Derivatives of (phenylsulfanyl)benzoic acids with multiple antileukotrienic activity

Article abstract of DOI:10.1135/cccc20042098

A series of derivatives of (phenylsulfanyl)benzoic acids bearing quinoline, 2,4-dihydroxy-3-propylacetophenone and 2,4-difluorobiphenyl moieties were prepared and their antileukotrienic activities evaluated. Some of the compounds were found to display mul

Full text of DOI:10.1135/cccc20042098

2098
Kuchař et al.:
DERIVATIVES OF (PHENYLSULFANYL)BENZOIC ACIDS WITH
MULTIPLE ANTILEUKOTRIENIC ACTIVITY
b2
Miroslav KUCHAŘa1,c,*, Vojtěch KMONÍČEKb1, Vladimíra PANAJOTOVÁ
,
a
c1
Antonín JANDERAb3, Bohumila BRUNOVÁ , Richard JUNEK ,
d
e
Věra BUCHAROVÁb4, Jan ČEJKA and Dalibor ŠATINSKÝ
a
VUFB, Research Institute for Pharmacy and Biochemistry, 102 01 Prague 10, Czech Republic;
1
e-mail: kuchar@zentiva.cz
b
c
1
REaD-VUFB, Ltd.,180 66 Prague 9, Czech Republic; e-mail: kmonicek@read.cz,
2
3
4
panajotova@read.cz, jandera@read.cz, bucharova@read.cz
Research Centre LN00B125, Léčiva, Ltd., 102 01 Prague 10, Czech Republic;
1
e-mail: junek@vufb.cz
d
e
Department of Chemistry of Solid State, Institute of Chemical Technology, Prague,
166 28 Prague 6, Czech Republic; e-mail: jan.cejka@vscht.cz
School of Pharmacy, Charles University, 500 05 Hradec Králové, Czech Republic;
e-mail: satinsky@faf.cuni.cz
Received August 18, 2003
Accepted May 24, 2004
A series of derivatives of (ph en ylsulfan yl)ben zoic acids bearin g quin olin e, 2,4-dih ydroxy-
3-propylacetoph en on e an d 2,4-difluorobiph en yl m oieties were prepared an d th eir an tileuko-
trien ic activities evaluated. Som e of th e com poun ds were foun d to display m ultiple
an tileukotrien ic effect in th e in h ibition of LTB4 biosyn th esis, bin din g to LTD4 an d LTB4 re-
ceptors, superior to th e stan dards (zileuton an d zafirlukast) used. Th e com poun ds h ad an
an tiin flam m atory effect, m an ifested with quin olin e derivatives by a sign ifican t in h ibition of
bron ch ospasm in duced by LTD4 an d/or album in . Th e results of regression an alysis corre-
spon d to th e observation th at th e m ost active com poun ds belon g to quin olin e derivatives
with th e lowest lipoph ilicity. X-ray an alysis of th e quin olin e com poun ds revealed th at an
in tram olecular h ydroph obic in teraction of th eir arom atic rin gs does n ot occur in th e solid
state.
Keyw ord s: (Ph en ylsulfan yl)ben zoic acids; An tileukotrien ic activity; Regression an alysis;
Lipoph ilicity; An tiin flam m atory an d an tiasth m atic effects; QSAR.
Leukotrien es (LT) are an im portan t group of biologically active com poun ds
form ed from arach idon ic acid un der th e in fluen ce of 5-lipoxygen ase
(5-LO)1. Peptidoleukotrien es C4 an d D4 were ch aracterized2 as com pon en ts
of th e slowly reactin g substan ce (SRS-A), wh ich in duces th e in flam m atory
reaction in bron ch ocon striction an d in creases th e vascular perm eability as-
sociated with acute h ypersen sitivity3. Furth erm ore, LTB4 stim ulates4 th e ag-
Collect. Czech. Chem. Commun. (Vol. 69) (2004)
doi:10.1135/cccc20042098

Derivatives of (Phenylsulfanyl)benzoic Acids
2099
gregation an d degran ulation of n eutroph iles, prom otes5 ch em otaxis an d
ch em okin esis of leukocytes an d oth er cells wh ich play an im portan t role in
th e developm en t of th e in flam m atory process. Th e LT an tagon ists an d/or
th e in h ibitors of LT biosyn th esis can be th erefore utilized6 in th e treatm en t
of th e allergic diseases of th e respiratory system . A great n um ber of an ti-
asth m atics with an an tileukotrien ic m ech an ism of action , such as th e
5-LO in h ibitor zileuton 7 or peptide LTD4 an tagon ists zafirlukast8 an d
m on telukast9 attest to th e in creasin g im portan ce of an tileukotrien ics in th e
treatm en t of asth m a.
A m ajority of an tileukotrien ics possess com m on structural features,
wh ich can be sum m arized as follows10:
a) the hydrophobic region in the proximity of polar group is in the “western”
part;
b) th e “eastern ” part is a carrier of an acidic group (carboxyl or its equiva-
len t);
c) a spacer of various flexibility con n ects both parts.
The fragm ents of quinoline9,11–13, 2,4-dihydroxy-3-propylacetophenone14–16
or biph en yl10,17 are frequen tly used as th e “western ” m oieties. It was foun d
out in quin olin e an tileukotrien ics th at th e distan ce between th e quin olin e
m oiety an d th e acidic fun ction is im portan t for leukotrien e receptor affin -
ity. For exam ple, th e in sertion of a m eth oxyph en yl spacer between quin o-
lin e an d th e carboxyl carrier led to th e ch rom on e derivative 1 with alm ost
105-fold LTD4 receptor affin ity in com parison with an origin al com -
poun d18. A sim ilar result, con cern in g th e distan ce between th e lipoph ilic
region an d carboxyl, was obtain ed from th e QSAR an alysis of an tileuko-
trien ic activities19,20 in th e series of 2,4-dih ydroxy-3-propylacetoph en on e
derivatives 2. Th is con clusion is in agreem en t with th e h ypoth esis10,21,22
con cern in g th e bin din g sites on LTB4 an d LTD4 receptors.
O
(
)
m
HO
O
O
Y
n
OH
(
)
O
OH
N
O
O
O
X
O
1
2 (n = 2–4, m = 0, 1)
Th is work was aim ed at th e preparation of derivatives, carryin g th e
above-m en tion ed m oieties, th at would exh ibit a broader spectrum of
an tileukotrien ic activities an d could be used in th e treatm en t of asth m a.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

2100
Kuchař et al.:
We h ave also tried to elucidate th e role of lipoph ilicity in th e an tileuko-
trien ic activities of th e com poun ds studied with regard to th e con siderable
exten t of th eir lipoph ilicities.
RESULTS
Th e series of com poun ds 3–5 were syn th esized usin g th e fragm en ts of quin -
olin e, 2,4-dih ydroxy-3-propylacetoph en on e an d 2,4-difluorobiph en yl as
th e lipoph ilic m oieties. Th e use of ph en ylsulfan ylben zoic acids as th e car-
boxyl carriers offers a sim ilar distan ce (correspon din g to a n um ber of atom s)
between th e quin olin e m oiety an d carboxyl in com parison with com -
poun d 1. Th e sulfur atom at th e proxim ity of th e carboxyl was described in
LTB4 an tagon ists23 an d LTD4 an tagon ists12,24. Th ree differen t “western ”
m oieties were used to ch an ge th eir lipoph ilicity an d con sequen tly th e total
lipoph ilicity.
O
Z
nO
)
(
OH
S
Pr
HO
Me
O
3, Z =
n = 0
X
4, Z =
n = 2–4
N
O
O
5, Z =
n = 3,4
F
F
n
n
3
5
4
X
Position of S to
Position of S to
Position of S to
O
p
COOH
O
p
COOH
O
p
COOH
p
o
p
o
p
o
o
3
4
3
4
3
4
4
p
p
o
o
o
o
p
2
3
4
2
3
4
3
4
3
4
p
p
p
p
p
p
o
o
o
o
a
b
c
d
e
f
a
b
c
d
e
f
a
b
c
d
e
f
H
H
p
p
p
H
m
m
p
p
p
H
p
m
m
m
m
m
p
Cl
Cl
Cl
m
m
m
p
g
g
g
h
i
m
j
p
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Derivatives of (Phenylsulfanyl)benzoic Acids
2101
Syn th esis of com poun ds 3–5 was accom plish ed usin g two m eth ods,
described in Sch em e 1. In th e first m eth od, m eth yl [(h ydroxyph en yl)-
sulfan yl]ben zoates 6 were treated with substituted alkyl h alides 8 in th e
presen ce of potassium carbon ate an d esters 9 were th en h ydrolyzed to af-
ford th e desired acids. In th e secon d m eth od, esters 6 were treated with
dih aloalkan es to obtain h aloalkoxy derivatives 7, used for th e alkylation of
ph en ols ZH to give esters 9. Esters 6 were obtain ed from [(m eth oxy-
ph en yl)sulfan yl]ben zoic acids th rough O-dem eth ylation with pyridin e h y-
droch loride an d subsequen t esterification with H2SO4/MeOH.
O
HO
OH
b2
S
ZH
b1
Z-Cl
6
8a,8b
a
e
O
O
X
nO
)
HO
Z
nX
)
9
(
(
O
O
S
c
S
8c–8g
7
6
f
d
e
O
O
Z
nO
Z
nO
)
(
)
(
O
OH
f
S
S
9
3–5
a) boiling methanol, H2SO4, 16 h; b1) ω,ω'-dihaloalkane, K2CO3, boiling 2-butanone, 10 h;
b2) K2CO3, tetrachloromethane, Cl2; c) ω,ω'-dihaloalkane, K2CO3, boiling 4-methylpentan-
2-one, 10 h; d) ZH, K2CO3, KI, boiling 4-methylpentan-2-one, 24 h; e) K2CO3, KI, boiling
5-methylpentan-2-one or 2-butanone; f) 1. KOH, boiling ethanol/water, 0.5 h, 2. dilute HCl
or acetic acid
SCHEME 1
2-(Ch lorom eth yl)quin olin e was prepared25 from 2-m eth ylquin olin e by
treatm en t with ch lorin e. Th e sam e m eth od was used for th e preparation of
6-ch loro-2-(ch lorom eth yl)quin olin e from 6-ch loro-2-m eth ylquin olin e.
All com poun ds were subjected to th e evaluation of an tileukotrien ic activ-
ity by testin g th e in h ibition of LTB4 biosyn th esis in vitro as a criterion of
5-LO in h ibition , an d affin ities to LTB4 an d LTD4 receptors, n ecessary for an -
tagon istic activities toward th ose LT. Th e com poun ds were also tested for
th eir an tiin flam m atory activities in vivo in th ree m odels of in flam m ation .
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

2102
Kuchař et al.:
Selected derivatives were subjected to th e evaluation of an tiasth m atic activ-
ity by th e in h ibition of bron ch ospasm s in duced by ovalbum in an d LTD4.
Two an tiasth m atics, 5-LO in h ibitor zileuton an d LTD4 an tagon ist zafir-
lukast, were used as stan dards. Th e results of an tileukotrien ic an d an ti-
in flam m atory activities are sum m arized in Tables I an d II, respectively; th e
values of bron ch ospasm in h ibition are sh own in Table III.
Th e log Pcalc an d log Pfrg values (see Experim en tal) were used for th e evalu-
ation of total lipoph ilicity an d lipoph ilicity of th e “western ” fragm en ts.
Th e reten tion ch aracteristics m easured by HPLC (log k) an d TLC (RM) m eth -
ods were used as th e experim en tal lipoph ilic param eters. Th e relation sh ips
between th e experim en tal an d calculated lipoph ilic variables were used for
th e evaluation of possible in tram olecular h ydroph obic in teraction s of th e
arom atic rin gs in com poun ds 3–5. All values are sum m arized in Table I.
DISCUSSION
Th e regression equation s represen tin g th e relation sh ips between log Pcalc
an d log k (Eq. (1)) an d RM (Eq. (2)) values did n ot sh ow an y im portan t sys-
tem atic deviation s from lin earity. Th is fact in dicates th e absen ce of
in tram olecular h ydroph obic in teraction s in th e ch rom atograph ic separa-
tion . Th e results of X-ray an alysis of quin olin e derivatives 3a an d 3c also
con firm th e un folded structure of both m olecules. Th e arom atic rin gs are
n ot coplan ar an d th eir distan ce is probably too large for π–π in teraction s.
Th e structural arran gem en ts of both com poun ds are sh own in Figs 1, 3 an d
2, 4, respectively. Statistically sign ifican t relation sh ip between both experi-
m en tal variables (Eq. (3)) con firm s th e sim ilarity of th e separation m ech a-
n ism s in both ch rom atograph ic system s.
log Pcalc = 2.237(±0.360) log k + 4.841(±0.473)
n = 20, r = 0.971, s = 0.243, F = 319.2
(1)
(2)
(3)
log Pcalc = 2.765(±0.346)RM + 6.933(±0.149)
n = 20, r = 0.982, s = 0.191, F = 529.6
log k = 1.214(±0.114)RM + 0.940(±0.049)
n = 20, r = 0.992, s = 0.057, F = 1155.8
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Derivatives of (Phenylsulfanyl)benzoic Acids
2103
TABLE I
An tileukotrien ic activities of com poun ds 3–5
In h ibition of LTB4
biosyn th esis
In h ibition of LTB4
bin din g
In h ibition of LTD4
bin din g
Com -
log Pcalc
RM
log k′
poun d
a
log
(1/IC50)+6
a
log
(1/IC50)+6
a
log
(1/IC50)+6
IC50
IC50
IC50
Quin olin e derivatives
3a
3b
3c
3d
3e
3f
0.01
0.33
0.05
0.20
0.17
0.19
0.08
8.000
6.481
7.301
6.699
6.770
6.721
7.097
16.7 4.777
70.3 4.153
32.9 4.482
44.2 4.355
5.0 5.301
30.1 4.521
31.3 4.504
0.07 7.155
6.11
5.77
6.11
5.77
6.75
6.41
6.41
–0.16
–0.50
–0.28
n d
0.769
0.354
0.627
n d
1.7
1.6
5.770
5.796
0.63 6.201
3.8
1.7
5.420
5.770
0
0.971
0.653
0.564
–0.22
–0.26
3g
0.27 6.569
2,4-Dih ydroxyacetoph en on e derivatives
4a
4b
4c
4d
4e
4f
4g
4h
4i
7.5
5.125
6.000
5.444
5.770
7.000
5.921
5.678
6.086
6.180
6.187
8.5 5.071
5.0 5.301
9.6 5.018
5.2 5.284
4.0 5.398
3.7 5.432
2.6 5.585
8.1 5.092
5.0 5.301
15.8 4.801
10.8
4.967
4.721
4.489
4.583
4.821
5.409
5.387
5.155
4.983
4.866
7.49
7.98
8.47
7.49
7.98
8.47
7.64
8.13
7.64
8.13
0.35
0.48
0.55
0.18
0.39
0.50
0.23
0.43
0.25
0.41
1.310
1.563
1.664
1.172
1.402
1.602
1.285
1.535
1.208
1.395
1.0
19.0
32.4
26.1
15.1
3.9
3.6
1.7
0.10
1.2
2.1
4.1
0.82
0.66
0.65
7.0
10.4
13.6
4j
2,4-Difluorobiph en yl derivatives
5a
5b
5c
5d
5e
5f
12.0
74.6
1.7
4.921
4.127
5.770
5.161
6.060
5.337
5.137
>100
>100
n i
n i
>100
>100
98.3
>100
22.7
n i
8.64
9.13
8.30
8.79
8.30
8.79
9.13
0.62
0.72
n d
1.629
1.859
n d
n i
8.1 5.092
4.007
n i
6.9
>100
n i
n d
n d
0.87
12.0 4.921
4.644
n i
0.41
n d
1.292
n d
4.6
7.3
>100
n i
>100
>100
5g
50.0
4.301
n i
0.79
1.890
Stan dards
Zileuton
0.17
1.12
>100
>100
>100
3.06
7.24
n d
n d
n d
n d
Zafirlukast
0.07
a
In µM con cen tration .
n d, n ot determ in ed; n i, n ot in cluded in regression an alysis.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

2104
Kuchař et al.:
TABLE II
An tiin flam m atory activities of com poun ds 3–5
Experim en tal pleuritis, % of
Ear edem a, % of
in h ibition c
CEa
% of
in h ibition b
Com poun d
in h ibition
A
B
C
D
E
3a
47
13
10
19
14
18
25
31
32
54
30
14
24
22
23
35
41
17
12
4n
26
17
28
33
11(s)
6n
1n
27
46
3b
23
20
13
16
5n
8n
3n
9n
3n
0
8n
5n
2n
2n
0
3c
29
3d
5n
20
15
3e
10
15
15
25
15
1n
3f
12
4(s)
4n
9n
7
12
13
8
8n
18
1n
3g
19
4a
8n
2n
11
2n
10
7n
26
7n
10n
14
17
4b
27
28
4c
27(s)
43(s)
46(s)
18
38(s)
46(s)
61(s)
11n
6n
4d
4e
4f
1n
9(s)
8n
5(s)
2n
5n
8n
5n
0
4g
29
9n
9
4h
4n
17
6n
16
4i
35
30
4j
35
26
5a
10(s)
2(s)
14(s)
10
17(s)
0
5(s)
7(s)
5(s)
6n
8
6n
5b
5c
7(s)
2(s)
10
15
5d
22
12
12
9
18
11
9n
8n
9n
8
5e
11
6(s)
26(s)
17
32
5f
15(s)
38(s)
36
47(s)
10(s)
49
6n
8n
5g
Zileuton
Zafirlukast
46
43d
20
13
43
n d
n d
n d
23
a
b
In h ibition of carrageen an edem a. In h ibition of: A, volum e of exudate in pleural cavity;
c
B, n um ber of cells; C, cellularity in a cell un it. In h ibition of: D, edem a of ear lobe; E, h y-
perem ia of ear lobe. After th e dose of 10 m g/kg.
n d, n ot determ in ed; s, % of stim ulation ; n , th e level of statistical sign ifican ce p > 0.05.
d
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Derivatives of (Phenylsulfanyl)benzoic Acids
2105
Given th e sm all n um ber of com poun ds in in dividual subgroups, th e rela-
tion sh ips of an tileukotrien ic activities were studied in th e wh ole series of
com poun ds 3–5. Reverse depen den ces on lipoph ilicity were foun d for th e
in h ibition of LTB4 biosyn th esis (Eq. (4)) an d for bin din g to LTD4 receptors
(Eq. (5)). Un fortun ately, th e depen den ce on lipoph ilicity accoun ts for on ly
62–71% of th e depen den ces of th ese activities on ph ysico-ch em ical param e-
ters. Th e lipoph ilic param eters log Pfrg, ch aracterizin g th e lipoph ilicity of
th e “western ” m oieties, were also used in th e regression an alysis. Th eir in -
sertion in stead of log Pcalc did n ot im prove th e statistical sign ifican ce of Eqs
(4)–(6). Th e outliers from th e regression were studied, but n o system atic de-
viation s were foun d th at would en able us to im prove th e regression by th e
use of oth er ph ysico-ch em ical param eters. Several in dicator variables ch ar-
acterizin g th e position of th e substituen ts in th e acidic part an d th e m oi-
eties in th e lipoph ilic part of com poun ds 3, 4 an d 5 were also in volved in
th e regression an alysis. Min or im provem en t of th e statistical sign ifican ce
was observed on ly in Eq. (7), wh ere th e in dicator variable Iorth o, ch aracteriz-
in g th e relative position of carboxyl to sulfur, was used.
TABLE III
In h ibition of bron ch ospasm in duced by ovalbum in or LTD4 (dose: 100 m g/kg; % of in h ibi-
tion at 2, 4, an d 10 m in in tervals)
Mediator
Com poun d
Ovalbum in
LTD4
3a
41, 45, 63
21, 27, 31
23, 36, 50
3, 15, 30
66, 72, 85
n d
69, 70, 75
14, 33, 43
11, 28, 23
14, 33, 43
6, 38, 54
3b
3d
3e
3g
4e
n d, 16, n d
n d, 98, n d
10, 54, 75
4f
n d
Zileuton
23, 28, 50
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

2106
Kuchař et al.:
In h ibition of LTB4 biosyn th esis:
log (1/C) = –0.643(±0.300) log Pcalc + 10.964(±2.323)
n = 24, r = 0.779, s = 0.549, F = 36.37
Bin din g to LTD4 receptors:
(4)
(5)
log (1/C) = –0.643(±0.341) log Pcalc + 10.019(±2.518)
n = 19, r = 0.785, s = 0.480, F = 30.00
FIG. 1
ORTEP view of 3a, sh owin g th e n um berin g sch em e. Th erm al ellipsoids are drawn at 50% prob-
ability
FIG. 2
ORTEP view of 3c, sh owin g th e n um berin g sch em e. Th erm al ellipsoids are drawn at 50% prob-
ability
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Derivatives of (Phenylsulfanyl)benzoic Acids
2107
Bin din g to LTB4 receptors:
log (1/C) = 5.222(±2.550) log Pcalc – 0.345(±0.174) (log Pcalc)2 –
– 14.461 (±10.138)
n = 20, r = 0.842, s = 0.229, F = 24.19
(6)
(7)
log (1/C) = 5.254(±2.465) log Pcalc – 0.348(±0.169) (log Pcalc)2 –
– 0.157(±0.149)Iorth o – 14.442(±8.832)
n = 20, r = 0.856, s = 0.220, F = 18.36
Apparen tly, it can be con cluded from th e results of th e regression an aly-
sis th at th e in h ibition of LTB4 biosyn th esis an d bin din g on LTD4 receptors
decrease with in creasin g lipoph ilicity. Probably, th e com poun ds are situ-
ated, accordin g to th eir lipoph ilicity, on th e descen din g part of th e n on lin -
FIG. 3
Packin g sch em e of 3a; dash ed lin es in dicate h ydrogen bon ds (a view in th e 0 → Y direction )
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

2108
Kuchař et al.:
ear depen den ce of th ese activities on total lipoph ilicity. It is th erefore n ot
surprisin g th at th e m ost active com poun ds with regard to both activities
belon g to th e group of quin olin e derivatives 3 with th e lowest lipoph ilicity.
Th e m ost active com poun d 3a m an ifested h igh er activities in both in -
stan ces th an th e stan dards (Table I). In th e case of LTB4 receptor bin din g, a
parabolic depen den ce facilitated th e calculation of th e optim um of
lipoph ilicity, i.e. log Popt –7.6, close to th e series of com poun ds 4, with th e
h igh est LTB4 receptor bin din g. Th e depen den ces of th e an tileukotrien ic ac-
tivities on lipoph ilicity reflect in all th ree in stan ces th e in fluen ce of
lipoph ilicity on th eir tran sport th rough th e biological system . As regards
th e in h ibition of bron ch osp asm in d u ced eith er by albu m in or LTD4
(Table III), th e m ost active com poun ds belon g to th e quin olin e derivatives
3. It can be assum ed th at th e com bin ation of th e in h ibition of LTB4 bio-
syn th esis an d LTD4 receptor an tagon ism in vitro is decisive for th e in h ibi-
tion of bron ch ospasm in duced by both m ediators in vivo. Th e location of
th e com poun ds, accordin g to th eir lipoph ilicity, on th e descen din g parts of
th e activity–lipoph ilicity depen den ces (Eqs (4), (5)) offers th e possibility of
in creasin g th e an tileukotrien ic activities by sh iftin g th e total lipoph ilicity
to a lower value; furth er work in th at direction is in progress.
FIG. 4
Packin g sch em e of 3c; dash ed lin es in dicate h ydrogen bon ds (a view in th e 0 → Y direction )
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Derivatives of (Phenylsulfanyl)benzoic Acids
2109
EXPERIMENTAL
Th e m eltin g poin ts were determ in ed on a Boetius-type Kofler block an d are n ot corrected.
Th e 1H NMR spectra (δ, ppm ; J, Hz) of 6% solution s of th e com poun ds in CDCl3 (or in
DMSO-d6) con tain in g TMS or 3-(trim eth ylsilyl)propan oic acid-d5 as th e in tern al stan dard
were m easured on a Bruker-250-DPX in strum en t, workin g at 250 MHz for 1H. Th e followin g
n um berin g was used for th e arom atic rin gs:
a) (arylsulfan yl)ben zoic acids
5'
O
6
3
6'
4'
3'
5
OH
S
2
2'
4
O
b) 2,4-difluorobiph en yl
6a
5a
6b
3b
2a
5b
3a
F
F
Th e purity of com poun ds 3–5 was evaluated by HPLC on an Allian ce Waters 2695 liquid
ch rom atograph (Waters Assoc., Milford (MA), U.S.A.) with UV detection (Waters 2487 dual
detector) at 251 µm ran ge. Crom asil C18 100 A (300 × 4.6 m m ) was obtain ed from
Ch rom servis (Czech Republic). Gradien t ch rom atograph y was perform ed with water (Q plus,
Millipore, Germ an y), aceton itrile (Merck, Darm stadt, Germ an y) with 0.1% of ph osph oric
acid (Merck, Darm stadt) as a m obile ph ase. Th e eluen t flow-rate was 1 m l/m in .
Values of log Pcalc were calculated usin g th e KOWWIN Program , Version 1.63 (Syracuse
Research Corp., U.S.A.); as log Pfrg values were used: 3.89 for 2-h ydroxy-3-propylaceto-
ph en on e, 2.59 for 2-m eth ylquin olin e an d 4.28 for 2,4-difluorobiph en yl.
Th e coefficien ts in th e regression equation s were calculated from th e experim en tal results
by m ultiple regression an alysis an d th eir statistical sign ifican ce was tested by th e Studen t
t-test. Th e statistical sign ifican ces of th e regression equation s were tested by th e stan dard de-
viation (s), coefficien t of m ultiple correlation (r) an d Fish er–Sn edecor criterion (F). Th e level
of statistical sign ifican ce p was better th an 0.01 of th e wh ole equation s an d in dividual vari-
ables (with th e exception of Iorth o in Eq. (7), wh ere p < 0.1).
Evaluation of Lipoph ilicity by Ch rom atograph ic Meth ods
TLC: silan ized silica gel FPKG60F254 (Merck, Darm stadt) im pregn ated with a silicon oil
Lukoil 100 (Syn th esia, Kolín , Czech Republic) was used as a station ary ph ase an d aceton e
with 40% of buffer (McIlvain e, pH 3.4) was used as a m obile ph ase. Each ch rom atogram
con tain ed ten com poun ds, two acids servin g as referen ce sam ples. In th e in dividual
ch rom atogram s, th e RF values of th e stan dards did n ot differ by m ore th an 0.02. Th e experi-
m en tal details h ave been described elsewh ere26. RM values were calculated from th e experi-
m en tal RF values accordin g to th e relation sh ip RM = log [(1/RF) – 1].
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

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Kuchař et al.:
HPLC: experim en ts were carried out usin g a liquid ch rom atograph with a LCP 4100 pum p
(ECOM, Prague, Czech Republic), an autosam pler Waters 717 plus, a UV detector Waters 486
(Waters Assoc., Milford) an d a data m odule CSW (DataApex, Czech Republic). Th erm oquest
Hypersil ODS 5 µm (Th erm o Hypersil-Keyston e, Asm oor Run corn , U.K.) in a 250 × 4.6 m m
I.D. colum n was used as a station ary ph ase an d th e m ixture of aceton itrile–buffer pH 5.75
(50:50) was used as a m obile ph ase. Th e detection was perform ed by UV absorption at
233 n m . Th e reten tion tim e of sodium n itrate (0.02% solution ) was taken as a t0 an d th e
capacity factor k was evaluated from th e reten tion tim e of th e solute, tR, by th e relation sh ip:
k = (tR – t0)/t0
.
Crystal Structure Determ in ation
Data an d refin em en t param eters are listed in Table IV. In tern ation al Tables for X-Ray Crys-
30
31
tallograph y27, an d program s SDP 28, CRYSTALS 29, SHELXS86
an d Ortep3
were used.
CCDC 208971 an d 208972 con tain s th e supplem en tary crystallograph ic data for th is paper.
Th ese data can be obtain ed free of ch arge via www.ccdc.cam .ac.uk/con ts/retrievin g.h tm l (or
from th e Cam bridge Crystallograph ic Data Cen tre, 12, Un ion Road, Cam bridge, CB2 1EZ,
UK; fax: +44 1223 336033; or deposit@ccdc.cam .ac.uk).
Crystal data for 3a. Mr = 386.45, space group Pc (No. 7), a = 5.582(5), b = 9.081(5), c =
18.701(5) Å, V = 947(1) Å3; λ = 1.54184 Å, D = 1.35 g cm –3, Z = 2, F(000) = 404, colorless
blocks, crystal fragm en t of dim en sion s 0.07 × 0.07 × 0.48 m m , µ(CuKα) = 17.17 cm –1. Th e
structure was solved by direct m eth ods an d due to th e lack of observed reflection s
isotropically refin ed, except for S, wh ich was refin ed an isotropically, by full-m atrix least-
squares. Hydrogen atom s were located on th e basis of th e expected geom etry an d th eir posi-
tion s refin ed.
Crystal data for 3c. Mr = 387.46, space group P21/c (No. 14), a = 8.7959(6), b = 10.6195(7),
c = 20.557(1) Å, V = 1916.7(2) Å3; λ = 1.54184 Å, D = 1.343 g cm –3, Z = 4, F(000) = 808,
colorless blocks, sin gle crystal of dim en sion s 0.21 × 0.21 × 0.25 m m , µ(CuKα) = 16.97 cm –1
.
Th e structure was solved by direct m eth ods32 an d refin ed an isotropically, by full-m atrix
least-squares. Hydrogen atom s were located based on th e expected geom etry an d ∆ρ m aps
an d th eir position s refin ed.
Meth yl 4-[(4-Hydroxyph en yl)sulfan yl]ben zoate (6a)
A solution of 4-[(4-h ydroxyph en yl)sulfan yl]ben zoic acid (46.9 g, 0.19 m ol) in m eth an ol
(480 m l) an d sulfuric acid (5 m l) was h eated un der reflux for 16 h . Meth an ol was evaporated
an d th e rest was poured in to ice water (600 m l). Ester 6a was obtain ed in a yield of 39.0 g
(78.9%), m .p. 184–186 °C with out purification . For C14H12O3S (260.3) calculated: 64.59% C,
4.65% H, 12.32% S; foun d: 64.52% C, 4.72% H, 11.99% S.
Meth yl Esters 6b, 6c an d 6d
Th ese esters were prepared sim ilarly:
Methyl 4-[(3-hydroxyphenyl)sulfanyl]benzoate (6b). Th e com poun d was prepared in 82.9%
yield with m .p. 86–87 °C (ben zen e–h exan e). For C14H12O3S·0.5C6H6 (299.3) calculated:
68.22% C, 5.05% H, 10.69% S; foun d: 68.49% C, 4.96% H, 10.94% S.
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Derivatives of (Phenylsulfanyl)benzoic Acids
2111
Methyl 2-[(3-hydroxyphenyl)sulfanyl]benzoate (6c). Th e com poun d was prepared in 78.8%
yield with m .p. 77–78.5 °C with out purification . For C14H12O3S (260.3) calculated: 64.59% C,
4.65% H, 12.32% S; foun d: 64.73% C, 4.75% H, 11.98% S.
Methyl 2-[(4-hydroxyphenyl)sulfanyl]benzoate (6d ). Th e com poun d was prepared in 77.1%
yield with m .p. 140–142 °C (ch loroform ). For C14H12O3S (260.3) calculated: 64.59% C,
4.65% H, 12.32% S; foun d: 64.53% C, 4.81% H, 11.96% S.
2-(Ch lorom eth yl)quin olin e (8a)
Th e com poun d was prepared by a m odified ch lorin ation 15 of quin aldin e in tetrach loro-
m eth an e in th e presen ce of an h ydrous potassium carbon ate. Th e crude product 8a was puri-
fied by crystallization from h exan e in th e total yield of 65.0%, m .p. 54–56 °C (lit.25 m .p.
56.5–57.5 °C).
TABLE IV
Data collection an d refin em en t param eters
Param eter
3a
3c
Crystal dim en sion s, m m
0.07 × 0.07 × 0.48
0.21 × 0.21 × 0.25
Diffractom eter an d radiation used, Å En raf-Non ius CAD4, CuKα, λ = 1.54184
Scan tech n ique
Tem perature, K
ω/2θ
293
No. an d θ ran ge of reflection s for
lattice param eter refin em en t, °
20; 28–31
20; 36–40
Ran ge of h, k an d l
0→5, –9→9, –18→18
–10→10, –12→12, 0→24
Stan dard reflection s m on itored in th e 60 m in ; 0.7%
in terval; in ten sity fluctuation
60 m in , 1.9%
Total n um ber of reflection s
m easured; 2θ ran ge
2216; 4–100°
7219; 4–136°
2480
No. of observed reflection s
Criterion for observed reflection s
Fun ction m in im ized
681
I ≥ 1.96σ(I)
w(|F0| – (|Fc|)2
Ch ebysh ev polyn om ial21
118
Weigh tin g sch em e
Param eters refin ed
305
Value of R, wR, an d S
0.1175, 0.1142 an d
1.0589
0.0047, 0.036 an d
1.168
Ratio of th e m axim um least-squares
sh ift to e.s.d. in th e last cycle
0.00007
0.0007
Maxim um an d m in im um h eigh ts in
0.58, –0.51
0.27, –0.36
fin al ∆ρ m ap, e Å–3
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Kuchař et al.:
6-Ch loro-2-(ch lorom eth yl)quin olin e (8b)
A m ixture of 6-ch loroquin aldin e (8.9 g, 50.0 m m ol) (prepared accordin g to33 from
4-ch loroan ilin e an d croton aldeh yde in th e presen ce of sulfuric acid an d sodium 4-n itro-
ben zen e-1-sulfon ate) an d an h ydrous potassium carbon ate in tetrach lorom eth an e (40 m l)
was h eated to 50–55 °C an d ch lorin e (4.7 g, 67.0 m m ol) was con tin uously bein g in troduced
over 2 h . Th e m ixture was cooled to 20 °C, th e solid was filtered off an d th e filtrate ex-
tracted twice with 100 m l of 2 M HCl. Th e com bin ed extracts were n eutralized with sodium
carbon ate an d th e precipitated crude 8b separated after coolin g to 5 °C. Pure 8b was pre-
pared in 63.9% yield, m .p. 118–120 °C (70% eth an ol). For C10H7Cl2N (212.1) calculated:
56.63% C, 3.33% H, 33.44% Cl, 6.60% N; foun d: 56.60% C, 3.48% H, 33.46% Cl, 6.35% N.
4-{[4-(Quin olin -2-ylm eth oxy)ph en yl]sulfan yl}ben zoic Acid (3a)
A m ixture of 6a (6.5 g, 25.0 m m ol), 8a (4.4 g, 25.0 m m ol), an h ydrous potassium carbon ate
(10.0 g) an d potassium iodide (0.4 g) in butan -2-on e (80 m l) was h eated at reflux for 8 h .
Th e h ot suspen sion was filtered, th e filtrate evaporated to dryn ess an d th e solid boiled with
m eth an ol (150 m l) to give, after coolin g an d filtration , 8.2 g (82.1%) of th e m eth yl ester of
3a, m .p. 125–127 °C. For C24H19NO3S (401.5) calculated: 71.80% C, 4.77% H, 3.49% N,
7.99% S; foun d: 71.38% C, 4.81% H, 3.23% N, 7.99% S. Th is ester (5.7 g, 14.2 m m ol) was
suspen ded in eth an ol (40 m l), a solution of potassium h ydroxide (2.3 g) in water (15 m l)
was added an d th e m ixture h eated at reflux for 15 m in . Th e clear solution was evaporated
an d th e residue dissolved in boilin g water (250 m l). After filtration , th e filtrate was acidified
with acetic acid an d th e precipitated crude product purified by crystallization from
propan -2-ol (100 m l) an d water (5 m l). Th e precipitated product was filtered off at 40 °C to
give 3a (5.2 g, 94.4%), m .p. 204–206 °C (propan -2-ol). For C23H17NO3S (387.5) calculated:
71.30% C, 4.42% H, 3.61% N, 8.28% S; fou n d: 71.15% C, 4.55% H, 3.38% N, 8.29% S.
1H NMR (DMSO-d6): 5.43 s (CH2O); 7.19 m (H-3,5,3′,5′); 7.49 d, J = 9.0 (H-2′,6′); 7.83 d, J =
8.7 (H-2,6); 8.43 d, J = 8.2 (H-4 quin ).
Acids 3b, 3c, 3d , 3e, 3f an d 3g
Th ese acids were prepared sim ilarly:
2-{[4-(Quinolin-2-ylmethoxy)phenyl]sulfanyl}benzoic acid (3b). Th e crude m eth yl ester of 3b
was obtain ed from 8a an d 6d in 92.1% yield, m .p. 134–136 °C. For C24H19NO3S (401.5)
calculated: 71.80% C, 4.77% H, 3.49% N, 7.99% S; foun d: 71.53% C, 4.80% H, 3.46% N,
8.30% S. Th e ester was h ydrolyzed an d acid 3b was obtain ed in 52.3% yield, m .p. 208–210 °C
(butan -2-on e). For C23H17NO3S (387.5) calculated: 71.30% C, 4.42% H, 3.61% N, 8.28% S;
foun d: 71.08% C, 4.61% H, 3.89% N, 8.06% S. 1H NMR (DMSO-d6): 5.41 s (CH2O); 8.02 m
(H-3,4,5,6,2′,3′,5′,6′); 8.38 d, J = 8.5 (H-4 quin ).
4-{[3-(Quinolin-2-ylmethoxy)phenyl]sulfanyl}benzoic acid (3c). Th e m eth yl ester of 3c was
prepared from 8a an d 6b, after crystallization from m eth an ol th e ester was obtain ed in
75.5% yield, m .p. 95–97 °C. For C24H19NO3S (401.5) calculated: 71.80% C, 4.77% H, 3.49% N,
7.99% S; foun d: 71.58% C, 4.81% H, 3.40% N, 7.81% S. Th e ester was h ydrolyzed an d acid
3c was obtain ed in 71.4% yield, m .p. 190–192 °C (propan -2-ol). For C23H17NO3S·H2O
(405.5) calculated: 68.12% C, 4.72% H, 3.45% N, 7.91% S; foun d: 68.45% C, 4.61% H,
3.61% N, 7.83% S. 1H NMR (DMSO-d6): 5.37 s (CH2O); 6.97–7.87 m (H-3,5,2′,4′,5′,6′);
7.95 d, J = 8.2 (H-4 quin ).
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Derivatives of (Phenylsulfanyl)benzoic Acids
2113
2-{[3-(Quinolin-2-ylmethoxy)phenyl]sulfanyl}benzoic acid (3d ). Th e crude m eth yl ester of 3d
was prepared in n early quan titative yield from 8a an d 6c, m .p. 52–55 °C; th e an alytical sam -
ple was prepared by crystallization from m eth an ol–eth er, m .p. 70–72 °C. For C24H19NO3S
(401.5) calculated: 71.80% C, 4.77% H, 3.49% N, 7.99% S; foun d: 71.83% C, 4.76% H,
3.18% N, 7.75% S. Acid 3d was prepared in 60.9% yield from th e crude ester by h ydrolysis,
purified by crystallization from butan -2-on e–h exan e, m .p. 169–171 °C. For C23H17NO3S
(387.5) calculated: 71.30% C, 4.42% H, 3.61% N, 8.28% S; foun d: 71.06% C, 4.50% H,
3.38% N, 8.13% S. 1H NMR (DMSO-d6): 5.37 s (CH2O); 6.84–7.85 m (H-3,4,5,6,2′,4′,5′,6′);
8.35 d, J = 9.0 (H-4 quin ).
4-({4-[(6-Chloroquinolin-2-yl)methoxy]phenyl}sulfanyl)benzoic acid (3e). Th e m eth yl ester of
3e was obtain ed from 8b an d 6a in 91.3% yield, m .p. 130–132 °C (m eth an ol). For
C
24H18ClNO3S (435.9) calculated: 66.13% C, 4.16% H, 8.13% Cl, 3.21% N, 7.36% S; foun d:
65.84% C, 4.14% H, 8.29% Cl, 3.60% N, 7.16% S. Th e ester was h ydrolyzed an d after
cryst allizat io n fro m d im et h ylfo rm am id e t h e acid 3 e was o b t ain ed in 93.0% yield ,
m .p. 232–235 °C. For C23H16ClNO3S (421.9) calculated: 65.48% C, 3.82% H, 8.40% Cl, 3.32% N,
7.60% S; foun d: 65.31% C, 3.91% H, 8.34% Cl, 3.60% N, 7.52% S. 1H NMR (DMSO-d6):
5.37 s (CH2O); 7.10 d, J = 9.0 (H-3′,5′); 7.16 d, J = 8.2 (H-3,5); 7.37 d, J = 9.0 (H-2′,6′); 8.32 d,
J = 8.5 (H-4 quin ).
2-({4-[(6-Chloroquinolin-2-yl)methoxy]phenyl}sulfanyl)benzoic acid (3f). Th e crude m eth yl ester
of 3f was prepared from 8b an d 6d in 85.4% yield, m .p. 158–160 °C. For C24H18ClNO3S
(435.9) calculated: 66.13% C, 4.16% H, 8.13% Cl, 3.21% N, 7.36% S; foun d: 65.77% C,
4.21% H, 8.30% Cl, 3.05% N, 7.32% S. Acid 3f was obtain ed by h ydrolysis, purified by re-
peated precipitation as th e sodium salt in 86.9% yield, m .p. 238–240 °C. For C23H16ClNO3S
(421.9) calculated: 65.48% C, 3.82% H, 8.40% Cl, 3.32% N, 7.60% S; foun d: 65.53% C,
3.91% H, 8.43% Cl, 3.37% N, 7.62% S. 1H NMR (DMSO-d6): 5.37 s (CH2O); 7.22 m (H-3′,5′);
7.50 d, J = 8.8 (H-2′,6′); 7.82 m (H-3,4,5); 8.07 m (H-4 quin ); 8.42 d, J = 8.5 (H-6).
2-({3-[(6-Chloroquinolin-2-yl)methoxy]phenyl}sulfanyl)benzoic acid (3g). Th e m eth yl ester of
3g was obtain ed from 8b an d 6c in 91.9% yield, m .p. 98–100 °C (m eth an ol). For
C
24H15ClNO3S (435.9) calculated: 66.13% C, 4.16% H, 8.13% Cl, 3.21% N, 7.36% S; foun d:
65.93% C, 4.27% H, 8.30% Cl, 3.09% N, 7.17% S. Acid 3g was obtain ed by h ydrolysis an d
purification th rough th e am m on ium salt in 37.7% yield, m .p. 209–211 °C (water). For
C
23H16ClNO3S (421.9) calculated: 65.48% C, 3.82% H, 8.40% Cl, 3.32% N, 7.60% S; foun d:
65.56% C, 3.98% H, 8.62% Cl, 3.35% N, 7.56% S. 1H NMR (DMSO-d6): 5.40 s (CH2O);
6.89 dd, J = 1.3, 7.9 (H-3); 7.17 m (H-4,5,2′,4′,6′); 7.41 t, J = 7.9 (H-5′); 7.88 dd, J = 1.9, 7.5
(H-6); 8,37 d, J = 8.8 (H-4 quin ).
Meth yl 4-{[3-(3-Ch loropropoxy)ph en yl]sulfan yl}ben zoate (7a)
A m ixture of 6b (11.7 g, 44.5 m m ol), 1-brom o-3-ch loropropan e (23.6 g, 0.15 m ol) an d an h y-
drous potassium carbon ate (14.0 g) in 4-m eth ylpen tan -2-on e (200 m l) was h eated to reflux
for 10 h . After coolin g to 20 °C, th e precipitate was filtered off an d th e filtrate evaporated.
Th e oil was dissolved in eth er (20 m l), diluted with h exan e (20 m l) an d th e crystallin e prod-
uct was filtered off after coolin g to 0 °C. Th e yield was 78.0%, m .p. 47–49 °C with out purifi-
cation . For C17H17ClO3S (336.8) calculated: 60.62% C, 5.09% H, 10.52% Cl, 9.52% S; foun d:
60.65% C, 5.12% H, 10.35% Cl, 9.42% S.
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

2114
Kuchař et al.:
In term ediates 7b, 7c an d 7d
Th ese com poun ds were prepared sim ilarly:
Methyl 4-{[4-(3-chloropropoxy)phenyl]sulfanyl}benzoate (7b). Prepared from 6a an d 1-brom o-
3-ch loropropan e in 92.8% yield, m .p. 65–67 °C with out purification . For C17H17ClO3S
(336.8) calculated: 60.62% C, 5.09% H, 10.52% Cl, 9.52% S; foun d: 60.46% C, 5.09% H,
10.35% Cl, 9.42% S.
Methyl 4-{[3-(4-bromobutoxy)phenyl]sulfanyl}benzoate (7c). Prepared from 6b an d 1,4-dibrom o-
bu tan e. Th e cru de produ ct was pu rified by colu m n ch rom atograph y on silica gel u sin g
dich lorom eth an e–h exan e (1:1) as a m obile ph ase. Pure 7c was obtain ed in 76.9% yield, m .p.
43–45 °C with out recrystallization . For C18H19BrO3S (395.3) calculated: 54.69% C, 4.84% H,
20.22% Br, 8.11% S; foun d: 54.71% C, 4.80% H, 20.09% Br, 8.07% S.
Methyl 2-{[4-(4-bromobutoxy)phenyl]sulfanyl}benzoate (7d ). Prepared from 6d an d 1,4-dibro-
m obutan e in 67.8% yield, m .p. 100–102 °C (ben zen e–h exan e). For C18H19BrO3S (395.3) cal-
culated: 54.69% C, 4.84% H, 20.22% Br, 8.11% S; foun d: 54.23% C, 4.83% H, 20.16% Br,
7.51% S.
4-{4-[2-(4-Acetyl-3-h ydroxy-2-propylph en oxy)eth oxy]ph en ylsulfan yl}ben zoic Acid (4a)
A m ixture of 4-(2-ch loroeth oxy)-2-h ydroxy-3-propylacetoph en on e (8c; 7.7 g, 30.0 m m ol)
prepared from 2,4-dih ydroxy-3-propylacetoph en on e an d 2-ch loroeth yl tosylate accordin g
to19, 6a (7.8 g, 30.0 m m ol), an h ydrous potassium carbon ate (13.8 g) an d potassium iodide
(0.6 g) in 4-m eth ylpen tan -2-on e (160 m l) were h eated to reflux for 45 h . Th e precipitate was
filtered off, th e filtrate evaporated to dryn ess an d th e solid dissolved in dich lorom eth an e
(20 m l) an d purified on silica gel with dich lorom eth an e as th e eluen t. Th e m eth yl ester of
th e title acid was isolated in th e yield of 8.4 g (58.2%), m .p. 117–119 °C (with out
recrystallization ). For C27H28O6S (480.6) calculated: 67.48% C, 5.87% H, 6.67% S; foun d:
67.31% C, 5.89% H, 6.67% S. A m ixture of th e m eth yl ester (8.0 g, 17.0 m m ol) in eth an ol
(40 m l) an d potassium h ydroxide (3.3 g) in water (10 m l) was h eated to reflux for 30 m in .
Th e residue after evaporation was diluted with water (20 m l), th e solution was filtered with
ch arcoal an d acidified to pH 1 with dilute h ydroch loric acid at 5 °C. Th e precipitated crude
product (7.7. g, m .p. 134–137 °C) was crystallized from m eth an ol in th e total yield of 5.5 g
(69.9%) with m .p. 146–148 °C (m eth an ol). For C26H26O6S (466.6) calculated: 66.93% C,
5.61% H, 6.87% S; foun d: 66.74% C, 5.61% H, 6.99% S. 1H NMR (CDCl3): 2.58 s (CH3CO);
4.41 s (CH2CH2); 7.01 d, J = 8.9 (H-3,5); 7.21 d, J = 9.2 (H-3′,5′); 7.50 d, J = 9.2 (H-2′,6′); 7.93 d,
J = 8.9 (H-2,6); 12.75 s (HO).
Acids 4c, 4d , 4g, 4h an d 4i
Th ese acids were prepared sim ilarly:
4-{4-[4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butoxy]phenylsulfanyl}benzoic acid (4c). Th e cor-
respon din g m eth yl ester was prepared from 4-(4-brom obutoxy)-2-h ydroxy-3-propyl-
acetoph en on e19 (8d ) an d 6a in 62.0% yield. Th e title acid was prepared by subsequen t h y-
drolysis in 59.9% yield, m .p.160–162 °C (90% eth an ol). For C28H30O6S (494.6) calculated:
68.00% C, 6.11% H, 6.48% S; foun d: 67.89% C, 6.26% H, 6.36% S. 1H NMR (CDCl3): 2.04 bs
(CH2CH2); 2.57 s (CH3CO); 4.11 m (OCH2 2×); 6.94 d, J = 8.9 (H-3′,5′); 7.07 d, J = 8.9 (H-3,5);
7.46 d, J = 8.9 (H-2′,6′); 7.87 d, J = 8.9 (H-2,6); 12.74 s (HO).
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Derivatives of (Phenylsulfanyl)benzoic Acids
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4-{3-[2-(4-Acetyl-3-hydroxy-2-propylphenoxy)ethyloxy]phenylsulfanyl}benzoic acid (4d ). Th e cor-
respon din g m eth yl ester was prepared from 8c an d 6b, m .p. 46–48 °C (after purification by
ch rom atograph y on silica gel, usin g toluen e–eth yl acetate as th e m obile ph ase) in 36.1%
yield. For C27H28O6S (480.6) calculated: 67.48% C, 5.87% H, 6.67% S; foun d: 67.05% C,
5.88% H, 6.34% S. Th e title acid was prepared by subsequen t h ydrolysis in 67.0% yield,
m .p. 146–148 °C (eth an ol). For C26H26O6S (466.6) calculated: 66.93% C, 5.61% H, 6.87% S;
foun d: 66.88% C, 5.83% H, 6.68% S. 1H NMR (DMSO-d6): 2.57 s (CH3CO); 4.39 s (CH2CH2);
7.05 m (H-2′,4′,6′); 7.33 m (H-3,5,5′); 7.83 m (H-2,6); 12.77 s (HO).
2-{3-[3-(4-Acetyl-2-hydroxy-3-propylphenoxy)propoxy]phenylsulfanyl}benzoic acid (4g). Th e cor-
respon din g m eth yl ester was prepared from 4-(3-ch loropropoxy)-2-h ydroxy-3-propylaceto-
ph en on e19 (8e) an d 6c in 59.0% yield, m .p. 73–75 °C (m eth an ol). Th e title acid was pre-
pared by subsequen t h ydrolysis in 78.2% yield, m .p. 142–144 °C. For C27H28O6S (480.6) cal-
culated: 67.48% C, 5.87% H, 6.67% S; foun d: 67.26% C, 5.94% H, 6.51% S. 1H NMR
(DMSO-d6): 2.22 quin tet, J = 6.1 (CH2); 2.58 s (CH3CO); 4.20 t, J = 6.2, 4.26 t, J = 6.1 (OCH2
2×); 6.80 dd, J = 1.1, 8.1 (H-3); 7.04–7.48 m (H-4,5,2′,4′,5′,6′); 7.92 dd, J = 1.1, 8.1 (H-6);
12.83 s (HO).
2-{3-[4-(4-Acetyl-2-hydroxy-3-propylphenoxy)butoxy]phenylsulfanyl}benzoic acid (4h ). Th e cor-
respon din g m eth yl ester was prepared from 8d an d 6c in 76% yield, m .p. 60–62 °C (m eth a-
n ol). Th e title acid was prepared by subsequen t h ydrolysis in 66.5% yield, m .p. 66–68 °C
(90% m eth an ol). For C28H30O6S (494.6) calculated: 68.00% C, 6.11% H, 6.48% S; foun d:
68.04% C, 6.36% H, 6.10% S. 1H NMR (DMSO-d6): 1.91 m (CH2CH2); 2.58 s (CH3CO); 4.07 m
(OCH2 2×); 7.01–7.47 m (H-4,5,2′,4′,5′,6′); 7.78 d, J = 9.1 (H-3); 7.92 dd, J = 1.5, 7.7 (H-6);
12.83 s (HO).
2-{4-[3-(4-Acetyl-2-hydroxy-3-propylphenoxy)propoxy]phenylsulfanyl}benzoic acid (4i). Th e cor-
respon din g m eth yl ester was prepared from 8e an d 6d an d isolated in 42.0% yield as an oil
after ch rom atograph y on silica gel with toluen e–eth yl acetate as th e m obile ph ase. For
C
28H30O6S (494.6) calculated: 68.00% C, 6.11% H, 6.48% S; foun d: 68.27% C, 6.30% H,
6.18% S. Subsequen t h ydrolysis led to acid 4i in 81.0% yield, m .p. 141–143 °C (m eth an ol).
For C27H28O6S (480.6) calculated: 67.48% C, 5.87% H, 6.67% S; foun d: 67.27% C, 6.00% H,
6.42% S. 1H NMR (DMSO-d6): 2.26 quin tet, J = 6.1 (CH2); 2.59 s (CH3CO); 4.25 t, J = 6.1
(CH2O); 4.29 t, J = 6.1 (CH2O); 6.67 dd, J = 1.2, 7.6 (H-6); 7.10 m (H-3′,5′); 7.18 dt, J = 1.2,
7.6 (H-4); 7.34 ddd, J = 1.8, 7.3, 8.8 (H-5); 7.48 m (H-2′,6′); 7.93 dd, J = 1.5, 7.6 (H-3).
4-{4-[3-(4-Acetyl-3-h ydroxy-2-propylph en oxy)propoxy]ph en ylsulfan yl}ben zoic Acid (4b)
A m ixture of 7b (9.0 g, 26.5 m m ol), 2,4-dih ydroxy-3-propylacetoph en on e (5.2 g, 26.5 m m ol),
an h ydrous potassium carbon ate (18.0 g) an d potassium iodide (0.8 g) in 4-m eth yl-
pen tan -2-on e (160 m l) was h eated at reflux for 24 h . Th e h ot suspen sion was filtered, th e
filtrate evaporated an d th e precipitate wash ed with eth er an d crystallized from m eth an ol to
give th e m eth yl ester of 4b (6.6 g, 50.4%), m .p. 58–61 °C. For C28H30O6S (494.6) calculated:
68.00% C, 6.11% H, 6.48% S; found: 67.65% C, 6.14% H, 6.38% S. A mixture of the ester (6.2 g,
12.5 mmol) in eth an ol (30 m l) an d potassium h ydroxide (2.25 g, 40.0 m m ol) in water (10 m l)
was stirred un der reflux for 30 m in . Th e solution was evaporated, th e solid dissolved in wa-
ter, filtered with ch arcoal an d th e filtrate acidified with acetic acid. Th e crude product was
collected by filtration an d crystallized from m eth an ol (150 m l) to give 4b (3.5 g, 50.8%),
m .p. 177–179 °C (m eth an ol). For C27H28O6S (480.6) calculated: 67.48% C, 5.87% H, 6.67% S;
foun d: 67.35% C, 5.85% H, 6.40% S. 1H NMR (CDCl3): 2.30 m (CH2); 2.55 s (CH3CO); 4.21 m
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2116
Kuchař et al.:
(CH2O 2×); 6.94 d, J = 8.20 (H-3′,5′); 7.04 d, J = 8.40 (H-3,5); 7.43 d, J = 8.20 (H-2′,6′); 7.83 d,
J = 8.40 (H-2,6); 12.72 s (HO).
Acids 4e, 4f an d 4j
Th ese acids were prepared sim ilarly:
4-{3-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy]propoxy)phenylsulfanyl}benzoic acid (4e). Th e
crude m eth yl ester of 4e obtain ed from 7a an d 2,4-dih ydroxy-3-propylacetoph en on e was pu-
rified by ch rom atograph y on silica gel usin g dich lorom eth an e an d ch loroform as eluen ts to
give th e pure ester (71.8%), m .p. 99–101 °C. For C28H30O6S (494.6) calculated: 68.00% C,
6.11% H, 6.48% S; foun d: 67.68% C, 6.16% H, 6.49% S. Hydrolysis led to 4e in 94.6% yield,
m .p. 104–106 °C (80% m eth an ol). For C27H28O6S (480.6) calculated: 67.48% C, 5.87% H,
6.67% S; foun d: 67.42% C, 5.95% H, 6.71% S. 1H NMR (CDCl3): 2.20 m (CH2); 2.57 s
(CH3CO); 4.21 m (CH2O 2×); 6.82–7.38 m (H-3,5,2′,4′,5′,6′); 7.87 d, J = 8.7 (H-2,6); 12.76 bs
(HO).
4-{3-[4-(4-Acetyl-3-hydroxy-2-propylphenoxy)butoxy]phenylsulfanyl}benzoic acid (4f). Th e crude
m eth yl ester of 4f was obtain ed from 7c an d 2,4-dih ydroxy-3-propylacetoph en on e as an oily
product in 74.2% yield. For C29H32O6S (508.6) calculated: 68.48% C, 6.34% H, 6.30% S;
foun d: 67.65% C, 6.23% H, 6.62% S. Hydrolysis led to crude 4f, wh ich was purified by ch ro-
m atograph y on silica gel to give th e title acid in 75.0% yield, m .p. 100–102 °C (with out
recrystallization ). For C28H30O6S (494.6) calculated: 68.00% C, 6.11% H, 6.48% S; foun d:
67.18% C, 6.10% H, 6.50% S. 1H NMR (DMSO-d6): 1.89 m (CH2 2×); 2.56 s (CH3CO); 4.10 m
(CH2O 2×); 7.00 m (H-2′,4′,5′); 7.31 m (H-6′); 7.29 d, J = 8.00 (H-3,5); 7.88 d, J = 8.00
(H-2,6); 12.78 bs (HO).
2-{4-[4-(4-Acetyl-3-hydroxy-2-propylphenoxy]butoxy}phenylsulfanyl)benzoic acid (4j). Th e crude
m eth yl ester of 4j was obtain ed from 7d an d 2,4-dih ydroxy-3-propylacetoph en on e as an oily
product in 65.0% yield. Th e h ydrolysis led to 4j after ch rom atograph y on silica gel in 69.5%
yield, m .p. 155–157 °C (with out recrystallization ). For C28H30O6S (494.6) calculated: 67.48% C,
5.87% H, 6.67% S; foun d: 67.57% C, 5.68% H, 6.45% S. 1H NMR (DMSO-d6): 1.95 m (CH2O
2×); 2.59 s (CH3CO); 4.15 m (CH2CH2); 6.69 d, J = 8.2 (H-6); 7.08 m (H-3′,5′); 7.17 dt, J =
1.2, 7.6 (H-4); 7.33 ddd, J = 1.8, 7.3, 8.8 (H-5); 7.45 m (H-2′,6′); 7.95 dd, J = 1.5, 7.6 (H-3).
1-Brom o-3-[(2′,4′-difluorobiph en yl-4-yl)oxy]propan e (8f)
A m ixture of 4-(2′,4′-difluoroph en yl)ph en ol (13.0 g, 63.0 m m ol), 1,3-dibrom opropan e (45.6 g,
0.226 m ol) an d an h ydrous potassium carbon ate (21.0 g) in butan -2-on e (180 m l) was h eated
at reflux for 10 h . Th e h ot m ixture was filtered an d th e filtrate evaporated to dryn ess. Th e
crystallin e solid was dissolved in aceton e (20 m l), th e solven t evaporated after filtration an d
th e residue th orough ly wash ed by stirrin g with h exan e (50 m l). Th e yield of pure 8f was
12.7 g (61.7%), m .p. 59–60 °C (eth an ol). For C15H13BrF2O (327.2) calculated: 55.07% C,
4.00% H, 24.42% Br, 11.61% F; foun d: 55.51% C, 3.95% H, 23.75% Br, 11.79% F. 1H NMR
(CDCl3): 2.34 quin tet, J = 6.2 (CH2); 3.62 t, J = 6.5 (CH2O); 4.15 t, J = 5.9 (CH2Br); 6.89 m
(H-5b,6b); 6.98 m (H-3a,5a); 7.35 m (H-3b); 7.42 m (H-2a,6a).
1-Brom o-4-[(2′,4′-difluorobiph en yl-4-yl)oxy]butan e (8g)
Th e com poun d was prepared sim ilarly from 4-(2′,4′-difluoroph en yl)ph en ol an d 1,4-dibrom o-
butan e in 65.6% yield, m .p. 60–61 °C (aceton e–h exan e). For C16H15BrF2O (341.2) calculated:
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Derivatives of (Phenylsulfanyl)benzoic Acids
2117
56.31% C, 4.43% H, 23.44% Br, 11.14% F; foun d: 56.71% C, 4.47% H, 23.25% Br, 11.36% F.
1H NMR (CDCl3): 1.90–2.15 m (CH2CH2); 3.50 t, J = 6.6 (CH2O); 4.03 t, J = 5.9 (CH2Br); 6.88 m
(H-5b,6b); 6.95 m (H-3a,5a); 7.35 m (H-3b); 7.41 m (H-2a,6a).
4-[(4-{3-[(2′,4′-Difluorobiph en yl-4-yl)oxy]propoxy}ph en yl)sulfan yl]ben zoic Acid (5a)
A m ixture of 6a (2.6 g, 0.01 m ol), 8f (3.3 g, 0.01 m ol), an h ydrous potassium carbon ate (4.6 g)
an d potassium iodide (0.2 g) in butan -2-on e (80 m l) was h eated at reflux for 8 h . Th e sus-
pen sion was filtered wh ile boilin g, th e filtrate evaporated to dryn ess an d th e crude, partially
crystallin e m eth yl ester of acid 5a (3.9 g, 77.5%) was dissolved in m eth an ol (45 m l). A solu-
tion of potassium h ydroxide (1.5 g) in water (15 m l) was added an d th e m ixture was h eated
at reflux for 2 h . Th e solven t was evaporated, water (30 m l) added, th e resultan t solution fil-
tered with ch arcoal an d th e filtrate acidified with dilute h ydroch loric acid. Th e crude acid
was crystallized from eth an ol–dim eth ylform am ide an d 5a (2.7 g, 75.3%) was obtain ed, m .p.
173–174 °C (eth an ol–dim eth ylform am ide). For C28H22F2O4S (492.5) calculated: 68.28% C,
4.50% H, 7.71% F, 6.51% S; foun d: 68.16% C, 4.37% H, 7.79% F, 6.27% S. 1H NMR
((DMSO-d6): 2.22 quintet, J = 6.3 (CH2); 4.23 t, J = 6.3 (CH2O 2×); 7.17 d, J = 8.5 (H-3,5); 7.43 m
(H-3a,5a); 7.49 m (H-6b); 7.82 d, J = 8.5 (H-2,6).
Acids 5b, 5c, 5d , 5e, 5f an d 5g
Th ese acids were prepared sim ilarly:
4-[(4-{4-[(2′,4′-Difluorobiphenyl-4-yl)oxy]butoxy}phenyl)sulfanyl]benzoic acid (5b). Th e m eth yl
ester of 5b was obtain ed from 6a an d 8f in 52.5% yield, m .p. 117–118 °C (eth an ol–
dim eth ylform am ide); h ydrolysis gave acid 5b in 93.0% yield, m .p. 197–200 °C (propan -2-ol).
For C29H24F2O4S (506.6) calculated: 68.76% C, 4.78% H, 7.50% F, 6.33% S; foun d: 68.51% C,
4.80% H, 7.28% F, 6.08% S. 1H NMR (DMSO-d6): 1.93 bs (CH2 2×); 4.12 bs (CH2O 2×); 7.05 d,
J = 7.5 (H-3′,5′,2a,6a); 7.14 d, J = 8.5 (H-3,5); 7.45 m (H-2′,6′); 7.53 m (H-6b); 7.84 d, J = 8.5
(H-2,6).
2-[(4-{3-[(2′,4′-Difluorobiphenyl-4-yl)oxy]propoxy}phenyl)sulfanyl]benzoic acid (5c). Th e m eth yl
ester of 5c was prepared from 6d an d 8g in 68.0% yield an d th e crude ester was h ydrolyzed
in to acid 5c, obtain ed after crystallization in 61.2% yield, m .p. 171–172 °C (propan -2-ol).
For C28H22F2O4S (492.5) calculated: 68.28% C, 4.50% H, 6.51% F, 7.71% S; foun d: 67.97% C,
4.50% H, 6.45% F, 7.56% S. 1H NMR (DMSO-d6): 2.24 quin tet, J = 6.3 (CH2); 4.24 m (CH2O
2×); 6.73 dd, J = 0.9, 8.2 (H-3); 7.10 d, J = 7.08 (H-3′,5′,1a,6a); 7.33 m (H-4); 7.46 m
(H-2′,6′,3a,5a); 7.53 m (H-6b); 7.89 dd, J = 1.6, 7.9 (H-6).
2-[(4-{4-[(2′,4′-Difluorobiphenyl-4-yl)oxy]propoxy}phenyl)sulfanyl]benzoic acid (5d ). Th e m eth yl
ester of 5d was prepared from 6d an d 8g in 75.4% yield, m .p. 155–157 °C (butan -2-on e).
Acid 5d was obtain ed by h ydrolysis in 91.3% yield, m .p. 193–195 °C (propan -2-ol). For
C
29H24F2O4S (506.6) calculated: 68.76% C, 4.78% H, 6.33% F, 7.50% S; foun d: 68.69% C,
4.95% H, 6.33% F, 7.37% S. 1H NMR ((DMSO-d6): 1.94 m (CH2 2×); 4.13 m (CH2O 2×); 6.73 dd,
J = 1.0, 8.2 (H-3); 7.08 d, J = 8.8 (H-3′,5′); 7.06 d, J = 8.8 (H-2a,6a); 7.16 bm (H-5,3b,5b); 7.33 m
(H-4).
2-[(3-{3-[(2′,4′-Difluorobiphenyl-4-yl)oxy]propoxy}phenyl)sulfanyl]benzoic acid (5e). Th e m eth yl
ester of 5e was prepared from 6c an d 8f in 96.5% yield an d with out purification h ydrolyzed
in to acid 5e, obtain ed in 87.4% yield after crystallization from eth an ol–dim eth ylform am ide,
m .p. 210–212 °C. For C28H22F2O4S (492.5) calculated: 68.28% C, 4.50% H, 7.71% F, 6.51% S;
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Kuchař et al.:
foun d: 67.90% C, 4.67% H, 7.75% F, 6.80% S. 1H NMR (DMSO-d6): 2.19 quin tet, J = 6.3
(CH2); 4.21 t, J = 6.3, 4.18 t, J = 6.3 (CH2O 2×); 6.80 m (H-4′); 7.04 m (H-3,5,2′,5′,6′,2a,6a);
7.28 t, J = 8.0 (H-4); 7.43 dd, J = 1.6, 8.8 (H-3a,5a); 7.50 m (H-6b); 7.71 m (H-6).
2-[(3-{4-[(2′,4′-Difluorobiphenyl-4-yl)oxy]butoxy}phenyl)sulfanyl]benzoic acid (5f). Th e m eth yl
ester of 5f was prepared from 6c an d 8g in 98.0% yield an d with out purification h ydrolyzed
in to acid 5f obtain ed in 66.4% yield after crystallization from propan -2-ol–
d im et h ylfo rm am id e, m .p. 175–177 °C. For C29H24F2O4S (506.6) calcu lated: 68.76% C,
4.47% H, 7.50% F, 6.33% S; found: 68.59% C, 4.82% H, 7.22% F, 6.11% S. 1H NMR ((DMSO-d6):
1.89 m (CH2 2×); 4.08 m (CH2O 2×); 6.90 m (H-4′,3b); 7.07 m (H-3,5,2′,5′,6′,2a,6a,5b); 7.29 t,
J = 8.2 (H-4); 7.41 dd, J = 1.6, 8.8 (H-3a,5a); 7.49 m (H-6b); 7.75 m (H-6).
4-[(3-{4-[(2′,4′-Difluorobiphenyl-4-yl)oxy]butoxy}phenyl)sulfanyl]benzoic acid (5g). Th e m eth yl
ester of 5g was prepared from 6b an d 8g in alm ost quan titative yield an d with out purifica-
tion h ydrolyzed in to acid 5g obtain ed in 61.5% yield after crystallization from eth an ol, m .p.
148–150 °C. For C29H24F2O4S (506.6) calculated: 68.76% C, 4.48% H, 7.50% F, 6.33% S;
foun d: 68.50% C, 4.99% H, 7.27% F, 6.21% S. 1H NMR ((DMSO-d6): 1.98 m (CH2 2×); 4.03 m
(CH2O 2×); 6.94 m (H-2′,4′,6′,2a,6a,3b,5b); 7.23 d, J = 8.8 (H-3,5); 7.33 m (H-6b); 7.40 dd, J =
1.6, 8.8 (H-3a,5a); 7.90 d, J = 8.8 (H-2,6).
Biological Evaluation
In h ibition of LTB4 biosyn th esis: th e production of LTB4 was determ in ed in rat poly-
m orph on uclear cells from th e pleural exudate elicited by h eat-in activated rat serum 34. Th e
cells were stim ulated with th e Ca2+ ion oph ore A23187 (Sigm a) an d in cubated with various
con cen tration s of th e tested drugs. LTB4 was determ in ed in th e supern atan ts usin g a com -
m ercial RIA kit (Am ersh am ). For th e LTB4 receptor bin din g study, a sligh tly m odified
m eth od of Ch en g et al.35 was used. Th e m em bran e fraction was prepared from a m ale
guin ea pig spleen ; 2 m g of th e m em bran es were in cubated with 0.3 n M 3H-LTB4 at 25 °C for
30 m in in 100 µl of th e in cubated m ixture. Non specific bin din g was determ in ed in th e pres-
en ce of 0.1 µM LTB4. Th e m em bran es were filtered th rough Wh atm an GF/C paper an d
wash ed with buffer th ree tim es; th e radioactivity was m easured by liquid scin tillation spec-
trom etry an d th e specific bin din g of 3H-LTB4 to th e receptor was determ in ed. Th e LTD4 re-
ceptor bin din g study was perform ed by th e m eth od of Brun s et al.36 Th e m em bran e fraction
was prepared from m ale guin ea-pig lun gs. 4 m g of th is fraction were in cubated with 0.4 n M
3H-LTD4 at 25 °C for 60 m in in 100 µl of th e in cubated m ixture. Non specific bin din g was
determ in ed in th e presen ce of 0.1 µM LTD4. Filtration of th e m em bran es, wash in g an d th e
m easurem en t of radioactivity were th e sam e as in th e previous in stan ce. Th e activities in vi-
tro were expressed in µM con cen tration s leadin g to a 50% in h ibition .
Th e in h ibition of carrageen an edem a was evaluated by th e m eth od of Win ter37, th e ex-
perim en tal con dition s h ave been described elsewh ere38. Th e effect was expressed as th e per-
cen tage of in h ibition after a dose of 100 m g/kg in com parison with an un treated con trol.
In h ibition of experim en tal pleuritis was evaluated by th e m eth od of Hidaka39 in a group of
Wistar Han fem ale rats pretreated with 1.0% carrageen an in salin e by in trapleural in jection .
Th e tested com poun ds in suspen sion with gum arabic were applied orally in a sin gle dose of
100 m g/kg 1 h before th e application of carrageen an . Th e volum e of th e exudate from th e
pleural cavity an d th e n um ber of cells in th e exudate (determ in ed with a Sysm ex coun ter)
were com pared with th ose of un treated an im als an d th e effect was expressed as th e percen t-
age of th e in h ibition . Arach idon ic acid in duced ear in flam m ation in m ice was perform ed by
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Derivatives of (Phenylsulfanyl)benzoic Acids
2119
th e m eth od of Opas40, th e ear pin n a in flam m ation was in duced by th e application of 20 µl of
arach idon ic acid solution in aceton e. Th e com poun d was adm in istered orally (200 m g/kg),
1 h before edem a in duction . Th e degree of ear h yperem ia an d th e weigh t of th e ear were
evaluated 1 h after th e application of arach idon ic acid. Th e results were expressed as th e
percen tage of th e in h ibition in com parison with an un treated con trol. Th e in h ibition of
bron ch ospasm was in duced by th e in traven ous in jection of 0.35 m g/kg of ovalbum in to a
presen tisized guin ea pig followin g th e m odified m eth od of Kreutn er et al.41 Th e m eth od of
Jon es an d Masson 42 was used for th e evaluation of th e in h ibition of bron ch ocon striction in -
duced by th e in traven ous in jection of 0.5 µg/kg of LTD4 to a guin ea pig. Th e tested com -
poun d was adm in istered p.o. in th e doses of 10, 30, 100 m g/kg, 60 m in before th e applica-
tion of album in or LTD4. Th e effect was expressed as th e percen tage of th e in h ibition of
bron ch ospasm in relation to th e un treated con trol.
This project was supported by a grant from the Ministry of Education, Youth and Sports of the
Czech Republic (Research Centre LN00B125).
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