MXPA99000800A - ANTITHROMBOTIC AND ANTIATHEROGENIC PHARMACEUTICAL COMPOSITION INCLUDING A THIENOPYRIDINE DERIVATIVE AND AN HMG-CoA-REDUCTASE INHIBITOR - Google Patents

Abstract

A pharmaceutical composition containing (a) a thienopyridine derivative of formula (I), wherein R is hydrogen or a C 1-4 alkoxycarbonyl group, or a pharmaceutically acceptable salt thereof;and (b) an HMG-CoA-reductase inhibitor, is disclosed.

Description

ANTITROMBOTIC PHARMACEUTICAL COMPOSITION DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition containing, as an active principle, an association of a derivative of thienopyridine and an inhibitor of HMG-CoA reductase.

More precisely, the present invention has for subject to a pharmaceutical composition containing: (i) a thienopyridine derivative of formula wherein R is hydrogen or a group (C, -C4) alkoxycarbonyl, or a pharmaceutically acceptable salt thereof, and (b) a HMG-CoA reductase inhibitor. It is known that the thienopyridine derivatives of formula (I) are potent anabolic agonists, which act by a mechanism of action that distinguishes them from other antiplatelet agents. Compounds, in particular 5- (2-chlorobenzyl) -4,5,5,7-tetrahydrothieno-2-e] pyridine of formula (I), R = hydrogen, - hereinafter referred to by its Common Name International - REF 29354 (OCI) "ticlopidine", used in the form of hydrochloride, and - (+). (S) _ oc - (2-chlorophenyl) -4,5,6,7-te ra i rotieno [ 3,2-cJ pyridinyl-5-methyl acetate, of formula (I), R = methoxycarbonyl, designated below by its ICD "clopidogrel", used in the form of hydrogen sulfate, are notable antithrombotic agents Gent et al. , Lancet, 1989, 8649, 1215-1220- JM Herbert et al., Cardiovasc Drug Rev., 1993, 11, 180-188) It has now been found that associating a thienopyridine derivative of formula (I) with an inhibitor of the HMG-CoA reducta: a, a potentialization of the antiatergenic power of the components is observed, more precisely an additive and / or synergistic activity of the two active principles, on the proliferation of the smooth muscle cells of the rabbit rteria. It has also been found that the association of a thienopyridine derivative of formula (I) of an HMG-CoA redutase inhibitor shows an additive and / or synergistic activity of the two active principles in an animal model of arterial thrombosis that predict a clinical preventive or curative antithrombotic activity. Thus, in accordance with the present invention, a therapeutically effective dose of a thienopyridine derivative of formula (I), or of one of its pharmaceutically acceptable salts [Component (a) j (is associated with a therapeutically dose - Effective of a fcomponent HMG-CoA reductase inhibitor (b) J - for the purpose of preparing pharmaceutical compositions intended to treat or prevent atherosclerosis, restenosis oost-angioplasty or the resulting thrombotic complications. containing the combination of a thienopyridine of formula (I) and an inhibitor of HMG-CoA reductase, the therapeutically effective dose of the component - (a) may vary from 10 to 250 mg of active principle (calculated - on free base or in salt), while the therapeutically effective dose of Component (b) may vary from 2 to 50 mg of active ingredient In accordance with the present invention, the thienopyridine derivative of formula (I) is chosen pref preferably between the pidine cycle and pharmaceutically acceptable salts, especially ticlopidine hydrochloride, clopidogre and pharmaceutically acceptable salts, especially clopidogrel hydrogen sulfate. When Component (a) in a dosage unit is ticiopidine hydrochloride, the amount of that active ingredient in the dosage unit can advantageously vary from 100 to 250 mg. said amount of active principle being preferably 150,175, 200, 225 or 250 mg per dosage unit. When, in the dosage unit, Component (a) is the hydrogen sulfate of clopidogrel, the amount of that active ingredient in the dosage unit can advantageously vary from 10 to 75 mg (calculated in free form), said unit being active ingredient preferably of 25, 35, 50, 65 or 75 mg in 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) H In which R. and R are a hydroxy group or, together they form an oxygen atom, R ~. is a group (C1-C1Q) alkyl, (C3-C10) cycloalkyl, (CC) alkenyl, fepyl or pheni 1 (C.sub.3 -C.sub.3) alkyl and R, is hydrogen or a methyl or hydroxyl group; (ii) pharmaceutically acceptable salts of the compounds of formula (II) in which R. and R ~ are hydroxy; (iii) the indole derivatives of formula (III) In which one of the R ° and R 'is a structure group wherein Q4 is a hydrogen, chlorine or fluorine atom or a group (C, -C4) alkyl, (C ^ C ^ alkoxy, (but other than t-butoxy), trifluoromethyl, phenoxy or benzyloxy, Q5 is a hydrogen atom, a chlorine atom, a fluorine atom, a phenoxy or benzyloxy group, Q5 is a hydrogen atom, a chlorine atom, a fluorine atom or a methyl, ethyl, methoxy or ethoxy group, and the other R ° and R 'is a group (C.-Cg) primary or secondary alkyl, (C3-Cg) cycloalkyl, benzyl, 2-pentathio or 3-phenylpropyl; - 0 and 2 is a hydrogen, fluorine, chlorine atom or a group (0., - C. ^ alkyl, (C ^ -Cg) cycloalkyl, (C.-C alkoxy (but other than t-butoxy) , trifluoromethyl, phenoxy or benzyloxy; Q- is a hydrogen, chlorine, fluorine atom or a group (C.C3) alkyl, (C.-C3) alkoxy, phenoxy or benzyloxy; - X is a methylene group, ethylene or 1,3-propylene: Qfi is a hydrogen atom or a group (C.-C-Jalkyl, with the following limitation). ^ ^ 5 and ^ 5a are hydrogen when R4 is hydrogen. (2) Q? Aes e ^ hydrogen when Q5 is hydrogen, (3) Q. and Q3 are not at the same time a trifluoromethyl, phenoxy or benzyloxy group, (4) Q3 is hydrogen when Q ~ is hydrogen, ( 5) Q2 and Q3 are not at the same time a trifluoromethyl, phenoxy or benzyloxy group; (iv) pharmaceutically acceptable esters of the compounds of formula (III), (v) pharmaceutically acceptable salts of the compounds of formula (III), (vi) the S-lactones of the compounds of formula (III), (vii) the tetrazole derivatives of formula (IV) wherein Q. and Q, ', are hydrogen, a halogen or a (C1-C4) alkyl group, (C C2) -alkoxy or trifluoromethyl; Q7, Q7 ', Q8 and Qo' are hydrogen, a halogen or a group (C.-C4) alkyl, (C.-C alkoxy; - Q9 is hydrogen or a group (C ^ C ^ alkyl, (C ^ C ^ alkoxyalkyl or - (-methoxyethoxy) methyl; (viii) pharmaceutically acceptable salts of the compounds of formula (IV), (ix) 8-lactones of the compounds of formula (IV), (x) pyridine derivatives of formula (V) (xi) pharmaceutically acceptable salts of the compounds of formula (V), (xii) the d-lactones of the compounds of formula (V), (xiii) the pyrrole derivatives of formula (VI) (xiv) pharmaceutically acceptable salts of the compounds of formula (VI), (xv) the 8-lactones of the compounds of formula (VI), The compounds which correspond to formulas (II) to (VI) have at least two chiral carbons, the compounds (II) to (V) may also be present in the cis or trans form. Component (b) can be chosen from the isomers of compounds (II) to (VI) or mixtures thereof. Compounds (II) to (VI) are described in literature. More particularly, 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 the formula (II), in which R 4 is the -hydrogen or a methyl group, are described in EP 33538, or can be prepared either according to the method described therein, either by semi-synthesis, or in certain cases, by total synthesis, for example in the case of the synthesis of evastatin (J. Am. Chem. Soc, 1981, 6538, ibid., 1982, 4251) or of lovastatin (tetrahedron Letters 1983, 24, 1811) . Siavastatin is also described in EP 33538. The naphthalene compounds of formula (II), in which 4 is hydroxyl are described in GB 2077264. Among those compounds, pravastatin, used in the form of sodium salt, constitutes a compound (b) particularly interesting. Among the characters of formula (III) the compound that has this formula in which R ° is 4-fluorosilicone, R 'is isopropyl, X is vinyl and Q, Q, and Q6 are hydrogen, in its form (E) , racemic or optically active and their pharmaceutically acceptable salts constitute a Component (b) particularly interesting for the pharmaceutical compositions of the present invention. Among the tetrazole derivatives of formula (IV), the compound having this formula, in which Q. and Q 'are each a fluorine atom, Q7, Q7', Qg and Q8 'are hydrogen and Qg is a The methyl group, in its (E), racemic or optically active form, preferably (ßR), (Ss) and its pharmaceutically acceptable salts, in particular with an amino acid, are also a particularly interesting Compound (b) for the compositions pharmaceutical compositions of the present invention. The pyridine derivative of formula (V), in its (E), racemic or optically active form, preferably (ßR), (SS), or cerivastatin, and its pharmaceutically acceptable salts, especially with an acid, are another Component (b) interesting for the pharmaceutical compositions of the present invention.

The 8-lactone of the pyrrole derivative of formula (VI), known as atorvastatin, constitutes an interesting Component (b) for the pharmaceutical compositions of the present invention. According to an advantageous aspect, the compositions of the present invention contain ticlopidine hydrochloride as Component (a) and simvastatin or pravastatin sodium as Component (b). Preferably, said compositions comprise from 100 to 250 mg. of tic1op_dine hydrochloride and 10 to 40 mg of simvastatin or pravastatin sodium. According to another advantageous aspect, the compositions of the present invention contain the hydrogensulfate of clopidogrel as Component (a) and simvastatin or pravastatin sodium as Component (b). Preferably, said compositions comprise from 10 to 75 mg. (calculated on free base) of clopidogrel hydrogen sulfate and 10 to 40 mg. of simvastatin or -pravastatin sodium. The associations of active ingredients according to the invention have been the object of pharmacological studies. Tests have been carried out with respect to the proliferation test of the muscle cells of the vascular wall that appears as a consequence of a desendoteilialization of the rabbit carotic artery. In itself, the thesis has fed New Zealand rabbits of 2.5-3 kg. with a synthetic food that contains 2% cholesterol and 6% peanut oil. --The animals have been treated simultaneously orally with Clopidogrel (5 mg / kg / d). The compounds have been administered 2 days before the endothelium injury and daily for 2 weeks. The myo-intimate proliferation of the rabbit carotid has been induced by air dissection, as described in the method described above (Fishman et al., Lab. Invest, 1975, 32, 339-347); Herbert et al., 1993, 13, 1171-1179). The animals were anesthetized intravenously by means of sodium pentobarbital (30 mg / kg), i.v.) and the left carotid was isolated. A hlpodermic syringe (27-Gauge) - as well as a distal part - has been inserted into an area close to the artery. The blood was drained and the arterial segment isolated in this way was washed with physiological serum, and the endothelial wound was induced by passing a dry air stream (240 ml / min for 5 minutes). Then, the needles have been removed, the blood circulation restored and the incision closed. Fourteen days after the injury, the animals were anesthetized (pentobarbital sodium, 30 mg / kg, i.v.). The arterial segment was isolated, rinsed with physiological saline and incubated for 18 hours in a 10% formaldehyde solution. The arterial segments were then dehydrated in ethanol, included in the paraffin, cut with myotome and colored with hematoxylinosine, the medial and intimal surfaces have been quantified by image analysis (Biocom imagenia 5000, Lyon, France). The results shown in TABLE 1 indicate that clopidogrel and simvastatin (5 mg / kg / d) administered orally daily in the rabbit inhibit the proliferation of muscle cells resulting from an endothelium injury by an air current. In all cases, the joint administration of clopidogrel and simvastatin resulted in a significant synergistic effect against the proliferation of smooth muscle cells. That is to say that when the products have been administered in association, the antiproliferative effect obtained has always been greater than the simple sum of the effects of the two tested products, taken separately, TABLE 1 Effect of the products alone or in association with myointimal proliferation resulting from a vascular endothelial lesion.

Products Dose% inhibition of myointimal proliferation Clopidogrel 5 mg / kg / d 31 + 4% Simvastatin 5 mg / kg / d 48 + 7% Clopidogrel + Simvastatin 5 + 5 mg / kg / d 92 + 9% Table values are average values + standard errors (n = 10).

On the other hand, the antithrombotic effect of the association according to the invention has been evidenced in a test for the formation of a thrombus on a silk thread present in an arteriovenous shunt implanted between the carotid artery and the jugular vein of the rabbit. as-has been described by Umetsu and al. (Thromb. Haemostas, 1978, 39, 74-83). - New Zealand rabbits of 2.5 to 3 kg have been treated. The animals were anesthetized by subcutaneous administration of sodium pentobarbital (30 mg / kg). Between the right carotid artery and the left guiding vein, two polyethylene tubes 12 cm long (internal diameter 0.6 mm, external diameter 0.9 mm) were tied by a central part of 6 cm. long (inner diameter: 0.9 mm) containing a 5 cm long silk thread. The central part of the shunt was then placed, then removed after 20 minutes of blood circulation in the shunt. Then -the weight of the thrombus present in the silk thread has been determined. In the same way as in the case of the effects measured against the proliferation of smooth muscle cells resulting from an endothelium injury by an air current, the antithrombotic activity of -clopidogrel has been potentiated by means of an association with the sim vastatin. Under these conditions, and as has been done before the proliferation of smooth muscle cells, a significant synergistic effect has been observed. The results obtained are shown in the following table 2.

TABLE 2 Effect of the products alone or in association against the formation of an arterial thrombus on a silk thread implanted in an arteriovenous shunt in the rabbit Products Dosage% inhibition of thrombosis Simvastatin 5 mg / kg 15 + 4% Clopidogrel 5 mg / kg 34 + 4% Clopidogrel + simvastatin 5 + 5 mg / kg 72 + 5% The values in the table are average values + standard errors (n = 5). The combination of thienopyridine and the HMG-CoA re ductase inhibitor is formulated in pharmaceutical compositions which can be used orally or parenterally, especially orally, in admixture with conventional acetic acid excipients. Said pharmaceutical compositions, object of the present invention, are preferably presented in the form of dosage units -which contain a predetermined amount of active principles, as specified above. The unit forms of oral administration comprise the tablets, the capsules, the powders, the granules, the microgranules. When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, taj._co, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or they can even be treated in such a way that they have a prolonged or delayed activity and that they release a predetermined quantity of active principle from the continuous form. A preparation in capsules is obtained by mixing the active ingredient with a diluent and pouring the obtained mixture into soft or hard capsules. The active principle can also be formulated in the form of microcapsules optionally with one or more carriers or additives. The active principles of the associations can also be presented in complex form with a cyclodextrin, for example a, ßo? ciciodextrin, 2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin. In formulating the associations of the active ingredients for the preparation of the pharmaceutical compositions of the present invention, the nature of Components (a) and (b) of the associations will be taken into account. Component (a), namely thienopyridine, is preferably used in the form of an addition salt with pharmaceutically acceptable acids. For example, Preferred components (a) are ticlopidine hydrochloride and clopidogrel hydrogensulfate which are acidic compounds. Usually, the thienopyridines, in the form of their addition salts with pharmaceutically acceptable acids, are not chemically incompatible with the HMG-CoA reductase inhibitors. However, some of these -the latter are used in the form of salts with alkali metals, as for example in the case of pravastatin sodium. Therefore it is preferable to keep the active ingredients separated according to well-known techniques from the literature. In this way, the pharmaceutical form containing the association of thienopyridine and the HMG-CoA reductase inhibitor can be presented, for example, as a capsule, transparent or opaque, containing two tablets of which one contains thienopyridine and the other contains the HMG-CoA reductase inhibitor. This presentation has the advantage of using the two active ingredients that constitute the association in the usual pharmaceutical form, each tablet being able to be covered by a film that allows either the immediate release of the two active principles, or a litararim. programmed in different times.

Another presentation may include capsules containing a mixture of iicrogranules of which some contain thienopyridine and the others enclose the HMG-CoA reductase inhibitor, said micro-granules being able to be coated with a film allowing the immediate or programmed release of the active principles. The pharmaceutical form containing the association according to the present invention may be presented as a double or triple layer tablet, more precisely as tablets prepared to undergo more than one compression. The result of this form can be either that of a two-layer tablet, separated for example by a film, or that of one compressed inside another tablet, the two parts possibly being colored differently. Another pharmaceutical form containing the association according to the present invention can be presented as a double capsule constituted by an internal gelatin capsule containing one of the two components and by an outer gelatin capsule containing the first capsule and the other -component. In this case, it is preferable that the internal capsule contain the HMG-CoA reductase inhibitor and the external capsule contain the thienopyridine. A pharmaceutical form of that type is described in US 5,310,555. In the associations according to the present invention, the dosage forms of the present invention preferably contain 250 mg of ticlopidine hydrochloride and 20 mg of simvastatin or of pravastatin sodium 250 mg of ticlopidine hydrochloride and 15 mg of simvastatin or 15 mg -of pravastatin sodium; 200 mg of ticlopidine hydrochloride and 15 mg of sim vastatin or 15 mg of pravastatin sodium; 175 mg of ticlopi-diñe hydrochloride and 20 mg of simvastatin or pravastatin sodium, 175 mg of ticlopidine hydrochloride and 15 mg of simvastatin or pravastatin sodium, 250 mg of ticlopidine hydrochloride and 10 mg of simvastatin or pravastatin sodium; 200 ticlopidine hydrochloride and 10 mg simvastatin or pravastatin sodium; 175 mg of ticlopidine hydrochloride and 10 mg of simvastatin or pravastatin sodium. Associations containing 250 mg of ticlopidine hydrochloride and 20 mg of simvastatin or pravastatin sodium for an attack therapy can also be envisaged. In other associations according to the present invention, the pharmaceutical forms preferably contain 87.5 mg of clopidogrel hydrogenesulfate and 20 mg of simvastatin or pravastatin sodium; 81.25 mg of clopidogrel hydrogenosulfan and 20 mg of simvastatin or pravastatin sodium; 87.5 mg of clopidogrel hydrogensulfate and 15 mg of simvastatin or pravastatin-sodium; 81.5 mg of clopidogrel hydrogensulfate and 15 mg of simvastatin or -pravastatin sodium; 62.5 mg of clopidogrel hydrogensulfate and 20 mg of simvastatin or pravastatin sodium; 62.5 mg of clopidogrel hydrogensulfate and 15 mg of simvastatin or pravastatin sodium; 93.75 mg of clopidogrel hydrogensulphate and 10 mg of simvastatin opravastatinasodica; 87.5 mg of clopidogrel hydrogensulphate and 10 mg of simvastatin or pravastatin sodium; - 81.25 mg of clopidogrel hydrogensulfate and 10 mg of simvastatin or pravastatin sodium; 62.5 mg of clopidogrel hydrogensulfate and 10 mg of simvastatin or pravastatin sodium. Associations containing 87.5 mg of clopidogrel hydrogen sulfate and 20 mg of simvastatin or pravastatin sodium can also be envisaged for attack therapy. The pharmaceutical compositions of the present invention are particularly indicated for the treatment of pathological conditions such as the disorders of the cardiovascular and cerebrovascular system, the thromboembolic L.-disorders associated with atherosclerosis or the di- "css as the unstable angina, stroke, retention of angioplasty, endoarterectomy, or installation of endovascular stent; of the thrombolysis, in the infarction, in the diaphragm of ischemic origin, in peripheral arterial diseases, in hemodialysis, in atrial fibrillations or even when vascular prostheses, aortocoronary by-pass or against stable or unstable angina are used. EXAMPLE 1 Association ticlopidine / simvastatin (200mg / 20mg) 1. Double layer compressed formula Layer n9 1 Ticlopidine (hydrochloride) 200.00 mg Microcrystalline cellulose 69.88 ppg Modified corn starch 31.20 mg Polyvidid 6.24 mg Citric acid 3.12 mg Stearic acid 0.78 mg Magnesium stearate 0.78 mg N9 layer 2 Simvastatin 20.00 mg Butylated hydroxyanisole 0.04 mg Ascorbic acid 5.00 mg Citric acid 2.50 mg Microscrystalline cellulose 10.00 mg Starch pregelatinized corn 20.00 mg Lactose 141.50 mg Magnesium stearate 1.00 mg Methylhydroxypropyl cellulose 1.65 mg Hydroxypropyl cellulose 1.65 mg Titanium dioxide 1.50 mg Talc 0.60 mg Yellow ferric oxide 0.092 mg Red ferric oxide 0.023 mg 2. Operational modes' The ticlopidine granulate is prepared by wet granulation. "Simvastatin granulate is prepared by wet granulation." The two granulates are compressed in the press allowing the manufacture of double-layer tablets EXAMPLE 2 Clopidogrel / Simvastatin Association (50 mg / 10 mg) 1. Double-layer compressed formula Layer n9 1 Clopidogrel hydrogen sulfate 65.00 mg (ie 50 mg base) Lactose anahydrogen 72.20 mg Modified corn starch 7.00 mg Macrogel 6000 5.00 mg Microcrystalline cellulose 3.60 mg Hydrogenated castor oil 2.20 mg n9 2 Simvastatin 10.00 mg Butylhydroxyanisole 0.02 mg Ascorbic acid 2,50 mg Citric acid 1, 75 mg Microscrystalline cellulose 5.00 mg Pregelatinized corn starch 10.00 mg Lactose 70.75 mg Magnesium stearate 0.50 mg Methylhydroxypropylcellulose 0.825 mg Hydroxypropylcellulose 0.825mg Titanium dioxide 0.75 mg Talcum 0.30 mg Yellow ferric oxide 0,046 mg Red ferric oxide 0.0115 mg Operating modes' The granulate of Clopidogrel is prepared by dry granulation - (compacted). "The Simvastatin granulate is prepared by wet granulation." The two granulates are pressed into the press allowing the manufacture of the double layer tablets.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional method for the manufacture of the objects or products to which it refers. Having described the invention as above, it is claimed as -property what is contained in the following:

Claims (12)

1. R E I V I N D I C A C I O N S Pharmaceutical composition containing: (a) a thienopyridine derivative of the formula wherein R is hydrogen or a group * (C-C-alkoxycarbonyl, or a -of its pharmaceutically acceptable salts, and (b) an HMG-CoA reductase inhibitor
2. 2.- Composition according to claim 1 characterized because Component (a) is present in a dose ranging between 10 and 250 mg of active principle and Component (b) is present in a dose of 2 to 50 mg of active principle,
3. 3. Composition according to claim 1, characterized because the thienopyridine derivative is ticlopidine hydrochloride
4. 4. Composition according to claim 3, characterized in that the amount of ticlopidine hydrochloride in a dosage unit is 100 to 250 mg.
5. 5. - Composition according to claim 1, characterized in that the thienopyridine derivative is the hydrogensulfate of clopidogrel.
6. 6. Composition according to claim 5, characterized in that the amount of hydrogen sulfate in the dosage unit is from 10 to 75 mg (calculated on free base).
7. 7. Composition according to claim 1, characterized in that the HMG-CoA reductase inhibitor is a compound selected from: The naphthalene derivatives of formula (II) H wherein R. and R2 are a hydroxy group or, together form an oxygen atom, R3 is a group (C ^ C ^ alkyl, (C3-C10) cycloalkyl, (C2-C1C1) alkenyl, phenyl or phenyl (C - C-) alkyl and 4 is hydrogen or a methyl or hydroxyl group: i) pharmaceutically acceptable salts of the compounds of formula di) in which R, and R2 are hydroxy; (iii) the indol derivatives of formula (III) in which - one of the R ° and R 'is a structure group wherein Q4 is a hydrogen, chlorine or fluorine atom or a group (C.-C alkyl, (C.-C alsoxi, (but other than t-butoxy), trifluoromethyl, phenoxy or benzyloxy, Q, - is a hydrogen atom, chlorine atom, de-fluorine atom or a phenoxy or benzyloxy group Q5a is a hydrogen, chlorine, fluorine atom or a methyl, ethyl, methoxy or ethoxy group; and R 'is a group (C.sub.-C, primary or sec.-cycloalkyl, (C3-Cg) cycloalkyl, benzyl, 2-phenylethyl or 3-phenylpropyl; Q.sub.2 is a hydrogen, fluorine, chlorine or group atom ( C.-C alkyl, (C3-Cg) cycloalkyl, (C1-C4) alkoxy (but other than t-buto xi), trifluoromethyl, phenoxy or benzyloxy; Q3 is a hydrogen, chlorine, fluorine atom or a group (C.-C,) alkyl, (C.-C3) alkoxy, phenoxy or benzyloxy; X is a methylene, ethylene or 1,3-propylene group; Qg is a hydrogen atom or a group (C.-C3) alkyl, with the following limitation: (1) Q and Qca are hydrogen when R4 is hydrogen, (2) Q5a is the idrogen when Q5 is hydrogen, (3) Q4 and Q3 are not at the same time a trifluoromethyl, phenoxy or benzyloxy group, (4) Q3 is hydrogen when Q2 is hydrogen, (5) Q2 and Q3 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 form (III), (vi) The S-lactones of the compounds of formula (III) ), (vii) The tetrazole derivatives of formula (IV) in which C4) -alkoxy or trifluoro ethyl; Q7, Q7 ', Qg and Qg' are hydrogen, a halogen or a group (C.-C alkyl, (C.-C alkoxy; -QQ is hydrogen or a group (C.-C ^ alkyl, (C.-C-alkoxyalkyl or (2-methoxyethoxy) methyl; (viii) pharmaceutically acceptable salts of the compounds of formula (IV), (ix) the S-lactones of the compounds of formula (IV), (x) the pyridine derivatives of formula (V) (xi) pharmaceutically acceptable salts of the compounds of formula (V) (xii) the S-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 S-lactones of the compounds of formula (VI).
8. 8. Composition according to claim 7, characterized in that the HMG-CoA reductase inhibitor is chosen from the sinvastatin., pravastatin sodium, evastatin, lovastatin, cerivastatin, atorvasat a, an indole derivative of formula (III) in which R "is 4-fluorophenyl n, R 'is isopropyl, X is vinyl and Q2 , Q3 and Qβ are the hydrogen in its racemic or optically active (E) form, the pharmaceutically acceptable salts of said indole derivative, a tetrazole derivative of formula (IV) in which Q1 and Q1 'are each a fluorine atom, Q7 Q7 '.Qg and Qg' are the hydrogen, in its (E) configuration form (ßR), (SS) and the pharmaceutically salts of the mentioned tetrazole derivative. according to claim 2 characterized in that Component (a) is the cyclopidine hydrochloride and the component (b) is between the sümastaira and the pravastatin sodium 10. Composition according to claim 9 characterized in that - encloses from 100 to 250 mg of ticlopidine hydrochloride and 10 to 40 mg of simvastatin or pravastatin sodium. 11. Composition according to claim 2, characterized in that the oj nmt-K (a) is the hydrogen sulfate of clopidogrel and the Component (b) is chosen between simvastatin and pravastatin sodium. 12. Composition according to claim 11, characterized in that it contains 10 to 75 mg (calculated on free base) of clopidogrel hydrogenosulfato and 10 to 40 mg of simvastatin or pravastatin sodium. 13, - Use for the manufacture of an antithrombotic drug of an association: (a) of a thienopyridine derivative of formula wherein R is hydrogen or a group (C.-C alkoxycarbonyl, or a pharmaceutically acceptable salt thereof, and (b) an inhibitor of HMG-CoA reductase. antiatherotide drug not of an association; (a) of a thienopyridine derivative of formula (I) wherein R is hydrogen or a group (C ^ C ^ alkoxycarbonyl, or a pharmaceutically acceptable salt thereof, and (b) an HMG-CoA reductase inhibitor.