Note: Descriptions are shown in the official language in which they were submitted.
CA 02476454 2004-08-16
WO 03/068224 pCT/EP03/01100
Use of inhibitors of the sodium-dependent chloridelbicarbonate exchanger for
the
treatment of thrombotic and inflammatory disorders
The invention relates to the use of inhibitors of the sodium-dependent
chloride/bicarbonate exchanger in human and veterinary medicine for the
prevention
and treatment of acute or chronic diseases caused by elevated levels of von
Willebrand factor in the blood. The inhibitors can therefore be employed for
the
treatment of thrombotic and inflammatory disorders.
Inhibitors of the cellular sodium-dependent chloride/bicarbonate exchanger
(NCBE)
are known (EP 0 855 392, EP 1 097 140). NCBE inhibitors are suitable because
of
the inhibition of the cellular Na+-dependent CI~/HC03 exchange mechanism for
the
prevention and treatment of arrhythmias, of infarctions and of angina pectoris
and
generally for cardioprotection, especially following ischemia and reperfusion
events.
In addition, these NCBE inhibitors can be used, because of their potentially
protective effects in pathological hypoxic and ischemic situations, for the
treatment of
all acute or chronic damage caused by ischemia or diseases induced primarily
or
secondarily thereby. Further potential indications for possible use are
protection of
tissues for organ transplants, renal failure, protection from ischemia-induced
damage
of the central nervous system, treatment of states of shock, diseases induced
by
proliferation, including cancer, fibrotic disorders, organ hypertrophies and
hyperplasias, impairments of respiratory drive etc.
However, the use of NCBE inhibitors for the treatment of thromboses which is
described in the prior art relates exclusively to the protective effect of the
NCBE
inhibitors against destruction of the tissue affected by the ischemia and not
at all to
the prevention of thrombus formation per se.
The mechanism of action of NCBE inhibitors which operates in the acute
ischemic
event comprises their reduction of the enhanced influx of sodium ions which
arises in
acutely hypoperfused tissue due to activation of the sodiumlhydrogen exchanger
(NHE) as a consequence of intracellular acidification. This delays the
situation of
tissue sodium overload. Since there is coupling of sodium and calcium ion
transport
in cardiac tissue, this prevents the life-threatening calcium overload of
heart cells. In
CA 02476454 2004-08-16
2
addition, with NCBE inhibitors there is suppression or delay of the
realkalinization of
the interior of cells owing to blockage of bicarbonate influx.
Thus, of course, as expected no protective effects of NCBE inhibitors against
these
acute events were observable where blood flow was normal and healthy either.
Numerous classes of substances which intervene in the interplay of coagulation
factors and thus cause cessation of the coagulation cascade are described in
the
prior art. Likewise, numerous action principles which do not suppress thrombus
formation, but cause the dissolution (lysis) of thrombi which have already
formed,
have been developed. Some of these action principles, which intervene at a
wide
variety of junction points in said cascade, have been introduced into therapy
to
prevent thrombogenesis, such as derivatives of the vitamin K group
(phylloquinones), factor VIII and factor IX products, platelet aggregation
inhibitors
such as acetylsalicylic acid, dipyridamole and ticlopidine, anticoagulants
such as
heparins or heparinoids.
The blood coaguation cascade can be divided mechanistically into two pathways
as
depicted in the following diagram,
Intrinsic Extrinsic
XII --~ Xlla VII + TF
1
XI ----~ Xla
IX ---~ IXa
X i Xa Platelet Aggregation
Prothrombin ~ Thrombin
1
Fibrinogen ---~ Fibrin
namely into an intrinsic and an extrinsic route, the two of which finally meet
in the
activation of factor X and the resulting generation of thrombin and
subsequently of
fibrin.
CA 02476454 2004-08-16
It is important in the therapeutic use of such blood coagulation inhibitors
that the
inhibition of coagulation achieved is not too strong or complete, which would
inhibit
the formation of microthrombi and microcoagulations which are vital and which
must
take place at the microtraumata which are continually happening. Only
imprecise
adjustment of the degree of inhibition of coagulation is possible as a result
of
differences in the response of the particular individ~!al at a particular
time, and the
degree must be carefully monitored where possible. If these many small
coagulation
processes which are permanently taking place are inhibited there is a high
risk of
extensive hemorrhage (hemophilia).
The disadvantage of the known therapeutic agents available on the market which
intervene as inhibitors in the coagulation event is therefore the high risk of
bleeding
complications. The risk of life-threatening hemorrhage exists especially
during high-
dose thrombolysis therapy, e.g. during therapy of acute myocardial infarction
or
pulmonary embolism. There is thus an urgent need for therapeutic agents which
do
not entail a risk of increased tendency to bleeding despite overdosage.
Many of the known anticoagulant substances act by exerting an effect on the
blood
platelets, the thrombocytes, and inhibiting their function or inhibiting their
activation.
The endothelium also evidently plays a central part in the coagulation event.
Thus,
for example, the von Willebrand factor (vWF) which is necessary for
coagulation is
produced for the most part in endothelial cells and is secreted by them
permanently
(constitutively) into the circulating blood in order to ensure the necessary
coagulation
processes in the blood. A considerable part of the produced vWF is stored in
cytoplasmic granules, called Weibel-Palade bodies, and released as required
through stimulation of endothelial cells. If endothelial cells are unable to
produce
vWF and deliver it to the blood, the result is the well known genetic vWF-
dependent
disease, von Willebrand-Jurgens syndrome, which is characterized by
hemorrhages
which can scarcely be stopped.
It is only in recent years that disorders caused by elevated concentrations of
vWF in
the blood, thus inducing, for example, an increased tendency to blood
coagulation
and inflammatory processes, have become known. Thus, Kamphuisen et al.
demonstrate on the basis of a large number of studies in their publication
"Elevated
factor VIII levels and the risk of thrombosis" (Arterioscler. Thromb. Vasc.
Biol.
CA 02476454 2004-08-16
4
21 (5):731-738 (2001 )) that there is a significant association between
elevated vWF
levels in the blood and an increased rate of thrombotic disorders. Factor VIII
forms
with vWF a complex as necessary precondition for blood coagulation. It has
been
possible to establish that high levels of von Willebrand factor and (vWF) and
of vWF-
bound factor VIII in the blood represent a clear thrombosis risk factor.
However,
antithrombotic agents which antagonize the stabilizing binding of vWF to
factor VIII
may also be disadvantageous because, in the event of overdosage, substantial
inhibition of blood coagulation and dangerous tendencies to bleeding must be
expected.
In the attempt to find effective compounds for the treatment of acute or
chronic
diseases caused by elevated levels of von Willebrand factor in the blood, it
has now
been found that the compounds employed according to the invention inhibit the
release of von Willebrand factor from endothelial cells. The compounds of the
invention inhibit the massive pH-dependent release of vWF which accumulates
during ischemia.
Whereas the secretion takes place normally and constitutively at the normal pH
of
blood which is known to be about 7.4, and part of the vWF is stored in Weibel-
Palade bodies, it has now been found that there is a delay and reduction in
the
release of vWF as the pH falls. Exocytosis of the Weibel-Palade bodies in
which the
vWF is packaged is increasingly inhibited as the pH declines. Thus, under
acidotic
conditions, there is a significant increase in Weibel-Palade bodies and thus
extensive accumulation of vWF in the endothelial cell, and a reduced
constitutive
and stimulated vWF secretion. This can be visualized by staining procedures
and
demonstrated by quantitative measurements of vWF in the supernatant. Such
acidotic states with significant pH reductions below 7 occur, for example, in
cases of
tissue ischemia. At the instant of realkalinization and endothelial cell
stimulation,
which corresponds to the reperfusion state, within seconds exocytosis takes
place,
and thus emptying of the Weibel-Palade bodies (WPB), thus leading to massive
release of the prothrombotic risk factor.
Besides vWF, the Weibel-Palade bodies also store the transmembrane protein P-
selectin (Wagner, D.D. 1993, Thromb. Haemost., 70:105-110).
CA 02476454 2004-08-16
P-Selectin is located in the vesicle membrane and, after vesicle fusion
(exocytosis),
is incorporated into the plasma membrane of the endothelial cell. This means
that
every Weibel-Palade body exocytosis leads not only to increased vWF release
but
also to increased P-selectin expression in the endothelial cell membrane. The
examples show vWF secretion (quantitive measurement by ELISA) during acidosis
and during subsequent reperfusion. In parallel, these quantitative
measurements are
confirmed by immunofluorescence data on the Weibel-Palade bodies. The measured
vWF is thus not only a marker of increased (increase in vWF secretion) or
reduced
(decrease in vWF secretion) tendency to thrombosis (via increase in platelet
aggregation), but also a direct marker of increased or reduced P-selectin
expression
in the endothelial cell membrane. P-Selectin serves as anchor for leukocytes
and
thus the initial inflammatory reaction (Vestweber, D., Blanks, J.E. 1999,
Physiol.
Rev., 79:181-213; Issekutz, A.C., Issekutz, T.B. 2002, J. Immunol., 168:1934-
1939).
The pathophysiological significance is wide-ranging and confirmed for
ischemia/reperfusion disorders, thromboses and arteriosclerosis (Massberg, S.,
et
al., 1998, Blood, 92:507-515; Kita, T., et al., 2001, Ann. N. Y. Acad. Sci.,
947:199-
205). Besides the significance of P-selectin as marker of inflammation and
initiator of
inflammation, it plays an essential part in the process of cancer
dissemination (Varki,
A., Varki, N.M. 2001, Braz. J. Med. Biol. Res. 34:711-717) and during various
inflammations of joints (arthritis) (Veihelmann, A. et al, 1999,
Microcirculation, 6:
281-290; Mclnnes, I.B., et al., 2001, J. Immunol., 167:4075-4082). Thus the
mode of
action of the substances described here may also find use as therapeutic agent
for
all the abovementioned P-selectin-associated disorders.
The invention therefore relates to the use of inhibitors of the cellular
sodium-
dependent chloride/bicarbonate exchanger for producing medicaments for the
prophylaxis and therapy of acute and chronic diseases caused by elevated
levels of
von Willebrand factor in blood and/or increased expression of P-selectin.
The invention further relates to the use of compounds of the formula I
R13 Y R15
i / O
~ 'S ~ O
R14 . HN_''~N
CA 02476454 2004-08-16
6
and/or all stereoisomeric forms of compounds of the formula I and/or mixtures
of
these forms in any ratio, and/or of the physiologically tolerated salts of the
compounds of the formula I
for producing a medicament for the prophylaxis and therapy of acute or chronic
diseases caused by elevated levels of von Willebrand factor in the blood
and/or
increased expression of P-selectin,
in which the symbols have the following meaning:
X equal to
R2 R5 R7 R 12
R11
~/ ~ Ra or
R1' \N R3 R4 R9 N
R6
R10
R(1 ) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; or
-CaH2a-Phenyl,
where the phenyl moiety is unsubstituted or substituted by 1, 2 or 3
identical or different residues from the series F, CI, Br, I, CF3,
methyl, methoxy, hydroxyl or NR(19)R(20);
R(19) and R(20) independently of one another
H or alkyl having 1, 2, 3 or 4 carbon atoms;
a zero, 1 or 2; or
R(1 ) -CbH2b-heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms,
where the heteroaryl moiety is unsubstituted or substituted by 1, 2 or 3
identical or different residues from the series F, CI, Br, I, CF3, CH3,
methoxy, hydroxyl or NR(21 )R(22);
R(21 ) and R(22) independently of one another
H or alkyl having 1, 2, 3 or 4 carbon atoms;
b zero, 1 or 2; or
R(1 ) -C~H2~-cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
CA 02476454 2004-08-16
c zero, 1 or 2;
R(2) and R(3) independently of one another
hydrogen, F, CI, Br, I, CF3, -CN, -N02, CH20R(23), CO-R(24) or O-R(25);
R(23) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(24) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
OR(26) or phenyl;
where phenyl is unsubstituted or substituted by 1, 2 or 3 identical
or different radicals from the group F, CI, Br, I, CF3, methyl,
methoxy, hydroxyl or NR(27)R(28);
R(27) and R(28) independently of one another
H or alkyl having 1, 2, 3 or 4 carbon atoms;
R(26) hydrogen or alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms;
R(25) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or
phenyl;
where phenyl is unsubstituted or substituted by 1, 2 or 3
identical or different radicals from the series F, CI, Br, I,
CF3, methyl, methoxy, hydroxyl or NR(29)R(30);
R(29) and R(30) independently of one another
H or alkyl having 1, 2, 3 or 4 carbon atoms; or
R(25) heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which
is
unsubstituted or substituted by 1, 2 or 3
identical or different radicals from the series F, CI, Br, I,
CF3, CH3, methoxy, hydroxyl or NR(31 )R(32);
R(31 ) and R(32) independently of one another
H or alkyl having 1, 2, 3 or 4 carbon atoms; or
R(2) and R(3) independently of one another
alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3, 4, 5,
6
or 7
carbon atoms; or
-CdH2d-phenyl where the phenyl moiety is unsubstituted or substituted by 1,
2 or 3 identical or different radicals from the series F, CI, Br,
CA 02476454 2004-08-16
g
I, CF3, methyl, methoxy, hydroxyl or NR(33)R(34);
R(33) and R(34) independently of one another
H or alkyl having 1, 2, 3 or 4 carbon atoms;
d zero, 1 or 2; or
R(2) and R(3) independently of one another
-CeH2e-heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, where the
heteroaryl moiety is unsubstituted or substituted by 1, 2 or 3
identical or different radicals from the series F, CI, Br, I, CF3,
CH3, methoxy, hydroxyl or NR(35)R(36);
R(35) and R(36) independently of one another
H or alkyl having 1, 2, 3 or 4 carbon atoms;
a zero, 1 or 2; or
R(2) and R(3) independently of one another
=SOt-R(37);
R(37) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl
having 3, 4, 5, 6 or 7 carbon atoms, or
-CgH2g-phenyl where the phenyl moiety is unsubstituted or substituted
by 1, 2 or 3 identical or different radicals from the series F, CI,
Br, I, CFg, methyl, methoxy, hydroxyl or NR(38)R(39);
R(38) and R(39) independently of one another
H or alkyl having 1, 2, 3 or 4 carbon atoms;
f zero, 1 or 2;
g zero, 1 or 2;
R(4) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, 1-naphthyl,
2-naphthyl, -CiH2i-cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or -C;H2i-
phenyl, where the phenyl moiety is unsubstituted or substituted by 1, 2 or 3
identical or different radicals from the series alkyl having 1, 2, 3, 4, 5, 6,
7 or 8
carbon atoms, F, CI, Br, I, CF3, SOjR(48), OR(49), NR(50)R(51 ), -CN, -N02
or CO-R(52);
i zero, 1 or 2;
CA 02476454 2004-08-16
9
R(48) alkyl having 1, 2, 3 or 4 carbon atoms or NR(53)R(54);
R(53) and R(54) independently of one another
hydrogen or alkyl having 1,2,3 or 4 carbon atoms;
j zero, 1 or 2;
R(49) hydrogen or alkyl having 1,2,3 or 4 carbon atoms;
81,50) and R(51 ) independQntly of one another
hydrogen or alkyl having 1,2,3 or 4 carbon atoms;
R(52) hydrogen, alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms or
OR(55);
R(55) hydrogen, alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms;
or
R(4) and R(6) together with the carbon atom bearing them cycloalkyl having 3,
4, 5,
6 or 7 carbon atoms or fluorenyl;
R(5), R(6), R(7) and R(8) independently of one another
hydrogen, F, CF3, O-R(56), alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms, -CkH2k-phenyl, where the
phenyl moiety is unsubstituted or substituted by 1,2 or 3 identical or
different
radicals from the series F, CI, Br, I, CF3, methyl, methoxy, hydroxyl or
NR(57)R(58);
R(57) and R(58) independently of one another
hydrogen or alkyl having 1,2,3 or 4 carbon atoms;
k zero, 1 or 2;
R(56) hydrogen, alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms, or
phenyl which is unsubstituted or substituted by 1, 2 or 3 identical
or different radicals from the series F, CI, Br, I, CF3,
methyl, methoxy, hydroxyl or NR(59)R(60);
R(59) and R(60) independently of one another
hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms, or
R(56) heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is
unsubstituted or substituted by 1, 2 or 3 identical or different
radicals from the series F, CI, Br, I, CF3, CH3, methoxy, hydroxyl or
NR(61 )R(62);
' CA 02476454 2004-08-16
R(61 ) and R(62) independently of one another
hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms; or
R(5) and R(7) together a second bond between the carbon atoms bearing the
radicals R(6) and R(8), where R(4), R(6) and R(8) are as defined above;
R(9) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, alke,~,yl having 2,
3, ~,
5, 6, 7 or
8 carbon atoms, or -C~H21-p -A;
II zero or 2; and
I zero, 1, 2, 3 or 4;
where I is not zero or 1 when II is 2;
R(10) hydrogen;
alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; or
alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
-CmH2m-mm -B~
mm zero or 2; and
m zero, 1, 2, 3 or 4;
where m is not zero or 1 when mm is 2;
R(11 ) and R(12) independently of one another
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
Z carbonyl or sulfonyl;
A and B independently of one another
1. aryl having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms, preferably
phenyl,
1-naphthyl or 2-naphthyl;
2. a radical as defined under 1. which is substituted by 1, 2 or 3 identical
or
CA 02476454 2004-08-16
I1
different radicals from the series alkyl having 1, 2, 3, 4, 5, 6, 7 or 8
carbon atoms, F, CI, Br, I, CF3, SO~R(63), OR(64), NR(65)R(66), -CN,
-N02 or CO-R(67);
3. heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;
4. a radical as defined under 3. which is substituted by 1, 2 or 3 identical
or different radicals from the series F, CI, Br, I, CF3, CH3, methoxy,
hydroxyl or NR(68)R(69);
5. cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
6. O-R(70); or
7. O-R(71 );
n zero, 1 or 2;
R(70) and R(71 ) independently of one another
1. hydrogen;
2. alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
3. -CoH2o_oo - Phenyl,
0o zero or 2; and
o zero, 1, 2, 3 or 4;
where o is not zero or 1 when oo is 2;
4. a radical as defined under 3. where the phenyl moiety is
substituted by 1, 2 or 3 identical or different
radicals from the series alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms, F, CI, Br, I, CF3, SOpR(72), OR(73), NR(74)R(75),
-CN, -N02 or CO-R(76); or
5, alkenyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(63) and R(72) independently of one another
alkyl having 1, 2, 3 or4 carbon atoms or NR(77)R(78);
R(67) and R(76) independently of one another
hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or OR(89);
R(89) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or
8 carbon atoms;
' CA 02476454 2004-08-16
12
R(64), R(65), R(66), R(68), R(69), R(73), R(74), R(75), R(77) and
R(78) independently of one another
hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
p independently of one another zero, 1 or 2;
R(13), R(14) and R(15) independently of one another
hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, CI, Br, I,
CF3, -
CN, -N02, SOq-R(79), CO-R(80) or O-R(81 );
q independently of one another zero, 1, or 2;
R(79) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
phenyl which is unsubstituted or substituted by 1, 2 or 3
identical or different radicals from the series F, CI, Br, I,
CF3, methyl, methoxy, hydroxyl or NR(82)R(83);
R(82), R(83) independently of one another
hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R(80) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
OR(84);
R(84) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon
atoms;
R(81 ) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
phenyl which is unsubstituted or substituted by 1, 2 or 3
identical or different radicals from the series F, CI, Br, I,
CF3, methyl, methoxy, hydroxyl or NR(82)R(83);
Y a covalent bond, CR(16)R(17), CO, S, S02, O or NR(18),
R(16) hydrogen or -OR(85);
R(85) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
CO-R(86);
R(86) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl,
which is unsubstituted or substituted by 1, 2 or 3 identical
CA 02476454 2004-08-16
13
or different radicals from the series F, CI, Br, I, CF3,
methyl, methoxy, or hydroxyl;
R(17) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(18) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, CO-R(87)
or S02R(88);
R(87) and R(88) independently of one another
alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl
having 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is
unsubstituted or substituted by 1, 2 or 3 identical or different
radicals from the series F, CI, Br, I, CF3, methyl, methoxy or
hydroxyl.
The invention further relates to the use of compounds of the formula I
for producing a medicament for the prophylaxis and therapy of acute or chronic
diseases caused by elevated levels of von Willebrand factor in the blood
andlor
increased expression of P-selectin, in which the meanings are:
X
R2
R1 N R3
R(1 ) alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which is unsubstituted
or
substituted by a radical from the series F, CI, CF3, methyl or
methoxy;
R(2) and R(3) independently of one another
hydrogen, F, CI, CF3, -CN, CO-R(24) or O-R(25),
R(24) hydrogen, alkyl having 1,2,3 or 4 carbon atoms, OR(26) or
phenyl which is unsubstituted or substituted by a radical from the
series F, CI, CF3, methyl or methoxy;
R(26) hydrogen, methyl or ethyl;
CA 02476454 2004-08-16
14
R(25) hydrogen, alkyl having 1,2,3 or 4 carbon atoms, phenyl which is
unsubstituted or substituted by a radical from the series F, CI,
CF3, methyl or methoxy; or
R(25) heteroaryl which is unsubstituted or substituted by a radical from
the series F, CI, CF3, CH3 or methoxy; or
R(2) and R(3) independently of one another
alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7
carbon
atoms; or
R(2) and R(3) independently of one another
phenyl which is unsubstituted or substituted by a radical from the series F,
CI,
CF3, methyl or methoxy; or
R(2) and R(3) independently of one another
heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which is
unsubstituted or substituted by a radical from the series F, CI, CF3, CH3 or
methoxy; or
R(2) and R(3) independently of one another
-SOt-R(37),
R(37) alkyl having 1,2,3 or 4 carbon atoms or phenyl which is
unsubstituted or substituted by a radical from the series F, CI,
CF3, methyl or methoxy;
f zero or 2;
R(13), R(14) and R(15) independently of one another
hydrogen, methyl, F, CI, CF3, -CN, S02-R(79), CO-R(80) or O-R(81 );
R(79) and R(81 ) independently of one another
alkyl having 1, 2, 3 or 4 carbon atoms or phenyl which is
unsubstituted or substituted by a radical from the series F, CI,
CF3, methyl or methoxy;
R(80) hydrogen, methyl or OR(84);
R(84) hydrogen or alkyl having 1, 2, 3, or 4 carbon atoms;
Y a covalent bond or methylene.
The invention further relates to the use of compounds of the formula II
CA 02476454 2004-08-16
1$
N \ R2
R'! -~~R3
N Rs~ II
0
/ ~ n_
/ \. Nr~N
H
and/or all stereoisorneric forms of the compounds of the formula II and/or
mixtures of
these forms in any ratio, and/or of the physiologically tolerated salts of the
compounds of the formula II for producing a medicament for the prophylaxis and
therapy of acute or chronic diseases which are caused by elevated levels of
von
Willebrand factor in the blood and/or increased expression of P-selectin, in
which the
symbols have the following meaning:
R(1 ) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -CaH2a-
phenyl,
where phenyl is unsubstituted or substituted by 1 to 3 substituents selected
from the group consisting of F, CI, Br, I, CF3, methyl, methoxy, hydroxyl and
NR(8)R(9);
R(8) and R(9) independently of one another hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
a zero, 1 or 2; or
R(1 ) -CbH2b-heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, where
heteroaryl is unsubstituted or substituted by 1 to 3 substituents selected
from
the group consisting of F, CI, Br, I, CF3, CH3~ methoxy, hydroxyl and
NR(10)R(11 );
R(10) and R(11 ) independently of one another hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms;
b zero, 1 or 2; or
R(1 ) -CdH2d-(C3-C7)-cyclalkyl having 3, 4, 5, 6 or 7 carbon atoms;
d zero, 1 or 2;
R(2) and R(3) independently of one another hydrogen, F, CI, Br, I, CF3, -CN, -
N02,
CA 02476454 2004-08-16
16
CH20R(17), CO-R(6) or O-R(7), O-(alkylene having 2, 3 or 4 carbon atoms)-
O-R(17) or NR(50)R(51 );
R(17) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms,
R(50) and R(51 ) independently of one another -(alkylene having 2, 3 or
4 carbon atoms)-O-R(52);
R(52) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, °l or 8 carbon
atoms;
R(6) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, OR(30) or
phenyl which is unsubstituted or substituted by 1 to 3 substituents
selected from the group consisting of F, CI, Br, I, CF3~ methyl,
methoxy, hydroxyl and NR(31 )R(32);
R(31 ) and R(32) independently of one another hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;
R30 hydrogen or alkyl having 1, 2, 3, 4, 5,'6, 7 or 8 carbon
atoms;
R(7) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, phenyl
which is unsubstituted or substituted by 1 to 3 substituents selected
from the group consisting of F, CI, Br, I, CF3, methyl, methoxy, hydroxyl
and NR(12)R(13);
R(12) and R(13) independently of one another hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms; or
R(7) heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, where
heteroaryl is unsubstituted or substituted by 1 to 3 substituents
selected from the group consisting of F, CI, Br, I, CFg, CH3, methoxy,
hydroxyl and NR(14)R(15);
R(14) and R(15) independently of one another hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms; or
R(2) and R(3) independently of one another alkyl having 1, 2, 3, 4, 5, 6, 7 or
8
carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or -CgH2g-
phenyl, in which phenyl is unsubstituted or substituted by 1 to 3 substituents
selected from the group consisting of F, CI, Br, I, CF3, methyl, methoxy,
hydroxyl and NR(18)R(19);
CA 02476454 2004-08-16
17
R(18) and R(19) independently of one another hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms;
g zero, 1 or 2; or
R(2) and R(3) -C~H2~-heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon
atoms, where
heteroaryl is unsubstituted or substituted by 1 to 3 substituents selected
from
the group consisting of F, CI, Br, I, CF3, methyl, methoxy, hydroxyl and
NR(20)R(21 );
R(20) arid R(21 ) independently of one another hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;
I zero, 1 or 2; or
R(2) and R(3) SO~-R(22);
n zero, 1 or 2;
R(22) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3,
4,
5, 6 or 7 carbon atoms or -CgH2S-phenyl which is unsubstituted or
substituted by 1 to 3 substituents selected from the group consisting of
F, CI, Br, I, CF3, methyl, methoxy, hydroxyl and NR(34)R(35);
R(34) and R(35);independently of one another hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms;
s zero, 1 or 2;
R(90) and R(91 ) independently of one another hydrogen, alkyl having 1, 2, 3,
4, 5, 6,
7 or 8 carbon atoms, F, CI, Br, I, CF3, -CN, -N02, SOp-R(16),
CO-R(23) or O-R24 or O-(alkylene having 2, 3 or 4 carbon atoms)-O-
R(33);
p zero, 1 or 2;
R(16) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl
which is unsubstituted or substituted by 1 to 3 substituents selected
from the group consisting of F, CI, Br, I, CF3, methyl, methoxy,
hydroxyl and NR(26)R(27);
R(26) and R(27) independently of one another hydrogen or alkyl having 1, 2,
3 or 4 carbon atoms;
CA 02476454 2004-08-16
18
R(23) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or OR(25);
R(25) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(24) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl
which is unsubstituted or substituted by 1 - 3 substituents selected from
the group consisting of F, CI, Br, I, CF3, methyl, methoxy, hydroxyl and
NR(28)R(29);
R(28) and R(29) independently of one another hydrogen or alkyl having 1, 2, 3
or 4 carbon atoms;
R(33) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms.
The invention further relates to the use of compounds of the formula II
for producing a medicament for the prophylaxis and therapy of acute and
chronic
diseases which aye caused by elevated levels of von Willebrand factor in the
blood
andlor increased expression of P-selectin, in which the symbols have the
following
meaning:
R(1 ) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -CaH2a-
phenyl
where the phenyl moiety is unsubstituted or substituted by 1, 2 or 3
identical.
or different radicals from the series F, CI, Br, I, CF3, methyl, methoxy,
hydroxyl or NR(8)R(9);
R(8) and R(9) independently of one another hydrogen or alkyl having 1, 2, 3
or 4 carbon atoms;
a zero, 1 or 2; or
R(1 ) -CbH2b-heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, where
the
heteroaryl moiety is unsubstituted or substituted by 1, 2 or 3 identical or
different radicals from the series F, CI, Br, I, CF3, methyl, methoxy,
hydroxyl
or NR(10)R(11 );
R(10) and R(11 ) independently of one another hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms;
b zero, 1 or 2; or
R(1 ) -CdH2d-cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
d zero, 1 or 2;
CA 02476454 2004-08-16
19
R(2) and R(3) independently of one another hydrogen, F, CI, Br, I, CF3, -CN, -
NO2,
CH20R(17), CO-R(6) or O-R(7);
R(17) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(6) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, OR(30) or
phenyl which is unsubstituted or substituted by 1, 2 or 3 identical or
different radicals from the series F, CI, Br, I, CF3, methyl, methoxy,
hydroxyl or NR(31 )R(32);
R(31 ) and R(32) independently of one another hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms;
R(30) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(7) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl
which is unsubstituted or substituted by 1, 2 or 3 identical or different
radicals from the series F, CI, Br, I, CF3, methyl, methoxy, hydroxyl or
NR(12)R(13);
R(12) and R(13) independently of one another hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms; or
R(7) heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which is
unsubstituted or substituted by 1, 2 or 3 identical or different radicals
from the series F, CI, Br, I, CF3, methyl, methoxy, hydroxyl or
NR(14)R(15);
R(14) and R(15) independently of one another hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms; or
R(2) and R(3) independently of one another alkyl having 1, 2, 3, 4, 5, 6, 7 or
8
carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or -CgH2g-
phenyl, where the phenyl moiety is unsubstituted or substituted by 1, 2 or 3
identical or different radicals from the series F, CI, Br, I, CF3, methyl,
methoxy,
hydroxyl or NR(18)R(19);
R(18) and R(19) independently of one another hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms;
g zero, 1 or 2; or
R(2) and R(3) independently of one another -C~H2~-heteroaryl having 1, 2, 3,
4, 5, 6,
7, 8 or 9 carbon atoms, where the heteroaryl moiety is unsubstituted or
CA 02476454 2004-08-16
substituted by 1, 2 or 3 identical or different radicals from the series F,
CI, Br,
I, CF3, methyl, methoxy, hydroxyl or NR(20)R(21);
R(20) and R(21 ) independently of one another hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms;
5 I zero, 1 or 2; or
R(2) and R(3) independently of one another SO~-R(22);
n zero, 1 or 2;
R(22) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl
10 having 3, 4, 5, 6 or 7 carbon atoms or -CSH25-phenyl which is
unsubstituted or substituted by 1, 2 or 3 identical or different
radicals from the series F, CI, Br, I, CF3, methyl, rnethoxy,
hydroxyl or NR(34)R(35);
R(34) and R(35) independently of one another
15 hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
s zero, 1 or 2;
R(91 ) hydrogen
R(90) SOp-R(16),
p zero, 1 or 2;
20 R(16) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is
unsubstituted or substituted by 1, 2 or 3 identical or different radicals
from the series F, CI, Br, I, CF3, methyl, methoxy, hydroxyl or
NR(26)R(27);
R(26) and R(27) independently of one another hydrogen or alkyl
having 1, 2, 3 or 4 carbon atoms.
The invention further relates to the use of compounds of the formula II for
producing
a medicament for the prophylaxis and therapy of acute or chronic diseases
which are
caused by elevated levels of von Willebrand factor in the blood andlor
increased
expression of P-selectin, in which the symbols have the following meaning:
R(1 ) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, -CdH2d-cycloalkyl
having 3,
4, 5, 6 or 7 carbon atoms with d equal to zero, 1 or 2 or -CaH2a-phenyl, where
CA 02476454 2004-08-16
21
the phenyl moiety is unsubstituted or substituted by 1, 2 or 3 identical or
different radicals from the series F, CI, Br, I, CF3, methyl, methoxy,
hydroxyl
or NR(8)R(9);
R(8) and R(9) independently of one another hydrogen or alkyl having 1,
2, 3 or 4 carbon atoms;
a zero, 1 or 2;
R(2) hydrogen, F, CI, Br, I, O-R(7) or SO~-R(22);
R(7) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl
which is unsubstituted or substituted by 1, 2 or 3 identical or different
radicals from the series F, CI, Br, I, CF3 methyl, methoxy, hydroxyl or
NR(12)R(13);
R(12) and R(13) independently of one another hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms;
n zero, 1 or 2;
R(22) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3,
4,
5, 6 or 7 carbon atoms or -CSH2S-phenyl which is unsubstituted or
substituted by 1, 2 or 3 identical or different radicals from the series F,
CI, Br, I, CF3, methyl, methoxy, hydroxyl or NR(34)R(35);
R(34) and R(35) independently of one another
hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
s zero, 1 or 2
R(3) hydrogen, -CN, or CO-R(6);
R(6) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
OR(30);
R(30) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(91 ) hydrogen,
R(90) SOp-R(16),
p zero, 1 or 2;
R(16) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is
unsubstituted or substituted by 1, 2 or 3 identical or different radicals
CA 02476454 2004-08-16
22
from the series F, CI, Br, I, CF3, methyl, methoxy, hydroxyl or
NR(26)R(27);
R(26) and R(27) independently of one another hydrogen or alkyl having 1, 2,
3 or 4 carbon atoms.
The invention further relates to the use of compounds of the formula II for
producing
a medicament for the prophylaxis and therapy of acute or chronic diseases
which are
caused by elevated levels of von Willebrand factor in the blood and/or
increased
expression of P-selectin, in which the symbols have the following meaning:
R(1 ) -CaH2a-phenyl, where the phenyl moiety is unsubstituted or substituted
by 1
or 2 identical or different radicals from the series F, CI, Br, CF3, methyl,
methoxy, hydroxyl or NR(8)R(9);
R(8) and R(9) independently of one another hydrogen or methyl;
a zero or 1;
R(2) F, CI, Br or I, in particular CI; or OR(7);
R(7) alkyl having 1, 2, 3 or 4 carbon atoms;
R(3) CO-R(6);
R(6) and R(91 ) hydrogen;
R(90) S02R(16) with R(16) equal to alkyl having 1, 2, 3 or 4 carbon atoms.
The invention further relates to the abovementioned use of the compounds of
the
formula II, where
the compound of the formula II is a compound of the formula Ila or Ilb,
NJ ~N
R1--~n ',--R3 R1--~N~F23
o _~ _ ._. . , o
..,..
(!la).
~c~1 ~l~b>,
R ~°
CA 02476454 2004-08-16
23
and the radicals R(1 ), R(2), R(3) and R(90) are as defined above.
The invention further relates to the use of compounds of the formula II and/or
all
stereoisomeric forms of the compounds of the formula II undlor mixtures of
these
forms in any ratio, andlor of the physiologically tolerated salts of the
compounds of
the formula II
for producing a medicament for the prophylaxis and therapy of acute or chronic
diseases which are caused by elevated levels of von Willebrand factor in the
blood
and/or increased expression of P-selectin,
in which the symbols have the following meaning:
R(1 ) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -CaH2a-
phenyl,
where the phenyl moiety is unsubstituted or substituted by 1, 2 or 3 identical
or different radicals from the series F, CI, Br, I, CF3, methyl, methoxy,
hydroxyl or NR(8)R(9);
R(8) and R(9) independently of one another hydrogen or alkyl having 1, 2, 3
or 4 carbon atoms;
a zero, 1 or 2; or
R(1 ) -CbH2b-heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, where
the
heteroaryl moiety is unsubstituted or substituted by 1, 2 or 3 identical or
different radicals from the series F, CI, Br, I, CF3~ methyl, methoxy,
hydroxyl
or NR(10)R(11 );
R(10) and R(11 ) independently of one another hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms;
b zero, 1 or 2; or
R(1 ) -CdH2d-cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms;
d zero, 1 or 2;
R(2) and R(3) independently of one another hydrogen, F, CI, Br, I, CF3, -CN, -
N02,
CH20R(17), CO-R(6), O-R(7), O-(alkylene having 2, 3, or 4 carbon atoms)-O-
R(17) or NR(50)R(51 );
R(17) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(6) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, OR(30) or
phenyl which is unsubstituted or substituted by 1, 2 or 3 identical or
CA 02476454 2004-08-16
24
different radicals from the series F, CI, Br, I, CF3, methyl, methoxy,
hydroxyl or NR(31 )R(32);
R(31 ) and R(32) independently of one another
hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R(30) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(50) and R(51 ) independently of one another -(alkylene having 2, 3, or
4 carbon atoms)-O-R(52);
R(52) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(7) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, or phenyl
which is unsubstituted or substituted by 1, 2 or 3 identical or different
radicals from the series F, CI, Br, I, CF3, methyl, methoxy, hydroxyl or
NR(12)R(13);
R(12) and R(13) independently of one another hydrogen or alkyl having 1, 2,
3 or 4 carbon atoms; or
R(7) heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, which is
unsubstituted or substituted by 1, 2 or 3 identical or different radicals
from the series F, CI, Br, I, CF3, methyl, methoxy, hydroxyl or
NR(14)R(15);
R(14) and R(15) independently of one another hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms; or
R(2) and R(3) independently of one another alkyl having 1, 2, 3, 4, 5, 6, 7 or
8
carbon atoms, cycloalkyl having 3, 4, 5, 6 or 7 carbon atoms or -Cg H2g-
phenyl, where the phenyl moiety is unsubstituted or substituted by 1, 2 or 3
identical or different radicals from the series F, CI, Br, I, CF3, methyl,
methoxy,
hydroxyl or NR(18)R(19);
R(18) and R(19) independently of one another hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms;
g zero, 1 or 2; or
R(2) and R(3) independently of one another C~H2~-heteroaryl having 1, 2, 3, 4,
5, 6,
7, 8 or 9 carbon atoms, where the heteroaryl moiety is unsubstituted or
substituted by 1, 2 or 3 identical or different radicals from the series F,
CI, Br,
I, CF3, methyl, methoxy, hydroxyl or NR(20)R(21 );
CA 02476454 2004-08-16
R(20) and R(21 ) independently of one another hydrogen or alkyl having
1, 2, 3 or 4 carbon atoms;
zero, 1 or 2; or
R(2) and R(3) independently of one another SO~-R(22);
5 n zero, 1 or 2;
R(22) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, cycloalkyl having 3,
4,
5, 6 or 7 carbon atoms or -CSH2S-phenyl which is unsubstituted or
substituted by 1, 2 or 3 identical or different radicals from the series F,
CI, Br, I, CFg, methyl, methoxy, hydroxyl or NR(34)R(35);
10 R(34) and R(35) independently of one another
hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
s zero, 1 or 2;
R(90) and R(91 ) independently of one another hydrogen, alkyl having 1, 2, 3,
4, 5, 6,
7 or 8 carbon atoms, F, CI, Br, I, CF3, -CN, -NO2, SOp-R(16), CO-R(23),
15 O-R(24) or O-(alkylene having 2,3 or 4 carbon atoms)-O-R(33);
p zero, 1 or 2;
R(16) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or phenyl which is
unsubstituted or substituted by 1, 2 or 3 identical or different radicals
from the series F, CI, Br, I, CF3, methyl, methoxy, hydroxyl or
20 NR(26)R(27);
R(26) and R(27) independently of one another hydrogen or alkyl having
1, 2, 3, or 4 carbon atoms;
R(23) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
OR(25);
25 R(25) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(24) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or
phenyl, which is unsubstituted or substituted by 1, 2 or 3
identical or different radicals from the series F, CI, Br, I, CF3,
methyl, rnethoxy, hydroxyl or NR(28)R(29);
R(28) and R(29) independently of one another
hydrogen or alkyl having 1, 2, 3 or 4 carbon atoms;
R(33) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
CA 02476454 2004-08-16
26
with the proviso that at least one of the radicals R(2) or R(3) is
O-(alkylene having 2, 3, or 4 carbon atoms)-O-R(17) or
NR(50)R(51 ).
The invention further relates to the use of
4'-[5-formyl-4-(2-methoxyethoxy)-2-phenyl-1-imidaze!ylrnett;yl]-3'-
mefihyisulfonyl-
biphenyl-2-sulfonylcyanamide of the following formula
% \ -, o
N ~N
H~I
S
O~ ~ / \ O
or 4'-{[benzyl(thiophene-2-sulfonyl)amino]methyl}-3'-methanesulfonylbiphenyl-2-
sulfonylcyanamide of the following formula
O=S
_
N.-~.NiS-O O ~S=O
H O
for producing a medicament for the prophylaxis and therapy of acute or chronic
diseases which are caused by elevated levels of von Willebrand factor in the
blood
and/or increased expression of P-selectin.
The invention further relates to the use of compounds of the formula III
R~oa Rios R~os R~o~
~N / ~ f11
I I ~ ~ S=O
Riot ~ ~ N-- iN
R~os
and/or all stereoisomeric forms of compounds of the formula III and/or
mixtures of
these forms in any ratio, and/or of the physiologically tolerated salts of the
CA 02476454 2004-08-16
27
compounds of the formula III for producing a medicament for the prophylaxis
and
therapy of acute or chronic diseases which are caused by elevated levels of
von
Willebrand factor in the blood and/or increased expression of P-selectin, in
which the
symbols have the following meaning:
R(101 )1. alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
2. alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbcn atoms, in which one to all
hydrogen atoms are replaced by fluorine;
3. alkenyl having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; or
4. -CnH2n-n~ -Y, nn zero or 2; and n zero, 1, 2, 3 or 4; where n is not zero
or 1 when nn is 2;
5. -CnH2n-nn -Y, nn zero or 2; and n 1, 2, 3 or 4; where n is not 1 when
nn is 2;
where 1, 2 or 3 hydrogen atoms in the divalent radical -C~H2~_nn- are replaced
independently of one another by a radical from the series
1. aryl having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms,
preferably phenyl, 1-naphthyl or 2-naphthyl;
2. amino;
3. NR(22)R(23);
4. alkoxycarbonyl;
5. COOR(16);
6. alkyl having 1, 2, 3 or 4 carbon atoms;
7. (Cg-C~4)-aryl-(C~-C4)-alkylcarbonjrl, preferably phenylacetyl;
R(102) 1. hydrogen;
2. alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
3. alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, in which one to
all hydrogen atoms are replaced by fluorine;
4. alkenyl having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms;
5. alkynyl having 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
6. -CnH2n_nn -Z, nn zero or 2; and n zero, 1, 2, 3 or 4; where n is
not zero or 1 when nn is 2;
CA 02476454 2004-08-16
28
7. -Cnhi2n-nn -z~ nn zero or 2; and n 1, 2, 3 or 4, where n is not 1
when nn is 2;
where 1, 2 or 3 hydrogen atoms in the divalent radical -CnH2n_nn- are
replaced independently of one another by a radical from the series
1. aryl having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms,
preferably phenyl, 1-naphthyl or 2-naphthyl;
2. amino;
3. NR(22)R(23);
4. (C~-C4)-alkoxycarbonyl;
5. COOR(16);
6. alkyl having 1, 2, 3 or 4 carbon atoms;
R(103) and R(104) independently of one another
hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
R(105), R(106) and R(107) independently of one another
hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, CI, Br, I,
CF3, -CN, -N02, SOq-R(8), CO-R(21 ) or O-R(10);
R(8) alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, NR(11)R(12) or
phenyl which is unsubstituted or substituted by 1, 2 or 3 identical or
different radicals from the series F, CI, Br, I, CF3, methyl, methoxy,
hydroxyl or NR(11 )R(12);
R(9) and R(21 ) independently of one another
hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or OR(13);
R(10) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, optionally
substituted by (C1-C4)-alkoxy; or phenyl which is unsubstituted or
substituted by 1, 2 or 3 identical or different radicals from the series F,
CI, Br, I, CF3, methyl, methoxy, hydroxyl or NR(11 )R(12);
R(11 ), R(12), R(19) and R(20) independently of one another
hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or (C~-C4)-alkanoyl,
preferably acetyl;
R(13) hydrogen or alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
XA carbonyl, -CO-NH-, -CO-CO- or sulfonyl;
Y and Z independently of one another
CA 02476454 2004-08-16
29
1. aryl having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms,
preferably phenyl, 1-naphthyl or 2-naphthyl;
2. a radical as defined under 1. which is substituted by 1, 2, 3, 4 or
identical or different radicals from the series alkyl having 1, 2,
5 3, 4, 5, 6, 7 or 8 carbon atoms, aryl having 6, 7, 8, 9, 10, 11, 12,
13 or 14 carbon atoms, preferably phenyl, 1-naphthyl or
2-naphthyl, F, CI, Br, I, CF3, SOqR(18), OR(16), NR(19)R(20),
-CN, N02 or CO-R(9), or where two radicals together form a
fused heterocyclyl radical, preferably methylenedioxy.
3. heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms;
4. a radical as defined under 3. which is substituted by 1, 2 or 3
identical or different radicals from the series F, CI, Br, I, CF3,
CH3, methoxy, hydroxyl or NR(11 )R(12);
5. cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms,
preferably cyclopropyl, cyclopentyl, cyclohexyl. 1,2,3,4-
tetrahydronaphthyl or indanyl;
6. a radical as defined under 5. substituted by aryl having 6, 7, 8, 9,
10, 11, 12, 13 or 14 carbon atoms, preferably phenyl, 1-naphthyl
or 2-naphthyl;
7. O-R(14);
8. O-R( 17 );
9. -S02-R(14);
10. arylalkylcarbonyl, preferably phenyl-CH2-CO-; or
11. heterocyclyl;
R(14) and R(17) independently of one another
1. hydrogen;
2. alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms;
3. alkenyl having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms;
4. -CnH2n-nn - phenyl,
nn zero or 2; and
n zero, 1, 2, 3 or 4; where n is not zero or 1 when nn is 2;
CA 02476454 2004-08-16
5. a radical as defined under 4., where the phenyl moiety is
substituted by 1, 2 or 3 identical or different radicals from the
series alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, F, CI,
Br, I, CF3, SOqR(15), OR(16), NR(11 )R(12), -CN, -N02 or CO-
5 R(9); or
R(15) and R(18) independently of one another
alkyl having 1, 2, 3 or 4 carbon atoms, alkyl having 1, 2, 3 or 4 carbon
atoms, in which one to all hydrogen atoms are replaced by fluorine,
preferably CF3, or NR(11 )R(12);
10 R(16) 1. hydrogen,
2. alkyl having 1, 2, 3 or 4 carbon atoms,
3. alkyl having 1, 2, 3 or 4 carbon atoms substituted by (C1-C4)-
alkoxy;
4. alkyl having 1, 2, 3 or 4 carbon atoms in which one to all
15 hydrogen atoms are replaced by fluorine, preferably CF3;
5. aryl having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms,
preferably phenyl, 1-naphthyl or 2-naphthyl;
6. a radical as defined under 5. which is substituted by 1, 2 or 3
identical or different radicals from the series F, CI, Br, I, CF3,
20 NR(19)R(20), -CN, N02 ;
R(22) and R(23) independently of one another hydrogen or CO-OR(24);
R(24) hydrogen, alkyl having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms or -C~H2~ -
phenyl
with n equal to 1, 2, 3 or 4;
q independently of one another zero, 1 or 2.
The invention further relates to the use of compounds of the formula IV
R~~a R~,s R R,»
~,s
/ ~ IV
S=O
~~N~N
H
CA 02476454 2004-08-16
31
and/or all stereoisomeric forms of the compounds of the formula IV and/or
mixtures
of these forms in any ratio, and/or of the physiologically tolerated salts of
the
compounds of the formula IV
for producing a medicament for the prophylaxis and therapy of acute or chronic
diseases which are caused by elevated levels of von Willebrand factors in the
blood
andlor increased expression of P-sslectin, in e~~hich the symbols have the
following
meanings:
R(111 )hydrogen, alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms, 1-naphthyl,
2-naphthyl, -CaH2a-cycloalkyl having 3,4,5,6 or 7 carbon atoms or -CaH2a-
phenyl, where the phenyl moiety is unsubstituted or substituted by 1 to 3
substituents from the group alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms, F,
CI, Br, I, CF3, SO~R(11 ), OR(17); NR(8)R(9), -CN, -N02 or CO-R(22);
R(11 ) alkyl having 1,2,3 or 4 carbon atoms or NR(20)R(21 );
R(20) and R(21 ) independently of one another hydrogen or alkyl having 1,2,3
or 4
carbon atoms; R(17) hydrogen or alkyl having 1,2,3 or 4 carbon atoms;
R(8) and R(9) independently of one another hydrogen or alkyl having 1,2,3 or
4 carbon atoms;
R(22) hydrogen, alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms or OR(30);
R(30) hydrogen, alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms;
a zero, 1 or 2;
n zero, 1 or 2; or
R(111 ) and R(113) together with the carbon atom bearing them cycloalkyl
having 3,
4, 5, 6 or 7 carbon atoms or fluorenyl;
R(112), R(113), R(114) and R(115) independently of one another hydrogen, F,
CF3,
O-R(10), alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms, cycloalkyl having 3, 4,
5, 6 or 7 carbon atoms, -C9H29-phenyl, where the phenyl moiety is
unsubstituted or substituted by 1 to 3 substituents from the group F, CI, Br,
I,
CF3, methyl, methoxy, hydroxyl or NR(18)R(19);
R(18) and R(19) independently of one another hydrogen or alkyl having 1,2,3
or 4 carbon atoms;
g zero, 1 or 2;
CA 02476454 2004-08-16
32
R(10) hydrogen, alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms, phenyl which is
unsubstituted or substituted by 1-3 substituents from the group of F, CI,
Br, I, CF3, methyl, methoxy, hydroxyl or NR(12)R(13);
R(12) and R(13) independently of one another hydrogen or alkyl having
1,2,3 or 4 carbon atoms; or
R(10) heteroaryl having 1,2,3,4,5,6,7,8 or 9-carbon atoms, which is
unsubstituted or substituted by 1-3 substituents from the group of F, CI,
Br, I, CF3, CH3, methoxy, hydroxyl or NR(14)R(15);
R(14) and R(15) independently of one another hydrogen or alkyl having
1,2,3 or 4 carbon atoms; or
R(112) and R(114) together a second bond between the carbon atoms bearing the
radicals R(113) and R(115), where R(111 ), R(113), R(115) are as defined
above;
R(116) and R(117) independently of one another hydrogen, F, CI, Br, I, CF3, -
CN,
-N02, SOp-R(16),CO-R(23) or O-R(24);
R(23) hydrogen, alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms or OR(25);
R(25) hydrogen, alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms;
R(24) hydrogen, alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms or phenyl which
is unsubstituted or substituted by 1-3 substituents from the group of F,
CI, Br, I, CF3, methyl, methoxy, hydroxyl or NR(28)R(29);
R(28) and R(29) H or alkyl having 1,2,3 or 4 carbon atoms;
R(16) alkyl having 1,2,3,4,5,6,7 or 8 carbon atoms, phenyl which is
unsubstituted or substituted by 1-3 substituents from the group of F, CI,
Br, I, CF3, methyl, methoxy, hydroxyl or NR(26)R(27);
R(26) and R(27) H or alkyl having 1,2,3 or 4 carbon atoms;
p zero, 1 or 2.
The invention further relates to the use of compounds of the formula IV and/or
all
stereoisomeric forms of the compounds of the formula IV and/or mixtures of
these
forms in any ratio, and/or of the physiologically tolerated salts of the
compounds of
the formula IV
CA 02476454 2004-08-16
33
for producing a medicament for the prophylaxis and therapy of acute or chronic
diseases which are caused by elevated levels of von Willebrand factors in the
blood
and/or increased expression of P-selectin, in which the symbols have the
following
meaning:
R(111 ) methyl, ethyl, 1-naphthyl, 2-naphthyl, cycloalkyl having 3, 4, 5, 6 or
7 carbon
atoms or phenyl which is unsubstituted or substituted by one substituent fror~
i
the group of alkyl having 1,2,3 or 4 carbon atoms, F, CI, CF3, S02R(11 ),
OR(17), NR(8)R(9), or CO-R(22);
R(11 ) methyl or dimethylamino;
R(17) hydrogen, methyl or ethyl;
R(8) and R(9) independently of one another hydrogen, methyl or ethyl;
R(22) hydrogen or alkyl having 1,2,3 or 4 carbon atoms; or
R(111 ) and R(1113) together with the carbon atom bearing them cycloalkyl
having 3,
4, 5, 6 or 7 carbon atoms or fluorenyl;
R(112) and R(114) hydrogen; or
R(112) and R(114) together a second bond between the carbon atoms bearing the
radicals R(113) and R(115);
R(113) and R(115) independently of one another hydrogen, CF3, O-R(10), alkyl
having 1, 2, 3 or 4 carbon atoms or phenyl which is unsubstituted or
substituted by one substituent from the group of F, CI, CF3, methyl, methoxy,
hydroxyl or NR(18)R(19);
R(18) and R(19) independently of one another hydrogen, methyl or ethyl;
R(10) hydrogen, alkyl having 1,2,3 or 4 carbon atoms or phenyl which is
unsubstituted or substituted by 1 substituent from the group of F, CI,
CF3, methyl, methoxy, hydroxyl or NR(12)R(13);
R(12) and R(13) independently of one another hydrogen, methyl or ethyl, or
R(10) heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms which is
unsubstituted or substituted by one substituent from the group of F, CI,
CF3, CH3, methoxy, hydroxyl or dimethylamino;
R(116) and R(117) independently of one another hydrogen, F, CI, CF3, S02-CH3,
CO-R(23) or O-R(24);
R(23) hydrogen or alkyl having 1,2,3 or 4 carbon atoms;
CA 02476454 2004-08-16
34
R(24) hydrogen, alkyl having 1,2,3 or 4 carbon atoms or phenyl which is
unsubstituted or substituted by 1 substituent from the group of F, CI,
CF3, methyl, methoxy, hydroxyl or NR(28)R(29);
R(28) and R(29) independently of one another hydrogen, methyl or ethyl.
In particular, there is also use of compounds of the formula IV in which the
biphenyl
ring is linked as in compounds of following formula
R"a O
R»z R~,s
Ri" / O =S- N
»s ~ ~R"~
and the sulfonylcyanamide group is in position 2.
The abovementioned compounds are known and can be prepared as described, for
example, in EP 0 855 392, EP 1 097 140, EP 1 097 141, EP 1 076 651,
EP 1 053 224 or EP 0 903 339.
Alkyl radicals and alkylene radicals may be straight-chain or branched. This
also
applies to the alkylene radicals of the formulae CaH2a,CbH2b, CdH2d,CgH2g,and
C~H21. Alkyl radicals and alkylene radicals may also be straight-chain or
branched
when they are substituted or present in other radicals, e.g. in an alkoxy
radical or in
an alkylmercapto radical or in a fluorinated alkyl radical.
Cycloalkyl also means alkyl-substituted rings.
Examples of alkyl radicals having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms are:
methyl,
ethyl, n-propyl, n-butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl,
isopentyl,
neopentyl, isohexyl, 3-methylpentyl, sec-butyl, tert-butyl, tent-pentyl. The
divalent
radicals derived from these radicals, e.g. methylene, 1,1-ethylene, 1,2-
ethylene, 1,1-
propylene, 1,2-propylene, 2,2-propylene, 1,3-propylene, 1,4-butylene, 1,5-
pentylene,
2,2-dimethyl-1,3-propylene, 1,6-hexylene, etc. are examples of alkylene
radicals.
CA 02476454 2004-08-16
Cycloalkyl radicals having 3, 4, 5, 6 or 7 carbon atoms are, in particular,
cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl which may, however, also be
substituted by alkyl having 1, 2, 3 or 4 carbon atoms. 4-Methylcyclohexyl and
2,3-
5 dimethylcyclopentyl may be mentioned as examples of substituted cycloalkyl
radicals.
Heteroaryl having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms means, in
particular,
radicals derived from phenyl or naphthyl in which one or more CH groups are
10 replaced by N and/or in which at least two adjacent CH groups are replaced
by S,
NH or O (to form a five-membered aromatic ring). It is further possible for
one or both
atoms at the fusion site in bicyclic radicals (as in indolizinyl) to be
nitrogen atoms.
Heteroaryl is, in particular, furanyl, thienyl, pyrrolyl, imidazolyl,
pyrazolyl, triazolyl,
15 tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,
pyrazinyl, pyrimidinyl,
pyridazinyl, indolyl, indazolyl, quinolyl, isoquinolyl, phthalazinyl,
quinoxalinyl,
quinazolinyl, cinnolinyl. Nitrogen-containing heterocycles having 1, 2, 3, 4,
5, 6, 7, 8
or 9 carbon atoms are, in particular, the aromatic systems 1-, 2- or 3-
pyrrolyl, 1-, 2-,
4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4- or 5-yl,
1,2,4-triazol-1-,
20 -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-
isoxazolyl, 1,2,3-
oxadiazol-4- or 5-yl, 1,2,4-oxadiazol-3-or 5-yl, 1,3,4-oxadiazol-2-yl or -5-
yl, 2-, 4- or
5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-
thiadiazol-3- or -
5-yl, 1,2,3-thiadiazol-4- or 5-yl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-
pyrimidinyl, 3- or 4-
pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-
benzimidazolyl,
25 1-, 3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-
, 3-, 4-, 5-, 6-, 7- or
8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-
cinnolinyl, 2-, 3-,
5-, 6-, 7- or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl.
The nitrogen-containing heterocycles are particularly preferably pyrrolyl,
imidazolyl,
30 quinolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl.
Thienyl stands for both 2- and for 3-thienyl. furyl stands for 2- and 3-furyl.
Monosubstituted phenyl radicals may be substituted in position 2, 3 or 4,
disubstituted in position 2,3, 2,4, 2,5, 2,6, 3,4 or 3,5, trisubstituted in
position 2,3,4,
CA 02476454 2004-08-16
36
2,3,5, 2,3,6, 2,4,5, 2,4,6 or 3,4,5. Corresponding statements also apply
analogously
to the nitrogen-containing heterocycles or the thiophene radical.
If the radical is di- or trisubstituted, the substituents may be identical or
different.
The invention further relates to the use of the abovementioned compounds of
the
formulae I, II, III and IV in combination with inhibitors of the
sodium/hydrogen
exchanger.
The invention further relates to the use of the abovementioned compounds of
the
formulae I, II, III and IV in combination with inhibitors of the
sodiumlhydrogen
exchanger from the following group of agents
i
w
H C-O S ~ N N H~ H C-O S ~ N~ NHZ
3 2 3 2
O NH2. O NH2
I
o~,
O S ~ / NYNH2. wS I / N~~NHZ
O NHz O O p NHZ
O
O N
~N ~ ~ N
NYNHZ O~S I ~ N~NHz
O O NH2 O O NHz
O ~
N\/NHZ
O 'T~
O N Hz
0 N~NHZ N
NH
( / ~ Z ~ / Nw N Hi
O N
~o
CA 02476454 2004-08-16
37
0
N -.~-~-, N . . .-
H .,,,, I
N
NH
NH
o N-
N H~
NHZ
NH2
N~"'~ .N Hz ~ .
0
tr H3
of
~.N'~NH2
N
NHZ
and/or all stereoisomeric forms of the abovementioned compounds and/or
mixtures
of these forms in any ratio, and/or of the physiologically tolerated salts of
the
abovementioned compounds
for producing a medicament for the prophylaxis and therapy of acute or chronic
diseases which are caused by elevated levels of von Willebrand factor in the
blood
and/or increased expression of P-selectin.
CA 02476454 2004-08-16
38
The invention further relates to the use of the compounds of the formulae I,
II, III
and/or IV in combination with cariporide
~'O35-CH3
N\ 'NH2
H3C '~~-
N H2
for producing a medicament for the prophylaxis and therapy of acute or chronic
diseases which are caused by elevated levels of von Willebrand factor in the
blood
and/or increased expression of P-selectin.
The invention further relates to the use of 4'-[5-formyl-4-(2-methoxyethoxy)-2-
phenyl-
1-imidazolylmethyl]-3'-methylsulfonylbiphenyl-2-sulfonylcyanamide in
combination
with cariporide for producing a medicament for the prophylaxis and therapy of
acute
or chronic diseases which are caused by elevated levels of von Willebrand
factor in
the blood and/or increased expression of P-selectin.
The abovementioned compounds are known and can be prepared as described, for
example, in EP 0 416 499, EP 0 556 673, EP 0 589 336, EP 0 622 356,
EP 0 699 666, EP 0 708 088, EP 0 719 766, EP 0 726 254, EP 0 787 728,
EP 0 972 767, DE 19529612, DE 19601303, WO 99 00379 or T.Kawamoto et al.,
Eur.J. Pharmacol. 420 (2001 ), 1-8.
Where the abovementioned compounds allow diastereoisomeric or enantiomeric
forms and result as mixtures thereof in the chosen synthesis, separation into
the
pure stereoisomers takes place either by chromatography on an optionally
chiral
support material or, if the racemic abovementioned compounds are able to form
salts, by fractional crystallization of the diastereomeric salts formed with
an optically
active base or acid as aid. Examples of suitable ehiral stationary phases for
separation of enantiomers by thin-layer or column chromatography are modified
silica gel supports (so-called Pirkle phases) and high molecular weight
carbohydrates such as triacetylcellulose. Gas chromatographic methods on
chiral
stationary phases can also be used for analytical purposes after appropriate
derivatization known to the skilled worker. To separate enantiomers of the
racemic
carboxylic acids, diastereomeric salts differing in solubility are formed
using an
CA 02476454 2004-08-16
39
optically active, usually commercially available, base such as (-)-nicotine,
(+)- and (-
-phenylethylamine,quinine bases, L-lysine or L- and D-arginine, the less
soluble
component is isolated as solid, the more soluble diastereomer is deposited
from the
mother liquor, and the pure enantiomers are obtained from the diastereomeric
salts
obtained in this way. It is possible in the same way in principle to convert
the racemic
compounds of the formula I containing a basic group such as an wn;ino group
with
optically active acids such as (+)-camphor-10-sulfonic acid, D- and L-tartaric
acid, D-
and L- lactic acid and (+) and (-)-mandelic acid into the pure enantiomers.
Chiral
compounds containing alcohol or amine functions can also be converted with
appropriately activated or, where appropriate, N-protected enantiopure amino
acids
into the corresponding esters or amides, or conversely convert chiral
carboxylic
acids with carboxyl-protected enantiopure amino acids into the amides or with
enantiopure hydroxy carboxylic acids such as lactic acid into the
corresponding
chiral esters. The chirality of the amino acid or alcohol residue produced in
enantiopure form can then be utilized for separating the isomers by carrying
out a
separation of the diastereomers which are now present by crystallization or
chromatography on suitable stationary phases and then eliminating the included
chiral moiety by suitable methods.
Acidic or basic products of the abovementioned compounds can exist in the form
of
their salts or in free form. Preference is given to pharmacologically suitable
salts, e.g.
alkali metal or alkaline earth metal salts, or hydrochlorides, hydrobromides,
sulfates,
hemisulfates, all possible phosphates, and salts of amino acids, natural bases
or
carboxylic acids.
Physiologically tolerated salts are prepared from the abovementioned compounds
able to form salts, including the stereoisomeric forms thereof, in a manner
known per
se. The carboxylic acids and hydroxamic acids form with basic reagents such as
hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic
bases,
for example trimethyl- or triethylamine, ethanolamine or triethanolamine or
else basic
amino acids, for example lysine, ornithine or arginine, stable alkali metal,
alkaline
earth metal or optionally substituted ammonium salts. Where the abovementioned
compounds have basic groups, stable acid addition salts can also be prepared
with
strong acids. Suitable for this purpose are both inorganic and organic acids,
such as
CA 02476454 2004-08-16
hydrochloric, hydrobrornic, sulfuric, phosphoric, methanesulfonic,
benzenesulfonic,
p-toluenesulfonic, 4-bromobenzenesulfonic, cyclohexylsulfamic,
trifluoromethylsulfonic, acetic, oxalic, tartaric, succinic or trifluoroacetic
acid.
Methanesulfonic acid salts of the abovementioned compounds are particularly
5 preferred.
Owing to the pharmacological properties, the abovementioned compounds are
suitable for the prophylaxis and therapy of acute or chronic diseases which
are
caused by elevated levels of von Willebrand factor in the blood and/or
increased
10 expression of P-selectin.
These include thrombotic disorders provoked by ischemic states with subsequent
reperfusion; such as thromboses in acute myocardial, mesenteric or else
cerebral
infarction; thrombotic disorders occurring during or after surgical
operations;
15 pulmonary embolisms; deep vein thromboses as occur at an increased rate
after
prolonged restriction of blood flow, especially in the lower extremities, for
example
after prolonged lying or sitting, and imflammatory disorders as occur during
ischemia
and subsequent reperfusion, during vasculitis (e.g. associated with
autoirnmune
disease or connective tissue disease).
20 These also include disorders which are caused by increased expression of P-
selectin, such as incipient inflammatory reactions; but also prophylaxis and
treatment
of arteriosclerosis; and prophylaxis and treatment of cancer; also
inflammation of
joints and arthritic disorders such as rheumatoid arthritis.
Administration of the medicaments of the invention can take place by oral,
25 inhalational, rectal or transdermal administration or by subcutaneous,
intraarticular,
intraperitoneal or intravenous injection. Oral administration is preferred.
The invention also relates to a process for producing a medicament, which
comprises converting at least one of the abovementioned compounds with a
30 pharmaceutically suitable and physiologically tolerated carrier and, where
appropriate, other suitable active ingredients, additives or excipients into a
suitable
dosage form.
The abovementioned compounds are mixed with the additives suitable for this
purpose, such as carriers, stabilizers or inert diluents, and converted by
conventional
CA 02476454 2004-08-16
41
methods into suitable dosage forms such as tablets, coated tablets, two-piece
capsules, aqueous alcoholic or oily suspensions or aqueous or oily solutions.
Examples of inert carriers which can be used are gum arabic, magnesia,
magnesium
carbonate, potassium phosphate, lactose, glucose or starch, especially corn
starch.
Preparation can moreover take place both as dry and as wet granules. Examples
of
suitable oily carriers or solvents are vegetable or animal oils., such as
sunflower oil or
fish liver oil.
For subcutaneous, intraperitoneal or intravenous administration, the active
compounds are converted into solution, suspension or emulsion if desired with
the
substances suitable for this purpose, such as solubilizers, emulsifiers or
other
excipients. Examples of suitable solvents are physiological saline or
alcohols, e.g.
ethanol, propanol, glycerol, as well as sugar solutions such as glucose or
mannitol
solutions, or else a mixture of the various solvents mentioned.
Also used are conventional aids such as carriers, disintegrants, binders,
coating
agents, swelling agents, glidants or lubricants, flavorings, sweeteners and
solubilizers. Excipients which are frequently used and which may be mentioned
are
magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars,
talc,
milk protein, gelatin, starch, cellulose and derivatives thereof, animal and
vegetable
oils such as fish liver oil, sunflower, peanut or sesame oil, polyethylene
glycol and
solvents such as, for example, sterile water and monohydric and polyhydric
alcohols
such as glycerol.
The abovementioned compounds are preferably produced and administered as
pharmaceutical products in dosage units, where one unit contains as active
ingredient a defined dose of the abovementioned compounds. They can for this
purpose be administered orally in doses of from 0.01 mglkg/day to 25.0
mg/kg/day,
preferably 0.01 mg/kg/day to 5.0 mg/kg/day or parenterally in doses of from
0.001
mg/kg/day to 5 mg/kg/day, preferably 0.001 mg/kglday to 2.5 mg/kg/day. The
dosage may also be increased in severe cases. However, lower doses also
suffice in
many cases. These data relate to an adult weighing about 75 kg.
The abovementioned compounds can be employed alone or in combination with
anticoagulant, platelet aggregation-inhibiting or fibrinolytic agents.
Coadministration
CA 02476454 2004-08-16
42
can take place, for example, with factor Xa inhibitors, standard heparin, low
molecular weight heparins such as enoxaparin, dalteparin, certroparin,
parnaparin or
tinzaparin, direct thrombin inhibitors such as hirudin, aspirin, fibrinogen
receptor
antagonists, streptokinase, urokinase and/or tissue plasminogen activator
(tPA).
In contrast to the previously described effects of inhibitors of the sodium-
dependent
chloride/bicarbonate exchanger on the aggregation of blood platelets, the
abovementioned compounds also show inhibition of excessive release of von
Willebrand factor. This novel antithrombotic action principle differs from the
previously disclosed antithrombotic action principles in a crucial and
advantageous
manner in that
a) it acts only in ischemic tissue in the subsequent reperfusion phase,
whereas
other cells not affected by the ischemia (preischemic) will remain completely
unaffected, and
b) there is no need to worry about any of the dangerous hemorrhagic
complications during the lysis therapy.
The invention is explained in more detail by means of examples below.
The following examples demonstrated the effects of an extracellular acidosis
(pHeX = 6.4) and are specific inhibitors of the sodium-dependent
chloride/bicarbonate
exchanger (NCBE) on the intracellular pH (pH;) anti the release of von-
Willebrand
factor (vWF). All the examples were carried out with human umbilical vein
endothelial cells (HUVEC). These comprise primary cell cultures isolated from
the
umbilical vein.
For the following examples, the cells were cultivated either on gelatinized
glass
plates (measurement of the intracellular proton concentration) or on cell
culture
plates (12-well culture plates, Falcon, New Jersey, USA; measurement of vWF
release) after the first passage.
Example 1:
CA 02476454 2004-08-16
43
Measurement of the intracellular pH
To measure the intracellular proton concentration (pH;), the HUVECs were
loaded
with the pH-sensitive fluorescent dye BCECF-AM (2',7'-bis(carboxyethyl)-
5(6)-carboxyfluorescein). A Deltascan spectrofluorometer (PTI, Hamburg) was
employed for the subsequent fluorescence measurement. This measuring system
consists essentially of a UV light source, a monochromator, a photon detect;,.
anu
the Felix and Oscar software packages (PTI, Hamburg) for controlling the
system via
a computer. After alternate excitation with the wavelengths 439.5 nm (pH-
independent) and 490 nm (pH-sensitive), the ratio of the measured emissions of
the
BCECF (ratio) was reported and the pH was found after a calibration. The
measuring
cell is designed so that the parameters of temperature and carbon dioxide
partial
pressure in the system are controlled during continuous perfusion. For the
reperfusion simulation, the experimental conditions were set at 37°C
and a carbon
dioxide partial pressure of 5% or 10% by gassing the system and perfusate. In
the
experiment there was initially preincubation with sodium bicarbonate buffer
pHex 6.4
for 60 minutes in order to simulate respiratory metabolic acidosis. The
initiation
perfusion was then changed to sodium bicarbonate buffer of pH 7.4 with 10 NM
histamine as reperfusion simulation.
These control experiments were compared with an experiment in which the NCBE
inhibitor 4'-[5-formyl-4-(2-methoxyethoxy)-2-phenyl-1-imidazolylmethyl]-3'-
methylsulfonylbiphenyl-2-sulfonylcyanamide (called compound 1 hereinafter) and
an
NHE inhibitor were added, each in a concentration of 10 NM to the reperfusion
buffer.
The results of several experiments have been summarized in Tables 1 and 2.
Table 1: Intracellular pH during extracellular acidosis (pH; (acidosis)) of at
least
15 minutes and under control conditions (Co).
Table 1:
pH; (Acidosis) 6.53 0.02 (mean SEM)
pH; (Co) 7.23 0.02 (mean SEM)
SEM is the standard deviation from the mean
CA 02476454 2004-08-16
44
Extracellular acidosis leads to intracellular acidification which persists
during the
acidosis. The intracellular acidotic pH is virtually identical to the
extracellular pH
(applied extracellular acidosis pHex = 6.4).
Table 2: Reperfusion with experimental buffer containing the abovementioned
compound 1 and cariporide, cariporide-containing control buffer (NHE) ,end
control
buffer (Co). The time to the half-maximum pH; change after 60 minutes of
acidosis
was found from the measurements during the first 30 seconds after reperfusion.
CA 02476454 2004-08-16
Table 2:
Time to D pH~max I 2 [s]
Mean SEM
Co 18 1.5
NHE 1902.9
Compound 1 450 32.7
+cariporide
Example 2
Measurement of vWF release after reperfusion
5
The measurements were carried out in a Heraeus Heracell incubator. This made
it
possible to calculate the umbilical vein endothelial cells under controlled ,"
physiological conditions (temperature 37°C, relative humidity 100%,
pC02 constant
at 5%) and to ensure rapid change of different cell culture media.
Said cells were initially incubated with acidotic medium (pH 6.4 composed of
the
ingredients: medium M199 w/Earle's 8~ amino acids, w/L-glutamine, w/o NaHC03,
w/o Hepes + 0.0848 NaHC03 / I) or pH standard medium (pH 7.4 composed of the
ingredients: medium M199 w/Earle's & amino acids, wIL-glutamine, w/o NaHC03,
wlo Hepes + 2.2008 NaHC03 / I) for one, three or 48 hours. Before starting the
reperfusion, samples of supernatant were taken to determine the vWF
concentration
under acidotic conditions (vWFacidosis) and control conditions (vWFco). To
simulate
reperfusion, the medium was changed to one with a pH of 7.4 (ingredients:
medium
M199 w/Earle's & amino acids, w/L-glutamine, w/o NaHC03, w/o Hepes + 2.200 g
NaHC03 / I + 10 NM histamine) to which the abovementioned NCBE inhibitor
compound 1 was added in a concentration of 10 NM. Change to the same medium
without corresponding addition of inhibitor served as control.
The samples taken from the supernatant were used to determine the vWF
concentration. This was done by an ELISA method (enzyme-linked immuno sorbent
assay) using specific antibodies. The vWF content of standard human plasma
(Behring, Marburg) is calculated using an international standard (2"d
International
Standard 87/718; National Institute for Biological Standards and Control,
London).
CA 02476454 2004-08-16
46
Table 3: vWF conzentration in the cell supernatant under acidotic
(vWFacidosis) and
under control conditions (vWFco), measured after incubation for 15 minutes.
The
vWF concentration under control conditions is set at 100%.
Table 3:
vW Fco
100%
vW Facdosis (constitutive) 46 1.1
vWFacidosis (stimulated, histamine
52 2.5%
50 NM)
The acidosis led to a distinct decrease in vWF secretion, both the
constitutive
secretion and the stimulated Weibel-Palade body secretion. The vWF secretion
was
reduced by a factor of 2 compared with control cells during acidosis (pHeX =
6.4).
Table 4: vWF secretion was measured during a 10-minute reperfusion time with
stimulation. The vWF secretion of the control cells (vWFco) was set at 100%.
The
vWF concentration during the reperfusion of preacidotic cells (vWFacidosis)
and the
vWF concentration during reperfusion of preacidotic cells in the presence of
10 NM of
the abovementioned compound 1 (vWF~ ~) have been indicated as values relative
to
the control values.
Table 4:
vW Fco
100%
vW Facidosis 193 8.0%
vW Fc ~ 157 18/a
During the reperfusion there was a large increase in vWF secretion by a factor
of 2.
Blockade of the NCBE transporter with the abovementioned compound 1 reduces
the increased vWF secretion by almost 50% and thus approaches the control
values.
CA 02476454 2004-08-16
47
The examples showed that extracellular acidosis as present for example during
ischemia led to an intracellular acidosis, resulting in reduced (constitutive
and
stimulated) vWF secretions. The subsequent reperfusion and stimulation of the
endothelial cells brought about rapid intracellular realkalinization. There
was a
simultaneous enhancement of the increased vWF secretion. A delay ~f the
realkalinization with the abovementioned compound 1 reduces the increased vWF
secretion and thus the possible thrombosis. The data show that the
intracellular pH
is determined by the extracellular pH. Secretion by the endothelial cells is
in turn
determined by the intracellular pH. It is thus possible, by inhibiting
realkalinization, to
reduce greatly the known endothelial cell activation during the reperfusion
phase and
the worry, connected therewith, about rethrombosis (vWF secretion) and
inflammation.
