Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-13
2002-12-10
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S118000
Reexamination Certificate
active
06492384
ABSTRACT:
The invention relates to compounds of the formula I
in which
R is H, unbranched or branched alkyl having 1-6 C atoms or cycloalkyl having 3-6 C atoms,
R
1
is Ar,
R
2
is Ar′,
R
3
is H, R, R
4
, Hal, CN, COOH, COOA or CONH
2
,
Ar, Ar′ are phenyl, naphthyl or biphenyl, in each case independently of one another unsubstituted or mono-, di- or trisubstituted by R, OH, Hal, CN, NO
2
, CF
3
, NH
2
, NHR, NR
2
, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO
2
NH
2
, SO
2
NHR, SO
2
NR
2
, —CONHR, —CONR
2
, —(CH
2
)
n
—NH
2
—(CH
2
)
n
—NHR, —(CH
2
)
n
—NR
2
, —O—(CH
2
)
n
—NH
2
, —O—(CH
2
)
n
—NHR, —O—(CH
2
)
n
—NR
2
, R
4
or together by —O—(CH
2
)
m
—O—, R
4
is —C(═NH)—NH
2
which is unsubstituted or monosubstituted by —COR, —COOR, —OH or by a conventional amino protective group or —NH—C(═NH)—NH
2
, —C(═O)—N═C(NH
2
)
2
,
A is alkyl having 1-4 C atoms,
Hal is F, Cl, Br or I,
m is 1 or 2,
n is 0, 1, 2 or 3,
p is 0 or 1,
and their salts.
The invention also relates to the optically active forms, the racemates, the diastereomers and the hydrates and solvates, e.g. alcoholates, of these compounds.
The invention is based on the object of finding novel compounds having useful 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 useful pharmacological properties together with good tolerability. In particular, they show factor Xa-inhibiting properties and can therefore be employed for the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarct, arteriosclerosis, inflammations, 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)phenylalkyl]azaheterocyclylamides as factor Xa inhibitors are described in WO 96/40679.
The antithrombotic and anticoagulating effect of the compounds according to the invention is attributed to the inhibiting action against the activated clotting protease, known under the name factor Xa, or to the inhibition of other activated serine 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, by the method of G. F. Cousins et al. in
Circulation
1996, 94, 1705-1712.
Inhibition of factor Xa can thus prevent thrombin being formed. 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 [sic] anticoagulating and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable procedure is described, for example, by J. Hauptmann et al. in
Thrombosis and Haemostatis
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 intrinsic 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 thus subsequent thrombin formation. The inhibition of factor VIIa by the compounds according to the invention and the measurement of the [sic] anticoagulating and antithrombotic activity can be determined by customary in vitro or in vivo methods. A customary procedure for the measurement of 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 another way. The inhibition of factor IXa by the compounds according to the invention and the measurement of the [sic] anticoagulating and antithrombotic activity can be determined by customary in vitro or in vivo methods. A suitable procedure is described, for example, by J. Chang et al. in
Journal of Biological Chemistry
1998, 273, 12089-12094.
The compounds of the formula I can be employed as pharmaceutical active compounds in human and veterinary medicine, in particular for the control and prevention of thromboembolic disorders such as thrombosis, myocardial infarct, arteriosclerosis, inflammations, apoplexy, angina pectoris, restenosis after angioplasty and intermittent claudication.
The invention relates to the compounds of the formula I and their salts, and to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that
a) they are set free from one of their functional derivatives by treating with a solvolysing or hydrogenolysing agent, by
i) liberating an amidino group from its oxadiazole derivative or oxazolidinone derivative by hydrogenolysis or solvolysis,
ii) replacing a conventional amino protective group by hydrogen by treating with a solvolysing or hydrogenolysing agent or liberating an amino group protected by a conventional protective group, or
b) in a compound of the formula I, one or more radicals R, R
1
, R
2
and/or R
3
are converted into one or more radicals R, R
1
, R
2
and/or R
3
, by, for example
i) hydrolysing an ester group to a carboxyl group
ii) reducing a nitro group
iii) acylating an amino group
iv) converting a cyano group into an amidino group and/or
c) a base or acid of the formula I is converted into one of its salts.
For all radicals which occur a number of times, it is a condition that their meanings are independent of one another.
Above and below, the radicals and parameters R, R
1
, R
2
, R
3
and n have the meanings indicated in the formula I, if not expressly stated otherwise.
R is alkyl, is unbranched (linear) or branched, and has 1 to 6, preferably 1, 2, 3, 4, 5 or 6, C atoms. R 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. R is also cycloalkyl and is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. R is furthermore H.
A is alkyl having 1, 2, 3 or 4 C atoms and is preferably methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.
Hal is preferably F, Cl or Br, but also I.
Ar and Ar′ are phenyl, benzodioxol-5-yl, naphthyl or biphenyl, in each case independently of one another unsubstituted or mono-, di- or trisubstituted by R, OH, OR, Hal, CN, NO
2
, CF
3
, NH
2
, NHR, NR
2
, pyrrolidin-1-yl, piperidin-1-yl, benzyloxy, SO
2
NH
2
, SO
2
NHA, SO
2
NR
2
, phenylsulfonamido, —(CH
2
)
n
—NH
2
, —(CH
2
)
n
—NHR, —(CH
2
)
n
—NR
2
, —O—(CH
2
)
n
—NH
2
, —O—(CH
2
)
n
—NHR, —O—(CH
2
)
n
Anzali Soheila
Bernotat-Danielowski Sabine
Buchstaller Hans-Peter
Dorsch Dieter
Gante Helga
Anderson Rebecca
Gante Helga
McKane Joseph K.
Merck Patent GmbH
Millen White Zelano & Branigan P.C.
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