Synthesis and anti-inflammatory activity of 8H-1-thia-8-aza-dibenzo[e,h] azulenes

Article abstract of DOI:10.1002/jhet.605

Figure represented. Synthesis of a novel class of fused heterotetracyclic compounds, 8H-1-thia-8-aza-dibenzo[e,h]azulenes (VII), is described. Starting N-benzoyl-protected 5H-dibenzo[b,f]azepine (XI, PG = Bz) was oxidized to 5-benzoyl-10,11-epoxy-10,11-di

Full text of DOI:10.1002/jhet.605

856
Synthesis and Anti-Inflammatory Activity of 8H-1-Thia-8-
aza-dibenzo[e,h]azulenes
Vol 48
ˇ ´ ´ ´
Ivana Ozimec Landek,* Dijana Pesic, Mladen Mercep [1], Barbara Stanic [1],
´
and Milan Mesic
´
GlaxoSmithKline Research Centre Zagreb Limited, Prilaz baruna Filipovica 29,
10000 Zagreb, Croatia
*E-mail: ivana.o.ozimec-landek@gsk.com
Received April 21, 2010
DOI 10.1002/jhet.605
Published online 15 April 2011 in Wiley Online Library (wileyonlinelibrary.com).
Synthesis of a novel class of fused heterotetracyclic compounds, 8H-1-thia-8-aza-dibenzo[e,h]azulenes
(VII), is described. Starting N-benzoyl-protected 5H-dibenzo[b,f]azepine (XI, PG ¼ Bz) was oxidized
to 5-benzoyl-10,11-epoxy-10,11-dihydro-5H-dibenzo[b,f]azepine (2), which subsequently rearranged in
Lewis acid-induced epoxide ring opening to give 5-benzoyl-5,11-dihydro-10H-dibenzo[b,f]azepin-10-
one (3). Vilsmeier reaction of 3 provided b-chlorovinyl aldehyde 4 that readily cyclized with ethyl 2-
mercaptoacetate to form dibenzazepino[4,5]-fused thiophene structure 5. Further transformation of sub-
stituent at C-2 position of 5 and N-deprotection led to final aminoalkoxy derivatives 9. All compounds
with tetracyclic skeleton were tested in vitro for their anti-inflammatory activity.
J. Heterocyclic Chem., 48, 856 (2011).
INTRODUCTION
preliminary biological results of dibenzo[e,h]azulenes
characterized by furan III [15], pyrrole IV [16], thio-
phene V [17], and imidazole ring VI [18] annulated to
the central oxepine or thiepine ring (Fig. 1). Preliminary
data revealed the ability of these polycyclic systems to
inhibit TNF-a production in vitro. Herein, we wish to
report on the continuation of our project with the study
of 8H-1-thia-8-aza-dibenzo[e,h]azulenes [19], a series
that embodies central azepine and [2,3]-fused thiophene
ring VII (Fig. 1) and may be perceived as a combination
of structural subunits I and II. Target molecules, both 8-
N-substituted and 8-N-unsubstituted, bearing an alkoxy
chain of variable length and a basic moiety at position
C-2 are expected to possess significant anti-TNF-a activ-
ity [20] and desirable pharmacokinetic properties.
Dibenzo[b,f]azepine framework is found within a num-
ber of medicinally important compounds, particularly
those acting at central nervous system (for example, see
refs. 2–4). Antidepressants imipramine (Ia, Y ¼ H) and
its 3-chloro analog clomipramine (Ia, Y ¼ Cl), as well as
antiepileptics carbamazepine (Ib) and oxcarbazepine (Ic)
are examples of compounds bearing such tricyclic moiety
that are well known as widely prescribed drugs (Fig. 1).
Furthermore, there is a growing pool of evidence that tri-
cyclic antidepressants-like imipramine and its derivatives
also possess pronounced anti-inflammatory and analgesic
properties (for example, see refs. 5–13).
On the other hand, some members of a series of 5-
substituted 2,3-diaryl-thiophenes (II) were also reported
to have significant anti-inflammatory activity through
strong inhibition of necrosis factor alpha (TNF-a) pro-
duction [14].
RESULTS AND DISCUSSION
In our continuing efforts aimed toward synthesis and
determination of anti-inflammatory activity of various
heterocyclic dibenzo[e,h]azulenes, we recently reported
on the synthesis, properties, structure determination, and
Chemistry. The tetracyclic structure VII is formed
by annulation of the thiophene ring onto the existing tri-
cyclic dibenzo[b,f]azepine moiety, as is shown by the
retrosynthetic sequence in Scheme 1. To enable this, the
C
V
2011 HeteroCorporation

July 2011
Synthesis and Anti-Inflammatory Activity of 8H-1-Thia-8-aza-dibenzo[e,h]azulenes
857
Figure 1. Structural combination into 8H-1-thia-8-aza-dibenzo[e,h]azulenes and structures of known heterocyclic dibenzo[e,h]azulenes.
double bond of the commercially available 5H-diben-
zo[b,f]azepine (iminostilbene, 1) is converted in four
steps into the b-chlorovinyl aldehyde functionality, a
useful three carbon synthon for the efficient regiospe-
cific annulation by the Fiesselmann reaction. According
to the designed synthetic route that comprises peracid
oxidation of the double bond and Vilsmeier reaction,
selection of the appropriate protective group (PG) for
iminostilbene nitrogen was of a key importance to
assure reactivity of the intermediates and chemoselectiv-
ity in following steps, as is discussed below.
It is reported that chemical properties of the epoxy
ring in X are dependent on the nature of the substituents
at the nitrogen atom. Thus, when iminostilbene was
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

ˇ ´ ´ ´ ´
I. Ozimec Landek, D. Pesic, M. Mercep, B. Stanic, and M. Mesic
858
Vol 48
reacted with organic peracids, 9-acridinecarbaldehyde
and its N-oxide were obtained instead of 5H-dibenzo[b,f]-
azepine-10,11-oxide (X, PG ¼ H) [21]. Additionally,
oxidation of the 10,11-double bond of N-alkyl- and N-
benzyl-dibenzo[b,f]azepines presumably provides 10,11-
oxides, but the oxirane ring is labile enough to facilitate
further conversion of the compound to diphenylamine
and acridone derivatives [22,23]. On the other hand, oxi-
dation of N-acyl-dibenzo[b,f]azepines with m-chloroper-
benzoic acid afforded the corresponding N-acyl-diben-
zo[b,f]azepine-10,11-oxides (X, PG ¼ acyl) that were
stable [22,23]. Moreover, considering reactivity of N-
acyl- and N-alkyl-dibenzo[b,f]azepines toward electro-
philes, it is found that N-alkyl and N-benzyl derivatives
readily react by introducing the substituent, including a
formyl group by means of the Vilsmeier reaction, into
the aromatic ring to form derivatives with para-substitu-
tion pattern to nitrogen [24]. On the contrary, N-acylated
derivatives show different behavior toward electrophiles
and from the observed deactivation of the aromatic rings
by N-acylation, it is expected that electrophilic attack
should occur preferentially at the 10(11)-position, i.e., at
the ethano bridge [25,26]. Obviously, an acyl-type PG
would assure desirable level of reactivity in oxidation
and correct directing in Vilsmeier reaction. However,
Vilsmeier reagent also reacts with an amide group adja-
cent to a potential C-nucleophile, as is the case with
alkylacyl groups like, e.g., acetyl [27,28]. Hence, ben-
zoyl group turned the best choice as PG since all antici-
pated issues regarding chemoselectivity during deprotec-
tion step were solved and it appeared as suitable for
synthesis of both N-substituted and N-unsubstituted 8H-
1-thia-8-aza-dibenzo[e,h]azulenes.
(58%). Reaction of 4 with ethyl 2-mercaptoacetate finally
afforded novel heterotetracyclic, 8H-1-thia-8-aza-diben-
zo[e,h]azulene structure 5 (61%). Ester group at C-2
allows further transformation toward more functionalized
final molecules. We were primarily interested in 8-N-
unsubstituted derivatives with x-aminoalkyl ether chains
at the C-2 position (like 9c), but 8-N-substituted com-
pounds (like 9a and 9b) would be equally attractive tar-
gets considering potential difference in anti-TNF-a activ-
ity. Our initial attempts to reduce 5 with 1–2 equiv. of
lithium aluminum hydride (LAH) in diethyl ether at room
temperature led to complex mixture where 6, with both
ester and amide group reduced, was the main product, and
7, with intact N-benzoyl group, isolated only in low yield
and with insufficient purity. However, the use of 4 equiv.
of LAH under the same conditions gave 6 almost exclu-
sively. Nevertheless, in our hands, cleavage of N-benzyl
bond in 6 failed under catalytic transfer hydrogenolysis
[31], with ceric ammonium nitrate [32] and with hydrobro-
mic acid [33]. With a large excess (60–100 equiv.) of so-
dium borohydride in methanol at the reflux temperature,
we succeeded in selective reduction of ester bond obtain-
ing 7 (69%), which on basic hydrolysis easily provided
8-N-deprotected 8 (69%). To avoid such a large excess of
sodium borohydride, we also tried the reaction with more
reactive lithium borohydride [34] in diethyl ether but
besides 7, a number of side products were obtained.
Finally, alcohols 6–8 were converted to their
x-(dimethyl)aminoalkyl ethers 9a–c by a phase transfer-
catalyzed alkylation with the appropriate x-(dimethyl)-
chloroalkylamine hydrochlorides in the presence of ben-
zyl triethyl ammonium chloride as a catalyst [35]. Pure
x-aminoalkyl ethers were isolated by column chroma-
tography as resins and biologically tested as free bases.
Anti-inflammatory activity. Novel tetracyclic com-
pounds were tested for their ability to inhibit TNF-a
secretion in lipopolysaccharide (LPS)-activated human
peripheral blood mononuclear cells (hPBMC) assay
[36,37]. Compounds belonging to series 9a–c, possess-
ing aminoalkoxy chain at C-2 position, showed potency
to inhibit TNF-a production in vitro in low micromolar
range with IC50 values for the most potent compounds
in the range of 1–3 lM.
Synthetic route to 8H-1-thia-8-aza-dibenzo[e,h]azulene
scaffold is depicted in Scheme 2. Benzoylation of the
starting iminostilbene (1) and subsequent peracid oxidation
of the double bond to provide 10,11-dihydro-10,11-epoxy-
derivative 2 proceeded smoothly as previously described
[22,25]. Lithium iodide induced ring opening and rear-
rangement [29] of oxirane 2 resulted in highly selective
formation of isomeric 10-keto derivative 3 (67%).
1
As is shown by H-NMR, methylene protons at C-11
in compound 3 are nonequivalent and form an AX spin
system, which gives rise to a pair of doublets at d ¼ 3.96
ppm and d ¼ 4.81 ppm with J ¼ 15.0 Hz. Most likely it
is the effect of a hindered rotation about the N-acyl bond,
which decreases the rate of ring inversion [30] thus keep-
ing the central seven-membered ring in a conformation of
a distorted symmetry with the two geminal protons sub-
jected to different magnetic environments.
In conclusion, 8H-1-thia-8-aza-dibenzo[e,h]azulenes
(VII), particularly derivatives with aminoalkoxy chain
linked at thiophene ring, were recognized as a novel class
of fused heterocyclic compounds showing anti-inflamma-
tory activity through inhibition of TNF-a secretion.
EXPERIMENTAL
To enable annulation of thiophene ring in the succeed-
ing step, tricyclic ketone 3 that contains active methylene
group was reacted with in situ formed Vilsmeier reagent
to give a key intermediate, b-chlorovinyl aldeyde 4
Chemistry—general methods. Commercial reagents were
used as received without additional purification. All used
chemicals and solvents were p.a. purity. Melting points were
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Synthesis and Anti-Inflammatory Activity of 8H-1-Thia-8-aza-dibenzo[e,h]azulenes
859
Scheme 2
determined using Bu¨chi Melting Point B-545 apparatus and
are uncorrected. IR spectra were recorded on Nicolet Magna
IR 760 FTIR spectrophotometer. NMR spectra were recorded
at room temperature on Bruker Avance DPX 300 spectrometer
at 300 MHz using tetramethylsilane as internal standard. Purity
of the compounds was estimated by high pressure liquid chro-
matography (HPLC)-MS system Waters 2690 þ Micromass
Quattro Micro, by HPLC-UV system Waters 2690 þ Waters
996 Photodiode Array Detector, or by GC-MS system Varian
Chrompack Saturn 2000. High resolution mass spectrometry
(HRMS) data were acquired using Q-TOF 2 Waters system.
Preparative HPLC separations were done using Waters Mass
Directed AutoPurification System. Microanalyses were per-
formed using Perkin-Elmer 2400 CHNS analyzer. Thin layer
chromatography (TLC) was performed on aluminum plates
Merck Silica gel 60 F254 with UV light detection at 254 nm
and/or 365 nm. Proportions of solvents used for TLC are by
volume. Column chromatography was performed on silica gel
60 (Merck, 0.063–0.200 nm).
5-Benzoyl-5H-dibenzo[b,f]azepine (XI, PG 5 Bz). Prepared
according to refs. 22 and 25 from commercially available 5H-
dibenzo[b,f]azepine (iminostilbene, 1); crystallized from n-hex-
ane; pale yellow crystals; 96%; mp 131–133ꢀC; IR (potassium
bromide): 3055, 3025, 1660 (C¼¼O), 1619, 1598, 1567, 1489,
1
1460, 1436, 1343, 1304, 1271, 1130, 1117 cmꢁ1; H-NMR (di-
methyl sulfoxide d6): d 7.20–7.56 ppm (m, 15H, arom. þ
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

ˇ ´ ´ ´ ´
I. Ozimec Landek, D. Pesic, M. Mercep, B. Stanic, and M. Mesic
860
Vol 48
HC¼¼CH); 13C-NMR (dimethyl sulfoxide d6): d 127.3 (CH),
127.4 (CH), 127.7 (CH), 128.5 (CH), 128.9 (CH), 129.4 (CH),
133.7 (C), 135.4 (C), 168.8 ppm (C¼¼O); MS: m/z 298 (MHþ,
100%); HRMS: m/z calcd for C21H16NO: 298.1232 (MHþ),
found: 298.1232.
tate 10:0.5) to give 1.10 g (58 %) of 4 as pale yellow powder.
The analytical sample is recrystallized from hexane/diethyl
ether 5:1; mp 138.5–139.5ꢀC; IR (potassium bromide): 3055,
2872, 1666 (C¼¼O), 1596, 1580, 1544, 1495, 1480, 1453,
1
1441, 1346, 1313, 1284, 1132, 1069 cmꢁ1; H-NMR (dimethyl
sulfoxide d6): d 7.20–7.80 (m, 12H, arom.), 7.93 (bd, 1H, J ¼
7.5 Hz, arom.), 10.65 ppm (s, 1H, CHO); 13C-NMR (dimethyl
sulfoxide d6): d 126.8 (CH), 127.5 (CH), 127.9 (CH), 128.1
(CH), 129.4 (CH), 129.9 (CH), 130.2 (CH), 130.7 (CH), 132.7
(CH), 134.5 (2 ꢂ C), 167.9 (C¼¼O amide), 190.8 ppm (CHO);
MS: m/z 360, 362 (MHþ, 100%, 40%); HRMS: m/z calcd for
C22H15ClNO2: 360.0791 (MHþ), found: 360.0801. Anal Calcd
for C22H14ClNO2: C, 73.44; H, 3.92; N, 3.89. Found: C,
73.65; H, 4.02; N, 3.84.
5-Benzoyl-10,11-dihydro-10,11-epoxy-5H-dibenzo[b,f]-
azepine (2). Prepared according to ref. 22 from XI (PG ¼
Bz); recrystallized from ethyl acetate; pale yellow crystals;
55%; mp 188–190ꢀC; IR (potassium bromide): 3064, 1661
(C¼¼O), 1583, 1493, 1446, 1344, 1305 cmꢁ1
;
1H-NMR (di-
methyl sulfoxide d6): d 4.58 (s, 2H, 2 ꢂ CH epox.), 7.00–7.70
ppm (m, 13H, arom.); 13C-NMR (dimethyl sulfoxide d6): d
57.4 (CH epox.), 127.4 (CH), 127.6 (CH), 127.7 (CH), 129.2
(CH), 129.3 (CH), 129.7 (CH), 130.1 (C), 130.9 (CH), 136.0
(C), 168.0 ppm (C¼¼O); MS: m/z 314 (MHþ, 100%); HRMS
m/z calcd for C21H16NO2: 314.1181 (MHþ), found: 314.1192.
Ethyl 8-benzoyl-8H-1-thia-8-aza-dibenzo[e,h]azulene-2-car-
boxylate (5). To the solution of 4 (0.87 g, 2.4 mmol) in pyri-
dine (6 mL), ethyl 2-mercaptoacetate (0.76 g, 4.6 mmol) and
triethylamine (2 mL) were added. The reaction mixture was
stirred at 70ꢀC for 1 h and then at reflux temperature for addi-
tional 2 h. Solvents were removed under reduced pressure and
the residue was partitioned between water and ethyl acetate.
The aqueous phase was extracted with ethyl acetate (2 ꢂ 25
mL). The combined organic extracts were washed with dil.
HCl (5%) and water, boiled with decolorizing charcoal for 5
min, filtered and filtrate dried (sodium sulfate), and solvent
evaporated. Recrystallization of thus obtained crude product
from ethyl acetate/hexane 1:2 gave 0.62 g (61%) of 5 as color-
less powder; mp 165–167.5ꢀC; IR (potassium bromide): 1712
(C¼¼O), 1667 (C¼¼O), 1600, 1495, 1480, 1468, 1446, 1424,
5-Benzoyl-5,11-dihydro-10H-dibenzo[b,f]azepin-10-one
(3). Lithium iodide (1.00 g, 0.0075 mol) was added to the so-
lution of 2 (2.22 g, 0.0071 mol) in chloroform (30 mL). The
reaction mixture was heated at reflux temperature for 1 h and
then allowed to cool to room temperature. The mixture was
washed with aq. sodium hydrogen sulfite (25 mL) and water
(30 mL). The organic phase was dried (sodium sulfate) and
solvent was evaporated. The crude product was purified by
column chromatography (silica gel, eluent: dichloromethane/
ethyl acetate 10:0.5) to give 1.50 g (67%) of 3 in the form of
pale yellow crystals; mp 185–186.5ꢀC; IR (potassium bro-
mide): 3068, 3050, 1674 (C¼¼O), 1657 (C¼¼O), 1596, 1580,
1567, 1489, 1474, 1447, 1416, 1329, 1284, 1255, 1235, 1158,
1
1383, 1329, 1290, 1257, 1206, 1076 cmꢁ1; H-NMR (dimethyl
1114, 1073, 1025 cmꢁ1 1H-NMR (dimethyl sulfoxide d6): d
;
sulfoxide d6): d 1.37 (t, 3H, CH3), 4.40 (q, 2H, CH2), 7.06–
7.10 (m, 2H, arom.), 7.18–7.30 (m, 4H, arom.), 7.30–7.85 (m,
7H, arom.), 8.33 ppm (s, 1H, thioph.); 13C-NMR (dimethyl
sulfoxide d6): d 14.1 (CH3), 61.4 (CH2), 127.3 (CH), 127.8
(CH), 128.2 (CH), 128.5 (CH), 128.6 (CH), 128.8 (CH), 128.9
(CH), 129.2 (CH), 129.7 (CH), 130.4 (CH), 133.9 (CH), 132.2
(C), 135.0 (C), 161.0 (C¼¼O), 168.6 ppm (C¼¼O); MS: m/z 426
(MHþ, 100%); HRMS: m/z calcd for C26H20NO3S: 426.1164
(MHþ), found: 426.1174. Anal Calcd for C26H19NO3S: C,
73.39; H, 4.50; N, 3.29; S, 7.54. Found: C, 72.93; H, 4.54; N,
3.58; S, 7.81.
3.96 (d, 1H from CH2, J ¼ 15.0 Hz), 4.81 (d, 1H from CH2, J
¼ 15.0 Hz), 7.22–7.55 (m, 12H, arom.), 7.97 ppm (d, 1H, J ¼
7.6 Hz, arom.); 13C-NMR (dimethyl sulfoxide d6): d 48.9
(CH2), 127.6 (CH), 127.9 (CH), 128.1 (CH), 128.3 (CH),
128.5 (CH), 128.7 (CH), 129.4 (CH), 129.8 (CH), 129.9 (CH),
130.2 (CH), 134.0 (CH), 129.3 (C), 132.4 (C), 135.4 (C),
142.1 (C), 144.0 (C), 168.6 (C¼¼O amide), 192.4 ppm (C¼¼O
ketone); MS: m/z 314 (MHþ, 100%); HRMS m/z calcd for
C21H16NO2: 314.1181 (MHþ), found: 314.1189. Anal Calcd
for C21H15NO2: C, 80.49; H, 4.82; N, 4.47. Found: C, 80.56;
H, 4.80; N, 4.27.
5-Benzoyl-11-chloro-5H-dibenzo[b,f]azepine-10-carbaldehyde
(4). To N,N-dimethylformamide (0.82 mL, 10.6 mmol) previ-
ously cooled to 0ꢀC, phosphorus(III) oxychloride (0.74 mL,
8.0 mmol) was added dropwise with continuous stirring and in
an inert atmosphere, while maintaining the reaction tempera-
ture below 10ꢀC. Dichloromethane (2.5 mL) was added and
the resulting mixture was stirred at room temperature for 2 h.
Then solution of 3 (1.66 g, 5.3 mmol) in dichloromethane (12
mL) was added dropwise and reaction mixture was stirred at
room temperature for 2 days, when by TLC checking (eluent:
dichloromethane/ethyl acetate 10:0.5), the reaction progress
was not further noticeable. Crushed ice was added and the
mixture was stirred until ice had melted. Then solid sodium
acetate (3 g) was added and the mixture was stirred for addi-
tional 5 min. The organic phase was separated and the aqueous
portion was extracted with dichloromethane (2 ꢂ 35 mL). The
combined organic extracts were washed with sat. aq. sodium
hydrogen carbonate and brine, dried (sodium sulfate), and sol-
vent evaporated. The crude product was purified by column
chromatography (silica gel, eluent: dichloromethane/ethyl ace-
(8-Benzyl-8H-1-thia-8-aza-dibenzo[e,h]azulen-2-yl)methanol
(6). To the suspension of LAH (0.78 g, 20.0 mmol) in diethyl
ether (50 mL), ester 5 (2.16 g, 5.1 mmol) was added in small
portions. The mixture was stirred at room temperature for 2 h,
when TLC (eluent: dichloromethane/ethyl acetate 10:0.5)
showed total conversion. The excess of LAH was destroyed by
dropwise addition of water/diethyl ether 1:1. The inorganic
precipitate was filtered off and washed few times with ether.
The filtrate was boiled with decolorizing charcoal for 5 min,
filtered and filtrate dried (sodium sulfate), and solvent evapo-
rated. The crude product was purified by column chromatogra-
phy (eluent as for TLC) providing 1.25 g (67%) of 6 as yel-
lowish foam; mp 83–86ꢀC; IR (potassium bromide): 3600–
3100 (broad, OH), 3060, 2925, 1489, 1452, 1370, 1326, 1237,
1135, 1028, 1008 cmꢁ1 1H-NMR (dimethyl sulfoxide d6): d
;
4.78 (d, 2H, J ¼ 5.7 Hz, CH2OH), 5.00, 5.06 (2 irregular dou-
blets, each 1H, benzylic CH2, J ¼ 14.9 Hz), 5.69 (t, 1H, J ¼
5.7 Hz, OH), 7.04–7.42 ppm (m, 14H, arom. þ thioph.); 13C-
NMR (dimethyl sulfoxide d6): d 54.1 (CH2), 58.7 (CH2), 121.1
(CH), 121.2 (CH), 124.2 (2 ꢂ CH), 125.1 (CH), 126.8 (CH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Synthesis and Anti-Inflammatory Activity of 8H-1-Thia-8-aza-dibenzo[e,h]azulenes
861
127.8 (2 ꢂ CH), 127.9 (CH), 128.2 (CH), 128.4 (CH), 128.9
(CH), 130.2 (C), 131.7 (C), 137.6 (C), 138.0 (C), 138.2 (C),
145.8 (C), 149.9 (C), 150.2 ppm (C); MS: m/z 370 (MHþ,
100%); HRMS: m/z calcd for C24H20NOS: 370.1266 (MHþ),
found: 370.1286. Anal Calcd for C24H19NOS: C, 78.02; H,
5.18; N, 3.79; S, 8.68. Found: C, 77.48; H, 5.30; N, 4.05; S,
8.55.
ammonia 90:10:1.5). Then, it was cooled to room temperature,
diluted with water, and product was extracted with dichloro-
methane (2 ꢂ 25 mL). The combined organic extracts were
washed with brine, dried (sodium sulfate), and solvent evapo-
rated. Column chromatography (eluent: dichloromethane/meth-
anol/ammonia) provided pure 9.
[2-(8-Benzyl-8H-1-thia-8-aza-dibenzo[e,h]azulen-2-ylmethoxy)-
ethyl]dimethylamine (9a, n 5 2). This compound was obtained
starting from 6 (0.20 g, 0.54 mmol) and 2-chloroethyl di-
methyl ammonium chloride (1.10 g, 7.6 mmol) as described in
procedure above; purified by column chromatography (eluent:
dichloromethane/methanol/ammonia 91:8:1.5); yellow resin;
0.15 g (63%); IR (film): 3061, 3029, 2936, 2854, 2817, 2769,
(8-Benzoyl-8H-1-thia-8-aza-dibenzo[e,h]azulen-2-yl)methanol
(7). To the solution of 5 (0.56 g, 1.3 mmol) in methanol
(30 mL), sodium borohydride (4.50 g, 0.12 mol) was added
portionwise. The reaction mixture was heated at reflux temper-
ature for 2 h. When TLC (eluent: dichloromethane/ethyl ace-
tate 5:1) showed total conversion, water (50 mL) was added
and product extracted with ethyl acetate (3 ꢂ 30 mL). The
combined organic extracts were dried (sodium sulfate) and sol-
vent evaporated. The crude product was purified by column
chromatography (eluent as for TLC) to give 0.40 g (69%) of 7
as colorless foam; mp 106–108ꢀC; IR (potassium bromide):
3600–3100 (broad, OH), 3058, 2922, 1651 (C¼¼O), 1598,
1597, 1488, 1453, 1369, 1327, 1238, 1135, 1104 cmꢁ1 1H-
;
NMR (deuteriochloroform): d 2.42 (s, 6H, 2 ꢂ CH3), 2.73 (t,
2H, J ¼ 5.5 Hz, CH2N), 3.77 (t, 2H, J ¼ 5.5 Hz, OCH2), 4.80
(s, 2H, Ar-CH2), 4.96, 5.02 (2 irregular doublets, each 1H,
benzylic CH2, J ¼ 14.6 Hz), 6.96–7.15 (m, 5H, arom.), 7.17–
7.25 (m, 7H, arom.), 7.34–7.39 ppm (m, 2H, arom.); 13C-NMR
(deuteriochloroform): d 45.1 (2 ꢂ CH3), 54.7 (CH2), 58.2
(CH2), 67.0 (CH2), 67.7 (CH2), 120.3 (CH), 120.5 (CH), 123.6
(CH), 123.7 (CH), 126.4 (CH), 127.3 (CH), 127.5 (2 ꢂ CH),
127.7 (CH), 127.80 (2 ꢂ CH), 127.84 (CH), 128.35 (CH),
128.43 (CH), 130.4 (C), 131.8 (C), 137.5 (C), 138.0 (C), 139.2
(C), 139.7 (C), 149.8 (C), 150.1 ppm (C); MS: m/z 441 (MHþ,
55%), 352 ([M-O(CH2)2N(CH3)2]þ, 100%); HRMS: m/z calcd
for C28H29N2OS: 441.2001 (MHþ), found: 441.2000. Anal
Calcd for C28H28N2OS: C, 76.33; H, 6.41; N, 6.36; S, 7.28.
Found: C, 76.24; H, 6.58; N, 6.89; S, 6.95.
1
1574, 1494, 1476, 1446, 1343, 1133, 1027 cmꢁ1; H-NMR (di-
methyl sulfoxide d6): d 4.82 (d, 2H, J ¼ 5.7 Hz, CH2), 5.79 (t,
1H, J ¼ 5.7 Hz, OH), 7.07–7.70 ppm (m, 14H, arom. þ thi-
oph.); 13C-NMR (dimethyl sulfoxide d6): d 58.7 (CH2), 127.5
(CH), 128.0 (CH), 128.2 (CH), 128.55 (CH), 128.58 (CH),
128.7 (CH), 129.0 (CH), 129.1 (CH), 129.9 (CH), 135.4 (C),
147.3 (C), 168.7 ppm (C¼¼O); MS: m/z 384 (MHþ, 100%);
HRMS: m/z calcd for C24H18NO2S: 384.1058 (MHþ), found:
384.1062. Anal Calcd for C24H17NO2S: C, 75.17; H, 4.47; N,
3.65; S, 8.36. Found: C, 74.88; H, 4.60; N, 3.89; S, 8.09.
[3-(8-Benzyl-8H-1-thia-8-aza-dibenzo[e,h]azulen-2-ylmethoxy)-
propyl]dimethyl-amine (9a,
(8H-1-Thia-8-aza-dibenzo[e,h]azulen-2-yl)methanol (8). To
the solution of 7 (0.18 g, 0.46 mmol) in ethanol (2 mL), potas-
sium hydroxide (1.0 g, 17.8 mmol) and water (1 mL) were
added. The reaction mixture was heated at reflux temperature
for 2 h, during which the product was separated at the flask
wall. When the reaction completed, solvent was evaporated,
water (10 mL) was added, and product was extracted with
dichloromethane (2 ꢂ 10 mL). The combined organic extracts
were dried (sodium sulfate) and solvent evaporated. Thus,
obtained crude product was purified by column chromatogra-
phy (eluent: dichloromethane/ethyl acetate 5:1) to give 90 mg
(69%) of 8 in the form of yellow crystals; mp 181–183ꢀC; IR
(potassium bromide): 3303, 3252 (OH and NH stretching),
3053, 2941, 1579, 1473, 1426, 1296, 1236, 1157, 1135, 1016
n 5 3). This compound was
obtained starting from 6 (0.20 g, 0.54 mmol) and 3-chloro-
propyl dimethyl ammonium chloride (1.20 g, 7.6 mmol) as
described in procedure above; purified by column chromatog-
raphy (eluent: dichloromethane/methanol/ammonia 91:8:1.5);
yellow resin; 0.15 g (61%); IR (film): 3061, 3029, 2941, 2855,
2814, 2764, 1597, 1488, 1453, 1372, 1326, 1238, 1210, 1135,
1096 cmꢁ1 1H-NMR (deuteriochloroform): d 1.88–1.98 (m,
;
2H, CH2CH2CH2), 2.35 (s, 6H, 2 ꢂ CH3), 2.56 (t, 2H, J ¼ 7.5
Hz, CH2N), 3.68 (t, 2H, J ¼ 6.4 Hz, OCH2), 4.76 (s, 2H, Ar-
CH2), 4.96, 5.02 (2 irregular doublets, each 1H, benzylic CH2,
J ¼ 14.6 Hz), 6.96–7.26 (m, 12H, arom.), 7.35–7.40 ppm (m,
2H, arom.); 13C-NMR (deuteriochloroform): d 27.1 (CH2),
44.7 (2 ꢂ CH3), 54.8 (CH2), 56.2 (CH2), 67.5 (CH2), 68.0
(CH2), 120.3 (CH), 120.5 (CH), 123.6 (CH), 123.7 (CH),
126.4 (CH), 126.9 (CH), 127.5 (2 ꢂ CH), 127.7 (CH), 127.8
(3 ꢂ CH), 128.35 (CH), 128.38 (CH), 130.4 (C), 131.9 (C),
137.5 (C), 137.9 (C), 139.5 (C), 139.6 (C), 149.8 (C), 150.1
ppm (C); MS: m/z 455 (MHþ, 50%), 352 ([M-
O(CH2)3N(CH3)2]þ, 100%); HRMS: m/z calcd for
C29H31N2OS: 455.2157 (MHþ), found: 455.2163. Anal Calcd
for C29H30N2OS: C, 76.61; H, 6.65; N, 6.16; S, 7.05. Found:
C, 76.69; H, 6.69; N, 6.46; S, 7.57.
cmꢁ1
;
1H-NMR (dimethyl sulfoxide d6): d 4.65 (d, 2H, J ¼
5.7 Hz, CH2), 5.58 (t, 1H, J ¼ 5.7 Hz, OH), 6.90–6.99 (m,
4H, arom.), 7.08 (s, 1H, thioph.), 7.12–7.21 (m, 3H, arom.),
7.25–7.28 (m, 1H, arom.), 7.31 ppm (s, 1H, NH); 13C-NMR
(dimethyl sulfoxide d6): d 58.6 (CH2), 120.5 (CH), 120.7
(CH), 123.0 (CH), 123.1 (CH), 125.7 (CH), 128.2 (CH), 128.3
(CH), 128.7 (CH), 129.3 (CH), 126.7 (C), 137.7 (C), 146.1
(C), 149.4 (C), 149.9 ppm (C); MS: m/z 280 (MHþ, 100%);
HRMS: m/z calcd for C17H14NOS: 280.0796 (MHþ), found:
280.0792. Anal Calcd for C17H13NOS: C, 73.09; H, 4.69; N,
5.01; S, 11.48. Found: C, 72.66; H, 4.71; N, 5.40; S, 11.34.
General procedure for the synthesis of x-aminoalkyl
ethers 9. To the solution of x-chloroalkyl dialkyl ammonium
chloride (5–14 equiv.) in 40% aq. NaOH (12 mL), benzyl
triethyl ammonium chloride (0.45 equiv.) and solution of the
alcohol 6–8 (1 equiv.) in toluene (10 mL) were added. The
reaction mixture was heated under vigorous stirring and reflux-
ing for 3 h (TLC control, eluent: dichloromethane/methanol/
[2-(8-Benzoyl-8H-1-thia-8-aza-dibenzo[e,h]azulen-2-ylmethoxy)-
ethyl]dimethylamine (9b, n 5 2). This compound was obtained
starting from 7 (75 mg, 0.20 mmol) and 2-chloroethyl di-
methyl ammonium chloride (0.14 g, 1.0 mmol) as described in
procedure above; reaction duration of about 2 h; purified by
column chromatography (eluent: dichloromethane/methanol/
ammonia 100:5:1); separated from N-debenzoyl-derivative 9c,
n ¼ 2, by preparative HPLC; yellow resin; 20 mg (23%); IR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

ˇ ´ ´ ´ ´
I. Ozimec Landek, D. Pesic, M. Mercep, B. Stanic, and M. Mesic
862
Vol 48
(film): 3058, 2926, 2855, 1657 (C¼¼O), 1494, 1474, 1344,
1130, 1100 cmꢁ1 1H-NMR (deuteriochloroform): d 2.52 (s,
cedure above; purified by column chromatography (eluent:
dichloromethane/methanol/ammonia 100:5:1); yellow resin; 50
mg (77%); IR (film): 3215 (NAH stretching), 3056, 2943,
2859, 1579, 1472, 1429, 1374, 1301, 1250, 1158, 1128, 1092
;
6H, 2 ꢂ CH3), 2.85 (t, 2H, J ¼ 5.3 Hz, CH2N), 3.85 (t, 2H, J
¼ 5.3 Hz, OCH2), 4.83 (s, 2H, Ar-CH2), 7.09–7.65 ppm (m,
14H, arom. þ thioph.); 13C-NMR (deuteriochloroform): d 44.8
(2 ꢂ CH3), 57.9 (CH2), 66.7 (CH2), 67.6 (CH2), 127.4 (CH),
127.6 (CH), 127.7 (CH), 127.8 (CH), 127.9 (CH), 128.2 (CH),
128.4 (CH), 128.6 (CH), 128.7 (CH), 129.4 (CH), 134.9 (C),
140.3 (C), 169.3 ppm (C¼¼O); MS: m/z 455 (MHþ, 100%),
366 ([M-O(CH2)2N(CH3)2]þ, 10%); HRMS: m/z calcd for
C28H27N2O2S: 455.1793 (MHþ), found: 455.1807. Anal Calcd
for C28H26N2O2S: C, 73.98; H, 5.76; N, 6.16; S, 7.05. Found:
C, 74.32; H, 5.95; N, 6.56; S, 7.17.
cmꢁ1
;
1H-NMR (deuteriochloroform): 1.94–2.03 (m, 2H,
CH2CH2CH2), 2.49 (s, 6H, 2 ꢂ CH3), 2.70–2.74 (m, 2H,
CH2N), 3.63 (t, 2H, J ¼ 6.1 Hz, OCH2), 4.68 (s, 2H, Ar-CH2),
5.24 (s, 1H, NH), 6.79–6.82 (m, 2H, arom.), 6.96–7.06 (m,
2H, arom.), 7.09 (s, 1H, thioph.), 7.13–7.20 (m, 2H, arom.),
7.31–7.35 ppm (m, 2H, arom.); 13C-NMR (deuteriochloro-
form): d 26.6 (CH2), 43.8 (2 ꢂ CH3), 55.9 (CH2), 66.8 (CH2),
67.4 (CH2), 119.7 (CH), 119.9 (CH), 122.7 (CH), 122.8 (CH),
127.4 (CH), 127.7 (CH), 127.9 (CH), 128.1 (CH), 128.7 (CH),
125.3 (C), 126.6 (C), 137.6 (C), 140.1 (C), 147.8 (C), 148.5
(C), 149.1 ppm (C); MS: m/z 365 (MHþ, 100%), 262 ([M-
O(CH2)3N(CH3)2]þ, 85%); HRMS: m/z calcd for C22H25N2OS:
365.1688 (MHþ), found: 365.1685. Anal Calcd for
C22H24N2OS: C, 72.49; H, 6.64; N, 7.69; S, 8.80. Found: C,
72.69; H, 6.28; N, 7.46; S, 9.14.
Biology—isolation of PBMCs, PBMC culture, and TNF-a
quantification. PBMCs were isolated from the peripheral
blood of healthy volunteers using density gradient centrifuga-
tion. Freshly taken, heparinized whole blood was mixed with
the same volume of sterile saline. Diluted blood samples were
layered over FicollPaqueTM Plus and centrifuged at 400 ꢂ g for
30 min. PBMCs were collected from the interface between the
plasma and the density gradient solution. After washing in RPMI
1640, cells were resuspended in RPMI 1640 containing 10% of
heat inactivated (56ꢀC, 30 min) fetal bovine serum (Biowhit-
taker). PBMCs (3.5 ꢂ 104) were cultured in 200 lL volumes in
96-well cell culture plates with flat bottom at 37ꢀC in humidified
atmosphere containing 5% CO2. Cells were stimulated on TNF-a
production with LPS (serotype 0111:B4, Sigma) at final concen-
tration of 1 ng/mL or left unstimulated (cultured in medium
alone). Initially, compounds were dissolved in DMSO as 10 mM
stock solutions. Final 10 lM and 3 lM (primary screening) or
10–0.3 lM range concentrations made in cell culture medium
were tested when added together with LPS. Final DMSO volume
ratio in all assays did not exceed 0.1% and had no significant in-
hibitory effect. Standard p38 inhibitor VX745 served as internal
TNF-a inhibitor in this test, with average IC50 value ꢃ 0.2 lM.
Negative and LPS control samples were prepared in sextaplicates
while testing compound samples in triplicates. Cell free superna-
tants were harvested after overnight period and quantified for
TNF-a content by enzyme-linked immunosorbent assay specific
for human TNF-a. To ensure the detection specificity and sensi-
tivity, assay was performed according to manufacturer instruc-
tions (R&D) using suggested pair of antibodies specific for
human TNF-a. Test sensitivity was 5 pg/mL. TNF-a content in
unknown samples was calculated by extrapolation from the stand-
ard curve made for recombinant TNF-a in serial dilutions of
known start concentration.
[3-(8-Benzoyl-8H-1-thia-8-aza-dibenzo[e,h]azulen-2-ylmethoxy)-
propyl]dimethylamine (9b, n 5 3). This compound was obtained
starting from 7 (75 mg, 0.20 mmol) and 3-chloropropyl di-
methyl ammonium chloride (0.15 g, 1.0 mmol) as described in
procedure above; reaction duration of about 2 h; purified by
column chromatography (eluent: dichloromethane/methanol/
ammonia 100:5:1); separated from N-debenzoyl-derivative 9c,
n ¼ 3, by preparative HPLC; yellow resin; 25 mg (27%); IR
(film): 3059, 2941, 2858, 2816, 2767, 1659 (C¼¼O), 1494,
1
1475, 1342, 1157, 1133, 1096, 844 cmꢁ1; H-NMR (deuterio-
chloroform): d 1.82–2.00 (m, 2H, CH2CH2CH2), 2.33 (s, 6H, 2
ꢂ CH3), 2.50–2.55 (m, 2H, CH2N), 3.68 (t, 2H, J ¼ 6.4 Hz,
OCH2), 4.78 (s, 2H, Ar-CH2), 7.13–7.60 ppm (m, 14H, arom.
þ thioph.); 13C-NMR (deuteriochloroform): d 27.2 (CH2), 44.8
(2 ꢂ CH3), 56.1 (CH2), 67.4 (CH2), 68.3 (CH2), 127.4 (CH),
127.5 (CH), 127.7 (CH), 127.8 (CH), 127.9 (CH), 128.1 (CH),
128.4 (CH), 128.6 (CH), 129.4 (CH), 134.9 (C), 141.1 (C),
169.3 ppm (C¼¼O); MS: m/z 469 (MHþ, 100%), 366 ([M-
O(CH2)3N(CH3)2]þ,
20%);
HRMS:
m/z
calcd
for
C29H29N2O2S: 469.1950 (MHþ), found: 469.1963. Anal Calcd
for C29H28N2O2S: C, 74.33; H, 6.02; N, 5.98; S, 6.84. Found:
C, 74.02; H, 6.42; N, 6.36; S, 7.15.
Dimethyl[2-(8H-1-thia-8-aza-dibenzo[e,h]azulen-2-ylmethoxy)-
ethyl]amine (9c, n 5 2). This compound was obtained starting
from 8 (50 mg, 0.18 mmol) and 2-chloroethyl dimethyl ammo-
nium chloride (0.13 g, 0.90 mmol) as described in procedure
above; purified by column chromatography (eluent: dichloro-
methane/methanol/ammonia 100:5:1); yellow resin; 50 mg
(80%); IR (film): 3260 (NAH stretching), 3055, 2938, 2858,
1580, 1472, 1428, 1301, 1248, 1158, 1128, 1101 cmꢁ1 1H-
;
NMR (deuteriochloroform): d 2.47 (s, 6H, 2 ꢂ CH3), 2.77 (t,
2H, J ¼ 5.5 Hz, CH2N), 3.76 (t, 2H, J ¼ 5.5 Hz, OCH2), 4.71
(s, 2H, Ar-CH2), 5.27 (s, 1H, NH), 6.79–6.83 (m, 2H, arom.),
6.95–7.05 (m, 2H, arom.), 7.10 (s, 1H, thioph.), 7.13–7.19 (m,
2H, arom.), 7.30–7.35 ppm (m, 2H, arom.); 13C-NMR (deuter-
iochloroform): d 44.2 (2 ꢂ CH3), 57.6 (CH2), 66.0 (CH2), 67.1
(CH2), 119.9 (CH), 120.0 (CH), 122.9 (CH), 123.0 (CH),
127.84 (CH), 127.88 (CH), 128.1 (CH), 128.2 (CH), 128.9
(CH), 127.1 (C), 128.0 (C), 138.2 (C), 139.4 (C), 147.5 (C),
148.4 (C), 148.9 ppm (C); MS: m/z 351 (MHþ, 100%), 262
([M-O(CH2)2N(CH3)2]þ, 97%); HRMS: m/z calcd for
C21H23N2OS: 351.1531 (MHþ), found: 351.1538. Anal Calcd
for C21H22N2OS: C, 71.97; H, 6.33; N, 7.99; S, 9.15. Found:
C, 72.25; H, 6.69; N, 7.46; S, 9.17.
Acknowledgments. The authors express their gratitude to Mr.
ˇ
Zeljko Osman and Mr. Genadij Razdorov for the mass spectroscopy
support, Mrs. Biserka Metelko for the NMR spectroscopy, and Mrs.
ˇ
Stefica Flegar for the IR spectra and elemental analysis data.
Dimethyl-[3-(8H-1-thia-8-aza-dibenzo[e,h]azulen-2-ylmethoxy)-
propyl]amine (9c, n 5 3). This compound was obtained start-
ing from 8 (50 mg, 0.18 mmol) and 3-chloropropyl dimethyl
ammonium chloride (0.24 g, 1.51 mmol) as described in pro-
REFERENCES AND NOTES
[1] Present address: Children’s Hospital Srebrnjak, Srebrnjak
100, 10000 Zagreb, Croatia.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

July 2011
Synthesis and Anti-Inflammatory Activity of 8H-1-Thia-8-aza-dibenzo[e,h]azulenes
863
ˇ
[18] Rupcic, R.; Modric, M.; Hutinec, A.; Cikos, A.; Stanic, B.;
ˇ ´
´
ˇ
´
[2] Mula, M.; Schmitz, B.; Sander, J. W. Expert Opin Pharmac-
other 2008, 9, 3159.
[3] Onali, P.; Dedoni, S.; Olianas, M. C. J Pharmacol Exp Ther
2010, 332, 255.
[4] Carril, M.; SanMartin, R.; Dominguez, E. Curr Org Chem
2007, 11, 1385.
[5] Chavant, F.; Deguil, J.; Pain, S.; Ingrand, I.; Milin, S.; Fau-
´
ˇ ´
´
Mesic, M.; Pesic, D.; Mercep, M. J Heterocycl Chem 2010, 47, 640.
[19] The substitutive nomenclature is used here for this class of
compounds but the correct IUPAC defined name is 8H-dibenzo[b,f]-
thieno[2,3-d]azepine.
ˇ
ˇ
´
´
ˇ ´
´
ˇ ´
[20] Mercep, M.; Mesic, M.; Pesic, D.; Zupanovic, Z.; Hrvacic,
B. US Patent 2,003,153,750, 2003; Chem Abstr 2008, 148, 472014.
[21] Kawashima, K.; Ishiguro, T. Chem Pharm Bull 1978, 26, 951.
[22] Ohta, T.; Miyata, N.; Hirobe, M. Chem Pharm Bull 1981,
29, 1221.
´
conneau, B.; Perault-Pochat, M.-C.; Lafay-Chebassier, C. J Pharmacol
Exp Ther 2010, 332, 505.
[6] Hwang, J.; Zheng, L. T.; Ock, J.; Lee, M. G.; Kim, S.-H.;
Lee, H.-W.; Lee, W.-H.; Park, H.-C.; Suk, K. Neuropharmacology
2008, 55, 826.
[23] Ohta, T.; Miyata, N.; Hirobe, M. Chem Pharm Bull 1984,
32, 3857.
[7] Perrot, S.; Javier, R.-M.; Marty, M.; Le Jeunne, C.;
Laroche, F. Rheumatology 2008, 47, 1117.
[24] Kricka, L. J.; Ledwith, A. Chem Rev 1974, 74, 101.
[25] Kricka, L. J.; Lambert, M. H.; Ledwith, A. J Chem Soc
Perkin Trans 1 1974, 52.
[8] Hashioka, S.; McGeer, P. L.; Monji, A.; Kanba, S. Cent
Nerv Syst Agents Med Chem 2009, 9, 12.
[26] Kricka, L. J.; Ledwith, A. J Chem Soc Perkin Trans 1 1973, 859.
[27] Marson, C. M. Tetrahedron 1992, 48, 3659.
[28] Paul, S.; Gupta, M.; Gupta, R. Synlett 2000, 1115.
[9] Bianchi, M.; Sacerdote, P.; Panerai, A. E. Pharmacol Bio-
chem Behav 1994, 48, 1037.
´
[29] Haasz, F.; Galamb, V. J Chem Res (S) 1993, 494.
[10] Abdel-Salam, O. M. E.; Nofal, S. M.; El-Shenawy, S. M.
Pharmacol Res 2003, 48, 157.
[30] Abraham, R. J.; Kricka, L. J.; Ledwith, A. J Chem Soc Per-
kin Trans 2 1974, 1648.
[11] Sacerdote, P.; Bianchi, M.; Panerai, A. E. Eur J Pharmacol
1997, 319, 287.
`
[31] Bajwa, J. S.; Slade, J.; Repie, O. Tetrahedron Lett 2000,
41, 6025.
[12] Butler, S. H.; Weil-Fugazza, J.; Godefroy, F.; Besson, J.-M.
Pain 1985, 23, 159.
[32] Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.;
Shyam Prasad, R.; Smith, A. D. J Chem Soc Perkin Trans 1 2000, 3765.
[33] Schindler, W.; Blattner, H. Swiss Pat. 405,319, 1966; Chem
Abstr 1966, 65, 90602.
[13] Gupta, A. K.; Singh, H.; Singh, G.; Ahluwalia, K. S. Indian
J Pharmacol 1978, 10, 35.
[14] Tsuji, K.; Nakamura, K.; Ogino, T.; Konishi, N.; Tojo, T.;
Ochi, T.; Seki, N.; Matsuo, M. Chem Pharm Bull 1998, 46, 279.
ˇ ´ ´ ´
[15] Pesic, D.; Ozimec Landek, I.; Mercep, M.; Mesic, M. J Het-
[34] Brown, H. C.; Krishnamurthy, S. Tetrahedron 1979, 35, 567.
[35] Menozzi, G.; Mosti, L.; Fossa, P.; Mattioli, F.; Ghia, M.
J Heterocycl Chem 1997, 34, 963.
erocycl Chem 2006, 43, 749.
ˇ ´
ˇ
[16] Pesic, D.; Ozimec Landek, I.; Cikos, A.; Metelko, B.;
ˇ
[36] Corral, L. G.; Haslett, A. J.; Muller, G. W.; Chen, R.;
Wong, L. M.; Ocampo, C. J.; Paterson, R. T.; Stirling, D. I.; Kaplan,
G. J Immunol 1999, 163, 380.
´ ´ ´
Gabelica, V.; Stanic, B.; Mercep, M.; Mesic, M. J Heterocycl Chem
2007, 44, 1129.
ˇ ´ ´ ´
[17] Ozimec Landek, I.; Pesic, D.; Novak, P.; Stanic, B.; Nujic,
´ ´
K.; Mercep, M.; Mesic, M. Heterocycles 2009, 78, 2489.
[37] Muller, G. W.; Corral, L. G.; Shire, M. G.; Wang, H.; Mor-
eira, A.; Kaplan, G.; Stirling, D. I. J Med Chem 1996, 39, 3238.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet