2-Aryl-3-phenylamino-4,5-dihydro-2h-benz[g]indazoles with analgesic activity

Article abstract of DOI:10.1016/S0014-827X(03)00142-3

A series of 2-aryl-3-phenylamino-4,5-dihydro-2H-benz[g]indazoles was synthesized and tested for antiarrhythmic, local anaesthetic and analgesic activity. The title compounds showed a good antinociceptive activity.

Full text of DOI:10.1016/S0014-827X(03)00142-3

Il Farmaco 58 (2003) 845ꢀ849
/
www.elsevier.com/locate/farmac
2-Aryl-3-phenylamino-4,5-dihydro-2h-benz[g]indazoles with
analgesic activity
Silvia Schenone a,*, Olga Bruno a, Angelo Ranise a, Chiara Brullo a,
Francesco Bondavalli a, Walter Filippelli b, Filomena Mazzeo b, Annalisa Capuano b,
Giuseppe Falcone b
a Dipartimento di Scienze Farmaceutiche, Facolta` di Farmacia dell’Universita` degli Studi di Genova, Viale Benedetto XV, 3, 16132, Genova, Italy
b Dipartimento di Medicina Sperimentale, sezione di Farmacologia ‘L. Donatelli’, Facolta` di Medicina e Chirurgia, II Universita` degli Studi di Napoli,
Via Costantinopoli 16, 80138, Napoli, Italy
Received 8 November 2002; accepted 18 February 2003
Abstract
A series of 2-aryl-3-phenylamino-4,5-dihydro-2H-benz[g]indazoles was synthesized and tested for antiarrhythmic, local
anaesthetic and analgesic activity. The title compounds showed a good antinociceptive activity.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: 2-Aryl-3-phenylamino-4,5-dihydro-2H-benz[g]indazoles; Analgesic activity
1. Introduction
in particular analgesic, antiinflammatory and antipyre-
tic, typical of the well-known pyrazolone derivatives,
but also antiarrhythmic activity, previously found by us
in non fused pyrazole derivatives [14].
We have recently synthesized compounds 1 [12] which
showed appreciable analgesic activity, but lower than
The pyrazole ring is present in a large number of
compounds endowed of pharmacological activity, either
as isolated ring or fused with other mono or policyclic
systems.
In particular examples of differently substituted
dihydro-benz[g]indazolic compounds are present in the
that of indomethacin; in some terms of the series (R?ꢁ
F, CH3) local anaesthetic and antiarrhythmic activities
were present.
/
literature showing antimicrobial [1ꢀ3] antiallergic [4]
/
and non-estrogenic contraceptive activity [5]. More
recently also tyrosine kinase inhibitors [6,7], dopamine
receptors ligands [8], antiinflammatory and analgesic [9]
compounds have been reported quite extensively in the
patent literature.
Being involved in a study on pyrazole derivatives,
with the purpose to perform a large program of
biological screening, we focused our attention on some
fused pyrazolic compounds and in particular on pyrano-
pyrazoles [10,11] and on dihydro-benz[g]indazoles
[12,13], bearing an arylamino pyrazole moiety. Some
terms of these series showed interesting activity profiles,
To better understand the SAR of these type of
compounds, we synthesized a new series of 3-aryla-
mino-4,5-dihydro-2H-benz[g]indazoles 2, bearing to-
gether with the previously studied substituents on the
phenyl ring in position 2, a methyl, electron-donating, or
a fluorine, weak electron-attracting substituent in para
position on the arylamino moiety.
* Corresponding author.
E-mail address: schensil@unige.it (S. Schenone).
´
0014-827X/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0014-827X(03)00142-3

846
S. Schenone et al. / Il Farmaco 58 (2003) 845ꢀ849
/
Table 1
Yields and melting points of compounds 2aꢀ
/l
Comp.
R
R’
Yield (%)
M.p. (8C)
2a
2b
2c
2d
2e
2f
CH3
CH3
CH3
CH3
CH3
CH3
F
CH3
OCH3
F
70
65
70
72
79
83
71
40
67
70
78
87
181ꢀ
192ꢀ
210ꢀ
207ꢀ
206ꢀ
150ꢀ
188ꢀ
201ꢀ
151ꢀ
182ꢀ
205ꢀ
196ꢀ
/
182
193
211
208
207
151
189
202
152
183
206
197
/
/
Cl
/
Br
/
CF3
CH3
OCH3
F
/
The synthesis of compounds 2aꢀl is outlined in
/
2g
2h
2i
/
Scheme 1. Reaction of 1-tetralone (3) with NaH in
anhydrous DMF followed by addition of p-tolyl or p-
fluoro-phenylisothiocyanate afforded the corresponding
F
/
F
/
2j
F
Cl
/
2k
2l
F
Br
CF3
/
oxocarbothioamides 4aꢀ
ported previously [12].
Reaction of 4aꢀb with the appropriate p-substituted
/
b in very good yields as re-
F
/
/
arylhydrazine at reflux, in presence of a catalytical
amount of acetic acid gave the 2-aryl-3-phenylamino-
Analyses for C, H, N were within 9
theoretical value.
/
0.3% of the
4,5-dihydro-2H-benz[g]indazoles (2aꢀ
good yields as crystal materials.
Compounds 2aꢀl were submitted to a preliminary
/
l) (Table 1) in
2.1.1. General procedure for N-aryl-1-oxo-1,2,3,4-
tetrahydronaphtalene-2-carbothioamides (4aꢀ4b)
/
/
screening for analgesic, antiarrhythmic and local anaes-
thetic activities.
To a cold solution of 1-tetralone (3) (14.62 g, 0.100
mol) in dry dimethylformamide (DMF, 60 ml), a 60%
sodium hydride dispersion in mineral oil (4.25 g, 0.105
mol) was added and the resulting mixture was stirred at
room temperature (r.t.) until the hydrogen evolution
subsided (15 min). The proper arylisothiocyanate (15.36
g, 0.103 mol for 4a, 15.77 g, 0.103 mol for 4b) was then
added and the mixture was stirred at r.t. for 4 h, poured
cautiously into cold water (500 ml) and extracted with
2. Experimental
2.1. Chemistry
Starting materials were purchased from Aldrich-Italia
(Milan).
Melting points were determined with a Buchi B 540
¨
petroleum ether (b.p. 40ꢀ
was cooled and acidified with 3 M HCl (pH 4ꢀ
The yellow solid precipitated was filtered, washed
with water and finally crystallized from absolute etha-
nol.
/
70 8C). The aqueous solution
5).
/
apparatus and are uncorrected. IR spectra were mea-
sured in CHCl3 with a Perkin-Elmer 398 spectrophot-
ometer. 1H NMR spectra were recorded in CDCl3
solution on a Varian Gemini 200 (200 MHz) instrument,
chemical shifts are reported as d (ppm) relative to TMS
4a: light yellow crystals, yield 80%, m.p. 154ꢀ
/
155 8C.
IR: 3300 and 1674 cmꢂ1 (NH, CO). H NMR: 2.36 (s,
3H, CH3), 2.60ꢀ3.40 (m, 4H, 2CH2), 3.70ꢀ3.85 (m, 1H,
CH), 7.20ꢀ7.60 (2m, 7H Ar), 8.01ꢀ8.10 (m, 1H, H-8),
1
/
/
1
as internal standard; J in Hz. H patterns are described
/
/
using the following abbreviations: sꢁ
/
singlet, tꢁtriplet,
/
10.62 (s, 1H, NH, disappears with D2O). Anal. Calc. for
C18H17NOS: C, 73.19; H, 5.80; N, 4.74. Found: C,
73.34; H, 5.75; N, 4.77%.
qꢁquartet, mꢁmultiplet.
/
/
All compounds were tested for purity by TLC (Merk,
Silica gel 60 F254, CHCl3 as eluant).
4b: light yellow crystals, yield 87%, m.p. 148ꢀ
/
149 8C.
IR: 3299 and 1669 cmꢂ1 (NH, CO). H NMR: 2.60ꢀ
3.35 (m, 4H, 2CH2), 3.70ꢀ3.85 (m, 1H, CH), 7.00ꢀ7.80
(2m, 7H Ar), 8.00ꢀ8.10 (m, 1H, H-8), 10.70 (s, 1H, NH,
1
/
/
/
/
disappears with D2O) Anal. Calc. for C17H14NOSF: C,
68.21; H, 4.71; N, 4.68. Found: C, 68.16; H, 5.03; N,
4.64%.
2.1.2. General procedure for 2-aryl-3-phenylamino-4,5-
dihydro-2H-benz[g]indazoles (2aꢀl)
/
To a solution of the relevant carbothioamide (10
mmol) in absolute ethanol (25 ml) was added the proper
arylhydrazine (ꢀ
/
15 mmol) (if necessary liberated with
alkali from the corresponding hydrochloride, extracted
Scheme 1.

S. Schenone et al. / Il Farmaco 58 (2003) 845ꢀ
/849
847
with diethyl ether and isolated under reduced pressure).
A small amount of glacial acetic acid (5 drops) was
added and the mixture was refluxed for 8 h.
By standing in a refrigerator a solid crystallized,
which was filtered and recrystallized from absolute
ethanol.
NH, disappears with D2O), 6.61ꢀ
/
7.98 (5m, 12H Ar).
Anal. Calc. for C23H17N3F2: C, 73.98; H, 4.59; N, 11.25.
Found: C, 73.75; H, 4.85; N, 11.15.
2j: light brown crystals, IR: 3412 cmꢂ1 (NH). 1H
NMR: 2.54 and 2.93 (2t, Jꢁ/7.5, 4H, 2CH2), 5.21 (s, 1H,
NH, disappears with D2O), 6.64ꢀ
/
8.00 (5m, 12H Ar).
Yields and melting points are reported in Table 1.
Anal. Calc. for C23H17N3ClF: C, 70.86; H, 4.40; N,
10.78. Found: C, 70.67; H, 4.42; N, 10.92%.
1
2a: light brown crystals, IR: 3412 cmꢂ1 (NH). H
NMR: 2.28 and 2.37 (2s, 6H, 2CH3), 2.57 and 2.94 (2t,
1
2k: light brown crystals, IR: 3412 cmꢂ1 (NH). H
Jꢁ
D2O), 6.60ꢀ
/
6.0, 4H, 2CH2), 5.20 (s, 1H, NH, disappears with
8.00 (5m, 12H Ar). Anal. Calc. for
NMR: 2.53 and 2.92 (2t, Jꢁ
NH, disappears with D2O), 6.60ꢀ
/
7.3, 4H, 2CH2), 5.20 (s, 1H,
/
/7.97 (5m, 12H Ar).
C25H23N3: C, 82.16; H, 6.34; N, 11.50. Found: C,
81.85; H, 6.47; N, 11.73%.
Anal. Calc. for C23H17N3BrF: C, 63.61; H, 3.95; N,
9.68. Found: C, 63.59; H, 3.75; N, 9.74%.
2l: light brown crystals, IR: 3412 cmꢂ1 (NH). 1H
1
2b: light brown crystals, IR: 3412 cmꢂ1 (NH). H
NMR: 2.27 (s, 3H, CH3), 2.55 and 2.95 (2t, Jꢁ
2CH2), 3.80 (s, 3H, OCH3), 5.20 (s, 1H, NH, disappears
with D2O), 6.60ꢀ8.05 (6m, 12H Ar). Anal. Calc. for
/
6.0, 4H,
NMR: 2.56 and 2.94 (2t, Jꢁ
NH, disappears with D2O), 6.62ꢀ
Anal. Calc. for C24H17N3F4.1/2H2O: C, 66.66; H, 4.20;
N, 9.72. Found: C, 66.56; H, 4.32; N, 9.76%.
/
7.8, 4H, 2CH2), 5.22 (s, 1H,
/8.00 (5m, 12H Ar).
/
C25H23N3O: C, 78.71; H, 6.08; N, 11.04. Found: C,
78.53; H, 6.27; N, 11.04%.
1
2c: light brown crystals, IR: 3413 cmꢂ1 (NH). H
2.2. Pharmacology
NMR: 2.28 (s, 3H, CH3), 2.57 and 2.91 (2t, Jꢁ
/
7.6, 4H,
2CH2), 5.15 (s, 1H, NH, disappears with D2O), 6.60ꢀ
/
The following experimental procedures were em-
ployed:
8.00 (5m, 12H Ar). Anal. Calc. for C24H20N3F.1/3 H2O:
C, 76.78; H, 5.55; N, 11.19. Found: C, 77.04; H, 5.65; N,
11.51%.
2.2.1. Analgesic activity
The acetic acid writhing test was used on mice [15].
1
2d: light brown crystals, IR: 3412 cmꢂ1 (NH). H
NMR: 2.20 (s, 3H, CH3), 2.55 and 2.93 (2t, Jꢁ
/
7.4, 4H,
Groups of ten mices (weight 20ꢀ25 g) of both sexes,
/
2CH2), 5.21 (s, 1H, NH, disappears with D2O), 6.60ꢀ
/
pregnant females excluded, were administered orally by
gavage in 1% methylcellulose suspension, using a single
dose of 50 mg/kg or scalar doses of 12.5, 25 and 50 mg/
kg for the most active compounds. Indomethacin
(Sigma Aldrich SrL, Milano, Italy) was used as reference
drug in all the tests for comparison purposes at the dose
of 5 mg/kg.
8.00 (5m, 12H Ar). Anal. Calc. for C24H20N3Cl.: C,
74.70; H, 5.22; N, 10.89. Found: C, 74.59; H, 5.28; N,
10.92%.
1
2e: light brown crystals, IR: 3412 cmꢂ1 (NH). H
NMR: 2.29 (s, 3H, CH3), 2.56 and 2.93 (2t, Jꢁ
/
7.0, 4H,
2CH2), 5.20 (s, 1H, NH, disappears with D2O), 6.60ꢀ
/
8.00 (5m, 12H Ar). Anal. Calc. for C24H20N3Br.: C,
66.98; H, 4.68; N, 9.76. Found: C, 66.75; H, 4.80; N,
9.90%.
Thirty minutes later the animals were injected intra-
peritoneally with 0.25 ml/mouse of 0.5% acetic acid
solution and writhes were counted during the following
25 min. The mean number of writhes for each experi-
mental group and percentage inhibition compared to the
control group were calculated. The experimental results
are listed in Table 2.
The estimation of ED50 values was obtained using the
Litchfield and Wilcoxon I formula, by means of the
computer program PHARM-PCS [7] [16].
2f: light brown crystals, IR: 3412 cmꢂ1 (NH). 1H
NMR: 2.28 (s, 3H, CH3), 2.57 and 2.93 (2t, Jꢁ
/
7.0, 4H,
2CH2), 5.20 (s, 1H, NH, disappears with D2O), 6.60ꢀ
/
8.00 (5m, 12H Ar). Anal. Calc. for C25H20N3F3.: C,
71.59; H, 4.81; N, 10.02. Found: C, 71.38; H, 4.61; N,
10.01%.
1
2g: light brown crystals, IR: 3174 cmꢂ1 (NH). H
NMR: 2.37 (s, 3H, CH3), 2.54 and 2.93 (2t, Jꢁ
/
6.0, 4H,
2CH2), 5.25 (s, 1H, NH, disappears with D2O), 6.63ꢀ
/
2.2.2. Antiarrhythmic activity
8.05 (5m, 12H Ar). Anal. Calc. for C24H20N3F: C, 78.03;
H, 5.46; N, 11.37. Found: C, 77.74; H, 5.70; N, 11.22%.
Ventricular fibrillation induced by aconitine hydro-
chloride, according to method suggested by Marmo,
[17], was used to study antiarrhythmic activity of test
1
2h: light brown crystals, IR: 3197 cmꢂ1 (NH). H
NMR: 2.54 and 2.94 (2t, Jꢁ/6.5, 4H, 2CH2), 3.81 (s, 3H,
compounds on groups of ten albino rats (weight 200ꢀ
/
OCH3), 5.25 (s, 1H, NH, disappears with D2O), 6.63ꢀ
/
250 g) of both sexes, pregnant females excluded.
Aconitine hydrochloride (15 mg/kg/i.v./min, Sigma Al-
drich Srl, Milano, Italy) was injected in the control
group and appearance time of extrasystoles and death
time were determined. The same procedure was applied
either in the groups treated with the reference compound
7.98 (5m, 12H Ar). Anal. Calc. for C24H20N3OF: C,
74.79; H, 5.23; N, 10.90. Found: C, 74.47; H, 5.15; N,
10.96%.
2i: light brown crystals, IR: 3412 cmꢂ1 (NH). 1H
NMR: 2.55 and 2.93 (2t, Jꢁ6.1, 4H, 2CH2), 5.20 (s, 1H,
/

848
S. Schenone et al. / Il Farmaco 58 (2003) 845ꢀ849
/
Table 2
Acetic acid writhing test: analgesic activity
Comp.
Dose (mg/kg)
Mean number of writhes in 25 min period after treatment 9
/
SE
Inhibition % relative to controls
Control
Indomethacin
acetic acid 0.5%
45.89
21.79
23.69
24.39
26.09
24.39
22.99
24.69
23.19
25.19
24.79
22.69
25.19
25.69
23.89
22.99
21.99
24.09
25.79
23.59
22.39
26.19
24.29
22.59
/
5.3
4.2
3.9
5.1
3.6
5.1
4.2
3.7
4.1
4.3
3.8
2.9
6.3
3.2
2.9
5.4
3.8
2.9
3.8
4.2
4.7
3.1
5.0
5.1
5
50
/
52.6
48.5
46.9
43.2
46.9
50.0
46.3
49.5
45.2
46.0
50.6
45.2
44.1
48.0
50.0
52.2
47.6
43.8
48.7
51.3
43.0
47.2
50.8
2a
2b
2c
/
50
/
12.5
25
/
/
50
/
2d
2e
2f
50
50
/
/
12.5
25
/
/
50
/
2g
2h
2i
50
50
/
/
12.5
25
/
/
50
/
2j
50
/
2k
12.5
25
/
/
50
/
2l
12.5
25
/
/
50
/
(quinidine, 25 mg/kg p.o. Sigma Aldrich Srl, Milano,
Italy) or in the test compounds (50 mg/kg p.o). No
compound showed appreciable activity.
increase of analgesic activity and, in the same time,
reduced all other activities present in the series 1.
The presence of an electron-withdrawing group on the
phenyl ring in 2, associated with either a methyl or a
fluorine substituent on the arylamino moiety produced
the more active compounds of the series: in fact antalgic
activity was clearly evident in 2c, 2f, 2k and 2l (50.0,
50.6, 51.3 and 50.8% of inhibition), showing an ED50 of
2.2.3. Local anaesthetic activity
According to Bianchi method [18], pain stimulation
was elicited in mice by Dieffenbach tweezers application
for 10 s on the tail root, in groups of ten mice (weight
20ꢀ/25 g) of both sexes, pregnant females excluded. The
41.37 (18.32ꢀ
/
93.44), 37.86 (15.35ꢀ
/
93.35), 33.86 (12.44ꢀ
/
efficacy of local anaesthetic activity was expressed as
percent of animals anaesthetized 5 and 30 min after
infiltration of the test compound (0.2 ml of 0.1%
glycofurol solution) into the tail root respect to lidocaine
(Sigma Aldrich Srl, Milano, Italy) at the same dose. No
compound showed appreciable activity.
92.14) and 40.87 (18.31ꢀ
/
93.43) mg/kg respectively. The
most active compound of the series resulted to be 2i,
bearing p-fluorine substituents on both the phenyl rings,
which produced an inhibition of 52.2% associated to an
ED50 of 33.856 (12.44ꢀ92.14) mg/kg.
/
The achievement of compounds 2 with this interesting
analgesic activity is a good starting point for future
work in this area of research and in this direction we are
going on in our laboratory.
3. Result and discussion
As a general and preliminary consideration com-
pounds 2aꢀl showed a different pharmacological profile
/
than that of the analogues 1.
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of the phenyl ring, showed a fair analgesic activity. The
insertion of another substituent in position 3 of the
arylamino group of compounds 2, produced a strongly
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