Guanidine derivatives as combined thromboxane A2 receptor antagonists and synthase inhibitors

Article abstract of DOI:10.1021/jm9707941

A new series of ω-disubstituted alkenoic acid derivatives derived from samixogrel 5 were designed and synthesized as combined thromboxane A₂ receptor antagonists/thromboxane A₂ synthase inhibitors with improved solubility and reduced

Full text of DOI:10.1021/jm9707941

J . Med. Chem. 1999, 42, 1235-1249
1235
Gu a n id in e Der iva tives a s Com bin ed Th r om boxa n e A2 Recep tor An ta gon ists a n d
Syn th a se In h ibitor s
Rainer Soyka,* Brian D. Guth, Hans M. Weisenberger, Peter Luger,† and Thomas H. Mu¨ller‡
Research and Development, Boehringer Ingelheim Pharma KG, Birkendorfer Strasse 65, 88397 Biberach, Germany,
Free University of Berlin, Institute for Crystallography, Takustrasse 6, 14195 Berlin, Germany, and Institute Oldenburg,
German Red Cross Transfusion Service, Brandenburger Strasse 21, 26133 Oldenburg, Germany
Received December 9, 1998
A new series of ω-disubstituted alkenoic acid derivatives derived from samixogrel 5 were
designed and synthesized as combined thromboxane A2 receptor antagonists/thromboxane A2
synthase inhibitors with improved solubility and reduced protein binding compared to 5.
Hexenoic acid derivatives with a 3-pyridyl group and 3-(2-cyano-3-alkyl-guanidino)phenyl
substituent were found to be optimal with regard to this dual mode of action. The most potent
compound, E-6-(3-(2-cyano-3-tert-butyl-guanidino)phenyl)-6-(3-pyridyl)hex-5-enoic acid, “ter-
bogrel” 32 inhibits the thromboxane A2 synthase in human gel-filtered platelets with an IC50
3
value of 4.0 ( 0.5 nM (n ) 4). Radioligand binding studies with H-SQ 29,548 revealed that 32
blocks the thromboxane A2/endoperoxide receptor on washed human platelets with an IC50 of
11 ( 6 nM (n ) 2) and with an IC50 of 38 ( 1 nM (n ) 15) in platelet-rich plasma. Terbogrel
inhibits the collagen-induced platelet aggregation in human platelet-rich plasma and whole
blood with an IC50 of 310 ( 18 nM (n ) 8) and 52 ( 20 nM (n ) 6), respectively. This was
shown to translate into a potent antithrombotic effect in vivo as demonstrated in studies using
a model of arterial thrombosis in rabbits (ED50 ) 0.19 ( 0.07 mg/kg; n ) 20). Thus, terbogrel
is the first compound with a guanidino moiety demonstrating both a potent TXA2 synthase
inhibition and a potent TXA2 receptor antagonism and has been selected for further clinical
development.
The importance of thromboxane A2 (TXA2) 1 (Chart
1) in coronary thrombotic syndromes is supported by
the antithrombotic effects of TXA2 inhibitors in various
animal studies1-4 as well as indirectly by the proven
clinical efficacy of aspirin in the secondary prevention
of myocardial infarction.5 Indeed, despite the therapeu-
tic efficacy of aspirin in various thrombotic syndromes,
which has been attributed exclusively to its thrombox-
ane inhibiting effect,6 aspirin is optimal neither in terms
of its efficacy nor side effect profile.7-9
Both the inhibition of TXA2 synthase (TxSI) and the
selective blockade of TXA2 receptors (TxRA) have been
pursued as alternative therapeutic strategies to prevent
the prothrombotic action of TXA2 without blocking
cyclooxygenase activity, as does aspirin. Selective block-
ade of TXA2 receptors does not interfere with arachi-
donic acid metabolism in activated platelets, but it does
prevent the activation of platelets by the binding of
TXA2 or endoperoxides (endo) to a common membrane
receptor (TXA2/endo) on the human platelet. Addition-
ally, on smooth muscle cells, TXA2/endo receptor block-
ade prevents the vasoconstrictive action of TXA2. While
a theoretically attractive approach, a high level of
receptor blockade may be required to produce clinically
relevant effects, thereby placing great demands on both
the pharmacodynamic and pharmacokinetic character-
istics of such a blocking agent. Alternatively, the selec-
tive inhibition of thromboxane synthase prevents the
conversion of prostaglandin endoperoxide intermediates
(PGH2, PGG2) to TXA2. This has the advantage that
other arachidonic acid metabolites can still be produced.
F igu r e 1. Schematic diagram of the antithrombotic effect of
combined TxA2/endo receptor blockade and thromboxane syn-
thase inhibition (TSI). Endoperoxides (ENDO) produced from
arachidonic acid (AA) in platelets can be metabolized to
prostacyclin (PGI2) in smooth muscle cells, endothelial cells,
and white blood cells (WBCs). The potential prothrombotic
effect of the endoperoxides is prevented through TxA2/endo
receptor blockade.
Thus, in the setting of platelet activation, as would occur
locally at a vascular injury site (Figure 1), the platelet-
produced endoperoxides can be taken up by other cells
(smooth muscle cells, endothelial cells, and white blood
cells) which can then produce prostaglandin I2 (prosta-
cyclin) 2 and other antithrombotic prostanoids.10,11
Prostacyclin is of particular interest since it is one of
the most effective inhibitors of platelet activation known
and it is a potent vasodilator. Therefore, with a throm-
boxane synthesis inhibitor the antithrombotic effect due
to the presence of locally produced prostacyclin could
exceed that expected by only blocking TXA2 receptors.
Additionally, the conversion of the endoperoxides to
† Free University of Berlin.
‡ Institute Oldenburg.
10.1021/jm9707941 CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/23/1999

1236 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Soyka et al.
Ch a r t 1
duced by cyclooxygenase in activated platelets bind and
activate the same membrane receptor as does TXA2
thereby causing platelet aggregation.18 If thromboxane
synthase inhibition leads to locally high concentrations
of endoperoxides as hypothesized, these metabolites
could, at least in part, take over the thrombogenic role
of TXA2.
The apparent solution to optimize therapeutic benefit
is to combine thromboxane synthase inhibition with
TXA2/endo receptor blockade.19,20 With such combined
treatment, the prostaglandin endoperoxides are syn-
thesized in activated platelets but their prothrombotic
effect is inhibited by the simultaneous TXA2/endo recep-
tor blockade (Figure 1). The endoperoxides can, how-
ever, be metabolized by other cell types to produce
antithrombotic prostanoids (e.g., prostacyclin and PGE1/
PGE2) which should provide a potent, local antithrom-
botic and vasodilatory action. A variety of compounds
with both properties have been reported.21 Ridogrel was
the first putative dual inhibitor of TXA2 to be tested
clinically, but as mentioned above, it yielded disappoint-
ing clinical results. Evaluation of the pharmacological
characteristics of ridogrel22 would suggest, however,
that the receptor affinity of the compound is indeed too
weak to adequately qualify as a compound with a dual
mode of action. In continuation of our previous work23
we looked for new compounds with strong and balanced
TXA2 receptor blockade and synthase inhibition.
Com p ou n d Design
In our previous publication23 we reported the synthe-
sis and biological properties of 6,6-disubstituted hex-5-
enoic acid derivatives as combined TXA2 synthase
inhibitors and receptor antagonists. The most interest-
ing molecule in this series was compound 5 (INN:
samixogrel) which reflects structural elements of the
synthase inhibitor isbogrel 6 and the receptor antago-
nist daltroban 7.
TXA2 synthase from human platelets is a cytochrome
P450 enzyme that contains one heme per polypeptide
chain.24 Essential structural features of TxSIs are a
basic nitrogen atom of a 3-substituted pyridine or an
N-substituted imidazole ring and a carboxylic acid group
separated by a distance of 0.85-1 nm.25 It was postu-
lated that the pyridine or imidazole moiety forms a
complex via the nitrogen atom with the heme group of
the catalytic site of TXA2 synthase.26 Assuming a
staggered conformation for the carboxyalkyl chain of 5,
the distance between the carbon atom of the carboxylic
acid and the nitrogen atom of the pyridine ring fulfills
the above-mentioned requirement.
Unfortunately compound 5 showed only moderate
plasma levels combined with an unexpected high vari-
ability after oral administration in human volunteers,
presumably due to the very low solubility of this
molecule in aqueous solutions under physiological con-
ditions. Due to the fact that the E-6-(3-pyridyl)-6-
phenyl-hex-5-enoic acid element is essential for potent
TXA2 synthase inhibition, we concentrated on the phe-
nylsulfonamide group of 5. Addition of different sub-
stituents to the p-chlorophenyl ring and the nitrogen
atom of the sulfonamide with the aim to increase
solubility in aqueous solution was, however, not suc-
E-type prostaglandins could help to reduce thrombus
formation due to their vasodilatory action. Finally, the
recently recognized leucocyte inhibiting activity of E-
type prostaglandins could help to reduce any ischemic
damage, which may occur distal to an obstructive
thrombus.12 This is an additional, potentially therapeu-
tic, effect not produced by prostacyclin.
The clinical experience using these two pharmacologi-
cal strategies alone to inhibit TXA2 has been disap-
pointing, however. For example, the first large clinical
trial with the selective and potent TXA2 receptor
antagonist Vapiprost 3 in PTCA patients showed no
effect on restenosis 6 months following the procedure.13
The clinical experience with thromboxane synthase
inhibition has not been better. The recent RAPT study
with Ridogrel 4, a potent TXA2 synthase inhibitor and
weak receptor antagonist, did not significantly affect the
primary endpoint of infarct-related artery patency at 2
weeks following streptokinase-induced lysis in acute
myocardial infarction patients.14 Various other smaller
studies have provided mixed results with these two
types of TXA2-blocking agents.15-17
A possible explanation of the only modest clinical
success with TXA2 synthase inhibition comes with the
recognition that the endoperoxide intermediates pro-

Thromboxane A2 Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1237
Sch em e 1
cessful. On the other hand we knew from our own
investigations23 that the p-Cl-phenylsulfonamide moiety
of samixogrel 5 could be directly connected to the
6-phenyl-hexenoic acid part preferentially in the meta
position without loss of activity. Unfortunately such
compounds revealed an unexpectedly strong unspecific
protein binding with concomitant reduction of antiplate-
let activity in the presence of plasma proteins. Because
it was known from the literature21 that the sulfonamide
moiety is not a prerequisite for TXA2 receptor antago-
nism, we looked for structural elements with steric and
electronic properties similar to phenylsulfonamides.
Starting with simple urea and thiourea derivatives, we
found that nonbasic guanidines were suitable substi-
tutes for the sulfonamide group. Due to synthetic
considerations (see Chemistry section) the p-chloro-
phenyl ring of 5 had to be replaced by alkyl groups.
Ch em istr y
The compounds described in Tables 1-3 were pre-
pared as depicted in Schemes 1-4. Compound 10 was
synthesized (Scheme 1) by reaction of compound 823
with commercially available diphenyl-N-cyano-carbon-
i
imidate 9 in PrOH at ambient temperature. Starting
from 10, compounds 26-33, 35, 36, 38-41 were ob-
tained by reaction with the corresponding amines in
refluxing iPrOH followed by saponification with aqueous
NaOH in moderate to good yields. Usage of com-
mercially available N-cyano-dithiocarbonimidic acid
dimethyl ester instead of 9 with the same protocol gave
only poor yields, especially in the substitution reaction
of the second methylthio group. Whereas aliphatic
amines, even if they were sterically hindered, reacted
easily with 10, anilines could not be transformed to the

1238 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Soyka et al.
N23: 132.9 ( 0.4 pm; C22-N21: 136.0 ( 0.4 pm) of
the cyano-guanidine moiety. This bond geometry com-
pares well with the unsubstituted cyano-guanidine.27
Repeated column chromatography of the mother
liquid after recrystallization of 32 gave the Z-isomer 53.
The regioisomers 34 and 37 were prepared from the
ketone 11,23 which was transformed to 12 by a Wittig
reaction via the intermediate 13 according to the above-
mentioned protocol.
Acidic hydrolysis of the N-cyanoguanidine 30 resulted
in the N-carbamoyl derivative 45, and 1,3-dipolar cy-
cloaddition with tributyltin azide gave the N-tetrazolyl
compound 49 in a yield of 64%.
The urea and thiourea derivatives 42 and 43 (Scheme
2) were prepared by reaction of 8 with tert-butyliso-
cyanate and tert-butylisothiocyanat in THF/DMF in the
presence of DMAP. Whereas 42 could be prepared in
52% yield, the reaction with the corresponding isothio-
cyanate gave 43 only in 10% yield after refluxing the
reactants for more than 40 h.
F igu r e 2. X-ray structure of compound 32‚0.5CH3COCH3
acetone (ORTEP37-plot).
Condensation of 8 with N-diphenoxymethylene-benz-
amide 1428 at room temperature gave compound 15
which was further transformed to 46 by reaction with
the cyclopentylamine in refluxing iPrOH. Compound 44
was obtained from 46 by cleavage of the benzoyl group
in refluxing HCl. Compound 50 was prepared by a
similar protocol via the intermediate 17 starting from
8 and commercially available 1,1-bis(methylthio)-2-
nitroethylene 16.
corresponding cyano-guanidines. The E-configuration of
the C-C double bond was generally confirmed by H
1
NMR spectroscopy and by X-ray analysis for compound
32 (Figure 2). Concerning the C-N double bond we
could not detect isomers at room temperature for any
1
compound in Table 1 by H NMR spectroscopy, presum-
ably due to the more formal character of this double
bond. This explanation is in accordance with the X-ray
analysis of 32 which shows that the bond length of the
C-N double bond (C22-N24: 132.9 ( 0.5 pm) does not
differ substantially from the other C-N bonds (C22-
The sulfonyl derivatives 47 and 48 (Scheme 3) were
prepared via the intermediates 20 and 21 which were
obtained by reaction of 8 with N-diphenoxymethylene-
Sch em e 2

Thromboxane A2 Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1239
Sch em e 3
methanesulfonamide 1828 and N-diphenoxymethylene-
phenylsulfonamide 19. Compound 19 was obtained by
treatment of diphenoxy-dichloromethane with phenyl-
sulfonamide in 26% yield.
In Vitr o P h a r m a cology
The compounds described above were initially tested
in the following three assays: (a) displacement of the
high-affinity radiolabeled ligand H-SQ 29,548 from the
PGH2/TXA2 receptor on human gel-filtered platelets, (b)
inhibition of TXB2 formation by human gel-filtered
platelets incubated with 14C-arachidonic acid, and (c)
inhibition of collagen-induced platelet aggregation in
human platelet-rich plasma (PRP).
3
Condensation of 8 with (bis-methylsulfanyl-methyl-
ene)malononitrile 2229 yielded compound 23. Direct
substitution of the methylthio group with tert-butyl-
i
amine in refluxing PrOH was not successful, but after
oxidation with mCPBA compound 51 could be obtained
in 43% yield. The squaric acid derivative 52 could be
obtained by reaction of 8 with 3,4-diethoxy-3-cyclobutene-
1,2-dione 24 to form compound 25 which was then
treated with tert-butylamine followed by saponification
of the methyl ester.
The results are listed as IC50/EC50 values in Tables
1-3. Starting from the N-cyano-guanidine derivatives,
we first examined the influence of the alkyl substituent
on both properties, TXA2 receptor antagonism and
synthase inhibition. It is remarkable that already the
unsubstituted derivative 26 exhibits potent antagonistic
activity whereas the synthase inhibitory potency is weak
compared to samixogrel 5 or ridogrel 4. Monoalkylation
of the terminal nitrogen atom of the N-cyano-guanidine
moiety (27, 29-39) improves the enzyme inhibition by
a factor of 100, but there is no strong relationship
between the bulkiness and substitution pattern of the
alkyl groups and synthase inhibition. Besides aromatic
systems (39), also alicycles from cyclopropyl (33) up to
cyclohexyl (36) as well as the very bulky group ada-
mantyl (38) were tolerated. The aliphatic part of the
compounds seems nonessential for the interaction with
the enzyme, but to inhibit the TXA2 synthase the
compounds have to penetrate the cell membrane be-
cause the enzyme is located within the mitochondria.
An increase in lipophilicity presumably facilitates the
Reaction of the ketone 5423 with the corresponding
carboxyalkyl-triphenylphoshonium bromides yielded the
compounds 55-57 which were then treated with HCl
in MeOH to form the methyl esters with simultaneous
cleavage of the acetyl moiety. Reaction with reagent 9
and then with tert-butylamine followed by cleavage of
the methyl ester under basic conditions resulted in the
compounds 58-60. The E-configuration of the C-C
1
double bond was confirmed by H NMR spectroscopy.
Reaction of the ketone 6130 with hydroxylamine gave
the oxime 62 as a mixture of E- and Z-isomers, which
was further treated with ethyl 5-bromopentanoate to
form compound 63. After reduction of the nitro group,
reaction with 9 and then tert-butylamine followed by
cleavage of the ethyl ester and separation of the E- and
Z-isomers by column chromatography yielded the oxime
ether derivatives 64 and 65.

1240 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Soyka et al.
Sch em e 4a
a
i
i
(a) Ph3P-(CH2)m-COOH (m ) 3, 5, 6), KOtBu, THF; (b) HCl, MeOH; (c) 9, PrOH; (d) (1)tert-butylamine, PrOH, (2) NaOH, EtOH; (e)
H2NOH‚HCl, pyridine, EtOH; (f) Br-(CH2)4-COOEt, KOtBu, DMF; (g) Ra-Ni, H2, EtOH.
Ta ble 1. Physical Constants and in Vitro Activity of Compoundsa
TXA2
receptor
antagonism
IC50 [µM]
TXA2
Inh. of
collagen-induced
plat. aggreg.
EC50 [µM]
synthase
inhibition
IC50 [µM]
no.
R
pos.
formula
mp [°C]
164
174-175
120-123
194
4
5
ridogrel
samixogrel
NH2
CH3-NH
(CH3)2N
C
C
18H17F3N2O3
25H25ClN2O4S
1.7c
0.019
0.035
0.016
0.12
0.018
0.007
0.027
0.011
0.017
21
0.004d
0.004
0.43
16
1
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
3
3
3
3
3
3
3
3
4
3
3
4
3
3
3
3
C19H19N5O2
C20H21N5O2
C21H23N5O2
C22H25N5O2
C23H27N5O2
C24H29N5O2
C23H27N5O2
22H23N5O2
22H23N5O2
24H27N5O2
25H29N5O2
25H29N5O2
29H33N5O2
1.0
0.46
1.0
0.4
0.35
0.69
0.31
0.9
42
0.25
0.026
0.024
0.025
0.003
0.004
0.38
(CH3)2CH-NH
186
(CH3)2CH-CH2-NH
(CH3)2CH-CH2-CH2-NH
(CH3)3C-NH
129b
108b
147b
cyclopropylamino
cyclopropylamino
cyclopentylamino
cyclohexylamino
cyclohexylamino
1-adamantylamino
C6H5-CH2-NH
C
C
C
C
C
C
178b
118-119
136-137b
156-157b
145-147
198
138-140
125-126
foam
3.9
0.03
0.047
1.3
0.003
0.003
0.18
0.5
5.8
31
0.083
0.032
0.13
0.003
0.011
0.32
0.5
1.6
6.9
6.8
C26H25N5O2
C25H26N6O2‚0.5H2O
C23H28N6O2‚H2O
3-pyridyl-CH2-NH
(CH3)2N-CH2-CH2-NH
1
2.9
a
b
d
For details, see Experimental Section. Decomposition. c 5.2 µM (ref 14b). 0.008 µM (ref 14c).
cell membrane penetration. This hypothesis is sup-
ported by the observation that the introduction of
hydrophilic groups (40, 41) decreases the synthase
inhibitory activity. It is of interest that the size and

Thromboxane A2 Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1241
Ta ble 2. Physical Constants and in Vitro Activity of Compoundsa
TXA2
TXA2
Inh. of
collagen-induced
plat. aggreg.
EC50 [µM]
receptor
antagonis
IC50 [µM]
synthase
inhibition
IC50 [µM]
no.
R
A
formula
C22H27N3O3
C22H27N3O2S
23H28N4O2‚0.5H2O
C23H29N5O3
30H32N4O3
C23H30N4O4S
C28H32N4O4S
C23H28N8O2
C25H30N4O4
C25H27N5O2
C25H27N3O4
mp [°C]
42
43
44
45
46
47
48
49
50
51
52
(CH3)3C-NH
(CH3)3C-NH
CdO
CdS
CdNH
165
1.3
0.038
1.7
0.04
0.022
3.9
9
2
137-139b
150
cyclopentylamino
(CH3)2CH-CH2-NH
cyclopentylamino
(CH3)3C-NH
C
21
12
16
6.1
3.3
22
15
0.12
59
dN-CONH2
dN-COPh
foam
171
0.61
0.11
0.33
0.055
0.3
0.44
0.003
0.83
0.2
C
0.004
0.025
0.003
0.93
0.31
0.05
0.23
dN-SO2CH3
dN-SO2Ph
dN-5-tetrazolyl
dCH-NO2
150-151
(CH3)3C-NH
foam
(CH3)2CH-CH2-NH
cyclohexylamino
(CH3)3C-NH
218b
155-157
188-189
150b
CdC(CN)2
(CH3)3C-NH
a
b
For details, see Experimental Section. Decomposition.
Ta ble 3. Physical Constants and in Vitro Activity of Compoundsa
TXA2
receptor
antagonism
IC50 [µM]
TXA2
Inh. of
collagen-induced
plat. aggreg.
EC50 [µM]
synthetase
inhibition
IC50 [µM]
no.
R
R1
config
formula
mp [°C]
53
58
59
60
64
65
(CH3)3C-NH
(CH3)3C-NH
(CH3)3C-NH
(CH3)3C-NH
(CH3)3C-NH
(CH3)3C-NH
CdCH-(CH)3-COOH
CdCH-(CH)2-COOH
CdCH-(CH)4-COOH
CdCH-(CH)5-COOH
)N-O-(CH2)4-COOH
)N-O-(CH2)4-COOH
Z
E
E
E
E
Z
C23H27N5O2
C22H25N5O2
C24H29N5O2
C25H31N5O2
C23H28N6O3
C23H28N6O3
162
146-148
96
136-138
161-162
172-173
2.6
1.6
0.4
0.006
0.005
0.005
0.23
48
13
3.7
1.7
5.2
17
0.081
0.33
0.077
0.31
0.51
a
For details, see Experimental Section.
shape of the alkyl group have only a minor effect on
the receptor antagonism too.
group by a tetrazole (49) or a nitro-methylene group (50)
reduces both TxSI and TxRA activities.
The importance of the meta position of the N-cyano-
guanidine group in contrast to the structure-activity
relationships (SARs) of 5 is demonstrated by the isomers
33/34 and 36/37. Receptor antagonistic as well as
synthase inhibitory activities are significantly reduced
by a change from the meta to the para position.
To get deeper insight into the SARs we have varied
the N-cyano part at the guanidine group. Replacement
of the N-cyano group simply by oxygen (42) or nitrogen
(44) reduces both TxRA and TxSI. This effect is not so
pronounced if the N-cyano group is replaced by sulfur
(43). Replacement of the cyano group by a carbamoyl
group (45) is associated with a significant decrease in
receptor antagonism and synthase inhibition whereas
the benzoyl derivative 46 reveals only a reduced TxRA
activity. We suppose that the increased lipophilicity of
compound 46 compared to 45 is responsible for the
improved synthase inhibition.
Replacement of the N-cyano part by a dicyano-
methylene group (51) results in the most potent TXA2
receptor antagonist we have found within our research
program. Unfortunately the TxSI is reduced by a factor
of 10 compared to the N-cyano guanidine 32. Both
activities are reduced if the guanidine moiety is sub-
stituted by a cyclobutenedione group (52).
Further investigations concentrated on the influence
of the carboxyalkyl chain. It is not surprising that SARs
for this part of compound 32 are very similar to those
found for compound 5. The importance of the E-
configuration is obvious by comparison of the isomers
32 and 53. The butenoic acid derivative 58 is a weak
TxSI due to the fact that the distance between the
pyridine nitrogen atom and the carboxyl acid group is
not optimal. The derivatives 59 and 60 with prolonged
carboxyalkenyl chains are potent synthase inhibitors,
but TxRA activity is reduced compared to 32.
Comparable structure-activity relationships are found
for the corresponding methylsulfonyl 47 and phenyl-
sulfony 48 derivatives. Substitution of the N-cyano
Finally we have synthesized the E- and Z-isomers 64
and 65 which are direct analogues to ridogrel 4. As we
expected, the E-isomer 64 is as potent as ridogrel with

1242 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Soyka et al.
F igu r e 3. Summary of in vitro studies in which various
amounts of terbogrel were added to platelet-rich plasma
collected from 15 human volunteers and then the receptor
occupancy was determined. In this system, the IC50 value was
30 nmol/L (note: in figure, concentration is given in ng/mL).
F igu r e 4. Summary of collagen-induced (1 µg/mL) aggrega-
tion in platelet-rich plasma in response to various concentra-
tions of terbogrel. Individual data points (N ) 20 in duplicate)
as well as the mean and standard deviation are shown.
blood cells are present which can convert prostaglandin
endoperoxides to prostacyclin thereby accounting for the
markedly higher potency of terbogrel in the whole blood
system. This is further supported by the measurement
of 6-keto-prostaglandin F1R in plasma from these stud-
ies. With the addition of the collagen stimulus (1 µg/
mL) there was a 6-fold increase in the concentration of
6-keto-prostaglandin F1R in the plasma over that in-
duced by collagen without terbogrel. It is tempting to
attribute the higher antiaggregatory potency of ter-
bogrel in whole blood, as compared to platelet-rich
plasma, to the production of prostacyclin, as measured
as its stable metabolite 6-keto-prostaglandin F1R. This
gives good supporting evidence for the existence of the
combined TXA2 receptor blockade and synthase inhibi-
tion mechanism in this system. Between 10 and 30 µM
terbogrel, the level of 6-keto-prostaglandin F1R began
to decrease which is probably due to cyclooxygenase
inhibition at these high concentrations. Iteration of the
biphasic dose-response curve resulted in an EC50 of
0.018 µM for 6-keto-prostaglandin F1R increase and an
IC50 of 50 µM for the presumed cyclooxygenase inhibi-
tion, respectively.
regard to synthase inhibition, but the receptor antago-
nism is significantly reduced in comparison to 32. It is
of interest that both isomers 64 and 65 are more potent
as receptor antagonists compared to the parent com-
pound 4.
From the series of N-cyano guanidine derivatives
described, compound 32 (INN: terbogrel) was selected
for further investigations due to its favorable physico-
chemical properties as well as its strong and balanced
receptor blockade and synthase inhibition. In a competi-
tive binding assay with the selective TXA2 receptor
blocker SQ 29,448 in gel-filtered human platelets,
terbogrel exhibited an IC50 of 11 nmol/L. Since binding
to plasma proteins may cause a loss of efficacy in vivo,
it is important to also test for receptor affinity in the
presence of plasma proteins. In a test system using
human platelet-rich plasma, as opposed to gel-filtered
platelets, such that plasma proteins are present, ter-
bogrel 32 demonstrated an IC50 of 38 ( 1 nmol/L (n )
15, Figure 3). Thus, there is little if any effect of plasma
proteins on the affinity of terbogrel to the TXA2 receptor
in contrast to samixogrel 5 (IC50 ) 790 nmol/L). This
result may be due to the decreased lipophilicity of 32
(log P (n-octanol/buffer pH 7.4) ) 1.04) and the in-
creased solubility in aqueous buffer (5.4 mg/100 mL at
pH 7) in comparison to 5 (log P ) 2.36; solubility ) 0.14
mg/100 mL at pH 7).
The inhibition of TXA2 formation and binding leads
to an inhibition of aggregation of collagen-stimulated
platelets. In platelet-rich plasma, terbogrel 32 inhibited
platelet aggregation stimulated by 1 µg/mL collagen
with an IC50 of 310 ( 18 nmol/L (n ) 8) (Figure 4). This
experimental system for profiling agents such as ter-
bogrel with a dual inhibition of thromboxane must be
viewed with caution, however. In platelet-rich plasma,
no cells capable of prostacyclin synthesis are present
thereby preventing this additional antiaggregatory mech-
anism in this experimental system.
In Vivo P h a r m a cology
Acute damage of an artery exposes thrombogenic
components of the vessel wall to the flowing blood,
which causes platelet activation and thrombus forma-
tion. In the presence of a stenosis and the increased
shear forces thereby produced, an occlusive arterial
thrombus readily forms. Folts demonstrated that the
mechanical removal of such platelet-rich thrombi in the
coronary artery of an anesthetized dog could temporarily
restore blood flow through the artery but that a new
thrombus quickly forms to reocclude the vessel.31 He
exploited this phenomenon of recurrent coronary throm-
bosis to make a widely used model for the testing of
antithrombotic agents.32 Effective antithrombotic agents
are those that can either slow or prevent the coronary
thrombus formation.
Doses of 0.1-3.0 mg/kg were administered as an
intravenous bolus in rabbits having recurrent arterial
thrombosis. A dose-dependent effect was seen primarily
in the length of thrombus inhibition since all doses
produced similar effects immediately after bolus ad-
ministration. A 50% inhibition throughout the 1 h
observation period could be produced by a dose of 0.19
If the redirection of arachidonic acid metabolites to
prostacyclin synthesis is of relevance, one would predict
that terbogrel has a higher antiaggregatory potency in
test systems in which prostacyclin synthesis can occur.
In the studies with whole blood aggregation, terbogrel
had an IC50 of 52 ( 20 nmol/L (n ) 6) which indicates
a substantially higher (∼6-fold) antiaggregatory potency
in this system as compared to platelet-rich plasma. In
whole blood, in contrast to platelet-rich plasma, white

Thromboxane A2 Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1243
mmol) and KOtBu (232.9 g, 2080 mmol) in THF (2800 mL) at
-30 °C. After 2 h of being stirred at 20 °C, the reaction mixture
was combined with water (500 mL) and then evaporated. The
residue was taken up in water (1000 mL) and washed with
EtOAc. The aqueous phase was neutralized by addition of citric
acid and extracted with EtOAc. The organic phase was
evaporated, and the residue was then recystallized from
EtOAc/diisopropyl ether and dried at 80 °C to yield 154 g (86%)
of 12, mp 155-156 °C: 1H NMR (DMSO-d6) 1.7 (q, 2H), 2.05
(s, 3H), 2.2 (m, 4H), 6.2 (t, 1H), 6.85 (d, 1H), 7.35 (m, 3H), 7.6
(m, 2H), 8.4 (m, 2H), 9.9 (s, 1H), 12.0 (bs, 1H); Anal.
(C19H20N2O3) C, H, N.
Meth yl 5E-6-(4-(Cya n im id o-p h en oxym eth ylen a m in o)-
p h en yl)-6-(3-p yr id yl)h ex-5-en oa te (13). Compound 12 (16.2
g, 50 mmol) was stirred in MeOH (70 mL) and 7 M HCl in
MeOH (100 mL) for 12 h at 20 °C. Water (200 mL) was added,
and the reaction mixture was adjusted to pH 9 by addition of
ammonia and immediately extracted with EtOAc. The organic
phase was washed with water, dried, and concentrated. The
F igu r e 5. Summary of occlusive frequency (number of oc-
clusive thrombi per hour) for the four terbogrel dose groups
tested (mean + SD) in the hour following bolus intravenous
administration.
i
residue was dissolved in PrOH (250 mL), and 9 (11.4 g, 50
( 0.07 mg/kg (n ) 20) (Figure 5). When one considers
the weaker TXA2 receptor binding affinity to rabbit
platelets in comparison to man (a 190-fold difference),
terbogrel demonstrated an impressive antithrombotic
efficacy.
In basic pharmacokinetic studies with radiolabeled
terbogrel in rats (10 mg/kg po), the compound is rapidly
and well (90%) absorbed with a systemic availability of
about 30%. The drug is mainly excreted (>80%) in the
bile, and the elimination occurred almost exclusively in
the feces. The terminal half-life in rats after oral
application is in the range from 7.5 to 10 h.
mmol) was added. The mixture was stirred for 6 h at 25 °C,
the crystals formed were filtered with suction and washed with
Et2O to yield 19.1 g (86%) of 15, mp 163-165 °C: 1H NMR
(DMSO-d6) 1.7 (q, 2H), 2.1 (q, 2H), 2.3 (t, 2H), 3.5 (s, 3H), 6.2
(t, 1H), 7.15 (d, 2H), 7.25-7.6 (m, 11H), 8.45 (m, 2H), 10.9 (s,
1H); IR (CH2Cl2) 2200 (CN), 1730 (CdO) cm-1. Anal. (C26H24
-
N4O3) C, H, N.
Meth yl 5E-6-(3-(Ben zoylim id o-p h en oxym eth ylen a m i-
n o)p h en yl)-6-(3-p yr id yl)h ex-5-en oa te (15). Compounds 8
i
(4.14 g, 14 mmol) and 14 (5 g, 35 mmol) were dissolved in -
PrOH (200 mL) and stirred for 4 h at 20 °C. The reaction
mixture was chilled to 0 °C, and the crystals formed were
filtered with suction to yield 5.8 g (80%) of 15, mp 112 °C: 1H
NMR (CDCl3) 1.7 (q, 2H), 2.25 (m, 4H), 3.6 (s, 3H), 6.1 (t, 1H),
7.0 (d, 1H), 7.1-7.5 (m, 13H), 7.95 (d, 2H), 8.5 (d + dd, 2H);
IR (CH2Cl2) 1730 (CdO) cm-1. Anal. (C32H29N3O4) C, H, N.
Con clu sion
We succeeded in the synthesis of combined TXA2
receptor antagonists and synthase inhibitors by replace-
ment of the phenylsulfonamide moiety of samixogrel 5
by alkyl-substituted nonbasic guanidines. The most
active compounds are N-cyano-guanidines that bind to
the TXA2/endo receptor and inhibit the TXA2 synthase
in the lower nanomolar range. Due to its potent anti-
aggregatory activity in vitro as well as in vivo, terbogrel
32 was selected for clinical investigations.
Meth yl 5E-6-(3-(1-Meth ylth io-2-n itr o-eth ylen a m in o)-
p h en yl)-6-(3-p yr id yl)h ex-5-en oa te (17). Compounds 8 (3 g,
10 mmol) and 16 (1.65 g, 10 mmol) were refluxed in PrOH
i
(50 mL) for 20 h. The mixture was filtered and evaporated,
and the residue was purified over a silica gel column using
CH2Cl2/EtOH 30:1 and subsequently recrystallized from TBME/
diisopropyl ether to yield 2.6 g (63%) of 17, mp 84 °C: 1H NMR
(CDCl3) 1.8 (q, 2H), 2.2 (t, 4H), 2.3 (q, 2H), 2.4 (s, 3H), 3.65 (s,
3H), 6.15 (t, 1H), 6.7 (s, 1H), 7.1-7.3 (m, 4H), 7.45 (m, 2H),
8.5 (m, 2H), 11.8 (s, 1H); IR (CH2Cl2) 1735 (CdO) cm-1. Anal.
(C21H23N3O4S) C, H, N, S.
Exp er im en ta l Section
N-Diph en oxym eth ylen eph en ylsu lfon am ide (19). Dichlo-
ro-diphenoxymethane (13.5 g, 50 mmol) and benzenesulfona-
mide (17.3 g, 110 mmol) were refluxed in EtOAc (60 mL) for
55 h. The reaction mixture was washed with sodium bicarbon-
ate solution and water. The organic phase was dried, concen-
trated and the residue was extracted with hot CH2Cl2. The
dichloromethane solution was evaporated and the residue was
purified by column chromatography using CH2Cl2 followed by
recrystallization from EtOAc/diisopropyl ether to yield 4.6 g
(26%) of 19, mp 121-122 °C: 1H NMR (CDCl3) 7.05 (m, 4H),
7.2-7.6 (m, 9H), 7.95 (dd, 2H); Anal. (C19H15NO4S) C, H, N,
S.
Meth yl 5E-6-(3-(m eth ylsu lfon im id o-p h en oxym eth yl-
en a m in o)p h en yl)-6-(3-p yr id yl)-h ex-5-en oa te (20). Com-
pounds 8 (7.4 g, 25 mmol) and 18 (7.3 g, 25 mmol) were stirred
in iPrOH (250 mL) for 24 h at 25 °C. The mixture was
concentrated, and the residue was purified by column chro-
matography with CH2Cl2/EtOH 20:1 followed by recrystalli-
zation from EtOAc/petroleum ether to yield 10.4 g (84%) of
20, mp 150-151 °C: 1H NMR (CDCl3) 1.75 (q, 2H), 2.2 (m,
4H), 2.9 (s, 3H), 3.6 (s, 3H), 6.1 (t, 1H), 7.0-7.5 (m, 11H), 8.5
(d + dd,2H), 9.25 (s, 1H); IR (CH2Cl2) 1740 (CdO) cm-1. Anal.
(C26H27N3O5S) C, H, N, S.
(a ) Ch em istr y. Melting points were determined in a Bu¨chi
capillary melting point apparatus and were not corrected.
Infrared (IR) spectra were recorded on a Perkin-Elmer model
298 spectrophotometer. 1H and 13C NMR spectra were mea-
sured on a Bruker AC200 and a Bruker AMX400 instrument.
Chemical shifts are reported in δ units relative to internal
tetramethylsilane. Mass spectra were recorded on a Finnigan
MAT 8230 or an AEI MS-902 mass spectrometer in either EI
or fast-atom-bombardment mode. Microanalyses were per-
formed on a CHN-Rapid (Heraeus). Silica gel (Baker 30-60
µm) was used for column chromatography. TLC was performed
on silica gel plates (Macherey-Nagel Polygram Sil G/UV 254
or Merck, silica gel 60, F-254).
Meth yl 5E-6-(3-(Cya n im id o-p h en oxym eth ylen a m in o)-
p h en yl)-6-(3-p yr id yl)h ex-5-en oa te (10). Compounds 8 (10.5
g, 35 mmol) and 9 (8.4 g, 35 mmol) were dissolved in PrOH
i
(100 mL) and stirred for 5 h at 20 °C. The reaction mixture
was concentrated, and the residue was chromatographed on
silica gel with CH2Cl2/EtOH 40:1 to yield 13.3 g (86%) of 10
as an oil: 1H NMR (CDCl3) 1.8 (q, 2H), 2.3 (m, 4H), 3.6 (s,
3H), 6.1 (t, 1H), 6.8-7.5 (m, 15H), 8.5 (d + dd, 2H), 8.8 (s,
1H); IR (CH2Cl2) 2160 (CN), 1730 (CdO) cm-1. Anal. (C26H24
-
N4O3) C, H, N.
Met h yl 5E-6-(3-(p h en ylsu lfon im id o-p h en oxym et h yl-
en a m in o)p h en yl)-6-(3-p yr id yl)-h ex-5-en oa te (21). Com-
pounds 8 (3 g, 10 mmol) and 19 (3.5 g, 10 mmol) were stirred
in iPrOH (60 mL) for 48 h at 25 °C. The mixture was
5E-6-(4-Acetam ido-ph en yl)-6-(3-pyr idyl)h ex-5-en oic acid
(12). Compound 11 (140 g, 580 mmol) was added to a mixture
of 4-carboxybutyl-triphenylphosphonium bromide (307.2 g, 690

1244 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Soyka et al.
concentrated, and the residue was purified by column chro-
matography with CH2Cl2 and by recrystallization from diethyl
ether/petroleum ether to yield 4.8 g (86%) of 21, mp 90-92
°C: 1H NMR (CDCl3) 1.75 (q, 2H), 2.2 (m, 4H), 3.6 (s, 3H), 6.1
(t, 1H), 7.1 (m, 3H), 7.1-7.55 (m, 11H), 7.8 (m, 2H), 8.5 (m,
2H), 9.5 (s, 1H); IR (CH2Cl2) 1740 (CdO) cm-1. Anal.
(C31H29N3O5S) C, H, N, S.
Meth yl 5E-6-(3-(2,2-Dicya n o-1-m eth ylth io-eth ylen a m i-
n o)p h en yl)-6-(3-p yr id yl)h ex-5-en oa te (23). Compounds 8
(13.4 g, 45 mmol) and 22 (7.7 g, 45 mmol) were refluxed in
iPrOH (130 mL) for 6-8 h. The reaction mixture was evapo-
rated, and the residue was recrystallized from EtOAc/diiso-
propyl ether to yield 8.4 g (44%) of 23, mp 125-127 °C: 1H
NMR (CDCl3) 1.8 (q, 2H), 2.2 (q, 2H), 2.35 (t + s, 5H), 3.65 (s,
3H), 6.15 (t, 1H), 7.05 (d, 1H), 7.1-7.3 (m, 3H), 7.4-7.6 (m,
2H), 8.45 (d + dd, 2H), 8.6 (bs, 1H); IR (CH2Cl2) 2220 (CN),
1740 (CdO) cm-1. Anal. (C23H22N4O2S) C, H, N, S.
29: 1H NMR (DMSO-d6) 1.1 (d, 6H), 1.7 (q, 2H), 2.2 (m, 4H),
4.0 (sep, 1H), 6.2 (t, 1H), 6.9 (d, 1H), 7.0 (s, 1H), 7.1 (d, 1H),
7.2-7.4 (m, 3H), 7.6 (dd, 1H), 8.45 (m, 2H), 9.0 (s, 1H), 12.0
(s, 1H); IR (KBr) 2160 (CN) cm-1. Anal. (C22H25N5O2) C, H, N.
5E-6-(3-(2-Cyan o-3-(2-m eth ylpr opyl)gu an idin o)ph en yl)-
6-(3-p yr id yl)h ex-5-en oic Acid (30). Preparation was per-
formed according to 29. Purification was effected by column
chromatography with 1,2-dichloroethane/EtOH 20:1 and by
subsequent recrystallization from EtOAc/diisopropyl ether;
yield 74%: 1H NMR (DMSO-d6) 0.85 (d, 6H), 1.7 (q, 2H), 1.8
(sep, 1H), 2.2 (m, 4H), 3.5 (t, 2H), 6.2 (t, 1H), 6.9 (d, 1H), 7.0
(s, 1H), 7.2-7.45 (m, 4H), 7.6 (dd, 1H), 8.45 (m, 2H), 9.0 (s,
1H), 12.0 (s, 1H); IR (KBr) 2170 (CN) cm-1. Anal. (C23H27N5O2)
C, H, N.
5E-6-(3-(2-Cya n o-3-(3-m eth ylbu tyl)gu a n id in o)p h en yl)-
6-(3-p yr id yl)h ex-5-en oic Acid (31). Preparation was per-
formed according to 29. Purification was effected by column
chromatography with CH2Cl2/EtOH 15:1 and by subsequent
recrystallization from EtOAc/TBME; yield 71%: 1H NMR
(CDCl3) 0.9 (d, 6H), 1.45 (q, 2H), 1.6 (sep, 1H), 1.85 (m, 2H),
2.25 (m, 2H), 2.4 (m, 2H), 3.35 (m, 2H), 5.45 (t, 1H), 6.1 (t,
1H), 6.9 (d, 1H), 7.0 (s, 1H), 7.15-7.45 (m, 4H), 7.6 (dd, 1H),
8.45 (s, 1H), 8.5 (m, 2H); IR (KBr) 2170 (CN) cm-1. Anal.
(C24H29N5O2) C, H, N.
5E-6-(3-(2-Cya n o-3-ter t-bu tyl-gu a n id in o)p h en yl)-6-(3-
p yr id yl)h ex-5-en oic a cid (32) a n d 5Z-6-(3-(2-Cya n o-3-ter t-
bu tyl-gu a n id in o)p h en yl)-6-(3-p yr id yl)h ex-5-en oic a cid
(53). Preparation was performed according to 29. Purification
was effected by recrystallization from EtOAc/diisopropyl ether;
yield 45%: 1H NMR (DMSO-d6) 1.3 (s, 9H), 1.65 (q, 2H), 2.2
(m, 4H), 6.2 (t, 1H), 6.85 (m, 3H), 7.1 (d, 1H), 7.25-7.4 (dd +
t, 2H), 7.6 (dt, 1H), 8.45 (m, 2H), 9.0 (s, 1H), 12.0 (s, 1H); IR
(KBr) 2160 (CN) cm-1. Anal. (C23H27N5O2) C, H, N.
Met h yl 5E-6-(3-(2,3-d ioxo-4-et h oxy-cyclob u t -4-en yl)-
a m in op h en yl)-6-(3-p yr id yl)-h ex-5-en oa te (25). Compounds
i
8 (3 g, 10 mmol) and 24 (1.7 g, 10 mmol) in PrOH (50 mL)
were stirred for 20 h at 25 °C. The reaction mixture was
concentrated, and the residue was purified by column chro-
matography with CH2Cl2/EtOH 20:1 to yield 3.3 g (78%) of 25
as a viscous oil: 1H NMR (CDCl3) 1.4 (t, 3H), 1.8 (q, 2H), 2.15-
2.4 (m, 4H), 3.65 (s, 3H), 4.8 (q, 2H), 6.1 (t, 1H), 6.9 (m, 1H),
7.1-7.4 (m, 4H), 7.5 (dt, 1H), 8.2 (bs, 1H), 8.5 (m, 2H); IR (CH2-
Cl2) 1810, 1745 (CdO) cm-1. Anal. (C24H24N2O5) C, H, N.
5E-6-(3-Cyan ogu an idin o)ph en yl-6-(3-pyr idyl)h ex-5-en o-
ic Acid (26). Compound 10 (2.2 g, 5 mmol) and (NH4)2CO3
(4.8 g, 50 mmol) were dissolved in MeOH (40 mL) and stirred
at 20 °C for 48 h. The reaction mixture was concentrated, and
the residue was dissolved in water. The aqueous phase was
extracted, with EtOAc. The organic phase was evaporated and
i
the residue was dissolved in PrOH (20 mL) and 5M NaOH (5
The mother liquid was concentrated and the residue was
twice chromatographed on silica gel with EtOAc/CH2Cl2/acetic
acid 55:45:5. The faster running fractions were collected and
evaporated, the residue was taken up in a minimum of EtOAc,
and the Z-isomer 53 was precipitated by addition of diethyl
ether; yield 3%: 1H NMR (DMSO-d6) 1.25 (s, 9H), 1.65 (q, 2H),
2.05 (q, 2H), 2.2 (t, 2H), 3.2 (m, 2H), 6.2 (t, 1H), 6.65 (s, 1H),
6.85 (s, 1H), 7.0 (t, 2H), 7.25 (t, 1H), 7.45 (dd, 1H), 7.6 (dt,
1H), 8.35 (d, 1H), 8.55 (dd, 1H), 8.9 (s, 1H), 12.0 (s, 1H); IR
(KBr) 2170 (CN) cm-1. Anal. (C23H27N5O2) C, H, N.
mL). The solution was heated to 50 °C for 0.5 h and concen-
trated, and the residue was taken up in water. The aqueous
phase was extracted with EtOAc and acidified by addition of
citric acid, and the precipitate was filtered with suction.
Purification was effected by column chromatography on silica
gel using CH2Cl2/EtOH 9:1 followed by recrystallization from
iPrOH/EtOAc; yield 0.68 g (38%): 1H NMR (DMSO-d6) 1.7 (q,
2H), 2.2 (m, 4H), 6.2 (t, 1H), 6.85 (m, 1H), 7.0 (s, 2H), 7.1 (s,
1H), 7.35 (m, 3H), 7.55 (dt, 1H), 8.45 (m, 2H), 9.1 (s, 1H), 12.0
(s, 1H); IR (KBr) 2200 (CN) cm-1. Anal. (C19H19N5O2) C, H, N.
5E-6-(3-(2-Cya n o-3-cyclop r op yl-gu a n id in o)p h en yl)-6-
(3-p yr id yl)h ex-5-en oic Acid (33). Preparation was per-
formed according to 29. Purification was effected by recrys-
tallization from water/iPrOH; yield 46%: 1H NMR (DMSO-
d6) 0.6 (m, 2H), 0.75 (m, 2H), 1.7 (q, 2H), 2.2 (m, 4H), 2.65 (m,
1H), 6.2 (t, 1H), 6.9 (m, 1H), 7.1 (d, 1H), 7.25-7.4 (m, 3H), 7.6
(dd, 1H), 7.65 (s, 1H), 8.45 (m, 2H), 8.85 (s, 1H), 12.0 (s, 1H);
IR (KBr) 2170 (CN) cm-1. Anal. (C22H23N5O2) C, H, N.
5E-6-(4-(2-Cya n o-3-cyclop r op yl-gu a n id in o)p h en yl)-6-
(3-p yr id yl)h ex-5-en oic Acid (34). Preparation was per-
formed according to 29 starting from 13. Purification was
effected by recrystallization from EtOAc/iPrOH; yield 28%: 1H
NMR (DMSO-d6) 0.65 (m, 2H), 0.8 (m, 2H), 1.7 (q, 2H), 2.2
(m, 4H), 2.7 (m, 1H), 6.2 (t, 1H), 7.1 (d,2H), 7.25-7.45 (m, 3H),
7.55 (dd, 1H), 7.8 (d, 1H), 8.45 (m, 2H), 8.9 (s, 1H), 12.0 (s,
1H); IR (KBr) 2170 (CN) cm-1. Anal. (C22H23N5O2) C, H, N.
5E-6-(3-(2-Cya n o-3-cyclop en t yl-gu a n id in o)p h en yl)-6-
(3-p yr id yl)h ex-5-en oic Acid (35). Preparation was per-
formed according to 29. Purification was effected by recrys-
tallization from EtOAc/diethyl ether; yield 66%: 1H NMR
(DMSO-d6) 1.4-2.0 (m, 10H), 2.2 (m, 4H), 4.1 (m, 1H), 6.2 (t,
1H), 6.9 (d, 1H), 7.0 (s, 1H), 7.2-7.4 (m, 4H), 7.6 (dd, 1H),
8.45 (m, 2H), 8.95 (s, 1H), 12.0 (s, 1H); IR (KBr) 2180 (CN)
cm-1. Anal. (C24H27N5O2) C, H, N.
5E-6-(3-(2-Cya n o-3-m eth yl)gu a n id in o)p h en yl)-6-(3-p y-
r id yl)h ex-5-en oic a cid (27). Compound 10 (2.2 g, 5 mmol)
and methylamine (2 mL, 50 mmol) in PrOH (20 mL) were
i
heated in a sealed tube to 50 °C for 5 h. The workup was
performed according to 26. Purification on silica gel with CH2-
Cl2/EtOH 15:1 and subsequent recrystallization from EtOAc/
IPrOH yielded 0.9 g (49%) of 27: 1H NMR (DMSO-d6) 1.7 (q,
2H), 2.2 (m, 4H), 2.8 (d, 3H) 6.2 (t, 1H), 6.9 (dd, 1H), 7.05 (s,
1H), 7.2-7.4 (m, 3H), 7.6 (dt, 1H), 8.45 (m, 2H), 8.9 (s, 1H),
12.0 (s, 1H); IR (KBr) 2180 (CN) cm-1. Anal. (C20H21N5O2) C,
H, N.
5E-6-(3-(2-Cya n o-3,3-d im eth yl)gu a n id in o)p h en yl)-6-(3-
p yr id yl)h ex-5-en oic a cid (28). Preparation was performed
according to 27 starting from 10 (1.45 g, 3.3 mmol) and
dimethylamine (3 g, 70 mmol). Purification on silica gel with
CH2Cl2/EtOH 9:1 and subsequent recrystallization from EtOAc/
diisopropyl ether yielded 0.3 g (24%) of 28: 1H NMR (DMSO-
d6) 1.7 (q, 2H), 2.2 (m, 4H), 3.0 (s, 6H), 6.2 (t, 1H), 6.8 (m, 2H),
7.05 (s, 1H), 7.2-7.4 (m, 2H), 7.6 (dt, 1H), 8.45 (m, 2H), 9.15
(s, 1H), 12.0 (s, 1H); IR (KBr) 2160 (CN) cm-1. Anal.
(C21H23N5O2) C, H, N.
5E-6-(3-(2-Cya n o-3-isop r op yl)gu a n id in o)p h en yl)-6-(3-
p yr id yl)h ex-5-en oic a cid (29). Compound 10 (1.85 g, 4.2
i
mmol) and isopropylamine (2 mL, 23 mmol) in PrOH (30 mL)
were refluxed for 0.5 h. The reaction mixture was chilled to
25 °C, 2 M NaOH (4 mL) was added, and the solution was
stirred at 25 °C for 4 h. The mixture was concentrated, and
the residue was taken up in water (50 mL) and acidified by
addition of citric acid. The precipitate was filtered with suction
and recrystallized from EtOH/EtOAc to yield 0.83 g (50%) of
5E-6-(3-(2-Cya n o-3-cycloh exyl-gu a n id in o)p h en yl)-6-(3-
p yr id yl)h ex-5-en oic Acid (36). Preparation was performed
according to 29. Purification was effected by recrystallization
from EtOAc/diethyl ether; yield 62%: 1H NMR (DMSO-d6)
1.1-1.4 (m, 6H), 1.5-1.9 (m, 7H), 2.2 (m, 4H), 3.6 (m, 1H),
6.2 (t, 1H), 6.9 (d, 1H), 7.0 (s, 1H), 7.1 (d, 1H), 7.2-7.4 (m,

Thromboxane A2 Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1245
3H), 7.6 (dd, 1H), 8.45 (m, 2H), 9.0 (s, 1H), 12.0 (s, 1H); IR
(KBr) 2180 (CN) cm-1. Anal. (C25H29N5O2) C, H, N.
(DMSO-d6 + CD3OD) 1.4-1.75 (m, 8H), 1.75-2.2 (m, 6H), 4.1
(m, 1H), 6.2 (t, 1H), 6.9 (d, 1H), 7.0 (s, 1H), 7.1 (d, 1H), 7.25-
7.4 (m, 2H), 7.6 (dt, 1H), 8.45 (m, 2H). Anal. (C23H28N4O2) C,
H, N.
5E-6-(4-(2-Cya n o-3-cycloh exyl-gu a n id in o)p h en yl)-6-(3-
p yr id yl)h ex-5-en oic Acid (37). Preparation was performed
according to 29 starting from 13. Purification was effected by
recrystallization from EtOAc/iPrOH; yield 39%: 1H NMR
(DMSO-d6) 1.1-1.4 (m, 5H), 1.5-1.95 (m, 7H), 2.2 (m, 4H),
3.65 (m, 1H), 6.2 (t, 1H), 7.05-7.2 (m, 3H), 7.25-7.4 (m, 3H),
7.6 (dd, 1H), 8.4 (m, 2H), 9.0 (s, 1H), 12.0 (s, 1H); IR (KBr)
2160 (CN) cm-1. Anal. (C25H29N5O2) C, H, N.
5E-6-(3-(2-Ca r b a m oyl-3-(2-m et h ylp r op yl)gu a n id in o)-
p h en yl)-6-(3-p yr id yl)h ex-5-en oic a cid (45). Compound 30
(1.34 g, 3.3 mmol) was stirred in 4 M HCl (50 mL) for 48 h at
25 °C. The solution was buffered to pH 5-6 by addition of
NaOAc and extracted with EtOAc (3×). The organic phase was
concentrated, and the residue was purified by column chro-
matography on silica gel with CH2Cl2/EtOH 19:1 to yield 0.76
g (54%) of 45 as a foam: 1H NMR (CDCl3) 0.75 (d, 6H), 1.8
(m, 3H), 2.1-2.4 (m, 4H), 2.8 (bs, 2H), 3.35 (q, 2H), 6.2 (t, 1H),
7.0 (d, 1H), 7.1 (m, 2H), 7.2 (m, 1H), 7.4 (dd, 1H), 7.5 (dt, 1H),
8.45 (m, 2H), 8.9 (bs,2H). Anal. (C23H29N5O3) C, H, N.
5E-6-(3-(2-Cya n o-3-(1-a d a m a n tyl)gu a n id in o)p h en yl)-6-
(3-p yr id yl)h ex-5-en oic Acid (38). Preparation was per-
formed according to 29. Purification was effected by recrys-
i
tallization from PrOH/water; yield 64%: 1H NMR (DMSO-
d6) 1.5-1.75 (m, 8H), 1.85-2.1 (m, 9H), 2.2 (m, 4H), 6.2 (t,
1H), 6.7 (s, 1H), 6.85 (m, 2H), 7.1 (d, 1H), 7.25-7.4 (m, 2H),
7.6 (dd, 1H), 8.45 (m, 2H), 9.05 (s, 1H), 12.0 (s, 1H); IR (KBr)
2180 (CN) cm-1. Anal. (C29H33N5O2) C, H, N.
5E-6-(3-(2-Cya n o-3-b en zylgu a n id in o)p h en yl)-6-(3-p y-
r id yl)h ex-5-en oic Acid (39). Preparation was performed
according to 29. Purification was effected by column chroma-
tography with CH2Cl2/EtOH 15:1 and by subsequent recrys-
tallization from EtOAc/TBME; yield 53%: 1H NMR (DMSO-
d6) 1.65 (q, 2H), 2.2 (m, 4H), 4.4 (d, 2H), 6.2 (t, 1H), 6.9 (d,
1H), 7.0 (d, 1H), 7.2-7.45 (m, 8H), 7.6 (dd, 1H), 7.8 (t, 1H),
8.45 (m, 2H), 9.15 (s, 1H), 12.0 (s, 1H); IR (KBr) 2160 (CN)
cm-1. Anal. (C26H25N5O2) C, H, N.
5E-6-(3-(2-Cyan o-3-(3-pyr idylm eth yl)gu an idin o)ph en yl)-
6-(3-p yr id yl)h ex-5-en oic Acid (40). Preparation was per-
formed according to 29. Purification was effected by recrys-
tallization from EtOAc/diisopropyl ether; yield 73%: 1H NMR
(DMSO-d6) 1.65 (q, 2H), 2.2 (m, 4H), 4.4 (d, 2H), 6.2 (t, 1H),
6.95 (m, 2H), 7.2-7.45 (m, 4H), 7.55-7.85 (m, 3H), 8.45 (m,
4H), 9.25 (s, 1H), 12.0 (s, 1H); IR (KBr) 2190 (CN) cm-1. Anal.
(C25H24N6O2‚0.5H2O) C, H, N.
5E-6-(3-(2-Ben zoyl-3-cyclop r op yl-gu a n id in o)p h en yl)-6-
(3-p yr id yl)h ex-5-en oic Acid (46). Preparation was per-
formed according to 29 starting from 15 and cyclopentylamine.
Recrystallization from EtOAc/iPrOH yields 46 in 76%: 1H
NMR (DMSO-d6) 0.9-1.3 (m, 8H), 1.95-2.25 (m, 6H), 4.3 (m,
1H), 6.25 (t, 1H), 6.95 (d, 1H), 7.2-7.65 (m, 8H), 7.95 (d, 2H),
8.45 (m, 2H), 10.75 (bs, 1H), 12.0 (bs, 1H). Anal. (C30H32N4O3)
C, H, N.
5E -6-(3-(3-t er t -Bu t yl-2-m e t h ylsu lfon yl-gu a n id in o)-
p h en yl)-6-(3-p yr id yl)h ex-5-en oic Acid (47). The prepara-
tion was performed according to 29 starting from 20 and tert-
butylamine. Purification was effected by recrystallization from
EtOAc/diisopropyl ether; yield 85%: 1H NMR (CDCl3) 1.35 (s,
9H), 1.85 (q, 2H), 2.2 (q, 2H), 2.35 (t, 2H), 3.05 (s, 3H), 4.8 (s,
1H), 6.15 (t, 1H), 7.0-7.25 (m, 4H), 7.45 (m, 2H), 8.5 (m, 2H),
8.6 (s, 1H). Anal. (C23H30N4O4S) C, H, N, S.
5E -6-(3-(3-t er t -Bu t yl-2-p h e n ylsu lfon yl-gu a n id in o)-
p h en yl)-6-(3-p yr id yl)h ex-5-en oic Acid (48). The prepara-
tion was performed according to 29 starting from 21 and tert-
butylamine. Purification was effected by column chromatog-
raphy with CH2Cl2/EtOH 30:1; yield 73%: 1H NMR (CDCl3)
1.3 (s, 9H), 1.85 (q, 2H), 2.2 (q, 2H), 2.35 (t,2H), 4.85 (bs, 1H),
6.15 (t, 1H), 6.9 (s, 1H), 7.1 (m, 2H), 7.2 (m, 1H), 7.35-7.5 (m,
5E-6-(3-(2-Cya n o-3-(2-d im eth yla m in oeth yl)gu a n id in o)-
p h en yl)-6-(3-p yr id yl)h ex-5-en oic Acid (41). Preparation
was performed according to 29. Purification was effected by
column chromatography with CH2Cl2/MeOH 9:1; yield 73%:
1H NMR (DMSO-d6) 1.65 (q, 2H), 2.1-2.3 (s + m, 10 H), 2.5
(m, 2H + DMSO), 3.35 (q, 2H), 6.2 (t, 1H), 6.9 (d, 1H), 7.1 (s,
1H), 7.2-7.4 (m, 4H), 7.6 (dt, 1H), 8.45 (m, 2H), 10.1 (s, 1H);
IR (KBr) 2180 (CN) cm-1. Anal. (C23H28N6O2‚H2O) C, H, N.
5E-6-3-(ter t-Bu tyla m in o-ca r bon yla m in o)p h en yl)-6-(3-
p yr id yl)h ex-5-en oic Acid (42). Compound 8 (2.4 g, 8 mmol),
tert-butylisocyanate (1 g, 10 mmol) and DMAP (50 mg) were
refluxed in a mixture of THF (30 mL) and DMF (3 mL) for 12
h. The reaction mixture was poured on water (50 mL) and then
extracted with EtOAc. The organic phase was concentrated,
and the residue was stirred in EtOH (20 mL) and 2 N NaOH
(7 mL) for 2 h at 40 °C. The solution was acidified with citric
acid, and the precipitate was filtered with suction. Purification
was performed by column chromatography on silica gel with
CH2Cl2/EtOH 15:1 followed by recrystallization from EtOAc/
diisopropyl ether; yield 1.6 g (52%): 1H NMR (DMSO-d6) 1.25
(s, 9H), 1.65 (q, 2H), 2.05-2.4 (m, 4H), 5.9 (s, 1H), 6.2 (t, 1H),
6.7 (m, 1H), 7.15 (s, 1H), 7.25-7.4 (m, 3H), 7.55 (dt, 1H), 8.3
5H), 7.95 (m, 2H), 8.5 (bs, 2H), 8.85 (bs, 1H); Anal. (C28H32
N4O4S) C, H, N, S.
-
5E-6-(3-(2-(3-(2-Meth ylp r op yl)-2-(tetr a zol-5-yl)gu a n id i-
n o)p h en yl)-6-(3-p yr id yl)-h ex-5-en oic Acid (49). Compound
30 (1.72 g, 4.2 mmol) and tributyltin azide (2.13 g, 6.4 mmol)
were refluxed in toluene (50 mL) for 4 h. The reaction mixture
was concentrated and the residue was purified by column
chromatography with CH2Cl2/EtOH 19:1 + 2% acetic acid and
by subsequent recrystallization from EtOAc to yield 1.21 g
(64%) of 49: 1H NMR (DMSO-d6) 0.95 (d, 6H), 1.7 (q, 2H), 1.9
(m, 1H), 2.2 (m, 4H), 3.3 (t, 2H), 6.2 (t, 1H), 6.9 (d, 1H), 7.1 (s,
1H), 7.3-7.45 (m, 2H), 7.6 (m, 2H), 8.3 (bs, 2H), 8.45 (m, 2H),
8.9 (bs, 1H). Anal. (C23H28N8O2) C, H, N.
5E-6-(3-(1-Cycloh exyla m in o-2-n it r o-et h ylen a m in o)-
p h en yl)-6-(3-p yr id yl)h ex-5-en oic Acid (50). The prepara-
tion was performed according to 29 starting from 17 and
cyclohexylamine. Purification was effected by recrystallization
from EtOAc/iPrOH; yield 55%: 1H NMR (DMSO-d6) 1.1-1.5
(m, 5H), 1.5-1.8 (m, 5H), 1.9 (m, 2H), 2.05-2.3 (m, 4H), 3.75
(m, 1H), 6.2 (s, 1H), 6.25 (t, 1H), 7.0 (s, 1H), 7.1 (d, 1H), 7.2-
7.4 (m, 2H), 7.45-7.6 (m, 2H), 8.45 (m, 2H), 10.1 (bs, 1H), 12.0
(bs, 1H). Anal. (C25H30N4O4) C, H, N.
(s, 1H), 8.45 (m, 2H), 12.0 (s, 1H); IR (KBr) 1695 (CdO) cm-1
.
Anal. (C22H27N3O3) C, H, N.
5E-6-3-(ter t-Bu tyla m in o-th ioca r bon yla m in o)p h en yl)-
6-(3-p yr id yl)h ex-5-en oic Acid (43). Preparation was per-
formed according to 42 starting from 8 (2.4 g, 8 mmol) and
tert-butylisothiocyanate (1.15 g, 10 mmol). The reaction time
was prolonged to 44 h. Recrystallization from EtOAc/TBME
yields 0.33 g (10%): 1H NMR (DMSO-d6) 1.45 (s, 9H), 1.65 (q,
2H), 2.05-2.3 (m, 4H), 6.2 (t, 1H), 6.85 (d, 1H), 7.25-7.5 (m,
5E-6-(3-(2,2-Dicya n o-1-ter t-bu tyla m in o-eth ylen a m in o)-
p h en yl)-6-(3-p yr id yl)h ex-5-en oic Acid (51). Compound 23
(2.1 g, 5 mmol) was dissolved in CH2Cl2 (100 mL), and mCPBA
(50%) (1.9 g, 6 mmol) was added in portions over a period of
1.5 h at 25 °C. tert-Butylamine (10 mL, 95 mmol) was added,
and the solution was stirred for 12 h at 25 °C. The reaction
mixture was washed with water, dried, and concentrated. The
saponification of the methyl ester was performed according to
29. Purification was effected by column chromatography with
CH2Cl2/EtOH 20:1 followed by recrystallization from EtOAc/
diisopropyl ether; yield 43%: 1H NMR (DMSO-d6) 1.35 (s, 9H),
1.65 (q, 2H), 2.2 (m, 4H), 6.25 (t, 1H), 6.9 (m, 2H), 7.1 (d, 1H),
7.25-7.45 (m, 2H), 7.55 (s, 1H), 7.6 (dt, 1H), 8.45 (m, 2H), 8.7
4H), 7.55 (dt, 1H), 8.45 (m, 2H), 9.35 (s, 1H). Anal. (C22H27
N3O2S) C, H, N, S.
-
5E-6-(3-(3-Cyclop en tylgu a n id in o)p h en yl)-6-(3-p yr id yl-
)h ex-5-en oic Acid (44). Compound 46 (1 g,2 mmol) was
heated in 2 M HCl (20 mL) for 48 h at 95 °C. The reaction
mixture was first neutralized with NH3, and then the pH value
was adjusted to 5 by addition of citric acid. The crystals formed
were filtered with suction to yield 0.5 g (63%) of 44: 1H NMR

1246 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7
Soyka et al.
(s, 1H), 12.0 (s, 1H); IR (KBr) 2205, 2180 (CN) cm-1. Anal.
(C25H27N5O2) C, H, N.
(m, 2H), 8.6 (s, 1H); IR (KBr) 2160 (CN) cm-1. Anal.
(C25H31N5O2) C, H, N.
5E-6-(3-(4-ter t-Bu t yl-2,3-d ioxo-4-cyclob u t -1-en yl)a m i-
n op h en yl)-6-(3-p yr id yl)h ex-5-en oic Acid (52). Compound
25 (3.0 g, 7 mmol) and tert-butylamine (2 mL, 19 mmol) in
iPrOH (50 mL) were stirred for 48 h at 25 °C. The solution
was concentrated and the residue was chromatographed on
silica gel with CH2Cl2/EtOH 25:1 to yield 2.38 g of the methyl
ester (mp 154-155 °C). The saponification of the methyl ester
was performed according to 29. Purification was effected by
column chromatography with CH2Cl2/EtOH 15:1 followed by
recrystallization from EtOAc/diisopropyl ether, yield 60%: 1H
NMR (DMSO-d6) 1.4 (s, 9H), 1.7 (q, 2H), 2.2 (m, 4H), 6.2 (t,
1H), 6.8 (d, 1H), 7.1 (s, 1H), 7.25-7.45 (dd + t, 2H), 7.55 (m,
2H), 7.85 (s, 1H), 8.45 (m, 2H), 9.8 (s, 1H), 12.0 (s, 1H); IR
(KBr) 1790 (CdO) cm-1. Anal. (C25H27N3O4) C, H, N.
4E/Z-5-(3-Acetyla m in op h en yl)-5-(3-p yr id yl)p en t-4-en o-
ic Acid (55). The preparation was performed using the same
protocol as for compound 12 starting from 54 and 3-carbox-
ypropyl-triphenylphosphonium bromide; yield 74% (viscous
oil): 1H NMR (CDCl3 + CD3OD) 2.15 (s, 3H), 2.4 (m, 4H), 6.15
(dt, 1H), 6.9 (d, 1H), 7.2-7.5 (m, 5H), 8.4 (m, 2H). Anal.
(C18H18N2O3) C, H, N.
6E-7-(3-Acet yla m in op h en yl)-7-(3-p yr id yl)h ep t -6-en o-
ic Acid (56). The preparation was performed using the same
protocol as for compound 12 starting from 54 and 5-carboxy-
pentyl-triphenylphosphonium bromide; yield 72% (viscous
oil): 1H NMR (CDCl3 + CD3OD) 1.4-1.7 (m, 4H), 2.15 (s, 3H),
2.4 (m, 4H), 6.15 (t, 1H), 6.85 (d, 1H), 7.2-7.5 (m, 5H), 8.4 (m,
2H). Anal. (C20H22N2O3) C, H, N.
7E-8-(3-Acet yla m in op h en yl)-8-(3-p yr id yl)oct -7-en oic
a cid (57). The preparation was performed using the same
protocol as for compound 12 starting from 54 and 6-carboxy-
hexyl-triphenylphosphonium bromide; yield 69%, mp 149-151
°C: 1H NMR (DMSO-d6) 1.2-1.5 (m, 6H), 2.05 (s, 3H), 2.15
(m, 4H), 6.2 (t, 1H), 6.85 (d, 1H), 7.25-7.4 (m, 3H), 7.5-7.6
(m, 2H), 8.45 (m, 2H), 9.9 (s, 1H), 12.0 (s, 1H). Anal.
(C21H24N2O3) C, H, N.
(3-Nit r op h en yl)-(3-p yr id yl)-k et oxim e (62). Compound
61 (26.5 g, 116 mmol) and NH2OH‚HCl (10.42 g, 115 mmol)
were refluxed for 2 h in a mixture of EtOH (200 mL) and
pyridine (50 mL). The reaction mixture was evaporated, and
the residue was suspended in EtOH/water and adjusted to pH
4-5 by addition of formic acid. The precipitate was filtered
with suction, washed with water, and dried at 60 °C to yield
24.6 g (87%) of 62 as an E/Z-mixture (1:1): 1H NMR (DMSO-
d6) 7.45 + 7.55 (m, 1H), 7.65-7.85 (m, 3H), 8.2-8.4 (m, 2H),
8.55-8.7 (m, 2H), 12.05 (s, 1H); IR (KBr) 1350, 1530 (NO2)
cm-1. Anal. (C12H9N3O3) C, H, N.
O-(4-Eth oxycar bon ylbu tyl)-(3-n itr oph en yl)-(3-pyr idyl)-
k etoxim e (63). Compound 62 (24.7 g, 100 mmol) was dis-
solved in DMF (200 mL), and KOtBu (12.6 g, 110 mmol) was
added followed by ethyl 5-bromopentanoate (22.4 g, 107 mmol).
The mixture was stirred for 0.5 h at 25 °C. The solvent was
evaporated, and the residue was taken up in water and
extracted with CH2Cl2. The organic phase was concentrated,
and the residue was purified by column chromatography with
cyclohexane/EtOAc 1:1 to yield 31.9 g (85%) of 63 (viscous oil)
as an E/Z-mixture: 1H NMR (CDCl3) 1.25 (t, 3H), 1.7 (m, 4H),
2.3 (m, 2H), 4.1 (q, 2H), 4.25 (m, 2H), 7.3 + 7.45 (m, 1H), 7.5-
7.8 (m, 3H), 8.2-8.4 (m, 2H), 8.6-8.75 (m, 2H); IR (KBr) 1730
(CdO), 1350, 1530 (NO2) cm-1. Anal. (C19H21N3O5) C, H, N.
E-O-(4-Eth oxyca r bon ylbu tyl)-(3-(2-cya n o-3-ter t-bu tyl-
gu a n id in o)p h en yl)-(3-p yr id yl)k etoxim e (64) a n d Z-O-(4-
Eth oxycar bon ylbu tyl)-(3-(2-cyan o-3-ter t-bu tyl-gu an idin o)-
p h en yl)-(3-p yr id yl)k etoxim e (65). Compound 63 (18 g, 48
mmol) was hydrogenated at 25 °C in EtOH (200 mL) with
Raney-Ni (2 g) for 5 h at a pressure of 5 bar. The mixture was
filtered, concentrated, and purified by column chromatography
with 1,2-dichloroethane/EtOH 19:1 to yield 9 g. The residue
i
was reacted with 9 (6.35 g, 26 mmol) in PrOH (130 mL) for
12 h at 25 °C. The reaction mixture was filtered, and the
filtrate was concentrated and reacted with tert-butylamine (13
mL, 112 mmol) according to the procedure described for
compound 29. Separation of the isomers was performed by
column chromatography with CH2Cl2/EtOH 30:1. The faster
running fraction yields 0.79 g (7.5%) of 64 after recrystalliza-
tion from EtOAc/diisopropyl ether: 1H NMR (DMSO-d6) 1.3
(s, 9H), 1.5-1.7 (m, 4H), 2.25 (t, 2H), 4.15 (t, 2H), 6.9 (s, 1H),
7.05 (m, 2H), 7.2 (d, 1H), 7.4 (m, 2H), 7.8 (dt, 1H), 8.6 (m, 2H),
9.05 (s, 1H), 12.0 (s, 1H); IR (CH2Cl2) 2160 (CN) cm-1. Anal.
(C23H28N6O3) C, H, N.
The slower running fraction yields 1.2 g (11%) of 65 after
recrystallization from EtOAc/diisopropyl ether: 1H NMR
(DMSO-d6) 1.25 (s, 9H), 1.45-1.7 (m, 4H), 2.2 (t, 2H), 4.15 (t,
2H), 6.9 (s, 1H), 7.1-7.2 (m, 3H), 7.35 (t, 1H), 7.5 (dd, 1H),
7.75 (dt, 1H), 8.5 (d, 1H), 8.65 (dd, 1H), 9.1 (s, 1H), 12.0 (s,
1H); IR (KBr) 2180 (CN) cm-1. Anal. (C23H28N6O3) C, H, N.
(b) X-ray analysis. Compound 32 exists in form of a
polycrystalline powder and had to be recrystallized. After
preliminary solubility tests, attempts were made to carry out
crystallization in various organic solvents or solvent mixtures.
By far the best crystals were obtained by slow evaporation
(about 2-3 days) from an acetone/water mixture.
Crystallographic data: unit cell parameters a ) 17.058(9)
Å, R ) 90.0(-)°, b ) 19.713(4) Å, â ) 109.79(4)°, c ) 15.446(6)
Å, γ ) 90.0(-)°; formula C23H27N5O2‚0.5CH3COCH3; formula
weight 434.54 g/mol; formula units/cell 8; calculated density
1.181 g/cm3; space group monoclinic C2/c; radiation wavelength
1.5418 Å (Cu KR, Ni-filtered); number of independent reflec-
tions 3989; number of unobserved reflections (I < 26) 281; final
R value 5.9%. Method of data collection: STOE four-circle
diffractometer, ω-2Θ scan technique. Method of structure
solution: direct methods using SHELXS86 program.33 Method
of refinement: the structure was refined first with isotropic
and then with anisotropic temperature factors by the “least
squares” method (XTAL34) using unit weights. Statement of
features on the final Fourier map: no significant features.
(c) Bioch em istr y. Ma ter ia ls a n d Meth od s. SQ 29,548-
[5,6-3H(N)] (code NET-936), the 6-keto-PGF1R RIA kit (code
4E-5-(3-(2-Cya n o-3-ter t-bu tyl-gu a n id in o)p h en yl)-5-(3-
p yr id yl)p en t-4-en oic Acid (58). Compound 55 (4.5 g, 14.5
mmol) was stirred in MeOH (150 mL) and HCl in MeOH (7M,
20 mL) for 18 h at 25 °C. The mixture was concentrated, and
the residue was taken up in water, adjusted to pH 8 by
addition of NaHCO3, and extracted with EtOAc. The organic
i
was evaporated, and the residue was dissolved in PrOH. 9
(4.3 g, 18 mmol) was added and the mixture was stirred for
18 h at 25 °C, filtered, and concentrated. This raw material
was then reacted with tert-butylamine (3 mL, 26 mmol)
according to the protocol described for compound 29. Purifica-
tion was effected by column chromatography with CH2Cl2/
EtOH 20:1 and by subsequent recrystallization from EtOAc/
iPrOH; yield 0.48 g (17%): 1H NMR (DMSO-d6) 1.3 (s, 9H),
2.35 (m, 4H), 6.2 (t, 1H), 6.8-6.95 (m, 2H), 7.15 (d, 1H), 7.3-
7.45 (t + dd, 2H), 7.6 (dt, 1H), 8.4 (m, 2H), 9.05 (s, 1H), 12.1
(bs, 1H); IR (KBr) 2180 (CN) cm-1. Anal. (C22H25N5O2) C, H,
N.
6E-7-(3-(2-Cya n o-3-ter t-bu tyl-gu a n id in o)p h en yl)-7-(3-
p yr id yl)h ep t-6-en oic Acid (59). The preparation was per-
formed using the same protocol as for compound 58 starting
from 56. Purification was effected by column chromatography
with CH2Cl2/EtOH 15:1 and by subsequent recrystallization
from EtOAc/diisopropyl ether; yield 30%: 1H NMR (CDCl3) 1.4
(s, 9H), 1.6 (m, 4H), 2.1 (m, 2H), 2.35 (m, 2H), 5.1 (s, 1H), 6.2
(t, 1H), 6.95 (d, 1H), 7.2 (m, 3H), 7.4 (t, 1H), 7.55 (dt, 1H),
8.45 (m, 2H), 8.8 (s, 1H); IR (KBr) 2160 (CN) cm-1. Anal.
(C24H29N5O2) C, H, N.
7E-8-(3-(2-Cya n o-3-ter t-bu tyl-gu a n id in o)p h en yl)-8-(3-
p yr id yl)oct-7-en oic Acid (60). The preparation was per-
formed using the same protocol as for compound 58 starting
from 57. Purification was effected by column chromatography
with CH2Cl2/EtOH 15:1 and by subsequent recrystallization
from EtOAc; yield 29%: 1H NMR (CDCl3) 1.4 (s + m, 11H),
1.55 (m, 4H), 2.1 (m, 2H), 2.35 (m, 2H), 5.05 (s, 1H), 6.2 (t,
1H), 6.95 (d, 1H), 7.2 (m, 3H), 7.4 (t, 1H), 7.55 (dt, 1H), 8.45

Thromboxane A2 Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1247
NEK-008), cAMP-[2,8-3H] (code NET-275), and sucrose-[14C-
(U)] (code NEC-100) were purchased from New England
Nuclear (Dreieich, Germany). U 46,619 was purchased from
Sigma and Sepharose 2B from Pharmacia. Collagen and SKF
dilution buffer were obtained from Hormon-Chemie or Ny-
comed (Munich, FRG). All other chemicals were of the highest
purity commercially available. All experiments were performed
at least in duplicate.
the dose-response relationship, all three postadministration
periods were averaged.
A one-way analysis of variance was applied to test for group
differences using SYSTAT software.35 Barlett’s test was
performed to confirm homogeneity of the group variances prior
to applying the analysis of variance. When a group difference
was detected, post hoc testing to compare individual mean
values was performed using Tukey’s test for multiple paired
comparisons.36 A P-value less than 0.05 was assumed to
indicate a significant difference. The plotting of the dose-
response data and calculation of the value for a 50% effective
dose (ED50 or X50) was done using Biosoft Fig-P software
(Cambridge, United Kingdom).
Thromboxane receptor binding, thromboxane synthase in-
hibition, collagen-induced aggregation in human platelet-rich
plasma, and whole blood- as well as collagen-induced prosta-
cyclin production were determined according to ref 23.
(d ) P h a r m a cology. In h ibition of Recu r r en t Th r om bu s
F or m a tion in An esth etized Ra bbits. Twenty rabbits of
either sex between 2.9 and 3.7 kg (New Zealand White,
Boehringer Ingelheim Pharma KG, Biberach, Germany) were
studied while under general anesthesia produced with xylazine
hydrochloride and ketamine hydrochloride administered in-
travenously through an ear vein. The jugular vein was
cannulated for the administration of terbogrel. The carotid
artery was cannulated with a saline-filled polyethylene can-
nula through which arterial blood pressure was measured
using an external transducer. Through a midline abdominal
incision, the abdominal aorta was exposed by retracting the
gut. Distal to the branch point of the renal arteries, the
abdominal aorta was dissected free and a 2.0 mm diameter
Doppler flow probe was implanted around the vessel. Flow
velocity through the vessel was measured using a pulsed
Doppler flow system (Triton Technologies, San Diego).
P r otocol. Upon completion of the surgical preparation and
stabilization of the arterial blood pressure, the aorta was
compressed distal to the flow probe for 5 min using a hemostat.
The resultant clot was dislodged mechanically, and a constric-
tive device was placed at the site of the vascular injury caused
by the clamp. The constrictor was tightened to produce a flow-
limiting stenosis to stimulate local thrombus formation. Upon
placement of the constrictor, flow through the aorta then
decreased spontaneously and progressively to zero. When flow
reached zero, the thrombus was dislodged mechanically but
without removing or modifying the severity of the stenosis. A
new thrombus then followed spontaneously, resulting in
reproducible and repetitive occlusive arterial thrombus forma-
tion.
Ack n ow led gm en t. We thank Dr. Klaus Wagner for
1
the assignment of the geometrical isomers by H and
13C NMR spectroscopy and Prof. Axel Prox and his staff
for the analytical and spectral data. We are grateful to
Norbert Birk, Ludwig Gutschera, and Ulrich Mu¨ller for
their skillful technical assistance.
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