Synthesis of 5, 6-dichloroindan-1-acids and their tetrazolyl derivatives as analgesic and anti-inflammatory agents

Article abstract of DOI:10.2174/157340612802084234

Indan derivatives, namely, 5-(5′,6′-dichloroindan-1′-yl)- tetrazole (12a) and 5-(5′,6′-dichloroindan-1′-yl)- methyltetrazole (12b), were synthesized conveniently from 5,6-dichloroindan-1- carboxylic acid (9a) and 5,6- dichloroindan-1-acetic acid (9b), respectively, as potential analgesic and anti-inflammatory agents. The analgesic and anti-inflammatory properties of 9a, 9b, 12a and 12b were evaluated by the acetic acid induced writhing in Swiss albino mice and the carrageenan-induced rat paw edema models, respectively. Compounds 9a and 12a exhibited significant analgesic activity with the doses of 50 and 100 mg/kg body weight, comparable to that of the positive controls, phenylbutazone, indomethacin and aminopyrine. The anti-inflammatory potencies of 9a and 12a were also comparable to that of the positive control, phenylbutazone. Compounds 9b and 12b showed analgesic and anti-inflammatory activities, but were weaker than that of compounds 9a and 12a.

Full text of DOI:10.2174/157340612802084234

874
Medicinal Chemistry, 2012, 8, 874-882
Synthesis of 5,6-Dichloroindan-1-Acids and their Tetrazolyl Derivatives as
Analgesic and Anti-inflammatory Agents
Rajib Kumar Pal1, Hasina Yasmin2, Lutfun Nahar3, Bidyut Kanti Datta4, Abul Kalam Azad Chowd-
hury5, Joydeb Kumar Kundu4, Sitesh Chandra Bachar4 and Satyajit Dey Sarker6*
1National Institute of Health, National Institute on Aging, 251 Bayview Blvd, Suite no. 100, Room no. 9C009, Baltimore,
MD 21224, USA
2Department of Pharmacy, State University of Bangladesh, Dhaka-1209, Bangladesh
3Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK
4Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Dhaka, Dhaka-1000, Bangladesh
5Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka-1000,
Bangladesh
6Department of Pharmacy, School of Applied Sciences, University of Wolverhampton, MA Building, Wulfruna Street,
Wolverhampton WV1 1LY, UK
Abstract: Indan derivatives, namely, 5-(5',6'-dichloroindan-1'-yl)-tetrazole (12a) and 5-(5',6'-dichloroindan-1'-yl)-
methyltetrazole (12b), were synthesized conveniently from 5,6-dichloroindan-1-carboxylic acid (9a) and 5,6-
dichloroindan-1-acetic acid (9b), respectively, as potential analgesic and anti-inflammatory agents. The analgesic and
anti-inflammatory properties of 9a, 9b, 12a and 12b were evaluated by the acetic acid induced writhing in Swiss albino
mice and the carrageenan-induced rat paw edema models, respectively. Compounds 9a and 12a exhibited significant an-
algesic activity with the doses of 50 and 100 mg/kg body weight, comparable to that of the positive controls, phenylbuta-
zone, indomethacin and aminopyrine. The anti-inflammatory potencies of 9a and 12a were also comparable to that of the
positive control, phenylbutazone. Compounds 9b and 12b showed analgesic and anti-inflammatory activities, but were
weaker than that of compounds 9a and 12a.
Keywords: Indan acids, Indanyl tetrazoles, 5,6-dichloroindan-1-carboxylic acid, 5,6-dichloroindan-1-acetic Acid, 5-(5',6'-
dichloroindan-1'-yl)-tetrazole, 5-(5',6'-dichloroindan-1'-yl)-methyltetrazole, Carrageenan, Analgesic activity, Anti-
inflammatory activity.
INTRODUCTION
of three tertiary nitrogen atoms gives tetrazole an acidic
strength similar to that of aliphatic carboxylic acids. The
metabolic stability of the tetrazole function, which is similar
to that of carboxylic group, has inspired the syntheses of
various potential therapeutic agents [17-19]. The replace-
ment of carboxylic group by tetrazol-5-yl to a series of 1-
substituted 3-(tetrazole-5-yl-methyl)-indole as analogues of
indomethacin were synthesized [20]. Among them, the most
active candidate was 1-(4-chlorobenzoyl)-3-(tetrazole-5-yl
methyl)-indole. Similarly, a series of 5-(2-anilinophenyl)-
tetrazoles were synthesized as analogs of flufenamic acid,
which showed activity comparable to that of their corre-
sponding acids. The most active anti-inflammatory tetrazoles
were 5-[2-(3-trifluoromethylanilino)-phenyl]-tetrazoles and
5-[2-(2,6-dichloro-3-methylanilino)-phenyl]-tetrazoles. A se-
ries of arryltetrazolylalkanoic acids were prepared, and the
maximum anti-inflammatory activity was observed with the
compounds containing meta-halogenated aromatic substitu-
ents and a propionic acid residue at position 2 of the tetra-
zole ring [16].
Indan ring system is regarded as an ideal chemical
feature associated with various biological activities [1].
Among indan derivatives, 1H-indene-3-acetic acid-5-fluoro-
2-methyl-1-[4-(methylsulfinyl)-phenyl]methylene (sulindac)
and indan-1,3-dione are well known anti-inflammatory agent
[2] and anticoagulant [3], respectively. Several indan deriva-
tives, particularly indan acid derivatives, have been synthe-
sized and their potential analgesic and anti-inflammatory
properties have also been reported to date [4-14].
Tetrazole, an aromatic azapyrrole, exists in a tautomeric
form. Although tetrazole itself does not exhibit any pharma-
cological activity, many of its derivatives possess interesting
biological properties [15, 16]. The combined inductive effect
*Address correspondence to this author at the Department of Pharmacy,
School of Applied Sciences, University of Wolverhampton, MA Building,
Wulfruna Street, Wolverhampton WV1 1LY, UK; Tel: +44 1902 322578;
Fax: +44 1902 322714; E-mail: S.Sarker@wlv.ac.uk
1875-6638/12 $58.00+.00
© 2012 Bentham Science Publishers

Indan Acids as Novel Analgesic and Anti-inflammatory Agents
Medicinal Chemistry, 2012, Vol. 8, No. 5 875
CN
Cl
Cl
CHO
CN
CN
Cl
Cl
Cl
Cl
NaCN, EtOH
CNCH2CO2Et, C5H5N
CO2Et
CO2Et
ꢀ, 1.5 h
Glacial AcOH, ꢀ, 20 h
1
3
2
Conc. HCl, ꢀ, 18 h
COOH
COOH
i. SOCl2, C6H6, D, 2 h
ii. AlCl3, CS2/C6H5NO2, stirring, 2 h, r.t.
Cl
Cl
Cl
COOH
Cl
5
O
4
Scheme 1. Synthesis of 5,6-dichloro-3-oxo-indan-1-carboxylic Acid (5).
COMe CO2Et
Cl
Cl
CHO
CO2Et
Cl
Cl
CH3COCH2CO2Et
Piperidine, 96 h, r.t.
COMe
1
6
ꢀ, 2 h
25% KOH in EtOH
COOH
COOH
COOH
Cl
Cl
i. SOCl2, C6H6, ꢀ, 2.5 h
Cl
Cl
ii. AlCl3, CS2, stirring, 2 h, r.t.
8
O
7
Scheme 2. Synthesis of 5,6-dichloro-3-oxo-indan-1-acetic acid (8).
CHEMISTRY AND ANALGESIC AND ANTI-
INFLAMMTORY ACTIVITIES
It was, therefore, hypothesized that a combination of
various substituted indanyl groups which was substituted at
position 5 of the tetrazole moiety would possibly have better
anti-inflammatory property. Working on this hypothesis,
Lahiri and his co-workers [21-24] synthesized several simple
6-methoxy and 5,6-dimethoxy substituted indanyl tetrazoles
and indanyl methyl tetrazoles with significant non-steroidal
anti-inflammatory effect with low ulcerogenicity. Later, 6-
chloro(indan-1'-yl)-tetrazole, 6-bromo(indan-1'-yl)-tetrazole,
6-chloro(indan-1'-yl)-methyltetrazole and 6-bromo(indan-1'-
yl)-methyltetrazole were synthesized with promising analge-
sic activity in the acetic acid induce writhing model [6].
Synthesis of 5,6-dichloroindan-1-carboxylic acid (9a), 5,6-
dichloroindan-1-acetic acid (9b), 5-(5',6'-dichloroindan-
1’-yl)-tetrazole (12a) and 5-(5',6'- dichloroindan-1’-yl)-
methyltetrazole (12b)
The protocols for the synthesis of 5,6-dichloroindan-1-
carboxylic acid (9a), 5,6-dichloroindan-1-acetic acid (9b), 5-
(5',6'-dichloroindan-1'-yl)-tetrazole (12a) and 5-(5',6'-
dichloroindan-1'-yl)-methyl-tetrazole (12b) are represented
in Schemes 1-3.
3,4-Dicholorobenzaldehyde (1) was treated with ethyl-
cyanoacetate in dry benzene (C6H6) in the presence of pyri-
dine (C5H5N) and glacial acetic acid (AcOH) to obtain 3,4-
dichlorophenyl cyanoacrylic ester (2), which was further
treated with NaCN to yield 3,4-dichlorophenyl ꢀ,ꢁ-
dicyanoethyl propionate (3) (Scheme 1). Compound 3 was
acid hydrolyzed to afford 3,4-dichlorophenyl succinic acid
(4), which on cyclization through the Freidel-Crafts acyla-
Since aromatic halogen substitution has been shown to be
a reasonable means of increasing the analgesic and anti-
inflammatory activity and widening the margin of safety [6,
13, 14], the objective of the current study was to synthesize
5,6-dichloroindan-1-carboxylic acid (9a), 5,6-dichloroindan-
1-acetic acid (9b), 5-(5',6'-dichloroindan-1'-yl)-tetrazole
(12a)
and 5-(5',6'-dichloroindan-1'-yl)-methyl-tetrazole
tion
reaction
produced
5,6-dichloro-3-oxo-indan-1-
(12b), and to evaluate their analgesic and anti-inflammatory
potentials in animal models.
carboxylic acid (5) with good yield. 5,6-Dichloro-3-oxo-

876 Medicinal Chemistry, 2012, Vol. 8, No. 5
Pal et al.
R
R
Cl
Cl
Cl
Cl
Zn-Hg, HCl
C6H6, ꢀ, 16-18 h
O
9a R = COOH
5 R = COOH
9b R = CH2COOH
8 R = CH2COOH
i, SOCl2, C6H6, ꢀ, 1.5 h
ii. NH4OH, C6H6, 5-10 oC
R
R
Cl
Cl
Cl
C6H6, D, 1.5 h
P2O5 or POCl3,
Na2S2O5
Cl
11a R = CN
10a R = CONH2
11b R = CH2CN
10b R = CH2CONH2
NaN3, NH4Cl
DMF, 130-140 oC, 48 h
N
N
N
N
N
N
H
N
N
H
Cl
Cl
Cl
Cl
12a (from 11a)
12b ( from 11b)
Scheme 3. Synthesis of 5-(5',6'-dichloroindan-1'-yl)-tetrazole (12a) and 5-(5',6'-dichloroindan-1'-yl)-methyl-tetrazole (12b).
indan-1-acetic acid (8) was obtained in good yield by con-
densation of 3,4-dichlorobenzaldehyde (1) and ethylace-
toacetate in presence of piperidine using the Knoevenagel
reaction followed by hydrolysis and cyclization (Scheme 2).
Analgesic activity of 5,6-dichloroindan-1-carboxylic acid
(9a), 5,6-dichloroindan-1-acetic acid (9b), 5-(5',6'-
dichloroindan-1'-yl)-tetrazole
(12a)
and
5-(5',6'-
dichloroindan-1'-yl)-methyltetrazole (12b)
The 3-oxo-derivatives (5 and 8) were reduced to com-
pounds 9a and 9b, respectively (Scheme 3), which were fur-
ther treated with thionyl chloride (SOCl2) to obtain acid
chlorides. Immediate addition of ammonia solution to the
acid chlorides at 1-5°C afforded respective amides 10a and
10b in excellent yields. The amides (10a and 10b) were de-
hydrated with P2O5 in dry C6H6 or in a mixture of POCl3 and
NaS2O5 (10:1 ratio) by refluxing for 2-4 h. After decompos-
ing the reaction mixtures and working up, the respective ni-
triles 11a and 11b were obtained. Subsequently, the nitriles
were allowed to react with activated NaN3 in presence of
NH4Cl in DMF at 130-140°C for 48 h to afford the target
compounds 5-(5',6'-dichloroindan-1'-yl)-tetrazole (12a) and
5-(5',6'-dichloroindan-1'-yl)-methyltetrazole (12b) as crystal-
line solid (Scheme 3). The structures of compounds were
confirmed by various spectral analyses as outlined in the
experimental section.
The acetic acid induced writhing response is a sensitive
procedure for the evaluation of peripherally acting analge-
sics. The analgesic activity of 9a, 9b, 12a and 12b (Table 1)
was measured by the acetic acid-induced writhing in Swiss
albino mice. The significant (p < 0.001) analgesic activity,
exhibited by the compounds 9a and 12a with the doses of 50
and 100 mg/kg body weight, was better than that of the ref-
erence compounds, phenylbutazone, indomethacin and
aminopyrine, with the doses of 100, 50 and 30 mg/kg body
weight, respectively. With the dose of 25 mg/kg body
weight, 9b exhibited almost similar potency (p < 0.001) to
that of indomethacin. Compound 9b (p < 0.001) and 12b (p
< 0.001) at 50 and 100 mg/kg weight, respectively, also
showed good therapeutic activity, but was less than that of
9a and 12a. This investigation revealed that all compounds
(9a, 9b, 12a and 12b) displayed good peripheral analgesic
activity with the doses of 50 and 100 mg/kg body weight.
The writhing response observed after the treatment with syn-

Indan Acids as Novel Analgesic and Anti-inflammatory Agents
Medicinal Chemistry, 2012, Vol. 8, No. 5 877
Table 1. Analgesic Activity of 5,6-dichloroindan-1-caroxylic Acid (9a), 5,6-dichloroindan-1-acetic acid (9b), 5-(5ꢀ,6ꢀ-dichloroindan-1ꢀ-
yl)-tetrazole (12a), 5-(5ꢀ,6ꢀ-dichloroindan-1ꢀ-yl)-methyltetrazole (12b) in the Acetic Acid Induced Writhing on Albino Mice
Dose
Writhing
Test Samples
9a
% Inhibition
(mg/kg Body Weight)
(Mean±SE); n=5
25
50
18.67 ± 1.56
6.17 ± 1.07
2.33 ± 0.56
23.83 ± 1.38
10.50 ± 1.07
8.11± 0.86
44.55 a
81.68 a
93.08 a
29.22 b
68.88 a
75.91 a
33.68 b
69.32 a
90.58 a
09.11 ns
61.89 a
69.32 a
50.49 a
42.08 a
59.40a
-------
100
25
9b
50
100
25
22.33± 1.64
10.33± 1.33
3.17± 0.64
30.33± 1.56
12.83± 1.50
10.33± 0.99
16.67 ±1.61
19.50 ± 1.52
13.67± 0.90
33.67± 1.91
12a
12b
50
100
25
50
100
100
50
Phenylbutazone
Indometacin
Aminopyrine
Control
30
-----
Probability values (calculated as compared to control using student’s t-test): a < 0.001, b<0.01, ns < not significant.
thesized compounds was assumed to be mediated through
peritoneal mast cell [25], acid sensing ion channels [26] and
the prostaglandin pathways [27].
be owing to the inhibition of the enzyme cyclooxygenase
leading to inhibition of prostaglandin biosynthesis.
Indan derivatives, namely, 5-(5',6'-dicholoroindan-1'-yl)-
tetrazole (12a) and 5-(5',6'-dicholoroindan-1'-yl)-methyl-
tetrazole (12b), were synthesized conveniently from 5,6-
dichloroindan-1-carboxylic acid (9a) and 5,6-dichloroindan-
1-acetic acid (9b), respectively. The observed significant
analgesic and anti-inflammatory activity of these newly syn-
thesized indan acids and indanyl tetrazoles, particularly of 9a
and 12a, could be a useful indicator for further development
of indan-based effective analgesic and anti-inflammatory
agents.
Anti-inflammatory activity of 5,6-dichloroindan-1-
carboxylic acid (9a), 5,6-dichloroindan-1-acetic acid (9b),
5-(5',6'-dichloroindan-1'-yl)-tetrazole (12a) and 5-(5',6'-
dichloroindan-1'-yl)-methyltetrazole (12b)
The anti-inflammatory activity of 9a, 9b, 12a and 12b
was observed in the carrageenan induced rat paw edema
model with the doses of 25 and 50 mg/kg body weight
(Table 2). The significant (p < 0.001) anti-inflammatory
activity, exhibited by the compound 9a and 12a with the
dose of 50 mg/kg body weight, was comparable to that of
reference standard phenylbutazone (dose of 100 mg/kg body
weight) after 3 h of carrageenan administration. Compounds
9b (p < 0.001) and 12b (p < 0.001) with the doses of 25 and
50 mg/kg body weight also displayed good anti-
inflammatory activity. Compound 12b exhibited almost
similar effect as that of phenylbutazone in 1, 2 and 3 h after
carrageenan administration. The inflammation in rat paw
induced by carrageenan is believed to be biphasic [28]. The
first phase of the inflammation is due to the release of hista-
mine or serotonin, and the second phase is caused by the
release of bradykinin, protease, prostaglandin and lysosome
[29, 30]. Therefore, it could be assumed that the significant
(p < 0.001) anti-inflammatory activity of 9a and 12a might
EXPERIMENTAL SECTION
General
The chemicals and solvents used in various reaction pro-
cedures were obtained from Merck Co. (Germany); BDH
(India) and SD Fine Chemicals (India). The starting material
3,4-dichloro-benzaldehyde 98% (25 g) was purchased from
Acros Organics, New Jersey, USA and used without purifi-
cation. The melting points were determined by using an
Adco Melting Point Apparatus and were uncorrected. Thin-
layer chromatography was performed on Kieselgel 60 F254
pre-coated plates (Merck). The absorption maxima (ꢀmax in
nm) were determined in absolute methanol by using a Gene-
sis-2 UV-Vis spectrophotometer. By using an 8010M FTIR
spectrometer, the characteristic IR absorption bands (ꢁmax in

878 Medicinal Chemistry, 2012, Vol. 8, No. 5
Pal et al.
Table 2. Anti-inflammatory Activity of 5, 6-dichloroindan-1-carboxylic acid (9a), 5, 6-dichloroindan-1-acetic acid (9b), 5-(5ꢀ, 6ꢀ-
dichloroindan-1ꢀ-yl)-tetrazole (12a) and 5-(5ꢀ, 6ꢀ-dichloroindan-1ꢀ-yl)-methyltetrazole (12b) in the Carrageenan-induced
Rat Paw Edema Model
Percent Change in Paw Edema (x ± SE)
Dose
Test Samples
mg/kg
1 h
2 h
3 h
4 h
24 h
70.0 ± 3.01 b
(19.35)*
73.4 ± 2.80 a
90.3 ± 2.88 a
87.6 ± 3.36 a
25
50
25
50
25
50
25
50
78.0±3.47e (13.04)
(26.45)
(30.11)
(27.84)
9a
63.3 ± 2.39 a
64.1 ± 2.32a
71.7 ± 2.63a
71.3 ± 2.93 a
78.5 ± 1.89d
(27.07)
(35.77)
(44.51)
(41.27)
(12.48)
72.8 ± 4.04 d
76.7 ± 5.36 c
93.2 ± 4.06a
91.4 ± 2.79 a
79.8 ± 3.31e
(16.13)
(23.15)
(27.86)
(24.71)
(11.03)
9b
71.5 ± 1.28 a
72.8 ± 1.43 a
84.1 ± 1.40a
91.2 ± 1.95 a
86.1 ± 2.01ns
(17.62)
(27.05)
(34.91)
(24.87)
(4.01)
72.2 ± 1.92 a
77.4 ± 1.77a
95.4 ± 2.18 a
96.6 ± 2.96 a
79.1± 2.82 e (11.82)
70.8±1.08a (21.07)
(16.82)
(22.44)
(26.16)
(20.42)
12a
12b
61.8 ± 2.10a
66.6 ± 1.69 a
74.4 ± 2.28 a
72.6 ± 1.84 a
(28.80)
(33.17)
(42.41)
(40.19)
72.4 ± 2.30 b
79.8 ± 2.51b
96.6 ± 3.01 a
94.6 ± 2.88 a
78.8± 2.7 e
(16.58)
(20.04)
(25.23)
(22.07)
(12.15)
65.2 ± 2.75 a
67.8 ± 2.77 a
78.8 ± 2.42 a
82.6 ± 2.68 a
74.5 ± 2.24 c
(24.88)
(32.06)
(39.01)
(31.96)
(16.94)
67.2 ± 2.16 a
68.4 ± 1.14 a
77.6 ± 3.0 a
76.2 ± 2.46 a
73.6 ± 1.65 b
Phenylbutazone
Control
100
----
(22.58)
(31.46)
(39.93)
(37.23)
(17.94)
86.8 ± 2.19
99.8 ± 3.54
129.2 ± 2.79
121.4 ± 2.10
89.7 ± 2.75
* Figures in parentheses indicate percent inhibition of paw edema.
a-c Probability values (calculated as compared to control using student’s t-test):
a < 0.001, b < 0.002, c < 0.01, d < 0.02, e < 0.05; ns < not significant All values are means of five rats.
cm-1) were recorded on KBr disk. The H NMR and 13C
NMR spectra of the synthesized compounds were recorded
on a Varian VXR-500 spectrometer and JEOL 500 spec-
trometer (500 MHz) as solutions in deuterodimethyl sulfox-
ide (DMSO-d6) using tetramethylsilane (TMS) as an internal
standard. Chemical shifts (ꢀ) were expressed in ppm units
downfield from TMS, and the coupling constant J in Hz. MS
analyses were performed on a Finnigan MAT95 spectrome-
ter. The studies involving mice and rats were approved by
the Ethical Review Committee (approval number:
SCB090111) Biological Science, University of Dhaka,
Bangladesh, and the experiments were carried out strictly in
accordance with the guidelines provided by the World
Health Organization.
tallized in aqueous ethanol (aq. EtOH, 25%) to obtain 3,4-
1
dichlorophenyl cyanoacrylic ester (2, 91.36% yield).
Crystalline solid, mp. 126-128ºC. FABMS (+ve ion
mode) m/z: [M+H]+ 212 and [M+H]+ 214 (intensity ratio:
3:1, respectively). HR-FABMS m/z: [M+H]+ 212.0032 calcd.
212.0034 for C10H8Cl2N.
Preparation of 3,4-dicholorophenyl Succinic Acid (4)
The 3,4-dichlorophenyl cyanoacrylic ester (2, 13.15 g,
0.05 mole) was treated with sodium cyanide (NaCN, 2.45 g,
0.05 mole) dissolving it in 10 mL of water. The reaction
mixture was refluxed in presence of 50% aq. EtOH (100 mL)
for 1.5 h. The reaction mixture was cooled and poured in 300
mL of water. Conc. HCl (150 mL) was added to it and kept
for overnight. The mixture was then extracted with chloro-
form (CHCl3, 50 mL) for three times. The pooled extract was
washed with water, dried over baked sodium sulfate
(Na2SO4) and evaporated. The product 3,4-dichlorophenyl
ꢀ,ꢁ-dicyanoethyl propionate (3, 89.78%, m.p. 104-106ºC)
thus formed was hydrolyzed by refluxing with conc. HCl
(150 mL) to obtain the target compound 4, separated as a
white solid upon cooling. The white solid (4) was then fil-
tered from the reaction mixture, washed with cool water,
dried and re-crystallized from hot water with a yield of
67.8%.
Synthesis of Compounds
Preparation of 3,4-dichlorophenyl Cyanoacrylate (2)
3,4-Dicholorobenzaldehyde (1, 10.5 g, 0.06 mole) was
treated with ethylcyanoacetate (6.78 g, 0.06 mole) in dry
C6H6 in presence of C5H5N (2 mL) and glacial AcOH (2
mL). The reaction mixture was refluxed for 20 h in an oil
bath. The mixture was then evaporated to dryness under re-
duced pressure. The solid residue was filtered, washed with
water, HCl (5%) and again with cold water, dried and crys-

Indan Acids as Novel Analgesic and Anti-inflammatory Agents
Medicinal Chemistry, 2012, Vol. 8, No. 5 879
Crystalline solid, mp. 196-198ºC. UV, (MeOH) ꢀmax in
Crystalline solid [5,6-dichloro-3-oxo-indan-1-carboxylic
1
nm: 226. IR, (KBr) ꢁmax in cm-1: 1695, 660. H NMR (500
acid (5)], mp. 182-184ºC. UV (MeOH) ꢀmax in nm: 254. IR
1
MHz, DMSO-d6) ꢂ: 7.53 (dd, 1H, J = 8.0, 1.7, H-6), 7.38 (d,
1H, J = 8.0 Hz, H-5), 7.33 (d, 1H, J = 1.7 Hz, H-2), 3.78 (dd,
1H, J = 7.0, 4.0, H-ꢀ), 2.84 (m, 2H, H-ꢁ). FABMS (+ve ion
mode) m/z: [M+H]+ 263 and [M+H]+ 265 (intensity ratio:
3:1, respectively). HR-FABMS m/z: [M+H]+ 262.9876
calcd. 262.9877 for C10H9Cl2O4.
(KBr) ꢁmax in cm-1: 1695, 1600, 640. H NMR (500 MHz,
DMSO-d6) ꢂ: 7.80 (s, 1H, H-4), 7.76 (s, 1H, H-7), 4.20 (t,
1H, J = 7.5 Hz, H-1), 2.94 (dd, 1H, J =14.0, 4.5, H-2a), 2.68
(dd, 1H, J = 14.0, 7.5, H-2b). FABMS (+ve ion mode) m/z:
[M+H]+ 245 and [M+H]+ 247 (intensity ratio: 3:1, respec-
tively). HR-FABMS m/z: [M+H]+ 244.9770, calcd. 244.9772
for C10H7Cl2O3.
Preparation of 3,4-dichlorobenzylidine-bis-acetoacetate (6)
Crystalline solied [5,6-dichloro-3-oxo-indan-1-acetic
Compound 1 (25 g; 0.143 mole) was condensed with
ethyl acetoacetate (37.22 g; 0.286 mole) in 1:2 molar ratio in
presence of piperidine (2.5 mL) and allowed the reaction
mixture to stay in anhydrous condition for 96 h at r. t. fol-
lowing the Hey and Kohn method [31]. After completion of
the reaction, a yellow solid mass was obtained. It was then
crushed in a mortar and pestle and washed with ether to re-
move piperidine. The white crystalline powder was re-
acid (8)], mp. 140-142ºC. UV (MeOH) ꢀmax in nm: 255. IR
1
(KBr) ꢁmax in cm-1: 1695, 1600, 640. H NMR (500 MHz,
DMSO-d6) ꢂ: 7.84 (s, 1H, H-4), 7.78 (s, 1H, H-7); 4.46 (m,
1H, H-1), 3.82 (dd, 1H, J = 13.5, 5.5, H-ꢁ), 3.65 (dd, 1H, J =
14.0, 2.5, H-2a), 3.44 (dd, 1H, J = 13.5, 7.5, H-ꢁ’), 2.82 (dd,
1H, J = 14.0, 3.5, H-2b); FABMS (+ve ion mode) m/z:
[M+H]+ 259 and [M+H]+ 261 (intensity ratio: 3:1, respecti-
vely); HR-FABMS m/z: [M+H]+ 258.9927 calcd. 258.9929
for C11H9Cl2O3.
crystallized
from
acetone-water
to
obtain
3,4-
dichlorobenzylidine-bis-acetoacetate (6, 49 g, 86.25% yield).
Preparation of 5,6-dichloroindan-1-acids (9a and 9b)
White crystalline solid, mp. 158-160°C. FABMS (+ve
ion mode) m/z: [M+H]+ 301 and [M+H]+ 303 (intensity ratio:
3:1, respectively). HR-FABMS m/z: [M+H]+ 301.0760,
calcd. 301.0762 for C10H8Cl2N.
Compounds 5 and 8 (0.018 mole each) were separately
treated with amalgamated zinc (20 g), water (15 mL), conc.
HCl (20 mL) and C6H6 (30 mL) as a solvent and refluxed
following the Clemmensen reduction process in a water-bath
for 16-18 h until the reaction mixtures gave no positive result
in the test for a keto functionality. The C6H6 layer was sepa-
rated and the aqueous layer was extracted with C6H6 (20 x 3
= 60 mL) and combined together. The combined C6H6 layers
were washed with water and dried over anhydrous Na2SO4.
After removal of the solvent under reduced pressure, the
yellowish white solid thus formed was dried and re-
crystallized from aq. EtOH (25%) to obtain separately the
target compounds, 5,6-dichloroindan-1-carboxylic acid (9a,
3.36 g, 80.96% yield) and 5,6-dichloroindan-1-acitic acid
(9b, 3.67 g, 83.38% yield).
Preparation of 3,4-dichlorophenyl Glutaric Acid (7)
Compound 6 (0.117 mole) was hydrolyzed in presence of
100 mL alcoholic solution of KOH (25%) by refluxing for
2.5 h. The alcohol was then distilled off under reduced pres-
sure, diluted with water, washed with CHCl3 and neutralized
by conc. HCl in cold condition with continuous stirring. The
precipitation thus formed was filtered and re-crystallized
from aq. EtOH to obtain target compound (7) as crystalline
solid in 81.3% yield.
Crystalline solid, mp. 168-170ºC. UV (MeOH) ꢀmax in
1
nm: 222. IR (KBr) ꢁmax in cm-1: 1700, 640. H NMR (500
White crystalline solid [5,6-dichloroindan-1-carboxylic
MHz, DMSO-d6) ꢂ: 11.88 (bs, 1H, COOH), 11.80 (bs, 1H,
COOH), 7.44 (dd, 1H, J = 8.0, 1.6, H-6), 7.40 (d, 1H, J =
8.0 Hz, H-5), 7.35 (d, 1H, J = 1.6 Hz, H-2), 2.53 (dd, 1H, J =
5.0, 4.5, H-ꢀ), 2.44 (m, 4H, H-ꢁand H-ꢂ); FABMS (+ve ion
mode) m/z: [M+H]+ 277 and [M+H]+ 279 (intensity ratio:
3:1, respectively). HR-FABMS m/z: [M+H]+ 277.0034 calcd.
277.0034 for C11H11Cl2O4.
acid (9a)], mp. 118-120ºC. UV (MeOH) ꢀmax in nm: 280. IR
1
(KBr) ꢁmax in cm-1: 1690, 1600, 640. H NMR (500 MHz,
DMSO-d6) ꢂ: 7.50 (s, 2H, H-4 and H-7), 4.00 (t, 1H, J = 8.0
Hz, H-1), 2.90 (ddd, 1H, J = 16.0, 8.5, 6.0, H-3a), 2.80 (ddd,
1H, J = 16.0, 8.0, 7.5, H-3b), 2.20 (m, 2H, H-2). 13C NMR
(125 MHz, DMSO-d6) ꢂ: 173.8 (1-COOH ), 145.0 (C-6),
142.3 (C-5), 129.6 (C-7), 128.5 (C-4), 126.5 (C-8), 126.3 (C-
9), 49.0 (C-1), 30.6 (C-3), 28.7 (C-2). FABMS (+ve ion
mode) m/z: [M+H]+ 231 and [M+H]+ 233 (intensity ratio:
3:1, respectively). HR-FABMS m/z: [M+H]+ 230.9981 calcd.
230.9980 for C10H9Cl2O2.
Preparation of 5,6-dichloro-3-oxo-indan-1-acid (5 and 8)
The diacids (4 and 7) (0.028 mole each) were separately
converted to respective diacylchlorides by refluxing with
SOCl2 (sp. gr. 1.631; 6.60 g; 0.056 mole) for 1.5 h in dry
C6H6 (40 mL). Benzene and excess SOCl2 were removed in
vaccuo to obtain diacylchlorides as liquid. Immediately, an-
hydrous aluminum chloride (AlCl3, 0.084 moles) was poured
into the reaction mixture in portion-wise in well stirred con-
dition using carbon disulfide (CS2, 40 mL) as a solvent. The
mixture was stirred for 2 h at r. t. Then it was decomposed in
ice water mixture (300 mL). The solvent CS2 was evaporated
on hot water bath. The precipitates formed after cooling of
the mixture were filtered, washed thoroughly with water,
dried and re-crystallized from aq. EtOH (25%) to obtain tar-
get compounds 5 (4.60 g, 67.05% yield) and 8 (4.85 g,
66.85% yield) separately.
Yellowish white crystalline solid [5,6-dichloroindan-1-
acitic acid (9b)], mp. 48-49ºC. UV (MeOH) ꢀmax in nm: 280.
IR (KBr) ꢁmax in cm-1: 1690, 1600, 640. 1H NMR (500 MHz,
DMSO-d6) ꢂ: 7.45 (s, 1H, H-7), 7.43 (s, 1H, H-4), 3.40 (t,
1H, J = 8.0 Hz, H-1), 2.80 (ddd, 1H, J = 12.5, 8.5, 4.0, H-
3a), 2.70 (dd, 1H, J = 16.0, 7.0, H-10a), 2.30 (dd, 1H, J =
16.0, 8.0, H-10b), 2.20 (ddd, 1H, J = 12.5, 7.5, 4.5, H-3b),
1.60 (m, 2H, H-2). 13C NMR (125 MHz, DMSO-d6) ꢂ: 173.3
(10-COOH ), 147.1 (C-6), 144.8 (C-5), 128.8 (C-7), 128.5
(C-4), 126.1 (C-8), 125.5 (C-8), 49.4 (C-1), 38.7 (C-10),
32.1 (C-3), 30.2 (C-2). FABMS (+ve ion mode) m/z: [M+H]+
245 and [M+H]+ 247 (intensity ratio: 3:1, respectively). HR-

880 Medicinal Chemistry, 2012, Vol. 8, No. 5
Pal et al.
FABMS m/z: [M+H]+ 245.0134 calcd. 245.0136 for
C11H11Cl2O2.
ture was slowly raised to 95°C where it was maintained for 2
h. After quenching the reaction with ice, the nitriles (11a and
11b) were extracted with ether and dried over anhydrous
Na2SO4. The dried ether layer was distilled off under re-
duced pressure. The residues obtained as crystalline solid for
5,6-dichloroindan-1-carbonitrile (11a, 1.36 g, 95% yield)
and 5,6-dichloeoindan-1-acetonitrile (11b, 1.33 g, 88.7%
yield) were re-crystallized from aq. EtOH (25%).
Preparation of 5,6-dichloroindan-1-amides (10a and 10b)
5,6-Dichloroindan-1-acids (9a and 9b) (1 mole each)
were treated individually with SOCl2 (1.5 mole) in dry C6H6
and refluxed for 1.5 h. The acid chlorides thus formed were
made free from excess SOCl2 in vacuo and immediately dis-
solved in dry C6H6. The solutions were added drop wise to
an excess solution of NH4OH (50 mL) at 1-5°C. The reaction
mixtures were saturated with NaCl and then extracted with
C6H6. The C6H6 layer of respective compound was then vig-
orously shaken with saturated sodium bicarbonate solution
and washed with distilled water, dried over anhydrous
Na2SO4. The combined C6H6 layers were then distilled off
under reduced pressure and the solid masses thus obtained
were re-crystallized from aq. EtOH (25%) to obtain the tar-
get compounds 5,6-dichloroindan-1-carboxamide (10a, 1.72
g, 86.25%) and 5,6-dichloroindan-1-acetamide (10b, 2.2 g,
88.0%).
Yellowish white crystalline solid [5,6-dichloroindan-1-
carbonitrile (11a)], mp. 94-96ºC. UV (MeOH) ꢀmax in nm:
280. IR (KBr) ꢁmax cm-1: 2241. 1H NMR (500 MHz, DMSO-
d6) ꢂ: 7.50 (s, 1H, H-7), 7.40 (s, 1H, H-4), 4.00 (t, 1H, J =
7.5, H-1), 3.00 (m, 1H, H-3a), 2.90 (m, 1H, H-3b), 2.60 (m,
1H, H-2a), 2.40 (m, 1H, H-2b). 13C NMR (125 MHz, DM-
SO-d6) ꢂ: 142.9 (C-6), 140.2 (C-5), 132.8 (C-7), 131.4 (C-4),
126.8 (C-8), 126.1 (C-9), 119.9 (CN), 34.1 (C-1), 31.5 (C-3),
30.9 (C-2). FABMS (+ve ion mode) m/z: [M+H]+ 212 and
[M+H]+ 214 (intensity ratio: 3:1, respectively). HR-FABMS
m/z: [M+H]+ 212.0035 calcd. 212.0034 for C10H8Cl2N.
White crystalline solid [5,6-dichloeoindan-1-acetonitrile
(11b)], mp. 56-58oC. UV, (MeOH) ꢀmax in nm: 280. IR (K-
White crystalline solid [5,6-dichloroindan-1-carboxamide
(10a)], mp. 180-182ºC. UV (MeOH) ꢀmax in nm: 280. IR
(KBr) ꢁmax in cm-1: 3335, 1662. 1H NMR (500 MHz, DMSO-
d6) ꢂ: 7.40 (s, 1H, H-7), 7.30 (s, 1H, H-4), 5.60 (s, 1H, NH),
5.60 (s, 1H, NH’), 3.80 (t, 1H, J = 7.5, H-1), 3.00 (m, 1H,
H-3a), 2.80 (m, 1H, H-3b), 2.40 (m, 1H, H-2a), 2.30 (m, 1H,
H-2b). 13C NMR (125 MHz, DMSO-d6) ꢂ: 175.0 (1-
CONH2), 144.7 (C-6), 141.4 (C-5), 131.7 (C-7), 130.6 (C-4),
126.6 (C-8), 126.3 (C-9), 51.2 (C-1), 31.3 (C-3), 30.7 (C-2).
FABMS (+ve ion mode) m/z: [M+H]+ 230 and [M+H]+ 232
(intensity ratio: 3:1, respectively). HR-FABMS m/z: [M+H]+
230.0139 calcd. 230.0139 for C10H10Cl2NO.
1
Br) ꢁmax cm-1: 2247. H NMR (500 MHz, DMSO-d6) ꢂ: 7.30
(s, 2H, H-4 and H-7), 3.66 (m, 1H, H-1), 3.04 (bd, 2H, J =
7.6 Hz, H-10), 2.81 (m, 2H, H-3), 2.43 (m, 1H, H-2a), 1.75
(m, 1H, H-2b). 13C NMR (125 MHz, DMSO-d6) ꢂ: 143.9 (C-
6), 143.4 (C-5), 131.0 (C-7), 130.6 (C-4), 126.7 (C-8), 125.3
(C-9), 118.1 (CN), 40.9 (C-10), 40.8 (C-1), 31.9 (C-3), 30.5
(C-2). FABMS (+ve ion mode) m/z: [M+H]+ 226 and
[M+H]+ 228 (intensity ratio: 3:1, respectively). HR-FABMS
m/z: [M+H]+ 226.0188 calcd. 226.0190 for C11H10Cl2N.
Preparation of 5-(5',6'-dichloroindan-1'-yl)-tetrazole (12a)
and 5-(5',6'-dichloroindan-1'-yl)-methyltetrazole (12b)
White crystalline solid [5,6-dichloroindan-1-acetamide
(10b)], mp. 138-1409ºC. UV (MeOH) ꢀmax in nm: 280. IR
(KBr) ꢁmax in cm-1: 3339, 1659. 1H NMR (500 MHz, DMSO-
d6) ꢂ: 7.20 (s, 2H, H-4 and H-7), 5.50 (s, 1H, NH), 5.40 (s,
1H, NH’), 3.60 (m, 1H, H-1), 2.80 (m, 2H, H-3), 2.53 (dd,
1H, J = 15.0, 7.0, H-10a), 2.44 (m, 1H, H-2a), 2.30 (dd, 1H,
J = 15.0, 7.0, H-10b), 1.71 (m, 1H, H-2b). 13C NMR (125
MHz, DMSO-d6) ꢂ: 173.3 (10-CONH2 ), 146.2 (C-6), 144.0
(C-5), 130.5 (C-7), 130.0 (C-4), 126.3 (C-8), 125.4 (C-9),
41.0 (C-1), 40.9 (C-10), 32.9 (C-3), 30.7 (C-2). FABMS
(+ve ion mode) m/z: [M+H]+ 244 and [M+H]+ 246 (intensity
ratio: 3:1, respectively). HR-FABMS m/z: [M+H]+ 244.0296
calcd. 244.0296 for C11H12Cl2NO.
Activated sodium azide (NaN3) was prepared by taking
NaN3 (10 g) in a glass mortar, adding 5-8 drops of hydrazine
hydrate to it, triturating the mixture and keeping it over
night. The mixture was taken into a beaker and dissolved in
8-10 mL of water. Acetone (500-600 mL) was added to it
until precipitation occurred. It was kept undisturbed for 2 h.
Then the crystals were collected by filtration and dried.
The 11a and 11b (1 mole each) were added separately to
activated sodium azide (2 moles) and ammonium chloride (2
moles), and refluxed at 130-140°C for 48 h using dimethyl-
formamide (DMF) as the solvent following the method of
Finnegan et al. [32]. Subsequently, the DMF was distilled off
under reduced pressure and the solid mass obtained was
taken up in warm 5% aq. KOH solution. The cooled alkaline
solution was filtered, extracted with ether, and the ether ex-
tract was made acidic (pHꢀ2) with conc. HCl to obtain the
precipitates of 5-(6'-haloindan-1'-yl)-tetrazoles (12a, 1.0 g,
50.01% yield) and 5-(6'-haloindan-1'-yl)-methyltetrazoles
(12b, 0.98 g, 49% yield) separately. The precipitates were
washed with water and re-crystallized from hot water.
Preparation of 5,6-dichloroindan-1-nitriles (11a and 11b)
5,6-Dichloroindan-1-amides (10a and 10b) (1 mole each)
was mixed separately with P2O5 (5 moles) and was refluxed
for 1.5 h using dry C6H6 following the method described
previously. The reaction mixture was cooled and decom-
posed by addition of ice-water. After complete decomposi-
tion, the mixture was extracted with C6H6. The C6H6 layer
was washed successively with 10% NaHCO3 solution and
distilled water and dried over anhydrous Na2SO4.
White crystalline solid [5-(5',6'-dichloroindan-1'-yl)-
tetrazole (12a)], mp. 158-160oC. UV (MeOH) ꢀmax in nm:
280 nm. IR (KBr) ꢁmax in cm-1: 271 (bending, C-N=N-N),
Alternatively, the nitriles could be prepared by dehydrat-
ing the amides. Compounds 10a and 10b (1 mole each) was
mixed individually with POCl3 (10 moles) and Na2S2O5 (1
mole) in a round bottom flask. When the reaction began, the
mixture was warmed to 70°C on a water bath. The tempera-
1
1578 (C-N, cyclic). H NMR (500 MHz, DMSO-d6) ꢂ: 7.30
(s, 1H, H-7), 7.20 (s, 1H, H-4), 4.70 (t, 1H, J = 7.5, H-1),
3.10 (m, 1H, H-3a), 3.00 (m, 1H, H-3b), 2.70 (m, 1H, H-2a),

Indan Acids as Novel Analgesic and Anti-inflammatory Agents
Medicinal Chemistry, 2012, Vol. 8, No. 5 881
2.40 (m, 1H, H-2b). 13C NMR (125 MHz, DMSO-d6) ꢀ:
144.0 (C-6), 141.9 (C-5), 131.9 (C-7), 130.7 (C-4), 126.6 (C-
8), 126.4 (C-9), 98.1 (C-10), 40.1 (C-1), 32.6 (C-3), 31.1 (C-
2). FABMS (+ve ion mode) m/z: [M+H]+ 255 and [M+H]+
257 (intensity ratio: 3:1, respectively). HR-FABMS m/z:
[M+H]+ 255.0201 calcd. 255.0204 for C10H9Cl2N4.
Where WC represents the average writhing produced by the
control group and Wt represents the average writhing pro-
duced by the test group, respectively.
Evaluation of Anti-inflammatory Activity
Adult Wister rats were used in this study. The anti-
inflammatory activity was studied by the method described
by Winter et al. [33]. The animals were randomly divided
into different groups consisted of five rats in each group. The
test compounds at doses of 25 and 50 mg/kg of body weight
were administered by gavage. Phenylbutazone was given per
oral at a dose of 100 mg/kg body weight as a standard anti-
inflammatory drug. One group of rats given only saline solu-
tion was served as control (Table 2). After 1 h of drug ad-
ministration, 0.1 mL of 1% (W/V) carrageenan in sterile
saline solution was injected into the subplanter surface of the
right hind paw for the production of acute inflammation.
Paw volumes were measured up to a fixed mark plethys-
mometrically (Ugo Basile, Italy) after 1, 2, 3, 4 and 24 h of
carrageenan injection. The percent inhibition of paw volume
was measured using the following formula.
White crystalline solid [5-(5',6'-dichloroindan-1'-yl)-
methyltetrazole (12b)], mp. 166-168oC. UV (MeOH) ꢁmax in
nm 280. IR (KBr) ꢂmax in cm-1: 269 (bending, C-N=N-N),
1
1556 cm-1. H NMR (500 MHz, DMSO-d6) ꢀ: 7.30 (s, 2H,
H-7), 7.20 (s, 2H, H-4), 3.65 (m, 1H, H-1), 3.30 (dd, 1H, J =
15.0, 6.0 Hz, H-10a), 3.00 (dd, 1H, J = 15.0, 9.0 Hz, H-10b),
2.90 (m, 2H, H-3a), 2.80 (m, 1H, H-2b), 2.30 (m, 1H, H-2a),
1.82 (m, 1H, H-2b); 13C NMR (125 MHz, DMSO-d6) ꢀ:
151.1 (C-6), 145.7 (C-5), 132.9 (C-7), 131.8 (C-4), 127.4 (C-
8), 126.5 (C-9), 99.8 (C-11, CꢃN), 44.2 (C-10), 32.9 (C-1),
31.2 (C-3), 29.2 (C-2). FABMS (+ve ion mode) m/z: [M+H]+
269 and [M+H]+ 271 (intensity ratio: 3:1, respectively). HR-
FABMS m/z: [M+H]+ 269.0360 calcd. 269.0361 for
C11H11Cl2N4.
Evaluation of Analgesic and Anti-inflammatory Activity
Vc - Vt
x 100
Percent inhibition =
Animals
Vc
Young Swiss albino mice aged 4-5 weeks weighed 20-25
g of either sex were used for the assessment of analgesic
activity, and adult Wister rats of either sex weighing 150±10
g were used for the assessment of anti-inflammatory activity.
They were collected from the animal house of the Interna-
tional Center for Diarrheal Diseases and Research, Bangla-
desh (ICDDR,B), Mohakhali, Dhaka. The ICDDR, B formu-
lated food pellets were supplied to the animals and water at
libitum. They were kept in polyvinyl cages under controlled
room temperature (25±2°C) in the laboratory environment
under 12 h dark and 12 h light cycle for seven days; were
fasted overnight and weighed before the experiment. The
study involving rats was approved by the Ethical Review
Committee Biological Science, University of Dhaka, Bang-
ladesh, and the experiments were carried out strictly in ac-
cordance with the guidelines provided by the World Health
Organization.
Where VC represents the average paw volume of the control
group and Vt represents the average paw volume of the test
group, respectively.
Statistical Analyses
Statistical analysis was performed using the SPSS-11.5
statistical Software for Windows. Experimental values were
expressed as mean ±SEM. Independent Sample t-test was
carried out for statistical comparison.
CONFLICTS OF INTEREST
There is no conflict of interest associated with work pre-
sented in this paper.
ACKNOWLEDGEMENTS
The authors are grateful to the Ministry of Science and
Technology, Government of Bangladesh, Dhaka, for grant-
Evaluation of Analgesic Activity
Adult Swiss albino mice were used to study the analgesic
activity by the acetic acid-induced writhing test as described
by Vogel and Vogel [27] with slight modifications. Animals
were divided into different groups consisted of five in each.
Test drugs were given orally to the respective groups of ani-
mals at dose levels of 25 and 50 mg/kg body weight and the
standard drugs phenylbutazone and indomethacin were given
at doses of 100 and 50 mg/kg body weight, respectively.
Control mice were treated with normal saline only. After 45
min of drug administration, acetic acid solution (0.7%, 0.10
mL/10g) was administered intraperitoneally (i.p.) to the each
group of animals. After an interval of ten minutes, numbers
of writhing were counted for another 10 min. The percent
inhibition of writhing was measured using the following
formula.
ing
a
special allocation No. BPROMA/SHA-9/B:
ANU:/2000/339 dt 22/05/2001 to perform some aspects of
this project. Some of the MS analyses were performed at the
EPSRC National Mass Spectrometry Service Centre in
Swansea, Wales, UK.
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Received: November 17, 2011
Revised: April 26, 2012
Accepted: April 26, 2012