Synthesis and analgesic activities of some 2-(benzazolylacetyl)amino-3- ethoxycarbonylthiophene derivatives

Article abstract of DOI:10.1080/104265090889503

In this study, some 2-[2-(benzazole-2-thioxy)acetylamino]-3- ethoxycarbonylthiophene and 2-[2-(benzazole-1-yl)acetylamino]-3- ethoxycarbonylthiophene compounds were obtained by the reaction of 2-chloroacetylamino-3-ethoxycarbonylthiophene derivatives and a suitable benzazole-2-thione or benzimidazole derivatives. Analgesic activities of the compounds were tested by using tail-flick and tail-immersion methods. It is reported that some of the compounds showed remarkable analgesic activities. Copyright Taylor & Francis Inc.

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Synthesis and Analgesic
Activities of Some 2-
(Benzazolylacetyl)amino-3-
ethoxycarbonylthiophene
Derivatives
Seref Demirayak a , Ahmet C. Karaburun a , Ismail
Kayagil a , Umit Uçucu a & Rana Beis b
a Anadolu University, Department of Pharmaceutical
Chemistry , Eskisehir, Turkey
b Anadolu University, Department of Pharmaceutical
Chemistry , Eskisehir, Turkey
Published online: 18 Aug 2006.
To cite this article: Seref Demirayak , Ahmet C. Karaburun , Ismail Kayagil ,
Umit Uçucu & Rana Beis (2005) Synthesis and Analgesic Activities of Some 2-
(Benzazolylacetyl)amino-3-ethoxycarbonylthiophene Derivatives, Phosphorus,
Sulfur, and Silicon and the Related Elements, 180:8, 1841-1848, DOI:
10.1080/104265090889503
To link to this article: http://dx.doi.org/10.1080/104265090889503
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Phosphorus, Sulfur, and Silicon, 180:1841–1848, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090889503
Synthesis and Analgesic Activities of Some
2-(Benzazolylacetyl)amino-3-ethoxycarbonylthiophene
Derivatives
Seref Demirayak
Ahmet C. Karaburun
Ismail Kayagil
Umit Uc¸ucu
Anadolu University, Department of Pharmaceutical Chemistry,
Eskisehir, Turkey
Rana Beis
Anadolu University, Department of Pharmacology, Eskisehir, Turkey
In this study, some 2-[2-(benzazole-2-thioxy)acetylamino]-3-ethoxycarbonyl-
thiophene and 2-[2-(benzazole-1-yl)acetylamino]-3-ethoxycarbonylthiophene com-
pounds were obtained by the reaction of 2-chloroacetylamino-3-ethoxycarbo-
nylthiophene derivatives and a suitable benzazole-2-thione or benzimidazole
derivatives. Analgesic activities of the compounds were tested by using tail-flick
and tail-immersion methods. It is reported that some of the compounds showed
remarkable analgesic activities.
Keywords Analgesic activity; benzazole; thiophene
INTRODUCTION
The role of thiophene derivatives in the design and synthesis of phar-
macologically important molecules has grown enormously since 1950.1,2
The electron-rich properties as well as the slightly smaller steric vol-
ume of thiophene, as compared with benzene, may play an important
role in fitting the necessary biological agents of this type, which have
been prepared based upon active benzene derivatives.
It is well known that, 2-aminothiophenes and their substituted
acyl derivatives I show analgesic and anti-inflammatory activities.1−8
Received July 8, 2004; accepted September 7, 2004.
Address correspondence to Seref Demirayak, Department of Pharmaceutical Chem-
istry, Faculty of Pharmacy, Anadolu University, 26470, Eskisehir, Turkey. E-mail:
sdemiray@anadolu.edu.tr
1841

1842
S. Demirayak et al.
FORMULA 1
It was reported that some of the compounds were superior to some
widespread analgesics such as acetylsalicylic acid, phenylbutazone,
aminopyrine and indomethacin. In light of the above findings, we aimed
to synthesize some 2-(2-benzazolylthio/1-benzimidazolyl-acetyl)amino-
3-ethoxycarbonylthiophene derivatives and investigate their analgesic
activities.
EXPERIMENTAL
Chemistry
Melting points were determined by using an Electrothermal 9100 dig-
ital melting point apparatus and were uncorrected. Spectroscopic data
were recorded on the following instruments; FTIR, Schimadzu 8400S
spectrophotometer, and 1H-NMR, Bruker DPX 400 NMR spectrometer
in DMSO-d6. Analyses for C, H, and N was within 0.4% of the theoretical
values.
2-Amino-3-ethoxycarbonylthiophenes, 1,9 benzazole-2-thione, 3,10
and benzimidazole, 5, derivatives11 were prepared according to the
literature methods. 2-Chloroacetylamino-3-ethoxycarbonylthiophene
derivatives, 2, were obtained by reacting the appropriate 2-amino-3-
ethoxycarbonylthiophene derivatives with chloroacetyl chloride in the
presence of triethylamine in THF, in a common procedure.9 Some char-
acteristics of the synthesized compounds were given in Table I.
General Method for the Preparation of
2-[2-(Benzazole-2-thioxy)acetylamino]-3-ethoxycarbonyl-4,5-
alkylsubstituted thiophene and 2-[2-(Benzazol-1-
yl)acetylamino]-3-ethoxycarbonyl-4,5-alkylsubstituted
thiophene derivatives, 4 and 6
A mixture of 2 (5 mmol), an appropriate 3 or 5 (5 mmol) and potas-
sium carbonate (6 mmol) in acetone (100 mL) was refluxed. In the case

Ethoxycarbonylthiophene Derivatives
1843
TABLE I Some Characteristics of the Compounds
Comp.
R
Rꢀ
Rꢀꢀ
X
m.p. (◦C)
Yield (%)
Mol. Formula
4a
4b
4c
4d
4e
4f
4g
4h
4i
(CH2)3
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)5
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
(CH2)4
H
H
CH3
Cl
NO2
H
H
CH3
Cl
H
H
NH
NH
NH
NH
NH
NH
O
O
O
S
—
205
159
164
193
229
167
113
121
129
140
176
173
72
75
82
82
87
77
81
73
84
75
65
67
C19H19N3O3S2
C20H21N3O3S2
C21H23N3O3S2
C20H20ClN3O3S2
C20H20N4O5S2
C21H23N3O3S2
C20H22N2O4S2
C21H24N2O4S2
C20H21ClN2O4S2
C20H22N2O3S3
C20H21N3O3S
4j
6a
6b
Cl
—
C20H20ClN3O3S
of the compounds 4, the reflux time is 2 h and in the case of the com-
pounds 6, the reflux time is 12 h. The solvent was evaporated at low
temperature. The residue was washed with water and then ethanol.
The raw product was recrystallized from ethanol.
4a IR(KBr)νmax(cm−1): 3170(N H), 1664(C O), 1561–1477(C N,
1
C C). H-NMR(400 MHz)(DMSO-d6) δ (ppm): 1.25(3H, t, J: 7.08 Hz
OCH2CH3), 2.26–2.31(2H, m, CH2 ), 2.75–2.80(4H, m, two CH2 ),
4.23(2H, q, J: 7.01 Hz, OCH2CH3), 4.32(2H, s, CO CH2 S), 7.11–
7.14(2H, m, Benzimidazole-C5.6 H), 7.45–7.50(2H, m, Benzimidazole-
C4,7 H), 11.70(1H, bs, N H), 12.70(1H, bs, N H).
4b IR(KBr)νmax(cm−1): 3170(N H), 1664(C O), 1561–1477(C N,
C C). 1H-NMR(400 MHz) (DMSO-d6) δ (ppm): 1.35(3H, t, J:
8.1 Hz OCH2CH3), 1.7–1.85(4H, m, Tetrahydrobenzothiophene-
C5,6 H), 2.6–2.7(2H, m, Tetrahydrobenzothiophene-C7 H), 2.8–
2.88(2H, m, Tetrahydrobenzothiophene-C4 H), 4.24(2H, q, J: 7.08 Hz,
OCH2CH3), 4.31(2H, s, CO CH2 S), 7.2–7.3(2H, m, Benzimidazole-
C5.6 H), 7.4–7.48(1H, m, Benzimidazole-C7 H), 7.65–7.7(1H, m,
Benzimidazole-C4 H), 11.70(1H, bs, N H), 12.70(1H, bs, N H).
4f IR(KBr)νmax(cm−1): 3170(N H), 1664(C O), 1561–1477(C N,
1
C C). H-NMR(400 MHz)(DMSO-d6) δ (ppm): 1.25(3H, t, J: 7.08 Hz,
OCH2CH3), 1.48–1.6(4H m, two CH2 ), 1.74–1.82(2H, m, CH2 ),
2.57–2.7(2H, m, CH2 ), 2.9–2.95(2H, m, CH2 ), 4.25(2H, q, J: 7.1 Hz,
OCH2CH3), 4.29(2H, s, CO CH2 S), 7.10–7.14(2H, m, Benzimidazole-
C5.6 H), 7.45–7.50(2H, m, Benzimidazole-C4,7 H), 11.70(1H, bs, N H),
12.80(1H, bs, N H).
4g IR(KBr)νmax(cm−1): 3170(N H), 1664(C O), 1561–1477(C N,
1
C C). H-NMR(400 MHz) (DMSO-d6) δ (ppm): 1.26 (3H, t, J: 7.07 Hz
OCH2CH3), 1.65–1.75(4H, m, Tetrahydrobenzothiophene-C5,6 H),

1844
S. Demirayak et al.
2.55–2.60(2H, m, Tetrahydrobenzothiophene-C7 H), 2.65–2.70(2H, m,
Tetrahydrobenzothiophene-C4 H), 4.24(2H, q, J: 7.1 Hz, OCH2CH3),
4.31(2H, s, CO CH2 S), 7.31–7.36(2H, m, Benzoxazole-C5.6 H), 7.63–
7.76(1H, m, Benzoxazole-C4,7 H), 11.68(1H, bs, N H).
4h IR(KBr)νmax (cm−1): 3170(N H), 1664(C O), 1561–1477(C N,
C C). 1H-NMR(400 MHz) (DMSO-d6) δ (ppm): 1.27 (3H, t, J:
7.09 Hz OCH2CH3), 1.68–1.76(4H, m, Tetrahydrobenzothiophene-
C5,6 H), 2.55–2.60(2H, m, Tetrahydrobenzothiophene-C7 H), 2.65–
2.70(2H, m, Tetrahydrobenzothiophene-C4 H), 4.25(2H, q, J: 7.11 Hz,
OCH2CH3), 4.42(2H, s, CO CH2–S), 7.14(1H, dd, J: 2.85 Hz, J:
8.35 Hz, Benzoxazole-C6 H), 7.44 (1H, d, J: 0.66 Hz, Benzoxazole-
C4 H), 7.52(1H, d, J: 8.33 Hz, Benzoxazole-C7 H), 11.67(1H, bs, N H).
4j IR(KBr)νmax(cm−1): 3170(N H), 1664(C O), 1561–1477(C N,
C C). 1H-NMR(400 MHz) (DMSO-d6) δ (ppm): 1.27 (3H, t, J:
7.09 Hz OCH2CH3), 1.6–1.75(4H, m, Tetrahydrobenzothiophene-
C5,6 H), 2.55–2.65(2H, m, Tetrahydrobenzothiophene-C7 H), 2.65–
2.75(2H, m, Tetrahydrobenzothiophene-C4 H), 4.26(2H, q, J: 7.1 Hz,
OCH2CH3), 4.46(2H, s, CO CH2 S), 7.35–7.39(1H, m, Benzothiazole-
C5 H), 7.45–7.49(1H, m, Benzothiazole-C6 H), 7.88(1H, d, J: 8.0 Hz,
Benzothiazole-C7 H), 8.03(1H, d, J: 8.01 Hz, Benzothiazole-C4 H),
11.71(1H, bs, N H).
6a IR(KBr)νmax(cm−1): 3238(N H), 1664(C O), 1535–1494(C N,
1
C C). H-NMR(400 MHz) (DMSO-d6) δ (ppm): 1.27(3H, t, J: 7.1 Hz
OCH2CH3), 1.7–1.82(2H, m, Tetrahydrobenzothiophene-C5,6 H), 2.6–
2.65(2H, m, Tetrahydrobenzothiophene-C7 H), 2.68–2.75(2H, m,
Tetrahydrobenzothiophene-C4 H), 4.16(2H, q, J: 7.08 Hz, OCH2CH3),
5.03(2H, s, CO CH2-S), 7.22–7.3(2H, m, Benzimidazole-C5.6 H), 7.38–
7.4(1H, m, Benzimidazole-C7 H), 7.7–7.85(1H, m, Benzimidazole-
C4 H), 8.04(1H, s, Benzimidazole-C2 H), 11.42(1H, s, NH).
6b IR(KBr)νmax(cm−1): 3238(N H), 1664(C O), 1535–1494(C N,
C C). 1H-NMR(400 MHz) (DMSO-d6) δ (ppm): 1.27–1.32(3H, m,
OCH2CH3), 1.68–1.8 (2H, m, Tetrahydrobenzothiophene-C5,6 H),
2.55–2.6 (2H, m, Tetrahydrobenzothiophene-C7 H), 2.62–2.75 (2H,
m, Tetrahydrobenzothiophene-C4 H), 4.21–4.28(2H, m, OCH2CH3),
5.49, 5.50(2H, two s, CO CH2 S), 7.24–7.32(1H, m, Benzimidazole-
C4 H), 7.61–7.80(2H, m, Benzimidazole-C7,8 H), 8.31, 8.34(1H, two s,
Benzimidazole-C2 H), 11.20, 11.21(1H, two s, NH).
Pharmacology
Swiss albino mice of either sex were used for in vivo tail-clip and
tail immersion (52.5◦C hot water) analgesic tests.12,13 Mice were as-
signed to groups of five animals each. Morphine sulfate (10 mg/kg) and

Ethoxycarbonylthiophene Derivatives
1845
TABLE II Effects of the Compounds on Tail-Clip Response
in Mice. A: Morphine sulfate, B: Acetylsalisylic Acid. Values
are Expressed as Mean S.E.M. of Five Mice in Each Group
(∗p ≤ 0.01 and ∗∗p ≤ 0.05)
Comp. Dose (mg/kg) (i.p.)
Reaction Time (sec.) % Analgesia Tail-Clip
A
B
10
100
100
100
100
100
100
100
100
100
100
100
100
100
14.37 0.62
14.34 0.66
13.15 0.7∗∗
6.98 2.05
1.30 0.19
11.52 1.56∗
12.62 0.56
11.70 0.66∗∗
4.21 2.71
12.84 0.15∗
4.29 0.86
11.68 0.42∗
1.54 0.29
25 0.07
95.38
95.15
86.01
38.00
0.11
74.49
82.86
76.40
24.50
84.40
19.83
74.77
1.07
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
6a
6b
1.51
acetylsalisylic acid (100 mg/kg) were used as the reference analgesic
agent. Test latencies (in seconds) were assessed 30 min after the admin-
istration of compounds. To avoid irreversible damage in tail structures
of mice, a maximum latency of 15 s. was imposed, if no response was ob-
served within that time. Percent analgesia was calculated by following
formula (% analgesia = {(postdrug latency)-(predrug latency)/(cutoff
time)-(predrug latency)} × 100). Results expressed as mean SEM, and
student’s t-test was used to assess statistical significances. Test results
are given in Tables II and III.
RESULTS AND DISCUSSION
Chemistry
The synthesis of the title 2-[2-(Benzazole-2-thioxy)acetylamino]-
3-ethoxycarbonylthiophene and 2-[2-(benzazole-1-yl)acetylamino]-3-
ethoxycarbonylthiophene derivatives, 4 and 6, were accomplished in
accordance with the sequence of reactions depicted in Scheme 1. The
starting compounds, 2-amino-3-ethoxycarbonyl-4,5-alkylsubstituted
thiophenes 1, were prepared according to Gewald’s Method6 by
the reaction of an appropriate cycloalkanone and ethyl cyanoac-
etate in the presence of sulphur and morpholine as a base
catalyst in ethanol. 2-Chloroacetylamino-3-ethoxycarbonylthiophene

1846
S. Demirayak et al.
SCHEME 1 (a) EtOH/Morpholine, (b) Et3N/THF, and (c) K2CO3/Acetone.
derivatives 2 were obtained by reacting the appropriate 2-amino-3-
ethoxycarbonylthiophene derivatives with chloroacetyl chloride in the
presence of triethylamine in THF in a common procedure.9 The result-
ing compounds 4 and 6 were prepared by reacting an appropriate 2 and
a benzazole-2-thione 3 or a benzimidazole 5 in the presence of potas-
sium carbonate in acetone.
The structures of the obtained compounds were elucidated by using
the spectral data. In the IR spectra, the characteristic amid N H and
C O stretching bands were observed at 3200–3100 and 1665 cm−1, re-
spectively. In the NMR spectra, methylene protons of acetyl residue,
which are common in all compounds, were observed at about 4.1–
4.2 ppm in case of the compounds 4 and 5 ppm in case of the com-
pounds 6. Because of the tautomeric equilibrium from N H in the
ring of benzimidazole, the compound 6b, which synthesized using 5(6)-
chlorobenzimidazole as starting material, is a mixture of two structural
isomers arising 5- and/or 6-chlorobenzimidazolyl residues. Thus, proton

Ethoxycarbonylthiophene Derivatives
1847
TABLE III Effects of the Compounds on
Tail-Immersion Response in Mice. A: Morphine
Sulfate, B: Acetylsalisylic Acid. Values are Expressed
as Mean S.E.M. of Five Mice in Each Group
Dose
Reaction
% Analgesia
Comp.
(mg/kg) (i.p.)
Time (sec.)
Tail-immersion
A
B
10
100
100
100
100
100
100
100
100
100
100
100
100
100
10.99 1.84
6.19 1.41
3.31 0.71
3.89 0.87
2.34 0.67
3.73 0.29
4.97 0.98
2.79 0.74
50.7
21.9
7.3
5.8
0.1
9.6
19
6.2
3
6.73
6.9
3
4a
4b
4c
4d
4e
4f
4g
4h
4i
5.39
2
2.54 0.38
3.70 0.72
4.08 0.89
3.28 0.40
5.66 2.12
4j
6a
6b
2.3
12.2
signals in the NMR spectra were observed as overlaped. The peaks ex-
pected singlets were obtained as two singlets. However, the integral
values of the peaks, belonging to the similar protons in each isomer,
were in accordance. The other protons were obtained as multiplets as
expected.
Pharmacology
Analgesic activities of the compounds were tested by using “tail-flick”
and “tail-immersion” methods. The analgesic activity in each group is
shown in Tables II and III. As control analgesic agents, morphine sulfate
(10 mg/kg) and acetylsalisylic acid (100 mg/kg) were used and in tail
clip method 95.38% and 95.15% and in tail immersion method 50.7%
and 21.9% analgesic activity were observed, respectively.
In tail clip method, among the compounds tested 2a, 2e, and 2h
showed remarkable activity in regard to the effects of morphine sulfate
and acetylsalisylic acid. The activity obtained is quite close to the ac-
tivity observed for both morphine sulfate and acetylsalisylic acid. The
other notable compounds 2d, 2f, and 2j showed about 75% activity. It is
noticeable that the effective compounds are carrying sulfanyl-bridged
benzazole residue. However, the compounds 6a and 6b which are di-
rectly attached to benzimidazole residues do not show any analgesic
activity.

1848
S. Demirayak et al.
The higher activity levels mentioned above were not observed in the
tail-immersion experiments. Thus, it could be said that the compounds
exhibited potent analgesic activity against physical stimuli, and they
were found as potent as acetylsalisylic acid (ip. 100 mg/kg).
REFERENCES
[1] J. B. Press, Chem. Heterocycl. Compd., 44, 353 (1985).
[2] J. B. Press, Chem. Heterocycl. Compd., 50, 397 (1991).
[3] M. Nakanishi, H Imamura, and Y. Maruyama Arzneim.-Forsch., 20, 998 (1970).
[4] M. Nakanishi, H. Imamura, K. Ikegami, and K. Goto, Arzneim.-Forsch., 20, 1004
(1970).
[5] M. Perissin, C. L. Duc, G. Narcisse, F. Bakri-Logeais, and F. Huguet, Eur. J. Med.
Chem. Chim. Ther., 15, 413 (1980).
[6] F. Russo, S. Guccione, G. Romeo, G. U. Barretta, S. Pucci, A. Caruso, et al. Eur. J.
Med. Chem., 28, 363 (1993).
[7] F. Russo, G. Romeo, N. A. Santagati, A. Caruso, V. Cutuli, and D. Amore, Eur. J.
Med. Chem., 29, 569 (1994).
[8] A. Santagati, G. Granata, V. Cutuli, N. G. Mangano, and A. Caruso, Arzneim.-
Forsch., 52, 448 (2002).
[9] K. Gewald, E. Schinke, and H. Bottcher, Chem. Ber., 99, 94 (1966).
[10] J. A. Van Allan and B. D. Deacon, Org. Synt., 30, 56 (1950).
[11] M. A. Phillips, J. Chem. Soc., 1143 (1931).
[12] F. E. D’Amour and D. L. Smith, J. Pharmacol. Exp. Ther., 72, 74 (1941).
[13] C. Schmauss and T. L. Yaksh, J. Pharmacol. Exp. Ther., 228, 1 (1984).