Synthesis and pharmacological activity of aminoindanone dimers and related compounds

Article abstract of DOI:10.1016/j.bmc.2007.09.041

A series of N-substituted 3-aminoindanones were synthesised and evaluated for smooth muscle relaxant activity and mediator release inhibition effects. A low level of smooth muscle relaxant activity has been identified in all derivatives. Data have revealed that the significant mediator release inhibition effects observed are related to the nature of the amine substituents. A structure activity relationship is proposed.

Full text of DOI:10.1016/j.bmc.2007.09.041

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry 16 (2008) 248–254
Synthesis and pharmacological activity of aminoindanone
dimers and related compounds
*
H. Sheridan,* S. Butterly, J. J. Walsh, C. Cogan, M. Jordan, O. Nolan and N. Frankish
Department of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Ireland
Received 22 May 2007; revised 17 September 2007; accepted 21 September 2007
Available online 26 September 2007
Abstract—A series of N-substituted 3-aminoindanones were synthesised and evaluated for smooth muscle relaxant activity and
mediator release inhibition effects. A low level of smooth muscle relaxant activity has been identified in all derivatives. Data have
revealed that the significant mediator release inhibition effects observed are related to the nature of the amine substituents. A struc-
ture activity relationship is proposed.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
(Groups I-III) used in this study. It was prepared by free
radical bromination of indan-1-one using n-bromosuc-
cinimide (NBS) and a catalytic amount of dibenzoyl
peroxide in CCl4. Cyclopentyl amine and 1- and 2-amin-
oindane were subsequently coupled with 1 at room
temperature using triethylamine as base and DCM as
solvent to yield amines 2, 8, 14 (Fig. 1). A range of N-al-
kyl and N-acyl derivatives were prepared using standard
methods. Compounds were screened as isomeric mix-
tures for smooth muscle relaxation and mediator release
effects.
Indane structures occur in many bio-active compounds.
The HIV-1 inhibitor Indinavir is one example of a pro-
tease inhibitor in clinical use that contains an indane
fragment.1 The nitro-indanone nivemedone was re-
ported to have anti-allergenic activity2 while Heinzel-
mann et al. demonstrated the bronchodialatory
activity of simple indanols in the 1940s.3 In addition
many synthetic and naturally occurring indanone deriv-
atives have been shown to demonstrate therapeutic ef-
fects including smooth muscle relaxant activity4–6 and
mediator release inhibition.7 As part of our continuing
investigation into the pharmacological activity and po-
tential therapeutic activity of naturally occurring and
synthetic monomeric4–6 and dimeric indanes and inda-
nones7,8 we now report on the smooth muscle relaxant
activity and mediator release inhibition activities dem-
onstrated by a series of aminoindanones. In the present
work, a series of substituted 1 and 2-N-indanyl and
cyclopentyl aminoindanones and their derivatives were
synthesised and tested for their in vitro smooth muscle
relaxant and mediator release inhibition.
O
O
II
I
NHR
NHR
8 R=H
2 R=H
3 R=CH3
9 R=CH3
4 R=CH2CH=CH
5 R=CH2C6H5
6 R=COCH3
10 R=CH2CH=CH
11 R=CH2C6H5
12 R=COCH3
7 R=SO2C6H4-p-CH3
13 R=SO2C6H4-p-CH3
O
2. Chemistry
III
NHR
3-Bromoindanone (1) was identified as the key intermedi-
ate in the preparation of the starting 3-aminoindanones
14 R=H
15 R=CH3
16 R=CH2CH=CH
17 R=CH2C6H5
18 R=COCH3
Keywords: Indanones; 3-Aminoindanones; Bi-indanyl amines; Smooth
muscle relaxant activity; Mediator release inhibition.
*
Corresponding author. Tel.: +353 1 8962825/8; e-mail addresses:
hsheridn@tcd.ie; nfrnkish@tcd.ie
19 R=SO2C6H4-p-CH3
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.09.041

H. Sheridan et al. / Bioorg. Med. Chem. 16 (2008) 248–254
249
(10À8 M)
inhibited
calcium
contractions
by
O
O
O
NBS
48.1 2.3% whereas the compounds had only minimal
activity (Fig. 2a–c), which was insufficient to allow the
construction of a full dose/inhibition curve or the calcu-
lation of EC50 values. The most potent of the synthetic
derivatives was the N-methyl, N-1-indanyl aminoin-
dan-1-one 2 (Fig. 2a), which inhibited contractions of
smooth muscle by 30.0 2.9% at a concentration of
1 · 10À5 M. The N-prop-2-enyl and N-ethanamide
derivatives of the same series (I) 4 and 6 inhibited con-
tractures (20.9 0.8% and 18.3 3.8%, respectively) to
a lesser extent. This is in contrast to the findings in
our previous studies,4–6 which showed that synthetic
analogues of naturally occurring indanones had EC50
values against calcium contractions of ileal smooth mus-
cle ranging from 1.3 · 10À6M to 1.1 · 10À5 M, with inhi-
bition at 1 · 10À5 M being as high as 70%, for the most
active compound. The observed results for the amino-
indanone derivatives although not high are in the same
order of activity as the naturally occurring indanones
onitin (EC50 1 · 10À4 M), onitisin (EC50 2 · 10À3 M)
and otinoside (EC50 7 · 10À4 M).9,10 No obvious struc-
ture activity relationship can be determined for this
series.
1
Dibenzoyl
peroxide
Br
Et3N/DCM
Amine
O
Et3N, R-Hal
N CH3
NH
Figure 1.
3. Results and discussion
A total of 18 compounds were screened for their smooth
muscle relaxant activity by measuring inhibition of con-
tractions of isolated segments of guinea-pig ileum which
were initiated by the addition of 25 ll of 1 M CaCl2
(a final concentration of 2.5 mM). The contractions
reached a stable maximum within 5–10 min. and could
be maintained for up to 45 min. On stabilisation of the
contraction, nifedipine (10À8 M) or test compounds
(10À5 M) were added to the preparation. Nifedipine
Mast cells, in addition to their role in allergy, inflamma-
tion and anaphylaxis may play a critical role in the
induction and maintenance of a variety of severe allergic
and auto-immune disease.11,12 Having previously estab-
lished that indane dimers inhibit mast cell histamine re-
lease7 the effect of the synthetic aminoindanones was
investigated by measuring the inhibition of histamine
release from rat peritoneal mast cells stimulated by the
addition of compound 48/80. The positive control diso-
dium cromoglycate (2 · 10À5 M) inhibited mast cell
histamine release by 8.1 3.3%. This value is approxi-
mately equal to that found by other workers at similar
concentrations of cromoglycate.8 However increasing
the concentration of cromoglycate to 1 · 10À4 M failed
to give any further increase in inhibition of histamine
release (unpublished observations), in contrast to the
findings of Tanazaki et al.,13 who observed an inhibition
of histamine release at this concentration of approxi-
mately 20%. The magnitude of the cromoglycate
response is dependent on both the concentration of com-
pound 48/80 used and also the time of addition of the
drug to the cells.13 Both in this study and that of Walsh
et al.,8 the concentration of Compound 48/80 was high
(10 lg/ml), potentially reducing the response of the
drug, and in this study, cromoglycate was also added
to the cells 10 min prior to compound 48/80, which
may also have had a bearing on the magnitude of the
result.
Compound 48/80-stimulated histamine release was also
significantly inhibited by several of the compounds
(1 · 10À5 M), ranging from 14.3 2.5% for N-acetyl
derivative (6) to 88.6% 0.6 for the N-benzyl-deriva-
tive 11. A comparison of the 1-indanylamino-N-inda-
none group (Group I, Fig. 3a) shows that the
N-prop-2-enyl derivative 4 was the most active com-
pound, inhibiting mast cell histamine release by
79.89 3.67% with the N-acetyl derivative 6 being the
Figure 2.

250
H. Sheridan et al. / Bioorg. Med. Chem. 16 (2008) 248–254
hanced activity relative to the 1 and 2 indanyl
aminoindanone derivatives with the exception of the
N-acetyl-cyclopentyl derivative 18 which is the least
active of all the derivatives investigated. In general
the N-acetyl derivatives are the least active of the com-
pounds investigated.
4. Conclusion
We have previously reported7 that a series of dimeric
indanones have mast cell stabilising activity, with the
most potent compound investigated in that study, 2-
(1-indanyl)-2-methylindane, inhibiting histamine release
by 23%. In the current study three compounds, 14, 15
and 16, inhibited histamine release by more than 80%.
This represents a considerable increase in activity over
our earlier studies. These compounds are currently
undergoing detailed mechanistic study.
5. Experimental protocols
Melting points were determined on a Me-Opta hot stage
and are uncorrected. Infrared spectra were recorded on
a Nicolet 205 FT-IR spectrophotometer. Ultra violet
spectra were recorded on a Varian Carey 3E UV–visible
spectrophotometer. Mass spectra were determined at
1
70 eV on an AEI MS 30 instrument. H NMR spectra
were recorded on a Bruker MSL 300 instrument at
300 MHz. 13C NMR were recorded at 75.47 MHz. Deu-
teriochloroform was used as solvent. TLCs were run on
commercially pre-coated plates (Merck, Kieselgel
60F254). Merck Kieselgel 230–400 mesh was used for
column chromatography.
5.1. Synthesis of 3-bromoindan-1-one (1)
Figure 3.
N-Bromosuccinimide (1 equiv) and dibenzoylperoxide
(5 mol%) were added to a solution of indan-1-one
(1 equiv) in CCl4 and the reaction was refluxed for
45 min. After cooling the reaction was washed with
water, dried over Na2SO4, filtered and evaporated in va-
cuo. The resultant oil was purified by column chroma-
tography over silica gel (eluant, pet. ether/EtOAc, 4:1)
to yield 1 as an oil. dH (CDCl3): 3.02 (1H, dd,
J = 19 Hz, 2.7 Hz), 3.30 (1H, dd J 6.8, 18.6 Hz), 5.52
(1H, dd, J 6.7, 2.8 Hz, CH), 7.21–7.27 (2H, m, ArH),
7.43 (2H, m, ArH).
least potent, inhibiting histamine release by
14.33 2.47%. Compounds in Group II showed activ-
ity ranging from 71.88 5.09% for the N-benzyl 11 to
4.26 6.8% for the N-acetyl derivative 12 (Fig. 3b).
There was no significant difference (P > 0.05) between
the N-methyl derivative 9, the N-propen-2-yl derivative
10 and the N-benzyl derivative 11. Compounds in
Group III showed activity ranging from 85.62 2.36
for the N-methyl compound 15 to À0.9 5.4% for
the N-acetyl derivative 18 (Fig. 3c). There was no sig-
nificant difference in the activity of 14, 15, 16 and 17
(P > 0.05). A comparison of similar compounds be-
tween the three groups showed that there was no sig-
nificant (P > 0.05) difference in activity between the
two N-methyl derivatives 3 and 9 and the 3-(N-cyclo-
pentyl-N-methylamino) indanone (15). There was also
no significant (P > 0.05) difference in activity between
the prop-2-enyl derivatives 4, 10 and 16. However of
the N-benzyl derivatives, 11 showed a significant
(P < 0.01) increase in activity in comparison to 5
whereas there was no significant (P > 0.05) difference
between 17 and 5. From these results it appears that
the N-cyclopentyl aminoindanone derivatives have en-
5.2. General procedure for the coupling of 3-bromoindan-
1-one (1) with 1-aminoindan, 2-aminoindan and cyclo-
pentylamine. Synthesis of 2, 8 and 14
Triethylamine (2 equiv) was added to a stirred solution
of 3-bromoindanone (1 equiv) and amine (1 equiv) in
dry DCM and the mixture was stirred at 0 ꢁC for 3 h.
The solvent was removed in vacuo and the residue was
purified directly by flash column chromatography on sil-
ica gel (eluant, pet. ether/EtOAc, 4:1).
5.2.1. (R,S)-3[2,3-Dihydro-1H-inden-1-ylamino]-1H-inden-
1-one (2). Prepared by coupling (1) with 1-aminoindan.

H. Sheridan et al. / Bioorg. Med. Chem. 16 (2008) 248–254
251
White solid (60%), mp 117.2–117.9 ꢁC (EtOH). kmax
(film) 3035 (ArCH), 1721 (CO), 1616 (NH) cmÀ1; dH
(CDCl3): 1.83 (1H, m, CH), 2.47 (1H, m, CH), 2.59
(1H, dd J 18.6, 3.5 Hz, CH), 2.85 (1H, m), 3.02 (1H,
m), 3.10 (1H, d J 6.8, 18.6 Hz, CH), 4.43 (1H, dd, J
6.7 Hz, CH), 4.65 (1H, q J 3.5, 6.7 Hz, CH), 7.21–7.27
(3H, m, ArH), 7.43 (2H, m, ArH), 7.65 (2H, dt J 1.2,
7.6 Hz, ArH), 7.75 (2H, t J 7.2 Hz, ArH); dC 30.4
(CH2), 36.0 (CH2), 46.7 (CH2), 55.1 (CH), 62.5 (CH),
123.2 (ArCH), 124.0 (ArCH), 124.8 (ArCH), 126.0
(ArCH), 126.3 (ArCH), 127.5 (ArCH), 128.6 (ArCH),
134.8 (ArCH), 136.6 (qC), 143.3 (qC), 145.3 (qC),
156.5 (qC), 204.6 (CO); MS: m/z 263 [M+].
30.5 (CH2), 34.3 (CH3), 38.0, 38.9 (CH2), 58.1 (CH),
61.8 (ArCH), 67.0 (ArCH), 70.0 (ArCH), 122.8 (ArCH),
124.5, 124.8 (ArCH), 126.2, 126.4 (ArCH), 127.4
(ArCH), 128.4 (ArCH), 134.7, 134.8 (qC), 142.9 (qC),
143.7 (qC), 156.0 (qC), 204.6 (CO); MS: m/z 277 [M+].
5.3.2. (R,S)-3[2,3-Dihydro-1H-inden-2-yl(methyl)amino]-
1H-inden-1-one (9). Prepared by methylation of 8 with
MeI. White solid (40%), mp 120.4–120.9 ꢁC, kmax
(KBr) 3075, 2985, 1707, 1602 cmÀ1; dH (CDCl3): 2.03
(3H, s, NCH3), 2.57 (1H, dd J 7.0, 18.9 Hz, CH), 2.77
(1H, dd J 3.8, 18.9 Hz, CH), 3.05 (4H, m), 3.52 (1H,
quin J 8 Hz, CH), 4.78 (1H, q J 3.8, 6.8 Hz, CH), 7.20
(4H, m, ArH), 7.43 (1H, dd J 6.8, 7.5 Hz, ArH), 7.65
(1H, dd J 6.1, 7.5 Hz, ArH), 7.75 (2H, t, J 6.1, 6.8 Hz,
ArH); dC 33.1 (CH3), 35.8 (CH2), 37.7 (CH2), 38.0
(CH2), 59.6 (CH), 65.1 (CH), 123.0 (ArCH), 124.3
(ArCH), 124.3 (ArCH), 126.4 (ArCH), 126.4 (ArCH),
128.4 (ArCH), 129.0 (ArCH), 134.7 (ArCH), 137.2
(qC), 141.2 (qC), 141.4 (qC), 155.6 (qC), 205.0 (CO);
MS: m/z 277 [M+].
5.2.2. (R,S)-3[2,3-Dihydro-1H-inden-2-ylamino]-1H-inden-
1-one (8). Prepared by coupling 1 with 2-aminoindan.
Buff solid (71%), mp 103–104 ꢁC (EtOH). kmax (KBr)
3051 (ArCH), 1706 (CO), 1604 (NH) cmÀ1 dH (CDCl3):
2.58 (1H, dd J 3.4, 18.5 Hz, CH), 2.84 (1H, dd J 6.8,
4.5 Hz, CH), 2.86 (1H, dd J 6.9, 14.1 Hz, CH), 2.99
(1H, dd J 6.7, 18.5 Hz, CH), 3.17 (1H, dd J 6.9,
19.1 Hz, CH), 3.23 (1H, dd J 6.9, 19.3 Hz, CH), 3.81
(1H, quin J 7.0 Hz, CH), 4.51 (1H, qJ 3.1, 6.7 Hz,
CH), 7.21 (4H, m, ArH), 7.43 (1H, m, ArH), 7.67 (3H,
m, ArH), dC 39.9 (CH2), 40.6 (CH2), 45.4 (CH2), 54.5
(CH), 58.1 (CH), 123.1 (ArCH), 124.4 (ArCH), 124.4
(ArCH), 124.4 (ArCH), 125.7 (ArCH), 125.7 (ArCH),
128.4 (ArCH), 134.6 (ArCH), 136.4 (qC), 141.1 (qC),
141.2 (qC), 155.9 (qC), 204.2 (CO); MS: m/z 263 [M+].
5.3.3. (R,S)-3(N-Cyclopentyl-N-methylamino)-indan-1-
one (15). Prepared by methylation of 14 with MeI. Oil
(80%), kmax (Film) 3054, 2989, 1707, 1609 cmÀ1; dH
(CDCl3): 1.66 (8H, m), 1.94 (3H, s, NCH3), 2.62 (1H, q J
18.9 Hz, CH), 2.66 (1H, q J 19.1 Hz, CH), 2.84 (1H, m
J 8.1 Hz, CH), 4.79 (1H, t J 3.2 Hz, CH), 7.41 (1H, t J
7.2 Hz, ArH), 7.63 (1H, t J 7.2 Hz, ArH), 7.72 (2H, m,
ArCH); dC 23.8 (CH2), 23.8 (CH2), 31.4 (CH2), 31.4
(CH2), 35.4 (CH2), 33.5 (CH3), 59.9 (CH), 65.4 (CH),
123.0 (ArCH), 126.6 (ArCH), 128.4 (ArCH), 132.4 (ArCH),
137.3 (qC), 152.3 (qC), 204.3 (CO); MS: m/z 229 [M+].
5.2.3. (R,S)-3(N-R,S)-1Cyclopentylamino)-indan-1-one (14).
Prepared by coupling 1 with cyclopentylamine. Oil
(85.8%), kmax (film) 3022 (ArCH), 1743 (CO), 1426
(CH) cmÀ1; dH (CDCl3): 1.65 (9H, bm), 2.50 (1H, dd J
3.1, 18.7 Hz), 3.01 (1H, dd J 6.6, 18.7 Hz), 3.25 (1H,
quin J 3.2 Hz), 4.45 (1H, q J 7.2, 18.7 Hz), 7.70 (1H,
m, ArH), 7.45 (3H, m, ArH), dC 23.7 (CH2), 23.8
(CH2), 33.1 (CH2), 34.0 (CH2), 45.6 (CH2), 54.8 (CH),
58.3 (CH), 123.2 (ArCH), 125.9 (ArCH), 128.5 (ArCH),
134.7 (ArCH), 136.6 (qC), 156.4 (qC), 204.8 (CO); MS
m/z: 214 [M+].
5.3.4. (R,S)-3[2,3-Dihydro-1H-inden-1-yl(prop-2-enyl)-
amino]-1H-inden-1-one (4). Prepared by alkylation of 2
with allyl bromide. Oil (35%), kmax (film) 3087 (ArCH),
1722 (CO), 1599 (NH) cmÀ1; dH (CDCl3): 2.05 (2H, bm,
CH2), 2.47 (1H, dd J 9.5 Hz, CH), 2.72 (2H, m, CH2),
3.11 (2H, bm, CH), 4.40 (1H, t J 3.0 Hz, CH), 4.50
(1H, t J 3.0 Hz, CH), 4.65 (1H, m, CH), 5.15 (2H, bm,
CH@CH2), 5.80 (1H, bm, CH=CH2), 7.20 (3H, bm,
ArH), 7.40 (1H, m, ArH), 7.50 (1H, m, ArH), 7.64
(1H, bm, ArH), 7.74 (1H, m, ArH), 7.86 (1H, m,
ArH); dC 27.9 (CH2), 30.2 (CH2), 41.3 (CH2), 49.4
(CH2), 57.0 (CH), 64.6 (CH), 116.4 (@CH2), 122.9
(ArCH), 124.1 (ArCH), 124.7 (ArCH), 126.1 (ArCH),
126.4 (ArCH), 127.3 (ArCH), 128.4 (ArCH), 134.7
(CH), 137.1 (qC), 137.2 (ArCH), 143.2 (qC), 144.4
(qC), 156.7 (qC), 204.9 (CO); MS: m/z 303 [M+].
5.3. General procedure for the alkylation of 2, 8 and 14.
Synthesis of 3–5, 9–11 and 15–17
Triethylamine (1.2 equiv) and alkyl halide (5 equiv) were
added to a solution of amine (1 equiv) in DCM and the
reaction mixture was stirred at room temperature for
2 h, the solvent was evaporated in vacuo and the residue
directly purified by column chromatography over silica
gel (pet. Ether/EtOAc, 4:1) to yield.
5.3.5. (R,S)-3[2,3-Dihydro-1H-inden-2-yl(prop-2-enyl)-
amino]-1H-inden-1-one (10). Prepared by alkylation of
8 with allyl bromide. Oil (40.8%). kmax (film) 3062,
2985, 1722, 1603 cmÀ1; dH (CDCl3): 2.65 (1H, dd J
6.7, 18.8 Hz, CH), 2.68 (1H, dd J 4.2, 18.8 Hz, CH),
2.98 (6H, m), 3.77 (1H, quin J 7.6 Hz, CH), 4.67 (1H,
dd J 4.2, 6.7 Hz, CH), 5.05 (1H, dd J 1.8, 10.2 Hz,
CH), 5.08 (2H, dd J 1.8, 10.2 Hz, CH@CH2), 5.80
(1H, m, @CH), 7.15 (4H, m, ArH), 7.42 (1H, dt J
7.8 Hz, ArH), 7.64 (1H, dt J 1.2, 7.7 Hz, ArH), 7.74
(2H, dd J 1.2, 7.0 Hz); dC 35.9 (CH2), 38.6 (CH2), 39.1
(CH2), 50.1 (CH2), 57.3 (CH), 61.0 (CH), 116.3 (CH2),
5.3.1. (R,S)-3[2,3-Dihydro-1H-inden-1-yl(methyl)amino]-
1H-inden-1-one(3). Prepared by methylation of 2 with
MeI. Oil (45%), kmax (film) 3063 (ArCH), 1730 (CO),
1604 (NH) cmÀ1; dH (CDCl3): 1.89 (3H, s, CH3), 2.08
(1H, m, CH), 2.62 (1H, dd J 3.7, 6.9 Hz, CH), 2.81
(1H, m, CH), 2.97 (1H, m, CH), 4.34 (1H, t J 7.7 Hz,
CH), 4.55 (1H, dd J 3.7, 6.9 Hz, CH), 4.63 (1H, t J
7.7 Hz), 4.77 (1H, dd J 3.7, 6.9 Hz), 7.24 (3H, m,
ArH), 7.44 (2H, m, ArH), 7.65 (1H, dq J 1.4, 7.3 Hz,
ArH), 7.75 (1H, dt J 7.7 Hz, ArH), 7.84 (1H, d J
7.7 Hz, CH); dC 26.6, 27.2 (CH2), 28.0 (CH), 30.3,

252
H. Sheridan et al. / Bioorg. Med. Chem. 16 (2008) 248–254
122.9 (ArCH), 124.1 (ArCH), 124.5 (ArCH), 126.3
(ArCH), 126.3 (ArCH), 126.4 (ArCH), 128.4 (ArCH),
134.7 (CH), 137.2 (ArCH), 141.3 (qC), 141.5 (qC),
156.3 (qC), 156.3 (qC), 204.7 (CO); MS: m/z 303 [M+].
(ArCH), 126.8 (ArCH), 127.9 (ArCH), 128.1 (ArCH),
128.1 (ArCH), 128.1 (ArCH), 128.4 (ArCH), 134.8
(ArCH), 137.3 (qC), 140.9 (qC), 151.7 (qC), 156.7
(qC), 205.1 (CO); MS: m/z 305 [M+].
5.3.6. (R,S)-3(N-prop-2-enyl-N-2-indanylamino)-indan-1-
one (10). Prepared by alkylation of 14 with allyl bro-
mide. Oil (82.6%). kmax (film) 3056 (ArH), 1728 (CO),
1602 (NH) cmÀ1; dH (CDCl3): 1.65 (6H, m), 2.67 (2H,
dq J 4.4, 19.0 Hz, CH2), 3.01 (3H, m), 4.71 (1H, dd J
6.2, 4.4 Hz, CH), 4.95 (2H, dd J 1.3, 10.2 Hz), 5.09
(2H, dd J 1.3, 17.3 Hz, @CH), 5.76 (1H, m, @CH),
7.40 (1H, t, ArH), 7.66 (3H, m, ArH); dC 23.2 (CH2),
23.7 (CH2), 29.7 (CH2), 31.4 (CH2), 39.0 (CH2), 50.8
(CH), 57.9 (CH), 115.6 (@CH2), 122.8 (@CH), 126.5
(ArCH), 128.2 (ArCH), 134.5 (ArCH), 137.9 (ArCH),
137.9 (qC) 156.6 (qC), 204.9 (CO); MS: m/z 255 [M+].
5.4. General procedure for the acylation of 2, 8 and 14.
Synthesis of 6, 12 and 18
Triethylamine (2.0 equiv) acetic anhydride (2 equiv) and
DMAP (1 equiv) were added to a solution of amine
(1.0 equiv) in DCM and the reaction mixture was stirred
at room temperature for 2 h. The reaction mixture was
washed with H2O, dried over Na2SO4, filtered and evap-
orated in vacuo to yield a residue that was purified by
column chromatography over silica gel (pet. ether/
EtOAc, 4:1) to yield.
5.4.1. (R,S)-3[2,3-Dihydro-1H-inden-1-yl(ethanamide)
amino)1H-inden-1-one (6). Prepared by acetylation of
2. Pale solid mp 134.0–134.2 ꢁC (62.5%), kmax (KBr)
3056, 2991, 1720, 1644 cmÀ1; dH (CDCl3): 2.14 (3H, s
CH3), 2.62 (6H, br m), 4.20 (1H, m, CH), 5.51 (1H,
m, CH), 7.45 (8H, br m, ArH); dC 27.4 (CH3), 29.8
(CH2), 29.8 (CH2), 30.1 (CH2), 42.8 (CH), 52.4 (CH),
123.3 (ArCH), 124.2 (ArCH), 124.5 (ArCH), 125.4
(ArCH), 125.5 (ArCH), 127.1 (ArCH), 127.2 (ArCH),
127.8 (ArCH), 134.4 (qC), 138.2 (qC), 143.4 (qC),
152.5 (qC), 202.2 (CO), 203.1 (CO);MS: m/z 305 [M+].
5.3.7. (R,S) 3[2,3-Dihydro-1H-inden-1-yl(benzyl)amino]-
1H-inden-1-one (5). Prepared by reaction of 2 with ben-
zyl bromide. Oil (85%), kmax (film) 3094 (ArH), 1714
(CO), 1595 (NH) cmÀ1; dH (CDCl3): 2.65 (1H, dq J
7.1, 19.3 Hz, CH), 2.76 (1H, dq J 3.7, 19.3 Hz, CH),
2.52 (4H, m), 3.60 (1H, q J 12.8, 17.9 Hz, CH), 3.75
(1H, q J 12.8, 17.9 Hz, CH), 4.39 (1H, dt J 7.3,
8.2 Hz, CH), 4.61 (1H, dd, J 4.0, 7.0 Hz, CH), 7.45
(11H, m, ArH), 7.85 (1H, d J 7.2 Hz, ArH), 8.01 (1H,
d J 7.2 Hz, ArH), dC 39.5 (CH2), 40.1 (CH2), 50.6
(CH2), 55.6 (CH2), 56.2 (CH), 63.2 (CH), 122.8 (ArCH),
124.0 (ArCH), 124.5 (ArCH), 126.2 (ArCH), 126.3
(ArCH), 126.3 (ArCH), 126.8 (ArCH), 128.0 (ArCH),
128.2 (ArCH), 128.4 (ArCH), 134.7 (ArCH), 139.6
(ArCH), 143.1 (ArCH), 143.4 (qC), 143.6 (qC), 144.2
(qC), 156.2 (qC), 156.5 (qC), 204.8 (CO); MS: m/z 353
[M+].
5.4.2. (R,S)-3[2,3-Dihydro-1H-inden-2-yl(ethanamide)
amino)1H-inden-1-one (12). Prepared by acetylation of
8. White solid mp 151.1–151.6 ꢁC (55%), kmax (KBr)
3049 (ArH), 1724 (CO), 1641 (CH) cmÀ1; dH (CDCl3:
2.15 (3H, s, CH3), 2.97 (8H, bm), 7.47 (8H, bm, ArH);
dC 20.9 (CH3), 23.0 (CH2), 23.8 (CH2), 29.5 (CH2),
52.3 (CH), 55.9 ( CH), 123.3 (ArCH), 124.4 (ArCH),
124.5 (ArCH), 126.0 (ArCH), 127.2 (ArCH), 129.5
(ArCH), 134.5 (ArCH), 135.6 (ArCH), 137.5 (qC),
139.6 (qC), 141.0 (qC), 154.0 (qC), 201.5 (CO), 202.8
(CO); MS: m/z 305 [M+].
5.3.8. (R,S)-3[2,3-Dihydro-1H-inden-2-yl(benzyl)amino]-
1H-inden-1-one (11). Prepared by benzylation of 8 with
benzyl bromide. Oil (40%), kmax (film) 3093 (ArH),
1728 (CO), 1693 (CH) cmÀ1; dH (CDCl3): 2.63 (1H, dd
J 6.7, 18.8 Hz, CH), 2.81 (1H, dd J 3.8, 18.8 Hz, CH),
3.04 (4H, m), 3.64 (2H, m, CH2), 3.76 (1H, t J
6.7 Hz), 4.67 (1H, m, CH), 7.31 (10H, m, ArH), 7.67
(1H, dt J 1.2, 7.7 Hz, ArH), 7.76 (1H, dt J 1.2, 7.7 Hz,
ArH), 7.87 (1H, t J 7.7 Hz, ArH); dC 35.2 (CH2), 38.6
(CH2), 38.7 (CH2), 50.9 (CH2), 56.9 (CH), 60.4 (CH),
122.8 (ArCH), 124.0 (ArCH), 124.5 (ArCH), 126.2
(ArCH), 126.3 (ArCH), 126.3 (ArCH), 126.8 (ArCH),
128.0 (ArCH), 128.0 (ArCH), 128.2 (ArCH), 128.2
(ArCH), 128.4 (ArCH), 134.7 (ArCH), 137.1 (qC),
139.9 (qC), 141.2 (qC), 141.4 (qC), 156.1 (qC), 204.6
(CO); MS: m/z 353 [M+].
5.4.3. N-Cyclopentyl-N-(R,S)-3-indan-1-onylethanamide
(18). Prepared by acetylation of 14. Cream solid mp
164.2–164.9 ꢁC (54%), kmax (KBr) 3062 (ArH), 1715
(CO), 1631 (CH) cmÀ1; dH (CDCl3: 2.01 (10H, bm),
2.10 (2H, bm, CH2), 2.89 (1H, bm, CH), 4.14 (1H,
bm, CH), 4.76 (1H, bm, CH), 7.42 (1H, bm, ArH),
7.58 (2H, bm, ArH), 7.82 (1H, bm, ArH); dC 23.0
(CH3), 24.0 (CH2), 25.4 (CH2), 29.4 (CH2), 30.9
(CH2), 42.2 (CH2), 52.0 (CH), 56.9 (CH), 123.4 (ArCH),
125.5 (ArCH), 127.8 (ArCH), 129.3 (ArCH), 134.5 (qC),
135.3 (qC), 169.1 (CO), 204.(CO): MS m/z 257 [M+].
5.3.9. (R,S)-3(N-Cyclopentyl-N-benzylamino)-indan-1-one
(17). Prepared by benzylation of 14 with benzyl bro-
mide. Oil (65%), kmax (film) 3022, 2986, 1743,
1421 cmÀ1; dH (CDCl3): 1.51 (8H, br m), 2.75 (2H, d J
5.5, CH2), 3.05 (1H, t J 7.7 Hz, CH), 3.56 (2H, dd J
3.5, 14.5 Hz, CH2), 4.68 (1H, t J 5.5 Hz, CH) 7.29
(6H, br m, ArH), 7.60 (1H, t J 7.3 Hz, ArH), 7.71
(1H, m, ArH), 7.76 (1H, m, ArH); dC 23.4 (CH2), 31.3
(CH2), 32.1 (CH2), 42.7 (CH2), 42.8 (CH2), 54.2
(CH2), 55.8 (CH), 57.6 (CH), 122.9 (ArCH), 126.5
5.5. General procedure for the preparation of p-toluene
sulfonamide derivatives of 2, 8 and 14. Synthesis of 7, 13
and 19
p-Toluene sulfonyl chloride (10 equiv) and pyridine (ex-
cess) were added to a stirring solution of amine (1 equiv)
in DCM and the reaction mixture was stirred for 0.5 h.
at 0 ꢁC and then at room temperature for a further 12 h.
After this time the reaction was extracted into aq. HCl
(2 M) and ether (1:1, v:v) and the organic layer was

H. Sheridan et al. / Bioorg. Med. Chem. 16 (2008) 248–254
253
washed (H2O, ·3), dried over Na2SO4, filtered and the
solvent evaporated in vacuo. The resulting residue was
directly purified by column chromatography over silica
gel (pet. ether/EtOAc, 3:1) to yield.
FT.03 transducers. Isometric contractions were re-
corded using a MacLab/4e system in conjunction with
the Chart 3.3.1 software package.
Sustained (>40 min) contractures were elicited by addi-
tion of CaCl solution sufficient to raise the calcium con-
centration in the bath to 2.5 mM. Test compounds
(1 · 10À5 M) and nifedipine (1 · 10À8 M), as a positive
control, were prepared in 0.5% (v/v) dimethylsulphoxide
(DMSO) and distilled water. The test compound solu-
tion was added to the organ bath once a stable contrac-
tion of the tissue had been achieved.
5.5.1. (R,S)-3[2,3-Dihydro-1H-inden-1-yl(p-toluene sul-
fonamide)amino]-1H-inden-1-one (7). Prepared by sulf-
onylation of 2. White needles mp 212.4–212.9 ꢁC
(43%), kmax (KBr) 3050, 2989, 1721, 1609 cmÀ1; dH
(CDCl3): 2.44 (3H, s CH3), 2.53 (6H, br m), 4.82 (1H,
m, CH), 5.33 (1H, m, CH), 7.43 (12H, br m, ArH); dC
21.5 (CH3), 30.3 (CH2), 31.1 (CH2), 44.5 (CH2), 54.1
(CH), 63.8 (CH), 123.4 (ArCH), 123.8 (ArCH), 124.0
(ArCH), 124.3 (ArCH), 124.5 (ArCH), 125.0 (ArCH),
125.5 (ArCH), 125.8 (ArCH), 127.2 (ArCH), 128.6
(ArCH), 129.5 (ArCH), 134.6 (ArCH), 137.1 (qC),
138.7 (qC), 140.7 (qC), 143.5 (qC), 143.8 (qC), 152.5
(qC), 202.6 (CO); MS: m/z 417 [M+].
5.6.2. Inhibition of compound 48/80-induced histamine
release from mast cells. The effect of compounds on Com-
pound 48/80-induced histamine release from rat perito-
neal mast cells was assessed as described previously.7
Briefly, Female Wistar rats (250–350 g) were killed in an
atmosphere of saturated CO2. A volume of 10 ml of pre-
warmed (37 ꢁC) buffered salt solution (BSS; NaCl
137 mM; KCl 2.7 mM; MgCl2 1.0 mM; CaCl2 0.5 mM;
NaH2PO4 0.4 mM mM; Glucose 5.6 mM; HEPES
10 mM) was injected ip and the abdomen was massaged
for 3 min. The BSS, along with suspended mast cells
and other cells, were aspirated, using a 10 ml syringe, fol-
lowing a mid-line incision. The aspirate was centrifuged
for 6 min at 1000 rpm, using a Sigma 204 centrifuge,
and the supernatant removed. The cells were washed three
times by re-suspending in BSS, at 4 ꢁC, and re-centrifug-
ing. Following the final wash, the pelleted cells were
stored at 4 ꢁC, for use as soon as possible. The harvesting
of mast cells and the release of histamine from these mast
cells was carried out according to a modified protocol de-
scribed by both Loeffler et al.14 and Amellal et al.15 The
mast cells were not purified by density gradient centrifu-
gation in accordance with Loeffler et al.14 where it was
demonstrated that consistent and uniform responses to
compound 48/80 and other releasing agents were achieved
without cell purification.
5.5.2. (R,S)-3[2,3-Dihydro-1H-inden-2-yl(p-toluene sul-
fonamide)amino]-1H-inden-1-one (13). Prepared by sulf-
onylation of 8. Oil (90%), kmax (KBr) 3098 (ArH),
1721 (CO), 1608 (CH) cmÀ1; dH (CDCl3): 2.39 (4H, bs,
2 · CH2), 2.48 (3H, s, CH3), 3.00 (2H, br m, CH2),
3.52 (2H, br m, 2·CH), 7.14–7.50 (12H, br m, ArH);
dC 21.5 (CH3), 37.4 (CH2), 37.0 (CH2), 38.0 (CH2),
54.8 (CH), 57.9 (CH), 123.1 (ArCH), 124.0 (ArCH),
124.2 (ArCH), 125.0 (ArCH), 125.6 (ArCH), 126.9
(ArCH), 126.9 (ArCH), 127.9 (ArCH), 128.7 (ArCH),
128.9 (ArCH), 129.5 (ArCH), 134.6 (ArCH), 136.9
(qC), 137.5 (qC), 138.2 (qC), 139.7 (qC), 143.3 (qC),
151.9 (qC), 201.8 (CO); MS: m/z 417 [M+].
5.5.3. N-Cyclopentyl-N-(R,S)-3-indan-1-onyl-p-toluene sul-
fonamide (19). Prepared by sulfonylation of 14. Waxy oil
(45%), kmax (KBr) 3094 (ArH), 1708 (CO), 1596
(NH) cmÀ1; dH (CDCl3): 2.10 (4H, br m), 2.50 (3H, s,
CH3), 3.50 (2H, br m, CH2), 3.23 (2H, br m, CH2),
3.00 (2H, br m, CH2), 3.52 (2H, br m, 2 · CH), 7.55
(8H, br m, ArH); dC 21.4 (CH3), 23.3 (CH2), 23.3
(CH2), 23.7 (CH2), 30.8 (CH2), 31.9 (CH2), 54.7 (CH),
59.1 (CH), 123.3 (ArCH), 125.9 (ArCH), 127.0 (ArCH),
129.1 (ArCH), 129.1 (ArCH), 129.6 (ArCH), 134.9
(ArCH), 134.9 (ArCH), 137.1 (qC), 138.6 (qC), 143.2
(qC), 152.5 (qC), 202.5 (CO); MS: m/z 341 [M+].
Test compounds (2 · 10À5 M) and disodium cromogly-
cate (2 · 10À5 M) were prepared in 0.5% DMSO (0.5%
v/v) in distilled water. Histamine release was stimulated
by Compound 48/80 (10 lg/ml) following 10 min incu-
bation with test compound or DSCG. Cell stimulation
was stopped after 2 min by the addition of 0.5 ml BSS
(4 ꢁC) and the incubation tubes were transferred imme-
diately to an ice bath. Basal histamine release was mea-
sured in the absence of Compound 48/80, and total
histamine content was assayed following heating to
100 ꢁC for 2 min.
5.6. Pharmacological methods
5.6.1. Inhibition of smooth muscle contraction. Smooth
muscle relaxant activity was assessed as inhibition of
calcium contractures of potassium-depolarised guinea-
pig ileum as described previously.4 Guinea pigs (250–
400 g) of either sex were killed by cervical dislocation
and exsanguination. The abdomen was opened by mid-
line incision and the ileum removed. The tissue was
stored at 4 ꢁC in Kreb’s solution (composition (mM):
NaCl 118, KCl 4.7, CaCl2 2.5 mM, MgCl2 1.15, NaH2-
PO4 1.17, NaHCO3 25, glucose 14.4). Segments of ileum
2.5 cm in length were suspended in a high potassium cal-
cium-free modified Kreb’s solution (composition (mM):
NaCl 12.5, KCl 45, MgCl2 1.15, NaH2PO4 1.17, NaH-
CO3 25, glucose 11.1) at 37 ꢁC, gassed with 95%O2/
5%CO2 under a resting tension of 1.5 g, from Grass
The histamine assay was carried out according to a
modified protocol described by Shore et al.16 A volume
of 0.4 ml of 1 M NaOH and 0.1 ml O-phthaldialdehyde
(oPT) (1% (w/v) in methanol) was added to 2 ml of
supernatant from each tube. This was incubated at room
temperature for 4 min. The reaction was stopped by the
addition of 0.2 ml of 3 M HCl. The presence of the fluo-
rescent product of the reaction was measured using
a Shimadzu RF-1501 spectrophotometer set at kex
=
360 nm and kem = 450 nm. The supernatant from each
incubation tube was assayed in duplicate.

254
H. Sheridan et al. / Bioorg. Med. Chem. 16 (2008) 248–254
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4. Sheridan, H.; Lemon, S.; Frankish, N.; McCardle, P.;
Higgins, T.; James, J.; Bhandari, P. Eur. J. Med. Chem.
1990, 25, 603–608.
Animals were sacrificed according to guidelines laid
down by the working party report (Laboratory Animals
(1996) 30, 293–316, Laboratory Animals (1997) 31, 1–
32), on Directive 86/609/EEC (No. L 358, ISSN 0378-
6978), which is endorsed by the Bioresources Ethical Re-
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5. Sheridan, H.; Frankish, N.; Farrell, R. Eur. J. Med. Chem.
1999, 34, 953–966.
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5.7. Statistics
Results are expressed as means SEM. Statistical anal-
ysis was performed using one way ANOVA, followed by
Bonferroni’s Multiple Comparison Test. Probability va-
lue (P) of less than 0.05 was taken as significant. n de-
notes the number of animals from which preparations
were used in that series of experiments.
8. Walsh, J.; Frankish, N.; Sheridan, H.; Byrne, W. US
Patent 6,423,752, 2002.
9. Ho, S.; Yang, M.; Wu, T.; Wang, C. Planta Med. 1985, 51,
148–150.
10. Yang, M. Planta Med. 1996, 52, 25–27.
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2006, 1088, 78–99.
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Immunol. Ther. Exp. 2002, 50, 179–185.
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References and notes
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