Synthesis and biological evaluation of amide derivatives of (6-chloro-2,3-dihydro-1H-inden-1-yl)acetic acid as potential anti-inflammatory agents with lower gastrointestinal toxicity

Article abstract of DOI:10.1248/cpb.56.626

A variety of amide derivatives of (6-chloro-2,3-dihydro-1H-inden-1-yl) acetic acid were synthesized and screened for their anti-inflammatory and related biological activities. These compounds were found to be longer acting and showed residual activity exceeding that of standard indomethacin. The studies with SKF-525A, a standard hepatic microsomal enzyme inhibitor showed that probably the test compound per se is the active species. The compound 6y showed best activity profile with ED₃₀ of 6.45 mg/kg however this compound was found to be toxic at 100 mg/kg p.o. Though these compounds exhibited appreciable analgesic and antipyretic activities but they failed to prevent the development of secondary inflammation in adjuvant induced arthritis assay. The compound 6x showed 94% inhibition of acetic acid induced writhing. Studies showed that antagonism of TNF-α is not possibly involved in the mechanism of action of these compounds. However these compounds were found to have only mild ulcerogenic potential at the tested dose level of 100 mg/kg p.o. in comparison to indomethacin.

Full text of DOI:10.1248/cpb.56.626

626
Chem. Pharm. Bull. 56(5) 626—634 (2008)
Vol. 56, No. 5
Synthesis and Biological Evaluation of Amide Derivatives of (6-Chloro-
2,3-dihydro-1H-inden-1-yl)acetic Acid as Potential Anti-inflammatory
Agents with Lower Gastrointestinal Toxicity
,1)
*
Meenakshi SHARMA and Saumendra Mohan RAY
Medicinal Chemistry Research Laboratory, Pharmacy Group, Birla Institute of Technology and Science; Pilani-333031,
India. Received October 12, 2007; accepted January 31, 2008; published online February 14, 2008
A variety of amide derivatives of (6-chloro-2,3-dihydro-1H-inden-1-yl)acetic acid were synthesized and
screened for their anti-inflammatory and related biological activities. These compounds were found to be longer
acting and showed residual activity exceeding that of standard indomethacin. The studies with SKF-525A, a
standard hepatic microsomal enzyme inhibitor showed that probably the test compound per se is the active
species. The compound 6y showed best activity profile with ED30 of 6.45 mg/kg however this compound was
found to be toxic at 100 mg/kg p.o. Though these compounds exhibited appreciable analgesic and antipyretic ac-
tivities but they failed to prevent the development of secondary inflammation in adjuvant induced arthritis assay.
The compound 6x showed 94% inhibition of acetic acid induced writhing. Studies showed that antagonism of
TNF-a is not possibly involved in the mechanism of action of these compounds. However these compounds were
found to have only mild ulcerogenic potential at the tested dose level of 100 mg/kg p.o. in comparison to in-
domethacin.
Key words Indene; amide derivative; anti-inflammatory; ulcerogenecity
Arylalkanoic acids are among the most widely investi- potential anti-inflammatory agents some of the compounds
gated compounds in the area of non-steroidal anti-inflamma- not only showed anti-inflammatory activity comparable to
tory agents. Features of a typical molecule, which are impor- Phenylbutazone but were also found to be much less ulcero-
tant for activity, include a carboxyl group separated by one or genic. The research in this area led to development of Cli-
more carbon atoms from a flat aromatic nucleus that is fur- danac,2) having ED30 of 0.85 mg/kg, which showed better
ther substituted by a lipophilic group. The lead compound for gastrointestinal tolerability. An isomer of Clidanac, 6-chloro-
aryl acetic acids is ibufenac from which ibuprofen and (S)- 5-(cyclopentylmethyl)indan-1-carboxylic acid was also de-
(ꢀ)-2-(3-chloro-4-cyclohexylphenyl) propionic acid have void of any mucosal damage in the rat stomach upto highest
come up.2) Ring chain modification of the aryl propionic acid tested dose of 400 mg/kg.6)
has led to development of indan moiety (Fig. 1). Indan ring
It has been shown that the biochemical differences be-
system has been found to act as an inert carrier, which serves tween the cyclooxygenase (COX) isoforms can be exploited
to hold biologically active functional moieties in a stereospe- to improve upon the selectivity of carboxyl containing non-
cific manner.3) This congener of indene is isosteric and steroidal anti-inflammatory drugs (NSAIDs) as COX-2 in-
bioisosteric with indolidine and indole respectively that are hibitors. Successful transformation of indomethacin and
also pharmacologically active chemical nuclei.
meclofenamic acid into selective COX-2 inhibitors by a sin-
Among the various indan-1-alkanoic acids2,4,5) prepared as gle chemical derivatisation (amidation or esterification) has
Fig. 1. Design of Amide Derivatives of (6-Chloro-2,3-dihydro-1H-inden-1-yl)acetic Acid
∗ To whom correspondence should be addressed. e-mail: rsoumendra@gmail.com
© 2008 Pharmaceutical Society of Japan

May 2008
627
been reported.7) Structurally diverse indomethacin amides in- amides 6a—y. The structure of amide derivatives were con-
hibited purified human COX-2 with IC50 values in the low firmed by the presence of two, one or no peak around
nanomolar range but did not inhibit ovine COX-1 activity at 3300 cmꢁ1 (NH stretch) corresponding to primary, secondary
concentrations as high as 66 mM.8)
and tertiary amides. Also disappearance of broad OH stretch
Keeping the above points in view, we designed (Fig. 1), at 3400—2400 cmꢁ1 indicates the formation of amide bond.
synthesized and biologically evaluated some amide deriva- The formations of amides were further confirmed by pres-
1
tives of 6-chloroindan-1-acetic acid for anti-inflammatory ence of a small singlet at 5—8 ppm in H-NMR. In most of
and related biological activities. The idea behind derivatisa- the cases there was an overlap of two peaks at around 2.3—
tion was to further lower the side effects of gastric irritation 2.5 ppm corresponding to doublet of doublet and multiplet.
and ulceration, which is associated with free carboxyl group. Even for most of the aromatic amides, the NH peak was
Neutralization of the carboxyl group by amidation was ex- mixed with the aromatic peaks at around 7.1—7.3 ppm.
pected to increase the activity profile of indan-1-alkanoic
acids by not only enhancing absorption due to increased Results and Discussion
lipophilicity but also by imparting COX-2 selectivity.
Anti-inflammatory Activity The anti-inflammatory ac-
Chemistry The starting reagent for the preparation of tivity of the test compounds was evaluated by carrageenan-
the key intermediate, (6-chloro-2,3-dihydro-1H-inden-1-yl)- induced rat paw edema model. The results (Table 1) show
acetic acid (5) was 3-chlorobenzaldehyde (1). Compound 1 that the test compounds exhibit variable anti-inflammatory
was reacted with two moles of ethylacetoacetate (EAA) in activity, and a few among them have significant acute as well
presence of catalytic amount of piperidine at room tempera- as residual anti-inflammatory activity at 24 h after a single
ture to obtain the substituted phenylbisacetoacetate (2). Acid oral dose of 100 mg/kg p.o. Most of these amide derivatives
hydrolysis (end product is acid) of 2 was carried out with 6N were found to have more activity than the parent acid. The
potassium hydroxide (KOH) in 50% ethanol to get the diacid compounds were slow acting and showed longer duration of
3. The IR spectra of 3 showed broad OH stretch at 3400— action. The peak activity of the test compounds was found to
1
2200 cmꢁ1 and CꢂO stretch at 1710 cmꢁ1. H-NMR of 3 be lower than that of indomethacin (10 mg/kg, p.o.) but their
showed doublet of doublet at d 2.58 and 2.70 ppm as well as residual activity at 24 h exceeded that of the latter. The
quintet at 3.60 ppm for CH2 and CH of glutaric acid side lipophilicity of acid 5 is increased by amidation which leads
chain respectively, multiplet at d 7.18 ppm for aromatic pro- to better absorption of these amide derivatives. Due to high
tons and small broad singlet at d 10.79 ppm indicating the lipophilicity of the amide derivatives in comparison to parent
presence of carboxyl group.
acid 5 (Table 1) these compounds are also likely to form lipid
Compound 3 was treated with aluminium chloride in the depots which might be the cause for their longer activity pro-
presence of catalytic amounts of sodium chloride when in- file. The compounds 6a, 6p, 6w showed nearly 50% inhibi-
tramolecular Friedel-Craft’s cyclization and hence ring clo- tion as the residual activity. The lower members in the
sure took place to give the ketonic product 4. The cyclization aliphatic amides (having low log P values) showed almost
was also tried with polyphosphoric acid but it gave poorer negligible activity; however compound 6a was found to have
yields of keto product with more impurities. Presence of dou- good anti-inflammatory activity. That may be due to close re-
blet of doublet at 2.46 and 2.58 ppm and doublet of doublet semblance of this compound to centrally acting muscle relax-
at 2.84 and 2.99 corresponding to CH2 of side chain and CH2 ant (E)-2-(4,6-difluoro-1-indanylidene)acetamide, which also
of the indan ring respectively as well as the presence of quin- possesses potent anti-inflammatory and analgesic activity. It
tet at 3.79 ppm indicates the ring closure. The presence of has been reported in literature that this muscle relaxant has
aromatic protons (doublets at 7.38 and 7.65 ppm and singlet been taken in phase I clinical trials.9) The tertiary amides (6l,
at 7.59) and acid protons (broad singlet at 10.91 ppm) further 6m) and the cyclic amides (6i, 6j) showed intermediate activ-
supports the proposed structure of compound 4.
ity. Among the aromatic series no generalized pattern of ac-
The ketone group of compound 4 was finally removed tivity was found. The m-chloroaniline derivative (6p) was
using Clemmensen’s reduction to give (6-chloro-2,3-dihydro- found to be the most active. The p-nitroaniline (6w) and p-
1H-inden-1-yl)acetic acid 5. Because of the different confor- toluidine (6t) derivatives also showed good anti-inflamma-
mational arrangement of proton present on CH of indan ring tory activity profile while p-acetamidoaniline (6v) derivative
both neighbouring CH2 peaks got split into two peaks (two showed least activity. The 4-aminopyridine derivative (6y)
doublets of doublet at 2.48, 2.81 ppm and two multiplets at was found to be toxic at 100 mg/kg p.o. where as its isomer
1.78, 2.42 ppm). The presence of multiplet at 2.88 ppm 3-aminopyridine derivative (6x) didn’t show any toxicity at
equivalent to two protons in addition to peaks obtained for the same dose level. However at lower dose levels the com-
compound 5 indicates the reduction of carbonyl group and pound 6y did not show any toxicity and in fact showed best
formation of indan ring system. The presence of aromatic anti-inflammatory activity with ED30 of 6.45 mg/kg p.o.
protons (multiplet at 7.11—7.16 ppm) and proton of COOH
Analgesic Activity The analgesic activity of the synthe-
group (small broad singlet at 11.18 ppm) further supports the sized compounds at dose of 100 mg/kg p.o. was determined
structure of compound 5. Compound 5 was treated with oxa- by acetic acid induced writhing assay. The results (Table 2)
lyl chloride in presence of catalytic amount of dimethylfor- reveal that the beneficial effect of increasing chain length
mamide to convert carboxyl group of 5 into acyl halide. The was apparent for analgesic activity to some extent with few
acyl halide thus obtained was not isolated or characterized. It exceptions. The compounds 6e, 6m, 6s and 6x exhibiting
was used directly in the next step. The acyl halide was re- poor anti-inflammatory activities showed good analgesic ac-
acted with various primary and secondary amines under tivities while compound 6t exhibiting good anti-inflamma-
Schotten-Baumann conditions for the formation of desired tory activity showed poor analgesic activity. Among the

628
Vol. 56, No. 5
Table 1. Carrageenan Induced Rat Paw Edema: Anti-inflammatory Activity
Increase in paw volume (ml)ꢃS.E.M. [% inhibition of edema]
Compound
1 h
2 h
3 h
4 h
6 h
24 h
Log P
1.92
2..31
2.80
3.27
3.07
3.75
4.24
4.75
3.74
4.24
3.54
3.82
2.00
1.57
3.59
4.53
4.37
4.41
3.90
4.00
3.76
3.14
3.83
2.74
2.78
6a
0.25ꢃ0.0145
[19.35]*
0.29ꢃ0.0149
[6.45]ns
0.28ꢃ0.0173
[9.68]ns
0.29ꢃ0.0149
[6.45]ns
0.28ꢃ0.0118
[9.68]ns
0.27ꢃ0.0124
[12.90]ns
0.26ꢃ0.0136
[16.13]ns
0.24ꢃ0.0154
[22.58]*
0.25ꢃ0.0116
[19.35]*
0.27ꢃ0.0143
[12.90]ns
0.23ꢃ0.0155
[25.81]*
0.28ꢃ0.0112
[9.62]ns
0.21ꢃ0.0138
[32.26]*
0.29ꢃ0.0178
[6.45]ns
0.20ꢃ0.0114
[35.48]*
0.15ꢃ0.0138
[51.61]*
0.26ꢃ0.0133
[16.13]ns
0.23ꢃ0.0125
[25.81]*
0.26ꢃ0.0169
[16.13]ns
0.19ꢃ0.0143
[38.71]*
0.28ꢃ0.0186
[9.68]ns
0.30ꢃ0.0145
[3.22]ns
0.17ꢃ0.0157
[45.16]*
0.26ꢃ0.0139
[16.34]ns
0.26ꢃ0.0136
[46.94]*
0.45ꢃ0.0117
[8.16]ns
0.43ꢃ0.0148
[12.24]ns
0.44ꢃ0.0117
[10.20]ns
0.37ꢃ0.0166
[24.48]*
0.42ꢃ0.0153
[14.28]ns
0.38ꢃ0.0149
[22.45]*
0.34ꢃ0.0192
[30.61]*
0.38ꢃ0.0137
[22.45]*
0.40ꢃ0.0161
[18.37]*
0.36ꢃ0.0154
[26.53]*
0.39ꢃ0.0121
[20.41]*
0.36ꢃ0.0118
[26.53]*
0.43ꢃ0.0163
[12.24]ns
0.31ꢃ0.0159
[36.73]*
0.25ꢃ0.0146
[48.98]*
0.32ꢃ0.0126
[34.69]*
0.34ꢃ0.0161
[30.61]*
0.36ꢃ0.0141
[26.53]*
0.26ꢃ0.0187
[46.94]*
0.42ꢃ0.0162
[14.29]ns
0.46ꢃ0.0134
[6.12]ns
0.24ꢃ0.0149
[51.02]*
0.35ꢃ0.0156
[28.57]*
0.32ꢃ0.0161
[48.39]*
0.57ꢃ0.0132
[8.06]ns
0.56ꢃ0.0273
[9.68]ns
0.55ꢃ0.0132
[11.29]ns
0.48ꢃ0.0134
[22.58]*
0.54ꢃ0.0148
[12.90]ns
0.48ꢃ0.0147
[22.58]*
0.42ꢃ0.0144
[32.26]*
0.44ꢃ0.0147
[29.03]*
0.48ꢃ0.0153
[22.58]*
0.44ꢃ0.0148
[29.03]*
0.55ꢃ0.0134
[11.29]ns
0.46ꢃ0.0136
[25.81]*
0.55ꢃ0.0152
[11.29]ns
0.42ꢃ0.0121
[32.25]*
0.31ꢃ0.0165
[50.0]*
0.40ꢃ0.0138
[35.48]*
0.44ꢃ0.0178
[29.03]*
0.52ꢃ0.0177
[16.13]ns
0.36ꢃ0.0151
[41.94]*
0.53ꢃ0.0167
[14.52]ns
0.56ꢃ0.0129
[9.67]ns
0.34ꢃ0.0176
[45.16]*
0.42ꢃ0.0162
[32.26]*
0.38ꢃ0.0125
[41.15]*
0.58ꢃ0.0132
[10.77]ns
0.59ꢃ0.0273
[9.23]ns
0.58ꢃ0.0132
[10.77]ns
0.50ꢃ0.0125
[23.08]*
0.58ꢃ0.0132
[10.77]ns
0.51ꢃ0.0129
[21.54]*
0.46ꢃ0.0165
[29.23]*
0.46ꢃ0.0132
[29.23]*
0.50ꢃ0.0136
[23.08]*
0.44ꢃ0.0164
[32.31]*
0.56ꢃ0.0150
[13.85]ns
0.48ꢃ0.0132
[26.15]*
0.59ꢃ0.0186
[9.23]ns
0.48ꢃ0.0137
[26.15]*
0.36ꢃ0.0159
[44.62]*
0.48ꢃ0.0142
[26.15]*
0.47ꢃ0.0136
[27.69]*
0.55ꢃ0.0134
[15.38]*
0.39ꢃ0.0149
[40.0]*
0.58ꢃ0.0179
[10.77]ns
0.59ꢃ0.0180
[9.23]ns
0.40ꢃ0.0136
[38.46]*
0.52ꢃ0.0148
[20.0]*
0.32ꢃ0.0141
[37.25]*
0.45ꢃ0.0128
[11.76]ns
0.45ꢃ0.0165
[11.76]ns
0.46ꢃ0.0128
[9.80]ns
0.44ꢃ0.0145
[13.72]*
0.45ꢃ0.0173
[11.76]ns
0.37ꢃ0.0166
[27.45]*
0.35ꢃ0.0127
[31.37]*
0.35ꢃ0.0151
[31.37]*
0.41ꢃ0.0163
[19.61]*
0.38ꢃ0.0135
[25.49]*
0.46ꢃ0.0088
[9.80]ns
0.42ꢃ0.0158
[17.65]*
0.47ꢃ0.0159
[7.84]ns
0.42ꢃ0.0162
[17.65]*
0.31ꢃ0.0132
[39.22]*
0.40ꢃ0.173
[21.57]*
0.41ꢃ0.0179
[19.61]*
0.43ꢃ0.0156
[15.69]*
0.34ꢃ0.0164
[33.33]*
0.44ꢃ0.0206
[13.72]*
0.47ꢃ0.0161
[7.80]ns
0.33ꢃ0.0182
[35.29]*
0.45ꢃ0.0151
[11.76]ns
0.13ꢃ0.0116
[55.17]*
0.25ꢃ0.0133
[13.79]ns
0.27ꢃ0.0125
[6.90]ns
0.26ꢃ0.0133
[10.34]ns
0.26ꢃ0.0108
[10.34]ns
0.26ꢃ0.0128
[10.34]ns
0.21ꢃ0.0091
[27.59]*
0.20ꢃ0.0162
[31.03]*
0.19ꢃ0.0131
[34.48]*
0.20ꢃ0.0085
[31.03]*
0.21ꢃ0.0113
[27.59]*
0.23ꢃ0.0125
[20.69]*
0.21ꢃ0.0138
[27.59]*
0.27ꢃ0.0153
[6.90]ns
0.25ꢃ0.0142
[13.79]ns
0.13ꢃ0.0083
[55.17]*
0.21ꢃ0.0121
[27.59]*
0.20ꢃ0.0130
[31.03]*
0.26ꢃ0.0144
[10.34]ns
0.21ꢃ0.0126
[27.59]*
0.21ꢃ0.0165
[27.59]*
0.26ꢃ0.0114
[10.34]ns
0.15ꢃ0.0142
[48.28]*
0.23ꢃ0.0112
[20.69]*
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
6t
6u
6v
6w
6x
6y
6y
toxic at 100 mg/kg
0.24ꢃ0.0142
[22.58]*
0.33ꢃ0.0136
[32.65]*
0.29ꢃ0.0154
[53.22]*
0.12ꢃ0.0147
[81.54]*
0.14ꢃ0.0135
[72.54]*
0.08ꢃ0.0123
[72.41]*
(25 mg/kg)
6y
0.25ꢃ0.0133
[19.35]*
0.35ꢃ0.0148
[28.57]*
0.37ꢃ0.0156
[40.32]*
0.37ꢃ0.0141
[43.08]*
0.33ꢃ0.0146
[35.29]*
0.17ꢃ0.0135
[41.38]*
(12.5 mg/kg)
6y
0.26ꢃ0.0154
[16.31]ns
0.41ꢃ0.0144
[16.33]ns
0.48ꢃ0.00138
[22.58]*
0.51ꢃ0.0157
[21.54]*
0.43ꢃ0.0151
[15.68]*
0.22ꢃ0.0143
[24.17]*
(6.25 mg/kg)
5
0.27ꢃ0.0165
[12.90]ns
0.16ꢃ0.0145
[48.39]*
0.40ꢃ0.0129
[18.37]*
0.22ꢃ0.0125
[55.10]*
0.50ꢃ0.0146
[19.35]*
0.23ꢃ0.0131
[62.90]*
0.52ꢃ0.0158
[20.0]*
0.26ꢃ0.0113
[60.0]*
0.43ꢃ0.0143
[15.69]*
0.28ꢃ0.0154
[45.10]*
0.22ꢃ0.0126
[24.14]*
0.25ꢃ0.0141
[13.79]ns
2.71
2.98
Indomethacin
Control
0.31ꢃ0.0163
0.49ꢃ0.0159
0.62ꢃ0.0185
0.65ꢃ0.0174
0.51ꢃ0.0166
0.29ꢃ0.0156
Data was analyzed by one way ANOVA followed by post-hoc test. ∗ Represents the significance level of pꢄ0.05, ns represents not significant at pꢄ0.05. Each value repre-
sents the meanꢃS.E.M. (nꢂ6). Log P values were calculated from website www.logp.com.
cyclic analogs the cyclopentyl derivative (6i) was equipotent cyclic piperidino derivative (6l) showed intermediate activity
to its linear counterpart, 6g whereas the cyclohexyl derivative while the piperazino derivative (6m) exhibited good anal-
(6j) was less active than its linear counterpart (6h). The gesic properties. Among aromatic amides there was slight

May 2008
629
Table 2. Acetic Acid-Induced Writhing Assay: Analgesic Activity
Compound
WrithingꢃS.E.M.
% inhibition
Compound
WrithingꢃS.E.M.
% inhibition
6a
6b
6c
6d
6e
6f
6g
6h
11.22ꢃ0.65*
27.74ꢃ0.87*
26.5ꢃ0.85*
20.5ꢃ0.76*
19.5ꢃ0.80*
22.17ꢃ0.95*
20.5ꢃ1.18*
19.33ꢃ0.99*
20.17ꢃ0.87*
22.33ꢃ0.88*
22.33ꢃ1.05*
24.5ꢃ0.78*
15.26ꢃ0.95*
12.18ꢃ1.13*
66.82
17.34
21.29
39.11
42.08
34.16
39.11
42.59
40.10
33.68
33.68
27.23
54.68
63.82
6m
6n
6o
6p
6q
6r
6s
6t
6u
6v
6w
6x
6y
Control
13.33ꢃ0.80*
25.17ꢃ0.70*
14.17ꢃ0.95*
15.17ꢃ0.60*
17.33ꢃ1.05*
16.5ꢃ0.99*
11.33ꢃ0.71*
23.33ꢃ0.88*
23.83ꢃ0.91*
19.5ꢃ0.89*
15.67ꢃ0.76*
2.0ꢃ0.37*
60.41
25.24
57.92
54.94
48.53
50.99
66.35
30.71
29.22
42.08
53.46
94.06
6i
6j
6k
6l
Indomethacin
Aspirin
toxic
33.67ꢃ1.12
Data was analyzed using student’s t-test: ∗ pꢄ0.005. Each value represents the meanꢃS.E.M. (nꢂ6).
Table 3. Lipopolysaccharide-Induced Pyresis: Antipyretic Activity
Change in rectal temperature (°C) and temperature index
Compound
1 h
2 h
3 h
4 h
TI
6a
6e
6i
6m
6p
6r
6s
6t
6w
ꢁ0.06ꢃ0.0125
0.28ꢃ0.0161
0.12ꢃ0.0153
0.28ꢃ0.0173
0.20ꢃ0.0141
0.24ꢃ0.0144
0.18ꢃ0.0126
0.37ꢃ0.0133
0.23ꢃ0.0136
0.22ꢃ0.0121
0.05ꢃ0.0112
0.25ꢃ0.0118
0.32ꢃ0.0179
0.05ꢃ0.0142
0.18ꢃ0.0130
0.30ꢃ0.0148
0.70ꢃ0.0162
0.11ꢃ0.0115
0.15ꢃ0.0136
0.38ꢃ0.0152
0.55ꢃ0.0128
0.42ꢃ0.0164
0.11ꢃ0.0142
ꢁ0.02ꢃ0.0131
0.29ꢃ0.0108
0.71ꢃ0.0156
0.08ꢃ0.0133
0.13ꢃ0.0152
0.62ꢃ0.0128
0.76ꢃ0.0141
0.18ꢃ0.0112
0.11ꢃ0.0138
0.44ꢃ0.0134
0.55ꢃ0.0147
0.51ꢃ0.0156
0.16ꢃ0.0168
0.03ꢃ0.0124
0.38ꢃ0.0125
0.96ꢃ0.0166
0.13ꢃ0.0126
0.11ꢃ0.0142
0.71ꢃ0.0137
0.84ꢃ0.0148
0.30ꢃ0.0120
0.11ꢃ0.0125
0.56ꢃ0.0155
0.64ꢃ0.0134
0.72ꢃ0.0145
0.28ꢃ0.0170
0.11ꢃ0.0115
0.59ꢃ0.0110
1.22ꢃ0.0143
0.17
0.70
1.75
2.58
0.79
0.61
1.56
2.11
1.88
0.77
0.17
1.51
3.21
6x
Aspirin
Indomethacin
Control
Each value represents the meanꢃS.E.M. (nꢂ6).
decrease in activity upon halogen substitution (6p, 6q, 6r) in compound 6a showed antipyretic activity comparable to that
comparison to aniline derivative (6o). Though m-toluidine of aspirin. The isopropyl (6e), halogen substituted amine (6p,
derivative (6s) showed poor anti-inflammatory activity than 6r), and 3-aminopyridino (6x) amide derivatives showed ap-
para derivative (6t) the results were opposite for analgesic preciable antipyretic activity. The data reveals that the test
activity. The 3-aminopyridinyl derivative (6x) and the amide compounds exhibited significant antipyretic property, but
derivative (6a) showed maximum inhibition of 94% and 66% these compounds did not exhibit antagonism of the initial
respectively and were more potent than standard drugs.
LPS-induced hypothermia as indicated by first temperature
Antipyretic Activity Few selected compounds were sub- index in Table 4 thus indicating that the antagonism of TNF-
jected to lipopolysaccharide (LPS)-induced hyperthermia a is not possibly involved in the mechanism of action of
assay. It is generally accepted that the NSAIDs exhibit their these compounds.13)
anti-inflammatory effect primarily through inhibition of
Anti-arthritic Activity Compounds were selected for
prostaglandin synthesis. However, relatively recent in vitro adjuvant-induced arthritis assay based on the inhibition of
studies have indicated that NSAIDs also interfere with pe- carrageenan-induced edema, analgesic and antipyretic activ-
ripheral proinflammatory cytokine production.10,11) It is well ity profile. Adjuvant-induced arthritis test in rats produced a
known that LPS produces a biphasic response in the rat. It biphasic response. The initial response started immediately
shows an initial hypothermia up to 3 h of its administration. after adjuvant administration and reached maximum on 3rd
It has been shown that this hypothermia is triggered by tu- day and then it started subsiding. The 2nd phase started from
mour necrosis factor-a (TNF-a).12) For determining the an- the 9th day and continued till the end of the experiment (14th
tipyretic activity two protocols were adopted, one in which day). Secondary lesions (appearance of nodules, and ery-
the initial hypothermic phase was excluded and other in thema in tail, nose and ears) started developing from the 10th
which the hypothermic phase was also monitored in order to day. Results of this test summarized in Table 5 show that
determine if inhibition of TNF-a is involved in mechanism compound 6w has the best profile in this assay. Compound
of action of these compounds. The test compounds (Table 3) 6a and 6w were found to be active and the animals did gain
exhibited significant antipyretic property at the dose level of more weight than those treated with indomethacin indicating
100 mg/kg p.o., as indicated by the temperature index. The a better toxicity profile compared to the reference drug. In

630
Vol. 56, No. 5
Table 4. Lipopolysaccharide-Induced Pyresis Model to Study the Inhibition of TNF-a
Change in rectal temperature (°C) and temperature index
Compound
1 h
2 h
3 h
TI
4 h
5 h
6 h
7 h
TI
6a
6w
Aspirin
Indo.
Control
ꢁ0.51ꢃ0.011 ꢁ1.37ꢃ0.013 ꢁ0.47ꢃ0.012
ꢁ0.49ꢃ0.013 ꢁ1.25ꢃ0.012 ꢁ0.35ꢃ0.016
ꢁ0.43ꢃ0.014 ꢁ1.31ꢃ0.011 ꢁ0.43ꢃ0.012
ꢁ0.36ꢃ0.012 ꢁ1.03ꢃ0.015 ꢁ0.11ꢃ0.013
ꢁ0.49ꢃ0.013 ꢁ1.12ꢃ0.014 ꢁ0.14ꢃ0.014
ꢁ2.35
ꢁ2.09
ꢁ2.17
ꢁ1.50
ꢁ1.75
0.03ꢃ0.014
0.18ꢃ0.013
0.01ꢃ0.013
0.17ꢃ0.012
0.23ꢃ0.015
0.11ꢃ0.012
0.40ꢃ0.015
0.09ꢃ0.012
0.28ꢃ0.013
0.63ꢃ0.013
0.19ꢃ0.011
0.59ꢃ0.012
0.18ꢃ0.014
0.41ꢃ0.013
0.94ꢃ0.016
0.27ꢃ0.015
0.71ꢃ0.011
0.31ꢃ0.011
0.55ꢃ0.014
1.18ꢃ0.012
0.60
1.88
0.59
1.41
2.98
Each value represents the meanꢃS.E.M. (nꢂ6); indo stands for indomethacin.
Table 5. Adjuvant-Induced Arthritis: Anti-arthritic Activity
Increase in paw volume (ml)ꢃS.E.M. [% inhibition of edema]
Compound
Secondary lesions
Weight change (g)
3rd day
8th day
13th day
13th daya)
6a
1.65ꢃ0.0142
[30.38]*
2.09ꢃ0.0162
[11.81]*
1.46ꢃ0.0175
[38.40]*
2.23ꢃ0.0156
[5.91]*
1.82ꢃ0.0158
[23.21]*
1.68ꢃ0.0176
[29.11]*
1.48ꢃ0.0154
[37.55]*
2.37ꢃ0.0170
1.56ꢃ0.0155
[26.76]*
1.47ꢃ0.0182
[30.99]*
1.55ꢃ0.0167
[27.23]*
2.03ꢃ0.0148
[4.69]*
1.79ꢃ0.0162
[15.96]*
1.14ꢃ0.0153
[46.48]*
1.16ꢃ0.0176
[45.53]*
2.13ꢃ0.0194
1.45ꢃ0.0163
[35.84]
1.89ꢃ0.0171
[16.37]*
2.21ꢃ0.0154
[2.21]*
2.19ꢃ0.0175
[3.10]*
1.56ꢃ0.0188
[30.97]*
1.38ꢃ0.0144
[38.93]*
1.23ꢃ0.0187
[45.57]*
2.26ꢃ0.0173
1.09ꢃ0.0164
[33.54]
1.41ꢃ0.0158
[14.02]*
1.60ꢃ0.0160
[2.44]*
1.61ꢃ0.0163
[1.83]*
1.21ꢃ0.0171
[26.22]*
1.06ꢃ0.0157
[35.37]*
1.07ꢃ0.0172
[34.76]*
1.64ꢃ0.0166
Moderate
Severe
6.67ꢃ0.144
4.33ꢃ0.150
3.58ꢃ0.169
3.25ꢃ0.181
5.98ꢃ0.142
6.92ꢃ0.158
5.42ꢃ0.133
3.14ꢃ0.141
6i
6p
Severe
6q
6t
Severe
Moderate
Moderate
Moderate
Severe
6w
Indomethacin
Control
Significance level ∗ pꢄ0.05 as compared with the control. Each value represents the meanꢃS.E.M. (nꢂ6); a) uninjected left paw.
Table 6. Evaluation of Ulcer Index
this biomodel though compounds 6a and 6w significantly re-
duced the primary inflammation of the right hind paw but
Compound
Dose (mg/kg)
Time
Ulcer index
these were not able to reduce the secondary inflammation of
left hind paw as well as the development of secondary le-
sions. Seeing the activity profile of other tested compounds it
can be said that in general these compounds exhibited poor
anti-arthritic activity at tested dose level of 100 mg/kg p.o.
Evaluation of Ulcerogenic Potential Some selected
compounds (based on anti-inflammatory and analgesic activ-
ity profile) were tested for their ulcerogenecity potential. The
tested compounds developed much lesser number of ulcero-
genic lesions as indicated by ulcer index in comparison to the
control (Table 6). The nitro derivative (6w) showed no ulcer
at tested dose level of 100 mg/kg p.o. It may, however, be
noted here that the administration of the test compounds at
Control
Indomethacin
6a
6o
6p
6t
6w
Control
6 h
6 h
6 h
6 h
6 h
6 h
6 h
14 d
14 d
14 d
14 d
0
30
100
100
100
100
100
30.83ꢃ2.07
2.5ꢃ0.43
11.17ꢃ0.70
1.83ꢃ0.60
7.67ꢃ0.67
0
0
Indomethacin
6a
6w
1
100
100
33.67ꢃ5.33
0
0
Each value represents the meanꢃS.E.M. (nꢂ6).
the dose level of 100 mg/kg p.o. even for 14 d did not cause erated using standard protocol. This indicates that probably
any ulceration of the gastric mucosa as revealed in the post the test compound per se is the active species.
mortem studies of sacrificed animals at the end of the adju-
vant-induced arthritis study.
Acute Toxicity Study The rats employed in anti-inflam-
matory screening were observed during 24 h. No mortality
Studies with SKF-525A We hypothesized that the high was present with these compounds except compound 6y at
residual anti-inflammatory activity of compounds could be the end of observation period. The compounds 6a and 6p
due to higher protein binding of its active metabolite(s). were also studied for their toxicity profile at higher dose lev-
These metabolites may arise via their hydrolytic metabolism els. No toxicity was observed with these compounds upto the
to deamidated product. We, therefore, studied the anti-in- highest tested dose of 1000 mg/kg.
flammatory activity of compounds 6a and 6p in carrageenan
induced rat paw edema model using SKF-525A, a standard Conclusions
hepatic microsomal enzyme inhibitor,14) pretreated rats. Ex-
From the anti-inflammatory activity results it was found
amination of Table 7 reveals that there is no significant dif- that compounds 6a, 6p, and 6w exhibited good anti-inflam-
ference between data generated from this test and those gen- matory activity. The compound 6y showed best anti-inflam-

May 2008
631
Table 7. Study with Cytochrome P450 Enzyme Inhibitor
Increase in paw volume (ml)ꢃS.E.M. [% inhibition of edema]
Compound
1 h
2 h
3 h
4 h
6 h
24 h
SKF-525A & 6a
0.16ꢃ0.0135
[23.81]
0.23ꢃ0.0147
[43.90]
0.32ꢃ0.0132
[46.67]
0.34ꢃ0.0151
[40.35]
0.30ꢃ0.0142
[36.17]
0.11ꢃ0.0133
[50.00]
6a
0.17ꢃ0.0141
[19.05]
0.22ꢃ0.0138
[46.34]
0.31ꢃ0.0144
[48.33]
0.33ꢃ0.0148
[42.10]
0.29ꢃ0.0152
[38.29]
0.107ꢃ0.0128
[51.36]
SKF-525A & 6p
6p
0.10ꢃ0.0153
[52.38]
0.11ꢃ0.0147
[47.62]
0.21ꢃ0.0146
[48.78]
0.23ꢃ0.0148
[43.90]
0.30ꢃ0.0143
[50.00]
0.32ꢃ0.0139
[46.67]
0.32ꢃ0.0154
[43.85]
0.34ꢃ0.0147
[40.35]
0.29ꢃ0.0161
[38.30]
0.30ꢃ0.0158
[36.17]
0.10ꢃ0.0125
[54.54]
0.11ꢃ0.0131
[50.00]
Control
0.21ꢃ0.0267
0.41ꢃ0.0148
0.60ꢃ0.0173
0.57ꢃ0.0203
0.47ꢃ0.0165
0.22ꢃ0.0135
Each value represents the meanꢃS.E.M. (nꢂ6). The Results obtained was analyzed by student’s t-test and the difference between the two groups was not found to be statisti-
cally significant.
(a) Ethylacetoacetate/pipieridine, 4 d; rt (b) Alcoholic KOH, 1 h reflux (c) AlCl3/NaCl, 180 °C, 30 min after cessation of liberation of HCl gas (d) Zn/Hg/HCl, 12 h reflux (e) i:
(COCl)2/DMF, 24 h rt; ii: NHRꢅRꢆ/Triethylamine, 12 h, rt.
Chart 1. Reagents and Conditions
pounds were ascertained by TLC, elemental microanalysis and spectral
matory activity at 25 mg/kg but it was found to be toxic at
100 mg/kg. These compounds were found to be longer acting
and showed residual activity exceeding that of standard in-
domethacin. These compounds showed moderate analgesic
analysis. Infrared-red spectra were recorded with a Shimadzu IR Prestige-21
FT-IR Spectrometer in KBr using powder diffraction technique. 1H-NMR
spectra were recorded on a 400 MHz Brucker Avance II NMR Spectrometer.
Mass Spectra of the compounds were recorded in a Jeol SX 102/DA-6000
activity profile with some variations from the anti-inflamma- spectrometer. Elemental microanalysis was done in a Perkin-Elmer 2400
CHN analyzer. Chart 1 was followed for the synthesis of 6-chloroindan-1-
acetic acid amides.
Diethyl 2,4-Diacetyl-3-(3-chlorophenyl)pentanedionate (2) 3-Chloro-
benzaldehyde (1) (28 g, 0.2 mol) was dissolved in ethylacetoacetate (56 g,
tory activity data. The compound 6x was found to be most
active with 94% inhibition in acetic acid induced writhings.
Significant anti-pyretic activity in LPS induced pyresis was
obtained and compound 6a showed lowest temperature index
equivalent to that of aspirin. However the antagonism of
TNF-a is not possibly involved in the mechanism of action
of these compounds. The adjuvant induced arthritis study re-
veals that these compounds though have long duration of ac-
tion are not effective in preventing the formation of second-
ary lesions. The compounds showed mild gastrointestinal
toxicity in comparison to standard indomethacin. Considera-
tion of results from the battery of the screening tests em-
ployed, it can be said that the test compounds 6a, 6p and 6w
have the potential to turn out as drug candidates and thus
they warrant further detailed studies regarding their pharma-
cological profile.
0.43 mol) in a dry conical flask and piperidine (2.5 ml) was added slowly at
ambient temperature and then kept for 3 d or more (up to seven days, de-
pending on room temperature) with the mouth stoppered. The solid product
thus obtained was crushed and then washed with solvent ether to get the de-
sired product in 70—75% yield.15) Recrystallisation from dil. alcohol gave
the analytical product, mp 120—121 °C, IR (cmꢁ1): 1722 (CꢂO stretching),
657 (C–Cl stretch), H-NMR: d (ppm) (CDCl3): 1.38 (t, CH3, 6H), 2.03 (s,
CH3, 6H), 3.38 (d, CH, 2H), 4.02 (qr, CH2, 4H), 4.46 (t, CH, 1H), 7.08 (m,
ArH, 4H).
1
3-(3-Chlorophenyl)pentanedioic Acid (3) Compound 2 (40 g, 0.1 mol)
was dissolved in a hot solution of KOH (160 g in 120 ml of water) and
160 ml of 50% ethanol was added. The hot reaction mixture was refluxed on
a water bath for 1 h. Alcohol was then removed by distillation, and after di-
lution with water it was cooled and washed with solvent ether. The aqueous
layer on acidification with cold conc. HCl with cooling gave crude 4 which
was filtered and recrystallized from hot water.15) Yield 80—85%; mp 147—
148 °C; IR (cmꢁ1): 3400—2200 (br OH stretch), 1710 (CꢂO stretching),
Experimental
1
Melting points were determined in open capillaries in a Buchi 530 melt-
ing point apparatus and are uncorrected. Identity and purity of the com-
663 (C–Cl stretch); H-NMR: d (ppm) (CDCl3): 2.58, 2.70 (dd, CH2, 4H),
3.60 (qn, CH, 1H), 7.18 (m, ArH, 4H), 10.79 (br s, COOH, 2H).

632
Vol. 56, No. 5
(6-Chloro-3-oxo-2,3-dihydro-1H-inden-1-yl)acetic Acid (4) Cycliza-
tion of compound 3 was carried by treating the acid (14 g, 0.058 mol) with
N-Butyl-2-(6-chloro-2,3-dihydro-1H-inden-1-yl)acetamide (6f) Yield
66.8% (semisolid); IR: 3275 (NH), 1635 (CꢂO), 660 (C–Cl) cmꢁ1 1H-
;
aluminium chloride (49 g, 0.37 mol) in presence of sodium chloride16) NMR: d (ppm) (CDCl3): 0.94 (t, CH3, 3H), 1.30 (m, CH2, 2H), 1.54 (qn,
(4.47 g, 0.08 mol) on an oil bath maintained at 180 °C for 30 min with stir-
ring. After decomposition of the hot reaction mixture with crushed ice, the
CH2, 2H), 1.78, 2.40 (m, CH2, 2H), 2.33, 2.63 (dd, CH2, 2H), 2.88 (m, CH2.
2H), 3.17 (t, CH2, 2H), 3.60 (qn, CH, 1H), 5.37 (s, NH, 1H), 7.11—7.19 (m,
crude keto acid 4 thus obtained was filtered. The crude product was finally ArH, 3H); MS (m/z): 266 [Mꢀ]; Anal. Calcd for C15H20ClNO: C, 67.79; H,
recrystallized from dilute acetic acid to get the pure compound. Yield 60—
65%; mp 188—190 °C; IR (cmꢁ1): 3400—2400 (br OH stretch), 1680, 1713
(CꢂO stretching), 657 (C–Cl stretch), 1H-NMR: d (ppm) (CDCl3): 2.46,
7.58; N, 5.27. Found: C, 68.01; H, 7.60; N, 5.28.
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-pentylacetamide (6g)
Yield 65.1% (semisolid); IR: 3281 (NH), 1640 (CꢂO), 658 (C–Cl) cmꢁ1
;
2.58 (dd, CH2, 2H), 2.84, 2.99 (dd, CH2, 2H), 3.79 (qn, CH, 1H), 7.38 (d, 1H-NMR: d (ppm) (CDCl3): 0.97 (t, CH3, 3H), 1.31 (m, CH2, 4H), 1.52 (qn,
ArH, 1H), 7.59 (s, ArH, 1H), 7.65 (d, ArH, 1H), 10.91 (br s, COOH, 1H).
(6-Chloro-2,3-dihydro-1H-inden-1-yl)acetic Acid (5) Compound 4
was subjected to Clemmensen’s reduction.17) 0.1 mol of compound 4 was
treated with 50 g of zinc amalgam, 50 ml of conc. HCl and 75 ml of water.
Around 200 ml of benzene was added as a co-solvent. The reaction mixture
was refluxed on steam bath for about 16 h (until the reaction mixture became
CH2, 2H), 1.79, 2.45 (m, CH2, 2H), 2.37, 2.66 (dd, CH2, 2H), 2.86 (m, CH2,
2H), 3.19 (t, CH2, 2H), 3.64 (qn, CH, 1H), 5.40 (s, NH, 1H), 7.09—7.17 (m,
ArH, 3H); MS (m/z): 280 [Mꢀ]; Anal. Calcd for C16H22ClNO: C, 68.68; H,
7.93; N, 5.01. Found: C, 68.90; H, 7.91; N, 4.99.
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-hexylacetamide (6h)
Yield 67.9% (semisolid); IR: 3291 (NH), 1638 (CꢂO), 657 (C–Cl) cmꢁ1
;
keto-negative). The organic layer was separated and the aqueous layer and 1H-NMR: d (ppm) (CDCl3): 0.95 (t, CH3, 3H), 1.31 (m, CH2, 6H), 1.53 (qn,
zinc granules were further extracted with benzene. The pooled organic phase CH2, 2H), 1.77, 2.43 (m, CH2, 2H), 2.35, 2.65 (dd, CH2, 2H), 2.88 (m, CH2,
was then dried over anhydrous sodium sulfate and was finally distilled off to 2H), 3.20 (t, CH2, 2H), 3.65 (qn, CH, 1H), 5.38 (s, NH, 1H), 7.09—7.18 (m,
get the reduced acid. The reduced acid obtained was a liquid and was sub- ArH, 3H); MS (m/z): 294 [Mꢀ]; Anal. Calcd for C17H24ClNO: C, 69.49; H,
jected to vacuum distillation to get the pure compound. Yield 80—85%; dis-
tilled at 148 °C/0.3 mmHg; IR (cmꢁ1): 3400—2400 (br OH stretch), 1700
(CꢂO stretching), 657 (C–Cl stretch); 1H-NMR: d (ppm) (CDCl3): 1.78,
8.23; N, 4.77. Found: C, 69.30; H, 8.25; N, 4.79.
N-Cyclopentyl-2-(6-chloro-2,3-dihydro-1H-inden-1-yl)acetamide (6i)
Yield 66.8% (cyclohexane); mp 136—138 °C; IR: 3310 (NH), 1640 (CꢂO),
1
2.42 (m, CH2, 2H), 2.48, 2.81 (dd, CH2, 2H), 2.88 (m, CH2, 2H), 3.56 (qn, 658 (C–Cl) cmꢁ1; H-NMR: d (ppm) (CDCl3): 1.52 (m, CH2, 4H) 1.86 (m,
CH, 1H), 7.11—7.16 (m, ArH, 3H), 11.18 (br s, COOH, 1H), MS 210.66 CH2, 4H), 1.79, 2.42 (m, CH2, 2H), 2.33, 2.64 (dd, CH2, 2H), 2.87 (m, CH2,
(Mꢀ).
2H), 3.61 (qn, CH, 1H), 3.68 (qn, CH, 1H), 5.32 (s, NH, 1H), 7.11—7.18
(m, ArH, 3H); MS (m/z): 278 [Mꢀ]; Anal. Calcd for C16H20ClNO: C, 69.18;
H, 7.26; N, 5.04. Found: C, 69.41; H, 7.29; N, 5.06.
General Method for the Synthesis of Amide Derivatives (6a—y)
A
solution of compound 6 in dry dichloromethane and catalytic amount of di-
methylformamide was treated with oxalyl chloride in 1 : 2.5 molar ratios
N-Cyclohexyl-2-(6-chloro-2,3-dihydro-1H-inden-1-yl))acetamide (6j)
under ice cold conditions. The solution was allowed to stand for 24 h at Yield 64.3% (cyclohe xane); mp 145—147 °C; IR: 3318 (NH), 1643
room temperature with occasional stirring. Excess oxalyl chloride was re- (CꢂO), 659 (C–Cl) cmꢁ1; 1H-NMR: d (ppm) (CDCl3): 1.18 (qn, CH2, 2H),
moved by co-distillation with dry benzene under reduced pressure. The acyl 1.40 (m, CH2, 4H), 1.74 (m, CH2, 4H), 1.79, 2.42 (m, CH2, 2H), 2.34, 2.64
halide thus obtained was not characterized or isolated and was used directly (dd, CH2, 2H), 2.86 (m, CH2, 2H), 3.61 (qn, CH, 1H), 3.68 (qn, CH, 1H),
in the next step. To a solution of the acyl halide in dry dichloromethane was 5.29 (s, NH, 1H), 7.08—7.16 (m, ArH, 3H); MS (m/z): 292 [Mꢀ]; Anal.
added a mixture of triethylamine (1.1 mol) and the appropriate amine in Calcd for C17H22ClNO: C, 69.97; H, 7.60; N, 4.80. Found: C, 70.10; H, 7.61;
dichloromethane with constant stirring under ice-cold conditions. The mix-
ture was kept at ambient temperature for 12 h. The resulting reaction mixture
was then extracted with 0.1 N HCl, water, saturated solution of NaHCO3,
N, 4.81.
N-Benzyl-2-(6-chloro-2,3-dihydro-1H-inden-1-yl))acetamide (6k)
Yield 69.7% (cyclohexa ne); mp 106—108 °C; IR: 3306 (NH), 1642 (CꢂO),
1H-NMR: d (ppm) (CDCl3): 1.77, 2.40 (m, CH2, 2H),
2.32, 2.57 (dd, CH2, 2H), 2.84 (m, CH2, 2H), 3.65 (qn, CH, 1H), 4.46 (s,
Bnz CH2, 2H), 5.81 (s, NH, 1H), 7.09—7.17 (m, ArH, 3H), 7.31 (m, ArH,
5H); MS (m/z): 300 [Mꢀ]; Anal. Calcd for C18H18ClNO: C, 72.11; H, 6.05;
brine and water. The organic phase was dried with anhydrous sodium sulfate 658 (C–Cl) cmꢁ1
;
and then distilled to obtain the title compounds.18)
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)acetamide (6a) Yield 57.8%
(water); mp 109—110 °C; IR: 3374, 3229 (NH), 1638 (CꢂO), 657 (C–Cl)
1
cmꢁ1; H-NMR: d (ppm) (CDCl3): 1.77, 2.43 (m, CH2, 2H), 2.35, 2.64 (dd, N, 4.67. Found: C, 72.33; H, 6.06; N, 4.69.
CH2, 2H), 2.85 (m, CH2, 2H), 3.62 (qn, CH, 1H), 5.49 (s, NH, 2H), 7.10—
7.18 (m, ArH, 3H); MS (m/z): 210 [Mꢀ]; Anal. Calcd for C11H12ClNO: C,
63.01; H, 5.77; N, 6.68. Found: C, 62.86; H, 5.76; N, 6.70.
1-[(6-Chloro-2,3-dihydro-1H-inden-1-yl)acetyl]piperidine (6l) Yield
69.1% (dil. alcohol); mp 108—110 °C; IR: 1624 (CꢂO), 657 (C–Cl) 663
1
cmꢁ1; H-NMR: d (ppm) (CDCl3): 1.65 (m, CH2, 6H), 1.75, 2.45 (m, CH2,
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-methylacetamide (6b) 2H), 2.72, 2.46 (dd, CH2, 2H), 2.85 (m, CH2, 2H), 3.37 (t, CH2, 4H), 3.66
Yield 58.9% (dil. alcohol); mp 102—103 °C; IR: 2270 (NH), 1632 (CꢂO),
(qn, CH, 1H), 7.10–7.17 (m, ArH, 3H); MS (m/z): 278 [Mꢀ]; Anal. Calcd
for C16H20ClNO: C, 69.18; H, 7.26; N, 5.04. Found: C, 69.31; H, 7.29; N,
658 (C–Cl) cmꢁ1
;
1H-NMR: d (ppm) (CDCl3): 1.78, 2.44 (m, CH2, 2H),
2.36, 2.67 (dd, CH2, 2H), 2.74 (s, CH3, 3H), 2.87 (m, CH2, 2H), 3.65 (qn, 5.06.
CH, 1H), 5.38 (s, NH, 1H), 7.11—7.18 (m, ArH, 3H); MS (m/z): 224 [Mꢀ];
1-[(6-Chloro-2,3-dihydro-1H-inden-1-yl)acetyl]piperazine (6m) Yield
Anal. Calcd for C12H14ClNO: C, 64.43; H, 6.31; N, 6.26. Found: C, 64.67; 57.8% (dil. alcohol); mp 215—216 °C; IR: 3347 (NH of piperazine), 1628
1
H, 6.30; N, 6.25.
(CꢂO), 661 (C–Cl); H-NMR: d (ppm) (CDCl3): 1.78, 2.37 (m, CH2, 2H),
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-ethylacetamide (6c) Yield
2.13 (s, NH, 1H), 2.79 (t, CH2, 4H), 2.42, 2.69 (dd, CH2, 2H), 2.86 (m, CH2,
60.4% (dil. alcohol); mp 98—100 °C; IR: 3281 (NH), 1630 (CꢂO), 657 2H), 3.32 (t, CH2, 4H), 3.65 (qn, CH, 1H), 7.10—7.18 (m, ArH, 3H); MS
(C–Cl) cmꢁ1; 1H-NMR: d (ppm) (CDCl3): 1.28 (t, CH3, 3H), 1.80, 2.43 (m, (m/z): 279 [Mꢀ]; Anal. Calcd for C15H19ClN2O: C, 64.63; H, 6.87; N, 10.05.
CH2, 2H), 2.36, 2.66 (dd, CH2, 2H), 2.88 (m, CH2, 2H), 3.31 (qr, CH2, 2H)
Found: C, 64.87; H, 6.85; N, 10.01.
3.64 (qn, CH, 1H), 5.35 (s, NH, 1H), 7.09—7.17 (m, ArH, 3H); MS (m/z):
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-(2-hydroxyethyl)acetamide
238 [Mꢀ]; Anal. Calcd for C13H16ClNO: C, 65.68; H, 6.78; N, 5.89. Found: (6n) Yield 60.3% (benzene); mp 60—62 °C; IR: 3278 (NH), 1632 (CꢂO),
C, 65.51; H, 6.77; N, 5.87.
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-propylacetamide (6d) 1H), 1.79, 2.46 (m, CH2, 2H), 2.40, 2.68 (dd, CH2, 2H), 2.86 (m, CH2, 2H),
657 (C–Cl), 3605 (OH) cmꢁ1 1H-NMR: d (ppm) (CDCl3): 2.15 (s, OH,
;
Yield 63.6% (dil. alcohol); mp 74—76 °C; IR: 3288 (NH), 1633 (CꢂO),
3.41 (t, CH2, 2H), 3.65 (qn, CH, 1H), 3.79 (t, CH2, 2H), 5.28 (s, NH, 1H),
7.11—7.18 (m, ArH, 3H); MS (m/z): 254 [Mꢀ]; Anal. Calcd for
C13H16ClNO2: C, 61.45; H, 6.36; N, 5.52. Found: C, 61.36; H, 6.34; N, 5.51.
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-phenylacetamide (6o)
1
657 (C–Cl) cmꢁ1; H-NMR: d (ppm) (CDCl3): 0.96 (t, CH3, 3H), 1.59 (m,
CH2, 2H), 1.82, 2.46 (m, CH2, 2H), 2.35, 2.60 (dd, CH2, 2H), 2.86 (m, CH2,
2H), 3.20 (t, CH2, 2H), 3.60 (qn, CH, 1H), 5.41 (s, NH, 1H), 7.09—7.16 (m,
ArH, 3H); MS (m/z): 252 [Mꢀ]; Anal. Calcd for C14H18ClNO: C, 66.79; H, Yield 73.7% (dil. alcohol); mp 146—148 °C; IR: 3282 (NH), 1648 (CꢂO),
7.21; N, 5.56. Found: C, 66.98; H, 7.22; N, 5.59.
663 (C–Cl) cmꢁ1 1H-NMR: d (ppm) (CDCl3): 1.81, 2.40 (m, CH2, 2H),
;
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-isopropylacetamide (6e) 2.47, 2.75 (dd, CH2, 2H), 2.87 (m, CH2, 2H), 3.70 (qn, CH, 1H), 7.24 (s,
Yield 62.5% (benzene); mp 104—106 °C; IR: 3294 (NH), 1631 (CꢂO), 658 NH, 1H), 7.10—7.21 (m, ArH, 4H), 7.31—7.48 (m, ArH, 4H); MS (m/z):
(C–Cl) cmꢁ1; 1H-NMR: d (ppm) (CDCl3): 1.28 (d, CH3, 6H), 1.80, 2.40 (m, 286 [Mꢀ]; Anal. Calcd for C17H16ClNO: C, 71.45; H, 5.64; N, 4.90. Found:
CH2, 2H), 2.33, 2.61 (dd, CH2, 2H), 2.87 (m, CH2, 2H), 3.61 (qn, CH, 1H), C, 71.67; H, 5.66; N, 4.92.
3.87 (m, CH, 1H), 5.26 (s, NH, 1H), 7.10—7.18 (m, ArH, 3H); MS (m/z):
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-(3-chlorophenyl)acetamide
252 [Mꢀ]; Anal. Calcd for C14H18ClNO: C, 66.79; H, 7.21; N, 5.56. Found: (6p) Yield 72.8% (dil. alcohol); mp 138—140 °C; IR: 3306 (NH), 1642
1
C, 66.58; H, 7.23; N, 5.57.
(CꢂO), 662 (C–Cl) cmꢁ1; H-NMR: d (ppm) (CDCl3): 1.80, 2.44 (m, CH2,

May 2008
633
2H), 2.47, 2.76 (dd, CH2, 2H), 2.88 (m, CH2, 2H), 3.71 (qn, CH, 1H), 7.17
(s, NH, 1H), 7.08—7.33 (m, ArH, 6H), 7.64 (s, ArH, 1H); MS (m/z): 320
[Mꢀ]; Anal. Calcd for C17H15Cl2NO: C, 63.76; H, 4.72; N, 4.37. Found: C,
63.89; H, 4.74; N, 4.39.
tained at temperature of 24ꢃ2 °C, relative humidity of 45% and kept under a
12 h light and dark cycle. The animals were fasted overnight for analgesic
and anti-inflammatory assays and 24 h for antipyretic and ulcerogenecity
studies. During fasting they had free access to water. The data obtained in
pharmacological experiments was subjected to statistical analysis using stu-
dent’s t-test, one way ANOVA, post hoc test, and the chosen level of signifi-
cance was pꢄ0.05. The protocol for the animal experiments was approved
by the Institutional Animal Ethics Committee (IAEC) as registered under
Committee for the Purpose of Control and Supervision of Experiments on
Animals (CPCSEA), Govt. of India.
Acute Anti-inflammatory Activity The anti-inflammatory activity of
the test compounds (6a—y) was determined by carrageenan-induced rat
hind paw edema assay as described by Winter et al.19) Female Wistar rats
weighing 170ꢃ20 g were administered the test compounds and standard in-
domethacin orally equivalent to 100 mg/kg and 10 mg/kg respectively. One
hour after dosing, 0.1 ml of 1% carrageenan was administered into the sub-
plantar region of the right hind paw. The paw volumes were measured using
an Ugo Basile plethysmometer at 0, 1, 2, 3, 4, 6 and 24 h after carrageenan
injection. The results (Table 1) are expressed as percentage inhibition of
edema formation. The percent inhibition of edema in each drug treated
group was calculated using the formula given below:
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-(4-chlorophenyl)acetamide
(6q) Yield 74.6% (dil. alcohol); mp 145—146 °C; IR: 3294 (NH), 1643
1
(CꢂO), 660 (C–Cl) cmꢁ1; H-NMR: d (ppm) (CDCl3): 1.81, 2.42 (m, CH2,
2H), 2.46, 2.76 (dd, CH2, 2H), 2.87 (m, CH2, 2H), 3.68 (qn, CH, 1H), 7.16
(s, NH, 1H), 7.09—7.17 (m, ArH, 3H), 7.30—7.58 (m, ArH, 4H); MS (m/z):
320 [Mꢀ]; Anal. Calcd for C17H15Cl2NO: C, 63.76; H, 4.72; N, 4.37. Found:
C, 63.93; H, 4.74; N, 4.38.
N-(4-bromophenyl)-2-(6-chloro-3-2,3-dihydro-1H-inden-1-yl)acet-
amide (6r) Yield 65.8% (dil. alcohol); mp 127—129 °C; IR: 3300 (NH),
1644 (CꢂO), 661 (C–Cl) cmꢁ1; 1H-NMR: d (ppm) (CDCl3): 1.80, 2.43 (m,
CH2, 2H), 2.47, 2.75 (dd, CH2, 2H), 2.86 (m, CH2, 2H), 3.70 (qn, CH, 1H),
7.15 (s, NH, 1H), 7.09—7.18 (m, ArH, 3H), 7.35—7.56 (m, ArH, 4H); MS
(m/z): 365 [Mꢀ]; Anal. Calcd for C17H15BrClNO: C, 55.99; H, 4.15; N, 3.84.
Found: C, 56.18; H, 4.17; N, 3.85.
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-(3-methylphenyl)acet-
amide (6s) Yield 71.3% (dil. alcohol); mp 109—111 °C; IR: 3313 (NH),
1649 (CꢂO), 661 (C–Cl) cmꢁ1; 1H-NMR: d (ppm) (CDCl3): 1.83, 2.39 (m,
CH2, 2H), 2.31 (s, CH3, 3H), 2.46, 2.75 (dd, CH2, 2H), 2.88 (m, CH2, 2H),
3.65 (qn, CH, 1H), 7.11 (s, NH, 1H), 6.91—7.19 (m, ArH, 5H), 7.47 (d,
ArH, 2H); MS (m/z): 300 [Mꢀ]; Anal. Calcd for C18H18ClNO: C, 72.11; H,
6.05; N, 4.67. Found: C, 72.36; H, 6.07; N, 4.69.
% inhibitionꢂ100(1ꢁVt/Vc)
where Vc and Vt are average edema volumes in control and treated groups re-
spectively.
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-(4-methylphenyl)acet-
amide (6t) Yield 70.4% (dil. alcohol); mp 194—195 °C; IR: 3320 (NH),
1648 (CꢂO), 659 (C–Cl) cmꢁ1; 1H-NMR: d (ppm) (CDCl3): 1.84, 2.39 (m,
CH2, 2H), 2.30 (s, CH3, 3H), 2.47, 2.74 (dd, CH2, 2H), 2.87 (m, CH2, 2H),
3.66 (qn, CH, 1H), 7.10 (s, NH, 1H), 7.05—7.16 (m, ArH, 5H), 7.45 (d,
ArH, 2H); MS (m/z): 300 [Mꢀ]; Anal. Calcd for C18H18ClNO: C, 72.11; H,
6.05; N, 4.67. Found: C, 72.31; H, 6.03; N, 4.69.
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-(4-methoxyphenyl)acet-
amide (6u) Yield 69.1% (dil. alcohol); mp 176—178 °C; IR: 3324 (NH),
1650 (CꢂO), 660 (C–Cl) cmꢁ1; 1H-NMR: d (ppm) (CDCl3): 1.78, 2.38 (m,
CH2, 2H), 2.44, 2.74 (dd, CH2, 2H), 2.88 (m, CH2, 2H), 3.67 (qn, CH, 1H),
3.84 (s, OCH3, 3H), 7.14 (s, NH, 1H), 6.86—7.18 (m, ArH, 5H), 7.51 (d,
ArH, 2H); MS (m/z): 316 [Mꢀ]; Anal. Calcd for C18H18ClNO2: C, 68.46; H,
5.75; N, 4.44. Found: C, 68.22; H, 5.77; N, 4.46.
N-[4-(Acetylamino)phenyl]-2-(6-chloro-2,3-dihydro-1H-inden-1-yl)ac-
etamide (6v) Yield 67.6% (dil. alcohol); mp 156—158 °C; IR: 3276 (NH),
1641 (CꢂO), 660 (C–Cl) cmꢁ1; 1H-NMR: d (ppm) (CDCl3): 1.81, 2.41 (m,
CH2, 2H), 2.03 (s, CH3, 3H), 2.46, 2.76 (dd, CH2, 2H), 2.87 (m, CH2, 2H),
3.71 (qn, CH, 1H), 7.13 (s, NH, 1H), 7.15 (s, NH, 1H), 7.10—7.17 (m, ArH,
3H), 7.56—7.64 (m, ArH, 4H); MS (m/z): 343 [Mꢀ]; Anal. Calcd for
C19H19ClN2O2: C, 66.57; H, 5.59; N, 8.17. Found: C, 66.35; H, 5.61; N,
8.19.
Analgesic Activity The analgesic activities of the compounds (6a—y)
were determined by acetic acid induced writhing test in mice as described by
Collier et al.20) with minor modifications. Female Swiss albino mice,
20ꢃ5 g, were administered the test drugs orally at 100 mg/kg. and the stan-
dard indomethacin and aspirin at 10 mg/kg and 100 mg/kg respectively. One
hour after the oral dosing they were injected i.p. with 0.1 ml/10 g of 1% v/v
acetic acid. Five minutes after the injection the writhing (full extension of
hind limbs) were noted for next 15 min. Animals giving 20 or more wriths
were selected for the study. The percent inhibition by individual drug as well
as by the reference standard drugs were calculated using the following for-
mula,
% inhibitionꢂ100[1ꢁWt/Wc]
where Wc represents the average writhing produced by the control group and
Wt represents the average writhing produced by the test groups.
Antipyretic Activity The antipyretic activity of the compounds was
evaluated by lipopolysaccharide induced pyrexia. Two protocols were
adopted, first in which initial hypothermic phase was excluded and only an-
tipyretic activity was evaluated and the second in which the hypothermic
phase was also evaluated in order to determine if these compounds also in-
hibit TNF-a. The method was that of Dogan et al.13) with minor modifica-
tions. Adult female Wistar rats (170ꢃ20 g) were used. Phenol extracted LPS
from Eschericia coli serotype 0111: B4 (Difco) was used. The experiment
was started at 0900 h. LPS dissolved in apyrogenic saline was injected at
dose of 100 mg/kg i.p. After 3 h test compounds and aspirin were given
orally at dose level of 100 mg/kg. Indomethacin was given at a dose level of
10 mg/kg. The rectal temperature was determined using telethermometer
probes immediately before and 4, 5, 6, 7 h after LPS administration. For
evaluation of antipyretic activity, the temperature index was calculated fol-
lowing the method of Winter et al.21) In the second protocol after half an
hour of oral administration of the drugs LPS dissolved in apyrogenic saline
was injected at dose of 100 mg/kg i.p. The rectal temperature was deter-
mined using telethermometer probes immediately before and 1, 2, 3, 4, 5, 6,
7 h after LPS administration. Two temperature indexes were calculated, first
at the end of 3rd hour and second at the end of 7th hour of observations.
Chronic Anti-inflammatory Activity The method used was essentially
that of Newbould.22) Only three compounds were selected for this study. Fe-
male albino rats weighing 160ꢃ10 g were chosen for the study. The animals
were given the test compounds at the dose level of 100 mg/kg p.o. once daily
for 14 d starting from the day before the administration of 0.1 ml Freund’s
complete adjuvant (Genie, Bangalore, India) into the subplantar surface of
right hind paw of each rat. Indomethacin was taken as the standard drug and
was given for 14 d at the dose level of 10 mg/kg p.o. Both hind paw volumes
up to the fixed mark at the level of lateral malleolus were measured before
and daily after adjuvant administration. The formation of nodules and ap-
pearance of erythema in tail, nose and ears were observed and graded as
mild, moderate and severe for comparison. Change in body weight of the an-
imals during the test period was also recorded for comparison. The results
are presented in Table 6.
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-(4-nitrophenyl)acetamide
(6w) Yield 65.8% (dil. alcohol); mp 137—139 °C; IR: 3280 (NH), 1639
1
(CꢂO), 659 (C–Cl) cmꢁ1; H-NMR: d (ppm) (CDCl3): 1.79, 2.43 (m, CH2,
2H), 2.47, 2.77 (dd, CH2, 2H), 2.89 (m, CH2, 2H), 3.70 (qn, CH, 1H), 7.21
(s, NH, 1H), 7.10—7.18 (m, ArH, 3H), 7.89—8.25 (m, ArH, 4H); MS (m/z):
331 [Mꢀ]; Anal. Calcd for C17H15ClN2O3: C, 61.73; H, 4.57; N, 8.47. Found:
C, 61.54; H, 4.58; N, 8.49.
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-pyridin-3-ylacetamide (6x)
Yield 60.3% (dil. alcohol); mp 196—198 °C; IR: 3321 (NH), 1650 (CꢂO),
658 (C–Cl) cmꢁ1 1H-NMR: d (ppm) (CDCl3): 1.83, 2.46 (m, CH2, 2H),
;
2.53, 2.81 (dd, CH2, 2H), 2.88 (m, CH2, 2H), 3.71 (qn, CH, 1H), 7.31 (s,
NH, 1H), 7.10—7.30 (m, ArH, 4H), 8.17—8.51 (m, ArH, 3H) ; MS (m/z):
287 [Mꢀ]; Anal. Calcd for C16H15ClN2O: C, 67.02; H, 5.27; N, 9.77. Found:
C, 67.23; H, 5.25; N, 9.73.
2-(6-Chloro-2,3-dihydro-1H-inden-1-yl)-N-pyridin-4-ylacetamide (6y)
Yield 58.6% (dil. alcohol); mp 157—159 °C; IR: 3330 (NH), 1648 (CꢂO),
660 (C–Cl) cmꢁ1 1H-NMR: d (ppm) (CDCl3): 1.80, 2.42 (m, CH2, 2H),
;
2.49, 2.79 (dd, CH2, 2H), 2.87 (m, CH2, 2H), 3.70 (qn, CH, 1H), 7.28 (s,
NH, 1H), 7.11—7.19 (m, ArH, 3H), 7.65—8.34 (m, ArH, 4H); MS (m/z):
287 [Mꢀ]; Anal. Calcd for C16H15ClN2O: C, 67.02; H, 5.27; N, 9.77. Found:
C, 66.86; H, 5.29; N, 9.80.
Biological Evaluation All synthesized compounds were evaluated for
analgesic and anti-inflammatory activity and few selected compounds were
screened for antipyretic, ulcerogenecity and anti-arthritic activity. The test
compounds, 6a—y, and standard drugs (indomethacin and aspirin) were ad-
ministered orally as suspensions in 0.5% carboxymethylcelluse sodium in
distilled water. Each group consisted of six animals. The animals were main-

634
Ulcerogenecity Test Only few amides from the series 6a—y were se-
Vol. 56, No. 5
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7) Kalgutkar A. S., Crews B. C., Rowlinson S. W., Marnett A. B., Kozak
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925—930 (2000).
lected for ulcerogenic studies. The method used to evaluate the ulcerogenic
potential of the test compounds was that of Velázquez et al.23) with minor
modifications. Twenty four hour fasted Wistar female rats (175ꢃ25 g) were
used. The test compounds and the standard drug indomethacin were dosed
orally at 100 mg/kg and 30 mg/kg respectively. After six hours of oral dosing
the rats were sacrificed using cervical dislocation. The stomachs were taken
out and cut along the greater curvature. After washing with saline the stom-
ach mucosa was examined for ulcers using a hand lens. The gastric lesions
were counted, and an ulcerative index (UI) for each animal was calculated
8) Kalgutkar A. S., Marnet A. B., Crews C. B., Remmel R. P., Marnett L.
S., J. Med. Chem., 43, 2860—2870 (2000).
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Rigdon G. C., Orr G. F., Davis R. G., Cooper B. R., Styles V. L.,
Thompson J. B., Hall W. R., J. Med. Chem., 46, 399—408 (2003).
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S., Mol. Pharm., 52, 421—429 (1997).
according to Szelenyl and Thiemer24)
UIꢂ(n lesion I)ꢀ(n lesion II)2ꢀ(n lesion III)3
Where:
;
Iꢂpresence of edema, hyperemia and single, submucosal, punctiform he-
morrages (petechiae)
12) Derijk R. H., Kampen V. M., Rooijen V., Berkenbosch F., Am. J. Phys-
iol., 26, R1—R8 (1994).
IIꢂpresence of submucosal, hemorrhagic lesions with small erosions;
IIIꢂpresence of deep ulcer with erosions and invasive lesions
13) Dogan D. M., Ataoglu H., Akarsu E. S., Fundam. Clin. Pharmacol.,
16, 303—309 (2002).
Metabolism Inhibition Study Using SKF-525A13) The rats were pre- 14) Somchit N., Wong C. W., Zuraini A., Bustamam A. A., Hasiah A. H.,
treated with SKF 525A (50 mg/kg i.p.). One hour later, the rats were dosed
Khairi H. M., Sulaiman M. R., Israf D. A., Drug Chem. Toxicol., 29,
orally the test drug 6a and 6p at 100 mg/kg. The remaining protocol fol-
237—253 (2006).
lowed was the same as that of anti-inflammatory screening by carrageenan 15) Lahiri S. C., Gupta J. K., J. Indian. Chem. Soc.., LIII, 1040—1043
induced rat paw edema model.
(1976).
16) Bruce D. B., Sorrie A. J. S., Thomson R. H., J. Chem. Soc., 1953,
2403—2406 (1953).
17) “Vogel’s Textbook of Practical Organic Chemistry,” ed. by Furniss B.
S., Hannaford A. J., Smith P. W. G., Tatchell A. R., Pearson Education,
New Delhi, 2004.
Acknowledgements One of the authors (M.S.) wishes to thank Birla In-
stitute of Technology & Science, Pilani, for financial help and laboratory fa-
cilities. She would also like to thank the University Grants Commission,
New Delhi, for the award of a Junior Research Fellowship.
18) Balsamo A., Barili P. L., Crotti P., Macchia F., Pecchia A., Cuttica A.,
Passerini N., J. Med. Chem., 18, 842—846 (1975).
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