Synthesis and anti-inflammatory activity of 1-acylaminoalkyl-3,4- dialkoxybenzene derivatives

Article abstract of DOI:10.1016/j.farmac.2004.12.003

New 1-acylaminoalkyl-3,4-dialkoxybenzene derivatives 17-31 were synthesized by the acylation of amines 9-16 with acyl chlorides. Amines 9-16 were obtained from aryl ketones 1-8. Aryl ketones 1-8 were synthesized by the acylation of corresponding aromatic

Full text of DOI:10.1016/j.farmac.2004.12.003

Il Farmaco 60 (2005) 203–207
http://france.elsevier.com/direct/FARMAC/
Synthesis and anti-inflammatory activity
of 1-acylaminoalkyl-3,4-dialkoxybenzene derivatives
L. Labanauskas a,*, A. Brukstus a, E. Udrenaite a,b, V. Bucinskaite a, I. Susvilo a, G. Urbelis a
a Faculty of Chemistry, Vilnius University, Naugarduko 24, 2006 Vilnius, Lithuania
b Faculty of Medicine, Vilnius University, Naugarduko 24, 2006 Vilnius, Lithuania
Received 21 June 2004; received in revised form 11 December 2004; accepted 28 December 2004
Abstract
New 1-acylaminoalkyl-3,4-dialkoxybenzene derivatives 17–31 were synthesized by the acylation of amines 9–16 with acyl chlorides.
Amines 9–16 were obtained from aryl ketones 1–8. Aryl ketones 1–8 were synthesized by the acylation of corresponding aromatic com-
pounds. As it was preliminary predicted by PASS (Prediction of Activity Spectra for Substance) program, all 1-acylaminoalkyl-3,4-
dimethoxy- and 3,4-diethoxybenzene derivatives possess anti-inflammatory activity. Activity of compounds 18, 19, 21, 24, 26, 27, 28, 29 was
similar to that of acetylsalicylic acid or ibuprofen however their acute toxicity was less than that of mentioned anti-inflammatory drugs.
A series of 1-acylaminoalkyl-3,4-dimethoxybenzene, 1-acylaminoalkyl-3,4-diethoxybenzene and 6-acylaminoalkyl-2,3-dihydro-1,4-
benzodioxine derivatives have been synthesized. These compounds possess moderate or strong anti-inflammatory activity and low toxicity.
© 2005 Elsevier SAS. All rights reserved.
Keywords: 1-Acylaminoalkyl-3,4-dialkoxybenzene derivatives; N-acylation; Anti-inflammatory activity
1. Introduction
spectra—on a BS-587A (80 MHz, Tesla, Czechoslovakia)
with TMS as an internal standard. Chemical shifts (d) are
reported in ppm, coupling constants (J) are given in Hz. All
new compounds were analyzed for C, H and N and the results
were in an acceptable range.
The search of biologically active compounds within the
class of carboxamides is rather popular because of their easy
synthesis and relative stability in biological media.
Amides 17–31 have been synthesized by the acylation of
amines 9–16 treating them with acyl chlorides in trichlo-
romethane solution in presence of triethylamine.Amines 9–16
were obtained by the reaction of ketones 1, 4–8 with forma-
mide in formic acid with further hydrolysis of obtained formy-
lamino derivatives or from aryl ketones 3, 4 by reduction of
their oximes with sodium in boiling butanol. Different ways
of synthesis were used because ketones 3 and 4 were not stable
under conditions of more convenient one step reductive ami-
nation. Aryl ketones 1–8 were synthesized by the acylation
of corresponding aromatic compounds with acyl chlorides in
dichloromethane solution in the presence of aluminum chlo-
ride (Scheme 1). Both means mN-H and mC=O in IR spectra of
synthesized compounds depend on many factors and show
no regularities. The 1H NMR spectral data allow to make some
conclusions about the symmetry of electron density disloca-
tion and conformation of molecules of synthesized com-
pounds. The means of chemical shift of hydrogen atoms of
both CH2O- or both CH3O- groups are equal for both
As a result of our investigations, it was also found out that
a big number of 1,2-dialkoxybenzene derivatives possess high
or moderate anti-inflammatory activity and low acute toxic-
ity [1–3]. Some data on the possibility of anti-inflammatory
activity of 1-acylaminoalkyl-3,4-dialkoxybenzene deriva-
tives were also generated by PASS program [4] and kindly
provided to us by SPECS, Rijswijk, the Netherlands. Due to
this reason, we have performed the synthesis of amides 17–31
and investigated their anti-inflammatory activity in vivo.
2. Chemistry
Melting points were determined in open capillaries and
are uncorrected. The IR spectra were recorded on a FT-IR
Spectrum BX (Perkin-Elmer, Sweden) in Nujol and 1H-NMR
* Corresponding author.
E-mail address: linas.labanauskas@chf.vu.lt (L. Labanauskas).
0014-827X/$ - see front matter © 2005 Elsevier SAS. All rights reserved.
doi:10.1016/j.farmac.2004.12.003

204
L. Labanauskas et al. / Il Farmaco 60 (2005) 203–207
with TMS as an internal standard. Chemical shifts (d) are
reported in ppm. All new compounds were analyzed for C, H
and N and the results were in an acceptable range.
1-(2-Bromo-4,5-dimethoxyphenyl)-1-ethanone (1) [5],
1-(2-chloro-4,5-dimethoxyphenyl)-1-ethanone (2) [5], 1-(2-
ethyl-4,5-dimethoxyphenyl)-1-ethanone (3) [6] and 1-(7-
ethyl-2,3-dihydro-1,4-benzodioxin-6-yl)-1-ethanone (8) [7]
were synthesized by the known methods. Experimental,
physico-chemical and spectral data for compounds 4–7 and
9–31 are given in Table 1.
1-(2-Ethyl-4,5-dimethoxyphenyl)-1-propanone (4), 1-(2-
ethyl-4,5-dimethoxyphenyl)-2-phenyl-1-ethanone (5), 1-(2-
bromo-4,5-diethoxyphenyl)-1-ethanone (6) and 1-(2-chloro-
4,5-diethoxyphenyl)-1-ethanone (7) To a solution of 0.1 mol
of aromatic compound and 0.11 mol of acyl chloride in 20 ml
abs., dichloromethane 0.12 mol (16.0 g) of anhydrous alumi-
num chloride was added portionwise under stirring and at the
temperature –5–0 °C (compounds 4, 5) or 5–10 °C (com-
pounds 6, 7). Reaction mixture was stirred 4 h at room tem-
perature and poured into 150 ml H2O. Dichloromethane solu-
tion was washed with 10% sodium carbonate, dried and
evaporated in vacuo. Obtained products were recrystallized
from 2-propanol.
1-(2-Bromo-4,5-dimethoxyphenyl)ethylamine (9), 1-(2-
chloro-4,5-dimethoxyphenyl)ethylamine (10), 1-(2-benzyl-
4,5-dimethoxyphenyl)ethylamine (13), 1-(2-bromo-4,5-
diethoxyphenyl)ethylamine (14), 1-(2-chloro-4,5-diethoxy-
phenyl)ethylamine
(15),
1-(7-ethyl-2,3-dihydro-1,4-
benzodioxin-6-yl)ethylamine (16) A mixture of 0.07 mol of
compound 1, 2 or 5–8, 13 g (0.28 mol) of formamide, 4 g
(0.07 mol) of 85% formic acid was heated at 170–180 °C for
4 h, cooled to room temperature, triturated with 100 ml of
water and refluxed with conc. HCl 2 h. To the obtained solu-
tion, sodium hydroxide was added to pH 13. Obtained amines
9, 10, 13–16 were extracted with toluene, dried over anhy-
drous sodium sulfate and isolated as hydrochlorides after treat-
ment with anhydrous HCl gas.
1-(2-Ethyl-4,5-dimethoxyphenyl)ethylamine (11), 1-(2-
ethyl-4,5-dimethoxyphenyl)ethylamine (12) A mixture of
0.04 mol of compound 3 or 4, 11.8 g (0.17 mol) hydroxy-
lamine hydrochloride and 120 ml pyridine was heated at
100 °C for 7 h, evaporated in vacuo and triturated with water.
Obtained crystalline oximes were filtered off, dried, dis-
solved in 100 ml of boiling 1-butanol and treated portionwise
with 4.5 g (0.195 mol) of sodium. 1-Butanol was removed in
vacuo. Amines 11 and 12 were extracted with boiling tolu-
ene, cooled, dried over anhydrous sodium sulfate and iso-
lated as hydrochlorides after treatment with anhydrous HCl
gas.
Scheme 1
.
dimethoxybenzene derivatives 4, 26 and cyclic compounds
30, 31 and differ by 0.02–0.09 ppm for all remaining
dimethoxy- and diethoxybenzene derivatives 5–7, 9–25,
27–29. It means that CH2O- and CH3O- groups differ not
only when electron donating (ethyl) and electron withdraw-
ing (carbonyl) groups are attached to the same benzene ring
but also even in the presence of two similar groups (ethyl and
2-aminoethyl) are there. The signal of CH2 in ethyl group is
usually triplet in the case of compounds 4, 5, 25, 26 and it is
multiplet in the case of compounds 11, 12, 19–24. It means
that hydrogen atoms of this group are different due to the
conformation of compounds 11, 12, 19–24. The form of sig-
nal of CH in aminoalkyl group (multiplet both for amines
9–16 and amides 17–31) confirms this conclusion.
3. Experimental
1-Acylaminoalkyl-3,4-dialkoxybenzenes (17–31) A mix-
ture of amine (hydrochloride or free base) 9–16 (0.01 mol),
0.01 mol corresponding acyl chloride, 0.025 mol triethy-
lamine and 20 ml anhydrous trichloromethane was refluxed
for 4 h. Then the reaction mixture was cooled, washed with
water, dried over anhydrous sodium sulfate and evaporated
in vacuo.Acyl derivatives 17–31 were obtained as solids after
crystallization from 2-propanol.
3.1. Chemistry
Melting points were determined in open capillaries and
are uncorrected. The IR spectra were recorded on a FT-IR
Spectrum BX (Perkin-Elmer, Sweden) in Nujol and 1H-NMR
spectra—on a BS-587A (80 MHz, Tesla, Czechoslovakia)

L. Labanauskas et al. / Il Farmaco 60 (2005) 203–207
205
Table 1
Experimental, physico-chemical and spectral data for compounds 4–7 and 9–31
Formula
Yield, M.p.
IR:
1H-NMR:
Compd
(%)
78
(oC)
(cm-1)
4
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
13H18O3
43-44
1679 (C=O) t 1.21 (6H, CH3), k 2.82 and 2.92 (4H, CH2), s 3.91 (6H, OCH3), s 6.72 and 7.15 (2H,
ArH)**
5
18H20O3
85
64
72
75-77
43-45
36-38
1688 (C=O) t 1.15 (3H, CH3), k 2.81 (2H, CH2), s 3.85 and 3.91 (6H, OCH3), s 4.18 (2H, CH2Ph), s
6.72, 7.22 and 7.36 (1H, 5H and 1H, ArH)**
6
12H15BrO3
12H15ClO3
1690 (C=O) t 1.41 (6H, CH3), s 2.53 (3H, COCH3), k 3.95 and 4.01 (4H, OCH2), s 6.81 and 6.95 (2H,
ArH)
7
1681 (C=O) t 1.48 and 1.50 (6H, CH3), s 3.11 (3H, COCH3), k 4.12 and 4.21 (4H, OCH2), s 7.02 (2H,
ArH)***
9
10H15BrClNO2 61
10H15Cl2NO2 56
215-216h 3408 (N-H) d 1.43 (3H, CHCH3), s 4.06 (6H, OCH3), m 5.32-5.64 (1H, CHCH3), s 6.95 and 7.10 (2H,
ArH), br. s 8.91 (NH2*HCl)*
252-254h 3406 (N-H) d 1.55 (3H, CHCH3), s 3.77 and 3.86 (6H, OCH3), m 4.01-4.22 (1H, CHCH3), s 7.09 and
7.83 (2H, ArH), br. s 10.57 (NH2*HCl)*
10
11
12
13
14
15
16
17
18
19
12H20ClNO2
13H21NO2
52
48
58
212-213h 3402 (N-H) t 1.14 (3H, CH2CH3), d 1.50 (3H, CHCH3), s 3.76 and 3.79 (6H, OCH3), m 4.23-4.65 (1H,
CHCH3), s 6.80 and 7.38 (2H, ArH), br. s 8.55 (3H, NH2*HCl)*
oil
3356, 3289
(N-H)
t 0.89 and 1.20 (6H, CH3), qt 1.69 (2H, CHCH2), m 2.30-2.90 (4H, CH2CH3, NH2) k 2.63
(2H, CH2), m 3.95-4.22 (1H, CHCH3), s 6.65 and 6.97 (2H, ArH)**
18H24ClNO2
208-210h 3399 N-H)
t 1.29 (3H, CH2CH3), m m 2.31-2.62 (2H, CH2CH3), m 3.13-3.55 (2H, CH2Ph), s 3.90 and
3.93 (6H, OCH3), m 5.45-5.61 (1H, CHCH3), m 6.83-8.20 (8H, ArH, NH2*HCl)*
12H19BrClNO2 51
12H19Cl2NO2 63
229-231h 3422 (N-H) t 1.32 (9H, CH2CH3), d 1.47 (3H, CHCH3), t 4.02 and 4.08 (4H, OCH2), m 4.26-4.77 (1H,
CHCH3), s 7.15 and 7.58 (2H, ArH), m 8.31-8.94 (NH2*HCl)*
218-220h 3139 (N-H) t 1.26 (9H, CH2CH3), d 1.46 (3H, CHCH3), t 3.97 and 4.04 (4H, OCH2), m 4.23-4.78 (1H,
CHCH3), s 6.85 and 7.49 (2H, ArH), m 8.40-9.04 (NH2*HCl)*
12H18ClNO2
18H20BrNO4
67
83
237-239h 3393 (N-H) t 1.11 (3H, CH2CH3), d 1.46 (3H, CHCH3), m 2.32-2.64 (2H, CH2CH3), t 4.21 (1H,
CHCH3), s 4.23 (4H, OCH2), s 6.71 and 7.21 (2H, ArH), br. s 8.59 (NH2*HCl)*
169-170
168-170
134-135
3317 (N-H); d 1.61 (3H, CHCH3), s 3.88, 3.94 and 3.96 (9H, OCH3), m 5.44-5.65 (1H, CHCH3), s
1632 (C=O) 7.20 and 7.34 (2H, ArH), dd 7.06 and 8.00 (4H, ArH), m 7.85-8.25 (1H, NH)***
3334 (N-H); d 1.64 (3H, CHCH3), s 3.89 and 3.95 (6H, OCH3), t 5.66 (1H, CHCH3), s 7.22 and 7.35
1636 (C=O) (2H, ArH), m 7.40-8.78 (3H, Py), s 9.15 (1H, NH)***
16H17ClN2O3 86
19H23NO3
19H22FNO3
21H27NO4
20H25NO4
22H29NO5
71
82
59
78
54
3324 (N-H); t 1.36 (3H, CH2CH3), d 1.64 (3H, CHCH3), m 2.61-3.02 (2H, CH2CH3), s 3.88 and 3.90
1628 (C=O) (6H, OCH3), m 5.45-5.68 (1H, CHCH3), s 6.88, 7.11 and 7.29 (2H, ArH), m 7.31-8.28
(6H, ArH, NH)***
20
21
22
23
C
C
C
C
113-115
178-180
125-127
165-168
3310 (N-H); t 1.35 (3H, CH2CH3), d 1.64 (3H, CHCH3), m 2.52-2.97 (2H, CH2CH3), s 3.88 and 3.91
1634 (C=O) (6H, OCH3), m 5.45-5.72 (1H, CHCH3), s 6.88 and 7.27 (2H, ArH), m 7.08-8.32 (5H,
ArH, NH)***
3378 (N-H); t 1.08 and 1.34 (6H, CH2CH3), m 1.80-2.23 and 2.52-3.15 (4H, CH2CH3),s 3.87, 3.90 and
1646 (C=O) 3.92 (9H, OCH3), m 5.32-5.65 (1H, CHCH3), s 6.88 and 7.26 (2H, ArH), m 7.05-7.54 (4H,
ArH), m 7.83-8.25 (1H, NH)***
3343 (N-H); t 1.34 (3H, CH2CH3), d 1.63 (3H, CHCH3), m 2.61-3.12 (2H, CH2CH3), s 3.87, 3.90 and
1647 (C=O) 3.94 (9H, OCH3), m 5.45-5.68 (1H, CHCH3), s 6.87 and 7.27 (2H, ArH), dd 7.05 and 7.99
(4H, ArH), br. s 8.00 (1H, NH)***
3307 (N-H); t 1.08 and 1.36 (6H, CH2CH3), m 1.88-2.24 and 2.62-3.15 (4H, CH2CH3), s 3.87, 3.92,
1620 (C=O) 3.91 and 3.95 (12H, OCH3), m 5.20-5.65 (1H, CHCH3), s 6.88 and 7.24 (2H, ArH), m
7.32-8.20 (5H, ArH, NH)***
24
25
26
C
C
C
19H22BrNO3
84
71
65
141-143
157-160
153-155
3309 (N-H); t 1.36 (3H, CH2CH3), d 1.66 (3H, CHCH3), m 2.52-2.94 (2H, CH2CH3), s 3.87 and 3.91
1630 (C=O) (6H, OCH3), m 5.50-5.70 (1H, CHCH3), s 6.89, 7.26, m 7.32-8.20 (5H, ArH, NH)***
3344 (N-H); t 1.27 (3H, CH2CH3), k 2.82 (2H, CH2CH3), m 3.10-3.47 (2H, CH2Ph), s 3.90, 3.91 and
1629 (C=O) 3.93 (9H, OCH3), m 5.50-5.70 (1H, CHCH3), m 6.83-8.20 (14H, ArH, NH)***
3320 (N-H); t 1.28 (3H, CH2CH3), k 2.80 (2H, CH2CH3), m 3.15-3.49 (2H, CH2Ph), s 3.90 (6H,
1635 (C=O) OCH3), m 5.53-5.94 (1H, CHCH3), s 6.85 and m 7.09-8.04 (11H, ArH), m 8.18-8.39 (1H,
NH)***
26H29NO4
25H26BrNO3
27
28
C
18H21BrN2O3 59
148-149
163-165
3319 (N-H); t 1.43 and 1.48 (9H, CH2CH3), d 1.63 (3H, CHCH3), t 4.12 and 4.21 (4H, OCH2), m 5.42-
1636 (C=O) 5.71 (1H, CHCH3), s 7.20 and 7.33 (2H, ArH), m 8.12-9.23 (4H, Py and NH)***
3307 (N-H); t 1.43 and 1.48 (9H, CH2CH3), d 1.60 (3H, CHCH3), s 3.96 (3H, OCH3), t 4.12 and 4.21
1629 (C=O) (4H, OCH2), m 5.50-5.89 (1H, CHCH3), s 7.03 and 7.31 (2H, ArH), dd 7.05 and 8.04 (4H,
ArH), m 7.92-8.31 (1H, NH)***
C
20H24ClNO4
20H24ClNO4
87
85
29
C
149-150
3305 (N-H); t 1.43 and 1.48 (9H, CH2CH3), d 1.62 (3H, CHCH3), s 3.95 (3H, OCH3), t 4.12 and 4.21
1634 (C=O) (4H, OCH2), m 5.47-5.74 (1H, CHCH3), s 7.05 and 7.31 (2H, ArH), m 7.12-7.45 (4H,
ArH), m 7.92-8.32 (1H, NH)***
(continued on next page)

206
L. Labanauskas et al. / Il Farmaco 60 (2005) 203–207
Table 1
(continued)
Formula
Yield, M.p.
IR:
(cm-1)
1H-NMR:
Compd
(%)
82
(oC)
30
C
19H20FNO3
19H20ClNO3
152-155
3329 (N-H); t 1.33 (3H, CH2CH3), d 1.56 (3H, CHCH3), m 2.56-2.98 (2H, CH2CH3), s 4.31 (4H,
1627 (C=O) OCH2), m 5.45-5.63 (1H, CHCH3), s 6.76, 7.11 and 7.52 (6H, ArH), br. s 7.9 (1H, NH)**
3292 (N-H); t 1.33 (3H, CH2CH3), d 1.53 (3H, CHCH3), m 2.68-2.98 (2H, CH2CH3), s 4.33 (4H,
1640 (C=O) OCH2), m 5.42-5.64 (1H, CHCH3), s 6.75, 7.09 (2H, ArH), m 7.52-8.10 (5H, ArH, NH)**
31
C
77
105-108
h Hydrochloride.
Solvent: *DMSO, **CDCl3,***(CD3)2CO;
Coupling: s - singlet, d - doublet (6 Hz for aliphatic hydrogens, 9 Hz for o-ArH and 2 Hz for m-ArH), t - triplet (6 Hz for aliphatic hydrogens);
q - quartet (6 Hz for aliphatic hydrogens); qt - quintuplet (6Hz for aliphatic hydrogens), dd - double doublet (2 and 9 Hz for ArH), m – multiplet
3.2. Pharmacology
3.2.3. Acute toxicity
The tests of acute toxicity of the compounds were done on
mice fasted for 24 h, water ad libitum. Groups of 6 mice were
treated perorally with the test compound at various dose lev-
els. The animals were watched for mortality and symptoms
until 8th day [10].
Adult maleWistar strain rats weighing 180–220 g and male
BALB/C strain mice weighing 18–22 g were used. The ani-
mals were allowed food and water ad libitum. They were
housed in rooms at 18–20 °C with a 12-h light/dark cycle and
relative humidity of 55–60%. The animals were randomly
allocated into groups at the beginning of all the experiments.
All test compounds and the reference drugs were adminis-
tered orally suspended in 0.5% carboxymethylcellulose solu-
tion. The data for activity and toxicity were evaluated statis-
tically using Student’s t-test. A level of P < 0.05 was adopted
for the test of significance.
4. Results and discussion
Anti-inflammatory activity was studied using carrageenin-
and bentonite-induced paw oedema in rats. The inhibition of
oedema was evaluated by the comparison of paw volume mea-
sured with an electronic onkograph immediately before and
1, 2, 3, and 5 h after the injection of carrageenin or bentonite.
Obtained data are given as an arithmetical means of measure-
ments (Table 2).Acetylsalicylic acid and ibuprofen were used
as a reference drugs.
The effects of the development of carrageenin- and
bentonite-induced oedema caused by p.o. administration of
the test compounds as well as the reference drug at a dose of
50 mg/kg are given in Table 2. Each reported value is
expressed as the percentage inhibition of the mean increase
of paw volume in treated animals as compared with untreated
controls. Also the LD50 mg/kg doses are given.
All tested 1,2-dimethoxybenzene derivatives 17–26 and
1,2-diethoxybenzene derivatives 27–29 possess moderate (17,
19–21, 23, 25, 27, 28) or strong (18, 22, 24, 26, 29) anti-
inflammatory activity. Both cyclic analogues—2,3-dihydro-
1,4-benzodioxine derivatives possess week (30) or no (31)
anti-inflammatory activity. The activity of compounds 17,
19–22, 23, 27, 28 is comparable to that of acetylsalicylic acid
or higher and the compounds 18, 24, 26, 27 possess the anti-
inflammatory activity comparable to that of ibuprofen. By
the summarized results of both carragenin and bentonite tests,
compound 29 was more active than ibuprofen. The influence
of substituents in structure of tested compounds is not clearly
expressed, although some observations could be mentioned.
The activity of the derivatives of compound 19 with various
substituents into benzene ring of acyl group was less (4-F,
20) or equal (4-CH3O, 22; 3-CH3O, 24) to that of unsubsti-
tuted compound 19. Benzyl derivative 25 was less active than
its structural analogue 22 containing methyl group. However
benzyl derivative 26 possessed the some activity like their
3.2.1. Carrageenin test
Carrageenin-induced hind-paw oedema in rats was pro-
duced by the method of Winter et al. [8]. Carrageenin solu-
tion (1.0% in sterile 0.9% NaCl solution) in a volume of 0.1 ml
was injected subcutaneously into the subplantar region of the
right hind paw 1 h after the administration of the test com-
pound. Control animals received only 0.5% carboxymethyl-
cellulose solution. Right hind paw volume was measured with
an electronic onkograph immediately before and 1, 2, 3, and
5 h after the carrageenin injection. The cross-section was cal-
culated from the experimental data of these measurements
and was reported in relative units. The increase of results was
matched with that of control rats. The values of arithmetical
means of the measurements at each recording time (1, 2, 3,
5 h) were calculated. Each experiment was made with group
of 10 animals (and one group of 10 animals was a control).
3.2.2. Bentonite test
Bentonite-induced hind paw oedema was studied analo-
gously [9]. Bentonite suspension (5% in sterile 0.9% NaCl
solution) in a volume of 0.1 ml was injected subcutaneously
into the subplantar region of the left hind paw 1 h after the
administration of the test compound. Control animals received
only 0.5% carboxymethylcellulose solution. Left hind paw
volume was measured with an electronic onkograph imme-
diately before and 1, 2, 3, and 5 h after the carrageenin injec-
tion. The increase of results was matched with that of control
rats. The values of arithmetical means of the measurements
at each recording time (1, 2, 3, 5 h) were calculated. Each
experiment was made with group of 10 animals (and one
group of 10 animals was a control).

L. Labanauskas et al. / Il Farmaco 60 (2005) 203–207
207
Table 2
Anti-inflammatory activity (50 mg/kg p.o.) and acute toxicity (LD50) data for compounds 17-31
0.1 ml of 1% carrageenin solution
0.1 ml of 5% bentonite suspension
Cross-section of rat paw Inhibition of rat paw oedema
LD50
Compound
Cross-section of rat paw Inhibition of rat paw oedema
(mg/kg)
(relative units)
85.41
68.84
56.63
60.21
66.02
58.16
62.43
71.83
58.59
65.51
57.05
62.26
67.13
57.75
67.56
81.22
(%) over control
0
(relative units)
82.32
65.12
57.79
59.11
62.72
65.53
58.36
70.22
54.99
68.00
53.34
60.59
63.80
51.78
76.72
82.32
64.54
65.28
(%) over control
0
Control
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
19.4
33.7
29.5
22.7
31.9
26.9
15.9
31.4
23.3
33.2
27.1
21.4
35.9
20.9
4.9
20.9
29.8
28.2
22.6
20.4
29.1
14.7
33.2
17.4
35.2
26.4
22.5
37.1
6.8
>1500
>1500
>1500
>1500
>1500
>1500
0
Acetylsalicylic acid 68.50
Ibuprofen 52.95
19.8
38.0
21.6
20.7
1216
500
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sas, Synthesis of 3-(3,4-dimethoxyphenyl)-1H-1,2,4-triazole-5-thiol and
2-amino-5-(3,4-dimethoxyphenyl)-1,3,4-thiadiazole derivatives exhibit-
ing anti-inflammatory activity, Pharmazie 56 (8) (2001) 617–619.
[3] L. Labanauskas, A. Brukstus, Gaidelis, V. Dauksas, E. Udrenaite,
Synthesis and anti-inflammatory activity of new 6-benzoyl-1,4-
benzodioxane derivatives, Pharm. Chem. J. 33 (5) (1999) 33–34 (rus).
[4] Yu.V. Borodina, D.A. Filimonov, V.V. Poroikov, Computer-aided pre-
diction of prodrug activity using the PASS system, Pharm. Chem. J.
(rus) 30 (1) (1996) 39–42.
[5] P. Gaidelis, V. Dauksas, E. Udrenaite, V. Kuliesius, Synthesis and
anti-inflammatory properties of 1,2-dialkoxy-4-dimethylamino-
propionyl)benzene and their 5-halogeno derivatives, Arzneim.-
Forsch./Drug Res. 44 (II) (7) (1994) 835–839.
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[7] V. Dauksas, E. Udrenaite, R. Martinkus, Synthesis and properties of
6,7-diethyl-5-acetyl-1,4-benzodioxan, Liet. TSR Aukst. Mokyklu
Mokslo Darb., Chem. Chem. Technol. 16 (1974) 181–185 (CA 83
(1975) 206184k).
[8] C.A. Winter, E.A. Risley, G.W. Nuss, Carrageenin-induced oedema in
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(Eds). Prous Science, Barcelona (2001) pp. 403–407
analogue 24 containing methyl group. Dimethoxyphenyl
derivative 20 was more active than their cyclic analogue—2,3-
dihydro-1,4-benzodioxine derivative 30. Ethyl derivative 22
possess higher activity than bromo derivative 17.
Evaluation of acute toxicity of most active compounds (18,
19, 21, 24, 26, 29) showed that all the compounds selected
for this study have low toxicity (LD50 > 1500 mg/kg), i.e. they
are less toxic than acetylsalicylic acid and much less toxic
than ibuprofen (Table 2).
In conclusion, the results of this study demonstrate that
1-acylaminoalkyl-3,4-dialkoxybenzene derivatives are the
subject of further more detailed examination.
5. Activity prediction
Data on the possibility of anti-inflammatory activity of
1-acylaminoalkyl-3,4-dialkoxybenzene derivatives were gen-
erated by PASS program [4] and kindly provided by SPECS,
Rijswijk, the Netherlands. Computerized system PASS pre-
dicts more than 100 pharmacological effects, mechanisms of
action and specific toxicities simultaneously. More informa-
tion on PASS is available in Refs. [11,12] and Internet [13].
Authors are grateful to SPECS company for the permision
for use and publication of prediction results.
References
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biological activity spectra for chemical substances. Bioactive Com-
pound Design: Possibilities for Industrial Use, BIOS Scientific Pub-
lishers, Oxford, 1996, pp. 47–56.
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anti-inflammatorypropertiesof8-(3-dimethylamino-propionyl)-1,6-benzo-
dioxokane, Arzneim.-Forsch./Drug Res. 45 (II) (11) (1995) 1202–1206.
[13] http://www.ibmh.msk.su/PASS/Ref.html.