Title of Invention	COMPOSITION CONTAINING AN INHIBITOR OF FACTOR Xa AND AN ANTI-PLATELET AGGREGATION AGENT
Abstract	A process for producing crystalline form I of cabergoline, which process comprises crystallization of the desired form from a toluene/diethyl ether mixture comprising raw cabergoline, followed by recovery and drying of the resulting crystals. A new solvate form V of cabergoline, useful as an intermediate, is also provided.

Full Text

The subject of the present invention related to a combination of direct or indirect selective inhibitors of factor Xa which act via antithrombin III, in combination with a compound with anti-platelet aggregation activity, for their activity in arterial thromboembolic diseases. The pharmaceutical compositions containing the combination of antithrombotic and anti-platelet aggregation active ingredients are also included in the invention. The active ingredients constituting the combination are present in the free state or in the form of one of their pharmaceutically acceptable salts. During the last decade, a lot of attention has been given to studying the role played by platelets in the development of diseases associated with atherosclerosis (myocardial infarction, angina, cerebral vascular accident, arterial diseases of the lower limbs and the like). Moreover, the well-established role of the blood clotting process in arterial thrombosis has allowed the development of numerous medicines which inhibit various clotting enzymes. The discovery of the essential role of thrombin and factor Xa in the thrombotic process has led to the use of anticoagulants being proposed in the prevention and treatment of arterial thrombosis. Among the anticoagulants available, heparin is the preferred medicine in the prevention and treatment of thromboembolic diseases. Heparin catalyses, in particular via anti¬thrombin III (AT III), the inhibition of two enzymes which are involved in the blood clotting cascade, namely factor Xa and factor Ila (or thrombin). The relative importance of these two activities in the overall activity of heparin remains unknown. Low-molecular-weight heparin (LMWH) preparations contain chains consisting of 4 to 30 monosaccharides which act like heparin on factor Xa and on thrombin but which have the property of being more selective for factor Xa than for thrombin. In spite of this different biological activity profile, low-molecular-weight heparin has an antithrombotic effect as has been demonstrated in studies on animals and on patients suffering from thromboembolic diseases or at risk of forming a thrombus (Hirsch J. et al., J. Thromb, Hemest., 1987, Leuven, Belgium Leuven University Press, 325-348). Unlike hepaxin and the LMWHs, some synthetic oligosaccharides, especially those described in EP 84999, have the property of selectively inhibiting factor Xa via antithrombin III but have no activity on thrombin. These synthetic oligosaccharides which correspond to the antithrombin-binding domain (ABD) of heparin are known and manifest an unthrombotic activity in venous thrombosis. These compounds are described in EP 529715 and EP 621282. The efficacy of these oligonucleotides in the prevention of arterial thrombosis was hardly probable because of their inability to inhibit thrombin. Indeed, it has long been known in the literature that thrombin plays a key role in arterial thrombosis and this is again confirmed by recent experiments (L. A. Marker, Blood, 1991, 77. 1006-1012). Thrombin inhibitors therefore constitute an effective means of preventing or combating this type of thrombosis. It has been observed, by comparing the efficacy of heparin to those of direct thrombin inhibitors (direct inhibitor means an inhibitor which inhibits thrombin without requiring AT III), that they are much more effective than heparin for preventing and treating arterial thrombosis (Arteriosclerosis and thrombosis, 1992, 12, 879-885, J. Am. Coll. Cardiol., 1994, 23, 993-1003). The reason for this lack of efficacy is that the heparin/AT III complex cannot, for reasons to do with steric hindrance, inhibit thrombin in a thrombus rich in platelets as is a platelet thrombus. The low activity of heparin in contrast to direct inhibitors is therefore linked to its need to use AT III. This explanation is further justified by the recent observation that the direct inhibitors of factor Xa which act without AT III are also effective, in animal models of arterial thrombosis (Circulation, 1991, 84, 1741-1748 Thrombosis Haemost., 1995 74, 640-645). A compound which, on the one hand, acts via AT III and, on the other hand, does not inhibit thrombin, would therefore be expected to possess no activity in arterial thrombosis. It has now been found, according to the present invention, quite surprisingly, that a direct or indirect selective inhibitor of factor Xa, alone or in combination with a compound with anti-platelet aggregation activity, can be used for their activity in thromboembolic diseases of arterial origin. Although it is known to date that the anti-factor Xa agents and the anti-platelet aggregation agents a(i:t via two different mechanisms of action, the combination or association of these products for use in arterial thromboembolic diseases has never been studied. Accordingly, the subject of the present invention is, according to one of its features, the use of one or more direct or indirect selective inhibitors of factor Xa, alone or in combination with one or more compounds with anti-platelet aggregation activity, for the preparation of medicines intended to prevent and to treat thromboembolic diseases of arterial origin. According to the invention, selective inhibitor of factor Xa is understood to mean a compound capable of selectively inhibiting factor Xa via antithrombin (AT III) but not exhibiting significant activity towards thrombin. Preferably, the inhibitor has no activity towards thrombin. According to another of its features, the subject of the present invention is also the use of a selective inhibitor of factor Xa which acts via AT III, alone or in combination with a compound with anti¬platelet aggregation activity, for the preparation of medicines intended to combat thromboembolic diseases of arterial origin. Advantageously, the said direct inhibitors of factor Xa are DX-9065a and its analogues. DX-9065a is in particular described in Thromb. Haemost. 1994, 71, 314-319 and in Drugs Fut. 1995, 206, 564-566 and also in EP 540051. Also advantageously, the indirect inhibitors of factor Xa are synthetic oligosaccharides. Among the direct selective inhibitors of factor Xa, DX-9065a is particularly advantageous, and consists of (2S)-2-[4-[ [ (3S)-l-acetimidoyl-S-pyrrolidinyl] oxy] phenyl] -3- (■7-amidino-2-naphthyl) -propanoic acid hydrochloride pentahydrate in which the acid has the structure (A) and its pharmaceutically acceptable salts, described in particular in Thromb. Haemost. 1994, 71, 314-319 and in Drugs Fut. 1995, 206, 564-566 and also in EP 540051. Among the indirect selective inhibitors of factor Xa and advantageously, the synthetic oligo- saccharides are pentasaccharides, such as those claimed in patents EP 84999 and US 5,378,829. Particularly advantageous pentasaccharides are in particular: methyl O-(2-deoxy-2-sulphoamino-6-O-sulfo-α-D-gluco- pyranosyl)- (1→4)-O-(p-D-glucopyranosyluronic acid)- (1→4)-O-(2-deoxy-2-sulphoamino-3,6-di-O-sulpho-α-D- glucopyranosyl- (1→4) -O- (2-O-sulpho-α-L-idopyranosyluronic acid)- (1^4) -2-deoxy-2-sulphoamino-6-O-sulpho-α-D-glucopyranoside whose anion has the structure (B) and its pharmaceutically acceptable salts, in particular its decasodium salt, known under its code name SR 90107 / ORG 31540, which is described in Chemical Synthesis to Glycoaminoglycans, Supplement to Nature 1991, 350, 30-33 designated hereinafter "PS"; methyl O-(3,4-di-O-methyl-2,6-di-O-sulpho-α-D-gluco- pyranosyl)- (1→4)-O-(3-O-methyl-2-0"Sulpho-β-D- glucopyranosyluronic acid)- (1→4) -O-(2,3, 6-tri-O-sulpho-α- D-glucopyranosyl) - (1→4) -O- (3-O-methyl-2-O-sulpho-α-L- idopyranosyluronic acid) - (1→4) -2, 3, 6-tri-O-sulpho-α-D-glucopyranoside known under its code name SANORG 32701, whose anion has the structure (C) — a - and its pharmaceutically acceptable salts, in particular its dodecasodium salt, which is described in US 5,378,829; methyl O-(2,3,4-tri-O-methyl-6-O-sulpho-α-D-gluco-pyranosyl)- (1→4)-O-(2,3-di-O-methyl-p-D-gluco-pyranosyluronic acid)- (1→4) -O-(2,3, 6-tri-O-sulpho-α-D-glucopyranosyl)- (1→4) -O-(2, 3-di-O-methyl-α-L-ido-pyranosyluronic acid)- (1→4) -O-2, 3, 6-tri-O-sulpho-α-D- glucopyranoside, known under its code name SANORG 34006, whose anion has the structure (D) and its pharmaceutically acceptable salts, in particular its nonasodium salt, which is also described in US 2,378,829. The anti-platelet aggregation agents which can be used in combination or in association with the oligosaccharides may be of various types, such as for example cyclooxygenase inhibitors such as aspirin, or the anti-platelet aggregation agents described in groups I to L below, such as ADP inhibitors such as ticlopidine and clopidogrel, serotonin inhibitors such as ketanserin, ritanserin, sarpogrelate (MCI-9042), SR 46349 or LY-53857, thromboxane inhibitors such as L 670596, SQ 30741, S-145, AA 2414, CV-6504, HN-11500 and ICI-192,605, thromboxane synthetase inhibitors such as ozagrel (OKY-046), Y-20811, RS-5186, FCE-22178, furegrelate (U-63557A) or mixed thromboxane and thromboxane synthetase inhibitors having the combined effects such as ridogrel (or R-68070) and isbogrel (CV-4151), or inhibitors of the GP Ilb-IIIa glycoprotein complex such as c7E3 or abciximab, integrelin, SC 52012, TP 9201, RO 44-9883, RO 43-8857, RO 43-5054, MK 0383 or tirofiban, Dup 728, L 703014, SC 54684, SC 58053, GR 144053, Bibu 104, Bibu 129 or thiazole derivatives such as SR 121787A and SR 121566; FK 633, orbofiban; or compounds increasing the intraplatelet cyclic AMP concentration such as PGEI (alprostadil) and prostacycline (epoprostenol), prostaglandin analogues such as iloprost and beraprost, cicaprost, taprostene, ataprost (OP-414 83) and ciprostene or dipyridamole or cilostazol. The compound of formula (B), preferably in decasodium salt form, is the subject of a preferred use according to the invention and is also the subj ect of the preferred antithrombotic for the pharmaceutical compositions of the invention as sole active ingredient or in combination with an anti-platelet aggregation agent. The anti-platelet aggregation agents are advantageously selected from aspirin or the groups (I) to (L) below: I - Ticlopidine and its analogues of formula in which X1 represents oxygen or sulphur; R14 represents hydrogen or a phenyl or benzoyl radical optionally substituted with at least one halogen atom or a lower alkyl, lower alkoxy, nitro, amino or sulphonylamino group; R1 and R12 each represent at least one atom or group selected from hydrogen, a halogen, or a hydroxyl, lower alkyl, lower alkoxy, nitro or amino group; R13 represents a hydrogen, a halogen or a hydroxyl, lower alkyl, lower alkoxy, nitro or amino group, and ni is zero or an integer from 1 to 15, it being possible for the R13 symbols to have different meanings in each radical CHR13 when n1 is greater than 1, or an addition salt with an acid or a pharmaceutically acceptable quaternary ammonium derivative of this derivative, as described in French patent FR 2,215,948. II - Clopidogrel and its analogues of formula in which Y2 represents a hydroxyl or a group OR2 in which R2 is a straight or branched alkyl group of 1 to 4 carbon atoms, or Y2 represents a group in which R21 and R22 are each independently of each other hydrogen or a straight or branched alkyl group of 1 to 4 carbon atoms, or R21 and R22 together form, and with the nitrogen atom to which they are attached, a pyrrolidino, morpholino, piperidino or 4-benzylpiperazino group; and X2 represents hydrogen, a halogen or an alkyl radical of 1 to 4 carbon atoms; and their addition salts with pharmaceutically acceptable inorganic or organic acids, when Y2 represents the groups OR2 or or with inorganic bases when Y2 represents OH, as well as the two enantiomers or their mixture, as described in European patent EP 99802. Ill - Ketanserin and its analogues of formula: in which: - Ar3 is an aryl radical; - X3 is a constituent selected from the group consisting of in which the said Ra1 is selected from hydrogen, or a lower alkyl, and qi is 2 or 3; - R3 is a constituent selected from a hydrogen, a hydroxy1 or a lower alkyl; - Alk3 is an alkylene having from 1 to 4 carbon atoms; and - Q3 is a quinazolinyl radical, its 1-, 2-, 3-, 4-position being linked to the end of the alkylene chain, the said quinazolinyl radical carrying at one or at both of its 2- or 4-positions an 0x0 or thioxo group, in which the benzene ring of the said quinazolinyl radical is optionally substituted with one to three substituents independently selected from the group consisting of a halogen, a lower alkyl, a lower alkyloxy, a trifluoromethyl, a nitro and a cyano, and in which the pyrimidino ring of the said quinazolinyl radical may be partially or completely saturated, it being possible for the said pyrimidino ring to be optionally substituted with one to three substituents independently selected from the group consisting of a lower alkyl, an aryl and an aryl(lower alkyl); in which the said aryl used in the definition of Ar3 and of Q3 is a ring selected from the group consisting of a phenyl, a substituted phenyl, a thienyl and a pyridinyl, in which the said substituted phenyl is substituted with 1 to 3 substituents independently selected from the group consisting of a halogen, a lower alkyl, a lower alkyloxy, a trifluoromethyl or an amino, and its pharmaceutically acceptable addition salts, as described in European patent EP 13612. IV - Ritanserin or one of its analogues of formula: in which: " R4 is a hydrogen, a hydroxyl or a lower alkyloxy; - R14 is a member of the group consisting of a hydrogen or a lower alkyl; - Alk4 is a lower alkylene radical; - X4 is selected from the group consisting of -S-, -CH2-and -C (R42)=C (R43)-, the said R42 and R43 being independently hydrogen or a lower alkyl; " A4 is a bivalent radical having the formula -CH2-CH2-, -CH2-CH2-CH2- or -C(R%) = C(R%)- in which R24 and R54 are each independently selected from the group consisting of a hydrogen, a halogen, an amino or a lower alkyl; and - Ar14 and Ar24 are independently selected from the group consisting of pyridinyl, thienyl and phenyl, the said groups being optionally substituted with a halogen, a hydroxyl, a lower alkyloxy and a trifluoromethyl, the isomeric stereochemical forms thereof as well as the pharmaceutically acceptable acid addition salts, as described in European patent EP 110435, V - Sarpogrelate or one of its derivatives of formula: in which: - Ar6 and Ar'6 may each independently denote either: a) a phenyl group which is unsubstituted or is mono- or polysubstituted with a halogen atom, an alkyl group of 1 to 4 carbon atoms, a nitro group, a hydroxy1 group, an alkoxy group of 1 to 4 carbon atoms, an acyloxy group of 1 to 4 carbon atoms, a dimethylamino group, a carboxyalkoxy group in which the alkyl portion contains from 1 to 4 carbon atoms, 9-anthryl or a naphthyl group; b) a heteroaromatic group selected from the pyridyl, thienyl and furyl groups; -.R61 and R62 each independently denote a hydrogen atom;- an alkyl group of 1 to 4 carbon atoms or alternatively R61 and R62 constitute with the nitrogen atom to which they are attached a 1-pyrrolidinyl, piperidino, morpholino or 1-piperazinyl group; - Me represents a hydrogen atom, a chlorine or bromine atom, a straight or branched alkyl group of 1 to 6 carbon atoms; - n6 represents 2 or 3; as well as their salts with inorganic or organic acids and more particularly the compound known under the code name SR 46349 B, as described in EP 373998. VII - LY 53857 or one of its analogues of formula: in which R71 is a hydrogen, a (C1-C3) alkyl, an allyl or a benzyl, and R72 is a (C2-C8)monohydroxyalkyl, a (C2-C8)dihydroxyalkyl or a monohydroxycycloalkyl having from 5 to 8 carbon atoms and the salts thereof with pharmaceutically acceptable acids, as described in US 3,580,916. VIII - L 670596 and the derivatives of tetrahydro- carbazole-1-alkanoic acids consisting of the compounds of formula: 9-o-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol- 1-yl-acetic acid; 9-(2,4-dichlorobenzyl)-6,8-difluoro-1,2,3, 4-tetra- hydrocarbazol-1-yl-acetic acid; 9-p-methylthiobenzyl-6,8-difluoro-1,2, 3, 4-tetrahydro- carbazol-1-yl-acetic acid; 9'-p-methylsulphinylbenzyl-6, 8-dif luoro-1, 2, 3, 4-tetra-hydrocarbazol"l-yl-acetic acid; 9-p-methylsulphonylbenzyl-6,8-difluoro-1,2,3,4-tetra-hydrocarbazol-1-yl-acetic acid; (-)9-p-methylsulphonylbenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid; (+)9-p-methylsulphonylbenzyl-6,8-difluoro-1,2,3,4- tetrahydrocarbazol-1-yl-acetic acid; 9-p-trifluoromethylbenzyl-6,8-difluoro-1,2,3,4-tetra- hydrocarbazol-1-yl-acetic acid; 9-p-fluorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol- 1-yl-acetic acid; 9-m-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol- 1-yl-acetic acid; 9-p-carbomethoxybenzyl-6,8-difluoro-1,2,3,4-tetrahydro- carbazol-1-yl-acetic acid; 9-p-dimethylcarbamoyl-6,8-difluoro-1,2,3,4-tetrahydro- carbazol-1-yl-acetic acid; 9-p-acetylbenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol- 1-yl-acetic acid; 9-p-dimethylaminosulphonylbenzyl-6,8-difluoro-1,2,3,4- tetrahydrocarbazol-1-yl-acetic acid; 9-p-acetamidobenzyl-6,8-difluoro-1,2,3,4-tetrahydro- carbazol-1-yl-acetic acid; 9-p-methylsulphonamidobenzyl-6,8-difluoro-1,2,3,4- tetrahydrocarbazol-1-yl-acetic acid; 9-p-methylureidobenzyl-6,8-difluoro-1,2,3,4-tetrahydro- carbazol-1-yl-acetic acid and 9-p-methoxybenzyl-6,8-difluoro-1,2, 3, 4-tetrahydro- carbazol-1-yl-acetic acid; which are described in EP 300 676. IX - SQ 30741 as well as the compounds of structure: in which rrig is an integer from 0 to 4; Ag is a group -CH=CH- or -CH2-CH2-; ng is an integer from 1 to 5; X9 is a halogen, an alkanoyloxy or a hydroxyl; p9 is 1 to 4; R91 is H or a lower alkyl; q9 is an integer from 1 to 12; R92 is H or a lower alkyl; and R93 is H, a lower alkyl, a lower alkenyl containing from 2 to 12 carbon atoms, an aryl, an arylalkyl, a lower alkoxy, an aryloxy, an amino. an alkylamino or an arylamino; in which the lower alkyl or the alkyl alone or as a constituent of another group contains from 2 to 12 carbon atoms and is unsubstituted or is substituted with a halogen, a CF3, an alkoxy, an aryl, an arylalkyl, a haloaryl, a cycloalkyl, an alkyl-cycloalkyl, a hydroxyl, an alkylamino, an alkanoylamino, an arylcarbonyl amino, a nitro, a cyano, a mereapto or an alkylthio; the aryl alone or as a constituent of another group contains from 6 to 10 carbon atoms on the cyclic portion and is unsubstituted or is substituted with one or two lower alkyls, 1 or 2 halogens, 1 or 2 hydroxy1 groups, 1 or 2 lower alkoxy groups, 1 or 2 alkylamino groups, 1 or 2 alkanoylamino groups, 1 or 2 arylcarbonylamino groups, 1 or 2 amino groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 mercapto groups and/or 1 or 2 alkylthio groups; and the cycloalkyl alone or as a constituent of another group contains from 3 to 12 carbon atoms, is unsubstituted or is substituted with 1 or 2 halogens, 1 or 2 lower alkyl groups, 1 or 2 lower alkoxy groups, 1 or 2 hydroxy1 groups, 1 or 2 alkylamino groups, 1 or 2 alkanoylamino groups, 1 or 2 arylcarbonylamino groups, 1 or 2 amino groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 mercapto groups and/or 1 or 2 alkylthio groups; (CH2)m9, (CH2) n9 and (CH2) P9 may be substituted with 1 or 2 lower alkyl and/or 1 or 2 halogen substituents; and (CH2)q9 may be substituted with one or more halogen, hydroxyl, alkoxy, amino, alkylamino, arylamino, carbamoyl, thiocarbamoyl, mercapto, alkylthio, arylthio, cyano or nitro groups; as well as all its stereoisomers, as described in US 4,638,012. X - S-145 and the compounds of formula: in which: - R101 is a hydrogen or a lower alkyl; - R102 is a substituted or unsubstituted aryl, an aralkyl or a heterocycle; - R103 is a hydrogen or a methyl; - X10 is an alkylene or an alkenylene which may be sub¬ stituted with one or more fluorine atoms and whose chain may be interrupted by an oxygen, a sulphur and/or a phenylene; " Y10 is a straight or branched alkylene or an alkenylene, an oxygen or a sulphur; - m10 is 0 or 1; - n10is 0, 1 or 2, which are described in EP 226 346. XI - AA 2414 and the compounds of formula: in which: - R111 is optionally a substituted phenyl group, - R112 is optionally a substituted amino group and - n11 is an integer from 3 to 10 or a hydroquinone derivative thereof, as described in EP 232 089 A2. XII - CV 6504 and the compounds of formula: in which: - R121 and R122, which are identical or different, represent a hydrogen atom, a methyl or hydroxy1 group, or alternatively R121 and R12 are linked so as to form - CH-CH-CH=CH-; - R123 is a hydrogen atom or a methyl group; - R124 is a heterocyclic group containing a nitrogen atom which may be substituted; - R125 is a hydrogen atom, a methyl or hydroxymethyl group which may be substituted, or a carboxyl group which may be esterifled, or in the form of an amide; - Zi2 is in which R12 is a hydrogen atom or a methyl group; - n12 is an integer from 0 to 12, m12 is an integer from 0 to 3, and k12 is an integer from 0 to 7, with the proviso that when m12 is 2 or 3, Z12 and k12 are capable of varying appropriately in the repeated unit described in [] and the hydroquinone derivatives of those described in EP 234729. XIII - HN 11500, Linotroban as well as the 2-thienyl- oxyacetic acid derivatives of formula; in which R13 is a phenyl or thienyl group which is substituted, where appropriate, once or several times with a halogen atom, a trifluoromethyl group or an alkyl group of 1 to 4 carbon atoms, as well as their pharmaceutically acceptable salts, as described in EP 284 892. XIV - ICI 192605 or a 2,4-diphenyl-l,3-dioxane derivative of formula: in which: - X14 is F, CI, Br, CF3, CN, OMe or NO2; - Yi4 or 2i4 is independently hydrogen or F and the other is hydrogen; and - R'14 is a (C1-C6)alkyl; the groups at the 2-, 4- and 5-positions of the dioxane ring having a cis stereochemistry, as well as their pharmaceutically acceptable salts, as described in EP 201354. XV - OKY 046 or ozagrel and its analogues of formula: in which: - R15 is a hydrogen atom or a (C1-C6) alkyl group; - A15 and B15, which are identical or different, represent a bond, a straight or branched (C1-C6)alkylene or a (C2-C8)alkenylene; - n15 and m15, which are identical or different, are 0 or 1, whereas A15 and B15 consist of 2, 3 or 4 carbon atoms, as well as its pharmaceutically acceptable salts, as described in DE 2,923,815. XVI - Y 20811 and the imidazole derivatives of formula: 1 c J C groups, aromatic carboxylic acyloxy groups, aliphatic carboxylic (C2-C5)acylamino groups, aromatic carboxylic acylamino groups, trifluoromethyl groups, halogen atoms, nitro groups, cyano groups, amino groups, (C1-C4)alkylamino groups, dialkylamino groups in which each alkyl portion is a (C1-C4) , carboxyl groups and esters and amides of the said carboxyl groups, the acyl portions of the said aromatic acyloxy groups and of the aromatic acylamino groups being carbocyclic (C6-C10)aryl groups which are unsubstituted or which are at least substituted with a (C1-C4)alkyl, a (C1-C4)alkoxy or a halogen substituent; - the substituents (b) being (C1-C4)alkyl groups, (C3-C6) cycloalkyl groups, (C6-c10) aryl groups, (C6-C10) aryl groups substituted with at least one substituent (a) and the heterocyclic groups having from 5 to 10 atoms in the ring, in which 1 to 3 of the said atoms are nitrogen and/or oxygen and/or sulphur heteroatoms, the said heterocyclic groups being unsubstituted or having at least one substituent selected from (a), (c) or oxygen atoms; and -■ the substituents (c) being (C1-C4)alkyl groups, (C6-C10) aryl groups and substituted (C6-C10) aryl groups having at least one substituent (a) and its pharma-ceutically acceptable salts, its amides and its esters, as described in EP 240 107. XVIII - FCE 22 178 and the compound of formula: in which: (C1-C4)alkyl, the other residues having the meaning defined above in (a), as well as their pharmaceutically acceptable salts, as described in DE 33 24 069. XIX - Furegrelate and its analogues of formula: in which: - Z19 is 4-pyridinyl, 3-pyridinyl, 4-methyl-3-pyridinyl, 4-methoxy-3-pyridinyl, 4-dimethylamino-3-pyridinyl, 4-amino-3-pyridinyl, 4-dimethylamino-3-pyridinyl, 4-amino-3-pyridinyl, 2-, 4-, 5- or 6-chloro-3-pyridinyl, an imidazolyl or a ( (C1-C3) alkyl) imidazoyl; - X193 is -(CH2)n19-, -0-, -S-, -SO-, -SO2- -CH2-O-, -O-CH2-, -CH2-NRI93-, -NR193-CH2-, -CHOH- or -CO- in which n19is an integer from 0 to 4 and R193 is a hydrogen, a methyl, with the proviso that Z191 is an optionally substituted or one of its pharmaceutically acceptable acid addition salts, as described in EP 069 521. XX - Ridogrel or one of its analogues of formula: in which: - R20 is a hydrogen, a (C1-C10) slkyl, a trif luoromethyl, an Ar20 radical or a radical Ar20- (C1-C10) alkyl; in which Ar20 is a phenyl, a naphthyl, a pyridinyl, a pyrimidinyl, a furanyl or a thienyl, the said phenyl and naphthyl being optionally substituted with up to 3 substituents independently selected from (C1-C6) alkyl, (C1-C6) alkoxy, a mono- and di ( (C1-C6) alkyloxy) methyl, an amino, a (C1- C5)alkylcarbonylamino, a carboxyl, a formyl, a halogen, a hydroxyl a nitro and a trifluoromethyl; -R20 is a hydrogen or a (C1-C6) alkyl; and - Alkao is a (C2-C10) alkylene radical; with the proviso that the radical C5H4N-C (R20)=N-O- and the radical -COOR20 sre not bonded to the same carbon atom, it being possible for these compounds to be in the form of an N-oxide, of an addition product with a pharmaceutically acceptable acid, of a metal salt or of an ammonium salt, or a stereochemically isomeric form of these compounds, as described in EP 221601. XXI - Isbogrel and its analogues of formula: in which: - R21 is a pyridyl group, - R21 is a phenyl group, a thienyl group, a furyl group, a naphthyl group, a benzothienyl group or a pyridyl group which may be optionally substituted with a lower alkoxy group, a lower alkyl group, a halogen atom, a trifluoromethyl group, a lower alkenyl group or a methylenedioxy group, - R21 is a hydrogen atom or a lower alkyl group, and - n21 is an integer from 0 to 6, as described in EP 098 690. XXII - Abciximab, a class IgGi monoclonal antibody manufactured according to WO/06133. XXIII - Integrelin and its analogues containing at least 5 contiguous amino acids of an oligopeptide selected from: (a) Gly-Ser-Pro-Arg-Cys-Asp-Leu-Lys-Glu-Asn-Leu-Leu-Lys-Asp-Asn-Cys-Ala-Pro-Z20: in which Z23, if present, is OH and the oligopeptide has less than 50 combined native amino acids described in WO 90/00178. XXIV - SC 52012 and its analogues of formula: in which: - R241 and R242 are each independently selected from hydrogen; a phenyl; a substituted phenyl in which each substituent may be selected from a group consisting of a (C1-C6)alkyl, a halogen, a (C1-C6) alkoxy, a trifluoro- methyl, a hydroxyl and a carboxyl; a (C1-C6)alkyl; a heterocycle consisting of a 5- or 6-membered ring comprising a heteroatom selected from: nitrogen, oxygen and sulphur, fused with a benzene ring; - P24 is hydrogen, a carboxyl or a (C1-C6) alkoxycarbonyl; - W24 is hydrogen or a (C1-C5) alkyl; - Y24 is a methylene, a (C2-C4) alkenyl, a (C2-C4) alkynyl or a carbonyl; - Z24 is a halogen, a (C1-C6) alkoxy, a (C1-C6) alkyl or a hydrogen; - n24 is an integer from 1 to 6; with the proviso that when P24, W24 and Z24 each represent hydrogen, Y24 is a methylene at the met a position of the aminoiminomethyl group and n24 is 3, then R241 cannot be phenyl; as well as the pharmaceutically acceptable salts described in EP 502536. XXV - TP 9201 A composition comprising a cyclic RGD containing a peptide having a hydrophobic entity adjacent to the carboxyl end of the said RGD sequence. XXVI - RO 44-9883 or one of its analogues of formula: or alternatively represents R°26-NH (CH2) t26f - R26 is an amidino or a guanidino, X26 or Y26 being CH and the other CH or N, - R'26 being hydrogen or an amidino, - t26 being an integer between 2 and 6, - R'26, R"26 and R"'26 being independently hydrogen or the conventional substituents of the nitrogen atom of the α- amino acids, or the conventional side chains of the a-amino acids, it being possible for the hydroxyl or carboxyl groups present in R', R" and R"' to be etherified, esterified or in the form of amides, and it being possible for the amino groups present in R', R" and R'" to be alkanoylated or aroylated; - Q26 is a group of formula atom to which they are bonded, Q26 may also represent the group: f which they are bonded a 1-naphthyl group as well as their hydrates and solvates and their pharmaceutically acceptable salts, as described in EP 505 868. XXVII - RO 43-8857 and its analogues of formula: whereas the carbonyl groups may also be present in the form of oxime, oxime ether, ketal or thioketal or enol ether groups and the hydroxy1 groups in the form of lower alkyl ether groups, di (lower alkyl)amino(lower alkyl) ether groups or in the form of lower alkylcarboxylic acid - n27 represents an integer from 0 to 4; - a27, C27 and d27 are independent of each other, 0 or 1 ; and - b27 denotes an integer from 0 to 2, whereas nevertheless a27 and b27 should be equal to 0 when C27 is 1 and C27 should be equal to 0 when a27 or b27 is different from 0; as well as their physiologically acceptable salts, as described in EP 381 033. pyrrolidinocarbonyl or a piperidinocarbony1, as well as their hydrates, their solvates and their pharmaceutically acceptable salts, as described in EP 445796. XXIX - MK 0383 and its analogues of formula: )ers ].ng 1 ] (C1-C10)alkyl group or a substituted or unsubstituted cycloalkyl group in which the said substituents are (C1-C10) alkoxy, (C1-C10) alkoxyalkyl, (C1-C10) alkoxyalkyloxy, (C1-C10) alkoxycarbonyl, (C1-C10) alkylcarbonyl, (C4-C10) aralkylcarbonyl, (C1-C10) alkylthiocarbonyl, (C1-C10) aralkylthiocarbonyl, thiocarbonyl, (C1-C10) -alkoxythiocarbonyl, aryl, a saturated heterocycle with 5 or 6 saturated members containing 1, 2, 3 or 4 heteroatoms in which the said heteroatoms are selected from the group consisting of N, 0 and S, (C1-C4) alkanoylamino, (C1-C6) alkoxycarbonyl- (C0-C6) alkyl-amino, (C1-C10) alkylsulphonylamino, (C4-C10) aralkyl-sulphonylamino, (C4-C10) aralkyl, (C1-C10) alkaryl, (C1-C10) alkylthio, (C4-C10) aralkylthio, (C1-C10) alkyl-sulphinyl, (C4-C10) aralkylsulphinyl, (C1-C10) alkyl-sulphonyl, (C4-C10)aralkylsulphonyl, aminosulphonyl, (C1-C10) alkylaminosulphonyl, (C4-C10) aralkylsulphonylamino, 0x0, thioxo, an unsubstituted, a monosubstituted or a disubstituted 1-ethynyl, 2-ethynyl or 3-propenyl group, in which the said substituents are selected from the group consisting of hydrogen, (C1-C10)alkyl and (C4-C10) aralkyl, carboxyl, hydroxyl, amino, (C1-C6) alkyl-amino, (C1-C6) dialkylamino, halogen in which the halogen is selected from F, CI, Br, and I, nitro, and cyano; it being possible for the nitrogen atom of the said heterocyclic ring to be, in addition, substituted with an additional R629 group to form a quaternary ammonium ion; - R29 snd R2 9 sre independently hydrogen, aryl or a (C1-C10)alkyl or cycloalkyl group, unsubstituted or substituted, in which the said substituent is a (C1-C10)alkoxyalkyl, aryl, a saturated heterecycle having from 4 to 8 members containing 1, 2, 3 or 4 heteroatoms in which the heteroatoms are selected from the groups consisting of N, 0 and S, (C4-C10) aralkyl, (C1-C10) alkaryl, (C1-C10) alkylthio, (C4-C10) aralkylthio, (C1- C10) alkylsulphinyl, (C4-C10) aralkylsulphinyl, (C1-C10) alkylsulphonyl, (C4-C10) aralkylsulphonyl, carboxyl, (C1-C10) alkylcarbonyl, (C1-C10) alkylthiocarbonyl, (C4- Cio) aralkylcarbonyl, (C4-C10) aralkylthiocarbonyl, (C1- C6) alkoxycarbonyl, (C4-C10) aralkoxycarbonyl, (C1-C6) alkoxy, (C1-C6) alkoxycarbonyl- (C1-C4) alkyl, (C4- C10) aralkoxycarbonyl- (C1-C4) alkyl, (C4-C10) aralkoxy, (C1- C6) alkylamino, (C1-C12) dialkylamino, (C1-C6) alkanoylamino, (C4-C10) aralkanoylamino, (C4-C10) aralkylamino, - R29 is aryl, (C1-C10) alkyl or cycloalkyl, (C4-C10) aralkyl, (C1-C10) alkoxyalkyl, (C1-C10) alkaryl, (C1-C10) alkylthioalkyl, (C1-C10) alkoxythioalkyl, (C1-C10) alkylamino, (C4-C10) aralkylamino, (C1-C10) alkanoylamino, (C4-C10) aralkanoylamino, (C1-C10) alkanoyl, (C4-C10) aralkanoyl, and a substituted or unsubstituted (C1-C10)carboxyalkyl in which the said substituent is aryl, (C1-C10)aralkyl; it being possible for each of the substituents of R29 to be, in addition, substituted with a substituent selected from the group defined for R29; - R529 is a saturated or unsaturated 4- to 8-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, 0 and S or in which: - R829 is hydroxyl, (C1-C10) alkyloxy, (C1-C10) alkaryloxy, (C4-C10) aralkyloxy, (C4-C10) aralkylcarbonyloxy, (C1-C10) alkoxyalkyloxy, (C1-C10) alkoxyalkylcarbonyloxy, (C1- C10) alkoxycarbonylalkyl, (C1-C10) alkylcarbonyloxyalkoxy, or an L- or a D-amino acid bonded via an amide bond, or an amino acid bonded via an amide bond and in which the carboxylic acid functional group of the said amino acid is optionally esterifled with a (C1-C6)alkyl or a (C4-C10) aralkyl, or R829 represents : a ring having from 4 to 8 members containing 0, 1, 2, 3 or 4 heteroatoms selected from N, 0 and S, in which the said ring is independently substituted on any of its atoms with R629, an aryl, or / is d for - m2 9 is an integer from 0 to 10; - n2 9 is an integer from 0 to 10; and - P29 is an integer from 0 to 3; as well as its pharmaceutically acceptable salts, as described in EP 478 363. -'R304 is an aryl, a (C1-C10) alkyl or a (C4-C10) aralkyl as described in US 5,206,373. XXXI - DUP 728 and its analogues of formula: it being understood that the carbon atom to which R32 and aminocarbonyl, 0x0 or aryl groups; - m32 is an integer from 1 to 10; - n32 is an integer from 0 to 9; - q32 is an integer from 0 to 2; - P32 is an integer from 1 to 6; - Z32 is 0, N, S; or their pharmaceutically acceptable salts or their optical isomers, as described in EP 478362. XXXIII - SC 54684 or one of its derivatives of formula: hydrogen, lower alkyl radicals, lower alkenyl radicals, hydrocarbon-containing aromatic radicals, hydrocarbon-containing aliyclic radicals, benzyl radicals, phenethyl radicals, it being possible for the said radicals to be substituted with a halogen, a lower alkoxy, a hydroxyl or a lower alkyl; - R332 is selected from the group consisting of a hydrogen, lower alkyl radicals, lower alkenyl radicals, lower alkynyl radicals, hydrocarbon-containing aromatic radicals, hydrocarbon-containing allcyclic radicals, benzyl radicals, phenethyl radicals, it being possible for the said radicals to be substituted with a halogen, a lower alkoxy, a hydroxyl or a lower alkyl; - A33 is selected from the group consisting of lower alkylene radicals, lower alkenylene radicals, lower alkynylene radicals, and alicyclic divalent radicals, the said radicals being optionally substituted with a hydroxyl, a lower alkoxy, a lower alkyl, a halogen, an alkoxycarbonylalkyl, an amino, an alkylamino, a dialkylamino, an acylamino, an alkylthio, a sulphonyl, or aromatic hydrocarbon-containing radicals optionally substituted with a halogen, nitro, lower alkoxy or lower alkyl; W33 is selected from the group consisting of hydrogen, lower alkyl radicals, lower alkenyl radicals, lower alkynyl radicals and alicyclic hydrocarbon radicals or hydrocarbon-containing aromatic radicals, the said radicals being optionally substituted with a hydroxyl, a lower alkoxy, a lower alkyl, a halogen, a nitro, an amino, an acyloxy, a phenyl or a naphthyl, it being possible for the phenyl and naphthyl groups to be optionally substituted with a halogen, a nitro, a lower alkoxy or a lower alkyl; Z33, Z'33 and Z"33 are independently selected from the group consisting of hydrogen, lower alkyl radicals, lower (C1-C6) alkyl, lower (C2-C6) alkenyl, lower (C2-C9)alkynyl, alkyloxycarbonyloxyalkyl, (C3-C6) cycloalkyl and aryl optionally substituted with a hydroxyl, a lower(C1-C6)alkoxy, a lower(C1-C9)alkyl, a halogen, nitro, amino, acyloxy, phenyl or naphthyl; - R234 is selected from the group consisting of a hydrogen, a lower (C1-C6) alkyl, a lower (C2-C6) alkenyl, a lower (C2-C6)alkynyl, a cycloalkyl, an aryl, monocyclic, bicyclic or tricyclic heterocyclic radicals comprising 1 to 3 heteroatoms independently selected from oxygen, nitrogen and sulphur, the said radicals being optionally substituted with one or more radicals selected from the group consisting of a hydroxyl, a lower (C1-C6) alkoxy, a lower(C1-C6)alkyl, a halogen, nitro, cyano, azido, ureido, ureylene, carboxyl, carbonyl derivatives, trifluoromethyl, acyloxy, alkylthio, arylthio, alkylsulphinyl, arylsulphinyl, alkylsulphonyl, arylsulphonyl, amino, alkylamino, trialkylsilyl, aminosulphonyl, dialkylamino, alkanoylamino, aroylamino, phenyl and naphthyl; as well as its pharmaceutically acceptable derivatives, salts and solvates, as described in EP 542363. B36 represents a cyano group or a nitre group, an amino group or an aminoalkyl of 1 to 6 carbon atoms optionally substituted on the nitrogen atom with one or two alkyl groups of 1 to 5 carbon atoms or with an aralkyl group, an amidino, guanidino, amidinoalkyl or guanidinoalkyl group optionally substituted with 1, 2 or 3 (C1-C5)alkyl groups or with an aralkyl group, in which the alkyl portion contains each time from 1 to 6 carbon atoms and in which two nitrogen atoms of an amidino group or of a guanidino group may also form together an alkylene chain of 2 to 4 carbon atoms, it being understood that a nitrogen atom in the abovementioned groups may also be substituted with a cyano, hydroxyl, alkoxy, amino, arylcarbonyl, aryloxycarbonyl, or aralkoxycarbonyl group or with an alkoxycarbonyl group of 2 to 6 carbon atoms as long as it does not exist in the form of an ammonium, or an ammonium or ammonioalkyl group of 1 to 6 carbon atoms substituted with 3 alkyl groups of 1 to 3 carbon atoms, E36, which is linked to a carbon atom of the group Y36 or of the group A36 and which has at the very minimum between itself and the first nitrogen atom of B36 at least 10 bonds, is a vinyl, a hydroxymethyl, a bis(hydroxycarbonyl)methyl, a bis(alkoxycarbonyl)-methyl, a CN, a sulpho, a phosphono, an 0-alkylphosphono or a 5-tetrazolyl, a carbonyl (substituted with a (C1-C7)alkoxy, with NH2, OH, aralkoxy, heteroarylalkoxy, aminoalkoxy or with an aminocarbonylalkoxy, in which the amino groups are themselves optionally mono- or disubstituted with alkyl, aryl or aralkyl, or an alkyleneiminoalkoxy containing from 5 to 7 members (in which one of the CH2 groups of the 5- to 7-membered alkylenimino ring is optionally replaced by a carbonyl, it being also possible for a group at the 4-position to be replaced by an oxygen atom, a sulphur atom, SO, imino, alkylimino, aralkylimino or arylimino, or at the 2- or 4-position by an SO2), with the proviso that if B36 is linked via a nitrogen atom to an aryl group of X36, E36 cannot be a vinyl linked by a methylene to the cyclic nitrogen of A36 if A36 is a pyrrolidine; - X36 is a group of formula in which is bonded to the radical A36 and X36, is bonded to the radical B36, and represents a bond, an optionally mono- or polyunsaturated alkylene group, or an optionally mono- or polyunsaturated arylene group, it being understood that between the alkylene group and the adjacent group there may also be in addition an oxygen atom or a sulphur atom or an SO, SO2, CO, CO- may be replaced by a carbonyl or hydroxymethylene group, or an arylene ring, in which two carbon atoms adjacent to the arylene ring may be optionally attached by a propylene, propenylene, butylene, butenylene, butadienylene, pentylene, pentenylene or pentadienylene bridge, a naphthalene ring completely or partially hydrogenated on the two rings or a tricyclic arylene ring optionally completely or partially hydrogenated, it being understood that in these cyclic systems, a methylene group may be replaced by a carbonyl or hydroxymethylene group, an optionally mono- or polyunsaturated cycloalkylene group, an optionally mono- or polyunsaturated bicyclo-alkylene group of 6 to 12 carbon atoms or an optionally mono- or polyunsaturated spiroalkylene group of 8 to 12 "carbon atoms, which may further carry 1 to 3 alkyl substituents, an alkylene group of 1 to 8 carbon atoms, which may be mono- or polyunsaturated, it being understood, however, that a double bond or a triple bond is not adjacent to a heteroatom, X363 represents a bond, an alkylene group of 1 to 7 carbon atoms, which may be mono- or polyunsaturated, it being understood that a double or triple bond cannot be adjacent to a triple bond of the radical X362, or a hydroxyalkylene group, or when X363 is not immediately after an optionally substituted amino group, a trialkylammonium group or a triple bond. or alternatively when the alkylene group of the radical mono- or polyunsaturated, it being understood, however, that a double bond or a triple bond cannot be adjacent to a heteroatom or to a triple bond of the radical Y361, an arylene group, aryl and arylene groups being as defined in application EP 483 667, it being understood that aryl and arylene groups are understood to mean mono-, bi- or tricyclic aromatic groups, which may be monosubstituted with an aryl, aralkyl or nitro group and/or which may be mono-, di- or trisubstituted with a fluorine, chlorine or bromine atom, with an alkyl group of 1 to 5 carbon atoms, with a hydroxyl, alkoxy, aralkoxy, trifluoromethyl, mercapto, alkylthio, alkylsulphinyl, alkylsulphonyl, amino, alkylamino, dialkylamino, alkylcarbonylamino, aralkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, alkylsulphonylamino, arylsulphonylamino, N-alkylcarbonylalkylamino, N-aralkylcarbonylalkylamino, N-arylcarbonylalkylamino, N-alkoxycarbonylalkylamino, N-alkylsulphonylalkylamino, N-arylsulphonylalkylamino, cyano, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminosulphonyl, alkylaminosulphonyl, dialkylaminosulphonyl, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, carboxyl, sulpho, alkoxycarbonyl, aminocarbonylamino, N-amino-carbonylalkylamino or aminoalkyl, the substituents being identical or different and it being possible for the amino groups of the abovementioned aminocarbonylamino, N-aminocarbonylalkylamino or aminoalkyl groups to be, in addition, mono- or disubstituted with an alkyl or aralkyl group, their geometric isomers and the addition salts, as described in EP 483 667. XXXVII - BIBU 129 or a cyclic urea derivative of formula: in which - X37 is a carbimino optionally substituted with alkyl, aralkyl, aryl, heteroaryl, or cyano, CO, CS, SO or SO2; - Y37 is (a) a straight (C2-C4)alkylene, or an alkenylene optionally substituted with Rc37 and/or Rd37, and in which each carbon atom is substituted with one or two identical or different substituents selected from F, CI, Br, alkyl, CF3, aralkyl, aryl, heteroaryl and alkylcarbonyl, and in which also one or two CH2 may be replaced by CO; (b) 1, 2-(C4-C7)cycloalkylene optionally substituted with Rc37 and/or Rd37; (c) 1,2-(C4-C7)cycloalkenylene; (d) 1,2-phenylene in which 1 or 2 CH are optionally substituted with N or 1 or 2 CH=CH with a CONR137. the said 1,2-phenylene being optionally substituted on its carbon backbone with F, CI, Br, (C1-C4)alkyl, CF3, OH, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, COOH, NO2, (RS7)2N, (RS7)2NCO, (RS7)2NS02, or with RS7NH (it being possible for -R371 itself to be substituted with an alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, hetero- arylcarbonyl, alkylsulphonyl, aralkylsulphonyl, or arylsulphonyl) position) may be replaced with a nitrogen atom, it being possible for a CH2 adjacent to the nitrogen atom to be in addition replaced with a carbonyl group); or a biphenylene (optionally substituted with one or two F, CI, Br, alkyl, CF3, OH, alkoxy, alkylthio. - C37 is an alkylene or an alkenylene (optionally substituted with OH, alkoxy or N(R137)2); alkylenecarbonyl (bonded to B37 via the CO) ; a phenylene (optionally substituted like for B37) ; indanylene, or 1,2,3,4- tetrahydronaphthylene (saturated ring linked to A37, the aromatic ring being linked to the carbamide portion); pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene or triazinylene (all optionally substi¬ tuted on the carbon-containing backbone with an alkyl; it being possible for one or two -CH=N- groups of these rings to be replaced with a group, and it being possible for a nitrogen atom to be attached to the B37 radical instead of R371 as long as the latter does not represent a bond or is not bonded to a heteroatom of the radical C37) ; or (C4-C5) cycloalkylene, as defined for B37; - a second radical selected from Ra37 to Rd37 represents a group of formula F37-E37-D37-, in which - D37 is a (C1-C5) alkylene or a (C2-C5) alkenylene; a phenylene (optionally mono- or disubstituted with one or more identical or different substituents selected from F, CI, Br, (C1-C4) alkyl, CF3, OH, alkoxy, alkylthio, alkyl- SO-, alkyl-SO2-, carboxyalkoxy, alkoxycarbonylalkoxy, aralkoxycarbonylalkoxy, (R32) 2N-, (RS7) 2NCO-, (R137) 2NSO2 or NO2 or R137NH- (R37NH- being optionally substituted as indicated above); a pyridinylene, pyrimidinylene, pyrazinylene, pyridazinylene or triazinylene ring (all optionally substituted on the carbon-containing backbone with an alkyl; it being possible for one or two -CH=N- groups of these rings to be replaced with a -CO-NR371 group, and it being possible for a nitrogen atom to be attached to the radical E37 instead of R137 as long as the latter does not represent a bond or is not bonded to a bis(aralkyl)amino, a carboxyalkyl, an alkoxycarbonylalkyl or an aralkoxycarbonylalkyl) ; a phenylene (optionally substituted like for B37) ; a pyridinylene, pyrimidinylene, pyrazinylene, pyridazylene or triazinylene ring (all optionally substituted on the carbon-containing backbone with an alkyl; it being possible for one or two -CH=N- groups to be replaced by a CO-NR371 group and it being possible for a nitrogen atom to be bonded to the D37 radical instead of the R371 radical), a (C4-C5) cycloalkylene group as defined for D37; a (C6-C7) cycloalkylene group as defined for D37; an alkylenearylene (aryl linked to D37) ; or an alkylene linked to W37 of D37; - F37 is a carbonyl group substituted with OH or (C1-C6) alkoxy (it being possible for a (C1-C3) alkoxy to be substituted on each of its positions with an aryl or a heteroaryl, or at the 2- or 3-position with a pyrrolidin-2-on-l-yl, morpholino, thiomorpholino or 1-oxido-thiomorpholino); sulpho; phosphono; O-alkylphosphono or tetrazol-5-yl; it being understood that when A37 = CN or an amino or an aminoalkyl (the amino and aminoalkyl radicals being optionally benzoylated or benzyloxycarbonylated on the nitrogen atom), the shortest distance between the nitrogen atom of these groups and F37 being at least 10 bonds; - a third radical selected from Ra37 to Rb37 is H, alkyl, perfluoroalkyl, aralkyl, aryl or heteroaryl, it being understood that this third radical, when it is linked to an unsaturated carbon atom of Y37, may also be an alkoxy, an alkylthio or (RS7)2N; - a fourth radical selected from Ra37 to Rd37 is H, an alkyl, an aralkyl, an aryl or a hd37 represent a bond; it should be understood that unless otherwise defined (a) all the alkyl, alkylene, alkenylene or alkoxy have from 1 to 3 carbon atoms; (b) aryl is phenyl (optionally substituted with a CF3, COOH, (R137) 2NCO, alkoxycarbonyl, alkylcarbonyl, alkylthio, alkylsulphinyl, alkylsulphonyl, NO2, (R337) 2N, alkyl carbonyl-NR373-, aralkylcarbonyl-NR373-, ar yl carbonyl-NR371-, heteroarylcarbonyl-NR371-, alkylsulphonyl-NR37'3, aralkylsulphonyl-NR371, arylsulphonyl-NR373, or (R373)N-sulphonyl; or with 1 to 3 F, Cl, Br, OH or a (C1-C4)alkyl or alkoxy); the heteroaryl is a 5-membered heteroaromatic ring with an oxygen atom, a sulphur atom or a nitrogen atom, a nitrogen atom and an oxygen atom,a sulphur atom or a nitrogen atom or two nitrogen atoms and an oxygen atom, a sulphur atom or a nitrogen atom, or a 6-membered heteroaromatic ring with one, two or three nitrogen atoms, and in which one or two -CH=N- groups may be replaced with a -CO-NR37roup, it being understood that the said heteroaromatic rings may be substituted with one or two alkyl groups or with a fluorine, chlorine or bromine atom or with a hydroxy1 or alkoxy group), and their tautomeric forms and their stereoisomers (or mixtures thereof) as well as their pharmaceutically acceptable salts as described in EP 503548. XXXVIII - SR 121787A or one of its analogs of formula: in which: - Ras3 represents hydrogen, a (C1-C5) alkyl, a (C3-C8) cycloalkyl, an aralkyl in which the alkyl portion is a C1-C5, an alkoxycarbonylalkyl group in which the alkoxy and alkyl portions are a C1-C3 or a carboxyalkyl group in which the alkyl portion is a C1-C3; - A38 represents either a methylene group optionally mono-or disubstituted with a (C1-C5)alkyl group; with an alkoxycarbonyl group in which the alkoxy portion is a C1 C5; with an alkoxycarbonylalkyl group in which the alkoxy and alkyl portions are a C1-C5; with a carboxyalkyl group in which the alkyl portion is a C1-C5; with a phenyl or benzyl group unsubstituted or substituted on the aromatic ring with a (C1-C5)alkyl, a (C1-C5)alkoxy, a hydroxyl, a halogen or a trifluoromethyl; with a pyridyl group; or an ethylene group; - R38 represents hydrogen, or a (C1-C5) alkyl group; an aryl group or an aralkyl group in which the alkyl portion is a C1-C5 optionally substituted with a hydroxyl, a (C1 C3)alkoxy, a halogen, a trifluoromethyl or a (C1-C5)alkyl; - Y38 represents hydrogen; a -COOR38 group in which Ra38 represents a (C1-C5)alkyl group, an aryl group or an aralkyl group in which the alkyl portion is a C1-C5 optionally substituted with a (C1-C5) alkyl; a -COR383 group in which the R383 represents a (C1-C5) alkyl; or one of their salts, as described in EP 719775. XXXIX - FK 633 and its peptide analogues of formula: substituents selected from the group consisting of a (C1-C6) alkyl group; mono- (or di- or tri) phenyl (C1-C6) alkyl) group which may have 1 to 3 substituents selected from the group consisting of a hydroxyl, (C1-C6)alkoxy and protected hydroxyl group; hydroxy(C1-C6 alkyl) group; protected hydroxy(C1-C6 alkyl) group; [C5-C6) cycloalkyl]-(C1-C6 alkyl) group; and heterocyclyl (C1-C6 alkyl) group, in which the heterocyclic portion is a 3- to 8-membered unsaturated heteromonocyclic group containing 1 to 4 nitrogen atoms, a 3- to 8-membered unsaturated heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, or a 3- to 8-inembered unsaturated heteromonocyclic group containing 1 to 2 sulphur atoms and 1 to 3 nitrogen atoms; - I39, m39 and n39 are each identical or different and equal to the integer 0 or 1 provided that: (i) when I39 is an integer 0, - A393 is then not a group of formula -NHCH2CH2CO- and in which - R40 is a protecting group selected from the group consisting of t-butoxycarbonyl and carbobenzyloxy; - Z40 is selected from the group consisting of -CN, -CONH2 and CO2 alkyl, as described in US 5,484,946. XXXXI - Alprostadil or its analogues of formula: Ded XXXXII - Epoprostenol and its analogues of formula: in which: - R42 represents a hydrogen or a pharmacologically acceptable cation, and - Z421 and Z422 are a hydrogen and/or a protecting group, as described in DE 2,720,999. XXXXIII - Iloprost and its analogues of formula: in which: - R144 is a pharmaceutically acceptable cation, a hydrogen atom or an n-alkyl group having from 1 to 12 carbon atoms; - R244 is a hydrogen atom, an acyl group having 2 to 10 carbon atoms, or an aroyl group of 7 to 13 carbon atoms; - R344 is a hydrogen atom, an acyl group of 2 to 10 carbon atoms or an aroyl group of 7 to 13 carbon atoms; - R444 is a hydrogen atom, a methyl group or an ethyl group; - R544 is an n-alkyl group of 1 to 5 carbon atoms; - n44 is an integer from 0 to 4; - A44 is a -CH2-CH2- or a trans -CH=CH-; - X44 is a -CH2-CH2- or a trans -CH=CH-, as described in EP 84856. XXXXV - Cicaprost or a 13,14,18,18,19,19-hexahydro-3-oxa-6a-carbaprostaglandin I2 (5E) derivative corresponding to the formula: r d - R455 represents an alkyl radical containing 1 to 5 carbon atoms, as well as the salts which they form with physiologically acceptable bases, as described in EP 119949. XXXXVI - Taprostene or a 2,3, 4-trinor-l, 5-inter-m-phenylene-6,9-epoxy-ll,15-dihydroxy-5-prostenoic acid derivative of formula: a: in which: - R471 represents a hydrogen atom or a lower alkyl group, - R472 represents a 2-methylhexyl group, a 3-propyl-cyclopentyl, 3-butylcyclopentyl, or a 4-propylcyclohexyl group; as defined in DE 3,316,356. XXXXVIII - Ciprostene or a carbacycline analogue of formula: t2) a phenoxy optionally substituted with one, two or three fluorine, chlorine or trifluoromethyl, a (C1-C3) alkyl, or a (C1-C3) alkoxy, with the proviso that R748 is a phenoxy or a substituted phenoxy only when R483 and R484, which are identical or different, are a hydrogen or a methyl, (3) a phenyl, a benzyl, a phenylethyl, or a phenylpropyl optionally substituted on the aromatic ring with one, two or three chlorine, fluorine, or trifluoromethyl, a (C1-C3) alkyl, a (C1-C3) alkoxy, with the proviso that at most two substituents are different from an alkyl; (4) cis-CH=CH-CH2-CH3, - X 48 is (1) a -COOR148 in which: - R 48 IS (a) a hydrogen (b) a (C1-C12) alkyl, (c) a (C3-C10) cycloalkyl, (d) a (C7-C12) aralkyl. (C3-C6) acetylalkyl; a (C7-C11) benzoalkyl optionally substituted with one, two or three chlorine, (C1-C3)alkyl, hydroxyl, (C1-C3) alkoxy, carboxyl, (C2-C5) alkoxycarbonyl or nitro; a pyridyl optionally substituted with one, two or three chlorine, (C1-C3)alkyl or (C1-C3)alkoxy; a (C5-C9)pyridylalkyl optionally substituted with one, two or three chlorine, (C1-C3)alkyl, hydroxyl, or (C1-C3)alkyl; a (C1-C4) hydroxyalkyl; a (C1-C4) di hydroxy alkyl, a (C1-C4)trihydroxyalkyl; with the additional limitation that only one radical from R2148 and R2248 is distinct from a hydrogen or an alkyl, (b) a cyclic amine selected from the group consisting of pyrrolidine, piperidino, morpholino, piperazino, hexamethylenimino, pyrrolino, or 3,4-didehydro-piperidinyl optionally substituted with one or two 1 I R4 9^ 3i^e basic entities selected from the group consisting of an amino, a lower alkylamino, a dialkylamino in which the alkyl entity has from 1 to 12 carbon atoms, a monohydroxy(lower alkyl)amino, a di-(lower hydroxyalkyl)alkylamino in which the alkyl entity has from 1 to 12 carbon atoms, a (lower alkoxy-lower alkyl)amino, a (lower alkenyl)amino, a cyclohexylamino, a phenylamino, a halophenylamino, a nitrophenylamino, a (lower alkoxyphenyl)amino, a [(lower dial kyl ami no) phenyl] amino,, a benzyl ami no, a semicarbazidyl, a hydrazinyl, a guanidyl, an ethylenimino, a piperidyl, a lower alkylpiperidyl, a lower alkoxypiperidyl, a hydroxypiperidyl, a pyrrolidyl, a lower alkylpyrrolidyl, a lower alkoxypyrrolidyl, a hydroxypyrrolidyl, a morpholyl, a lower alkylmorpholyl, a lower alkoxymorpholyl, a hydroxymorpholyl, a tetrahydropyridyl, a lower alkyltetrahydropyridyl, a lower alkoxytetra-hydropyridyl, a hydroxytetrahydropyridyl, a hexamethylenimino, a lower alkylhexamethylenimino, a lower alkoxyhexamethylenimino, a hydroxy-hexamethylenimino, a tetrahydroquinolyl, a lower alkyltetrahydroquinolyl, a lower alkoxytetra- lower alkenyl group, a lower alkanoyl group, a benzoyl group or a phenylalkyl group; - R502 represents a hydrogen atom, a lower alkyl group or a group of formula: - R503 represents a lower alkyl group, a cycloalkyl group, a cycloalkylalkyl group, a phenyl group or a phenylalkyl group; - A50 represents a lower alkylene group; - the carbon-carbon bond between the 3- and 4-positions of the carbostyrile backbone is a single bond or a double bond; - and the position of the group corresponding to the formula : on the carbostyrile backbone is the 4-, 5-, 6-, 7- or 8-position with the proviso that a single group of formula above can be attached to the entire carbostyrile backbone, thus, when R50 at the 4- position represents the 5-, 6-, 7- or 8-positions do not have such a group, it being possible for the phenyl group of the abovementioned benzoyl, phenylalkyl or phenyl groups to have one or more substituents, as described in BE 878 548. The preferred antiplatelet aggregating agents are aspirin, ticlopidine, clopidogrel or antagonists of glycoprotein Ilb/IIIa. It will be noted, however, that the use of aspirin is not recommended in patients having undergone a revascularization procedure such as a percutaneous angioplasty. The preferred glycoprotein Ilb/IIIa antagonists are: - ethyl N-(l-ethoxycarbonylmethylpiperidin-4-yl)-N-{4-[4- {(N-ethoxycarbonylimino)(amino)methyl}phenyl]thiazol-2- yl}-3-aminopropionate, designated SR 121787A, and its pharmaceutically acceptable salts, and - N-(l-carboxymethylpiperidin-4-yl)-N-{4-[4-{(amino)- (imino)methyl}phenyl]thiazol-2-yl}-3-aminopropionic acid, and its pharmaceutically acceptable salts, such as the trihydrochloride, designated SR 121566. The formulae of SR 121787 and of SR, 121566 are recalled below: The selective inhibitor of factor Xa, alone or in combination with an anti-platelet aggregation agent, is particularly useful for the treatment or prophylaxis of pathological conditions such as disorders of the cardiovascular or cerebrovascular system such as thromboembolic disorders associated with atherosclerosis or with diabetes such as unstable angina, cerebral attack, restenosis following angioplasty, endarterectomy or fitting of metallic endovascular prostheses, or such as thromboembolic disorders associated with rethrombosis following thrombolysis, with infarction, with dementia of ischaemic origin, with peripheral arterial diseases, with haemodialysis, with atrial fibrillations, or during the use of vascular prostheses, of aortocoronary bypasses or for stable or unstable angina, or for patients treated by a revascularization procedure at the risk of thrombosis including percutaneous angioplasties, endovascular prostheses, vascular prostheses, aortocoronary bypasses. As examples of pharmaceutically acceptable organic salts, there may be mentioned oxalate, maleate, fumarate, methanesulphonate, benzoate, ascorbate, pamoate, succinate, hexamate, bismethylenesalicylate, ethanedisulphonate, acetate, propionate, tartrate, salicylate, citrate, gluconate, lactate, malate, cinnamate, mandelate, citraconate, aspargate, palmitate, stearate, itaconate, glycolate, p-aminobenzoate. glutamate, benzenesulphonate and theophylline acetate as well as the salts formed from an amino acid such as the lysine or histidine salt. As examples of pharmaceutically acceptable inorganic salts, there may be mentioned hydrochloride, hydrobromide, sulphate, sulphamate, phosphate and nitrate. The neutralization of activated factor X (Xa) (by antithrombin III) can be catalysed by the pentasaccharide (PS) such as low-molecular-weight heparin. Unlike the low-molecular weight heparin, the pentasaccharide is completely devoid of activated thrombin. In addition, the pentasaccharide hardly modifies the haemostasis tests and in particular the activated partial thromboplastin time (APTT) test on human plasma and unlike heparin, it does not potentiate ADP or platelet aggregation induced by collagen. However, the antithrombotic effects of the pentasaccharide have been demonstrated after intravenous (i.V.) and subcutaneous (s.c. ) administration in different animal models with different types of induced thromboses (the venous stasis model in rats, the arteriovenous shunt model in rats, the Wessler model in rabbits) (Hobellen PMJ et al, Tromb. & Haemost., 1996, 63(2), 265-270 and Amar J. et al, Br. J. Haematol., 1990, 76, 94-100) . As regards the risk of bleeding, the loss of blood at high PS dose tested in rats (21.7 mg/kg) is identical to that observed with 200 units anti-Xa/kg of heparin, thus indicating that PS only slightly increases blood loss compared with standard heparin or LMWHs. To illustrate the invention and by way of example, there will be given below the results obtained during the study of the potentiation of the antithrombotic effect in rabbits by co-administration of a selective inhibitor of factor Xa and of an anti-platelet aggregation agent. As selective inhibitor of factor Xa, SR 90107/ORG 31540 (or PS) was selected and the anti-platelet aggregation agent was selected from the antagonists of glycoprotein Ilb/IIIa, namely SR 121787A. The aim of this test was therefore to determine the arterial antithrombotic effects of the co¬administration of an anti-Xa, the pentasaccharide SR 90107/ORG 31540 and of an antagonist of the GPIIb/IIIa receptors, SR 121787A. New Zealand male rabbits weighing 2.7 to 3 kg, obtained from the Lago breeding unit (France) were used. They were housed under standard conditions. The formation of the thrombus was induced by external electrical stimulation of the left common carotid according to the Hladovec I. et al, method (Experimental arterial thrombosis in rats with continuous registration, Throm. Diathes. Haemor. 1971; 26: 407-410). The rabbits were anaesthetized with pentobarbital at the dose of 30 mg/kg iv. A segment of the left carotid artery was exposed and insulated by a piece of insulating film. Electrodes were inserted under the artery. A partial stricture inducing a 20% reduction in flow rate was made in the artery- The latter was then stimulated with the aid of a 2.5 mA current delivered by a constant current stimulator for 3 minutes. The thrombotic occlusion was evaluated by continuous measurement of the flow rate of blood in the carotid by means of an NARCO electromagnetic flow meter. This measurement was made over an observation period of 45 minutes. For the treatment, solutions of SR 90107/ORG 31540 and of SR 121787A were prepared immediately before use in a saline solution. The solutions of SR 90107/ORG 31540 were injected by the IV route 5 minutes before induction of thrombosis in a volume of 1 ml/kg. SR 121787A was administered by the oral route 2 hours earlier. The results were calculated and expressed as % reduction in blood flow rate at various times relative to time 0. They are grouped together in Figure 1. In the control animals, the flow rate was gradually reduced from 20.9±2.1 to 3.812.5 ml/min (n = 8: mean for 8 animals) over 15 minutes and 1.5±1.4 ml/min over 20 min. It then stayed at this level for up to 45 minutes. SR 90107/ORG 31540, at the dose of 300 nmol/kg, had no influence on this reduction in flow rate. 600 nmol/kg of SR 90107/ORG 31540 reduced it slightly but not significantly. SR 121787A administered 2 hours before as sole active ingredient at the oral dose of 10 mg/kg, did not significantly modify the course of the carotid output whereas 20 mg/kg almost completely inhibited the drop in the latter. The co-administration of the pentasaccharide SR 90107/ORG 31540 and of the antagonist of the GPIIb/IIIa receptor SR 121787A, at doses which are separately inactive (300 nmol/kg iv and 10 mg/kg po. respectively), completely protected against reduction in flow rate and therefore against the arterial thrombosis thus induced. No toxicological effect of SR 90107/ORG 31540 was observed on any animal species whatsoever, regardless of the concentration tested in the appropriate toxicity studies and by repeated assays (over a period of 4 weeks with up to 10 mg/kg subcutaneously). SR 90107/ORG 31540 is not mutagenirectoc in the AMES test, or in the DNA repair test. Thus, the use of a direct selective inhibitor of factor Xa, such as DX-9065a or of an indirect selective inhibitor of factor Xa, such as an oligosaccharide, alone or in combination with an anti-platelet aggregation agent, is particularly beneficial for pathological conditions such as disorders of the cardiovascular and cerebrovascular system such as thromboembolic disorders associated with atherosclerosis or with diabetes such as unstable angina, cerebral attack, restenosis following angioplasty, endartemy or fitting of metallic endovascular prostheses or such as thromboembolic disorders associated with rethrombosis following thrombolysis, with infarction, with dementia of ischaemic origin, with peripheral arterial diseases, with haemodialysis, with atrial fibrillations or during the use of vascular prostheses or of aortocoronary bypasses, or for stable or unstable angina, or for patients treated by a revascularization procedure at risk of thrombosis including percutaneous angioplasties, endovascular prostheses, vascular prostheses, aortocoronary bypasses. In addition, the use of a direct selective inhibitor of factor Xa, such as DX-9065a or of an indirect selective inhibitor of factor Xa, such as an oligosaccharide, alone or in combination with the anti¬platelet aggregation agents, does not increase the haemorrhagic risk. The combination of a direct selective inhibitor of factor Xa, such as DX-9065a or of an indirect selective inhibitor of factor Xa, such as an oligosaccharide and of the anti-platelet aggregation agent may be formulated in pharmaceutical compositions which can be used by the oral or parenteral route, in particular by the subcutaneous route, in the form of a mixture with conventional pharmaceutical excipients. Thus, according to another of its features, the invention relates to the pharmaceutical compositions comprising one or more direct or indirect selective inhibitors of factor Xa acting via antithrombin III in combination with one or more compounds with anti-platelet aggregation activity, and optionally one or more pharmaceutically acceptable vehicles. The preferred pharmaceutical compositions of the invention comprise an antagonist of glycoprotein Ilb/IIIa as anti-platelet aggregation agent and methyl O-(2-deoxy- 2-sulphoamino-6-O-sulfo-α-D-glucopyranosyl)- (1→4)-O-(P-D- glucopyranosyluronic acid- (1→4 ) -O-(2-deoxy-2-sulphoamino- 3, 6-di-O-sulpho-α-D-glucopyranosyl-(1→4) -O-(2-O-sulpho-α- L-idopyranosyluronic acid)- (1→4) -2-deoxy-2-sulphoamino-6- O-sulpho-α-D-glucopyranoside whose anion has the structure (B) or one of its pharmaceutically acceptable salts, as indirect selective inhibitor of factor Xa. Another preferred group of pharmaceutical compositions consists of the compositions comprising methyl O-(2-deoxy-2-sulphoamino-6-O-sulfo-α-D-gluco- pyranosyl)- (1→4)-O-(p-D-glucopyranosyluronic acid-(1→4) - O-(2-deoxy-2-sulphoamino-3,6-di-O-sulpho-α-D- glucopyranosyl- (1→4) -O- (2-O-sulpho-α-L-idopyranosyluronic acid) - (1→4)-2-deoxy-2-sulphoamino-6-O-sulpho-α-D-gluco-pyranoside whose anion has the structure (B) or one of its pharmaceutically acceptable salts, as indirect selective inhibitor of factor Xa, and aspirin, as anti-platelet aggregation agent. The pharmaceutical compositions which are the subject of the present invention are preferably provided in the form of dosage units containing a predetermined quantity of the active ingredients, as specified below. The unit forms for administration by the oral route comprise tablets, gelatin capsules, powders, granules, microgranules. The anti-platelet aggregation agent may be formulated according to methods well known to persons skilled in the art. The same applies to the selective inhibitor of factor Xa. In the formulation of the combinations of active ingredients for the preparation of the pharmaceutical compositions according to the present invention, the nature of the active ingredients entering into the combination will be taken into account. Thus, when the selective inhibitor of factor Xa is an oligosaccharide, the latter is preferably used in the form of an addition salt in the composition, for example in the form of a sodium salt. Normally, the oligosaccharides in the form of their addition salts with pharmaceutically acceptable acids are not chemically incompatible with the nonsalifled anti-platelet aggregation agents. However, some of the latter are also used in the form of acid addition salts. In any case, it is preferable to keep the active ingredients separate according to techniques well known in the literature. The pharmaceutical compositions of the present invention are particularly suitable in the treatment or prophylaxis of pathological conditions such as disorders of the cardiovascular and cerebrovascular system such as thromboembolic disorders associated with atherosclerosis or with diabetes such as unstable angina, cerebral attack, restenosis following angioplasty, endarterectomy or fitting of metallic endovascular prostheses, or such as thromboembolic disorders associated with rethrombosis following thrombolysis, with infarction, with dementia of ischaemic origin, with peripheral arterial diseases, with haemodialysis, with atrial fibrillations, or during the use of vascular prostheses, of aortocoronary bypasses or for stable or unstable angina, or for patients treated by a revascularization procedure at risk of thrombosis including percutaneous angioplasties, endovascular prostheses, vascular prostheses and aortocoronary bypasses. The combinations according to the invention may be formulated in pharmaceutical compositions for administration to mammals, including humans, for the treatment of the abovementioned diseases. The combinations according to the invention may be used at daily doses of the selective inhibitor of factor Xa or of the anti-platelet aggregation agent of 0.1 to 100 mg per kilo of body weight of the mammal to be treated. In human beings, the dose may vary for each of the components from 1 to 500 mg per day, according to the age of the subject to be treated and the type of treatment: prophylactic or curative. Preferably, the pentasaccharide is administered at doses of between 0.30 mg and 30 mg per patient and per day. In the pharmaceutical compositions of the present invention, the active ingredients are generally formulated in dosage units containing from 0.1 to 50 mg of the said active ingredient per dosage unit. The compositions of the invention are prepared so as to be able to be administered by the digestive or parenteral route and are provided in various forms, such as for example of injectable or oral solutions, sugar-coated tablets, plain tablets or gelatin capsules. The injectable solutions are the preferred pharmaceutical forms. In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, transmucosa, local or rectal administration, the active ingredient may be administered in unit forms for administration, in the form of a mixture with conventional pharmaceutical carriers, to animals and to human beings. The appropriate unit forms for administration comprise the forms to be administered by the oral route, such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, the forms for sublingual or buccal administration, the forms for subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and the forms for rectal administration. When a solid composition in the form of tablets is prepared, the principal active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arable and the like. The tablets may be coated with sucrose or other appropriate materials or they may be treated such that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active ingredient. A preparation of gelatin capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard gelatin capsules. The water-dispersible powders or granules may contain the active ingredient in the form of a mixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or with flavour correctors. For a rectal administration, suppositories are used which are prepared with binding agents which melt at the rectal temperature, for example cocoa butter or polyethylene glycols. For a parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions are used which contain pharmacologically compatible dispersing agents and/or wetting agents, for example propylene glycol or butylene glycol. For transmucosa administration, the active ingredients may be formulated in the presence of a promoter such as a bile salt, a hydrophilic polymer such as for example hydropropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethyl cellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone, pectins, starches, gelatin, casein, acrylic acids, acrylic esters and their copolymers, vinyl polymers or copolymers, vinyl alcohols, alkoxy polymers, polyethylene oxide polymers, polyethers or their mixture. The active ingredients may also be formulated in the form of microcapsules, optionally with one or more carriers or additives. The active ingredients may also be provided in the form of a complex with a cyclodextrin, for example α, β - or γ=-Cyclodextrin, 2-hydroxypropyl-β-cyclodextrin or methyl-p-cyclodextrin. One of the active ingredients, for example the oligosaccharide, inhibitor of factor Xa, may also be released by a balloon containing it and by an endovascular expander introduced into the blood vessels. The pharmacological efficacy of the active ingredient is thus not affected. Preferably, the selective inhibitor of factor Xa is administered by the intravenous or subcutaneous route. In the therapeutic combinations according to the present invention, the pharmaceutical forms preferably contain 8 to 30 mg of selective inhibitor of factor Xa and 10 to 200 mg of anti-platelet aggregation compound. The combination of 15 to 25 mg of selective inhibitor of factor Xa and of 10 to 30 mg of anti¬platelet aggregation agent is particularly advantageous. Better still, the pharmaceutical forms of the present invention comprise 20 mg of a pentasaccharide, selective inhibitor of factor Xa, and 20 mg of an anti-platelet aggregation agent. We claim 1. A composition for arterial thromboembolic diseases containing a synergistic combination of a direct or indirect selective inhibitor of factor Xa acting via antithrombin III in combination with a compound with anti-platelet aggregation activity. 2. The composition as claimed in Claim 1, comprising an antagonist of glycoprotein Ilb/IIIa as anti-platelet aggregation agent and methyl O-(2-deoxy-2-sulphoamino-6-O-sulfo-α-D-glucopyranosyl)-(l→4)-O-(P-D-glucopyranosyluronic acid-(l→4)-O-(2-deoxy-2-sulphoamino-3,6-di-O-sulpho-a-D-glucopyranosyl-(l→4)-O-(2-O-sulpho-α-L-idopyranosyluronic acid)-(l→4)-2-deoxy-2-sulphoamino-6-O-sulpho-α-D-glucopyranoside whose anion has the structure (B) or one of its pharmaceutically acceptable salts, as indirect selective inhibitor of factor Xa. 3. The composition as claimed in claim 2, wherein the antagonist of glycoprotein Ilb/IIIa is selected from - ethyl N—(l-ethoxycarbonylmethylpiperidin-4-yl)-N-{4-[4-{(N— ethoxycarbonylimino) (amino)methyl}phenyl]thiazol-2-yl}-3- aminopropionate, -N-(l-carboxymethylpiperidin-4-yl)-N-{4-[4-{(amino) (imino)methyl}phenyl]thiazol- 2-yl}-3-aminopropionic acid ,and its pharmaceutically acceptable salts such as the trihydochloride salt. 4. A pharmaceutical composition containing the composition as claimed in any of the preceeding claims and pharmaceutically acceptable vehicles.

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1273-mas-1998-abstract.pdf

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