MXPA98007091A - Inhibitors of protease being - Google Patents

Abstract

The invention relates to a compound having the formula (I), wherein A, B, X, Y and r are as defined in the description, or a prodrug thereof or a pharmaceutically acceptable salt thereof. The compounds of the invention have anticoagulant activity and can be used to treat or prevent diseases related to thrombi.

Description

SERINE PROTEASE INHIBITORS The invention relates to a serine protease inhibitor having an alkynylamino side chain, a pharmaceutical composition containing the same, as well as the use of said inhibitor for the manufacture of a medicament for treating and preventing diseases related to thrombin. Serine proteases are enzymes which, among other things, play an important role in the blood coagulation cascade. Members of this group of proteases are, for example, thrombin, trypsin, factors Vlla, IXa, Xa, Xla, Xlla, and protein C. Thrombin is the serine protease that regulates the last step in the coagulation cascade. The main function of thrombin is the cutting of fibrinogen to generate fibrin monomers, which form an insoluble gel by cross-linking. In addition, thrombin regulates its own production by activating factors V and VII I earlier in the cascade. It also has important actions at the cellular level, where it acts on specific receptors to cause the aggregation of platelets, activation of endothelial cells and proliferation of fibroblasts. Thus, thrombin has a central regulatory role in hemostasis and thrombus formation. Since thrombin inhibitors can have a wide range of therapeutic applications, extensive research has been conducted in this area. In the development of synthetic inhibitors of seripa proteases, and more specifically of thrombin, interest has grown in small synthetic peptides that are recognized by proteolytic enzymes in a manner similar to that of natural substrates. As a result, new peptide-like inhibitors, such as the thrombin transition state inhibitors, have been prepared. The search for more effective and more selective thrombin inhibitors continues without decreasing, in order to obtain thrombin inhibitors, which can be administered in smaller dosages and which have less side effects and less severe. In addition, special attention has been paid to oral bioavailability. Potent intravenous thrombin inhibitors are clinically effective in acute care settings requiring the treatment of thrombin-related diseases. However, particularly the prevention of thrombin-related diseases such as myocardial infarction, thrombosis and stroke, require long-term therapy, preferably by orally dosing an anticoagulant. Most of the peptide-like thrombin inhibitors described in previous publications contain arginine side chains. Thrombin inhibitors may also contain arginine lysine side chains, such as the N-Me-D-Cha-Pro-Lys-COOH inhibitor and derivatives thereof, described by Jones et al. , J. Enzyme Inhibition, 9 (1995), 43-60, and the N-Me-D-Phe-Pro-Lys-X inhibitors, X being a carboxamide or carboxylic acid, described by Lewis et al. , Thrombosis and Haemostasis, 74 (4) (1995), 1 107-12. In addition, Brady et al. , Bioorganic & Medical Chemistry, 3 (1995), 1063-78, describe a D-Phe-Pro-Lys-ketoester. Other thrombin inhibitors are described in WO 94/25051, wherein the side chain of lysine or arginine is replaced by aminocyclohexyl portions. A problem with thrombin inhibitors containing arginine and lysine is that they have low oral bioavailability. It has now been found that inhibitors of serine protease, and in particular thrombin, inhibitors Xa and Vlla, having an alkynylamino side chain, according to formula I wherein A is H, optionally D, L-substituted a-hydroxyacetyl, R1, R -0-C (0) -, R1-C (0) -, R1-S02-, R2OOC- (CH R2) m-S02- , R2OOC- (CHR2) m-, H2NCO- (CHR2) m-, or an N-protecting group, wherein R1 is selected from (1 -12C) alkyl, (2-12C) alkenyl, (2-12C) alkynyl and (3-8C) cycloalkyl, said groups may be optionally substituted with (3-8C) cycloalkyl, (1 -6C) alkoxy, oxo, OH, COOH, CF3 or halogen, and from (6-14C) aryl, (7 -15C) aralkyl and (8-16) aralkenyl, the aryl groups of which can be optionally substituted with (1-6C) alkyi, (3-8C) cycloalkyl, (1-6C) alkoxy, OH, COOH, CF3 or halogen; each group R2 is independently H or has the same meaning as R1; m is 1, 2 or 3; B is a ligation, an amino acid of the formula -NH-CH [(CH2) pC (0) OH] -C (O) - or an ester derived therefrom and being p 0, 1, 2, or 3, -N ((1 -12C) alkyl) -CH2-CO-, -N ((2-12C) alkenyl) -CH2-CO-, -N ((2-12C) alkynyl) -CH2-CO-, -N (benzyl) ) -CH2-CO-, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1-Piq, D-3-Piq or an L- or D-amino acid having a hydrophobic side chain, basic or neutral, said amino acid may optionally be N- (1 -6C) alkyl substituted; or A and B together are the residue R3R4N-CHR5-C (O) -, wherein R3 and R4 independently are R1, R1-OC (O) -, R1-C (O) -, R1-SO2-, R2OOC- (CHR2) m-SO2-, R2OOC- (CHR2) m-, H2NCO- (CHR2) m-, or an N-protecting group, or one of R3 and R4 is connected with R5 to form a 5- or 6-membered ring together with "NC to which they are bound, said ring can be fused with an aliphatic or aromatic 6-membered ring, and R5 is a hydrophobic, basic or neutral side chain, X is an L-amino acid with a hydrophobic side chain, serine, threonine, a cyclic amino acid containing an additional heteroatom selected from N, O or S, and optionally substituted with (1-6C) alkyl, (1-6C) alkoxy, benzyloxy or oxo, or X is -NR2-CH2-C ( ) - or the fragment where n is 2 3 or 4, and W is CH or N, Y is H, -CHF2, -CF3, -CO-NH- (1 -6C) alkylene-C6Hs, -COOR6 and R6 where H is or (1 - 6C) alkyl, -CONR7R8 and R7 and R8 independently being H or (1-6C) alkyl or R7 and R8 together being (3-6C) alkylene, or Y is a heterocycle selected from 2-thiazole, 2-thiazoline, 2- benzothiazole, 2-oxazole, 2-oxazoline and 2-benzoxazole, said heterocycles may be optionally substituted with (1-6C) alkyl, phenyl, (1-6C) alkoxy, benzyloxy or oxo; and r is 0, 1, 2 or 3; or a prodrug thereof or a pharmaceutically acceptable salt thereof, are selective and potent inhibitors. In addition, some of the compounds of the invention show good bioavailability after oral administration. The compounds of the present invention are useful for treating and preventing diseases mediated by thrombin and associated with thrombin. This includes a number of thrombotic and prothrombotic states in which the coagulation cascade is activated, which includes, but is not limited to, deep vein thrombosis, pulmonary embolism, thrombophlebitis, arterial occlusion of thrombosis or embolism, arterial reoculusion during or after angioplasty or thrombolysis, restenosis following arterial injury or invasive cardiological procedures, embolism or postoperative venous thrombosis, apoplexy, myocardial infarction, cancer and metastasis, and neurodegenerative diseases. The compounds of the invention can also be used as anticoagulants in extracorporeal blood circuits, as is necessary in dialysis and surgery. The compounds of the invention can also be used as anticoagulants in vitro.

Preferred compounds according to the invention have the formula I, wherein X is an L-amino acid with a hydrophobic side chain, serine, threonine or -NR2-CH2-C (0) -.

Other preferred compounds of formula I are those, wherein A is as previously defined; B is a ligation, an amino acid of the formula -NH-CH [(CH2) PC (O) OH] -C (O) - or an ester derived therefrom and being p 0, 1, 2 or 3, -N ( (1 -6C) alkyl) -CH2-CO-, -N ((2-6C) alkenyl) -CH2-CO-, -N (benzyl) -CH2-CO-, D-1 -Tiq, D-3- Tiq, D-Atc, Aic, D-1 -Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain, said amino acid may optionally be N- (1-6C) substituted alkyl; or A and B together are the residue R3R4N-CHR5-C (O) -; and X is a cyclic amino acid optionally containing an additional heteroatom selected from N, O or S, and optionally substituted with (1-6C) alkyl, (1-6C) alkoxy, benzyloxy or oxo, or X is -NR2-CH2-C (0) - or the fragment More preferred are compounds of formula I, wherein A is H, 2-hydroxy-3-cyclohexyl-propionyl-, 9-hydroxy-fluorene-9-carboxyl, R1, R1-S02-, R2OOC- (CHR2) m- SO2-, R2OOC- (CHR2) m-, HzNCO- (CHR2) m-, or an N-protecting group, wherein R1 is selected from (1 -12C) alkyl, (2-12C) alkenyl, (6-14C) ) aryl, (7-15C) aralkyl and (8-16) aralkenyl; each group R2 is independently H or has the same meaning as R1; B is a ligation, D-1 -Tiq, D-3-Tiq, D-Atc, Aic, D-1 -Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain, said amino acid optionally being N- (1 -6C) alkyl substituted; or A and B together are the residue R3R4NCH R5-C (O); Y is -CO-N H- (1 -6C) alkylene-C6Hs, -COOR6, - CONR7R8, or Y is a heterocycle selected from 2-thiazole, 2-thiazoline, 2-benzothiazole, 2. oxazole, 2-oxazoline and 2-benzoxazole. In particular, those compounds are preferred, wherein A is H, R1-SO2- or R2OOC- (CHR2) m-; B is a ligation, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1 -Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain; or A and B together are the residue R3R4N-CHR5-C (O) -, wherein at least one of R3 and R4 is R OOC- (CHR2) m- or R1-SO2- and the other independently is (1 - 12C) aIlkyl, (2-12C) alkenyl, (2-12C) alkynyl, (3-8C) cycloalkyl, (7-15C) aralkyl, R1-SO2- or R2OOC- (CHR2) m-, and Rs is a chain hydrophobic lateral; Y is -CO-NH- (1-6C) alkylene-C6Hs, -COOR6 and R6 with H or (1 -3C) alkyl, -CONR7R8, and R8 being independently H or (1 -3C9alkyl or R7 and R8 being together ( 3-5C) alkylene, or Y is a heterocycle selected from 2-thiazole, 2-benzothiazole, 2-oxazole or 2-benzoxazole When A is R2OOC- (CHR) 2-m, preferably B is a D-amino acid which has a hydrophobic side chain, or A and B together are the residue R3R4N-CH Rs-C (O) -, wherein at least one of R3 and R4 is R2OOC- (CHR2) m- and the other independently is (1) -12C) alkyl (2-6C) alkenyl, (3-8C) cycloalkyl, benzyl, R1-S02- or R2OOC- (CHR2) m-; and X is 2-azetidine carboxylic acid, proline, pipecolic acid, -thiazolidin carboxylic acid, 3,4-dehydro-proline, 2-octahydroindol carboxylic acid or - [N (3-8C) cycloalkyl] -CH2-C (O). Compounds wherein A is HOOC-CH2-; B is D-Phe, D-Cha, D-Coa, D-Dpa, p-CI-D-Phe, p-OMethyl-D-Phe, p-Oethyl-D-Phe, D-Nle, m-CI- D-Phe, 3,4-di-OMe-D-Phe, D-Chg; or A and B together are the R3 residue R N-CHRs-C (0) -, wherein at least one of R3 and R4 is HOOC-CH2- and the other independently is (1-4C) alkyl, (1-4C) alkylSO- or HOOC-CH2- and R5 is (3-8C) cycloalkyl, (3-8C) cycloalkyl (1-4C) alkyl, phenyl, benzyl, optionally substituted with chloro or (1-4C) alkoxy. Particularly preferred are those compounds wherein Y is a heterocycle selected from 2-thiazole, 2-benzothiazole, 2-oxazole or 2-benzoxazole. When A is R1-SO2-, preferably B is a ligation, D-1 -Tiq, D-3-Tiq, D-Atc, Aic, D-1 -Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain; or A and B together are the residue R3R4N-CHRs-C (O) -, wherein at least one of R3 and R4 is R1-SO2- and the other independently is (1-12C) alkyl or R1-S02-; X is 2-azetidine carboxylic acid, proline, pipecolic acid, 4-thiazolidin carboxylic acid, 3,4-dehydro-proline, 2-octahydroindol carboxylic acid, - [N (cyclopentyl) J-CH2-C (O) - or the fragment More preferred are those compounds wherein A is ethyl-SO 2 - or benzyl-SO 2 -; B is a ligature, D-Phe, D-Cha, D-Coa, D-Dpa, p-CI-D-Phe, p-OMethyl-D-Phe, p-Oethyl-D-Phe, D-Nle, m -CI-D-Phe, 3,4-di-OMe-D-Phe, D-Chg; or A and B together are the residue R3R4N-CH R5-C (0) -, wherein at least one of R3 and R4 is Ethyl-S02- or Benzyl-S02- and the other independently is (1 -12C) alkyl or R1-S02- and Rs is (3-8C) cycloalkyl, (3-8C) cycloalkyl (1-4C) alkyl, phenyl, benzyl, diphenylmethynyl, said groups are optionally substituted with chloro or (1-4C) alkoxy. Most preferred are those compounds wherein Y is -CO-N? -CH2-C6? 5- -CO-NH-CH2CH2-C6H5 or -CONR7R8, R7 and R8 independently being H or (1 -3C) alkyl or R7 and R8 together being (3-5C) alkylene, or Y is a heterocycle selected from 2-thiazole, 2-benzothiazole, 2-oxazole or 2-benzoxazole. Most preferably, r is 1 in the compounds of formula I. The N-protecting group as defined in the definition of portion A is any N-protecting group as used in the peptides. Suitable N-protecting groups can be found in T.W. Green and P.G.M. Wuts: Protective Groups in Organic Synthesis, Second Edition (Wiley, NY, 1991) and in The Peptides, Analysis, Synthesis, Biology, vol. 3 E. Gross and J. Meienhofer, Eds. , (Academic Press, New York, 1981). The term optionally substituted D, L α -hydroxyacetyl means a group of the formula HO-CRaRb-C (O) -, wherein Ra and Rb independently are H, a hydrophobic side chain, or Ra and Rb together form a ring of 5 or 6 members, which is optionally fused with one or two rings of 6 aliphatic or aromatic members, and said ring of 5 or 6 members consists of carbon atoms and optionally a heteroatom selected from N, O and S. The groups D, Preferred L-hydroxyacetyl are 2-hydroxy-3-cyclohexyl-propionyl- and 9-hydroxy-fluoren-9-carboxyl. The term (1-12C) alkyl means a branched or unbranched alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl, t-butyl, isopentyl, heptyl, dodecyl and the like. Preferred alkyl groups are (1-6C) alkyl groups, having 1-6 carbon atoms. Most preferred are (1-4C) alkyl groups. Preferred in the definition of R6, R7 and R8 are (1 -3C) alkyl groups, having 1 -3 carbon atoms, such as methyl, ethyl isopropyl. A (2-12C) alkenyl group is a branched or unbranched unsaturated hydrocarbon group having 2 to 12 carbon atoms. Preferred are the (2-6C) alkenyl groups. Examples are ethenyl, propenyl, allyl and the like. The term (1-6C) alkylene means a branched or unbranched alkylene group having 1 to 6 carbon atoms, such as - (C 2) m- and m is 1 to 6, -CH (CH 3) -, -CH ( CH3) - (CH2) -, etc. Preferred alkylene groups in the definition of Y are ethylene and methylene. A (2-12C) alkynyl group is a branched or unbranched hydrocarbon group containing a triple bond and having 2 to T2 carbon atoms. The preferred (2-6C) alkynyl groups are, such as, ethynyl and propynyl. A group (6-14C) aryl is an aromatic portion of 6 to 14 carbon atoms. The aryl group may also contain one or more hetero atoms, such as N, S, or O. Examples of aryl groups are phenyl, naphthyl, (iso) quinolyl, indanyl, and the like. The phenyl group is most preferred. The (7-15C) aralkyl and (8-16C) aralkenyl groups are respectively alkyl and alkenyl groups, substituted by one or more aryl groups, the total number of carbon atoms being 7 to 15 and 8 to 16, respectively. The term (1-6C) alkoxy means an alkoxy group having 1-6 carbon atoms, the alkyl portion having the meaning as previously defined.

The term (3-8C) cycloalkyl means a cycloalkyl group having 3-8 carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Cyclopentyl and cyclohexyl are the preferred cycloalkyl groups. The term halogen means fluorine, chlorine, bromine or iodine. The term ester derivative means any ester derived, preferably (1-4C) alkyl esters, such as methyl-, ethyl- or t-butyl esters. The terms 1- and 3-Tiq mean 1, 2,3,4-tetrahydroisoquinoline-1-or -3-carboxylic acid, respectively; 1 - and 3-Piq are 1 - and 3-carboxypehydroisoquinoline, respectively; Atc is 2-aminotetralin-2-carboxylic acid; Aic is amino indane carboxylic acid; Phe is phenylalanine; Cha is cyclohexylalanine; Dpa is diphenylalanine; Coa is cyclooctylalanine; Chg is cyclohexylglycine; Nle is norleucine; Asp is aspartic acid. The term "hydrophobic side chain" means a (1-12C) alkyl, optionally substituted with one or more (3-8C) cycloalkyl groups or (6-14C) aryl groups (which may contain a heteroatom, eg, nitrogen), such such as cyclohexyl, cyclooctyl, phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, and the like, said hydrophobic side chain can be optionally substituted with substituents such as halogen, trifluoromethyl, lower alkyl (e.g., methyl or ethyl), lower alkoxy (e.g. , methoxy), phenyloxy, benzyloxy and the like. In the definitions, the term substituted means: substituted by one or more substituents.

Amino acids having basic side chain are, for example, but not limited to, arginine and lysine, preferably arginine. The term "amino acids having a neutral side chain" refers to amino acids such as methionine sulfon and the like. The cyclic amino acids are, for example, 2-azetidine carboxylic acid, proline, pipecolic acid, 1-amino-1-carboxy (3-8C) cycloalkane (preferably 4C, 5C or 6C), 4-piperidine carboxylic acid, 4-thiazolidine carboxylic acid, 3,4-dehydro-proline, azaproline, 2-octahydroindol carboxylic acid, and the like. Preferred are 2-azetidine carboxylic acid, proline, pipecolic acid, 4-thiazolidin carboxylic acid, 3,4-dehydro-proline and 2-octahydroindol carboxylic acid. The term "prodrug" means a compound in which the alkynylamino side chain of the compound of formula I is protected, for example, by a hydroxy group, (1-6C) alkoxy or (1-6C) alkoxycarbonyl. The invention further includes a process for preparing a compound of formula I, including coupling of suitably protected amino acids or amino acid analogues, followed by removal of the protecting groups. The compounds according to formula I can be prepared in a conventional manner for such compounds. The modified amino acid having an alkynylamino side chain is introduced in a similar manner for known methods for other amino acids. For this purpose, appropriately protected Na amino acid derivatives (and the protected side chain if reactive side chains are present) or peptides are activated and coupled to amino acid derivatives or carboxyl peptides suitably protected either in solution or on a solid support. The protection of a-amino functions generally takes place by urethane functions, such as the acid-labile tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl group (Z) and substituted analogues or the 9-fluorenyl-methyloxycarbonyl group (Fmoc) labile to the base. The Z group can also be removed by catalytic hydrogenation. Other suitable amino protecting groups include Nps, Bmv, Bpoc, Msc, etc. A good review of the protective amino groups is given in The Peptides, Analysis, Synthesis, Biology, Vol. 3 E. Gross and J. Meienhofer, Eds. , (Academic Press, New York, 1981). The protection of carboxyl groups can take place by ester formation, for example base-labile esters such as methyl- or ethylesters, acid-labile esters such as tert-butyl esters, or hydrogenolytically labile esters such as benzyl esters. The protection of the alkynylamino side chain can be achieved by using the aforementioned groups. Activation of the carboxyl group of the suitably protected amino acids or peptides can take place by the method of azide, mixed anhydride, active ester or carbodiimide, especially with the addition of racemization and catalytic suppressor compounds such as 1-hydroxygenzotriazole, N-hydroxysuccinimide, -hydroxy-4-oxo-3,4-dihydro-1, 2,3-benzotriazine, N-hydroxy-5-norbonmen-2,3-dicarboximide. See, for example, The Peptides, Analysis, Synthesis, Biology (see above) and Pure and Applied Chem. 59 (3), 331 -344 (1987). The compounds of the invention, which may be in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt. Pharmaceutically acceptable salts can also be obtained by treating the free base of formula I with an organic or inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid , maleic acid, malonic acid, methanesulfonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid. The compounds of this invention possess one or more chiral carbon atoms, and therefore, can be obtained as a pure enantiomer, or as a mixture of enantiomers, or as a mixture containing diastereomers. Methods for obtaining the pure enantiomers are well known in the art, for example, crystallization of salts, which are obtained from optically active acids and the racemic mixture, or chromatography using chiral columns. For direct or reverse phase columns can be used for diastereomers. The compounds of the invention can be administered enterally or parenterally, and for humans, preferably in a daily dosage of 0.001-100 mg per kg of body weight, preferably 0.01 -10 mg per kg of body weight. Compounds mixed with pharmaceutically suitable auxiliaries, for example, as described in the standard reference, Gennaro et al. , Remington's Pharmaceutical Sciences, (18th ed. Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture), can be compressed into solid dosage units, such as pills, tablets or can be processed into capsules or suppositories. By means of pharmaceutically suitable liquids, the compounds can also be applied in the form of a solution, suspension, emulsion, for example, to be used as an injection preparation, or an atomizer, for example, to be used as a nasal spray. To make dosage units, for example, tablets, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general, any pharmaceutically acceptable additive, which does not interfere with the function of the active compounds, can be used. Suitable carriers, with which the compositions can be administered, include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.

The invention is further illustrated by the following examples.

EXAMPLES The terms -Lisininyl? [COCO] -OH, -Lysininyl-OMe and -Lisininyl- (2-thiazolyl) mean a residue of the following formula: NH-CH-C (O) - Y wherein Y = GOOH! OCH3 and 2-thiazolyl, respectively. Azt = 2-azetidine carboxylic acid; Boc = tert-butyloxycarbonyl; Cbz = benzyloxycarbonyl; Bzl = benzyl.

EXAMPLE 1 HOOC-CH-D-Cha-Pro-Lisininyl- (2-tiazoyl) (a) 1-amino-4-chloro-2-butyne 1,4-dichloro-2-butyne hydrochloride (73.8) g) was dissolved in chloroform (600 ml). Hexamine (84.0 g) was added and the reaction mixture was heated under reflux for 2.5 h and then cooled for 24 h at 5 ° C. The hexamine complex was filtered (220 g). A solution of the complex in ethanol (1 t) was stirred for 24 h at room temperature with concentrated hydrochloric acid (180 ml). The precipitated ammonium chloride was filtered and the filtrate was concentrated under reduced pressure until the crystallization was incipient. The diethyl ether addition then precipitated 1-amino-4-chloro-2-butyne hydrochloride. Recrystallization from ethanol / ether gave 1-amino-4-chloro-2-butyne hydrochloride (59.75 g) = TLC: Rf = 0.60, silica gel, dichloromethane / methanol / water 70/30/5 v / v / v. (b) 1-Acetylamino-4-chloro-2-butyne 1-amino-4-chloro-2-butyne hydrochloride (59.75 g) was dissolved in 10% aqueous sodium acetate solution (335 ml). Acetate d was added ethyl acetate (500 ml), and acetic anhydride (70 ml) was added dropwise at room temperature. A solution of 25% aqueous sodium acetate was added at pH 5 and the solution was stirred for 30 min at room temperature. The ethyl acetate layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with water, brine and dried over sodium sulfate, filtered and evaporated in vacuo, yielding 1-acetylamino-4-chloro-2-butyne as a yellow syrup (58.8 g). TLC: Rf = 0.99, silica gel, dichloromethane / methanol / water 70/30/5 v / v / v. (c) Acetamido (4-acetamido-2-butynyl) -malonic acid diethyl ester To a cold (0 ° C) solution of sodium hydride (60% dispersion in mineral oil, 3.48 g) in dioxane (70 ml) Absolute ethanol (70 ml) was added in the form of drops. The mixture was allowed to warm to room temperature and a solution of diethyl acetamido malonate (20.5 g) in dioxane (70 ml) was added dropwise. Sodium iodide (9.07 g) was added and a solution of 1-acetylamino-4-chloro-2-butyne (1 1 g) in dioxane (140 ml) was added in the form of drops. After the addition of another 100 ml of ethanol, the mixture was refluxed for 2.5 h. The reaction mixture was cooled and the formed precipitate was filtered. Purification using silica chromatography (levigant: ethyl acetate / methanol 9/1 v / v) yielded diethyl ester of acetamido (4-acetamido-2-butynyl) malonic acid. (15.9 g). TLC: Rf = 0.25, silica gel, ethyl acetate, (d) 2,6-diamino-4-hexynoic acid dihydrochloride (H-Lysine dihydrochloride) Acetaldehyde (4-acetamido-2-) diethyl ester was dissolved butynyl) -malonic (7.64 g) in a mixture of acetic acid (140 ml) and a 6M hydrochloric acid solution (290 ml), and was heated overnight at 95 ° C. The mixture was concentrated in vacuo. The residue was recrystallized from ethanol / water yielding 2,6-diamino-4-hexynoic acid dihydrochloride as a crystalline powder (4.0 g). (e) Boc-Lysininyl (Cbz) -OH Copper sulfate pentahydrate (II) (287 mg) was added to a solution of 2,6-diamino-4-hexynoic acid dihydrochloride (500 mg) in 17 ml of dioxane. / water 3/2 v / v and the pH was adjusted to 9 by adding a 2M sodium hydroxide solution. N- (Benzyloxycarbonyloxy) -succinimide (573 mg) in dioxane was added dropwise at room temperature, together with a 2M sodium hydroxide solution, to maintain the pH around 9-9.5. After the addition was completed, the The reaction mixture was stirred overnight at room temperature. The mixture was filtered and the precipitate thus obtained was suspended in dioxane (20 ml). Di-tert-butyl dicarbonate (500 mg) was added and the pH adjusted to 12-13 by adding a 4m sodium hydroxide solution. The reaction mixture was stirred overnight at room temperature. The mixture was filtered and the filtrate was diluted with water. A solution of 4M hydrochloric acid was added until pH 2 and the water layer was extracted twice with dichloromethane. The combined organic phases were washed with water and dried over sodium sulfate and the solvent was removed by evaporation, yielding Boc-lisininyl (Cbz) -OH (540 mg).

TLC: Rf = 0.70, silica gel, ethyl acetate / pyridine / acetic acid / water 63/20/6/11 v / v / v / v. (f) Boc-lisininyl (Cbz) -NMeOMe N-O-dimethyl-hydroxylamine hydrochloride (363 mg) was added and [2- (1 H-benzotriazol-1-yl) -1.1, 3,3-tetramethiuronium tetrafluoroborate] (1.2 g) to a solution of Boc-lisininyl (Cbz) -OH (1.4 g) in dichloromethane (50 ml) and the pH was adjusted to pH 9-10 by adding N, N-diisopropylethylamine. The reaction mixture was stirred for 1 h at room temperature. The mixture was washed successively with a cold 2M hydrochloric acid solution, water 5% aqueous sodium hydrogenated carbonate solution and water. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica (levigant: ethyl acetate / heptane 3/2 v (v) to produce Boc-lisininyl (Cbz) -N MeOMe (1.37 g). TLC: Rf = 0.70, silica gel, acetate ethyl / heptane 4/1 v / v. (g) Boc-lisininyl (Cbz) - (2-thiazolyl) A solution of 2-bromothiazole 81.78 g) in diethyl ether (10 ml) was added dropwise to a cold stirred solution (-78, SC ) of n-butyl lithium (10.9 mmol) in diethyl ether (10.9 ml). After the solution had been stirred at -78 ° C for 30 min, a solution of Boc-lisininyl (Cbz) -NMeOMe (1.37 g) in dry tetrahydrofuran (15 ml) was added slowly. The mixture was stirred at -78 ° C for 1 h, then a 5% aqueous sodium hydrogenated carbonate solution was added. The mixture was allowed to warm to room temperature and the layers were separated. The aqueous layer was extracted with diethyl ether. The combined organic layers were washed with water, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (levigant: ethyl acetate / heptane 1/1 v / v) to give Boc-lisininyl (Cbz) - (2-thiazolyl) (1.21 g). TLC: Rf = 0.72, silica gel, ethyl acetate / heptane 371 v / v. (h) H-lysininyl (Cbz) - (2-thiazolyl) .TFA Boc-lysininyl (Cbz) - (2-thiazolyl) (1.21 g) was dissolved in trifluoroacetic acid (TFA) / dichloromethane (15 ml; 1/1 v (v) and stirred for 1 h at room temperature The crude amine was isolated as a yellow oil in quantitative yield after solvent removal by evaporation, and was used immediately to prepare N-Boc-N- (tert-butyloxycarbonylmethyl) -D-Cha-Pro-lisininyl (Cbz) - (2-thiazolyl) TLC: Rf = 0.25, silica gel, ethyl acetate / pyridine / acetic acid / water 63/20/6/1 1 v / v / v / v. (i) H-D-Cha-OMe.HCI To cold dry (-20 ° C) methanol (195 ml) thionylchloride was added dropwise (28 ml). H-D-Cha-OH.HCl (40 g) was added and the reaction mixture was heated under reflux for 5 h. The mixture was concentrated in vacuo and coevaporated with methanol (3 times). The residue was crystallized from methanolddiethylether, yielding H-D-Cha-OMe.HCl as a white crystalline powder (40.9 g). TLC: Rf = 0.66, silica gel, n-butanol / acetic acid / water 10/1/3 v / v / v. (j) N- (t-butyloxycarbonylmethyl-Cha-OMe t-Butyl-bromoacetate (36 g) was added to a stirred solution HD-Cha-OMe.HCl (40.9 g) in 400 ml of acetonitrile. The mixture was adjusted to 8.5 with N, N-diisopropyl-ethylamine The mixture was stirred for 16 hours at room temperature and evaporated in vacuo, the residue was dissolved in dichloromethane and the solution was washed with water, dried in sulphate Sodium and evaporated in vacuo The chromatography on silica gel in heptane (ethyl acetate 9/1 (v / v) gave 64 g of N- (t-butyloxycarbonylmethyl) -D-Cha-OMe.) TLC: Rf = 0.25 , silica gel, ethyl acetate / heptane 1/1 v (v. (k) N-butyloxycarbonylmethine-N-Boc-D-Cha-OMe The pH of a solution of N- (t-butyloxycarbonylmethyl) -D-Cha-OMe (64 g) and di-t-butyl dicarbonate 840.3 g) in N, N-dimethylformamide (500 ml) was adjusted to 8.5 with N, N-diisopropylethylamine. The mixture was stirred for 16 hours at room temperature. The solvent was removed in vacuo. Dichloromethane and water were added to the residue. The organic layer was separated, washed with cold 1N hydrochloric acid, water, 5% sodium hydrogenated carbonate and water. The organic layer was dried over sodium sulfate and the filtrate was evaporated to give an amorphous solid of N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-OMe in a yield of 59.6 g. TLC: Rf = 0.50, silica gel, ethyl acetate / heptane 1/1 v / v.

(I) N- (t-Butyloxycarbonylmethyl) -N-Boc-D-Cha-OH A solution of N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-OMe (59.6 g) in 900 ml of dioxane / Water 9/1 (v / v) was treated with sufficient 6N sodium hydroxide to maintain the pH at 12 for 6 hours at room temperature. After acidification, the mixture was poured into water and extracted with dichloromethanol. The organic layer was washed with water and dried over sodium sulfate. The filtrate was evaporated and yielded 4 g of N- (t-butyloxy-carylmethyl) -N-Boc-D-Cha-OH. TLC: Rf = 0.60, silica gel, dichloromethane / methanol 9/1 v / v. (m) N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-OSu A solution of N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-OH (12.5 g) in 200 ml of acetonitrile was added. treated with N-hydrosuccinimide (4.1 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (6.84 g) overnight at room temperature. The reaction mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and concentrated to provide the active ester, which was directly used in the next step. (n) N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-OH H-Pro-OH was dissolved. HCl (7.5 g) in 100 ml of water. The pH of the reaction mixture was adjusted to 8 with a 1 N sodium hydroxide solution, after which N- (t-butyroxycarbonylmethyl) -N-Boc-D-Cha-OSu was added in the form of drops. , dissolved in 100 ml of N, N-dimethylformamide. The reaction was stirred overnight at room temperature at pH "8. The reaction mixture was cooled and adjusted to pH" 2 with 1N hydrochloric acid. The aqueous layer was extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo. Purification of silica gel, using a gradient of ethyl acetate / methanol 9/1? 1/1 (v / v) gave 1.0 g of the desired dipeptide. TLC: Rf = 0.81, silica gel, ethyl acetate / pyridine / acetic acid / water 163/20/6/1 1 v / v / v / v. (o) N-Boc-N- (tert-butyloxycarbonylmethyl) -D-Cha-Pro-lysinyl (Cbz) - (2-thiazolyl) N-Boc-N- (tert-butyloxycarbonylmethyl) -D-Cha-Pro-OH (1.31 g) was dissolved in dry N, N-dimethylformamide 815 ml). After the addition of triethylamine (750 μl), the reaction mixture was placed under nitrogen and cooled to -15 ° C. Subsequently, chloroformate of sobutyl (352 μl) was added and the mixture was allowed to stir for 15 min at -15 ° C. H-lisininyl (Cbz) - (2-thiazolyl) .TFA (1.15 g) was dissolved in dry N, N-dimethylformamide (10 ml) and added as drops to the cold mixed anhydride solution, maintaining the pH at 8.5 by the addition of triethylamine. The reaction mixture was stirred for 30 min at -15 ° C. The reaction mixture was evaporated to dryness. The residue was dissolved in ethyl acetate and successively washed with water, 5% aqueous sodium hydrogenated carbonate solution, water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica (levigant: dichloromethane (methane 95 / v / v) to yield N-Boc-N- (tert-butyloxycarbonyl) -D-Cha-Pro-Lisininyl (Cbz) - (2-thiazolyl) (1.77 g). (p) HOOC-CH? -D-Cha-Pro-Lisininyl- (2-thiazolyl) N-Boc-N- (tert-butyloxycarbonylmethyl) -D-Cha-Pro-lysinylriyl (CDz) - (2) was treated -thiazolyl) (1.77 g) with trifluoroacetic acid (thioanol 10/1 v / v (20 ml) for 4 h at room temperature.) The reaction mixture was concentrated in vacuo and the residue dissolved in water. The aqueous layer was loaded directly onto a Supelcosil LC-18-BD preparative HPLC column using a gradient levigation system of 20% A / 70% B / 10%% C at 20%. A / 50% B / 30% C over 45 min, at a flow rate of 20 ml / min. (A: 0.5 M phosphate buffer pH 2.1, B: water, C: acetonitrile / water / v / v). Production of two diastereomers: * 300 mg Massa: ESI +: 518.5 [AH] +; 259.8 [AH2] 2+ Rt (LC): 28.81 min; 20% A / 80% B at 20% A / 20% B / 60 % C in 40 min * 500 mg Massa: ESi +: 518.5 [AH] +; 259.8 [AH2] 2+ Rt (LC): 29.88 min; 20% A / 80% B at 20% A / 20% B / 60 % C in 40 min EXAMPLE 2 N-Me-D-Phe-Pro-LisininylwrCOCOI-OH (a) Boc-lysininyl (Cbz) -OMe [2- (1 H-benzotpazol) -1,1,3,3-tetramethyluronium tetrafluoroborate] ( 1.83 g) was added to a solution of Boc-lysininyl (Cbz) -OH (2.15 g) in a 9: 1 dichloromethane: methanol mixture (25 ml) and the pH was adjusted to 7-8 by adding N, N- düsopropylethylamine. The reaction mixture was stirred for 1 h at room temperature. The mixture was washed with 1 N hydrochloric acid, water, 5% sodium hydrogenated carbonate solution and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica in ethyl acetate / heptane 6/4 v / v. -Resistance 2.17 g. Rf = 0.5, silica gel, in ethyl acetate: heptane 3/1 v / v. (b) 2-Acetoxy-3- (t-butyloxycarbonylamino) -7- (benzyloxycarbonylamino) -hept-5-in-nitrile At -78 ° C, to a stirred solution of 2 g of Boc-linisninyl-OMe in 60 ml of dichloromethane was added 18.2 ml of a precooled solution of diisobutylaluminum hydride (1.0 M solution in hexane) at such a rate to maintain the temperature below -70 ° C. The solution was stirred for half an hour. The mixture was poured into a solution of citric acid in water and extracted with dichloromethane. The combined extracts were washed with water, 5% sodium hydrogenated carbonate solution and water, dried over anhydrous sodium sulfate and filtered The filtrate was concentrated in vacuo to yield 2.25 g of an oil. The solution was cooled to 0 ° C, and 0.31 g of benzyl triethyl ammonium chloride, 1.2 ml of acetic anhydride and a solution of 2.5 g of sodium cyanide in 75 ml of water were added. The mixture was stirred vigorously for 30 min at 0-5 ° C. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulfate and evaporated to dryness. heptane: ethyl acetate 8: 2 (v / v) and gave 1.4 g of 2-acetoxy-3- (t-butyloxycarbonylamino) -7- (benzyloxycarbonylamino) -hept-5-in-nitrile. silica, in heptane: ethyl acetate 171 v / v. (c) H-lisininyl (Cbz) wrCHOHCOl-OH At -20 ° C, 6.5 g of gaseous hydrogen chloride were led to a solution of 1.4 g of 2-acetoxy-3- (butyloxycarbonylamino J- (benzyloxycarbonylamino) - Hept-5-in-nitrile in a mixture of diethyl ether / methanol 9/1 v / v. The mixture was stirred overnight at 0-4 ° C. The mixture was then cooled to -20 ° C., and 6.75 was added. ml of water The reaction mixture was stirred for 4 h at 20 ° C. The organic layer was separated The pH of the aqueous phase was adjusted to 10 with 1 N sodium hydroxide, followed by extraction with 1-butanol. Combined extracts were washed with brine and concentrated in vacuo and gave 650 mg of H-lisininyl (Cbz)? [CHOHCO] -OH.Rf = 0.17 in ethyl acetate (pyridine (acetic acid / water 63/20/6/1 1 v / v / v / v. (d) N-Boc-N-Met-D-Phe-OH Commercially available HN-Me-D-Phe-OH (1 1 g) was dissolved in a dioxane / water A mixture (165 ml) followed by the addition of di-tert-butyl dicarbonate (19.1 g). The pH of the reaction mixture was maintained at 8.5-9 using sodium hydroxide as the base. Then, the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic phase was washed with 0.1 N hydrochloric acid and saturated sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness to give 17.1 g of product. TLC: Rf = 0.35, silica gel, dichloromethane / methanol 8/2 v / v. (e) N-Boc-N-Me-D-Phe-Pro-OH N-Boc-N-Me-D-Phe-OH (17.1 g) and H-Pro-OMe.HCl (10.1 g) were coupled. according to the procedures as described for the synthesis of N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Obzl (see example 1). The obtained dipeptide, N-Boc-N-Me-D-Phe-Pro-OMe (22.6 g), was dissolved in dioxane / water 9/1 (200 ml) and treated with 4N sodium hydroxide (21.7 ml). ) at room temperature overnight. The reaction mixture was diluted with 300 ml of ice water, and acidified (pH 2) using 4N hydrochloric acid and extracted with dichloromethane. The combined organic layers were washed with saturated sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness to give the crude product. Crystallization from diethylether / heptane 273 v / v yielded pure N-Boc-N-Me-D-Phe-Pro-OH (12.6 g). TLC: Rf = 0.20, silica gel, toluene / ethyl acetate 6/4 v / v. (f) N-Boc-N-Me-D-Phe-Pro-Lisininyl (Cb <) \? / fCHOHCQl-OH Isobutyl chloroformate (0.101 g) was added to a solution of N-Boc-N-Me- D-Phe-Pro-OH (0.195 g) in n, N-dimethylformamide (10 ml) at -20 ° C, and the pH of the mixture was adjusted to 8 with triethylamine. A solution of H-lisininyl (Cbz)? [CHOHCO] -OH (0.3 g) in N, N-dimethylformamide (10 ml) of which the pH was adjusted to 8.5 with triethylamine, was added to the reaction mixture to - 20 ° C. The mixture was stirred overnight. The reaction was incomplete, therefore, a solution of N-Boc-N-Me-D-Phe-Pro-OH (293 mg) in NN-dimethylformamide (5 ml) was treated at 0 ° C with N-hydroxysuccinimide ( 95 mg) and 1,3-dicyclohexylcarbodiimide at pH 8.5 and added to the reaction mixture. The mixture was stirred for 4 h at room temperature. The volatiles were removed in vacuo. The residue was dissolved in dichloromethanol. The solution was washed with water, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel in ethyl acetate / pyridine / acetic acid / water 63/5/1.5 / 2.75 v / v / v / v. The fractions were extracted and gave 0.26 g of N-Boc-N-Me-D-Phe-Pro-Lisininyl (Cbz)? [CHOHCO] -OH. Rf = 0.24 in ethyl acetate / pyridine / acetic acid / water 63/5 / 1.5 / 2.75 v / v / v / v on silica. (g) N-Boc-N-Me-D-Phe-Pro-Lisininl (Cbz) v? / rCOCQ1-OH A solution of N-Boc-N-Me-D-Phe-Pro-Lisininyl ( Cbz)? [CHOHCO] -OH (260 mg) in 20 ml of dichloromethane with 1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3- (1 H) -one (180 mg) . The mixture was stirred for 31 h at room temperature, washed with a solution of sodium thiosulfate and water. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness and gave 0.35 g of N-Boc-N-Me-D-Phe-pro-Lisininyl (Cbz)? [COCO] -OH along with some degradation products of the reagent.

Rf = 0.36 in ethyl acetate / pyridine / acetic acid / water 63/20/6/1 1 v / v / v / on silica. (h) N-Me-D-Phe-pro-Lisininylvi fCOCO-OH A solution of N-Boc-N-Me-D-Phe-Pro-Lisininyl (Cbz)? [COCO] -OH (0.3 g) was stirred. in a mixture of trifluoroacetic acid / thioanisole 10/1 v / v (10 ml) for 4 h at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water and washed with diethyl ether. The residue was dried in vacuo and gave 430 mg of crude N-Me-D-Phe-Pro-Lysininyl [COCO] -OH, which was purified on a preparatory HPLC Supelcosil LC-18-DB column using a gradient levigation of A 20%; B 80%; C 0% a A 20%; B 70%; C 10%, over 45 min at a flow rate of 20 ml / min. Yield of two diastereomers: * 53.7 mg; MS: FAB + 429.1 [M + H]; FAB "426.9 [M-H] Rt (LC): 15.25 min; A: 20%; B: 80%; C: 0% a A: 20%; B: 20%; C: 60% in 40 min * 51.6 mg; MS: FAB + 429.1 [M + H]; FAB '426.8 [M-H] Rt (LC): 16.30 min; TO 20%; B: 80%; C: 0% to A: 20%; B: 20%; C: 60% in 40 min.

EXAMPLE 3 N-Me-D-Cha-Pro-Lisininylvi rCOCOI-OH (a) N-Me-N-Boc-D-Cha-Pro-OH N-Me-N-Boc-D-Cha-Pro was prepared OH according to the same procedures described in Example 2 (é), starting from N-RIe-N-Boc-D-Cha-OH and H-Pro-OMe.HCI. TLC: Rf = 0.26, silica gel, ethyl acetate / methanol 4/1 v / v. (b) Boc-lisininyl (Cbz) wrCHOHCOl-OMe A solution of 2-acetoxy-3- (t-butyloxycarbonylamido) -J- (benzyloxycarbonylamino) -hept-5-in-nitrile (36 g) in diethyl ether / methanol was cooled. 3/1 v / v (1 I) at -20 ° C. Hydrogen chloride gas was passed through the solution until a concentration of 3M (109 g) was reached, after which the mixture was stirred overnight at 0-4 ° C. Water (170 ml) was added at such a rate so that the temperature would be maintained < 5 ° C. Then, the reaction mixture was allowed to warm and stir for a further 5 hours at room temperature. The organic phase was separated. The pH of the aqueous layer was adjusted to 10 with dilute sodium hydride, followed by extraction with 1-butanol. The combined extracts were washed with brine, dried over sodium sulfate and evaporated to dryness to give H-lisininyl (Cbz)? [CHOHCO] -OMe (58 g). Di-tert-butyl dicarbonate (18.4 g) was added to a solution of H-Lisininyl (Cbz)? [CHOHCO] -OMe (58 g) in methanol and the pH was adjusted to 8 by adding triethylamine. The reaction mixture was stirred at room temperature. After the reaction is completed, concentrated in vacuum. The residue was dissolved in ethyl acetate and washed with 0.1 N hydrochloric acid solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica (levigant: heptane / ethyl acetate gradient 7/3 v / v, to ethyl acetate / methanol 8/2 v / v. The fractions were extracted and gave 4.76 g of Boc-Lisininil (Cbz)? [CHOHCO] -OMe. TLC: Rf = 0.40, silica gel, dichloromethane / methanol 9/1 v / v. Additionally, it was isolated and secondary product and characterized as Boc-Lisininil (Cbz)? [CHOHCO] ] -OBu (0.94 g) TLC: Rf = 0.47, silica gel, dichloromethane / methanol 9/1 v / v. (c) H-lisininyl (Cbz) \? rCHOHCOl-OMe.TFA According to the method as described in example 1 h, Boc-Lisininyl (Cbz)? [C? OHCO] -Ol / le (500 mg) was converted to the title compound (500 mg) and it was immediately used in the coupling. TLC: Rf = 0.12, silica gel, dichloromethane / methanol 95/5 v / v. (d) N-Me-N-Boc-D-Cha-Pro-Lisininyl (Cbz) v? / rCHOHC01-OMe To a cold solution (0 ° C) of N-Me-N-Boc-D-Cha-Pro -OH (546 mg) in N, N-dimethylformamide (10 ml) were successively added 1-hydroxy benzotriazole (202 mg), dicyclohexyl carbodiimide (308 mg) and H-Lisininyl (Cbz)? [CHOHCO] -OMe.TFA ( 516 mg), after which the pH of the solution was adjusted to 8 with triethylamine. The reaction mixture was stirred for 1 hour at 0 ° C and then kept at room temperature overnight. The mixture was cooled to -20 ° C and dicyclohexylurea was removed by filtration. The filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed successively with 1N hydrochloric acid, water, 5% sodium hydrogenated carbonate and water, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel in heptane / ethyl acetate 1/1 -% (v / v) as a levigant. The fractions containing N-Me-N-Boc-D-Cha-Pro-Lisininyl (Cbz)? [CHOHCO] -OMe were extracted and evaporated. Yield: 544 mg. TLC: Rf = 0.39, silica gel, dichloromethane / methanol 95/5 v / v. (e) N-Me-N-Boc-D-Cha-Pro-Lisininyl (Cbz)? rCHOHCOl-OH N-Me-N-Boc-D-Cha-Pro-Lisininyl (Cbz)? [CHOHCO] - OMe (544 mg) in dioxane / water 7/3 (v / v) (13 ml) and treated with 2N sodium hydroxide solution (0.61 ml) for 1 hour at room temperature. The reaction mixture was diluted with water (30 ml), 2N hydrochloric acid solution was added until pH 2 and the aqueous layer was extracted with dichloromethane. The combined organic phases were washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to provide the desired product. Yield: 560 mg. TLC: Rf = 0.47, silica gel, dichloromethane / methanol 4/1 v / v. (f) N-Me-N-Boc-D-Cha-Pro-Lisininyl (Cbz)? rCOCO1-OH N-Me-N-Boc-D-Cha-Pro-Lisininyl (Cbz)? [COCO] - OH (500 mg) in 2.3 ml of a 0.5 M solution of 1-hydroxy-1,2-benziodoxol-3- (1 H) -one-1-oxide in dimethyl sulfoxide and stirred overnight at room temperature. The reaction mixture was quenched with a solution of sodium thiosulfate (1.25 g) in 150 ml of water, cooled with an ice bath, after which the pH of the solution was adjusted to 2 with 2N hydrochloric acid. . the aqueous layer was extracted with dichloromethane and the combined organic layers were washed with a saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to give crude N-Me-N-Boc-D-Cha-Pro-Lysininyl (Cbz)? [COCO] -OH. TLC: Rf = 0.71, silica gel, ethyl acetate / pyridine / acetic acid / water 88/31/18/7 v / v / v / v. (g) N-Me-D-Cha-Pro-Lisininylvi / rCOCOl-OH Crude N-Me-N-Boc-D-Cha-Pro-T_isimnil (Cbz)? [COCCr] -OH was treated under the same conditions as was described in Example 2h to give, after purification with HPLC, 175 mg of N-Me-D-Cha-Pro-Lisininyl (Cbz) [COCO] -OH as a diastereomeric mixture. Rt (LC): 22.19 and 22.83 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 min.

EXAMPLE 4 3.3-Diphenylpropionyl-Pro-Lisininyl? I / TCOCOI-OH (a) 3,3-diphenylpropionyl-prolyl-OH 3,3-Diphenylpropionyl-prolyl-OH (5.2 g) was prepared according to the same procedures as described in example 2e, using acid 3,3-diphenylpropionic (5.0 g) and H-Pro-OMe. HCI (3.66 g). TLC: Rf = 0.65, silica gel, ethyl acetate / pyridine / acetic acid / water 63/20/6/11 v / v / v / v (b) 3,3-diphenylpropionyl-Pro-Lisininyl (Cbz) \? / RCHOHC01-OMe According to the same procedures as described in example 3, 3 , 3-diphenylpropionyl-prolyl-Ol-l (648 mg) was coupled with H-Lisininyl (Cbz)? [CHOHCO] -OMe.TFA (722 mg) to give the protected tripeptide 3,3, -diphenylpro? Ionil-Pro -Lisininyl (Cbz)? [CHOHCO] -OMe (1 .13 g), after purification. TLC: Rf = 0.40, silica gel, cichloromethane / methanol 95/5 v / v. (c) 3,3-diphenylpropionyl-Pro-Lisininyl? rCOC01-OH 3,3-Diphenylproplonyl-Pro-Lysinol (Cbz)? [CHOHCO] -OMe was saponified (860 mg) according to the same procedure as described in example 3 (e). The crude product was oxidized in dichloromethane (80 ml) using 1,1-triacetoxy, 1,1-dihydro-1,2-benziodoxol-3 (1 H) -one (594 mg) as described in example 2g. Subsequent deprotection in TFA and thioanisole (example 2h) gave 3,3-diphenylpropionyl-Pro-lisininyl [COCO] -OH (229 mg) as a diastereomeric mixture. Rt (LC): 20.31 min, 20% A, 60% B and 20% C to 20% A, 80% C in 30 min.

EXAMPLE 5 BenciíSO ^ -norLeu (c¡clo) -Glv-L¡sin¡n¡lv? rCOCQ1-OH norLeu (cycle) -Gly means a structural fragment of the formula (a) N-Boc-La-amino-e-caprolactam To a stirred solution of (10 g) in dioxane / water (271 v / v) (30 ml) was added a 1 N sodium hydroxide solution (7.8 ml). ) followed by di-t-butyl dicarbonate (18.8 g). The mixture was stirred for 16 h at room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude material was triturated by hexane, filtered and dried under vacuum to yield N-Boc-L-a-amino-e-caprolactam (16 g). TLC: Rf = 0.85, silica gel, ethyl acetate / heptane 171 v / v. (b) Boc-norLeu (cycle) -Glv-OMe N-Boc-L-a-amino-e-caprolactam (10 g) was dissolved in dichloromethane (100 ml). At -20 ° C a 1 M solution of bis (trimethylsilyl) amide in tetrahydrofuran / cyclohexane (1/1 v / v) (1 equiv.) Was added slowly, and the mixture was stirred for 30 min. Methyl bromoacetate (4 ml) was subsequently added and the mixture was stirred for 2 h at room temperature. Additional bis (trimethylsilyl) amide in tetrahydrofuran / cyclohexane (1/1 v / v) was added to force completion of the reaction. The mixture was diluted with dichloromethane and washed with 0.1N hydrochloric acid solution, water, 5% aqueous sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography on silica (levigant: heptane / ethyl acetate 6/4 v / v) to yield N-Boc-norLeu (cyclo) -Gly-OMe (12 g).

TLC: Rf = 0.55, silica gel, ethyl acetate / heptane 6/4 v / v. (c) BenzylSO? -norLeu (cycle) -Glv-OMe N-Boc-norLeu (cyclo) -Gly-OMe (5.4 g) was dissolved in 505 TFA / dichloromethane 1/1 (v / v) (40 ml) and was stirred for 1 h at room temperature. The reaction mixture was evaporated in vacuo. The crude mine was dissolved in dichloromethane (40 ml), cooled (0 ° C) and benzylsulfonyl chloride (3.43 g) was added. Triethylamine was added to maintain the pH at 8 during the reaction. The mixture was stirred for 1 h at room temperature, after which the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 5% sodium hydrogenated carbonate solution, water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to yield BenzylS 2-norLeu (cyclo) - Gly-OMe (6.1 g) TLC: Rf = 0.88, silica gel, dichloromethane / methanol 9/1 v / v. (d) BenzylSO? -norLeu (cycle) -Glv-OH A solution of benzylSO.sub.2 -norLeu (cyclo) -Gly-OMe (6.1 g) in 100 ml of dioxane / water 9/1 was treated with sufficient 1 N sodium hydroxide. to maintain the pH at 13 for 2 hours at room temperature. After acidification, the mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water and dried over sodium sulfate. Filtration followed by evaporation of the solvent gave the desired compound (6.3 g).

TLC: Rf = 0.73, silica gel, ethyl acetate / pyridine / acetic acid / water 63/20/6/11 v / v / v / v. (e) BenzylSO? -norLeu (cyclo) -Glv-Lisininyl \? / rCOCOl-OH The title compound was prepared according to the same procedures as described in Example 3, starting from benzylSO2-norLeu (cycle) -Gly-OH (385 mg and H-Lisininyl (Cbz)? [CHOHCO] -OMe.TFA (520 mg) The protected tripeptide (625 mg) was saponified, oxidized and deprotected (see example 4) to give bencilSO2-norLeu (cyclo) -Gly-Lisininyl? [COCO] -OH pure (68 mg) as a diastereomeric mixture, after purification with HPLC.Rt (LC): 25.9 min, 20% A, 80% B at 20% a, 20% B and 80% C in 40 min.

EXAMPLE 6 EthylSO-D-Cha-Pro-Lysin-n-lM. rCOC01-OMe (a) Boc-D-Cha-Pro-Opac (-OPac = phenacyl ester) Boc-D-Cha-Pro-OPac was prepared according to a similar manner, as described in Example 2, using Boc -D-Cha-OH and H-Pro-OPac. TLC: Rf = 0.5, silica gel, dichloromethane / methanol 95/5 v / v. (b) Ethyl, -D-Cha-Pro-OPac Boc-D-Cha-Pro-OPac (3.8 g) was dissolved in 50% TFA / dichloromethane (25 ml) and stirred for 30 minutes at room temperature. The reaction mixture was evaporated in vacuo. The crude amine was dissolved in dichloromethane (50 ml) and ethanesulfonyl chloride (0.8 ml) was added at -78 ° C. Triethylamine was added to maintain the pH at 8 during the reaction. The mixture was stirred for 3 h at 0 ° C, after which water (25 ml) was added. After further stirring for 30 minutes at room temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in diethyl ether and washed with 1 N hydrochloric acid solution, water, sodium hydrogen carbonate solution and brine, dried over sodium sulfate, filtered and evaporated in vacuo. Trituration of the crude material with methanol gave EtIISO2-D-Cha-Pro-OPac (3.0 g). TLC: Rf = 0.6, silica gel, dichloromethane / methanol 95/5 v / v. (c) EthylSO-D-Cha-Pro-OH To a solution of ethyl S02-D-Cha-Pro-OPac (10 g) in tetrahydrofuran (250 ml) was added 1WI solution of tetrabutylammonium fluoride in tetrahydrofuran (84 ml) . The reaction mixture was stirred for 30 minutes at room temperature and was poured into water (1 L), the aqueous solution was extracted with ethyl acetate. The combined organic layers were washed successively with 1 N hydrochloric acid solution and water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by crystallization from ethyl acetate / diisopropyl ether to yield EthylS02-D-Cha-Pro-OH (6.0 g). TLC: Rf = 0.2, silica gel, ethyl acetate / pyridine / acetic acid / water 163/20/6/1 1 v / v / v / v. (d) EthylS07-D-Cha-Pro-Lysin1n1lv? / fCOC01-OMe Coupling of EthylS02-D-Cha-Pro-OH (515 mg) and H-Lisininil (Cbz)? [CHOHCO] -OMe.TFA, as described in Example 3 (d), provided the protected tripeptide (550 mg). Oxidation followed by deprotection (see example 2) gave, after purification with HPLC, the desired product (130 mg) as a mixture of diastereomers. Rt (LC): 38.2 and 38.5 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 min.

EXAMPLE 7 Et¡ISOg-D-Cha-Pro-Lisin¡nH \? rCOC01-OH In analogy to Example 6, EthylSO2-D-Cha-Pro-Lisininyl [CHOHCO] -OMe (550 mg) was mounted. The subsequent saponification, oxidation and deprotection, according to the methods as described in example 3 and 2, provided 180 mg of EthylSO2-D-Cha-Pro-Lisininyl [COCO] -OH (diastereomeric mixture) after purification with H PLC. Rt (LC): 35.7 and 36.0 min, 20% A, 80% B to 20% A, 20% B and 60% C.

EXAMPLE 8 1 -Piq-Pro-LisininylwrCOCOI-OH (a) 2-Cbz- (4aR, 8aR) -perhydroxsoquinoline-1 (R, S) -carboxylic acid. (= N- (Cbz) -I -Piq-OH) N- (Cbz) -1 -Piq-OH has been synthesized as described in EP0643073, example 1.

TLC: Rf = 0.85, silica gel, ethyl acetate / pyridine / acetic acid / water 63/20/6/11 v / v / v / v. (b) N- (Cbz) -1 -Piq-Pro-OH The coupling of N- (Cbz) -1 -Piq-OH (500 mg) and H-Pro-OtBu (270 mg), according to the methods as described in example 2, produced N- (Cbz) -1-Piq-Pro-OtBu (634 mg). The removal of the t-butyl ester was achieved in a mixture of dichloromethane (1 ml), trifluoroacetic acid (3 ml), anisole (0.15 ml) for 1 h at room temperature. The reaction mixture was concentrated in vacuo at low temperature and the residue dissolved in water at a pH of 9.5. The aqueous phase was washed with diethyl ether, after which the aqueous layer was acidified to pH 2.5 by 2M hydrochloric acid solution. The aqueous layer was extracted with ethyl acetate and the organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to yield N- (Cbz) -1-Piq-Pro-OH (588 mg). TLC: Rf = 0.54, silica gel, ethyl acetate / pyridine / acetic acid / water 60/3/1/2 v / v / v / v. (c) 1-P1a-Pro-Lisininyl \? / rCOCOl-OH Coupled with the portion of Lisininil according to the methods as described in Example 3. The purified protected tripeptide (667 mg) was saponified, oxidized and deprotected (see example 2) to provide, after purification with HPLC, a simple isomer of 1 -Piq-Pro-Lisininyl [COCO] -OH (33 mg).

Rt (LC): 20.08 min, 20% A, 80% B at 0% A, 20% B and 60% C.

EXAMPLE 9 HOOC-CH, -D-Cha-Pro-Lisininlv? rCOCQ1-OH According to the methods as described in example 3, 685 mg N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-OH (see example 1) were coupled to H-Lis ninil (Cbz)? TCHO? CO] -OMe.TFA (see example 3c), after which the protected tripeptide (658 mg) was saponified, oxidized, deprotected and purified to yield 158 mg HOOC-C? 2-D -Cha-Pro-Lisininyl? [COCO] -OH as a mixture of diastereomers. Rt (LC): 22.3 min, 20% A, 80% B to 20% A, 20% B and 60% C.

EXAMPLE 10 HOOC-CH? -D-Cha-N-cyclopentyl-Glv-L-syninyl \? / RCOCO1-OH (a) N-cyclopentyl-GIv-OMe H-gly-OMe was dissolved. HCI (46.4 g) in 400 ml of methanol, cyclopentanone (34 g) and sodium cyanoborohydride (14 g) were added and the reaction was allowed to proceed for 16 h at room temperature. The reaction mixture was quenched with 6M hydrochloric acid to pH 2 and stirred for 30 min at room temperature. The solvent was removed by evaporation under reduced pressure, the residue was dissolved in water and washed with diethyl ether. The pH was adjusted to pH > 10 by addition of 6M NaOH solution, the product was extracted with dichloromethane, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.

The compound was crystallized from ethyl acetate as the HCl salt. Yield: 43.5 g. TLC: Rf = 0.71, silica gel, ethyl acetate / pyridine / acetic acid / water 88/31/18/7 v / v / v / v. (b) N- (t-butyloxycarbonylmethin-N-Boc-D-Cha-N-cyclopentyl-Glv-OH) N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-N-cyclopentyl-Gly-OH was prepared according to the procedure described in Example 1 for the dipeptide portion, using N-butyloxycarbonylmethi-N-Boc-D-Cha-O? and N-cyclopentyl-Gly-OMe TLC: Rf = 0.30, silica gel , dichloromethane / methanol 9/1 v / v. (c) HOOC-CH D-Cha-N-cyclopentyl-Glv-Lisininyl? rCOC01-OH According to the methods as described in Example 3, N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-N-cyclopentyl-Gly-OH (547 mg) was coupled to H-Lisininyl ( Cbz)? [CHOHCO] -OMe.TFA (see example 3 (c)), after which the protected tripeptide (660 mg) was saponified, oxidized, deprotected and purified to yield 212 mg HOOC-CH2-D-Cha -N-cyclopentyl-Gly-Lisininyl? [COCO] -OH as a mixture of diastereomers. Rt (LC): 28.5 and 29.1 min., 20% A, 80% B to 20% A, 20% B and 60% C.

EXAMPLE 1 1 HOOC-Chb-D-Phe-pro-LisininylyrCOCOI-OH N- (t-butyloxycarbonylmethyl) -N-Boc-D-Phe-Pro-OH was prepared according to the procedures described in Example 19, using N - (t-butyloxycarbonylmethyl) -N-Boc-D-Phe-OH and H-Pro-Obzl.HCl. TLC: Rf = 0.63, silica gel, ethyl acetate / pyridine / acetic acid / water 664/31/18/7 v / v / v / v.

HOOC-CH9-D-Phe-Pro-Lisiniml \ yrCOCOl-O? According to the methods described in example 3, 677 mg of N- (t-butyloxycarbonylmethyl) -N-Boc-D-Phe-Pro-OH was coupled with H-Lisininyl (Cbz)? [CHOHCO] -OMe.TFA , after which the obtained tripeptide (814 mg) was saponified, oxidized, deprotected and purified by HPLC to give HOOC-CH2-D-Phe-Pro-Lisininyl [COCO] -OH (284 mg) as a mixture of diastereomers . Rt (LC): 16.1 and 17.0 min, 20% A, 80% B to 20% A, 20% B and 60% C.

EXAMPLE 12 HOOC-CH? -Dp-CI-Phe-Pro-Lisinium [??? rCOCQ1-OH (a) N- (t-butyloxycarbonylmethyl) -N-Boc-Dp-Cl-Phe-OH According to analogous procedures as described in Example 1, HDp-CI-Phe-OH. HCl (10 g) was converted to N- (t-butyloxycarbonylmethyl-N-Boc-Dp-CI-Phe-OH) Yield: 16.7 g TLC: Rf = 0.27, silica gel, ethyl acetate / methanol 9/1 , v / v. (b) N- (t-butyloxycarbonyl-N-pN-Boc-Dp-CI-Phe-OSu (Su = succinimide) A solution of N- (t-bufidoxycarbonylmethyl) -N-Boc-t) -p-C1-Phe- OH (14.67 g) in 250 ml of acetonitrile was treated with N-hydroxysuccinimide hydrochloride (4.1 1 g) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (6.86 g) overnight at room temperature. The reaction mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and concentrated to give 19.1 1 g of active ester, which was directly used in the next step. (c) N- (t-butyloxycarbonylmethyl-Boc-Dp-CI-Phe-Pro-OH H-Pro-OH. HCl (10.79 g) was dissolved in 100 ml of NN-dimethylformamide and 100 ml of water. The pH of the reaction mixture was adjusted to 8 with a 1 N sodium hydroxide solution, after which N- (t-butyloxycarbonylmethyl) -N-Boc-Dp-CI-Phe-OSu (19.1 g) , dissolved in 120 ml of N, N-dimethylformamide, was added dropwise The reaction was stirred overnight at room temperature at pH * 8. The reaction mixture was cooled and adjusted to pH * 2 with hydrochloric acid 1 N. The aqueous layer was extracted with dichloromethane, the organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo, purification on silica gel, using a gradient of ethyl acetate / methanol 9/1. > 1/1, provided 7.04 g of the desired dipeptide TLC: Rf = 0.24, silica gel, ethyl acetate / methanol 8/2 v / v. (d) HOOC-CH? -Pp-CI-Phe-Pro-Lysyninyl? / rCOC01-OH According to the methods described in Example 3, N- (t-butyloxycarbonylmethyl) -N-Boc-Dp-CI -Phe-Pro-OH (500 mg) was coupled with H-lisininyl (Cbz)? [CHOHCO] -OMe.TFA, after which the obtained tripeptide (572 mg) was saponified, oxidized, deprotected and purified by HPLC to give HOOC-CH2-D-? - CI-Phe-pro-Lisininyl? [COCO] -OH (129 mg) as a mixture of diastereomers. Rt (LC): 22.3 and 23.1 min, 20% A, 80% B to 20% A, 20% B and 60% C.

EXAMPLE 13 HOOC-CH, -P-Cha-Pro-Lisinini-u, rCOC01-NH, N- (t-butylox? Carbonylmethyl) -N-Boc-D-Cha-Pro-OH was prepared as described in the example 1 . Boc-Lysininyl (Cbz)? [CHOHCO] -OBu was prepared as described in Example 3 (b). (a) Boc-Lysininyl (Cbz)? rCHOHC01-OH To a solution of Boc-lysininyl (Cbz)? [CHOHCO] -OBu (320 mg) in a dioxane / water mixture 9/1 v / v (1 1. 2 ml), 1 ml of a 1 N sodium hydroxide solution was added. The reaction mixture was stirred for 3 h at room temperature. The mixture was adjusted to pH 7 by adding 1 N hydrochloric acid solution and most of the dioxane was removed by evaporation. The mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo, yielding 308 mg of Boc-Lysininyl (Cbz)? [CHOHCO] -OH. TLC: Rf = 0.46, silica gel, dichloromethane / methanol 8/2 v / v. (b) Boc-LisininiKCbz rCHOHCOI-NH, 1-hydroxy-benzotriazole hydrate 81 17 mg), N-methylmorpholine (132 μl), ammonium chloride (107 mg) and 1- (3-dimethylaminopropyl) hydrochloride were added. 3-ethylcarbodiimide (186 mg) were added to a solution of Boc-Lysininyl (Cbz)? [CHOHCO OH (30 mg) in "N, N-dimethylformamide (16.6 ml) .The reaction mixture was stirred for 3 h at room temperature. The mixture was poured into water and extracted with ethyl acetate.The combined organic layers were washed with 1 N hydrochloric acid solution, water, 5% sodium hydrogenated carbonate solution and water.The organic layer was dried over sulphate. The residue was purified by chromatography on silica (levigant: gradient dichloromethane / methanol 98/2 v / v 96/4 v / v) to produce Boc-Lisininyl (Cbz)? [CHOHCO] - NH2 (17 mg) TLC: Rf = 0.14, silica gel, dichloromethane / methanol 97/3 v / v. (c) H-L-syninyl (Cbz)? / rCHOHC01-NH? .TFA H-Lisininyl (Cbz)? [CHOHCO] -NH2.TFA was prepared as described in example 1 (h). (d) N- (t-butyloxycarbonylmethyl-N-Boc-D-Cha-Pro-Lisininyl (Cbz)? RCHOHCQ1-NH, 1-hydroxy-benzotriazole hydrate (50 mg) and dicyclohexylcarbodiimide (60 mg) were added to a solution of N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-OH (119.6 mg) in N, N-dimethylformamide (2 ml) at 0 ° C. The reaction mixture was stirred for half an hour. at 0 [deg.] C. A solution of H-Lisininyl (Cbz) [CHOHCO] -NH2.TFA (100 mg) in N, N-dimethylformamide (1 ml), from which p 8 was adjusted with N, N -dipsopropylethylamine was added to the cold solution, after 1 hour, the mixture was allowed to warm to room temperature and stirred overnight.The reaction mixture was cooled to -20 ° C., filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 5% sodium hydrogenated carbonate solution, water, 2% aqueous citric acid solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica (levigant: gradient dichloromethane / methanol 97/3 v / v / 5/5/5 v / v) to produce N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro -Lisininl (Cbz)? [CHOHCO] -NH2 (93.5 mg). TLC: Rf = 0.34, silica gel, dichloromethane / methanol 95/5 v / v. (e) N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininyl (Cbz rCOCQl-NH? N- (t-Butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininyl (Cbz)? [COCO] -NH2 was prepared as described in Example 2 (g). The mixture was washed with a solution of sodium thiosulfate, 5% sodium hydrogenated carbonate solution and water. TLC: Rf = 0.38, silica gel, dichloromethane / methanol 95/5 v / v. (f) HOOC-CH; -D-Cha-pro-Lisin! n! lwrCOCQI-NH7 HOOC-CH2-D-Cha-Pro-Lysinyl? [CsCO] -NH2 was prepared as described in example 2 (h) . The aqueous layer was loaded directly onto a preparatory HPLC DeltaPak column using a gradient levigation system of 20% A, 70% B, 10% C at 20% A, 30% B, 50% C over 40 min, at a flow rate 50 ml / min. (A: phosphate buffer 0.5 M pH 2.1, B: water, C: acetonitrile / water = 3/2 v / v) 87 mg of N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininil (Cbz)? [COCO] -NH2 produced T35 mg of HOOC-C? SD-Cha-Pro-Lisininyl? [COCO] -NH2. Massa: Cl +: 478.4 [M-Hf; CT: 476.4 TM-H] "Rt (LC): 21.10 and 21.41 min (diastereomeric mixture), 20% A, 80% B, 0% C to 20% A, 20% B, 60% C over 40 min.

EXAMPLE 14 HOOC-CH? -D-Cha-Pro-Lisininilu / rCOCOI-OEt N- () t-Butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-? H was prepared as described in Example 1. Boc-Lisininyl (Cbz)? [CHOHCO] -OMe was prepared as described in Example 3 (b). (a) H-Lisininil (Cbz) v? fCHOHC01-OEt.HCl Boc-Lysininyl (Cbz)? [CHOHCO] -OMe (2.14 g) was dissolved in a 3M hydrochloric acid solution in ethanol (100 ml) at -20 ° C. After the reaction mixture was stirred for 6 h at room temperature, it was concentrated in vacuo yielding H-Lisininyl (Cbz)? [CHOHCO] -OEt.HCl (2.36 9) - TLC: Rf = 0.17 and Rf = 0.25 (diastereomeric mixture), silica gel, dichloromethane / methanol 95/5 v / v. (b) N- (t-butyloxycarbonylmethine-N-Boc-D-Cha-Pro-Lisininyl (Cbz) v? / rCOHC01-OEt N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro- was prepared Lysininyl (Cbz)? [COHCO] -OEt from H-Lisininyl (Cbz)? - COHCO] -OEt.?CI (2.40 g) and N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro -OH (2.38 g) as described in Example 13 (d), but triethylamine was used in place of N, N-diisopropylethylamine The crude product was purified by chromatography on silica (levigant: heptane / acetate gradient) of ethyl 1/1 v / va dichloromethane / methanol 97/3 v / vr 95/5 v / v) to produce N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininyl (Cbz)? [ COHCO] -O? T (1.2 g) TLC: Rf = 0.5, silica gel, dichloromethane / methanol 95/5 v / v. (c) N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininyl (Cbz)? rCOCQl-OEt N- (t-Butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininyl (Cbz)? [COCO] -OEt was prepared as described in Example 13 (e). TLC: Rf = 0.51, silica gel, dichloromethane / methanol 97/3 v / v. (d) HOOC-CH, -D-Cha-pro-Lysyninyl rCOC01-OEt HOOC-CH2-D-Cha-Pro-Lisininyl [COCO] -OEt was prepared as described in example 13 (f). The aqueous layer was loaded directly onto a preparatory HPLC DeltaPak column using a gradient levigation system of 20% A, 80% B, 0% C at 20% A, 54% B, 26% C over 45 min, at a Flow rate of 80 ml / min. (A: phosphate buffer 0.5 M pH 2.1, B: water, C: acetonitrile / water = 3/2 v / v) 293 mg of N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-pro-Lisininil (Cbz)? [COCO] -OEt produced 62 mg of HOOC-C? 2-D-Cha-Pro-Lisininyl? [COCO] -OEt. Massa: ESI +: 507.9 [MHf Rt (LC): 26.45 and 27.30 min (mixture of diastereomers): 20% A, 80% B, 0% C to 20% A, 20% B, 60% C over 40 min.

EXAMPLE 15 HOOC-CH9-D-Cha-Pro-LisininylwrCOCO1-M-azetidine) N- (t-Butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-OH was prepared as described in Example 1. N was prepared - (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininyl? [COCO] - (1-azetidine) in a similar manner as described in example 13, starting from Boc-Lisininil (Cbz) ? [CHOHCO] -OBu. Deprotection (see example 13 (f)) of 427 mg of N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininyl? [COCO] - (1-azetidine) gave, after HPLC purification , 105 mg of product. HPLC conditions: DeltaPak column using a gradient levigation system of 20% A, 80% B, 0% C at 20% A, 45% B, 35% C over 45 min, at a flow rate of 80 ml / min.

(A: 0.5 M phosphate buffer pH 2.1, B: water, C: acetonitrile / water 3/2 v / v) Massa: FAB +: 518.3 [M + H] +; FAB ": 516.2 [M + H] 'Rt (LC): 26.24 and 26.70 (mixture of diastereomers): 20% A, 80% B, 0% C to 20% A, 20% B, 60% C over 40 min .

EXAMPLE 16 HOOC-CH? -D-Cha-N-cyclopentyl-Glv-Lisin-nylwrCOCO1-M-azetidine) N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-N-cyclopentyl-glycine was prepared in accordance to the procedure in example 1. N- (t-Butyloxycarbonylmethyl) -N-Boc-D-Cha-N-cyclopentyl-Gly-Lisininyl [COCO] - (1-azetidine) was prepared in a similar manner as described in Example 15. The deprotection of 401 mg of N- (t-butyloxycarboniimethyl) -N-Boc-D-Cha-N-cyclopentyl-Gly-Lisininyl? [COCO] - (1-azetidine) gave, after purification with HPLC, 107 mg of the product. Massa: FAB +: 546.2 [M + H] +; FAB ": 544.0 [M + H]" Rt (LC): 35.85 min: 20% A, 80% B, 0% C to 20% A, 20% B, 60% C over 40 min.

EXAMPLE 17 HOOC-CH? -D-Cha-Pro-LisynnilviArCOCQ1-NHCH? Ph N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-OH was prepared as described in Example 1 . H-Lisininyl (Cbz)? [CHOHCO] -OMe.TFA was prepared as described in example 3 (c). (a) N- (t-butyloxycarbonylmethine-N-Boc-D-Cha-Pro-Lisininyl (Cbz) v?; rCHOHCO1-OMe N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro- was prepared Lisininyl (Cbz)? [CHOHCO] -OMe in a similar manner as described in example 13 (d) of H-Lisininyl (Cbz)? [CHOHCO] -OMe.TFA (1.09 g) and N- (t) -butyloxycarbonylmethi) -N-Boc-D-Cha-Pro-OH (1.18 g) The crude product was purified by chromatography on silica (levigant: gradient of heptane / ethyl acetate 4/6 v / v 3/7 v / v) to produce N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininyl (Cbz)? [CHOHCO] -OMe (0.99 g) TLC: Rf = 0.5, silica gel, dichloromethane / methanol 95/5 v / v. (b) N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininyl (Cbz) vifrCHOHC01-OH To a solution of N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro- Lisininyl (Cbz)? [CHOHCO] -OMe (0.98 g) in a dloxane / water 9/1 v / v mixture (20 ml) was added 1 ml of a 1 N sodium hydroxide solution. The mixture was emptied in ice water, was it adjusted ap? 2 by adding a 1 N hydrochloric acid solution and extracting with ethyl acetate. The combined organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo yielding 1.05 g N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininyl (Cbz)? [CHO CO] -OH. TLC: Rf = 0.4, silica gel, ethyl acetate / methanol 7/3 v / v. (c) N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininyl (Cbz) v? / FCHOHCOl-NHCHpPh 1-Hydroxy-benzotriazole hydrate (150 mg), N-methylmorpholine (150 mg) was added. μl), benzylamine (155 μl) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (190 mg) to a solution of N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininil ( Cbz)? [CHOHCO] -OH (502 mg) in N, N-dimethylformamide (16.6 ml). The reaction mixture was stirred for 17 h at room temperature. The mixture was poured into a cold 1 N hydrochloric acid solution and extracted with ethyl acetate. The combined organic layers were washed with water, 5% sodium hydrogenated carbonate solution and water. The organic layer was dried over magnesium sulfate, filtered and evaporated to yield N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininp (Cbz)? [C? OHCO] -NHCH2Ph (512.4 mg). TLC: Rf = 0.5, silica gel, dichloromethane / methanol 95/5 v / v. (d) N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininyl (Cbz)? CQCQ1-MHCH, Ph N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro was prepared - Lisininyl (Cbz)? [COCO] -NHCH2Ph as described in example 13 (e). TLC: Rf = 0.32, silica gel, dichloromethane / methanol 97/3 v / v. (e) HOOC-CH? -D-Cha-Pro-Lisininyl? rCOCOI-NHCH? Ph HOOC-CH2-D-Cha-Pro-Lysyninyl? [COCO] -NHCH2Ph was prepared as described in the example 13 (f). Rt (LC): 39.05 min: 20% A, 80% B, 0% C to 20% A, 20% B, 60% C over 40 min.

EXAMPLE 18 HOOC-CH9-D-Cha-Pro-LysininylwrCOCQ1-N (CHa)? HOOC-CH2-D-Cha-Pro-Lisininyl [COCO] -N (CH3) 2 was prepared in a similar manner as described in example 17, starting with N- (t-butyloxycarbonylmethyl) -N-Boc -D-Cha-Pro-Lisininil (Cbz)? [CHOHCO] -O ?. Rt (LC): 32.84 min: 20% A, 80% B, 0% C to 20% A, 20% B, 60% C over 40 min.

EXAMPLE 19 HOOC-CH? -D-Dpa-Pro-Lysinol (2-thiazolyl) (a) Boc-D-Dpa-Pro-OBzl To a cold (0 ° C) solution of Boc D-Dpa-OH (5.2 g) in N, N-dimethylformamide (50 ml) were successively added -hydroxy benzotriazole (3.1 g), dicyclohexyl carbodiimide (3.3 g), H-Pro-OBzl. HCI (4.07 g) and triethylamine (2.46 ml). The mixture was stirred at 0 ° C for 1 hour and then kept at room temperature overnight. The mixture was cooled to -20 ° C and the dicyclohexylurea was removed by filtration. The filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed successively with 5% sodium hydrogenated carbonate, water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel (levigant: heptane / ethyl acetate 4/6 v / v) yielding Boc-D-Dpa-Pro-OBzl (8.7 g).

TLC: Rf = 0.95, silica, ethyl acetate / pyridine / acetic acid / water 520/31/18/7 v / v / v / v. (b) Boc-D-Doa-Pro-OH 10% palladium in carbon (1 g) was added to a solution of Boc-D-Dpa-Pro-OBzl (7.0 g) in methanol (140 ml). The mixture was hydrogenated at atmospheric pressure at room temperature for 1 hour. The palladium catalyst was removed by filtration and the solvent was removed by evaporation under reduced pressure yielding Boc-D-Dpa-Pro-OH (5.5 g). TLC: Rf = 0.59, silica, ethyl acetate / pyridine / acetic acid / water 520/31/18/7 v / v / v / v. (c) Boc-D-Dpa-Pro-Lisininyl- (2-thiazolyl) The anhydride coupling mixed between Boc-D-Dpa-Pro-OH and H-Lisininyl (Cbz) - (2-thiazolyl) .TFA (see Example 1) was made according to the procedures described in Example 22, yielding N-Boc-D-Dpa-Pro-Lisininyl- (2-tazolyl) (560 mg). TLC: Rf = 0.1, silica, toluene / ethyl acetate 3/7 v / v. (d) HD-Dpa-Pro-Lisininyl (Cbz) - (2-thiazolyl) .TFA N-Boc-D-Dpa-Pro-Lysynyl- (2-thiazolyl) (560 mg) was dissolved in dry dichloromethane (2.5 ml). ) and trifluoroacetic acid (2.5 ml) and stirred for 1 h at room temperature. The solution was concentrated in vacuo and coevaporated with toluene, yielding H-D-Dpa-Pro-Lys (Cbz) - (2-thiazolyl). TFA (670 mg).

TLC: Rf = 0.51, silica, toluene / ethyl acetate 1/1 v / v. (e) N- (t-Butyloxycarbonylmethin-D-Dpa-Pro-Lisininyl (Cbz) - (2-thiazolyl) HD-Dpa-Pro-Lys (Cbz) - (2-fiazolyl) was dissolved. (570 mg) in acetonitrile (10 ml), tert-butyl bromoacetate (141 μl) was added.The solution was maintained at pH 8 with N, N-diisopropylethylamine and stirred for 2 days at room temperature. it was concentrated in vacuo, dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate and concentrated again.The residue was subjected to silica chromatography, using ethyl acetate / toluene% as a levigant, producing N- (t-butyloxycarbonylmethyl) -D-Dpa-Pro-Lisininyl (Cbz) - (2-thiazolyl) (499 mg) TLC: Rf = 0.47, silica, dichloromethane / methanol 96/4 v / v / v. (f) HOOC-CH? -D-Dpa-Pro-Lisininyl-f2-thiazoTop ^ Deprotection and purification of N- (t-butyloxycarbonylmethyl) -D-Dpa-Pro-Lisininyl- (Cbz) - (2-thiazolyl) ) were made according to the procedures described in example 22. The yield of a mixture of two diastereomers: 177 mg. R. (LC): 32.57 and 33.22 min, 20% A and 80% B at 20% A, 20% B and 60% C in 40 min.

EXAMPLE 20 HOOC-CH? -D-Cha-N-cyclopentyl-Glv-LisininHwrCOCO1-NH? N- (t-Butyloxycarbonylmethyl) -N-Boc-D-Cha-N-cyclopentyl-glycine was prepared according to the procedure for the preparation of the dipeptide in Example 1. N- (t-butyloxycarbonylmethyl) -N-Boc was prepared -D-Cha-N-cyclopentyl-Gly-Lisininyl? [COCO] -NH2 in a similar manner as described in example 13, starting from Boc-Lisininyl (Cbz)? [CHOHCO] -OMe. Rt (LC): 34.09 min: 20% A, 80% B, 0% C to 20% A, 20% B, 60% C over 40 min.

EXAMPLE 21 HOOC-CH? -D-Cha-Pro-Lisininyl Yi / rCOCOI-NHCHs HOOC-CH2-D-Cha-Pro-L¡simn¡l? [COCO] -N? CH3 was prepared in a similar manner as described in Example 17, starting from N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-Pro-Lisininyl (Cbz)? [CHO? CO] -OH. Rt (LC): 29.61 min: 20% A, 80% B, 0% C to 20% A, 20% B, 60% C over 40 min.

EXAMPLE 22 N-Me-D-Nle-Pro-Lisininyl- (2-thiazolyl) (a) H-D-Nle-OMe. HCI To 270 ml of methanol, cooled to -15 ° C, 18.2 g of thionylchloride were added. Subsequently, the temperature was allowed to rise to -10 ° C then it was kept constant for 20 min, after which, 10 g of H-D-Nle-OH was added. The temperature decreased slowly and was maintained at constant reflux for 5 h. The product was crystallized from methanol and diethyl ether at 4 ° C and this produced 12.9 g. TLC: Rf = 0.61, silica, n-butanol / acetic acid / water 10/1/3 v / v / v. (b) Boc-D-Nle-OMe H-D-Nle-OMe was dissolved. HCl (12.9 g) in 200 ml of dry methanol followed by the addition of di-tert-butyl dicarbonate (15.5 g) and triethylamine (19.8 ml). The reaction was stirred for 3 h at room temperature, after which the mixture was concentrated in vacuo. Then, the residue was dissolved in ethyl acetate and washed with water. The product was chromatographed on silica gel using heptane / ethyl acetate 3/1 v / v. Yield: 16.9 g. TLC: Rf = 0.55, silica, heptane / ethyl acetate ~ 3/1 v / v. (c) N-Me-Boc-D-Nle-OMe Boc-D-Nle-OMe (16.9 g) was dissolved in 200 ml of dry N, N-dimethylformamide under nitrogen. Then methyl iodide (24.9 ml) was added, cooled to 0 ° C, sodium hydride (3.31 g, dispersion in 60% oil) was added and the mixture was allowed to react for 16 h at room temperature. The mixture was concentrated in vacuo, dissolved in ethyl acetate, washed with 0.1 N hydrochloric acid, water, sodium bicarbonate (5%) and water, dried and concentrated again. This produced 18.8 g of alkylated product. TLC: Rf = 0.56, silica, heptane / ethyl acetate 3/1 v / v. (d) N-Me-Boc-D-Nle-OH N-Me-Boc-D-Nle-OMe (18 g) was dissolved in 400 ml of dioxane / water 9/1 (v / v) and the pH of the solution was adjusted to 12 with 1 N NaOH. The reaction was allowed to proceed for 2 h, keeping the pH constant at 12. The working procedure involved acidification with hydrochloric acid, cooling on ice, adding extra water (400 ml) and extraction with dichloromethane. The organic layer was washed with brine, dried, filtered and concentrated in vacuo. This produced 18.9 g. TLC: Rf = 0.26, silica, dichloromethane / methanol 9/1 v / v. (e) N-Me-Boc-D-Nle-Pro-OH First the N-Me-Boc-D-Nle-OH N-succinimide ester was prepared. 18 g of this derivative were dissolved in acetonitrile (250 ml) and 1-ethyl-3- [3- (dimethylamino) propyl] -carbodiimide hydrochloride (EDCl) (14.5 g) and N-hydroxy-succinimide (HONSu) (8.J g) were added. The reaction required 16 h at room temperature, after which the solvent was removidq, the residue was dissolved in ethyl acetate and washed with water and dried. This produced 24.3 g of ONSu crude ester. The next step was to dissolve proline. HCl (20.9 g) in 300 ml of N, N-dimethylformamide and 3DO ml of water and the pH was adjusted to 8 with 2N NaOH solution. A solution of the ONSu ester (24.3 g in 300 ml of N, N-dimethylformamide) was added dropwise to this solution at a pH of 8. The reaction was completed after 5 h, after which the organic solvent was removed extensively by evaporation under reduced pressure. Extra water (300 ml) was added and the mixture acidified. The product was extracted with ethyl acetate and washed with water. After drying, filtration and concentration, the product was obtained as a yellow oil in 22.2 g. the crude product was subjected to chromatography on silica, using ethyl acetate / methanol 8/2 v / v as a levigant. Yield: 13.2 g. TLC: Rf = 0.65, silica, ethyl acetate / pyridine / acetic acid / water = 163/20/6/1 1 v / v / v / v. (f) N-Me-Boc-D-Nle-Pro-Lisininyl (Cbz) - (2-thiazolyl) N-Me-Boc-D-Nle-Pro-OH (376 mg) was dissolved in N, N-dimethylformamide dry (3 ml). After the addition of N, N-diisopropylethylamine (0.19 ml), the reaction mixture was placed under nitrogen and cooled to -20 ° C. Subsequently isobutyl chloroformate (13.6 μl) was added and the mixture was allowed to stir for 15 min at -20 ° C. H-Lisininyl (Cbz) - (2-thiazoliyl) .TFA (see example 1) was dissolved in N, Dry N-dimethylformamide (3 ml) and added in the form of drops to the cold mixed anhydride solution, maintaining the pH at 8.5 by the addition of N, N-diisopropylether. The reaction mixture was stirred for 15 min at -20 ° C and 1 h at room temperature. The reaction mixture was stirred for 15 min at -20 ° C and 1 h at room temperature The reaction mixture was evaporated to dryness The residue was dissolved in ethyl acetate and washed successively with 5% aqueous sodium bicarbonate solution. %, water and brine, dried over sodium sulfate and concentrated in vacuo The residue was purified by chromatography on silica (levigant: ethyl acetate / heptane 1/1 v / v) to produce Boc-N-Me-D -Nle-Pro-Lisininil (Cbz) - (2-thiazolyl) (408 mg).

TLC: Rf = 0.21, silica, ethyl acetate / heptane 1/1 v / v. (g) N-Me-D-Nle-Pro-Lisininyl- (2-thiazolyl) Boc-N-Me-D-Nle-Pro-Lisininyl (Cbz) - (2-thiazolyl) (408 mg) was prepared according to the procedure described in example 1 p. The crude product was loaded onto a preparatory HPLC DeItapack C18 RP column using a gradient levigation system of 20% A / 80% B at 20% A / 30% B / 50% C over 40 minutes, at a flow rate of 80 ml / min. Yield of two diastereomers: 10 105, mg. Rt (LC): 19.17 min, 2O% A, 80% B to 20% A, 20% B and 60% C in 40 • min. 1 10 mg. Rt (LC): 21 .47 min. 20% A, 80% B to 2O% A, 20% B and 60% C in 40 min.

EXAMPLE 23 N-Me-D-Phe-Pro-L-syninyl- (2-thiazoyl (a) N-Me-Boc-D-Phe-Pro-OH • Synthesis of N-Me-Boc-D-Phe -Pro-OH starting with HD-Phe-OH was made according to the procedures described in Example 2. 20 (b) N-Me-D-Phe-Pro-Lisininyl- (2-thiazoline) The mixed anhydride coupling between N-Me-Boc-D-Phe-Pro-OH and H-Lisininyl (Cbz) - (2-thiazolyl) .TFA (see example 1), deprotection and purification were done according to the described procedures. in example 22.

Performance of two diastereomers: 89 mg, Rt (LC): 8.45 min, 20% A, 60% B and 20% C at 100% C in 40 min. 63 mg. Rt (LC): 10.98 min, 20% A, 60% B and 20% C to 100% C in 40 min.

EXAMPLE 24 N-Me-D-Cha-Pro-Lisininyl- (2-thiazolyl) (a) N-Me-Boc-D-Cha-Pro-OH The synthesis of N-Me-Boc-D-Cha- Pro-OH starting with HD-Cha-OH was done according to the procedures described in example 3. (b) N-Me-D-Cha-Pro-Lisininyl- (2-thiazolyl) anhydride coupling mixed between N-Me-Boc-D-CTia-Pro-OH and H-Lisininyl (Cbz) - (2- thiazolyl) .TFA 8 see example 1), deprotection and purification were done according to the procedures described in example 22. Yield of two diastereomers: 140 mg. Rt (LC): 12.93 min, 20% A, 60% B and 20% C to 100% C in 40 min. 139 mg. Rt (LC): 14.31 min, 20% A, 60% B and 20% C to 100% C in 40 min.

EXAMPLE 25 EthylSO? -D-Cha-Pro-OH (a) EthylSO? -D-Cha-Pro-OH The synthesis of EthylS02-D-Cha-Pro-OH starting with Boc-D-Cha-OH and H-Pro -OPac was done according to the procedures described in example 6. (b) EtIISO? -D-Cha-Pro-L¡siniriil-r2-fiazolílo) The anhydride coupling mixed between EthylSO2-D-Cha-Pro-OH and H-Lisininyl (Cbz) - (2-thiazolyl) .TFA (see example 1), deprotection and purification were made according to the procedures described in example 22. Diastereomer yield: 127 mg. Rt (LC): 44.52 and 45.58 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 min.

EXAMPLE 26 2-propylpentanoyl-Asp (OMe) -Pro-Lisininyl- (2-thiazolyl) (a) Boc-Asp (OMe) -OH H-Asp (OMe) -OH (10.0 g) was dissolved in dioxane / water 2/1 (150 ml) and cooled on ice. Sodium bicarbonate (4.6 g) and di-tert-butyl dicarbonate (13.1 g) were added in portions. The mixture was stirred for 16 h, while the pH was maintained at 8.5 with sodium bicarbonate. Water (400 ml) was added and the mixture washed extensively with heptane, cooled in ice, acidified with 1 N hydrochloric acid to pH 2.5 and extracted with ethyl acetate (300 ml). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo, yielding Boc-Asp (OMe) -OH (10.25 g). TLC: Rf = 0.58, silica, ethyl acetate / pyridine / acetic acid / water 163/20/6/1 1 v / v / v / v. (b) Boc-Asp (OMe) -Pro-OBzl Boc-Asp (OMe) -Pro-OBzl has been synthesized as described in WO 95/35312, example 1, replacing N-methylmorpholine with N-ethylmorpholine. TLC: Rf = 0.40, silica, dichloromethane / methanol 95/5 v / v. (c) H-Asp (OMe) -Pro-OBzl. HCl Boc-Asp (OMe) -Pro-OBzl (7.25 g) was dissolved in dry ethyl acetate (25 ml) and cooled in ice. Saturated ethyl acetate was added with hydrochloric acid (45 ml) and the mixture was stirred at 0CC for 5 h. The excess hydrochloric acid was removed by a flow of nitrogen and the resulting solution was concentrated in vacuo yielding H-Asp (OMe) -Pro-OBzl. HCl as a white solid (6.21 g). TLC: Rf = 0.17, silica, dichloromethane / methanol 95/5 v / v. (d) 2-propylpentanoyl-Asp (OMe) -Pro-OBzl A solution of H-Asp (OMe) -Pro-OBzl. HCl (6.21 g), dry dichloromethane (10 ml) and N, N-diisopropylethylamine (200 μl) were added at 0 ° C to a solution of 2-pripylpentanoic acid anhydride, which has been prepared by dissolving 2-propyl acid pentanoic acid (1.63 ml) in dichloromethane (15 ml), cool on ice, add 1,3-dicyclohexylcarbodiimide (1.1 g) and stir this solution for 5 min. the mixture was stirred at room temperature, maintaining the pH at 8.5 by the addition of N, N-diisopropylethylamine, for 16 h after which 0.5 eq of 2-propylpentanoic acid anhydride was added and the solution was stirred for another 4 h . The 1,3-dicylohexylurea was then removed by filtration. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate.

This solution was washed successively with 1 N hydrochloric acid, saturated sodium hydrogen carbonate and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica using toluene / ethyl acetate 8/2 v / v as a levigant, yielding 2-propylpentanoyl-Asp (OMe) -Pro-OBzl (6.54 g). TLC: Rf = 0.65, silica, dichloromethane / methanol 95/5 v / v. (e) 2-propylpentanoyl-As (OMe) -Pro-OH 10% palladium on carbon (750 mg) was added to a solution of 2-propylpentanoyl-Asp (OMe) -Pro-OBzl (705 mg) in methanol (10 mg). ml). The mixture was hydrogenated at atmospheric pressure at room temperature for 2 hours. The palladium catalyst was removed by filtration and the solvent was removed by evaporation under reduced pressure, yielding 2-propylpentanoyl-Asp (OMe) -Pro-OH (580 mg). TLC: Rf = 0.48, silica, ethyl acetate / pyridine / acetic acid / water 163/20/6/1 1 v / v / v / v. (f) 2-propylpentanoyl-Asp (OMe) -Pro-Lisininyl- (2-thiazolyl) The coupling of anhydride mixed between 2-propylpentanoyl-Asp (OMe) -Pro-OH and H-Lisininyl (Cbz) - (2- thiazolyl) .TFA (see example 1), deprotection and purification were made according to the procedures described in example 22. Yield of a mixture of two diastereomers: 186 mg. Rt (LC): 23.16 and 24.30 min, 20% A, 60% B and 20% C to 100% C in 40 min.

EXAMPLE 27 1 -Piq-Pro-Lisinin- (2-tiazoirio (a) 1-Piq-Pro-OH The synthesis of 1 -Piq-Pro-OH was done according to the procedures described in Example 8 . (b) 1 -Piq-Pro-Lisininyl- (2-thiazolyl) The anhydride coupling mixed between 1-Piq-Pro-OH and H-Lisininyl (Cbz) - (2-thiazolyl) .TFA (see example 1) , deprotection and purification were made according to the procedures described in example 22. Yield of two diastereomers: 92 mg. R. (LC): 23.75 min, 20% A, 0% B to 20% A, 20% B and 60% C in 40 min. 97 mg. R. (LC): 25.72 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 min.

EXAMPLE 28 HOOC-CH? -D-Cha-N-cyclopentyl-Glv-Lisin-N- (2-thiazole [o) (a) N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-N- Cyclopentyl-Glv-OH The synthesis of N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-N-cyclopentyl-Gly-OH was made, starting with HD-Cha-OH. HCI, according to the procedures described in example 10. (b) HOOC-CH? -D-Cha-N-cyclopentyl-Glv-Lisininyl- (2-thiazolyl) The coupling of anhydride mixed between N- (t-butyloxycarbonylmethyl) -N-Boc-D-Cha-N-cyclopentyl -Gly-OH and? -Lisinlnil (Cbz) - (2-thiazolyl) .TFA (see example 1), deprotection and purification were made according to the procedures described in example 22. Yield of a mixture of two diastereomers: 107 mg. Rt (LC): 20.39 and 20.82 min, 20% A; 60% B and ~ 20% C to 100% "C in 40 min.

EXAMPLE 29 HOOC-CH, -D-Phe-Pro-Lysinyni- (2-thiazole-o) (a) N- (t-butyloxycarbonylmethyl) -N-Boc-D-Phe-Pro-OH N synthesis was made - (t-butyloxycarbonylmethyl) -N-Boc-D-Phe-Pro-OH, starting from HD-Phe-OH.HCl, according to the procedures described in Example 1 1. (b) HOOC-CH? -D-Phe-Pro-L-syninyl- (2-thiazolyl) The anhydride coupling mixed between N- (t-butyloxycarbonylmethyl) -N-Boc-D-Phe-Pro-OH and H-Lisininyl (Cbz) - (2-thiazolyl) .TFA 8 see example 1); deprotection and purification were done according to the procedures described in example 22. Yield of two diastereomers: 143 mg. Rt (LC): 24.98 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 min. 149 mg. Rt (LC): 26.91 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 min.

EXAMPLE 30 HOOC-CH? -Dp-Ci-Phe-Pro-Lysynin- (2-thiazolyl) (a) N- (t-butyloxycarbonylmethyl) -N-Boc-Dp-CI-Phe-Pro -OH The synthesis of N- (t-butyloxycarbonylmethyl) -N-Boc-Dp-CI-Phe-Pro-OH was made, starting from HDp-Cl-Phe-OH.HCl, according to the procedures described in Example 12 (b) HOOC-CH Dp-CI-Pbe-Pro-Lisininyl-r2-thiazolyl) The anhydride coupling mixed between N- (t-butyloxycarbonylmethyl) -N-Boc-Dp-CI-Phe-Pro-OH and H- Lisininyl (Cbz) - (2-thiazolyl) .TFA (see example 1), deprotection and purification were made according to the procedures described in example 22. Yield of a mixture of two diastereomers: 187 mg. Rt (LC): 28.86 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 min.

EXAMPLE 31 Additionally, the following compounds can be prepared by using the methods of the present invention: -HOOC-CH2-D-Cha-Pec-Lisininyl? [COCO] -OH-HOOC-CH2-D-Cha-Pec-Lysininyl- (2-thiazoyl) -HOOC-CH2-D-Cha- (N-cyclohexyl) -Gly-Lisininyl? [COCO] -OH-HOOC-CH2-D-Cha- (N-cyclohexyl) -Gly-Lisininyl- (2 -thiazolyl) -HOOC-CH2-D-Cha- (N-cyclopropyl) -Gly-Lisininyl? [COCO] -OH-HOOC-CH2-D-Cha- (N-cyclopro? il) -Gly-Lisininyl- (2 -thiazolyl) -N-Me-D-Phe- (N-cyclopentyl) -Gly-Lisininyl? [COCO] -OH-N-Me-DtPhe- (N-cyclopentyl) -Gly-Lisinnyl- (2-thiazolyl) - 2-propyl-pentanoyl-Asp (OMe) -Pro-Lisininyl? [COCO] -OH -2-propyl-pentanoyl-Asp-Pro-Llsiniri? L [COCO] -OH -2-propiI-pentanoyl-Asp-Pro -Lisininyl- (2-thiazolyo) -2-hydroxy-3-cyclohexyl-propionyl-Pro-Lisinyl-1-tCOCO] -OH -2-hydroxy-3-cyclohexyl-propionyl-Pro-Lisininyl- (2-thiazolyl) -1- Piq- (Ncyclopenphyl) -Gly-Lisininyl? TCOCU] -OH -1 -Piq- (N-cyclopentyl) -Gly-Lisininyl- (2-thiazolyl) -Diphenylpropionyl-Pro-Lisininyl- (2-thiazolyl) -N -Me-D-Nle-N-Me-D-Nle -Pro-Lisininyl? [COCO] -OH-Ethyl? 2-p-Phe-Pro-Lysyninyl? [COCO] -OH-EthylSO2-D-Phe-Pro-Lisininyl- (2-thiazolyl) -EthylSO2 -N (Me) -D-Cha-Pro-Lislninil? [COCO] -O? -EstS02-N (Me) -D-Cha-Pro-Lisininyl- (2-thiazolyl) -Ethyl? 2-N (Me) -D-Cha-Pro-Lisininyl- (2-oxazolyl) -HOOC-CH2-N (Me) -D-Cha-Pro-Lisininyl- (2-thiazolyl) -HOOC-CH2-N (Me) -D-Cha-Pro-Lisininyl- (2-oxazolyl) EXAMPLE 32 Anti-Thrombin Assay Thrombin (Factor lia) is a factor in the coagulation cascade. The anti-thrombin activity of the compounds of the present invention was assessed by spectrophotometrically measuring the hydrolysis rate of the s-2238 chromogenic substrate exerted by thrombin. This assay for anti-thrombin activity in a buffer system was used to assess the IC50- value of a test compound.

Test medium: Shock absorber tromethamine-NaCl-poTyfil glycol OOO , (TNP). Reference compound: 12581 (Kabi) Vehicle: shock absorber TNP. The solubilization can be assisted with dimethyl sulfoxide, methanol, ethanol, acetonitrile or tert-butyl alcohol, which are free of adverse effects in concentrations up to 2.5% in the final reaction mixture.

Reagents Technique *: 1. Shock absorber of tromethamine-NaCl (TN). Buffer composition: Tromethamine (Tris) 6.05J g (50 mmol), NaCl 5.844 g (100 mmol), water at 1 I. The pH of the solution is adjusted to 7.4 at 37 ° C with HCl (10 μm I 1) 2. TNP damper: Polyethylene glycol 6000 is dissolved in TN buffer to give a concentration of 3 g «l" 1. 3. Solution S-2238: one bottle of S-2238 (25 mg, Kabi Diagnostica, Sweden) is dissolved in 20 ml of TN buffer to give a concentration of 1.25 mg «ml" 1 (2 mmol «l" 1 ). 4. Thrombin solution: Human thrombin (16,000 nKat »f rasco" 1, Centraal Laboratorium voor bloedtransfusie, Amsterdam, The Netherlands) is dissolved in TNP buffer to give a constant solution of 835 nKat »ml" 1. Immediately before use, this solution is diluted with TNP buffer to give a concentration of 3.34 nKat «ml'1. - * all the ingredients used are of analytical grade. - For aqueous solutions, ultra pure water (Mílli-Q quality) is used.

Preparation of reference test and reference compounds The test and reference compounds are dissolved in MifN-Q water to give constant concentrations of 10'2 moW1. The dilutions, including the constant solution, are used in the test (Final concentrations in the reaction mixture: 3 * 10"^, 10" 3; 3 * 10"4; -4; 3"10" s; 10"5; 3"10'6 and 10-6 moW1, respectively).

Procedure At room temperature, 0.75 ml and 0.025 ml of test compound or reference or vehicle solutions are pipetted alternately into the cavities of a microtiter plate and these solutions are diluted with 0.1 15 ml and 0.0165 ml of TNP buffer, respectively. An aliquot of 0.30 ml of S-2238 solution is added to each well and the plate is pre-heated and pre-incubated with shaking in an incubator (Amersham) for 10 min. at 37 ° C. Following the pre-incubation, the hydrolysis of S-2238 is initiated by the addition of 0.030 ml of thrombin solution to each cavity. The plate is incubated (with agitation for 30 s) at 37 ° C. Starting after 1 min of incubation, the absorbance of each sample is measured at 405 nm every 2 min for a period of 90 min, using a kinetic microtitre plate reader (Twinreader plus, Flow Laboratories). All data is collected on an IBM personal computer using LOTUS-MEASU RE. For each concentration of compound (expressed in mol "l" 1 of the reaction mixture) and for the blank, the absorbance is plotted against the reaction time in min.

Evaluation of responses: For each final concentration, the maximum absorbance was calculated from the test chart. The ICso value (final concentration, expressed in μmoM "1, causing 50% inhibition of the maximum absorbance of the blank) was calculated using the logit transformation analysis according to HaTner et al. (Arznéim.-Forsch. / Drug Res. 1977; 27 (II): 1871 -3).

In the following table, the ICso values of compounds of the invention are listed:

Claims (15)

1. CLAIMS 1 . A compound that has the formula I wherein A is H, optionally substituted D, L-a-hydroxyacetyl, R1, R -OC (O) -, R1-C (O) -, R1-S02-, R2OOC- (CHR2) m-SO2-, R OOC - (CHR2) m-, H2NCO- (CHR2) m-, or an N-protecting group, wherein R1 is selected from (1 -12C) alkyl, (2-12C) alkenyl, (2-12C) alkynyl and ( 3-8C) cycloalkyl, said groups may be optionally substituted with (3-8C) cycloalkyl, (1 -6C) alkoxy, oxo, OH, COOH, CF3 or halogen, and from (6-14C) aryl, (7-15C) ) aralkyl and (8-16) aralkenyl, the aryl groups of which may be optionally substituted with (1-6C) alkyl, (3-8C) cycloalkyl, (1-6C) alkoxy, OH, COOH, CF3 or halogen; each group R2 is independently H or has the same meaning as R1; m is 1, 2 or 3; B is a ligation, an amino acid of the formula -NH-CH [(CH2) PC (0) OH] -C (O) - or an ester derived therefrom and being p 0, 1, 2, or 3, -N ((1 -12C) alkyl) -CH2-CO-, -N ((2-12C) alkenyl) -CH2-CO-, -N ((2-12C) alkynyl) -CH2-CO-, -N (benzyl) ) -CH2-CO-, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1 -Piq, D-3-Piq or an L- or D-amino acid having a hydrophobic side chain, said hydrophobic side chain means a (1-12C) alkyi, optionally substituted with one or more (3-8C) cycloalkyl groups or (6-14C) aryl groups (which may contain a heteroatom, eg, nitrogen) such as cyclohexyl, cyclo-octyl, phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, and the like, said bidro-Tob side chain can be optionally substituted with substituents such as halogen, trifluoromethyl, lower alkyl (e.g., methyl or ethyl), lower alkoxy (e.g. methoxy), phenyloxy, benzyloxy, and the like, or B is an L- or D-amino acid having a basic side chain, being p or example, but not limited to, arginine and lysine, or B is an L- or D-amino acid having neutral side chain, such as methionine sulfon and the like, said hydro-ovic, thymic or neutral amino acid optionally being N- (1 -6C) substituted alkyl; or A and B together are the residue R3R N-CHR5-C (0) -, wherein R3 and R4 independently are R1, R1-0-C (0) -, R1-C (0) -, R1-S02- , R2OOC- (CHR2) m-S02-, R2OOC- (CHR2) m-, H2NCO- (CHR2) m-, or an N-protecting group, or one of R3 and R4 is connected with Rs to form a ring of 5 or 6 members together with "NC" to which they are attached, said ring may be fused with an aliphatic or aromatic 6-membered ring; and RB is a hydrophobic, basic or neutral side chain; X is an L-amino acid with a hydrophobic side chain, said hydrophobic side chain means a (1-12C) alkyl, optionally substituted with one or more (3-8C) cycloalkyl groups or (6-14C) aryl groups (which may containing a heteroatom, eg, nitrogen), such as cyclohexyl, cyclo-octyl, phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, and the like, said hydrophobic side chain may be optionally substituted with substituents such as halogen, trifluoromethyl, lower alkyl (e.g. , methyl or ethyl), lower alkoxy (eg, methoxy), phenyloxy, benzyloxy and the like, or X is serine, threonine, or X is a cyclic amino acid, eg, 2-azetidine carboxylic acid, proline, pipecolic acid, -amino-1-carboxy (3-8C) cycloalkane, 4-piperidine carboxylic acid, 4-thiazolidin carboxylic acid, 3,4-dehydro-proTina, azaproline, 2-octahydroindol carboxylic acid, and the like, said cyclic amino acid optionally contains a additional heteroatom selected from N, O or S, and is optionally substituted with (1 -6C) alkyl, (1-6C) alkoxy, benzyloxy or oxo, or X is -NR2-CH2-C (0) - or the fragment where n is 2 3 or 4, and W is CH or N, Y is H, -CHF2, -CF3, -CO-NH- (1 -6C) alkylene-C6Hs, -COOR6 and R6 where H or (1 - 6C) alkyl, -CONR7R8 and R7 and R8 independently being H or (1-6C) alkyl or R7 and R8 together being (3-6C) alkylene, or Y is a heterocycle selected from 2-thiazole, 2-thiazoline, 2- benzothiazole, 2-oxazole, 2-oxazoline and 2-benzoxazole, said heterocycles may be optionally substituted with (1-6C) alkyl, phenyl, (1-6C) alkoxy, benzyloxy or oxo; and r is 0, 1, 2 or 3; or a prodrug thereof or a pharmaceutically acceptable salt thereof.
2. 2. The compound of claim 1, wherein X is an L-amino acid with a hydrophobic side chain, serine, threonine or -NR-CH2-C (O) -.
3. 3. The compound of claim 1, wherein A is as previously defined; B is a ligation, an amino acid of the formula -NH-CH [(CH2) pC (0) OH] -C (O) - or an ester derived therefrom, and being p 0, 1, 2 or 3, -N ((1-6C) alkyl) -CH2-CO-, -N ((2-6C) alkenyl) -CH2-CO-, -N (benzyl) -CH2-CO-, D-1-Tiq, D-3 -Tiq, D-Atc, Aic, D-1 -Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain, said amino acid may optionally be N- (1 -6C) substituted alkyl; or A and B together are the residue R3R4N-CHR5-C (O) -; and X is a cyclic amino acid optionally containing an additional heteroatom selected from N, O or S, and optionally substituted with (1-6C) alkyi, (1-6C) alkoxy, benzyloxy or oxo, or X is -NR2-CH2-C (0) - or the fragment
4. 4. The compound of claim 3, wherein A is H, 2-hydroxy-3-cyclohexyl-propionyl-, 9-hydroxy-fluoren-9-carboxyl, R1, R1-S0-, R2OOC- (CHR2) * m-S02 -, R20 € > C- (CHR2) m-, H2NCO- (CHR2) m-, or an N-protecting group, wherein R1 is selected from (1 -12C) alkyl, (2-12C) alkenyl, (6-14C) aryl, (7-15C) aralkyl and (8-16) aralkylene; each group R2 is independently H or has the same meaning as R1; B is a ligation, D-1-Tiq, D-3-Tiq, D-Atc, Aic, D-1 -Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain, said amino acid may optionally be N- (1-6C) alkyl substituted; or A and B together are the residue R3R4N-CHRs-C (0) -; Y is -CO-NH- (1-6C) alkylene-C6Hs, -COOR6, -CONR7R8, or Y is a heterocycle selected from 2-thiazole, 2-thiazoline, 2-benzothiazole, 2-oxazole, 2-oxazoline and -benzoxazole
5. 5. The compound of claim 4, wherein A is H, R1, R1-SO2-, R2OOC- (CHR2) m-; B is a ligation, D-1 -Tiq, D-3-Tiq, D-Atc, Aic, D-1 -Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain; or A and B together are the residue R3R4N-CHRs-C (0) -, wherein at least one of R3 and R4 is R2OOC- (CHR2) m- or R1-SOz- and the other independently is (1-12C) ) alkyl, (2-12C) alkenyl, (2-12C) alkynyl, (3-8C) cycloalkyl, (7-15C) aralkyl, R1-S02- or R2OOC- (CHR2) m-, and Rs is a hydrophobic side chain; Y is -CO-NH- (1 -6C) alkylene-C6Hs, -COOR6 and R6 where H or (1 -3C) alkyl, -CONR7R8, R7 and R8 are independently H or (1 -3C) alkyl or R7 and R8 together being (3-5C) alkylene, or Y is a heterocycle selected from 2-thiazole, 2-benzothiazole, 2-oxazole, or 2-benzoxazole.
6. 6. The compound of claim 5, wherein A is R2OOC- (CHR2) m-; B is a D-amino acid having a hydrophobic side chain; or A and B together are the residue R3R N-CHRs-C (O) -, wherein at least R3 and R4 is R2OOC- (CHR2) m- and the other independently is (1-12C) alkyl, (2- 6C) alkenyl, (3-8C) cycloalkyl, benzyl, R1-S0 - or R2OOC- (CHR) m-; and X is 2-azetidine carboxylic acid, proline, pipecolic acid, 4-thiazolidin carboxylic acid, 3,4-dehydro-proline, 2-octahydroindol carboxylic acid or - [N (3-8C) cycloalkyl] -CH2-C (0 ) -.
7. 7. The compound of claim 6, wherein A is H? SC-CH-; B is D-Phe, D-Cha, D-Coa, D-Dpa, p-CI-D-Phe, p-OMethyl-D-Phe, p-Oethyl-D-Phe, D-Nle, m-CI- D-Phe, 3,4-di-OMe-D-Phe, D-Chg; or A and B together are the residue R3R4N-CHR5-C (O) -, wherein at least one of R3 and R4 is HOOC-CH2- and the other independently is (1-4C) alkyl, (1-4C) alkyl-D02- or HOOC-CH- and R5 is (3-8C) cycloalkyl, (3-8C) cycloalkyl (1-4C) alkyl, phenyl, benzyl, optionally substituted with chloro or (1-4C) alkoxy.
8. 8. The compound of claim 7, wherein Y is a heterocycle selected from 2-thiazole, 2-benzothiazole, 2-oxazole or 2-benzoxazole.
9. 9. The compound of claim 5, wherein A is R1-S? 2-; B is a ligation, D-1 -Tiq, D-3-Tiq, D-Atc, Aic, D-1 -Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain; or A and B together are the residue R3R4N-CHRs-C (0) -, wherein at least one of R3 and R4 is R1-S02- and the other independently is (1-12C) alkyl or R1-SO2-; X is 2-azetidine carboxylic acid, proline, pipecolic acid, 4-thiazolidin carboxylic acid, 3,4-dehydro-proline, 2-octahydroindol carboxylic acid, - [N (cyclopentyl)] - CH2-C (0) - or the fragment
10. 10. The compound of claim 9, wherein A is EtiI-SO2- or Benzyl-SO2-; B is a ligature, D-Phe, D-Cha, D-Coa, D-Dpa, p-CI-D-Phe, p-OMethyl-D-Phe, p-Oethyl-D-Phe, D-Nle, m -CI-D-Phe, 3,4-dl-OMe-D-Phe, D-Chg; OA and B together are the residue R3R4N-CH R5-C (0) -, wherein at least one of R3 and R4 is Ethyl-S02- or Benzyl-S02- and the other independently is (1-12C) alkyl or R1-S02- and R5 is (3-8C) cycloalkyl, (3-8C) cycloalkyl (1-4C) alkyl, phenyl, benzyl, diphenylmethynyl, said groups are optionally substituted with chloro or (1-4C) alkoxy. eleven .
11. The compound of claim 10, wherein Y is -CO-NH-CH2 - '"?' EHs, ^ - 'W-lN fí-? Eifl &Hl- &6 s ~ o ^ CCHV ^ R8, or 7Rt - and D 8RS ~: -sterttd? independently H or (1 -3C) alkyl or R7 and R8 together being (3-5C) alkylene, or Y is a heterocycle selected from 2-thiazole, 2-benzothiazole, 2-oxazole or 2-benzoxazole
12. 12. The compound of any of claims 1 to 11, wherein r is 1.
13. 13. A pharmaceutical composition comprising the compound of any of claims 1 to 12 and pharmaceutically suitable auxiliaries.
14. The compound of any of claims 1 to 12 for use in therapy.
15. 15. The use of the compound of any of claims 1 to 12 for the manufacture of a medicament for treating or preventing diseases related to thrombin.