated on the cells of 5 ani-
mals. Graphical data were obtained from the mean þ/ꢁ the
standard error of the mean (S.E.M.). Statistical analysis of
arachidonic acid-induced mouse ear oedema was performed
using Students t-test when comparing untreated (positive
control) groups with treated groups. P values of <0.05 were
considered significant.
1
a colourless oil that solidified on standing (0.74 g, 26%): H
NMR (CDCl3, 400 MHz) dppm ¼ 2.09 (s, 3H, NCH3), 2.58
(s, 3H, COCH3), 3.53 (CH2), 3.79 (CH2), 7.25e7.35 (m, 6H,
6 ꢀ Ar-H ), 7.41 (d, J ¼ 7.5 Hz, 1H, Ar-H ), 7.54 (m, 2H,
2 ꢀ Ar-H ); 13C NMR dppm ¼ 29.5 (COCH3), 41.0 (NCH3),
59.5 (CH2), 61.5 (CH2), 126.5 (2C), 127.1, 129.5 (2C), 129.9
(2C), 130.2, 130.3 (9 ꢀ tert. C), 138.2, 138.4, 140.0 (3 ꢀ quat.
C), 202.9 (C]O).
Acknowledgments
We acknowledge Enterprise Ireland (Research Innovation
Fund IF/2001/014) for financial support.
7.2. Mast cell stabilising activity
A 250e300 g female Wistar rat was selected, and sacrificed
by CO2 inhalation. The animal was immediately injected with
15 ml of HEPES buffer solution (at 37 ꢂC) into the peritoneal
cavity, and massaged gently in this region for 90 s, to facilitate
cell recovery. A midline incision was made and the
peritoneum was exposed. The pale fluid was aspirated using
a blunted plastic Pasteur pipette, and collected in a plastic
centrifuge tube. The fluid was then centrifuged at 1000 rpm
for 5 min, and the supernatant discarded to reveal a pale cell
pellet. The cell pellets were re-suspended in fresh buffer and
re-centrifuged. Cell suspensions of this nature appeared to
be relatively consistent, as judged by basal and total readings
for histamine content, and were not routinely purified further.
Aliquots of the cell suspension were incubated with the test
compounds or the control, disodium cromoglycate, before
challenge with Compound 48/80. The reaction was terminated
by addition of iced buffer, and aliquots centrifuged and
analysed spectrophotometrically for released histamine after
complexation with o-phthalaldehyde.
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