MXPA98003479A

MXPA98003479A - Tromb inhibitors

Info

Publication number: MXPA98003479A
Application number: MXPA/A/1998/003479A
Authority: MX
Inventors: Adriaan Anton Van Boeckel Constant; Diederikjan Grootenhuis Peter; Egbert Peter Adang Anton; Albertus Maria Peters Jacobus
Original assignee: Egbert Peter Adang Anton; Akzo Nobel Nv; Grootenhuis Peter Diederik Jan; Albertus Maria Peters Jacobus; Adriaan Anton Van Boeckel Constant
Priority date: 1995-11-03
Filing date: 1998-04-30
Publication date: 1998-11-16

Abstract

The invention relates to inhibitors of non-slow-binding thrombin of the formula: ABC-Lys-D wherein A is H, 2-hydroxy-3-cyclohexyl-propionyl-, R 1, R 1 -O-CO-, R 1 -CO -R1-SO2-, (CHR2) nCOOR3 or a protective N group, wherein R1 is selected from C1-6 alkylene-COOH, C1-12 alkyl, C2-12 alkenyl, C6-14 aryl, aralkyl C7-15 and aralkenyl of C8-16 the aryl group of which can be substituted with C1-6alkyl, C1-12alkoxy, hydroxy or halogen, R2 is H or have the same meaning as R1, R3 is selected of H, C1-12 alkyl, C2-12 alkenyl, C6-14 aryl, C7-15 aralkyl and C8-16 aralkenyl. the aryl group of which can be substituted with C 1-6 alkyl, C 2-12 alkoxy, hydroxy, or halogen, n is an integer from 1 to 3, B is a L-Asp ligature or a ester derivative thereof , Leu, norLeu, -N (benzyl) -Ch2-CO-, N (2-indiano) -CH2-CO-, D-1-Piq, D-3-Piq, D-3-Piq, D-Ti1, Atc or a D-amino acid having aromatic hydrophobic side chain; C is Azt; Pro, Pec, norLeu (cyclo) Gly, an amino acid of one of the formulas -N [C 3-8 cycloalkyl] -CH2-CO-; D is selected from COOH, tetrazole, oxazole, thiazole and benzothiazole, or A and C have the above meanings, B is C3-8 D-cycloalkylanine, and D is tetrazole and oxazole, thiazole or benzothiazole, or a prodrug thereof or a pharmaceutically acceptable salt thereof with the exception of the compound Me-D-Phe-Pro-Lys-COOH. The compounds can be used as antithrombotic agents

Description

THROMBINE INHIBITORS The present invention relates to inhibitors of non-slow binding thrombin, a process for the preparation of said inhibitors, pharmaceutical compositions containing the same and the use of these thrombin inhibitors as antithrombotic agents. Much attention has been focused on the inhibition of thrombin as potential anticoagulants. Enzyme thrombin inhibitors, a key serine protease within the blood coagulation cascade, have for some time been considered as potential candidates for anticoagulant prophylaxis and therapy. In particular, the multiple roles played by thrombin in its actions on coagulation factors, blood circulation components and vessel wall cells makes them a particularly attractive target in a variety of pathological states. In addition, the limitations associated with The currently used anticoagulants, in particular the presentation of bleeding complications, require the investigation of more specific action agents. Many peptide-like inhibitors of septa have been described, among which are the thrombin transition state inhibitors. Many of the latter compounds, however, are inhibitors of slow binding The use of slow binding inhibitors of thrombin can be criticized In vivo, thrombin is generally generated in plasma and thrombin inhibitors work mainly by decreasing the generation of thrombin through the amplification steps mediated by inhibitory thrombin. To decrease said amplification cascade, a non-slow binding inhibitor may be preferable. A higher dose of a slow-binding inhibitor may be necessary to achieve the same effect, with a correspondingly increased risk of side effects. The relevant thrombin inhibitors are described by Brady et al., Bioorganic & Medicinal Chemistry 3 (1995), 1063-78 wherein D-Phe-Pro-Arg-amide and D-Phe-Pro-Lys-X have been described, X being a ketoester or amine. These compounds are described as being slow binding thrombin inhibitors, and likewise these compounds are excluded from the present invention. In the search for non-slow binding thrombin inhibitors Jones et al., J. Enzyme Inhibition, 9 (1995), 43-60, I attempt to obtain an improvement using D-Cha-Pro-Lys-COOH derivative. However, although these derivatives proved to be more potent thrombin inhibitors, still exhibit slow binding properties In a recent attempt to obtain potent non-slow binding thrombin inhibitors Levis et al., Thrombosis and Haemostasis, 74 (4) (1995), 1107, prepared derivatives of Me-D-Phe-Pro-Lys-X X being carboxyamide or carboxylic acid These compounds, among which Me-D-Phe-Pro-Lys-COOH is specifically described, are classified as slow binding inhibitors. This compound is therefore does not meet the requirements of the present invention and is excluded from protection A thrombin inhibitor with an alkyl substituted lysine is disclosed in US 4,523,308. In other references other Phe-Pro-Lys sequences were described, for example by Iwanowicz and others in Bioorganic & Medicinal Chemistry Letters, 2 (1992), 1607-12, which describes derivatives of D-Phe-Pro-Lys-X, X being a ketoester. Such compounds can also be described as slow-binding thrombin inhibitors. Other types of peptides for inhibition. of different sepana proteases are also described Tsutsumi and others in J Med Chem, 37. (1994), 3492-3502, described peptide-like compounds having terminal C ends of tpazol and benzothiazole. These tpazol derivatives were found to be 300 times more potent than the corresponding thiophene analogs In addition, it is postulated that the C-terminal heterocyclic groups could provide a critical hydrogen-binding interaction with the protease histamine prolyl-endopeptidase. It was further suggested that this aspect may be able to be extended to other proteases of septas Thrombin proteases were not specifically mentioned The explanation of the Tsutsumi mechanism was later confronted by Edwa rds and others in J Med Chem, 38 (1995), 76-85 but also these authors found that the elastase inhibitors of type D-Phe-Val-Pro-Val-X, X being thiazole and benzothiazole are non-slow binding inhibitors of the relevant serine protease These authors suggest the development of peptidyl α-ketoheterocycles as inhibitors of other septa proteases. The present invention relates to the surprising finding that the teachings of Edwards, Tsutsumi and others can also be applied to thrombin inhibitors. The application of terminal C heterocycles to the compounds as described by Lewis, Jones and Brady provide thrombin inhibitors that have non-slow binding properties for thrombin. In addition, many of these compounds show biological half-lives improvements and achieved bioavailability. The invention therefore relates to inhibitors of non-slow-binding thrombin of the formula: ABC-Lys-D wherein A is H, 2-hydroxy-3-cyclohexyl-propionyl-, R ,, R, -0-CO -, R? -CO- R S02-, - (CHR2) nCOOR3 or a protective N group, wherein Ri is selected from C 1-6 alkylene-COOH, C 1-12 alkyl, C 2-12 alkenyl, C6-14, aralkyl of C7-15 and aralkenyl of C8-16 the group of aplo of which can be substituted with alkyl of C1-6, alkoxy of C1-12, hydroxy or halogen, R2 is H or has the same meaning that R ,, R3 is selected from H, C1-12 alkyl, C2-12 alkenyl, C6-14 aplo, C7-15 aralkyl and C8-16 aralkenyl, the group aplo of which can be substituted with alkyl of C1-6, C2-12 alkoxy, hydroxy, or halogen n is an integer of 1 to 3 B is a L-Asp ligature or an ester derivative thereof, Leu, norLeu, -N (benzyl) - CH2-CO-, -N (2-indane) -CH2-CO-, D-1-Piq, D-3-Piq, D-TÍ1, Atc or a D-amino acid having aromatic side chain a hydrophobic; C is Azt, Pro, Pee, norLeu (cyclo) Gly, an amino acid of one of the formulas -N [C 3-8 cycloalkyl] -CH 2 -CO- or N (benzyl) -CH 2 -CO-; D is selected from COOH, tetrazole, oxazole, tlazole and benzothiazole; or A and C have the above meanings, B is C3-8 D-cycloalkylalanine and D is tetrazole and oxazole, tlazole or benzothiazole; or a prodrug thereof, or a pharmaceutically acceptable salt thereof; with the exception of the compound Me-D-Phe-Pro-Lys-COOH The compounds of the present invention are useful for treating and avoiding thrombin-mediated and thrombin-associated diseases. This includes a number of thrombotic and prothrombotic states in which it is activated. the coagulation cascade including, but not limited to, deep vein thrombosis, pulmonary embolism, thrombophlebitis, arterial occlusion from thrombosis or embolism, arterial reocclusion during or after angioplasty or thrombosis, restenosis following arterial damage or cardiological procedures invasive, thrombosis or postoperative venous embolism, acute or chronic atherosclerosis, 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 needed in dialysis or surgery. The compounds of the invention can also be used as in vitro anticoagulants. Preferred compounds according to this invention are the compounds wherein D is COOH. furthermore, preferably A is H, C 1-12 alkyl, C 7-15 -CO-aralkyl, SO 2 -C 1-12 alkyl, -SO 2 -aryl of 06-14, or -SO 2 -anaryl of 07-15; B is a ligature L-Asp, norLeu, D-1-Piq, or D-Phe; and C is Pro, norLeu (cyclo) Gly, or -N- (cyclopentyl) -CH2-CO-. Most preferred are non-slow binding thrombin inhibitors wherein A is -S02-benzyl, B is a ligation, and C is norLeu (c? Clo) Gly, or wherein A is -S02-ethyl, B is D-Phe, and C is Pro; or wherein A is hydrogen, B is D-1-Piq, and C is Pro. Other preferred compounds according to the invention are those wherein D is oxazole or tlazole, in addition, preferably A is H, alkyl of 01-12, 2-hydroxy-3-c? Clohex? L-prop? On? Lo-, -00- (CH2) nCOOH, -CO-aralkyl of 07-15, -S02-ar? Lo of 06-14, - S02-aralkyl of 07-15, -S02-alkyl of 01-12, - (CHR2) nCOOR3, R2 being H or alkyl of 01-12 and R3 being H, alkyl of 01-12 or benzyl, and C is Pro, norLeu (c? Clo) Gly, or -N [(C? -Calkalkyl of C 3-8] -CH2-CO- Particularly preferred are the non-slow-binding thrombin inhibitor where A is - (CH2) nCOOR3l R3 where H, alkyl of 01-12 or benzyl, B is D-cycloalkylanam of C3-8, or D-Phe optionally monosubstituted with alkoxy or halogen, and C is Pro The most preferred compounds of the invention are compounds wherein D It is especially preferred the non-slow binding inhibitor HOOC-CH2-D-Cha-Pro-Lys- (2-thiazolyl) .The protective N group as defined in the definition of p Orción A is any protective N group as used in peptides. Suitable protective N 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. Moienhofer, Eds., (Academic Press, New York, 1981 ). As used herein, "alkyl" is a branched or unbranched alkyl group having from 1 to 12 carbon atoms, such as methyl, ethyl, isopentyl, dodecyl, and the like. The term "C 1-6 alkylene" means a branched or unbranched alkylene group having from 1 to 6 carbon atoms, such as - (CH 2) m - and m is 1 to 6, -CH (CH 3), -CH (CH 3) - (CH2), etc. The preferred alkylene group is methylene Alkenyl is a branched or unbranched unsaturated alkenyl group having from 2 to 12 carbon atoms Examples are ethenyl, propenyl, allyl, and the like The aralkyl and aralkenyl groups are alkyl and alkenyl respectively, substituted by one more groups on the ryl, the total number of carbon atoms being from 7 to 15 and from 8 to 16, respectively. Preferred aralkyl groups are v g of the formulas - (CH2) p-CH ( C6H5) 2, P being 1 to 2, or - (CH2) q-C6H5 optionally substituted with halogen, q being 1, 2 or 3 Aplo in the definition mentioned above and in the definition of aplo, as used in the compound of the invention , is an aromatic portion of 6 to 14 carbon atoms The aplo group may also contain one or more heteroatoms, such as N, S, or O Examples of aplo groups are phenyl, naphthyl, iso-quinolyl, indanyl, and the like More preferred is the phenyl group The aplo group can be substituted with one or more alkyl groups, preferably methyl, alkoxy groups, preferably, ethoxy, hydroxy or halogen The term halogen, means fluorine, bromine or iodine The preferred halogen is chlorine The terms D-1-P? Q and D-3-P? Q mean 1 and 3-carboxyperhydroisoquinolma, respectively The term Tiq means 1,2,3,4-terahydroisoquinoline carboxylic acid Atc is 2-am? Notetral? N-2-carboxylic acid ? l? co The terms Azt and Pee mean 2-azet? d? na carboxylic acid and pipeco acid linico, respectively NorLeu (c? clo) Gly means a structural fragment of the formula The term hydrophobic aromatic side chain means a C1-12 alkyl substituted with one or more aryl groups of 06-14 (containing a heteroatom, e.g., nitrogen) such as phenyl, pyridinyl, naphthyl, tetrahydronaphthyl and the like, whose chain Hydrophobic side may be substituted with hydrophobic substituents such as halogen (preferably chlorine), trifluoromethyl, lower alkyl (for example methyl or ethyl), lower alkoxy (for example methoxy), phenyloxy, benzyloxy, and the like. The term C3-8 cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Tetrazole, oxazole, thiazole and benzothiazole have the following formulas respectively: The invention also includes prodrugs of the compounds of the general formula which, after administration, are metabolized to the active compounds. Suitable prodrugs are, for example, protected N-alkoxycarbonyl derivatives (preferably N-ethoxycarbonyl) of the general formula. the term "pharmaceutically acceptable salt" herein refers to salts that retain the desired biological activity of the present compound and preferably do not impart any undesirable toxic effects. Examples of said salts are acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, citric acid and the like. The salts can also be formed with organic acids such as, for example, acetyl acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid , pamoic acid, alginic acid, polyglutamic acid and the like. Salts can be formed with polyvalent metal cations such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel and the like, or with an organic cation formed of N, N ', dibencylethylenediamine or ethylenediamine, or combinations thereof (e.g., a zinc tannate salt) The compounds of this invention have one or more chiral carbon atoms and can therefore be obtained as a pure enantiomer, or as a mixture of enantiomers, or as a mixture that contains diasteromers. The methods for obtaining the pure enantiomers are well known in the art, v crystallization of salts obtained from optically active acids and the racemic mixture, or chromatography using chiral columns For the diastereomers, direct phase or reverse phase columns can be used. invention further includes a process for preparing a compound of the formula, the process including coupling appropriately protected amino acids, or amino acid analogues, followed by the removal of protecting groups. The compounds according to the general formula can be prepared in a conventional manner for said compounds. For that purpose, amino acid derivatives or peptides protected by Na (and protected by side chain if reactive side chains are present) are activated and coupled to the amino acid derivatives or peptides suitably protected by carboxyl either in solution or in a solid support. The protection of the a-amino functions generally takes place by the urethane functions such as acid-labile tert-butyloxycarbonyl group (Boc), benzyloxycarbonyl group (Z) and substituted analogues of the labile 9-fluoren-1-methyloxycarbonyl (Fmoc) group with base The Z group can also be removed by catalytic hydrogenation. Other suitable protective groups include Nps, Bmv, Bpoc, Aloe, MSC, etc. A good general review of the amino protecting 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 the formation of esters, v gr, labile esters with bases similar to methyl or ethyl, labile esters with similar acid to terbutyl or hydrogenolytically labile esters similar to benzyl The protection of side chain functions such as sine can take place using the groups mentioned above. The amino acid or properly protected peptide can be taken up by the azide, mixed anhydride, active ester or carbodiimide method, especially with the addition of racemization suppressor compounds such as 1-hydroxybenzotriazole, Nh idroxysuccinimide, 3-hydroxy-4-oxo-3,4-dihydro-1, 2,3- benzotriazine, N-hydroxy-5-norbornene-2,3-dicarboximide. Acids based on phosphorus anhydrides can also be used. See, v.gr. The Peptides, Analysis, Synthesis, Biology, supra and Pure and Applied Chem. 59 (3), 331-344 (1987). It is also possible to prepare the compounds by the Merrifield solid phase method. Different solid supports and different strategies are known, see, v .gr Barany and Merrifield in The Peptides, Analysis, Synthesis, Biology, Vol. 2, E. Gross and J. Meienhofer, , (Acad. Press, NY, 1980 ), Kneib-Cordonier and Mullen Int. J Peptide Protein Res., 30, 705-739 (1987) and Fields and Noble Int. J. Peptide Protein Res., 35, 161-214 (1990) Removal of protecting groups and, in the case of solid phase peptide synthesis, the separation of solid support can take place in different ways depending on the nature of the protecting groups and the type of linker to the solid support. Usually the deprotection takes place under acidic conditions and in presence of pupils See v gr volumes 3, 5 and 9 of the sesions of The Peptides Analysis, Synthesis, Biology, supra Another possibility is the application of enzymes in synthesis of said compounds, for revisions (See for example HD Jakubke in The Peptides, Analysis, Synthesis Biology, Vol. 9, S. Udenfriend and J. Meienhofer, , (Acad. Press, N. Y., 1987). However, the compounds are useful for the manufacture of medicaments which have use to treat disease states involving unsuitable blood coagulation. In such a case the particular compound synthesized will normally be associated with a pharmaceutical carrier. Pharmaceutical vehicles vary from such relatively simple things as sterilized water for injection to such relatively complicated things as microspheres and biodegradable implants. As drugs, the compounds are preferably administered orally, subcutaneously, topically, intranasally, intravenously, intramuscularly or locally (v. gr., via an implant). The administration of deposits is also possible. The exact dose and regime for the administration of these compounds and compositions will necessarily depend on the neof the individual to whom the medication is to be administered, the degree of distress or need and, of course, the criteria of the practicing physician. In general, parenteral administration requires lower doses than other methods of administration are more dependent on absorption. However, the doses on the scale of 0 001-100 mg per kg of body weight, preferably 0 01-10 mg per kg of weight, are illustrative. The medically manufactured with the compounds can also be used as an adjuvant in acute anticoagulant therapy. In such a case, the medically is administered with other compounds useful to treat said disease states. The compounds can also be used with implantable pharmaceutical devices such as those described in U.S. Patent 4,767,628, the content of which is incorporated by reference. The device will then contain sufficient amounts of compound to slowly release the compound (e.g., for more than one month.) Methods for formulating medicaments that can be adapted to contain the compound for enteral or parenteral administration are described in the Gennaro standard reference. and others, Remington's Pharmaceutical Sciences, (18th ed., Mack Publisching Company, 1990, see especially Part 8 Pharmaceutical Preparations and Their Manufacture) pages 1519 to 1580 Mixed with pharmaceutically suitable auxiliaries, the compounds can be compressed into solid dose units, such as pills, tablets or be processed in capsules or suppositories Pro means of pharmaceutically acceptable liquids the compounds can also be applied in the form of a solution, suspension, emulsion, v gr, can be used as an injection preparation, or as a spray, v gr, to be used as a nasal spray To formulate said dosage units, v gr, the tablets contemplate the use of conventional additives such as dye fillings, polymeric binders and the like. In general, any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. Suitable vehicles 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 explained by reference to the following illustrative examples. Example 1 3,3-Diphenylprop-on-l-Pro-Lys- (2-t-azole) 3,3-D? -phenolpropionyl-prolyl-methyl ester To a cold solution (0) ° C) of 3,3-d-phenolpropionic acid (50 g) in ethyl acetate (100 ml) was added successively DCCI (1,3-dichlohexylcarbodimide, 503 g), HOBt (1-hydroxybenzotpazol hydrate, 328 g), H-PRO-OMe HCl (366 g) and tetylamine (3 ml) The reaction mixture was stirred at 0 ° C for 1 hour and then maintained at room temperature overnight The reaction mixture was cooled to -20 ° C and DCU (1,3-d? c? clohex? lurea) was removed by filtration The filtrate was washed successively with 5% sodium hydrogen carbonate, water, 5% potassium hydrogen sulfate and saturated aqueous sodium chloride, dried over aqueous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica (eluent dichloromethane / ethyl acetate, 9/1 v / v ) to give 568g of 3,3-d-phenolpropyl ester or proline as a crystalline powder CLF-Rf = 0.75, gel silica, dichloromethane / ethyl acetate = 7/3 v / v 3.3-Diphenolpropionyl-prolyl-OH The 3,3-diphenylpropionyl-propylmethyl ester (56) was dissolved in dioxane / water, 7/3 v v (60 ml) was treated with a solution of 4 M sodium hydroxide (6.2 ml) in portions for 30 minutes at room temperature, maintaining the pH at 10-10.5. After 30 minutes the reaction mixture was diluted with water (60 ml), a solution of 4 M hydrochloric acid was added until pH 2.0 and the water layer was extracted with ethyl acetate. The combined organic phases were washed with water, saturated aqueous sodium chloride and dried over sodium sulfate and the solvent was removed by evaporation to give 3,3-diphenylpropionyl-propyl-OH as a syrup (518 g) CFL: Rf = 065, silica gel, APAA (ethyl acetate / pipdin / acetic acid / water) 63/20/5/11 v / v / v / v Boc-Lvs (Cbz) -NMeOMe Boc-Lys (Cbz) -OH DCHA (10 g) was suspended in dichloromethane (200 ml). The suspension was washed with 0 1 N hydrochloric acid solution twice. 2- (1 H-benzotpazol-1α and 1) -1,3,3,3- tetrafluoroborate was added. tetramet? luron? o (6 0 g) and hydrochloric acid O N-dimethyl-hydroxylamine (182 g) to the resulting organic phase and the pH was adjusted to pH 8 by adding tetylamine. The reaction mixture was stirred for 1 hour at room temperature. The mixture was washed successively with cold 2N hydrochloric acid water solution, 5% sodium hydrogen carbonate and water. The organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica (eluent dichloromethane / methanol; 5/5 v / v) Boc-Lys (Cbz) -NMeOMe (7.2 g). CLF-R, = 0.55, silica gel dichloromethane / methanol 97/5 v / v Boc-Lvs (Cbz) - (2-thiazolyl) To a cold stirred solution (-78 ° C), of n-butyllithium ( 53.9 moles) in diethyl ether (58 ml), a solution of 2-bromothiazole (10.5 g) in diethyl ether (30 ml) was added dropwise. The solution was stirred at -78 ° C for 30 minutes, after which a solution of Boc-Lys (Cbz) -NMeOMe (82 g) in THF (tetrahydrofuran, 75 ml) was slowly added. The mixture was stirred at -78. C. for 1 hour, then 5% aqueous sodium hydrogen carbonate 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 (eluant dichloromethane / methanol, 3/1 v / v) Boc-Lys (Cbz) - (2-t? azohlo) (86 g) CLF Rf = 0 77, silica gel ethyl acetate / heptane = 3/1 v / v H-Lys (Cbz) - (2-tαolol) TFA Boc-Lys (Cbz) - ( 2-t-azolyl) (500 mg) was dissolved in TFA (trifluoroacetic acid) / 50% dichloromethane (5 ml) and stirred for 1 hour at room temperature The H-Lys (Cbz) - (2-t? Azole) crude was isolated with quantitative yield after removal of the solvent by evaporation and used immediately in the next step. CLF: Rf = 0.25, silica gel, APAA = 63/20/5/11 v / v / v / v. 3.3-Diphenylpropionyl-Pro-Lys (Cbz- (2-thiazolyl) To a cold (0 ° C) solution of 3,3-diphenylpropionyl-propyl-OH (384 MG) in dimethyl formamide (5 ml) DCCI was added successively (270 mg), HOBt (176 mg), H-Lys (Cbz) - (3-thiazolyl) .TFA (515 mg) and N-ethylmorpholine (0.28) .The reaction mixture was stirred at 0 ° C for 1 hour. The mixture was cooled to -20 ° C and stirred by DCU filtration, the filtrate was evaporated to dryness, the residue was dissolved in ethyl acetate and washed successively with sodium hydrogen carbonate. 5% aqueous, water, 5% aqueous potassium hydrogen sulfate and saturated aqueous sodium chloride, dried over sodium potassium and concentrated in vacuo.The residue was purified by chromatography on silica (eluent: ethyl acetate / heptane; 4/1 v / v) to give 3,3-diphenylpropion? L-Pro-Lys (Cbz) - (2-thiazolyl) (332 mg) .CFF.Rf = 040, silica gel, ethyl acetate / heptane; 3/1 v / v. 3,3-Diphenylpropionyl-Pro-Lys- (2- thiazolyl) 3,3-Diphenylpropion? l-Pro-Lys (Cbz) - (2-5 thiazolyl) (320 mg) was treated with TFA / thioanisole 10/1 v / v (3 3 ml) for 3 hours at room temperature The reaction mixture was concentrated in vacuo and the residue was dissolved in water. The aqueous phase was extensively washed with diethyl ether. The water layer, containing 3, 3-d? Phen? Lprop? On? L-Pro-Lys- (2 -thiazolyl) was loaded directly onto a preparative HPLC Supercosil LC-18-DB column using a gradient elution system of 20% A / 60% B / 20% C at 20% A / 80% C for 45 minutes at a flow rate of 20 ml / min (A: buffer solution of 0.5 M sodium phosphate pH 2.1, B: water, C: acetonitrile / water, 3/2 v / v) Yield: 47 mg of 3.3- Diphenylpropyl-Pro-Lys- (2-5 thiazolyl). CLF: Rf = 0.57, silica gel, APAA; 63/20/6/11 v / v / v / v. Rt (CL): 32.9 min 20% A / 60% B / 20% C to 20% A / 0% B / 80% C in 40 min. Example 2 In a manner similar to that described in Example 1, they were prepared. (to). H-D-Phe-Pro-Lys- (2-t? Azolyl) Rt (CL) 2567 min; 20% A / 80% B / 0% C to 20% A / 20% B / 60% C in 40 minutes (b) HD-1-T? Q-Pro-Lys- (2-t? Azole) R, (CL) 2340 min, 20% A / 80% B / 0% C to 20% A / 20% B / 20% C in 40 minutes (c) HD- (p-CI) -Phe-Pro-Lys - (2-t? Azo lo) R, (CL) 3047 min, 20% A / 80% B / 0% C to 20% A / 20% B / 60% in 40 minutes (d) lndanegl? C? L - (Nc? Clopropyl) -Gly-Lys- (2-t? Azol? L) R, (CL) 2788 min, 20% A / 80% B / 0% C to 20% A / 20% B / 60% in 40 minutes (e) HD-Phe- (Nc? Clopentyl) -Gly-Lys- (2-t? Azohlo) R, (CL): 31.07 min; 20% A / 80% B / 0% C to 20% A / 20% B / 60% in 40 minutes. (F). Acetyl-D-Phe- (N-cyclopropyl) -Gly-Lys- (2-thiazolyl) Rt (CL): 33.73 min; 20% A / 80% B / 0% C to 20% A / 20% B / 60% in 40 minutes. (g) .H-D-Cha-Pro-Lys- (2-thiazolyl) R, (CL): 30.59 min; 20% A / 80% B / 0% C to 20% A / 20% B / 60% in 40 minutes. (Cha = cyclohexylalanine) (h). H-D-Phe- (N-cyclopropyl) -Gly-Lys- (2-thiazolyl) Rt (CL): 5.1 min isocratic; 55/45 MeOH / 24 mM phosphate pH = 7. (i). 3,3-Diphenylpropionyl- (N-cyclopropyl) -Gly-Lys- (2-thiazolyl) Rt (CL): 8.1 min isocratic; 75/25 MeOH / 24 mM phosphate pH = 7. (j). HD-Phe- (N-cyclopropyl) -Gly-Lys- (2-thiazolyl) Rt (CL): 30.59 min, 20% A / 80% B / 0% C at 20% A / 20% B / 60% C in 40 minutes. (Atc = 2-aminotetralin-2-carboxylic acid) (I). H-D-Phe- (N-benzyl) -Gly-Lys- (2-thiazolyl) Rt (CL): 16.99 min; 20% A / 80% B / 0% C to 20% A / 20% B / 60% C in 40 minutes. (n) p-chloro-3-phenylpropionyl- (N-cyclopropyl) -Gly-Lys- (2-tiazolyl) Rt (CL): 36.15 min; 20% a / 60% b / 20% C to 20% a / 0% B / 80% in 40 minutes. (or). (N-benzyl) -Gly- (N-cyclopentyl) -Gly-Lys- (2-thiazolyl) Rt (CL): 28.14 min; 20% A7 80% B / 0% C to 20% A / 80% C in 40 minutes. EXAMPLE 3 HOOC-CH? -D-Cha- (Nc? Clopent? N-Glv-Lvs- (2-t? Aolol) N-Cyclopentyl-GIv-OMe To a solution of 23.2 g of H-Gly-OMe HCl in 200 ml of methanol was added 156 g of cyclopentanone The mixture was stirred for 15 minutes and 7 g of sodium cyanoborohydride were added The pH was adjusted to 6 The reaction mixture was stirred for 16 hours at room temperature. 1g of cyclopentanone was added to the reaction and stirring continued The reaction was monitored on CLF When all the starting material had disappeared, the mixture was acidified to pH 2 and stirred for 30 minutes The solvent was removed and the residue was diluted with The solution was washed with ether, the pH adjusted to 12 with 6N sodium hydroxide and extracted with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated in vacuo to give the give 16 g of an oil Rf = 046 in ethyl acetate / pipdine / acetic acid o / water 63/20/6/11 v / v / v / v on silica N- (t-but? lox? carbon? l-met? l) -D-Cha-QMe To a stirred solution of 26g HD -Cha-OMe-HCI composed in 300 ml of acetonitoplo was added 17 g of t-butyl-bromine acetate. The reaction pH was adjusted to 8 5 with dnsopropylethylamine. The mixture was stirred for 16 hours at room temperature and evaporated to room temperature. The residue was dissolved in dichloromethane and the solution was washed with water, dried over sodium sulfate and evaporated in vacuo. Chromatography on silica gel in hexane ethyl acetate 9: 1 v / v gave 20 g of the title product. Rf = 0.46 in ethyl acetate / pyridine / acetic acid / water 15.75 / 5 / 1.5 / 2.75 v / v / v / v on silica. NN, Boc, (t-but? Loxycarbonyl-methyl) -D-Cha-QMe The pH of a solution of 20 g of N- (t-butyloxy-met? L) -D-Cha-OMe and 17 g of dicarbonate of di-t-butyl was adjusted to pH 85 with 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 1N hydrogen chloride, water, 5% sodium hydrogen carbonate and water. The organic layer was dried over sodium sulfate and the filtrate was evaporated to an amorphous solid in a yield of 28 g Rf = 060 in ethyl acetate / pipdine / acetic acid / water 252/20/6/11 v / v / v / v on silica NN-Boc, (t-but? lox? carbon? l-met? l) -D-Cha-OH A solution of 28 g of N, N-Boc, (t-but? lcarbon? l- methanol) -D-Cha-OMe in 420 ml of dioxian water 9/1 was treated with enough 1N sodium hydroxide to maintain the pH at 13 for 90 minutes, 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. The filtrate was evaporated and yielded 24 g of the title compound Rf = 023 in dichloromethane / methanol 9/1 v / v on silica N, N -Boc, (t-but? Lox? Carbon? L-met? L) -D-Cha- (Nc? Clopent? Lo) -Gly-QMe To a solution of 24 g of N, N-Boc, (t- butyloxycarbonyl-met? l) -D- Cha-OH in 300 ml of N, N-dimethylformamide was added 10.2g of N-cyclopentyl-Gly-OMe and 21 2 g of 2- (IH-benzotriazo-1-yl) 1,1-3,3-tetramethyluronium tetrafluoroborate (TBTU) (for its acronym in English). The pH of the mixture was adjusted to 8.5. The mixture was stirred overnight at room temperature and concentrated by evaporation. Water and ethyl acetate were added to the residue. The organic layer was separated and washed with 1N hydrogen chloride, water, 5% sodium hydrogen carbonate and water and dried over sodium sulfate. The filtrate was evaporated and the residue chromatographed on silica gel in hexane ethyl acetate 82 as eluent. The fractions containing the title product were mixed and evaporated. Yield 17g Rf = 057 in hexane / ethyl acetate 7/3 v / v on silica NN-Boc, (t-butylox? carbon? l-met? nD-Cha- (Nc? lcopent? lo) -Glv-OH Using the same procedure as for N, N-Boc, (t-butyloxycarbon? L-met? L) -D-Cha-OH, 17 g of N, N-Boc, (t-but? Lox? Carbon? L-met? L) were saponified - D-Cha- (Nc? Clopentyl) -Gly-OMe and gave 15 g of an amorphous solid. Chromatography on silica gel with dichloromethane / methanol 95/5 v / v as eluent gave 12 g of the title compound. Rf = 0 30 in methylene chloride / methanol 9/1 v / v on silica HOOC-CH7-D-Cha- (Nc? Clo? Ent? L) -Glv-Lys- (2-t? Azol? N Using N , N-Boc, (t-butylox? Carbon? L-methyl) -D-Cha- (N-cyclopentyl) -Gly-OH in similar procedures as described by example 1, this compound was prepared Rt (CL) : 23.57 min; 20% A, 60% B, 10% C to 20% A, 80% C in 40 minutes (a). In a similar manner as described above using Proline. HCl and HONSu (as in example 11) was prepared HOOC-CH2-D-Cha-Pro-Lys- (2-o). Rt (CL): 31.44 min, 20% A, 805 B, 0% C to 20% A, 20% B, 60% C in 40 minutes. Example 4 3-phenolpropion? L-Pro-Lys? [COCO] -OH Boc-Lvs (Cbz) -OMe Boc-Lys (Cbz) -OH (25 g) was dissolved in dichloromethane / methanol = 9/1 v / v (500 ml) TBTU (21 1 g) was added and the solution was adjusted to pH 8 by the addition of tetylamine. The reaction mixture was stirred for one hour at room temperature. The mixture was washed successively with 2N hydrogen chloride solution. cold, water, carbonate 5% sodium acid and water The organic layer was dried over sodium sulfate, filtered and evaporated The residue was purified by chromatography on silica (eluent ethyl acetate / heptane = 1/4 v / v) to give Boc-Lys (Cbz) -OMe (26 7g) CLF Rf = 079, silica gel, ethyl acetate / heptane = 3/1 v / v Boc-Lys (Cbz)? fcianoacetatoj To a cold solution (-78 ° C) of Boc-Lys (Cbz) -OMe (20 g) of dry dichloromethane (600 ml) was added dropwise diisobutyl aluminum hydride (127 ml of 1M solution in hexane) at a rate to maintain the temperature of reaction below -70 ° C. The resulting solution was stirred at -78 ° C for 30 minutes. A solution of 5% citric acid (500 ml) was added to the reaction mixture. The two layer mixture was stirred at room temperature for 10 minutes, the layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined dichloromethane layers were washed with water and dried over sodium sulfate and filtered. The solution was placed under nitrogen and cooled in an ice water bath. A solution of sodium cyanide (24.85 g) and benzyltriethylammonium chloride (2.89 g) in water (500 ml) is added. Under vigorous stirring, acetic anhydride is added in portions (6x6 ml) over a period of 30 minutes. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined dichloromethane layers were washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography over silica (eluent dichloromethane. / ethylacetate = 9/1 v / v) to give Bocys (Cbz)? [c? anacetate] (172 g) CLF Rf = 060, silica gel, dichloromethane / ethyl acetate = 7 / 3 v / v Boc-Lvs (Cbz) u / fCHOHCQl-OMe A solution of Boc-Lys (Cbz)? [cyanoacetate] (17 2 g) in ethyl ether / methanol = 3/1 v / v (500 ml) was cooled to -20 ° C under nitrogen and 54 7 g of gaseous doric acid was introduced while maintaining a temperature below -5 ° C The reaction mixture was kept at 4 ° C overnight. Water (85 ml) was added dropwise to the reaction mixture keeping the temperature below 5 ° C. After stirring for 4 hours at room temperature, the organic layer was separated and washed with water. The aqueous layer was saturated with sodium chloride and extracted with sec-butanol / dichloromethane = 3/2 v / v. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to give 17.4 g of the crude amine. The residue was taken up in dimethylformamide (DMF, 200 ml), bis (tert-butyl) anhydride (8.7 g) and triethylamine were added until pH 8. The reaction mixture was stirred at room temperature overnight. The solvent was removed by reduced evaporation. The residue was dissolved in ethyl acetate, washed with water and brine successively, dried over sodium sulfate, filtered and evaporated under vacuum. The residue was purified by chromatography on silica (eluent: ethyl acetate / heptane = 1/1 v / v) to give Boc-Lys (Cbz)? [CHOHCO] -OMe (622 g). CLF. Rf = 075, silica gel, ethyl acetate / heptane = 3/1 v / v 3-Phenylpropionyl-Pro-Lvs (Cbz) j / fCHOHC01-OMe Boc-Lys (Cbz)? [CHOHCO] -OMe (60 mg ) was dissolved in tpfluoroacetic acid / dichloromethane (6 ml) and stirred for 1 hour at room temperature. The crude amine was isolated in quantitative yield after removal of the evaporating solvent and used immediately to prepare 3-phenolpropyl L-Pro-Lys (Cbz)? [CHOHCO] OMe 3-Phenylpropionyl-ProOH was dissolved in dry DMF (5 ml). After the addition of triethylamine (196 ml), the reaction mixture placed under nitrogen and cooled to -15 ° C. Subsequently, isobutyl chloroformate (183 ml) was added and the mixture was allowed to stir for 15 minutes at -15 ° C. The crude amine was dissolved in dry DMF (5ml), neutralized using triethylamine and added dropwise to the cold mixed anhydride solution. The reaction was stirred for 1 hour at -15 ° C and then maintained at 0 ° C for overnight, the mixture was evaporated to dryness. The residue was dissolved in ethyl acetate and successively washed with water, 5% sodium hydrogen carbonate and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica (eluent: dichloromethane / methanol = 95/5 v / v) to give 3-phenylpropionyl-Pro-Lys (Cbz)? [CHOHOC] -OMe (246 mg). CLF-R, = 0.92, silica gel, APAA = 63/20/6/11 v / v / v / v 3-Phenylpro-ionyl-Pro-Lvs? RCHOHCOIOMe To a solution of 3-phenylpropionyl-ProLys (cbz) v | / [CHOHCO] -OMe (196 mg) in methanol (5 ml) was added palladium on charcoal 10% (50 mg) and 216 ml of 2N hydrogen chloride solution the mixture was hydrogenated at atmospheric pressure and ambient temperature for 1 hour The palladium catalyst was removed by filtration and the solvent was removed by evaporation under reduced pressure to give 3-phenolprop? on? l-Pro-Lys? [CHOHCO] OMe quantitatively CLF Rf = 0 13, silica gel, d? Chloromethane / methanol = 9/1 v / v 3-phenylpropyl-Pro-Lvs- (Boc) v? / FCHOHC01-OMe To a solution of phenylpropionyl-Pro- Lys [CHOHCO] -OMe (196 mg) in dry DMF (5 ml) was added bis (tert-butyl) anhydride (102 mg) and the pH was adjusted to pH 8.5 by adding triethylamine. The reaction mixture was stirred at room temperature overnight. The mixture was evaporated in vacuo and the resulting residue was purified by chromatography on silica (eluent: dichloromethane / methanol = 98/2 v / v to give 3-phenylpropionyl-Pro-Lys (Boc)? [CHOHCO] OMe (198 mg) LCF: R, = 0.43, silica gel, dichloromethane / methane 091/1 v / v 3-phenylproionyl-Pro-Lvs (Boc) v? / FCHOHCO1-OH Phenylpropionyl-Pro-Lys (Boc)? [CHOHCO] -OMe (185 mg) was dissolved in dioxane / water = 7/3 (5 ml) and treated with 2M sodium hydroxide solution (267 ml) in portions for 30 minutes at room temperature, maintaining the pH at 10 -10.5 After 30 minutes the reaction mixture was diluted with water (20 ml), 2M hydrogen chloride solution was added until pH 2.0 and the water layer was extracted with dichloromethane The combined organic phases were washed with water (50 ml) brine (50 ml) and dried over sodium sulfate, filtered and concentrated in vacuo to give 3-phenylpropyl-Pro-Lys (Boc)? [CHOHCO] -OH (228 mg), CLF Rf = 060, silica gel, APAA = 63/20/6/11 v / v / v / v 3-phenolpropionyl-Pro-Lys- (Boc) v? / rCHOHCQl-OMe To a solution of femlprop? on? l-Pro-Lys? [CHOHCO] -OMe (220mg) in dry dichloromethane ( 5 ml) was added 255 mg of periodinane (Dess-Martin reagent). After 1 hour of stirring at room temperature, 2% sodium thiosulfate solution (15 ml) was added and the mixture was stirred at room temperature. The organic layer was separated, washed with water and dried over sodium sulfate, filtered and evaporated in vacuo to give crude keotacate 3-phenylpropionyl-Pro-Lys (Boc)? [CHOHCO] OMe (411 mg) LCF: R, = 0.47, silica gel, dichloromethane / methane 63/20/6/11 v / v / v / v 3-phenylproionyl-Pro-Lvs (Boc)? / RCHOHCOl-OH 3-phenylprop? On? L-Pro -Lys (Boc)? [CHOHCO] -OMe (411 mg) was treated with trifluoroacetic acid / 90% water for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and the residue dissolved in water and loaded directly. , in a preparative CLAR LC-18-DB Supelcosil column using a gradient elution system of 20% A / 70% B / 10% C at 20% A / 0% B / 80% C for 45 minutes, at a flow rate of 20 ml / mm (A. 05 M phosphate pH buffer, pH 2 a, B water, C aceton? tr? lo / water = 3/2) Yield 71 mg of 3-phenolprop ? on? l-Pro-Lys (Boc)? [CHOHCO] -OH R. (CL) 24 9 min, % A / 80% B to 20% B / 60% C in 40 minutes In a similar manner to the one described above were prepared (a) 3,3-d? Phen? L? Rop? On? L-Pro-Lys ? [COCO] -OH Rt (CL) 3642 min, 20% A / 80% B / 0% C at 20% A / 20% B / 60% C in 40 minutes (b) 3,3-d? Fen? lprop? on? l-Pro-Lys? [COCO] -OH Rt (CL) 3429 min; 20% A / 80% B / 0% C to 20% A / 20% B / 60% C in 40 minutes. (c). 3,3-diphenylepropionyl-Pro-Lys? [COCO] -OH R, (CL) 39.52 min; 20% A / 80% B / 0% C to 20% A / 20% B / 60% C in 40 minutes (d). 3,3-d? Phenylpropionyl-Pro-Lys? [COCO] -OH Rt (CL) 31 31 min; 20% A / 80% B / 0% C to 20% A / 20% B / 60% C in 40 minutes. (e) Naphthylsulfonyl-Asp-Pro-Lys? [COCO] -OH Rt (CL) 3045 min; 20% A / 80% B / 0% C to 20% A / 20% B / 60% C in 40 minutes Example 5 HD-Cha-Pro-Lys- (2-benzothiazole) Boc-Lvs (Cbz) -v? /. CHOHl- (2-benzot? Azolyl) A cold solution (-78 ° C) from Boc -Lys (Cbz) -OMe (1g) in dichloromethane (25 ml) was added dropwise dnsobutyl aluminum hydride (DiBAL-H, and 76 of a 1M solution of hexane) so that the reaction temperature was maintained by below -70 ° C The resulting solution was stirred at -78 ° C for 30 minutes A solution of 5% citric acid was added to the reaction mixture The two-layer mixture was stirred at room temperature for 10 minutes, the layers were separated, and the aqueous layer was extracted twice with dichloromethane. The combined dichloromethane layers were washed with water, 5% sodium hydrogen carbonate, water and dried Sodium sulfate and filtered The solution was placed under nitrogen and 2- (trimethylsilyl) benzothiazole (0.79 g) was added and the reaction mixture was stirred for 16 hours at room temperature. After evaporation to dryness the residue was dissolved in dry tetrahydrofuran (15 ml) and tetrabutyl ammonium fluoride (3.8 ml of a 1M solution in THF) was added. The mixture was stirred for two hours at room temperature and water was added. The product was extracted with dichloromethane and purified by chromatography on silica (eluent: dichloromethane / ethyl acetate; 9/1 v / v) to give 724 mg of Boc-Lys (Cbz) -? [CHOH] - (2-benzothiazolyl). CLF: Rf = 0.35, silica gel, dichloromethane / ethyl acetate = 7/3 v / v. Boc-Lvs (Cbz) - (2-benzothiazole i I o) To a solution of Boc-Lys (Cbz) -? [CHOH] - (2-benzothiazolyl) (700 mg) in dry dichloromethane (10 ml) was added 1 periodinane g (Dess-Martin reagent). It was then stirred for 1 hour at room temperature, 2% sodium thiosulfate solution and the mixture was stirred for another 30 minutes at room temperature. The organic layer was washed with water, dried over sodium sulfate, filtered and evaporated under vacuum. The residue was purified by chromatography on silica (eluent: ethyl acetate / heptane, 3/1 v / v) to give 193 mg of Boc-Lys (Cbz) - (2-benzothigolol) CLF-Rf = 0 85, silica gel, ethylacetate / heptane = 3/1 v / v Boc-D-Cha-Pro-Lvs (Cbz) - (2-benzothiazolyl) Boc-Lys (Cbz) - (2-benzoth? azole) (193 mg) was dissolved in 50% TFA / dichloromethane (2 ml) and stirred for 1 hour at room temperature The crude amine was isolated quantitative yield after solvent removal by evaporation and was used immediately to prepare Boc. D-ChaPro-Lys (Cbz) -2-benzothiazolyl) Boc-D-Cha-Pro-Oh was dissolved in dry dimethylformamide (4 ml) After the addition of dnsopropylethylamine (DIPEA, 66 ml), the reaction mixture was placed under nitrogen and cooled to -15 ° C Isobutylchloroformate (50 ml) was subsequently added and the mixture was allowed to stir for 15 minutes at -15 ° C. The crude amine was dissolved in dry DMF (4 ml), neutralized using dnsoporpylethylamine and p was added The solution was stirred for 1 hour at -15 ° C and then kept at 0 ° C overnight. The mixture was evaporated to dryness. The residue was dissolved in ethyl acetate and washed successively. with water, 5% sodium hydrogen carbonate, water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica (eluent ethyl acetate / heptane, 1/1 v / v) give Boc-D-Chapro-Lys (Cbz) - (2-benzothiazole) (191 mg), CLF Rf = 066, silica gel ethyl acetate / heptane = 3/1 v / v HD-Cha-Pro- Lys- (2-benzot? Aolol) Boc-D-Cha-Pro-Lys (Cbz) - (2-benxot? Aolol) was treated with tlfluoroacetic acid / thioanisole 10/1 v / v (2 2 ml ) for 3 5 hours at room temperature The reaction mixture was concentrated in vacuo and the residue dissolved in water The aqueous phase was extensively washed with diethyl ether The water layer containing HD-Cha-Pro-Lys- (2-benxothiazole) it was directly charged in a Supel column LC-18-DB preparative CLAR cosile a gradient elution system of 205 A780% B at 205 A / 20% B / 20% B / 60% C for 40 minutes, at a flow rate of 20 ml / min. (A. pH regulator solution of sodium phosphate 05mM pH 2.1, B: water, C: acetonitrile / water, 3/2 v / v). Yield: 98 mg of H-D-Cha-Pro-Lys- (3-benzothiazolyl). R, (CL): 42 min 20% A / 80% B at 20% A / 20% B / 60% C in 40 minutes. Example 6 HD-Cha-Pro-Lvs (2-terazolyl) Boc-Lvs (Cbz) w (CHOAc) - (2-tetrazolyl) To solution of Boc-Lys (Cbz) [cyanoacetate] (5.4 g) in 39ml of dimethylformamide was added 801 mg of ammonium chloride and 975 mg of sodium azide. The reaction mixture was heated to 80 ° C and stirred under nitrogen for 48 hours. The precipitated salt was filtered and the solution was evaporated under reduced pressure to dryness. This yielded 4.9 g of the desired compound CLF: Rf = 042, silica gel, toluene / ethanol = 6/4 v / v Boc-Lvs (Cbz) v? (CHOH) - (2-tetrazole) Boc-Lys ( Cbz)? (CHOAc) - (2-tetrazolyl) (1 25 g) was dissolved in 60 ml of dioxane / water 7/3 and 264 ml of 2N sodium hydroxide solution was added The solution was stirred at room temperature for 2 hours. 5 hours after which the reaction seemed to be complete The pH was adjusted to 5 and the resulting mixture was evaporated to dryness under reduced pressure The residue was dissolved in methanol / dichloromethane 1/1 and the insoluble salt was filtered This resulted in 1 27 g of deacetylated product CLF Rf = 040, silica gel, toluene / ethanol = 6/4 v / v Boc-Lvs (Cbz) - (2-tetrazole) to a solution of 056 g of Boc-Lys- (Cbz) )? (CHOH) - (2-tetrazolyl) in 37 ml of dry dichloromethane, 1 38 g of Dess-Martin pepodane reagent The mixture was stirred at room temperature for 30 minutes after which the reaction was quenched with a 10% sodium thiosulfate solution in water. The organic layer was extracted with water and Sodium carbonate acid (5% in water), the water layers were combined and extracted with 1-butanol. The 1-butanol layer was evaporated to dryness under reduced pressure. The residue was chromatographed on a column of silica gel using the eluent ethyl acetate / pipdiano / acetic acid / water = 263/20/6/11 v / v / v / v Yield 022 g CLF Rf = 0 30, silica gel, ethyl acetate / pipdin / acetic acid / water = 63/20/6/11 v / v / v / v H-Lvs- (Cbz) - (2-tetrazole) TFA Boc-Lys (Cbz) - (2-tetrazole) (021 g) was dissolved in 16 ml of trifluoroacetic acid / water 9/1 The mixture was stirred for 1 hour at room temperature after which the solution was concentrated under vacuum to give an oil yield 034 g used immediately to prepare Boc-D-Cha-Pro-Lys (Cbz) - (2-tetrazolyl) of tppeptides Boc-D-Cha-Pro-Lys (Cbz) - (2-tetrazolyl) Boc-D-Cha-Pro-OH (0.19 g ) was prepared according to the procedure described in Example 1 for the portion of dipeptides Coupling for H-Lys (Cbz) - (2-tetrazolyl) (0.17g) was performed in a similar manner as described in Example 5 Purification on silica gel (eluent: ethyl acetate / pyridine / acetic acid / water = 163/20/6/11 v / v / v / v) yielded 021 g of the desired compound CLF: Rf = 0.17, silica ethyl acetate / pyridine / acetic acid / water = 63/20/6/11 v / v / v / v. H-D-Cha-Pro-Lvs- (2-tetrazolyl) The removal of the protective groups and the purification of HPLC was carried out in a procedure analogous to that described by Example 5. Yield: 20 mg. Rt (CL) 23 3 and 24.5 min, 20%, A / 80% B to 20% A, 20% B and 60% C in 40 minutes. Example 7 HOOC-CH7-CO-D-Cha-Pro-Lvs- (2-t-azole) HD-Cha-Pro-Lvs (Cbz) - (2-t-azole) TFA Boc-D- Cha-ProLys (Cbz) - (2-t-azolyl) was prepared according to the procedure described for Example 5 030 of this tppeptide was dissolved in 3 ml of tlfluroacetic acid / dichloromethane 1/1 v / v and the solution was stirred for 1 hour at room temperature The solution was evaporated to dryness under reduced pressure and coevaporated three times with toluene. Quantitative yield, oil, used immediately for the next step CLF Rf = 030, silica gel, ethyl acetate / pipdma / acetic acid. co / water = 163/20/6/11 v / v / v / v (t-butyl-OOC-CH-CO) -D-Cha-Pro-Lvs (Cbz) - (2-thiazolyl). HD-Cha-Pro-Lys (Cbz) - (2-thiazolyl). TFA (0.33 g) was dissolved in 3 ml of dry dichloromethane and 76 mg of tertiary monobutyl malonate were added and the pH adjusted to approximately 8 with triethylamine . Then, benzotriazolyl-oxitris (dimethylamino) -phosphonium hexafluorophosphate (211 mg) was added and the reaction mixture was stirred at room temperature for 2 hours and at 4 ° C for the next 16 hours. The solution was concentrated in vacuo, dissolved in ethyl acetate and washed three times with water and brine. The organic layer was again concentrated in vacuo after drying over magnesium sulfate. The residue was chromatographed on silica gel using heptane / ethyl acetate 2/8 v / v as eluent. This produced 270 mg of the asylated tripeptide. CLF: Rf = 011, silica gel, heptane / ethyl acetate = 8/2 v / v. HOOC-CH? -CO-D-Cha-Pro-Lvs- (2-thiazolyl). The removal of the protecting groups and the purification with HPLC was carried out in a procedure analogous to that described for example 5. Yield: 124 mg. Rt (CL): 38.23 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 minutes. EXAMPLE 8 HOOC- (CH7) 7-CO-D-Cha-Pro-Lys- (2-thiazolyl) (HOOC- (CH7) 7-CO) -D-Cha-Pro-Lvs (Cbz) - (2-thiazolyl) ). H-D-Cha-Pro-Lys (Cbz) - (2-thiazolyl). TFA (0.33 g) was dissolved in 3 ml of dry dichloromethane and 0.335 ml of pyridine. To this solution was added 48 mg of succinic anhydride and the resulting solution was stirred at room temperature under nitrogen. After 4 hours the reaction seemed to complete and it was extinguished with a few drops of water. The mixture was concentrated under vacuum, dissolved in ethyl acetate, washed with dilute acid, water and brine and dried over magnesium sulfate. After removal of the salt, the organic layer was concentrated in vacuo which resulted in 320 mg of an oil. CLF: Rf = 0.37, silica gel, dichloromethane / methanol 9/1 v / v. HOO- (CH?)? - CO-D-Cha-Pro-Lvs- (2-thiazolyl) The removal of the protecting groups and the purification of HPLC were carried out in an analogous procedure described for Example 5. Performance: 187 mg. Rt (CL) 38.31 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 minutes. EXAMPLE 9 HOOC-CH (CH 3) -D-Cha-Pro-Lvs- (2-tαolol) (t-Butyl-OOC-CH (CH 3)) - D-Cha-Pro-Lvs (Cbz) - (2-t-azole) HD-Cha-Pro-Lys (Cbz) - (2-t-azole) TFA (033 g) was dissolved in 2 000 acetonitoplo Then, 050 g of terbutilic ester of 2-bromoproponic acid followed by 25 mg of sodium iodide The pH of the solution was adjusted to 8 with diisopropylethylamine and maintained at that basicity for 12 days at room temperature The reaction mixture was concentrated in vacuo , it was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate and concentrated again, the residue was chromatographed on silica gel using ethyl acetate / toluene 1/1 v / v as eluent. Yield: 279mg CLF: 0.75, silica gel, ethyl acetate. HOOC-CH (CH -) - D-Cha-Pro-Lvs- (2-thiazolyl). The removal of the protecting groups and the purification with HPLC were carried out in a procedure analogous to that described for example 5. Yield: 40 mg and 29 mg (separated diastereomers). Rt (CL): 30.06 min and 34.87 min (separated diastereomers), 20% A, 80% B to 20% A, 20% B and 60% C in 40 minutes. Example 10 HOOC- (CH?) 7-D-Cha-Pro-Lvs- (2-thiazolyl). (t-Butyl-OOC- (CH7) 7-D-Cha-Pro-Lys (Cbz) - (2-thiazolyl) HD-Cha-Pro-Lys (Cbz) - (2-thiazolyl) .TFA (0.21) It was dissolved in 5 ml of acetonitrile, then 1.84 ml of terbutilic acrylacid ester was added in three portions, the pH of the solution was adjusted to 8 with diisopropylethylamine and maintained at that basicity for 13 days at room temperature. The residue was chromatographed on silica using ethyl acetate / toluene 2/1 v / v as the eluent. 92 mg CLF: Rf = 0.62, silica gel, ethyl acetate, HOOC- (C-.) D-Cha-Pro-Lvs- (2-t-yl-il) The removal of the protective groups and the purification of HPLC was carried out in a procedure analogous to that described for example 5. Yield: 40 mg Rt (CL): 32.83 min, 20% A, 80% B at 20% A, 20% B and 60% C in 40 minutes Example 11 N-Me-D-nor-Leu-Pro- L? S- (2-thiazolyl) H-D-nor-Leu-OMe.HCl To 270 ml of methanol, cooled to -15 ° C, was added 18.2 g of thionyl chloride. Subsequently, the temperature was allowed to rise to -10 ° C and then held constant for 20 min after which 10 g of H-D-norLeu-OH was added. The temperature was increased slowly and at reflux temperature kept constant for 5 hours. The product was crystallized from methanol and diethyl ether at 4 ° C and this gave 129 g CLF Rf = 0.61, silica gel, n-butanol / acetic acid / water 10/1/3 v / v / v Boc D-norLeu-OMe. H-D-norLeu-OMe.HCl (12.9 g) was dissolved in 200 ml of dry methanol followed by the addition of di-tert-butyl dicarbonate (15.5 g) and tetylamine (19.8 ml). The reaction was stirred for 3 hours at room temperature after which the mixture was concentrated under vacuum. The residue was then dissolved in ethyl acetate and washed with water. The product was chromatographed on silica using heptane / ethyl acetate 3/1 v / v Yield 16 9 g CLF Rf = 055, silica gel, heptane / ethyl acetate 3/1 v / v N-Me-Boc-D-norLeu-OMe. Boc-D-norLeu-OMe (16.9 g) was dissolved in 200 ml of dry dimethylformamide under nitrogen. Then, methyl iodide (24.9 ml) was added, cured at 0 ° C, sodium hydride (3.31 g) was added and the mixture was allowed to react for 16 hours at room temperature. The mixture was concentrated in vacuo, dissolved in ethyl acetate and washed with dilute hydrogen chloride (0.1 N), water, sodium hydrogen carbonate (5%) and water, dried and concentrated again. This produced 18.8 g of alkylated product CLF: = 0.56, silica gel, heptane / ethyl acetate 3/1 v / v. N-Me-Boc-norLeu-OH N-Me-Boc-norLeu-OMe (18 g) was dissolved in 400 ml of dioxane / water 9/1 v / v and the pH of the solution was adjusted to 13 with sodium hydroxide 1N. The reaction was allowed to proceed for 2 hours, keeping the pH constant at 12. The working procedure involved a pH adjustment to 2, cooling on ice, extra water addition (400 ml) and extraction with dichloromethane. The organic layer was washed with brine, dried, filtered and concentrated in vacuo. This yielded 18 9 of the product which contained some dioxane CLF = 026, silica gel, dichloromethane / methanol 9/1 v / v N-Me-Boc-D-norLeu-Pro -OH First N-succinimide ester was prepared starting from N-Me-Boc-D-norLeu-OH 18 g of this derivative was dissolved in acetonitoplo (250 ml), and then EDCI (14 5) and N-hydroxy- was added. succmimide (HONSu) (87 g) The reaction required 16 hours at room temperature after which the solvent was removed, the residue was dissolved in ethyl acetate and washed with water and dried This yielded 24.3% ester of ONSu raw. The next step can dissolve proline. HCl (20.9) in 300 ml of dimethylformamide and 300 ml of water and the pH was adjusted to 8 with 2N sodium hydroxide solution. A solution of ONSu ester (24.3 g in 300 ml of dimethylformamide) was added dropwise to this solution keeping the pH constant. The reaction was completed after 5 hours, after which the organic solvent was removed largely by evaporation under reduced pressure. Extra water (300 ml) was added and the pH adjusted to 2. 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 222 g The crude product was chromatographed on silica using ethyl acetate / methanol 8/2 v / v as eluent Yield 132 g CLF Rf = 065, silica gel , ethyl acetate / pipdine / acetic acid / water = 163/20/6/11 v / v / v / v N-Me-D-norLeu-Pro-Lys- (3-t? azole) mixed anhydride coupling between N-Me-Boc-norLeu-Pro-OH and H-Lys (Cbz) - (2-t? aolol) TFA, deprotection and purification were carried out according to the procedures described in Example 5 Yield 107mg Rt (CL) 2322 min, 20% A, 80% B at 20% At 20% B and 60% C at 40 minutes Example 12 N-MeD-Cha-Pro-Lvs- (2-thiazolyl) . All steps leading to this tripeptide were carried out in a similar manner as described for example 11, and starting with Boc-D-Cha-OH. Yield: 253 mg. Rt (CL): 31.82 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 minutes. Example 13 N-Me-D-PheN-cyclopentyl-GIv-OMe N-Me-Boc-D-Phe-N-cyclopentyl-GIv-OMe N-Me-Boc-D-Phe-OH (prepared according to the example eleven) (26 g) and N-cyclopentyl-Gly-OMe (21 g see example 3) was dissolved in 300 ml of dimethylformamide. Then, TBTU (36 G) were added and the pH was adjusted to 8 with diisopropylethylamine (20 ml). The reaction mixture was stirred for 16 hours and concentrated in vacuo, dissolved in ethyl acetate, washed with sodium acid carbonate (5%) and brine, dried over magnesium sulfate and again concentrated in vacuo. Yield: 24.8 g. CLF: Rf = 0.62, silica gel, dichloromethane / methanol 95/5 v / v. N-Me-Boc-D-Phe-N-cyclopentyl-Gly-OH. N-Me-Boc-D-Phe-N-cilcopentil-Gly-OMe (17.3 g) was dissolved in 150 mol of tetrahydrofuran / water 135/15 v / v and 4 g of sodium hydroxide (in water) were added. After 2 hours the reaction was stopped by adjusting the pH to 2 and the product was extracted with dichloromethane. After washing with water, drying over magnesium sulfate, concentrating in vacuo and crystallization from dichloromethane / diethyl ether, the reaction yielded 131 g. CLF: Rf = 0.52, silica gel, dichloromethane / methanol 9/1 v / v. N-Me-D-Phe-N-cyclopentyl-Glv-Lvs- (2-thiazolyl) The following steps were carried out according to the procedure described for Example 11. Yield. 110 mg. Rt (CL) 33.43 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 minutes. Example 14 N-Me-D-Phe-Pro-Lys- (2-thiazolyl). N-Me-Boc-D-Phe-OH was prepared according to the description for Example 1 The coupling of mixed anhydride to H-Lys (Cbz) - (2-thiazolyl), deprotection and purification were performed according to with example 5. Yield: 148 mg. Rt (CL): 27.22 min, 205 A, 80% B to 20% A, 20% B and 60% C in 40 minutes. Example 15 3,3-D? Phenylpropionyl-Pro-Lys (ethoxycarbonyl) - (2-thiazole?). 3,3-Diphenylpropylone-Pro-Lys- (2-thiazolyl) was prepared with Example 1. A solution of 20mg of this dipeptide in dioxane / water 4/1 (4 ml) was made and the pH was adjusted with 1 N sodium hydroxide to 13. Then 22 mg of ethyl chloroformate was added and the solution was stirred for 2 hours at room temperature. The mixture was diluted with water and extracted with dichloromethane, washed with water, dried over magnesium sulfate, concentrated in vacuo and finally, dried by freezing with tert-butanol / water 1/1 v / v Yield: 15 mg. CLF: Rf = 0.92, silica gel, ethyl acetate / pipdine / acetic acid / water = 63/20/6/11 v / v / v / v Example 16 HOOC-CH D-Cha-Pro-Lvs- (2 -oxazolyl) Boc-Lvs (Cbz) v? FCHOHl- (2-oxazolyl) To a solution of 0975 g of Boc-Lys (Cbz) -OMe in 26 ml of dichloromethane at -78 ° C under a nitrogen atmosphere was 6 ml of a solution of 1M disobutylaluminum hydride in hexane was added. After 15 minutes the reaction was completed, the reaction mixture was poured into 150 ml of a 2% citric acid solution and filtered. The organic layer was separated, washed with water and brine, dried with magnesium sulfate and concentrated The residue was coevaporated with toluene to give 0 92 g of Boc-Lys (Cbz) -H This aldehyde (089 g) was dissolved in 1.4 ml of toluene and 090 g of 2- (tr? Met? L? L) oxazole (prepared according to Edwards, PD, Wolanin, DJ, Andisik DW, and Davis W, J Med Chem 38, 76 (1995)) was added and was heated to 80 ° C. After 60 hours the reaction mixture was concentrated, and The residue was dissolved in 5 ml of tetrahydrofuran, treated with 3 ml of a 3M tetrabutylammonium fluoride in tetrahydrofuran solution and stirred at room temperature for 2 hours. The mixture was concentrated, dissolved in ethyl acetate, washed with of 3% aqueous sodium carbonate acid and brine, dried (magnesium sulfate) and the purification was evaporated by column chromatography on silica gel eluting with a gradient of ethyl acetate / diclomethane = 2/1 (v / v) ) to ethyl acetate gave an oil which was rechromatographed on silica gel eluting with a gradient of ethyl acetate / heptane = 1/1 (v / v) to ethyl acetate / heptane = 1/3 (v. / v) to give 0.22 g of the title compound CLF: Rf = 07 silica gel, ethyl acetate. Boc-Lvs (Cbz) - (2-oxazole) To a solution of 0.22 g of Boc-Lys- (Cbz) -? [CHOH] - (2-oxazolyl) in 10 ml of dichloromethane was added 0.22 g of periodian (Dess-Martin reagent) After 1.5 hours of stirring at room temperature, 10 ml of 5% sodium thiosulfate was added and the mixture was stirred for 15 minutes at room temperature. The organic layer was separated, washed with water , 5% aqueous sodium hydrogen carbonate and brine was dried over magnesium sulfate and concentrated. Purification by chromatography on silica gel eluting with heptane / ethyl acetate = 1/1 (v / v) yielded 162 mg of compound of title CLF Rf = 0 5, silica gel, heptane / ethyl acetate = 1/3 (v / v) (tBuOOCCH7) (Boc) -D-Cha-Pro-Lvs (Cbz) - (2-oxazole? lo) The procedure described for Example 5 was used The deprotection of 0 16 g of Boc-Lys (Cbz) - (2-oxazole) and coupling with 0 19 g of (tBuOOCCH2) (Boc) -D-Cha- Pro-OH gave 0 19 g of (tBuOOCCH2) (Boc) -D-Cha-Pro-Lys (Cbz) - (2-oxazole) C) LF Rf = 03, silica gel, heptane / ethyl acetate = 1/3 (v / v) HOOCCH7-D-Cha-Pro-Lvs- (2-oxazole) The compound described for the example was used 5 was used 0 19 g of (tBuOOCCH2) (Boc) -D-Cha-Pro-Lys (Cbz) - (2-oxazole) gave 52mg of the title compound Rt (CL) 2845 min, 20% A / 80 % B to 20% A / 20% B / 60% C in 40 minutes Example 17 Et? LSO7-norLeu- (c? Clo) Glv-Lvs (2-t? Azol? Lo) Boc- La-am i no- e-capro lactam To a stirred solution of La-amino-e-caprolactam (10g) in dioxane / water (2/1 v / v) (30 ml) was added a solution of 1N sodium hydroxide (78ml) followed by di-t-butyl carbonate (188 g) The mixture was stirred for 16 hours at room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried over sodium sulfate, filter and evaporate in vacuo. The crude material is triturated by hexane, filtered and dried in vacuo to give Boc-La-amino-e-caprolactam (16 g) CLF Rf = 085 ethyl acetate / heptane 1/1 v / v sovereign e Boc-norLeu (c? clo) Gly-OMe Boc-The amino-e-caprolactam (10 g) was dissolved in dichloromethane (100 ml) At 20 ° C a 1M solution of bis (tr? met? ls? 1) amide in THF / cyclohexane (1/1 v / v) (1 equivalent) slowly and the mixture was stirred for 30 minutes. Methyl bromoacetate (4 ml) was subsequently added and the mixture was stirred for 2 hours. at room temperature Bis (tr? met? l? l) am? da in THF / cyclohexane (1/1) v / v) was added to force the reaction to terminate The mixture was diluted with dichloromethane and washed with solution of 0 1 N hydrochloric acid, water, 5% aqueous sodium hydrogen carbonate solution and brine was dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography on silica (eluent-heptane / ethyl acetate). ethyl 6/4 v / v to give Boc-norLeu (cyclo) Gly-OMe (12 g) CLF-Rf = 0.55, ethyl acetate / heptane 6/4 v / v on silica EtilSQ7-norLeu (cyclo) Glv-OMe Boc-norLeu (cycle) Gly-OMe (3 g) was dissolved in 50% TFA / dichloromethane (30 ml) and stirred for 1 hour at room temperature The reaction mixture was evaporated in vacuo. The crude amine was dissolved in dichloromethane (30 ml) and a solution of ethansulfonyl chloride (1 29) in dichloromethane (10 ml). ml) were added slowly at 0 ° C. Thiethylamine was added to maintain pH 8 during the reaction. The mixture was stirred for 1 hour at room temperature, whereby the mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and it was washed with 5% sodium hydrogen carbonate solution, water and brine dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography on silica (eluent dichloromethane / ethyl acetate 95/5 v / v% To give et? S02-norLeu (c? clo) Gly-OMe (1 45) CLF Rf = 030, dichloromethane / ethyl acetate 9/1 v / v on silica Et? lSQ7-norLeu (c? clo) Glv -OH To a solution of et? LS02-norLeu (c? Clo) Gly-OMe (1 45 g) in 50 ml of dioxane / water 9/1 v / v was treated with sufficient 1N 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 with sodium sulfate. The filtrate was evaporated and yielded 600 mg of the title compound. CLF: Rf = 0.45, ethyl acetate / pyridine / acetic acid / water 63/20/6/11 v / v / v / v on silica. EtIISO7-norLeu (cycle) Glv-Lvs (Cbz) - (2-thiazolyl) EthylSO2-norLeu (cyclo) Gly-OH (482 mg) was dissolved in dry dimethylformamide (4 ml). After the addition of ethyl diisopropylamine (036 ml) the reaction mixture was placed under nitrogen and cooled to -20 ° C. Subsequently isobutyl chloroformate (140 ml) was added and the mixture was allowed to stir for 15 minutes at -20 ° C H-Lys (Cbz) - (2-tαolol) .TFA was dissolved in dry dimethylformamide (3 ml ) and added dropwise to the cold mixed anhydride solution, maintaining the pH at 8.5 by the addition of ethyl diisopropylamine. The reaction mixture was stirred for 15 minutes at -20 ° C. The mixture was evaporated to dryness. The residue was dissolved in ethyl acetate and washed successively with 5% aqueous sodium hydrogen carbonate solution, water and brine, dried Sodium sulfate and concentrated in vacuo The residue was purified by chromatography on silica (eluent d? chloromethane / methanol = 95/5 v / v) to give Et? lS02-norLeu (c? clo) Gly-Lys (Cbz) - (2-t-azole) (607 mg) CLF: Rf = 0.63, ethyl acetate / pipdine / acetic acid / water 60/3/1/2 v / v / v / v on silica. EtilSQ7-norLeu (cycle) Glv-Lvs- (2-thiazolyl) EthylSO2-norLeu (cyclo) Gly-Lys- (2-thiazolyl) (600 mg) was treated with trifluoroacetic acid / thioanisole 10/1 v / v (10 ml ) for 4 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue dissolved in water. The aqueous phase was washed extensively with diethyl ether. The aqueous layer was concentrated in vacuo, coevaporated with dilute hydrochloric acid and extracted from water. The crude product was loaded onto a preparative HPLC Deltapack C18 RP column using a gradient elution system of 20% A / 80% B at 205 A / 40% B / 40% C for 40 minutes, at a flow rate of 50 ml / mm Yield 233 mg of Et? LS02-norLeu (cyclo) -Gly-Lys- (2-t? Aolol) Rt (CL) 26 73 min 20% A / 80% B to 20% A / 20 % B / 60% C in 40 minutes Example 18 Benc? LSo7-norLeu (c? Clo) Glv-Lys- (2-t? Aolol) This compound was prepared in a similar manner as described in Example 17 Rt. (CL) 3705 min 20% A / 80% B at 20% A / 20% B / 60% C in 40 minutes Example 19 7-Methoxy? -2-Naft? Lsulfon? L-norLeu (c? Clo) Glv- Lys- (2-tαolol) This compound was prepared in a similar manner as described in Example 17. Rt (CL): 26.40 min. 20% A / 60% B / 20% C to 100% C in 40 minutes. Example 20 (4aR, 8aR) -perhydroisoquinoline-1 (R) -carbonyl-Pro-Lys- (2-thiazolyl) 2-Cbz (4aR, 8aR) -perhydroisoquinoline-1 (R, S) -carboxylic acid Acid 2 was synthesized -Cbz (4aR, 8aR) -perhydroisoquinoline-1 (R, S) -carboxylic acid as described in EP0643073, example 1. CLD: Rf: 0.85, ethyl acetate / pyridine / acetic acid) water 63/20/6/11 v / v / v / v on silica. 2-Cbz- (4aR, 8aR) -perhydroisoquinoline-1 (R, S) -carbonyl-ProO-tBu. To a cold solution (0 ° C) of 2-Cbz (4aR, 8aR) -perhydroisoquinoline-1 (R, S) -carboxylic acid (500 mg) in dimethylformamide (5 ml) was added successively DCCI (1.3 -dicyclohexylcarbodiimide, 342 mg), HOBT (1-hydroxybenzotriazole hydrate, 319 mg), H-Pro-OtBu (270 mg)) and triethylamine (055 ml). The reaction mixture was stirred at 0 ° C for 1 hour and then maintained at room temperature overnight. The mixture was cooled to -20 ° C and DCU (1,3-dicyclohexylurea) was removed by filtration. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate. This solution was washed successively with 5% aqueous sodium hydrogen carbonate solution, 3% aqueous citric acid solution, water, and brine, dried over sodium sulfate. Sodium and concentrated in vacuo The residue was purified by chromatography on silica (eluent heptane / ethyl acetate 4/1 v / v) to give 2-Cbz (4aR, 8aR) -perh? dro? soqu? nol? na-1 (R, S) -carbon? L-Pro-O-tBu) (634 mg) CLF Rf 090, ethyl acetate / pipdine / acetic acid / water 53/20/6/11 v / v / v / v on silica 2-Cbz acid (4aR.8aR) -perh? Dro? Soau? Nol? Na-1 (RS) -carbon? L-Pro-OH 2-Cbz ester (4aR, 8aR) -perh? Dro? Soqu? Nol Na-1 (R, S) -carbon? l-Pro-butyl (600 mg) was stirred in a mixture of dichloromethane (1 ml), trifluoroacetic acid (3 ml) anisole (0 15 ml) for 1 hour at room temperature The reaction mixture was concentrated under vacuum at low temperature and the residue was dissolved in water at pH 9. The aqueous phase was washed with diethyl ether. , so the aqueous layer was acidified to pH 25 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 give 2- Cbz (4aR, 8aR) -perh? Dro? Soqu? Nol? Na-1 (R, S) -carbon? L-Pro-OH (588 mg) CLF Rf = 054, ethyl acetate / pipdma / acetic acid / water 60/3/1/2 v / v / v / v on silica 2-Cbz (4aR, 8aR) -perh? Dro? Soqu? nol? na-1 (R, S) -carbon? l-Pro-Lys (Cbz) - (2-t? azo lo) 2-Cbz (4aR, 8aR) -perh? dro? soqu? nol? na was dissolved -1 (R, S) -carbonyl-Pro-OH (500 mg) in dry dimethylformamide (5 ml) After the addition of ethyl d ti sop pl amine (041 ml), the reaction mixture was placed under nitrogen and cooled to -20 ° C Subsequently, isobutyl chloroformate (156 ml) was added and the mixture was allowed to stir for 15 minutes at -20 ° C. H-Lys (Cbz) - (2-thiazolyl) .TFA (594 mg) was dissolved in dry dimethylformamide (3 ml) and added dropwise to the cold mixed anhydride solution, maintaining the pH 8.5 by the addition of ethyl. diisopropylamine The reaction mixture was stirred for 15 minutes at -20 ° C. The reaction mixture was evaporated to dryness. The residue was dissolved in ethyl acetate and successively washed with 5% aqueous sodium hydrogen carbonate solution, water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica (eluent dichloromethane / methanol = 95/5 v / v%) to give 2-Cbz (4aR, 8aR) -perhydroisoquinoline-1 (R, S) -carbonyl-Pro-Lys (Cbz) - (2-thiazolyl) (880 mg). CLF: Rf = 0.42, ethyl acetate / heptane 3/1 v / v on silica. (4aR, 8aR) -perhydroisoquinoline-1 (R) -carbonyl-Pro-Lys- (2-thiazolyl) (4aR, 8aR) -perhydroisoquinoline-1 (R) -carbonyl-Pro-Lys- (2-thiazolyl) (875 mg) was treated with trifluroacetic acid / thioanisole 10/1 v / v (10 ml) for 4 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue dissolved in water, the aqueous phase was washed extensively with diethyl ether. The water layer was concentrated in vacuo, coevaporated with dilute hydrochloric acid and lyophilized with water. The crude product was loaded on a preparative Deltapack C18 RP CLAR column using a gradient elution system of 20% A / 80% B at 20% A / 53% B / 27% C for 40 minutes at a flow rate of 50 ml / min. Yield: 211 mg of (4aR, 8aR) -perhydroisoquinoline-1 (R) -carbonyl-Pro-Lys- (2-thiazolyl).

Rt (CL): 28 min. 20% A / 80% B to 20% A / 20% B / 60% C in 40 minutes. Example 21 EthylSO-D-Cha-Pro-Lvs- (2-thiazolyl) Boc-D-Cha-Pro-OBzl (Bzl = benzyl) Boc-D-Cha-Pro-OBzl was prepared according to a manner similar to described in Example 1 using Boc-D-Cha and Pro-OBzl. CLF: Rf = 0.5, dichloromethane / methanol 95/5 v / v on silica. EtilSQ7-D-Cha-Pro-OBzl EthylSO2-D-Cha-Pro-OBzl (3.8 g) was dissolved in TFA / 50% 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 to -78 ° C. Triethylamine was added to maintain pH 8 during the reaction. The mixture was stirred for 3 hours at 0 ° C, then 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, 5% sodium hydrogen carbonate solution, and brine and dried over sodium sulfate, filtered and evaporated in vacuo. crude with methanol gave Et? lS02-D-Cha-Pro-OBzl (3.0 g) CLF Rf = 06, dichloromethane / methanol 95/5 v / v on silica Et? lSQ7-D-Cha-Pro-OH To one solution of Et? lSO2-D-Cha-Pro-OBzl (10 g) in tetrahydrofuran (250 ml) was added a 1M solution of tetrabutylammonium fluoride (84 ml). The reaction mixture was stirred for 30 minutes at room temperature and washed with water (11) 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. ethyl / dnsopropyl ether to give Et? lSO2-D-Cha-Pro-OH (60 g) CLF Rf = 02, ethyl acetate ilo / pipdin / acetic acid / water 163/20/6/11 v / v / v / v on silica Et? lSQ7-D-Cha-Pro-Lvs (Cbz) - (2-t? aolol) Et? lS02-D-Cha-Pro-OH (397 mg) was dissolved in dry dimethylformamide (3 ml), then the addition of ethyl dnsopropyl amine (0 19), the reaction mixture was placed under nitrogen and cooled to -20. ° C Subsequently, isobutyl chloroformate (130 ml) was added and the mixture was allowed to stir for 14 min at -20 ° C. H-Lys- (Cbz) - (2-thiazolyl) TFA was dissolved in dry dimethylformamide (3 ml) and it was added dropwise to the cold-mixed anhydride solution maintaining the pH at 8 5 by the addition of ethyl-dn sopropyl amine. The reaction mixture was stirred for 15 minutes at -20 ° C and 1 hour at room temperature. The reaction was evaporated to dryness. The residue was dissolved in ethyl acetate and washed successively with 5% aqueous sodium hydrogen carbonate solution, water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica (eluent: ethyl acetate / heptane 2/1 v / v) to give EthylSO2-D-Cha-Pro-Lys (Cbz) - (2-thiazolyl) (575 mg). CLF: Rf = 0.32, ethyl acetate / heptane 2/1 v / v on silica. EthylSQ7-D-Cha-Pro-Lvs- (2-thiazolyl) EthylSO2-D-Cha-Pro-Lys- (2-thiazolyl) (570 mg) was treated with trifluoroacetic acid / thioaniso 10/1 v / v (44 ml ) for 4 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue dissolved in water. The aqueous phase was washed extensively with diethyl ether. The water layer was concentrated in vacuo, coevaporated with dilute hydrochloric acid and lyophilized with water. The crude product was loaded onto a preparative HPLC Deltapack C18 RP column using a gradient elution system of 20% A / 80% B at 20% A / 30% B / 50% C for 40 minutes, at a flow rate of 80 ml / min. Yield 275 mg of EthylS02-D-Cha-Pro-Lys- (2-thiazolyl). Rt (CL): 26.06 min. 20% A / 60% B / 20% C to 100% C in 40 minutes. Example 22 Ethyl SQ7-D-Phe-Pro-Lvs- (2-thiazolyl) Boc-D-Phe-Pro-OBzl This compound was prepared according to a similar manner to that described in Example 1 using Boc-D-Phe and Pro-OBzl CLF: Rf = 0.9, ethyl acetate / pyridine / acetic acid / water 60/3/1/2 v / v / v / v on silica. Ethyl D-Phe-Pro-OH This compound was prepared according to a manner similar to that described in Example 21 using Boc-D-Phe and Pro-OBzl. CLF: Rf = 0.48, ethyl acetate / pyridine / acetic acid / water 163/20/6/11 v / v / v / v on silica. EtOH-D-Phe-Pro-Lvs (Cbz) - (2-thiazolyl) EthylSO2-D-Phe-Pro-Lys (Cbz) - (2-thiazolyl) was prepared according to a manner similar to that described in example 21, using EthylSO2-D-Phe-Pro-Lys (Cbz) - (2-thiazolyl) CLF: Rf: 0.32, ethyl acetate / heptane 8/2 v / v on silica. Eti ISQ7-D-Phe-Pro-Lvs- (2-thiazolyl) EthylSO2-D-Phe-Pro-Lys (Cbz) - (2-thiazolyl) (336 mg) was treated with trioroacetic acid 10/1 v / v ( 44 ml) for 4 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue dissolved in water. The aqueous phase was washed extensively with diethyl ether. The water layer was concentrated in vacuo, coevaporated with dilute hydrochloric acid and lyophilized with water. The crude product was loaded onto a preparative HPLC Deltapack C18 RP column using a gradient system of 20% A / 65% B / 15% C at 20% A / 20% B / 60% C for 40 minutes, at a rate flow rate of 50 ml / min). Yield: 160 mg of EthylS02-D-Phe-Pro-Lys- (2-thiazolyl).

R, (CL): 39.47 min.20% A / 80% B at 20% B / 60% C in 40 minutes. Example 23 D-Hpl-Pro-Lvs- (2-thiazolyl) (Hpl = 3-hexahydrophenyl lactic acid) HD-Hpl-OMe HD-Cha-OH (1.0 g) was dissolved in a 1N hydrochloric acid mixture (48 ml) ), water (194) and acetic acid (9.7 ml). At 0 ° C a solution of sodium nitrite (3.4) in water (5.8) was slowly added and the mixture was stirred overnight at room temperature. Subsequently 37% hydrochloric acid (4.8 ml) was added and the mixture was stirred for 15 minutes at room temperature The reaction mixture was evaporated and the residue was dissolved in ether / acetone. After filtration, the solution was concentrated in vacuo and the crude material was stirred in methane (25 ml) for 18 hours The pH was 1.5 The reaction mixture was evaporated to dryness and the residue was purified by chromatography on silica (eluent - toluene / methanol 97/3 v / v to give HD-HIp-OMe (612 mg) CLF. Rf = 0.9, ethyl acetate / pipdma / acetic acid / water 163/20/6/11 v / v / v / v on silica THP-D-Hpl-OMe (THP = tetrahydropranus) To a stirred solution of HD Hpl-OMe (450 mg) in dichloromethane (2 ml) was added successively 3,4-d? H? Dro-2 H-p? Rano (0285 ml) and pipdinium p-toluenesulfonate (60 mg) The mixture was stirred for 6 hours at room temperature and diluted with ether. This mixture was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The crude material was purified by chromatography on silica (eluent: ethyl acetate / heptane 1/4 v / v) to give THP-D-Hpl-OMe (498 mg). CLF: Rf: 0.64, ethyl acetate / heptane 1/2 v / v on silica. THP-D-Hpl-OH. To a solution of THP-D-Hpl-OMe (10.3) in dioxane / water 9/1 (200ml) was treated with sufficient 1N sodium hydroxide to maintain the pH at 12 for 18 hours at room temperature. After acidification, the mixture was poured into water (500 ml) and extracted with dichloromethane. The organic layer was washed with water and dried over sodium sulfate. The filtrate was evaporated and gave 6.6 g of the title compound. CLF Rf = 0.78, ethyl acetate / pyridine / acetic acid / water 163/20/6/11 v / v / v / v on silica. THP-D-Hpl-Pro-OH. To a solution of THP-D-Hpl-Pro-OH (5.87 g) in acetonitoplo (75 ml). EDC (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride) (4.84) and N-hydroxysuccinimide (2.9 g) were successively added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. This solution was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude material was dissolved in dimethylformamide (100 ml) and added to a solution of proline.HCl (6.99g) in dimethylformamide / water, 1/1, v / v (200 ml), which was adjusted to a pH of 85 by sodium hydroxide. After stirring overnight the reaction mixture was concentrated in vacuo and the residue dissolved in water. This aqueous solution was adjusted at pH 2 5 at 0 ° C, followed by extraction with ethyl acetate, the combined organic layers were washed successively with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude material was purified by chromatography on silica (eluent ethyl acetate / methane, 8/2 6/4, v / v%) to give THP-D-Hpl-Pro-OH (675) CLF Rf = 052, ethyl acetate / pipdine / acetic acid / water 163/20 / 6/11 v / v / v / v on silica THP-D-Hpl-Pro-Lvs (Cbz) - (2-tαolol) THP-D-Hpl-Pro-OH (390mg) was dissolved in dimethylformamide dried (5 ml), after the addition of ethyl dusopropyl amine (0 19 ml), the reaction mixture was placed under nitrogen and cooled to -20 ° C. Subsequently isobutyl chloroformate (130 ml) was added and the mixture was added. allowed to stir for 15 minutes at -20 ° C H-Lys (Cbz) - (2-t-azole) TFA (1 05 eq) was dissolved in dry dimethylformamide (5ml) and added dropwise to the anhydride solution cold mixed, maintaining the pH at 85 by addition of ethyl dnsopropyl amine The reaction mixture was stirred for 15 minutes at -20 ° C and 2 5 hours at room temperature The reaction mixture was evaporated to dryness. The residue was dissolved in ethyl acetate and washed successively with 5% aqueous sodium hydrogen carbonate solution, water and brine was dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica (eluent: ethyl acetate / heptane 2/1 v / v) to give THP-D-Hpl-Pro-Lys (Cbz) - (2-thiazolyl) (497 mg). CLF: Rf = 0.42 in ethyl acetate / heptane 2/1 v / v on silica. D-Hpl-Pro-Lvs- (2-thiazolyl) THP-D-Hpl-Pro-Lys (Cbz) - (2-thiazolyl) (470 mg) was treated with trifluoacetic acid / thioanisole 10/1 v / v (38.5 ml) for 4 hours at room temperature. The reaction mixture was concentrated in vacuo and the residue dissolved in water. The aqueous phase was washed extensively with diethyl ether. The water layer was concentrated in vacuum, coevaporated with dilute hydrochloric acid and lyophilized with water. The crude product was loaded onto a preparative HPLC Deltapack C18 RP column using the elution system of a gradient of 20% A / 65% B / 15% C at 20% A / 20% B / 60% C for 40 minutes, at a rate of 50 ml / min. Yield: 75 mg of D-Hpl-Pro-Lys- (2-thiazolyl). Rt (CL): 40.00 min 20% A / 80% B at 20% A / 20% B / 60% C in 40 minutes. Example 24. HOOC-CH7-D-Phe-Pro-Lvs- (2-thiazolyl) HD-Phe-OMe-HCl To cool (-20 ° C) and dry methanol (11) thionyl chloride was added dropwise (130 ml). H-D-Phe-OH. HCl (147.6) was added and the reaction mixture was heated under reflux for 30 minutes and then kept at room temperature overnight. The mixture was concentrated in vacuo and coevaporated with methanol (3 times) the residue was crystallized with methanol / diethyl ether to give H-D-Phe-OMe.HCl as a white crystalline powder (187.4 g). CLF: Rf = 0.54, silica gel, n-butanol / acetic acid / water 10/1/3 v / v. N- (t-bu ti loxy carboni I meti l) -D-Phe-OMe t-Butyl-bromine acetate (65 ml) was added to a stirred solution of HD-Phe-OMe-HCl (65.2 g) in 400 ml of acetonitrile, the pH of the mixture was adjusted to 8.5 with N, N-diisopropylethylamine. 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 over sodium sulfate and evaporated in vacuo. Chromatography on silica gel in heptane / ethyl acetate 9/1 (v / v) gave 96.4 g of N- (t-butyloxycarbonylmethyl) -D-Phe-OMe. CLF: R, = silica gel, ethyl acetate / pyridine / acetic acid / water 376/31/18/7 v / v / v / v. N- (t-Butyloxycarbonylmethyl) -N-Boc-D-Phe-OMe The pH of the solution of N- (t-Butyloxycarbonylamethyl) -N-Boc-D-Phe-OMe (96.4 g) and di-t-dicarbonate butyl (72.2 g) in N, N-dimethyl formamide (400 ml) was adjusted to 8.5 with N, N-diisopropylethylamine. The mixture was stirred for 48 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 hydrogen chloride, water, saturated sodium hydrogen carbonate solution and water. The organic layer was dried over sodium sulfate and the filtrate was evaporated. The residue was chromatographed on silica in toluene / ethyl acetate 9/1 (v / v) as eluent. Fractions containing N- (t-Butyloxycarbonylmethyl) -N-Boc-D-Phe-OMe were combined and evaporated. Yield: 115.3 g. CLF: Rf = 0.77, silica gel, toluene / ethyl acetate 9/1 v / v. N- (t-Butyloxycarbonylamino-N-Boc-D-Phe-OH To a solution of N- (t-Butyloxycarbonylamethyl) -N-Boc-D-Phe-OMe (115.3 g) in 800 ml of dioxane / water = 9/1 (v / v) was treated with enough 2N sodium hydroxide to maintain the pH at 12 for 16 hours at room temperature.After acidification, the mixture was poured into water and extracted with dichloromethane. The organic was washed with water and dried over sodium sulfate The filtrate was evaporated and yielded 104 g of N- (t-Butyloxycarbonylamethyl) -N-Boc-D-Phe-OMe, CLF: Rf = 0.10, silica gel, toluene / ethyl acetate 7/3 v / v. N- (t-Butyloxycarbonylmethyl) -N-Boc-D-Phe-Pro-OBzl To a cold solution (0 ° C) of N- (t-Butyloxycarbonylmethyl) -N-Boc-D-Phe-OH (5.3 g) 3n N, N-dimethyl formamide (40 ml) were successively added 1-hydroxy benzotriazole (2.8 g), dicyclohexylcarodiimide (3.2 g), H-Pro-OBzl, HCl (378 g) and triethylamine (2.16 ml) The mixture was stirred at 0 ° C for 1 hour and then maintained at room temperature during the no The mixture was cooled to -20 ° C and diclohexylurea was removed by filtration The filtrate was evaporated to dryness The residue was dissolved in ethyl acetate and washed successively with 5% sodium hydrogen carbonate, water, citric acid 2%. % and brine Dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel in heptane / ethyl acetate 6 / r (v / v) as eluent. Fractions containing N- (t-Butyloxycarbonylamethyl) - N-Boc-D-Phe-Pro-OBzl were combined and evaporated. Performance. 4.35 g. TLC: Rf = 0.74, silica gel, heptane / ethyl acetate 1/1 v / v N- (t-But? loxycarbon? lametin-N-Boc-D-Phe-Pro-OH Palladium on 10% charcoal (450mg) was added to a solution of N- (t-Butylox? carbonylamet? l) -N-Boc-D-Phe-Pro-OBzl (4.35) in methanol (50 ml) The mixture was hydrogenated at atmospheric pressure at room temperature for 45 minutes. The palladium catalyst was removed by filtration and the solvent was removed by evaporation under reduced pressure to give 348 g N- (t-Butyloxycarbonylamino) -N-Boc-D-Phe-OH, CLF Rf = 0.63, silica gel. ethyl acetate / pipdine / acetic acid / water 664/31/18/7 v / v / v / v. N- (t-But? loxycarbon? lamet? l) -N-Boc-D-Phe-Pro- Lvs (Cbz) - (2-t-azole) To a cooled solution (-20 ° C) of 375 mg N- (t-But? Loxycarbon? Lamet? L) -N-Boc-D-Phe-Pro -OH and 276 ml N, N-dnsopropylethylamine in 10 ml of N, Nd? Methyl formamide, was added 100 ml of isobutyl chloroformate. The reaction mixture was stirred for another 30 minutes at -20 ° C H-Lys (Cbz). ) - (s-thiazolyl) TFA (362 mg) was dissolved in 5 ml of N, Nd? met? l formamide and adjusted to pH 8 with N, Nd? soprop? let? lam? na This solution was slowly added to the reaction mixture The reaction mixture was stirred for 15 minutes at -20 ° C and then allowed to warm to room temperature. The reaction mixture was evaporated to dryness and the residue was dissolved in ethyl acetate. The organic phase was washed with 5% sodium hydrogen carbonate water and brine, dried over sodium sulfate and concentrated to give 622 mg of the crude product The purification of silica gel, using dichloromethane / methanol 97/3 v / v as eluent gave 394 mg of N- (t-Butyloxycarbonylmethyl) -N-Boc-D-Phe-Pro-Lys (Cbz) - (2-thiazolyl). CLF: Rf = 0.50, silica gel, dichloromethane / methanol 95/5 v / v. HOOC-CH7-D-Phe-ProLvs- (2-thiazolyl). The protected tripeptide (394 mg) was treated with trifluoroacetic acid and thioanisole according to the procedures described in Example 1 to give, after purification of HPLC, 206 mg of HOOC-CH2-D-Phe-Pro-Lys- (2 -thiazolyl). R, = 24.9 min. 20% A, 80% B to 20% A, 20% B and 60% C in 40 minutes. Example 25 HOOC-CH7-D-p-OCH --- Phe-Pro-Lvs- (2-thiazolyl). HOOC-CH2-D-p-OCH3-Phe-ProLys- (2-thiazolyl) was prepared in a similar manner as described in Example 24, starting with H-D-p-OCH3-Phe-OH HCl. Deprotection (see for example 1) 345 mg N- (t-but? Loxycarbonylmethyl) -N-Boc-Dp-OCH3-Phe-Pro-Lys (Cbz) - (2-thiazolyl) gave, after purification with HPLC , 253 mg of product R, (CL) 28.9 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 minutes Example 26 HOOC-CH7-D / LmF-Phe-ProLvs- ( 2-t-azolyl) N- (t-butyl? Carbon? Lmet? NN-Boc-D / LmF-Phe-OH) According to analogous procedures as described in Example 24, HD / LmF- Phe-OH HCl (5 g) was converted to N- (t-but? Lox? Ccarbon? Lmet? L) -N-Boc-D / LmF-PheOH Yield 8 g CLF Rf = 065, silica gel, ethyl acetate / methanol 9/1 v / v N- (t-but? lox? carbon? lmet? l) -N-Boc-D / LmF-Phe-OMe To a cold solution (0 ° C) of N- (t- but? lox? carbon? lmet? l) -N-Boc-D / LmF-Phe-OH (79 g) in N, Nd? met? l (80 ml) was successively added 1-h? drox? bepzotpazol (4 g), dicyclohexyl carbidbidmide (45 g), H-Pro-OMe HCl (36 g) and tetylamine (325 ml) the mixture was stirred at 0 ° C for 1 hour and then maintained at room temperature. 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 5% sodium hydrogen carbonate, water, citric acid at 2% and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel in heptane / ethyl acetate 7/3 v / v, to give 6 9 g of the product CLF Rf = 064 heptane / ethyl acetate 1/1, v / v N- (t-bu ti loxi carbo nil met i DN-Boc-D / LmF-Phe-OH 69 g of N- (t-but? lox? carbon? lmet? l ) -N-Boc-D / LmF-Phe-Pro-OMe, dissolved in dioxane / water 9/1 v / v (60 ml), treated with 1N sodium hydroxide solution (138 ml) in portions for 16 hours maintaining the pH at 10 - 10.5. The reaction mixture was diluted with ice water and acidified with a 2N hydrogen chloride solution to pH 2. The aqueous layer was extracted with dichloromethane. AfterThe organic phase was washed with cold water, dried over sodium sulfate and concentrated to give 14. 7 g of crude material. Purification on silica gel in ethyl acetate / methanol 9/1 v / v gave 522 g. CLF: Rf = 0.20, silica gel, ethyl acetate / methanol 8/2 v / v. N- (t-butyloxycarbonylmethyl) -N-Boc-D / LmF-Phe-Pro-Lvs (Cbz) - (2-thiazolyl) Coupling of N- (t-butyloxycarbonylmethyl) -N-Boc-D / LmF-Phe-OH (601.3 mg) with H-Lys (Cbz) - (2-thiazolyl) was carried out under the same conditions as described in Example 24. Yield: 684.3 mg. CLF: Rf = 0.74, silica gel, dichloromethane / methanol 95/5 HOOC-CH7-D / LmF-Phe-Pro-Lvs- (2-thiazolyl) N- (t-butyloxycarbonylmethyl) -N-Boc -D / LmF-Phe-Pro-Lys (Cbz) - (2-thiazolyl) (673.5 mg) was treated under the same conditions with trifluoroacetic acid and thioanisole as described in Example 1 to give 259 mg of pure product after purification with HPLC Example 27 H OOC-C H 7-Dp-CF 3 -Phe-Pro-Lvs- (2-thiolol) N- (t-Butylox? carbon? lmeth? l) -N-Boc-D / Lp-CF3-Phe-OH According to analogous procedures as described in Example 24, HD / Lp-CF3-Phe-OH. HCl (10 12 g) was converted to N- (t-butyloxycarbon? Lmet? L) -N-Boc-D / L-m-F-Phe-OH Yield 1323 g CLF: Rf = 0.64, silica gel, ethyl acetate / methanol 9/1, v / v N- (t-butyloxycarbonylmethyl) -N-Boc-Dp-CF -, - Phe-Pro-Lvs ( Cbz) - (2-thiazole) An amount of 610 N- (t-butyloxycarbonylmethyl) -N-Boc-Dp-CF3-Phe-OH was coupled with H-Pro-OBzl HCl according to the same procedure as it was described in Example 24. After working, the diastereomers could be separated by silica gel, using heptane / ethyl acetate 75/25 v / v, to give 0.63 g of N- (t-but-lox? carbonylmethyl) ) -N-Boc-Dp-CF3-Phe-Pro-OBzl pure CLF. Rf = 035, silica gel, heptane / ethyl acetate 7/3 v / v N- (t-butyloxycarbonylmethyl) -N-Boc-Dp-CF3-Phe-Pro-Lvs (Cbz) - (2-thiazolyl) ) N- (t-butyloxycarbonylmethyl) -N-Boc-Dp-CF3-Phe-Pro-OBzl (630 mg) was reduced and subsequently coupled to H-Lys (Cbz) - (2-thiazolyl) using the procedures as described in example 24 Yield 317 7 mg CLF Rf = 046, dichloromethane / methanol 95/5 v / v HOOC-CH7-Dp-CH3-Phe-Pro-Lys- (2-t? azol? l) The removal of the protected groups of N- (t-but? Lox? Carbon? Lmet? L) -N-Boc-Dp-CF3-Phe-Pro-Lys (Cbz) - (2-t? Azol? Lo) ( 3065 mg) was carried out using the same method as described in Example 24 After purification by HPLC, 157 mg of the product Rt (CL) = 36.7 min, 20% A, 80% B to 20% A, 20 were isolated. % B and 60% C in 40 minutes. Example 28 HOOC-CH7-Dp-CH Phe-Pro-Lvs- (2-thiazolyl) N- (t-butyloxycarbonyl) -N-Boc-DpC I -Phe-OH According to the analogous procedures described in example 24, HDp-CI-Phe-OH. HCl (10 g) was converted to N- (t-butyloxycarbonylmethyl) -N-Boc-D-p-CI-OH. yield: 16.7 g. CLF Rf = 027, silica gel, ethyl acetate / methanol 9/1, v / v N- (t-butyloxycarbonylmethyl) -N-Boc-Dp-CI-Phe-Pro-ONSu To a solution of N- (t -but? loxycarbonylmethyl) -N-Boc-Dp-CI-Phe-OH (1467 g) in 250 ml of acenotinitrile was treated with N-hydroxysuccinimide (4 11 g) and 1- (3-d? met? lam hydrochloride ? noprop?) -3-ethylcarbodimide (EDCI) (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 11 g of active ester, which was used directly in the next step N- (t-but? Lox? Carbon? Lmet? L) - N-Boc-Dp-CI-Phe-Pro-OH H-Pro-OH HCl (1079 g) was dissolved in 100 ml of N, Nd? Met? L formamide and 100 ml of water The pH of the reaction mixture was adjusted to 8 with 1N sodium hydroxide solution, whereby N- (t-but? lox? carbon? lmet? l) -N-Boc-Dp-CI-Phe-Pro-ONSu (19 11), dissolved 3n 120 ml of N, Nd? met formamide, was added dropwise. The reaction was stirred overnight at room temperature at pH. The reaction mixture was cooled and adjusted to pH 2 with 1N hydrochloric acid. The aqueous layer was extracted with dichloromethane The organic phase was washed with water, dried over sodium sulfate and evaporated in vacuo Purification of the silica gel, using a gradient of ethyl acetate / 1 CLF Rf = 024, silica gel, acetate ethyl / methanol 8/2 v / v N- (t-but? lox? carbonylmet? nN-Boc-Dp-CI-Phe-Pro-Lvs (Cbz) - (2-thiazolyl) According to the procedures described in Example 24, the N- (t-but? lox? carbon? lmeth? ) -N-Boc-Dp-CI-Phe-OH (3694 mg) in the white compound. Yield 249 1 mg CLF Rf = 025, silica gel, dichloromethane / methanol 97/3 v / v / HOOC-CH7-Dp-CI-Phe-Pro-Lvs- (2-t? Aolol) As described in Example 1, 231 5 mg of N- (t-but? lox? carbon? lmet? l) -N-Boc-Dp-CI-Phe-Pro-Lys- (2-t? aolol) was deprotected and was purified to obtain 1098 mg of the product Rt = 338 mm, 20% A, 80% B at 20% A, 20% B and 60% C in 40 minutes Example 29 HOOC-CH7-Dp-CI-Phe-Pro-Lys - (2-tαolol) HOOC-CH 2 -Dp-CI-Phe-Pro-Lys- (2-tαolol) was prepared in a similar manner as described in Example 26, starting with H - D / Lo-CI-Phe-OH HCl The two diastereoisomers were separated in the protected tppeptide stage. The deprotection of 230 mg of N- (t-but? Lox? Carbon? Lmet? L) -N-Boc-Dp- CI-Phe-Pro-Lys (Cbz) - (2-tαolol) according to the method described in example 1, gave 116 mg of the product after purification R, = (CL) = 300 min, % A, 80% to 20% B and 60% C in 40 mm Example 30 HOOC-CH? -D / Lm.p-di-CI-Phe-Pro-Lvs (2-thiazole) This compound was prepared in a similar manner to that described in Example 26, starting from HD / Lm , pd? -CI-Phe-OH HCl Removal of the blocking groups of the protected tpeptide (720 g) followed by purification by HPLC. As described in example 1, gave 1700 mg of the product R, (CL) = 307 min. and 31 1 min, 20% A, 80% B to 20% A, 20% BY 60% in 40 min Example 31 HOOC-CH7-D / Lo, pd? -CI-Phe-Pro-Lvs (2-t? Aolol) This compound was prepared in a similar manner as described in example 26, starting from HD / Lo, pd? -CI-Phe-OH HCl The removal of the blocking groups of the protected tpeptide (1 07 g) followed by purification by HPLC As described in the example 1, gave 100 mg of the product Rt (CL) = 34 4 min and 36 1 min, 20% A, 80% B to 20% A, 20% B Y 60% in 40 min Example 32 HOOC-CH7-D-Tyr-Pro-Lvs- (2-t? Azole) Cbz-D-Tyr (tBu) -OH N-Benzyloxycarbonyloxysuccinimide (475 g) was added to a suspension of D-Tyr (tBu) -OH (50 g) in N, Nd? met? l formamide (40 ml) The pH of the solution was adjusted to 8 using tetylamine The reaction mixture was stirred overnight at room temperature and then evaporated to dryness under vacuum. The residue was dissolved in dichloromethane and diluted with ice water. The pH of the water layer was adjusted to pH 2 with 2N hydrogen chloride. The organic layer was separated and the aqueous phase was extracted with dichloromethane The aqueous layers were combined and washed with water, dried over sodium sulfate and concentrated. Yield 995 g CLF Rf = 031, heptane / ethyl acetate 1/1 Cbz-D-Tyr (tBu) -OMe Tetraflorboborate was added from [2- (1 H-benzotr [azol-1-yl] -1,1,3-tetramethyluronium] (745 g) to a solution of Cbz-D-Tyr (tBu) -OH (995 g) in dichloromethane (45) and methanol (5 ml) The pH of the mixture is adjusted or to 8 with N, Nd? soprop? let? lam? na The reaction mixture was stirred for 1 hour at room temperature and then cooled with 5% sodium hydrogen carbonate. The organic phase was separated and washed with water, 2% citric acid and brine, dried over sodium sulfate and concentrated under reduced pressure Yield 102 g CLF Rf = 074, heptane / ethyl acetate 1/1 HD-Tyr (tBu) -OMe HCl Palladium on carbon was added 10% vegetable (1.2 g) to a solution of Cbz-D-Tyr (tBu) -OMe (102 g) in methanol (100 ml) and 4N hydrogen chloride (5 ml) The mixture is hydrogenated at atmospheric pressure at room temperature for 2 hours The palladium catalyst was removed by filtration. The filtrate was concentrated to a small volume followed by crystallization of diethyl ether. Yield: 10.2 g. CLF: Rf = 0.74, heptane / ethyl acetate 1/1 HOOC-CH? -D-Tyr-Pro-Lvs- (2-thiazolyl) This compound was prepared in a manner similar to that described in Example 24, starting from HD-Tyr (tBu) -OMe.HCI. Deprotection of 586 mg of N- (t-butyloxycarbonylmethyl) -N-Boc-D-Tyr (tBu) -Pro-Lys (Cbz) - (2-thiazolyl), according to the procedures described in example 2, gave 283 mg of the product, after purification by CLAR Rt (CL) = 20.9rr.in, 20% A, 80% B to 20% A, 20% B and 60 C in 40 min. EXAMPLE 33 HOOC-CH7-D / Lp-CH3-Phe-Pro-Lvs- (2-thiazole) HD / Lp-CH3-Phe-OH HCl A suspension of sodium hydride (328 g 60% dispersion in oil mineral) in ethanol (40 ml) was added to a solution of a-chloro-p-xylene (10 g), diethyl acetamidomalonate (193 g) and sodium iodide (8 55 g) in dioxane (80 ml) and ethanol (20 ml) The reaction mixture was heated to reflux at 80 ° C for 90 minutes The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate The organic phase was washed with 5% sodium hydrogen sulfate, sulfite 5% sodium acid, water, 5% sodium hydrogen carbonate and brine was dried over sodium sulfate and concentrated in vacuo. The product was crystallized with heptane to give 198 g of the condensation product This was treated with hydrogen chloride 6N (420ml) and acetic acid (210ml) overnight at 95 ° C to give, after evaporation to dryness, 21 6 g of the product CLF Rf 0 15, silica gel, ethyl acetate / pipdine / acetic acid / water 664/31/18/7 v / v / v / v HOOC-CH7-D / Lp-CH3-Phe-Pro-Lvs- (2-t? azollo) According to the methods described in Example 24, HOOC-CH2-D / Lp-CH3-Phe-Pro-Lys- (2-t-azole) was prepared starting from HD / Lp-CH3- Phe-OH HCl Removal of the blocking groups of the protected tpeptide (582 mg) and the purification with HPLC was carried out under conditions similar to those described in example 1 Yield 120 mg Rt (CL) = 31 9 min, % A, 80% B to 20% A, 20% B and 60% in 40 min Example 34 HOOC-CH7-Dm-CI-Phe-Pro-Lvs- (2-t? Azole) Starting from bromide of 3 -chlorobenzene, HD / Lm-CI-Phe-OH CHI was prepared as described in Example 33, then the fully protected tppeptide resembled that of the same procedures as described in Example 26 In final step 1 g of N- (t-but? Lox? Carbon? Lmet? L) -N-Boc-D / Lm-CI-Phe-Pro-Lys (Cbz) - (2-thiazolyl) was treated with tpfluoroacetic acid and thioanisole (see example) 1) After the p urification with HPLC were isolated 195 mg of HOOC-CH2-Dm-CI-Phe-Pro-Lys- (2-t? asol? lo) RT (CL) = 31 7 min, 20% A, 80% B to 20% B and 60% C in 40 mm Example 35 HOOC-CH7-D-DPA-Pro-Lvs- (2-t? Azol? Lo (DPA = d? Phen? Lalan? Na) This compound was prepared in a similar manner to that described in Example 24, starting with HD-DPA-OH HCl Deprotection of 570mg N- (t-but? lox? carbon? lamet? l) -N-Boc-D-DPA-Pro-Lys (Cbz) - (2-tiazohl, according to the methods described in example 1, after purification by HPLC gave 194 mg of the final product Rt (CL) = 356 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 min. EXAMPLE 36 HOOC-CH7-Dm-OH-Phe-Pro-Lvs- (2-t-azole) This compound was prepared in a similar manner to that described in Example 24, starting from of HD-DPA-OH HCl The phenolic hydroxyl function was also protected with a Boc group during the introduction of the Boc group on the N-terminus The deprotection (see example 1) of 1 21 g N- (t-but? lox? carbon ? lamet? l) -N-Boc-D-DPA-Pro-Lys (Cbz) - (2- toluene) after purification by CLAR gave the desired diastereoisomer Yield 99 mg Rt (CL) = 23 8 mm, 20% A, 80% B to 20% A, 20% B and 60% C in 40 min Example 37 HOOC-CH7-Dm-OH-Phe-Pro-Lvs- (2-t? Azole) Boc-D / Lm-OH-Phe-OH HD / Lm-OH-Phe-OH.HCl ( 525 g) was dissolved in dioxane (55 ml), water (28 ml) and a 1 N sodium hydroxide solution (29.0). Di-t-butyl dicarbonate (6.95 g) was added and the reaction mixture was stirred overnight at room temperature to pH 9. The reaction mixture was diluted with water (200 ml) and extracted with heptane. The aqueous layer was diluted with ethyl acetate (150 ml) and acidified to pH 2 with 1N hydrogen chloride. The organic phase was separated and the water layer was extracted with ethyl acetate. The organic layers were combined and washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Yield: 8.49 g. CLF: Rt = 0.67, silica gel, ethyl acetate / pyridine / acetic acid / water 126/20/6/11 v / v / v / v. Boc-D / Lm-OCH3-Phe-OMe A mixture of Boc-D / Lm-OH-Phe-OH (8.49 g), sodium carbonate (239 g), and iodomethane (20.3 ml) in N, N-dimethyl formamide (60 ml) was stirred at 60 ° C for 48 hours. The reaction mixture was then poured into ice water and acidified to pH 2.5 with 2N hydrogen chloride, followed by extraction with ethyl acetate. The organic layers were combined and washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica gel chromatography using heptane / ethyl acetate 7/3 v / v Yield 666 g CLF Rt = 0 32, silica gel, ethyl acetate / pipdin / acetic acid / water 126/20 / 6/11 v / v / v / v HD / Lm-QCH3-Phe-OMe TFA Boc-D / Lm-OCH3-Phe-OMe (666 g) was dissolved in dichloromethane (20 ml) and tpfluoroacetic acid (20 ml) and it was stirred at room temperature for 2 hours the solvent was removed under reduced pressure and the crude product was coevaporated twice with toluene. Yield 956 g CLF Rt = 032, silica gel, ethyl acetate / pipdma / acetic acid / water 126/20 / 6/11 v / v / v / v HOOC-CH? -Dm-OH-Phe-Pro-Lvs- (2-t? Azole) HD / Lm-OCH3-Phe-OMe TFA was used to collect N - (t-but? lox? carbon? lmet? l) -N-Boc-D / Lm-OCH3-Phe-Pro-Lys (Cbz) - (2-thiazolyl) according to the same route as described in Example 24, the treatment of 624 mg of the protected tppeptide with tpfluoroacetic acid and thioanisole (see example 1), followed by purification by HPLC 114 mg of product Rt (CL) = 293 mm and 298 min, 205 A, 80% B to 20% A, 20% B and 60% C in 40 minutes Example 38 HOOC-CH7-D / Lp-Br-Phe-Pro-Lvs- (2-t-azole) Boc-D / Lp-Br-Phe-OH A suspension of HD / Lp -Br-Phe-OH (2 44g) in 25 ml of t-butanol / water 1/1 v / v was adjusted to pH 9 with sufficient solution of dilute sodium hydroxide (1 N) Di-t-dicarbonate was added Butyl (327 g) and the reaction mixture was stirred overnight while the pH was maintained at 9 The reaction mixture was diluted with water followed by extraction with heptane The water layer was diluted with ethyl acetate and subsequently acidified at pH 2.5 using 2N hydrogen chloride. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic layers were combined and washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Yield: 3.35 g. CLF: Rt = 032, silica gel, ethyl acetate / pipdine / acetic acid / water 126/20/6/11 v / v / v / v. Boc-D / L-p-Br-Phe-Pro-OH Boc-D / L-p-Br-Phe-Pro-OH (3.35 g) was coupled with H-Pro-OMe. HCl and subsequently saponified with sodium hydroxide according to the same methods as described in the example 26 Performance. 3 13 g. CLF: Rf = 045, silica gel, ethyl acetate / methanol 9/1. Boc-D / Lp-Br-Phe-Pro-Lvs (Cbz) - (2-thiazolyl) Coupling of Boc-D / Lp-Br-Phe-Pro-OH (750m) with H-Lys (Cbz) - 2 (toluene) was carried out under the same conditions as described in example 24 Yield 1 01 g CLF Rf = 085, silica gel, dichloromethane / methanol 9/1 v / v HD / Lp-Br-Phe -Pro-Lvs (Cbz) - (2-t? Azole) .TFA Boc-D / Lp-Br-Phe-Pro-Lys (Cbz) - (2-t? Azohlo) (1 01 g) was dissolved in tpfluoroacetic acid (TFA, 10 ml) and stirred for 1 hour at room temperature The solvent was removed under reduced pressure Yield 879 mg CLF Rf = 075, silica gel, dichloromethane / methanol 63/20/6/11 v / v / v / v N- t-butyloxycarbonylmethyl) -D / L -? - Br-Phe-Pro-Lvs (Cbz) - (2-thiazole ? lo) t-Butyl bromoacetate (264 ml) was added to a solution of HD / Lp-Br-Phe-Pro-Lyz (Cbz) - (2-thiazolyl) .TFA (879 mg) in acetonitrile (25 ml) . The pH of the reaction mixture was adjusted to 8 with N, N-diisopropylethalamine whereby the reaction mixture was allowed to stand overnight at room temperature. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate. The organic phase was washed with water, 5% sodium hydrogen carbonate and brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified over silica gel using dichloromethane / methanol 95/5 v / v to give 850 mg of the protected tppptide CLF Rf = 091, silica gel, ethyl acetate / pyridine / acetic acid / water 63/20/6/11 v / v / v / v HOOC-CH7-D / Lp-Br-Phe-Pro-Lvs- (2-thiazole) N- (t-but? loxycarbon? lmet? l) -D / Lp-Br-Phe-Pro- Lys (Cbz) - (2-thiazolyl) (850 mg) was treated under the same conditions with tpfluoroacetic acid and thioanisole as described in Example 1 to obtain, after purification by HPLC, 123 mg of the product Rt (CL ) = 339 min and 34 4 mm, 20% A, 80% B to 20% A, 20% B and 60% C in 40 min Example 39 HOOC-CH7-D / Lp-Br-Phe-Pro-Lvs- (2-t-azole) This compound was prepared in a similar manner to that described in example 38, starting from of HDpF-Phe-OH The deprotection (see example 1) DE 563 MG N- (t-butyloxycarbonylmethyl) -DpF-Phe-Pro-Lys (Cbz) - (2-thiazolyl) gave, after purification by HPLC, 182 mg of the product Rt (CL) = 29.7, 20% A, 80% B to 20% A, 20% B and 60% C in 40 min. Example 40 HOOC-CH7-D / L-m-p-di-CI-Phe-Pro-Lvs- (2-thiazolyl) This compound was prepared in a manner similar to that described in Example 38, starting from H-D-p-F-Phe-OH. The deprotection (see example 1) of 480 mg N- (t-butyloxycarbonylmethyl) -DpF-Phe-Pro-Lys (Cbz) - (2-thiazolyl) gave, after purification by HPLC, 191 mg of the product Rt (CL) = 36.8 min and 37.8 min, 20% A, 80% B to 20% A, 20% B and 60% C in 40 min Example 41 BzLSO7-norLeu (c? Clo) Glv-Lvsw-COCOl-OH (Bzl = benc Cbz-Lyz (Boc) -OMe Cbz-Lyz (Boc) -OH (29 g) was dissolved in dichloromethane / methanol = 9/1 v / v (500 ml) Tetrafluoroborate 2- (1 H-benzotr? azol-1- (1) 1, 1, 3,3-tetramethyluronium (236 g) were added and the solution was adjusted to pH 8 by addition of tetylamine. The reaction mixture was stirred for 2 hours at room temperature. The mixture was washed successively with 1N hydrogen chloride solution, water, 5% sodium hydrogen carbonate, and water and dried over sodium sulfate. The filtrate was evaporated and the residue was chromatographed on silica gel in ethyl acetate / heptane = 1 / 4 v / v as eluent. Fractions containing Cbz-Lys (Boc) -OMe were combined and evaporated. Yield: 29.1 g. CLF: Rf = 0.85, silica gel, ethyl acetate / heptane = 3/1 v / v. Cbz-Lys (Boc)? Fcianoacetate 1 To a cold solution (-78 ° C) of Cbz-Lys (Boc) -OMe (29.1 g) of dry dichloromethane (800 ml) was added dropwise diisobutyl aluminum hydride (222). ml of 1M solution in hexane) at a rate to maintain the reaction temperature below -70 ° C. The resulting solution was stirred at -78 ° C for 1 h. A solution of 5% citric acid (600 ml) was added to the reaction mixture. The two layer mixture was stirred at room temperature for 10 minutes, the layers were separated and the aqueous layer was extracted with dichloromethane. The combined dichloromethane layers were washed with water and dried over sodium sulfate and filtered. The solution was placed under nitrogen and cooled on an ice water bath. A solution of sodium cyanide (36.3 g) and benzyltriethylammonium chloride (4.2 g) in water (600 ml) was added under vigorous stirring, added in portions acetic anhydride (2 x 9 ml) over a period of 30 minutes The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined layers of dichloromethane were washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography on silica (eluent heptane / ethyl acetate = 1/1 v / v) give Cbz-Lys (Boc) Tfc? anoacetate] (26 3 g) CLF-Rf = 060, silica gel, dichloromethane / ethylacetate = 7/3 v / v Cbz-Lvs (Boc)? rCHOHCO1-OMe A solution of Cbz-Lys (Boc)? [CHOHCO] (26.3 g) in diethyl ether / methanol = 3/1 v / v (600 ml) was cooled to -20 ° C under nitrogen and 66 g of gaseous hydrochloric acid was added. introduced by keeping the temperature below -5 ° C. The reaction mixture was kept at 4 ° C overnight. Water was added dropwise (100 ml) to the reaction mixture keeping the temperature below 5CC after stirring for 16 minutes. at room temperature, the organic layer was separated and washed with water The aqueous layer was saturated with sodium chloride and extracted with sec-butane / d? chloromethane = 2/2 v / v The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo to give 254 g of the crude amine. The residue was absorbed in N, Nd? met? lformamide (400 ml) and b? s anhydride. (tert-butyl) (16 g) were added and tetylamine until pH 8 The reaction mixture was stirred at room temperature overnight The solvent was removed by evaporation under reduced pressure The residue was dissolved in ethyl acetate, washed with water and brine successively, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by chromatography on silica (eluent ethyl acetate / heptane = 4/6 v / v) to give Cbz-Lys (Boc)? [CHOHCO] -Me (15 8 g) CLF Rf = 0 75, silica gel, ethyl acetate / pipdma / acetic acid / water = 63/20/6/11 v / v / v / v H-Lvs (Boc)? rCHOHCO.-OMe Palladium on 10% charcoal (92 mg) and 2.18 ml of a 1N hydrochloride solution were added to a solution of Cbz-Lys (Boc)? [CHOHCO] ] -OMe (0.92 g) in N, N-dimethylformamide (20 ml). The mixture was hydrogenated at atmospheric pressure at room temperature for 3 h. The palladium catalyst was removed by filtration and the solvent was removed by evaporation under reduced pressure to give H-Lys (Boc)? [CHOHCO] -OMe.HCI quantitatively.

CLF: Rf: 0.47, silica gel, ethyl acetate / pyridine / acetic acid / water = 88/31/18/7 v / v / v / v BzlSO7-norLeu (c? Clo) Glv-Lvs (BocmCHOHCO1-OMe (S) -3-Benzylsulfonylamido-2-oxo-1-azepinacetic acid was prepared according to the procedure in Example 18. To a cold (0 ° C) solution of (S) -3-benzylsulfonylamido-2-oxo acid -1-azepinacetic (BzlS02-norLeu (cyclo) Gly) (400 mg) in N, N-dimethylformamide (20 ml) was successively added 1-hydroxybenzotriazole (238 mg), dicyclohexylcarbodiimide (267 mg), H-Lys (Boc) [CHOHCO] -OMe.HCl (3.85 mg) and treietilamma (0.32 ml) The mixture was stirred at 0 ° C for 1 hour and then kept at room temperature overnight The mixture was cooled to -0 ° C and dicylohexylurea was removed by filtration The filtrate was evaporated to dryness The residue was dissolved in ethyl acetate and washed successively with 5% sodium hydrogen carbonate, water, 2% citric acid, saturated aqueous sodium chloride, dried over sodium sulfate, sodium and concentrates The residue is chromatographed on silica gel in dichloromethanemethanol = 9/1 (V / v) as eluent. Fractions containing BzlSO2-norLeu (cyclo) Gly-Lys (Boc)? [CHOHCO] .OME were combined and evaporated. Yield: 663 mg. CLF: Rf = 0.91, silica gel, ethyl acetate / pyridine / acetic acid / water = 63/20/6/11 v / v / v / v. BzlSO7-norLeu (cycle) Glv-Lvs (Boc)? RCHOHCO1-OH BzlSO2-norLeu (cycle) Gly-Lys (Boc)? [CHOHCO] -OMe (650 mg) was dissolved in dioxane / water = 7/3 v / v (20 ml) and treated with 2M sodium hydroxide solution (1.05 ml) in portions for 1 h at room temperature, maintaining the pH at 12-13.The reaction mixture was diluted with water (20 ml), chloride was added of 2M hydrogen to pH 2.0 and the water 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 give BzlS02-norLeu (cyclo) Gly -Lys (Boc)? [CHOHCO] -OH (740 mg) CLF: Rf = 0.44, silica gel, ethyl acetate / pyridine / acetic acid / water = 63/20/6/11 v / v / v / v BzlS07-norLeu (c? Clo) Glv-Lvs (BocmCOCOT-OH To a solution of BnS02-norLeu (c? Clo) Gly-Lys (Boc)? [CHOHCO] -OH (740 mg) in dry dichloromethane (20 ml) 450 mg of pepodinan (Dess-Martin reagent) was added after 1 hr of stirring at room temperature, a solution of 2% sodium thiosulfate (20 ml) was added and the mixture was stirred for 30 minutes at room temperature. The organic layer was separated, washed with water, dried over sodium sulfate, filtered and evaporated in vacuo to give crude BzlSO2-norLeu (cyclo) Gly-Lys (Boc)? [COCO] -OH (497 mg) . CLF: Rf = 0.45, silica gel, ethyl acetate / pyridine / acetic acid / water = 63/20/6/11 v / v / v / v. BzlSO? -norLeu (cycle) Glv-Lvs? RCOCO1-OH BzlSO2-norLeu (cycle) Gly-Lys (Boc)? [COCO] -OH (/ 497 mg, crude) was treated with trifluoroacetic acid / water 90% ( 10 ml) for 1 h at room temperature. The reaction mixture was concentrated in vacuo and the residue was dissolved in water and loaded directly into a preparative DeltaPak RP-C? 8 HPLC using a gradient elution system of 20% A / 80% B to 20% A / 45 % B / 35% C for 45 minutes at a flow rate of 80 ml / min. Yield: 200 mg of BzlS02-norLeu (cycle) Gly-Lys? [COCO] -OH. R »(CL) 26 37 min, 20% A / 80% B at 20% A / 20% B / 60% C in 40 mm Example 42 H- (NCH 3) -D-norLeu-Pro-Lvs? FCOCQl-OH Boc- (N-CH3) -NorLeu-Pro-OH This compound was prepared according to Example 11 In a manner similar to that described in Example 1, H- (N-CH3) -D-NorLeu-Pro- was prepared. Lys? [COCO] -OH Yield 69 mg Rt () CL) 1327 min, 20% A / 80% B at 20% A / 10% B / 60% C in 40 min Example 43 HD-Phe-Pro-Lvs? rCOCO1-OH Boc-D-Phe-Pro-OMe To a cold solution (0 ° C) of Boc-D-Phe-OH (5 g) in N, N-dimethylformamide (200 ml) was successively added 1-hydroxybenzotpazole (429 g), dicyclohexyl carbodnide (429 g), H-Pro-OMe HCl (3 1 g) and N-ethylmorphohene (3 ml) The mixture was stirred at 0 ° C for 1 hour and then maintained at room temperature during 2 days 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 5% sodium hydrogen carbonate., 0 1M hydrogen chloride solution, saturated with aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel in heptane / ethyl acetate = 6/4 (v. / v) as eluent Fractions containing Boc-D-Phe-Pro-OMe were combined and evaporated. Yield 5 g CLF Rf = 090, silica gel, ethyl acetate / pipdin / acetic acid / water = 163 / 20/6/11 / v / v / v / v Boc-D-Phe-Pro-OH Boc-D-Phe-Pro-OMe (8 3 g) was dissolved in d? Oxane / water = 6/4 v / v (150 ml) and treated with 2M sodium hydroxide solution (16 5 ml) in portions for 1 h at room temperature maintaining the pH at 12.5. A 2M hydrogen chloride solution was added to the reaction mixture until pH 3.0 and the water layer was extracted with ethyl acetate. The combined organic phases were washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give Boc-D-Phe-Pro-OH (6.9 g). CLF: Rf = 0.30, silica gel, ethyl acetate / pyridine / acetic acid / water = 213/20/6/11 v / v / v / v. In a manner similar to that described in example 1, it was prepared: H-D-Phe-Pro-Lys? [COCO] -OH. Yield: 417mg. R, (CL): 16.22 min; 20% A / 80% B to 20% A / 20% B / 60% C in 40 min. Example 44 H- (N-CH 3) D Phe- (N-cyclopentyl) -Glv-Lvs?, COCOf-OH Boc- (N-CH 3) -D-Phe- (N-cyclopentyl) -Glv-OH This compound was prepared as described in Example 3 using Boc- (N-CH3) -D-Phe-OH and HCl.H- (Nc? clopentyl) -Gly-OMe This compound was prepared as described in Example 3 using Boc- (N-CH3) -D-Phe-OH and HCl.H- (N-cyclopentyl) -Gly-OMe CLF Rf = 0 52, silica gel, d? Chloromethane / methanol = 9/1 v / v In In a manner similar to that described in Example 1, H- (N-CH3) -D-Phe- (Nc? clopentyl) -Gly-Lys? [COCO] -OH Yield 87 mg R, (CL) was prepared : 23.92 min, 20% A / 80% B at 20% A / 20% B / 60% C at 40 mm. Example 45 Ethylsulfonyl-D-Phe-Pro-Lvs? FCOCOl-OH Ethylsulfonyl-D-Phe-Pro-OH This compound was prepared according to Example 22 In a manner similar to that described in Example 41, it was prepared: Ethylsulfonyl -D-Phe-por-Lys? [COCO] -OH. Yield: 90 mg. R t (CL) 28.04 min; 20% A / 80% B to 20% A / 20% B / 60% C in 40 min. Example 46. (4aR, 8aR) -perhidroisoqu? Nolina-1 (R) -carbon? L-Pro-Lys? rCOCOl-OH 2-Cbz- (4aR, 8aR) -perh? dro? soqu? nol? na-1 (R) -carbon? l-Pro-OH This compound was prepared according to example 20 in a manner similar to the one described in Example 41 was prepared (4aR, 8aR) -perh? dro? soqu? nol? na-1 (R) -carbon? l-Pro-Lys? [COCO] -OH Yield 170 mg Rt (CL) 1895 min, 20% A / 80% B at 20% A / 20% B / 60% C in 40 min Example 47 HOOC-CH7-D-Coa-Pro-Lys- (2-t? azol? l) (Coa = cyclo-octylalanine) Cyclo-octylmethyl bromide Cyclooctylmethanol (8.16 g) was dissolved in 47% HBr solution (70 ml) and refluxed for 1 hour at 30 ° C. The reaction mixture was poured into ice water (500 ml) and saturated sodium acid carbonate solution was added. The aqueous solution was extracted with dichloromethane. The combined organic phases were washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo. The residue is chromatographed on silica gel in toluene as eluent. The fractions containing cyclo-octylmethyl bromide were combined and evaporated. Yield: 9.85 g. CLF: Rf = 0.95, silica gel, toluene. (R) S-ethyl-2-acetylamino-2-cyano-3-cyclo-octyl propionate Potassium terbutylate (6.85 g) and acetamido cyanoacetate (8.1 g) were dissolved in dimethyl sulfoxide (100 ml) at room temperature. Cyclo-octylmethyl bromide was dissolved in dimethyl sulfoxide (25 ml) and added dropwise to the reaction mixture. The mixture was stirred at room temperature for 44 hours. After pouring into 500 ml of water, the precipitate was filtered and dried to dryness (R, S) -et? L-2-acet? Lamino-2-cyano-3-c? Clo-octyl (2 95). g) CLF- Rf = 0 50, silica gel, heptane / ethyl acetate = 3/7 v / v DH-DL-Cyclo-octylalanine-OH HCl Propionate of (R, S) -et? l was suspended -2-acet? Lam? No-2-c? Ano-3-cyclo-octyl (2.95 g) in 100 ml of a 20% strength hydrogen chloride solution and heated to reflux for 22 hours The reaction mixture it was cooled to 5 ° C and the precipitate formed was filtered, washed with diethyl ether and dried. Yield 269 g HD, Lc? clo-oct? lalan? na-OH HCl (HD, L-Coa-OH.HCl) CLF Rf = 027, silica gel, ethyl acetate / pipdma / acetic acid / water = 63/20/6/11 v / v / v / v In a manner similar to that described in example 24, HOOC was prepared -CH2-D-Coa-Pro-Lys- (2-t? Azole) Yield 162 mg Rt (CL) 3835 mm, 20% A / 80% B to 20% A / 20% B / 60% C in 40 min In a manner similar to that described in Example 24, Example 48 HOOC-CH2-D-2-Nal-Pro was prepared -Lys- (2-t? Azole) (Nal = naft? Lalan? Na) Yield 423 mg Rt (CL) 38 35 min, 20% A / 80% B at 20% A / 20% B / 60% C in 40 min Example 49 HOOC-CH2-D-norLeu-Pro-Lys- (2-t? Azole) Yield 344 mg Rt (CL) 24 84 mm, 20% A / 80% B to 20% A / 20% B / 60% C in 40 min Example 50 HOOC-CH2-D-Leu-Pro-Lys- (2-t? Azole) Yield 138 mg Rt (CL): 24.50 min; 20% A / 80% B to 20% A / 20% B / 60% C in 40 min. Example 51 Analysis of anti-thrombin Thrombin (Factor lia) is a factor in the coagulation cascade. The antithrombin activity of compounds of the present invention was evaluated by spectrophotometrically measuring the hydrolysis regime of chromogenic substrate s-2238 exerted by thrombin. This analysis for antithrombin activity in a pH regulator system was used to evaluate the Clso value of the test compound.

Test Medium: pH-regulating solution of tromethamine-NaCl-polyethylene glycol 6000 (TPN). Reference Compound 12581 (Kabi) Vehicle: TNP pH regulatory solution. The solubilization may be assisted with dimethyl sulfoxide, methanol, ethanol, acetonitrile or tert-butyl alcohol which have no adverse effects in concentrations up to 2.5% in the final reaction mixture. Reagents of Technique *: 1. pH-regulating solution of tromethamine-NaCl (TN). Composition of the buffer solution: Trometamine (Tris) 6.057 g (50 mmol), NaCl 5.844 g (100 mmol), water at 1 It. The pH of the solution was adjusted to 74 at 37 ° C with HCl (10 mmol) "') .2 TNP pH regulator solution Polyethylene 6000 glycol was dissolved from TN buffer to give a concentration of 3 g-1"' 3. S-2238 solution An S-2238 vial was dissolved (25 mg, Kabi Diagnostica, Sweden) in 20 ml of TF pH buffer to give a concentration of 1.25 mg ml'1 (2 mmoles-1"1) 4. Thrombin solution Human thromboma (16,000 nKatvial) 1, Centraal Laboratopum voor Bloedtransfusie, Amsterdam, The Netherlands) was dissolved in pH regulator solution of TNP to give a k solution of 835 nKat ml'1. Immediately before using this solution it was diluted with TNP buffer to give a concentration of 3.34 nKatml'1. - * All ingredients used are analytical grade - Ultra pure water was used for aqueous solutions (Mill-Q quality) Test preparation and reference compound solutions The test and reference compounds were dissolved in Milli-Q water to give mother concentrations of 10"2 mol 1" 'Each concentration was diluted in steps with the vehicle to give concentrations 10'3, 10'4 and 10"5 moM'1 The dilutions, including the k solution, are used in the analysis (final concentrations in the reaction mixture 310_3, 10"3, 310" 4, 10"4, 310" 5, 10"5, 310" 6, and 10'6 respectively) Procedure At room temperature, the solutions or vehicles of 0075 ml and 0025 ml of test compound or reference compound were pipetted alternately into the wells of a microtitre plate and these solutions were diluted with 0 115 ml and 0 0165 ml of pH regulator solution of TNP, respectively An aliquot of 0.030 ml of solution S-2238 was added to cad to well and plate was preheated and preincubated with shaking in an incubator (Amersham) for 10 minutes at 37 ° C. After preincubation, the hydrolysis of S-2238 was initiated by the addition of 0.030 ml of thrombin solution to each well. The plate was incubated (with shaking for 30 seconds) at 37 ° C. Starting after 1 minute of incubation, the absorbance of each sample at 405 nm was measured every 2 minutes for a period of 90 minutes using a kinetic microtiter plate reader (Twinreader plus, Flow Laboratories). All data was collected on an IBM personal computer using LOTUS-MEASURE. For each compound the concentration (expressed in reaction mixture mol-1"1) and for the blank the absorbance, plotted against the reaction time in minutes. Evaluation of responses: For each final concentration, the maximum absorbance of the The Cl50 value (final concentration, expressed in μmol 1"1, was calculated, causing a 50% inhibition of the maximum absorbance of the blank) using the logical transformation analysis according to Hafner et al. (Arzneim. -Forsh / Drug Res 1977, 27 (11) 1871-3) In the following table, the Cl50 values of the compounds of the invention are listed.

Claims

CLAIMS 1. A thrombin inhibitor of the formula: ABC-Lys-D wherein A is H, 2-hydroxy-3-cyclohexyl-propionyl-, Ri, Ri-O-CO-, RrCO- R SO2-, - ( CHR2) nCOOR3 or a protective N group, wherein Ri is selected from C1-6 alkylene-COOH, C1-12 alkyl, C2-12 alkenyl, C6-14 aryl, C7-15 aralkyl and C8 aralkenyl -16 the aryl group of which can be substituted with C 1-6 alkyl, C 1-12 alkoxy, hydroxy or halogen; R2 is H or has the same meaning as R1; R3 is selected from H, C1-12 alkyl, C2-12 alkenyl, C6-14 aryl, C7-15 aralkyl and C8-16 aralkenyl, the aryl group of which can be substituted with C1-6 alkyl , C2-12 alkoxy, hydroxy, or halogen; n is an integer from 1 to 3; B is a L-Asp ligature or an ester derivative thereof, Leu, norLeu, -N (benzyl) -CH2-CO-, -N (2-indane) -CH2-CO-, D-1-Piq, D-3-Piq, D-TÍ1, Atc or a D-amino acid having aromatic hydrophobic side chain; C is Azt, Pro, Pee, norLeu (cyclo) Gly, an amino acid of one of the formulas -N [C 3-8 cycloalkyl] -CH 2 -CO- or N (benzyl) -CH 2 -CO-; D is selected from COOH, tetrazole, oxazole, tlazole and benzothiazole; or A and C have the above meanings, B is C3-8 D-cycloalkylanine and D is tetrazole and oxazole, thiazole or benzothiazole; or a prodrug thereof; or a pharmaceutically acceptable salt thereof, with the exception of the compound Me-D-Phe-Pro-Lys-COOH.
2. The thrombin inhibitor of claim 1, wherein D is COOH: 3.
The thrombin inhibitor of claim 2, wherein A is H, C1-12 alkyl, -C7-15 -CO-aralkyl, SO2-C1-12 alkyl, -SO2-C6-14 aryl, or -SO2-aralkyl of C7-15; B is a ligature L-Asp, norLeu, D-1-Píq, or D-Phe, and C is Pro, norLeu (cycle) Gly, or -N- (c? Clopentyl) -CH2-CO-.
The thrombin inhibitor according to claim 3, wherein A is -SO2-benzyl, B is a ligation, and C is norLeu (c? Clo) Gly, or wherein A is -SO2-et? Lo , B is D-Phe, and C is Pro, or wherein A is hydrogen, B is D-1-P? Q, and C is Pro
5 The thrombin inhibitor of claim 1, wherein D is oxazole or tlazole
6 The thrombin inhibitor of claim 5, wherein A is H, C 1-12 alkyl, 2-hydroxy? -3-c? Clohex? L-prop? On? Lo-, -CO- (CH2) nCOOH, -CO-aralkyl of C7-15, - S02-aryl of C6-14 -S02-aralkyl of C7-15, -S02-alkyl of C1-12, - (CHR2) nCOOR3, R2 being H or alkyl of C1-12 and R3 being H, alkyl of C1-12 or benzyl; and C is Pro, norLeu (cyclo) Gly, or -N [C 3-8 cycloalkyl] -CH2-CO-.
7. A process for preparing a thrombin inhibitor of claim 1, the process including coupling suitably protected amino acids or amino acid analogs, followed by removal of the protecting groups.
8. A pharmaceutical composition comprising the thrombin inhibitor of any of claims 1-6, and pharmaceutically acceptable auxiliaries.
9. The thrombin inhibitor of any of claims 1-6 for use in therapy.
10. Use of the thrombin inhibitor of any of claims 1-6, for the manufacture of an antithrombotic medicament.