MXPA01006708A

MXPA01006708A - Thrombin inhibitors

Info

Publication number: MXPA01006708A
Application number: MXPA/A/2001/006708A
Authority: MX
Inventors: Sun Hwa Lee; Koo Lee; Won Hyuk Jung; Cheol Won Park; Sang Koo Lee; Hee Dong Park
Original assignee: Lg Life Sciences Ltd
Priority date: 1998-12-29
Filing date: 2001-06-28
Publication date: 2002-05-09

Abstract

The present invention relates to thrombin inhibitors of formula (I), wherein A, B, C, D, E, F and n have the meaning given in the description, that are useful as anticoagulants. In particular, this invention relates to peptide derivatives having high antithrombotic activity and high oral bioavailability.

Description

THROMBIN INHIBITORS TECHNICAL FIELD The present invention relates to thrombin inhibitors which are useful as anticoagulants. In particular, this invention relates to peptide derivatives having a high antithrombotic activity and high oral bioavailability.

BACKGROUND OF THE INVENTION Thrombosis is characterized by excessive blood clotting. The condition plays an important role in cardiovascular and other related diseases, and thrombotic events are the basis of a significant proportion of the mortality and morbidity that is associated with cardiovascular disease. Thrombosis can cause a range of clinical conditions that are characterized by the location of the blood vessel in which the clot forms. Thrombin is a serine protease similar to trypsin that plays a key role in the blood coagulation cascade by catalyzing the conversion of fibrinogen to insoluble fibrin. This enzyme also activates Factor V and Factor VIII for its own production, and also activates platelets with force. Therefore, thrombin has long been recognized as a regulator in thrombosis and hemostasis, and its inhibition has become the main therapeutic target in the treatment of cardiovascular diseases such as myocardial infarction, unstable angina, deep vein thrombosis and embolism pulmonary. Indirect thrombin inhibitors, such as heparin and warfarin (coumarin) have been used as antithrombotic therapies, however, have several limitations. Heparin demonstrates a low bioavailability and is associated with side effects, such as bleeding problems; in addition, it is not able to inhibit thrombin bound to the clot. Warfarin is an effective oral anticoagulant, but it has a narrow therapeutic window and also requires monitoring of patients. Hirudin, a natural protein inhibitor, has been associated with complications of hemorrhage. 15 Most thrombin inhibitors with low molecular weight are generally based on peptides or peptidomimetic templates A that operate through a direct mechanism of action against the target enzyme. Examples above are the tripeptide aldehydes such as D-Fe-Pro-Arg-H and Me-D-Fe-Pro-Arg-H which proved to be effective inhibitors of Thrombin (Bajusz et al., Med. Chem. 1990, 33, 1729). Recently, D-Fe-Pro-Agmatine and its derivatives have been described as thrombin inhibitors in E.U.A. 4,346,078 and WO93 / 11152 (agmatine = 1-amino-4-guanidinobutane). These compounds are distinguished from earlier tripeptide compounds, because the agmatine compounds lack a carbonyl moiety that is found in similar compounds that contain an Arg side chain. More recently, certain tripeptide thrombin inhibitors have been discovered, in which incorporated 4-amidinobenzilamaine at position P1 in place of agmatine (WO 94/29336). These amidine-based compounds have been shown to have good antithrombotic activity (WO 95/23609). However, this class of compounds generally has little or no oral bioavailability. Certain thrombin inhibitors carrying the single amino acid D-diphenylalanine at the P3 position have been described (WO 93/11152, E.U.A. 5510369, WO 97/15190). These compounds have been shown to have greater potency against thrombin compared to the corresponding analogues of D-phenylalanine (J. Med. Chem. 1992, 35, 3365; J. Med. Chem. 1997, 40, 830). In addition, some of this class of compounds exhibited good oral bioavailability (J. Med. Chem. 1997, 40, 3687; J. Med. Chem. 1997, 40, 3726). In some thrombin inhibitors and Factor Xa inhibitors, amidinothiophene groups have been shown to be the best substitutes for para-benzamidine (WO 95/23609, WO 98/24784, Bioorg, Med Chem. Lett, 1998, 8, 1683). In addition, 2,5-thiophene and other 5-membered heterocyclic portions have been useful as a para-phenylene counterpart in the inhibitors of other enzymes that attack the drug, such as thymidylase synthase and glycine amide ribonucleotide formyltransferase (J. Med. Chem. 1991, 34, 1594; Cancer Research 1994, 54, 1021; WO 97/41115). Therefore, there is a need in the art for thrombin inhibitors to have better oral bioavailability and stability compared to those described above. It has been found that the compounds of the present invention, according to the definitions given below, are potent inhibitors of thrombin in vitro and in vivo. In particular, certain compounds of this invention exhibit high bioavailability after oral administration.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds that are included in formula I below that modulate and / or inhibit serine protease thrombin, as well as to acceptable pro-drugs, pharmaceutically active metabolites and pharmaceutically acceptable salts thereof (said compounds, Pro-drugs, metabolites and salts are called "agents"). The invention is also directed to pharmaceutical compositions containing said agents and their therapeutic use in the treatment of diseases mediated by thrombin, such as myocardial infarction, unstable angina, deep vein thrombosis and pulmonary embolism, as well as other disease states. which are associated with blood coagulation and related coagulant factors.

In general terms, the invention relates to thrombin inhibitors of Formula I: and pharmaceutically acceptable salts thereof, wherein: n is 1, 2 or 3; A is a hydrogen, alkyl, C3.7 cycloalkyl, aryl, -SO2R1, -COR1, -CO2R2, PO (OR1) 2, - (CH2) mCO2R1, - (CH2) mSO2R1, - (CH2) mSO3R? (CH2) MPO (OR1) 2, wherein: R1 is a hydrogen, C1-6 alkyl, C3_7 cycloalkyl, aryl, - (CH2) maryl, or -NR3R4, and R2 is C- | 6 alkyl, C3.7 cycloalkyl, aryl, - (CH2) maryl or alkenyl, m is 1, 2 or 3 wherein: aryl is unsubstituted or substituted phenyl or an aromatic heterocyclic ring with 5-6 members, R3 and R4 are independently hydrogen , C? .6 alkyl or C3.7 cycloalkyl and B is hydrogen or C-? -6 alkyl and C and D are independently hydrogen, phenyl unsubstituted or substituted with one or two substituents selected from CM alkyl, alkoxy of CM, CF3, methylenedioxy, halogen, hydroxy or -NR3R4, C3.7 cycloalkyl or a 5-6 membered heterocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and 1-3 heteroatoms selected from the group consisting of N , O and S, and E is wherein: X is S, O or NR, Y and Z are independently N or CR; wherein R5 is hydrogen or alkyl of CM and R6 is hydrogen, halogen, CF3 or alkyl of CM, and F is -C (NH) N (R7) 2, -C (NH2) NN (R7) 2, -C ( NH2) NOH or -CH2NH (R7) 2, wherein R7 is the same or different, R7 is hydrogen, CM perfluoroalkyl or CM alkyl- The invention also relates to pharmaceutical compositions comprising: an effective amount of an agent selected from the compounds of Formula I and pharmaceutically acceptable salts, pharmaceutically active metabolites and pharmaceutically acceptable pro-drugs thereof; and a pharmaceutically acceptable carrier or vehicle for said agent. The invention also provides methods of treatment of cardiovascular diseases, such as myocardial infarction, unstable angina, deep vein thrombosis and pulmonary embolism, as well as other disease states that are associated with an excess of W thrombin. The compounds of the invention of Formula I are useful for mediating the activity of trypsin-like serine proteases. In particular, the compounds are useful as anticoagulant agents and as agents for the modulation and / or inhibition of the serine protease activity similar to trypsin, whereby treatments for thrombosis and other cardiovascular diseases, including infarction, are provided. to the myocardium, unstable angina, deep vein thrombosis and pulmonary embolism. The terms and abbreviations used in the present invention have their normal meaning, unless otherwise indicated. When employed herein, the following 15 definitions will apply: In accordance with common practice used in the art, A is used in structural formulas herein to represent the bond that is the point of attachment of the portion or substituent to the nucleus or the base structure. Where the chiral carbons are included in chemical structures, unless a particular orientation is represented, it is intended to encompass both stereoisomeric forms.

An "alkyl group" means a straight or branched chain monovalent radical of carbon atoms and saturated and / or unsaturated hydrogen atoms, such as methyl (Me), ethyl (Et), propyl, isopropyl, butyl (Bu), P isobutyl, t-butyl (t-Bu), ethenyl, pentenyl, butenyl, propenyl, ethynyl, butynyl, propynyl, pentynyl, hexynyl and the like, which may be unsubstituted (ie, containing only carbon or hydrogen) or substituted by one or more suitable substituents, as defined below (eg, one or more halogens, such as F, Cl, Br, or I, preferably with F and Cl). A "lower alkyl group" represents an alkyl group whose P? chain contains from 1 to 8 carbon atoms. A "cycloalkyl group" represents a monocyclic, bicyclic or tricyclic, monovalent, non-aromatic radical containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms in the ring, each of which may be saturated or unsaturated, and which may be unsubstituted or substituted by one or more appropriate substituents, as defined below, and to which one or more heterocycloalkyl groups, aryl groups, or groups may be fused. heteroaryl, wherein these by themselves can be substituted or unsubstituted by one or more substituents. A "heterocycloalkyl group" represents a monocyclic radical, bicyclic or tricyclic monovalent non-aromatic that is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 atoms in the ring, which includes 1, 2, 3, 4, 6, 5 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the radical is unsubstituted or substituted by one or more appropriate substituents according to the definitions given below, and to which one or more cycloalkyl groups, aryl groups or heteroaryl groups, which, by themselves, can be W substituted or unsubstituted by one or more suitable substituents. An "aryl group" represents a monovalent monocyclic, bicyclic or aromatic monovalent tricyclic radical comprising 6, 10, 14 or 18 carbon atoms in the ring that can be substituted or unsubstituted by one or more appropriate substituents defined below, and to which one or more cycloalkyl groups, heterocycloalkyl groups or groups can be fused P? heteroalkyl, which, by themselves, may be substituted or unsubstituted by one or more suitable substituents. Therefore, the term "aryl group" includes a benzyl group (Bzl), or a tricyclic radical comprising 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or 18 atoms in the ring, including 1, 2, 3, 4 or 5 heteroatoms selected from nitrogen, Oxygen and sulfur can be substituted or unsubstituted by one or more suitable substituents as explained below, and to which k one or more cycloalkyl groups, heterocycloalkyl groups or aryl groups can be fused which, by themselves, can be substituted or not substituted by one or more appropriate substituents. 20 A "heterocycle" is a heteroaryl or heterocycloalkyl group (each of which, as defined above, is optionally substituted).

An "acyl group" is a radical -C (O) -R, wherein R is a substituent and is explained below. A "thioacyl group" is a radical -C (S) -R, wherein R is a substituent and is explained below. A "sulfonyl group" is a radical -SO2R, wherein R is a substituent and is explained below. A "hydroxy group" represents the -OH radical. An "amino group" represents the radical -NH2. An "alkylamino group" represents the radical -NHRa, wherein Ra is an alkyl group. A "dialkylamino group" represents the radical -NRaRb, wherein Ra and Rb are independently an alkyl group. An "alkoxy group" represents the radical -ORa, wherein Ra is an alkyl group. Examples of alkoxy groups include methoxy, ethoxy, propoxy and the like. An "alkoxycarbonyl group" represents the radical -C (O) ORa > wherein Ra is an alkyl group. An "alkylsulfonyl group" represents the radical -S02Ra, wherein Ra is an alkyl group. An "alkylaminocarbonyl group" represents the radical -C (O) NHRa, wherein Ra is an alkyl group. A "dialkylaminocarbonyl group" represents the radical -C (O) NRaRb, wherein Ra and Rb are independently an alkyl group.

A "mercapto group" represents the radical -SH. An "alkylthio group" represents the radical -SRa, wherein Ra is an alkyl group. A "carboxy group" represents the radical -C (O) OH. A "carbamoyl group" represents the radical -C (O) NH2. An "aryloxy group" represents the radical -ORc, wherein Rc is an aryl group. A "heteroaryloxy group" represents the radical -OR, wherein R is a heteroaryl group. An "arylthio group" represents the radical -SRC, wherein Rc is an aryl group. A "heteroarylthio group" represents the radical -SRd, wherein Rd is a heteroaryl group. A "leaving group" (Lv) is any suitable group that will be replaced by a substituent reaction. One skilled in the art will know that any conjugated base of a strong acid can function as a leaving group. Illustrative examples of suitable leaving groups include, but are not limited to -F, -Cl, -Br, alkyl chlorides, alkyl bromides, alkyl iodides, alkyl sulfonates, alkyl benzenesulfonates, alkyl p-toluenesulfonates, methanesulfonates of alkyl, triflate and any other group comprising a bisulfate, methyl sulfate or sulfonate ion. Typical protection groups, reagents and solvents are well known in the art. An expert in the field would know about the possible protection groups, reagents and solvents; it is intended that these be within the scope of this invention. The term "appropriate organic portion" is any organic portion that is recognized, by means of routine tests performed by those skilled in the art, for not adversely affecting the inhibitory activity of the inventive compounds. Illustrative examples of suitable organic moieties include, but are not limited to, hydroxyl groups, alkyl groups, oxo groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkoxy groups, carboxy groups, amino groups, alkylamino groups, dialkylamino groups, carbamoyl groups, arylthio groups, heteroarylthio groups, and the like. The term "substituent" or "appropriate substituent" refers to any appropriate substituent that can be recognized or selected by means of routine tests performed by those skilled in the art. Illustrative examples of suitable substituents include hydroxy groups, halogens, oxo groups, alkyl groups, acyl groups, sulfonyl groups, mercapto groups, alkylthio groups, alkyloxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, heteroaryl groups, carboxy groups, amino groups , alkylamino groups, dialkylamino groups, carbamoyl groups, aryloxy groups, heteroaryloxy groups, arylthio groups, heteroarylthio groups, and the like. The term "optionally substituted" expressly indicates that the specified group is not substituted or substituted by one or more appropriate substituents, unless the substituents are specifically specified, in which case the term indicates that the group is not substituted or substituted by substituents specified. As defined above, several W groups can be substituted or unsubstituted (i.e., they are optionally substituted), unless otherwise indicated herein (eg, by indicating that the specified group is not substituted). The terms "understand" and "include" are used in an open, non-limiting sense. A "pharmaceutically acceptable prodrug" is a compound which can be converted under physiological conditions or by solvolysis to the specified compound or a pharmaceutically acceptable salt of said compound.A "pharmaceutically active metabolite" is a pharmacologically active product produced through metabolism in the body of a specified compound or a salt thereof. The metabolites of a compound can be identified by using routine techniques known in To the technique and its activities determined by tests such as those described herein. A "pharmaceutically acceptable salt" is a salt that retains the The biological effectiveness of acids and free bases of the specified compound, and that is not biologically or otherwise undesired. A compound of the invention may possess a sufficiently acidic or basic group, or both functional groups, and react accordingly with any number of inorganic or organic bases, and inorganic or organic acids, to form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include those salts prepared P by reacting the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulphates, pyrosulfates, bisulfates, sulphites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates , chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, P? malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylene sulphonate, phenylacetate, phenylpropionate, phenylbutyrates, citrates, lactates, -hydroxybutyrates, glycolates, tartrates, methane sulfonates, propansulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelates. Some abbreviations appearing in this application are indicated below: Boc: t-butoxycarbonyl Pro: proline 20 EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride HOBT: 1-hydroxybenzonitrile hydrate TFA: trifluoroacetic acid AcOH: acetic acid DMF: dimethylformamide EtOAc: ethyl acetate HCl: hydrochloric acid ta: room temperature TEA: triethylamine EM FAB: fast atom bombardment mass spectrum If the compound of the invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable commercially available method, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or with an organic acid, including acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyrovic acid, oxalic acid, glycolic acid, salicylic acid; a pyranosidyl acid, including glucuronic or galacturonic acid; an alpha-hydroxy acid, including citric acid or tartaric acid; an amine acid, including aspartic acid or glutamic acid; an aromatic acid, including benzoic acid or cinnamic acid; a sulfonic acid, including p-toluenesulfonic acid or ethanesulfonic acid, or the like. If the compound of the invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, the treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), a alkali metal hydroxide or an alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonium, primary, secondary and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium. In the case of solid agents, those skilled in the art understand that the compounds and salts of the invention can exist in different crystalline or polymorphic forms, which in their entirety are within the scope of the present invention and the specified formulas. Preferred compounds of the invention include, but are not limited to the following: 1. N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, 2. N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(5-aminomethyl-2-thienyl) methyl] amide, 3. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, 4. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidrazone-2-thienyl) methyl] amide, . N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-aminomethyl-2-thienyl) methyl] amide, 6. N-benzylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amida, 7. N-t-butoxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, 8. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, 9. N-aminosulfonyl-D-3,4-dichlorophenylalanyl-L-prolyl - [(5-amidino) 2-thienyl) methyl] amide, 10. N-methoxycarbonyl-D-dicyclohexylalanyl-L-prolyl - [(5-amidino-2-thyl) methyl] P-amide, 11. N-aminosulfonyl-D-diphenylalanyl- L-prolyl - [(4-amidino-2-thienyl) methyl] amide, 12. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-thienyl) methyl] amide, 13. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(4-aminomethyl-2-thienyl) methyl] amide, 14. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2- thienyl) methyl] amide, 15. N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-3-thienyl) methyl] amide, P 0 16. N-methylsulfonyl-D-diphenylalanyl-L-prolyl- [(5-amidino-3-thienyl) methyl] amide, 17. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidrazone-3-thienyl) methyl] amide, 18. N-methylsulfonyl-D- diphenylalanyl-L-prolyl - [(5-aminomethyl-3-thienyl) methyl] amide, 19. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-3-thienyl) methyl] amide, twenty. N-cyclohexylsulfamoyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] 15-amide, 21. N-allyloxycarbonyl-D-d-phenylalanyl-L-prolyl - [(5-amidino-2-t Enyl) methyl] amide, 22. N-benzylsulfonyl-D-cyclohexylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, 23. N-cyclohexylsulfamoyl-D-cyclohexylalanyl-L-prolyl - [(5-amidin-2-thienyl) methyl] amide, 24. N-methylsulfamoyl-D-cyclohexylalanyl-prolyl - [(5-amidino-2 -thienyl) methyl] amide, . N-methylsulfonyl-D-cyclohexylglycinyl-L-prolyl - [(5-amidino-2-thienyl) methylamide, 26. N- (t-butoxycarbonyl) methyl-D-diphenylalanyl-L-prolyl - [(5-amidino -2-thienyl) methyl] amide, 27. N- (t-butoxycarbonyl) methyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, 28. N-carboxymethyl- D-diphenylalanyl-L-prolyl - [(5-amidino-2-thyl) methyl] amide, P 29. M'methyl-N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(5-amidino -2-thienyl) methyl] -amide, 30. N-hydroxysulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, 31. N-methylsulfonyl-D-diphenylalanyl-L-azetidine-2-carboxyl- [ (5-amidino-2-thienyl) methyljamide, 32. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-methyl-2-thienyl) methyl] rio amide, 33. N-methylsulfonyl- D-diphenylalanyl-L-prolyl - [(5-amidino-2-furanyl) methyl] amide, 34. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-furanyl) methyl] amide, . N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-3-furanyl) methyl] amide, 36. N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-thiazolyl) methyl] amide, 37. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-1-methyl) -2-pyrrolyl) methyl] amide, I 38. N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(5-amidino-3-thienyl) methyl] amide, 39. N-carboxymethyl-D-diphenylalanyl-L- prolyl - [(4-amidino-2-thiazole) methyl] amide, 40. N- [2- (methoxycarbonyl) ethyl] -D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, 41. N- (2-carboxyethyl) -D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, 42. N-Boc-D-Diphenylalanyl-L-prolyl - [( 5-amidrazone-2-thienyl) methyl] amide, 43. D-diphenylalanyl-L-prolyl - [(5-amidrazone-2-thienyl) methyl] amide, 44. N-methoxycarbonyl-D-diphenylalanyl-L-azetadine- 2-carboxyl - [(5-amidino-2-thienyl) methyljamide, 45. N- (2-carboxyethyl) -D-diphenylalanyl-L-azetadine-2-carboxyl - [(5-amidin-2-thien) l) methyljamide, 46. N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(5-hydroxyamidino-2-thienyl) methyl] amide, 47. N- (methoxycarbonyl) methyl-D-diphenylalanyl-L-prolyl- [ (5-hydroxyamidi no-2-t-phenyl) methyljamide, 48. D-diphenylalanyl-L-prolyl - [(5-amidino-2-thyl) methyl] amide, IO 49. N- (3-carboxypropyl) -D-diphenylalanyl -L-prolyl - [(5-amidino-2-thienyl) methyl] amida, 50. N- (MeO) 2PO-D-diphenylalanyl-L-prolyl - [(5-amino-2-thienyl) methyl] amide, 51. N- (Me) 2 P (O) -D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, 52. N- (HO) 2 P (O) -D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, 53. N-methyl-D-diphenylalanyl-L-prolyl - [(5-amidin-2-thienyl) methyl] amide, 54. N-phenyl-D-diphenylalanyl-L-prolyl - [(5-amidino -2-alkyl) methyl] amide, 55. N - [(N, N-diethylcarboxyamido) methyl] -D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyljamide, 56. N - [(N, N-diethylcarboxyamido) ethyl] -D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyljamide, 0 57. N-aminosulfonyl-D-diphenylalanyl-prolyl- [(5-amidino-2-thiazole) methyl] amide, 58. N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-thiazole) methyl] amide, 59. N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-tiazole) methyljamide, 60. N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-5-thiazole) methyl] amide, 61. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thiazole) methyl] amide, 62. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-thiazole) methyl] amide, 63. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-thiazole) methyljamide, 64. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-5-thiazole) methyl] amide, 65. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thiazole) methyl] amide, 66. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-thiazole) methyl] amide, 67. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-thiazole) methyl] amide, 68. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-5-thiazole) methyl] amide, 69. N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thiazole) methyl] amide,? 70. N-Carboxymethyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-thiazole) methyl] amide, 71. N-carboxymethyl-D-d-phenylalanyl-L-prolyl - [(2-amidino-5-thiazole) methyljamide, 72. N-aminosulfonyl-D-d-phenylalanyl-L-prolyl - [(5-amino-2-oxazolyl) methyljamide, 73. N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-oxazolyl) methyl] amide, 74. N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-oxazolyl) methyljamide, 5 75. N-aminosulfonii-D-diphenylalanyl-L-prolyl - [(2-amidino-5-oxazolyl) methyl] ]amide, 76. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-oxazolyl) methyljamide, 77. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-oxazolyl) methyl] amide, 78. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-oxazolyl) methyljamide, 79. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-5-oxazolyl) methyl] amide, 0 80. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-oxazolyl ) methyl] amida, 81. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-oxazolyl) methyl] amide, 82. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(4-amidin-2-oxazolyl) methyl] amide, 83. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-5-oxazolyl) methylalide, 84. N-carboxymethyl-D-diphenylalanyl-prolyl - [(5-amidino-) 2-oxazolyl) methyl] amide, 85. N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-oxazolyl) methyl] amide, 86. N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(4-amidin-2-oxazolyl) methyljamide, 87. N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(2-amidino-5-oxazolyl) methyl] amide, 88. N-aminosuifonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-isoxazolyl) methyl] amide, 89. N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-isoxazolyl) methyljamide, 90. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-isoxazole) methyl] amide, 91. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-oxazolyl) methyl] amide, 92. N-methoxycarbonyl-D-phenylalanyl-L-prolyl - [(2-amidino-4-isoxazolyl) methyl-amide, 93. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-isoxazolyl) methyl] ] amide, 94. N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-isoxazolyl) methyljamide, 95. N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-isoxazolyl) methyl] amide, 96. N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-pyrazolyl) methyljamide, 97. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidin-2-pyrazolyl) methyljamide, 98. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-) 2-pyrazolyl) methyl] amide, 99. N-Carboxymethyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-pyrazolyl) methylamide, 100. N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-pyrrolyl) methylamide, 101. N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-pyrrolyl) methyl] amide, 102. N-aminosulfonyl-D-d-phenylalanii-L-prolyl - [(5-amidin-3-pyrrolyl) methyl] amide, 103. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-pyrrolyl) methyl] amide, 104. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidin-2-pyrrolyl) methyl] amide, 105. N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-3- pyrrolyl) methyl] amide, 106. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-pyrrolyl) methyl] amide, 107. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-pyrrolyl) methyl] amide, P 108. N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-3-pyrrolyl ) methyl] amide, 109. N-Carboxymethyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-pyrrolyl) methyl] amide, 110. N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(4-amidin -2-pyrrolyl) methyl] amide, 111. N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(5-amidin-3-pyrrolyl) methyl] amide, 112. N-aminosulfonyl-D-dicyclohexylalanyl -L-prolyl - [(5-amidino-2-thienyl) methylj amide, P? 113. N-Methylsulfonyl-D-dicyclohexylanyl-L-prolyl - [(5-amidino-2-thyl) methyl-methyl, 114. N-carboxymethyl-D-dicyclohexylalanyl-L-prolyl - [(5-amidin-2-thienyl) methyl] amide, 115. N-aminosulfonyl-D-bis- (para-methoxyphenyl) alanyl-L-piOlyl - [(5-amidino-2-thienyl) methyljamide, 116. N-methylsulfonyl-D-bis- (para-methoxyphenyl) alanyl-L- prolyl - [(5-amidino-2-thienyl) -15-methyljamide, 117. N-methoxycarbonyl-D-bis- (para-methoxyphenyl) alanyl-L-prolyl - [(5-amidino-2-k thienyl) methyl] amide , 118. N-Carboxymethyl-D-bis- (para-methoxyphenyl) alanyl-L-prolyl - [(5-amidino-2-thienyl) methyljamide, 20 119. N-aminosulfonyl-D-bis- (para-aminophenyl) alanyl-L-prolyl - [(5-amidino-2-thienyl) methyljamide, 120. N-methylsuifonyl-D-bis- (para-aminophenyl) aanil-L-prolyl - [(5-amidino-2-thienyl) methyljamide , 121. N-methoxycarbonyl-D-bis- (para-aminophenyl) alanyl-L-prolyl - [(5-amidino-2-thienyl) methyljamide, 122. N-carboxymethyl-D-bis- (para-aminophenyl) alanil -L-prolyl - [(5-amidino-2-thienyl) methyljamide, 123. N-aminosulfonyl-D-bis- (para-chlorophenyl) alanyl-L-prolyl - [(5-amidin-2-thienyl) methyljamide, 124. N-methylsulfonyl-D-bis- (para-chlorophenyl) alanyl-L-prolyl - [(5-amidino-2-thienyl) methyljamide, 125. N-methoxycarbonyl-D-bis- (para-clo riphenyl) alanyl-L-prolyl - [(5-amidino-2-thienyl) methyljamide, 126. N-carboxymethyl-D-bis- (para-chlorophenyl) alanyl-L-prolyl - [(5-amidino-2-thienyl Methyljamide, The compounds of the present invention can be prepared according to the general procedure described below: As explained in Example 1 and Example 8 (Scheme 1), a protected amino acid, such as N-Boc-D- Diphenylalanine is coupled to a proline methyl ester using a coupling agent such as EDC and HOBT.

The resulting dipeptide is treated with a strong acid such as hydrochloric acid gas or trifluoroacetic acid to remove the protection group of t-butoxycarbonyl (Boc). The resulting free amine reacts with a sulfonylating reagent such as sulfamoyl chloride and a base such as triethylamine. The carbamate-containing compounds are prepared by chloroformates. The product is then hydrolyzed with a base such as lithium hydroxide, and the resulting acid is coupled with the desired amine, such as 5- (aminomethyl) thiophene-2-carbonitrile. The coupled product is converted to amidine by a three step sequence including sequential treatment with hydrogen sulfide, methyl iodide and ammonium acetate. The amidrazone compound is obtained by treatment with hydrazine instead of ammonium acetate in the final step. The nitrile intermediate is also converted to methylamine by catalytic hydrogenation in the presence of a strong acid such as hydrochloric acid.

SCHEME 1 1 HjS 1 HjS Hj, Pd-C, HCl 2. Mel 2. Mel 3 NH4OAc 3. NH2NH2 An alternative route, as depicted in Scheme 2, is to hydrolyze the dipeptide protected by Boc before functionalizing the amino group, and then coupling the resulting acid with the desired amine. The coupling product protection group is removed and subsequently OR} fpr > Free the amine.

SCHEME 2 N-Boc-D-diphenylalanine can be coupled directly with the proline coupled with amine, as explained in Example 32 (Scheme 3). The product is deprotected and subsequently sulphonylated.

SCHEME 3 Another method for synthesizing the compounds of the invention, particularly N-carboxyalkyl substituted compounds, is carried out in accordance with the explanations in Example 28 and Example 29 (Scheme 4). The compound containing the free amine reacts with an alkylating agent such as t-butylbromoacetate and a base such as diisopropylethylamine (DI PEA). The resulting compound is treated with hydroxylamine hydrochloride in the presence of a base such as sodium carbonate, and the resulting amidoxime is catalytically hydrogenated in the presence of an acetic anhydride to produce the amidine. The t-butyl group is removed with an acid such as trifluoroacetic acid and hydrochloric acid to give the product as a result.

SCHEME 4 The coupling of amides used to form the compounds of this invention is typically carried out by the carbodiimide method with reagents such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC). Another method for forming the amide or peptide linkage includes, but is not limited to, synthetic routes through an acid chloride, azide, mixed anhydride or activated ester. The addition and removal of one or more protection groups is a common practice. Methods for proper protection and deprotection are provided in "Protective Groups in Organic Synthesis", 3rd edition, by T. W. Green and Peter G. M. Wuts (1999), John Wiley & Sons, Inc., editors. The amide coupling reactions are carried out in an inert organic solvent, such as dimethylformamide, dimethylacetamide, tetrahydrofuran, dirchloromethane, chloroform, and other similar common solvents or a mixture of said solvents. Compounds that regulate, modulate or potently inhibit the conversion of fibrinogen to fibrin by the thrombin enzyme and, therefore, inhibit thrombosis and coagulation, are desirable and represent preferred embodiments of the present invention. The present invention is also directed to methods of modulating the serine protease activity similar to trypsin, for example, in mammalian tissues, by administering an agent of the invention. The activity of the compounds herein, as modulators of trypsin-like serine protease activity, such as thrombin activity, can be measured by any of the methods available to those skilled in the art, including in vivo assays and / or in vitro. These properties can be evaluated, for example, by one or more of the biological test procedures described in the examples below. The active agents of the invention can be formulated into pharmaceutical compositions according to the following descriptions. The pharmaceutical compositions of this invention encompass an effective modulating, regulating or inhibiting amount of a compound of Formula I and an inert pharmaceutically acceptable carrier or diluent. In one embodiment of the pharmaceutical compositions, effective levels of the agents of the invention are provided to provide the therapeutic benefits, including modulation of serine protease similar to trypsin. "Effective levels" refers to levels at which the effects of trypsin-like serine protease such as thrombin are regulated to a minimum. These compositions are prepared in unit dosage form for the route of administration, for example, parenteral or oral administration. The compositions of the invention can be produced in the generally known ways for the preparation of pharmaceutical compositions, for example, by using conventional techniques such as mixing; dissolve, granulate, prepare dragees, levigate, emulsify, encapsulate, trap or lyophilize. The pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, which can be selected from excipients and auxiliaries that facilitate the processing of the active compounds into preparations for pharmaceutical use.

The pharmaceutical compositions also encompass suitable solid or gel phase vehicles or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols. Therefore, if a solid carrier is used, the preparation can be formed into tablets, placed in a hard gelatin capsule in powdered or pill form, or a troche or lozenge. The amount of the solid carrier may vary, but will generally be from about 25 mg to 1 g. If a liquid vehicle is used, the preparation is carried out in the form of a syrup, emulsion, capsule, sterile injectable solution or suspension in an ampoule or vial, or a non-aqueous liquid suspension. To obtain a stable water-soluble dosage form, a pharmaceutically acceptable salt of an agent of the invention is dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic or citric acid. If a soluble salt form is not available, the agent can be dissolved in a suitable cosolvent or combinations of cosolvents. Examples of suitable cosolvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0-60% of the total volume. In an exemplary embodiment, a compound of Formula I is dissolved in DMSO and diluted with water. The composition may also be in the form of a solution or a salt of the active ingredient in a suitable aqueous vehicle such as isotonic water or saline or a dextrose solution.

A pharmaceutical carrier for the hydrophobic compounds is a cosolvent system including benzyl alcohol, a non-polar surfactant, an organic water-miscible polymer and an aqueous phase. The cosolvent system can be a VPD cosolvent system. VPD is a solution of 5% benzylic alcohol at 3% w / v, 8% w / v of the non-polar surfactant polysorbate 80, and 65% w / v polyethylene glycol 300, brought to volume in absolute ethanol. The VPD cosolvent system (VPD: 5W) contains VPD diluted 1: 1 with 5% dextrose in a water solution. This cosolvent system dissolves the hydrophobic compounds well, and produces on its own a low toxicity in the systemic administration. Naturally, the proportions of a cosolvent system can be varied considerably without impairing its solubility and toxicity characteristics. In addition, the identity of the cosolvent components can vary: for example, other non-polar surfactants of low toxicity can be used in place of polysorbate 80; the polyethylene glycol fraction size can be varied; other biocompatible polymers can replace polyethylene glycol, for example: polyvinylpyrrolidone; and other sugars or polysaccharides can be substituted for dextrose. As an alternative, other administration systems for the hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are recognized examples of delivery vehicles or vehicles for hydrophobic drugs. Also, certain organic solvents such as dimethisulfoxide can be used, although, generally, at the expense of greater toxicity. In addition, the compounds can be administered using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the agent P therapeutic. Various sustained release materials known to those skilled in the art have been established. Sustained-release capsules can, depending on their chemical nature, release the compounds over a period of a few weeks to more than 100 days. Depending on their chemical nature and the biological stability of the therapeutic reagent, other strategies for stabilizing the proteins may be employed. pO It will be estimated that the actual doses of the agents used in the compositions of the present invention will vary according to the particular complex employed, the particular composition formulated, the route of administration and the site, host and disease treated in particular. Those skilled in the art can determine the optimum doses for a certain set of conditions when using conventional dose determination tests, in view of the experimental data for an agent. For oral administration, an example for a daily dose used ranges from 0. 001 to about 1000 mg / kg of body weight, more preferably between 0.001 to about 50 mg / kg of body weight and more still preferred 1-20 mg / kg, with courses of treatment that are repeated at appropriate intervals. Prodrug administration is typically dosed at chemically equivalent weight levels to the weight levels of the fully active form. For intravenous administration, the most preferred doses will range from about 0.01 to about 10 mg / kg / minute during an infusion at a constant rate. With certain advantages, thrombin inhibitors can be administered in Doses divided two, three or four times a day, In addition, they can be administered in intranasal form by appropriate intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches known to those skilled in the art. a transdermal delivery system, dose administration will, of course, be continuous rather than intermittent throughout the dose regimen. The therapeutically effective amounts of the agents of the invention can be used to treat diseases mediated by modulation or regulation of serine. trypsin-like protease An "effective amount" refers to the amount of an agent that, when administered to a mammal that requires such treatment, is sufficient to perform the treatment for a disease mediated by the activity of one or more serine proteases similar to trypsin, such as thrombin. Therefore, a therapeutically effective amount of a compound of Formula I, a salt, a metabolite or prodrug thereof, is an amount that is sufficient to modulate, regulate or inhibit the activity of one or more protein kinases, such as way that reduces or alleviates the conditions of a disease mediated by this activity. The amount of a particular agent that will correspond to such amount will vary depending on factors such as the particular compound, the clinical condition and its severity, the identity (eg, weight) of the mammal that requires treatment, but can be determined routinely by a skilled in the art. "Treatment" refers to at least alleviating the condition of a disease in a mammal, such as a human suffering, at least in part, from the activity of one or more serine proteases similar to trypsin, such as thrombin, and includes: preventing the clinical condition from occurring in a mammal, particularly when the mammal is predisposed to have the clinical condition but has not yet been diagnosed; modulate and / or inhibit the clinical condition; and / or alleviate the clinical condition. An appropriate formulation depends on the route of administration chosen. The compounds of the invention can be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous or intramuscular form, which are well known to those skilled in the pharmaceutical art. An effective but non-toxic amount of the desired compound can be used as an anti-aggregation agent. To treat ocular formation of fibrin, the compounds may be administered intraocularly or topically, as well as orally or parenterally. For injection, the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible pH regulators, such as Hank's solution, Ringer's solution or a physiological saline pH regulator. For transmucosal administration, appropriate penetrants are used in the formulation for the insulator that must be penetrated. In general, such penetrants are well known in the art.

For oral administration, the compounds can be easily formulated by combining active compounds with pharmaceutically acceptable carriers known in the art. These vehicles "facilitate the compounds of the invention can be formulated in the form of tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions and the like, for oral ingestion by a patient under treatment." Pharmaceutical preparations for oral use can obtained by a solid excipient mixed with the active ingredient (agent), optionally by grinding the resulting mixture, and processing the mixture of granules after * 10 of having added suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; and cellulose preparations, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as interlaced polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof as sodium alginate. Dragee cores have appropriate coatings.

For this purpose, concentrated sugar solutions may be employed which may contain gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and organic solvents or mixtures of suitable solvents. Dyes or pigments can be added to tablets or dragee coatings for identification or to characterize the different combinations of active agents. Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft gelatin capsules and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients mixed with fillers such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active agents can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration must present appropriate doses for such administration. For buccal administration, the compositions may be in the form of tablets or troches formulated in conventional manner. For intranasal or inhalation administration, the compounds for use in accordance with the present invention are conveniently supplied in the form of an aerosol spray of pressurized packaging or a nebulizer using an appropriate propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoromethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the unit dose can be determined by providing a valve to supply the measured quantity. Capsules and gelatin cartridges for use in an inhaler or insufflator and the like can be formulated containing a powder mixture of the compound and an appropriate powder base such as lactose or starch. The compounds can be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dose form, for example, in ampoules or multiple dose containers, with an added preservative. The compositions may be in the form of suspension, solution or emulsion in oily or aqueous vehicles, and may contain formula agents such as suspending, stabilizing and / or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in a water soluble form. In addition, suspensions of the active agents can be prepared as suspensions of appropriate oily injection. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters, such as ethyl oleate or triglycerides or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspension may also contain stabilizers or appropriate agents that increase the solubility of the compounds to facilitate the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for constitution with an appropriate vehicle, for example, sterilized water without pyrogens, before use. The compounds can also P formulated in rectal compositions, such as suppositories or enemas retention, for example, that contain conventional suppository bases, such as cocoa butter or other glycerides. In addition to the formulations described above, the compounds can also be formulated as a depot preparation. Such long-acting formulations can be administered by FIO implant (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (eg, as an emulsion in an acceptable oil) or ion exchange resins, or as moderately soluble derivatives, for example, as a moderately soluble salt . The thrombin inhibitors can also be co-administered with appropriate anticoagulant agents or thrombolytic agents, such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of different vascular pathologies. For example, thrombin inhibitors increase the efficacy of thrombolytic reperfusion mediated by tissue plasminogen activators. The thrombin inhibitors can be administered first, after thrombus formation, and subsequently the tissue plasminogen activator or other plasminogen activator is administered. They can also be combined with heparin, aspirin or warfarin. Anticoagulant therapy is indicated for the treatment and prevention of a variety of thrombotic conditions, particularly coronary artery disease and cerebrovascular disease.

Those skilled in the art are aware of the circumstances that require anticoagulant therapy. The term "patient" as used herein refers to mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats and mice. The dose regimen using thrombin inhibitors is chosen in accordance with a variety of factors, including type, species, age, weight, gender and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient and the particular compound or salt thereof that have been used. A trained physician or veterinarian can easily determine and prescribe the effective amount of the drug required to prevent, counterattack or stop the progress of the condition. The inhibition of thrombin is not only useful in the anticoagulant therapy of people who have thrombotic conditions, but whenever an inhibition of blood coagulation is required to prevent the coagulation of all the stored blood and to prevent coagulation in other biological samples for tests or storage. Therefore, thrombin inhibitors can be added or contacted with any medium that contains or is thought to contain thrombin, and in which it is desired to inhibit blood coagulation, for example, when the blood of a mammal enters the bloodstream. contact with material selected from the group consisting of vascular grafts, stents, orthopedic prostheses, cardiac prostheses and extracorporeal circulation systems. The agents of the invention can be prepared using the reaction routes and synthetic schemes described below, using commercially available techniques from readily available materials. The preparation of the preferred compounds of the present invention is described in detail in the following examples, but the skilled artisan will recognize that the described chemical reactions can easily be adapted to prepare various protein kinase inhibitors of the invention. For example, the synthesis of compounds not illustrated with examples according to the invention can be satisfactorily performed by modifications obvious to those skilled in the art, for example, by appropriate protective groups, when switching to other suitable reagents known in the art, or when performing routine modifications of reaction conditions. Alternatively, other reactions described herein or known in the art will be recognized as applicable for the preparation of other compounds of the invention.

EXAMPLE 1 Preparation of N-aminosulfonyl-D-diphenylalanyl-L-propy3-5-amino-2-thienyl) methypamide TFA A) 5- (Bromomethytofen-2-carbonitrile) A mixture of 5-methylthiophen-2-carbonitrile (9.9 g, 80.5 mmole), benzoyl peroxide (0.23 g, 095 mmole) and N-bromosuccinimide (15 g, 84.3 mmole) ) in carbon tetrachloride (200 ml) was heated under reflux for 6 hours.The resulting suspension was filtered and the filtrate was diluted with dichloromethane (400 ml), washed with a saturated solution of sodium bicarbonate, dried over sodium sulfate, magnesium and concentrated in vacuo The residue was purified by column chromatography (EtOAc: n-hexane, 1: 4) and gave the title compound as a yellow oil (14.0 g, 86%). 1 H NMR (CDCl 3) d 7.50 (d, 1 H), 7.13 (d, H), 4.68 (s, 2H) E FAB: 203 [M + 1] * B) 5- (Aminomethyl) thiophene-2-carbonitrile. HCl To a cold solution of 5- (bromomethyl) thiophene-2-carbonitrile (4.2 g, 20.8 mmol) in THF (500 mL) was added sodium hydride (60% dispersion in oil, 1.0 g, 25 mmol) in portions. To this solution was added di-t-butyl-iminodicarboxylate (4.9 g, 22.9 mmol) in portions. After stirring for 3 hours, the resulting solution was diluted with ethyl acetate (400 ml), washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (EtOAc: n-hexane, 1: 4) and yielded 5- (N, N-Boc2-aminomethyl) thiophene-2-carbonitrile as a yellow foam. This solid was dissolved in ethyl acetate (150 ml) and cooled to 0 ° C. Bubbles were created in the HCl gas through the solution for 10 min, and the mixture was allowed to warm to room temperature. The solvent was removed in vacuo to yield 2.4 g (yield: 86%) of the title compound as a pale yellow solid. 1 H NMR (CD 3 OD) d 7.48 (d, 1 H), 7.20 (d, 1 H), 4.21 (s, 2 H). EM FAB: 175 [M + 1] * C) N-aminosulfonyl-D-diphenylalanyl-L-proline methyl ester To a stirred solution of chlorosulfonyl isocyanate (6.3 g, 45 mmol) in dichloromethane (25 ml) was added dropic acid dropwise (2.13 g, 45 mmol) ). The mixture was heated under reflux for 5 hours and cooled to give a solution of 1.8 N sulfamoyl chloride in dichloromethane. To a cold (0 ° C) solution of methyl ester of D-diphenylalanyl-L-proline.HCl (2.5 g, 6.47 mmol) in dichloromethane (100 ml) was added a solution of 1.8 N sulfamoyl chloride (6 ml) and triethylamine (2.7 ml). After the completion of the reaction, the resulting solution was diluted with dichloromethane (40 ml), washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (EtOAc: n-hexane, 2: 1) to yield the title compound (1.88 g, 67%). 1 H NMR (CDCl 3) d 7.38-7.20 (m, 4H), 7.18 (m, 6H), 5.85 (d, 1 H), 5.29 (s, 2H), 4.95 (dd, 1 H), 4.75 (m, 1 H), 4.14 (d, 1 H), 3.67 (s, 3H), 2.70 (m, 1H), 1.74 (m, 3H), 1.38 (m, 1H).

D) N-Aminosulfonyl-D-diphenylalanyl-L-proline To a suspension of N-aminosulfonyl-D-diphenylalanyl-L-proline methyl ester (1.88 g, 4.36 mmole) in a mixture of water (100 ml) and methanol ( 150 ml) was added 0.5N lithium hydroxide (40 ml), and the mixture was stirred overnight at room temperature. The resulting solution was acidified to pH 2 by adding 1N HCl and the solvent was partially removed by evaporation in vacuo. The precipitations were collected by filtration to yield the title compound as a white crystalline solid (1.68 g, 92%). 1 H NMR (CD 3 OD) d 7.40 (m, 2 H), 7.33 (m, 2 H), 7.24 (m, 6 H), 4.95 (dd, 1 H), 4.29 (d, 1 H), 4.05 (m, 1 H) , 3.75 (m, 1 H), 2.87 (m, 1 H), 1.83-1.72 (m, 3H), 1.43 (m, 1 H).

EM FAB: 417 [M + 1j * E) N-Aminosulfonyl-D-diphenylalanyl-L-prolyl-r (5-cyano-2-thienyl) metin amide A mixture of N-aminosulfonyl-D-diphenylalanyl-L-proline (0.2 g, 0.48 mmol), 5- (aminomethyl) thiophene-2-carbonitrile.HCl (0.1 g, 0.57 mmol), EDC (0.14 g, 0.72 mmol), HOBT (0.08 g, 0.62 mmol), and triethylamine (0.2 ml), 1.44 mmole) in DMF (2 ml) was stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in EtOAc and washed successively with a saturated solution of sodium bicarbonate, 1 N HCl, and brine. After drying the solution over magnesium sulfate and concentrating in vacuo, the residue was purified by column chromatography (EtOAc: n-hexane, 2: 1) to yield the title compound (0.2 g, 78%). 1 H NMR (CDCl 3) d 1.38 (m, 1 H), 1.50 (m, 1 H), 1.92 (m, 2 H), 2.61 (m, 1 H), 3.63 (m, 1 H), 4.12 (m, 1 H), 4.40 (m, 2H), 4.52 (m, 1 H), 4.89 (m, 1 H), 5.25 (m, 2H), 6.87 (m, 1 H), 7.15-7.55 (m, 11 H) . EM FAB: 537 [M + 1j * F) N-Aminosulfonyl-D-diphenylalanyl-L-prolyl-r (5-amidino-2-thienyl) methinamide.TFA A solution of the coupling compound prepared in Step E (0.2 g, 0.37 mmol) in pyridine ( 2 ml) was saturated with gaseous H2S.

After allowing the mixture to stand for one day, the solvent was removed in vacuo to yield the thioamide as a yellow solid. To this material was added acetone (2 ml) and iodomethane (0.07 ml, 1.12 mmol), and the mixture was heated under reflux for 1 hour. After evaporating the solvent in vacuo, the resulting methylthioamidate was dissolved in acetonitrile (2 ml). To this solution was added ammonium acetate (0.09 g, 1.12 mmol) for 10 minutes and the mixture was heated under reflux for 1 hour. The solution was cooled and concentrated, and the residue was purified by column chromatography using 10% methanol in chloroform to yield the title compound which was purified one more time by preparative HPLC (gradient TFA (0.1%) - H2O-MeO). The pure fractions were lyophilized to yield a white solid as a TFA salt (0.15 g, 60%). 1 H NMR (CD 3 OD) d 1.46 (m, 1 H), 1.62 (m, 1 H), 1.73 (m, 1 H), 1.85 (m, 1 H), 2.90 (m, 1 H), 3.76 (m, 1 H), 4.05 (q, 1 H), 4.31 (d, 1 H), 4.59 (m, 1 H), 4.62 (m, 1 H), 4.98 (m, 1 H), 7.25-7.51 (m, 11 H), 7.77 (m, 1 H). EM FAB: 555 [M + 1J * EXAMPLE 2 Preparation of N-aminosulfonyl-D-p-phenylalanyl-L-prolyl-rf5-aminomethyl-2-thieni-D-methylamide.HC! N-Aminosulfonyl-D-diphenylalanyl-L-prolyl - [(5-cyano-2-thienyl) methyljamide prepared in Example 1, Step E (0.1 g, 0.19 mmol) was dissolved in methanol (2 mL). To this solution was added 10% palladium on carbon (100 mg) and 3 drops of concentrated HCl, and the mixture was stirred for 2 days under H2 (4.21 kg / cm2). The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (gradient 0.1% TFA-H2O-MeOH) to yield the title compound (40 mg, 36%) as a white solid. 1 H NMR (CD 3 OD) d 1.41 (m, 2 H), 1.50 (m, 1 H), 1.72 (m, 1 H), 1.82 (m, 1 H), 2.98 (m, 1 H), 3.75 (m, 1 H), 4.05 (m, 3H), 4.38 (m, 3H), 4.98 (m, 1 H), 7.20-7.51 (m, 12H). EM FAB: 542 [M + 1] * EXAMPLE 3 Preparation of N-methylsulfonyl-D-diphenylalanyl-L-prolyl-f (5-amidino-2-thieni-O-methylamide.

A) N-Methylsulfonyl-D-diphenylalanyl-L-proline To a cold (0 ° C) solution of methyl ester of D-diphenylalanyl-L-proline.HCl (2 g, 5.67 mmol) in dichloromethane (100 ml) was added. added methanesulfonyl chloride (0.52 ml, 6.8 mmol) and triethylamine (3.1 ml, 22.7 mmol), and the mixture was stirred for 2 hours at room temperature. After the completion of the reaction, the resulting mixture was washed with 1 N HCl and then with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (EtOAc: n-hexane, 1: 2) to yield N-methylsulfonyl-D-diphenylalanyl-L-proline methyl ester (2.1 g, 86%) of. This compound was hydrolyzed essentially according to the procedure of Example 1, Step D, to yield the title compound (1.8 g, 90%). 1 H NMR (CD 3 OD) d 1.45 (m, 1 H), 1.70-1.90 (m, 3 H), 2.91 (m, 4 H), 3.85 (m, 1 H), 4.1 1 (m, 1 H), 4.32 (m , 1 H), 4.98 (m, 1 H), 7.18-7.42 (m, 10H). EM FAB: 417 [M + 1j * B) N-Methylsulfonyl-D-diphenylalanyl-L-prolyl-r (5-cyano-2-thienyl) methylene amide The title compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L-proline and 5- (aminomethyl) thiophene-2-carbonitrile.HCl essentially according to the coupling procedure of Example 1, Step E; 88% yield. 1 H NMR (CDCl 3) d 1.45 (m, 2 H), 1.72 (m, 1 H), 2.06 (m, 1 H), 2.56 (m, 1 H), 2.80 (s, 3 H), 3.61 (m, 1 H), 4.28 ( m, 1H), 4.36 (d, 1H), 4.50 (m 2H), 4.83 (m, H), 5.44 (m, 1H), 6.96 (m, 1H), 7.22-7.51 (m, 11H). EM FAB: 537 [M + 1j * C) N-Methylsulfonyl-D-diphenylalanyl-L-prolyl-r (5-amidino-2-thieniphenyl-amide.TFA) The title compound was prepared from the compound obtained in Step B using the procedure described in Example 1 , Step E, yield 54%, 1 H NMR (CD3OD) d 1.42 (m, 1H), 1.64 (m, 1H), 1.81 (m, 2H), 2.87 (s, 3H), 2.95 (m, 1H), 3.72. (m, 1H), 4.04 (m, 1H), 4.31 (d, 1H), 4.58 (m 2H), 5.02 (m, 1H), 7.18-7.42 (m, 9H), 7.50 (m, 2H), 7.78 (m, 1H) EM FAB: 554 [M + 1] * EXAMPLE 4 Preparation of N-methylsulfonyl-D-diphenylalanyl-L-prolyl-r (5-amidrazone-2-thieni-Dermipamide.TFA A solution of N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-cyano-2-thienyl) methi-amide. TFA prepared in Example 3, Step B (0.2 g, 0.37 mmol) in pyridine (2 ml) was Saturated with gaseous H2S. After allowing the mixture to stand for 1 day, the solvent was removed in vacuo. The yellow solid obtained was dissolved in acetone (2 ml) and iodomethane (0.07 ml, 1.12 mmol) and the mixture was heated under reflux for 1 hour. After evaporating the solvent in vacuo, the residue was dissolved in acetonitrile (2 ml). To this solution was added 80% hydrazine (0.07 ml, 1.12 mmol) for 10 minutes, and the mixture was stirred for 1 hour. The solution was concentrated and the crude product was purified by preparative HPLC (gradient of TFA (0.1%) - H2-O-MeOH) to yield the title compound as a white solid (0.14 g, 55%). 1 H NMR (CD 3 OD) d 1.39 (m, 1 H), 1.52 (m, 1 H), 1.80 (m, 2 H), 2.92 (m, 4 H), 3.69 (m, 1 H), 4.03 (m, 1 H ), 4.31 (d, 1 H), 4.50 (m, 2 H), 5.02 (m 1 H), 7.02 (m, 1 H), 7.21-7.55 (m, 11 H). EM FAB: 569 [M + 1] * EXAMPLE 5 Preparation of N-methylsulfonyl-D-diphenylalanyl-L-prolyl-r (5-aminomethyl-2-thieni-P-methylamide.

The title compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-cyano-2-thienyl) methyljamide.TFA (see Example 3, Step B) using essentially the procedure described in Example 2; 42% yield. 1 H NMR (CD 3 OD) d 1.47 (m, 1 H), 1.60 (m, 1 H), 1.79 (m, 2 H), 2.84 (s, 3 H), 2.93 (m, 1 H), 3.71 (m, 1 H ), 4.03 (m, 1 H), 4.31 (m, 3H), 4.46 (m 2H), 4.98 (m, 1 H), 7.25-7.50 (m, 12H). EM FAB: 541 [M + 1j * EXAMPLE 6 Preparation of N-benzylsulphonyl-D-diphenylalanyl-L-prolyl-r (5-amidino-2-thieni-P-methyl-aramid.

A) N-Benzylsulfonyl-D-diphenylalanyl-L-proline This compound was prepared by the procedure described in Example 3, Step A, with the exception that benzylsulfonyl chloride was used instead of methanesulfonyl chloride; 46% yield. 1 H NMR (CD 3 OD) d 1.40 (m, 1 H), 1.68-1.88 (m, 3 H), 2.88 (m, 1 H), 3.93 (m, 1 H), 4.15 (m, 1 H), 4.37-4.43 (m, 3 H) ), 5.02 (m, 1H), 7.17-7.48 (m, 15H). EM FAB: 493 [M + 1] * B) N-Benzylsulfonyl-D-diphenylalanyl-L-prolyl-r (5-cyano-2-thienyl) methyl-1-amide This compound was prepared from N-benzylsulfonyl-D-diphenylalanyl-L-proline using the procedure described in Example 1, Step E; 85% yield. 1 H NMR (CDCl 3 d 1.38 (m, 1 H), 1.46 (m, 1 H), 1.69 (m, 2 H), 2.15 (m, 1H), 3.60 (m, 1H), 3.99 (d, 1H), 4.13 (d, 1H), 4.28 (m, 2H), 4.47 (m 2H), 4.69 (m, 1H), 4.88 (m , 1H), 6.89 (m, 1H), 7.18 (m, 2H), 7.18-7.52 (m, 14H). EMFAB: 613 [M + 1j * C) N-Benzylsulfonyl-D-diphenylalanyl-L-prolyl (5-amidino-2-thienyl) methinamide.TFA This title compound was prepared from the compound prepared in Step B using the procedure described in the Example 1, Step F; 45% yield 1 H NMR (CD 3 OD) d 1.46 (m, 1 H), 1.62 (m, 1 H), 1.82 (m, 2 H), 3.00 (m, 1 H), 3.78 (m, 1 H), 4.03 (d, 1 H), 4.21 ( s, 2H), 4.32 (d, 1H), 4.59 (s, 2H), 5.12 (d, 1H), 7.09 (m, 1H), 7.15-7.45 (m, 15H), 7.57 (m, 1H).

EM FAB: 630 [M + 1] EXAMPLE 7 Preparation of N-t-butoxycarbonyl-D-diphenylalanyl-L-prolyl-r (5-amidino-2-thieni-methylamide.TFA A) N-Boc-D-diphenylalanyl-L-prolyl-1 (5-amidino-2-thienyl) methnamide To a solution of N-Boc-D-diphenylalanyl-L-proline (2 g, 4.8 mmol) in DMF (20 ml) was added 5- (aminomethyl) thiophene-2-carbonitrile.HCl (1 g, 5.7 mmol, prepared in Example 1, Step B), EDC (1.4 g, 7.2 mmol), HOBT (0.8 g, 6.2 mmol) and triethylamine (2 mL, 14.4 mmol), and the mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was dissolved in EtOAc and washed successively with a saturated solution of sodium bicarbonate, 1 N HCl and brine. After drying the solution over magnesium sulfate and concentrating it in vacuo, the residue was purified by column chromatography (EtOAc: n-hexane, 2: 1) to yield the title compound (2.3 g, 86%). 1 H NMR (CD 3 OD) d 7.44 (m, 2 H), 7.21 (m, 1 H), 4.98 (s, 2 H), 4.40 (m, 2 H), 3.79 (m, 1 H), 3-10-2.97 (m , 3H), 2.17-1.88 (m, 3H), 1.74 (m, 1 H).

EM FAB: 558 [M + 1j * B) Nt-Butoxycarbonyl-D-d-phenylalanyl-L-prolyl-1 (5-amidino-2-thieniD methylamide.TFA The title compound was prepared from the compound obtained in Step A using the procedure described in Example 1, Step F: 54% yield, 1 H NMR (CD3OD) d 7.78 (d, 1 H), 7.45 (m, 2H), 7.22 (m, 1 H), 7.16 H), 4.59 (s, 2H), 4.40 (m, 2H), 3.81 (m, 1 H), 3.09 (m, 1 H), EM FAB: 576 [M + 1] * EXAMPLE 8 Preparation of N-R-terthoxycarbonyl-D-diphenylalanyl-L-prolyl-r (5-amidino-2-thieni-D-methylamide.

A) D-Diphenylalanyl-L-prolyl-f (5-cyano-2-tethenyl) methylamide. HCl To a cold solution of N-Boc-D-diphenylalanyl-L-prolyl - [(5-cyano) 2-thienyl) methyljamide prepared in Example 7, Step A (0.2 g, 0.37 mmol), in methanol (20 ml), acetylchloride (2 ml) was added dropwise. After stirring for 3 h at room temperature, the solution was removed until dry to yield the title compound as a white solid (0.271 g, 100%). 1 H NMR (CDCl 3) d 8.52 (m, 1 H), 7.55-7.12 (m, 11 H), 6.84 (d, 1 H), 4.77 (d, 1 H), 4.57 (d, 1 H), 4.50 (dd, 1 H) , 4.23 (d, 1H), 4.18 (dd, 1H), 3.77 (t, 1H), 2.43 (q, 1H), 1.94) m, 1H), 1.62 (m, 1H), 1.48 (m, 1H), 1.30 (m, 1H). EM FAB: 459 [M + 1] * B) N-Methoxycarbonyl-D-diphenylalanyl-L-prolyl- [Y5-cyano-2-thienyl) methylamide D-Diphenylalanyl-L-prolyl - [(5-cyano-2-thienyl) methyljamide.HCl (0.271 g) dissolved in dichloromethane (2 ml) and cooled to 0 ° C. To this was added triethylamine (0.22 ml, 1.59 mmoles) and methyl chloroformate (0.04 ml, 0.67 mmoles) and the mixture was stirred for 2 h at room temperature. The solution was concentrated and the residue was purified by column chromatography (EtOAc: n-hexane, 2: 1) to yield the title compound (0.18 g, 67%). 1 H NMR (CDCl 3) d 1.50 (m, 1 H), 1.67 (m, 1 H), 1.88 (m, 2 H), 3.01 (m, 1 H), 3.20 (s, 3 H), 3.81 (m, 1 H), 4.09 (m, 1H), 4.29 (d, 1H), 4.55 (m, 1H). 4.63 (m, 1H), 4.93 (m, 1H), 5.18 (m, 1H), 7.12-7.54 (m, 11H), 7.68 (m, 1H). EMFAB: 516 [M + 1j * C) N-Methoxycarbonyl-D-diphenylalanyl-L-pro-yl-r (5-amidino-2-thienyl) methylamide The title compound was prepared from the compound obtained in Step B according to to the procedure described in Example 1, Step F; 63% yield. 1 H NMR (CD 3 OD) d 1.49 (m, 1 H), 1.65 (m, 1 H), 1.85 (m, 2 H), 2.91 (m, 1 H), 3.30 (s, 3 H), 3.84 (m, 1 H ), 4.07 (m, 1 H), 4.36 (m, 1 H), 4.52 (m, 1 H), 4.66 (m, 1 H), 5.14 (m, 1 H), 7.18-7.52 (m, 1 1 H), 7.81 (m, 1 H).

EXAMPLE 9 Preparation of N-aminosulfonyl-D-3,4-dichlorophenylalanyl-L-prolyl-f (5-amidino-2-thieni-P-methylpamide.TFA A) N-Aminosulfonyl-D-3,4-dichlorophenylalanyl-L-proline The title compound was prepared from D-3,4-dichlorophenylalanyl-L-proline methyl ester (see J. Med. Chem. 1997, 40, 3726) using the procedure described in Example 1, Step C and D; 60% yield. 1 H NMR (CD 3 OD) d 1.30 (m, 1 H), 1.74 (m, 1 H), 1.88-1.93 (m, 2 H), 2.78 (m, 3 H), 3.71 (m, 1 H), 4.30-4.41 (m m, 2H), 5.23 (m, 1 H), 7.11-7.42 (m, 3H). E FAB: 410 [M + 1j * B) N-Aminosulfonyl-D-3,4-dichlorophenylalanyl-L-prolyl (5-amidino-2-thieni-O-methylamide.TFA The compound was prepared from the compound obtained in Step A using the procedure described in Example 1, Step E and F, 32% yield, 1 H NMR (CD3OD) d 1.38 (d, 1 H), 1.67 (m, 1 H), 1.84-2.01 (m, 2 H), 2.84 (m, 2 H), 3.02 ( m, 1 H), 3.88 (m, 1H), 4.25-4.52 (m, 4H), 7.18-7.62 (m, 5H) EM FAB: 547 [M + 1] * EXAMPLE 10 Preparation of N-methoxycarbonyl-D-dicyclohexylalanyl-L-prolyl-f (5-amidino-2-thieni-P-methylamide.TFA The title compound was prepared from D-dicyclohexylalanyl-L-proline methyl ester (see J. Med. Chem. 1997, 40, 3726) using the procedure described in Example 7, Step A and Example 8; 24% yield. 1 H NMR (CD 3 OD) d 1.09-2.18 (m, 27 H), 3.19-3.34 (m, 4 H), 3.92 (m, 1 H), 4.21-4.52 (m, 3 H), 5.05 (m, 1 H), 7.47 (m, 1 H), 7.71 (m, 1H). EM FAB: 546 [M + 1] * EXAMPLE 11 Preparation of N-aminosulfonyl-D-diphenylalanyl-L-prolyl-r (4-amidino-2-thieni-D-methylamide.

A) 4-Bromo-2- (hydroxymethyl) thiophene 4-Bromothiophen-2-carboxaldehyde (4 g, 18.8 mmol) was dissolved in dichloromethane / methanol (9/1, v / v, 100 ml) and the solution was cooled to 0 ° C. To this was added sodium borohydride (0.35 g, 9.4 mmol) and the mixture was stirred for 3 hours at room temperature. The reaction mixture was neutralized by the addition of 1N HCl, extracted with dichloromethane, and the extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (EtOAc: n-hexane, 1: 4) to yield the title compound (3.5 g, 97%). 1 H NMR (CDCl 3) d 4.52 (s, 2 H), 7.19 (m, 1 H), 7.42 (m, 1 H). EM FAB: 194 [M + 1] * B) 2- (Hydroxymethyl) thiophene-4-carbonitrile A mixture of 4-bromo-2- (hydroxymethyl) thiophene (3.5 g, 18.1 mmole) and cuprous cyanide (2.5 g, 28.2 mmole) in DNF (100 ml), heated under reflux for 6 hours. The reaction mixture was diluted with 100 ml of dichloromethane, washed with aqueous ammonia, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (EtOAc: n-hexane, 2: 1) to yield the title compound (1.88 g, 75%). 1 H NMR (CDCl 3) d 4.46 (s, 2 H), 7.12 (m, 1 H), 7.46 (m, 1 H). EM FAB: 140 [M + 1] * C) 2- (Bromomethyl) thiophene-4-carbonitrile To a cold (0 ° C) solution of 2- (hydroxymethyl) thiophene-4-carbonitrile (1.14 g, 8.2 mmol) in dichloromethane (50 ml), triphenylphosphine ( 2.8 g, 10.6 mmol) and carbon tetrabromide (3.3 g, 9.9 mmol). After stirring for 3 hours at room temperature, the solvent was removed in vacuo and the residue was chromatographed using EtOAc and n-hexane (1: 4) to yield the title compound (1.6 g, 96%). 1 H NMR (CDCl 3) d 4.38 (s, 2 H), 7.15 (m, 1 H), 7.40 (m, 1 H). EM FAB: 203 [M + 1] * D) 2- (AminomethylD-phenyl-4-carbonitrile.HCl This compound was prepared from 2- (bromomethyl) thiophene-4-carbonitrile (1.6 g, 8.0 mmol) using the procedure described in Example 1, Step B; 85% yield.1H NMR (CD3OD) sm d (m, 1 H).

E) N-Aminosulfonyl-D-diphenylalanyl-L-prolyl-r (4-amidino-2-tethenyl) metipamide.TFA This compound was prepared from 2- (aminomethyl) thiophen-4 - carbonitri.HCl and N-aminosulfonyl-D-diphenylalanyl-L-proline using the procedure described in Example 1, Steps E and F; 40% yield. 1 H NMR (CD 3 OD) d 1.47 (m, 1 H), 1.65 (m, 1 H), 1.74 (m, 1 H), 1.89 (m, 1 H), 2.92 (m, 1 H), 3.86 (m, 1 H ), 4.15 (m, 1 H), 4.31 (m, 1 H), 4.61 (m, 2 H), 4.99 (m, 1 H), 7.25-7.51 (m, 11 H), 7.77 (m, 1 H) . EM FAB: 555 [M + 1j * EXAMPLE 12 Preparation of N-methylsulfonyl-D-diphenylalanyl-L-prolyl-r (4-amidino-2-thieni-P-methylamide.

This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L-proline (Example 3, Step A) and 2- (aminomethyl) thiophene-4-carbonitrile.HCl (Example 11, Step D) in essence according to the procedure of Example 1, Step E and F; 59% yield. 1 H NMR (CDCl 3) d 1.51 (m, 1 H), 1.64 (m, 1 H), 1.92 (m, 2 H), 2.91-3.01 (m, 4 H), 3.72 (m, 1 H), 4.12 (m, 1 H), 4.28 (d, 1H), 4.55 (m, 2H), 5.07 (m, 1H), 7.18-7.52 (m, 11H), 7.74 (m, 1H). EM FAB: 554 [M + 1] * EXAMPLE 13 Preparation of N-methylsulfonyl-D-diphenylalanyl-L-prolyl-f (4-aminomethyl-2-thieni-P-methylamide.

This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(4-cyano-2-thienyl) methyl] amide (Example 12) according to the procedure of Example 2; 38% yield. 1 H NMR (CD 3 OD) d 1.42 (m, 1 H), 1.65 (m, 1 H), 1.81 (m, 2 H), 2.78 (s, 3 H), 2.90 (m, 1 H), 3.82 (m, 1 H) , 4.11 (m, 1 H), 4.35 (m, 3H), 4.45 (m, 2H), 5.02 (m, 1H), 7.20-7.55 (m, 12H). EM FAB: 541 [M + 1] * EXAMPLE 14 Preparation of N-methoxycarbonyl-D-diphenylalanyl-L-prolyl-r (4-amidino-2-thienipmetinamide. TFA This compound was prepared from N-Boc-D-diphenylalanyl-L-proline and 2- (aminomethyl) thiophene-4-carbonitrile.HCl (Example 11, Step D) according to the procedure described in Example 1, Step E and F; 32% yield. 1 H NMR (CD 3 OD) d 1.49 (m, 1 H), 1.65 (m, 1 H), 1.82 (m, 2 H), 2.92 (m, 1 H), 3.45 (s, 3 H), 3.83 (m, 1 H), 4.07 (m, 1H), 4.36 (m, 2H), 4.59 (m, 1H), 5.14 (m, 1H), 7.18-7.48 (m, 11 H), 7.75 (m, 1 H).

EM FAB: 516 [M + 1j * EXAMPLE 15 Preparation of N-aminosulfonyl-D-diphenylalanyl-L-prolyl-y (5-amidino-3-tieni-p-methylamide.TFA A) 2-lodothiophen-4-carboxaldehyde To a solution of 3-thiophenecarboxaldehyde (500 mg, 4.46 mmol) in a 1: 1 mixture of acetic acid and water (10 ml) was added 95% sulfuric acid (0.31 ml). To this was added successively HI0 (305 mg, 1.34 mmol) 5 and iodine (680 mg, 2.67 mmoies), and the mixture was stirred for 3 hours at 60 ° C. After completion of the reaction, an aqueous solution of NaHSO 3 (6 ml) was added, the mixture was basified to pH 12 by the addition of 10N NaOH, and extracted with dichloromethane. The extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (EtOAc: n-hexane, 3:97) to yield the title compound (390 mg, 37%). 1 H NMR ( 3) d 9.76 (s, 1 H), 8.08 (d, 1 H), 7.68 (d, 1 H). EM FAB: 239 [M + 1] * B) 4- (Hydroxymethyl-2-vodothiophene) A solution of 2-iodothiophen-4-carboxaldehyde (5 g, 21 mmol) in methanol (100 ml) was cooled to 0 °. C. To this was added sodium borohydride 1.2 g (31.5 mmol) and the mixture was stirred for 30 minutes at 0 ° C. The reaction mixture was quenched by the addition of a saturated solution of ammonium chloride and concentrated. The residue was dissolved in EtOAc, washed with brine, dried over magnesium sulfate and concentrated in vacuo, the crude material was purified by column chromatography (EtOAc: n-hexane, 1: 4), yield 4.53 g (90%). 1 H NMR ( 3) d 7.15 (s, 2 H), 4.52 (s, 2 H) EM FAB: 241 [M + 1] * C) 4- (Hydroxymethip-2-thiophene-2-carbonitrile) This compound was prepared from 4- (hydroxymethyl) -2-iodothiophen (1.2 g, 5 mmol) according to the procedure described in Example 11, Step A; yield 536 mg (77%). 1 H NMR ( 3) d 7.58 (s, 1 H), 7.48 (s, 1 H), 4.47 (s, 2H). EM FAB: 140 [M + 1] * D) 4- (Bromomethyl) thiophene-2-carbonitrile This compound was prepared from 4- (hydroxymethyl) thiohen-2-carbonitrile (536 mg, 3.85 mmol) according to the procedure described in Example 11, Step C; yield 754 mg (97%). 1 H NMR ( 3) d 7.59 (s, 1 H), 7.49 (s, 1 H), 4.89 (s, 2H). EM FAB: 203 [M + 1] * E) 4- (Aminomethyl) thiophene-2-carbonitrile.HCl This compound was prepared from 4- (bromomethyl) thiophene-2-carbonitrile (188 mg, 4.7 mmol) according to the procedure described in Example 1, Step B; yield 231 mg (95%). 1 H NMR (CD 3 OD) d 7.75 (s, 1 H), 7.64 (s, 1 H), 4.65 (s, 2H).

F) N-Amnosulphonyl-D-diphenylalanyl-L-prolyl-f (5-amidino-3-thienyl) methylamide.TFA This compound was prepared from 4- (aminomethyl) thiophene-2-carbonitrile.HCl and N -aminosulfonyl-D-diphenylalanyl-L-proline using the procedure described in Example 1, Step E and F; 41% yield. 1 H NMR (CD 3 OD) d 7.83 (d, 1 H), 7.82 (d, 1 H), 7.43 (m, 2 H), 7.36 (m, 2 H), 7.24 (m, 6 H), 4.45 (dd, 1 H) , 4.32 (d, 1 H), 4.21 (dd, 1 H), 4.04 (m, 1 H), 3. 76 (m, 1 H), 2.88 (m, 1 H), 1.83-1.45 (m, 4H). EM FAB: 555 [M + 1] * EXAMPLE 16 Preparation of N-methylsulfonyl-D-diphenylalanyl-L-prolyl-r (5-amidino-3-thieni-P-methylamide.

A) N-Methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-cyano-3-thienyl) metip "-amide This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L-proline (Example 3, Step A) and 4- (aminomethyl) thiophene-2-carbonitrile.HCl (Example 15, Step E) using the procedure described in Example 1, Step E, yield 89% .1H NMR (3) d 7.60 ( d, 1 H), 7.38 (m, 5H), 7.23 (m, 6H), 4.81 (dd, 1 H), 4.39-4.36 (m, 3H), 4.23 (m, 1 H), 3.58 (m, 1 H), 2.83 (s, 3H), 2.55 (m, l) 1 H), 1.70 (m, 2H), 1.41 (m, 2H). EM FAB: 537 [M + 1j * B) N-Methylsulfonyl-D-d-phenylalanyl-L-prolyl - [(5-amino-3-thienyl) methylamide. TFA This compound was prepared from the compound obtained in Step A using the procedure described in Example 1, Step F; 53% yield. 1 H NMR (CD3OD) d 7.62 (d, 1 H), 7.51 (d, 1 H), 7.54-7.23 (m, 10H), 4.99 (d, 1 H), 4.39 (m, 4H), 4.11 (dd, 1 H), 3.78 (m, 1 H), 2.95 (m, 1H), 2.90 (s, 3H), 1.82-1.43 (m, 4H).

EXAMPLE 17 Preparation of N-methylsulfonyl-D-diphenylalanyl-L-prolyl-r (5-amidrazone-3-thieni-P-methylpamide.

This compound was prepared from N-methylsulfonyl-D-d-phenylalanyl-prolyl - [(5-cyano-3-t-eneyl) methylalide (Example 16, Step A) using the procedure described in Example 4; 63% yield. 1 H NMR (CD 3 OD) d 7.52 (d, 1 H), 7.42 (d, 1 H), 7.34-7.10 (m, 10 H), 4.99 (d, 1 H), 4.29 (m, 3 H), 4.00 (dd, 1 H), 3.68 (m, 1 H), 3.27 (m, 1 H), 2.91 (m, 1 H), 2.80 (s, 3 H), 1.79-1.32 (m, 4 H). FAB MS: 569 [M + 1] * EXAMPLE 18 Preparation of N-methylsulfonyl-D-diphenylalanyl-L-prolyl-r (5-aminomethyl-3-thieni-P-methylpamide.

This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-cyano-3-thienyl) methylamide (Example 16, Step A) using the procedure described in Example 2; 75% yield. 1 H NMR (CD 3 OD) d 7.47 (d, 2 H), 7.36 (m, 2 H), 7.26 (m, 6 H), 6.93 (d, 1 H), 6.87 (d, 1 H), 5.00 (d, 1 H) , 4.44 (s, 2H), 4.30 (m, 2H), 4.12 (s, 2H), 3.79 (m, 1 H), 2.92 (m, 1 H), 2.85 (s, 3H), 1.78-1.32 (m, 4H). EM FAB: 541 [M + 1j * EXAMPLE 19 Preparation of N-methoxycarbonyl-D-diphenylalanyl-L-prolyl-r (5-amidino-3-thieni-P-methylpamide.

This compound was prepared from N-Boc-D-diphenylalanyl-L-proline and 2- (aminomethyl) thiophene-2-carbonitrile.HCl (Example 15, Step E) according to the procedure described in Example 7, Step A; 47% yield. 1 H NMR (CD 3 OD) d 1.48 (m, 1 H), 1.61 (m, 1 H), 1.83 (m, 2 H), 2. 92 (m, 1 H), 3.45 (s, 3 H), 3.81 (m, 1 H), 4.08 (m, 1 H), 4.37 (d, 1 H), 4.55 (q, 2H), 5.15 (m, 1 H), 7.15-7.49 (m, 12H). EM FAB: 516 [M + 1] * EXAMPLE 20 Preparation of N-cyclohexyl sulphamoyl-D-p-phenylalanyl-L-prolyl-f (5-amidino-2-thieni-P-methylamide.

A) Cyclohexylsulfamoyl chloride To a solution of cyclohexylsulfamic acid (5 g, 27.9 mmol) in benzene (30 ml) was added phosphorus pentachloride (6.4 g, 30.7 mmol) dropwise and the mixture was heated under reflux for 4 hours. After removing the solvent, the residue was distilled under reduced pressure to yield the title compound (5 g, 91%).

B) N-Cyclohexylsulfamoyl-D-diphenylalanyl-L-prolyl-r (5-amidino-2-thieni-D-methylamide.TFA Tu This compound was prepared from cyclohexylsulfamoyl chloride in essence according to the procedure of Example 3, yield 41% 1 H NMR (CD3OD) d 7.76 (d, 1 H), 7.49-7.10 (m, 10H), 7.03 (d, 1 H), 4.97 (m, 1 H), 4.60 (dd, 1 H), 4.50 (dd, 1 H), 4.30 (d, 1 H), 4.04 (m, 1 H), 3.85 (m, 1 H), 3.05 (m, 1 H), 2.73 (m, 1 H), 1.86 (m, 3 H), 1.75 (m, 2 H), 1.55 (m, 3H), 1.28-1.00 (m, 6H). I) EM FAB: 637 [M + 1] * EXAMPLE 21 Preparation of N-allyloxycarbonyl-D-diphenylalanyl-L-prolyl-f (5-amidino-2-thieni-P-methamide.TFA This compound was prepared from allyl chloroformate, essentially according to the procedure of Example 8; 56% yield. 1 H NMR (CD 3 OD) d 7.79 (d, 1 H), 7.41-7.18 (m, 10 H), 7.12 (d, 1 H), 5.74 (m, 1 H), 5.15 (d, 2 H), 5.08 (d, 1 H), 4.86 (dd, 1 H), 4.65 (m, 1 H), 4.53 (dd, 1 H), 4.36 (d, 2H), 4.23 (dd, 1 H), 4.09 (dd, 1 H), 3.81 (m, 1 H), 2.92 (m, 1 H), 1.85-1.49 (m, 4H). EM FAB: 560 [M + 1] * EXAMPLE 22 Preparation of N-methylsulfonyl-P-cyclohexlalanyl-L-pro! Il-r (5-amidino-2-thieni-P-methylamide.TFA This compound was prepared from methyl ester.HCl D-cihexilalanyl-L-proline in essence according to the procedure of Example 3; 41% yield. 1 H NMR (CD3OD) d 7.77 (d, 1H), 7.18 (d, 1H), 5.05 (m, 1H), 4.58 (m, 2 H), 4.41 (dd, 1H), 4.30 (dd, 1H), 3.85 (m, 1H), 3.39 (m, 1H), 2.85 (s, 3H), 2.23 (m, 1H), 2.12-1.15 (m, 15H), 1.10 (m, 2H). EM FAB: 484 [M + 1j * EXAMPLE 23 Preparation of N-benzylsulfonyl-D-cyclohexylalanyl-L-prolyl-r (5-amidino-2-thieni-P-methylamide.

This compound was prepared from methyl ester.HCl D-cidohexylalanyl-L-proline and benzylisulfonyl chloride using the procedure described in Example 3; 45% yield 1 H NMR (CD 3 OD) d 7.68 (d, 1 H), 7.52-7.30 (m, 5 H), 7.12 (d, 1 H), 4.98 (m, 1 H), 4.56 (s, 2 H), 4.42 (d, 1 H), 4.32 (d, 1H), 4.22 (d, 1H), 4.12 (m, 1H), 3.77 (m, 1H), 3.46 (m, 1H), 2.21 (m, 1H), 2.04 (m, 3H), 1.92 -1.12 (m, 11H), 0.95 (m, 2H).

EM FAB: 560 [M + 1] * EXAMPLE 24 Preparation of N-cyclohexylsulfamoyl-D-cyclohexyllanyl-L-prolyl-r (5-amidino-2-thieni-P-methylamide.TFA This compound was prepared from D-cyclohexylalanyl-L-proline HCl and cyclohexylsulfamoyl chloride using the procedure described in Example 3; performance 39%. 1 H NMR (CD 3 OD) d 7.43 (d, 1 H), 6.95 (d, 1 H), 4.62 (m, 3 H), 4.45 (dd, 1 H), 4.27 (m, 1 H), 4.12 (m, 1 H), 3.42 (m, 1 H), 3.22 (m, 1 H), 2.37 (m, 1 H), 2.20-1.10 (m, 24H), 0.91 (m, 2H). EM FAB: 567 [M + 1] * EXAMPLE 25 Preparation of N-methylsulfamoyl-D-cyclohexylalanyl-L-prolyl-r (5-amidino-2-thieni-P-methylamide.

A) Methisulfamoyl chloride This compound was prepared from methylsulfamic acid (5 g, 45.9 mmol) using the procedure described in Example 20, Step A; 70% yield.

B) N-Methylsulfamoyl-D-cyclohexylalanyl L-prolyl-r (5-amidino-2-thienyl) methylamide.TFA This compound was prepared from D-cyclohexylalanyl-L-proline.HCl and methylisulfamoyl chloride using the procedure described in Example 3; 30% yield. 'H NMR (CD3OD) d 7.84 (d, 1 H), 7.20 (d, 1 H), 4.59 (m, 2 H), 4.42 (m, 1 H), 4.18 (m, 1 h), 3.92 (m, 1 H), 3.55 (m, 1 H), 2.53 (s, 3H), 2.22 (m, 1 H), 2.02 (m, 3H), 1.91-1.15 (m, 11 H), 1.01 (m, 2H). EM FAB: 499 [M + 1j * EXAMPLE 26 Preparation of N-methylsulfonyl-D-cyclohexylglycinyl-L-prolyl-K5-arnidino-3-thieni-P-methylamide.TFA This compound was prepared from methyl ester. HCl D-cyhexylglycinyl-L-proline and 4- (aminomethyl) thiophene-2-carbonitrile.HCl (Example 15, Step F) in essence according to the procedure of Example 3; 46% yield. 1 H NMR (CD 3 OD) d 7.85 (s, 1 H), 7.84 (s, 1 H), 4.45 (dd, 1 H), 4.37 (d, 2 H), 4.01 (d, 1 H), 3.89 (m, 1 H), 3.68 (m, 1 H), 2.90 (s, 3 H), 2.24-1.05 (m, 14 H). EM FAB: 470 [M + 1] * EXAMPLE 27 Preparation of N-methoxycarbonyl-D-cyclohexylqlicinyl-L-prolyl-r (5-amidino-3-thieni-P-methylpamide.

This compound was prepared from N-Boc-D-cyclohexylglycinyl-L-proline and 4- (aminomethyl) thiophene-2-carbonitrile.HCl (Example 15, Step F) in essence according to the procedure of Example 7, Step A and Example 8; 42% yield. 1 H NMR (CD 3 OD) d 7.82 (s, 1 H), 7.75 (s, 1 H), 4.55 (d, 2 H), 4.48 (d, 1 H), 4.33 (d, 1 H), 4.14 (d, 1 H), 4.02 (m, 1 H), 3.69 (m, 1 H), 3.39 (s, 3H), 2.40-1.05 (m, 14H). EM FAB: 450 [M + 1j * EXAMPLE 28 Preparation of N- (t-butoxycarboniPmethyl-D-diphenylalanyl-L-prolyl-r (5-aminino-2-thien-Pmetnamnamide.2AcOH A) N- (t-Butoxycarbonyl) methyl-D-diphenylalanyl-L-prolyl-r (5-cyano-2-thieni-D-methylamide To a cold solution (0 ° C) of D-diphenylalanil-L-prolyl - [(5- cyano-2-thienyl) methyl] amide.HCl prepared in Example 8, Step A (3.03 g, 6.06 mmol) in acetonitrile (60 ml) was added diisopropylethylamine (4.22 ml, 24.24 mmol) and t-butylbromoacetate (4.22 ml, 0.09 mmoles), and the mixture was stirred for 2 days at room temperature, After concentrating the reaction mixture in vacuo, the residue was purified by column chromatography (EtOAc: n-hexane, 7: 3) to yield the title compound. (2.51 g, 72%). 1 H NMR (CDCl 3) d 8.12 (t, 1 H), 7.37 (m, 5 H), 7.19 (m, 5 H), 6.93 (d, 1 H), 4.61 (dd, 1 H), 4.49 (dd, 1 H) , 4.25 (d, 2H), 4.12 (dd, 1 H), 3.24 (s, 2H), 2.67 (m, 1 H), 2.07 (m, 1 H), 1.67 (m, 1 H), 1.43 (m , 2H), 1.37 (s, 9H), 1.25 (m, 1 H). EM FAB: 573 [M + 1] * B) N- (t-Butoxycarbonyl) methyl-D-diphenylalanyl-L-prolyl (5-hydroxyamidino-2-thienyl) methinamide To a solution of the compound obtained in Step A (2.31 g, 4.03 mmol) in a mixture 4: 1 ethanol and water (60 ml) was added hydroxylamine hydrochloride (1.04 g, 14.91 mmol) and sodium carbonate (726 mg, 6.85 mmol), and the mixture was heated under reflux for 1 hour. After concentrating the reaction mixture in vacuo, the residue was diluted with EtOAc, washed with brine, dried over magnesium sulfate and concentrated in vacuo to yield the title compound (2.36 g, 96%). 1 H NMR (CDCl 3) d 8.13 (t, 1 H), 7.42-7.35 (m, 4 H), 7.27-7.11 (m, 6 H), 7.01 (d, 1 H), 6.83 (d, 1 H), 4.87 ( s, 1 H), 4.56 (dd, 1 H), 4.44 (dd, 1 H), 4.27 (m, 3H), 3.32 (m, 1 H), 3.25 (dd, 1 H), 2.73 (m, 2H), 1.80-1.42 (m, 4H), 1.41 (s, 9H). MS FAB: 606 [M + 1j * O N- (t-Butoxycarbonyl) methyl-D-diphenylalanyl-prolyl-R5-amidino-2-thien-P-methyl-amide.2AcOH The compound prepared in Step B (2.36 g , 3.89 mmole) was dissolved in methane! (45 ml). To this solution was added 10% palladium on carbon (240 mg), acetic anhydride (0.74 ml, 7.78 mmol), and the mixture was stirred for 8 hours under H2 (1 atm). The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (gradient H2O-MeOH) to yield the title compound (1.6 mg, yield 70%). 1 H NMR (CD 3 OD) d 7.81 (d, 1 H), 7.59 (d, 2 H), 7.44 (t, 2 H), 7.35-7.16 (m, 7 H), 4.98 (d, 1 H), 4.61 (s, 2 H) ), 4.44 (d, 1 H), 4.06 (m, 1 H), 3.62 (q, 2H), 3.62 (dd, 1 H), 2.91 (m, 1 H), 1.77 (m, 3H), 1.47 ( s, 9H), 1.35 (m, 1 H). EM FAB: 590 [M + 1] * EXAMPLE 29 Preparation of N-carboxymethyl-D-diphenylalanyl-L-prolyl-r (5-amidino-2-thienyl) methypamide.2TFA To a cold (0 ° C) solution of N- (t-butoxycarbonyl) methyl-D-diphenylalanii-L-prolyl - [(5-amidino-2-thienyl) methyljamide.2AcOH (1.4 g, 2.37 mmol, see Example 28 ) in dichloromethane (15 ml) was added TFA (15 ml) and the mixture was stirred for 3.5 hours. After concentrating the reaction mixture in vacuo, the residue was purified by preparative HPLC (gradient of 0.1% TFA-H O-MeOH) to yield the title compound (1.2g, 80%). 1 H NMR (CD 3 OD) d 7.80 (d, 1 H), 7.62 (d, 2 H), 7.48 (m, 2 H), 7.39-7.22 (m, 6 H), 7.18 (d, 1 H), 5.32 (d, 1 H), 4.60 (dd, 2H), 4.58 (d, 1 H), 4.06 (m, 1 H), 3.84 (d, 2H), 3.49 (m, 1 H), 2.84 (m, 1 H), 1.80 (m, 3H), 1.30 (m, 1 H). EM FAB: 534 [M + 1] * EXAMPLE 30 Preparation of N-methyl-N-carboxymethyl-D-diphenylalanyl-L-prolyl-r (5-amidino-2-thieniPmetimamida.2TFA) A) N-Methyl-N- (t-butoxycarbonyl) methyl-D-diphenylalanyl-L-prolyl- [Y5-amidino-2-thienopynamidine.2TFA A solution of N- (t-butoxycarbonyl) methyl -D-diphenylalanyl-L-prolyl- [(5-cyano-2-thienyl) methyl] amide prepared in Example 28, Step A (0.18 g, 0.32 mmol) in pyridine (2 ml) was saturated with gaseous H2S . After the mixture was allowed to stand for 1 day at room temperature, the solvent was removed in vacuo to obtain the thioamide as a yellow solid. To this material was added acetonitrile (2 ml) and iodomethane (0.2 ml, 3.15 mmol) and the mixture was heated under reflux for 4 hours. After the solvent was evaporated in vacuo, the resulting methylthioamidate was dissolved in acetonitrile (2 ml). To this solution was added ammonium acetate (0.24 g, 3.15 mmol), and the mixture was heated under reflux for 2 hours. The solution was cooled and concentrated, and the residue was purified by preparative HPLC (gradient 0.1% TFA-H2O-MeOH) to yield the title compound (0.14 g, 64%). 1 H NMR (CD 3 OD) d 7.79 (d, 1 H), 7.50 (m, 2 H), 7.41-7.10 (m, 9 H), 5.01 (d, 1 H), 4.70-4.40 (m, 3 H), 4.02 (m , 1 H), 3.59 (m, 1 H), 3.37 (s, 2H), 3.20 (m, 1 H), 2.91 (s, 3H), 1.78 (m, 3H), 1.56 (m, 10H). EM FAB: 604 [M + 1] * B) N-Met.lN-carboxymethyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thieni-P-methylamide.2TFA) The compound was prepared from the compound obtained in Step A using the procedure described in Example 29, yield 64%, 1 H NMR (CD3OD) d 7.81 (d, 1 H), 7.62 (d, 1 H), 7.43-7.12 (m, 10 H), 5.22 (d, 1 H), 4.69 ( d, 1 H), 4.61 (m, 2H), 3.93 (m, 1 H), 3.71 (s, 2H), 3.50 (m, 1 H), 3.13 (m, 1 H), 2.84 (s, 3H) 1.81 (m, 3H).

EXAMPLE 31 Preparation of N-hydroxysulfonyl-D-diphenylalanyl-L-prolyl-r (5-amidino-2-thieni-P-methylillamide.

A) N-N-methoxysulfonyl-D-diphenylalanyl-L-prolyl - [(5-cyano-2-thienyl) methylene amide. DIPA To a cold solution (0 ° C) of D-diphenylalanyl-L-prolyl - [( 5-cyano-2-thienyl) methyl] amide.HCl (175 mg, 0.344 mmol) in dichloromethane (10 ml), chlorosulfonic acid (0.033 ml, 0.5 mmol) of diisopropylethylamine (DIPA, 0.226 ml, 1.3 mmol) was added and The mixture was stirred for 3 hours at room temperature. After the conclusion of the reaction, the reaction mixture was diluted with dichloromethane, washed with 1 N HCl and then with brine, dried over magnesium sulfate and concentrated in vacuo to yield the title compound (230 mg, 99%). 1 H NMR (CDCl 3) d 1.20-1.35 (m, 15H), 1.44 (m, 2H), 1.63 (m, 1 H), 2.00 (m, 1H), 2.62 (m, 1 H), 2.91 (m, 2H) ), 3.44 (m, 2H), 3.80 (m, 1 H), 4.24 (d, 1 H), 4.29 (d, 1 H), 4.40-4.58 (m, 2H), 4.83 (d, 1 H), 6.97 (d, 1 H), 7.12-7.45. B) N-Hydroxysulfonyl-D-diphenylalanyl-L-prolyl-r (5-amidino-2-thienyl) methylamide.TFA To a solution of the compound prepared in Step A (230 mg) in ethanol (5 ml) was added hydroxylamine hydrochloride (74 mg, 1.03 mmol) and diisopropylamine (195 mg, 1.4 mmol) and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo to yield a white solid (380 mg). This solid was dissolved in methanol (5 ml) and palladium on charcoal 10% (120 mg) and acetic acid (0.5 ml) was added. Then, the mixture was stirred for 36 hours under H2 (1 atm), the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (gradient of 0.1% TFA-H2O-MeOH) to yield the title compound (130 mg, 57%). 1 H NMR (CD 3 OD) d 1.45-1.90 (m, 4 H), 2.88 (m, 1 H), 3.86 (m, 1 H), 4.06 (m, 1 H), 4.23 (d, 1 H), 4.43 (m, 1 H), 4.64 (m, 1 H), 5.00 (d, 1 H), 7.11- 7.40 (m, 9H), 7.45 (m, 2H), 7.70 (d, 1 H). EM FAB: 556 [M + 1] * EXAMPLE 32 Preparation of N-methylsulfonyl-D-d-phenylalanyl-L-azetidine-2-carboxyl-! Y5-amidino-2-thien-P-methylpamide.TFA A) N-Boc-L-azetidine-2-carboxyl-1 (5-cyano-2-thienipyrimnamide To a cold (0 ° C) solution of N-Boc-L-2-azetidinecarboxylic acid (0.5 g, 4.94 mmole) in DMF (3 ml) was added 5- (aminomethyl) thiophene-2-carbonitrile.HCl (0.48 g, 2.74 mmole), EDC (0.62 g, 3.24 mmole), HOBT (0.40 g, 2.99 mmole) and triethylamine (1.04 ml, 7.47 mmol), and the mixture was stirred for 2 hours at room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc, washed successively with a saturated solution of sodium bicarbonate, 1N HCl. , and brine.

After drying the solution over magnesium sulfate and concentrating it in vacuo, the residue was purified by column chromatography (EtOAc: n-hexane, 2: 1) to yield the title compound (0.54 g, 68%). 1 H NMR (CDCl 3) d 7.46 (d, 1 H), 6.97 (d, 1 H), 4.75-4.50 (m, 3 H), 3.92 (m, 1 H), 3.79 (m, 1 H), 2.52-2.40 (m, 2H), 1.42 (s, 9H). EM FAB: 322 [M + 1] * B) N-Boc-D-phenylalanyl-L-azetidine-2-carboxyl-f (5-cyano-2-thienylmethylamide To a cold solution (0 ° C) of the compound prepared in Step A (1.4 g, 2.37 mmoles) in dichloromethane 15 ml, TFA (15 ml) was added and the mixture was stirred for 3 hours at room temperature, the resulting solution was concentrated in vacuo to yield the deprotected compound.

Boc as a salt of TFA (0.52 g, 93%). This product (0.2 g, 0.6 mmol) was dissolved in DMF (6 mL) and Boc-D-diphenylalanine (0.18 g, 0.54 mmol), EDC (0.13 g, 0.7 mmol) and HOBT (0.09 g, 0.54 mmol) were added. ). The mixture was stirred until clear and cooled to 0 ° C. After adding triethylamine (0.3 ml, 2.16 mmol), the resulting mixture was stirred for a further 2 hours at room temperature. The solvent was removed in vacuo and the residue was dissolved in EtOAc and subsequently washed with a saturated solution of sodium bicarbonate, 1N HCl and brine. After drying the solution over magnesium sulfate and concnetrating it in vacuo, the residue was purified by column chromatography (EtOAc: n-hexane, 2: 1) to yield the title compound (0.2 g, 69%). 1 H NMR (CDCl 3) d 8.30 (bs, 1 H), 7.45-7.14 (m, 11 H), 6.96 (d, 1 H), 4.83 (bs, 1 H), 4.67-4.48 (m, 3 H), 4.43 (m, 1 H), 4.32 (m, 1 H), 4.04 (m, 1 H), 2.97 (m, 1 H), 2.21 (m, 1 H), 2.02 (m, 1 H), 1.28 (s) , 9H). EM FAB: 545 [M + 1j * O N-Methylsulfonyl-D-phenylalanyl-L-azetidine-2-carboxyl-f (5-amidino-2-tethenyl) metipamide.TFA This compound was prepared from the compound obtained in Step B using the same procedure described in Example 8, with the exception that methanesulfonyl chloride was used in place of methyl chloroformate; 47% yield. 1 H NMR (CD 3 OD) d 7.78 (d, 1 H), 7.45-7.18 (m, 11 H), 4.65 (d, 1 H), 4.61 (s, 2 H), 4.34-4.19 (m, 3 H), 3.48 (m , 1 HOUR). 2.81 (s, 3H), 2.09 (m, 2H). EM FAB: 540 [M + 1] * EXAMPLE 33 Preparation of N-methylsulfonyl-D-d-phenylalanyl-L-prolyl-r (4-amidino-5-methyl-2-thieni-P-methylamide.

A) 5-Aminomethyl-2-methylthiophen-3-carbonitrile.HCl This compound was prepared from 4-bromo-5-methylthiophen-2-carboxaldehyde using the procedure described in Example 11, Step A to D; 22% yield. 1 H NMR (CD 3 OD) d 2.59 (s, 3 H), 4.52 (s, 2 H), 7.00 (s, 1 H), 7.25 (s, 1 H). EM FAB: 153 [M + 1] * B) N-Methylsulfonyl-D-diphenylalanyl-L-prolyl-r (4-amidino-5-methylene-2-thieni-D-methyl-aramid. This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L-proin ( Example 3, Step A) and 2-aminomethyl-5-methylthiophen-4-carbonitrile.HCl using the procedure described in Example 1, Step E and F, yield 38%, 1 H NMR (CD3OD) d 1.48 (m, 1 H ), 1.62 (m, 1 H), 1.90 (m, 2H), 2. 65 (s, 2H), 2.90-3.03 (m, 4H), 3.62 (m, 1 H), 4.02 (m, 1 H), 4.34 (d, 1 H), 4.52 (m, 2H), 5.11 (m , 1 H), 7.19-7.56 (m, 11 H). EM FAB: 568 [M + 1J * EXAMPLE 34 Preparation of N-methylsulfonH-D-diphenylalanyl-L-prolyl-f (5-amidino-2-furani-P-methylamide.TFA This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L-proline (see Example 3, Step A) and 5- (aminomethyl) furan-2-carbonitrile.HCl using the procedure described in Example 1, Step E and F; 20% yield. H NMR (CD3OD) d 7.48 (m, 3H), 7.35 (m, 2H), 7.25 (m, 6H), 6.62 (d, 1 H), 5.02 (d, 1 H), 4.44 (m, 2H), 4.02 (dd, 1 H), 3.71 (m, 1 H), 2.93 (m, 1 H), 2.85 (s, 3H), 1.79-1.39 (m, 4H). EM FAB: 538 [M + 1] * EXAMPLE 35 Preparation of N-methoxycarbonyl-D-diphenylalanyl-L-prolyl-r (5-amidino-2-furaniPmetipamide.TFA This compound was prepared from N-Boc-D-diphenylalanyl-L-proline and 5- (aminomethyl) furan-2-carbonitrile.HCl using the procedures described in Example 7, Step A, and Example 8; 35% yield. 1 H NMR (CD 3 OD) d 7.49 (d, 1 H), 7.39 (d, 2 H), 7.34 (t, 2 H), 7.25 (m, 6 H), 6.57 (d, 1 H), 5.15 (d, 1 H) , 4.59 (d, 1 H), 4.37 (dd, 2H), 4.05 (dd, 1 H), 3.85 (m, 1 H), 3.39 (s, 3H), 2.89 (m, 1 H), 1.82-1.46 (m, 4H). EM FAB: 518 [M + 1j * EXAMPLE 36 Preparation of N-aminosulfonyl-D-diphenylalanyl-L-prolyl-r (5-amidino-2-furaniPmetinamide.TFA A) 4- (Aminomethyl) furan-2-carbonitrile.HCl This compound was prepared from 2-bromo-4- (hydroxymethyl) furan (see Acta. Chemica, Scandinavica, 1991, 45, 914) using the procedure described in Example 11, Step B to D; 61% yield. 1 H NMR (CD 3 OD) d 7.54 (s, 1 H), 7.12 (s, 1 H), 4.32 (s, 2 H). EM FAB: 159 [M + 1] * B) N-aminosulfonyl-D-diphenylalanyl-L-prolyl-r (5-amidino-3-furan-P methylamide.TFA This compound was prepared from N-aminosulfonyl-D diphenylalanyl-L-proline (see Example 1, Step D) and 4- (aminomethyl) furan-2-carbonitrile.HCl using the procedure described in Example 1, Step E and F, yield 36% .1H NMR (CD3OD) d 7.83 (s, 1 H), 7.47 (s, 1 H), 7.43 (d, 2H), 7.35 (t, 2H), 7.25 (m, 6H), 4.93 (d, 1 H), 4.31 (d, 2H), 4.11 (dd, 1 H), 4.02 (dd, 1 H), .45 (m, 4H).

EXAMPLE 37 Preparation of N-aminosulfonyl-D-diphenylalanyl-L-prolyl-r (4-amidino-2-thiazoii-P-metinamide.TFA A) 2- (Aminomethyl) thiazole-2-carbonitrile.HCl To a cold (0 ° C) solution of 2- (Boc-aminomethyl) thiazole-4-carboxamide (200 mg, 0.78 mmol., See Angew. Chem. Int. Ed. Engl. 1996, 35, 1503) in dichloromethane (7 ml), triethylamine (0.32 ml, 2.34 mmole) and acetic anhydride (0.22 ml, 1.56 mmole) were added, and the mixture was stirred for 1 hour. After removing the solvent, the residue was purified by column chromatography (EtOAc: n-hexane, 3: 7). 2- (N-Boccaminomethyl) thiazole-4-carbonitrile (150 mg, 0.627 mmol) thus obtained was dissolved in methanol (10 ml) and cooled to 0 ° C. To this was added dropwise acetylchloride (30 equivalent) and the mixture was stirred for 1 hour at room temperature. The solvent was removed in vacuo to yield the title compound (90 mg, 81%). .94 (s, 1 H), 5.44 (s, 1 H), 4.59 (s, 2H).

B) N-aminosulfonyl-D-diphenylalanyl-L-prolyl-f (4-amidino-2-thiazole) metipamide.TFA This compound was prepared from N-aminosulfonyl-D-diphenylalanyl-L-proline (see Example 1, Step D) and 2- (aminomethyl) thiazole-4-carbonitrile.HCl using the procedure described in Example 1, Step E and F; 48% yield. 1 H NMR (CD 3 OD) d 8.56 (s, 1 H), 7.45 (d, 2 H), 7.35 (t, 2 H), 7.25 (m, 6 H), 4.95 (d, 1 H), 4.67 (m, 2 H), 4.34 (d, 1 H), 4.11 (dd, 1 H), 3.78 (m, 1 H), 2.89 (m, 1 H), 1.90-1.45 (m, 4H). FAB MS: 556 [M + 1] * EXAMPLE 38 Preparation of N-methylsulfonyl-D-diphenylalanyl-L-pro-yl-r (5-amidino-1-methyl-2-pyrolyl-P-methylpamide.

This compound was prepared from N-methylsulfonyl-D-diphenylalanyl-L-proline (see Example 3, Step A) and 5- (aminomethyl) -1-methylpyrol-2-carbonitrile using the procedure described in Example 1, Step E and F; 17% yield. 5- (Aminomethyl) -1-methyl-piroI-2-carbonitrile was prepared from 1,5-d.methyl-pyrol-2-carbonitrile using the procedure described in Example 1, Steps A and B. 1 H NMR ( CD3OD) d 1.40 (m, 1 H), 1.65 (m, 1 H), 1.84 (m, 2H), 2.81 (s, 3H), 2.97 (m, 1 H), 3.69 (s, 3H), 3.78 ( m, 1 H), 4.02 (m, 1 H), 4.30 (d, 1 H), 4.56 (m, 2H), 5.00 (m, 1 H), 6.22 (d, 1 H), 6.88 (d, 1 H), 7.23-7.50 (m, 9H), 7.65 (m, 1 H). EM FAB: 551 [M + 1] * EXAMPLE 39 Preparation of N-carboxymethyl-D-diphenylalanyl-L-prolyl-l-5-amidin-3-thieni-P-methynamide.2TFA This compound was prepared from D-diphenylalanyl-L-prolyl - [(5-cyano-3-thienyl) methyl] amide.HCl (obtained during the preparation of Example 19) using the procedures described in Examples 28 and 29; 41% yield. 1 H NMR (CD3OD) d 7.91 (s, 1 H), 7.88 (s, 1 H), 7.67 (d, 2 H), 7.50 (t, 2H), 7.38-7.25 (m, 6H), 5.34 (d, 1 H), 4.58 (d, 1 H), 4.42 (dd, 2H), 4.07 (dd, 1 H), 3.78 (dd, 2H), 3.53 (m, 1 H), 2.89 (m, 1 H), 1.83-1.72 (m, 3H), 1.31 (m, 1 HOUR). EM FAB: 534 [M + 1j * EXAMPLE 40 Preparation of N-carboxymethyl-D-diphenylalanyl-L-prolyl-r 4-amidino-2-tiazoli-Prnipaipamide.2TFA A) D-diphenylalanyl-L-prolyl-f (4-cyano-2-thiazolyl) methynamid.HCl This compound was prepared from 2- (aminomethyl) thiazole-4-carbonitrile.HCl (see Example 37) , Step A) using the procedures described in Example 7, Step A, and Example 8, Step A. 1 H NMR (CDCl 3) d 8.56 (s, 1 H), 7.54-7.23 (m, 10 H), 4.77 (d, 1 H), 4.57 (d, 1H), 4.55 (dd, 1H), 4.23 (m, 2H), 3.77 (m, 1H), 2.41 (m, 1 H), 1.94 (m, 1 H), 1.62- 1.35 (m, 3H). EM FAB: 460 [M + 1j * B) N-Carboxymethyl-D-diphenylalanyl-L-prolyl-rf4-amidino-2-thiazopP methypamide.2TFA This compound was prepared from the compound obtained in Step A using the procedures described in Examples 28 and 29; Overall performance 35%. 1 H NMR (CD 3 OD) d 8.63 (s, 1 H), 7.65 (d, 2 H), 7.52 (t, 2 H), 7.45- 7.23 (m, 6 H), 5.31 (d, 1 H), 4.74 (s, 2 H) ), 4.55 (d, 1 H), 4.13 (m, 1 H), 3.78 (dd, 2H), 3.52 (m, 1 H), 2.86 (m, 1 H), 1.81 (m, 3H), 1.37 ( m, 1 H). EM FAB: 535 [M + 1] * EXAMPLE 41 Preparation of N- (2-carboxytyP-D-diphenylalanyl-L-proly (5-amidino-2-thieniDmethylpamide.2TFA A) N-r2- (methoxycarboni0etip-D-diphenylalanyl-L-prolyl-IY5-cyano-2-thieni-P-metiflamide A mixture of D-diphenylalanyl-L-prolyl - [(5-cyano-2-thienyl) methyl] amide. (400 mg, 0.81 mmol, prepared in Example 8, Step A), sodium carbonate (690 mg, 6.5 mmol), sodium iodide (609 mg, 4,065 mmol), tetrabutylammonium bromide (79 mg, 0.244 mmol) and methyl 3-bromopropionate (0.2 ml, 1626 mmol) in toluene (8 ml) was heated under reflux for 5 hours.The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (EtOAc: n-hexane; : 3) to produce the title compound (180 mg, 41%).

H NMR (CDCl 3) d 7.97 (t, 1 H), 7.42 (d, 1 H), 7.38-7.13 (m, 10H), 6.93 (d, 1 H), 4.52 (dd, 2H), 4.31 (d, 1 H), 4.22 (dd, 1 H), 4.14 (dd, 1 H), 3.61 (s, 1H), 3.44 (m, 2 H), 2.87 (m, 1H), 2.70 (m, 2H), 2.34 (m, 2H), 2.23 (m, 1 H), 1.82 (m, 1 H), 1.53 (m, 1 H), 1.24 (m, 1 H). EM FAB: 545 [M + 1j * B) N-r2- (methoxycarbonyl) etin-D-diphenylalanyl-L-prolyl-r (5-amidino-2-thieni-Pemetrylamide). This compound was prepared from the compound obtained in Step A (160 mg) using the procedure described in Example 28, Steps B and C, yield 54%, 1 H NMR (CD3OD) d 7.74 (d, 1 H), 7.35-7.11 (m, 10H), 6.98 (d, 1 H), 4.72 (dd, 1 H), 4.30 (dd, 1 H), 4.17 (s, 2H), 4.16 (dd, 1 H), 3.53 (s, 3H), 3.52 (m, 1 H), 2.89 (m, 2H), 2.75 (m, 1 H), 2.38 (m, 2H), 1.89 (m, 2H), 1.62 (m, 1H), 1.40 (m, 1 H) EM FAB: 562 [M + 1] * C) N- (2-carboxyethyl) -D-diphenylalanyl-L-prolyl-r (5-amidin-2-thienyl) methylamide.2TFA A mixture of the compound prepared in Step B (91 mg, 0.16 mmol), LiOH 0.5 N (10 mL), and water (3 mL) was stirred for 3 hours at room temperature. The reaction mixture was neutralized with 1 N HCl and concentrated in vacuo. The residue was purified by preparative HPLC (gradient of 0.1% TFA-H2O-MeOH) to yield the title compound (55mg, 44%). 1 H NMR (CD 3 OD) d 7.81 (d, 1 H), 7.62 (d, 2 H), 7.50 (t, 2 H), 7.42- 7.32 (m, 6 H), 7.21 (d, 1 H), 5.12 (d, 1 H), 4.61 (dd, 2H), 4.50 (d, 1 H), 4.11 (m, 1 H), 3.60 (m, 1 H), 2.78 (m, 1 H), 2.68 (m, 2H), 1.83 (m, 3H), 1.30 (m, 1 H). EM FAB: 548 [M + 1] * EXAMPLE 42 Preparation of N-Boc-D-Diphenylalanyl-L-prolyl-r (5-amidrazone-2-thieni-P-methylamide.TFA This compound was prepared from N-Boc-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyljamide (Example 7, Step A) using the procedure described in Example 4. 1 H NMR (CD3OD) ) d 7.67 (d, 1 H), 7.49-7.17 (m, 10H), 7.12 (d, 1H), 5.10 (d, 1 H), 4.60 (dd, 2H), 4.33 (d, 1H), 4.07 ( m, 1 H), 3.80 (m, 1H), 2.93 (m, 1 H), 1.89-1.73 (m, 2H), 1.58 (m, 1 H), 1.47 (m, 1 H), 1.29 (s, 9H).

EXAMPLE 43 Preparation of D-Diphenylalanyl-L-prolyl-r (5-amidrazone-2-thieniPmetimamide.2TFA) To a solution of the compound obtained in Step A (0.05 g, 0.071 mmol) in methanol was added a 0.4 N HCl solution in methanol (0.9 ml) and the mixture was stirred for 2 hours. The solvent was removed in vacuo and the residue was purified by preparative HPLC (gradient of 0.1% TFA-H2O-MeOH) to yield the title compound (45 mg, 88%). 1 H NMR (CD 3 OD) d 7.69 (d, 1 H), 7.59 (m, 2 H), 7.47 (m, 2 H), 7.40 (m, 2 H), 7.30 (m, 4 H), 7.19 (d, 1 H), 5.10 (d, 1 H), 4.61 (dd, 2H), 4.45 (d, 1 H), .07 (m, 1 H), 3.58 (m, 1 H), 2.82 (m, 1 H), 1.78 ( m, 3H), 1.33 (m, 1 H).

EXAMPLE 44 Preparation of N-methylsulfonyl-D-diphenylalanyl-L-prolyl-f (5-amidrazone-2-thieni-P-methylpamide.

The title compound was prepared from methyl ester. HCl D-phenylalanyl-L-proline using the procedures described in Example 7, Steps A and B, followed by Example 4. 1 H NMR (CD3OD) d 8.52 (m, 1 H), 7.72 (d, 1 H), 7.19 (d, 1 H), 4.58 (m, 2H), 4.41 (dd, 1 H), 4.31 (m, 1 H), 3.85 (m, 1 H), 3.58 (m, 1 H), 2.87 (s) , 3H), 2.28-0.85 (m, 17H).

EXAMPLE 45 In Vitro Enzyme Tests to Determine Inhibition Constants Thrombin activity was measured spectrophotometrically by tosyl acetate-Gli-Pro-Arg-p-nitroanilide (Chromozym TH, Boehringer Mannheim) as a substrate. The thrombin used in this test was prepared from human plasma according to the protocol of Ngai and Chang (see, Biochem, J. 1991, 280, 805). Each compound was dissolved in DMSO to produce a standard solution of 1mM, and dilutions thereof were made with the pH regulator of the assay (0.1M TrisHCI, 0.15M NaCl, 0.1% polyethylene glycol 8000, pH 7.8). The different concentrations of the inhibitor were mixed with 0.3 NIH thrombin units dissolved in O.dml of the pH regulator. The mixture was incubated for 10 minutes at room temperature before adding 0.2 ml of the substrate to obtain a final concentration of 20 μM. The release of p-nitroaniline by hydrolysis of the substrate was monitored for 5 minutes, measuring the increase in optical density at 381 nm with a UV2100S spectrometer (Shimadzu). A plot for the reciprocal value of the initial velocity at the concentration of the inhibitor was derived from the progress curves by adapting the data using a linear regression program. Inhibition constants (Ki values) were subsequently obtained from the Dixon graphic equation (see Biochem J. 1953, 55 170). Under these conditions, the Km value for the substrate hydrolysis was 5.2 μM according to the determinations of a non-linear regression analysis of the initial velocity assuming the Michaelis-Menten kinetics. In certain studies with very potent inhibitors (Ki <0.1 nM), where the degree of thrombin inhibition was very high, a more sensitive test was used. In this test, the concentration of Chromozym TH and thrombin was adjusted to 80 μM and 1.5 mU / ml respectively, and the hydrolysis reaction was monitored for 1.5 hours. Table 1 shows the thrombin inhibitory activity (Ki values) obtained with the exemplary compounds of the present invention. It can be appreciated that the compounds of the present invention exhibit excellent inhibitory activity against thrombin.

EXAMPLE 46 Pharmacokinetic studies to determine oral bioavailability Male Sprague-Dawley rats (250-300 g) were individually housed in a surgical plate (Dae Jong Instrument Company, Seoul, Korea) in a supine position. The femoral artery and the femoral vein (only iv) of the rats were cannulated with polyethylene tubing (PE-50, Clay Adams, Parsippany, NJ, USA) under light ether anesthesia. After having fully recovered from anesthesia, the rats received 30 mg / kg of the test compound dissolved in distilled water by oral priming, or 10 mg / kg through the femoral vein for the intravenous (iv) study. Blood samples (0.25 ml) were taken from the femoral artery at 0 (for control), 1 (only v), 5, 15, 30, 60, 90 (only iv), 120, 180 and 240 minutes after of the administration of the dose. Beagle male dogs (7-10 kg, Hazleton Research Product Inc., Kaiamazoo, Ml, USA) were individually housed in a metabolic cage for a plasma disposition study. The dogs were orally administered 10 mg / kg of the test compound dissolved in distilled water via gavage or 2 mg / 0.2 ml / kg injection through the cephalic vein using INTROCAN®. Blood samples were withdrawn through the cephalic vein at 0 (for control), 1, 5 (only iv), 15, 30, 60, 90, 120, 180, 240, 360 (only po) and 480 (only po) minutes after the administration of the dose.

The blood samples were placed in a heparinized tube (25U / ml), deproteinized with 2 volumes of methanol, and centrifuged. The resulting supernatant (60 μL) was analyzed by HPLC elution with a mixture of an aqueous solution of 0.1% trifluoroacetic acid and acetonitrile at a ratio of 81% to 19%. The plasma concentration of the test compound was recorded and used to calculate the pharmacokinetic parameters: Maximum plasma concentration of the test compound (Cmax), maximum plasma concentration time (Tma?), Area under the curve (AUC) and Absorbed fraction of the test compound (F). In general, the compounds of the present invention demonstrate good oral absorption in rats and dogs. In particular, compounds that include a portion of D-dnylalanine exhibit increased absorption compared to corresponding compounds containing a portion of D-cyclohexylalaine. Table 2 shows the pharmacokinetic results for some exemplary compounds of the invention that were obtained by oral administration in rats.

EXAMPLE 47 In vivo studies of the compounds claimed herein were carried out according to the following procedure.

Male Sprague-Dawley rats (body weight 250-300 g, 3-4 / group) were anesthetized by intraperitoneal injection with a urethane solution (1.25 g / kg). The abdomen was surgically opened by an incision in the central line and the inferior vena cava was carefully dissected to clear it from the surrounding connective tissue. The iliolumbar vein and sperm were linked with a silk thread. Thrombus formation was initiated through the infusion of a thromboplastin preparation (Simplastin®) using an infusion pump (Model 100, TIC Life Science, USA) via the left femoral vein at 0.5 ml / kg / min. Simplastin® (Organon Teknika, USA) was reconstituted with 4 ml of distilled water and then administered in diluted form 1: 2.5 in distilled water. At the beginning of the infusion for 30 seconds, the vena cava was ligated below the left renal vein. At the end of the infusion, the vena cava was also ligated above the iliac veins, 16 mm from the superior ligature. After 15 minutes of stasis, the thrombus formed inside the vessel was carefully removed and weighed. Prior to weighing, the excess blood was removed by drying wet clot on the wet Whatman filter paper (see, Millet, J., Theveniaux, J., Brown, N. L. Thromb, Haemost, 1992, 67, 176).

The saline (control) or test compounds (1 mg / kg) were injected as a bolus through the femoral vein, starting 5 minutes before the thromboplastin infusion. The injection volume per bolus was 0.5 ml / kg. The antithrombotic activity was expressed as a percentage where: Antithrombotic activity (%) = 100 x (A - B) / A A = average weight of clot of control group B = average weight of clot of group I of test compound The results show that the compounds of the present invention are effective in the prevention of thrombotic occlusions. In particular, compounds containing both D-dnylalanine and amidine moieties exhibit excellent antithrombotic activity. For example, at a dose of 1 mg / kg, the compounds of Examples 1, 3, 11, 15, 19, 29 and 41 are 100% effective in inhibiting thrombus formation in the model of venous thrombosis in rats TABLE 1 TABLE 2 Pharmacokinetic parameters after oral dosing in rats (30mg / kg) Example (ng / m ') (min) AUC (μg.min / ml) 1 2.2 60 253 5 1.8 32 280 8 9.6 60 1615 11 2.1 45 254 14 4.5 80 850 19 5.2 80 1297 29 9.5 15 1390 35 7.1 45 965 39 4.6 15 212 40 11.1 25 1126 41 4.9 20 503 All the documents mentioned in the present, including foreign priority documents, are incorporated by reference. It should be understood that the foregoing description is exemplary and explanatory in nature, and is intended to illustrate the invention and its preferred embodiments. Through routine experimentation, the person skilled in the art will recognize the obvious modifications and variations that can be made without departing from the spirit of the invention; consequently, the present is intended to be defined not only in the foregoing description, but by the following claims and their equivalents.

Claims

NOVELTY PE THE INVENTION CLAIMS

1. - A compound having the formula (I): pharmaceutically acceptable salts thereof, wherein: n is 1, 2 or 3; A is a hydrogen, alkyl, C3-7 cycloalkyl, aryl, -S02R1, -SO3R1, -COR1, -CO2R2, PO (OR1) 2, - (CH2) mCO2R1, - (CH2) mSO2R1, - (CH2) mSO3R1 , or - (CH2) MPO (OR1) 2, wherein: R1 is a hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, - (CH2) maryl, or -NR3R4, and R2 is C1 alkyl -6, C3-7 cycloalkyl, aryl, - (CH2) maryl or alkenyl, m is 1, 2 or 3 wherein: aryl is unsubstituted or substituted phenyl or an aromatic heterocyclic ring with 5-6 members, R3 and R4 they are independently hydrogen, C 1-6 alkyl, or C 3-7 cycloalkyl; B is hydrogen or Ci-e alkyl; C and D are independently hydrogen, phenyl unsubstituted or substituted by one or two substituents selected from C 1-4 alkyl, C 1-4 alkoxy, CF 3, methylenedioxy, halogen, hydroxy or -NR 3 R 4, C 3-7 cycloalkyl or a of 5-6 membered heterocyclic ring which may be saturated or unsaturated, and which consists of carbon atoms and 1-3 heteroatoms selected from the group consisting of N, O and S; E is wherein: X is S, O or NR5, Y and Z are independently N or CR6; wherein R5 is hydrogen or alkyl of C- and R6 is hydrogen, halogen, CF3 or alkyl of d.4, and F is -C (NH) N (R7) 2, -C (NH2) NN (R7) 2, -C (NH2) NOH or -CH2NH (R7) 2, wherein R7 is the same or different and is hydrogen, C1-4 perfluoroalkyl or C1-4 alkyl.

2. The compound according to claim 1, further characterized in that C and D are independently selected from the group consisting of phenyl unsubstituted or substituted with one or two substituents selected from the group consisting of C1-4 alkyl, alkoxy C1-4, methylenedioxy, halogen, hydroxy or NR3R4 wherein R3 and R4 are defined above; C3.7 cycloalkyl, and a 5-6 membered heterocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and 1-3 heteroatoms selected from the group consisting of N, O and S.

3 The compound according to claim 1, further characterized in that A is selected from the group consisting of hydrogen, aryl, -SO2R1, -SO3H, -COR1, -CO2R2, -PO (R1) 2 > -PO (OR1) 2, and (CH2) mCO2R1 wherein R1 and R2 are defined above.

4. The compound according to claim 3, further characterized in that A is selected from the group consisting of -SO2NR3R4, -PO (R1) 2, -PO (OR1) 2, - (CH2) mCO2R1 or aryl.

5. The compound according to claim 2, further characterized in that A is selected from a group consisting of hydrogen, -SO2R1, -POid-ßalkylh, -PO (OC? ^ Alkyl) 2, -CO (C? alkyl), - (CH2) mCO2H and - (CH2) mC? 2 (C? -6alkyl), wherein m is 1 or 2; and R1 is C6-6 alkyl, aryl, - (CH) maryl, hydroxy or -NR3R4 wherein R3 and R4 are as previously defined,

6. The compound according to claim 2, further characterized in that C and D are independently selected from the group consisting of phenyl, pyridyl or cyclohexyl unsubstituted or substituted with one or two substituents selected from the group consisting of C1-6alkyl, C1-alkoxy, methylenedioxy, halogen, hydroxy and NR3R4, wherein R3 and R4 are as previously defined.

7. The compound according to claim 2, further characterized in that C and D are independently selected from the group consisting of phenyl or cyclohexyl.

8. The compound according to claim 1, further characterized in that E is selected from the group consisting of where, when X is S, O or NR5, Y represents CH and Z represents CR6, or Y represents CR6 and Z represents CH; when X is S, O or NH, Y represents n and Z represents CR6, or Y represents CR6 and Z represents R5, and R6 is as previously defined.

9. The compound according to claim 8, further characterized in that R5 and R6 are independently hydrogen or C1-4 alkyl.

10. The compound according to claim 1, further characterized in that F is selected from the group consisting of -C (NH) NH2, -C (NH2) NOH, -C (NH2) NNH2, and -CH2NH2.

11. The compound according to claim 1, further characterized in that the compound is selected from the group consisting of: N-aminosulfonyl-D-diphenylamine-L-prolyl - [(5-amidino-2-thienyl) methyl] amide , N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(5-aminomethyl-2-thienyl) methylamide, N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienH) methyl] amide , N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidrazono-2-thienyl) methyljamide, N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-aminomethyl-2-thienyl) methyl] amide , N-benzylsulphonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, Nt-butoxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) ) methyl] amide, N-methoxycarbonyl-D-diphenylalanyl-L-prslyl - [(5-amidin-2-thieni-P-methyl-amide, N-aminosulfonyl-D-3,4-di-orophenylalanyl-L-prolyl - [(5-) amidino-2-thienyl) methyl] amide, N-methoxycarbonyl-D-dicyclohexylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyI] amide, N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [( 4-amidino-2-thienyl) met jamide, N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-thienyl) methylamphamide, N-methylsulfonyl-D-diphenylalanyl-prolyl] - [(4-amimethyl-2) -thienyl) meti jamide, N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-thienyl) methyl] amide N-aminosulfonyl-D-diphenylalanyl-L-prolyI - [(5-amidino-3 -thienyl) methylamide, N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-3-thienyl) methylamide, N-methylsulfonyl-D-diphenylalanyl-L-proynyl [[5-amidrazone-3] -thienyl) methanamide, N-methylsulfonyl-D-phenylalanyl-L-proylyl - [(5-aminomethyl-3-thienyl) methylamide, N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-3 -thienyl) methyl] amide, N-cyclohexylsulphamoyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyljamide, N-allyloxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amino) -2-thienyl) methyljamide, N-benzyl-sulphonyl-D-cyclohexylalani-L-prolyl - [(5-amino-2-thienyl) methyl-amide, N-cyclohexylsulfamoyl-D-cyclohexylalanyl-L-prolyl - [(5-thienyl) -2-thienyl) -amidino- 2-thieniI) methyljamide, N-methylsuifamoyl-D-cyclohexylIanyl-L-prol il - [(5-amidino-2-thieni!) methyljamide, N-methylsulfonyl-D-cyclohexylglycinyl-L-prolyl - [(5-amidino-2-thienyl) methyljamide, N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyljamide, N-methyl-N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, N-hydroxysulfonyl-D -diphenylalanyl-L-prolyl - [(5-amidino-2-t-enyl) methyljamide, N-methylsulfonyl-D-diphenylalanyl-L-azetidine-2-carboxyl - [(5-amidino-2-thienyl) methylamide] , N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-5-methyl-2-thienyl) methyl] amide, N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino -2-furanyl) methyl] amide, N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-furanyl) methyljamide, N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino -3-furanyl) methyljamide, N-aminosulfonyl-D-diphenylalanyl-L-proyl - [(4-amidino-2-thiazolyl) methyl-amide, N-methylsulfonyl-D-diphenylalanyl-L-prolyl- [ (5- amidino-1-methyl-2-pyrrolyl) methyl] amide, N-carboxymethyl-D-diphenylamine-L-prolyl - [(5-amidino-3-thienyl) methyljamide, N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-thiazolyI) methyl] amide, N- (2-carboxyethyl) -D-diphenylalanyl-L-prolyl - [(5-amidyl)] no-2-thienyl) methyl] amide, N-Boc-D-diphenylalanyl-L-prolyl - [(5-amidrazono-2-thienyl) methylamide, D-diphenylalanyl-L-prolyl - [(5-ami drazono-2-thienyl) methyljamide, N-methoxycarbonyl-D-diphenylalanyl-L-azetadine-2-carboxyl - [(5-amidino-2-thienyl) methyljamide, N- (2-carboxyethyl) -D- diphenylalanyl-L-azetadine-2-carboxyl - [(5-amidino-2-thienyl) methylamide, D-diphenylalan-L-prolyl- | 5-amino-2-thienyl) methyljamide, N- (3-carboxypropyl) -D-diphenylalan-L-prolyl- | 5-amidino-2-thienyl) methyljamide, N- (MeO) 2PO-D-diphenylalan-L-prolyl- | X5-amidino-2-thienyl) methyljamide, N- (Me) 2P (O) -D-diphenylalani-L-prolyl- |; (5-amidino-2'-thienyl) methyljamide, N- (HO) 2P (O) -D-diphenylalani-L-prolyl- | 5-amidino-2-thienyl) methyl] amide, N-methyl-D-diphenylalani-L-prolyl- [5-amidino-2-thiethieniyl)) mmeettiilljjaammiiddaa ,, N-phenyl-D-diphenylalani-L-prolyl- [(5 -amidino-2-thienyl) methyl] amide, N - [(N, N-diethylcarboxamido) methyl] -D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyljamide, N - [( N, N-diethylcarboxyamido) ethylj-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thienyl) methylamide, N-aminosulfonyl-D-diphenylalanyl-L-prolyl- [( 5-amidino-2-thiazolyl) methyljamide, N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-thiazolyl) methyljamide, N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [( 4-amidino-2-thiazole I) methyljamide, N-aminosulfonyl-D, p-phenylalanyl-L-prolyl - [(2-amidino-5-thiazolyl) methylamide, N-methylsulfonyl-D-diphenylalanyl-L- prolyl - [(5-amidino-2-thiazolyl) methyljamide, N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-thiazole) methyl] amide, N-methylsulfonyl-D-diphenylalanyl-L- prolyl - [(4-amidino-2-thiazoli) methyljamide, N-methylsulfonyl-D-diphenylalanyl-L-prolyl] - [(2-amidino-5-thiazoline ) methyljamide, N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thiazoli) methyljamide, N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-thiazoli) methyljamide) , N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-thiazole) methyl] amide, N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-5-thiazoline ) methyl] amide, N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-thiazole) methyljamide, N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4) -thiazoli) methyl] amide, N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(2-amidino-5-thiazole) methyl] amide, N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(5-amidino -2-oxazoyl) methyljamide, N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(2-amido-4-oxazoyl) methyl] amide, N-aminosulfonyl-D-diphenylalanyl-L-prolyl- [ (4-amidino-2-oxazoyl) methyljamide, N-aminosulfonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-5-oxazoyl) methyl] amide, N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(5- am id i no-2-oxazo il) methyljamide, N-methylsulfonyl-D-diphenylalanyl-L-prolyl - [(2-amidino-4-oxazoyl) methyljamide, N-methylsulfonyl-D-phenylalanyl-L-prolyl - [(4-amidino-2-oxazoyl) methyljamide, N-methylsulfonyl-D-diphenylamine-L-prol I - [(2-amidino-5-oxazoyl) methyljamide, N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-oxazoyl) methyl] amide, N-methoxycarbonyl-D-diphenylalanyl -L-prolyl - [(2-amidino-4-oxazoyl) methyljamide, N-methoxycarbonyl-D-diphenylalanyl-L-prolyl - [(4-amidino-2-oxazo-yl) -metiijamide, N-methoxycarbonyl-D-d-phenylalan L-prolyl - [(2-amidino-5-oxazoyl) methyl] amide, N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-oxazoyl) methyljamide, N-carboxymethyl -D-diphenylalanyl-L-proiiI - [(2-amidino-4-oxazolyl) methylamide, N-carboxymethyl-D-diphenylalan-L-prolyl - [(4-amidino-2-oxazolyl) methyljamide, N-carboxymethyl-D-diphenylalan -prolyl- [(2-amidino-5-oxazolyl) methyl] amide, N-aminosulfon-1D-diphenylalan-1-prolyl - [(2-amidino-4-isoxazol l) methyljamide, N-aminosulfon-1D-diphenylalan-L-prolyl- [(4-amidino-2-isoxazoli l) methyljamide, N-methylsulfon lD-diphenylalan-L-prolyl- [(2-amidino-4-isoxazol l) methylamide, N-methylsulfon-1D-diphenylalan-1-prolyl- [(4-amidino-2-isoxazol l) methyljamide, N-methoxycarbon lD-diphenylalan-L-prolyl - [(2-amidino-4-isoxazol l) methyljamide, N-methoxycarbon lD-diphenylalan-L-prolyl - [(4-amidino-2-isoxazole I) methyljamide, N-carboxymethyl-D-diphenylalan -prolyl - [(4-t O amidino-2-suloxazoli l) methyljamide, N-carboxymethyl-D-diphenylalan-L-prolyl - [(2-amidino-4-isoxazol l) methyljamide, N-aminosulfon-1-diphenylalan-L-prolyl- [ (4-amidino-2-pyrazolyl) methyljamide, N-methylsulfon-1D-diphenylalan-1-prolyl - [(4-amidin-2-pyrazolyl) methyl] amide, N-methoxycarbon-1D-diphenylalan-prolyl - [(4 - amidino-2-pyrazolyl) methyalkamide, N-carboxymethyl-D-diphenylalan-L-prolyl - [(4-amidino-2-pyrazolyl) methyl] amide, N-aminosulfon-lD-diphenylalan-L-prolyl - [(5- amidino-2-pyrrolyl) methylamide, N-aminosulfon-1D-diphenylalan-L-prolyl - [(4-amidino-2-pyrroyl) methyl] amide, N-aminosulfon-lD-diphenylalan-L-prolyl - [(5-amidino-3-pyrrolyl) -methyl-amide, N-methylsulfon-lD-diphenylalan-L-prolyl - [(5-amidino-2-pyrrolyl) -methyl] -amide , N-methylsulfon-1D-diphenylalan-L-prolyl - [(4-amido-2-pyrrolyl) -methyl-amide, N-methylsulfon-1D-diphenylalan-1-prolyl - [(5-amidino-3-pyrrolyl) methyl-amide, N- methoxycarbon lD-diphenylalan-L-prolyl - [(5-amidino-2-pyrrolyl) methyljamide, N-methoxycarbon-1D-diphenylalan-L-prolyl - [(4-amidino-2-pyrrolid) methyl] amide, N-methoxycarbon I -difenilalan L-prolyl - [(5-amidino-3-pyrrolyl) methyl] amide, N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(5-amidino-2-pyrrolyl) methyl] amide, N-carboxymethyl- D-diphenylalanyl-L-prolyl - [(4-amidino-2-pyrrolyl) methylamide, N-carboxymethyl-D-diphenylalanyl-L-prolyl - [(5-amidino-3-pyrrolyl) methyl] amide, N-aminosulfonyl- D-bis- (para-methoxyphenyl) alanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, N-methylsulfonyl-D-bis- (para-methoxyphenyl) alanyl-L-prolyl - [( 5-amidino-2-thienyl) methyl] amide, N-methoxycarbonyl-D- bis- (pair a-methoxyphenyl) alanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, N-carboxymethyl-D-bis- (para-methoxyphenyl) alanyl-L-prolyl - [(5-amidino-2) thienyl) methyl] amide, N-aminosulfonyl-D-bis- (para-aminophenyl) alanyl-L-protyl - [(5-amidino-2-thienyl) methyljamide, N-methylsulfonyl-D-dicyclohexylalanyl-L-β-rolyl - [(5-amidino-2-thienyl) methyljamide, N-carboxymethyl-D-dicyclohexylalanyl-L-prolyl - [(5-amidino-2-thienyl) methyl] amide, and pharmaceutically acceptable salts thereof.

12. A method for modulating trypsin-like serines proteases characterized in that it comprises the administration of an effective amount of the compound as claimed in claim 1 to a mammal.

13. A method for inhibiting trypsin-like serines proteases characterized in that it comprises the administration of an effective amount of the compound as claimed in claim 1 to a mammal.

14. A method for modulating thrombin that encompasses the administration of an effective amount of the compound as claimed in claim 1 to a mammal.

15. - A method for inhibiting thrombin comprising the administration of an effective amount of the compound as claimed in claim 1 to a mammal.