Synthesis and Biological Activity of 4H-Thieno[3,2-c]Chromene Derivatives

Article abstract of DOI:10.1007/s10593-015-1642-4

The formyl group of 4H-thieno[3,2-c]chromene-2-carbaldehyde was transformed into the respective nitrile, amide, ester, carboxylic, hydroxamic, or hydroxy group. Electrophilic substitution in 4H-thieno[3,2-c]chromene-2-carbaldehyde was shown to occur at the C-8 atom, while oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in methanol led to 4-methoxy-4H-thieno[3,2-c]chromene-2-carbaldehyde. The latter compound was found to possess high antiulcer activity.

Full text of DOI:10.1007/s10593-015-1642-4

DOI 10.1007/s10593-015-1642-4
Chemistry of Heterocyclic Compounds, Vol. 50, No. 12, March, 2015 (Russian Original Vol. 50, No. 12, December, 2014)
SYNTHESIS AND BIOLOGICAL ACTIVITY OF
4H-THIENO[3,2-c]CHROMENE DERIVATIVES
Yu. P. Bogza1, A. L. Katsiel'1, A. N. Sharypova1,
T. G. Tolstikova2, and A. S. Fisyuk1,3
*
The formyl group of 4H-thieno[3,2-c]chromene-2-carbaldehyde was transformed into the respective
nitrile, amide, ester, carboxylic, hydroxamic, or hydroxy group. Electrophilic substitution in
4H-thieno[3,2-c]chromene-2-carbaldehyde was shown to occur at the С-8 atom, while oxidation with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone in methanol led to 4-methoxy-4H-thieno[3,2-c]chromene-
2-carbaldehyde. The latter compound was found to possess high antiulcer activity.
Keywords: 4H-thieno[3,2-с]chromene, antiulcer activity, electrophilic substitution, oxidation, reduction.
Derivatives of 4H-thieno[3,2-с]chromene are of interest as biologically active agents. Examples with
significant anti-inflammatory [1-4], antiallergic [3, 4], analgesic [1], antiparkinsonian [1], antibacterial [5],
antifungal [5, 6], and mucolytic [7-9] activity are known among these compounds. Derivatives of 4H-thieno-
[3,2-с]chromene are used for the treatment of diabetes and hyperlipidaemia [10], cancer [11-14], and symptoms
associated with menopause [15], which motivates the synthetic studies and characterization of such compounds.
Previously we have reported simple and convenient methods for the synthesis [16, 17] of 4Н-thieno-
[3,2-с]chromene-2-carbaldehydes that are difficult to obtain otherwise [18], based on Pd-catalyzed
intramolecular arylation of iodo derivatives of 4-(aryloxy)methylthiophene-2-carbaldehydes. At the same time,
the chemical properties of 4Н-thieno[3,2-с]chromene-2-carbaldehyde prepared by these methods remain
essentially unknown.
In order to remedy this lack of information, we studied the reactions of 4H-thieno[3,2-c]chromene-
2-carbaldehyde (1) at the benzene ring or methylene bridge, performed functional group transformations at the
С-2 position, as well as characterized the antiulcer and anti-inflammatory activity of one of the prepared
compounds.
Heating compound 1 with hydroxylamine hydrochloride in concentrated formic acid transformed the
formyl group into nitrile, but the yield of nitrile 4 did not exceed 35% in this case. A better yield of compound 4
(76%) was obtained by reaction of aldehyde 1 with ammonia and iodine in THF at room
_______
*To whom correspondence should be addressed, e-mail: fisyuk@chemomsu.ru.
1 F. M. Dostoevskii Omsk State University, 55a Mira Ave., Omsk 644077, Russia.
2N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of
Sciences, 9 Akademika Lavrentieva Ave., Novosibirsk 630090, Russia; е-mail: tgtolstik@nioch.nsc.ru.
3Omsk State Technical University, 11 Mira Ave., Omsk 644050, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1862-1868, December, 2014.
Original article submitted September 30, 2014.
1712
0009-3122/15/5012-1712©2015 Springer Science+Business Media New York

temperature for 36-40 h. Hydrolysis of nitrile 4 in the presence of sodium hydroxide and hydrogen peroxide
gave 90% yield of amide 5, while reaction with hydrazoic acid generated in the reaction medium from sodium
azide and triethylammonium chloride in toluene gave 65% yield of the tetrazole 6.
In order to study the direction of electrophilic substitution in 4H-thieno[3,2-c]chromene-2-carb-
aldehyde (1), we performed its bromination and iodination. The interaction of compound 1 with bromo-
O
O
I
O
I
Pd cat.
[16]
CHO
Pd cat.
[17]
CHO
S
S
S
CHO
2
3
1
A. NH2OH·HCl B. NH3, I2, H2O
HCOOH
THF, room temp.
36–40 h
, 5 h
NaOH, H2O2
EtOH, H2O
NaN3
Et3N·HCl
O
55–60°C
5–6 h
toluene, 
40–48 h
S
CN
4
O
O
O
N
S
S
NH
NH2
6
N
N
5
succinimide (NBS) as well as with iodosuccinimide (NIS) in glacial acetic acid occurred very slowly, but the
addition of catalytic amounts of HClO4 to the reaction mixture produced after 4 h the derivatives 7a,b with
halogen at the C-8 atom, in 90 and 60% yields, respectively.
O
O
OMe
S
O
S
S
CH2OH
CHO
8
X
7a (X = Br)
b (X = I)
CHO
9
NaBH4 room temp.
EtOH 1–1.5 h
DDQ
MeOH, CH2Cl2
NBS or NIS
room temp., 24 h
AcOH, HClO4
room temp., 4 h
O
1
H
10°C – room temp.
2 h
Ag2O
THF, H2O
N
S
OH
12
O
O
O
MeOH
SOCl2
NH2OH·HCl
MeONa, MeOH
65–70°C, 1.5–2 h
, 2.5 h
S
S
CO2H
CO2Me
10
11
1713

TABLE 1. Physicochemical Characteristics of Compounds 4-12
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °С (solvent)
Yield, %
C
H
N
4
5
6
C12H7NOS
67.39
67.59
62.15
62.32
56.30
56.24
3.36
3.31
4.01
3.92
3.23
3.15
6.71
6.57
6.11
6.06
22.01
21.86
121-122 (EtOH)
181-183 (EtOH)
76*
90
C12H9NO2S
C12H8N4OS
220-222
65
(EtOH–EtOAc)
207-208 (EtOH)
7a
7b
8
C12H7BrO2S
C12H7IO2S
C12H10O2S
C13H10O3S
C12H8O3S
C13H10O3S
48.94
48.83
42.27
42.13
65.92
66.03
63.25
63.40
62.19
62.06
63.29
63.40
2.48
2.39
2.15
2.06
4.70
4.62
4.17
4.09
3.58
3.47
4.01
4.09
—
—
—
—
—
—
90
60
97
81
85
95
197-198 (EtOH)
Oil (oil [19])
9
97-99 (MeOH)
10
11
210-212 (THF–hexane)
93-94 (MeOH)
(94-96 [19])
12
C12H9NO3S
57.98
58.29
3.78
3.67
5.81
5.66
194-196 (EtOH-H2O)
97
______
*Obtained by method B.
Reduction of the formyl group in compound 1 with sodium borohydride in ethanol gave (4H-thieno-
[3,2-c]chromen-2-yl)methanol (8) in 97% yield.
Oxidation of the aldehyde 1 with wet silver oxide in THF led to the formation of 4Н-thieno[3,2-c]-
chromene-2-carboxylic acid (10) in 85% yield, which was then converted to the methyl ester 11 by the action of
thionyl chloride in methanol. The yield of compound 11 was 95%.
Oxidation of methylene group in the presence of an aldehyde group presents a challenge. We were able
to oxidize the methylene bridge in 4H-thieno[3,2-c]chromene-2-carbaldehyde (1) by using 2,3-dichloro-5,6-di-
cyano-1,4-benzoquinone (DDQ) [20] in dichloromethane in the presence of methanol and thus obtained
4-methoxy-4H-thieno[3,2-c]chromene-2-carbaldehyde (9) in 81% yield.
The structures of all obtained compounds were confirmed by elemental analysis data (Table 1), IR
spectra, 1Н and 13C NMR spectra.
The antiulcer and anti-inflammatory activity of the previously unknown thieno[3,2-c]chromene derivative 9
was investigated (Table 2).
Table 2 shows that compound 9 at 100 mg/kg dose significantly reduced the development of injury to
stomach caused by indometacin, correspondingly decreasing the Paul's index to 0.75 and therefore exhibited
high (7.3) antiulcer activity. Since the compound 9 did not show anti-inflammatory activity, data are not
presented.
TABLE 2. Antiulcer Activity of 4-Methoxy-4H-thieno[3,2-c]chromene-
2-carbaldehyde (9)
Groups
Number of ulcers
Paul's index
5.50
Antiulcer activity
I. Control group:
indometacin (20 mg/kg per os)
II. Test group:
33
9
—
0.75
7.3
indometacin (20 mg/kg per os) +
+ compound 9 (100 mg/kg per os)
1714

Thus, we have studied the reactions of 4H-thieno[3,2-c]chromene-2-carbaldehyde at the formyl group.
Halogenation of this compound was used as example to establish that electrophilic substitution occurred at the
С-8 position, while reaction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone resulted in selective oxidation of
the methylene fragment and the formation of 4-methoxy-4H-thieno[3,2-c]chromene-2-carbaldehyde,
characterized with high antiulcer activity.
EXPERIMENTAL
IR spectra were recorded on a FT-801 FT-IR spectrometer in KBr pellets. The 1H and 13C NMR spectra
were acquired on a Bruker DRX 400 instrument (400 and 100 MHz, respectively) in acetone-d6 (compounds 5,
6), DMSO-d6 (compounds 10, 12), and in CDCl3 (the rest of the compounds), with TMS as internal standard.
Mass spectra were recorded on an Agilent 6890N instrument (EI ionization, 70 eV, evaporator temperature 230-
250°С). Elemental analysis was performed on a Carlo Erba 1106 CHN-analyzer. Melting points were
determined on a Kofler hot bench. The reaction progress and the purity of the obtained compounds were
controlled by TLC on Sorbfil UV-254 plates, visualization with iodine vapor or UV light.
4Н-Thieno[3,2-c]chromene-2-carbonitrile (4). А. A mixture of 4Н-thieno[3,2-с]chromene-2-carb-
aldehyde (1) (0.324 g, 1.5 mmol) and NH2OH·HCl (0.208 g, 3.0 mmol) in conc. HCOOH (3 ml) was refluxed for
5 h. The reaction mixture was poured into ice water and extracted with Et2O. The combined ether extracts were
washed with water, dried over Na2SO4, and the solvent was removed by evaporation. The product was purified by
flash chromatography on alumina (eluent 1:1 СHCl3–petroleum ether). Yield 0.112 g (35%).
B. Iodine (0.761 g, 3.0 mmol) was added to a mixture of 4Н-thieno[3,2-с]chromene-2-carbaldehyde (1)
(0.324 g, 1.5 mmol) in 28% aqueous ammonia (9 ml) and THF (7.5 ml) at room temperature. The reaction
mixture was stirred for 36-40 h. Then 5% solution of Na2S2O3 (12 ml) was added to the reaction mixture, and
the aqueous layer was extracted with EtOAc (3×10 ml). The extract was dried over Na2SO4, and solvent was
removed on a rotary evaporator. The product was purified by flash chromatography on silica gel (0.035-0.070 mm,
eluent 1:1 CHCl3–hexane) and recrystallized from MeOH or EtOH. Yield 0.243 g (76%). Light-yellow crystals.
1
IR spectrum, ν, cm-1: 2209 (C≡N). H NMR spectrum, δ, ppm (J, Hz): 5.25 (2H, s, CH2); 6.95-7.02 (2H, m,
H-6,8); 7.23-7.29 (1H, m, H-7); 7.32 (1H, dd, 3J = 7.6, 4J = 1.4, H-9); 7.34 (1H, s, H-3). 13C NMR spectrum, δ,
ppm: 65.5 (С-4); 107.6 (С-2); 114.3 (С-9a); 117.2 (C-6); 118.6 (CN); 122.5 (C-8); 123.7 (C-9); 131.2 (2C,
C-3,3a); 134.1 (C-7); 140.0 (C-9b); 153.0 (C-5a). Mass spectrum, m/z (Irel, %): 213 [M]+ (57), 212 (100), 140 (10).
4Н-Thieno[3,2-с]chromene-2-carboxamide (5) [9, 21]. A solution of nitrile 4 (0.640 g, 3.0 mmol) and
NaOH (0.136 g, 3.4 mmol) in EtOH (23 ml) was stirred at room temperature and treated with 40% solution of
H2O2 (2×3 ml with interval of 1 h). The reaction mixture was heated at 55-60°С until the reaction was complete
(5-6 h). The crystals formed were filtered off, washed with water, dried, and recrystallized from EtOH. Yield 0.624
g (90%). Colorless needles. IR spectrum, ν, cm-1: 3346, 3208 (NH2), 1650 (C=O, amide I), 1595 (N–C=O, amide
1
3
4
II). H NMR spectrum, δ, ppm (J, Hz): 5.26 (2H, s, CH2); 6.92 (1H, dd, J = 8.1, J = 1.0, H-6); 7.00 (1H, td,
3J = 7.5, J = 1.0, H-8); 7.19-7.25 (1H, m, H-7); 7.40 (1H, dd, J = 7.5, J = 1.5, H-9); 7.55 (1H, s, H-3).
13C NMR spectrum, δ, ppm: 66.5 (C-4); 117.7 (C-6); 120.7 (C-9b); 123.1 (C-8); 124.3 (C-9); 126.7 (C-7); 130.9
(C-3); 133.3 (C-9a); 137.4 (C-3a); 139.9 (C-2); 153.7 (C-5a); 163.8 (CONH2).
4
3
4
5-(4Н-Thieno[3,2-c]chromen-2-yl)-2H-tetrazole (6). A mixture of 4Н-thieno[3,2-c]chromene-2-carbo-
nitrile (4) (0.213 g, 1.0 mmol), Et3N·HCl (0.206 g, 1.5 mmol), and NaN3 (0.098 g, 1.5 mmol) in toluene (8 ml)
was refluxed for 40-48 h. After cooling, the mixture was extracted with water, the aqueous layer was acidified
with concentrated HCl. The precipitate formed was filtered off, dried, and recrystallized from
EtOH–EtOAc mixture. Yield 0.166 g (65%). Brown powder. IR spectrum, ν, cm-1: 3487 (NH), 1600 (C=N).
1H NMR spectrum, δ, ppm (J, Hz): 3.12 (1H, br. s, NH); 5.33 (2H, s, CH2); 6.94 (1H, d, 3J = 8.1, H-6); 6.98-7.03
3
13
(1H, m, H-8); 7.21-7.26 (1H, m, H-7); 7.42 (1H, d, J = 7.6, H-9); 7.66 (1H, s, H-3). C NMR spectrum, δ,
1715

ppm: 66.5 (C-4); 117.6 (C-6); 120.2 (C-9b); 122.8 (C-9a); 123.1 (C-8); 124.2 (C-9); 127.0 (C-7); 130.9 (C-3); 131.2
(C-3a); 133.8 (C-2); 136.4 (C-5 tetrazole); 153.6 (C-5a).
8-Halo-4Н-thieno[3,2-c]chromene-2-carbaldehydes 7a,b (General Method). A mixture of 4Н-thieno-
[3,2-с]chromene-2-carbaldehyde (1) (0.260 g, 1.2 mmol) and N-bromo- or N-iodosuccinimide (1.3 mmol) in
AcOH (3 ml) with added catalytic amount of HClO4 was stirred for 4 h at room temperature. After the reaction
was complete, the mixture was poured into water and the precipitate formed was filtered off. The product was
purified by flash chromatography on 0.035-0.070 mm silica gel, eluent CHCl3.
8-Bromo-4Н-thieno[3,2-c]chromene-2-carbaldehyde (7a). Yield 0.319 g (90%). Amber colored
crystals. IR spectrum, ν, cm-1: 1648 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 5.28 (2H, s, CH2); 6.84 (1H, d,
3
4
13
3J = 8.7, H-6); 7.33 (1H, dd, J = 8.6, J = 2.3, H-7); 7.47-7.51 (2H, m, H-3,9); 9.87 (1H, s, CHO). C NMR
spectrum, δ, ppm: 65.8 (С-4); 114.5 (С-8); 118.9 (С-6); 120.9 (С-9a); 126.5 (C-7); 132.5 (C-9b); 132.6 (C-3);
133.7 (C-9); 140.6 (C-3a); 142.7 (C-2); 152.1 (C-5a); 182.2 (CHO).
8-Iodo-4Н-thieno[3,2-c]chromene-2-carbaldehyde (7b). Yield 0.246 g (60%). Amber colored
crystals. IR spectrum, ν, cm-1: 1650 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 5.29 (2H, s, CH2); 6.72 (1H, d,
3J = 8.5, H-6); 7.48 (1H, s, H-3); 7.51 (1H, dd, 3J = 8.6, 4J = 2.1, H-7); 7.66 (1H, d, 4J = 2.1, H-9); 9.86 (1H, s,
CHO). 13C NMR spectrum, δ, ppm: 65.8 (С-4); 84.2 (C-8); 119.3 (С-6); 119.6 (C-9b); 121.4 (С-9a); 132.4 (2С,
C-3,9); 139.7 (C-7); 140.4 (C-3a); 142.7 (C-2); 152.9 (C-5a); 182.1 (CHO).
(4Н-Thieno[3,2-c]chromen-2-yl)methanol (8) [19]. A solution of 4Н-thieno[3,2-с]chromene-2-carb-
aldehyde (1) (0.216 g, 1.0 mmol) in abs. EtOH (5 ml) was treated with NaBH4 (0.038 g, 1.0 mmol). The
reaction mixture was stirred at room temperature for 1-1.5 h. After the reaction was complete, H2O (10 ml) was
added and the product was extracted with Et2O (3×10 ml). The organic extracts were combined, dried over
Na2SO4, the solvent was removed by evaporation. The product was purified by column chromatography
(0.060-0.200 mm silica gel, eluent CH2Cl2). Yield 0.212 g (97%). Yellow oil. IR spectrum, ν, cm-1: 3445 (OH).
1H NMR spectrum, δ, ppm: 2.05 (1H, br. s, OH); 4.75-4.81 (2H, m, CH2OH); 5.21 (2H, s, 4-CH2); 6.71 (1H, s,
13
H-3); 6.88-6.96 (2H, m, H-6,8); 7.09-7.16 (1H, m, H-7); 7.22-7.26 (1H, m, H-9). C NMR spectrum, δ, ppm:
60.1 (CH2OH); 66.2 (C-4); 116.6 (C-6); 120.3 (C-9a); 121.9 (C-3); 122.6 (C-8); 122.8 (C-9); 128.7 (C-7); 131.2
(C-9b); 132.5 (C-3a); 143.4 (C-2); 152.0 (C-5a).
4-Methoxy-4H-thieno[3,2-c]chromene-2-carbaldehyde (9). A solution of 4Н-thieno[3,2-c]chromene-
2-carbaldehyde (1) (0.099 g, 0.457 mmol) in CH2Cl2 (5 ml) was treated with MeOH (0.022 ml, 0.543 mmol)
and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.124 g, 0.548 mmol). After stirring for 24 h at room
temperature, the reaction mixture was treated with 5% aqueous NaHCO3 (10 ml) and extracted with CH2Cl2
(3×15 ml). The combined organic extracts were washed with saturated NaCl solution and dried over Na2SO4.
The solvent was evaporated at reduced pressure, the residue was purified by column chromatography
(0.035-0.070 mm silica gel, eluent CH2Cl2). The product was recrystallized from МеОН. Yield 0.091 g (81%).
1
Colorless crystals. IR spectrum, ν, cm-1: 1663 (С=О). H NMR spectrum, δ, ppm (J, Hz): 3.57 (3H, s, OCH3);
6.16 (1H, s, 4-СН); 7.05-7.10 (1H, m, H-8); 7.12-7.15 (1H, m, H-6); 7.32-7.37 (1H, m, H-7); 7.50-7.54 (1H, dd,
4
13
3J = 7.7, J = 1.6, H-9); 7.67 (1H, s, H-3); 9.88 (1H, s, CHO). C NMR spectrum, δ, ppm: 55.5 (OCH3); 96.4
(C-4); 117.8 (2С, С-6,9a); 122.7 (C-8); 124.2 (C-7); 131.2 (C-9b); 131.3 (C-9); 134.2 (C-3); 142.1 (C-3a);
143.4 (C-2); 150.3 (C-5a); 182.4 (CHO).
4Н-Thieno[3,2-c]chromene-2-carboxylic Acid (10) [21]. A suspension of Ag2O was prepared from
concentrated aqueous solution of AgNO3 (0.493 g, 2.9 mmol) and 5 М aqueous NaOH (1.45 ml), and was added
to a stirred solution of aldehyde 1 (0.303 g, 1.4 mmol) in THF (3 ml) at a temperature not exceeding 10°C. The
cooling bath was removed, and the reaction mixture was stirred for further 2 h. Then the reaction mixture was
filtered through paper filter with suction, the filtrate was diluted with water to 20 ml, and acidified with conc.
HCl while cooling. The precipitate was filtered off and recrystallized from THF–hexane mixture. Yield 0.276 g
(85%). Light-green powder. IR spectrum, ν, cm-1: 2500-3250 (COOH), 1655 (C=O). 1Н NMR spectrum, δ, ppm
3
(J, Hz): 5.26 (2H, s, CH2); 6.95 (1H, d, J = 8.0, H-6); 6.92-7.04 (1H, m, H-8); 7.20-7.28 (1H, m, H-7); 7.42
3
4
13
(1H, dd, J = 7.5, J = 1.3, H-9); 7.58 (1H, s, H-3); 13.21 (1H, s, СОOH). C NMR spectrum, δ, ppm: 65.3
1716

(CH2); 116.8 (C-6); 119.1 (C-9a); 122.3 (C-8); 123.6 (C-9); 130.5 (C-3); 130.7 (C-7); 132.5 (C-9b); 133.0 (C-3a);
137.6 (C-2); 152.5 (C-5a); 162.8 (COOH).
Methyl 4Н-Thieno[3,2-c]chromene-2-carboxylate (11) [19, 21, 22]. A solution of 4Н-thieno[3,2-c]-
chromene-2-carboxylic acid (10) (0.929 g, 4.0 mmol) in MeOH (6.0 ml) was cooled and treated over 10 min
with SOCl2 (0.43 ml, 6.0 mmol). The mixture was refluxed for 2.5 h. The precipitate formed was filtered off and
1
recrystallized from MeOH. Yield 0.936 g (95%). Light-yellow crystals. IR spectrum, ν, cm-1: 1714 (C=O). H
NMR spectrum, δ, ppm (J, Hz): 3.89 (3H, s, ОСH3); 5.25 (2H, s, CH2); 6.91-7.01 (2H, m, H-6,8); 7.18-7.24
3
4
(1H, m, H-7); 7.34 (1H, dd, J = 7.7, J = 1.5, H-9); 7.51 (1H, s, H-3). 13C NMR spectrum, δ, ppm: 52.2
(ОCH3); 65.8 (C-4); 117.0 (C-6); 119.5 (C-9b); 122.2 (C-8); 123.6 (C-9); 130.2 (C-7); 130.4 (C-3); 131.6 (C-2);
131.7 (С-3a); 139.5 (C-9a); 152.9 (C-5a); 162.6 (C=O).
N-Hydroxy-4Н-thieno[3,2-c]chromene-2-carboxamide (12). Sodium metal (0.101 g, 4.4 mmol) was
dissolved in anhydrous MeOH (3 ml), then solution of NH2OH·HCl (0.140 g, 2.0 mmol) in anhydrous MeOH
(10 ml) was added, and the mixture was stirred for 20 min. The precipitate of NaCl was removed by filtration
and washed with anhydrous MeOH (10 ml), then ester 11 (0.492 g, 2.0 mmol) was added to the filtrate. The
obtained solution was heated on steam bath at 65-70°C until the reaction was complete (1.5-2 h). Methanol was
removed on rotary evaporator, the residue was dissolved in minimum amount of Н2О and acidified with АсОН
to pH 4. The precipitate formed was filtered off and recrystallized from a mixture of EtOH–H2O. Yield 0.480 g
1
(97%). Beige crystals. IR spectrum, ν, cm-1: 3355 (NH), 3250-2500 (OH), 1645 (C=O). H NMR spectrum, δ,
ppm (J, Hz): 5.24 (2H, s, CH2); 6.93 (1H, d, 3J = 8.0, H-6 ); 6.98 (1H, t, 3J = 7.5, H-8); 7.15-7.27 (1H, m, H-7);
7.38 (1H, d, 3J = 7.5, H-9); 7.43 (1H, s, H-3); 9.24 (1H, br. s, NH); 11.32 (1H, br. s, OH). 13C NMR spectrum, δ,
ppm: 65.4 (C-4); 116.8 (C-6); 119.3 (C-9b); 122.4 (C-8); 123.5 (C-9); 125.0 (C-7); 130.2 (C-3); 132.4 (C-3a);
132.6 (C-2); 135.0 (C-9a); 152.2 (C-2); 152.5 (C-5a).
Biological Studies. The antiulcer effect was studied on standard model of ulcers experimentally induced by
introducing 20 mg/kg of indometacin into stomach. The study was performed on 12 adult male rats of Vistar line
with mass of 200-220 g. The study compound was introduced as single dose of 100 mg/kg into the stomach 1 h
before the induction of ulcers. The animals were sacrificed 24 h later by decapitation under ether anesthesia.
The antiulcer effect was evaluated according to the following parameters:
1) Reduction in the number of ulcers and area of ulcers in the stomach lining by calculation of Paul's index
(product of the average number of ulcers on the number of animals with ulcers, divided by 100);
2) The antiulcer activity (AA), calculated by dividing the Paul's index (PI) of control group with the Paul's
index (PI) of test group (AA = PI control/ PI test). [20]. The study compounds were considered effective in
cases when AA reached 2 and more units.
The anti-inflammatory effect was determined by the histamine-induced mouse paw edema index. Mice
were divided in groups, and the study compound (100 mg/kg) was introduced three times at 1 h intervals. One
hour after the first introduction of study compounds all mice were injected with 0.05 ml of 0.1% aqueous
histamine solution (as phlogogenic agent) in the subplanar pad area of hind paw. Three hours after the last
injection the animals were sacrificed by craniocervical dislocation, the hind paws were removed below ankle
and each was weighed. The anti-inflammatory effect was estimated by the reduction in swelling index,
compared to control. The swelling index was determined by dividing the mass difference between healthy and
inflamed paw with the mass of healthy paw, expressed as percentage [23].
The work was performed with financial support from the Russian Foundation for Basic Research
(project 12-03-98013Р_Sibir_а) and grant "Young Scientists of Omsk State University" (project MU-4/2014).
The NMR spectra were acquired on equipment of the Collective Use Center of the Institute of Organic
Chemistry, Siberian Branch of Russian Academy of Sciences.
1717

REFERENCES
1.
2.
3.
4.
5.
6.
7.
M. I. Hegab and M. M. Abdulla, Arch. Pharm. Chem. Life Sci., 339, 41 (2006).
K. C. Majumdar and A. Biswas, Monatsh. Chem., 135, 1001 (2004).
Y. Makisumi, JP Pat. Appl. 48000597 (1972).
Y. Makisumi, JP Pat. Appl. 48000596 (1973).
V. V. Mulwad and J. M. Shirodkar, Indian J. Heterocycl. Chem., 12, 311 (2003).
M. J. Meegan and D. V. Tyndall, J. Chem. Res., Synop., 239 (1981).
D. F. Rogers, R. W. Godfrey, K. Castro, S. Majumdar, and P. K. Jeffery, Agents Actions, 33, 358
(1991).
8.
9.
S. E. Webber and J. G. Widdicombe, Agents Actions, 24, 65 (1988).
C. G. Rimbault, EP Pat. Appl. 0193493.
10.
11.
M. Taguchi, R. Suzuki, and A. Mikami, WO Pat. Appl. 2006080439.
A. L. Smith, P. E. Brennan, F. F. Demorin, G. Liu, N. A. Paras, and D. M. Retz, WO Pat. Appl.
2006066172.
12.
13.
14.
15.
16.
17.
L. Bao and A. Kimzey, WO Pat. Appl. 2004093803 (2004).
T. D. Mckee, R. K. Suto, T. Tibbitts, and J. Sowadski, WO Pat. Appl. 2004028535.
T. D. Mckee, R. K. Suto, T. Tibbitts, and J. Sowadski, WO Pat. Appl. 03074497.
T. A. Grese, WO Pat. Appl. 9709044.
A. L. Katsiel, A. N. Sharipova, and A. S. Fisyuk, Mendeleev Commun., 18,169 (2008).
A. S. Fisyuk, Yu. P. Bogza, L. V. Belyaeva, and V. B. Belyaev, Chem. Heterocycl. Compd., 48, 1078
(2012). [Khim. Geterotsikl. Soedin., 48, 1160 (2012).]
18.
19.
20.
21.
R. A. Navarro, L. C. Bleye, A. Gonzalez-Ortega, and M. C. S. Ruiz, Heterocycles, 55 (12), 2369 (2001).
B. Chandra Sekhar, D. V. Ramana, and S. R. Ramadas, Sulfur Lett., 9, 271 (1989).
Y.-C. Xu, E. Lebeau, J. W. Gillard, and G. Attardo , Tetrahedron Lett., 34, 3841 (1993).
J. Barbosa, K. G. Carson, M. W. Gardyan, J. P. Healy, Q. Han, R. Mabon, P. Pabba, J. Tarver, Jr.,
K. M. Terranova, A. Tunoori, and X. Xu, US Pat. Appl. 2012302562.
S. Do, R. Goldsmith, T. Heffron, A. Kolesnikov, S. Staben, A. G. Olivero, M. Siu, D. P. Sutherlin,
B.-Y. Zhu, P. Goldsmith, T. Bayliss, A. Folkes, and N. Pegg, US Pat. Appl. 2009247567.
А. N. Mironov (editor), Manual of Preclinical Studies of Medicines [in Russian], Vol. 1, Grif & Co.,
Moscow (2012).
22.
23.
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