Note: Descriptions are shown in the official language in which they were submitted.
CA 02364908 2001-08-30
EM99002.DOC - 1 -
Pyrazol-3-one derivatives
The invention relates to compounds of the
formula I
Ra
Y~
R~ / O I
N-N
/ ~X~ Rs
Rz
in which
R1, Rz in each case independently of one another are
H, A, cycloalkyl- [C (R~R~~ ) ] n- or Ar- [C (R~R~~ ) ] n-,
R3, R4 in each case independently of one another are
H, Ar, Het, R5, where at least one of the two
radicals is R5,
R5 is phenyl, naphthyl or biphenyl [sic], which is
substituted by -C(=NH)-NH2 which can also be
monosubstituted by -COA, Ar-[C(R~R'~)]n-CO-,
COOA, OH or by a conventional amino protective
group , -NH-C ( =NH ) -NH2 , -CO-N=C ( NHZ ) 2 .
~~N.O ~~N.O
or N
HN-~ CH
~ 3
and which can optionally additionally be mono-
or disubstituted by A, Ar' , Het, OR6, NR6R6~,
N02, CN, Hal, NR6COA, NR6COAr' , NR6SOZA,
2 5 NR6S02Ar' , COOR6 , CO-NR6R6 ~ , CORD , CO-Ar' ,
SOzNR6R6 ~ , S ( 0 ) nAr' Or S ( 0 ) ,;A,
R6, R6~ in each case independently of one another are
H, A, CR~R~~-Ar' or CR~R~~-Het,
R', R'~ in each case independently of one another are H
or A,
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X, Y in each case independently of one another are
( CR~R~ ~ ) n,
A is alkyl having 1-20 C atoms, in which one or
two CH2 groups can be replaced by O or S atoms
and/or by -CH=CH- groups and/or 1-7 H atoms can
be replaced by F,
Ar is phenyl, naphthyl or biphenyl [sic], which is
unsubstituted or mono-, di- or trisubstituted
by A, Ar' , Het, OR6, NR6R6~, N02, CN, Hal,
NR6COA, NR6COAr' , NR6SOZA, NR6SOZAr' , COOR6,
CO-NR6R6 ~ , CON6Ar' , CORD , COAr' , S02NR6R6 ~
,
S(0)nAr' Or S(0)nA,
Ar' is phenyl or naphthyl, which is unsubstituted
or mono-, di- or trisubstituted by A, OR',
NR~R~~ , NOz, CN, Hal, NR~COA, NR~SOzA, COORS,
CO-NR~R~ ~ , CORD , SOZNR~R7 ~ or S ( 0 ) nA,
Het is a mono- or binuclear saturated, unsaturated
or aromatic heterocycle having 1 to 4 N, 0
and/or S atoms, which can be unsubstituted or
mono-, di- or trisubstituted by A, OR', NR'R'~ ,
NO2, CN, Hal, NR7COA, NR~SOzA, COOR', CO-NR~R~~
,
CORD , SOZNR~R~ ~ , S ( 0 ) nA and / or carbonyl
oxygen,
Hal is F, Cl, Br or I,
n is 0, 1 or 2,
and their pharmaceutically tolerable salts and
solvates.
The invention also relates to the optically
active forms, the racemates, the diastereomers and also
the hydrates and solvates, e.g. alcoholates, of these
compounds.
The invention was based on the object of
finding novel compounds having valuable properties, in
particular those which can be used for the production
of medicaments.
It has been found that the compounds of the
formula I and their salts have very valuable
pharmacological properties together with good
tolerability. In particular, they exhibit factor Xa-
inhibiting properties and can therefore be employed for
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- 3 -
the control and prevention of thromboembolic disorders
such as thrombosis, myocardial infarct,
arteriosclerosis, inflammation, apoplexy, angina
pectoris, restenosis after angioplasty and intermittent
claudication.
The compounds of the formula I according to the
invention can furthermore be inhibitors of the clotting
factors factor VIIa, factor IXa and thrombin of the
blood-clotting cascade.
Aromatic amidine derivatives having
antithrombotic action are disclosed, for example, in
EP 0 540 051 B1. Cyclic guanidines for the treatment of
thromboembolic disorders are described, for example, in
WO 97/08165. Aromatic heterocycles having factor Xa-
inhibitory activity are disclosed, for example, in
WO 96/10022. Substituted N-[(aminoiminomethyl)phenyl-
alkyl]azaheterocyclylamides as factor Xa inhibitors are
described in WO 96/40679.
The antithrombotic and anticoagulant effect of
the compounds according to the invention is attributed
to the inhibitory action against the activated clotting
protease, known under the name factor Xa, or to the
inhibition of other activated serin proteases such as
factor VIIa, factor IXa or thrombin.
Factor Xa is one of the proteases which is
involved in the complex process of blood clotting.
Factor Xa catalyses the conversion of prothrombin into
thrombin. Thrombin cleaves fibrinogen into fibrin
monomers, which, after crosslinking, contribute
elementarily to thrombus formation. Activation of
thrombin can lead to the occurrence of thromboembolic
disorders. Inhibition of thrombin, however, can inhibit
the fibrin formation involved in thrombus formation.
The inhibition of thrombin can be measured, for
example, according to the method of G.F. Cousins et
al., in Circulation 1996, 94, 1705-1712.
Inhibition o.f factor Xa can thus prevent
thrombin being formed.
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The compounds of the formula I according to the
invention, and their salts, intervene in the blood-
clotting process by inhibition of factor Xa and thus
inhibit the formation of thrombi.
The inhibition of factor Xa by the compounds
according to the invention and the measurement of the
anticoagulating and antithrombotic activity can be
determined by customary in vitro or in vivo methods . A
suitable process is described, for example, by
J. Hauptmann et al., in Thrombosis and Haemostasis
1990, 63, 220-223.
The inhibition of factor Xa can be measured,
for example, by' the method of T. Hara et al., in
Thromb. Haemostas. 1994, 71, 314-319.
After binding to tissue factor, the clotting
factor VIIa initiates the extrinsic part of the
clotting cascade and contributes to the activation of
factor X to factor Xa. Inhibition of factor VIIa thus
prevents the formation of factor Xa and thereby
subsequent thrombin formation.
The inhibition of factor VIIa by the compounds
according to the invention and the measurement of the
anticoagulant and antithrombotic activity can be
determined by customary in vitro or in vivo methods . A
customary process for measuring the inhibition of
factor VIIa is described, for example, by H.F. Ronning
et al., in Thrombosis Research 1996, 84, 73-81.
The clotting factor IXa is generated in the
intrinsic clotting cascade and is likewise involved in
the activation of factor X to factor Xa. Inhibition of
factor IXa can therefore prevent factor Xa being formed
in other ways.
The inhibition of factor IXa by the compounds according
to the invention and the measurement of the
anticoagulant and antithrombotic activity can be
determined by customary in vitro or in vivo methods . A
suitable process is described, for example, by J. Chang
et al., in Journal of Biological Chemistry 1998, 273,
12089-12094.
26. JUI. 2001 17.71 ~~- 0049 6151 727191- -w ~~-gin, uUu- ~-~, LlL-.. --_
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' _ g _
TtiG compounds of the formula I oan be employed
~a pharmacoutic3l active cruupcunds in human and
veterinary tnedicine, in particular for the control and
prAVention of thromboembolic disorders such ~s
thrombosis, myocardial infarct, artQrioaalcrosis,
inflammation, apoploxy, angina pecturla, restenosis
after angiopldaty and intermittent ~:laudicatioa.
Tha invention relatoa to the cvmpc:»tds of the
formula I and them Salts, arid ro a process for tho
preparati.~n of compounds of the formulas I acc:crding to
Claim 1 and their 'a~l~s, characterized in that
a) they are liberated rrom one of their f~.inctionaZ
derivatives by trRating with a aolvolysing vz
hydrogenolysing agent by
i) liborating en amidinr~ group from its
oxadiazole derivativo or oxazolidinone
derivativo by hydrogenolyalb or solvolysis,
~'. 0
ii) replacing a conventional eu~tiino protective
group by hydrvQen by treating with a
solvolysing or hydrogonolysluc~ agent or
liberating an amino Qro»p protoctod by a
rnnventional protoative group,
yr
b) iu t~ compound of the formula I, converting vne cr
morQ radicals RI, R~, R3 ana/vr R4 into onA or morn
za~dlcals Rl. Hs. R3 and/or R4,
by, for dxr~mple,
i) hydrolysing an later group to a c~arbo.:yl
group,
ii) reducing a nitre r~raup,
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iii) acylating an amino group,
iv) converting a cyano group into an amidino
group
and/or
c) converting a base or acid of the formula I into
one of its salts.
For all radicals which occur a number of times,
it is recognized that their meanings are independent of
one another.
Above and below, the radicals or parameters R1,
R2, R3, R4, X and Y have the meanings indicated in the
formula I, if not expressly stated otherwise.
A is alkyl, is unbranched (linear) or branched,
and has 1 to 20, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9
or 10 C atoms. A is preferably methyl, furthermore
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or
tert-butyl, in addition also pentyl, 1-, 2- or
3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,
1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl,
1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1-
or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-
methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl,
furthermore preferably, for example, trifluoromethyl.
A is very particularly preferably alkyl having 1-6 C
atoms, preferably methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, sec-butyl, tert-butyl, pentyl or
hexyl.
Cycloalkyl is preferably cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
Hal is preferably F, C1 or Br, but also I.
Ar is phenyl, naphthyl or biphenyl [sic], which
is unsubstituted or mono-, di- or trisubstituted by A,
Ar' , Het, OR6, NR6R6~, NO2, CN; Hal, NR6COA, NR°COAr' ,
NR6SOzA, NR6SO2Ar' , COOR6, CO-NR6R6~ , CON6Ar' , CORD, COAR' ,
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_ '
SOZNR6R6~ , S (O) nAr' or S (O) nA. Preferred substituents for
biphenyl [sic] are fluorine, SOzNH2 or SOZNHA.
Ar' is phenyl or naphthyl, which is
unsubstituted or mono-, di- or trisubstituted by A,
Het, OR6, NR6R6~, NOZ, CN, Hal, NR6COA, NR6SOZA, NR6SOZAr' ,
COOR6 , CO-NR6R6 ~ , CORD , S02NR6R6 ~ or S ( O ) nA .
Ar is preferably unsubstituted phenyl, naphthyl
or biphenyl [sic], furthermore preferably phenyl,
naphthyl or biphenyl [sic], which is mono-, di- or
trisubstituted, for example, by methyl, ethyl, propyl,
isopropyl, butyl, fluorine, chlorine, bromine,
hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy,
hexyloxy, cyano, nitro, trifluoromethyl, amino,
methylamino, ethylamino, dimethylamino, diethylamino,
pyrrolidin-1-yl, piperidin-1-yl, sulfonamido,
methylsulfonamido, ethylsulfonamido, propylsulfonamido,
butylsulfonamido, tert-butylsulfonamido, tert-
butylaminosulfonyl, dimethylsulfonamido,
phenylsulfonamido, methoxycarbonyl, carboxyl,
dimethylaminocarbonyl, phenylaminocarbonyl, acetyl,
propionyl, benzoyl, methylsulfonyl or phenylsulfonyl.
Ar' is preferably unsubstituted phenyl or
naphthyl, furthermore preferably phenyl or naphthyl,
which is mono-, di- or trisubstituted, for example, by
methyl, ethyl, propyl, isopropyl, butyl, fluorine,
chlorine, bromine, hydroxyl, methoxy, ethoxy, propoxy,
butoxy, pentyloxy, hexyloxy, cyano, nitro,
trifluoromethyl, amino, methylamino, ethylamino,
dimethylamino, diethylamino, pyrrolidin-1-yl,
piperidin-1-yl, sulfonamido, methylsulfonamido,
ethylsulfonamido, propylsulfonamido, butylsulfonamido,
dimethylsulfonamido, phenylsulfonamido, methoxy
carbonyl, carboxyl, dimethylaminocarbonyl, phenylamino
carbonyl, acetyl, propionyl, benzoyl, methylsulfonyl or
phenylsulfonyl.
Ar is particularly preferably, for example,
phenyl, naphthyl, biphenyl [sic], o-, m- or p-tolyl,
o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-,
m- or p-isopropylphenyl, o-, m- or p-tent-butylphenyl,
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- g -
o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-,
m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl,
o-, m- or p-(N-methylaminocarbonyl)phenyl, o-, m- or p-
acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or
p-ethoxyphenyl, o-, m- or p-(N,N-dimethylamino)phenyl,
o-, m- or p-(N,N-dimethylaminocarbonyl)phenyl, o-, m-
or p-(N-ethylamino)phenyl, o-, m- or p-(N,N-
diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-
or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or
p-(methylsulfonamido)phenyl, 3-fluoro-2'-sulfamoyl-
biphenyl-4-yl, 3-fluoro-2'-N-tert-butylsulfamoyl-
biphenyl-4-yl, 2'-sulfamoyl-biphenyl-4-yl, 2'-N-tert-
butylsulfamoylbiphenyl-4-yl, o-, m- or p-(pyrrolidin-1-
yl)phenyl, o-, m- or p-(piperidin-1-yl)phenyl,
furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or
3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or
3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or
3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or
3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-
chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-
5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N,N-
dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl,
2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6- 2,4,6- or
3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-
hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-
4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-
bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-
methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-
acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-
methylphenyl, 3-chloro-4-acetamidophenyl or 2,5-
dimethyl-4-chlorophenyl.
Ar' is preferably, for example, phenyl,
naphthyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl,
o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,
0-, m- or p-tert-butylphenyl, o-, m- or p-
hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-
aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m-
or p-(N-methylaminocarbonyl)phenyl, o-, m- or p-
acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m- or
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p-ethoxyphenyl, o-, m- or p-(N,N-dimethylamino)phenyl,
o-, m- or p-(N,N-dimethylaminocarbonyl)phenyl, o-, m-
or p-(N-ethylamino)phenyl, o-, m- or p-(N,N-
diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-
or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or
p-(methylsulfonamido)phenyl, 3-fluoro-2'-sulfamoyl-
biphenyl-4-yl, 3-fluoro-2'-N-tert-butylsulfamoyl-
biphenyl-4-yl, 2'-sulfamoyl-biphenyl-4-yl, 2'-N-tert-
butylsulfamoylbiphenyl-4-yl, o-, m- or p-(pyrrolidin-1-
yl)phenyl, o-, m- or p-(piperidin-1-yl)phenyl.
Het is preferably, for example, 2- or 3-furyl,
2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-
imidazolyl, 1-, ,3-, 4- or 5-pyrazolyl, 2-, 4- or 5-
oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-
thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-
pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore
preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-
triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-
oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,
1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or
-5-yl, 1,2,3-thiadiazol-4- or -5-yl, 3- or 4-
pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-
indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or 5-
benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl,
2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-
benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-,
4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-
2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-
quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-,
4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or
8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,
7- or 8-2H-benzo[1,4]oxazinyl, furthermore preferably
1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3
benzothiadiazol-4- or -5-yl or 2,1,3-benzoxadiazol-5
yl.
The heterocyclic radicals can also be partially or
completely hydrogenated.
Het can thus also be, for example, 2,3-dihydro-2-, -3-,
-4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl,
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tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl,
tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-,
-4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or
-5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-,
-2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or
-5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-
dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-
1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-
piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-,
-3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or
-5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-
1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or
3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-,
-5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-,
-2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl, 2-, 3-,
5-, 6-, 7- or 8-3,4-dihydro-2H-benz [1,4]oxazinyl,
furthermore preferably 2,3-methylenedioxyphenyl,
3,4-methylenedioxyphenyl, 2,3-ethylenedioxyphenyl,
3,4-ethylenedioxyphenyl, 3,4-(difluoromethylenedioxy)-
phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3-(2-oxo-
methylenedioxy)phenyl or alternatively 3,4-dihydro-
2H-1,5-benzodioxepin-6= or -7-yl, in addition
preferably 2,3-dihydrobenzofuranyl or 2,3-dihydro-2-
oxofuranyl.
Het is unsubstituted or mono-, di- or
trisubstituted by A, OR', NR'R'~ , N02, CN, Hal, NR~COA,
NR' S02A, COORS , CO-NR'R' ~ , COR' , SOzNR'R' ~ , S ( 0 ) nA and/ or
carbonyl oxygen.
Het is very particularly preferably, for
example, furyl, thienyl, thiazolyl, imidazolyl,
[2,1,3]-benzothiadiazolyl, oxazolyl, pyridyl, indolyl,
piperidinyl or pyrrolidinyl.
R1 is preferably, for example, H, A, cycloalkyl
CHZ- or Ar-CHZ-, particularly preferably H, methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or
tert-butyl, pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-
or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-
or 4-methylpenyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-
dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-
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methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-
trimethylpropyl, furthermore preferably, for example,
trifluoromethyl. H, methyl, ethyl, propyl, isopropyl,
butyl, pentyl or hexyl is very particularly preferred.
R2 is preferably, for example, H, A, cycloalkyl-
CHZ- or Ar-CHZ-, very particularly preferably H, methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or
tert-butyl, pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-
or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-
or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-
dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-
methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-
trimethylpropyl, 'furthermore preferably, for example,
trifluoromethyl. H is very particularly preferred.
R3 is preferably, for example, H, Ar, Het,
phenyl, naphthyl or biphenyl [sic], which is
substituted by -C(=NH)-NHz which can also be
monosubstituted by -COA, Ar-CHz-CO-, COOA, OH or by a
conventional amino protective group,
2 0 -NH-C ( =NH ) -NH2 , -CO-N=C ( NHZ ) a ,
N.
~N.O f ~ 0
or
HN--~ N
O CHs
R3 is very particularly preferably, for example,
H, phenyl, phenyl, naphthyl or biphenyl [sic], which is
monosubstituted by NHzS02-,
or phenyl, naphthyl or biphenyl [sic], which is
substituted by -C(=NH)-NH2
~~N~O f ~N~O
HN-~ ~r N=
3 0 ~ CH3 .
R4 is preferably, for example, H, Ar, Het,
CA 02364908 2001-08-30
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or phenyl, naphthyl or biphenyl [sic], which is
substituted by -C(=NH)-NHz which can also be
monosubstituted by -COA, Ar-CHz-CO-, COOA, OH or by a
conventional amino protective group,
-NH-C ( =NH ) -NHz , -CO-N=C ( NHz ) z ,
N,
f ~N . o f ~''~ o
or
HN--~ N
Q CH3
R4 is very particularly preferably, for example,
H, phenyl, phenyl, naphthyl or biphenyl [sic], which is
mono substituted by NHzSOz-,
or phenyl, naphthyl or biphenyl [sic], which is
substituted by -C(=NH)-NHz
'p ~~N~O
or N
HN--
O CH3
R6, R6~ are in each case independently of one
another preferably, for example, H, methyl, ethyl,
propyl, butyl or benzyl, very particularly preferably
H, methyl, ethyl, propyl or butyl.
R', R'~ are in each case independently of one
another preferably, for example, H, methyl, ethyl or
propyl, very particularly preferably H.
X, Y are in each case independently of one
another preferably, for example, (CHz)n, where n is very
particularly preferably 0 or 1.
The compounds of the formula I can have one or
more chiral centres and therefore occur in various
stereoisomeric forms. The formula I includes all these
forms.
Accordingly, the invention relates in
particular to those compounds of the formula I in which
at least one of the radicals mentioned has one of the
CA 02364908 2001-08-30
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preferred meanings indicated above. Some preferred
groups of compounds can be expressed by the following
subformulae Ia to Ie, which correspond to the formula I
and in which the radicals not designated in greater
detail have the meaning indicated in the formula I, but
in which
in Ia R1, R2 in each case independently of one
another is [sic] H or A;
in Ib R3, R4 in each case independently of one
another is [sic] H, Ar or R5, where at
least one of the two radicals is R5,
R5 is phenyl, naphthyl or biphenyl [sic],
which is substituted by -C(=NH)-NH2 which
can also be monosubstituted by -COA,
Ar- ( CHZ ) n-CO- , COOA, OH or by a
conventional amino protective group,
-NH-C ( =NH ) -NH2 , -CO-N=C ( NH2 ) 2
,
~~N.O ~~N.O
or Ni/
HN-- ~~
2 o O CH3 .
in Ic Rl is A,
R2 is H,
R3, R4 in each case independently of one
another is [sic] H, Ar or RS, where at
least one of the two radicals is R5,
R5 is phenyl, naphthyl or biphenyl [sic],
which is substituted by -C(=NH)-NHz which
can also be monosubstituted by -COA,
3 0 Ar- ( CHZ ) n-CO- , COOA, OH or by a
conventional amino protective group,
-NH-C ( =NH ) -NHZ , -CO-N=C ( NHz ) 2 ,
CA 02364908 2001-08-30
- 14 -
{~N~O
or N-
HN-
O CHs .
in Id Rl is A,
Rz is H,
R3, R4 in each case independently of one
another is [sic] H, Ar or R5, where at
least one of the two radicals is R5,
RS is phenyl, naphthyl or biphenyl [sic],
which is substituted by -C(=NH)-NHz which
can also be monosubstituted by -COA,
Ar- ( CH2 ) n-CO- , COOA, OH or by a
conventional amino protective group,
-NH-C ( =NH ) -NHZ , -CO-N=C ( NHZ ) 2 ,
~~N~O
or N_
HN--~
~ CHg
A is alkyl having 1-6 C atoms,
X, Y in each case independently of one
another is [sic] (CHZ)n:
in Ie R1 is A,
Rz is H,
R3, R4 in each case independently of one
another is [sic] H, Ar or R5, where at
least one of the two radicals is R',
RS is phenyl, naphthyl or biphenyl [sic]
which is substituted by -C(=NH)-NHZ or
~~N~O
N =
CH3
CA 02364908 2001-08-30
- 15 -
Ar is biphenyl [sic] which is
monosubstituted by SOZNR6R6~,
R6, R6~ in each case independently of one
another is [sic] H or A,
A is alkyl having 1-6 C atoms,
X, Y in each case independently of one
another is [sic] (CHZ)n.
The compounds of the formula I and also the
starting substances for their preparation are otherwise
prepared by methods known per se, such as are described
in the literature (e.g. in the standard works such as
Houben-Weyl, Methoden der organischen Chemie [Methods
of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart),
namely under reaction conditions which are known and
suitable for the reactions mentioned. In this case, use
can also be made of variants which are known per se,
but not mentioned here in greater detail.
The starting substances can, if desired, also
be formed in situ, such that they are not isolated from
the reaction mixture, but immediately reacted further
to give the compounds of the formula I.
Compounds of the formula I can preferably be
obtained by liberating compounds of the formula I from
one of their functional derivatives by treating with a
solvolysing or hydrogenolysing agent.
Preferred starting substances for solvolysis or
hydrogenolysis are those which otherwise correspond to
the formula I, but instead of one or more free amino
and/or hydroxyl groups contain corresponding protected
amino and/or hydroxyl groups, preferably those which
instead of an H atom which is linked to an N atom carry
an amino protective group, in particular those which
instead of an HN group carry an R'-N group, in which R'
is an amino protective group, and/or those which
instead of the H atom of a hydroxyl group carry a
hydroxyl protective group, e.g. those which correspond
to the formula I, but instead of a group -COOH carry a
CA 02364908 2001-08-30
- 16 -
group -COOR", in which R" is a hydroxyl protective
group.
Preferred starting substances are also the oxadiazole
derivatives, which can be converted into the
corresponding amidino compounds.
The liberation of the amidino group from its
oxadiazole derivative can be cleaved [sic], for
example, by treating with hydrogen in the presence of a
catalyst (e. g. water-moist Raney nickel). Suitable
solvents are those indicated below, in particular
alcohols such as methanol or ethanol, organic acids
such as acetic acid or propionic acid or mixtures
thereof. As a rule, the hydrogenolysis is carried out
at temperatures between approximately 0 and 100° and
pressures between approximately 1 and 200 bar,
preferably at 20-30° (room temperature) and 1-10 bar.
The oxadiazole group is introduced, for
example, by reaction of the cyano compounds with
hydroxylamine and reaction with phosgene, dialkyl
carbonate, chloroformic acid ester, N,N'
carbonyldiimidazole or acetic anhydride.
A number of - identical or different -
protected amino and/or hydroxyl groups can also be
present in the molecule of the starting substance. If
the protective groups present are different from one
another, in many cases they can be removed selectively.
The expression "amino protective group" is
generally known and relates to groups which are
suitable for protecting (for blocking) an amino group
from chemical reactions, but which are easily removable
after the desired chemical reaction has been carried
out at other positions in the molecule. Typical groups
of this type are, in particular, unsubstituted or
substituted acyl, aryl, aralkoxymethyl or aralkyl
groups. Since the ,amino protective groups are removed
after the desired reaction (or reaction sequence),
their nature and size is otherwise uncritical; however,
those having 1-20, in particular 1-8, C atoms are
preferred. The expression "acyl group" is to be
CA 02364908 2001-08-30
- 17 -
interpreted in the widest sense in connection with the
present process. It includes acyl groups derived from
aliphatic, araliphatic, aromatic or heterocyclic
carboxylic acids or sulphonic acids and also, in
particular, alkoxycarbonyl, aryloxycarbonyl and
especially aralkoxycarbonyl groups. Examples of acyl
groups of this type are alkanoyl such as acetyl,
propionyl, butyryl; aralkanoyl such as phenylacetyl;
aroyl such as benzoyl or toluyl; aryloxyalkanoyl such
as POA; alkoxycarbonyl such as methoxycarbonyl,
ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC
(tert-butyloxycarbonyl), 2-iodoethoxycarbonyl;
aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-
methoxybenzyloxycarbonyl, FMOC; arylsulfonyl such as
Mtr. Preferred amino protective groups are BOC and Mtr,
and in addition CBZ, Fmoc, benzyl [sic] and acetyl.
The liberation of the compounds of the formula
I from their functional derivatives is possible -
depending on the protective group used - e.g. using
strong acids, expediently using TFA or perchloric acid,
but also using other strong inorganic acids such as
hydrochloric acid or sulfuric acid, strong organic
carboxylic acids such as trichloroacetic acid or
sulfonic acids such as benzene- or p-toluenesulfonic
acid. The presence of an additional inert solvent is
possible, but not always necessary. Suitable inert
solvents are preferably organic, for example carboxylic
acids such as acetic acid, ethers such as
tetrahydrofuran or dioxane, amides such as DMF,
halogenated hydrocarbons such as dichloromethane, in
addition also alcohols such as methanol, ethanol or
isopropanol, and also water. Mixtures of the
abovementioned solvents are additionally suitable. TFA
is preferably used in excess without addition of a
further solvent, perchloric acid in the form of a
mixture of acetic acid and 70~ strength perchloric acid
in the ratio 9:1. The reaction temperatures for the
cleavage are expediently between approximately 0 and
CA 02364908 2001-08-30
- 18 -
approximately 50°, it is preferably carried out between
15 and 30° (room temperature).
The groups BOC, OBut and Mtr can, for example,
preferably be cleaved using TFA in dichloromethane or
using approximately 3 to 5N HCl in dioxane at 15-30°,
the FMOC group using an approximately 5 to 50~ strength
solution of dimethylamine, diethylamine or piperidine
in DMF at 15-30°.
Hydrogenolytically removable protective groups
(e. g. CBZ, benzyl or the release of the amidino group
from its oxadiazole derivative), can be removed, for
example, by treating with hydrogen in the presence of a
catalyst (e.g. 'of a noble metal catalyst such as
palladium, expediently on a support such as carbon).
Suitable solvents here are those indicated above, in
particular, for example, alcohols such as methanol or
ethanol or amides such as DMF. As a rule, the
hydrogenolysis is carried out at temperatures between
approximately 0 and 100° and pressures between
approximately 1 and 200 bar, preferably at 20-30° and
1-10 bar. Hydrogenolysis of the CBZ group is readily
possible, for example, on 5 to 10~ Pd/C in methanol or
using ammonium formate (instead of hydrogen) on Pd/C in
methanol/DMF at 20-30°.
Suitable inert solvents are, for example,
hydrocarbons such as hexane, petroleum ether, benzene,
toluene or xylene; chlorinated hydrocarbons such as
trichloroethylene, 1,2-dichloroethane, carbon
tetrachloride, trifluoromethylbenzene, chloroform or
dichloromethane; alcohols such as methanol, ethanol,
isopropanol, n-propanol, n-butanol or tert-butanol;
ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran (THF) or dioxane; glycol ethers such as
ethylene glycol monomethyl or monoethyl ether (methyl
glycol or ethyl glycol), ethylene glycol dimethyl ether
(diglyme); ketones such as acetone or butanone; amides
such as acetamide, dimethylacetamide, N-
methylpyrrolidone (NMP) or dimethylformamide (DMF);
nitriles such as acetonitrile; sulfoxides such as
CA 02364908 2001-08-30
- 19 -
dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic
acids such as formic acid or acetic acid; nitro
compounds such as nitromethane or nitrobenzene; esters
such as ethyl acetate or mixtures of the solvents
mentioned.
The biphenyl-SOZNHZ [sic] group is preferably
employed in the form of its tert-butyl derivative. The
tert-butyl group is removed, for example, using TFA
with or without addition of an inert solvent,
preferably with addition of a small amount of anisole
(1-10o by volume).
A cyano group is converted into an amidino
group by reaction with, for example, hydroxylamine and
subsequent reduction of the N-hydroxyamidine using
hydrogen in the presence of a catalyst such as, for
example, Pd/C.
For the preparation of an amidine of the formula I
(e. g. Ar - phenyl monosubstituted by C(=NH)-NHZ),
ammonia can also be added to a nitrite. The addition is
preferably carried out in several stages in that, in a
manner known per se, a) the nitrite is converted, using
H2S, into a thioamide, which is converted using an
alkylating agent, e.g. CH3I, into the corresponding
S-alkylimidothio ester, which for its part reacts with
NH3 to give the amidine, b) the nitrite is converted
using an alcohol, e.g. ethanol, in the presence of HC1
into the corresponding imido ester and this is treated
with ammonia, or c) the nitrite is reacted with lithium
bis(trimethylsilyl)amide and the product is then
hydrolysed.
The radical -X-R3 is introduced into the
pyrazolone system, where X = CH2, for example, by
reaction of compounds of the formula II
R°
Y~
R, / ~ II
N-N
/ H
R2
CA 02364908 2001-08-30
- 20 -
in which Rl, Rz and R4 in each case are those radicals
according to Claim 1 which are not alkylatable and Y
has the meaning indicated in Claim 1, with a compound
of the formula III
R3-CHZ-L III .
In the compounds of the formula III, R3 is a
radical which is not alkylatable according to Claim 1,
such as, for example, a phenyl radical substituted by
5-methyl[1,2,4]oxadiazol-3-yl and in which L is Cl, Br,
I or a free or reactive functionally modified OH group.
L is preferably 'Cl, Br, I or a reactive modified OH
group such as, for example, an activated ester, an
imidazolide or alkylsulfonyloxy having 1-6 C atoms
(preferably methylsulfonyloxy) or arylsulfonyloxy
having 6-10 C atoms (preferably phenyl- or p-
tolylsulfonyloxy).
The pyrazolone ring system is synthesized
according to known methods by reaction of a suitable ~3
keto ester with hydrazine or a hydrazine derivative.
It is additionally possible to convert a
compound of the formula I into another compound of the
formula I by converting one or more radicals R1, Rz, R3
and/or R4 into one or more radicals Rl, Rz, R3 and/or R4,
for example, by acylating an amino group or reducing
nitro groups (for example by hydrogenation on Raney
nickel or Pd-carbon in an inert solvent such as
methanol or ethanol) to give amino groups.
Esters can be hydrolysed, for example, using
acetic acid or using NaOH or KOH in water, water-THF or
water-dioxane at temperatures between 0 and 100°.
In addition, free amino groups can be acylated
in a customary manner using an acid chloride or
anhydride or alkylated using an unsubstituted or
substituted alkyl halide, expediently in an inert
solvent such as dichloromethane or THF and/or in the
presence of a base such as triethylamine or pyridine at
temperatures between -60 and +30°.
CA 02364908 2001-08-30
- 21 -
A base of the formula I can be converted into
the associated acid addition salt using an acid, for
example by reaction of equivalent amounts of the base
and of the acid in an inert solvent such as ethanol and
subsequent evaporation. Acids which are particularly
suitable for this reaction are those which yield
physiologically acceptable salts. Thus, it is possible
to use inorganic acids, e.g. sulfuric acid, nitric
acid, hydrohalic acids such as hydrochloric acid or
hydrobromic acid, phosphoric acids such as
orthophosphoric acid, sulfamic acid, in addition
organic acids, in particular aliphatic, alicyclic,
araliphatic, aromatic or heterocyclic mono- or
polybasic carboxylic, sulfonic or sulfuric acids, e.g.
formic acid, acetic acid, propionic acid, pivalic acid,
diethylacetic acid, malonic acid, succinic acid,
pimelic acid, fumaric acid, malefic acid, lactic acid,
tartaric acid, malic acid, citric acid, gluconic acid,
ascorbic acid, nicotinic acid, isonicotinic acid,
methane- or ethanesulfonic acid, ethanedisulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid,
p-toluenesulfonic acid, naphthalenemono- and
-disulfonic acids, laurylsulfuric acid. Salts with
physiologically unacceptable acids, e.g. picrates, can
be used for the isolation and/or purification of the
compounds of the formula I.
On the other hand, compounds of the formula I
can be converted using bases (e. g. sodium or potassium
hydroxide or carbonate) into the corresponding metal
salts, in particular alkali metal or alkaline earth
metal salts, or into the corresponding ammonium salts.
Physiologically acceptable organic bases, such as, for
example, ethanolamine, can also be used.
On account of their molecular structure,
compounds of the formula I according to the invention
can be chiral and can correspondingly occur in various
enantiomeric forms. They can therefore be present in
racemic or in optically active form.
CA 02364908 2001-08-30
- 22 -
Since the pharmaceutical activity of the
racemates or of the stereoisomers of the compounds
according to the invention can differ, it may be
desirable to use the enantiomers. In these cases, the
final product or else even the intermediates can be
separated into enantiomeric compounds by chemical or
physical measures known to the person skilled in the
art or even employed as such in the synthesis.
In the case of racemic amines, diastereomers
are formed from the mixture by reaction with an
optically active resolving agent. Suitable resolving
agents are, for example, optically active acids, such
as the R and S forms of tartaric acid, diacetyltartaric
acid, dibenzoyltartaric acid, mandelic acid, malic
acid, lactic acid, suitably N-protected amino acids
(e.g. N-benzoylproline or N-benzenesulfonylproline) or
the various optically active camphorsulfonic acids.
Chromatographic resolution of enantiomers with the aid
of an optically active resolving agent (e. g.
dinitrobenzoylphenylglycine, cellulose triacetate or
other derivatives of carbohydrates or chirally
derivatized methacrylate polymers immobilized on silica
gel) is also advantageous. Suitable eluents for this
are aqueous or alcoholic solvent mixtures such as, for
example, hexane/isopropanol/acetonitrile, e.g. in the
ratio 82:15:3.
The invention additionally relates to the use
of the compounds of the formula I and/or their
physiologically acceptable salts for the production of
pharmaceutical preparations, in particular by a non
chemical route. In this connection, they can be brought
into a suitable dosage form together with at least one
solid, liquid and/or semi-liquid vehicle or excipient
and, if appropriate, in combination with one or more
further active compounds.
The invention additionally relates to
pharmaceutical preparations comprising at least one
compound of the formula I and/or one of its
physiologically acceptable salts.
CA 02364908 2001-08-30
- 23 -
These preparations can be used as medicaments
in human or veterinary medicine. Suitable vehicles are
organic or inorganic substances which are suitable for
enteral (e.g. oral) or parenteral administration or
topical application and do not react with the novel
compounds, for example water, vegetable oils, benzyl
alcohols, alkylene glycols, polyethylene glycols,
glycerol triacetate, gelatin, carbohydrates such as
lactose or starch, magnesium stearate, talc, petroleum
jelly. Tablets, pills, coated tablets, capsules,
powders, granules, syrups, juices or drops, in
particular, are used for oral administration,
suppositories are used for rectal administration,
solutions, preferably oily or aqueous solutions, in
addition suspensions, emulsions or implants, are used
for parenteral administration, and ointments, creams or
powders are used for topical application. The novel
compounds can also be lyophilized and the lyophilizates
obtained used, for example, for the production of
injection preparations. The preparations indicated can
be sterilized and/or can contain excipients such as
lubricants, preservatives, stabilizing agents and/or
wetting agents, emulsifiers, salts for influencing the
osmotic pressure, buffer substances, colourants,
flavourings and/or several [sic] further active
compounds, e.g. one or more vitamins.
The compounds of the formula I and their
physiologically acceptable salts can be used in the
control and prevention of thromboembolic disorders such
as thrombosis, myocardial infarct, arteriosclerosis,
inflammation, apoplexy, angina pectoris, restenosis
after angioplasty and intermittent claudication.
As a rule, the substances according to the
invention are preferably administered here in doses of
between approximately 1 and 500 mg, in particular
between 5 and 100 mg, per dose unit . The daily dose is
preferably between approximately 0.02 and 10 mg/kg of
body weight. The specific dose for each patient
depends, however, on all sorts of factors, for example
CA 02364908 2001-08-30
- 24 -
on the efficacy of the specific compound employed, on
the age, body weight, general state of health and sex,
on the diet, on the time and route of administration,
and on the excretion rate, pharmaceutical combination
and severity of the particular disorder to which the
therapy applies. Oral administration is preferred.
Above and below, all temperatures are indicated
in °C. In the following examples "customary working up"
means: if necessary, water is added, the mixture is
adjusted, if necessary, depending on the constitution
of the final product, to a pH of between 2 and 10 and
extracted with ethyl acetate or dichloromethane, the
organic phase i,s separated off, dried over sodium
sulfate and evaporated, and the residue is purified by
chromatography on silica gel and/or by crystallization.
Rf [sic] values on silica gel; eluent: ethyl
acetate/methanol 9:1.
Mass spectrometry (MS):
EI (electron impact ionization) M+
FAB (fast atom bombardment) (M+H)+
Example 1
4.3 g of caesium carbonate are added to 4.0 g
of 3-(7-bromomethylnaphthalen-2-yl)-5-methyl[1,2,4]oxa
diazole and 2.1 g of ethyl isobutyrylacetate in 50 ml
of acetonitrile. The suspension is stirred at room
temperature for 20 hours. The mixture is filtered, the
solvent is removed and the residue is chromatographed
on a silica gel column. Ethyl 4-methyl-2-[7-(5-
methyl[1,2,4]oxadiazol-3-yl)naphthalen-2-ylmethyl]-3-
oxopentanoate ("AA") is obtained as a colourless oil,
FAB 381
O-N O
-~~ I
w w ~o
i
0
_. ~-<;... .. _. .. .~ .. .. ,..
CA 02364908 2001-08-30
- 25 -
A solution of 1.30 g of "AA" and 0.62 ml of
hydrazinium hydroxide in 10 ml of acetic acid is heated
to boiling for 24 hours. After customary working up, 5-
isopropyl-4-[7-(5-methyl[1,2,4]oxadiazol-3-
yl)naphthalen-2-ylmethyl]-1,2-dihydropyrazol-3-one
("AB"), FAB 349 is obtained
O_N O
N \ \ ~NH
N
H
A solution of 60 mg of "AB" in 5 ml of methanol
is treated with 60 mg of Raney nickel and 30 mg of
acetic acid and hydrogenated at room temperature for 18
hours. The catalyst is filtered off, the solvent is
removed and the compound
7-[5-isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-4-
ylmethyl]-2-amidinonaphthalene, diacetate, FAB 309 is
obtained.
Example 2
A solution of 100 mg of "AB" and 68 mg of 3-(3-
bromomethylphenyl)-5-methyl[1,2,4]oxadiazole in 10 ml
of acetonitrile is treated with 94 mg of caesium
carbonate and stirred at room temperature for 20 hours.
After customary working up and chromatography on silica
gel, 5-isopropyl-2-[3-(5-methyl[1,2,4]oxadiazol-3-yl)-
benzyl]-4-[7-(5-methyl[1,2,4]oxadiazol-3-yl)naphthalen-
2-ylmethyl]-1,2-dihydropyrazol-3-one, FAB 521, is
obtained.
Analogously to Example 1, the following
compound is obtained therefrom by hydrogenation
3-[4-(7-amidinonaphth-2-ylmethyl)-5-isopropyl-3-
oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl]benzamidine,
diacetate, FAB 441
CA 02364908 2001-08-30
- 26 -
NH
HZN ~ \ \ ~ ~N
N NH
H I
NH2
The following compound is obtained analogously
4-[4-(7-amidinonaphth-2-ylmethyl)-5-isopropyl-3
oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl]benzamidine.
The following compound is obtained analogously
by reaction of "AB" with 3-(7-bromomethylnaphthalen-2
yl)-5-methyl[1,2,,4]oxadiazole and subsequent
hydrogenation
7-[4-(7-amidinonaphth-2-ylmethyl)-5-isopropyl-
3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl]-2-
amidinonaphthalene, diacetate, FAB 491.
Example 3
Analogously to Example 1, by reaction of 3-(5-
methyl[1,2,4]oxadiazol-3-yl)benzyl bromide with methyl
isobutyrylacetate the compound ethyl 4-methyl-2-[3-(5-
methyl[1,2,4]oxadiazol-3-yl)benzyl]-3-oxopentanoate
("AC") is obtained as a colourless oil, FAB 317
0-
/
N
"AC".
By reaction with hydrazinium hydroxide, 5-
isopropyl-4-[3-(5-methyl[1,2,4]oxadiazol-3-yl)benzyl]-
1,2-dihydropyrazol-3-one, FAB 299 ("AD"), is obtained
therefrom
CA 02364908 2001-08-30
- 27 -
O-
NH
"AD".
By hydrogenation, the compound 3-[5-isopropyl
3-oxo-2,3-dihydro-1H-pyrazol-4-ylmethyl]benzamidine is
obtained therefrom.
Analogously, the following compounds are
obtained by reaction of "AD" with
3-(3-bromomethylphenyl)-5-methyl[1,2,4]oxadiazole,
3-(7-bromomethylriaphthalen-2-yl)-5-methyl[1,2,4]oxa-
diazole,
2-(tent-butylaminosulfonyl)-4'-bromomethylbiphenyl
and, after subsequent hydrogenation, the following
compounds
3-[4-(3-amidinobenzyl)-5-isopropyl-3-oxo-2,3-
dihydro-1H-pyrazol-2-ylmethyl]benzamidine, triacetate,
FAB 391;
7-[4-(3-amidinobenzyl)-5-isopropyl-3-oxo-2,3-
dihydro-1H-pyrazol-2-ylmethyl]-2-amidinonaphthalene,
4'-[4-(3-amidinobenzyl)-5-isopropyl-3-oxo-2,3-
dihydro-1H-pyrazol-2-ylmethyl]-2-(tert-
butylaminosulfonyl)biphenyl,
and the following compound is obtained therefrom
by removal of the tert-butyl group
4'-[4-(3-amidinobenzyl)-5-isopropyl-3-oxo-2,3-
dihydro-1H-pyrazol-2-ylmethyl]-2-aminosulfonylbiphenyl.
Analogously, the following compound is obtained
7-[4-(4-amidinobenzyl)-5-isopropyl-3-oxo-2,3-
dihydro-1H-pyrazol-2-ylmethyl]-2-amidinonaphthalene.
Example 4
Analogously to Example 1, the following
compound is obtained by reaction of 5-isopropyl-1,2-
dihydropyrazol-3-one with 3-(7-bromomethylnaphthalen-2-
CA 02364908 2001-08-30
- 28 -
yl)-5-methyl[1,2,4]oxadiazole and subsequent
hydrogenation
5-isopropyl-2-[7-amidinonaphthalen-2-ylmethyl]-
1,2-dihydropyrazol-3-one ("AB"), diacetate, FAB 309.
Example 5
Analogously to Example 1, starting from 3-(7-
bromomethylnaphthalen-2-yl)-5-methyl[1,2,4]oxadiazole
and ethyl 3-oxobutyrate, reaction with hydrazine and
subsequent reaction with 3-(7-bromomethylnaphthalen-2-
yl)-5-methyl[1,2,4]oxadiazole and hydrogenation the
following compound is obtained
7-[4-(7-amidinonaphth-2-ylmethyl)-5-methyl-3-oxo-
2,3-dihydro-1H-pyrazol-2-ylmethyl]-2-
amidinonaphthalene.
If ethyl 3-oxobutyrate is replaced by ethyl
3-oxoheptanoate, the following compound is thus
obtained analogously
7-[4-(7-amidinonaphth-2-ylmethyl)-5-butyl-3-oxo-
2,3-dihydro-1H-pyrazol-2-ylmethyl]-2-
amidinonaphthalene.
Example 6
Analogously to Example 1, starting from 2
(tert-butylaminosulfonyl)-4'-bromomethylbiphenyl and
ethyl isobutyrylacetate, reaction with hydrazine and
subsequent reaction with 3-(3-bromomethylphenyl)-5
methyl[1,2,4]oxadiazole, hydrogenation and removal of
the tert-butyl group, the following compound is
obtained
3-[4-(2-aminosulfonylbiphenyl-4'-ylmethyl)-5-
isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-
ylmethyl]benzamidine, trifluoroacetate, FAB 504.
The following compound is obtained analogously
CA 02364908 2001-08-30
- 29
7-[4-(2-aminosulfonylbiphenyl-4'-ylmethyl)-5
isopropyl-3-oxo-2,3-dihydro-1H-pyrazol-2-ylmethyl]-2-
amidinonaphthalene, trifluoroacetate, FAB 554.
Example 7
Analogously to Examples 1 and 2, the compounds
below are obtained
7-(4-benzyl-5-isopropyl-3-oxo-2,3-dihydro-1H-
pyrazol-2-ylmethyl)-2-amidinonaphthalene,
7-[2-benzyl-5-isopropyl-3-oxo-2,3-dihydro-1H-
pyrazol-4-ylmethyl]-2-amidinonaphthalene.
Example 8
Analogously to Example 1, on replacement of
hydrazine by phenylhydrazine the following compound is
obtained
7-(5-isopropyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-ylmethyl]-2-amidinonaphthalene.
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The following examples relate to pharmaceutical
preparations:
Example A: Injection vials
A solution of 100 g of an active compound of
the formula I and 5 g of disodium hydrogenphosphate is
adjusted to pH 6.5 in 3 1 of double-distilled water
using 2N hydrochloric acid, sterile-filtered, filled
into injection vials, lyophilized under sterile
conditions and aseptically sealed. Each injection vial
contains 5 mg of active compound.
Example B: Suppositories
A mixture of 20 g of an active compound of the
formula I is fused with 100 g of soya lecithin and
1400 g of cocoa butter, poured into moulds and allowed
to cool. Each suppository contains 20 mg of active
compound.
Example C: Solution
A solution of 1 g of an active compound of the
formula I, 9 . 38 g of NaH2P04 ~ 2H20, 28 . 48 g of
NazHP04~12H20 and 0.1 g of benzalkonium chloride in
940 ml of double-distilled water is prepared. The
solution is adjusted to pH 6.8, made up to 1 1 and
sterilized by irradiation. This solution can be used in
the form of eye drops.
Example D: Ointment
500 mg of an active compound of the formula I
are mixed with 99.5 g of petroleum jelly under aseptic
conditions.
Example E: Tablets
A mixture of 1 kg of active compound of the
formula I, 4 kg of lactose, 1.2 kg of potato starch,
0.2 kg of talc and 0.1 kg of magnesium stearate is
compressed to give tablets in a customary manner such
that each tablet contains 10 mg of active compound.
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Example F: Coated tablets
Analogously to Example E, tablets are pressed
and are then coated in a customary manner with a
coating of sucrose, potato starch, talc, tragacanth and
colourant.
Example G: Capsules
2 kg of active compound of the formula I are
filled into hard gelatin capsules in a customary manner
such that each capsule contains 20 mg of the active
compound.
Example H: Ampoules
A solution of 1 kg of active compound of the
formula I in 60 1 of double-distilled water is sterile-
filtered, filled into ampoules, lyophilized under
sterile conditions and aseptically sealed. Each ampoule
contains 10 mg of active compound.
