Title of Invention	A PHARMACEUTICAL COMPOSITION CONTAINING THIENOPYRIDINE DERIVATIVE AND HMG-CoA REDUCTASE INHIBITOR
Abstract	The present invention relates to a pharma- ceutical composition containing: (a) a thienopyridine derivative of formula in which R is hydrogen or a (C1-C4)alkoxycarbonyl group, or one of its pharmaceutically acceptable salts; and (b) an HMG-CoA reductase inhibitor.

Full Text

The present invention relates to a pharmaceuti¬ cal composition containing as active prinC1ple a combi¬ nation of a thienopyridine derivative and an HMG-CoA reductase inhibitor. More espeC1ally, the subject of the present invention is a pharmaceutical composition containing (a) a thienopyridine derivative of formula in which R is hydrogen or a (C1-C4)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-chloro-benzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine of for¬mula (I) , R = hydrogen, hereinafter designated by its international nonproprietary name (INN) "ticlopidine", used in hydrochloride form, and (+)-[methyl (S)-a-(2-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]-pyridin-5-ylacetate] of the formula (I) , R = methoxy-carbonyl, hereinafter designated by its INN "clopido-grel", used in hydrogen sulphate form, are exceptional antithrombotic agents (Gent et al., Lancet, 1989, 8649, 1215-1220 - J-M. Herbert et a.1., 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 espeC1ally an additive and/or synergistic activity of the two active prinC1ples with respect to the pro¬liferation 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 prinC1ples in an animal model of arterial thrombosis which is predictive of a preventive or curative clini¬cal antithrombotic activity. Thus, according to the present invention, a therapeutically effective dose of a thienopyridine derivative of formula (I) , or of one of its pharmaceu-tically 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 reduc¬tase inhibitor, the therapeutically effective dose of Component (a) can vary from 10 to 250 mg of active prinC1ple (calculated as free base or as salt) , whereas the therapeutically effective dose of Component (b) can vary from 2 to 50 mg of active prinC1ple. According to the present invention, the thieno¬pyridine derivative of formula (I) is preferably selected from ticlopidine and the pharmaceutically acceptable salts, in particular ticlopidine hydro¬chloride, and clopidogrel and the pharmaceutically acceptable salts, in particular clopidogrel hydrogen sulphate. When Component (a) in a dosage unit is ticlopi¬dine hydrochloride, the amount of this active prinC1ple in the dosage unit can advantageously vary from 100 to 250 mg, the said amount of active prinC1ple preferably being 150, 175, 200, 225 or 250 mg per dosage unit. When in the dosage unit Component (a) is clopi¬dogrel hydrogen sulphate, the amount of this active prinC1ple in the dosage unit can advantageously vary from 10 to 75 mg (calculated as free base) , the said amount of active prinC1ple 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 selec¬ted from (I) the naphthalene derivatives of formula (II) in which Ri and R2 are a hydroxyl group or alternatively together form an oxygen atom, R3 is a (C1-C1o)alkyl, (C3-C10) cycloalkyl, (C2-C10)-alkenyl, phenyl or phenyl(C1-C3)alky1 group and R4 is hydrogen or a methyl or hydroxyl group; (ii) the pharmaceutically acceptable salts of the compounds of formula (II) in which Ri and R2 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 Q4 is a hydrogen, chlorine or fluorine atom or a (C1-C4) alkyl, (C1-C4) alkoxy (but other than t-butoxy), trifluoromethyl phenoxy or benzyloxy group, Qs is a hydrogen, chlorine or fluorine atom or a phenoxy or benzyloxy group and Qsa 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 (C1-Cs) alkyl, (Ca-Ce)-cycloalkyl, benzyl, 2-phenylethyl or 3-phenylpropyl group; Q2 is a hydrogen, fluorine or chlorine atom or a (C1-C4) alkyl, (Ca-Cs) cycloalkyl, (C1-C4)-alkoxy (but other than t-butoxy), trifluoro¬methyl , phenoxy or benzyloxy group; Q3 is a hydrogen, chlorine or fluorine atom or a (C1-C3) alkyl, (C1-C3) alkoxy, phenoxy or benzyloxy group; X is a methylene, ethylene or 1,3-propylene group; Qs is a hydrogen atom or a (C1-C3) alkyl group; with the limitation that (1) Qs and Qsa are hydrogen when R4 is hydrogen, (2) Qsa is hydrogen when Q5 is hydrogen, (3) Q4 and Q3 are not at the same time a tri¬ fluoromethyl, phenoxy or benzyloxy group, (4) Q3 is hydrogen when Q2 is hydrogen, (5) Q2 and Q3 are not at the same time a tri¬ fluoromethyl, 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 5-lactones of the compounds of formula (III) , (vii) the tetrazole derivatives of formula (IV) in which Qi and Q^" are hydrogen, a halogen or a (C1-C4)alkyl, (C1-C4) alkoxy or trif luoromethyl group; - Q7/ Q7"/ Qs/ and Qg" are hydrogen, a halogen or a (C1-C4)alkyl or (C1-C4) alkoxy group; Qg is hydrogen or a (C1-C4) alkyl, (C1-C4)-alkoxyalkyl or (2-methoxyethoxy)methyl group; (viii) the pharmaceutically acceptable salts of the compounds of formula (IV), (ix) the 5-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 5-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 6-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 C1s 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 espeC1ally, the indole derivatives of formula (III) are described in WO 84/02131, the tetra-zole derivatives of formula (IV) are described in EP 65855 0, the pyridine derivatives of formula (V) are described in DE 4 040026 and the pyrrole derivatives of formula (VI) are described in EP 409281. The naphthalene compounds of formula (II) in which R4 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 syn¬thesis or, in some cases, by total synthesis, for example in the case of the synthesis of raevastatin (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 R4 is hydroxyl are described in GB 2,077,264. Among these compounds, pravastatin, used in the form of the sodium salt, constitutes an espeC1ally advantageous Component (b). Among the indoles of formula (III) , the com-pound having this formula in which R° is 4-fluoro-phenyl, R" is isopropyl, X is ethylene and Qz, Q3 and Qs are hydrogen, in its racemic or optically active (E) form, and its pharmaceutically acceptable salts, con¬stitute an espeC1ally advantageous Component (b) for the pharmaceutical compositions of the present inven¬tion . Among the tetrazole derivatives of formula (IV) , the compound having this formula in which Qi and Qi" are each a fluorine atom, Q7, Q7" , Qg and Qs" are hydrogen and Q9 is a methyl group, in its racemic or optically active, preferably (PR,5S), (E) form, and its pharmaceutically acceptable salts, in particular with an amino aC1d, also constitute an espeC1ally advan¬tageous Component (b) for the pharmaceutical composi¬tions of the present invention. The pyridine derivative of formula (V) , in its racemic or optically active, preferably (PR,5S) , (E) form, or cerivastatin, and its pharmaceutically accept¬able salts, constitute another advantageous Component (b) for the pharmaceutical compositions of the present invention. The 6-lactone of the pyrrole derivative of the formula (VI), known as atorvastatin, constitutes an advantageous Component (b) for the pharmaceutical com¬positions of the present invention. According to an advantageous aspect, the com¬positions of the present invention contain ticlopidine hydrochloride as Component (a) and simvastatin or pravastatin sodium as Component (b). Preferably, such compositions contain from 100 to 250 mg of ticlopidine hydrochloride and from 10 to 40 mg of simvastatin or of pravastatin sodium. According to another advantageous aspect, the compositions of the present invention contain clopido-grel hydrogen sulphate as Component (a) and simvastatin or pravastatin sodium as Component (b). Preferably, such compositions contain from 10 to 75 mg (calculated as free base) of clopidogrel hydrogen sulphate and from 10 to 40 mg of simvastatin or prevastatin sodium. The combinations of active prinC1ples according to the invention were subjected to pharmacological studies. Experiments were carried out to implement the test for proliferation of vascular wall muscle cells occurring following a de-endothelialization of the carotid artery of rabbits. Briefly, New Zealand rabbits weighing 2.5-3 kg were fed with a synthetic feed containing 2% of cholesterol and 6% of groundnut oil. The animals were treated orally with clopidogrel (5 mg/kg/d). The animals were simultaneously treated orally with simvastatin (5 mg/kg/d). The compounds were administered 2 days before lesion of the endothelium and daily for 2 weeks. Myointimal proliferation of the rabbit carotid was induced by drying in the air accord¬ing to the method described previously (Fishman et al., Lab. Invest., 1975, 32, 339-347; Herbert et al. , 1993, 13, 171-1179). The animals were anaesthetized intra¬venously with pentobarbital sodium (30 mg/kg, i.v.) and the left carotid was isolated. A hypodermic syringe (27 gauge) was inserted into a proximal portion of the artery and also into a distal portion. The arterial segment thus isolated was emptied of its blood and washed with physiological saline, and endothelial injury was induced by passing a stream of dry air through it (24 0 ml/min for 5 minutes). The needles were then withdrawn, the blood C1rculation was re-established and the inC1sion was closed up. Four¬teen days after the lesion, the animals were anaesthe¬tized (pentobarbital sodium, 30 mg/kg, i.v.). The arterial segment was isolated, rinsed with physio¬logical saline and incubated for 18 hours in 10% form¬aldehyde solution. The arterial segments were then dehydrated in ethanol, included in paraffin, cut with a microtome and stained with haematoxylin-eosin. The medial and intimal surfaces were quantified by image analysis (Biocom Imagenia 5000. Lvons, France). The results shown in TABLE 1 indicate that clopidogrel and simvastatin (5 mg/kg/d) administered orally daily in rabbits inhibit the proliferation of smooth muscle cells following a lesion of the endo¬thelium with a stream of air. In all cases, the joint administration of clopidogrel and simvastatin resulted in a significant synergistic effect with respect to the proliferation of smooth muscle cells. That is to say, when the products were administered in combination, the antiproliferative effect obtained was always greater than the simple sum of the effects of the two test products taken separately. TABLE 1 Effect of the products alone or in combination with respect to myointimal proliferation following a lesion of the vascular endothelium. Moreover, the antithrombotic effect of the com¬bination according to the invention was demonstrated in a test for formation of a thrombus on a silk thread present in an arteriovenous shunt implanted between the carotid artery and the jugular vein of rabbits, as described by Umetsu et al. (Thromb. Haemostas., 1978, 39, 74-83). New Zealand rabbits weighing 2.5 to 3 kg were treated. The animals were anaesthetized by subcutaneous administration of pentobarbital sodium (30 mg/kg). Two polyethylene tubes 12 cm in length (internal diameter: 0.6 mm; external diameter: 0.9 mm), attached by a central portion 6 cm in length (internal diameter: 0.9 mm) containing a silk thread 5 cm in length, were placed between the right carotid artery and the left jugular vein. The central portion of the shunt was then placed in position, and thereafter with¬drawn after 2 0 minutes of C1rculation of blood in the shunt. The weight of the thrombus present on the silk thread was then determined. In the same manner as in the case of the effects measured with respect to the proliferation of smooth muscle cells following a lesion of the endo¬thelium by a stream of air, the antithrombotic activity of clopidogrel was potentiated by a combination with simvastatin. Under these conditions, and as with respect to the proliferation of smooth muscle cells, a significant synergistic effect was observed. The results obtained are recorded in TABLE 2 below. TABLE 2 Effect of the products alone or in combination with respect to the formation of an arterial thrombus on a silk thread implanted in an arteriovenous shunt in rabbits. The combination of the thienopyridine and the HMG-CoA reductase inhibitor is formulated in pharmaceu¬tical compositions which can be used orally or paren- terally, in particular orally, mixed with traditional pharmaceutical exC1pients. The said pharmaceutical compositions which are the subject of the present invention preferably take the form of dosage units containing a predetermined amount of the- active prinC1ples, as is speC1fied above. The single-dose forms for oral administration comprise tablets, gelatin capsules, powders, granules and micro-granules . When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arable or the like. The tablets can be coated with sucrose or other suitable materials, or can alternatively be treated in such a way as to have sustained or delayed activity and to release a predetermined amount of active prinC1ple continuously, A gelatin capsule preparation is obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gelatin capsules. The active prinC1ple may also be formulated in the form of microcapsules, where appropriate with one or more vehicles or additives. The active prinC1ples of the combinations can " also take the form of a complex with a cyclodextrin, for example a-, P- or y-cyclodextrin, 2-hydroxypropyl-P-cyclodextrin or methyl-P-cyclodextrin. In the formulation of the combinations of the active prinC1ples for the preparation of the pharma¬ceutical compositions according to the present inven¬tion, the nature of Components (a) and (b) of the com¬binations will be borne in mind. Component (a), namely the thienopyridine, is preferably used in the form of an addition salt with pharmaceutically acceptable aC1ds. For example, preferred Components (a) are ticlo-pidine hydrochloride and clopidogrel hydrogen sulphate, which are aC1dic compounds. Normally, the thienopyridines, in the form of their addition salts with pharmaceutically acceptable aC1ds, are not chemically incompatible with HMG-CoA reductase inhibitors. However, some of the latter are used in the form of salts with alkali metals, as, for example, in the case of pravastatin sodium. It is hence preferable to keep the active prinC1ples separated according to techniques which are well known from the literature. Thus, the pharmaceutical dosage form containing the combination of the thienopyridine and the HMG-CoA reductase inhibitor can be presented, for example, as a transparent or opaque gelatin capsule containing two tablets, of which one contains the thienopyridine and the other contains the HMG-CoA reductase inhibitor. This presentation has the advantage of using the two active prinC1ples constituting the combination in the pharmaceutical dosage form which is commonly used, it being possible for each tablet to be coated with a film which permits either the immediate release of the two active prinC1ples or a programmed release over dif¬ferent times. Another presentation can envisage gelatin capsules containing a mixture of microgranules, of which some contain the thienopyridine and the others contain the HMG-CoA reductase inhibitor, it being possible for the said microgranules to be coated with a film permitting the immediate or programmed release of the active prinC1ples. The pharmaceutical dosage form containing the combination according to the present invention can be presented as a double- or triple-layer tablet, more espeC1ally as tablets prepared by subjecting the pro¬ducts to more than one compression. The outcome of such a dosage form can be either a two-layer tablet, the layers being separated, for example, by a film, or a tablet inside another tablet, the two parts being, where appropriate, coloured differently. I Another pharmaceutical dosage form of the com¬bination according to the present invention can be presented as a double gelatin capsule, consisting of an inner gelatin capsule containing one of the two com¬ponents and an outer gelatin capsule containing the first capsule and the other component. In this case, it is preferable for the inner capsule to contain the HMG-CoA reductase inhibitor and the outer capsule to contain the thienopyridine. A pharmaceutical dosage form of this type is described in US 5,310,555. In the combinations according to the present invention, the pharmaceutical dosage forms of the pre¬sent invention preferably contain 250 mg of ticlopidine hydrochloride and 2 0 mg of simvastatin or of prava¬statin 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 simvastatin or 15 mg of pravastatin sodium; 175 mg of ticlopidine hydrochloride and 20 mg of simvastatin or of pravastatin sodium; 175 mg of ticlopidine hydro¬chloride and 15 mg of simvastatin or of pravastatin sodium; 250 mg of ticlopidine hydrochloride and 10 mg of simvastatin or of pravastatin sodium; 200 mg of ticlopidine hydrochloride and 10 mg of simvastatin or of pravastatin sodium; 175 mg of ticlopidine hydro¬chloride and 10 mg of simvastatin or of pravastatin sodium. Combinations containing 250 mg of ticlopidine hydrochloride and 20 mg of simvastatin or of prava¬statin sodium can also be envisaged for therapy in the acute situation. In other combinations according to the present invention, the pharmaceutical dosage forms preferably contain 87.5 mg of clopidogrel hydrogen sulphate and 20 mg of simvastatin or pravastatin sodium; 81.25 mg of clopidogrel hydrogen sulphate and 20 mg of simvastatin or pravastatin sodium; 87.5 mg of clopidogrel hydrogen sulphate and 15 mg of simvastatin or pravastatin sodium; 81.25 mg of clopidogrel hydrogen sulphate and 15 mg of simvastatin or pravastatin sodium; 62.5 mg of . I ^ clopidogrel hydrogen sulphate and 2 0 mg of simvastatin or pravastatin sodium; 62.5 mg of clopidogrel hydrogen sulphate and 15 mg of simvastatin or pravastatin sodium; 93.75 mg of clopidogrel hydrogen sulphate and 10 mg of simvastatin or pravastatin sodium; 87.5 mg of clopidogrel hydrogen sulphate and 10 mg of simvastatin or pravastatin sodium; 81.25 mg of clopidogrel hydrogen sulphate and 10 mg of simvastatin or pravastatin sodium; 62.5 mg of clopidogrel hydrogen sulphate and 10 mg of simvastatin or pravastatin sodium. Combina¬tions containing 87.5 mg of clopidogrel hydrogen sulphate and 20 mg of simvastatin or pravastatin sodium can also be envisaged for therapy in the acute situa¬tion. The pharmaceutical compositions of the present invention are espeC1ally indicated in the treatment of pathological states such as disorders of the cardio¬vascular and cerebrovascular system, for instance the thromboembolic disorders assoC1ated with athero¬sclerosis or with diabetes such as unstable angina, stroke, restenosis after angioplasty, endarterectomy or fitting of metallic endovascular prostheses, with rethrombosis after thrombolysis, with infarction, with dementia of ischaemic origin, with peripheral arterial diseases, with haemodialysis and with atrial fibrilla¬tion, or alternatively when vascular prostheses or aortocoronary bridges are used, or in relation to stable or unstable angina. EXAMPLE 1 Ticlopidine/simvastatln combination (200 mg/20 mg) 1. Double-layer tablet formula Layer No. 1 Ticlopidine (hydrochloride) 200.00 mg Microcrystalline cellulose 69.88 mg Modified maize starch 31.20 mg Povidone 6.24 mg C1tric aC1d 3.12 mg stearic aC1d 0.78 mg Magnesium stearate 0.78 mg Layer No. 2 Simvastatin 20.00 mg Butylated hydroxyanisole 0.04 mg Ascorbic aC1d 5.00 mg C1tric aC1d 2.50 mg Microcrystalline cellulose 10.00 mg Pregelatinized maize starch 20.00 mg Lactose 141.50 mg Magnesium stearate 1.00 mg Methylhydroxypropylcellulose 1.65 mg Hydroxypropylcellulose 1.65 mg Titanium dioxide 1.50 mg Talc 0.60 mg Yellow iron oxide 0.092 mg Red iron oxide 0.023 mg 2. Procedure ♦ The ticlopidine granule is prepared by wet granulation. ♦ The simvastatin granule is prepared by wet granulation. ♦ The two granules are compressed on a press permitting the manufacture of double-layer tablets. EXAMPLE 2 Clopldogrel/simvastatin combination (50 mg/10 mg) 1. Double-layer tablet formula Layer No. 1 Clopidogrel hydrogen sulphate 65.00 mg (equivalent to 50 mg of base) Anhydrous lactose 72.20 mg Modified maize starch 7.00 mg Macrogel 6000 5,00 mg Microcrystalline cellulose 8.60 mg Hydrogenated castor oil 2.20 mg Layer No. 2 Simvastatin 10.00 mg Butylated hydroxyanisole 0.02 mg Ascorbic aC1d 2.50 mg C1tric aC1d 1.75 mg Microcrystalline cellulose 5.00 mg Pregelatinized maize starch 10.00 mg Lactose 70.75 mg Magnesium stearate 0.50 mg Methylhydroxypropylcellulose 0.825 mg Hydroxypropylcellulose 0.825 mg Titanium dioxide 0.75 mg Talc 0.3 0 mg Yellow iron oxide 0.046 mg Red iron oxide 0.0115 mg 2. Procedures ♦ The clopidogrel granule is prepared by dry granulation (compaction). ♦ The simvastatin granule is prepared by wet granulation. ♦ The two granules are compressed on a press permit¬ting the manufacture of double-layer tablets. WE CLAIM: 1. A synergistic pharmaceutical composition containing: (a) a thienopyridine derivative of formula in which R is hydrogen or a (C1-C4)alkoxycarbonyl group, or one of its pharmaceutically acceptable salts; and (b) an HMG-CoA reductase inhibitor. 2. The composition as claimed in claim 1, wherein Component (a) is present at a dose of between 10 and 250 mg of active principle and Component (b) is present at a dose of 2 to 50 mg of active principle. 3. The composition as claimed in claim 1, wherein the thienopyridine derivative is ticlopidine hydrochloride. 4. The composition as claimed in claim 3, wherein the amount of ticlopidine hydrochloride in the dosage unit is from 100 to 250 mg. 5. The composition as claimed in claim 1, wherein the thienopyridine derivative is clopidogrel hydrogen sulphate. 6. The composition as claimed in claim 5, wherein the amount of hydrogen sulphate in the dosage unit is from 10 to 75 mg (calculated as free base). 7. The composition as claimed in 1, wherein the HMG-CoA reductase inhibitor is a compound selected from the group consisting of: (i) the naphthalene derivatives of formula (II) in which Ri and R2 are a hydroxyl group or alternatively together form an oxygen atom, R3 is a (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, phenyl or phenyl(C1- C3)alkyl group and R.4 is hydrogen or a methyl or hydroxyl group; (ii) the pharmaceutical^ acceptable salts of the compounds of formula (II) in which Ri and R2 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 Q4 is a hydrogen, chlorine or fluorine atom or a (C1-C4)alkyl, (C1-C4)alkoxy (but other than t-butoxy), trifluoromethyl, phenoxy or benzyloxy group, Q5 is a hydrogen, chlorine or fluorine atom or a phenoxy or benzyloxy group and Qsa is a -19- hydrogen, chlorine or fluorine atom or a phenoxy or benzyloxy group and Qsa 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 (C1-C6)alkyl, (C3-C6)cycloalkyl, benzyl, 2-phenylethyl or 3-phenylpropyl group; Q2 is a hydrogen, fluorine or chlorine atom or a (CrC4)alkyl, (C3-C6)cycloalkyl, (Cp C4)alkoxy (but other than t-butoxy), trifluoromethyl, phenoxy or benzyloxy group; Q3 is a hydrogen, chlorine or fluorine atom or a (Cl-C3)alkyl, (C1-C3)alkoxy, phenoxy or benzyloxy group; X is a methylene, ethylene or 1,3-propylene group; Qg is a hydrogen atom or a (C1-C3)alkyl group; with the limitation that (1) Q5 and Q5 a are hydrogen when R4 is hydrogen, (2) Qsa is hydrogen 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 formula (III), (vi) the 5-lactones of the compounds of formula (III), (vii) the tetrazole derivatives of formula (IV) in which Qi and Qi" are hydrogen, a halogen or a (C1-C4)alkyl, (C1-C4)alkoxy or trifluoromethyl group; Qi, Qi, Qg, and Qg" are hydrogen, a halogen or a (C1-C4)alkyl or (C1-C4)alko)^ group; Qg is hydrogen or a (C1-C4)alkyl, (C1-C4)alkoxyalkyl or (2-methoxyethoxy)methyl group; (viii) the pharmaceutically acceptable salts of the compounds of formula (IV), (ix) the 6-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 6-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), and (xv) the .delta.-lactones of the compounds of formula (VI). 8. The composition as claimed in claim 7, wherein the HMG-CoA reductase inhibitor is selected from the group consisting of simvastatin, pravastatin sodium, mevastatin, lovastatin, cerivastatin, atorvastatin, an indole derivative of formula (III) in which R° is 4-fluorophenyl, R" is isopropyl, X is ethylene and Q2, Q3 and Qe are hydrogen, in its racemic or optically active (E) form, the pharmaceutically acceptable salts of the said indole derivative, a tetrazole derivative of formula (IV) in which Qj and Qi" are each a fluorine atom and Q7, Q7", Qg and Qg" are hydrogen, in its (E) form of ((3R,6S) configuration, and the pharmaceutically acceptable salts of the said tetrazole derivative. 9. The composition as claimed in claim 2, wherein Component (a) is ticlopidine hydrochloride and Component (b) is selected from the group consisting of simvastatin and pravastatin sodium. 10. The composition as claimed in 9, which contains from 100 to 250 mg of ticlopidine hydrochloride and from 10 to 40 mg of simvastatin or of pravastatin sodium. 11. The composition as claimed in claim 2, wherein Component (a) is clopidogrel hydrogen sulphate and Component (b) is selected from the group consisting of simvastatin and pravastatin sodium. 12. The composition as claimed in claim 11, which contains from 10 to 75 mg (calculated as free base) of clopidogrel hydrogen sulphate and from 10 to 40 mg of simvastatin or of pravastatin sodium.

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