MXPA97009908A - Cetoheterociclic compounds, use of the same and compositions that contain them - Google Patents

Abstract

Novel compounds, their salts and compositions related thereto which have activity against mammalian factor Xade are described, the compounds are useful in vitro or in vivo to prevent or treat coagulation disorders.

Description

CETOHETEROCICLIC INHIBITORS OF THE FACTOR Xa FIELD OF THE INVENTION This invention relates to novel compounds that contain ketoheterocyclics, which are potent and highly selective inhibitors of isolated factor Xa or, when assembled in the insane-prothrombin complex. In another aspect, the present invention relates to novel peptides and peptide mimetic analogs, their pharmaceutically acceptable salts and their pharmaceutically acceptable compositions which are useful as potent and specific inhibitors of blood coagulation in mammals. In still another aspect, the invention relates to methods for using these inhibitors as therapeutic agents for disease states in mammals, characterized by alterations in coagulation.

BACKGROUND OF THE INVENTION Hemostasis, the control of bleeding, occurs by surgical means or by the physiological properties of vasoconstriction and coagulation. This invention is particularly related to the coagulation of blood and the ways in which it helps maintain the integrity of the circulation in mammals after damage, inflammation, disease, congenital defects, dysfunction or other alterations. Under normalized hemostatic circumstances, the body maintains an acute balance of clot formation and the elimination of clots (fibrinolysis). The blood coagulation cascade involves the conversion of a variety of inactive enzymes (zymogens) to activating enzymes that ultimately convert the fibrinogen of the soluble plasma protein to an inelatable matrix of strongly interlaced fibrin. Davie, E.J. and coauthored, "The Coagulation Cascade: Initiation, Maintenance and Regulation", Biochemistry, 30: 10363-10370 (1991). These zymogens of plasma glycoprotein include factor XII, factor XI, factor IX, factor X, factor VII, and prothrombin. Blood coagulation follows the intrinsic pathway, where all protein components are present in the blood, or the extrinsic pathway, where the tissue factor of the membrane protein plays a critical role. Clot formation occurs when fibrinogen is divided by thrombin to form fibrin. Loe blood clots are composed of activated platelets and fibrin. Lae blood platelets that adhere to damaged blood vessels are activated and incorporated into the clot and, thus, play an important role in the initial formation and stabilization of haemostatic "plugs". In certain diseases of the cardiovascular system, deviations from normal hemostasis alter the balance of clot formation and clot dissolution to the formation of a life-threatening thrombus, when thrombi occlude blood flow in coronary vessels (heart attacks) to the myocardium) or in the veins of the legs and lungs (venous thrombosis). Although platelets and blood coagulation are both involved in thrombus formation, certain components of the coagulation cascade are primarily responsible for the amplification or acceleration of processes involving platelet accumulation and fibrin deposition. Thrombin is a key enzyme in the coagulation cascade, as well as in hemostasis. Thrombin plays a central role in thromboeia by its ability to catalyze the conversion of fibrinogen to fibrin and by its potent activation activity of platelets. Under normal circumstances, thrombin also plays an anticoagulant role in the ostaeia graciae to its ability to convert protein C to activated protein C (aPC) in a form that depends on the thrombus odulin. However, in the atherosclerotic arteries, these thrombin activities can initiate the formation of a thrombus, which is a major factor in the pathogenesis of vaso-occlusive conditions, such as myocardial infarction., unstable angina, non-orogenic attack and reocclusion of coronary arteries after angioplasty or thrombolytic therapy. Thrombin is also a potent inducer in smooth muscle cell proliferation and, therefore, may be implicated in a variety of proliferative responses, such as retenection after angioplasty and graft-induced embolism. Additionally, thrombin is chemotactic for leukocytes and, therefore, may play a role in inflammation (Hoover, R.J. and coauthors, Cell, 14: 423 (1978)).; Etingin, C.R. and coauthors, Cell, 61, 657 (1990). These observations indicate that the inhibition of thrombin formation or the inhibition of thrombin itself may be effective in preventing or treating thrombosis, limiting restenosis and controlling inflammation. Direct or indirect inhibition of thrombin activity has been the focus of a variety of recent anticoagulant strategies, as summarized by Cleason, G. "Synthetic Peptide and Peptidomimetice and Subst rates and Inhibitors of Thrombin and Other Proteases in the Blood Coagulation System ", Blood Coag. Fibrinol. 5, 411-436 (1994).

Several classes of anticoagulants currently used in clinical practice directly or indirectly affect thrombin (ie, heparins, low molecular weight heparins, heparin-like compounds, and coumarins). The formation of thrombin is the result of the proteolytic cleavage of its prothrombin precursor in the Arg-Thr ligature at positions 271-272, and the Arg-Ile ligature in positions 320-321. This activation is catalyzed by the prothrombinase complex, which is assembled on the membrane surface of platelets, monocytes and endothelial cells. The complex is made up of factor Xa (a serine protease), the factor Va (a cofactor), ionee calcium and the acid phospholipid surface. Factor Xa is the activated form of its precursor, factor X, which is secreted by the liver as a precursor of 58 kd, and has been converted to the active form, factor Xa, in the blood coagulation trajectory both extrinsic and intrinsic Factor X is a member of the family of blood coagulation glycoproteins, which depend on the binding of the calcium ion, which contain gamma-carboxyglutamyl (Gla), and which depend on vitamin K, which also includes factors VII. and IX, prothrombin, protein C and protein S (Furie B. and co-authors, Cell, 53, 505 (1988)). The activity of factor Xa to effect the conversion of prothrombin to thrombin depends on its inculcation in the prothrombinase complex. The prothrombinase complex converts the zyrogen prothrombin to an active precoagulant thrombin. Therefore, it should be understood that factor Xa catalyzes the penultimate step in the blood coagulation cascade, ie, the formation of serine protease-thrombin. In turn, thrombin then acts to divide the soluble fibrinogen in the plasma to form the insoluble fibrin. The location of the prothrombinase complex at the convergence of intrinsic and extrinsic coagulation trajectories, and the significant amplification resulting from the generation of thrombin (several hundred thousand times faster to effect the conversion of prothrombin to thrombin than factor Xa in soluble form), mediated by the complex in a limited number of target catalytic units, present at sites of vascular injury, suggests that inhibition of thrombin generation is a convenient method for blocking uncontrolled precoagulant activity. It has also been suggested that compounds that selectively inhibit factor Xa may be useful as an in vitro diagnostic agent or for therapeutic administration in certain thrombotic disorders; see, for example, WO 94/13693. Unlike thrombin, which acts on a variety of protein substrates, as well as in a specific receptor, factor Xa seems to have a single physiological substrate, namely prothrombin. Plasma contains an endogenous inhibitor of both factor Vlla factor factor (TF) complex and factor Xa complex, called tissue factor pathway inhibitor (TFPI). TFPI is a protease inhibitor of the Kunitz type, with three Kunitz tandem domains. TFPI inhibits the FT / fVIIa complex in a two-step mechanism that includes the initial interaction of the second Kunitz domain of TFPI with the active site of factor Xa, thereby inhibiting the proteolytic activity of factor Xa. The second step comprises the inhibition of the FT / fVIIa complex by the formation of a quaternary complex, FT / fVIIa / TPFI / fXa, as described in Girard, T.J. and co-authors "Functional Significance of the Kunitz-type Inhibitory Domains of Lipoprotein-associated Coagulation Inhibitor" Nature, 336. 516-520 (1989). It has been reported that polypeptides derived from hematophagous organisms are highly potent inhibitors and factor Xa specific. U.S. Patent 4,588,587 discloses anticoagulant activity in the saliva of the Mexican leech, Haementeria officinalis. He was demoed by Nutt E. and coautoree, "The Amino Acid Sequence of Antistasin, a Potent Inhibitor of Factor Xa Reveáis to Repeated Internal Structure", J. Biol. Chem., 263, 10162-1C167 (1988) that a major component of this saliva was the factor inhibitor polypeptide Xa, antistaein (ATS). Another potent and highly specific factor Xa inhibitor, termed the tick anticoagulant peptide (TAP), has been isolated from the total body extract of the soft tick Omithidoroe moubata. according to Waxman, L. and co-authors, "Tick Anticoagulant Peptide (TAP) is a Novel Inhibitor of Blood Coagulation Factor Xa", Science, 248. 593-596 (1990). Other polypeptide types of factor Xa inhibitors have been reported, including the following: Condra, C. and co-authors, "Iolation and Structural Characterization of a Potent Inhibitor of Coagulation Factor Xa from the Leech Haementeria ghilianii" .. Tromb. Haemost. , 6__ 437-441 (1989); Blankenehip, D.T. and co-authors, "Amino Acido Sequence of Haementeria ghillianii ", Biochem Biophys. Res.

Commun. 166. 1384-1389 (1990), Brankamp, R.G. and coauthors, "Ghilantene: Anticoagulants, Antimetastatic Protein from the South American Leech Haementeria ghilianii". J. Lab. Clin. Med. 115. 89-97 (1990); Jacobs, J.W. and co-authors, "Isolation and Characterization of a Coagulation Factor Xa Inhibitor from Black Fiy Salivary Glands", Thromb. Haemost., 64. 235-238 (1990); Rigbi, M. and co-inventors, "Bovine Factor Xa Inhibiting Factor and Pharmaceutical Compositione Containing the Same", European patent application 352,903; Cox, A.C. "Coagulation Factor X Inhibitor From the Hundred-pace Snake Deinagkistrodon acutus. Veno", Toxicon, 31, 1445-1457 (1993); Cappello, M. and coauthors, "Ancylostoma Factor Xa Inhibitor: Partial Purification and its Identification as a Major Hookworm-derived Anticoagulant In Vitro", J. Infect. Dls., 167. 1474-1477 (1993); Seymour, J.L. and co-author, "Ecotin is a Potent Anticoagulant and Reversible Tight-binding Inhibitor of Factor Xa", Biochemistry, 33, 3949-3958 (1994). Factor Xa inhibitor compounds that are not inhibitors of the long polypeptide type have been reported, inter alia, by: Tlawell, R.R. and coauthors, "Strategiee for Anticoagulation With Synthetic Protease Inhibitors, Xa Inhibitors Versus Thrombin Inhibitors", Thromb. Res. 19, 339-349 (1980); Turner, A.D. and co-authors, "p Amidino Esters as irreversible Inhibitors of Factor IXa and Xa and Thrombin," Biochemistry, 25, 4929-4935 (1986); Hitomi, Y. and coauthors, "Inhibitory Effect of New Synthetic Protease Inhibitor (FUT-175) on the Coagulation Syetem", Haemoetaeie, 15, 164-168 (1985); Sturzebecher, J. and coautoree, "Synthetic Inhibitors of Bovine Factor Xa and Thrombin, Comparieon of Their Anticoagulant Efficiency", Thromb Res., 54, 245-252 (1989); Kam, C, M, and coauthors, "Mecanis Based Isocoumarin Inhibitor for Trypein and Blood Coagulation Serine Proteases; New Anticoagulants", Biochemistry 27, 2547-2557 (1988); Hauptmann, J. and coautoree, "Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitor", Thromb, Haemoet. 63, 220-223 (1990); Miyadera, A. and co-inventors, Japanese patent application JP 6327488; Nagahara, T. and coautoree, "Dibaeic (Amidinoaryl) Propanoyl Acid Derivativee and Novel Blood Coagulation Factor Xa Inhibitors", J. Med. Chem. 37, 1200-1207 (1994); Vlasuk, G.P. and co-inventors, "Inhibitore of Thromboeis", W0 93/15756; and Brunck, T.K. and co-inventors, "Novel Inhibitor of Factor Xa", W0 94/13693. Varioe enzyme inhibitors of the trypsin-like enzyme (such as trypsin, enterokinase, thrombin, calilcrein, plas ina, urokinase, plasminogen activators and the like) have been the subject of patent descriptions. For example, Austen and co-inventors, in U.S. Patent No. 4,593,018, disclose oligopeptide aldehydes that are specific inhibitors of enterokinase; Abe. And co-inventors, in U.S. Patent No. 5,153,176 discloses tripeptide aldehydes having inhibitory activity against multiple serine proteases, such as plasmin, thrombin, trypsin, kallikrein, factor Xa, urokinase, etc .; Brunck and co-inventors, in European Patent Publication WO 93/14779, disclose substituted tripeptide aldehydes which are specific inhibitors of trypsin; U.S. Patent No. 4,316,889, U.S. Patent No. 4,399,065, U.S. Patent No. 4,478,745, which decribe thrombin inhibitors which are arginine aldehydes; Balasubramanian and co-inventors, in U.S. Pat. No. 5,380,713, describes aldehyde dipeptide and tripeptide which are useful for antitrypsin and antithrombin activity; Webb and co-inventors, in U.S. Patent No. 5,371,072, disclose tripeptide derivatives of alfacetoamide as inhibitors of thrombin and thrombin; Gesellchen and co-inventors, in European Patent Publications 0479489A2 and 0643073 A, describe tripeptide thrombin inhibitors; Veber and coinventoree, in the European patent publication W0 94/25051, deduce 4-cyclohexylamine derivatives that selectively inhibit thrombin with respect to other tripeline-like enzymes; Tapparelli and coauthors, J. Biol. Chem. 268. 4734-4741 (1993) describe eelective boronic acid peptide derivatives as thrombin inhibitors. Alternatively, agents that inhibit the carboxylase enzyme, which depends on vitamin K, talee like coumarin, have been used to treat coagulation disorders. There is a need for effective therapeutic agents for the regulation of hemostasis and for the prevention and treatment of thrombus formation and other pathological processes in the vasculature, induced by thrombin, such as restenosis and inflammation.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to novel peptides and peptide analogues mimetic, pharmaceutically acceptable isomers, saltse, hydrate, eolvatoe and prodrug derivatives; and to those pharmaceutically acceptable compounds which have particular biological properties and which are useful as potent inhibitors and specific for the coagulation of blood in mammals. In another aspect, the invention relates to aspects for using these inhibitors as diagnostic reagents or as therapeutic agents for disease states in mammals, which have alterations in coagulation, for example, in the treatment or prevention of any acute syndrome of the coronary or cerebrovascular, thrombotic mediated, any thrombotic syndrome occurring in the venous system, any coagulopathy and any thrombotic complications associated with circulation or extracorporeal instrumentation, and for the inhibition of coagulation in biological samples. In certain embodiments, this invention relates to novel compounds containing arginine and an arginine mimetic, which are potently and eumably selective inhibitors of isolated factor Xa when assembled in the prothrombin complex. Eetoe compueetoe show selectivity towards factor Xa, unlike other proteins in the coagulation cascade (for example, thrombin, etc.) or the ribrinolytic cascade, and are useful as diagnostic reagents and as antithrombotic agents. In the preferred modality, the present invention provides compueetoe of the formula: where: = 0, 1, 2, 3, 4; n = 0, 1. 2, 3, 4; p = 0, 1, 2, 3, 4; q = 0, 1, 2, 3, 4; Y = NH, S, 0, CH2, CH-OH, CH2CH2, C = 0; A = piperidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, heteroaryl of 3 to 6 carbon atoms, or is absent; R? = H or alkyl of 1 to 3 carbon atoms; J = 0 or H2; R2 = H or alkyl of 1 to 3 carbon atoms; D - N, CH, NCH2, NCH2 CH2, CHCH2; R3 = H or alkyl of 1 to 3 carbon atom; E = 0 or H2; R * = H 0 CH 3; M = NH, N_CH3, 0, S, SO, SO2 or CH2 or absent eetá; 0 = piperidinyl, pyrrolidinyl, cycloalkyl of 3 to 8 carbon atoms, phenyl, substituted phenyl, naphthyl, pyridyl, or is absent; G = N, CH or H; Rs - H or alkyl of 1 to 3 carbon atoms, or is absent if G is H; Rs = H or CH3; U = is selected from the group consisting of where N = 0-4; 7 and Re are independently selected from a group consisting of H, alkyl of 1 to 10 carbon atoms, aryl, arylalkyl, halogen, nitro, an amino group of the formula -NR 9 R 10, an acylamino group of the formula -NHCORi 1, hydroxy, an acyloxy group of the formula -OCOR12, alkyloxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, trifluoromethyl, carboxy, cyano, phenyl, an aromatic heterocyclic group, alkyloxycarbonyl of 1 to 4 carbon atoms , an aminocarbonyl group of the formula CONR13R14, eulfo, sulfonamido of the formula SO2NR15R16 and hydroxyalkyl of 1 to 6 carbon atoms; wherein R9, Rio, R11, R12, R13, RIA, RIS, Rie are the same or different and are equal to H, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 3 carbon atoms or aryl; and if M is absent: K = C or N; W = H, arylacil, heteroarylacyl, aryl-C1-3-sulfonyl, arylsulfonyl, arylsulfonyl, substituted, aryl-alkenyl, C1-4-sulphonyl, alkyl-C-e-sulfonyl, heteroaryl-C1-3-alkylsulfonyl, heteroarylsulfonyl , aryloxycarbonyl, Ci-β -carbonyl alkyloxy, aryl-C?-3-carbonyl alkyloxy, arylaminocarbonyl, Ci-β-aminocarbonyl alkyl, C 1-3 arylalkyl-aminocarbonyl, HOOC-C 0-3 alkylcarbonyl, or absent if G ee H; X = H, alkyl of 1 to 3 carbon atoms, NR'R ", NHC (NR'R") = NH, NH-C (NHR ') = NR ", NH-C (R') = NR", SC (R 'R ") = NH, SC (NHR') = NR", C (NR'R ") = NH, C (NHR ') = NR" or CR' = NR "; where R ', R "are the same or different and are H, alkyl of 1 to 6 carbon atoms, arylalkyl of the 3 carbon atom, aryl, or where R'R" forms a cyclic ring containing (CH2) p, where p = 2-5, as long as, when X is H or alkyl of 1 to 3 carbon atoms, then A must contain at least one N atom.; Z = H, alkyl of 1 to 3 carbon atoms, NR'R ", NHC (NR'R") = NH, NH-C (NHR ') = NR ", NH-C (R') = NR"; SC (NR'R ") = NH, SC (NHR ') = NR", C (NR'R ") = NH, C (NHR') = NR" or CR '= NR "; where R', R "are the same or different and are H, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 3 carbon atoms, aryl; or where R'R "forms a cyclic ring containing (CH2) p, where p = 2-5, as long as, when Z is H or alkyl of 1 to 3 carbon atoms, then 0 must contain at least minus one N atom; and all isomers, their salts, their hydrates, their solvates and their prodrug pharmaically acceptable derivatives. In certain aspects of this invention, compounds are provided that are useful as diagnostic reagents. In another aspect, the present invention includes pharmaical compositions that comprise a pharmaically effective amount of the compounds of this invention and a pharmaically acceptable carrier. In yet another aspect, the present invention includes methods comprising the use of the above compounds and the above pharmaical compositions to prevent or treat disease states characterized by alterations in the blood coagulation process in mammals; or to prevent coagulation in stored blood products and in stored blood samples. Optionally, the methods of this invention comprise administering the pharmaical composition in combination with an additional therapeutic agent, such as an antithrombotic agent and / or a thrombolytic agent and / or an anticoagulant. Preferred proteins also include their pharmaically acceptable isomers, hydrates, sol atoe, eals and prodrug derivatives.

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS According to the present invention and as used herein, the following terms are defined with the following meanings, unless explicitly stated otherwise: The term "alkenyl" refers to an unsaturated, straight chain aliphatic radical. or branched chain, trivalent. The term "alkyl" refers to saturated aliphatic groups, which include straight chain, branched chain and cyclic groups, having the specified number of carbon atoms or, if the number is not specified, having up to 12 carbon atoms . The term "cycloalkyl" when used herein, refers to a monocyclic, bicyclic or tricyclic aliphatic ring, having from 3 to 14 carbon atoms, and preferably from 3 to 7 carbon atoms. The term "aryl" refers to an unsubstituted or substituted aromatic ring, substituted with one, doe or three substituents selected from lower alkoxy, lower alkyl, lower alkylamino, hydroxy, halogen, cyano, hydroxyl, mercapto, nitro, thioalkoxy, carboxyaldehyde , carboxyl, carboalkoxy and carboxyamide; including, but not limited to: carbocyclic aryl, heterocyclic aryl and biaryl groups and the like; All of which may be optionally substituted. Preferred aryl groups include: phenyl, halogenophenyl, lower alkyl-phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl and aromatic heterocyclic. The term "heteroaryl," as used in the preamble, refers to any aryl group containing 1 to 4 heteroatoms, selected from the group that connects nitrogen, oxygen and sulfur. The term "arylalkyl" refers to one, two or tree aryl groups having the number of carbon atoms designated, attached to an alkyl group having the number of carbon atoms denoted. Suitable arylalkyl groups include, but are not limited to: benzyl, picolyl, naphthyl ethyl, phenethyl, benzhydryl, trityl and the like, all of which may optionally be substituted. The term "halo" or "halogen", when used herein, refers to substituents Cl, Br, F or I. The term "methylene" refers to -CH2-. The term "pharmaically acceptable saltse" includes the salts of the compounds derived from the combination of a compound and an organic or inorganic acid. These compounds are useful in both the free base form and the salt form. In practice, the use of the salt form counts for the use of the base form; both acid addition and base addition salts are within the scope of the present invention. "Pharmaically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically undesirable or otherwise, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, acid sulfuric acid, nitric acid, foephoric acid and the like; and with organic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, acid methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and similaree. The "pharmaceutically acceptable bae addition salts" include lae derived from inorganic lae baeee, such as the salts of eodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and similar. The ammonium, potassium, eodium, calcium and magnesium saltse are particularly preferred. Lae ealee derived from pharmaceutically acceptable non-toxic organic bacteria include the salts of primary, secondary and tertiary amines, amine substituted amines which include the naturally occurring substituted amines, cyclic amine and alkaline ion exchange lae, talen as resin. ieopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lieine, arginine, histidine, caffeine, procaine, hydraraine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine , N-ethylpiperidine, polyamine and the like. The non-toxic organic bases, particularly preferred, are: isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline and caffeine. "Biological property" for the purposes herein, means an effector or antigenic activity or activity in vivo, which is effected directly or indirectly by a compound of this invention. The effector functions include the binding to the receptor or ligand, any enzymatic activity or any enzyme-regulating activity, any carrier-binding activity, any hormonal activity, any activity to promote or inhibit the transfer of cells to an extracellular matrix or to a molecule of cell surface or any structural paper. Antigenic functions include the possession of an epitope or an antigenic site that is capable of reacting with the antibodies that confront it. The nomenclature used to describe the peptide compounds of the invention follows conventional practice, where it is assumed that the N-terminal amino group is on the left and the carboxy group on the right of each amino acid residue in the peptide. In the formulas representing selected specific embodiments of the present invention, the amino and carboxy termini groups, although often not specifically shown, will be understood to be in the form they would assume at physiological pH values, unless specified. otherwise. Thus, N-terminal H + 2 and 0-C-terminal at physiological pH are understood to be present, although not necessarily specified or shown, either in specific examples or in generic formulas. The free functional groups, in the side chains of the amino acid residues, can also be modified by amidation, acylation or other substitution, which, for example, can change the solubility of the compounds without affecting their activity. In the peptides herein defined, each residue encoded by gene, when appropriate, is repreened by a single-letter designation, which corresponds to the trivial name of the amino acid, according to the following conventional list: Amino Acid Symbol Symbol of an eola letter three letters Alanine A Wing Arginine R Arg Asparagine N Asn Aspartic Acid D Asp Cysteine C Cys Glutamine 0 Gln Glutamic Acid Glu Glycine G Gly Hietidine H Ieoleucine I He Leucine L Leu L Kine L Methy M Methelin M Phenylalanine F Phe Proline P Pro Serine S Be Threonine T Thr Tryptophan W Trp Tyrine And Tyr Valine V Val Additionally, the following abbreviations are given in this application: "Ala" refers to L-alanine. "D-Ala" refers to D-alanine. "Arg" refers to L-arginine. "D-Arg" refers to D-arginine. "Bn" refers to benzyl. "t-Boc" refers to te r-butoxy carboni lo. "BOP" refers to benzotriazol-1-yloxy-tris- (dimethylamine) phosphonium hexafluorophosphate. "Cbz" refers to benzyloxycarbonyl. "DCM" refers to dichloromethane. "DIEA" refers to di-isopropylethylamine. "DMF" refers to N, N-dimethyl ormamide. "EDC" refers to ethyl-3- (3-dimethylamino) -propylcarbodiimide hydrochloride. "EtOAc" refers to ethyl acetate. "Gly" refers to glycine. "HOSu" refers to N-hydroxysuccinimide. "D-Lye" refers to D-lysine. "MeOH" refers to methanol. "MeSEt" refers to methylethyl sulfide. "NaOAc" refers to sodium acetate. "Ph" refers to phenyl. "D-Pro" refers to D-proline. "Pro" refers to L-proline. "TEA" refers to triethylamine. "TFA" refers to trifluoroacetic acid. "THF" refers to tetrahydrofuran. "Cough" refers to p-toluene sulfonic acid. The non-genetically encoded amino acids are abbreviated as described above or have the genes commonly accepted in the field. In the compounds of this invention, the carbon atoms bonded to four non-identical substituents are asymmetric. Consequently, the compounds can exist as diastereoisomers, enantiomers or mixtures thereof.

The syntheses described herein may employ racemates, enantiomer or diastereomers as starting materials or as intermediates. The diaetereomeric oroductoe which are the result of said synthesis can be separated by chromatographic methods or by crystallization methods, or by other methods known in the art. In the same way, mixtures of enantiomeric products can be separated using the same techniques or by other methods known in the field. Each of the asymmetric carbon atoms, when present in the compositions of this invention, may be in one of configurable (R or S) or both and be within the scope of the present invention. In certain preferred specific embodiments of the compounds shown in the present invention, the L-form of any amino acid residue, having an optical omer, which is to be referred to, unless the D-form is expressly indicated. As described above, the final product, in some cases, may contain a small amount of the products that have D or L residue; However, these products do not affect their therapeutic or diagnostic application. The compounds of the present invention are peptides or compounds containing amino acid subunit which are partially defined in terms of amino acid residues of the designated classes. The amino acid residues can generally be grouped into four main eubclases, as follows: Acidoe: the residue has a negative charge due to the loss of the H ion at physiological pH, and the residue is attracted by aqueous solution.

Bacic: the residue has a positive charge due to the association with the H ion at physiological pH, and the residue is attracted by the aqueous solution. Neutral / non-polar: the residuals are not loaded at physiological pH and the residue is repelled by the aqueous solution, so that they look for internal poeicionee in the conformation of a peptide in which it is contained when the peptide is in aqueous medium, these residues are designated herein "hydrophobic". Neutral / polar: the residues are not charged to the physiological pH, but the residue is attracted by the aqueous solution so that they look for the external positions in the conformation of a peptide in which they are contained, when the peptide is in an aqueous medium. Of course, it will be understood that, in a molecular collection of molecules, individual molecules, some molecule will be charged and some will not, and there will be an attraction or rejection of an aqueous medium, to a greater or lesser degree. To adjust the definition of "loaded" a significant percentage (at least about 25%) of the individual molecules are charged to the phiological pH. The degree of attraction or rejection required for the classification as polar or non-polar is arbitrary and, consequently, the amino acids contemplated specifically by the invention have been classified in one or the other sense. Most amino acids that are not specifically named can be classified on the basis of their known behavior. The amino acid residues may additionally be cyclized or non-cyclic and aromatic or non-aromatic, classifications that are explained by the member with respect to the constituent group of the side chain of the residues, and whether the chain is small or large. The residue is considered small if it contains a total of four carbon atoms or less, including the carboxyl carbon. The small residues, of course, are always non-aromatic for the amino acids of the proteins that occur in nature. For the amino acids of the proteins that occur in nature, the classification is carried out according to the following scheme: Acids: aspartic acid and glutamic acid; Basic / non-cyclic: arginine, lieine; Basic / cyclic: hietidine; Neut / small: glycine, serine, cysteine, alanine; Neutral / polaree / grandee / non-aromatic: threonine, asparagine glutamine; Neut ros / pola res / grandes / aromáticoe: tiroeina; Neutroe / no polarea / grandee / no aromatic: valine, ieoleucine, leucine, methionine; Neutral / non-polar / large / aromatieos: phenylalanine and tryptophan. The secondary amino acid proline, encoded by genes, even though it is technically within the group of neutral / non-polare / grandee / cyclic and non-aromatic, is a special case because of its known effect on the secondary conformation of the peptide chains and, therefore, it is not included in this defined group. Certain amino acids that are commonly found, which are not encoded by the genetic code, include, for example: beta-alanine (b-Ala) or other omega-amino acids, such as 2,3-diamino propionic (2,3-Dap) 2, 4-diaminobutyl rich (2,4-Dab), 4-aminobutyl rich (g-Abu) and so on; alpha-aminoieobutyral acid (Aib), earcosine (Sar), ornithine (Orn), citrulline (Cit), homoarginine (Har) homoliein (homoLye), n-butylamidinoglycine (Bag), 4-guanidinophenylalanine (4-Gpa), 3 -guanidinophenylalanine (3-Gpa), 4-amidinophenylalanine (4-Apa), 3-amidinophenylalanine (3-Apa), 4-aminocyclohexylglycine (4-Acg), 4-aminophenylalanine (4-NH2-Phe), 3-aminophenylalanine ( 3-NH2-Phe), 3- (3-pyridyl) Ala (3-Py-Ala), 3- (3-piperidinyl) -Ala (3-Pip-Ala), 3- (3-Me-3-pyridyl) ) -Ala (3-Me-3-Py-Ala), 3- (4-pyridyl) -Ala (4-Py-Ala), 3- (4-piperidinyl) -Ala (4-Pip-Ala), 3 (3-amidino-3-piperidinyl) Ala (3-amidino-3-Pip-Ala), 3- (4-amidino-4-piperidinyl) Ala (4-amidino-4-Pip-Ala), 4-aminomethylphenylalanine ( 4H2NCH2-Phe), and 4-aminomethylphenylglycine (4H2NCH2-Phg). These also fall within particular categories. Based on the above definitions: Sar, b-Ala, g-Abu and Aib are neut ros / pequee; Orn, Har, homoLye, Bag, 2,3-Dap, 2,4-Dab, 4-Gpa, 3-Gpa, 4-Apa, 3-Apa, 4-Acg, 4-NH2-Phe, 3-NH2- Phe, they are basic: Cit is neutral / polar / large / non-aromatic; and the various omega-amino acids are classified according to their size as neutral / non-polaroid / small (b-Ala, ie, 3-aminopropionic, 4-aminobutyl) or grandee (all others). The substitutions of amino acids for those indicated in the structure / formula provided can be included in compueetoe peptides within the scope of the invention, and can be classified within that general scheme according to their structure. In all of the peptides of the invention, one or more amide bonds (-C0-NH) can be optionally replaced by another ligation that is isoetherea, such as -CH2NH-, -CH2S-, -CH2CH2, -CH = CH- (cis and trans), -COCH2-, -CH (0H) CH2- and -CH2SO-. This replacement can be effected by methods known in the art. The following references describe the preparation of peptide analogs that include eeae alternative linker portions: Spatola, A.F. Vega Data (March 1983), volume 1, expedition 3, "Peptide Backbone Modifications" (general summary); Spatola, A.F. in "Chemietry and Biochemistry of Amino Acids, Peptides and Proteine", B. Weinetein, editors, Marcel Dekker, New York, page 267 (1983) (general summary); Morley, J.S. Trends Pharm Sci (1980). pages 463-468 (general summary); Hudson, D. and coauthors, Int J Pept Prot Res (1979) 14: 177-185 (-CH2NH-, -CH2CH2-); Spatola, A.F. and co-authors, Life ', < .! U986) ¿ü: 11-4 '? - 12A i¡t-CI-2 ^) i -ann. M.M. J. (; hern r. C Beijing Ti an ° (i 98?) -H 7-3 l 4 i - GH = CH-, is y + r-.n =]; ?? l? N.- | u ? s +, RG and co-authors J ried Chom 'J 990) J3: i ".92 ~ 1398 f" 0CH2 -'; Jen mgs-Uhite, C. and ro u + o? is 1 .- + raho r I * .. tt (19B?) -: 2 13 (-COCH2); Szell-e, t. and coi ventores, European application EP 45665; CR: 9 _: 39405 (19821 (-rH (OH) OH2 -); Hollad y, HU Te + ra he ett > I9..3J J - '• * 01 - • - •' + IH 'í ( OH'CH2- i; V llruby,. '.3. Life C, C1 (1982) 31: IHQ-l'-jg í' H2"L < PREFERRED MODALITIES In the preterm modalities, the present and in tion provides compounds of the formula: where: m = 0, 1, 2, 3, 4; n = 0, 1, 2, 3, 4; p = 0, 1, 2, 3, 4; q = 0, 1, 2, 3, 4; Y = NH, S, 0, CH2, CH-OH, CH2CH2, C = 0; A = piperidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, heteroaryl of 3 to 6 carbon atoms, or is absent; R? = H or alkyl of 1 to 3 carbon atoms; J = 0 or H2; R2 = H or alkyl of 1 to 3 carbon atoms; D = N, CH, NCH2. NCH2CH2, CHCH2; R3 = H or alkyl of 1 to 3 carbon atoms; E = O 0 H2; RA = H or CH3; M = NH, N_CH3, 0, S, SO, SO2 or CH2 or absent eetá; 0 = piperidinyl, pyrrolidinyl, cycloalkyl of 3 to 8 carbon atoms, phenyl, substituted phenyl, naphthyl, pyridyl, or is absent; G = N, CH or H; R5 = H or alkyl of 1 to 3 carbon atoms, or is absent if G is H; Ré = H or CH 3; U = is selected from the group you were connected to where N = 0-4; R? and R <e> is independently selected from a group that connects H, alkyl of 1 to 10 carbon atoms, aryl, arylalkyl, halogen, nitro, an amino group of the formula -NR9 0, an acylamino group of the formula -NHCOR11, hydroxy , an acyloxy group of the formula -OCOR12, alkyloxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, rifluoromethyl, carboxy, cyano, phenyl, an aromatic heterocyclic group, as defined below, alkyloxycarbonyl of 1 to 4 carbon atoms, an aminocarbonyl group of the formula CONR13R1-;, sulfo, eulfonamido of the formula SO2NR15R16 and hydroxyalkyl of 1 to 6 carbon atoms; wherein R9, Rio, R11, R12, RA, Rie, Rie are the same or different and are equal to H, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 3 carbon atoms or aryl; and if M is absent: With; W = H, arylacyl, heteroarylacyl, aryl-C1-3-alkylsulfonyl, arylsulfonyl, substituted arylsulfonyl, aryl-alkenyl, C1-4-sulphonyl, Ci-s-alkylsulfonyl, heteroaryl-C3-alkylsulfonyl, heteroarylenesulfonyl, aryloxycarbonyl, C1-6alkyloxycarbonyl, aryl-C1-3alkyloxycarbonyl, arylaminocarbonyl, Ci-e-aminocarbonylkylaryl, C1-3alkylamino-aminocarbonyl, HOOC-Co-3-carbonyl-alkyl, or eetá aueente ei G es H; X = H, alkyl of 1 to 3 carbon atoms, NR'R ", NHC (NR'R") = NH, NH-C (NHR ') = NR ", NH-C (R') = NR", SC (NR 'R ") = NH, SC (NHR') = NR", C (NR'R ") = NH, C (NHR ') = NR" or CR' = NR "; where R ', R "are equal or different and are H, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 3 carbon atoms, aryl, or where R'R" forms a cyclic ring containing (CH2) p, wherein = 2-5, as long as, when X is H or alkyl of 1 to 3 carbon atoms, then A must contain at least one N atom; Z = H, alkyl of 1 to 3 carbon atoms, NR ' R ", NHC (NR'R") = NH, NH-C (NHR ') = NR ", NH-C (R') = NR"; SC (NR'R ") = NH, SC (NHR ') = NR ", C (NR'R") = NH, C (NHR ') = NR "or CR' = NR"; wherein R ', R "are the same or different and are H, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 3 carbon atoms, aryl, or where R'R" forms a cyclic ring containing (CH2) ) p, where p = 2-5, as long as, when Z is H or alkyl of 1 to 3 carbon atoms, then 0 must contain at least one N atom; and its isomers, its saltse, its hydrates, its solvates and its prodrug pharmaceutically acceptable derivatives. Some preferred compounds of the present invention include those of the formula where: m = 0, 1, 2, 3, 4; n = 0, 1, 2, 3, 4; p = O, 1, 2, 3, 4; q = O, 1, 2, 3, 4; Y = NH, S, O, CH2, CH-OH, CH2CH2, C = 0; A = piperidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, heteroaryl of 3 to 6 carbon atoms, or aether; M = NH, N-CH3, 0, S, SO, SO2 or CH2 or absent eetá; Q = piperidinyl, pyrrolidinyl, cycloalkyl of 3 to 8 carbon atoms, phenyl, substituted phenyl, naphthyl, pyridyl, or is absent; U = is selected from the group that connects where N = 0-4; R7 and Re are independently selected from a group that connects H, alkyl of 1 to 10 carbon atoms, aryl, arylalkyl, halogen, nitro, an amino group of the formula -NR9R10, an acylamino group of the formula -NHCORn, hydroxy , an acyloxy group of the formula -OCOR12, alkyloxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, trifluoromethyl, carboxy, cyano, phenyl, an aromatic heterocyclic group, as defined below, alkyloxycarbonyl of 1 to 4 carbon atoms, an aminocarbonyl group of the formula CONR13R14, sulfo, sulfonamido of the formula SO2NR15R16 and hydroxyalkyl of 1 to 6 carbon atoms; wherein R9, Rio, R11, R12, A, R15, R1 are the same or different and are equal to H, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 3 carbon atoms or aryl; and if M is absent: K = C or N; W = H, arylacyl, heteroarylacyl, aryl-C1-3-sulfonyl, arylsulfonyl, substituted arylsulfonyl, aryl-alkenyl of C? - «-sulfonyl, Ci-β-sulfonyl alkyl, heteroaryl-C3-sulphonyl-alkyl, heteroarylsulfonyl, aryloxycarbonyl, Ci-β -carbonyl alkyloxy, aryl-C?-3-carbonyl alkyloxy, arylaminocarbonyl, Ci-β-aminocarbonyl alkyl, Cι 3 -aminocarbonyl arylalkyl, HOOC-C alqu 3 alkyl- carbonyl, or absent if G ee H; X = H, alkyl of 1 to 3 carbon atoms, NR'R ", NHC (NR'R ") = NH, NH-C (NHR ') = NR", NH-C (R') = NR ", SC (NR'R") = NH, SC (NHR ') = NR " , C (NR'R ") = NH, C (NHR ') = NR" or CR' = NR "; wherein R ', R "is equal or different and is H, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 3 carbon atoms, aryl, or where R'R" forms a cyclic ring containing (CH2) ) p, where p = 2-5, as long as, when X is H or alkyl of 1 to 3 carbon atoms, then A must contain at least one N atom; Z = H, alkyl of 1 to 3 carbon atoms, NR'R ", NH-C (NR'R") = NH, NH-C (NHR ') = NR ", NH-C (R') = NR "; SC (NR 'R ") -NH, SC (NHR') = NR", C (NR'R ") = NH, C (NHR ') = NR" or CR' = NR "; wherein R ', R "are equal or different and are H, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 3 carbon atoms, aryl; or where R'R "forms a cyclic ring containing (CH2) p, where p = 2-5, as long as when Z ee H or alkyl of 1 to 3 carbon atoms, then Q must contain at least minus one atom of N, and its isomers, salts, hydrate, sueeolvatoe and its pharmaceutically acceptable prodrug derivatives A preferred Y component is S, 0, CH2, CH2CH2 A preferred e-analyte is piperidinyl, pyrrolidinyl, cyclopentyl, cyclohexyl , phenyl, heteroaryl of 3 to 6 carbon atoms, or absent eetá A preferred substituent D is N, CH, NCH2 A preferred substituent M is NH, 0, S, CH2, or is absent A preferred Q substituent is piperidinyl , pyrrolidinyl, cycloalkyl of 3 to 8 carbon atoms, phenyl, substituted phenyl, or is absent A preferred substituent U is selected from: where n = 0-2; R7 and Re are independently selected from a group consisting of H, alkyl of 1 to 10 carbon atoms, aryl, arylalkyl, halogen, nitro, trifluoromethyl, carboxy or cyano; and the M is absent: A preferred component K is ee C or N. A preferred component W is aryl-C1-3-alkylsulfonyl, arylsulfonyl, arylsulfonyl, substituted, aryl-alkenyl, C1-4-sulphonyl, Ci-β-sulfonyl alkyl, heteroarylalkyl, C1 -3-sulfonyl, heteroarylsulfonyl, Ci-β -carbonyl alkyloxy, C1-3 alkylaryloxycarbonyl. A preferred substituent X is NR'R ", NH-C (NR'R") = NH, NH-C (NHR ') = NR ", NH-C (R') = NR", SC (NR'R " ) = NH, SC (NHR ') = NR ", C (NR'R") = NH, C (NHR') = NR ", where R ', R" are the same or different and are H, alkyl of 1 to 6 carbon atoms A preferred substituent Z is NH-C (NR'R ") = NH, NH-C (NHR ') = NR", NH-C (R') = NR ", SC (NR 'R ") = NH, SC (NHR ') = NR", C (NR'R ") = NH, C (NHR') = NR"; where R ', R "are the same or different and are H, alkyl of 1 to 6 carbon atoms The preferred compound, as a whole, can be selected from any combination of the formulas presented in this application, with one or more of preferred groupings of substituents at a particular location Some preferred embodiments of the invention are shown in the following Table 1.

TABLE 1 Inhibitory activity (CIso) uM STRUCTURE Factor Xa Prothrombinase Thrombin HD-Arg-Gly-Arg-thiazole 0.011 0.010 41 BnS? 2- (D) -Arg-Gly-Arg-thiazole 0.00065 0.00045 Other preferred compounds of the present invention are shown, but are not limited to the following list of compuets , which have the general structure: W - (basic amino acid) - (neutral / small amino acid) - (Arg or basic amino acid) - heterocycle. PhCH5CH2-S? 2- (D) -Arg-Gly-Arg-thia2: ol C6HnCH2CH2-S02- (D) -Arg-Gly-Arg-thiazole Me2C-C6H4S02- (D) -Arg-Gly-Arg-thiazole C ? oH7S? 2- (D) -Arg-Gly-Arg-thiazole Mß3SiCH2CH2CH2S02- (D) -Arg-Gly-Arg-thiazole BnS? 2- (D) -4-Apa-Gly-Arg-thiazole BnS? 2 - (D) -4-Gpa-Gly-Arg-thiazole BnS02 - (D) -Acg-Gly-Arg-thiazole BnS? 2 - () -homo-Lys-Glyrg-thiazole BnS? 2- (D) - Arg-Sar-Arg-thiazole BnS02- (D) -Arg-Pro-Arg-thiazole BnS02- (D) -Arg-Gly-4-Acg-thiazole BnS02- (D) - rg-Gly- (3-NH2Phe) -thiazole BnS02- (D) -Arg-Gly- (4-NH2Phe) -thiazole BnS02- (D) -Arg-Gly-Gpa-thiazole Boc-D- (2,3-Dap) -Gly-Arg-thiazole Boc-D- (2,4-Dab) -Gly-Arg-thiazole g-Abu-Gly-Arg-t-aiazole Boc-D-Orn-Gly-Arg-thiazole Boc-D-homoLye -Gly-Arg-t-azole Boc-Bag-Gly-Arg-thiazole Boc-D-4-Gpa-Gly-Arg-thiazole Boc-D-3-Gpa-Gly-Arg-thiazole Boc-D-4-Apa-Gly-Arg-t-iazole Boc -D-3-Apa-Gly-Arg-iazole Boc-D-4-Acg-Gly-Arg-thiazole Boc-D- (4-NH2Phe) -Gly-Arg-thiazole Boc-D- (3-NH2Phe) - Gly-Arg-thiazole BnS02-D- (2,3-Dap) -Gly-Arg-thiazole BnS? 2-D- (2,4-Dab) -Gly-Arg-thiazole BnS02-D-0rn-Gly-Arg -thiazole BnS02-Bag-Gly-Arg-thiazole BnS02-D-3-Gpa-Gly-Arg-thiazole BnS? 2 -D-3-Gpa-Gly-A rg-thiazole BnS02-D-0rn-Gly-Arg- thiazole BnSO? -Bag-Gly-Arg-thiazole BnS? 2-D-3-Gpa-Gly-Arg-thiazole BnS? 2 -D-3-Gpa-Gly-A rg-thiazole BnS? 2-D- (4-NH2Phe) -Gly-Arg-thiazole BnS? 2-D- (3-NH2Phe) -Gly-rg-thiazole BnS? 2 -D- (2,3-Dap) -Gly-Arg-benzothiazole BnS? 2 -D- (2 , 4-Dab) -Gly-Arg-benzothiazole BnS02-D-0rn-Gly-Arg-benzothiazole BnS? 2-Bag-Gly-Arg-benzothiazole BnS? 2-D-4-Gpa-Gly-Arg-benzothiazole BnS? 2 -D-3-Gpa-Gly-Arg -benzothiazole BnS? 2 -D-4-Apa-Gly-A rg-benzothiazole BnS? 2 -D-3-Apa-Gly-A rg-benzothiazole BnS? 2-D-4-Acg-Gly-A rg-benzothiazole BnS02-D- (4-NH2Phe) -Gly-A rg-benzothiazole BnS? 2-D- (3-NH2Phe) -Gly-A rg-benzothiazole BnS02-D-Arg-Gly- (2,4-Dab) -benzothiazole BnS02-D-Arg-Gly- (homoLys) -benzothiazole BnS02-D- Arg-Gly- (4-Gpa) -benzothiazole BnS02-D-Arg-Gly- (3-Gpa) -benzothiazole BnS02-D-Arg-Gly- (4-Apa) -benzothiazole BnS? 2 -DA rg-Gl and - (3-Apa) -benzothiazole BnS? 2-D-Arg-Gly- (4-NH2Phe) -benzothiazole BnS02 -D-A rg-Gl y- (3-NH Phe) -benzothiazole Me3SiCH2CH2CH2S02- (D) -A rg-Gly-rg -benzothiazole BnS02- (D) -homo-Lys -Gly-rg-benzothiazole BnS02 - (D) -homo-Lye -Gly -Arg -benzoxazole PhCH2CH2S02- (D) -Arg-Gly-Arg-benzothiazole BnS? 2 - (D) -A rg-Sar-rg-benzothiazole BnS? 2 - (D) -A rg-Pro-A rg-benzothiazole BnS? 2- (D) -Arg-Gly-Acg-benzothiazole BnS? 2- (D) -A rg-Gly-Arg -benzo ti azole PhCH2CH2S? 2- (D) -Arg-Gly-4-Acg-benzothiazole BnS02 - (D) -Arg-Glyrg-oxazole Boc-D- (2,3-Dap) -Gly-rg-oxazole Boc-D- (2,4-Dab) -Gly-rg-oxazole g-Abu -Gly-Arg-oxazole Boc-D-Orn-Gly-Arg-oxazole Boc-D-homoLye-Gly-Arg-oxazole Boc-Bag-Gly-Arg-oxazole Boc-D-4-Gpa-Gly-Arg-oxazole Boc-D-3-Gpa-Gly-A rg-oxazole Boc-D-4-Apa-Gly-A rg-oxazole Boc-D-3-Apa-Gly-A rg-oxazole Boc-D-4-Acg- Gly-A rg-oxazole Boc-D- (4-NH2 Phe) -Gly-A rg-oxazole Boc-D- (3-NH2 Phe) -Gly-A rg-oxazole BnS02-D- (2,3-Dap ) -Gly-Arg-oxazole BnSO? -D- (2, -Dab) -Gly-A rg-oxazole BnSO? -D-Orn-Glyrg-oxazole BnS02-Bag-Gly-A rg-oxazole BnS02 -D-3-Gpa-Gly-A rg-oxazole BnS02 -D-3-Apa-Gly-A rg-oxazole BnS02 - D- (4-NH2 Phe) -Gly-Arg-oxazole BnS? 2 -D- (3-NH2 Phe) -Gly-A rg-oxazole BnS02-D- (2,3-Dap) -Gly-rg-oxazole BnS02-D- (2,4-Dab) -Gly- rg-oxazole BnS02 -D-0 rn-Gly-A rg-oxazole BnS02-Bag-Gly-A rg-oxazole BnS? 2 -D-4 -Gpa-Gly-A rg-oxazole BnS02 -D-3-Gpa - Gly-A rg-oxazole BnS02-D-4-Apa-Gly-A rg-oxazole BnS02-D-3-Apa-Gly-A rg-oxazole BnSO? -D- -Acg-Gly-A rg-oxazole BnS? 2-D- (4-NH2 Phe) -Gly-A rg-oxazole BnS? 2-D- (3-NH2 Phe) -Gly-rg-oxazole BnSO ? D-A rg-Gly- (2,4-Dab) -oxazole BnS02 D-A rg-Gly- (ho oLys) -oxazole BnS02D-Arg-Gly- (4-Gpa) -oxazole BnSO? D-A rg-Gly- (3-Gpa) -oxazole BnS02 D-A rg-Gly- (4-Apa) -oxazole BnSO? D-A rg-Gly- (3-Apa) -oxazole BnS? 2 D-A rg-Gly- (4-NH2Phe) -oxazole BnS? 2D-Arg-Gly- (3-NH2Phe) -oxazole BnS? 2 -D- (2, 3-Dap) -Gly-A rg-benzoxazole BnS? 2-D- (2,4-Dab) -Gly-rg-benzoxazole BnS? 2 -D-Orn-Glyrg -benzoxazole BnS02-Bag-Gly-rg-benzoxazole BnS02 -D-4 -Gpa -Gly-A rg-benzoxazole BnS? 2 -D-3-Gpa-Gly-Arg-benzoxazole BnS02 -D-4-Apa-Gly- A rg-benzoxazole BnS02-D-3-Apa-Gly-A rg-benzoxazole BnS? 2-D-4-Acg-Gly-A rg-benzoxazole BnS02-D- (4-NH2 Phe) -Gly-rg-benzoxazole BnS02 -D- (3-NH Phe) -Gly-A rg-benzoxazole BnSO? D-A rg-Gly- (2,4-Dab) -benzoxazole BnS02 D-A rg-Gly- (homoLye) -benzoxazole BnSO? D-A rg-Gly- (4 -Gpa) -benzoxazole BnSO? DA rg-Gly- (3-Gpa) -benzoxazole BnS? 2 DA rg -Gl and- (4 -Apa) -benzoxazole BnS02 DA rg-Gly- (3 -Apa) -benzoxazole BnS02 DA rg-Gly- (4 - NH2 Phe) -benzoxazole BnS02 DA rg-Gly- (3-NH2 Phe) -benzoxazole ß3 SICH2 CH2 CH2 SO2 - (D) -A rg-Gly-A rg-Benzoxazole BnS02 -D-homo-Lye -Gly-A rg -benzoxazole BnS02-D-homo-Lys-Gly-A rg-benzoxazole PhCH2CH2S? 2- (D) -A rg-Gly-A rg-Benzoxazole BnS? 2 - (D) -A rg-Sa rA rg-benzoxazole BnS 2- (D) -Arg-Gly-Acg-benzoxazole BnS02- (D) -A rg-Gly-A rg-benzoxazole PhCH2 CH2 SO2 - (D) -A rg-Gly-4-Acg-Benzoxazole BnS02- ( D) -Arg-Glyrg-benzoxazole BnS02- (D) -Arg-Gly-Acg-benzoxazole PhCH2 CH2 SO2 - () -A rg-Gly-4-A rg-benzoxazole PhCH2CH2S? 2- (D) - Arg-Gly-4-Acg-benzoxazole Mß3SiCH2CH2CH2S02- (D) -A rg-Gly-A rg-benzoxazole BnSO? - (D) -A rg-Gly-A rg-oxazoline Boc -D- (2, 3 -Dap) -Gly -A rg-oxazole i na Boc-D- (2,4-Dab) -Gly -Arg -oxazol i na g-Abu-Gly-A rg-oxazole i na Boc-D-Orn-Gly-A rg-oxazoline Boc-D-homoLye -Gly-A rg-oxazole ina Boc-Bag-Gly-A rg- Oxazole I Boc-D-4-Gpa-Gly-A rg-oxazoline Boc-D-3-Gpa-Gly-A rg-oxazoline Boc-D-4-Apa-Gly-A rg-oxazoline Boc-D-3 -Apa-Gly-A rg-oxazole ina Boc-D-4-Acg-Gly-A rg-oxazole i na Boc-D- (4-NH2 Phe) -Gly-A rg-oxazole i na Boc-D- ( 3-NH2 Phe) -Gly-A rg-oxazole i na BnSO? -D- (2, 3-Dap) -Gly-A rg-oxazole ina BnS02-D- (2,4-Dab) -Gly-A rg-oxazoline BnS02-D-0rn-Gly-A rg-oxazoline BnS02- Bag-Gly-A rg-oxazoline BnS02-D-3-Gpa-Gly -A rg-oxazole na BnS02 -D-3-Apa-Gly-A rg-oxazoline BnS02-D- (4-NH2 Phe) -Gly -A rg-oxazoline BnS02-D- (3-NH2 Phe) -Gly-A rg-oxazole na BnS02-D- (2,3-Dap) -Gly-Arg-oxazoline BnS? 2-D- (2, 4-Dab) -Gly-rg-oxazol i na BnSO? -D-Orn-Gly-A rg-oxazoline BnS? 2 -Bag-Gly-Arg-oxazoline BnS? 2 -D-4-Gpa-Glyrg-oxazoline BnSO? -D-3-Gpa-Glyrg-oxazoline BnS? 2 -D-4-Apa-Gly-rg-oxazoline BnSO? -D-3-Apa-Glyrg-oxazoline BnS? 2 -D-4-Acg-Gly-Arg-oxazoline BnS02-D- (4-NH2Phe) -Gly-rg-oxazoline BnSO? -D- (3-NH2 Phe) -Gly-rg-oxazoline BnS02 -A rg-Gly- (2,4-Dab) -oxazol i na BnS? 2 DA rg-Gly- (omoLys) -oxazoline BnS02 DA rg- Gly- (4 -Gpa) -oxazole i na BnS? 2 DA rg-Gl y- (3-Gpa) -oxazoline BnSO? DA rg -Gl and - (4 -Apa) -oxazol i na BnS? 2 DA rg-Gly- (3-Apa) -oxazol i na BnS02 DA rg-Gly- (4-NH2 Phe) -oxazol ina BnS02D-Arg -Gly- (3-NH2Phe) -oxazoline BnS02- (D) -A rg-Gly-A rg-imidazole BnS02- (D) -A rg-Gly-A rg-pyridine BnS02- (D) -A rg-Gly -A rg-2- (l-methyl tet razol) BnS02- (D) -A rg-Gly-A rg-2- (4-methyl tet razol) MeS02- (D) -Arg-Gly-Arg-thiazole BnS02 - (D) - (4-H2NCH2 -Phe) -Gly-A rg-thiazole BnS02 - (D) - (4-H2 CH2 -Phg) -Gly- rg- iazole BnS02 - (D) - (3-Py- Ala)) -Gly-rg-thiazole BnS02 - (D) - (3-Me-3-Py-A la) -Gly-rg-thiazole BnS02 - (D) - (3-Pipla)) -Gly- rg-thiazole BnS02 - (D) - (4-Pip-Ala)) -Gly-A rg-thiazole BnS02 - (D) - (3-amidino-3-Pip-Ala)) -Gly-rg-thiazole. This invention also comprises prodrug derivatives of the compounds contained herein. The term "prodrug" refers to a pharmacologically inactive derivative of an original drug molecule, which requires biotransformation, whether eepontaneous or enzymatic, within the body to release the active drug. Prodrugs are variations or derivatives of the compounds of this invention which have metabolically dividing group and which, by means of eololysis under physiological conditions, or by enzymatic degradation, are transformed to the compounds of the invention which are pharmaceutically active in vivo. The prodrug compounds of this invention can be referred to as single, double, triple, etc., depending on the number of biotransformation steps required to release the active drug within the organism, and which indicate the number of functionalities present in a precursor type form. Pro-drug forms often offer advantages of solubility, tissue compatibility or delayed release in the mammalian organism (see Bundgard H. Dßsign of Prodrugs. pages 7 to 9, 21 to 24. Elsevier Amsterdam 1985 and P Silverman, R.B. The Organic Chemistry of Drug Deeper and Drug Action. pages 352 to 401, Academic Preee, San Diego, California, 1992). The prodrugs commonly known in the art include well-known acid derivatives by those who practice this technique, such as, for example, the esters prepared by reaction of the original acids with a suitable alcohol, or the amides prepared by reaction of the original acidic compound with a Amine, or group Baeicoe reacted to form an acylated base derivative. In addition, the prodrug derivatives of this invention can be combined with other preparations contemplated herein, to increase bioavailability.

PREPARATION OF THE COMPOUNDS The compounds of the present invention can be synthesized either by solid phase or liquid phase methods described in and referenced in ordinary textbooks, or by a combination of both methods. These methods are well known in the art. See Bodansky, M. in "The Principies of Peptide Synthesie," Hafner,., Rees, C.W., Trost, B.M., Lehn, J.M., Schleyer, P. v. R, Zahradnik, R., Editors, Springer-Verlag. Berlin, 1984. The starting materials are reactants obtainable commercially and the reactions are carried out in common laboratory glass artifacts, and in common reaction vessels and reaction conditions, including temperature and pressure. ambientalee normalee, a menoe that is indicated in another way. The ketoheterocyclic compounds of the present invention can be prepared by methods described by Dondoni, A and coautoree, Syntheeie, 1162-1176 (1993); Edwards, P.D. and coauthors, J. Amer. Chem. Soc. 114, 1854-1863 (1992); Tsuteumi, S. and coautoree, J. Med. Chem. 37, 3492-3502 (1994) (; and Ed arde, PD and coautoree, J. Med. Chem. 38, 76-85 (1995). Any of these methods are obtainable in the trade from sellers of chemical substances such as Aldrich, Sigma, Nova Biochemicale, Bachem Bioeciencee, and eimilaree, or they can be easily synthesized by known procedures. of the amino acid derivatives used in these methods are protected by blocking groups to prevent cross reaction during the coupling procedure Examples of suitable blocking groups and their use are described in "Peptides: Analysis, Synthesis, Biology", Academic Press, Volume 3 (Gross E. and Meienhofer, J. Editores, 1981) and volume 9 (1987), the description of which is incorporated herein by reference, and three diagrams of exemplary entities are immediately indicated below, and the specific synthesis are described in the examples. The reaction products are isolated and purified by conventional method, typically by solvent extraction, in a compatible solvent. The products can be further purified by column chromatography or other suitable methods.

SCHEME 1 H ° BnS? 8-.0) -Arg. { To? Ki.? . T] HF BnS02- (D) -Arg (Cough) -Gly-OH ^ L S- * Copulation \ NH MN NM-TOI SCHEME 2 P = protective group; R = protected amino acid with protective or substituted group or protected or substituted dipeptide unit.

THE COMPOSITIONS AND FORMULATIONS The compounds of this invention can be isolated as the free acid or the base or can be converted to salts of various inorganic and organic acids and organic and inorganic bases. Said salee is within the scope of this invention. Non-toxic and physiologically compatible lae eals are particularly useful, although other suitable salts may be used in the isolation and purification procedures. Many methods are useful for the preparation of the ealees described above and are known to those skilled in the art. For example, the reaction of the free acid or free base form of a compound of the above-mentioned ester with one or more molar equivalents of the desired acid or base in a solvent or a mixture of solvents, wherein the eal, or in an solvent such as water, after the solvent has been removed by evaporation, distillation or by freeze drying. Alternatively, the free acid or free form of the product can be passed over an ion exchange reactor to form the desired salt or a salt form of the product can be converted to another, using the same general procedure. Typically, diagnostic applications of the compounds of this invention will use formulations such as a solution or a suspension. In the management of thrombotic disorders, the compounds of this invention can be used in compositions such as tablets, capsules or elixirs for oral administration, suppositories, sterile solutions or suspensionee for injectable or similar administration, or they can be incorporated into formed articles. It can be administered to subjects in need of treatment (typically mammals), using the compounds of this invention, which provide maximum efficacy. The doeie and method of administration will vary from one subject to another and will depend on such factors as the type of mammal that is being treated, sex, diet, concurrent medication, general clinical condition, the particular protocols used, the specific use for which said compounds are used and of another fact, which will be recognized by technicians in the medical arts. The formulations of the compounds of this invention are prepared for storage or for administration, by mixing the compound having a desired degree of purity with carriers, excipients, stabilizers, physiologically acceptable, and can be provided in sustained release or delayed release formulations. . Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro editor, 1985). These materials are non-toxic to recipients at the doses and concentrations used, and include regulators such as phosphate, citrate, acetate and other organic acid salts.; antioxidants such as ascorbic acid, low molecular weight peptides (approximately menoe of ten residues), such as polyarginine; proteins, such as serum albumin, gelatin or immunoglobulinae; hydrophilic polymers such as polyvinyl pyrrolidinone; amino acids such as glycine, glutamic acid, aspartic acid or arginine; monosaccharides, disaccharides and other carbohydrates, including celluloea or its derivatives, glucose, mannose or dextrin; agent quelatadoree talee as EDTA; sugar alcohol, tap like mannitol or sorbitol; counter ions, tap as eodium and / or non-ionic surfactants such as Tween, Pluronics or polyethylene glycol. The dose formulations of the compounds of this invention that are to be used for therapeutic administration must be sterile. Sterility is easily achieved by filtration through sterile membranes, such as 0.2 micron membrane, or by other conventional methods. The formulations will typically be stored in lyophilized form or as an aqueous solution. Typically the pH of the preparations of this invention will be between 3 and 11, better still, from 5 to 9 and most preferably from 7 to 8. Although the preferred route of administration is by injection, such as intravenous injection (bolus and / or infusion) another method of administration can also be anticipated, for example, by subcutaneous, intramuscular, colonic, rectal, nasal or intraperitoneal administration, using a variety of talee administration forms such as suppositories, implant pellets or small cylinders, aerosols, formulations for administration oral and topical formulations, such as ointments, drops and skin patches. The compounds of this invention are conveniently incorporated into shaped articles such as implants, which may employ inert materials, such as polymeric or biodegradable or silicone eintéticoe; for example, Silastic, rubber oil or other polymer is commercially obtainable. It is also possible to administer the components of this invention in the form of seven ae of lipoeomic euminote, talee as veeiclee unilaminaree pequee, veeiclee unilaminaree large and veeiclee multilaminaree. Lae lipoeomae can be formed from a variety of lipid, such as coleeterol, ethethylamine or foefatidilcolinae. It is also possible to introduce the compounds of this invention through the use of antibodies, antibody fragments, growth factors, hormones or other target portions, to which the molecules of the compound are coupled. The compounds of this invention can also be coupled with suitable polymers as drug carriers that are chosen as the destination. Said polymers may include: polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl ethacrylate ida phenol, polyhydroxyethyl aspartamide phenol or polyethylene oxide polylysine and substituted with palmitoyl residues. Additionally, the factor Xa inhibitors of this invention can be coupled to a class of biodegradable polymers useful for obtaining controlled release of a drug, for example, polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid copolymers, poly-epsilon caprolactone , polyhydroxybutyrate acid, polyoleoteree, polyacetalee, polydi-hydropyrans, polycyanoacrylates and interlaced or amphipathic block copolymers, formed from hydrogels. The semi-permeable polymers and polymer matrixes can also be formed into shaped articles, such as valve, extensions, tubes, prostheses and the like. The liquid, therapeutic compound formulations are generally placed in a container having a sterile access port, for example, a bag or ampoule of intravenous solution having a pierceable plug for a needle for hypodermic injection. Therapeutically effective doses can be determined either by an in vitro method or in vivo. For each particular compound of the present invention, individual determinations can be made to determine the optimum dose required. The therapeutically effective dose scale will naturally be influenced by the administration route, the therapeutic objectives and the patient's condition. For injection by hypodermic needle it can be assumed that the dose will be delivered to body fluids. For the other routes of administration, the absorption efficiency must be determined individually for each inhibitor by methods well known in pharmacology. Consequently, it may be necessary for the therapist to titrate the dose and modify the route of administration as required to obtain the optimal therapeutic effect. The determination of effective dose, that is to say, the levels of doeis necessary to obtain the revised results, will be within the scope of the one who is an expert in the matter. Typically, the application of the compound is started at lower dose levels, increasing the level of doeis haeta to obtain the desired effect. The typical dose could vary from about 0.001 mg / kg to about 1000 mg / kg, preferably from 0.01 mg / kg to 100 mg / kg, better still, from 0.10 mg / kg to 20 mg / kg. The compounds of this invention may be advantageously administered several times a day, and another regimen of doe may also be administered. Typically, ee makes up from about 0.5 to 500 mg of a composition or mixture of compound of this invention, such as the free acid or free base form, or as a pharmaceutically acceptable salt, with a carrier, carrier, excipient, agglutinates , preservative, stabilizer, dye, flavoring, etc., physiologically acceptable, as required by accepted pharmaceutical practice. The amount of active ingredient in such compositions is such that an adequate dosage is obtained in the indicated scale. Typical adjuvants that can be incorporated into tablets, capsules and the like are: a binder, such as acacia gum, corn starch or gelatin, and excipients such as cellulose microc rietalin, a disintegrating agent such as corn starch or alginic acid , a lubricant such as magnesium stearate, a sweetening agent such as sucrose or lactose or a flavoring agent. When a capsule shape, in addition to the above materials, can also contain a liquid carrier, such as water, saline or fatty oil. Other types of material may be used as a revelation or as a modification of the physical form of the dosie unisad. The injectable compositions for injection may be formulated in accordance with conventional pharmaceutical practice. For example, dilution or euepeneion of an active composition in a vehicle such as an oil or in a synthetic fatty vehicle, such as ethyl oleate, or in a liposome may be convenient. It is possible to incorporate regulators, coneve rvado ree, antioxidants and eimilaree, in accordance with accepted pharmaceutical practice. In practicing the method of this invention, the compounds of this invention can be used alone or in combination, or in combination with other therapeutic or diagnostic agents. In certain preferred embodiments, the compounds of this invention may be co-administered together with other compounds typically prescribed for these conditions, in accordance with generally accepted medical practice, for example, anticoagulant agents, thrombolytic agents and other antithrombotic agents, including antiviral agents. accumulation of platelets, tissue plasminogen activators, urokinase, prourokinase, streptokinase, heparin, aepirin or warfarin. The components of this invention can be used in vivo, usually in mammals such as primatee, talee as humanoe, svejae, horses, cattle, pigs, dogs, cats, ratae and ratonee or in vitro. The preferred compounds of the present invention are characterized by their ability to inhibit thrombus formation, with acceptable effects on classical measures of coagulation, platelet and platelet function parameters, and acceptable levels of bleeding complications., associated with its use. Conditions characterized by undesirable thrombosis would include those involving the arterial and venous vasculature. With regard to the arterial vasculature conorania, the abnormal formation of thrombi characterizes the rupture of an established atherosclerotic plaque, which is the main cause of acute myocardial infarction and unstable angina, as well as the characterization of occlusal coronary thrombus formation it is the result of either thrombolytic therapy or percutaneous transluminal coronary angioplasty (PTCA). With respect to the venous vasculature, abnormal function of the thrombus characterizes the condition observed in patients who underwent major surgery in the lower extremities or in the abdominal area, who frequently suffer from thrombus formation in the venous vasculature, which results in resulting in reduced blood flow to the affected limb, and a predisposition to pulmonary embolism. Abnormal thrombus formation further characterizes disseminated intravascular coagulopathy, which commonly occurs within the amboe system and during evacuation during aseptic shock, certain viral infections and cancer, and is a condition in which there is a rapid consumption of coagulation factor and coagulation. sietemic that gives rise to the formation of thrombi that threaten life, which occur throughout the microvasculature, which leads to the wide failure of the organ. The components of the present invention, selected and implemented as described herein, are believed to be useful in preventing or treating a condition characterized by indelible thrombosis, such as in: (a) the treatment or prevention of any acute coronary artery syndrome, thrombotic-mediated, which includes myocardial infarction, unstable angina, refractory angina, thrombocyte rheo-occlusion that occurs after thrombolytic therapy or postcoronary angioplasty; (b) the treatment or prevention of any thrombotic-mediated cerebrovaecular syndrome, which includes both embolic and thrombotic attack and transient ischemic attacks; (c) the treatment or prevention of any thrombotic syndrome that occurs in the venous system, including deep vein thrombosis or pulmonary embolism that occurs either spontaneously or in the setting of malignant tumor, surgery or trauma; (d) the treatment or prevention of any coagulopathy including dielechematic intravascular coagulation (which includes the establishment of septic shock or other infection, surgery, pregnancy, trauma or malignancy, whether or not associated with multiple organ failures); thrombotic thrombocytopenic purpura, thromboangilitis obliterans or thrombotic diseases associated with heparin-induced thrombocytopenia; (e) treatment prevention of thrombotic complications with extracorporeal circulation (eg, renal dialysis, cardiopulmonary bypass or other oxygenation procedure, plasmapheresis); (f) the treatment or prevention of thrombotic complications associated with inetrumentation (eg, cardiac catheterization or other intravaecular catheterization, intra-aortic balloon pump, coronary branching, or cardiac valve); and (g) those that are involved with the adjustment of proenetic and disposable. Anticoagulant therapy is also useful to prevent the coagulation of stored whole blood and to prevent the coagulation of other biological samples for testing or storage. Thus, compounds of this invention may be added or contacted with any medium that contains or is suspected of containing factor Xa, and where it is desired to inhibit blood coagulation, for example, when puts the mammal's blood in contact with materialee talee such as grafts, extensions, orthopedic vascular prostheses; extensions, valve and cardiac prostheses, eietemae of extracorporeal circulation and eimilaree. Without further description, it is believed that whoever is skilled in the art, using the foregoing description and illustrative examples below, can form and use the compotetoe of the present invention and implement the methods claimed. Therefore, the following working examples indicate specifically preferred modalities of the invention, but should not be construed as limiting in any way, for the remainder of the description.

EXAMPLE 1 PREPARATION OF Boc-Arg (Cough) -N (Me) QMe To a suspension of 2 g, 4.7 mmol, of Bos-Arg (Tos) -OH in 20 ml of DMF, at 0 ° C, was added 1 g, 10.3 mmol, of MeNHOMe-HCl, 2 ml of DIEZ and 2.5 g, 5.6 mmoles of BOP. The solution was stirred at 0ßC for 10 hours. The DMF was evaporated in vacuo. The oily residue was dissolved in 200 ml of EtOAc and 20 ml of water. The organic layer was washed with saturated NaHC03, with 20 ml of water, with 10 ml of 1 M HCl and with 2 x 20 ml of saturated NaCl. The organic layer was dried magnesium eulfate, filtered and evaporated to give an euepeneion. The euspension was filtered, washed with 10 ml of ethyl acetate and dried to give 1.5 g, 70% yield, of Boc-Arg (Tos) -N (Me) OMe. FAB-MS (M + H) + = 472.

EXAMPLE 2 PREPARATION OF Boc-Apg (T? S) -TIAZOL p NH HN ^ NH-Tos To a solution of 2.5 g, 29.9 mmol, of thiazole in 25 ml of THF, at -78 ° C, 1.6 moles, 19 ml of n-BuLi in hexane, was added dropwise. The mixture was stirred for 30 minutes. Then a solution of 1.7 g, 3.6 mmol, of Boc-Arg (Tos) -N (Me) 0Me in 50 ml of THF, was added to the lithiumiazole mixture at -78 ° C. The solution was stirred for 2 hours. 1M (30 ml) of HCl was added to the reaction mixture and warmed to room temperature. The mixture was extracted with 100 ml EtOAc. The organic layer was washed with 30 ml of saturated NaCl, dried over magnesium sulfate, filtered and evaporated. The crude oily residue was purified by flash column chromatography on silica gel (50% EtOAc in CH 2 Cl 2) to give 1.5 g, 84% yield, of Boc-Arg (Tos) -thiazole, as a white powder. DC1-MS (M + H) + = 496.

EXAMPLE 3 PREPARATION OF B? C- (D) -Arg (CbZ2) OSu To a solution of 1 g, 1.8 mmole, of Boc- (D) -Arg (CbZ2) 0H in 10 ml of CH2CI2, 466 mg, 4.06 mmole of HOSu, 1 ml of DIEA and 846 mg, 4.4 mmoles were added. EDC. The solution was stirred for 48 hours. The solvent was evaporated and the residue was dissolved in 50 ml of EtOAc and 10 ml of water. The organic layer was washed with 10 ml of NaHC03 cured, 10 ml of water, 10 ml of 1 M HCl and 3 x 10 ml of saturated NaCl. The organic layer was dried over magnesium sulfate, filtered and evaporated. The oily residue was used directly in Example 4 without further purification, or was purified by flash column chromatography on silica gel (50% EtOAc in hexane) to give 1 g, 85% yield of Boc- (D) -Arg (CbZ2) 0Su.

EXAMPLE 4 PREPARATION OF B? C- (D ') - r 3 (CbZ2) -Glv-OH To a solution of 1 g, 1.6 mmol, of Boc- (D) -Arg (CbZ2) 0Su in 10 ml of dioxane, was added a solution of 300 mg, 4 mmolee, of Gly and 400 mg, 4.76 mmole, of NaHCO 3 in 10 ml of water. The solution was stirred for 24 hours. The solvents were evaporated and the residue was dissolved in a mixture of 20 ml of EtOAc and 6 ml of 1 N HCl. The separated organic layer was washed with 10 ml of saturated NaCl, dried over MgSO-4, filtered and evaporated to give a solid residue, which was used directly without further purification. ES-MS (M + H) + = 600.

EXAMPLE 5 PREPARATION OF H-Arg (T? S) -TIAZOL To a solution of 300 mg, 0.6 mmole, of Boc-Arg (Toe) -thiazole in 10 ml of CH2Cl2 at 0 ° C, ee added 10 ml of TFA The solution was stirred at O'C for 2 hours. The solvent and excess TFA were evaporated to an oily residue, which was used directly without further purification in Example 6.

EXAMPLE 6 PREPARATION OF Boc- (D) -Arg (CbZ2) -Gly-A rg (Cough) -TIAZOL To a solution of 300 mg, 0.6 mmol, of Boc- Arg (Tos) -thiazole in 10 ml of CH 2 Cl 2 at 0 ° C, 10 ml of TFA was added. The solution was stirred at O'C for 2 hours. The solvent and excess TFA were evaporated to an oily residue, which was redissolved in 10 ml of CH2Cl2. The solution was cooled to O'C, treated with 2 ml of DIEA, 400 mg, 0.67 mmoles, Boc- (D) -Arg (CbZ2) -Gly and 350 mg, 0.79 mmoles, of BOP. The solution was stirred at O'C for 2 hours. The solvent was evaporated and the residue was dissolved in 50 ml of EtOAc. The organic solution was washed with 10 ml of saturated NaHC 3, with 10 ml of water, with 10 ml of 1 N HCl and 10 ml of saturated NaCl. The organic layer was dried over magnesium sulfate, filtered and evaporated. The oily residue was pored by rapid column over SiO 2 (EtOAc) for 474 mg, 81% yield of Boc- (D) -Arg (CbZ 2) -Gly-A rg (Toe) - thiazole, like a powder. ES-MS (M + H) + = 977.

EXAMPLE 7 PREPARATION OF H- (D) -Arg-GlV-Arg-TIAZOL A 100-mg portion of Boc- (D) -Arg (CbZ2) -Gly-Arg (Toe) -thiazole, 1 ml of anieol and 4 drops of MeSEt was placed in a HF separating vessel, and cooled under N2. liquid. 10 ml of HF was then condemned in the reaction mixture and stirred at O'C for 1.25 hours. The HF was removed under vacuum to give a gum-like residue, which was titrated with 20 ml of 50% Et2? -hexane and the organic wash was removed by filtration. The gummy residue was dissolved in 30 ml of 30% aqueous HOAc and filtered through the anterior cone funnel. The filtrate was lyophilized to a powder which was purified by RP-HPLC to give 28 mg (60% yield) of (D) -Arg-Gly-Arg-thiazole. FAB-MS (M + H) + = 455.2.

EXAMPLE 8 PREPARATION OF B? C- (D) -Arq (T? S) -Glv-OBn To a suspension of 1 g, 2.34 mmol, of Boc- (D) -Arg (Toe) -0H in 10 ml of CH2Cl2, 1 ml of DIEA was added to O'C.

To the clear solution was added 0.52 g, 2.50 mmoles, of Gly-OBn-HCl and 1.2 g, 2.8 mmolee, of BOP. The solution was stirred for 4 hours at O'C. The solvent was evaporated and the residue was dissolved in a mixture of 100 ml of EtOAc and 20 ml of water. The organic layer was washed with 10 ml of saturated NaHCO 3, 10 ml of water, 10 ml of 1 N HCl and 3 x 10 ml of saturated NaCl. It was dried over MgSO *, filtered and evaporated. The solid residue was purified by column chromatography on silica gel (EtOAc) to give 1.12 g of the title compound, as a powder. ES-MS (M + H) + = 576.3.

EXAMPLE 9 PREPARATION OF H- D) -ArgCTos) -Glv-OBn A 1 g portion, 1.74 mmol, of Boc- (D) -Arg (Tos) -Gly-OBn was dissolved in 10 mL of CH2Cl2, cooled to O'C, and treated with 10 mL of TFA. The solution was stirred at O'C for 3 hours. The solvent and excess TFA were evaporated to give the title compound as an oil that was used directly in Example 10.

EXAMPLE 10 PREPARATION OF BnS02- (D) -Arg (Tos) -Glv-0Bn The oily residue of the compound of Example 9 was dissolved in 5 ml of DMF, cooled to O'C and neutralized with 1 ml of TEA. To the solution was added 397 mg, 2.0 mmol, of BnSO? Cl and the solution was stirred at O'C for 3 hours and at 25'C for 3 hours. The DMF was removed and the residue was dissolved in 100 ml EtOAc and 20 ml water. The organic layer was separated, washed with 10 ml of saturated NaHC 3, 10 ml of water, 10 ml of 1 N HCl and 3 x 10 ml of saturated NaCl, dried over MgSO 4, filtered and evaporated. The solid residue was purified by column chromatography on silica gel (EtOAc) to give 328 mg, yield 30%, of the title compound, as a powder. ES-MS (M + H) + 630.5.

EXAMPLE 11 PREPARATION OF BnSIa - (D) -ArqfTos) -Glv-OH 300 mg, 0.47 mmolee, of the compound of Example 10 was dissolved in 10 ml of MeOH and then 50 mg of 10% Pd / C was added. The reaction was hydrogenated under normal preionion overnight, filtered through Celite, rinsed with 3 x 10 ml of MeOH and concentrated in vacuo to give 242 mg, 84%, of the desired compound, which was left in further purification. . ES-MS (M + H) + 540.0 EXAMPLE 12 PREPARATION OF BnSOs - (D) -ArgCTos) -Gly-ArgCTos) -TIAZQL A 100 mg portion of the compound of Example 11 was coupled with 0.19 mmole of H-Arg (Toe) -thiazole (prepared following the procedure of Example 5), as prescribed in the procedure of Example 6. Purification by RP- HPLC gave 110 mg, 63% yield, of the title compound. FAB-MS (M + H) + 917.8.

EXAMPLE 13 PREPARATION OF BnSOa-fD) - rq-Glv-Arq-TI ZOL The compound of Example 13 was partitioned with HF according to the procedure described in Example 7, purified by reverse phase HPLC to give 35 mg of the title compound (47% yield) as a powder. ES- MS (M + H) + = 609.6.

EXAMPLE 14 Evasion of the compounds of this invention is guided by in vitro protease activity analyzes (see below) and in vivo studies to evaluate the antithrombotic efficacy and the effects on haemostasis and haematological parameters (see example 15, below).

The compounds of the present invention are dissolved in a regulator to give solutions containing concentrations such that the analytical concentrations vary from 0 haeta 100 μmolee. In the analysis for thrombin, prothrombinase and factor Xa, ee adds a chromogenic eynthetic substratum to a solution containing the test compound and the enzyme of interest, and determines the reeidual catalytic activity of that enzyme, spectrophotometrically. The CIso of a compote is determined from the change of subetrato. The CI is the concentration of the test compound that gives 50% inhibition of substrate change. The components of the present invention, conveniently, have a magnitude less than 500 nanometers in factor Xa analysis, preferably less than 200 nanometers, and, better still, the components have an approximate ratio of 100 nanometers or less in the analysis of the factor Xa. The compounds of the present invention conveniently have a CI of less than 4.0 μmoles in the prothrombinase analysis, preferably less than 200 nM and, the most preferred components, have an IC50 of about 10 nanomolar or less in the prothrombinase analysis. Conveniently, the compositions of the present invention have a CI of more than 100.0 μmole in the thrombin analysis, preferably more than 10.0 μmole, and the most preferred compounds have a CIso of more than 100.0 μmol in the thrombin analysis.

AMIDOLITICAL ANALYSIS TO DETERMINE PROTEASE INHIBITION ACTIVITY Analysis of factor Xa and thrombin was carried out at room temperature in 0.02 mole of regulator Trie-HCl, pH 7.5, which contained 0.15 mole of NaCl. The rates of hydrolysis of the para-nitroanilide S-2765 eubover (Chromogenix) for factor Xa and the substrate Chromozym TH (Boehringer Mannheim) for thrombin, after preincubation of the enzyme with the inhibitor, after 5 minutes at the Ambient temperature was determined using a 96-well plate reader Softmax (Molecular Devices) monitored at 405 nm to measure the appearance of p-nitroaniline depending on time. The inhibition of prothrombinase analysis was carried out in a free platelet system, with modifications to the method described by Sinha, U. and coautoree, Tromb. Res., 75. 427-436 (1994). Specifically, the activity of the prothrombinase complex was determined by measuring the time course of thrombin generation, using the p-nitroanilide substrate Chromozym TH. The analysis consists in the preincubation (during 5 minutes) of the selected compounds that are going to be tested as inhibitors with the complex formed from factor Xa (0.5 nanomoles), factor Va (2 nanomoles), phosphatidyl serine: phosphatidyl choline ( 25:75, 20 μmolee) in 20 mmolee of regulator Trie-HCl, pH 7.5, which contained 0.15 moles of NaCl, 5 mmoles of CaCl 2 and 0.1% of bovine serum albumin. Aliquots of the complex-inhibitor mixture were added to 1 nanomol of prothrombin and 0.1 mmol of Chromozym TH. The cleavage velocity of the substrate at 405 nm was monitored for two minutes. Eight different inhibitor concentrations were analyzed, in duplicate. A normal thrombin generation curve was used, by an equivalent amount of untreated complex, for the determination of percent inhibition.

EXAMPLE 15 A series of studies were conducted in rabbits to evaluate the antithrombotic efficacy and the effects on haemostaeia and hematological parameters of the compound (D) -A rg-Gly-Arg-thiazole.

ANTITHROMBOTIC EFFICACY IN A VENOUS THROMBOSIS MODEL IN RABBIT The model of deep vein thromboeia in rabbit was used, which was described by Hollenbach, S. and coauthors, Thro bv, Haemost. 71, 357-362 (1994), to determine the antithrombotic activity in vivo of the test compounds. Rabbits were anesthetized with intramuscular injections of mixtures of Ketamine, Xylazine and Acepromazine. A standard protocol consisted in the inertia of a thrombogenic cotton thread and a copper wire apparatus in the abdominal vena cava of the affected rabbit. A non-occluding thrombus was allowed to develop in the central venous circulation, and the inhibition of thrombus growth was used as a measure of the antithrombotic activity of the compounds studied. Control or saline control agents were administered through a catheter in the marginal atrial vein. A femoral vein catheter was used to sample the blood before and during the infusion of the test compound in the sustained form. The onset of thrombus formation begins immediately after the advancement of the cotton strand apparatus into the central venous circulation. The test patterns were administered from the moment = 30 minutes and the moment = 150 minutes, when the experiment was terminated. The euthanasia was performed on the rabbits and the thrombus was extirpated by surgical dissection and characterized by weight and histology. Blood samples were analyzed for changes in atheological and coagulation parameters.

EFFECTS OF CD) -Arg-Glv-Arg-TIAZQL IN THE MODEL OF VENOUS THROMBOSIS IN CONEJO The administration of (D) -Arg-Gly-Arg-thiazole in the model of venous thrombosis in rabbits demonstrated the antithrombotic efficacy at the highest dose evaluated. There was no significant effect of the composite on the prolongation of aPTT and PT with the maximum doeis (100 μg / kg + 2.57 μg / kg / min) (see table 2). (D) -Arg-Gly-Arg-thiazole had no effect on the haematological parameters, compared to saline controls (see Table 3).

TABLE 2 ANTITROMBOTIC EFFECTS OF (D) -A g-Gly-Arq-TI ZOL IN RABBITS Baseline% of inhiVecee that ee i ridel regimen bición of c rementa with res of dosie thromboeie pecto a (μg / kg + μg / kg / min) ntt aPTT PT control saline 0.0 0.96 ± 0.01 l.OO ± 0. 00 50 + 1.28 -7.84 1.00 ± 0.03 l.OO ± 0. 00 75 + 1.93 42.95 1.02 ± 0.03 1. OO ± 0. 00 100 + 2.57 117.72 1.08 ± 0.02 0.83 ± 0. 00 All measurements are an average of all samples after administration to sustained vehicle state or (D) -Arg-Gly-Arg-thiazole. The values are expressed as the mean ± DN (standard deviation).

TABLE 3 EFFECTS OF (D) -Arg-GlV-Arg-TIAZOL ON HEMATOLOGICAL PARAMETERS Dosie RBC WBC PLT Het scheme (μg / kg + x 106 μl x IOS μl x 103 μl% μg / kg / min) n # salt of 7 5.96 + 0.66 3.38 + 0.83 338 ± 77 35.2 + 2.81 control 50 + 1.28 6 5.66 ± 0.25 3.70 ± 0.50 349 ± 75 36.913.90 75 + 1.93 5 5.7410.42 4.2310.99 413164 35.313.01 100 + 2.57 6 6.0810.42 4.1519.52 439161 35.511.01 All measurements are an average of the samples after administration to the vehicle or (D) -Arg-Gly-Arg-thiazole. The values are the average l DN.

Claims (4)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound, which is rotated because it is represented by the formula: where: m = 0, 1, 2, 3, 4, n = 0, 1, 2, 3, 4, p = 0, 1, 2, 3, 4; q = 0, 1, 2, 3, 4; Y = NH, S, 0, CH2, CH-OH, CH2CH2, C = 0; A = piperidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, heteroaryl of 3 to 6 carbon atoms, or is absent; Ri = H or alkyl of 1 to 3 carbon atoms; J r o o H2; R2 = H or alkyl of 1 to 3 carbon atoms; D = N, CH, NCH2, NCH2CH2, CHCH2; R3 = H or alkyl of 1 to 3 carbon atoms; E: 0 or H2; R4: H or CH3; M = NH, N-CH3, 0, S, SO, SO2 or CH2 or absent eetá; Q = piperidinyl, pyrrolidinyl, cycloalkyl of 3 to 8 carbon atoms, phenyl, substituted phenyl, naphthyl, pyridyl, or ethereal; G = N, CH or H; Rs = H or alkyl of 1 to 3 carbon atoms, or absent if G ee H; Re-H or CH3; U = is selected from the group that connects where N = 0-4; R7 and Re are independently selected from a group that connects H, alkyl of 10 carbon atoms, aryl, arylalkyl, halogen, nitro, an amino group of the formula -NR9R10, an acylamino group of the formula -NHCORn, hydroxy, an acyloxy group of the formula -OCOR 2, alkyloxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atom, trifluoromethyl, carboxy, cyano, phenyl, an aromatic heterocyclic group as defined hereinafter; C 1-4 alkyloxycarbonyl, an aminocarbonyl group of the formula CONR13R1-V, sulfo, eulphonamido of the formula SO? NRisRiß and hydroxyalkyl of 1 to 6 carbon atoms; wherein R9, Rio, R11, R12, R13, R14, Ris, Rie are the same or different and are equal to H, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 3 carbon atoms or aryl; and if M is absent: K = C or N; W = H, arylacil, heteroacylacyl, arylalkyl of C 1-3 -sulfonyl, arylsulfonyl, substituted arylsulfonyl, aryl-alkenyl of C? -, -sulfonyl, Ci-β-sulphonyl alkyl, heteroaryl-C 1-3 alkyl- sulfonyl, heteroarylenesulfonyl, aryloxycarbonyl, C 1-6 alkyloxycarbonyl, arylalkyloxy of C? -3-carbonyl, arylaminocarbonyl, C 1-6 alkyl-aminocarbonyl, arylalkyl of C 1-3 -aminocarbonyl, HOOC-alkyl of Co-3-carbonyl , or absent if G ee H; X = H, alkyl of 1 to 3 carbon atoms, NR'R ", NHC (NR'R") = NH, NH-C (NHR ') = NR ", NH-C (R') = NR", SC (NR 'R ") = NH, SC (NHR') = NR", C (NR'R ") = NH, C (NHR ') = NR" or CR' = NR "; where R ', R "is equal or different and is H, alkyl of 1 to 6 carbon atoms, arylakyl of 1 to 3 carbon atoms, aryl or wherein R'R" forms a cyclic ring containing (CH2) P, where p = 2-5, provided that when X is H or alkyl of 1 to 3 carbon atoms, A must contain at least one N atom; Z = H, alkyl of 1 to 3 carbon atoms, NR'R ", NHC (NR'R") = NH, NH-C (NHR ') = NR ", NH-C (R') = NR"; SC (NR'R ") = NH, SC (NHR ') = NR ", C (NR'R") = NH, C (NHR ') = NR "or CR' = NR"; wherein R ', R "are the same or different and are H, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 3 carbon atoms, aryl, or where R'R" forms a cyclic ring containing (CH2) ) P, where p = 2-5, provided that, when Z is H or alkyl of 1 to 3 carbon atoms, Q must contain at least one N atom; and all of its isomers, its salts, its hydrate, its solvates and its pharmaceutically acceptable prodrug derivatives.

2. The compound according to claim 1, characterized in that it has the formula: where: m = 0, 1, 2, 3, 4; n = 0, 1, 2, 3, 4; p = 0, 1, 2, 3, 4; q = 0, 1, 2, 3, 4; Y = NH, S, 0, CH2, CH-OH, CH2CH2, C = 0; TO = piperidinyl, pyrrolidinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, heteroaryl of 3 to 6 carbon atoms, or absent; M = NH, N-CH3, 0, S, SO, SO2 or CH2 or is auent; Q = piperidinyl, pyrrolidinyl, cycloalkyl of 3 to 8 carbon atoms, phenyl, substituted phenyl, naphthyl, pyridyl, or is absent; U = ee selects from the group that connects where N = 0-4; R? and Re eected independently of a H-linked group, alkyl of 10 carbon atoms, aryl, arylalkyl, halogen, nitro, an amino group of the formula -NR 9 R 10, an acylamino group of the formula -NHCORn, hydroxy, a acyloxy group of the formula -OCOR12, alkyloxy of the 4 carbon atoms, alkyl of 1 to 4 carbon atom, trifluoromethyl, carboxy, cyano, phenyl, an aromatic heterocyclic group, as defined below, C1-4 alkyloxy -carbonyl, an aminocarbonyl group of the formula CONR13R14, sulfo, sulfonamido of the formula SO2NR15R16 and hydroxyalkyl of 1 to 6 carbon atoms; wherein R9, Rio, R11, R12, R13, IA, Rie, R6 are the same or different and are H, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 3 carbon atoms or aryl; and if M is absent: K *? K - C or N; W-H, arylacil, heteroarylacyl, C3-sulphonyl arylalkyl, arylsulfonyl, arylsulfonyl, substituted, aryl-alkenyl, C- * -sulfonyl, alkyl-Ca-8-sulfonyl, heteroaryl-C1-3-alkylsulphonyl, heteroarylsulfonyl , aryloxycarbonyl, Ci-β-carbonyl alkyloxy, C 1 -3-carbonyl arylalkyloxy, arylaminocarbonyl, C 1-6 alkyl-aminocarbonyl, C 1-3 arylalkyl-aminocarbonyl, HOOC-Co-3-carbonyl alkyl, or is present in the G ee H; X = H, alkyl of 1 to 3 carbon atoms, NR'R ", NHC (NR'R") = NH, NH-C (NHR ') = NR ", NH-C (R') = NR", SC (NR 'R ") = NH, SC (NHR') = NR", C (NR'R ") = NH, C (NHR ') = NR" or CR' = NR "; where R ', R "Eon equal or different and H, alkyl of 1 to 6 carbon atoms, arylalkyl of 1 to 3 carbon atoms, aryl, or wherein R'R" forms a cyclic ring containing (CH2) P, wherein = 2-5, provided that, when X is H or alkyl of 1 to 3 carbon atoms, then A must contain at least one N atom; Z = H, alkyl of 1 to 3 carbon atoms, NR 'R', NH-C (NR'R ") = NH, NH-C (NHR ') = NR", NH-C (R') = NR "; SC (NR 'R") = NH, SC ( NHR ') = NR ", C (NR'R") = NH, C (NHR') = NR "or CR '= NR"; wherein R ', R "are equal or different and are H, alkyl of 1 to 6 carbon atoms, arylakyl of 1 to 3 carbon atoms, aryl, or where R'R" forms a cyclic ring containing (CH2) ) P, where p = 2-5, provided that, when Z is H or alkyl of 1 to 3 carbon atoms, then 0 must contain at least one N atom; and everything was eroded, its salts, its hydrates, its solvate and its prodrug, pharmaceutically acceptable derivatives.

3. The compound in accordance with the claim 1, further characterized in that it has an IC50 for menoe factor Xa of about 200 nM.

4. The compound according to claim 1, characterized in that it has a Clso for the menoe protro binaea of about 2.0 μM. 5.- The compoteto in accordance with the claim 1, characterized in that it has a Clus for thrombin of more than about 1.0 μM. 6. A compound characterized in that it is selected from a group that connects: HDA rg-Gly-A rg-thiazole BnS? 2- (D) -A rg-Gly-A rg-thiazole PhCH2CH2-S? 2- (D ) -A-Rg-Gly-A rg-thiazole C6HnCH2CH2-S02- (D) -A rg-Gly-A rg-thiazole Me2C-Cß HA S? 2- (D) -A rg-Gly-A rg-thiazole Ci or H7S02- (D) -A rg-Gly-A rg-thiazole Mß3SiCH2CH2CH2S02- (D) -A rg-Gly-A rg-thiazole BnS02 - (D) -4-Apa -Gly-A rg-thiazole BnS? 2 - (D) -4-Gpa-Gly-Arg-thiazole BnS? 2- (D) -Acg-Gly-A rg-thiazole BnS02 - () - homo -Lys-Gl and -A rg-thiazole BnS02 - (D ) -Arg-Sar-A rg-thiazole BnS02 - (D) -Arg-Pro-A rg-thiazole BnS02- (D) -Arg-Gly-4-Acg-thiazole BnS? 2- (D) -Arg-Gly - (3-NH2Phe) -thiazole BnS02- (D) -Arg-Gly- (4-NH2Phe) -thiazole BnS02 - (D) -Arg-Gly-Gpa-thiazole Boc-D- (2,3-Dap) -Gly-A rg-thiazole Boc D- (2,4-Dab) -Gly-A rg-thiazole g-Abu-Gly-Arg-thiazole Boc-D-Orn-Gly-A rg-thiazole Boc-D-homoLys-Gly-A rg-thiazole Boc -Bag-Gly-A rg-thiazole Boc-D-4 -Gpa -Gly -A rg-thiazole Boc-D-3-Gpa-Gly-Arg-thiazole Boc-D-4 -Apa -Gly-A rg-thiazole Boc-D-3-Apa-Gly-A rg-thiazole Boc-D-4-Acg-Gly-A rg-thiazole Boc-D- (4-NH2Phe) -Gly-A rg-thiazole Boc-D- (3 -NH2 Phe) -Gly-A rg-thiazole BnS? 2-D- (2,3-Dap) -Gly-A rg-thiazole BnS02-D- (2, 4-Dab) -Gly-A rg-thiazole BnS02-D-0rn-Gly-A rg-thiazole BnS? 2-Bag-Gly-A rg-thiazole BnS02-D-3-Gpa-Gly-A rg-thiazole BnS02-D- (4-NH2Phe) -Gly-A rg-thiazole BnS02-D- (3-NH2 Phe) -Gly-rg-thiazole BnS02 -D- (2, 3 -Dap) -Gly-rg-benzothiazole BnS02 -D- (2,4-Dab) -Gly -A rg-benzothiazole BnS02 -D-Orn-Glyrg-benzothiazole BnS02 -Bag-Gly-Arg-benzothiazole BnSO? -D-4-Gpa -Gly-rg-benzothiazole BnS02 -D-3 -Gpa -Gly-rg-benzothiazole BnS02 -D-4 -Apa-Gl and -A rg-benzothiazole BnSO? -D-3-Apa -Gly-A rg-benzothiazole BnS02-D-4-Acg-Gly-Arg-benzothiazole BnS02 -D- (4-NH2 Phe) -Gly-rg-benzothiazole BnS02-D- (3-NH2Phe ) -Gly-Arg-benzothiazole BnSO? -D-A rg-Gly- (2, 4 -Dab) -benzothiazole BnSO? -D-Arg-Gly- (homoLys) -benzothiazole BnS? 2 -D-Arg-Gly- (4-Gpa) -benzothiazole BnS? 2 -D-A rg-Gly- (3-Gpa) -benzothiazole BnSO? -D-A rg-Gly- (4-Apa) -benzothiazole BnSO? -DA rg-Gly- (3-Apa) -benzothiazole BnS? 2 -DA rg-Gly- (4-NH2 Phe) -benzothiazole BnS02-D-Arg-Gly- (3-NH2Phe) -benzothiazole Mß3 S1CH2 CH2 CH2 SO2 - (D) -A rg-Gly-A g-benzothiazole BnS? 2- (D) -homo-Lys-Gly-A rg-benzothiazole BnS? 2- (D) -homo-Lys-Gly-A rg-benzoxazole PhCH2CH2S? 2- (D) -A rg-Gly-A rg-benzothiazole BnS? 2- (D) -Arg-Sar-Arg-benzothiazole BnS02- (D) -A rg-Pro -A rg-benzothiazole BnS0 - ( D) -Arg-Gly-Acg-benzothiazole BnS02- (D) -A rg-Gly-A rg-benzothiazole PhCH2CH2S02- (D) -Arg-Gly-4-Acg-benzothiazole BnS02- (D) -A rg-Gly-A rg-oxazole Boc-D- (2,3-Dap) -Gly-Arg-oxazole Boc-D- (2, 4-Dab) -Gly-A rg-oxazole g-Abu-Gly-A rg-oxazole Boc-D-Orn-Gl and -A rg-oxazole Boc-D-homoLye-Gly-A rg-oxazole Boc-Bag-Gly-A rg-oxazole Boc-D-4 -Gpa-Gl and -A rg-oxazole Boc-D-3-Gpa-Gly-A rg-oxazole Boc-D-4-Apa-Gly-A rg-oxazole Boc-D-3-Apa-Gly-A rg -oxazole Boc-D-4-Acg-Gly-Arg-oxazole Boc-D- (4-NH2 Phe) -Gly-A rg-oxazole Boc-D- (3-NH2 Phe) -Gly-A rg-oxazole BnS02 -D- (2, 3-Dap) -Gly-A rg-oxazole BnS02-D- (2, 4-Dab) -Gly-A rg-oxazole BnS02-D-0rn-Gly-A rg-oxazole BnS? 2 -Bag-Gly-A rg-oxazole BnS? 2 -D-3-Gpa-Gly-A rg-oxazole BnS? 2 -D-3-Apa-Gly-A rg-oxazole BnS02-D- (4-NH2 Phe ) -Gly-A rg-oxazole BnS02-D- (3-NH2Phe) -Gly-Arg-oxazole BnS02-D- (2,3-Dap) -Gly-A rg-oxazole BnS? 2-D- (2, 4-Dab) -Gly-rg-oxazole BnS? 2 -D-Orn-Gly-A rg-oxazole BnS02 -Bag-Gly-rg-oxazole BnS? 2 -D-4-Gpa-Glyrg-oxazole BnS? 2-D-3-Gpa-Gly-Arg-oxazole BnS02-D-4-Apa-Gly-A rg-oxazole BnS? 2-D-3-Apa-Gly-Arg-oxazole BnS? 2 -D-4- Acg-Glyrg-oxazole BnS? 2 -D- (4-NH2Phe) -Gly-Arg-oxa zol BnS02-D- (3-NH2 Phe) -Gly-A rg-oxazole BnSO? D-A rg-Gly- (2, 4-Dab) -oxazole BnSO? DA rg-Gly- (homoLye) -oxazole BnS02 DA rg-Gly- (4-Gpa) -oxazole BnS? 2 DA rg-Gly- (3-Gpa) -oxazole BnS02D-Arg-Gly- (4-Apa) - oxazole BnSO? DA rg-Gly- (3-Apa) -oxazole BnS02 DA rg-Gly- (4-NH2 Phe) -oxazole BnS? 2 DA rg-Gly- (3-NH2 Phe) -oxazole BnS? 2-D- (2 , 3-Dap) -Gly-A rg-benzoxazole BnS? 2 -D- (2, 4-Dab) -Gly-A rg-benzoxazole BnS02 -D-Orn-Gly-A rg-benzoxazole BnSO? -Bag-Gly-A rg-benzoxazole BnS? 2 -D-4-Gpa-Gly-A rg-benzoxazole BnS? 2 -D-3-Gpa-Gly-A rg-benzoxazole BnS02 -D-4 -Apa-Gly -A rg-benzoxazole BnS02 -D-3-Apa-Gly-A rg-benzoxazole BnS02 -D-4-Acg-Gly-A rg-benzoxazole BnS02-D- (4-NH2 Phe) -Gly-A rg-benzoxazole BnS02-D- ( 3-NH2 Phe) -Gly-A rg-benzoxazole BnSO? DA rg-Gly- (2, 4-Dab) -benzoxazole BnS02 DA rg-Gly- (homoLye) -benzoxazole BnS02 -A rg-Gly- (4 -Gpa) -benzoxazole BnS02 DA rg-Gly - (3-Gpa) -benzoxazole BnS02 -A rg-Gly- (4 -Apa) -benzoxazole BnS02 -A rg-Gly- (3-Apa) -benzoxazole BnS02 DA rg-Gly- (4-NH2Phe) -benzoxazole BnSO? DA rg-Gly- (3-NH2Phe) -benzoxazole Mß3SiCH2CH2CH2S? 2- (D) -A rg-Gly-A rg-Benzoxazole BnS02-D-homo-Lye-Gly-A rg-benzoxazole PhCH2CH2S? 2 - (D ) -A-Rg-Gly-A rg-Benzoxazole BnS02 - (D) -A rg -Sa rA-benzoxazole BnS? 2- (D) -Arg-Gly-Acg-benzoxazole BnS02- (D) -A rg-Gly -A rg-benzoxazole PhCH2CH2S? 2- (D) -Arg-Gly-4-Acg-Benzoxazole BnS02- (D) -A rg-Gly-A rg-benzoxazole BnS02- (D) -Arg-Gly-Acg-benzoxazole PhCH2CH2S? 2- (D) -A rg-Gly-4 -A rg-benzoxazole PhCH2CH2S? 2- (D) -Arg-Gly-4-Acg-benzoxazole ß3SiCH2CH2CH2S02- (D -Arg-Gly-A rg-benzoxazole BnSO? - (D) -A rg-Gly-A rg-oxazole i na Boc-D- (2,3-Dap) -Gly-A rg-oxazole i na Boc-D- (2, 4-Dab) - Gly-A rg-oxazoline g-Abu-Glyrg-oxazole i na Boc -DO rn -Gly- rg-oxazole i na Boc-D-homoLye -Gly- rg-oxazole i na Boc -Bag-Gly-A rg -oxazol i na Boc-D-4-Gpa-Gly-A rg-oxazoline Boc-D-3-Gpa-Gly-A rg-oxazole i na Boc-D-4-Apa-Gly-A rg-oxazol i na Boc-D-3-Apa-Gly -A rg-oxazole i na Boc-D-4-Acg-Gly-A rg-oxazole i na Boc -D- (4 -NH2 Phe) -Gly -A rg-oxazole na Boc-D- (3-NH2 Phe) -Gly-A rg-oxazole i na BnSO? -D- (2, 3-Dap) -Gly-A rg-oxazoline BnSO? -D- (2, 4-Dab) -Gly-A rg-oxazole i na BnSO? -D-O rn-Gly-A rg-oxazol i na BnSO? -Bag-Gly-A rg-oxazoline BnS02 -D-3-Gpa-Gly-A rg-oxazoline BnS02 -D-3-Apa-Gly-A rg-oxazoline BnS02 -D- (4-NH2 Phe) -Gly- Arg-oxazoline BnS? 2 -D- (3-NH2 Phe) -Gly-A rg-oxazoline BnS? 2 -D- (2,3-Dap) -Gly-A rg-oxazole BnS02-D- (2, 4-Dab) -Gly-A rg-oxazole i na BnS02 -D-0rn-Gly-A rg-oxazoline BnS? 2 -Bag-Gly-A rg-oxazole i na BnS? 2 - D-4-Gpa-Gly-A rg-oxazoline BnS? 2 -D-3-Gpa-Gly-A rg-oxazole BnS? 2 -D-4-Apa-Gly-A rg-oxazole ina BnS02-D-3-Apa-Gly-A rg-oxazoline BnS02 -D-4-Acg-Gly-A rg-oxazoline BnS02-D- ( 4-NH2Phe) -Gly-A rg-oxazoline BnS02-D- (3-NH2 Phe) -Gly-A rg-oxazole ina BnSO? DA rg-Gly- (2, 4-Dab) -oxazol i na BnS02 DA rg-Gly- (homoLye) -oxazol i na BnS02 DA rg-Gly- (4 -Gpa) -oxazol i na BnS02 DA rg-Gly- (3-Gpa) -oxazol i na BnS? 2D-Arg-Gly- (4-Apa) -oxazoline BnS? 2 DA rg-Gly- (3-Apa) -oxazole i na BnS? 2 DA rg-Gly- (4-NH2 Phe) -oxazol i na BnSO? D-A rg-Gly- (3-NH 2 Phe) -oxazol i na BnS02 ~ (D) -A rg-Gly-Arg -i midazole BnSO? - (D) -A rg-Gly-A rg-pyridine BnS02- (D) -Arg-Gly-Arg-2- (l-methyltetrazole) BnS02- (D) -A rg-Gly-A rg-2- ( 4-methyl tet razol) MeS02- (D) -Arg-Gly-A rg-thiazole BnS02- (D) - (4-H2NCH2-Phe) -Gly-A rg-thiazole BnS02- (D) - (4-H2NCH2 -Phg) -Gly-A rg-thiazole BnS02- (D) - (3-Py-Ala)) - Gly-Arg-thiazole BnS02- (D) - (3-Me-3-Py-Ala) -Gly- A rg-thiazole BnS02- (D) - (3-Pip-Ala)) -Gly-A rg-thiazole BnS02- (D) - (4-Pip-Ala)) - Gly-A rg-thiazole BnS? 2 - (D) - (3-amidino-3-Pip-Ala)) -Gly-A rg-thiazole. 7. The compound in accordance with the claim 6, further characterized because it is selected from the group that connects: HDA rg-Gly-A rg-thiazole BnS02 - (D) - rg-Gly-A rg-thiazole MeS02- (D) -A rg-Gly-A rg- thiazole BnS02 - (D) -Arg-Gly-Arg-benzoxazole BnS? 2- (D) - (3-Pip-Ala) -Gly-A rg-thiazole BnS02- (D) - (4-Pip-Ala) - Gly-A rg-thiazole BnS02- (D) - (3-amidino-3-Pip-Ala) -Gly-A rg-thiazole. 8. A pharmaceutical composition for preventing or treating a condition in a mammal, which is characterized by undesirable thromboeia, characterized in said composition because it comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1, 2 or 6. A method for preventing or treating a condition in a mammal that is characterized by undesirable thrombosis, characterized in that said method comprises comprising administering to the mammal a therapeutically effective amount of a compound of claim 1, 2 or 6. 10. The method of compliance with the claim 9, further characterized in that the condition is selected from the group consisting of: acute coronary syndrome, myocardial infarction, unstable angina, refractory angina, coronary occlusion thrombus occurring after post-tropositic therapy or post-coronary angioplasty; a thrombotic-mediated cerebrovascular syndrome, embolic attack, thrombotic attack, transient ischemic attack, venous thrombosis, deep vein thrombosis, pulmonary embolus, coagulopathy, disseminated intravaecular coagulation, thrombotic purple thrombocytopenia, thromboangilitis obliterans, thrombotic diseases with heparin-induced thrombocytopenia, thrombotic complications associated with extracorporeal circulation, thrombotic complications associated with inetrumentation, such as cardiac catheterization or other intravascular catheterization, intra-aortic balloon pump, coronary implant or cardiac valve, and conditions that require the fitting of prosthetic devices. 11. A method for inhibiting the coagulation of biological mueetrae, characterized in that it comprises the administration of a compound of claim 1, 2 or 6.