Evaluation of anti-inflammatory, anti-nociceptive, and anti-ulcerogenic activities of novel synthesized thiazolyl and pyrrolyl steroids

Article abstract of DOI:10.1002/ardp.201000366

Developing new therapeutic agents that can overcome gastrointestinal injury and at the same time could lead to an enhanced anti-inflammatory effect becomes an urgent need for inflammation patients. Thiazolyl and pyrrolyl steroids were synthesized via straight forward and efficient methods and their structures were established based on their correct elemental analysis and compatible IR, ¹H-NMR, ¹³C-NMR, and mass spectral data. The dihydrothiazolyl-hydrazonoprogesterone 12 and the aminopyrrolylprogesterone 16a showed anti-inflammatory, antinociceptive, and anti-ulcerogenic activity with various intensities. Edema were significantly reduced by both doses of tested compounds (25 and 50 mg/kg) at 2, 3, and 4 h post-carrageenan. The high dose of compound 16a was the most effective in alleviating thermal pain. Gastric mucosal lesions, caused in the rats by the administration of ethanol or indomethacin (IND), were significantly inhibited by each of the two tested compounds. These results provide a unique opportunity to develop new anti-inflammatory drugs which devoid the ulcerogenic liabilities associated with currently marketed drugs. Novel steroid hybrids incorporating the pyrrole or thiazole moiety through different linkages have been developed. The modified steroids 12 and 16a showed anti-inflammatory, anti-nociceptive, and/or non-ulcerogenic activities. These encouraging results may be of interest for finding new potent prescriptions. Copyright

Full text of DOI:10.1002/ardp.201000366

Arch. Pharm. Chem. Life Sci. 2011, 344, 595–604
595
Full Paper
Evaluation of Anti-inflammatory, Anti-nociceptive, and
Anti-ulcerogenic Activities of Novel Synthesized Thiazolyl
and Pyrrolyl Steroids
Rafat M. Mohareb1,2, Gamal A. Elmegeed3, Ayman R. Baiuomy4,5, Emad F. Eskander3,
and Marian G. William3,6
1 Organic Chemistry Department, Faculty of Pharmacy, October University of Modern Sciences and Arts
(MSA), Elwahaat Road, October City, Egypt
2 Chemistry Department, Faculty of Science, Cairo University, Cario, Egypt
3 Hormones Department, National Research Centre, Dokki, Cairo, Egypt
4 Pharmacology Department, National Research Centre, Dokki, Cairo, Egypt
5 Faculty of Medicine and Medical Sciences, Taif University, KSA
6 Blessing and mercy to the soul of our dear fellow (late) Marian G. William.
Developing new therapeutic agents that can overcome gastrointestinal injury and at the same time
could lead to an enhanced anti-inflammatory effect becomes an urgent need for inflammation patients.
Thiazolyl and pyrrolyl steroids were synthesized via straight forward and efficient methods and
their structures were established based on their correct elemental analysis and compatible IR,
1H-NMR, 13C-NMR, and mass spectral data. The dihydrothiazolyl-hydrazonoprogesterone 12 and
the aminopyrrolylprogesterone 16a showed anti-inflammatory, antinociceptive, and anti-ulcerogenic
activity with various intensities. Edema were significantly reduced by both doses of tested compounds
(25 and 50 mg/kg) at 2, 3, and 4 h post-carrageenan. The high dose of compound 16a was the most
effective in alleviating thermal pain. Gastric mucosal lesions, caused in the rats by the administration of
ethanol or indomethacin (IND), were significantly inhibited by each of the two tested compounds. These
results provide a unique opportunity to develop new anti-inflammatory drugs which devoid the
ulcerogenic liabilities associated with currently marketed drugs.
Keywords: Anti-inflammatory / Anti-nociceptive / Non-ulcerogenic / Pyrrole / Steroids / Thiazoles
Received: November 25, 2010; Revised: February 11, 2011; Accepted: February 16, 2011
DOI 10.1002/ardp.201000366
Introduction
complications arising from the steroid therapy have imposed
limitations on the clinical use of this class of drugs [1]. A
considerable research effort has been devoted to the structural
modifications of glucocorticoids, with the hope of increasing
their potencies while minimizing their propensity to elicit
systemic adverse effects [2, 3].
Steroids have attracted much attention because of their wide
spectrum of special biological activities. They can regulate a
variety of biological processes and thus can be processed as
drugs for treatment of many diseases. Glucocorticoids (GC)
are widely used for the treatment of chronic inflammatory
diseases such as asthma, rheumatoid arthritis, inflammatory
bowel disease and autoimmune diseases. Although the
beneficial effects of GC in the management of inflammatory
and allergic conditions have been appreciated for over 50 years,
Modified steroids have attracted a great deal of attention.
Their preparation is a stimulating challenge to the organic
chemist, often demanding development of new and generally
useful reactions. Moreover, the biological properties of modi-
fied steroids have proved to be of interest [4–6]. There has been
considerable interest in the synthesis and biological study of
several heterocyclic steroids as high potent anti-inflammatory
agents [7–9]. The incorporation of an azole ring to the 2,3-
positions of various steroids was effective in the production of
a variety of compounds possessing anti-inflammatory proper-
Correspondence: Gamal A. Elmegeed, Hormones Department, National
Research Center, 12622 Dokki, Cairo, Egypt.
E-mail: gamalae@hotmail.com
Fax: þ2 02 33370931
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Arch. Pharm. Chem. Life Sci. 2011, 344, 595–604
ties [10, 11]. Developing new therapeutic agents that can over-
come gastrointestinal injury and at the same time could lead
to an enhanced anti-inflammatory effect becomes an urgent
need for inflammation patients.
by intramolecular cyclization to afford compound 8 in 81%
yield (Scheme 1). Under the same experimental conditions,
compound 5 reacted also with either chloroacetone 9 or a-
bromoacetophenone 11 to afford the corresponding dihydro-
thiazolylhydrazonoprogesterone derivatives 10 and 12, respec-
tively (Scheme 1). The proposed structures of compounds 8, 10,
and 12 were confirmed based on their correct analytical data
In light of the above discoveries, and in continuation of
studies involving the synthesis of novel biologically active
modified steroids [9, 12, 13]. In the present study, some novel
steroid hybrids incorporating the pyrrole or thiazole moiety
through different linkages have been developed and it is
expected to exhibit anti-inflammatory, anti-nociceptive,
and/or non-ulcerogenic activities.
1
and compatible IR, H-NMR, 13C-NMR, and mass spectra data
(see Section Materials and Methods). For example the 13C-NMR
spectrum of compound 12 showed signals at d ¼ 76.4 (d), 102.0
(d), 134.7 (s) (C-thiazole), 117.4 (d), 129.0 (d), 113.6 (d), 144.7 (s),
134.6 (s), 126.4 (d), 128.5 (d), 120.3 (d) (C-phenyl).
Results and discussion
The reaction of 20-hydrazonoprogestrone
3
with
equimolar amount of a-bromoacetophenone 11 in refluxing
dioxane/piperidine solution afforded the corresponding 20-
(20-oxo-20-phenylethylhydrazono)progesterone derivative 13
in 70% yield (Scheme 2). The behavior of compound 13
towards some active methylene reagents was investigated
in the aim of forming new pyrrolyl steroids. Thus, compound
13 reacted with either malononitrile 14a or ethyl cyano-
acetate 14b to afford the corresponding aminopyrrolyl-
progesterone derivatives 16a in 82% and 16b in 81% yield,
respectively (Scheme 2). The reaction takes place via the non-
isolable intermediates 15a and 15b, respectively, which
readily undergo intramolecular cyclization to afford the
isolated products 16a and 16b. All the elemental and spectral
data of the latter products are in accordance with proposed
structures (see Section Materials and Methods).
Chemistry
The present study was designed to synthesize new steroidal
heterocyclic derivatives with structures justifying non-
ulcerogenic, anti-inflammatory, and/or anti-nociceptive
activities. Pyrroles and azoles represent molecular frame-
works that serve as platform for developing pharmaceutical
agents for various applications. Many derivatives of these
rings proved to be anti-inflammatory and/or anti-nociceptive
agents [14–16].
The reactivity of progesterone (1) towards hydrazines was
studied in the aim to form amino steroids. Thus, progester-
one reacted with hydrazine hydrate 2 (70%) in refluxing
absolute ethanol/acetic acid solution to form 20-hydrazono-
progesterone 3 in 80% yield (Scheme 1). The reaction of
compound 3 with equimolar amount of phenylisothio-
cyanate 4 under reflux in absolute ethanol/triethylamine
solution gave the corresponding 20-phenylthiosemicarba-
zono-progesterone 5 (Scheme 1). The structure of compound
5 was established based on its elemental and spectral data.
The IR spectrum revealed the presence of two NH groups
Anti-inflammatory Assay
The effect of systemic injection of the newly modified
steroids 12 or 16a on edema formation was studied using
a carrageenan induced paw inflammation. Each compound
was injected subcutaneously (s.c.), in either one of two doses
(25 and 50 mg/kg), 30 min before sub-planter carrageenan.
Each of the two tested compounds decreased paw edema in
dose dependent manner compared to control group (pre-
drug) (Table 1). Indomethacin (IND) was given at 18 mg/
kg, s.c., 30 min before carrageenan as positive control.
Data are expressed as mean ꢁ S.E., n ¼ 6 per group. The
values in parenthesis in Table 1 indicate the percentage
(%) of increase in paw volume (edema) from basal (zero time)
values.
stretching at n ¼ 3590–3350 cmꢀ1 and C S stretching at
–
–
n ¼ 1195 cmꢀ1. Moreover, the 1H-NMR spectrum of com-
pound 5 showed a multiple signal at d ¼ 7.15–7.38 ppm
(5H) for the aromatic protons and showed also two D2O-
exchangeable singlets at d ¼ 9.19 and 9.45 ppm for the
two NH protons. The 13C-NMR showed, beside the expected
–
–
signals due to the steroid moiety, signals at d ¼ 186.0 (s, C S),
137.4 (s), 126.4 (d), 129.5 (d), 123.3 (d) (C-phenyl). The mass
spectrum of compound 5 showed molecular ion peak
(Mþ þ 1) at m/z ¼ 464 (38%).
The edema response was significantly reduced by the
administration of compound 12 at a low dose of 25 mg/kg
compared with the control group at 2, 3 and 4 h post-
carrageenan (ꢀ29, ꢀ37.8, ꢀ42.9%). The higher dose
(50 mg/kg) significantly inhibited edema by ꢀ34.2, ꢀ34.6,
and ꢀ42.6% at 2-h, 3-h, and 4-h time points, respectively.
On the other hand, the small dose of compound 16a
inhibited the edema response by ꢀ27.4 and ꢀ38.7 at 3 and
4h post-carrageenan. Also the higher dose inhibited the
The azole moiety often shows some special biological
activity when it is incorporated to some biologically active
compounds [17, 18]. The basicity and hydrophilicity of an
azole in theory might alter the biological function of a
steroid [19]. The reaction of compound 5 with ethyl chloro-
acetate 6 in absolute ethanol afforded the corresponding
dihydrothiazolylhydrazonoprogesterone derivative 8. The reac-
tion takes place via the intermediacy of compound 7 followed
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597
Scheme 1. Synthesis of compounds 3, 5, 8,
10 and 12.
edema response by ꢀ30.3, ꢀ39.2% at 3-h and 4-h time points
effect was marked with compounds 12 at 25 mg/kg and
compound 16a at 50 mg/kg with increase in hot-plate latency
by 36.0% and 46.0% after one hour of drug administration
(Table 2, Fig. 2).
(Fig. 1).
Tests of Anti-nociceptive Studies
Effect of tested compounds on thermal pain
The hot plate latency was significantly increased denoting
analgesic effect after one hour of the administration of com-
pounds 12 or 16a at both doses administered (25 and 50 mg/kg)
compared to the saline treated group. The anti-nociceptive
Effect of tested compounds on acetic acid-induced writhing
Each of compounds 12 and 16a significantly reduced the
number of abdominal writhes induced by i.p. administration
of dilute acetic acid in mice (Table 3, Fig. 3). The degree of
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R. M. Mohareb et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 595–604
Scheme 2. Synthesis of compounds 13 and
16a,b.
inhibition of the writhing response by these compounds
ranged from ꢀ55.0% to ꢀ77.5% as compared to the saline-
treated control group. The higher dose (50 mg/kg) of either of
compound or and 16a was the more effective in this respect.
The degree of inhibition of the writhing response of the high
dose of compound 16a (ꢀ77.5%) was significantly higher than
that of IND (ꢀ52.5%).
Carrageenan control
+ 12 (25 mg/kg)
+ 12 (50 mg/kg)
140
120
100
80
+ 16a (25 mg/kg)
+ 16a (50 mg/kg)
+ Indomethacin (18 mg/kg)
*
*
Testes of Gastric Ulcerogenic Studies
*
*
*
In order to evaluate the potential anti-ulcerogenic properties
of the tested compounds 12 and 16a, we examined the effect
of the high dose (50 mg/kg) on the development of gastric
mucosal lesions caused by ethanol or the non-steroidal anti-
inflammatory drug IND. The number and severity of gastric
mucosal lesions caused in the rats by the administration of
96% ethanol (Table 4, Fig. 4) or IND (Table 5, Fig. 5) were
significantly inhibited by either one of the two tested com-
pounds administered at a 50 mg/kg dose in the study.
*
60
*
40
20
0
0
1
2
3
4
5
Time (h)
Figure 1. Effect of tested compounds on the carrageenan paw
edema formation. Tested compounds were given (25 and
50 mg kgS1, i.p.) 30 min prior to carrageenan injection and ratswere
evaluated for paw edema at 1, 2, 3, and 4 h post carrageenan. The
results are expressed as a percentage change from control (pre-
drug) values, each point represents the mean ꢁ S.E. of six rats per
group. Asterisks indicate significant change from the control group at
the corresponding time point.
Materials and methods
Synthetic methods, analytical and spectral data
Starting steroid, progesterone, was purchased from Sigma
Company, USA. All solvents were dried by distillation
prior to using. All melting points were measured using
an Electrothermal apparatus and are uncorrected. The IR
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Arch. Pharm. Chem. Life Sci. 2011, 344, 595–604
Novel Thiazolyl and Pyrrolyl Steroids
599
Table 1. The anti-inflammatory effect of the tested compounds on carrageenan induced paw edema
Group
Basal
1 h
2 h
3 h
4 h
Control (saline)
12 (25 mg/kg)
12 (50 mg/kg)
16a (25 mg/kg)
16a (25 mg/kg)
IND (18 mg/kg)
0.28 ꢁ 0.006
0.34 ꢁ 0.014
0.32 ꢁ 0.009
0.311 ꢁ 0.007
0.318 ꢁ 0.004
0.288 ꢁ 0.004
0.53 ꢁ 0.02
(88.3 ꢁ 7.0)
0.527 ꢁ 0.03
(56.2 ꢁ 4.3)ꢂ
0.50 ꢁ 0.04
(56.8 ꢁ 5.1)
0.568 ꢁ 0.032
(84.1 ꢁ 5.1)
0.61 ꢁ 0.01
(92.7 ꢁ 5.2)
0.48 ꢁ 0.02
(67.4 ꢁ 5.6)ꢂ
0.6 ꢁ 0.018
(107.8 ꢁ 7.6)
0.600 ꢁ 0.016
(76.5 ꢁ 5.0)
0.59 ꢁ 0.013
(112.2 ꢁ 7.3)
0.58 ꢁ 0.024
(69.8 ꢁ 4.1)ꢂ
0.556 ꢁ 0.014
(73.4 ꢁ 4.6)ꢂ
0.565 ꢁ 0.017
(81.5 ꢁ 5.1)ꢂ
0.56 ꢁ 0.021
(78.2 ꢁ 6.0)ꢂ
0.435 ꢁ 0.019
(51.4 ꢁ 4.3)ꢂ
0.60 ꢁ 0.013
(113.3 ꢁ 8.4)
0.555 ꢁ 0.010
(64.7 ꢁ 4.8)ꢂ
0.528ꢁ 0.008
(65.0 ꢁ 5.4)ꢂ
0.526 ꢁ 0.004
(69.5 ꢁ 4.2)ꢂ
0.54 ꢁ 0.01
0.547 ꢁ 0.02
(70.9 ꢁ 7.5)ꢂ
0.613 ꢁ 0.014
(97.1 ꢁ 4.6)
0.601 ꢁ 0.021
(89.5 ꢁ 6.8)
(68.9 ꢁ 5.3)ꢂ
0.415 ꢁ 0.015
(44.4 ꢁ 2.9)ꢂ
0.47 ꢁ 0.01
(64.6 ꢁ 4.10)ꢂ
Results are expressed as percentage change for control (pre-drug) values. Data are expressed as mean ꢁ S.E., n ¼ 6 rats/group. Asterisks
indicate significant change from control value. The s.c. administration of all tested compounds inhibited the carrageenan induced
paw edema (two-way ANOVA; treatment effect: F13,280 ¼ 30; P < 0.001; time effect: F3,280 ¼ 23.8; P < 0.001, time x drug effect:
F39,280 ¼ 3; P < 0.001). The values in parenthesis indicate the percentage (%) of increase in paw volume from basal (zero time) values.
spectra were recorded in (KBr discs) on a shimadzu FT-IR 8201
PC spectrometer and expressed in cmꢀ1. The 1H-NMR and
13C-NMR spectra were recorded with Jeol instrument (Japan),
at 270 and 125 MHz, respectively, in DMSO-d6 or CDCl3 as
solvent and chemical shifts were recorded in ppm relative
to TMS. The spin multiplicities were abbreviated by the
letters: s – singlet, d – doublet, t – triplet, q – quartet,
and m – multiplet (more than quartet). Mass spectra were
recorded on a GCMS-QP 1000 Ex spectra mass spectrometer
operating at 70 eV. Elemental analyses were carried out by
the Microanalytical Data Unit at the National Research
Center, Giza, Egypt and the Microanalytical Data Unit at
Cairo University, Giza, Egypt. The reactions were monitored
by thin layer chromatography (TLC) which was carried out
using Merck 60 F254 aluminum sheets and visualized by UV
light (254 nm). The mixtures were separated by preparative
TLC and gravity chromatography. For the nomenclature of
steroid derivatives, we used the definitive rules for the
nomenclature of steroids published by the Joint
Commission on the Biochemical Nomenclature (JCBN) of
IUPAC [20, 21]. All described compounds showed the charac-
teristic spectral data of cyclopentanoperhydrophenanthrene
nuclei of pregnene series and were similar to those reported
in literatures [22, 23].
Synthesis of 20-hydrazonopregn-4-en-3-on (3)
To a mixture of compound 1 (0.65 g, 2 mmol) and hydrazine
hydrate (70%) 2 (0.1 g, 2 mmol) in absolute ethanol (30 mL),
glacial acetic acid (3.0 mL) was added. The reaction mixture
Table 2. Percentage increase in hot plate latency in mice treated
with tested compounds in comparison with tramadol
Drug
0 time (basal)
1 h
% Change
Saline
13.2 ꢁ 0.6
14.25 ꢁ 0.51
12.2 ꢁ 0.64
13.55 ꢁ 1.2
13.0 ꢁ 1.1
14.65 ꢁ 1.1
19.38 ꢁ 1.4
16.48 ꢁ 1.2
18.28 ꢁ 1.1
18.98 ꢁ 0.9
20.3 ꢁ 1.6
12 (25 mg/kg)
12 (50 mg/kg)
16a (25 mg/kg)
16a (50 mg/kg)
Tramadol (20 mg/kg)
36.0ꢂ
35.1ꢂꢂ
34.9ꢂꢂ
46.0
Figure 2. Reaction time on the hot- plate in seconds after the
administration of tested compounds at doses of 25 and 50 mg/kg.
Shown are basal (pre-drug: first column) and 60 min (post-drug:
second column) values. The percentage change from basal (pre-
drug) values is shown (n ¼ 6/group). Asterisks indicate significant
change from the saline control group at the respective time point
(ANOVA and Duncan’s multiple comparison tests).
12.86 ꢁ 1.1
57.9ꢂꢂ
Data are expressed as mean ꢁ S.E., n ¼ 6 per group.
ꢂ
ꢂꢂ
¼ P < 0.05, ¼ P < 0.01 vs. corresponding basal values.
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Table 3. Effect of tested compounds on the number of writhes in
the acetic acid test in mice
Group
Number of abdominal
constrictions/30 min
% Inhibition vs.
control
Saline
80.0 ꢁ 5.3
36.0 ꢁ 3.5ꢂ
18.0 ꢁ 1.4ꢂ
35.0 ꢁ 2.7ꢂ
28.0 ꢁ 3ꢂ
12 (25 mg/kg)
12 (50 mg/kg)
16a (25 mg/kg)
16a (50 mg/kg)
IND (18 mg/kg)
55.0%
77.5%
56.3%
65.0%
52.5%
38 ꢁ 2.8ꢂ
Data are expressed as means and S.E.M. (n ¼ 6/group). IND: indo-
ꢂ
methacin. ¼ P < 0.05 vs. control values.
Figure 4. Effect of test compounds administrated at 50 mg/kg, on
the number and severity of gastric mucosal lesions caused by s.c.
injection of EtOH (96%) in rats. The percentage decrease in the
number or severity of gastric lesions from the EtOH (96%) control
group is represented above the respective group bar. Asterisks indi-
cate significant change from the corresponding EtOH (96%) control
group (ANOVA and Duncan’s multiple comparison tests).
was heated under reflux for 3 h until all the reactants had
disappeared as indicated by TLC. The reaction mixture was
left to cool at room temperature, poured over ice/water
mixture and extracted with diethyl ether (3 ꢃ 20 mL). The
organic layer was dried over anhydrous calcium chloride.
Removal of the solvent in vacuo afforded the corresponding
product, which was crystallized from dioxane to give pale
brown crystals of compound 3, yield 0.52 g (80%), mp 175–
Figure 3. Effect of tested compounds on acetic acid-induced wri-
thing. Test compounds were administered at 25 and 50 mg/kg and
the number of abdominal writhes induced by i.p. injection of acetic
acid in mice was determined over 30 min period (mean ꢁ S.E. of 6
mice/group). The percent decrease in the number of writhes from the
saline control group is represented above the respective group bar.
Asterisks indicate significant change from the saline control group
(ANOVA and Duncun’s multiple comparison tests).
1778C, IR (KBr, cmꢀ1): n ¼ 3342 (NH2), 2956–2878 (CH-aliphatic),
1
–
–
–
1702 (C-3, C O), 1668 (C N). H-NMR (DMSO-d , ppm): d ¼ 0.87
–
6
(s, 3H, CH3-19), 1.09 (s, 3H, CH3-18), 1.38 (s, 3H, CH3), 6.24 (s, 2H,
NH2, D2O-exchangeable). 13C-NMR (DMSO-d6, ppm): d ¼ 19.1
(t, C-1), 37.0, (t, C-2), 198.8 (s, C-3), 124.3 (d, C-4), 160.9 (s, C-5),
35.7 (t, C-6), 31.0 (t, C-7), 37.4 (d, C-8), 41.3 (d, C-9), 43.0 (s, C-10),
24.9 (t, C-11), 36.2 (t, C-12), 42.7 (s, C-13), 56.0 (d, C-14), 27.6
Table 4. Effect of the tested compounds on gastric mucosal injury
caused by 96% ethanol in rats
Table 5. Effect of the tested compounds on gastric mucosal injury
caused by indomethacin in rats
Group
Number of
lesions/rat
Severity of
lesions/rat
Group
Number of
lesions/rat
Severity of
lesions/rat
Ethanol control
Ethanol þ 12
Ethanol þ 16a
20.6 ꢁ 2.1
2.4 ꢁ 0.7ꢂ
2.4 ꢁ 1.5ꢂ
63.8 ꢁ 4.0
3.6 ꢁ 1.1ꢂ
3.2 ꢁ 1.9ꢂ
IND (control)
IND þ 12
3.6 ꢁ 0.6
1.2 ꢁ 0.7ꢂ
2.0 ꢁ 0.4ꢂ
5.3 ꢁ 0.8
1.8 ꢁ 0.9ꢂ
2.6 ꢁ 0.5ꢂ
IND þ 16a
Statistical comparison of the difference between the ethanol
ꢂcontrol group and other treated groups is indicated by asterisks;
¼ P < 0.05, NS ¼ not significant vs. control values.
Statistical comparison of the difference between the indometha-
cin (IND) control group and other treated groups is indicated by
asterisks; ¼ P < 0.05 vs. control values
ꢂ
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Novel Thiazolyl and Pyrrolyl Steroids
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18), 464 (Mþ þ 1, 38), 312 (60), 272 (40), 92 (100). Calcd.
for C28H37N3OS (463.678): C, 72.53; H, 8.04; N, 9.06; S, 6.92;
found: C, 72.76; H, 8.26; N, 9.27; S, 6.75%.
Synthesis of 20-thiazolylhydrazonopregn-4-ene-3-one
derivatives (8, 10, and 12)
To a solution of compound 5 (0.92 g, 2 mmol) in absolute
ethanol (30 mL) either ethylchloroacetate 6 (0.24 g, 2 mmol),
chloroacetone 9 (0.18 g, 2 mmol), or a-bromoacetophenone
11 (0.4 g, 2 mmol) were added. The reaction mixture was
heated under reflux for 6–8 h until all the reactants mixture
had disappeared as indicated by TLC. The reaction mixture was
left to cool at room temperature, poured over an ice/water
mixture and neutralized with dilute hydrochloric acid and
extracted with anhydrous diethyl ether (3–4 ꢃ 20 mL). The
organic layer was dried over anhydrous calcium chloride.
Removal of the solvent in vacuo afforded the corresponding
product, which was crystallized from the appropriate solvent.
Figure 5. Effect of tested compounds administrated at 50 mg/kg on
the number and severity of gastric mucosal lesions caused by s.c.
injection of IND in rats. The percentage decrease in the number or
severity of gastric lesions from the indomethacin (IND) control group
is represented above the respective group bar. Asterisks indicate
significant change from the corresponding IND control group
(ANOVA and Duncan’s multiple comparison tests).
20-[(40-Hydroxy-30-phenyl-20,30-dihydrothiazol-20-yl)-
hydrazono]pregn-4-ene-3-one (8)
Orange crystals from absolute ethanol, yield 0.81 g (81%),
mp 96–988C, IR (KBr, cmꢀ1): n ¼ 3495–3415 (NH, OH), 3035
–
(CH-aromatic), 2985, 2875 (CH-aliphatic), 1710 (C-3, C O),
–
(t, C-15), 23.8 (t, C-16), 30.2 (d, C-17), 23.1 (q, C-18), 24.8 (q, C-19),
164.0 (s, C-20), 13.7 (q, C-21). MS (EI): m/z (%): 328 (Mþ, 29), 313
(Mþ-CH3), 271 (C19H27O, 100). Calcd. for C21H32N2O (328.491):
C, 76.78; H, 9.82; N, 8.53; found: C, 76.52; H, 9.53; N, 8.35%.
1663 (C N), 1635 (C C); 1H-NMR (DMSO-d6, ppm): 0.78
–
–
–
–
(s, 3H, CH3-19), 0.97 (s, 3H, CH3-18), 1.13 (s, 3H, 21-CH3),
4.82 (s, 1H, thiazole 20-H), 5.23 (s, 1H, OH, D2O-exchangable),
5.80 (s, 1H, C4-H), 6.45 (s, 1H, thiazole 50-H), 7.52–7.72
(m, 5H, C6H5), 9.27 (s, 1H, NH, D2O-exchangeable). MS (EI):
m/z (%): 507 (Mþ þ 2, 14), 505 (Mþ, 34), 490 (Mþ-CH3, 32), 328
(Mþ-C9H7NOS, 100), 77 (63). Calcd. for C30H39N3O2S (505.276):
C, 71.25; H, 7.77; N, 8.31; S, 6.34; found: C, 71.52; H, 7.52;
N, 8.56; S, 6.16%.
Synthesis of hydrazono-N-phenylmethanethioamide-pregn-
4-en-3-one (5)
A mixture of equimolar amounts of compound 3 (0.65 g,
2 mmol) and phenylisothiocyanate 4 (0.27 g, 2 mmol) in
dioxane (30 mL), containing a catalytic amount of pipredine
(0.5 mL) was heated under reflux for 4 h until all the reac-
tants mixture had disappeared as indicated by TLC. The
reaction mixture after cooling at room temperature was
poured into ice/water mixture and neutralized with dilute
hydrochloric acid. The formed solid product was filtered off,
dried, and crystallized from absolute ethanol to yield 0.71 g
(78%) of compound 5, yellowish brown crystals, m.p. 190–
1928C, IR (n, cmꢀ1): 3590–3350 (2 NH), 3050 (CH-aromatic),
20-[(40-Methyl-30-phenyl-20,30-dihydrothiazol-20-yl)-
hydrazono]pregn-4-ene-3-one (10)
Brown crystals from dioxane, yield 0.82 g (82%), mp 132–
1348C, IR (KBr, cmꢀ1): n ¼ 3435 (NH), 3038 (CH-aromatic),
–
–
–
2980, 2872 (CH-aliphatic), 1704 (C-3, C O), 1667 (C N),
–
1618 (C C); 1H-NMR (DMSO-d6, ppm): d ¼ 0.82 (s, 3H, CH3-
–
–
19), 1.02 (s, 3H, CH3-18), 1.16 (s, 3H, 21-CH3), 1.29 (s, 3H, 40-
CH3), 5.02 (s, 1H, thiazole 20-H), 5.68 (s, 1H, C4-H), 6.42 (s, 1H,
thiazole 50-H), 7.32–7.67 (m, 5H, C6H5), 9.27 (s, 1H, NH, D2O-
exchangeable). MS (EI): m/z (%): 505 (Mþ þ 2, 23), 503 (Mþ, 54),
489 (Mþ-CH3, 30), 271 (C19H27O, 55), 77 (100). Calcd.
for C31H41N3OS (503.741): C, 73.91; H, 8.20; N, 8.34; S, 6.37;
found: C, 73.69; H, 8.03; N, 8.60; S, 6.18%.
–
–
2985, 2864 (CH-aliphatic), 1715 (C O), 1645 (C N), 1595
–
–
1
–
–
–
(C C), 1195 (C S). H-NMR (CDCl , ppm): 0.75 (s, 3H, CH -19),
–
3
3
0.92 (s, 3H, CH3-18), 1.15 (s, 3H, 21-CH3), 5.78 (s, 1H, C4-H), 7.15–
7.38 (m, 5H, C6H5), 9.19, 9.45 (2 s, 2H, 2 NH, D2O-exchangeable).
13C-NMR (CDCl3, ppm): d ¼ 21.2 (t, C-1), 36.4, (t, C-2), 197.4
(s, C-3), 124.0 (d, C-4), 158.9 (s, C-5), 35.3 (t, C-6), 32.3 (t, C-7),
37.7 (d, C-8), 42.3 (d, C-9), 45.2 (s, C-10), 26.9 (t, C-11), 36.3
(t, C-12), 42.8 (s, C-13), 57.2 (d, C-14), 27.8 (t, C-15), 23.2
(t, C-16), 31.2 (d, C-17), 23.2 (q, C-18), 24.3 (q, C-19), 156.0
20-[(40,30-Diphenyl-20,30-dihydrothiazol-20-yl)-
hydrazono]pregn-4-ene-3-one (12)
–
(s, C-20), 13.9 (q, C-21), 186.0 (s, C S), 137.4 (s), 126.4 (d),
–
Yellowish brown crystals from absolute ethanol, yield 0.79 g
(78%), mp 127–1288C, IR (KBr, cmꢀ1): n ¼ 3443 (NH), 3042 (CH-
129.5 (d), 123.3 (d) (C-phenyl). MS (EI): m/z (%): 465 (Mþ þ 2,
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–
aromatic), 2983, 2868 (CH-aliphatic), 1709 (C-3, C O), 1665
20-[10-(2 00-Amino-3 00-cyano-400-phenyl-1’’H-pyrrol-17-yl)-
ethylidenamino]pregn-4-en-3-on (16a)
–
1
–
–
–
(C N), 1603 (C C); H-NMR (DMSO-d , ppm): d ¼ 0.85 (s, 3H,
–
6
CH3-19), 1.04 (s, 3H, CH3-18), 1.18 (s, 3H, 21-CH3), 5.12 (s, 1H,
thiazole 20-H), 5.73 (s, 1H, C4-H), 6.50 (s, 1H, thiazole 50-H),
6.92–7.60 (m, 10H, 2C6H5), 9.92 (s, 1H, NH, D2O-exchange-
able). 13C-NMR (DMSO-d6, ppm): d ¼ 35.2 (t, C-1), 34.7, (t, C-2),
198.2 (s, C-3), 124.6 (d, C-4), 171.9 (s, C-5), 32.7 (t, C-6),
31.3 (t, C-7), 35.4 (d, C-8), 51.3 (d, C-9), 37.8 (s, C-10), 22.5
(t, C-11), 35.4 (t, C-12), 42.2 (s, C-13), 56.3 (d, C-14), 27.4
(t, C-15), 23.5 (t, C-16), 32.8 (d, C-17), 21.1 (q, C-18), 22.7
(q, C-19), 164.4 (s, C-20), 18.20 (q, C-21), 76.4 (d), 102.0 (d),
134.7 (s) (C-thiazole), 117.4 (d), 129.0 (d), 113.6 (d), 144.7 (s),
134.6 (s), 126.4 (d), 128.5 (d), 120.3 (d) (C-phenyl). MS (EI): m/z (%):
567 (Mþ þ 2, 10), 566 (Mþ þ 1, 45), 550 (Mþ-CH3, 32), 271
(C19H27O, 67), 77 (100). Calcd. for C36H43N3OS (565.312):
C, 76.42; H, 6.77; N, 7.43; S, 5.67; found: C, 76.69; H, 7.01;
N, 7.63; S, 5.82%.
Brown crystals from ethanol (70%), yield 0.81 g (82%),
mp 230–2328C, IR (KBr, cmꢀ1): n ¼ 3353 (NH2), 2947–2875
–
–
–
(CH-aliphatic), 2225 (CN), 1697 (C-3, C O), 1647 (C N), 1612
–
–
–
(C C). 1H-NMR (CDCl3, ppm): d ¼ 0.98 (s, 3H, CH3-19), 1.07
(s, 3H, CH3-18), 1.17 (s, 3H, 21-CH3), 5.80 (s, 1H, C4-H), 6.15
(s, 2H, NH2, D2O-exchangeable), 6.52 (s, 1H, pyrrole 50-H), 6.72–
7.25 (m, 5H, C6H5). 13C NMR (DMSO-d6, ppm): d ¼ 35.1 (t, C-1),
34.0, (t, C-2), 198.4 (s, C-3), 125.3 (d, C-4), 172.9 (s, C-5), 32.7
(t, C-6), 31.4 (t, C-7), 35.4 (d, C-8), 50.3 (d, C-9), 37.0 (s, C-10), 22.5
(t, C-11), 37.4 (t, C-12), 42.2 (s, C-13), 56.3 (d, C-14), 27.0 (t, C-15),
22.8 (t, C-16), 31.2 (d, C-17), 22.1 (q, C-18), 23.8 (q, C-19), 165.4
(s, C-20), 13.7 (q, C-21), 124.7 (s), 114.5 (d), 113.4 (s), 106.0 (s)
(C-pyrrole), 117.4 (s, CN), 127.0 (d), 129.6 (d), 128.5 (d), 136.3 (s)
(C-phenyl). MS (EI): m/z (%): 495 (Mþ þ 1, 54), 479 (Mþ-CH3, 30),
271 (C19H27O, 39), 77 (100). Calcd. for C32H38N4O (494.670):
C, 77.70; H, 7.74; N, 11.33; found: C, 77.52; H, 7.95;
N, 11.53%.
Synthesis of 20-(20-oxo-20-phenylethylhydrazono)pregn-
4-ene-3-one (13)
A solution of equimolar amounts of compound 3 (0.65 g,
2 mmol) and a-bromoacetophenone 11 (0.40 g, 2 mmol) in
dioxane (30 mL) containing a catalytic amount of piperidine
(0.5 mL) was heated under reflux for 6 h until all the reac-
tants mixture had disappeared as indicated by TLC. The
reaction mixture, cooled, poured over an ice/water mixture
and neutralized with dilute hydrochloric acid. The solid
product was filtered off, dried, and crystallized from
methanol.
20-[10-(200-Amino-300-ethoxycarbonyl-400-phenyl-100H-
pyrrol-17-yl)ethylidenamino]-pregn-4-en-3-on (16b)
Pale brown crystals from methanol, yield 0.88 g (81%),
mp 170–1728C, IR (KBr, cmꢀ1): n ¼ 3348 (NH2), 2957–2883
–
–
–
–
(CH-aliphatic), 1735 (C O, ester), 1698 (C-3, C O), 1647 (C N),
–
–
1605 (C C). 1H-NMR (CDCl3, ppm): d ¼ 0.93 (s, 3H, CH3-19),
–
–
1.02 (s, 3H, CH3-18), 1.13 (s, 3H, 21-CH3), 1.32 (t, 3H, CH3-ester),
4.25 (q, 2H, CH2-ester), 5.82 (s, 1H, C4-H), 6.18 (s, 2H,
NH2, D2O-exchangeable), 6.48 (s, 1H, pyrrole 50-H), 6.82–
7.35 (m, 5H, C6H5). MS (EI): m/z (%): 541 (Mþ, 62),
526 (Mþ-CH3, 30), 271 (C19H27O, 60), 77 (100). Calcd.
for C34H43N3O3 (541.723): C, 75.38; H, 8.00; N, 7.76; found:
C, 75.22; H, 8.17; N, 7.92%.
Compound 13: Brown crystals, yield 0.63 g (70%), mp 145–
1478C, IR (KBr, cmꢀ1): n ¼ 3394 (NH), 2930–2859 (CH-aliphatic),
1
–
–
–
1698, 1712 (2 C O), 1656 (C N). H-NMR (CDCl , ppm): d ¼ 0.98
–
3
(s, 3H, CH3-19), 1.07 (s, 3H, CH3-18), 1.19 (s, 3H, 21-CH3), 3.95
(s, 2H, CH2COPh), 5.80 (s, 1H, C4-H), 7.04–7.91 (m, 5H, C6H5), 8.94
(s, 1H, NH, D2O-exchangeable). MS (EI): m/z (%): 446 (Mþ, 63),
431 (Mþ-CH3, 32), 341 (Mþ-COPh, 100), 105 (75). Calcd.
for C29H38N2O2 (446.624): C, 77.99; H, 8.58; N, 6.27; found: C,
77.78; H, 8.36; N, 6.52%.
Pharmacological assay
Animals
Sprague-Dawley strain rats weighing 120–130 g or
Swiss albino mice 20–25 g body weight were used
throughout the experiments, supplied by the Animal
House Colony of the National Research Centre, Cairo,
Synthesis of pyrrolyl progesterone derivatives (16a,b)
General procedure
Egypt, and acclimated for one week in
a specific
To a solution of compound 13 (0.89 g, 2 mmol) in absolute
ethanol (30 mL) containing a catalytic amount of triethyl-
amine (0.5 mL), an equimolar amount of malononitrile 14a
(0.13 g, 2 mmol) or ethyl cyanoacetate 14b (0.22 g, 2 mmol)
was added. The reaction mixture was heated under reflux for
5 h until all the reactants mixture had disappeared as
indicated by TLC. The reaction mixture was left to cool at
room temperature, poured over an ice/water mixture
and neutralized with dilute hydrochloric acid. The solid
product that formed, in each case, was filtered off, dried
and crystallized from the appropriate solvent.
pathogen-free (SPF) barrier area where temperature
25 ꢁ 18C and humidity 55%. Animals were controlled
constantly with a 12 h light/dark cycle at the National
Research Centre animal facility breeding colony.
Animals were individually housed with ad libitum access
to standard laboratory diet and tap water. All animal
procedures were performed after approval from the
Ethics Committee of the National Research Centre and
in accordance with the recommendations for the
proper care and use of laboratory animals (NIH publication
No. 85–23, revised 1985).
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Arch. Pharm. Chem. Life Sci. 2011, 344, 595–604
Novel Thiazolyl and Pyrrolyl Steroids
603
Testes of inflammation: carrageenan-induced paw
edema assay
tested compounds (50 mg/kg; 0.5 ml, s.c.) on gastric damage
caused by ethanol (96%) was evaluated. Rats were fasted for
18 h, but allowed water ad libitum. They were administered
either saline (control) or one of the tested compounds 30 min
prior to ethanol (96%, 1 mL, p.o.). Rats were killed 1 h after
ethanol administration, stomachs excised, opened along the
greater curvature, rinsed with saline, extended on a plastic
board and examined for mucosal lesions. The number and
severity of mucosal lesions were noted and lesions were
Paw edema was induced by sub-plantar injection of 100 mL of
1% sterile carrageenan lambda in saline into the right hind
paw of rats [24]. Contralateral paw received an equal volume
of saline. Paw volume was determined immediately before
carrageenan injection and at selected times thereafter using
a plethysmometer (Ugo Basile, Milan, Italy). The edema com-
ponent of inflammation was quantified by measuring the
paw volume (mL) at zero time (before carrageenan injection)
and at 1, 2, 3, and 4 h after carrageenan injection and
comparing it with the pre-injection value for each animal.
Edema was expressed as a percentage of change from control
(pre-drug, zero time) values. The effect of systemic adminis-
tration of compounds 12 and 16a (25 or 50 mg/kg, s.c.,
0.2 mL, n ¼ 6/group) given 30 min before induction of
inflammation by subplantar carrageenan was studied. The
control group of carrageenan-treated rats received an equal
volume of saline 30 min before subplantar carrageenan
injection (n ¼ 6 each). Another group administered IND
(18 mg/kg, s.c.) served as control positive.
´
scaled as described by Mozsik et al. [26].
Statistical analysis
Data are expressed as mean ꢁ SE. Data were analyzed by one-
way analysis of variance, followed by a Tukey’s multiple
range tests for post hoc comparison of group means. When
there were only two groups a two-tailed Student’s t test was
used. For all tests, effects with a probability of P < 0.05 were
considered to be significant and that with a probability of
P < 0.001 were considered to be highly significant.
Conclusion
Tests of nociception
Hot plate assay
This study described a straight forward and efficient syn-
thesis of novel modified steroids containing fused pyrrole
or thiazole nucleus in addition to the pharmacophoric fea-
tures of the steroid moiety. The novel synthesized modified
steroids 12 and 16a showed anti-inflammatory, antinocicep-
tive and anti-ulcerogenic activities with various intensities.
Edema was significantly reduced by both doses of tested
compounds (25 and 50 mg/kg) at 2, 3, and 4 h post-carra-
geenan. The high dose of the pyrrolyl steroid 16a was the
most effective in alleviating thermal pain. Gastric mucosal
lesions caused in the rat by the administration of 96%
ethanol or IND was significantly inhibited by either one of
the two tested compounds. These results provide a unique
opportunity to develop new anti-inflammatory drugs which
devoid the ulcerogenic liabilities associated with currently
marketed drugs. Finally, the encouraging results of the anti-
inflammatory, anti-nociception and anti-ulcerogenic activity
displayed by these compounds may be of interest for further
derivatization and further drug-ability and physical studies
in the hope of finding new potent prescriptions.
The hot plate test was performed using an electronically
controlled hot plate (Ugo Basile, Italy) heated to 538C
(ꢁ 0.18C). Each mouse was placed unrestrained on hot plate
for the baseline measurement just prior to saline or drug admin-
istration. Different groups of mice (n ¼ 6/group) were given
compounds 12 or 16a (25 or 50 mg/kg; 0.2 ml, orally), tramadol
(20 mg/kg, 0.2 ml, orally) (control þ ve) or saline (control ꢀ ve).
Measurements were then taken 60 min after drug adminis-
tration. The experimenter was blind to doses. Latency to lick
a hind paw or jump out of the apparatus was recorded for the
control and drug-treated groups. The cut-off time was 30 s.
Acetic acid induced writhing
Separate groups of 6 mice each were administered vehicle
(saline), compounds 12 or 16a (25 or 50 mg/kg; 0.5 mL, orally)
or IND (18 mg/kg, 0.5 mL, orally). After 60 min, mice received
an i.p. injection of 0.6% acetic acid (0.2 mL) [25]. The number
of writhes (constrictions of abdomen, twisting of trunk, and
extension of hind legs) during 30 min observation period
following acetic acid injection was compared with the
control group and drug-treated groups.
The authors have declared no conflict of interest.
References
Gastric ulcerogenic study
Gastric mucosal damage was evoked in rats by the adminis-
tration of IND (20 mg/kg, 0.2 mL, s.c.). The effect of com-
pounds 12 or 16a (50 mg/kg; 0.5 mL, orally) administered
at time of IND injection was studied. Rats were killed 24 h
after IND administration. In other experiments, the effect of
[1] B. J. Lipworth, Arch. Intern. Med. 1999, 159, 941–955.
[2] I. E. Bush, Pharmacol. Rev. 1962, 14, 317–445.
[3] B. Shroot, J. C. Caron, M. Ponec, Br. J. Dermatol. 1982, 107, 30–34.
[4] T. Kwon, A. S. Heiman, E. T. Oriaku, K. Yoon, H. J. Lee, J. Med.
Chem. 1995, 38 (6), 1048–1051.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

604
R. M. Mohareb et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 595–604
[5] D. P. Jindal, P. Piplani, H. Fajrak, C. Prior, I. G. Marshall, Eur.
J. Med. Chem. 2001, 36, 195–202.
[16] Y. Harrak, G. Rosell, G. Daidone, S. Plescia, D. Schillaci, M. D.
Pujola, Bioorg. Med. Chem. 2007, 15, 4876–4890.
[6] S. Ferrer, D. P. Naughton, M. D. Threadgill, Tetrahedron 2003,
59, 3437–3444.
[17] A. Tanitame, Y. Oyamada, K. Ofuji, M. Fujimoto, K. Suzuki,
T. Ueda, H. Terauchi, M. Kawasaki, K. Nagai, M. Wachi,
J. Yamagishi, Bioorg. Med. Chem. 2004, 12, 5515–5524.
[7] R. M. Hoyte, J. Zhong, R. Lerum, A. Oluyemi, P. Persaud,
C. O’Connor, D. C. Labaree, R. B. Hochberg, J. Med. Chem.
2002, 45, 5397–5405.
[18] J. C. Hackett, Y. W. Kim, B. Su, R. W. Brueggemeier, Bioorg.
Med. Chem. 2005, 13, 4063–4070.
[8] F. Wu¨st, K. E. Carlson, J. A. Katzenellenbogen, Steroids 2003,
68, 177–191.
[19] F. F. Wong, C. Chen, T. Chen, J. Huang, H. Fang, M. Yeh,
Steroids 2006, 71, 77–82.
[9] G. A. Elmegeed, W. W. Wardakhan, A. R. Baiuomy, Pharmazie
2005, 60, 328–333.
[20] IUPAC, Joint Commission on Biochemical Nomenclature
(JCBN), Pure Appl. Chem. 1989, 61, 1783–1822.
[10] G. H. Phillips, Mechanism of Topical Corticoid Activity,
Livingstone, Edinburgh, UK 1981, 1.
[21] IUPAC, Joint Commission on Biochemical Nomenclature
(JCBN), Eur. J. Biochem. 1989, 186, 429–458.
[11] D. Criscuolo, F. Fraioli, V. Bonifacio, D. Paolucci, A. Isidori,
Int. J. Clin. Pharmacol. Ther. Toxicol. 1980, 18, 37–41.
[22] E. Gacs-Baitz, L. Minuti, A. Taticchi, J. Chem. Res, Synop. 1996,
7, 324–325.
[12] H. Y. Hana, W. K. B. Khalil, A. I. Elmakawy, G. A. Elmegeed,
J. Steroid Biochem. Mol. Biol. 2008, 110, 248–249.
[23] M. Frenkel, K. N. Marsh, TRC Data Series: Spectral Data
for Steroids, College Station, Thermodynamics Research
Center, Texas, TX 1994, 386.
[13] M. El-Far, G. A. Elmegeed, E. F. Eskander, H. M. Rady, M. A.
Tantawy, Eur. J. Med. Chem. 2009, 44, 3936–3946.
[24] C. A. Winter, E. A. Risley, G. W. Nuss, Proc. Soc. Exp. Biol. Med.
1962, 111, 544–552.
[14] S. Ushiyama, T. Yamada, Y. Murakami, S. Kumakura,
S. Inoue, K. Suzuki, A. Nakao, A. Kawara, T. Kimura, Eur.
J. Pharmacol. 2008, 578, 76–86.
[25] R. Koster, M. Anderson, E. J. De Beer, Fed. Proc. 1959, 18,
412–413.
´
´
[26] G. Y. Mozsik, F. Moron, T. Javor, Prostaglandins Leukot. Med.
´
[15] S. A. F. Rostom, I. M. El-Ashnawy, H. A. Abd El Razik, M. H.
Badr, H. M. A. Ashour, Bioorg. Med. Chem. 2009, 17, 882–895.
1982, 9, 71–84.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com