Synthesis and biological evaluation of new antiinflammatory 1-benzothiophene-2-carboxanilides

Article abstract of DOI:10.1135/cccc20001082

3-Substituted 1-benzothiophene-2-carboxanilides 2-5 and their corresponding sulfones 6-8 were synthesized. The antiinflammatory effect of compounds 2-8 was evaluated in tests of LTB₄ biosynthesis, carrageenin edema and ear inflammation. With th

Full text of DOI:10.1135/cccc20001082

1
082
Svoboda et al.:
SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW
ANTIINFLAMMATORY 1-BENZOTHIOPHENE-2-CARBOXANILIDES
Jiří SVOBODAa1,*, Michal ŠTÁDLER , Antonín JANDERA ,
a
b
b1
b2
Vladimíra PANAJOTOVÁ and Miroslav KUCHAŘ
a
Department of Organic Chemistry, Prague Institute of Chemical Technology, 166 28 Prague 6,
Czech Republic;e-mail: jiri.svoboda@vscht.cz
Research Institute for Pharmacy and Biochemistry, 130 60 Prague 3, Czech Republic;
e-mail: v.panajotova@read.vufb.cz, kuchar@vufb.cz
1
b
1
2
Received Jan uary 26, 2000
Accepted March 27, 2000
3
-Substituted 1-ben zoth ioph en e-2-carboxan ilides 2–5 an d th eir correspon din g sulfon es 6–8
were syn th esized. Th e an tiin flam m atory effect of com poun ds 2–8 was evaluated in tests of
LTB4 biosyn th esis, carrageen in edem a an d ear in flam m ation . W ith th e exception of
3
-h ydroxyam ides 5a–5c, low in h ibitory activities again st COX an d LT biosyn th esis were ob-
served.
Key w ord s: Ben zoth ioph en es; Sulfon es; An tiin flam m atory activity; 5-LO in h ibition ; Calcu-
lated log P values.
Non steroidal an tiin flam m atory drugs (NSAIDs) possessin g an tiin flam -
m atory, an algesic, an d an tipyretic activities h ave been widely used in treat-
1
m en t of acute an d subch ron ic in flam m atory con dition s . In early 1970s it
was reported th at NSAIDs preven t th e production of prostaglan din s (PGs)
by in h ibitin g th e en zym e cyclooxygen ase (COX), wh ich catalyzes th e con -
version of arach idon ic acid (eicosa-5,8,11,14-tetraen oic acid) to prosta-
2
,3
glan din s . For m an y years it was believed th at COX was a sin gle en zym e
COX-1) con stitutively expressed in m ost tissues. In con trast to COX-1,
(
COX-2 is an in ducible isoen zym e, wh ich is essen tially un detectable un der
n orm al ph ysiological con dition s; h owever, its expression is m arkedly ele-
4
vated durin g in flam m ation . It was sh own th at com poun ds in h ibitin g se-
lectively COX-2 do n ot cause ulcers in stom ach or in testin es. Th e
observation supports th e h ypoth esis th at th e con stitutive COX-1
isoen zym e protects th e gastroin testin al tract wh ereas th e in ducible COX-2
isoform m ediates in flam m atory PG production .
Leukotrien es (LTs) represen t an oth er class of arach idon ic acid m etabo-
lites, syn th esized by leucocytes in respon se to a variety of in flam m atory
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1
-Benzothiophene-2-carboxanilides
1083
an d im m un ological stim uli. 5-Lipoxygen ase (5-LO) starts th e m etabolism of
5
arach idon ic acid th rough LTA to LTB , a poten t ch em otactic agen t for
4
4
leucocytes th at was th ough t to be a key com pon en t in a variety of in flam -
m ation diseases, an d peptidoleukotrien es LTC , LTD , an d LTE , wh ich are
4
4
4
im plicated in allergic h yperactivity disorders such as asth m a. Elevated lev-
els of th ese LTs, associated with several in flam m atory an d allergic disorders,
h ave been foun d in various path ological tissues. Th us, com poun ds restrict-
in g LT syn th esis by in h ibition of 5-LO will h ave th erapeutic utility in such
6
,7
path ological con dition s. Recen tly it h as been sh own
th at som e h ydrox-
am ic acids, e.g. zileuton possessin g th e 1-ben zoth ioph en e m oiety, can be
stron g 5-LO in h ibitors.
Classical NSAIDs, such as ibuprofen , h ave been foun d active prim arily via
in h ibition of COX path ways. Piroxicam 1, an en ol-carboxam ide type of
8
NSAID, is also a poten t COX in h ibitor. Ten idap [5-ch loro-2-oxo-3-
(
2-th en oyl)in dolin e-1-carboxam ide] con tain in g a sim ilar fragm en t, is dis-
tin guish ed by th e in h ibition of both COX an d 5-LO. In our research on
n ew an tiin flam m atory agen ts with dual m ech an ism of 5-LO an d COX in h i-
bition , we decided to study a n ew type of en ol-am ide com poun ds based on
replacem en t of th e 1,2-ben zoth iazin e m oiety of piroxicam by th e
9
1
-ben zoth ioph en e skeleton . In our precedin g paper we reported syn th esis
of 3-substituted 1-ben zoth ioph en e-2-carboxan ilides 2–5. Wh ile com poun ds
con tain th e HO–C=C–CONHAr fragm en t respon sible for th e activity of
5
piroxicam , th e h ydroxy group in com poun ds 3 an d 4 was m asked by substi-
tution with ch lorin e an d m eth oxy group, respectively, or was com pletely
rem oved as in 2. Som e prelim in ary results of th e biological activity tests of
com poun ds 2–5 were also presen ted. Th e aim of th is paper is to report syn -
th eses of n ew oxidized derivatives 6–8 an d to sh ow full results of biological
screen in g of th is class of substan ces.
X
X
OH
O
H
H
N
N
N
N
H
S
Ar
S
Ar
N
S
CH3
O
O
O
O
O2
2
3
, X = H
, X = Cl
6, X = Cl
7, X = OCH3
8, X = OH
1
4, X = OCH3
, X = OH
5
Syn th esis of am ides 2–5 started with easily accessible10,11 1-ben zoth io-
ph en e-2-carbon yl ch loride (9a) and its 3-chloro derivative 9b (Schem e 1). To
in troduce th e m eth oxy an d h ydroxy fun ction s in position 3, substitution
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

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084
Svoboda et al.:
of ch lorin e in 9b with sodium m eth oxide in N,N-dim eth ylform am ide was
successfully accom plish ed an d ester 10a was subsequen tly h ydrolyzed to
th e correspon din g acid 10b. Treatm en t of acid 10b with th ion yl ch loride
un der stan dard con dition s afforded 3-m eth oxy ch loride 9c.
X
OCH3
COR
OCH3
COR
CH3ONa
X = Cl
MCPBA
R = OCH3
S
COCl
S
S
O
O
9
9
a, X = H
b, X = Cl
10a, R = OCH3
10b, R = OH
c, R = Cl
11a, R = OCH3
11b, R = OH
9d, R = Cl
1
. NaOH 2. HCl
1. NaOH 2. HCl
SOCl2
SOCl2
9
SCHEME 1
Am in olysis of ch lorides 9a–9c with 4-substituted an ilin es (H, Cl, CH O)
3
an d 2-am in opyridin e led to am ides 2a–2c, 3a–3d an d 4a–4d (Sch em e 2).
Deprotection of th e 3-m eth oxy group in 4a–4d with boron tribrom ide in
dich lorom eth an e afforded th e required 3-h ydroxyam ides 5a–5d .
Experim en tal details of th ese tran sform ation s were described in th e preced-
9
in g paper .
X
Cl
ArNH2
MCPBA
X = Cl
9a–9c
S
CONHAr
S
CONHAr
O
O
2a–2c, 3a–3d, 4a–4d
6a–6d
OH
BBr3
4a–4d
S
CONHAr
5a–5d
2–8
Ar
a
C6H5
OH
LiOH
b
4-ClC6H4
6a–6d
c
4-CH3OC6H4
2-pyridyl
S
CONHAr
d
O O
8a–8d
OCH3
ArNH2
9d
S
CONHAr
O O
a–7d
7
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1
-Benzothiophene-2-carboxanilides
1085
For th e preparation of a series of oxidized am ides 6–8, we in ten ded to
m ake use of am ides 2–5 (Sch em e 2). Oxidation of sulfur in 1-ben zo-
1
2
th ioph en e com poun ds can be ach ieved by various m eth ods . In our case,
oxidation of 3-ch loroam ides 4a–4d with 3-ch loroperoxyben zoic acid
(
(
MCPBA) in 1,2-dich loroeth an e proceeded sm ooth ly providin g good yields
58–80%) of am ides 6a–6d .
However, th is m eth od failed for th e preparation of th e series of
3
-m eth oxyam ides 7a–7d . Attem pted oxidation of am ide 4a with MCPBA
both at room an d at elevated tem peratures always afforded com plex m ix-
tures of products from wh ich am ide 7a can be isolated in low yields of
about 18%. Th e yield could n ot be im proved by application of h ydrogen
peroxide in acetic acid or by urea–h ydrogen peroxide com plex. Th at is wh y
we search ed for a n ew strategy for th e syn th esis of m eth oxyam ides 7a–7d .
Oxidation of ester 10a with MCPBA led selectively to sulfon e 11a, wh ich
was obtain ed in 65% yield (Sch em e 1). Th e ester group of 11a was carefully
h ydrolyzed with aqueous sodium h ydroxide to give 56% yield of rath er un -
stable 3-m eth oxy-1-ben zoth ioph en e-2-carboxylic acid 1,1-dioxide (11b).
Acid 11b was also obtain ed by direct oxidation of acid 10b with 30%
h ydrogen peroxide in acetic acid, th ough on ly in a m oderate yield. Sub-
sequen tly, acid 11b was treated with th ion yl ch loride to afford th e corre-
spon din g ch loride 9d , wh ich was im m ediately tran sform ed by am in olysis
with arom atic am in es (vide infra) to give am ides 7a–7d in satisfactory
yields.
In order to obtain 3-h ydroxyam ides 8a–8d , we tried to deprotect13 th e
m eth oxy group of am ides 7a–7d . Attem pted reaction of am ide 7a with bo-
ron tribrom ide, un like th at of am ides 4a–4d , did n ot proceed at all an d th e
startin g com poun d was recovered even after lon g-term h eatin g with an ex-
cess of boron tribrom ide in dich lorom eth an e.
Fin ally, we used for in troduction of th e h ydroxy group th e well-kn own
reactivity14 of th e vin yl sulfon e m oiety of th ioph en e derivatives, wh ere
h alogen s in position 3 are pron e to n ucleoph ilic substitution . Th us, reac-
tion of am ides 6a–6c with lith ium h ydroxide in 1,4-dioxan e at room tem -
perature proceeded sm ooth ly an d am ides 8a–8c were obtain ed in good
yields.
Th e an tiin flam m atory effect of com poun ds 2–8 was assessed by tests
m easurin g th eir in fluen ce on in h ibition of LTB biosyn th esis, carrageen in
4
edem a an d ear in flam m ation (Table I). On th e basis of th e results it can be
em ph asised th at in vivo an tiin flam m atory effect of com poun ds un der study
is n ot presum ably related to th eir in h ibition of LT syn th esis. Som e com -
poun ds bein g h igh ly active in th e in h ibition of th e ear edem a, e.g. com -
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1
086
Svoboda et al.:
TABLE I
Log P values an d biological activities of com poun ds 2–8
logPa
EE in h , %
d
b
LTB in h
4
c
Com poun d
e
f
CE in h , %
%
/IC50
A
B
C
D
2
2
2
3
3
3
3
4
4
4
4
5
5
5
5
6
6
6
6
7
7
7
7
8
8
8
a
b
c
a
b
c
d
a
b
c
d
a
b
c
d
a
b
c
d
a
b
c
d
a
b
c
3.70
4.35
3.78
4.34
4.99
4.42
3.71
3.78
4.43
3.86
3.15
3.52
4.17
3.60
2.89
1.95
2.60
2.03
1.32
0.75
1.40
0.83
0.12
0.57
1.22
0.65
3.73
4.44
3.66
4.44
5.15
4.37
3.88
3.66
4.37
3.59
3.09
4.06
4.77
3.99
3.49
3.60
4.31
3.53
3.03
2.82
2.82
2.75
2.25
3.22
3.93
3.15
0/–
0/–
0/–
n dg
9
9
34
8
3i
1(s)h
n d
n d
13
50
11
n d
n d
n d
11
16
n d
13
n d
12
16
26
48
61
18
30
26
9
10
22/–
15/–
11/–
6(s)
3(s)
4(s)
0
9
19
12/>100
0/–
14
3i
14
6i
n d
7i
13
9
0/–
8/–
n d
17/>100
94/1.24
99/1.46
93/1.82
13/>100
98/3.33
86/2.55
98/5.56
0/–
6i
14
2(s)
10
6i
3(s)
16
6i
22(s)
10
12
2i
39
17
23
7i
3i
3i
12
12
12
10
10
19
36
20/–
30/>100
0/–
0/–
24
5i
13/–
21/–
25
27
46
67j
61
11
17
9
6i
0/–
0
13
68
Zileuton
Piroxicam
Ten idap
100/0.17
n d
22
14
100/1.04
a
Log P values were calculated, A: by th e use of KOWWIN program , B: by th e fragm en t
b
m eth od usin g log P experim en tal values available for th e greatest fragm en ts. In h ibition of
LT B4 biosyn th esis. Carrageen in edem a in h ibition after a dose of 100 m g/kg. Ear edem a
c
d
in h ibition after a dose of 200 m g/kg, C: ear lobe weigh t, D: degree of ear lobe h yperem ia.
e
f
g
h
I
Dose of 20 µM. Given in µM. Not determ in ed. Stim ulation of ear lobe weigh t. Sign ifi-
j
can ce level p > 0.05. Dose of 10 m g/kg.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1
-Benzothiophene-2-carboxanilides
1087
poun ds 6d an d 7d , are com pletely in active as LTB syn th esis in h ibitors.
4
On ly h ydroxy substituted derivatives 5a–5c sh owed an in dication for such
a relation ; it is likely to be rath er a ran dom effect, because with an alogously
substituted sulfon es 8a–8c n o relation was observed between th e m en -
tion ed effects.
To evaluate th e structure–activity relation sh ips at a sem iquan titative
level, log P values for all derivatives 2–8 were estim ated usin g two m eth ods
of calculations; by the KOWWIN program and by the fragment method (Table I).
In con sisten t results of calculation s by th e two applied m eth ods were regis-
tered; especially th e log P values calculated for sulfon es 6–8 by th e
KOWWIN m eth od are n ot quite correct. Th e software con siders too low val-
ues of correction for th e in teraction s between SO an d CONH h ydroph ilic
2
groups an d uses aliph atic fragm en t con stan ts also for h eterocyclic substitu-
en ts an d th erefore th e calculated log P values of th e m en tion ed sulfon es are
too low. Verification of correct total lipoph ilicity of com poun ds un der
study by an in depen den t experim en tal m eth od is in progress. Th erefore,
th e in fluen ce of lipoph ilicity on activity can be studied on ly separately in
th e groups of eith er 1-ben zoth ioph en es 2–5 or th eir sulfon es 6–8. Th e in h i-
bition of LTB biosyn th esis in th e series of com poun ds 2–5 depen ds on ly
4
m argin ally on th e total lipoph ilicity. However, th e in h ibitory activity was
substan tially in creased by in troducin g of th e h ydroph ilic 3-h ydroxy group
in com poun ds 5a–5c. Th e presen ce of th e local region of low lipoph ilicity
could be probably th e reason of th e observed in crease. Th e secon d possibil-
ity, i.e. th e presen ce of en ol-carboxam ide m oiety, is obviously n ot n eces-
sary, as it is dem on strated by th e relatively h igh in h ibitory activity of
ch loro derivatives 6a–6c. In th eir structure th e m en tion ed fragm en t is m iss-
in g but oth er local low lipoph ilic region is presen t. It can be sh own by low
in h ibitory activities of derivatives 8a–8c, th at th e presen ce of an oth er h y-
droph ilic region in th eir structure acts obviously con tradictory. Th e in h ibi-
tion of carrageen in edem a is ch aracteristic of COX in h ibitors. It is eviden tly
supported by th e ch an ge from th ioph en e derivatives 2–5 to sulfon es 6–8,
wh ich is accom pan ied by a decrease of lipoph ilicity of th e m olecules.
A n ew type of poten tially an tiin flam m atory com poun ds based on th e
en ol-am ide structure h as been syn th esized. Several com poun ds studied
h ave sh own an in h ibitory activity again st 5-LO apparen tly with out th e re-
lation to th e presen ce of en ol-carboxam ide m oiety.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1
088
Svoboda et al.:
EXPERIMENTAL
Meltin g poin ts were determ in ed on a Boetius block an d are un corrected. 1H NMR spectra
were taken on spectrom eters Varian -Gem in i 300 HC. Deuterioch loroform an d DMSO-d6
(
com poun ds 6b, 6d, 7b, 7c) were used as solven ts, th eir sign als servin g as in tern al stan dards.
3
Ch em ical sh ifts are given in th e δ-scale (ppm ), couplin g con stan ts J(H,H) in Hz. IR spectra
λ in n m ) were recorded on a Nicolet FTIR 740 spectrom eter in ch loroform or KBr (com -
(
poun ds 6d , 7a–7d ).
Calculation of log P
Th e program KOWWIN Version 1.6 (Syracuse Res. Corp. (NY), U.S.A.) was used in th e calcu-
lation s. For th e above-m en tion ed approxim ation s used by th e program , we also calculated
1
5
log P by th e fragm en t m eth od . Calculation s of log P of com poun ds 2a, 3d , an d 6a are
given as exam ples:
log Pcalc (2a) = log P(1-ben zoth ioph en e) + log P(ben zen e) + fΦΦ(–CONH–) – 2 f(H) = 3.12 +
+
2.13 – 1.06 – 0.46 = 3.73
log Pcalc (3d) = log P(1-ben zoth ioph en e) + log P(pyridin e) + fΦΦ(–CONH–) + f(Cl) – 3 f(H) –
–
0.42 [f(–CONH–) + f(–N=)] = 3.12 + 0.65 – 1.06 + 0.94 – 0.69 + 0.42 (1.06 +
+
1.12) = 3.88
log Pcalc (6a) = log P(1-ben zoth ioph en e 1,1,-dioxide) + log P(ben zen e) + fΦΦ(–CONH–) +
Φ
+
–
f(Cl) – 3 f(H) – 0.42 [f(–CONH–) + f (SO )] = 0.92 + 2.13 – 1.06 + 0.94 –
0.69 + 1.36 = 3.60
2
For 1-ben zoth ioph en es 2–5, th e calculated values are in good agreem en t with log P values
1
5
calculated by th e fragm en t m eth od wh ere available experim en tal log P values are used.
However, we quoted great differen ces between both m eth ods for calculation of log P values
of sulfon es 6–8 (Table I).
3
-Ch loro-N-ph en yl-1-ben zoth ioph en e-2-carboxam ide 1,1-Dioxide (6a)
9
A m ixture of am ide 3a (ref. ) (3.20 g, 11.1 m m ol), 85% 3-ch loroperoxyben zoic acid (5.64 g,
3
2.7 m m ol) (MCPBA), an d 1,2-dich loroeth an e (150 m l) was stirred at 60 °C for 6 h . After
coolin g, th e solution was wash ed with saturated aqueous sodium h ydrogen carbon ate (2 ×
0 m l) an d dried with an h ydrous m agn esium sulfate. Th e residue after evaporation of th e
5
solven t was crystallized from xylen e to afford 2.83 g (80%) of am ide 6a, m .p. 188–190 °C.
For C15H10ClNO S (319.8) calculated: 56.34% C, 3.15% H, 11.09% Cl, 4.38% N, 10.03% S;
3
foun d: 56.03% C, 3.21% H, 11.18% Cl, 4.21% N, 10.04% S. IR (CHCl ): 3 369 (NH), 1 687
3
1
(
CO), 1 154 (SO ). H NMR (CDCl ): 7.21 t, 1 H, J = 7.5 (H-4′); 7.39 t, 2 H (H-3′); 7.65 d, 2 H,
2
3
J = 8.0 (H-2′); 7.45 m , 2 H (H-5 an d H-6); 7.49 m , 2 H (H-4 an d H-7); 8.31 s, 1 H (NH).
In an an alogous way th e followin g com poun ds were obtain ed:
3
-Chloro-N-(4-chlorophenyl)-1-benzothiophene-2-carboxamide 1,1-dioxide (3b ). Yield 67%.
M.p. 221–223 °C (xylen e). For C15H Cl NO S (354.2) calculated: 50.86% C, 2.56% H,
9
2
3
2
0.02% Cl, 3.95% N, 9.05% S; foun d: 50.30% C, 2.62% H, 20.21% Cl, 3.64% N, 9.05% S.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1
-Benzothiophene-2-carboxanilides
1089
1
IR (CHCl ): 3 367 (NH), 1 690 (CO), 1 155 (SO ). H NMR (DMSO-d ): 7.47 d, 2 H, J = 8.8;
3
2
6
7
.71 d, 2 H; 7.84–7.94 m , 3 H; 8.12 d, 1 H, J = 7.0 (H-7); 11.02 s, 1 H (NH).
-Chloro-N-(4-methoxyphenyl)-1-benzothiophene-2-carboxamide 1,1-dioxide (3c). Yield 74%.
M.p. 205–207 °C (xylen e). For C16H12ClNO S (349.8) calculated: 54.94% C, 3.46% H,
3
4
1
0.14% Cl, 4.00% N, 9.17% S; foun d: 55.24% C, 3.45% H, 10.48% Cl, 3.98% N, 9.35% S.
1
IR (CHCl ): 3 371 (NH), 1 681 (CO), 1 155 (SO ). H NMR (CDCl ): 3.82 s, 3 H (OCH ); 6.91 d,
3
2
3
3
2
1
H, J = 8.8; 7.57 d, 2 H; 7.74–7.80 m , 2 H (H-5 an d H-6); 7.80–7.86 m , 2 H (H-4 an d H-7);
0.34 s, 1 H (NH).
3
-Chloro-N-(2-pyridyl)-1-benzothiophene-2-carboxamide 1,1-dioxide (3d ). Yield 58%. M.p.
2
8
3
7
32–234 °C (xylen e). For C14H ClN O S (320.7) calculated: 52.43% C, 2.83% H, 11.05% Cl,
9
2
3
.73% N, 10.00% S; fou n d: 52.25% C, 2.95% H, 11.01% Cl, 8.67% N, 9.91% S. IR (KBr):
1
360 (NH), 1 662 (CO), 1 151 (SO ). H NMR (DMSO-d ): 7.26 dt, 1 H, J = 7.2, J2 = 1.6;
2
6
1
.54 t, 1 H, J = 7.7; 7.65 m , 2 H; 7.99 dd, 1 H, J1 = 6.2, J2 = 2.8; 8.17 dd, 1 H; 8.42 dd, 1 H,
J1 = 8.2, J2 = 1.6; 8.49 d, 1 H, J = 6.0; 11.82 s, 1 H (NH).
Methyl 3-methoxy-1-benzothiophene-2-carboxylate 1,1-dioxide (11a). Yield 65%. M.p. 164–165 °C
(
1
m eth an ol); ref.16 m .p. 162–163 °C. For C11H10O S (254.3) calculated: 51.96% C, 3.96% H,
5
1
2.61% S; foun d: 51.88% C, 3.90% H, 12.76% S. IR (CHCl ): 1 718 (CO), 1 156 (SO ). H NMR
3
2
(
CDCl ): 3.97 s, 3 H (OCH ); 4.44 s, 3 H (OCH ); 7.66 dt, 1 H, J = 7.2, J2 = 1.2; 7.71 dt, 1 H;
3 3 3 1
7
.75 dd, 1 H, J1 = 7.2, J2 = 1.3; 7.79 dd, 1 H.
3
-Meth oxy-1-ben zoth ioph en e-2-carboxylic Acid 1,1-Dioxide (11b)
9
Method A. Ester 11a (ref. ) (12.02 g, 47.3 m m ol) was added to a solution of sodium h y-
droxide (5.67 g, 142 m m ol) in aqueous m eth an ol (700 m l, 1 : 1 v/v) an d th e m ixture was
stirred at 40 °C for 2 h . Th e m ixture was diluted with water (200 m l), acidified with con cen -
trated h ydroch loric acid, extracted with ch loroform (2 × 250 m l), th e organ ic layer was
wash ed with water an d dried with an h ydrous m agn esium sulfate. Evaporation of th e solven t
gave 10.44 g (92%) of pure acid 11b, m .p. 166–167 °C (decom p.). For C10H O S (240.2)
8
5
calculated: 50.00% C, 3.36% H, 13.35% S; foun d: 49.70% C, 3.35% H, 12.98% S. IR (CHCl ):
3
1
2
7
700–3 150 (COOH), 1 165 (SO ). H NMR (CDCl ): 4.03 s, 3 H (OCH ); 7.72 t, 1 H, J = 7.2;
2
3
3
.74 t, 1 H; 7.82 d, 1 H; 7.85 d, 1 H.
Method B. Aqueous 30% h ydrogen peroxide (1.64 m l, 20.8 m m ol) was added to a solution
of acid 10b (0.50 g, 2.08 m m ol) in acetic acid (10 m l), th e m ixture was stirred at 50 °C for
0 h an d evaporated to dryn ess. Th e residue was purified by colum n ch rom atograph y (silica
gel, ch loroform –m eth an ol, 99 : 1) to give 0.32 g (56%) of acid 11b.
3
3
-Meth oxy-1-ben zoth ioph en e-2-carbon yl Ch loride 1,1-Dioxide (9d )
Th ion yl ch loride (37.5 m l, 0.52 m ol) was added dropwise un der stirrin g at room tem pera-
ture to a slurry of acid 11b (17.90 g, 74.5 m m ol) in toluen e (400 m l). Th e m ixture was
stirred at 75–80 °C for 2.5 h an d th e solven t was evaporated to afford 18.53 g (96%) of ch lo-
ride 9d , m .p. 215–217 °C (toluen e). Th is product was used for preparation of am ides 7a–7d
1
with out furth er purification . H NMR (CDCl ): 4.06 s, 3 H (OCH ); 7.77 t, 1 H, J = 7.2;
3
3
7
.81 t, 1 H; 7.86 d, 1 H; 7.93 d, 1 H.
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1
090
Svoboda et al.:
3
-Meth oxy-N-ph en yl-1-ben zoth ioph en e-2-carboxam ide 1,1-Dioxide (7a)
Method A. An ilin e (2.34 g, 25.1 m m ol) was added dropwise to a cooled (0 °C) solution of
ch loride 9d (5.0 g, 19.3 m m ol) in dry ch loroform (100 m l), th en trieth ylam in e (4.02 m l,
9 m m ol) was added an d th e m ixture was stirred at room tem perature for 6 h . Th e m ixture
2
was diluted with ch loroform (100 m l) an d subsequen tly wash ed with 2% aqueous h ydro-
ch loric acid (2 × 70 m l), saturated aqueous sodium h ydrogen carbon ate solution (50 m l), an d
water (50 m l) an d th en dried with an h ydrous m agn esium sulfate. Th e residue after evapora-
tion of th e solven t was crystallized from toluen e to afford 4.02 g (66%) of am ide 7a, m .p.
1
83–185 °C. For C16H13NO S (315.3) calculated: 61.45% C, 4.16% H, 4.44% N, 10.17% S;
4
foun d: 61.40% C, 4.16% H, 4.40% N, 9.90% S. IR (KBr): 3 370 (NH), 1 683 (CO), 1 161 (SO ).
2
1
H NMR (CDCl ): 3.98 s, 3 H (OCH ); 6.66 d, 1 H, J = 8.2; 7.26 t, 2 H (H-3′); 7.33 dd, 2 H, J =
3
3
1
7
.4, J2 = 1.8 (H-2′); 7.49 m , 2 H (H-5 an d H-6); 7.61 t, 1 H; 7.84 d, 1 H; 10.42 s, 1 H (NH).
Method B. A m ixture of am ide 4a (0.50 g, 1.76 m m ol), MCPBA (0.895 g, 5.19 m m ol), an d
,2-dich loroeth an e (15 m l) was stirred at 50 °C for 16 h , diluted with ch loroform (150 m l)
1
an d worked up as for 6a. Th e crude product was purified by colum n ch rom atograph y (silica
gel, ch loroform –m eth an ol, 99 : 1) to afford am ide 7a (0.099 g; 18%), m .p. 180–183 °C.
Th e followin g am ides 7b–7d were obtain ed by m eth od A:
N-(4-Chlorophenyl)-3-methoxy-1-benzothiophene-2-carboxamide 1,1-dioxide (7b). Yield 62%.
M.p. 148–150 °C (toluen e). For C16H12ClNO S (349.8) calculated: 54.94% C, 3.46% H,
4
1
0.14% Cl, 4.00 % N, 9.17% S; foun d: 55.20% C, 3.40% H, 10.11% Cl, 3.80% N, 9.09% S.
1
IR (KBr): 3 368 (NH), 1 668 (CO), 1 163 (SO2). H NMR (DMSO-d ): 3.97 s, 3 H (OCH ); 6.74 d,
6
3
1
7
H, J = 7.7; 7.27 d, 2 H, J = 8.8; 7.33 t, 1 H, J = 7.7; 7.46 d, 2 H; 7.64 t, 1 H; 7.85 d, 1 H, J =
.8; 10.30 s, 1 H (NH).
3
-Methoxy-N-(4-methoxyphenyl)-1-benzothiophene-2-carboxamide 1,1-dioxide (7c). Yield 73%.
M.p. 212–215 °C (toluen e). For C17H15NO S (345.4) calculated: 59.12% C, 4.38% H, 4.06% N,
5
9
1
8
1
.28% S; foun d: 58.99% C, 4.39% H, 4.07% N, 9.13% S. IR (KBr): 3 370 (NH), 1 659 (CO),
1
160 (SO ). H NMR (DMSO-d ): 3.88 s, 3 H (OCH ); 3.96 s, 3 H (OCH ); 6.64 d, 1 H, J =
2
6
3
3
.2; 6.98 d, 2 H, J = 8.2; 7.23 d, 2 H; 7.27 t, 1 H, J = 7.7; 7.60 t, 1 H, J = 7.7; 7.82 d, 1 H;
0.30 s, 1 H (NH).
3
-Methoxy-N-(2-pyridyl)-1-benzothiophene-2-ca rboxa mide 1,1-dioxide (7 d ). Yield 34%.
M.p. 220–223 °C (toluen e). For C15H12N O S (316.3) calculated: 56.95% C, 3.82% H, 8.86% N,
2
4
1
1
0.13% S; foun d: 57.12% C, 3.78% H, 8.58% N, 10.11% S. IR (KBr): 3 424 (NH), 1 718 (CO),
1
164 (SO ). H NMR (CDCl ): 4.39 s, 3 H (OCH ); 7.02 dt, 1 H, J = 6.6, J = 1.3; 7.38 dt, 1 H,
2
3
3
1
2
J = 7.2, J = 1.6; 7.44 dt, 1 H; 7.50 dt, 1 H; 7.84 dd, 1 H, J = 8.2, J = 1.1; 7.96 dd, 1 H; 8.30 dd,
1
2
1
2
1
H, J1 = 6.6, J2 = 1.1; 8.61 dd, 1 H, J1 = 8.2, J2 = 1.7; 12.16 s, 1 H (NH).
3
-Hydroxy-N-ph en yl-1-ben zoth ioph en e-2-carboxam ide 1,1-Dioxide (8a)
A solution of lith ium h ydroxide (0.22 g, 9.38 m m ol) in water (20 m l) was added dropwise to
a solution of am ide 6a (1.00 g, 3.13 m m ol) in 1,4-dioxan e (50 m l), th e m ixture was stirred
at room tem perature for 6 h an d extracted with dich lorom eth an e (100 m l). Th e form ed
aqueous layer was acidified with 5% h ydroch loric acid (pH 3) an d extracted with dich loro-
m eth an e (3 × 30 m l). Com bin ed organ ic extracts were dried with an h ydrous m agn esium sul-
fate an d evaporated to dryn ess. After crystallization from eth an ol, 0.60 g (63%) of am ide 8a
was obtain ed, m .p. 166–168 °C. For C15H11NO S (301.3) calculated: 59.79% C, 3.68% H,
4
4
.65% N, 10.64% S; foun d: 59.27% C, 3.69% H, 4.54% N, 10.60% S. IR (KBr): 3 340 (OH),
Collect. Czech. Chem. Commun. (Vol. 65) (2000)

1
-Benzothiophene-2-carboxanilides
1091
1
2
637 (CO), 1 158 (SO2). 1H NMR (CDCl ): 5.28 bs, 1 H (OH); 7.22 t, 1 H, J = 7.7 (H-4′); 7.40 t,
H (H-3′); 7.59 dd, 2 H (H-2′); 7.74 m , 2 H (H-5 an d H-6); 7.85 m , 2 H (H-4 an d H-7).
Am ides 8b an d 8c were obtain ed in an an alogous way.
3
N-(4-Chlorophenyl)-3-hydroxy-1-benzothiophene-2-carboxamide 1,1-dioxide (8b). Yield 61%.
M.p. 194–196 °C (eth an ol). For C15H10ClNO S (335.8) calculated: 53.66% C, 3.00% H,
4
1
0.56% Cl, 4.17% N, 9.55% S; foun d: 53.34% C, 3.04% H, 10.38% Cl, 4.07% N, 9.59% S.
1
IR (KBr): 3 342 (OH), 1 636 (CO), 1 159 (SO ). H NMR (CDCl ): 7.35 d, 2 H, J = 8.8; 7.53 d,
2
3
2
H; 7.75 dt, 1 H, J1 = 7.4, J2 = 1.6; 7.78 dt, 1 H; 7.83 dd, J1 = 7.6, J2 = 1.6; 7.86 dd, 1 H.
-Hydroxy-N-(4-methoxyphenyl)-1-benzothiophene-2-carboxamide 1,1-dioxide (8c). Yield 54%.
M.p. 169–171 °C (eth an ol). For C16H13NO S (331.3) calculated: 58.00% C, 3.95% H, 4.23% N,
3
5
9
1
2
.68% S; foun d: 57.87% C, 4.11% H, 4.16% N, 9.93% S. IR (KBr): 3 339 (OH), 1 633 (CO), 1
52 (SO2). 1H NMR (CDCl ): 3.82 s, 3 H (OCH ); 5.75 bs, 1 H (OH); 6.92 d, 2 H, J = 8.8; 7.47 d,
3
3
H; 7.76 m , 2 H; 7.84 m , 2 H.
Biological Evaluation
In h ibition of carrageen in edem a was evaluated by th e m eth od of Win ter17. Th e experim en -
1
8
tal con dition s h ave been described elsewh ere . Arach idon ic acid-in duced ear in flam m ation
1
9
in m ice was ach ieved usin g th e m eth od of Opas , ear lobe in flam m ation was in duced by
application of 20 µl arach idon ic acid solution in aceton e. Th e substan ce was adm in istered
orally 16 h before edem a in duction . Th e degree of ear lobe h yperem ia an d th e ear lobe
weigh t were evaluated 1 h after application of arach idon ic acid. Th e results were expressed
in term s of percen tage in h ibition relative to th e un treated con trol. In h ibition of LTB4
biosyn th esis was evaluated by determ in ation of th e LTB4 production in rat polym orph o-
2
0
n uclear cells from pleural exudate in duced by h eat-activated rat serum . Th e cells were
stim ulated with Ca ion oph ore A 23187 (Sigm a) an d in cubated with various con cen tration s
of th e substan ces tested. LTB4 was determ in ed in supern atan t usin g a com m ercial RIA kit
(
Am ersh am ).
This project was supported by the Grant Agency of Czech Republic (grant No. 203/97/0212).
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2
3
4
5
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3. Greene T. W., WutsP. G. M.: Protective Groups in Organic Synthesis, p. 143. Wiley, New
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6. Societe d'EtudesScientifiqueset Indu ts riellesde I'lle-de-France: Ger. 1937514 (1970);
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7. Winter J.: Proc. Soc. Exp. Biol. Med. 1962, 111, 544.
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