On the bioisosteric potential of diazines: Diazine analogues of the combined thromboxane A2 receptor antagonist and synthetase inhibitor ridogrel

Article abstract of DOI:10.1021/jm960341g

In this SAR study the bioisosteric potential of diazines in the field of combined antithrombotic thromboxane A₂ synthetase inhibitors and receptor antagonists was investigated. In this context, two series of (E)- and (Z)- ω-[[(aryldiazinylmethy

Full text of DOI:10.1021/jm960341g

4058
J . Med. Chem. 1996, 39, 4058-4064
On th e Bioisoster ic P oten tia l of Dia zin es: Dia zin e An a logu es of th e Com bin ed
Th r om boxa n e A2 Recep tor An ta gon ist a n d Syn th eta se In h ibitor Rid ogr el†
Gottfried Heinisch,*,‡ Wolfgang Holzer,§ Friedbert Kunz, Thierry Langer,‡ Peter Lukavsky,*,‡
Christoph Pechlaner, and Hans Weissenberger|
Institute of Pharmaceutical Chemistry, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria, Institute of
Pharmaceutical Chemistry, University of Vienna, Pharmaziezentrum, Althanstrasse 14, A-1090 Vienna, Austria,
University hospital for internal medicine, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria,
Department of Biochemistry, Dr. Karl Thomae GmbH, Birkendorfer Str. 65, D-88397 Biberach, Germany
Received May 7, 1996X
In this SAR study the bioisosteric potential of diazines in the field of combined antithrombotic
thromboxane A2 synthetase inhibitors and receptor antagonists was investigated. In this
context, two series of (E)- and (Z)-ω-[[(aryldiazinylmethylene)amino]oxy]alkanoic acids were
synthesized of which pentanoic acid derivatives with a 2-pyrazinyl, 4-pyridazinyl, or 5-pyrim-
idinyl group were found to exhibit this dual activity, while 4-pyrimidinyl as well as 3-pyridazinyl
analogues showed only receptor antagonistic activity and 2-pyrimidinyl congeners were inactive.
In the series of diazine analogues of Ridogrel (1), replacement of the 3-pyridyl group by a
2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl moiety led to compounds that inhibit thromboxane
A2 synthetase in gel-filtered human platelets comparable to 1 (IC50 of 0.006, 0.016, and 0.039
µM, respectively, versus 0.007 µM). Radioligand-binding studies with [3H]SQ 29,548 in washed
human platelets revealed that these diazine analogues block the thromboxane A2 receptor with
an IC50 of 11, 6.0, and 1.5 µM, respectively. This compares well with the IC50 ) 1.7 µM of 1.
Finally, testing of inhibition of collagen-induced platelet aggregation in human platelet-rich
plasma with 2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl congeners of Ridogrel indicated that
these heteroaromatic moieties may serve as bioisosteric substitutes of a 3-pyridyl group in
dual-acting antiplatelet agents.
One of the metabolic pathways of arachidonic acid is
initiated in human blood platelets by the enzyme
cyclooxygenase leading to the formation of an unstable
cyclic endoperoxide, prostaglandin H2 (PGH2). Once
produced inside platelets, PGH2 is converted by the
enzyme thromboxane synthetase (TxS) to thromboxane
A2 (TXA2),1 a potent vasoconstrictor and platelet-ag-
gregating agent. TXA2 migrates to the cell surface and
binds to the TXA2/prostaglandin endoperoxide receptor
(R-receptor2) thereby initiating a cascade of events that
leads to platelet aggregation.
F igu r e 1.
acting TxSI (IC50 ) 6 × 10-9M),6 but only a weakly
active TxRA (IC50 ) 1.7 × 10-6 M).7 During the last
decade, much effort has been devoted to structural
modifications within the class of combined TxSI/TxRA
with the objective to obtain antiplatelet agents exhibit-
ing both activities equipotently in a nanomolar or sub-
nanomolar range. A large number of these compounds
are derived from Ridogrel, thus containing a 3-pyridyl
system and a carboxyalkyl chain as characteristic
moieties (for a review see ref 8). For both TxSI and
TxRA activity, a distance of 8.5-10 Å between the
carbon atom of the carboxylic group and the sp2-
hybridized nitrogen atom of the pyridine ring is es-
sential.9
Many studies provide evidence that TXA2 is involved
in the pathogenesis of thrombotic/vasoocclusive dis-
orders.3 First attempts to interfere with the formation
and pathological action of TXA2 led to the development
of compounds inhibiting the key enzyme of TXA2 forma-
tion, namely TxS. However, most thromboxane syn-
thetase inhibitors (TxSI) proved to be poor antiplatelet
agents due to the fact that inhibition of TxS leads to an
accumulation of PGH2, which may also bind to the
TXA2/prostaglandin endoperoxide receptor mimicking
the prothrombotic effects of TXA2.3 This lack of efficacy
of TxSIs could be overcome by using them in combina-
tion with a TXA2 receptor antagonist (TxRA).4
Besides the large number of dual active 3-pyridyl
derivatives, only a few examples of combined TxSI/TxRA
containing other N-heteroaromatic rings are described
in the literature, e.g., as 1-imidazolyl-derived com-
pounds.10
One of the first antiplatelet agents identified and
developed as a combined TxSI and TxRA is Ridogrel (1,
Figure 1).5 It is a highly potent, selective, and long-
† Dedicated with best personal wishes to Prof. Dr. Ernst Mutschler
on the occasion of his 65th birthday.
In continuation of our ongoing investigations of the
bioisosteric potential of diazines, we now became inter-
ested in two series of diaza analogues of Ridogrel, both
derived from diazinyl phenyl ketones (2-7) or diazinyl
3-(trifluoromethyl)phenyl ketones (8-13) (see Figure 2).
‡ Institute of Pharmaceutical Chemistry, University of Innsbruck.
§ University of Vienna.
University hospital for internal medicine, University of Innsbruck.
| Dr. Karl Thomae GmbH.
X Abstract published in Advance ACS Abstracts, August 15, 1996.
S0022-2623(96)00341-X CCC: $12.00 © 1996 American Chemical Society

Bioisosteric Potential of Diazines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 4059
Ta ble 1. Physical and Biological Data of Compounds E-21a -f-23a -f and Z-21a -f-23a -fa
R
N
O(CH2)nCOOH
IC50 (µM)
TXA2
receptor
antagonism
TXA2
synthetase
inhibition
EC50 (µM) inhibition
of collagen- induced
platelet aggregation
synth
method
yield,
%
recryst
solvent
mp,
°C
compd
R
config
n
formula
E-21a 3-pyridb
Z-21a 3-pyrid
E-21b 4-pyrid
Z-21b 4-pyrid
E-21c 2-pyrime
Z-21c 2-pyrim
E-21d 4-pyrim
Z-21d 4-pyrim
E-21e 5-pyrim
Z-21e 5-pyrim
E-21f 2-pyrazg
Z-21f 2-pyraz
E-22a 3-pyrid
Z-22a 3-pyrid
E-22b 4-pyrid
Z-22b 4-pyrid
E-22c 2-pyrim
Z-22c 2-pyrim
E-22d 4-pyrim
Z-22d 4-pyrim
E-22e 5-pyrim
Z-22e 5-pyrim
E-22f 2-pyraz
Z-22f 2-pyraz
E-23a 3-pyrid
Z-23a 3-pyrid
E-23b 4-pyrid
Z-23b 4-pyrid
E-23c 2-pyrim
Z-23c 2-pyrim
E-23d 4-pyrim
Z-23d 4-pyrim
E-23e 5-pyrim
Z-23e 5-pyrim
E-23f 2-pyraz
Z-23f 2-pyraz
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
E
Z
3
3
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
5
5
A
A
A
A
A,B
B
A
A
A
A
A
A
A
A
A
A
A,B
B
A
A
A
A
A
A
A
A
A
A
A,B
B
A
A
A
A
A
70
75
65
76
81
82
76
79
75
75
76
73
77
79
69
94
80
75
92
43
80
72
77
94
87
80
90
90
81
79
73
77
18
73
51
53
DIPEc
108 C15H15N3O3
4% (273)
2% (273)
245
DIPE/EAd 114 C15H15N3O3
DIPE/EA
DIPE/EA
H2O
DIPE/EA
DIPE/EA
DIPE/PEf
DIPE/PE
DIPE
DIPE
DIPE
DIPE/EA
DIPE/EA
DIPE/EA
DIPE/EA
133
89
C
C
15H15N3O3
15H15N3O3
21% (273)
0% (273)
0% (273)
34% (273)
38% (273)
46% (273)
17% (273)
47% (273)
19% (273)
47% (278)
217
227
163
0% (273)
0% (273)
274
255
40% (278)
191
91
94
203
204
59
81
145 C15H15N3O3
126
135
C
C
15H15N3O3
15H15N3O3
107 C15H15N3O3
79
130
C
C
15H15N3O3
15H15N3O3
130 C15H15N3O3
87
C
C
C
C
C
15H15N3O3
16H17N3O3
16H17N3O3
16H17N3O3
16H17N3O3
149
103
94
104
71
33
>100.000
>100.000
0.260
72
13
8.800
H2O/EtOH 165 C16H17N3O3
DIPE
3%
15%
30
25
20
7.2
47
24
>100.000
>10.000
>100.000
>100.000
80
84
C
C
16H17N3O3
16H17N3O3
DIPE/EA
EAh
oili C16H17N3O3
DIPE/PE
DIPE
DIPE
94
86
73
71
103
102
103
73
C
C
C
C
C
C
C
C
16H17N3O3
16H17N3O3
16H17N3O3
16H17N3O3
17H19N3O3
17H19N3O3
17H19N3O3
17H19N3O3
0.075 ( 0.008
0.573 ( 0.21
0.079 ( 0.006
0.620
DIPE
DIPE/EA
DIPE/EA
DIPE/EA
DIPE/EA
H2O/EtOH 147 C17H19N3O3
DIPE
DIPE/EA
DIPE/EA
EAh
DIPE/PE
DIPE
7.1
7.7
3.800 ( 2.9
>10.000
0% (273)
0% (273)
112
90
104
62
C
C
C
17H19N3O3
17H19N3O3
17H19N3O3
5.0
25
>10.000
>10.000
236
oili C17H19N3O3
94
84
71
C17H19N3O3
8.8
>10.000
127
131
216
C
C
17H19N3O3
17H19N3O3
A
DIPE
a
d
For details, see the Experimental Section. b pyrid ) pyridazinyl. c DIPE ) diisopropyl ether. EA ) ethyl acetate. e pyrim ) pyrimidinyl.
f PE ) petroleum ether. pyraz ) pyrazinyl. Column chromatography. No satisfactory elemental analysis obtained.
g
h
i
their TxS inhibitory and TxR antagonistic activities, and
on their effect on human platelet aggregation.
Syn th esis
The compounds listed in Tables 1 and 2 were prepared
as depicted in Scheme 1; for the synthesis of the starting
aryl diazinyl ketones 2-13, see ref 11. In general,
preparation of the target (E)- and (Z)-ω-[[(aryldiazinyl-
methylene)amino]oxy]alkanoic acids 21-25 was carried
out starting from mixtures of (E)- and (Z)-aryl diazinyl
ketoximes 14 and 15 which were prepared by reaction
of ketones 2-13 with hydroxylamine according to ref
11. Alkylation of the oximes 14 and 15 with appropriate
ethyl ω-bromoalkanoates (Scheme 1) yielded mixtures
of (E)- and (Z)-ketoxime ethers 16a ,b, 17a ,b, 18a ,b ,
16d -f, 17d -f, 18d -f, 19b, 20b, 19d -f, and 20d -f
(method A). Chromatographic separation then led to
pure (E)- and (Z)-isomers which finally gave the target
free carboxylic acids 21a ,b, 22a ,b, 23a ,b, 21d -f, 22d -
f, 23d -f, 24b, 25b, 24d -f, and 25d -f in isomerically
pure form upon alkaline hydrolysis.
F igu r e 2.
Considering the different positions of the nitrogen atoms
in the diazine systems employed, we envisaged elonga-
tion and shortening, respectively, of the ω-carboxyalkyl
side chain by one methylene group compared to the lead
compound Ridogrel in order to obtain compounds cover-
ing the optimal distance range 8.5-10 Å between an
sp2-hybridized nitrogen atom of the diazine systems and
the carbon atom of the carboxylic group. Here we report
on the synthesis of these novel compounds (21-25), on

4060 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Heinisch et al.
Ta ble 2. Physical and Biological Data of Compounds E-24a -f-25a -f and Z-24a -f-25a -fa
CF3
R
N
O(CH2)nCOOH
IC50 (µM)
TXA2
receptor
antagonism
TXA2
synthetase
inhibition
EC50 (µM) inhibition
of collagen-induced
platelet aggregation
synth yield,
recryst
solvent
mp,
°C
compd
R
config
n
method
%
formula
E/Z-24a 3-pyridb
E/Zc
E
Z
E
Z
E
Z
E
Z
4
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
5
4
B
A
A
B
B
A
A
A
A
A
A
B
A
A
B
B
A
A
A
A
A
A
l
85
73
80
88
81
73
82
75
72
77
79
61
84
80
84
59
82
52
79
85
72
74
DIPEd/PEe 47
C17H16F3N3O3
10
>100.000
78
52
30
272
214
19
71
32
12
190
65
E-24b
Z-24b
E-24c
Z-24c
E-24d
Z-24d
E-24e
Z-24e
E-24f
Z-24f
4-pyrid
4-pyrid
2-pyrimf
2-pyrim
4-pyrim
4-pyrim
5-pyrim
5-pyrim
2-pyrazh
2-pyraz
DIPE
DIPE
99
98
C
C
17H16F3N3O3
17H16F3N3O3
6.0
1.8
99
0.016 ( 0.02
6.633 ( 0.09
DIPE/EAg 110 C17H16F3N3O3
>10.000
DIPE/PE
DIPE/PE
DIPE/PE
DIPE/PE
DIPE/PE
DIPE/PE
DIPE/PE
DIPE/PE
DIPE/EA
DIPE
79
89
49
78
87
68
67
40
C
C
C
C
C
17H16F3N3O3
17H16F3N3O3
17H16F3N3O3
17H16F3N3O3
17H16F3N3O3
52
>10.000
>10.000
>100.000
1.4
2.5
1.5
0.36
11
0.039 ( 0.03
6.100 ( 1.4
0.006 ( 0.002
2.900
E
Z
C17H16F3N3O3
17H16F3N3O3
C18H18F3N3O3
C
1.5
E/Z-25a 3-pyrid
E/Zi
E
241
186
26% (291)
291
E-25b
Z-25b
E-25c
Z-25c
E-25d
Z-25d
E-25e
Z-25e
E-25f
Z-25f
1
4-pyrid
4-pyrid
2-pyrim
2-pyrim
4-pyrim
4-pyrim
5-pyrim
5-pyrim
2-pyraz
2-pyraz
3-pyridyl
131
105
108
C
C
C
18H18F3N3O3
18H18F3N3O3
18H18F3N3O3
29
21
0.693 ( 0.18
>10.000
Z
E
Z
E
Z
E
Z
E
DIPE/EA
EAj
oilk C18H18F3N3O3
126 C18H18F3N3O3
oilk C18H18F3N3O3
DIPE/EA
EAj
1.1
>10.000
25
184
200
291
251
47% (291)
41
DIPE/EA
DIPE/PE
DIPE/PE
DIPE/PE
106
87
57
C
C
C
C
C
18H18F3N3O3
18H18F3N3O3
18H18F3N3O3
18H18F3N3O3
19H19F3N2O3
Z
E
61
1.7m
0.007 ( 0.002
a
b
d
For details, see the Experimental Section. pyrid ) pyridazinyl. c E/Z ratio ) 2:1. DIPE ) diisopropyl ether. e PE ) petroleum
ether. f pyrim ) pyrimidinyl. EA ) ethyl acetate. pyraz ) pyrazinyl. E/Z ratio ) 3:1. Column chromatography. No satisfactory
elemental analysis obtained. From J anssen. See ref 7.
g
h
i
j
k
l
m
Since pure (E)-ketoxime E-14c11 could be obtained
easily by fractional crystallization, pure (E)-ketoxime
ethers E-16c, E-17c, and E-18c became available by
alkylation of E-14c with the appropriate ethyl ω-bromo-
alkanoates. Alkaline hydrolysis finally gave isomeri-
cally pure acids E-21c, E-22c, and E-23c.
new compounds. A detailed presentation of these
spectroscopic investigations has been published re-
cently.13,14
Resu lts a n d Discu ssion
The compounds listed in Tables 1 and 2 were initially
tested for in vitro inhibition of collagen-induced platelet
aggregation in human platelet-rich plasma (PRP). The
most potent compounds out of this first test series, all
(E)- and (Z)-aza-Ridogrel derivatives 24 and congeners
thereof lacking of the trifluoromethyl group (22), were
further tested in the following two assays: (a) displace-
ment of the high-affinity radiolabeled ligand [3H]SQ
29,548 from the PGH2/TXA2 receptor on human gel-
filtered platelets and (b) inhibition of TXB2 formation
by human gel-filtered platelets incubated with [14C]-
arachidonic acid.
The test results are listed as IC50/EC50 values in
Tables 1 and 2. Formally, the six possible position
isomers of the three diazine rings can be divided into
two groups: the first group of ring systems repre-
sents “aza 3-pyridyl” moieties with an additional nitro-
gen atom in position 2 (3-pyridazinyl system), 4 (4-
pyridazinyl system), 5 (5-pyrimidinyl system), or 6 (2-
pyrazinyl system). The second group consists of two
ring systems, i.e., the 2-pyrimidinyl and the 4-pyrim-
idinyl system, which lack of a nitrogen atom in position
3 related to the oxime ether side chain.
For a more convenient synthesis of compounds 16c-
20c, 19a , and 20a ethyl ω-(aminooxy)alkanoates 29-
31 were reacted with ketones 4, 8, and 10. This
approach (method B) gave higher yields than the
reaction sequence according to method A. The required
educts 29-31 were prepared via a slight modification
of a two-step procedure previously described for the
preparation of ethyl (aminooxy)acetate12 consisting of
alkylation of N-hydroxyphthalimide with ethyl ω-bromo-
alkanoates and subsequent hydrazinolysis (Scheme 2).
Since 19a and 20a could not be separated by column
chromatography or crystallization, these esters were
hydrolyzed to give (E) and (Z) mixtures of the free
carboxylic acids 24a and 25a , the isomer ratio of which
1
was established by H-NMR spectroscopy.
The configuration of the target compounds 21-25 was
1
assigned mainly by H-NMR spectroscopy considering
the chemical shifts observed for the heteroaromatic
protons adjacent to the CN double bond.15 By compari-
son of these chemical shift patterns with those of the
corresponding (E)- and (Z)-ketoximes 14 and 15 (the
configurational assignment of which had been carried
out previously11 by homonuclear NOE difference spec-
troscopy as well as 13C-NMR spectroscopy), unequivocal
assignment of the stereochemistry was possible for all
Starting with the oxime ethers 21-23 derived from
the parent diazinyl phenyl ketones 2-7, we first exam-
ined the influence of the presence of different diazine

Bioisosteric Potential of Diazines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 4061
Sch em e 1a
position 2 (compounds 22a ) also leads to TxSI inactive
compounds. In contrast, formal incorporation of the
additional nitrogen atom into position 4 (4-pyridazinyl
derivative E-22b) results in a compound with slight
TxSI activity (IC50 of 260 nM). An additional nitrogen
atom in position 5 or 6 (5-pyrimidinyl or 2-pyrazinyl
derivatives) results in higher TxSI activity: the pen-
tanoic acid derivatives E-22e and E-22f inhibit TxS with
IC50 values of 75 and 79 nM, respectively. The (Z)-
isomers turned out to be much less potent. Thus, the
3-pyridyl moiety in Ridogrel-type compounds can be
replaced only by 4-pyridazinyl, 5-pyrimidinyl, or 2-pyraz-
inyl moieties without complete loss of TxSI activity. In
this series elongation of the side chain does not lead to
compounds with enhanced TxSI activity.
Tests of compounds 22a -f, 23b, 23d , and Z-23e with
regard to their thromboxane receptor antagonism gave
the following results: a 2-pyrimidinyl system is also
deleterious for TxRA activity, whereas the 4-pyrimi-
dinyl-derived acids 22d and 23d exhibit receptor an-
tagonistic activity in the range 5.0-30 µM. Employ-
ment of a “4-, 5-, or 6-aza-3-pyridyl” system is associated
with TxRA activity in a similar range (IC50 7.1-104
µM), while 3-pyridazinyl derived acids 22a exhibit only
low TxRA activity (IC50 71 and 104 µM, respectively).
It should be noted that the configuration at the CN
double bond does not influence TxRA activity as sig-
nificantly as observed in the assay for TxSI activity. Nor
did we find in this series marked differences in activity
between pentanoic and hexanoic acid derivatives.
a
Reagents and conditions: (a) see ref 11; (b) NaH, DMF,
In a further step of our study, we prepared and tested
compounds 24 and 25 as diazine analogues of Ridogrel.
Since we had found within the series of compounds 21-
23 that butanoic acids were more or less inactive as
inhibitors of human platelet aggregation, we now lim-
ited the variation of the length of the side chain to
pentanoic and hexanoic acid derivatives.
Br(CH2)3,4,5COOEt; (c) Na2CO3, CH3OH/H2O, HCl‚H2NO-
(CH2)3,4,5COOEt; (d) MPLC (eluent: CH2Cl2/CH3COOEt); (e) 1 N
NaOH, EtOH.
Sch em e 2a
Here, we observed structure-activity relationships
similar to those we had found within the series of
compounds 21-23: the 4-pyridazinyl analogue of
Ridogrel, E-24b exhibits comparable antiaggregatory
activity (EC50 ) 52 µM) since replacement of the
3-pyridyl moiety in 1 by the 4-pyridazinyl system does
not significantly affect both TxSI and TxRA activity. The
corresponding (Z)-isomer (Z-24b) is also active as an
antiplatelet compound, but its activity results mainly
from its micromolar TxRA activity (IC50 ) 1.8 µM), since
TxSI activity is strongly reduced due to (Z) configura-
tion. Elongation of the carboxyalkyl side chain by one
methylene group (E-25b and Z-25b) reduces both TxSI
and TxRA activity. The 3-pyridazinyl analogues E/Z-
24a which were tested as a 2:1 mixture of (E)- and (Z)-
isomers, exhibited no TxSI and low TxRA activity.
Replacement of the 3-pyridyl moiety in 1 by a 2-pyrim-
idinyl system is also deleterious for both activities and
results in a low antiplatelet activity. In contrast,
incorporation of a 4-pyrimidinyl system (E-24d and
Z-24d ) leads to a receptor antagonistic activity similar
to that of 1, which is not affected by elongation of the
side chain, but again no TxSI activity at all could be
detected. Like the 4-pyridazinyl analogues, also 5-py-
rimidinyl and 2-pyrazinyl congeners (E-24e and E-24f)
exhibit TxSI activity in the nanomolar range. Again,
TxSI activity is significantly reduced upon change from
(E) to (Z) configuration at the CN double bond, while
a
Reagents and conditions: (a) CH3COONa, DMSO, Br(CH2)3,4,5
-
COOEt, 50 °C; (b) N2H4‚H2O, EtOH, 70 °C; (c) ethereal HCl, 40
°C.
systems on platelet antiaggregatory activity. All aza
3-pyridyl pentanoic acid derivatives E-22a ,b,e,f inhibit
collagen-induced platelet aggregation with EC50 values
in the range ∼90-300 µM. In the second group, only
the 4-pyrimidinyl derivative E-22d exhibits platelet
antiaggregatory activity comparable to that of the
analogues of the first group. Butanoic acids 21 turned
out to be less potent while some hexanoic acids 23
showed higher antiplatelet activity (see Table 1). The
most potent representative within this series (EC50
)
59 µM) is compound E-23b. It is of interest to note that
similar trends with regard to the length of the side chain
and the nature of the diazine system are observed also
with (Z) configurated compounds Z-21, Z-22, and Z-23.
In order to gain insight into the bioisosteric potential
of the six isomeric diazine systems with regard to
thromboxane synthetase inhibition and receptor an-
tagonism, the appropriate assays with selected com-
pounds, as mentioned above, were performed. The 2-
or the 4-pyrimidinyl-derived compounds 22c and 22d
did not show any TxSI activity. Within the group of
aza-3-pyridyl analogues, the second nitrogen atom in

4062 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Heinisch et al.
EtOAc (ratio thus adjusted to result in Rf values of about 0.25
for the faster eluted component, i.e., the (Z)-isomer).
TxRA activity is 10-fold higher in (Z)-isomers. In fact,
the most potent TxRA in this series is the 5-pyrimidinyl
derived pentanoic acid Z-24e (IC50 ) 0.36 µM), but its
TxSI activity is in the mixeomolar range due to the (Z)
configuration. On the other hand, the most potent TxSI
of the Ridogrel analogues (IC50 ) 6.0 nM), the 2-pyraz-
inyl derivative E-24f, exhibits a 10-fold lower TxRA
activity compared to that of 1.
(Z)-Eth yl 4-[[[P h en yl(3-p yr id a zin yl)m eth ylen e]a m in o]-
oxy]bu ta n oa te (Z-16a ) a n d th e (E)-Isom er E-16a . Com-
pounds Z-16a and E-16a were prepared from 14a 11 and ethyl
4-bromobutanoate. Chromatographic separation by MPLC
afforded 430 mg (46%) of Z-16a (faster eluted component) and
310 mg (33%) of E-16a (slower eluted component).
Compound Z-16a was obtained as a yellowish oil: 1H NMR
(acetone-d6) δ (ppm) 9.26 (dd, J 4,6 ) 1.9 Hz, J 5,6 ) 4.8 Hz, 1H,
pyridazine H-6), 7.84 (dd, J 4,6 ) 1.9 Hz, J 4,5 ) 8.4 Hz, 1H,
pyridazine H-4), 7.80 (dd, J 5,6 ) 4.8 Hz, J 4,5 ) 8.4 Hz, 1H,
pyridazine H-5), 7.25-7.60 (m, 5H, Ph), 4.21 (t, 2H, OCH2),
4.05 (q, 2H, OCH2CH3), 2.34 (t, 2H, CH2CO), 1.97 (quint, 2H,
Con clu sion
On the basis the structure-activity relationships
observed in this study, it turned out that only the
2-pyrazinyl, 4-pyridazinyl, and 5-pyrimidinyl systems
are appropriate bioisosteric moieties for the 3-pyridyl
system in the dual active platelet antiaggregatory
compound Ridogrel. While 2-pyrimidinyl analogues
showed neither TxSI nor significant TxRA activity and
3-pyridazinyl as well as 4-pyrimidinyl congeners were
only active as TxRA, the 2-pyrazinyl, 4-pyridazinyl, and
5-pyrimidinyl analogues exhibit a dual activity compa-
rable to that of Ridogrel. Thus, it might be of interest
to utilize the bioisosteric potential of the latter hetero-
aryl groups for further developments of antiplatelet
compounds with combined TxSI/TxRA activity.
CH2CH2CH2), 1.17 (t, 3H, OCH2CH3); IR (oil) 1715 (CdO) cm-1
;
MS m/ z 313 (M+, 1), 182 (100), 181 (55), 115 (21), 87 (26), 77
(23). Anal. (C17H19N3O3) C, H, N.
Compound E-16a was obtained as a yellowish oil: 1H NMR
(acetone-d6) δ (ppm) 9.17 (dd, J 4,6 ) 1.8 Hz, J 5,6 ) 4.9 Hz, 1H,
pyridazine H-6), 8.16 (dd, J 4,6 ) 1.8 Hz, J 4,5 ) 8.6 Hz, 1H,
pyridazine H-4), 7.70 (dd, J 5,6 ) 4.9 Hz, J 4,5 ) 8.6 Hz, 1H,
pyridazine H-5), 7.40 (s, 5H, Ph), 4.28 (t, 2H, OCH2), 4.06 (q,
2H, OCH2CH3), 2.39 (t, 2H, CH2CO), 2.05 (quint, 2H, CH2CH2-
CH2), 1.18 (t, 3H, OCH2CH3); IR (oil) 1720 (CdO) cm-1; MS
m/ z 313 (M+, 2), 182 (100), 181 (55), 115 (20), 87 (23), 77 (20).
Anal. (C17H19N3O3) C, H, N.
The synthesis of compounds 16b, 16d -f, 17a -f, 18a -f,
19b, 19d -f, 20b, and 20d -f from educts 14a -f, 15b, or 15d -
f,11 and ethyl 4-bromobutanoate, ethyl 5-bromopentanoate, or
ethyl 6-bromohexanoate was carried out similarly as described
for the preparation of 16a from 14 and ethyl 4-bromobu-
tanoate.15
Exp er im en ta l Section
(a ) Ch em istr y. Melting points were determined on a
Reichert-Kofler hot-stage microsope and are uncorrected.
Infrared spectra were run from KBr pellets or neat oils
between NaCl disks on a Mattson Galaxy Series FTIR 3000
spectrophotometer or on a J ASCO IRA-1 spectrophotometer.
Mass spectra (MS, electron-impact ionization, 70 eV) were
taken on a Varian MAT 311A or on a Varian MAT 44/S
instrument. NMR spectra were recorded on a Varian Gemini
200 spectrometer (200 MHz for 1H, 50 MHz for 13C), on a
Gen er a l P r oced u r e for th e P r ep a r a tion of Ketoxim e
Eth er s 16c-18c, 19a , 19c, 20a , and 20c. Meth od B.
A
mixture of 3 mmol of aryl diazinyl ketone 4, 8, or 10,11 3.6
mmol of the appropriate ethyl ω-(aminooxy)alkanoate hydro-
chloride (29-31), and 3.6 mmol of Na2CO3 in 12 mL of MeOH
and 24 mL of water was stirred at 70 °C until the solids were
dissolved completely. After 10 min of additional heating, the
reaction mixture was acidified to pH 4 with acetic acid and
stirred for 3 h at 70 °C. After being cooled to room temper-
ature, the reaction mixture was diluted with 20 mL of
saturated NaHCO3 solution and exhaustively extracted with
CH2Cl2. The combined organic layers were dried over anhy-
drous MgSO4 and rotary-evaporated to give an oily residue.
The residue was purified by column chromatography (eluent:
CH2Cl2 + EtOAc ) 1 + 1), and then chromatographic separa-
tion of (E)- and (Z)-isomers was performed by MPLC using
mixtures of CH2Cl2/EtOAc (ratio thus adjusted to result in Rf
values of about 0.25 for the faster eluted component, i.e., the
(Z)-isomer).
1
Bruker AC 80 (80 MHz for H, 20 MHz for 13C), or on a Bruker
AM 300 spectrometer (300 MHz for 1H, 75 MHz for 13C). The
center of the solvent signal was used as an internal standard,
which was related to tetramethylsilane with δ 2.49 (DMSO-
d6), 2.04 (acetone-d6), or 7.24 (CDCl3) for 1H, and δ 39.5
(DMSO-d6), 29.8 (acetone-d6), or 77.0 (CDCl3) for 13C, respec-
tively. Microanalyses were obtained for C, H, N and are within
(0.3% of the theoretical value unless noted otherwise. TLC
was performed on silica gel plates (Macherey-Nagel Polygram
SIL G/UV 254 or Merck, silica gel 60, F-254) and visualized
using an UV lamp or iodine vapour. Column chromatography
was performed using Merck silica gel 60 (230-400 mesh), and
medium-pressure liquid chromatography (MPLC) was carried
out using Merck LiChroprep Si 60 (230-400 mesh), detection
at 280 nm. Petroleum ether refers to the fraction of bp 40-
60 °C. The yields given and separations of (E)- and (Z)-isomers
are not optimized. Detailed synthetic procedures as well as
spectroscopic data for the full set of compounds are given in
ref 15.
(Z)-Eth yl 4-[[[P h en yl(2-pyr im idin yl)m eth ylen e]am in o]-
oxy]bu ta n oa te (Z-16c) a n d th e (E)-Isom er E-16c. Com-
pounds Z-16c and E-16c were prepared from 411 and 29.
Chromatographic separation by MPLC afforded 376 mg (40%)
of Z-16c (faster eluted component) and 526 mg (57%) of E-16c
(slower eluted component).
Compound Z-16c was obtained as a yellowish oil: 1H NMR
(CDCl3) δ (ppm) 8.88 (d, J 4/6,5 ) 4.8 Hz, 2H, pyrimidine H-4/
6), 7.25-7.50 (“s”, 5H, Ph), 7.32 (t, J 4/6,5 ) 4.8 Hz, 1H,
pyrimidine H-5), 4.19 (t, 2H, OCH2), 4.08 (q, 2H, OCH2CH3),
2.31 (t, 2H, CH2CO), 1.96 (quint, 2H, CH2CH2CH2), 1.21 (t,
3H, OCH2CH3); IR (oil) 1730 (CdO) cm-1; MS m/ z 313 (M+,
1), 183 (31), 182 (49), 115 (45), 87 (66), 85 (19), 80 (100), 77
(32). Anal. (C17H19N3O3) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ketoxim e
Eth er s 16a -f-20a -f. Meth od A. To an ice-cooled suspen-
sion of 144 mg (3.6 mmol) of NaH (60% suspension in paraffine
oil, washed with dry n-hexane) in 6 mL of dry DMF was added
a solution of 3 mmol of aryl diazinyl ketoxime (14a -f, 15b, or
15d -f)11 in 6 mL of dry DMF. After the mixture was stirred
for 10 min at 0 °C, 3.3 mmol of the appropriate ethyl
ω-bromoalkanoate in 6 mL of dry DMF was added slowly. After
complete addition, stirring was continued for 1 h at room
temperature. Then the reaction mixture was poured onto ice,
diluted with 10 mL of saturated aqueous NaHCO3 solution,
and extracted exhaustively with CH2Cl2. The combined
organic layers were dried over anhydrous MgSO4 and rotary
evaporated to give an oily residue. The residue was purified
by column chromatography (eluent: CH2Cl2 + EtOAc ) 1 +
1), and then chromatographic separation of (E)- and (Z)-
isomers was performed by MPLC using mixtures of CH2Cl2/
Compound E-16c was obtained as a yellowish oil: 1H NMR
(CDCl3) δ (ppm) 8.78 (d, J 4/6,5 ) 4.8 Hz, 2H, pyrimidine H-4/
6), 7.40 (“s”, 5H, Ph), 7.24 (t, J 4/6,5 ) 4.8 Hz, 1H, pyrimidine
H-5), 4.35 (t, 2H, OCH2), 4.08 (q, 2H, OCH2CH3), 2.35 (t, 2H,
CH2CO), 2.03 (quint, 2H, CH2CH2CH2), 1.21 (t, 3H, OCH2CH3);
IR (oil) 1730 (CdO) cm-1; MS m/ z 313 (M+, 1), 183 (35), 182
(55), 115 (85), 87 (98), 85 (31), 80 (100), 77 (33). Anal.
(C17H19N3O3) C, H, N.
The preparation of compounds 17c, 18c, 19a , 19c, 20a , and
20c from 4, 8, or 1011 and ethyl 5-(aminooxy)pentanoate
hydrochloride (30) or ethyl 6-(aminooxy)hexanoate hydrochlo-

Bioisosteric Potential of Diazines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 4063
ride (31) was carried out similarly as described for the
preparation of 16c from 4 and 29.15
channel aggregometer (Labor aggregometer, FRG) and re-
corded on two recorders (LKB Clinicon 2066A, Goerz, AU) at
a paper speed of 0.5 mm/s.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of E t h yl
ω-(Am in ooxy)a lk a n oa te Hyd r och lor id es 29-31. N-Hy-
droxyphthalimide (8.2 g, 50 mmol) was dissolved in 50 mL of
DMSO at 60 °C, 4.1 g (50 mmol) of NaOAc was added
portionwise, and the resulting red solution was stirred for
another 10 min. Then a solution of 50 mmol of the appropriate
ethyl ω-bromoalkanoate in 10 mL of DMSO was added
dropwise. After 30 min of additional heating, the reaction
mixture was cooled to room temperature, diluted with 100 mL
of water and 30 mL of 2 N NaOH, and then exhaustively
extracted with diethyl ether. The combined organic layers
were washed with water and saturated aqueous NaCl solution,
dried over anhydrous Na2SO4, and rotary-evaporated to give
an oily residue. The residue was purified by distillation in a
kugelrohr apparatus to yield ethyl N-ω-(phthalimidooxy)-
alkanoates 26-28. A solution of 25 mmol of 26-28 in 50 mL
of EtOH was heated to 75 °C and treated with 1.3 mL (25
mmol) of N2H4‚H2O. After complete addition, the reaction
mixture was cooled to 40 °C, and then 6 mL of saturated
ethereal HCl was added. The precipitated 1,4-dihydroxy-
phthalimide was filtered off and washed several times with
CH2Cl2. The filtrate was rotary-evaporated to dryness and
recrystallized from EtOAc to give ethyl ω-(aminooxy)alkanoate
hydrochlorides 29-31 in 76-88% yield.
PRP 250 (400 µL) and 50 µL of a solution of the test
compound or vehicle solution (8 g/L NaCl, 200 mg/L KCl, 1g/L
NaHCO3, 50 mg/L NaH2PO4‚H2O, 306 mg/L CaCl2‚2H2O, 203
mg/L MgCl2‚6H2O) were incubated 10 min at room tempera-
ture followed by 5 min at 37 °C before addition of collagen (20
µL; 0.53 µg/mL final concentration). After the addition of
collagen, the optical density of the stirred PRP 250 (500 units/
min) was recorded for 4 min. All experiments were performed
at least as duplicates. Values were expressed as percent
inhibition of aggregation, which represented the percentage
of light transmission standardized to PRP 250 and PPP
samples, yielding 0% and 100% light transmission, respec-
tively. The EC50, i.e., the concentration of the test compound
required for half the maximal inhibition of collagen-induced
platelet aggregation, was calculated from the concentration
versus inhibition of aggregation curve.
Th r om b oxa n e Syn t h et a se In h ibit ion . Inhibition of
TXB2 formation by human gel-filtered platelets incubated with
[14C]arachidonic acid was measured as described before.7 This
test procedure allowed the quantification of free AA, 12-
hydroxyeicosatetraenoic acid (12-HETE); 12-hydroxyhepta-
decatrienoic acid (HHT); prostaglandins D2, E2, and F2R; and
thromboxane B2 (TXB2). Thromboxane synthetase inhibition
is characterized by a decrease in TXB2 and a corresponding
increase in the “classical” prostaglandins. Cyclooxygenase
inhibition is seen by a decrease of andoperoxide-derived
products and an increase in 12-HETE.
Gen er a l P r oced u r e for th e P r ep a r a tion of Acid s 21a -
f-25a -f. To a solution of 1 mmol of compounds 16a -f-20a -f
in 6 mL of EtOH was added 0.6 mL (1.1 mmol) of 2 N NaOH.
The reaction mixture was stirred for 24 h at room temperature,
acidified to pH 3-4 with 2 N HCl, diluted with 20 mL of water,
and exhaustively extracted with CH2Cl2. The combined
organic layers were dried over anhydrous MgSO4 and evapo-
rated to dryness. For yields, recrystallization solvents, and
melting points, see Tables 1 and 2.
Th r om boxa n e R ecep t or An t a gon ism . The binding of
the test compounds was determined by measuring the dis-
placement of the high-affinity ligand [3H]SQ 29,548 according
to ref 7. Nonspecific binding was determined by adding U
46,619 (30 µM final concentration), replacing the test com-
pound. IC50 values listed in Tables 1 and 2 represent the
concentration of test compound causing 50% displacement of
[3H]SQ 29,548.
(E)-4-[[[P h en yl(3-p yr id a zin yl)m eth ylen e]a m in o]oxy]-
bu ta n oic Acid (E-21a ). Compound E-21a was prepared from
E-16a and obtained as colorless crystals upon recrystalliza-
tion: 1H NMR (CDCl3) δ (ppm) 9.17 (dd, J 4,6 ) 1.9 Hz, J 5,6
4.8 Hz, 1H, pyridazine H-6), 8.80 (s, 1H, OH), 8.11 (dd, J 4,6
)
)
1.9 Hz, J 4,5 ) 8.6 Hz, 1H, pyridazine H-4), 7.54 (dd, J 5,6 ) 4.8
Hz, J 4,5 ) 8.6 Hz, 1H, pyridazine H-5), 7.40 (“s”, 5H, Ph), 4.30
(t, 2H, OCH2), 2.43 (t, 2H, CH2CO), 2.05 (quint, 2H, CH2CH2-
CH2); IR (KBr) 1715 (CdO) cm-1; MS m/ z 285 (M+, <1), 267
(30), 168 (20), 131 (18), 119 (24), 76 (20), 69 (100). Anal.
(C15H15N3O3) C, H, N.
Ack n ow led gm en t. We thank Dr. Karl-Hans Onga-
nia for recording mass spectra. We are grateful to Dr.
Paul J anssen for providing us with Ridogrel.
Refer en ces
(Z)-4-[[[P h en yl(3-p yr id a zin yl)m eth ylen e]a m in o]oxy]-
bu ta n oic Acid (Z-21a ). Compound Z-21a was prepared from
Z-16a and obtained as colorless crystals upon recrystalliza-
tion: 1H NMR (CDCl3) δ (ppm) 10.40 (s, 1H, OH), 9.21 (dd,
J 4,6 ) 1.9 Hz, J 5,6 ) 4.8 Hz, 1H, pyridazine H-6), 7.63 (dd, J 4,6
(1) (a) Hamberg, M.; Svensson, J .; Samuelsson, B. Thromboxanes:
A new group of biologically active compounds derived from
prostaglandin endoperoxides. Proc. Natl. Acad. Sci. U.S.A. 1975,
72, 2294-8. (b) Bhagwat, S. S.; Hamann, P. R.; Still, W. C.;
Bunting, S.; Fitzpatrick, F. A. Synthesis and structure of the
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511-3.
(2) Mais, D. E.; Saussy, D. L.; Chaikhouni, A.; Kochel, P. J .; Knapp,
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24
) 1.9 Hz, J 4,5 ) 8.7 Hz, 1H, pyridazine H-4), 7.57 (dd, J 5,6
)
4.8 Hz, J 4,5 ) 8.7 Hz, 1H, pyridazine H-5), 7.25-7.50 (m, 5H,
Ph), 4.22 (t, 2H, OCH2), 2.34 (t, 2H, CH2CO), 1.99 (quint, 2H,
CH2CH2CH2); IR (KBr) 1723 (CdO) cm-1; MS m/ z 285 (M+,
<1), 267 (71), 266 (36), 237 (26), 182 (21), 168 (44), 108 (44),
91 (78), 87 (20), 43 (100). Anal. (C15H15N3O3) C, H, N.
The preparation of compounds 21b-f, 22a -f-25a -f from
16b-f, 17a -f-20a -f was carried out similarly to the proce-
dure given for the synthesis of 21a .15
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5,6-3H(N) (code NET-936) and sucrose-14C(U) (code NEC-100)
were purchased from New England Nuclear (Dreieich, FRG),
Sepharose 2B from Pharmacia, and Collagen and SKF dilution
buffer from Hormon-Chemie (Munich, FRG). All other chemi-
cals were of the highest purity commercially available.
Colla gen -In d u ced P la telet Aggr ega tion in Vitr o. Blood
was obtained from healthy volunteers who had refrained from
taking any medication for at least 14 days prior to venipunc-
ture. The blood was mixed with trisodium citrate solution
(3.8% w/v) at ratio of 9:1. Platelet-rich plasma (PRP) and
platelet-poor plasma (PPP) were obtained from the blood by
centrifugation (Rotixa KS, Hettich) at 1000 rpm for 10 min at
10 °C and 4000 rpm for 10 min at 10 °C, respectively. PRP
was then adjusted to a concentration of 2.5 × 105 cells/mL
(PRP 250). Platelet aggregation tests were performed in a two-
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