MXPA01002400A - FACTOR VIIa INHIBITORS - Google Patents

Abstract

The present invention relates to novel compounds, their preparation, their use and pharmaceutical compositions containing the compounds which have a strong antithrombotic effect through reversible inhibition of activated blood coagulation factor VIIa (FVIIa).

Description

INHIBITORS OF THE FACTOR Vlla FIELD OF THE INVENTION The present invention relates to novel compounds, their preparation, their use and pharmaceutical compositions containing the compounds with a strong anti-thrombotic effect through the reversible inhibition of factor Vlla (FVIIa) of activated blood coagulation.

BACKGROUND OF THE INVENTION Thrombus formation is usually the result of tissue injury that initiates the coagulation cascade and has the effect of slowing or preventing blood flow in wound healing. Other factors that are not directly related to tissue injury such as atherosclerosis and inflammation may also initiate the coagulation cascade and may give rise to pathological consequences. Blood coagulation is a complex process that includes a progressively amplified series of enzymatic activation reactions in which plasma zymogens are activated sequentially by limited proteolysis. From the mechanical point of view, the cascade of blood coagulation has been divided into the intrinsic and extrinsic pathways, which converge in the activation of factor X; the subsequent generation of thrombin proceeds through a single common route (see Scheme 1). Intrinsic Extrinsic x "-Xa Plat? l? t? ggfctjdlißrt 10 4 * / PrcthfW? ibin Mrhrombi'n i FiMnogan - Fi? rin Scheme 1: Cascade of blood coagulation 15 The present invention suggests that the intrinsic pathway plays an important role in the maintenance and growth of fibrin formation, while the extrinsic pathway is crucial in the initiation phase of blood coagulation (H). Cole, Aust., J. 20 Med. Sci. 16 (1995) 87; GJ Broze, Blood Coagulation and Fibrinolysis 6, Suppl. 1 (1995) S7-S13). In general, it is accepted that blood coagulation begins physically with the formation of a tissue factor (TF) / factor Vlla complex. Once formed, this complex quickly initiates the coagulation by activating factors IX and X. The factor X activated, newly generated, that is, factor Xa, then forms a one-to-one complex with factor Va and phospholipids to form a prothrombinase complex, which is responsible for the conversion of soluble fibrinogen into insoluble fibrin through the activation of thrombin from its prothrombin precursor. As time progresses, the activity of the Vlla factor / tissue factor complex (extrinsic pathway) is suppressed by a Kunitz-type protease inhibitor protein, TFPI, which, when complexed with factor Xa, can directly inhibit the proteolytic activity of the protein. Vlla factor / tissue factor. To maintain the coagulation process in the presence of an inhibited extrinsic system, additional factor Xa is produced by the thrombin-mediated activity of the intrinsic pathway. Thus, thrombin plays a double autocatalytic function, mediating its own production and the conversion of fibrinogen into fibrin. The autocatalytic nature of thrombin generation is an important safeguard against uncontrolled hemorrhage and ensures that, once a certain threshold concentration of prothrombinase is present, blood coagulation will proceed to its completion. The ability to form blood clots is vital for survival. However, in certain disease states, the formation of blood clots within the circulatory system is itself a source of morbidity. However, it is not desirable in these disease states to completely inhibit the coagulation system because a haemorrhage would be life-threatening. Thus, it is more desirable to develop agents that inhibit coagulation by inhibiting factor Vlla without directly inhibiting thrombin. In multiple clinical applications there is a great need for the prevention of intravascular blood clots or some anticoagulant treatment. The drugs currently available are not satisfactory in many of the specific clinical applications. For exampleNearly 50% of patients who have undergone a total hip replacement develop deep vein thrombosis (DVT). Currently approved treatments are low molecular weight heparin (LMWH) in fixed doses and heparin in variable doses. Even with these dose schemes, 10% to 20% of patients develop DVT, and 5% to 10% develop complications of hemorrhage. Another clinical situation for which better anticoagulants are necessary refers to individuals who undergo transluminal coronary angioplasty and individuals at risk of myocardial infarction or suffering from crescendo angina. The present treatment, traditionally accepted, which consists of administering heparin and aspirin, is associated with a 6% to 8% of sudden vessel closure rate within 24 hours of the procedure. The rate of bleeding complications that require transfusion treatment due to the use of heparin is also about 7%. In addition, although delayed closures are important, the administration of heparin after the completion of the procedures is of little value and can be detrimental. Inhibitors of blood coagulation more Heparin and the related sulfated polysaccharides, LMWH and heparin sulfate are widely used. These molecules exert their anticoagulant effects by favoring the binding of a natural regulator of the coagulation process, anti-thrombin III, to thrombin and factor Xa. The The heparin inhibitory activity is directed primarily at thrombin, which is inactivated approximately 100 times faster than factor Xa. Hirudin and hirulog are two additional thrombin-specific anticoagulants currently in clinical trials. However, these anticoagulants, which inhibit thrombin, are also associated with complications in bleeding. Preclinical studies in baboons and dogs have shown that the enzymes of choice involved in the early stages of the coagulation cascade, such as factor Xa or factor Vlla, they avoid the formation of clots without producing effects collateral bleeding observed in direct thrombin inhibitors (T. Yokoyama, AB Kelly, Marzec UM, Hanson SR, Kunitada S., Harker LA, Circulation 92 (1995) 485-491; LA Harker, SR Hanson, AB Kelly, Thromb Hemostas 74 (1995) 464-472; CR Benedict, J. Ryan, J. Todd, K. Kuwabara, P. Tyburg, Jr., J. Cart right, D. Stern, Blood 82 (1993) 2059-2066 ). Specific inhibition of the catalytic factor VIIa / TF complex using monoclonal antibody (International Patent Application No. WO 92/06711) and a protein such as FVIIa inactivated with chloromethyl ketone (International Patent Application No. Wo 96/12800 and WO 97/47651) is an extremely effective means of controlling the formation of thrombi caused by acute arterial injury or thrombotic complications related to bacterial septicemia. There is also experimental evidence suggesting that inhibition of factor VIIa / TF activity inhibits restenosis after balloon angioplasty (L. A. Harker, S. R. Hanson, N. J. Wilcox, A. B. Kelly, Haemostasis 26 (1996) Sl-76-82). Bleeding or haemorrhage studies have been performed on mandrels and indicates that inhibition of the factor VIIa / TF complex has the widest window of safety with respect to the therapeutic efficacy and bleeding risk of any anticoagulant method tested including inhibition of thrombin, platelets and factor Xa (L.A. Harker, S. R. Hanson, A. B. Kelly, Thormb.Hostas.74 (1995) 464-472). A specific inhibitor of factor Vlla would have a substantial practical value in the practice of medicine. In particular, a Vlla factor inhibitor would be effective under circumstances where the drugs of choice present, heparin and related sulfated polysaccharides, are ineffective or only marginally effective. Thus, there is a need for a Vlla factor-specific low blood clotting inhibitor that is effective, but does not cause unwanted side effects. The present invention satisfies this need by providing derivatives of formula I that inhibit factor Vlla activity and providing related advantages as well. The compounds of the formula I are inhibitors of the factor Vlla enzyme which coagulates the blood. The invention also relates to the processes for the preparation of the compounds of the formula I, the methods of inhibiting the activity of factor Vlla and the inhibition of blood coagulation, the use of the compounds of the formula I in the treatment and prophylaxis of diseases that can be cured or prevented by the inhibition of factor Vlla activity such as thromboembolic diseases including thrombosis, restenosis, infarction and angina, and the use of the compounds of formula I in the preparation of medicines that can be applied in such diseases. The invention further relates to compositions containing a compound of the formula I in a mixture or otherwise in association with an inert carrier, in particular pharmaceutical compositions containing a compound of the formula I together with carrier substances or excipients and / or pharmaceutically acceptable auxiliary substances or additives.SUMMARY OF THE INVENTION The present invention provides compounds that specifically inhibit factor Vlla activity. In particular, an object of the present invention are the compounds of the formula I. R1-ABD-In-R2 (I) wherein R1 represents: R13, R12C (0) or 1 to 3 amino acids, the N-terminal of the which may be substituted with a substituent selected from the series consisting of R14C (0), R15S (0) 2 and an amino protecting group, wherein R12 is selected from the series consisting of alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkenyloxy, alkynyloxy, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, heteroalkyl, heteroalkenyl and heteroalkynyl, all of which residues may be substituted, R13 is selected from the series consisting of an amino protecting group , hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, R 14 and R 15 are independently selected from the series consisting of alkyl, aryl, aryl alkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl. A is the group A1-A2-A3, where Al is NH, A2 is CHR93, where R93 is 4-amidinophenylmethyl, A3 is C (O) 20B is the group B1-B2-B3, where Bl is NR95 , wherein R95 is selected from the series consisting of hydrogen and alkyl, B2 is CHR97, wherein R97 is ethyl which is substituted at the 2-position by a substituent selected from the series consisting of hydroxycarbonyl, alkyloxycarbonyl and arylalkyloxycarbonyl, B3 is C (O), D is the group D1-D2-D3, where D1 is NH, D2 is CR81R82, wherein R81 and R82 are independently selected from the series consisting of hydrogen and the residues are not substituted or substituted alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, D3 is C (O), is (El-E2-E3) n, where N is zero, two or three, The is NR70, in wherein R70 is selected from the series consisting of: hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl. E2 is CR71R72, wherein R71 and R72 are independently selected from the series consisting of hydrogen and alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, substituted or unsubstituted residues. E3 is C (O), R2 is selected from the series consisting of: NR21R22, OR23 and R24, wherein R21, R22, R23 and R24 are independently selected from the series consisting of: hydrogen and unsubstituted or substituted alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, alkyl and heteroalkyl residues contain 1 to 13 carbon atoms, wherein in a heteroalkyl residue one or more carbon atoms are substituted with heteroatoms selected from the series consisting of: N, O and S; Alkenyl, alkynyl, heteroalkenyl and heteroalkynyl contain from 2 to 13 carbon atoms, wherein in a heteroalkenyl and heteroalkynyl residue one or more carbon atoms are substituted with heteroatoms selected from the series consisting of: N, 0 and S; Aryl and heteroaryl contain 5 to 13 carbon atoms in the ring where in a heteroaryl residue one or more carbon atoms are replaced with heteroatoms selected from the series consisting of: N, O and S; Heterocycloalkyl contains 3 to 8 carbon atoms in the ring of which 1 to 3 carbon atoms are replaced with heteroatoms selected from the series consisting of: N, O and S; in any of its stereoisomeric forms and mixtures of these in any proportion, and salts pharmaceutically acceptable of these.

DETAILED DESCRIPTION OF THE INVENTION The present invention provides the peptides of the formula I. Rl-A-B-D-In-R2 (I) where Rl, R2, A, B, D, E and n are as defined above, which are compounds that inhibit Vlla factor activity but do not substantially inhibit the activity of other proteases involved in the blood coagulation pathway. In the compounds of the formula I structural units are contained, for example, in groups A, B, D or E or in the group Rl in case Rl represents 1, 2 or 3 amino acids, which are amino acids or derivatives of these or amino acid analogs or mimetic structures, and which in peptide mode are linked to adjacent groups through C (0) -N amide bonds formed between the carboxyl group of one of these amino acids, etc., and an amino group of another amino acid, etc. As is common in the chemistry of peptides, a divalent residue of an amino acid or a group such as A, B, D or E as presented in formula I is obtained from the respective amino acid by formally removing a hydrogen atom from a amino group and a hydroxyl group of a carboxyl group. When used in the present, the term 'Á &-á8¿j. £ k £ xte ¡s ^. "amino acid" is used in its broadest sense to understand the 20 amino acids that occur in nature, which are translated from the genetic code and comprise the building blocks of proteins, which include, unless it is specifically established in another mode, L-amino acids and D-amino acids, as well as chemically modified amino acids - such as amino acid analogs, naturally occurring amino acids that are not normally incorporated into proteins such as norleucine, and chemically synthesized compounds having properties known in the art as characteristics of an amino acid. For example, the analogs or mimetics of phenylalanine or proline, which allow the same conformational restriction of the compounds Peptides such as natural Phe or Pro are included within the definition of "amino acids" and are known to those skilled in the art. These analogs and mimetics are known herein as "functional equivalents" of an amino acid. Other examples of amino acids and analogues of amino acids are listed by Roberts and Vellaccio (The Peptides: Analysis, Synthesis, Biology, eds, Gross and Meienhofer, vol.5, p.341, Academic Press, Inc. New York 1983, which is incorporated herein by reference). reference). Abbreviations of amino acids, analogues of amino acids and mimetic structures as well as other Abbreviations used in the application are mentioned in the Table Table 1: Abbreviations used in the application Compound / residue Abbreviation Acetic acid - AcOH Acetylaminomethyl Acm Alanine Ala Allyloxycarbonyl Alloc p-amidinophenylalanine pAph 2-aminobutyric acid 2-Abu Arginine Arg Asparagine Asn Aspartic acid Asp Benzyl Bzl t-butyloxycarbonyl Boc t-butyl tBu cyclohexylglycine Chg Cyclohexyl Chx Cyclohexylalanine Cha Cysteine Cys 2, 4-diaminobutyric acid Dab 2, 3-diaminopropionic acid Dap Dichloromethane DCM ^^ - a B * «fa. -.- tk > é k * # ¿* Compound / residue Abbreviation Diisopropylcarbodiimide DIC Diisopropylethylamine DIEA N, N-dimethylformamide DMF Dimethylsulfoxide DMSO 9-Fluorenylmethyloxycarbonyl Fmoc Glutamic acid Glu Glutamine Gln Glycine Gly Histidine His N-hydroxybenzotriazole HOBt 4-Hydroxymethylphenoxyacetic acid HMPA Isoleucine Ie Leucine Leu Lysine Lys Methyl N-methylimidazole NMI N-methylmorpholine NMM 2,2,5,7,8-pentamethylchroman-6-sulfonyl Pmc Ornithine Orn Phenyl Ph Phenylalanine Phe Phenylglycine Phg Proline Pro Serine Ser * «Ca» sc t •% & amp; & amp; amp & amp; * < * aaa ^ faS * íf5a¿g-w ^ a? iia ^^^^^^ faith !! ^^ > . & & amp; t s * iES iSj * i *. &'' * Compound / residue Abbreviation Tetrahydrofuran THF Tetramethylfluoroformamidine TFFH hexafluorophosphate Threonine Thr Trifluoroacetic acid TFA Trityl - Trt Tryptophan Trp Valine Val Unless otherwise indicated, the abbreviated amino acids as specified above have L configuration. The amino acids of configuration D are defined by the prefix D using three letter code (e.g., D-Ala, D- Cys, D-Asp, D-Trp, D-pAph). Equal abbreviations, for example, Phe (4-CN) and Phe [4-C (-S- CH2-CH2-S-) -Ph] define the amino acid residue phenylalanine which in position 4 of the phenyl group carries a cyano substituent or a 2-phenyl-1, 3-dithiolan-2-yl substituent, respectively. An abbreviation such as, for example, Dap [-C- (= NH) -NH2] defines the residue of the amino acid 2, 3-diaminopropionic acid in which the amino group in the side chain, ie the amino group in the position 3, is substituted with an amidino-C (= NH) -NH2 group (carbamimidoyl group) by means of which a group results guanidino -NH-C (= NH) -NH2 attached at the 3-position of the unitary propionic acid. Abbreviations such as, for example, 0rn [- C = NH) -NH2] or Cys (Me) define the residue of the amino acid ornithine in which the amino group in the side chain 5 carries an amidino group, or the residue of the amino acid cysteine in that the mercapto group carries a methyl group, respectively. The terms TOTU, HATU and BOP mean 0- [cyan (ethoxycarbonyl) methyleneamino] -1,1,3, 3-tetramethyluronium-10-tetrafluoroborate, 0- (7-azabenzotriazol-1-yl) -1, 1, 3, 3 tetramethyluronium hexafluorophosphate and 1-benzotriazolyloxytris- (dimethylamino) phosphonium hexafluorophosphate, respectively. When used in the present, the term "Specific" when used with reference to the inhibition of Vlla factor activity means that a compound of formula I can inhibit factor Vlla activity without substantially inhibiting the activity of other specific proteases, including plasmin and thrombin (using the same inhibitor concentration). These proteases are involved in the cascade of blood coagulation and fibrinolysis. When used herein, the term "substituent" refers to any of several groups chemicals that are substituted on the main chain l > < ^ l n. '^^ MaÉt-SK .. peptide or the side chain of a peptide, peptide analog, mimetic or organic compound described herein. A substituent may include any of a variety of different portions known to those skilled in the art (see, for example, Giannis and Kolter, Angew, Chem. Int. Ed. Engl. 32 (1993) 1244-1267, which is incorporated in the present as a reference). When used herein, the term "alkyl" is used in the broadest sense to understand straight, branched or cyclic saturated or unsaturated chains of about 1 to 13 carbon atoms where, of course, an unsaturated alkyl group contains at least 2 carbon atoms and a cyclic alkyl group at least 3 carbon atoms. An unsaturated group contains one or more double bonds and / or triple bonds. Thus, the term "alkyl" includes, for example, methyl, ethyl, N-propyl, isopropyl, n-butyl, isobutyl sec-butyl, tert-butyl, 1-methylbutyl, 2,2-dimethylbutyl, 2- methylpentyl, 2,2-dimethylpropyl, n-pentyl and n-hexyl, the alkylene groups, cyclic chains of carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, as well as combinations of linear or branched chains and cyclic chains of atoms of carbon such as a methylcyclohexyl, cyclohexylmethyl, 1-cyclohexylethyl, 2-cyclohexylethyl, cyclopentylmethyl, 1-cyclopentylethyl group, 2- cyclopentylethyl, cyclopropylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, or cyclopropylmethylene. Thus, alkyl also comprises cyclic alkyl groups bearing one or more alkyl substituents. Other examples of alkyl are the specific unsaturated groups mentioned below. In addition, it should be recognized that an alkyl as defined herein may be substituted with one or more identical or different substituents, for example 1, 2, 3 or 4 substituents, which may be present in any suitable position, desired. Preferably, the term "alkyl" means linear or branched, saturated chains of 1 to 6 carbon atoms, linear or branched unsaturated chains of 2 to 6 carbon atoms or cyclic alkyl groups of 3 to 8 atoms carbon, in particular from 3 to 6 or from 6 carbon atoms in the ring. With respect to unsaturated alkyl chains, C2-C6 alkenyl and C2-C6 alkynyl are preferred. Examples of the unsaturated alkyl groups are alkenyl and alkynyl groups such as vinyl, prop-1-enyl, prop-2-enyl (= allyl), but-2-enyl, buten-3-yl, 3-methylbut-2-enyl, ethynyl, prop-2-ynyl, but-2-ynyl and the like. Similarly, the term "acyl" is used in its broadest sense to mean linear, branched chains or saturated or unsaturated cyclics from about 1 to 13 carbon atoms or aryl groups having from 5 to 13 carbon atoms in the ring that are attached to a carbonyl portion -C (0) - and are joined by the carbonyl group. An acyl group can be considered as a derivative of the respective compound containing a C (O) -OH carboxyl group by formally removing the hydroxyl group. Thus, the term "acyl" comprises, for example, groups such as formyl, acetyl, benzoyl and the like. A group of preferred acyl groups comprises the straight, branched or cyclic saturated or unsaturated chains mentioned in the above having the preferred range of carbon atoms, which also contain a carbonyl group by means of which they are united. The term "aryl" refers to aromatic groups containing about 5 to 13 carbon atoms in the ring and at least one "ring" group having a biconjugated electron system. Preferably the term "aryl" refers to the aromatic groups having 6 to 10 carbon atoms in the ring. Examples of the aryl include, for example, phenyl, naphthyl such as 1-naphthyl and 2-naphthyl, fluorenyl, biphenylyl group, and analogs and derivatives thereof, all of which optionally may be substituted with one or more, for example 1, 2 , 3 or 4 identical or different substituents which may be present in any desired position, convenient. For example, a monosubstituted phenyl group can be substituted at the 2, 3 or 4 position, a phenyl group disubstituted at the 2,3, 2,4, 2,5, 2,6, 3,4 or 3,5 position. The term "arylalkyl" refers to an alkyl as already defined, substituted with one or more, for example, 1 or 2 identical or different aryl groups. Convenient arylalkyl groups include benzyl, phenylethyl such as the 1-phenylethyl and 2-phenylethyl, diphenylmethyl, diphenylethyl groups such as 1,2-diphenylethyl and 2,2-diphenylethyl, phenylpropyl such as 1-10 phenylpropyl, 2-phenylpropyl and 3-phenylpropyl, diphenylpropyl, 2,3-diphenylpropyl and 3, 3-diphenylpropyl, naphthylmethyl, naphthylethyl, 1-naphthylethyl and 2-naphthylethyl, naphthylpropyl, 1-naphthylpropyl, 2-naphthylpropyl and 3-naphthylpropyl, 1, 2, 3, 4-tetrahydro- l-15 naphthyl, 1, 2, 3, -tetrahydro-2-naphthyl and the like, all of which may optionally be substituted. The terms "heteroalkyl", "heteroalkenyl", "heteroalkynyl", "heteroalkylalkyl" and "heteroaryl" as used herein refer to a group Alkyl, arylalkyl and aryl, respectively, wherein one or more carbon atoms, for example 1, 2 or 3 carbon atoms, are replaced with identical or different heteroatoms such as N, 0 or S. In addition, the term "heterocycloalkyl" it is used with reference to a group Cyclic alkyl in which one or more carbon atoms of the -3- ~ ^ £ ^ ^ c ^ Sb ^ ^^^ »^^^^ afl ^^« il ^^ * ^^^^ ring are substituted with heteroatoms. Preferably the term "heterocycloalkyl" means a cyclic alkyl group having from 3 to 8 carbon atoms in the ring, of which 1, 2 or 3 are replaced with the same or different heteroatoms such as N, 0 or S. All these groups can be be joined by any desired, convenient position that includes the nitrogen atoms of the ring, suitable in the case of nitrogen heterocycles. Suitable heteroaryl groups, heteroarylalkyl groups, heteroalkyl groups and heterocycloalkyl groups include, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thienyl, 3-thienyl, indolyl, imidazolyl, furyl, piperonyl, -pyr? -methylmethyl, 3- pyridylmethyl, 4-pyridylmethyl, 1- (2-pyridyl) ethyl, 1- (3-pyridyl) ethyl, 1- (4-pyridyl) ethyl, 2- (2-pyridyl) ethyl, - (3-pyridyl) ethyl, 2- (4-pyridyl) ethyl, picolyl, pyrrolidinyl, piperidinyl, tetrahydrofuryl, tetrahydrofuran-2-ylmethyl, morpholinyl, 4-morolinyl, 2- (4-morfoiinyl) ethyl, piperazinyl, 2- (4-methylpiperazin-1-yl) ethyl and the like, all of which optionally may be substituted with one or more, for example, 1, 2, 3 or 4 same or different substituents. The peptides of the invention may be modified at the N-terminus and / or the C-terminus by reaction with suitable reagents or by introduction (or by the presence of) a amino protecting group or a carboxyl protecting group, respectively. The N-terminus of a peptide or peptide analog may be chemically modified such that the N-terminal amino group is substituted, for example, by an acyl group (eg, acetyl, cyclopentylcarbonyl, isoquinolylcarbonyl, furoyl, tosyl, benzoyl, pyrazincarbonyl). or other groups of these). By reaction with an isocyanate, chloroformate, alkylating agent or by the introduction of another such group, all of which may be substituted by a substituent as already described. It should be recognized that the term "amino group" is widely used herein to refer to any free amino group, including a primary, secondary or tertiary amino group, present in a peptide. In comparison, the term "N-terminal" refers to the a-amino group of the first amino acid present in a peptide written in the traditional manner. The N-terminus of a peptide of the invention can be protected by linking an amino protecting group thereto. The term "amino protecting group" is widely used herein to refer to a chemical group that can react with a free amino group, including, for example, the a-amino group present at the N-terminus of a peptide of the invention. By virtue of the reaction with this, one amino protecting group protects the amino group from another Reactive mode against undesirable reactions that may occur, for example, during a synthetic process or due to the activity of the exopeptidase on a final compound. Modification of an amino group may also provide additional advantages, including, for example, increasing the solubility or activity of the compound. Various amino protecting groups are described herein or are otherwise known in the art and include, for example, acyl groups such as an acetyl group, tert-butyloxycarbonyl, alkyloxycarbonyl, benzyloxycarbonyl or benzoyl groups, as well as an amino acyl residue, which itself may be modified by an amino protecting group. Other amino protecting groups are described, for example, in The Peptides, eds. Gross, and Meienhofer, vol. 3 (Academic Press, Inc., New York, 1981); and in Greene and Wuts, in protective Groups in Organic Synthesis, 2nd edition, pages 309-405 (John Wiley &Sons, New York, 1991), each of which is incorporated herein by reference. The product of any such modification of the N-terminal amino group of a peptide or peptide analogue of the invention is referred to herein as an "N-terminal derivative". Similarly, a carboxyl group, such as the carboxyl group present in the C-terminus of a peptide can be chemically modified using a group .? »A_ &v carboxyl protector. The terms "carboxyl group" and C-terminal, are used in a manner consistent with the terms "amino group" and "N-terminal" as already defined. A carboxyl group such as is present in a C-terminal 5 of a peptide can be modified by reduction of the C-terminal carboxy group with an alcohol or aldehyde or by the formation of an oral ester [sic] or by substitution of the carboxyl group with substituent such as thiazolyl, cyclohexyl or another group. Oral esters are well known in the art and include, for example, alkyloxymethyl groups such as methoxymethyl, ethoxymethyl, isopropoxymethyl and the like; 1- (C 1 -C) alkyloxyethyl groups such as methoxyethyl, ethoxyethyl, propoxyethyl, isopropoxyethyl and the like; the 2-oxo-l, 3-dioxolen-4-ylmethyl groups as can be 5-methyl-2-oxo-l, 3-dioxolen-4-ylmethyl, 5-phenyl-2-oxo-1,3-dioxolen-4-ylmethyl and the like; the groups (C 1 -C 3 alkylthio) methyl such as methylthiomethyl, ethylthiomethyl, isopropylthiomethyl and the like; asyloxymethyl groups, such as pivaloyloxymethyl, acetoxymethyl and the like; the ethoxycarbonylmethyl group; methyl groups substituted with 1-acyloxymethyl such as 1-acetoxyethyl; the 3-phthalidyl or 5,6-dimethylphthalidyl groups; the groups 1- ((C 1 -C 4 alkyloxy) carbonyloxy) ethyl such as the group 1-25 (ethoxycarbonyloxy) ethyl; and the 1- (alkylamino group ^ ^^^^ C? -C4) carbonyloxy) ethyl such as the 1- (methylaminocarbonyloxy) ethyl group. A peptide of the invention may be modified by linking a carboxyl protecting group thereto. Carboxy protecting groups are well known in the art and, by virtue of being attached to a peptide, protect a carboxyl group against undesirable reactions (see, for example, Green and Wuts, supra, pages 224-276 (1991), which is incorporated herein by reference). The artisan The expert will recognize that such modifications as those already described, which may be effected in the N-terminal amino group or the C-terminal carboxyl group of a peptide, may likewise be carried out with any amino group or reactive carboxyl group present, for example. , in a side chain of an amino acid or amino acid analogue in a peptide of the invention. Methods for making such modifications are described herein or are otherwise known in the art. The choice to include an L or a D-amino acid in a The compound of the present invention may depend, in part, on the desired characteristics of the peptide. For example, the incorporation of one or more D-amino acids may confer greater stability in the compound in vitro or in vivo. The incorporation of one or more D-amino acids can also increase or decrease the pharmacological activity of compound. In some cases it may be desirable to allow the compound to remain active for only a short period of time. In such cases, the incorporation of one or more L-amino acids in the compound may allow the endogenous peptidases in an individual to digest the compound in vivo, thereby limiting the individual's exposure to the active compound. The skilled person can determine the desirable desirable characteristics of the compound of the invention taking into consideration, for example, the age and general health of an individual. In general, the present invention relates to compounds of formula I in all their stereoisomeric forms and mixtures of two or more stereoisomers in all proportions, for example to pure enantiomers, pure diastereomers, mixtures of two enantiomers in all proportions included the racemates, mixtures of diastereomers, cis isomers, trans isomers, E isomers or Z isomers. The invention also relates to the compounds of the formula I in all their tautomeric forms. Furthermore, the invention relates to the prodrugs of the compounds of the formula I, for example, the esters, amides, aldehydes or alcohols is that they can be obtained from carboxyl groups as already mentioned, or acyl derivatives such as the alkylcarbonyl derivatives of C? -C6, C? -C6alkyloxycarbonyl or C? -C4alkyloxycarbonyl which can be obtained from groups » The present invention also relates to acylatable eta which includes amino groups, imino groups, guanidino groups and amidino groups, and the invention also relates to the active metabolites of the compounds of the formula I. In the compounds of the formula I the Rl group is preferably R12 (0). A specific series of R12 designations is formed by the alkyl, alkenyl, alkynyl, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkenyloxy, alkynyloxy, aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl, heterocycloalkyl, heteroalkyl, heteroalkenyl and heteroalkynyl groups, all of which residues they may be unsubstituted or substituted. R12 is preferably alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylamino, alkenylamino, alkynylamino, aryl, heteroaryl, arylalkyl or heteroarylalkyl, more preferably alkenyloxy, alkenylamino or aryl, all of which residues may be unsubstituted or substituted. Particularly preferably R12 is alkenyloxy or alkenylamino such as C2-C6 alkenyloxy or C2-Cd alkenylamino each containing a double bond, for example, allyloxy or allylamino. In addition, preferably R12 is C2-C6 alkenyloxy. The residues representing R12 can be unsubstituted or substituted. In the substituted R12 residues the residues are preferably replaced with one or more identical substituents selected from the series consisting of halogen, ie, fluorine, bromine or iodine, trifluoromethyl, hydroxy, nitro, amino, cyano, carboxy, aminocarbonyl, alkylsulfonyl, aminosulfonyl, alkyloxy, alkylcarbonylamino and mono or dialkylamino. Of the same, the residues representing R13, R14 and R15 can be unsubstituted or substituted, for example, by the substituents can be present in R12, where R14 and R15 are independent from each other and can be identical or different. E group A in the compounds of the formula I which is the divalent 4-amidinophenylalanine residue -NH-CH [-CH2-C6H4- (4- C (= NH) -NH2)] -C (O) -, is preferably a residue (L) -4- amidinophenylalanine (residue = (S) -4-amidinophenylalanine). He Group B which is the divalent glutamic acid residue -NH- CH [CH2-CH2-C (O) OH] -C (O) - or a pharmaceutically acceptable salt or ester thereof, is preferably an acidic residue (L) - Glutamic (residue of the acid = (S) -glutamate or a pharmaceutically acceptable salt or ester of this R95 is preferably hydrogen or C?-C4 alkyl, more preferably hydrogen or methyl, particularly preferably hydrogen. R81 and R82 substituted can independently carry one or more, for example one, two, three or four identical or different residues which & preferred are selected from the series consisting of amino, aminocarbonyl, amidino, guanidino, aminoalkyl, hydroxyl, mercapto, which may all be substituted with a protecting group, and acetimido (-C (= NH) -CH3), nitro and cyano. With respect to the nitro groups, in the compounds of the formula I according to the invention, preferably up to two nitro groups are present. Suitable protecting groups for the mentioned groups are known to those skilled in the art and can be found in the aforementioned references such as Greene and Wuts, Protective Groups in Organic Synthesis, 2nd edition (John Wiley &Sons, New York, 1991), which is incorporated herein by reference. Examples of the protecting groups are the aforementioned amino protecting groups such as tert-butyloxycarbonyl, benzyloxycarbonyl and allyloxycarbonyl which may also be protective groups on the amidino groups and the guanidino groups, the nitro group which can be used to protect the guanidino group , or groups such as benzyl, methyl, trityl or acetylaminomethyl which can be used to protect groups such as hydroxyl, mercapto and others. Preferably R81 and R82 are selected from the series consisting of hydrogen, alkyl as C? -C6 alkyl, aryl as phenyl, arylalkyl as phenylalkyl of C? ~ C2 and heteroarylalkyl as heteroarylalkyl of C? ~ C2 / which all can to be substituted or unsubstituted and in which the heteroaryl is preferably the residue of a monocyclic or bicyclic aromatic ring system containing one or two heteroatoms in the ring identical or different such as N, O or S, R81 is preferably hydrogen and R82 is an unsubstituted or substituted residue as defined. Particularly preferably, group D represents a residue selected from the series consisting of: Arg, Dap, Dab, Orn, Lys, 10 Dap (-C (= NH) -NH2], Dab [-C (= NH) -NH2). Lys [-C (= NH) -NH2], Lys [-C (= NH) -CH31, Om [-C (= NH) -CH3], Dab [-C (= NH) -CH3], Dap [- C (= NH) -CH31, Dab (Alloc), Asn, Gip, Met, Ser. Thr, Ser (Bzl), Thr (Bzl), Cys (Me), Cys (Bzl), Cys (Acm), Arg. { NO2), His, Trp, Phg, Gly, Ala, Val, Lie, Leu, Phe, Ph (4-NO2), Phe (4-NH-C (= NH) -NH2), 2-Abu, Ala ( 3-CN), Ala. { 3-C (= NH) -NH2], 2-Abu (4-CN) and 2-Abu [4-C (= NH) -NH2I, 15 A subgroup of residues from which waste D is selected in particular Preferred is formed by the series consisting of: Arg, Dap, Dab, Orp, Lys, Dap [-C (= NH) -NH2], Dab [-C (= NH) -NH2], Lys [-C (= NH) -NH2], 20 Asn, Ser , Thr, Ser (Bzl), Arg (N02), Trp, Phg, Ala, Val, He, Leu, Phe, 2-Abu, Ala (3-CN), Ala (3-C (= NH) -NH2) , 2-Abu (4-CN) and 2-Abu (4-C (= NH) -NH2).

The number n of preference is zero, one or two, preferably zero or one. If n is zero, group R2 is directly linked to the carbonyl group representing D3. Yes ^ M ^^^ • ggStesSjÉ ^ ?? ^^ n is different from zero, the group R2 is bonded to the carbonyl group representing the terminal group E3. If n is two or three, the E groups can all be identical or different. The substituted residues R71 and R72 can independently carry one or more, for example, one, two three or four identical or different residues which are preferably selected from the series consisting of: alkyl, alkyloxy, halogen, trifluoromethyl, nitro, cyano, alkylsulfonyl, alkylcarbonyl, phenylcarbonyl and 2-phenol-1,3-dithiolan-2-yl, which may also be substituted. A subset of substituents which may be present in R71 and R72 is formed by the series consisting of: alkyl, alkyloxy, halogen, trifluoromethyl, nitro, cyano, alkylsulfonyl and alkylcarbonyl, which may also be substituted. Preferably, R71 is hydrogen and R72 is an unsubstituted or substituted residue as defined. R 72 is preferably alkyl, in particular C 3 -C 8 alkyl, including cyclic alkyl such as cycloalkylalkyl, such as C 1 -C 2 cycloalkylalkyl, or aryl, in particular phenyl or arylalkyl, in particular C 1 -C 2 phenylalkyl, or heteroarylalkyl, in particular C 1 -C 2 heteroarylalkyl, where all these residues may be unsubstituted or substituted, and where the heteroaryl is preferably a 5-membered or 6-membered monocyclic aromatic ring containing one or two identical ring heteroatoms or íj & & different such as N, O and S. The group or groups E, in particular in the case where the number n is 1, is preferably selected from the series consisting of Phe which is substituted or unsubstituted in the group phenyl, Cha and Chg. E is particularly preferably selected from the series consisting of: Cha, Chg and Phe [4-C (-S-CH2-CH2-S-) -Ph]. The group R70 present in the group E is preferably hydrogen, alkyl, in particular CX-C4 alkyl, including methyl, or arylalkyl, in particular phenylalkyl C, which includes benzyl and 2-phenylethyl which may not be substituted or substituted in the phenyl group. Particularly preferably R70 is hydrogen. The substituted residues R21, R22, R23 and R24 can independently carry one or more, for example, 1, 2, 3 or 4 identical or different residues which are preferably selected from the series consisting of: halogen, in particular F, Cl, Br, hydroxyl, trifluoromethyl, nitro, cyano, dialkylamino, alkyloxy such as methyloxy, alkylenedioxy, alkylsulfonyl, aminosulfonyl and oxo (= 0), which may also be substituted. Examples of alkylenedioxy are methylenedioxy (0-CH2-0) or 1,2-ethylenedioxy. Examples of dialkylamino are dimethylamino, diethylamino or dibutylamino, examples of alkylsulfonyl are methylsulfonyl, ethylsulfonyl or butylsulfonyl. R2 is preferably NR21R22, wherein R21 and R22 are as ^^^^^^^^^^^^^^^^^^^^^^^ ii ^^^^^^^^^^^ i ^^^^^ i ^^^^^^^^ ^^^^^^^^ ñ ^^^^^^^ T ^^^^^^^ defined. R21 is preferably hydrogen, C? -C4 alkyl or C? -C4 phenylalkyl which is unsubstituted or substituted in the phenyl group. Particularly preferably R21 is hydrogen, ie, particularly preferably NR21R22 is NHR22, and thus particularly preferably R2 is NHR22. R22 is preferably a residue selected from the series consisting of hydrogen, alkyl, in particular C 1 -C 12 alkyl, including cyclic alkyl such as cycloalkylalkyl, such as cycloalkylalkyl C? -C4, aryl, in particular C6? C? 3 aryl, arylalkyl, in particular C? -C alkyl substituted with one or two C6-C12 aryl residues, heteroarylalkyl, in particular C? -C4 alkyl substituted with a monocyclic or bicyclic heteroaryl residue containing one or two identical heteroatoms or different as N, O or S, and heterocycloalkylalkyl, in particular C 1 -C 4 alkyl substituted with a 4, 5, 6 or 7 membered monocyclic heterocycloalkyl group containing one or two identical or different heteroatoms such as N, O or S, whose waste can all be not replaced or replaced as indicated in the above. Particularly preferably R22 is a residue selected from the series consisting of hydrogen, benzyl, naphthylmethyl, pyridylmethyl, phenylethyl, naphthylethyl, pyridylethyl, phenylpropyl, naphthylpropyl, pyridylpropyl, fluorenyl, diphenylmethyl, diphenylethyl and diphenylpropyl, whose residues are unsubstituted or substituted with one or more, for example, 1, 2, 3 or 4 identical or different substituents, which are preferably selected from the series consisting of F, Cl, Br, hydroxy, methoxy, methylenedioxy, nitro, cyano, dialkylamino, alkylsulfonyl, aminosulfonyl and trifluoromethyl, which may also be substituted. A series of particularly preferred compounds of the formula I is formed by the compounds in which simultaneously the number n is different from zero, R2 is NHR22 and R22 is hydrogen. Another series of particularly preferred compounds is formed by the compounds in which simultaneously N is 0, R2 is NHR22 and R22 is different from hydrogen, where in this series of compounds a preferred denotation of group D is Asn. The preferred compounds of the formula I are those compounds in which one or more of the groups or residues have the preferred denotations, all combinations of the preferred denotations being the object of the present invention. A group of preferred compounds of the invention is formed by the compounds of formula I, wherein: R 1 is R 12 (O) wherein R 12 is as defined, A is as defined, B is as defined, and Preference B is NH-CHR97- 25 C (O) wherein R97 is ethyl which is substituted at the position The hydroxycarbonyl or a salt of this or alkyloxycarbonyl such as C 1 -C 4 alkyloxycarbonyl, D is NH-CHR82-C (0) , where RF82 is as defined, En is (El-E2-E3) n, where n is zero, one or two, El is NH, E2 is CHR72, where the residues R72 are independent of each other and are identical or different are as defined, E3 is C (O), and R2 is as defined, in any of its stereoisomeric forms or a mixture thereof in any proportion, and the pharmaceutically acceptable salts, amides and esters thereof. A group of particularly preferred compounds is formed by the compounds of formula I, wherein: R 1 is allyloxycarbonyl or allylaminocarbonyl, A is the residue of (L) -4-amidinophenylalanine, B is the residue of (L) -glutamic acid or a pharmaceutically acceptable salt or (L) -glutamic acid ester, D is a residue selected from the series consisting of: Arg, Dap, Dab, Orn, Lys, Dap (-C (= NH) -NH2], Dab [-C (= -NH) -NH2], Lys [-C (= NH) -NH.], Lys [ -C (= NH) -CH3j, Om [-C (= NH) -CH3], Dab [-C (= NH) -CH3], Dap [-C (= NH) -CHS], Dab (Alloc), Asn, Gln, Met. Ser, Thr, Ser (Bzl), Thr (Bzl), Cys (Me), Cys (Bzl), Cys (Acm), Arg (N02), His, Trp, Phg, Gly, Ala, Val, Lie, Leu, Phe, Phe (4-N02), 5 Phe (4-NH-C (= NH) -NH2), 2-Abu, Ala (3-CN), Ala [3-C (= NH ) -NH2], 2-Abu (4-CN) and 2-Abu [4-C (= NH) -NH2j1 n is zero or one, E is a residue selected from the series consisting of: Cha, Chg, and Phe [4-C (-S-CH2-CH2-S-) -PH], R2 is NHR22, R22 is hydrogen or a residue selected from the series consisting of: benzyl, naphthylmethyl, pyridylmethyl, phenylethyl, naphthylethyl, pyridylethyl, phenylpropyl, naphthylpropyl, pyridylpropyl, fluorenyl, diphenylmethyl, diphenylethyl and diphenylpropyl, whose residues are unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of: F, Cl, Br, hydroxy, methoxy, methylenedioxy, nitro, cyano, dialkylamino, Alkylsulfonyl, aminosulfonyl and trifluoromethyl, in any of their stereoisomeric forms or a mixture thereof in any proportion, and the pharmaceutically acceptable salts, amides and esters thereof. The specific examples of the compounds of the Invention include, for example, the compounds that are mentioned in Table 2 below and in the section of the examples and their pharmaceutically acceptable salts, amides and esters. The compounds of the formula I can be prepared, for example, according to the methods of solid phase chemistry by a process consisting of: al) copulating a compound of the formula Fmoc-En-0H, wherein n is 1 , 2 or 3, to an acid-sensitive linker bound to a resin or in general to a solid support, dissociate the Fmoc protecting group, copulate a compound of the formula Fmoc-Dl-D2-C (O) OH to the amino group obtained free and again dissociate the Fmoc protecting group, or for the preparation of the compound of the formula I in which n is 0, copulate a compound of the formula Fmoc- 15 Dl-D2-C (0) OH to a sensitive linker to the acid bound to a resin or in general to a solid support, and to dissociate the Fmoc protecting group, a2) copulate a compound of the formula Fmoc-Bl-B2-C (O) OH to the free amino group obtained in step a) and dissociating the Fmoc protecting group, a3) coupling a compound of the formula R1-A1-A2-C (O) OH to the free amino group obtained in the country or a2), and a4) dissociating the compound obtained according to steps a) to a3) of the resin by means of trifluoroacetic acid.

The resin or filler used in this process can be of a type in a way that a carboxy group in the compound that is coupled to the resin or the linker, respectively, is transformed into an amide group C (0). ) -NH2, for example, a Knorr linker or an Rink amide resin the preparation of a compound in which the number n is two or three can also be carried out step by step by assembling the unit En as follows. In step a) instead of a compound of the formula Fmoc-En-OH where n is two or three, first a The compound of the formula Fmoc-En-OH wherein n is one is coupled to an acid-sensitive linker attached to a resin, then the protective group Fmoc is dissociated and a second compound of the formula Fmoc-En-OH wherein n is one, it is coupled to the free amino group obtained. For the preparation of a compound in which n is three, then the protective group Fmoc dissociates and a third compound of the formula Fmoc-En-OH where n is one, is coupled to the free amino group obtained. Finally, the protective group Fmoc is dissociated in steps a2) to a4) below. Another process for the preparation of the compounds of the formula I consists of: bl) coupling the carboxylic acid of the side chain of a compound of the formula Fmoc-Bl-CHR97-C (O) OPG, wherein R97 is 2- hydroxylcarbonylethyl and PG is a group protective, to a type of benzyl alcohol linker ^^^^^^^^^^ & ^^^^^ g ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^ 5 ^^^? ^^^^^^^^^^^^ fe ^^^^^^^^^^^^ g ^^ sensitive to acid attached to a functionalized amino resin, b2) dissociate the protective group PG, b3) coupling a compound of the formula H2N-D2-D3-En-R2, where n is zero, one or two three, to the free carboxylic acid obtained in step b2), b4) dissociating the group Fmoc protector, b5) coupling a compound of the compound R1-A1-A2-C (0) OH to the free amino group obtained in step b), and b6) dissociating the compound obtained according to steps b) from the resin b5) by means of trifluoroacetic acid. The same way for the modification of the first process described above, in this process the structural unit H2N-D2-D3-En-R2, can be assembled step by step on the resin.

According to another process similar to this process, the compounds of formula I can also be prepared by first coupling a carboxylic acid group that is present in a side chain in group D2 of group D, ie, which is present in one of groups R81 and R82, to a linker attached to the resin. Similarly for the above compound of the formula Fmoc-Bl-CHR97-C (0) OPG, such a compound can, for example, have the formula Fmoc-NH-CR81R82-C (0) OPG, wherein R82 is as defined on the condition that it contains a group C (0) 0H and R81 is as defined. For example, R81 may be hydrogen and R82 may be hydroxycarbonylmethyl, and the compound of the formula Fmoc-NH-CR81R82-C (0) OPG may, thus, be a protected aspartic acid derivative. After deprotecting the C (0) OPG group, the carbonyl group of which is the D3 group in the formula I, the free carboxylic acid group obtained is coupled with a compound type H2N-En-R2 or H-R2. Then, after deprotecting the Fmoc protecting group, the amino group obtained is coupled with a compound of the formula Fmoc-Bl-10 B2-C (0) OH and, after deprotecting the amino group, the product is coupled with a compound of the formula R1-A1-A2- C (0) OH. Again the resin or linker used can be of a type such that the carboxyl group in the compound that is coupled to the resin or the linker, is transformed into an amide group C (0) -NH2. For example, by using an amide resin, an aspartic acid unit attached to the resin can be converted to an asparagine unit in the final compound. A compound of the invention can be synthesized chemically using, for example, an automated synthesizer (see Example 1). The selective modification of a reactive group such as a group present on an amino acid side chain or an N-terminal or C-terminal reactive group in a peptide can impart characteristics desirable as may be higher solubility or better function s ^^^^^^^^^^^^^^^^ j j ^^^^^^^^^^^^^^^^^^^^^^^^^ j ^^^^^^^^^ ü ^ ^? Where solid synthesis methods are employed, the chemical composition of a compound can be manipulated while the nascent peptide is bound to the resin or after the peptide has been dissociated from the resin to obtain, for example, an N-derivative. terminal such as an acylated compound, for example, acetylated, N-terminal. Similar modifications can also be made to a carboxyl group of a compound, which includes a C-terminal carboxyl group which, for example, can be amidated. The compounds can also be prepared by coupling protected amino acids according to the methods of traditional medical chemistry, or organic chemistry in the solution phase, and deprotecting the chosen molecule by standard procedures known in the art. In general, the reactions suitable for the synthesis of the compounds of the formula I by the solid phase methods or the in-phase methods in solution as well as the experimental details such as the coupling agent such as carbodiimides, TOTU or HATU, or solvents or Reaction temperatures are well known to those skilled in the art and can also be found in the standard references including the references mentioned herein as well as the following examples. A synthesized compound can be purified using well-known methods such as reverse phase high performance liquid chromatography (RP-HPLC, see Example I) or other separation methods based on, for example, size, charge or hydrophobicity of the compound. Likewise, well-known methods such as amino acid sequence analysis or mass spectrometry (MS) can be used to characterize the structure of a compound of the invention (see Example I). Different compounds containing different arrangements of the substituents have different levels of inhibitory activity for factor Vlla. For example, the choice of substituents influences the binding affinity of the compounds. These compounds were synthesized according to the procedures described in the examples. Peptide testing for the inhibitory activity was performed using the assay described in Example 22. By using such methods, one skilled in the art can synthesize a compound as already described, including a modification thereof, and determine the inhibitory activity of the factor Vlla of the compound. A composition of the present invention can be provided as a homogeneous composition or as a mixture of compounds containing the different combinations of substituents. The flexibility that allows the choice of substituents allows a great control over the biological properties and MEaS ^^ «ate ^,« 3i ^ j ^^ fJ ^ «» a = - «physicochemical of the compounds and composition of the invention. The invention offers compounds that specifically inhibit the activity of factor VII. Such compounds preferably have a Ki < 500 nM, more preferred < 50 nM, for Vlla factor activity and does not substantially inhibit the activity of other proteases involved in the coagulation and fibrinolysis cascade in relation to the inhibition of factor Vlla (using the same inhibitor concentration). These other proteases include, for example, factor Xa, thrombin and plasmin. The following Table 2 shows the inhibitory activities of factor Vlla (see Example 22 for the method of Ki determination) of the compounds selected from the Formula I which also exemplify the invention.

Table 2: Inhibitory activities of factor Vlla of the selected compounds of formula I twenty Ki (μ; Alloc-pAph-Glu-Arg-Cha-NH2 0.046 Allylaminocarbonyl-pAph-Glu-Arg-Cha-NH2 0.042 Alloc-pAph-Glu-Arg-Chg-NH2 0.238 Ailoc-pAph-Glu-Dap [-C (= NH) -NH2] -Cha-NH2 0.012 Alioc-pA? H-Glu-Ala [3-C (= NH) -NH2] -Cha-NH2 0.03 Alloc-pAph-Glu-Asn-Cha-NH2 0.021 Alloc-pAph-Glu -Dab-Cha-NH2 * "0.055 Alloc-pAph-Glu-Dap [-C { = NH) -NH2] -NH2 0.26 Alloc-pAph-Glu-Gly-Cha-NH2 0.12 Alloc-pAph-Glu-Thr (Bzl) -NH- (CH2) rCH { Ph) 2 0.17 Alloc-pAph-Glu-Dab-NH- (CH2) r-Ph 0.38 Alloc-Aph-Glu-Asp-NH-CH2-Chx 0.15 Alloc -pAph-Glu-Da? [- C (= NH) -CH,] - Cha-NH_ 0.11 Alloc-pAph-Glu-Dab [-C (= NH) -NH2] -Cha-NH2 - '- «" 0.012 Alloc-pAph-Glu-2-Abu (4-CN) -Cha-NH2"" "" 0.063 Allac-pAph-Glu-Ala (3-CN) -Cha-NH2 0 12 Alloc-pAph-Glu-Asn-1 -naphthylmethylamide 0.031 Alloc-pAph-Glu-Asn-1 - (1 -na? hthyt)? thylam! 0.021 Alloc-pAph-Glu-Asp-2-naphthylmethylamide 0.027 Alloc-pAph-Glu-Asn-3,4-dichlorobenzylamid ? c 0.026 ^^^^^^^^^^^^^ M ^^^^^^ gi Alloc-pAph-Glu-Asn-2- (3-chlorophenyl) ethylamide 0.023 Alioc-pAph-Glu-Arg (NO2) -Cha -NH2 0.014 Alloc-pAph-Glu-Cys (Bzl) -Cha-NH2 0.026 Alloc-pAph-Glu-Trp-Cha-NH2 0.017 Alloc-pAph-Glu-Phg-Cha-NH2 0.017 AIIoc-pAph-Glu-Asn- 9-fluorenylamide 0.023 Alloc-pAph-Glu-Asn-3,5-bistrifluoromethylbenzylamide 0.033 AIIoc-pAph-Glu-Phß (4-guanidino) -Cha-NH2 0 12 Alloc-pAph-Glu-D-Ph? (4 -guanidine) -Cha-NH2 11.3 A! loc-pAph-Glu-Om [-C (= NH) -CH3] -Cha-NH2 0 13 10 Alloc-pAph-Glu-Dab [-C (= NH) -CH3] -Cha-NH2 0 19 Alloc-pAph-Glu-Dap [-C (= NH) -NH2] -Phe [4-C (-S- (CH2) 2-S-) - Ph] -NH2 0.015 Alloc-pAph-Glu-Gln-NH2 1.5 Alloc-pAph-Glu-Orn-NH2 6.2 Alloc-pAph-Glu-Gly-Cha-NH2 0.12 Alloc-pAph-Glu-Cys (Acm) -Cha-NH2 ° 12 15 Alloc -pAph-Glu-Cys (Me) -Cha-NH2 0 2 ° Alloc-pAph-Giu-Cys (Bzl) -Cha-NH2 0.026 Alloc-pAph-Glu-Thr (Bzl) -Cha-NH2 0.019 Alloc-pAph- Glu-Dab { Alloc) -Cha-NH2 0 15 Alloc-pAph-Glu-His-Cha-NH2 ° 14 Alloc-pAph-Glu-Met-Cha-NH2 0.11 Alioc-pAph-Glu-Phe (4-N02) -Cha-NH2 0.046 Alloc-pAph-Glu-D-Lys [-C (= NH) -NH2] -Cha-NH2 22 Alloc-pAph-GIu-D-Arg-Cha-NHj 12 Alloc-pAph-Glu-Asn-3,4- methylened? oxybepzylam? 0.12 Alloc-pAph-Glu-Asn-2- (4-morpholinyl) ethylamid? 0.41 Alloc-pAph-Glu-Asn-2- (2-naphthyl) ethylamide 0.052 Alloc-pAph-Glu-Asn-2-. { 1 -naphthyl) ethylamide 0.022 Alloc-pAph-Glu-Asn-2-tetrahydrofurapylmethylam? 0 17 0 1 1 Alloc-pAph-Glu-Asn-3-methylbutylamide ^ y ^ £ ^^? _ * lfe ?; * «¿* .JÜ ^ .. & Alloc-pAph-Glu-Asn-2- (2-pyridyl) ethylamide or 071 Alloc-pAph-Glu-Asn-1, 2,3,4-tetrahydro-1 -naphthylamide 0.045 Alloc-pAph-Glu-Asp-N, N-dibenzylamide or 41 Alloc-pAph ~ Glu-Asn-N-methyl-N- (1 -na? Hthylm? Thyl) amid 1.7 Allsc-pAph-Glu-Asn-2,2-dipylethylamide 0.049 Alloc-pAph -Glu-Asn-2,4-difluorobenzylamide 0.051 Alloc-pAph-Glu-Asn-2- (4-sulfamoyl? H? Nyl) ethylamof 35 ° Alloc-pAph-Glu-Asn-4-dim? Ythylam? Nobenzyla ide 0.11 A! Loc-pAph-Glu-Asn- (CH3-) C a-NH2 0.062 Alloc-pAph-Glu-Asn-3-phenylpropylam? 0.026 Alloc-pAph-Glu-Asn-aS-diphepylpropytamide 0.024 Alloc-pAph-Glu -Asn-4-methoxybenzylamide 0.083 AIIoc-pAph-Glu-Asn-3,4-dichlorobenzylamide 0.026 The thrombin inhibitory activities of the above compounds can be expressed in Ki values which are generally considerably higher than the inhibitory activities of the Vlla factor indicated above., for example, about 200 or about 500 or about 1000 times as high as the inhibitory activities of factor Vlla. Also, the inhibitory activities of factor Xa of the above compounds, as determined can be expressed in Ki values which are generally considerably higher than the inhibitory activities of the factor Vlla indicated above, for example, about 100 times as high as the factor inhibitory activities. Vlla.

These results demonstrate that the compounds of the '* formula I are useful as inhibitors of factor Vlla, but do not substantially inhibit the activity of factor Xa or serine proteases such as thrombin, which are involved. i in the process of coagulation ^ of blood and fibrinolysis. A compound of the invention can be advantageously used as an anticoagulant, which can be in contact with a blood sample to prevent coagulation. For example, an effective amount of a compound of the invention can be contacted with a freshly drawn blood sample to prevent coagulation of the blood sample. When used herein, the term "effective amount" when used in relation to a compound of the invention means an amount of a compound that inhibits factor Vlla activity. The skilled artisan will realize that an effective amount of a compound of the invention can be determined using the methods described herein (see, Example 22) or otherwise known in the art. In view of the disclosed utility of a compound of the invention, the skilled artisan will also realize that an agent such as heparin can be substituted with a compound of the invention. Such use of a compound of the invention may result, for example, in cost savings compared to other anticoagulants.

In addition, a compound of the invention can be administered to an individual for the treatment of a variety of clinical conditions, including, for example, the treatment of a cardiovascular disorder or a complication associated, for example, with infection or surgery. Examples of cardiovascular disorders include restenosis after angioplasty, respiratory distress syndrome in adults, multiple organ failure, cerebrovascular accident, and disseminated intravascular coagulation disorder. Examples of related complications associated with surgery include, for example, deep and proximal venous thrombosis, which may occur after surgery. Thus, a compound of the invention is useful as a medicament for reducing or inhibiting unwanted coagulation in an individual. Since a compound of the invention can inhibit the activity of factor Vlla, such a compound can, in general, be useful for reducing or inhibiting blood coagulation in an individual. When used herein, the term "individual" means a vertebrate, which includes a mammal such as a human, in which the factor Vlla is involved in the coagulation cascade. Blood coagulation in an individual can be reduced or inhibited by administering to the individual a therapeutically effective amount of a compound of the invention.

When used herein, the term "therapeutically effective amount" means the dose of a compound that must be administered to an individual to inhibit Vlla factor activity in the individual. More specifically, a therapeutically effective amount of a compound of the invention inhibits the catalytic activity of factor Vlla directly, within the prothrombinase complex or as a soluble subunit, or indirectly by inhibiting the assembly of factor Vlla in the prothrombinase complex. . Preferred compounds can inhibit factor Vlla activity with a Ki < 500 nM, and more preferably compounds with a Ki < 50 nM. A therapeutically effective amount can be determined using the methods described, for example, in Example 22 or otherwise known in the art. In the practice of a therapeutic method of the invention, the particular dose to obtain a therapeutically effective amount of a pharmaceutical composition to be administered to the individual will depend on some considerations, including, for example, the nature or severity of the disease, the program of administration and the age and physical characteristics of the individual. A suitable dosage can be established using the well-known clinical methods in medicine. So that, the invention offers a method for specifically inhibiting Vlla factor activity by contacting the factor Vlla with a compound having the formula Rl-A-B-D-En-R2. The invention further provides a method for reducing or inhibiting blood pool formation in an individual by administering a therapeutically effective amount of a compound of the invention. A compound of the invention will generally be administered to an individual as a composition containing one or more compounds of the formula I and a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to a medium or composition that is not toxic to an individual or that has acceptable toxicity as determined by the appropriate regulatory agency. When used herein, the term "pharmaceutically acceptable carrier" comprises any of the normal pharmaceutical carriers comprising solid carrier substances such as corn starch, lactose, fats, waxes, etc., or liquids such as, for example, phosphate-buffered saline, water , emulsions such as oil / water or water / oil emulsions and / or normal additives, for example, any of the different types of wetting agents. Suitable pharmaceutical carriers for their formulations are described in Martin in Remington's Pharmaceutical Sciences, 15th ed. (Mack Publishing Co., Easton, 1975) which is incorporated herein by reference. Such compositions, in general, will contain a therapeutically effective amount of a compound of the invention together with a convenient amount of the carrier so as to contain the appropriate dosage for administration to an individual. Thus, the claimed compounds may be useful as drugs to inhibit factor Vlla activity and blood coagulation in an individual. The pharmaceutical compositions or medicaments of the invention can be administered orally, for example, in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or mixtures thereof. aerosol. However, the administration can also be carried out rectally, for example, in the form of suppositories, or parenterally, for example, intravenously, intramuscularly or subcutaneously, in the form of solutions for injection or solutions for infusion, microcapsules, implants or rods or percutaneously or topically, for example, in the form of ointments, solutions or tinctures, or in other forms, for example, in the form of aerosols or nasal sprays. The amount of the active ingredient of the formula I or its pharmaceutically acceptable salt or derivative in a unit dose of a pharmaceutical composition is usually from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg, but depending on the type of pharmaceutical preparation the amount may also be higher. Ipil daily dose of the compounds of the formula I to be administered can be a single daily dose or can be divided into several, for example, administrations in two, three or four parts. The pharmaceutically acceptable carriers may also include, for example, other means, compounds or modifications to the factor Vlla inhibitor compound of formula I which improves its pharmacological function. A pharmaceutically acceptable medium can include, for example, a pharmaceutically acceptable salt. An acid addition salt of a compound of the formula I can be formed, for example, with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or perchloric acid, or with an organic carboxylic acid such as acetic acid. , oxalic acid, maleic acid, malic acid, formic acid, lactic acid, tartaric acid, citric acid, succinic acid or malonic acid, or an organic sulfonic acid such as methanesulfonic acid or p-toluenesulfonic acid. An acid group in a compound of the formula I, for example a carboxylic acid group, can be present as a metal salt, the cation of which is based on the alkali and alkaline earth metals as .Yes- ^ S iSSEi .j & k '~. sodium, lithium, potassium, calcium or magnesium or also non-toxic ammonium salt including quaternary ammonium salts and acid addition salts with amines, for example as ammonium salt, methylammonium, dimethylammonium, trimethylammonium, tetramethylammonium, ethyl-ionium, triethylammonium or tetraethylammonium. Examples of modifications that improve the pharmacological function of the compound include, for example, esterification, such as the formation of C? -C6 alkyl, esters, preferably C? -C6 alkyl esters, wherein the alkyl group It is a linear or branched chain. Other acceptable esters include, for example, cycloalkyl (C5-C7) esters and aryl alkyl esters such as benzyl esters. These esters can be prepared from the compounds described herein using the traditional methods well known in the art of peptide chemistry. Pharmaceutically acceptable modifications may also include, for example, the formation of peptides and amides. Such modifications of the amides, which may be carried out in the compounds of the invention, include, for example, those derived from ammonia, alkylamines (from Ci-Cß), primary and dialkyl (from C?-C6) secondary amines, where the groups alkyl are straight or branched chain, or arylamines having different substitutions. In the case of the secondary amines, the amine may also be in the form of a 5- or 6-membered heterocycle which may contain an unsubstituted or substituted nitrogen atom, an oxygen atom or a sulfur atom in addition to the nitrogen of the amide. Methods for the preparation of such amides are well known in the art. In another embodiment of the invention, a compound of the invention can be used in an assay to identify the presence of factor Vlla or to isolate factor Vlla in a substantially purified form. Preferably, the compound of the invention is labeled with, for example, a radioisotope, and the labeled compound is detected using the routine method useful for detecting the particular label. In addition, a compound of the invention can conveniently be used as a probe to detect the location or amount of factor Vlla activity in vivo, in vi tro or ex vivo. It will be understood that modifications that do not substantially affect the activity of the different embodiments of this invention are included within the invention described herein. Accordingly, the following examples are proposed to illustrate but not to limit the present invention.

Example 1: Peptide synthesis procedures and synthesis procedures in general.

The raw materials used in the synthesis were obtained from chemical sellers such as Aldrich, Sigma, Fluka, Nova Biochem and Advanced Chemtech. During the synthesis, the functional groups of the amino acid derivatives used were protected by blocking groups to avoid side reactions during the coupling steps. Examples of suitable protecting groups and their use are described in The Peptides, supra, 1981, and in volume 9, Udenfried and Meienhofer (eds.), 1987, which is incorporated herein by reference. The peptide synthesis in solid phase, general, was used to produce the compounds of the invention. Such methods are described, for example, by Steward and Young, Solid Phase Peptide Synthesis (Freeman &Co., San Francisco, 1969), which is incorporated herein by reference. Unless indicated otherwise, the peptides were synthesized in resin (TentaGel S NH2 (Rapp Polymere, Tübingen, Germany) An acid-sensitive linker, p- [(R, S) -a- [1- (9H-Fluoren-9-yl) methoxyformamido] -2,4-dimethoxybenzyl] phenoxyacetic acid (Knorr Linker) was coupled to the solid support (Bernatowicz et al., Tetr.Lett 30 (1989) 4645, which is incorporated herein as reference.) Otherwise, the peptides were synthesized in resin from polystyrene cross-linked with 1% divinylbenzene modified with an acid sensitive linker (Rink resin) (Rink, Tetr.Lett.28 (1987) 3787; Sieber, Tert Lett.28 (1987) 2107, each of which is incorporated in The present reference: When the peptides were first synthesized by coupling the carboxylic acid of the side chain of a compound of the formula Fmoc-Bl-CHR97-C (O) OPG to the resin, the modified TentaGel S NH2 resin was used by the binding of the HMPA linker Coupling was performed using N, N'-diisopropylcarbodiimide (DIC) in the presence of an equivalent amount of HOBt, with the exception of Alloc-pAph-OH, where two equivalents (eq.) of HOBt were used. All couplings were performed in N, N-dimethylformamide (DMF) or DMF / DMSO (1/1 mixture) at room temperature (TA) The completion of the coupling was monitored by the ninhydrin test A second (double) coupling was performed where the coupling in the first so it was incomplete. The deprotection of the FMOC group was carried out using 50% piperidine in DMF for 2 + 10 minutes [sic]. The amount of Fmoc released was determined from the absorbance at 300 nm of the solution after deprotection, the volume of the washings and the weight of the resin that was used in the synthesis.

^^^^^^^^^^^ The cycle of each coupling was as follows: Step Action / Reagent Solvent 1. 2. 4 ml 3. Coupling (min 1 h) 4. Washing (3 x 5 ml) DMF 5. Ninhydrin test 6. Deprotection (2 + 10 min) piperidine / DMF 5 ml 50% 7. Wash 6 x 5 ml DMF 8. Repeat starting in step 2 After finishing the assembly of the peptide in the resin, the final deprotection of the Fmoc was performed, if necessary. The resin peptide was then washed successively with DMF and DCM and the peptide was then cleaved and deprotected by a mixture of TFA / thioanisole (95/5) for 1.5 hours, unless otherwise specified. The resin was washed with DCM and the DCM of the wash combined with TFA released. The solution was evaporated, the product precipitated by anhydrous diethyl ether and the precipitated solid was isolated by filtration or centrifugation and drying in vacuo on solid KOH granules. The solid was redissolved in a mixture of water and acetonitrile and lyophilized. The dried peptide was subjected to HPLC purification using a suitable gradient of 0.1% TFA in water and acetonitrile (ACN). After collecting the peak fiüteS - .jK,. < In% containing the proposed synthetic product, the peptide solution was lyophilized and the peptide was subjected to an included spectra of) and / or NMR and / or amino acid analysis to confirm the synthesis of the correct compound. For HPLC analysis, a sample of the product was analyzed using the Beckman HPLC system (consisting of the solvent supply system 126, detector module programmable 166 autosampler 507e, controlled by the data station with Gold Nouveau software) and YMC ODS-AM column of 4.6 x 250 mm at 230 nm and flow rate of 1 ml / min. For the purification of the product, a sample of The crude lyophilized peptide was dissolved in a mixture of 0.1% aqueous TFA containing 10% to 50% ACN. The peptide solution was usually filtered through a syringe connected to a 0.45 μ filter "ACRODISC" 13 CR PTFE (Gelman Sciences, Ann Arbor MI). An adequate volume of The filtered peptide solution was injected into a semipreparative C18 column (Vydac Protein and Peptide C18, 128TP1022 (22 x 250 mm), The Separation Group, Hesperia CA, or YMC ODS-A column (20 x 250 mm); YMC, Inc. Wilmington, NC). The flow velocity of a gradient or isocratic mixture of 0.1% TFA buffer and ACN (HPLC grade) as eluent is kept using a Beckman "SYSTEM GOLD" HPLC (Beckman, System Gold, Programmable Solvent Module 126 and Programmable Detector Module 166 Controlled by "SYSTEM GOLD" software). The elution of the peptide was monitored by UV detection at 230 nm. After identifying the peak corresponding to the compound in synthesis using MS, the compound was collected, lyophilized and biologically tested. The MS was performed using a VG Platform instrument (Fisons Instruments) in ES + mode. For NMR, for common samples were measured in DMSO-d6 (Aldrich) using a Bruker Avance DPX 300 instrument.

Example 2: Synthesis of Alloc-pAph-OH The same procedure is applicable for Alloc-D-pAph-OH Alloc-Phe (4-CN) -OH 57 g (300 mmol) of H-Phe (4-CN) -OH were dissolved in 100 ml of 1M NaOH with the addition of 2M NaOH at pH 10 with cooling with ice. With vigorous stirring, allyl chloroformate (7.5 ml) were added slowly (the pH was maintained at 10 by 2M NaOH). The reaction mixture was stirred at 0 ° C for 15 minutes and at RT for 30 minutes, acidified with HCl to pH 2, extracted with ethyl acetate (3 times), dried with MgSO 4 and evaporated. The residue was re-crystallized from ethyl acetate / hexane to obtain a white solid. Yield: 7.0 g (85%).

Alloc-Phe [4-C (= S) -NH2] -OH 5 2.74 g of Alloc-Phe (4-CN) -OH were dissolved in a mixture of pyridine (50 ml) and triethylamine (20 ml) and passed H2S through it for 30 minutes. The reaction mixture was kept overnight at RT and evaporated. Drying in high vacuum gave 3.21 g of a solid foam of crude thioamide, which is converted directly to the methylthioimidate.

Alloc-Phe [4-C (= NH) -SCH3] -OH Hl 1 g of Alloc-Phe [4-C (= S) -NH2] -OH was dissolved in acetone (50 ml) and methyl iodide (5 ml) was added. The reaction mixture was kept overnight at RT, volatile solvents were evaporated (fast, 35 ° C max) and the residue was treated with diethyl ether. After one hour at 0 ° C, the ether was decanted, the product washed with diethyl ether and dried empty. A yellow solid foam was obtained which was converted directly to the amidine.

Alloc-pAph-OH All Alloc-pHe (4-C (= NH) -SCH3) -OH-HI was dissolved in 50 ml of methanol with 300 μl of acetic acid, and 6E they added 0.5 g of ammonium. The mixture was heated for 3 hours at 55 ° C, evaporated and 10 ml of acetone were added. After 2 hours at 0 ° C, the solid product was filtered, washed with a little cold acetone, a little cold methanol and diethyl ether and dried in vacuo to obtain a yellowish solid. Yield: 0.53 g.

Example 3: Synthesis of Alloc-pAph-Glu-Arg-Cha-NH2 To 1 g of TentaGel S NH2 resin (Substitution 0.26 mmol / g), the Knorr amide linker was attached. In accordance with the general procedures mentioned in Example 1, the following protected amino acids were coupled: Fmoc-Cha-OH, Fmoc-Arg (Pmc) -OH, Fmoc-Glu (OtBu) -OH and Alloc-pAph. The peptide was dissociated and deprotected by TFA / thioanisole (95/5) for 3 hours and processed as described in Example 1. The crude compound was purified using HPLC as described in Example 1 and characterized by MS. (M + H) +: found 729.1, calculated 729.4.

Example 4: Synthesis of Allyl-NH-C (O) -pAph-Glu-Arg-Cha-NH2 To 0.5 g of TentaGel S NH2 resin (0.26 mmol / g substitution), Knorr amide linker was attached. In accordance with the general procedures of Example 1, the following protected amino acids were coupled: Fmoc-Cha-OH, Fmoc-Arg (Pmc) -OH, Fmoc-Glu (OtBu) -OH and Fmoc-Phe (4-CN). After deprotection of the Fmoc at ^ -the N-terminus, the resin was treated with a solution d @ Sfl mmol of allyl isocyanate in 3 ml of DMF for 2 hours. The resin was then washed with DMF and triethylamine / pyridine (1/2) and treated with a saturated solution of H2S in pyridine / triethylamine overnight. The resin was washed with acetone and the thioamide resin was reacted with methyl iodide (3 ml) of a 10% solution of methyl iodide in acetone) for 6 hours. The methylthioimidated resin was washed with acetone, methanol and treated with a solution of 0.2 g of ammonium acetate, 100 μl of acetic acid in 3 ml of methanol at 55 ° C for 3 hours. The resin was washed with methanol, DMF and DCM and the peptide was dissociated and deprotected by TFA / thioanisole (95/5) for 3 hours and processed as described in example 1. The crude material was purified using HPLC as described in Example 1 and characterized by MS. (M + H) +: found 728.3, calculated 728.4.

Example 5: Synthesis of Alloc-pAph-Glu-Arg-Chg-NH2 To 1 g of TentaGel S NH2 resin (Substitution 0.26 mmol / g), the Knorr amide linker was attached. In accordance with * jtafrd --- S! . * iá & ii * iif ****? ''; ^ < ..A, ^ a? -fcs¿ í¿. ^ The general procedures that are mentioned in example 1, the following protected amino acids were coupled: Fmoc-Chg-OH, Fmoc-Arg (Pmc) -OH, Fmoc-Glu (OtBu) -OH and Alloc-pAph. The peptide was dissociated and deprotected by TFA / thioanisole (95/5) during; 3 hours and processed as described in example 1. The crude compound was purified using HPLC as described in example 1 and characterized by MS. (M + H) +: found 718.8, calculated 715.5.

Example 6: Synthesis of Alloc-D-pAph-Glu-Arg-Cha-NH2 To 1 g of TentaGel S NH2 resin (Substitution 0.26 mmol / g), the Knorr amide linker was attached. According to the general procedures mentioned in Example 1, the following protected amino acids were coupled: Fmoc-Cha-OH, Fmoc-Arg (Pmc) -OH, Fmoc-Glu (OtBu) -OH and Alloc-D-pAph -OH (synthesized according to the same procedure as Alloc-pAph-OH in Example 2). The peptide was dissociated and deprotected by TFA / thioanisole (95/5) for 3 hours and processed as described in Example 1. The crude compound was purified using HPLC as described in Example 1 and characterized by MS. (M + H) +: found 729.2, calculated 729.4.

J ^^ tóS ^^^ ife¡ Example 7: Synthesis of Alloc-pAph-Glu-Phe (4-guanidino) - Cha-NH2 To 0.25 g of TehtaGel S NH2 resin (substitution 0.26 5 mmol / g), the ligaddr 'amide of Knorr was added. According to the general procedures mentioned in Example 1, the following protected amino acids were coupled: Fmoc-Cha-OH, Fmoc-Phe (4-NH-C (= NBoc) -NH-Boc) -OH, Fmoc Glu (OtBu) -OH and Alloc-pAph-OH. The peptide was dissociated and deprotected by TFA / thioanisole (95/5) for one hour and processed as described in Example 1. The crude compound was purified using HPLC as described in Example 1 and characterized by MS. (M + H) +: found 771.1, calculated 777.4. Example 8: Synthesis of Alloc-pAph-Glu-Dap [-C (= NH) NH2] - Cha-NH2 To 0.25 g of TentaGel S NH2 resin (0.26 substitution 20 mmol / g), Knorr amide linker was attached. According to the general procedures mentioned in Example 1, the following protected amino acids were coupled: Fmoc-Cha-OH, Fmoc-Dap [-C (= N-Boc) -NH-Boc] -OH, Fmoc-Glu (OtBu) - OH and Alloc-pAph-OH. The peptide was dissociated and deprotected by TFA / thioanisole (95/5) for one hour and processed as described in Example 1. The crude compound was purified using HPLC as described in Example 1 and characterized by MS. (M + H) Í-- found 729.1, calculated 729.4. TO Example 9: Synthesis of Alloc-pAph-Glu-Dap [-C (= NH) -CH3] -Cha-NH2 To 0.25 g of resin TentaGel S NH2 (Substitution 0.26 mmol / g), Knorr amide linker was attached. In accordance with the general procedures of Example 1, the following protected amino acids were coupled: Fmoc-Cha-OH, Fmoc-Dap (Alloc) -OH, and Fmoc-Glu (OtBu) -OH. With the N-terminal Fmoc protecting group, the resin was washed with DMF / NMM / AcOH (5 / 0.5 / 1) in mixture, and under constant mixing with a stream of argon, the Alloc group was deprotected by the addition of 100 mg of Pd (P (PH) 3) 4 over a period of 4 hours. The resin was washed with acetone, DMF and treated with 150 mg solution of 2-methylnaphthyl acetimioimidate in 4 ml of ethanol / DMSO (3/1) for 1 hour. After washing with DMF, the Fmoc group was deprotected (1 + 5 mm) and the N-terminal Alloc-PaPhe-OH was coupled. The peptide was dissociated and deprotected by TFA / Thioanisole (95/5) for 1 hour and processed as described in Example 1. The crude compound was purified using HPLC as described in ^^ jS ^^^^^^.

Example 1 and characterized by MS. (M + H) +: found 700.1, calculated 700.4.

Example 10: Synthesis Alloc-pAph-Glu-Ala [3-C (= NH) ~ NH2] Cha-NH2 To 0.25 g of Tentagel S NH2 resin (substitution 0.26 mmol / g, Knorr amide linker was attached) According to the general procedures of example 1, the following protected amino acids were coupled: Fmoc-Cha-OH, Fmoc-Ala (3-CN) -OH, Fmoc-Glu- (OtBu) -OH and Alloc-Phe (4-CN) -OH A mixture of pyridine and triethylamine (2/1) was saturated with H2S (TA), 15-30 min) and this solution was added to the prewashed resin with pyridine / triethylamine (2/1). After standing overnight, the resin was washed with acetone and treated with a solution of 20% methyl iodide in acetone overnight. The resin was then washed with acetone and methanol. The methylthioimidate bound to the resin was then converted to amidine by heating (water bath 55 ° C, 3 hours) of the resin with a solution of 10 eq of ammonium acetate of methanol containing 5% acetic acid. After this final conversion, the resin was washed with methanol, DMF, DCM. The peptide was dissociated and deprotected by TFA / thioanisole (95/5) for 1 hour and processed as described in Example 1. The crude compound was purified by using HPLC as described in Example 1 and characterized by MS. (M + H) +: found 685.9, calculated 16.4. # J > - Example 11: Synthesis of Alloc-pAph-Glu-Asn-Cha-NH2 At 0.125 g of Rink resin (Substitution 0.78 mmol / g), after deprotection Fmoc, the following protected amino acids were coupled according to the general procedures described in Example 1: Fmoc-Cha-OH, Fmoc-Asn-OH, Fmoc-Glu (OtBu) -OH and Alloc-pAph-OH. The peptide was dissociated and deprotected by TFA / thioanisole (95/5) for 1 hour and processed as described in example 1. The crude compound was purified using HPLC as described in example 1 and characterized by MS. (M + H) +: found 686.9, calculated 687.3.

Example 12: Synthesis of Alloc-pAph-Glu-Dab-Cha-NH2 To 0.25 g of resin TentaGel S NH2 (substitution 0.26 mmol / g), the amide linker of Knorr was added. In accordance with the general procedures mentioned in Example 1, the following protected amino acids were coupled: Fmoc-Cha-OH, Fmoc-Dab (Boc) -OH, Fmoc-Glu (OtBu) -OH and Alloc-25 pAph. The peptide was dissociated and deprotected by t? ^ SíJa? i ^^ ti ^ - ^ UL ^ -ssimí),? ¡SS! ^ S ^^ s ^ »l ~, s ^^ .. -» »*, _. ii8 * aatt ~ 3ia Í ÉMa? '' faith 'TFA / thioanisol (95/5)? - before one hour and processed as described in Example 1. The crude compound was purified using HPLC as described in Example 1 and characterized by MS. (H ^ # *: found 673.2, calculated 5 673.4.

Example 13: Synthesis of Alloc-pAph-Glu-Ala [3-C (= NH) -NH2] - NH2 To 0.25 g of resin TentaGel S NH2 (substitution 0.26 mmol / g), the amide linker of Knorr was added. In accordance with the general procedures of Example 1, the following protected amino acids were coupled: Fmoc-Ala (3-CN) -OH, Fmoc-Glu- (OtBu) -OH and Alloc-Phe (4-CN) -OH. A mix of pyridine and triethylamine (2/1) was saturated with H2S (TA), 15-30 min) and this solution was added to the prewashed resin with pyridine / triethylamine (2/1). After standing overnight, the resin was washed with acetone and treated with a solution of 20% methyl iodide in acetone during the night The resin was then washed with acetone and methanol. The methylthioimidate bound to the resin was then converted to amidine by heating (55 ° C, water bath, 3 hours) the resin with a solution of 10 eq of ammonium acetate of methanol containing 5% acetic acid. After this conversion, final, the resin was washed with methanol, DMF, DCM. The ^ S peptide was dissociated and deprotected by TFA / thioanisole (95/5) for 1 hour and processed as described in example 1. The crude compound was purified using HPLC as described in example 1 and 5 characterized by MS. (M + H) +: found 533.3, calculated 533.2.

Example 14: Synthesis of Alloc-pAph-Glu-Gly-Cha-NH2 At 0.150 g of Rink resin (Substitution 0.78 mmol / g), after Fmoc deprotection, the following protected amino acids were coupled according to the general procedures described in Example 1: Fmoc-Cha-OH, Fmoc-Gly-OH , Fmoc-Glu (OtBu) -OH and Alloc-pAph-OH. The peptide was dissociated and deprotected by TFA / thioanisole (95/5) for 1 hour and processed as described in example 1. The crude compound was purified using HPLC as described in example 1 and characterized by MS. (M + H) +: found 630.1, calculated 630.3. Example 15: Synthesis of Alloc-pAph-Glu-Asn- (Phe-CH2-CH2-) - GLy-NH2 For the N-substituted glycines, the procedure of Zuckermann et al. (J. Am. Chem. Soc. 114) was used. írf ~ w r. (1992) 10646, which is incorporated herein by reference). To 0.1 g of Ring resin (0.78 mmol substitution) after deprotection of Fmoc, bromoacetic acid was coupled through DCM / DMF. After 10 minutes, the resin was washed with DCM and the coupling repeated once more. After washing, with DCM and DMF, the resin was treated with a 1M solution of 2-phenylethylamine in DMSO overnight. After washing with DMF, the resin now bears the residue (Ph-CH2-CH2-) NH-10 CH2-C (0) attached to the linker and reacted with the symmetric anhydride of Fmoc-Asn / Trt) -Oh in DCM / DMF. After deprotection of the Fmoc, according to the general procedures of Example 1, the following protected amino acids were coupled: Fmoc-Glu (OtBu) -Oh and Alloc-pAph-OH. The peptide was dissociated and deprotected by TFA / thioanisole (95/5) for 1 hour and processed as described in the example, the crude compound was purified using HPLC as described in Example 1 and characterized by MS. (M + H) +: found 649.9, calculated 695.3.- Example 16: Al is loc-pAph-Glu-Thr- (Bzl) -NH-CH2- CH2-CH (Ph) 2 H-Thr- (Bz l) -NH-CH2-CH2-CH (Ph) 2-HCl , ^ ^ J1 > '~ * ati2 & 6 ** Lg & ~ "*" • &. * »0.62 g (2 mmol) d Boc-Thr (Bzl) -OH were dissolved in 10 ml of DCM, 2 mmol of triethylamine were added and the solution was cooled to 0 ° C. With stirring, 2 mmol of isobutyl chlorofuwate were slowly added. The cooling bath was removed, the solution was stirred for 15 minutes and 2.5 mmol of 3,3-diphenylpropylamine in 2 ml of DMF was added and stirred for 1 hour at room temperature. The solution was evaporated, dissolved in ethyl acetate and extracted with a 0.5 M solution of KHS04, solution saturated NaHCO3 and brine dried with MgSO4 and evaporated. The oily product was dissolved in 10 ml of DCM, and 10 ml of a 4M solution of hydrochloric acid in dioxane was added. After 10 minutes, the solvents were evaporated, the hydrochloride of the product was precipitated with diethyl ether, filtered, washed with diethyl ether and dried in vacuo to obtain a white solid. MS analysis. (M + H) +: found 403.1, calculated 403.2.

Alloc-pA? H-Glu-Thr (Bzl) -NH-CH2-CH2-CH (Ph) 2 20 To 0.5 g of resin TentaGel S NH2 (substitution 0.26 mmol / g), 4-hydroxymethylphenoxyacetic acid (3 eq. activated with DIC / HOBt for 1.5). Fmoc-Glu (OH) -O allyl was attached to the resin by the side chain using DIC / HOBt / NMI in DMF overnight. The aillo protective group was eliminated rinsing the resin with pd (PPh3) 4 in DMF / AcOH / NMM (10/2/1) for 4 hours in argon. The deprotected carboxyl * group was activated with a solution of 0.5 mmol BOP, 0.5 mmol of HOBt, 1.5 mmol DIEA and 0.5 mmol of H-Thr (Bzl) -NH-CH2-CH2-CH (Ph) 2 HCl in 1.5 ml of DMF for 2 hours. After deprotection of Fmoc, Alloc-pAph-OH was coupled according to the general procedure of Example 1. The peptide was dissociated and deprotected by TFA / thioanisole (95/5) for 1.5 hours and processed as described in Example 1. The crude compound was purified using HPLC as described in example 1 and characterized by MS. (M + H) +: found 805.0, calculated 805.4.

Example 17: Synthesis Alloc-pAph-Glu-Dab-NH-CH2-CH2-Ph To 0.2 g of TentaGel S NH2 resin (0.26 mmol / g substitution) was bound 4-hydroxymethylphenoxyacetic acid (2.5 eq, activated with DIC / HOBt during 4 hours) . The hydroxyl group was substituted with bromine by treating the resin with CBr4) 5 eq) / PPh3 (5 eq.) In DCM for 4 hours. The resin derived from the bromine was treated with a 2 M solution of phenylethylamine in DCM overnight. The Fmoc-Dab (Boc) -OH was coupled to the resin using TFFH / DIEA (acyl fluoride generated in situ). In accordance with the general procedure of example 1, the following protected amino acids were coupled: Fmoc-Glu (OTBu) -OH and Alloc-pAph-Oh the peptide was dissociated and deprotected with • Yes TFA / triisopropylsilane (99/1) for 2 h. The TFA was evaporated, the peptide was dissolved in H20 / ACN and lyophilized. The crude material was purified using HPLC as described in example 1 and characterized by MS. (M + H) +: found 624.2, calculated 624.3.

Example 18: Synthesis of Alloc-pAph-Glu-NH-CH2-CH2-CN To 0.2 g of TentaGel S NH2 resin (0.26 mmol / g substitution) was added 4-hydroxymethylphenoxyacetic acid (3 eq, activated with DIC / HOBt for 1.5 h). The Fmoc-Glu (OH) -O allyl was attached to the resin via the side chain using DIC / HOBt / NMI in DMF overnight. The allyl protecting group was removed by stirring the resin with Pd (PPh3) 4 in DMF / AcOH / NMM (10/2/1) for 4 hours in argon. The deprotected carboxyl group was activated with DIC (3 eq.) / HOBt (3 eq.) For 10 minutes and 2-cyanoethylamine (3 eq.) In DMF was added to the resin for 3 hours. After deprotection of the Fmoc, Alloc-pAph-OH was coupled according to the general procedure of Example 1. The peptide was dissociated and deprotected with TFA / triisopropylsilane (99/1) for 2 h. The TFA was evaporated, the peptide was dissolved in H20 / ACN and lyophilized. The crude material was purified using HPLC as described in example 1 and characterized by MS. (M + H) +: found 473.1, calculated K 2 Example 19: Synthesis of Alloc-pAph-Glu-Asn-NH-CH2-Chx To 0.1 g of TenfaGel S NH2 resin (0.26 mmol / g substitution) was attached the linker * measure of Knorr. The Fmoc-Asp (OH) -O-allyl was coupled to the linker through the side chain and the allyl protecting group was removed as in example 18. The deprotected carboxy group was activated with DIC (5 eq) / HOBt (5 eq.) And cyclohexylmethylamine (5 eq.) In DMF was added 2.5 hours. After deprotection of Fmoc, Fmoc-Glu (OtBu) -OH and Alloc-pAph-OH were coupled according to the general procedure of Example 1. The peptide was dissociated and deprotected with TFA / triisopropylsilane (99/1) for 2 hours. The TFA was evaporated, the peptide was dissolved in H20 / ACN and lyophilized. The crude material was purified using HPLC as described in example 1 and characterized by MS. (M + H) +: found 629.9, calculated 630.3. Example 20: Synthesis of Alloc-pAph-Glu-Asn-NH-CH2-CH2-Ph -tert-butyl ester hydrochloride 2- (S) - [2- (S) -alloyloxycarbonyl) lam? No-3- (4-carbamimido? -25 phenyl) acid ester -propionylamino] -petandioic ^^^^^^^^^^^^^ l ^ * l ^ toi _ ^^^^^^^^^^^^^^^^^^^^^ * ^^^^^ ^ g ^^^^^^^^^^^^^ 2- (S) - [2- (S) - Allyloxycarbonylamino-3- (4-carbamimidoyl-phenyl) -propionic acid hydrochloride] (3.48 g, 10.6 mmol) and the 5-tert-butyl ester 5-methyl ester hydrochloride of 2- (S) -amino petandioic acid (2.7 g, 10.6 mmol) in 20 ml of DMF were added at -15 ° C TOTU (3.83 g. , 11.67 mmol) and N-ethylmorpholine (2.7 ml, 21.2 mmol). The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation, ethyl acetate was added to the residue and the organic layer was extracted with aqueous sodium carbonate aqueous solution, potassium hydrogen sulfate solution and water. The organic layer was evaporated. Yield 2.8 g (50%) MS: m / z = 491.3 (M + H) +. 15 5- (S) - [2- (S) -alloyloxycarbonylamino-3- (4-carbamimidoyl-phenyl) -propionylamino] -petandioic acid 5-tert-butyl ester 1-methyl ester To 5-tert-butyl ester hydrochloride 2- (S) - [2- (S) -alyloxycarbonyl-3- (4-carbamimidoyl-phenyl) -propionylamino] -petandioic acid hydrochloride (3.06 g, 5.8 mmol) in 100 ml of water and 30 ml of THF was added lithium hydroxide hydrate (0.49 g, 11.6 mmol). The solution was stirred at room temperature for 12 hours, evaporated and dried by freezing. The residue was purified by chromatography on Sephadex LH20 using N-butanol / glacial acetic acid / water (17/1/2) as eluent. The pure fractions were combined. The solvent was evaporated, the residue was taken up in water and the aqueous solution was dried by freezing. Yield: 2.7 g (97%). MS: m / z = 477.4 (M + H) +. 4- (S) - [2- (S) -alloxycarbonylamino-3- (4-carbamimidoyl-phenyl) -propionylamino] -4- (2-carbamoyl) (S) - (2-phenylethylcarbamoyl) hydrochloride -ethylcarbamoyl) -butyric (Alloc-pAph-Glu-Asn-NH-CH2-CH2-Ph) To the 5-tert-butyl ester of 2- (S) - [2- (S) -5-allyloxycarbonylamino-3- (4-carbamimidoyl-phenyl) -propionylamino] -petandioic acid (48 g, 0.1 mmol) and the hydrochloride of 2- (S) -amino-N-phenylethyl-succinamide (27 mg, 0.1 mmol) in 5 ml of DMF were added at 0 ° C HATU (39 mg, 0.1 mol), and collidine (24.2 mg, 0.2 mmol). The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation the residue was purified by chromatography on Sephadex LH20 using N-butanol / glacial acetic acid / water (17/1/2) as eluent. The pure fractions were combined. The solvent was evaporated, the residue was taken in water and the aqueous solution was by freezing, 'cleavage: 45 mg (66%). MS: m / z (M + H) +.

Example 21: Synthesis of Alloc-pAph-Glu-Asn-NH- (3-chlorobenzyl) * -: To the 2- (S) - [2- (S) -alyloxycarbonylamino-3- (4-carbamimidoyl-phenyl) -propionylamino] -petandiioic acid 5-tert-butyl ester (50 mg, 0.105 mmol) and the trifluoroacetate of 2 - (S) -amino-Nl- (3-chlorobenzyl) succinamide (61 mg, 0.16 mol) in 5 ml of DMF were added at 0 ° C TOTU (36 mg, 0.11 mmol) and N-ethylmorpholine (57 μl, 0.4 mmol). The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation, the residue was purified by chromatography on Sephadex LH20 using N-butanol / glacial acetic acid / water (17/1/2), as eluent. The pure fractions were combined. The solvent was evaporated, the residue was taken up in water and the aqueous solution was dried by freezing. Yield of 4- (S) - [2- (S) -alloxycarbonylamino] -3- (4-carbamimido-l-phenyl) -propionylamino] -4- (2-carbamo? Ll- (S) - (3 -chlorobenzylcarbamoyl) -ethylcarbamoyl) -butyric acid (Alloc-pAph-Glu-Asn-NH- (3-chlorobenzyl or Alloc-pAph-Glu-Asn-3-chlorobenzylamide): 28 mg (41%) MS: m / z = 658.3 (M + H) +. . < - 'I'I'I'I'I'l'l'l'l'l'l'l'l'l'l'l'l'l'l'l'l'l'l'l'l'l'l'l'l'l Other exemplary compounds prepared in the same way as the previous examples are mentioned in table 2 above.

Example 22: Determination of Ki for the inhibition of FVIIa.

The inhibitory activity (Ki) of each compound towards factor Vlla / tissue factor activity was determined using a main chromogenic assay as described previously (JA Ostrem, F. Al-Obeidi, P. Safar, A. Safarova, SK Stringer, M. Patek, MT Croos, J. Spoonamore, JC LoCascio, P. Kasireddy, DS Torpe, N. Sepetov, M. Labl, P. Wildsgoose, P. Strop, Discovery of Novel, potent, and specific family of factor Xa inhibitors via combinatorial chemistry, Biochemistry 37 (1998) 1053-1059). Kinetic assays were performed at 25 ° C in medium-area microtiter plates (Costar Copr., Cambridge, MA) using a kinetic plate reader (Molecular Devices Spectramax 250). A common assay consisted of 25 μl of human factor Vlla and TF (5 nM and 10 nM, respective final concentration) combined with 40 μl of inhibitor dilutions in 10% DMSO / TBS / PEG buffer (50 mM Tris, 15 mM NaCl , CaCl 2, 5 mM, PEG 8 k at 0.05%, pH 8.15).

After a 15 minute preincubation period, the assay was initiated by the addition of 35 μl of the chromogenic substrate S-2288 (D-Iie-Pro-Arg-pNA, Pharmacia Hepar Inc., final concentration 500 μM). The apparent inhibition constants were calculated from the slope of the progress curves during the linear part of the time course, usually between 1 and 5 minutes after the addition of the substrate for the test. The real Ki was subsequently determined for each compound by correcting the substrate concentration (S) and the Km using the formula Ki = Ki app / (1+ (S) Km) (IH Segal, Enzyme Kinetics, pp 100-125 (John Wiley &Sons, New York, 1975)).

Claims (21)

1. *fa.; CLAIMS 1. A compound of the formula I.R1-ABD-En-R2 (I) 5 wherein R1 represents: R13, R12C (0) or 1 to 3 amino acids, the N-terminal of which may be substituted with a selected substituent of the series consisting of R14C (0), R15S (0) 2 and an amino protecting group, wherein R12 is selected from the series consisting of alkyl, Alkenyl, alkynyl, alkyloxy, alkylamino, alkenylamino, alkynylamino, alkenyloxy, alkynyloxy, aryl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, heteroalkyl, Heteroalkenyl and heteroalkynyl, whose residues may all be substituted, R13 is selected from the series consisting of a protecting group of the amino, hydrogen, alkyl, aryl, aplakyl, heteroaryl, heteroarylalkyl, Heterocycloalkyl and heterocycloalkylalkyl, R14 and R15 are independently selected from the series consisting of alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkyl. A is the group A1-A2-A3, where Al is NH, A2 is CHR93, wherein R93 is 4-amidinophenylmethyl, A3 is C (0) B is the group B1-B2-B3, wherein 10 Bl is NR95, wherein R95 is selected from the series consisting of hydrogen and alkyl, B2 is CHR97, wherein R97 is ethyl which is substituted at the 2-position by a substituent selected from the series consisting of hydroxycarbonyl, alkyloxycarbonyl and arylalkyloxycarbonyl, B3 is C (O), D is the group D1-D2-D3, where D1 is NH, D2 is CR81R82, wherein R81 and R82 are selected independently of the series consisting of hydrogen and the unsubstituted or substituted residues alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl, D 3 is C (O), ^^ Sg * g «^^^^^^^^ i ^^^ g ^^^^ ^ ^ En (El-E2-E3) n, where N is zero, two or three, He is NR70, wherein R70 is selected from the series consisting of: hydrogen, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl. E2 is CR71R72, wherein R71 and R72 are independently selected from the series consisting of hydrogen and the substituted, or unsubstituted, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl residues. E3 is C (O), R2 is selected from the series consisting of: NR21R22, 15 OR23 and R24, wherein R21, R22, R23 and R24 are independently selected from the series consisting of: hydrogen and the alkyl, aryl residues , unsubstituted or substituted, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl and heterocycloalkylalkyl, alkyl and heteroalkyl contain from 1 to 13 carbon atoms, wherein in a heteroalkyl residue one or more carbon atoms are substituted with heteroatoms selected from the series consisting of : N, O and S; 25 Alkenyl, alkynyl, heteroalkyl ilo and heteroalkynyl "Oto" & l & amp; & Gtií & r & &., > jcJ * 3¿ £? If they "contain from 2 to 13 atoms" of carbon, where in a heteroalkenyl and heteroalkynyl residue one or more carbon atoms are substituted with heteroatoms selected from the series consisting of: N, 0 and S; Aryl and heteroaryl contain 5 to 13 carbon atoms in the ring where in a heteroaryl residue one or more carbon atoms are replaced with heteroatoms selected from the series consisting of: N, 0 and S; Heterocycloalkyl contains 3 to 8 carbon atoms in the ring of which 1 to 3 carbon atoms are replaced with heteroatoms selected from the series consisting of: N, O and S; In any of its stereoisomeric forms and mixtures thereof in any proportion, and the pharmaceutically acceptable salts of 2. The compound as claimed in claim 1, wherein the residues representing R12 may be substituted with substituents selected from the series consisting of halogen., ie, fluorine, bromine or iodine, trifluoromethyl, hydroxy, nitro, amino, cyano, carboxy, aminocarbonyl, alkylsulfonyl, aminosulfonyl, alkyloxy, alkylcarbonylamino and mono or dialkylamino. 3. The compound as claimed in claims 1 and / or 2, wherein the residues representing R81 and R82 can be independently substituted with substitutes selected from the series consisting of Sn amino, aminocarbonyl, amidino, guanidino, aminoalkyl, hydroxyl, mercapto, which can all be substituted with a protective group, and acetimido, nitro and cyano. . The compound as claimed in one or more of claims 1 to 3, wherein the residues representing R71 and R72 can be independently substituted with substitutes selected from the series consisting of alkyl, alkyloxy, halogen, trifluoromethyl, nitro, cyano , alkylsulfonyl, alkylcarbonyl, phenylcarbonyl and 2-phenyl-1,3-dithiolan-2-yl. The compound as claimed in one or more of claims 1 to 4, wherein the residues representing R21, R22, R23 and R24 can be independently substituted with substitutes selected from the series consisting of halogen, trifluoromethyl, hydroxy, nitro, cyano, alkyloxy, alkylenedioxy, alkylsulfonyl, aminosulfonyl y = 0. 6. The compound as claimed in one or more of claims 1 to 5, wherein the linear or branched, saturated alkyl chains having 1 to 6 carbon atoms, the linear or branched, unsaturated alkenyl and alkynyl chains have 2 or more carbon atoms. to 6 carbon atoms and the cyclic alkyl groups have from 3 to 8 carbon atoms. 8? L 7. The compound as claimed in one or more of claims 1 to 6, - < fen where: Rl is R12C (0), where R12 is as defined, D is NH-CHR82-C (0), where R82 is as defined, En is (El-E2-E3) n, where n is zero, one or two, The is NH, E2 is CHR72, where R72 is as defined E3 is C (0). The compound as claimed in one or more of claims 1 to 7, wherein n is 0 or 1 and R2 is NHR22, wherein R22 is as defined. 9. The compound as claimed in one or more of claims 1 to 8, wherein R1 is allyloxycarbonyl or allylaminocarbonyl. 10. The compound as claimed in one or more of claims 1 to 9, wherein A is the (L) -4-amidinophenylalanine residue. 11. The compound as claimed in one or more of claims 1 to 10, wherein B is the acid residue (L) -glutamate or a pharmaceutically acceptable salt or ester thereof. The compound as claimed in one or more of claims 1 to 11, wherein D is a residue selected from the series consisting of: Arg, Dap, Dab, Orn, Lys, Oap (-C (= NH) -NH2], Dab [-C (= NH) -NH], Lys [-C (= NH) -NH2], Lys. -C (= NH) -CH31, Dab (Alloc), Asn, Glp, Met, Ser. Thr, Ser (Bzl), Thr (Bzl), Cys (Me), Cys (Bzl), Cys (Ac), Arg (N02), Hís, T, Phg, Gly, Ala, Val, lie, Leu, Phe, Phe (4-N02), 5 Phe (4-NH-C (= NH) -NH2), 2-Abu, Ala (3-CN), Ala [3-C (= NH) -NH2], 2-Abu (4-CN) and 2-Abu {4-C (= NH) -NH2I, 13. The compound as claimed in one or more of claims 1 to 12, wherein E is a residue selected from the series consisting of Cha, Chg and Phe [4-10 C (-S-CH2-CH2-S-) Ph]. The compound as claimed in one or more of claims 1 to 13, wherein R22 is a residue selected from the series consisting of hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl and Heterocycloalkylalkyl, whose residues may all be substituted with substituents selected from the series consisting of halogen, hydroxy, alkyloxy, alkylenedioxy, nitro, cyano, dialkylamino, alkylsulfonyl, aminosulfonyl and trifluoromethyl, which may also be substituted. 15. The compound of formula I as claimed in one or more of claims 1 to 14, wherein: Rl is allyloxycarbonyl or allylamcarbonyl, A is the residue of (L) -4-am? Dinophenylalanine, B is the residue of (L) -glutamic acid or a salt Pharmaceutically acceptable or (L) - acid ester glutamic, D is a residue selected from the series consisting of: Arg, Dap, Dab, Orn, Lys. Dap. { -C (= NH) -NH2], Dab [-C (= NH) -ftH_). Lys [-C (= NH) -NH2], Lys [-C (= NH) -CH3], 5 Dab (Alloc), Asn, Gln, Met, Ser, Thr, Ser (Bzl), Thr (Bzl), Cys (Me), Cys (Bzl), Cys (Acm), Arg (N02), His, Trp, Phg, Gly, Ala, Val, lie, Leu, Phe, Ph? (4-N02), Phe (4- NH-C (= NH) -NH2), 2-Abu, Ala (3-CN), Ala [3-C (= NH) -NH2], 2-Abu (4-CN) and 2-Abu [4- C (= NH) -NH2J, n is zero or one, 10 E is a residue selected from the series consisting of: Cha, Chg, and Phe [4-C (-S-CH2-CH2-S-) -PH], R2 is NHR22, R22 is hydrogen or a residue selected from the series consisting of: benzyl, naphthylmethyl, pyridylmethyl, Phenylethyl, naphthylethyl, pyridylethyl, phenylpropyl, naphthylpropyl, pyridylpropyl, fluorenyl, diphenylmethyl, diphenylethyl and diphenylpropyl, whose residues are unsubstituted or substituted by one or more identical or different substituents selected from the series 20 consists of: F, Cl, Br, hydroxy, methoxy, methylenedioxy, nitro, cyano, dialkylamino, alkylsulfonyl, aminosulfonyl and trifluoromethyl, in any of their stereoisomeric forms or a mixture thereof in any proportion, and the pharmaceutically acceptable salts, amides 25 and esters of these.16. The compound of the formula I as claims in one or more of claims 1 to 14, which is Alloc-pAph-Glu-Arg-Cha-NH2, Allylaminc-carbonyi-pAph-Gi? -Arg-Cha-NH2, Alloc-pAph-Giu-Arg- Chg-NH2, Alloc-pAph-Glu-Dapt-C (= NH) - H2] -Cha-NH2f Alloc-pAph-Glu-AlayS-CÍ-sNH ^ NHzl-Cha-NHj, Alloc-pAph-Glu-Asn- Cha-N H2, Alloc-pAph-Glu-Dab-Cha-NHl, Alloc-pAph-Glu-Dap [-C. { = NH) -NH2] -NH2, Alloc-pAph-Glu-Gly-Cha ~ NH2, Alloc ^ Aph ^ lu-ThrtBzlJ-NH-ICI-bJj-CHIPhJj, Alloo-pAph-Glu-Dab-NH ^ (CH2) rPh, Alloc-pAph-Glu-Asp-NH-CHz-Cpx, Alloc-pAph-Glu-Dap [-C. { = NH) -CH3] -Cha-NH2l Alloc-pAph-Glu-Dab [-C (= NH) -NH2] -Cha-NH2l Al loc-pAph-Glu-2-Abu (4-CN) -Cha-N H2l Alloc-pAph-Glu-Ala (3-CN) -Cha-NH2, AJIoc-pAph-Glu-Asn-1-naphlhylmethylam? D ?, Alloc-pAph-Glu-Asn-1-. { 1-paphthyl) ethylamide, Alloc-pAph-Glu-Asn-2-naphthylmethylam? D ?, Aioc-pAph-Giu-Asn-3,4-dichlorobenzylam? De, Alloc-pAph-Glu-Asn-2- ( 3-chlorophysic) ethylamide, Alloc-pAph-Gl -Arg (N02) -Cha-NHa, Alloc-pAph-Glu-Cys (Bzl) -Cha-NH2, Alloc-pAph-Glu-Tf-Cha-NH2. Alloc-pAph-Glu-Phg-Cha-NH2, Alloc-pAph-Glu-A3n-9-f! Uorenylamide, Alloc-pAph-Glu-Asn-3,5-b? Stfluorornethylbenzylamide, Alloc-pAph-Glu- Dap [-C (* = NH) -NH2] -Phe [4-C (-S- (CH2) 2-S-) - Ph] -NH2I Is- Alloc-? -Glu-Cys (Bzl.}. -Cha-NH2l AIloc-pAph-Glu-T r (Bzl) -C a-NH2l Alloc-pAph-GJu-Phe (4-N02) -Cha-NH2, AHc ^ Ap - GIu-Asn-a ^ -met ylenedioxybenzyla ide, Alloc ^ Aph-Gl? -Asr > 2- <2-naphthyl) ethyíam¡de, Alloc-pAph-Glu-Asn-2- (1-nap t yl) et ylamicl ?, Alloc-pAph-Glu-Asn ^ -ía-pyridy ethyíamide, Alloc-pAph-Glu-Asn ^^ - dip enyiet yla ide, AHoc-pAph-Glu-Asn-2,4-difluorobepzylamidß, or Alloc pAph- ^ lu-Asn-4-dinr? ethylaminobenzylamide, Or a pharmaceutically acceptable salt, amide or ester thereof 17. A process for the preparation of a compound as claimed in one or more of claims 1 to 16, which consists of: al) copulating a compound of the formula Fmoc-En-OH, where n is 1, 2 or 3 , to an acid-sensitive linker bound to a resin, to dissociate the Fmoc protecting group, to couple a compound of the formula Fmoc-Dl-D2-C (O) OH to the obtained free ring group and again to dissociate the Fmoc protecting group, or for the preparation of the compound of the formula I in which n is 0, copulate a compound of the formula F or Dl-D2-C (0) OH to an acid-responsive ligand and dissociate the Fmoc protecting group, a2) copulate a compound of the formula Fmoc-Bl-B2-C (O) OH to the free ammo group obtained in the step a) and dissociate the Fmoc protecting group, a3] copulate a compound of the formula R1-A1-A2-C (O) OH to the free amino group obtained in step a2), and a4) dissociate the compound obtained in accordance with the steps a) to a3) of the resin by means of trifluoroacetic acid, 10 or bl) coupling the carboxylic acid of the side chain of a compound of the formula Fmoc-Bl-CHR97-C (O) OPG, wherein R97 is 2-hydroxycarbonyl and PG is a protective group, to a type of benzyl alcohol linker 15 sensitive to acid bound to a functionalized ammo resin, b2) dissociate the protective group PG, b3) coupling a compound of the formula H2N-D2-D3-En-R2, where n is zero, one or two three, to the acid carboxylic Free obtained in step b2), b4) dissociate the protective group Fmoc, b5) coupling a compound of the compound R1-A1-A2-C (O) OH to the free ammo group obtained in step b4), and b6) dissociate of the ream the compound obtained according to 25 with steps b) to b5) by means of acid trifluoroacetic, J "L? or cl) coupling amino acids protected by traditional medical chemistry and deprotecting for the molecule chosen by 5 the normal procedures known in the art, where Rl, R2, Al, A2, Bl, B2, Dl, D2, D3 and E are defined as in claims 1 to 16, and Fmoc is 9-fluorenylmethyloxycarbonyl 18. The compound as claimed in one or more of claims 1 to 16 or a pharmaceutically acceptable salt thereof for use as a pharmacist 19. A pharmaceutical composition containing an effective amount of a compound as claimed in one or more of claims 1 to 16 or a pharmaceutically salt. Acceptable thereof, and a pharmaceutically acceptable carrier. The compound as claimed in one or more of claims 1 to 16 or a pharmaceutically acceptable salt thereof for use as a factor inhibitor. 20 Vlla. The compound as claimed in one or more of claims 1 to 16 or a pharmaceutically acceptable salt thereof for use in the inhibition or reduction of blood coagulation, inflammatory response, 25 thromboembolic diseases or vascular restenosis.