Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-01-22
2001-04-17
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S824000
Reexamination Certificate
active
06218403
ABSTRACT:
The present invention relates to a pharmaceutical composition containing as active principle a combination of a thienopyridine derivative and an HMG-CoA reductase inhibitor.
More especially, the subject of the present invention is a pharmaceutical composition containing
(a) a thienopyridine derivative of formula
in which R is hydrogen or a (C
1
-C
4
)alkoxycarbonyl group, or one of its pharmaceutically acceptable salts; and
(b) an HMG-CoA reductase inhibitor.
The thienopyridine derivatives of formula (I) are known to be potent platelet aggregation inhibitors, acting via a mechanism of action which distinguishes them from other platelet aggregation inhibitors.
These compounds, in particular 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2]pyridine of formula (I), R=hydrogen, hereinafter designated by its international nonproprietary name (INN) “ticlopidine”, used in hydrochloride form, and (+)-[methyl (S)-&agr;-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridin-5-ylacetate] of the formula (I), R=methoxycarbonyl, hereinafter designated by its INN “clopidogrel”, used in hydrogen sulphate form, are exceptional antithrombotic agents (Gent et al., Lancet, 1989, 8649, 1215-1220—J-M. Herbert et al., Cardiovasc. Drug Rev., 1993, 11, 180-188).
It has now been found that, by combining a thienopyridine derivative of formula (I) and an HMG-CoA reductase inhibitor, a potentiation of the anti-atherogenic power of the two components is observed, more especially an additive and/or synergistic activity of the two active principles with respect to the proliferation of rabbit artery smooth muscle cells.
It has also been found that the combination of a thienopyridine derivative of formula (I) and an HMG-CoA reductase inhibitor is provided with an additive and/or synergistic activity of the two active principles in an animal model of arterial thrombosis which is predictive of a preventive or curative clinical antithrombotic activity.
Thus, according to the present invention, a therapeutically effective dose of a thienopyridine derivative of formula (I), or of one of its pharmaceutically acceptable salts [Component (a)], is combined with a therapeutically effective dose of an HMG-CoA reductase inhibitor [Component (b)] so as to prepare pharmaceutical compositions intended for treating or preventing atherosclerosis, postangioplasty restenosis or the thrombotic complications resulting therefrom.
In a dosage unit containing the combination of a thienopyridine of formula (I) and an HMG-CoA reductase inhibitor, the therapeutically effective dose of Component (a) can vary from 10 to 250 mg of active principle (calculated as free base or as salt), whereas the therapeutically effective dose of Component (b) can vary from 2 to 50 mg of active principle.
According to the present invention, the thienopyridine derivative of formula (I) is preferably selected from ticlopidine and the pharmaceutically acceptable salts, in particular ticlopidine hydrochloride, and clopidogrel and the pharmaceutically acceptable salts, in particular clopidogrel hydrogen sulphate.
When Component (a) in a dosage unit is ticlopidine hydrochloride, the amount of this active principle in the dosage unit can advantageously vary from 100 to 250 mg, the said amount of active principle preferably being 150, 175, 200, 225 or 250 mg per dosage unit.
When in the dosage unit Component (a) is clopidogrel hydrogen sulphate, the amount of this active principle in the dosage unit can advantageously vary from 10 to 75 mg (calculated as free base), the said amount of active principle preferably being 25, 35, 50, 65 or 75 mg as free base per dosage unit.
According to the present invention, the HMG-CoA reductase inhibitor is advantageously a compound selected from
(I) the naphthalene derivatives of formula (II)
in which R
1
and R
2
are a hydroxyl group or alternatively together form an oxygen atom, R
3
is a (C
1
-C
10
)alkyl, (C
3
-C
10
)cycloalkyl, (C
2
-C
10
)alkenyl, phenyl or phenyl(C
1
-C
3
)alkyl group and R
4
is hydrogen or a methyl or hydroxyl group;
(ii) the pharmaceutically acceptable salts of the compounds of formula (II) in which R
1
and R
2
are hydroxyl;
(iii) the indole derivatives of formula (III)
in which
one of the substituents R° and R′ is a group of structure
in which Q
4
is a hydrogen, chlorine or fluorine atom or a (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy (but other than t-butoxy), trifluoromethyl, phenoxy or benzyloxy group, Q
5
is a hydrogen, chlorine or fluorine atom or a phenoxy or benzyloxy group and Q
5a
is a hydrogen, chlorine or fluorine atom or a methyl, ethyl, methoxy or ethoxy group;
and the other substituent R° and R′ is a primary or secondary (C
1
-C
6
)alkyl, (C
3
-C
6
)cycloalkyl, benzyl, 2-phenylethyl or 3-phenylpropyl group;
Q
2
is a hydrogen, fluorine or chlorine atom or a (C
1
-C
4
)alkyl, (C
3
-C
6
)cycloalkyl, (C
1
-C
4
)alkoxy (but other than t-butoxy), trifluoromethyl, phenoxy or benzyloxy group;
Q
3
is a hydrogen, chlorine or fluorine atom or a (C
1
-C
3
)alkyl, (C
1
-C
3
)alkoxy, phenoxy or benzyloxy group;
X is a methylene, ethylene or 1,3-propylene group;
Q
6
is a hydrogen atom or a (C
1
-C
3
)alkyl group; with the limitation that
(1) Q
5
and Q
5a
are hydrogen when R
4
is hydrogen,
(2) Q
5a
is hydrogen when Q
5
is hydrogen,
(3) Q
4
and Q
3
are not at the same time a trifluoromethyl, phenoxy or benzyloxy group,
(4) Q
3
is hydrogen when Q
2
is hydrogen,
(5) Q
2
and Q
3
are not at the same time a trifluoromethyl, phenoxy or benzyloxy group;
(iv) the pharmaceutically acceptable esters of the compounds of formula (III),
(v) the pharmaceutically acceptable salts of the compounds of formula (III),
(vi) the &dgr;-lactones of the compounds of formula (III),
(vii) the tetrazole derivatives of formula (IV)
in which
Q
1
and Q
1
′ are hydrogen, a halogen or a (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy or trifluoromethyl group;
Q
7
, Q
7
′, Q
8
, and Q
8
′ are hydrogen, a halogen or a (C
1
-C
4
)alkyl or (C
1
-C
4
)alkoxy group;
Q
9
is hydrogen or a (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxyalkyl or (2-methoxyethoxy)methyl group;
(viii) the pharmaceutically acceptable salts of the compounds of formula (IV),
(ix) the &dgr;-lactones of the compounds of formula (IV),
(x) the pyridine derivatives of formula (V)
(xi) the pharmaceutically acceptable salts of the compounds of formula (V),
(xii) the &dgr;-lactones of the compounds of formula (V),
(xiii) the pyrrole derivatives of formula (VI)
(xiv) the pharmaceutically acceptable salts of the compounds of formula (VI),
(xv) the &dgr;-lactones of the compounds of formula (VI).
The compounds corresponding to the formulae (II) to (VI) possess at least two chiral carbons, it also being possible for the compounds (II) to (V) to be present in cis or trans form. Component (b) can be selected from the isomers of the compounds (II) to (VI) or the mixtures thereof.
The compounds (II) to (VI) are described in the literature. More especially, the indole derivatives of formula (III) are described in WO 84/02131, the tetrazole derivatives of formula (IV) are described in EP 658550, the pyridine derivatives of formula (V) are described in DE 4040026 and the pyrrole derivatives of formula (VI) are described in EP 409281.
The naphthalene compounds of formula (II) in which R
4
is hydrogen or a methyl group are described in EP 33538, or may be prepared either according to the method described in this document or by partial synthesis or, in some cases, by total synthesis, for example in the case of the synthesis of mevastatin (J. Am. Chem. Soc., 1981, 6538; ibid. 1982, 4251) or of lovastatin (Tetrahedron Letters. 1983, 24, 1811). Simvastatin is also described in EP 33538.
The naphthalene compounds of formula (II) in which R
4
is hydroxyl are described in GB 2,077,264. Among these compounds, pravastatin, used in the form of the sodium salt, constitutes an especially advantageous Component (b).
Among the indoles of formula (III), the compound having t
Daste Georges
Herbert Jean Marc
Alexander Michael D.
Dupont Paul E.
Krass Frederick
Sanofi-Synthelabo
LandOfFree
Antithrombotic and antiatherogenic pharmaceutical... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Antithrombotic and antiatherogenic pharmaceutical..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Antithrombotic and antiatherogenic pharmaceutical... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2533956