Synthesis, structural characterization and thromboxane A2 receptor antagonistic activity of 3-substituted 2-[(arylsulfonyl)imino]-2,3- dihydrothiazolyl derivatives

Article abstract of DOI:10.1016/S0223-5234(99)80082-8

A series of new 2-[(arylsulfonyl)imino]-2,3-dihydrothiazolyl derivatives substituted on the heterocyclic N by a phenoxyacetic moiety was prepared according to a Hantzsch's synthesis between N, N'-disubstituted thioureas and chloroacetaldehyde. The regiochemistry of the cyclocondensation reaction was established by high resolution NMR methods. Potential thromboxane A₂/prostaglandin H₂ (TxA₂/PGH₂) receptor antagonism was evaluated using human platelet aggregation assays and radioligand binding studies. The results showed that the affinity for the TxA₂/PGH₂ receptor was strongly dependent on the position of the oxyacetic acid side chain. On the basis of the X-ray crystal analysis of compound 9f, a molecular modelling was undertaken on compounds 3d, 3e, and 3f. Comparison with the 3D structure of sulotroban was discussed.

Full text of DOI:10.1016/S0223-5234(99)80082-8

Eur. J. Med. Chem. 34 (1999) 311−328
© Elsevier, Paris
311
Original article
Synthesis, structural characterization
and thromboxane A2 receptor antagonistic activity
of 3-substituted 2-[(arylsulfonyl)imino]-2,3-dihydrothiazolyl derivatives
Fabrice Lacana, Martine Varache-Lembègea, Joseph Vercauterena, Jean-Michel Légerb,
Bernard Masereelc, Jean-Michel Dognéd, Alain Nuhricha*
aGroupe d’Étude des Substances Naturelles d’Intéret Thérapeutique, Faculté de Pharmacie, Université Victor-Segalen (Bordeaux 2),
Laboratoires de Pharmacie chimique, Chimie Thérapeutique et Pharmacognosie, 3, place de la Victoire, 33076 Bordeaux Cedex, France
bLaboratoire de Chimie Analytique, Faculté de Pharmacie, Université Victor-Segalen (Bordeaux 2),
3, place de la Victoire, 33076 Bordeaux Cedex, France
cDépartement de Pharmacie, Université de Namur, FUNDP. 61, rue de Bruxelles, B-5000 Namur, Belgium
dLaboratoire de Chimie Pharmaceutique, Université de Liège. 3, rue Fusch, B-4000 Liège, Belgium
(Received 3 June 1998; accepted 28 October 1998)
Abstract – A series of new 2-[(arylsulfonyl)imino]-2,3-dihydrothiazolyl derivatives substituted on the heterocyclic N by a phenoxyacetic
moiety was prepared according to a Hantzsch’s synthesis between N, N’-disubstituted thioureas and chloroacetaldehyde. The regiochemistry
of the cyclocondensation reaction was established by high resolution NMR methods. Potential thromboxane A2/prostaglandin H2
(TxA2/PGH2) receptor antagonism was evaluated using human platelet aggregation assays and radioligand binding studies. The results showed
that the affinity for the TxA2/PGH2 receptor was strongly dependent on the position of the oxyacetic acid side chain. On the basis of the X-ray
crystal analysis of compound 9f, a molecular modelling was undertaken on compounds 3d, 3e, and 3f. Comparison with the 3D structure of
sulotroban was discussed. © Elsevier, Paris
2,3-Dihydrothiazole derivatives / thromboxane A2 antagonists / receptor binding / platelet anti-aggregants / three dimensional
structure analysis
1. Introduction
On the other hand, TxA2 is a very potent inducer of
bronchial smooth muscle contractions [3]. Therefore,
agents with a TxA2 antagonistic activity could also prove
valuable in anti-asthma therapy. From tempting investi-
gations recently reported in this area [4–6], we were
interested in the design of new compounds acting as
thromboxane receptor antagonists.
Numerous TxRA (prostanoids or non-prostanoids) in-
tegrate a benzene sulfonamide group in their struc-
ture [7–10]. It has been postulated that this molecular part
would overlap with the ω side chain of TxA2 1 (figure 1)
and play an essential role in binding for the receptor [11].
Among most of the non-prostanoid TxRA, the arylsulfo-
nyl residue is separated by a spacer from a carboxylic
acid group: sulotroban 2 is a typical example [12].
The thiazole nucleus has been rarely exploited as a
carrier in the TxRA family [13, 14]. Therefore, the
Thromboxane synthase inhibitors (TxSI) and throm-
boxane receptor antagonists (TxRA) have focused exten-
sive interest since the early 1980’s, with discovery of the
multiple biological effects mediated by TxA2 and its
precursor PGH2. The central role of these prostanoids in
blood platelet aggregation and vasoconstriction [1] led to
considerable effort in the development of compounds
able to inhibit the biosynthesis of TxA2 and/or to avoid
the binding of TxA2/PGH2 on their common receptor [2].
Although this approach appeared as an attractive way for
treatment of thrombotic vascular diseases, clinical trials
on these compounds have produced very disappointing
results.
* Correspondence and reprints

312
Intermediates N, N≠-disubstituted thioureas 7a–g be-
came accessible via displacement of the methylthio group
by an appropriate methoxyaniline (table I). Condensation
of 7a–g with chloroacetaldehyde according to the method
of Kawamura et al. [19] gave the 4-hydroxythiazolidine
derivatives 8a–g, which were subsequently converted
into 2,3-dihydrothiazoles 9a–g by an acid-catalysed de-
hydration (table I). After cleavage of the methoxy group
with boron tribromide, the resulting phenols 10a–g were
alkylated with ethyl bromoacetate to afford the phenoxy-
acetates 11a–g (table II). Finally, the expected 2,3-
dihydrothiazolyl-3-phenoxyacetic acids 3a–g were ob-
tained by subsequent hydrolysis and acidification
(table II).
Since two distinct cyclization pathways are possible
for the arylsulfonamido-thioureas 7 (figure 3), the struc-
ture of the final products 3a–g was assigned on the basis
of NMR experiments (Heteronuclear Multiple-Quantum
Correlation [20], Heteronuclear Multiple-Bond Correla-
tion [21], and 1H-1H COSY (homonuclear correla-
tion) [22]. As an example, the NMR characteristics for
compound 3f are listed in table III.
1
The H-1H COSY spectrum shows a doublet at 7.47
ppm correlated to another doublet at 6.99 ppm. These
1
protons are J coupled to tertiary carbon peaks at 128.6
ppm and 106.7 ppm, respectively (HMQC spectrum). On
the other hand, the magnitude of the coupling constant
(J = 4.7 Hz) is indicative of vicinal protons. The chemical
shift values are in good agreement with previously
reported data for thiazole derivatives [23–25] and allow
the assignment of the signal at 7.47 ppm to H-4, and the
signal at 6.99 ppm to H-5.
The long-range proton-carbon correlation (HMBC
spectrum) shows correlations between these protons and
a quaternary carbon at 165.8 ppm. This chemical shift is
consistent with that of an imino carbon [26] and allows us
to attribute this absorption to the C-2.
Figure 1. Structures of TxA2, sulotroban and planned com-
pounds.
objective of our search was to synthesize a series of new
2,3-dihydrothiazoles 3 endowed with both an arylsulfo-
nyl group and a phenoxyacetic system and to investigate
the importance of the spatial arrangement between these
two pharmacophoric components towards pharmacologi-
cal properties in vitro on human blood platelets.
The regiochemistry of the cyclocondensation was un-
ambiguously established by the HMBC analysis. The
correlation between the carbon signal at 129.6 ppm
(C-13) and the proton signal at 7.47 ppm (H-4) confirms
the localization of the phenoxyacetic group on the
3-position in the heterocycle (“exo”isomer, figure 3).
2. Chemistry
The general synthetic pathway for preparation of
compounds listed in tables I and II is depicted in figure 2.
Requisite starting arylsulfonamides 4a–c were ob-
tained from the corresponding benzenesulfonyl chlorides
and ammonia, as described [17]. Treatment of 4a–c with
carbon disulfide and sodium hydroxide in DMF accord-
ing to a previously described method [18] gave the
N-(dithiomethylene)sulfonamides 5a–c as sodium salts,
which were then alkylated with methyl iodide, followed
by acidification to yield the methyl carbamodithioates
6a–c.
3. Pharmacology
The compounds prepared were examined in vitro for
inhibitory activity against aggregation of human platelet
rich plasma (PRP) induced by arachidonic acid, diluted
collagen, ADP, or the stable PGH2 analogue U-46619,
which is a thromboxane mimetic on the PGH2/TxA2
receptor [27]. A screening test for investigation of throm-

313
Table I. Physical data for methoxyphenyl intermediates 7, 8 and 9
• Ortho-methoxy derivatives
Compound
R
Recryst. solvent
Yield
Mp (°C)
7a
7d
8a
8d
9a
9d
H
CH3
H
CH3
H
CH3
toluene
heptane/THF
EtOH
EtOH
EtOH
70
85
52
63
60
68
174a
147b
149
177
148
178
EtOH
aLit: 172 °C [15].
bThis compound showed a transformation at 147 °C and then melted at 154 °C. Lit: 145–146 °C [16].
• Meta-methoxy derivatives
Compound
R
Recryst. solvent
Yield
Mp (°C)
7b
7e
7g
8b
8e
8g
9b
9e
9g
H
CH3
F
H
CH3
F
H
CH3
F
toluene
toluene
heptane/toluene
EtOH
EtOH
EtOH / THF
EtOH
toluene
77
80
72
64
62
61
51
74
63
134c
163
132
159
148
202
147
134
176
EtOH
cLit: m.p. 132 °C [15].
• Para-methoxy derivatives
Compound
R
Recryst. solvent
Yield
Mp (°C)
7c
7f
8c
8f
9c
9f
H
CH3
H
CH3
H
CH3
toluene
heptane/THF
EtOH
EtOH/THF
H2O / THF
DMSO
80
69
62
61
56
60
138
144d
209
202
185
209
dThis compound showed a transformation at 144 °C and then melted at 162 °C.
Lit: m.p. 145–146 °C [16].
boxane receptor antagonism was undertaken by radioli-
gand binding studies with [3H] SQ-29548 in washed
human platelets. Sulotroban was tested as a reference
compound.
3.1. Platelet aggregation studies
The results, summarized in table IV, indicated the
remarkable significance of the oxyacetic group in the

314
Table II. Physical data for phenolic derivatives 10, esters 11 and acids 3.
• Ortho-substituted derivatives
Compound
R
Recryst. solvent
Yield
Mp (°C)
10a
10d
11a
11d
3a
H
CH3
H
CH3
H
CH3
EtOH
EtOH
EtOH
toluene
H2O/THF
H2O/THF
53
51
58
53
64
51
207
212
101
126
166
206
3d
• Para-substituted derivatives
Compound
R
Recryst. solvent
Yield
Mp (°C)
10b
10e
10g
11b
11e
11g
3b
H
CH3
F
H
CH3
F
H
CH3
F
toluene/EtOH
EtOH
heptane/THF
EtOH
heptane/THF
heptane/THF
H2O/THF
H2O/THF
H2O/THF
58
56
45
68
50
68
53
54
44
188
228
172
131
121
119
179
163
187
3e
3g
• Para-substituted derivatives
Compound
R
Recryst. solvent
Yield
Mp (°C)
10c
10f
11c
11f
3c
H
CH3
H
CH3
H
CH3
EtOH
EtOH
EtOH
EtOH/THF
H2O/THF
H2O/THF
40
53
76
65
67
61
186
253
152
169
250
258
3f
anti-platelet activity. Thus, methoxy (9d–f) or phenolic
(10d–f) derivatives were completely free of anti-
aggregant effect.
and U-46619. Among the tested compounds, 3g, with a
4-fluorophenyl sulfonylimino moiety, exhibited the high-
est anti-aggregating properties.
Whatever the inducer chosen, the optimal pattern for
compounds 3a–g was the meta position for the acidic
chain.
Although the agreement was not complete, the rank
order potencies followed the same general trends in
inhibiting platelet aggregation induced by AA, collagen
On the other hand, none of the compounds was
effective in inhibiting primary aggregation induced by
adenosine diphosphate (ADP). Therefore this pharmaco-
logical profile outlined the specificity of compounds 3b,
3e and 3g for antagonizing platelet aggregation mediated
through the TxA2 / PGH2 receptor pathway [9, 28].

315
Figure 2. Synthesis of 2,3-disubstituted 2,3-dihydrothiazoles.
Reagents: (a) NaOH/CS2/DMF; (b) MeI; (c) HCl; (d) MeO-Ph-NH2/THF/∆; (e) ClCH2CHO/K2CO3/acetone; (f) HCl/EtOH/∆; (g)
BBr3/CH2Cl2; (h) BrCH2CO2Et/K2CO3/DMF/60 °C; (i) NaHCO3/H2O/∆; (j) HCl.

316
Figure 3. Different cyclisation pathways for N, N’-disubstituted thioureas 7.
3.2. Radioligand binding assays
from its binding site of human platelet membranes. Since
their low solubility prevented us from measuring IC50 or
Ki values, we determined the percentage of [3H] SQ-
29548 displaced by 1 µM of each drug.
The compounds were evaluated for their ability to
displace the TxA2 receptor antagonist [3H] SQ-29548
Table III. NMR data for compound 3f.
Position
1H NMR δ (ppm), J (Hz)
1H-1H COSY
13C NMR δ (ppm) HMQC
HMBC
2
4
5
6
165.8
7.47; 6.99
6.99
7.47
7.66; 7.33; 2.34
7.66; 7.33; 2.34
7.33; 2.34
7.66; 2.34
7.33
7.47 (d, J = 4.7)
6.99 (d, J = 4.7)
6.99
7.47
128.6
106.7
138.4
125.4
128.8
141.8
20.4
7.47
6.99
7, 11
8, 10
9
7.66**
7.33*
7.33; 2.34
7.66; 2.34
7.66
7.33
12
2.34 (s,3H)
7.33
2.34
13
129.6
126.8
114.5
157.2
64.1
7.47; 7.33; 7.04
7.33
7.33; 7.04
7.33; 7.04; 4.75
14, 18
15, 17
16
7.33**
7.04*
7.04
7.33
7.33
7.04
19
4.75 (s, 2H)
4.75
20
169.4
4.75
*BB≠ part of AA≠BB≠ system; **AA≠ part of AA≠BB≠ system.

317
Table IV. Pharmacological activities in vitro.
Inhibition of palelet aggregation
Competition with
Compound
R1
R2
AAa
ADPb
Collagena
U 46619a
[3H] SQ-29548c
9d
9e
9f
10d
10e
10f
3a
3b
3c
3d
3e
3f
3g
o-OCH3
m-O-CH3
p-O-CH3
o-OH
m-OH
p-OH
o-OCH2-CO2H
m-OCH2-CO2H
p-OCH2-CO2H
o-OCH2-CO2H
m-OCH2-CO2H
p-OCH2-CO2H
m-OCH2-CO2H
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
CH3
CH3
CH3
F
–
–
–
–
–
–
–
24
–
–
84
–
24
11.5
0 %
0 %
0 %
0 %
0 %
0 %
15 %
100 %
0 %
0 %
100 %
0 %
18 %
100 %
–
–
–
–
–
–
–
94
–
–
138
–
90
15
–
–
–
–
–
–
–
43
–
–
75
–
21
10.5
*
*
*
*
*
*
0
15.8 %
0
0
79.0 %
0
17.5 %
41.7 %
sulotroban
b
aIC50 (µM). Values reported are an average of three determinations. None of the compounds at 360 µM were effective in inhibiting ADP
c
induced platelet aggregation of human PRP (1st wave). The mentioned values indicate the percentage of inhibition on the second phase. %
displacement of [3H]SQ-29546 in washed platelets/concentration of tested compound: 10–6 M. *: not tested; –: no activity.
Compounds 3b, 3e and 3g showed significant binding
affinities for the human platelet TxA2/PGH2 receptor.
Surprisingly, the most potent antagonist was 3e, whose
activity was superior to that of sulotroban. The lack of
correlation between the platelet aggregation results and
the radioligand-binding data has been described else-
where for other TxRA [8, 28, 29] and may be attributable
to the experimental conditions. Indeed, aggregation as-
says were carried in plasma rich platelets, while radioli-
gand binding experiments were determined on washed
platelets. Consequently, the obvious divergences in the
biological activities may be considered as the result of the
probable binding of the test compounds to serum pro-
teins [30].
4.1. Crystal structure analysis of compound 9f
A projection of the molecule showing the numbering of
atoms is given in figure 4. Crystallographic data and a
summary of data collection and structure refinement are
given in table V. The atomic coordinates for non-
hydrogen atoms are listed in table VI. Some bond
lengths, angles, and selected geometric parameters are
provided in tables VII and VIII, respectively. Globally, the
parameters observed were in agreement with the expected
values [31, 32]. The C(12)–N(11) bond (1.332 Å) is
shorter than the C(12)–N(16) bond (1.357 Å) and thus
indicates some double-bond character. Furthermore, the
unusually increased value (128.7°) for the exocyclic bond
angle N(11)–C(12)–S(13) compared to the value (109.1°)
of the endocyclic angle S(13)–C(12)–N(16) is an accu-
mulative evidence which supports the imino struc-
ture [33]. The fold in the molecular conformation is
reinforced by a short intramolecular distance between the
sulfur atom of the heterocycle and an oxygen of the
sulfone function: S(13) O(10) space (2.86 Å) is shorter
than the calculated sum of Van der Waals’ radii for O and
S (3.25 Å) [34]. This value is in favour of a virtual
five-membered ring S(13) O(10)–S(8)–N(11)–C(12).
4. Three dimensional structure analysis
The X-ray study was undertaken in order to understand
whether the differences in biological activities of the
compounds tested were related to their three dimensional
structure. Unfortunately, none of the most active com-
pounds (3b, 3e, 3g) provided single crystals suitable for
X-ray analysis. Therefore, the crystallographic study was
realized on the methoxy derivative 9f.

318
Figure 4. Projection of 9f showing atom numbering and thermal ellipsoids.
4.2. Molecular modelling
We set up a first reference conformer for the series
(3d–f) by taking the X-ray data of compound 9f that only
misses the acidic side chain as a methoxy substituent.
Next, introducing the oxyacetic pattern successively in
either ortho, meta, or para position on the phenyl fixed on
the thiazolyl system, the minimum energetically opti-
mized conformers were then searched by varying at 20°
intervals the three torsion angles (θ4, θ5, θ6) shown in
figure 5. The reference conformer chosen for sulotroban
was the folded structure (called “hairpin” conforma-
tion [11]) since this one was considered as representative
of the active geometry of thromboxane A2. Atoms which
were selected for superimpositions are indicated in fig-
ure 5 (a-m and a≠-m≠).
For sake of simplification, only interesting energeti-
cally minimized conformations of 3d, 3e, and 3f have
been depicted in figure 6. Some typical intramolecular
distances are shown in table IX. The fitting experiments
between sulotroban and 3d or 3f, both inactive, gave a
poor overlapping, especially evident for the oxyacetic
acid side chain. On the contrary, structural superimposi-
tion performed with 3e provided a good match with
sulotroban. Further corroboration was supplied by com-
paring some intramolecular distances. For example, the
calculated values between the sulfur atom of the sulfone
function and the carbon atom of the carboxylic group
showed the best similarity for 3e (8.184 Å) and su-
lotroban (8.057 Å). These results could provide an
Conformational analysis was focused on the phenoxy-
acetic acid moiety in order to investigate the possible
relationships between its spatial arrangement and biologi-
cal activity.
Table V. Crystal and relevant X-ray data for compound 9f.
Empirical formula
Formula Weight
Crystal system
Space group
a (Å)
b (Å)
C17H16N2O3S2
360.5
orthorhombic
Pca21
19.272 (5)
6.575 (1)
13.414 (4)
1700 (1)
4
1.409
752
1.54178
ω / 2θ
2.90
c (Å)
Volume Å3
Z
Dc (g cm-3)
F(000)
λ (CuKα) Å
Scan type
Absorption cœfficient (mm-1)
Temperature (K)
θ range for data collection
(deg)
293
2.0 - 65.0
Refinement method
Data / restraints / parameters
Final R indices [I>3σ (I)]
Diagonal-matrix-squares on F
1482 / 1460 / 281
R
=
0.061, wR
= 0.070,
S = 1.02

319
Table VI. Positional parameters and their estimated standard deviations for 9f.
x
y
z
Beq
C (1)
C (2)
C (3)
C (4)
C (5)
C (6)
C (7)
S (8)
O (9)
O (10)
N (11)
C (12)
S (13)
C(14)
C(15)
N(16)
C (17)
C(18)
C(19)
C(20)
C(21)
C(22)
C(23)
C(24)
0.2150 (2)
0.2321 (2)
0.2771 (2)
0.3070 (2)
0.2919 (2)
0.2461 (3)
0.1698 (3)
0.3686 (0)
0.3538 (2)
0.3698 (1)
0.4404 (1)
0.4720 (2)
0.4533 (1)
0.5177 (2)
0.5509 (2)
0.5263 (1)
0.5567 (2)
0.6204 (2)
0.6505 (2)
0.6176 (2)
0.5541 (2)
0.5237 (2)
0.6520 (2)
0.6159 (3)
–0.2386 (8)
–0.0465 (6)
0.0840 (6)
0.0274 (5)
–0.1562 (6)
–0.2897 (6)
–0.3839 (9)
0.1852 (1)
0.1892 (5)
0.3764 (5)
0.0629 (5)
0.0541 (5)
0.1876 (1)
0.0574 (7)
–0.0708 (6)
–0.0723 (5)
–0.1942 (5)
–0.1398 (6)
–0.2567 (7)
–0.4306 (5)
–0.4898 (6)
–0.3688 (6)
–0.5325 (5)
–0.7000 (7)
0.5849 (4)
0.6258 (4)
0.5791 (3)
0.4879 (3)
0.4450 (4)
0.4942 (4)
0.6415 (6)
0.4263 (1)
0.3236 (3)
0.4835 (3)
0.4385(3)
0.5267 (3)
0.6345 (1)
0.7018 (3)
0.6424 (3)
0.5442 (3)
0.4674 (3)
0.4277 (3)
0.3550 (3)
0.3211 (3)
0.3615 (4)
0.4349 (3)
0.2473 (3)
0.2005 (6)
4.0 (2)
3.6 (2)
3.1 (1)
2.7 (1)
3.9 (2)
4.1 (2)
6.0 (3)
2.9 (0)
4.3 (1)
3.8 (1)
3.0 (1)
2.9 (1)
3.6 (0)
3.9 (2)
3.4 (1)
2.8 (1)
2.7 (1)
3.3 (1)
3.3 (2)
3.1 (1)
3.7 (1)
3.3 (1)
4.0 (1)
5.5 (3)
explanation for the unexpected activity observed for the
meta substituted derivatives of the studied series, com-
parative to sulotroban which is a para phenoxyacetic
compound. This observation confirms the key role of the
spatial arrangement of the carboxylic group in the inter-
action of TxRA with the binding site in the TxA2
receptor [35].
5. Conclusion
In conclusion, this study shows that the incorporation
of a dihydrothiazolyl moiety in the intermediate chain of
non prostanoid arylsulfonamido TxRA can lead to com-
pounds exhibiting a TxA2 antagonist activity. On the
basis of the conformational analysis, it appears that this
Table VII. Bond lengths (Å) for compound 9f.
C(1)–C(2)
C(1)–C(6)
C(1)–C(7)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
C(4)–S(8)
C(5)–C(6)
S(8)–O(9)
S(8)–O(10)
S(8)–N(11)
N(11)–C(12)
C(12)–S(13)
1.416 (6)
1.397 (7)
1.499 (8)
1.371 (6)
1.403 (5)
1.369 (6)
1.779 (4)
1.409 (7)
1.407 (4)
1.473 (3)
1.610 (3)
1.332 (5)
1.730 (4)
C(12)–N(16)
1.357 (5)
1.758 (4)
1.325 (6)
1.400 (5)
1.431 (5)
1.385 (6)
1.383 (5)
1.371 (6)
1.384 (6)
1.394 (6)
1.367 (5)
1.395 (6)
1.446 (7)
S(13)–C(14)
C(14)–C(15)
C(15)–N(16)
N(16)–C(17)
C(17)–C(18)
C(17)–C(22)
C(18)–C(19)
C(19)–C(20)
C(20)–C(21)
C(20)–O(23)
C(21)–C(22)
O(23)–C(24)

320
Table VIII. Selected geometric parameters for compound 9f.
Valency angles (°)
C2–C1–C6
C2–C1–C7
C6–C1–C7
C1–C2–C3
C2–C3–C4
C3–C4–C5
C3–C4–S8
C4–C5–C6
C1–C6–C5
C4–S8–O9
C4–S8–O10
C4–S8–N11
O9–S8–O10
O9–S8–N11
S8–N11–C12
N11–C12–S13
N11–C12–N16
116.9 (4)
120.5 (5)
122.5 (5)
121.9 (4)
119.5 (4)
120.9 (3)
121.6 (3)
119.4 (4)
121.8 (4)
109.3 (2)
105.5 (2)
103.6 (2)
119.8 (2)
106.4 (2)
120.3 (3)
128.7 (3)
122.2 (3)
S13–C12–N16
C12–S13–C14
S13–C14–C15
C14–C15–N16
C12–N16–C15
C12–N16–C17
N16–C17–C18
N16–C17–C22
C18–C17–C22
C17–C18–C19
C18–C19–C20
C19–C20–C21
C19–C20–O23
C21–C20–O23
C20–C21–C22
C17–C22–C21
C20–O23–C24
109.1 (3)
92.0 (2)
110.0 (3)
114.0 (4)
114.8 (3)
122.3 (3)
119.7 (3)
120.2 (3)
120.0 (4)
120.3 (4)
120.2 (4)
120.3 (4)
114.9 (3)
124.8 (4)
118.9 (4)
120.2 (4)
117.0 (4)
Torsion angles (°)
C3–C4–S8–O10
C3–C4–S8–N11
C5–C4–S8–O9
C5–C4–S8–N11
C4–S8–N11–C12
–7.4 (3)
109.3 (3)
45.1 (3)
–68.0 (3)
–72.5 (3)
S8–N11–C12–S13
C15–N16–C17–C18
C21–C20–O23–C24
C19–C20–O23–C24
O10–S8–N11–C12
–9.6 (2)
–73.4 (4)
7.4 (4)
–172.3 (4)
40.3 (3)
Intramolecular distance (Å)
S(13) ... (O10)
2.86
heterocyclic pattern is intervening by shape effects and
dictates a folded conformation to the molecule. The
promising results obtained with compounds 3b, 3e, and
3g allow us to think that the 2,3-dihydrothiazolyl linkage
is of interest for designing new TxA2 antagonists. Evalu-
ation of activity on rat bronchial smooth muscle is subject
to an on-going study.
6. Experimental protocols
6.1. General
High-resolution NMR spectra (1H, 13C, HMQC,
HMBC, 1H-1H COSY) were recorded on a Bruker AMX
500 spectrometer. IR spectra (KBr pellets) were obtained
Figure 5. Nomenclature of torsion angles and identification of atoms selected for molecular superimpositions (italic letters).

321
Figure 6. Overlap comparison of selected minimum energy conformers for sulotroban (folded conformation, solid lines) and for
dihydrothiazolyl derivatives 3d, 3e, 3f (dashed lines).
on a Shimadzu IR 470 spectrometer. Melting points were
determined with an electrothermal digital capillary melt-
ing point apparatus and are uncorrected. Elemental analy-
ses were performed by the Service Central d’Analyse du
CNRS (Vernaison, France) and were within ± 0.4% of the
calculated values.
6.2. Chemistry
6.2.1. General procedure for the preparation of methyl
esters of carbamodithioic acids 6
To a solution of the appropriate arylsulfonamide 4
(0.05 mol) in 30 mL DMF was added 3 mL of a solution
Table IX. Comparison of the distances between selected structural elements.
Compounds
Distances (Å)
Sulotroban
3d
3e
3f
S (sulfonyl) - O (ether)
S (sulfonyl) - C (carboxylate)
6.568
8.057
4.526
5.746
6.233
8.184
7.532
9.683

322
of sodium hydroxide (16 g, 0.4 mol) in water (20 mL),
giving a precipitate of sulfonamide sodium salt. After the
mixture was stirred for 10 min, carbon disulfide
(1.63 mL, 0.027 mol) was added. The heterogeneous
mixture became clear after a few minutes. More NaOH
solution (1.5 mL) and carbon disulfide (0.95 mL,
0.016 mol) were added and this operation was reiterated
10 min later (the disodium salt 5 remained in solution and
was not isolated). After cooling (3–4 °C), methyl iodide
(exactly 7.1 g, 0.05 mol) was added slowly with vigorous
stirring. The reaction medium was stirred at room tem-
perature for 2 h, then poured into water (150 mL). Any
insoluble material was filtered off. Upon careful acidifi-
cation of the filtrate with diluted hydrochloric acid
(pH = 1) under constant stirring, the resultant yellow
precipitate was collected and dried. The crude product
was used without further purification. The following
methyl carbamodithioates were prepared:
and then recrystallized from a convenient solvent. Ac-
cording to this method, the following compounds were
prepared:
6.2.2.1.
N-[[(2-Methoxyphenyl)amino]thioxomethyl]-
phenylsulfonamide 7a
IR (KBr, cm–1) 3 300 (νNH); 1 385 (νas-SO ); 1 145
2
1
(νs-SO ). H NMR (DMSO-d6) δ 3.80 (s, 3H, OCH3);
2
7.10–7.45 (m, 4H, ArO); 7.55–7.80 (m, 5H, ArSO2);
10.30 (br s, 2H, 2 × NH). Anal. C14H14N2O3S2 (C, H, N,
S).
6.2.2.2.
N-[[(3-Methoxyphenyl)amino]thioxomethyl]-
phenylsulfonamide 7b
IR (KBr, cm–1) 3 320 (νNH); 1 370 (νas-SO ); 1 140
2
1
(νs-SO ). H NMR (DMSO-d6) δ 3.75 (s, 3H, OCH3);
2
6.95–7.05 (m, 3H, ArO); 7.35–7.45 (m, 1H, ArO);
7.50–7.85 (m, 5H, ArSO2); 10.50 (br s, 2H, 2 × NH).
Anal. C14H14N2O3S2 (C, H, N, S).
6.2.1.1. Phenylsulfonylcarbamodithioic acid, methyl
ester 6a
6.2.2.3.
N-[[(4-Methoxyphenyl)amino]thioxomethyl]-
phenylsulfonamide 7c
This compound was obtained in 76% yield from
benzenesulfonamide; m.p. 144 °C (lit. [18] m.p. 142 °C).
IR (KBr, cm–1) 3 300 (νNH); 1 380 (νas-SO ); 1 140
2
1
(νs-SO ). H NMR (DMSO-d6) δ 3.80 (s, 3H, OCH3);
2
7.05–7.35 (AA≠BB≠ system, 4H, ArO); 7.60–7.80 (m,
5H, ArSO2); 10.50 (br s, 2H, 2 × NH). Anal.
C14H14N2O3S2 (C, H, N, S).
6.2.1.2. (4-Methylphenyl)sulfonylcarbamodithioic acid,
methyl ester 6b
This compound was obtained in 78% yield from
p-toluenesulfonamide; m.p. 139 °C (lit. [18] m.p.
138–139 °C).
6.2.2.4. N-[[(2-Methoxyphenyl)amino]thioxomethyl]-4-
methylphenylsulfonamide 7d
IR (KBr, cm–1) 3 300 (νNH); 1 380 (νas-SO ); 1 150
2
1
(νs-SO ). H NMR (DMSO-d6) δ 2.35 (s, 3H, CH3); 3.75
6.2.1.3. (4-Fluorophenyl)sulfonylcarbamodithioic acid,
methyl ester 6c
2
(s, 3H, OCH3); 7.05–7.35 (m, 4H, ArO); 7.30–7.70
(AA≠BB≠ system, 4H, ArSO2); 10.20 (br s, 2H, 2 × NH).
Anal. C15H16N2O3S2 (C, H, N, S).
This compound was obtained in 81% yield from
4-fluorophenylsulfonamide; m.p. 146 °C. IR (KBr, cm–1)
3 200 (νNH); 1 340 (νas-SO ); 1 155 (νs-SO ).
2
2
6.2.2.5. N-[[(3-Methoxyphenyl)amino]thioxomethyl]-4-
1H NMR (CDCl3) δ 2.53 (s, 3H, SCH3); 7.30–7.40 (m,
2H, Ar); 7.80–7.90 (m, 2H, Ar); 9.50 (br s, 1H, NH).
methylphenylsulfonamide 7e
IR (KBr, cm–1) 3 300 (νNH); 1 380 (νas-SO ); 1 140
2
1
(νs-SO ). H NMR (DMSO-d6) δ 2.40 (s, 3H, CH3); 3.72
2
6.2.2. General procedure for the preparation of N,
N≠-disubstituted thioureas 7
(s, 3H, OCH3); 6.90–7.45 (m, 4H, ArO); 7.33–7.67
(AA≠BB≠ system, 4H, ArSO2); 10.20 (br s, 2H, 2 × NH).
Anal. C15H16N2O3S2 (C, H, N, S).
To a refluxing solution of methyl arylsulfonylcarbam-
odithioate 6 (0.01 mol) in THF (30 mL), was added
dropwise with stirring a solution of appropriate o-, m-, or
p-methoxyaniline (0.01 mol) in THF (10 mL). After heat-
ing at reflux for 20 h and removing the solvent in vacuo,
the resulting oily residue was dissolved in the minimum
amount of toluene (for compounds 7a–b), ethanol (for
7c–f) or carbon tetrachloride (for 7g). Upon trituration on
cooling, the precipitate was collected by suction filtration
6.2.2.6. N-[[(4-Methoxyphenyl)amino]thioxomethyl]-4-
methylphenylsulfonamide 7f
IR (KBr, cm–1) 3 330 (νNH); 1 375 (νas-SO ); 1 150
2
1
(νs-SO ). H NMR (DMSO-d6) δ 2.34 (s, 3H, CH3); 3.75
2
(s, 3H, OCH3); 7.04–7.35 (AA≠BB≠ system, 4H, ArO);
7.30–7.70 (AÁBB≠ system, 4H, ArSO2); 10.30 (br s, 2H,
2 × NH). Anal. C15H16N2O3S2 (C, H, N, S).

323
6.2.2.7. N-[[(3-Methoxyphenyl)amino]thioxomethyl]-4-
Hz, 1H, OH); 7.54–7.74 (m, 5H, ArSO2). Anal.
C16H16N2O4S2 (C, H, N, S).
fluorophenylsulfonamide 7g
IR (KBr, cm–1) 3 300 (νNH); 1 380 (νas-SO ); 1 140
2
1
(νs-SO ). H NMR (DMSO-d6) δ 3.70 (s, 3H, OCH3);
2
6.2.3.4.
N-[4-Hydroxy-3-(2-methoxyphenyl)-2-thiazo-
7.00–7.10 (m, 3H, ArO); 7.33–7.39 (m, 2H, ArSO2);
7.40–7.46 (m, 1H, ArO); 7.83–7.88 (m, 2H, ArSO2);
10.50 (br s, 2H, 2 × NH). Anal. C14H13FN2O3S2 (C, H, F,
N, S).
lidinylidene]-4-methylphenylsulfonamide 8d
IR (KBr, cm–1) 3 375 (νOH); 1 280 (νas-SO ); 1 145
2
1
(νs-SO ). H NMR (DMSO-d6) δ 2.35 (s, 3H, CH3); 3.18
2
(m, 1H, thiaz. H-5); 3.62 (s, 3H, OCH3); 3.70 (dd, J =
12.0 and 6.5 Hz, 1H, thiaz. H-5≠); 5.53 (m, 1H, thiaz.
H-4); 7.00–7.38 (m, 4H, ArO); 7.06 (d, J = 7.1 Hz, 1H,
OH); 7.34–7.62 (AA≠BB≠ system, 4H, ArSO2). Anal.
C17H18N2O4S2 (C, H, N, S).
6.2.3. General procedure for the preparation of 4-
hydroxythiazolidines 8
Appropriate
N-[[(methoxyphenyl)amino]thioxo-
methyl]arylsulfonamide 7 (0.01 mol) was dissolved in
acetone (30 mL) with stirring at room temperature. To
this solution was added potassium carbonate (1.32 g,
0.01 mol). After heating at reflux temperature, was added
dropwise a 50% aqueous solution of chloroacetaldehyde
(3.14 g, 0.04 mol) diluted in acetone (10 mL). After
vigorous stirring for 2.5 h, the mixture was allowed to
cool and the remaining insoluble material was removed
by filtration. The solvent was evaporated under reduced
pressure and the residue was mixed with diethylether
(20 mL), then allowed to stand at 0 °C for 4 h. The
precipitate was collected and recrystallised from a suit-
able solvent.
6.2.3.5.
N-[4-Hydroxy-3-(3-methoxyphenyl)-2-thiazo-
lidinylidene]-4-methylphenylsulfonamide 8e
IR (KBr, cm–1) 3 400 (νOH); 1 280 (νas-SO ); 1 140
2
1
(νs-SO ). H NMR (DMSO-d6) δ 2.35 (s, 3H, CH3); 3.19
2
(d, J = 12.0 Hz, 1H, thiaz. H-5); 3.70 (s, 3H, OCH3); 3.71
(dd, J = 12.0 and 6.0 Hz, 1H, thiaz. H-5≠); 5.72 (m, 1H,
thiaz. H-4); 6.93–7.34 (m, 4H, ArO); 7.13 (d, J = 6.6 Hz,
1H, OH) 7.34–7.68 (AA≠BB≠ system, 4H, ArSO2). Anal.
C17H18N2O4S2 (C, H, N, S).
6.2.3.6.
N-[4-Hydroxy-3-(4-methoxyphenyl)-2-thiazo-
lidinylidene]-4-methylphenylsulfonamide 8f
6.2.3.1.
N-[4-Hydroxy-3-(2-methoxyphenyl)-2-thiazo-
IR (KBr, cm–1) 3 400 (νOH); 1 265 (νas-SO ); 1 145
lidinylidene]phenylsulfonamide 8a
2
1
IR (KBr, cm–1) 3 430 (νOH); 1 280 (νas-SO ); 1 145
s-SO2
(ν
). H NMR (DMSO-d6) δ 2.35 (s, 3H, CH3); 3.16
2
1
(d, J = 12.1 Hz, 1H, thiaz. H-5); 3.70 (dd, J = 12.1 and 6.0
Hz, 1H, thiaz. H-5≠); 3.76 (s, 3H, OCH3); 5.60 (m, 1H,
thiaz. H-4); 6.98–7.21 (AA≠BB≠ system, 4H, ArO); 7.05
(d, J = 5.5 Hz, 1H, OH); 7.34–7.64 (AA≠BB≠ system,
4H, ArSO2). Anal. C17H18N2O4S2 (C, H, N, S).
(νs-SO ). H NMR (DMSO-d6) δ 3.20 (dd, J = 12.1 and
2
2.5 Hz, 1H, thiaz. H-5); 3.59 (s, 3H, OCH3); 3.71 (dd, J
= 12.1 and 6.5 Hz, 1H, thiaz. H-5≠); 5.53 (m, 1H, thiaz.
H-4); 7.01–7.37 (m, 4H, ArO); 7.05 (d, J = 7.1 Hz, 1H,
OH); 7.55–7.74 (m, 5H, ArSO2). Anal. C16H16N2O4S2
(C, H, N, S).
6.2.3.7.
N-[4-Hydroxy-3-(3-methoxyphenyl)-2-thiazo-
6.2.3.2.
N-[4-Hydroxy-3-(3-methoxyphenyl)-2-thiazo-
lidinylidene]-4-fluorophenylsulfonamide 8g
lidinylidene]phenylsulfonamide 8b
IR (KBr, cm–1) 3 400 (νOH); 1 280 (νas-SO ); 1 135
IR (KBr, cm–1) 3 400 (νOH); 1 280 (νas-SO ); 1 145
2
1
2
(νs-SO ). H NMR (DMSO-d6) δ 3.19 (d, J = 12 Hz, 1H,
(νs-SO ). 1H NMR (DMSO-d6) δ 3.21 (d, J = 12.1 Hz, 1H,
thiaz. 2H-5); 3.70 (s, 3H, OCH3); 3.73 (dd, J = 12.1 and
6.0 Hz, 1H, thiaz. H-5≠); 5.74 (m, 1H, thiaz. H-4);
6.93–7.35 (m, 4H, ArO); 7.17 (br s, 1H, OH); 7.56–7.81
(m, 5H, ArSO2). Anal. C16H16N2O4S2 (C, H, N, S).
thiaz. 2H-5); 3.71 (dd, J = 12 and 6.1 Hz, 1H, thiaz. H-5≠);
3.75 (s, 3H, OCH3); 7.00–7.45 (m, 4H, ArO); 7.13 (d, J
= 7.3 Hz, 1H, OH); 7.40–7.85 (AA≠BB≠ system, 4H,
ArSO2). Anal. C16H15FN2O4S2 (C, H, F, N, S).
6.2.4. General procedure for the preparation of the
2,3-dihydrothiazoles 9
Concentrated hydrochloric acid (5 mL) was added to a
stirred suspension of the appropriate N-[4-hydroxy-3-
(methoxyphenyl)-2-thiazolidinylidene]arylsulfonamide 8
(0.01 mol) in ethanol (30 mL). The mixture was refluxed
for 1.5 h. After cooling to room temperature, the depos-
6.2.3.3.
N-[4-Hydroxy-3-(4-methoxyphenyl)-2-thiazo-
lidinylidene]phenylsulfonamide 8c
IR (KBr, cm–1) 3 400 (νOH); 1 260 (νas-SO ); 1 140
2
(νs-SO ). 1H NMR (DMSO-d6) δ 3.16 (d, J = 12.0 Hz, 1H,
thiaz. 2H-5); 3.70 (dd, J = 12.0 and 6.0 Hz, 1H, thiaz.
H-5≠); 3.77 (s, 3H, OCH3); 5.60 (m, 1H, thiaz. H-4);
6.98–7.20 (AA≠BB≠ system, 4H, ArO); 7.05 (d, J = 7.3

324
ited crude product was collected and recrystallised from a
convenient solvent. The following products were ob-
tained:
3.80 (s, 3H, OCH3); 6.99 (d, J = 4.8 Hz, 1H, thiaz. H-5);
7.06–7.33 (AA≠ BB≠ system, 4H, ArO); 7.33–7.66
(AA≠BB≠ system, 4H, ArSO2); 7.45 (d, J = 4.8 Hz, 1H,
thiaz. H-4). Anal. C17H16N2O3S2 (C, H, N, S).
6.2.4.1.
N-[2,3-Dihydro-3-(2-methoxyphenyl)-2-thia-
6.2.4.7. N-[2,3-Dihydro-3-(3-methoxyphenyl)-2-thiazo-
zolylidene]phenylsulfonamide 9a
IR (KBr, cm–1) 1 560 (νC=C Thiaz); 1 285 (νas-SO );
lylidene]-4-fluorophenyl-sulfonamide 9g
2
IR (KBr, cm–1) 1 560 (νC=C Thiaz); 1 285 (νas-SO );
1 150 (νs-SO ). 1H NMR (DMSO-d6) δ 3.58 (s, 3H,
OCH3); 6.992 (d, J = 4.7 Hz, 1H, thiaz. H-5); 7.07–7.48
(m, 4H, ArO); 7.35 (d, J = 4.7 Hz, 1H, thiaz. H-4);
7.54–7.74 (m, 5H, ArSO2). Anal. C16H14N2O3S2 (C, H,
N, S).
2
1 150 (νs-SO ). 1H NMR (DMSO-d6) δ 3.75 (s, 3H,
2
OCH3); 7.01–7.43 (m, 4H, ArO); 7.06 (d, J = 4.7 Hz, 1H,
thiaz. H-5); 7.37–7.85 (AA≠BB≠ system, 4H, ArSO2);
7.54 (d,
J = 4.7 Hz, 1H, thiaz. H-4). Anal.
C16H13FN2O3S2 (C, H, F, N, S).
6.2.4.2.
N-[2,3-Dihydro-3-(3-methoxyphenyl)-2-thia-
6.2.5. General procedure for the preparation of the
zolylidene]phenylsulfonamide 9b
IR (KBr, cm–1) 1 560 (νC=C Thiaz); 1 285 (νas-SO );
phenol derivatives 10
2
1 145 (νs-SO ). 1H NMR (DMSO-d6) δ 3.73 (s, 3H,
OCH3); 7.042 (d, J = 4.5 Hz, 1H, thiaz. H-5); 7.09–7.42
(m, 4H, ArO); 7.52 (d, J = 4.5 Hz, 1H, thiaz. H-4);
7.55–7.79 (m, 5H, ArSO2). Anal. C16H14N2O3S2 (C, H,
N, S).
Under nitrogen atmosphere,
a
stirred mixture
of N-[2,3-dihydro-3-(methoxyphenyl)-2-thiazolylidene]-
arylsulfonamide 9 (0.005 mol) in anhydrous dichlo-
romethane (5 mL) was cooled to 0 °C and boron tribro-
mide (2.50 g, 0.01 mol) was then added. The mixture was
stirred for 2 h at room temperature, and poured into water
(100 mL). Following 1 h hydrolysis, the aqueous layer
was removed by decanting and the gummy residue was
triturated with diethyl ether until solid. The product was
collected by vacuum filtration, dried, then recrystallized.
6.2.4.3.
N-[2,3-Dihydro-3-(4-methoxyphenyl)-2-thia-
zolylidene]phenylsulfonamide 9c
IR (KBr, cm–1) 1 565 (νC=C Thiaz); 1 295 (νas-SO );
2
1 150 (νs-SO ). 1H NMR (DMSO-d6) δ 3.79 (s, 3H,
OCH3); 7.022 (d, J = 4.8 Hz, 1H, thiaz. H-5); 7.05–7.34
(AA≠BB≠ system, 4H, ArO); 7.47 (d, J = 4.8 Hz, 1H,
thiaz. H-4); 7.55–7.78 (m, 5H, ArSO2). Anal.
C16H14N2O3S2 (C, H, N, S).
6.2.5.1.
N-[2,3-Dihydro-3-(2-hydroxyphenyl)-2-thia-
zolylidene]phenylsulfonamide 10a
IR (KBr, cm–1) 3 350 (νOH); 1 560 (νC=C Thiaz); 1 275
(νas-SO ); 1 135 (νs-SO ). 1H NMR (DMSO-d6) δ
2
6.91–72.32 (m, 4H, ArO); 6.96 (d, J = 4.7 Hz, 1H, thiaz.
H-5); 7.34 (d, J = 4.5 Hz, 1H, thiaz. H-4); 7.52–7.78 (m,
5H, ArSO2); 10.22 (s, 1H, OH). Anal. C15H12N2O3S2 (C,
H, N, S).
6.2.4.4.
N-[2,3-Dihydro-3-(2-methoxyphenyl)-2-thia-
zolylidene]-4-methylphenyl-sulfonamide 9d
IR (KBr, cm–1) 1 565 (νC=C Thiaz); 1 280 (νas-SO );
1 145 (νs-SO ). 1H NMR (DMSO-d6) δ 2.35 (s, 3H, CH32);
3.61 (s, 3H,2OCH3); 6.97 (d, J = 4.7 Hz, 1H, thiaz. H-5);
7.07–7.48 (m, 4H, ArO); 7.33 (d, J = 4.7 Hz, 1H, thiaz.
H-4); 7.34–7.64 (AA≠BB≠ system, 4H, ArSO2). Anal.
C17H16N2O3S2 (C, H, N, S).
6.2.5.2.
N-[2,3-Dihydro-3-(3-hydroxyphenyl)-2-thia-
zolylidene]phenylsulfonamide 10b
IR (KBr, cm–1) 3 400 (νOH); 1 560 (νC=C Thiaz); 1 280
(νas-SO ); 1 145 (νs-SO ). 1H NMR (DMSO-d6) δ
2
6.81–72.31 (m, 4H, ArO); 7.01 (d, J = 4.7 Hz, 1H, thiaz.
H-5); 7.48 (d, J = 4.7 Hz, 1H, thiaz. H-4); 7.54–7.80 (m,
5H, ArSO2); 9.96 (s, 1H, OH). Anal. C15H12N2O3S2 (C,
H, N, S).
6.2.4.5.
N-[2,3-Dihydro-3-(3-methoxyphenyl)-2-thia-
zolylidene]-4-methylphenyl-sulfonamide 9e
IR (KBr, cm–1) 1 560 (νC=C Thiaz); 1 280 (νas-SO );
1 145 (νs-SO ). 1H NMR (DMSO-d6) δ 2.34 (s, 3H, CH32);
3.74 (s, 3H,2OCH3); 6.99–7.43 (m, 4H, ArO); 7.02 (d, J
= 4.7 Hz, 1H, thiaz. H-5); 7.34–7.68 (AA≠BB≠ system,
4H, ArSO2); 7.51 (d, J = 4.7 Hz, 1H, thiaz. H-4). Anal.
C17H16N2O3S2 (C, H, N, S).
6.2.5.3.
N-[2,3-Dihydro-3-(4-hydroxyphenyl)-2-thia-
zolylidene]phenylsulfonamide 10c
IR (KBr, cm–1) 3 450 (νOH); 1 560 (νC=C Thiaz); 1 275
(νas-SO ); 1 145 (νs-SO ). 1H NMR (DMSO-d6) δ
2
6.2.4.6.
N-[2,3-Dihydro-3-(4-methoxyphenyl)-2-thia-
6.88–72.21 (AA≠BB≠ system, 4H, ArO); 6.99 (d, J = 4.7
Hz, 1H, thiaz. H-5); 7.43 (d, J = 4.8 Hz, 1H, thiaz. H-4);
7.53–7.78 (m, 5H, ArSO2); 9.92 (s, 1H, OH). Anal.
C15H12N2O3S2 (C, H, N, S).
zolylidene]-4-methylphenyl-sulfonamide 9f
IR (KBr, cm–1) 1 560 (νC=C Thiaz); 1 285 (νas-SO );
1 150 (νs-SO ). 1H NMR (DMSO-d6) δ 2.35 (s, 3H, CH32);
2

325
6.2.5.4.
N-[2,3-Dihydro-3-(2-hydroxyphenyl)-2-thia-
6.2.6.1. 2-[2,3-Dihydro-2-[(phenylsulfonyl)imino]thia-
zolylidene]-4-methylphenyl-sulfonamide 10d
zol-3-yl]phenoxyacetic acid, ethyl ester 11a
IR (KBr, cm–1) 3 320 (νOH); 1 565 (νC=C Thiaz); 1 260
IR (KBr, cm–1) 1 730 (νC=O); 1 565 (νC=C Thiaz); 1 280
1
(νas-SO ); 1 145 (νs-SO ). 1H NMR (DMSO-d6) δ 1.16 (t, J
(νas-SO ); 1 135 (νs-SO ). H NMR (DMSO-d6) δ 2.34 (s,
2
3H, CH3); 6.90–7.31 2(m, 4H, ArO); 6.94 (m, 1H, thiaz.
H-5); 7.31 (m, 1H, thiaz. H-4); 7.31–7.67 (AA≠BB≠
system, 4H, ArSO2); 10.20 (s, 1H, OH). Anal.
C16H14N2O3S2 (C, H, N, S).
2
2
= 7.1 Hz, 3H, CH3-CH2); 4.10 (q, J = 7.1 Hz, 2H,
CH3-CH2); 4.69 (s, 2H, OCH2); 7.00 (d, J = 4.8 Hz, 1H,
thiaz. H-5); 7.17–7.45 (m, 4H, ArO); 7.34 (d, J = 4.8 Hz,
1H, thiaz. H-4); 7.51–7.75 (m, 5H, ArSO2). Anal.
C19H18N2O5S2 (C, H, N, S).
6.2.5.5.
N-[2,3-Dihydro-3-(3-hydroxyphenyl)-2-thia-
zolylidene]-4-methylphenyl-sulfonamide 10e
6.2.6.2.
3-[2,3-Dihydro-2-[(phenylsulfonyl)imino]
IR (KBr, cm–1) 3 350 (νOH); 1 570 (νC=C Thiaz); 1 275
thiazol-3-yl]phenoxyacetic acid, ethyl ester 11b
1
(νas-SO ); 1 140 (νs-SO ). H NMR (DMSO-d6) δ 2.32 (s,
IR (KBr, cm–1) 1 760 (νC=O); 1 555 (νC=C Thiaz); 1 295
2
2
3H, CH3); 6.82–7.32 (m, 4H, ArO); 6.98 (br s, 1H, thiaz.
H-5); 7.32–7.70 (AA≠BB≠ system, 4H, ArSO2); 7.46 (br
s, 1H, thiaz. H-4); 9.99 (s, 1H, OH). Anal. C16H14N2O3S2
(C, H, N, S).
(νas-SO ); 1 150 (νs-SO ). 1H NMR (DMSO-d6) δ 1.20 (t, J
2
2
= 7.1 Hz, 3H, CH3-CH2); 4.18 (q, J = 7.1 Hz, 2H,
CH3-CH2); 4.81 (s, 2H, OCH2); 7.04–7.44 (m, 4H, ArO);
7.05 (d, J = 4.7 Hz, 1H, thiaz. H-5); 7.51 (d, J = 4.7 Hz,
1H, thiaz. H-4); 7.55–7.83 (m, 5H, ArSO2). Anal.
C19H18N2O5S2 (C, H, N, S).
6.2.5.6.
N-[2,3-Dihydro-3-(4-hydroxyphenyl)-2-thia-
zolylidene]-4-methylphenyl-sulfonamide 10f
IR (KBr, cm–1) 3 395 (νOH); 1 570 (νC=C Thiaz); 1 275
1
6.2.6.3.
4-[2,3-Dihydro-2-[(phenylsulfonyl)imino]
(νas-SO ); 1 140 (νs-SO ). H NMR (DMSO-d6) δ 2.33 (s,
2
3H, CH3); 6.87–7.20 2(AA≠BB≠ system, 4H, ArO); 6.96
(d, J = 4.7 Hz, 1H, thiaz. H-5); 7.32–7.66 (AÁBB≠
system, 4H, ArSO2); 7.41 (d, J = 4.7 Hz, 1H, thiaz. H-4);
9.90 (s, 1H, OH). Anal. C16H14N2O3S2 (C, H, N, S).
thiazol-3-yl]phenoxyacetic acid, ethyl ester 11c
IR (KBr, cm–1) 1 755 (νC=O); 1 555 (νC=C Thiaz); 1 290
(νas-SO ); 1 150 (νs-SO ). 1H NMR (DMSO-d6) δ 1.21 (t, J
2
2
= 6.8 Hz, 3H, CH3-CH2); 4.18 (q, J = 6.8 Hz, 2H,
CH3-CH2); 4.85 (s, 2H, OCH2); 7.01 (d, J = 3.8 Hz, 1H,
thiaz. H-5); 7.07–7.35 (AA≠BB≠ system, 4H, ArO); 7.47
(d, J = 3.8 Hz, 1H, thiaz. H-4); 7.53–7.79 (m, 5H,
ArSO2). Anal. C19H18N2O5S2 (C, H, N, S).
6.2.5.7.
N-[2,3-Dihydro-3-(3-hydroxyphenyl)-2-thia-
zolylidene]-4-fluorophenyl-sulfonamide 10g
IR (KBr, cm–1) 3 350 (νOH); 1 560 (νC=C Thiaz); 1 275
(νas-SO ); 1 140 (νs-SO ). 1H NMR (DMSO-d6) δ
2
6.82–72.31 (m, 4H, ArO); 7.03 (d, J = 4.6 Hz, 1H, thiaz.
H-5); 7.36–7.84 (AA≠BB≠ system, 4H, ArSO2); 7.50 (d,
J = 4.7 Hz, 1H, thiaz. H-4); 9.95 (s, 1H, OH). Anal.
C15H11FN2O3S2 (C, H, F, N, S).
6.2.6.4.
2-[2,3-Dihydro-2-[[(4-methylphenyl)sulfonyl]
imino]thiazol-3-yl]phenoxyacetic acid, ethyl ester 11d
IR (KBr, cm–1) 1 730 (νC=O); 1 560 (νC=C Thiaz); 1 260
(νas-SO ); 1 145 (νs-SO ). 1H NMR (DMSO-d6) δ 1.18 (t, J
2
2
= 7.1 Hz, 3H, CH3-CH2); 2.35 (s, 3H, CH3); 4.11 (q, J =
7.1 Hz, 2H, CH3-CH2); 4.69 (s, 2H, OCH2); 6.98 (d, J =
4.7 Hz, 1H, thiaz. H-5); 7.11–7.45 (m, 4H, ArO);
7.32–7.66 (AA≠BB≠ system, 4H, ArSO2). 7.33 (d, J = 4.7
Hz, 1H, thiaz. H-4); Anal. C20H20N2O5S2 (C, H, N, S).
6.2.6. General procedure for the preparation of the
phenoxyacetate ethyl esters 11
To a suspension of N-[2,3-dihydro-3-(hydroxyphenyl)-
2-thiazolylidene]-arylsulfonamide 10 (0.01 mol) and po-
tassium carbonate (2.64 g, 0.02 mol) in anhydrous DMF
(30 mL), was added ethyl bromoacetate (2.09 g,
0.0125 mol). The mixture was heated at 80 °C for 2.5 h
with vigorous stirring and then cooled to room tempera-
ture. The mixture was poured into water (100 mL) and
extracted with ethyl acetate (3 × 50 mL). The EtOAc
solution was washed with water (3 × 50 mL) and dried
over Na2SO4. Removal of the solvent under reduced
pressure left the crude product as an oily residue. Tritu-
ration with diethyl ether (10 mL) gave the expected ester
as a white solid which was purified by recrystallisation.
6.2.6.5.
3-[2,3-Dihydro-2-[[(4-methylphenyl)sulfonyl]
imino]thiazol-3-yl]phenoxyacetic acid, ethyl ester 11e
IR (KBr, cm–1) 1 760 (νC=O); 1 560 (νC=C Thiaz); 1 290
(νas-SO ); 1 150 (νs-SO ). 1H NMR (DMSO-d6) δ 1.20 (t, J
2
2
= 7.1 Hz, 3H, CH3-CH2); 2.35 (s, 3H, CH3); 4.17 (q, J =
7.1 Hz, 2H, CH3-CH2); 4.79 (s, 2H, OCH2); 7.02 (d, J =
4.7 Hz, 1H, thiaz. H-5); 7.03–7.44 (m, 4H, ArO);
7.34–7.68 (AA≠BB≠ system, 4H, ArSO2). 7.49 (d, J = 4.7
Hz, 1H, thiaz. H-4); Anal. C20H20N2O5S2 (C, H, N, S).

326
6.2.6.6.
4-[2,3-Dihydro-2-[[(4-methylphenyl)sulfonyl]
NMR (DMSO-d6) δ 4.76 (s, 2H, OCH2); 7.01 (d, J = 4.7
Hz, 1H, thiaz. H-5); 7.05–7.34 (AA≠BB≠ system, 4H,
ArO); 7.47 (d, J = 4.5 Hz, 1H, thiaz. H-4); 7.53–7.79 (m,
5H, ArSO2); 10.50 (br. s, 1H, OH). Anal. C17H14N2O5S2
(C, H, N, S).
imino]thiazol-3-yl]phenoxyacetic acid, ethyl ester 11f
IR (KBr, cm–1) 1 755 (νC=O); 1 555 (νC=C Thiaz); 1 295
(νas-SO ); 1 145 (νs-SO ). 1H NMR (DMSO-d6) δ 1.22 (t, J
2
2
= 7.1 Hz, 3H, CH3-CH2); 2.34 (s, 3H, CH3); 4.18 (q, J =
7.1 Hz, 2H, CH3-CH2); 4.85 (s, 2H, OCH2); 6.96 (d, J =
4.7 Hz, 1H, thiaz. H-5); 7.06–7.34 (AA≠BB≠ system, 4H,
ArO); 7.33–7.66 (AA≠BB≠ system, 4H, ArSO2); 7.47 (d,
J = 4.7 Hz, 1H, thiaz. H-4). Anal. C20H20N2O5S2 (C, H,
N, S).
6.2.7.4.
2-[2,3-Dihydro-2-[[(4-methylphenyl)sulfonyl]
imino]thiazol-3-yl]phenoxyacetic acid 3d
IR (KBr, cm–1) 2 500–3 500 (νOH); 1 720 (νC=O);
1 560 (νC=C Thiaz); 1 260 (νas-SO ); 1 150 (νs-SO ). 1H
2
2
NMR (DMSO-d6reset)
CH ); 4.61 (s, 2H,
OCH2); 6.97 (m, 1H, δth2ia.3z5. (Hs, -53H);, 7.130–7.45 (m, 4H,
ArO); 7.33–7.64 (AA≠BB≠ system, 4H, ArSO2); 7.33 (m,
1H, thiaz. H-4); 10.40 (br. s, 1H, OH). Anal.
C18H16N2O5S2 (C, H, N, S).
6.2.6.7.
3-[2,3-Dihydro-2-[[(4-fluorophenyl)sulfonyl]
imino]thiazol-3-yl]phenoxyacetic acid, ethyl ester 11g
IR (KBr, cm–1) 1 750 (νC=O); 1 555 (νC=C Thiaz); 1 275
(νas-SO ); 1 140 (νs-SO ). 1H NMR (DMSO-d6) δ 1.20 (t, J
2
2
= 7.1 Hz, 3H, CH3-CH2); 4.17 (q, J = 7.1 Hz, 2H,
CH3-CH2); 4.79 (s, 2H, OCH2); 7.06 (d, J = 4.8 Hz, 1H,
thiaz. H-5); 7.06–7.44 (m, 4H, ArO); 7.36–7.87
(AA≠BB≠ system, 4H, ArSO2); 7.52 (d, J = 4.8 Hz, 1H,
thiaz. H-4). Anal. C19H17FN2O5S2 (C, H, F, N, S).
6.2.7.5.
3-[2,3-Dihydro-2-[[(4-methylphenyl)sulfonyl]
imino]thiazol-3-yl]phenoxyacetic acid 3e
IR (KBr, cm–1) 2 500–3 450 (νOH); 1 730 (νC=O);
1 555 (νC=C Thiaz); 1 275 (νas-SO ); 1 140 (νs-SO ). 1H
2
2
NMR (DMSO-d6) δ 2.35 (s, 3H, CH3); 4.59 (s, 2H,
OCH2); 6.98–7.41 (m, 4H, ArO); 7.00 (d, J = 5.1 Hz, 1H,
thiaz. H-5); 7.33–7.67 (AA≠BB≠ system, 4H, ArSO2);
7.48 (d, J = 4.8 Hz, 1H, thiaz. H-4); 10.20 (br. s, 1H, OH).
Anal. C18H16N2O5S2 (C, H, N, S).
6.2.7. General procedure for the preparation of
phenoxyacetic acids 3
A mixture of ethyl ester 11 (0.003 mol) and sodium
hydrogencarbonate (0.504 g, 0.003 mol) in water
(80 mL) was refluxed for 1.5 h under vigorous stirring.
After cooling, the clear solution was acidified with
hydrochloric acid. The precipitate obtained was collected
by filtration, washed with water, then recrystallized from
250 mL of a mixture H2O/THF (50:50).
6.2.7.6.
4-[2,3-Dihydro-2-[[(4-methylphenyl)sulfonyl]
imino]thiazol-3-yl]phenoxyacetic acid 3f
IR (KBr, cm–1) 2 500–3 500 (νOH); 1 745 (νC=O);
1 560 (νC=C Thiaz); 1 290 (νas-SO ); 1 145 (νs-SO ). 1H
2
NMR (see text). Anal. C18H16N2O5S2 (C, H, N, S2).
6.2.7.1.
2-[2,3-Dihydro-2-[(phenylsulfonyl)imino]
thiazol-3-yl]phenoxyacetic acid 3a
IR (KBr, cm–1) 2 500–3 500 (νOH); 1 715 (νC=O);
6.2.7.7.
3-[2,3-Dihydro-2-[[(4-fluorophenyl)sulfonyl]
1 560 (νC=C Thiaz); 1 280 (νas-SO ); 1 140 (νs-SO ). 1H
imino]thiazol-3-yl]phenoxyacetic acid 3g
2
2
NMR (DMSO-d6) δ 4.61 (s, 2H, OCH2); 6.99 (d, J = 4.3
Hz, 1H, thiaz. H-5); 7.11–7.45 (m, 4H, ArO); 7.35 (d, J =
4.3 Hz, 1H, thiaz. H-4); 7.53–7.77 (m, 5H, ArSO2); 10.50
(br. s, 1H, OH). Anal. C17H14N2O5S2 (C, H, N, S).
IR (KBr, cm–1) 2 550–3 450 (νOH); 1 735 (νC=O);
1 565 (νC=C Thiaz); 1 280 (νas-SO ); 1 150 (νs-SO ). 1H
2
2
NMR (DMSO-d6) δ 4.70 (s, 2H, OCH2); 7.03–7.43 (m,
4H, ArO); 7.05 (d, J = 4.7 Hz, 1H, thiaz. H-5); 7.36–7.85
(AA≠BB≠ system, 4H, ArSO2); 7.51 (d, J = 4.7 Hz, 1H,
thiaz. H-4); 10.60 (br. s, 1H, OH). Anal. C17H13FN2O5S2
(C, H, F, N, S).
6.2.7.2.
3-[2,3-Dihydro-2-[(phenylsulfonyl)imino]
thiazol-3-yl]phenoxyacetic acid 3b
IR (KBr, cm–1) 2 500–3 450 (νOH); 1 735 (νC=O);
1 560 (νC=C Thiaz); 1 290 (νas-SO ); 1 140 (νs-SO ). 1H
2
2
6.3. X-ray crystallography
NMR (DMSO-d6) δ 4.63 (s, 2H, OCH2); 7.00–7.49 (m,
4H, ArO); 7.02 (d, J = 4.9 Hz, 1H, thiaz. H-5); 7.49 (d, J
Single crystals of compound 9f, suitable for X-ray
analysis, were obtained from dimethylsulfoxide solution,
and a prism of dimensions 0.15 × 0.20 × 0.30 mm was
selected. Intensities of 1 711 independent reflexions were
collected on an Enraf-Nonius CAD-4 diffractometer with
Cu Kα radiation (λ = 1.54178 Å) from a graphite
monochromator. Lorentz and polarization corrections as
= 4.8 Hz, 1H, thiaz. H-4); 7.54–7.80 (m, 5H, ArSO2
);
10.20 (br. s, 1H, OH). Anal. C H14N2O5S2 (C, H, N, S).
17
6.2.7.3.
4-[2,3-Dihydro-2-[(phenylsulfonyl)imino]
thiazol-3-yl]phenoxyacetic acid 3c
IR (KBr, cm–1) 2 500–3 500 (νOH); 1 730 (νC=O);
1 560 (νC=C Thiaz); 1 290 (νas-SO ); 1 150 (νs-SO ). 1H
2
2

327
well as an empirical (æ scan) absorption correction were
applied. After data reduction, 1 460 reflexions were used
in the refinements. The crystal structure was solved by
direct methods using MULTAN 80 software [36].
Diagonal-matrix least-squares refinements were carried
aggregometer (Bio Data Corporation, PAP4). Platelet
poor plasma was used to preadjust the photometric
measurement to the minimal optical density. The tests
were realized in silanized cuvettes containing a stir bar
(1 100 rotations/min), under a final mixture volume of
250 µL (the dilution was made with 50 mM Tris-HCl
buffer before adding the test sample). Thus, a portion of
1.5 µL solution of tested compound in dimethylsulfoxide
(DMSO) was added to 225 µL of PRP and was incubated
at 37 °C for 3 min. The medium was then stimulated with
a convenient aggregating agent: arachidonic acid (3 µL,
60 mM final), U-46619 (4 µL, 1–5 µM final), ADP
(10 µL, 1.5–3 µM final), or diluted collagen (10 µL,
1 µg/mL final).
out by minimizing the function ΣW (ԽFoԽ – ԽFcԽ
)2 where
Fo and Fc are the observed and calculated structure
factors. The final cycle of refinement included 281
variable parameters and led to the following unweighted
and weighted agreement factors: R = 0.061 and wR =
0.070 (S = 1.02).
The residual electron density in the final difference
Fourier map was between 0.22 and –0.16 e Å–3.
6.4. Computational studies
The IC50 value was defined as the concentration
required to reduce by 50% the maximum aggregation
response 6 min after the addition of the aggregating
agent.
The calculations of energy-minimized conformations
were performed with the slightly modified Allinger’s
MM2 force field program [37] implemented in Chem3D
software V 3.5 [38]. Specific parameters for the aromatic
rings were added from available data reported ear-
lier [39]. Missing parameters were guessed from the
default option in the Chem3D MM2 program. Bond
stretching parameters and angle bending parameters were
corrected according to the X-ray crystal values obtained
for compound 9f. Geometric optimization on the torsion
angles was carried out only for conformers with an
energy difference of less than 3 kcal/mol from the lowest
total energy. Sulotroban, whose molecular modelling has
been previously reported [11] was employed as a tem-
plate for overlap comparisons. Molecular superimposi-
tions were carried out using the OVERLAY procedure
within Chem3D program.
6.5.2. Binding assays on human washed platelets
Human platelet-rich plasma obtained as described
above was further centrifuged at 1 000 g for 10 min to
precipitate platelets. Thereafter, the pellet was washed
twice and resuspended in Tyrode-Hepes buffer (pH 7.4)
free of calcium and magnesium and then adjusted to a
final platelet concentration of 2 × 108 platelets/mL.
Aliquot fractions (500 µL) were incubated with 100 µL of
[3H] SQ-29548 (46.0 Ci/mmol, 5 nM final) for 60 min at
25 °C. The displacement was initiated by addition of
400 µL of the tested compound (final concentration: 10–6
M) dissolved in a mixture of DMSO/phosphate buffer
(10 mM, pH 7.4) (30:70). Incubation was performed for
30 min at 25 °C and the reaction was stopped by addition
of 4 mL of ice-cold Tris-HCl buffer (10 mM, pH 7.4).
The reaction mixture was rapidly filtered through a
Whatman GF/C glass-fibre filter and washed with ice-
cold buffer (2 × 4 mL). The radioactivity on the glass
filter was measured using a liquid-scintillation counter.
Non-specific binding of [3H] SQ-29548 to the platelets
was estimated in the presence of unlabelled SQ-29548
(50 µM). Each drug was examined at 1 µM and its
potency expressed as the percentage of [3H] SQ-29548
specifically displaced from the TxA2 receptor.
6.5. Pharmacological evaluation
6.5.1. Inhibitory effect on human PRP aggregation
6.5.1.1. Preparation of platelet-rich plasma (PRP)
Blood was collected by venipuncture from volunteers
who had not taken any medication for at least 10 d and
was diluted (9:1) with 3.8% trisodium citrate in a
polypropylene tube. Centrifugation at 90 g at room tem-
perature for 20 min gave platelet-rich plasma as a super-
natant. The remaining blood was centrifuged at 2 000 g
for 5 min to give platelet-poor plasma (PPP). The platelet
concentration of PRP was adjusted to 3–4 × 105
cells/mm3 by dilution with PPP.
Acknowledgements
6.5.1.2. Measurement of inhibition of platelet
aggregation
The aggregation tests were performed according to the
turbidimetric Born’s method [40], using a four channel
We thank Andrée Carrère for manuscript preparation;
we are also grateful to Annie Lagardère and Stéphane
Larrouture for analytical assistance, and to Noël Pinaud
for high resolution NMR spectral data.

328
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