MXPA99000215A - Derivatives of tia - Google Patents

Abstract

A compound of formula (See Formula) as well as its pharmaceutically usable salts and esters are described, wherein R 1, R 2 and R 3 have the meaning given in claim 1, inhibit the binding of adhesive proteins to the surface of different cell types and therefore influence cell-cell and cell-matrix interactions. They can be used in the form of pharmaceutical preparations for the control or prevention of neoplasms, tumor metatasis, tumor development, osteoporosis, Paget's disease, diabetic retinopathy, macular generation, restenosis after vascular intervention, psoriasis, arthritis, fibrosis, renal insufficiency, as well as infections caused by viruses, bacteria or hong

Description

DERIVATIVES OF TIAZOL Field of Invention The present invention relates to novel thiazole derivatives. The derivatives inhibit the binding of adhesive proteins to the surface of different cell types influencing cell-cell and cell-cell interactions.

Description of the invention.

The invention relates especially to thiazole derivatives of the formula I where R1 is R7HN- R7HN R8HN-: c = C-NH- RsN * REF .: 29169 R < is R is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, carboxyl, chyl-O-CO- or aralkyl-O-CO-; R 4 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl; R5 and R6 are each, independently, hydrogen, alkyl, cycloalkyl or heteroaryl; R 'and Rc are each, independently, hydrogen, alkyl, cycloalkyl or aralkyl or R7 and R8 together with the N atoms to which they are attached form a heterocyclic ring of 5 to 8 members which may be substituted by alkyl; R9 is hydrogen, alkyl or cycloalkyl; R10 is aryl, aralkyl, heterocyclyl, tert-cyclylalkyl, hydroxyl, hydrogen or alkyl, or R10 is carboxyl, carboxyalkyl, alkyl-O-CO-, aralkynyl-O-CO-, alkyl-CO-, aralkyl-CO-, heteroarylalkyl- CO-, alkylsulfonyl, arylsulfonyl or heteroarylsulfonyl and k is zero, or R 10 is an alpha-amino acid linked via the amino group and 1 is zero and k is 1; A is carbonyl or sulfonyl; B is hydrogen, alkenyl or cycloalkyl; a to m are zero or positive integers, being zero to 2, but not being zero when R1 is NH2; where b is zero to 4; being c, d, f, g, k, 1 and m each, independently, zero or 1, whereby c, f and g are not simultaneously zero and so m is not zero when f or g is 1; i is zero or 1, whereby k and 1 are also zero when i is zero; e is zero to 3; h is zero to 5; j is zero to 2; and the sum of e, h and j is 2 to 7; and its pharmaceutically useful salts and esters.

The compounds of formula I and their pharmaceutically usable salts and esters are novel and have valuable pharmacological properties. In particular they inhibit the binding of adhesive proteins such as fibrinogen, vitronectin, von Willenrand factor, f ibronbec t in, thrombospondin and osteopontin to the vitronectin receptors (such as, for example, avb3, avbs, vbß, avbs, etc.) on the surface of various cell types. Accordingly, said compounds influence cell-cell and cell-matrix interactions and can be used in the treatment and prophylaxis of diseases that are caused by a poor function of the binding of adhesive proteins to vitronectin receptors. In particular, vitronectin receptors can be used as prophylaxis or treatment of neoplasms, tumor metastasis, tumor development, osoporosis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis after vascular intervention, psoriasis, arthritis, fibrosis, kidney failure, as well as infections caused by viruses, bacteria or fungi.

Objects of the present invention are the compounds of the formula I and their salts and esters mentioned above per se and their use as therapeutically active substances, a process for the preparation of said compounds, intermediates, pharmaceutical compositions, medicaments containing said compounds, their salts or esters, the use of said compound, solvates and salts for the prophylaxis and / or therapy of diseases, especially in the treatment or prophylaxis of, for example, neoplasms, tumor metastasis, tumor development, osoporosis, Paget's disease, diabetic retinopathy , macular degeneration, restenosis after vascular intervention, psoriasis, arthritis, fibrosis, renal insufficiency, as well as infections caused by viruses, bacteria or fungi, and the use of said compounds and salts for the production of drugs for the treatment or prophylaxis of, for example neoplasms, tumor mestátasis, tumor development, osoporosis is, P disease aget, diabetic retinopathy, restinosis after vascular intervention, psoriasis, arthritis, fibrosis, renal failure, as well as infections caused by viruses, bacteria or fungi.

In the present description the term "alkyl", alone or in combination, means a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms, preferably a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms. to 4 carbon atoms. Examples of straight-chain and branched C?-C8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyls, the isomeric hexyl, the isomeric heptyls and the isomeric octyl, preferably methyl, ethyl, propyl, isopropyl, butyl, ter. Butyl and pentyl.

The term "cycloalkyl", alone or in combination, means a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms. Examples of C3-C8 cycloalkyl are cyclopropyl, methyl-cyclopropyl, cyclopropyl, cyclobutyl, me t -yl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, me t-1-cyclohexyl, dimethyl-cyclohexyl. cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl and particularly cyclopentyl.

The term "alkoxy", alone or in combination, means a group of the formula alkyl-O- wherein the term "alkyl" has the meaning indicated above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxyl, sec.butoxy and t er. butoxy co, preferably methoxy and ethoxy.

The term "alkoxy lo-alkoxy", alone or in combination, means an alkoxy group as previously defined wherein a hydrogen atom has been replaced by an alkoxy group. Examples of alkoxy lo-al coxyl are methoxy-methoxy and methoxy, ethoxy, preferably 2-metoxyl-ethoxy.

The term "aryl" alone or in combination, means a phenyl or naphthyl group carrying, optionally, one or more substituents each independently selected from alkyl, alkoxy, halogen, carboxyl, alkoxycarbonyl, aminocarbonyl, hydroxyl, amino, nitro and the like, such as phenyl, p-tolyl, 4-methoxyphenyl, 4-tert-butynyl phenyl, 4-fluoro-phenyl, 2-chloro-phene, 3-chlorophene, 4-chlorophenyl, 4-hydroxy phenyl, 1-naphthyl and 2- naphthyl. Preferred are phenyl, alkoxypheni, 2-hydroxy-3, 5-di chloro phenyl or chloro phenyls, nitrophenyls and aminophenyls, especially phenyl and ortho-, meta and para-mono-chlorophenyls, particularly para- and me-chlorophenyls, and para- and meta-me toxi-phenyl.

The term "aryloxy", alone or in combination, means a group of the formula aryl-O- where the term "aryl" has the meaning indicated above. Phenyloxy is an example of such an aryloxy group.

The term "aralkyl", alone or in combination, means an alkenyl or cycloalkyl group as previously defined wherein a hydrogen atom has been replaced by an aryl group as previously defined, such as benzyl, 2-phenylethyl and similar, preferably benzyl.

The term "aralkoxy", alone or in combination, means an alkoxy group as previously defined wherein a hydrogen atom has been replaced by an aryl group as previously defined. Benzyloxy is a preferred example of an aralkoxy group.

The term "arylene", alone or in combination, means a phenylene or naphthylene group optionally carrying one or more substituents selected from alkyl, cycloalkyl, alkoxy, halogen, hydroxyl, amino, nitro,, aryloxy, aralkoxy and alkoxy-alkoxy , preferably alkoxy, benzyloxy, chloro or alkoxy-alkoxy. examples are ortho-, meta or even phenolics, toluenes, me t-oxy phenylenes, ter. -but oxyphenylenes, chlorofilenes, chlorofilenes, hydroxyphenylenes, naphthylenes, benzyl-1-oxyphenylene, etc. Preferred are meta- and para-phenylenes, with the phenylene substituents previously given with the definition of R2 in the meta- or para-position and, optionally, one or more substituents chosen from alkyl, cycloalkyl, optionally being present on the arylene ring, alkoxy, halogen, hydroxyl, amino, aryloxy and alkoxy-alkoxy. Particular preference is given to meta- and para-phenol which additionally carry a substituent chosen from alkoxy, benzyloxy, chlorine and alkoxy-alkoxy, particularly methoxy-phenylene, benzyloxymethylene and 2-methoxy-ethoxy-phenylene. Meta- and para-phenylene are very particularly preferred.

The term "heterocyclyl", alone or in combination, means a saturated, partially unsaturated or aromatic 5 to 10 membered heterocycle containing one or more heteroatoms chosen from nitrogen, oxygen and sulfur. If desired, it may be substituted on one or more carbon atoms by halogen, alkyl, alkoxy, oxo, etc., and / or on a secondary nitrogen atom (ie -NH-) by alkyl, cycloalkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiary nitrogen atom (ie = N-) by oxide, with halogen, alkyl, cycloalkyl and alkoxy being preferred. Examples of these heterocyclic groups are pyrrolidinyl, piperdinyl, piperazinyl, morpholinyl, thioforminyl, pyrazolyl, imidazolyl (for example imidazo-4-yl and 1-benzyloxycarbonyl-imidazol-4-yl), pyrazoyl, pyridyl. , pyrazinyl, pyridinyl, hexahydro-pi rimidinii, furyl, thienyl, thiazolyl, oxazolyl, indolyl (for example 2-indolyl), quinolyl (for example 2-quinolyl, 3-quinolyl and l-oxido-2-quinolyl), isoquinolyl (for example 1-isoquinolyl and 3 -i soquinol i), tet rahydroquinolyl (for example 1,2,3,4-tetrahydro-2-quinolyl, 1, * 2, 3, 4-tetrahydroisoquinolyl (for example 1, 2,3,4-t et ahidro-1-oxo-i soquinolyl) and quinoxal inyl, 5- or 6-membered rings, especially piperidino and pyridyl, are preferred.

The term "heteroaryl", alone or in combination, means the aromatic compounds that fall under the definition of "het erocicli lo" and which can carry the substituents described herein. 5- and 6-membered rings, especially pyridyl, are preferred.

The term "amino", alone or in combination, means a primary, secondary or tertiary amino group linked via the nitrogen atom, with the secondary amino group carrying an alkyl or cycloalkyl substituent and the tertiary amino group carrying two substituents of similar or different alkyl or cycloalkyl or the two nitrogen substituents forming a ring, such as, for example, -NH2, methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-ylo or piperidino, etc. ' ., preferably amino, dimethylamino and diethylamino and particularly primary amino.

The term "halogen" means fluorine, chlorine, bromine or iodine and preferably. chlorine or bromine and particularly chlorine.

As examples of "alpha-amino acids" linked via the amino group, alpha-amino acids having the L or D configuration are considered, wherein the carboxyl group present is optionally derivatized as an ester or amide. Examples of these alpha-amino acids are L-valine, L-phenylalanine, L-leucine, L-is ol eucine, L-serine, L-threonine, 3- (1-naphthyl) -L-alanine, 3- (2 -naf t il) -L-alanine, Ni sopropil-glycine, bet a-cyclohexyl-L-alanine, L-phenylglycine and L-proline. Preferred are alanine, valine, phenylalanine, leucine, beta-cyclohexyl-alanine and phenylglycine, especially phenylglycine and valine.

The term "carboxyl", alone or in combination, means a -COOH group.

The term "carboxyalkyl" alone or in combination means an alkyl group as previously described wherein a hydrogen atom has been replaced by a carboxyl group. The carboxymethyl group is preferred.

The term "alkyl-0-CO-", alone or in combination, means an alkyl ester group, being alkylated as previously defined. Groups of methyl ester, ethyl ester, isomeric propyl ester and isomeric butyl ester are preferred. Especially preferred are the methyl ester, ethyl ester and ester ester groups. but Ilic. The term "alkylo-CO-", alone or in combination, means an alkylcarbonyl group, with alkyl being as previously defined, examples being methylcellulose, ylcarbonyl and the propylcarbonyls and buylcarbonyl. the isomers. The carbon fiber is particularly preferred.

The term "aralkyl-O-CO", alone or in combination, means an aralkyl ester group, with aralkyl being as previously defined, the benzyl ester group is especially preferred.

The term "terocyl alkyl", alone or in combination, means an alkyl group as previously defined wherein one hydrogen atom has been replaced by a heterocyclyl group. Examples of these heterocyclics are pyridylmethyl and piperidylmethyl.

The term "he t eroa ri la 1 loi", alone or in combination, means an alkyl group as previously defined wherein a hydrogen atom has been replaced by a heteroaryl group. Preference is given, for example, to 2-pi ri di lmethyl and 3-pi r idi lme i 1 o.

The term "alkylsulfonyl", alone or in combination, means a group Or alkyl-S-I or wherein alkyl is as previously defined, the preferred alkyl sui-fonols are metildonyl, et-sulfonyl and especially propylsulfonyl.

The term aryl sulfonyl 'alone or in combination means a group OR II aryl-S-II or where aryl is as previously defined. The most preferred are phenol 1 sui foni 1 o, 1 -na ft i 1 ul, p-toluenesulfonyl and 2-naphthylsulfonyl.

The term "heteroarylsulfonyl", alone or in combination, means a group heteroaryl-S-II or wherein the heteroaryl is as previously defined. Preferred heteroarylsulfonyl are 2-thiophenol fonyl and 3,5-dimethylisoxazole-4-sulphonyl.

Examples of physiologically usable salts of the compounds of formula I are salts with physiologically compatible mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid; or with organic acids such as me tans ul phonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. Compounds of formula I with free carboxyl groups can also form salts with physiologically compatible bases, examples of these salts are alkali metal, alkaline earth metal, ammonium and alkali metal salts, such as Na, K, Ca or te salt. trame ti lamonio. The compound of formula I may also be present in the form of z itterions.

In the nomenclature used in the present description the ring atoms of the thiazole ring are numbered as follows: wherein the substituent R1 is linked in position 2, the substituent R2 is linked in position 4 and R is linked in position 5 or the substituent R is linked at the 5-position and the substituent R3 is linked at the 4-position of the thiazolic ring The invention expressly includes pharmaceutically appropriate derivatives of the compounds of formula I. For example, the COOH groups in R2 can be teri fi ed. The alkyl and aralkyl esters are examples of suitable esters.

Preferred esters are methyl, ethyl, propyl, butyl, benzyl and (R / S) -l- ((i-sopropoxy-carbonyl) -oxy) -ethyl esters. Methyl, ethyl and ter esters are especially preferred. Butyl The compounds of formula I can also be solvated, for example hydrated. The solvation can be carried out in the course of the manufacturing process or can take place, for example, as a consequence of the hygroscopic properties of an initially anhydrous compound of the formula I (hydration).

The compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure terephite days, mixtures of di steroids, racemates tereoi soméricos or racemate mixtures tereoi s orné rich days.

A preferred embodiment of the invention comprises compounds of formula I wherein f and g are not both simultaneously 1.

A further preferred embodiment comprises compounds of formula I wherein f and g are not the same.

Preferred compounds of formula I are also those wherein R2 is especially those where R2 is R9 9 - C- N - ameno- A - NH (CH ^ n (CH), - (CH ^, - COOH (IVa) (C = 0) k (N-H), R? Also preferred are compounds of formula I wherein R2 is Also preferred compounds of formula I are those wherein R is rilßno-fNJr Preferred compounds are compounds of formula I wherein R2 is linked in position 5 and R3 is linked in position 4 of the thiazole ring. Especially preferred compounds of formula I are those in which R2 is defined according to formula III, IVa, IVb or V and is linked in position 5 of the thiazole ring, R3 being linked in position 4 of the thiazole ring.

Also preferred compounds of formula I are those wherein R2 is - 9C- r- (ap.leno ^ CHae- -A- H (CH2) h- • (CH) - (CH ^ j -COOH, (C = 0)? (Via) (-H), R 310 - 9C-N f-) f- (C 2) e A_ / NH} - (CH2) h (CH) - (CH ^ -COOH (C = 0) k (VIb) (-H), R10 and wherein in the compounds of formula VIb is equal to 1 when c means zero.

The compounds of formula are also preferred I where R is and where g is equal to 1 when c is equal to zero.

Also preferred are compounds of formula I wherein R is The compounds of formula I in which R 2 is the same as the formula Vid, A is equal to carbonyl and R 2 is linked in position 4 of the thiazolic ring are especially preferred. Compounds wherein R2 is equal to the formula Vid, A is equal to carbonyl, e is equal to 1 and R2 is linked in position 4 of the thiazolic ring are particularly preferred.

Also preferred is the embodiment of the invention wherein in the formula I f and g are both 1, R 2 corresponds to the formula V, A is carbonyl and B is hydrogen.

Further preferred are compounds of formula I wherein c is 1, d is zero, f _ and g are both zero and A is equal to carbonyl.

Also preferred are compounds of formula I wherein c is 1, d is 1 and f, g and m are zero Preferred compounds of the above-described are compounds wherein arylene is a phenylene or substituted phenylene wherein the phenylene may be mono- or muteinic by alkoxy, alkoxy-alkoxy, halogen, aralkoxy, especially benzyloxy. Especially preferred are compounds in which marylene is meta- or para-phenol or substituted meta-or para-phenylene wherein the previously mentioned phenylene substituents with the definitions of R2 are in meta- or para-position to each other and wherein the substituted phenylene carries on the ring one or more additional members thereof selected from the group of alkoxy, alkoxy. alkoxy, halogen or aralkoxy, especially benzyloxy.

Especially preferred are compounds wherein arylene is meta- or para-phenylene or substituted meta- or para-phenylene wherein the phenylene substituents previously given with the definitions of R2 are located meta- or para- to each other and wherein the substituted phenylene carries on the ring a further substituent selected from the group of alkoxy, alkoxy-alkoxyhalogen or aralkoxy, especially benzyloxy. Especially preferred substituents on phenylene are methoxy, 2-methoxy-ethoxy, chloro and benzyloxy.

Especially preferred are compounds of formula I wherein arylene is meta- or para-phenylene.

To the preferred compounds described above belong those in which R1 R7HN-; C = - - C- H- 8HN 'RaN * Especially preferred are compounds of formula I wherein R 1 is Also preferred is a compound of formula I wherein R3 is hydrogen, alkyl, cycloalkyl, carboxyl, alkyl-0-CO- or substituted or unsubstituted phenyl, the phenyl being substituted by one or more substituents, preferably a substituent selected from the group of halogen , nitro and amino, preferably nitro and / or amino. Particularly preferred meanings of R 3 are the following: hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, cyclopentyl, methyl-0-CO-, carboxyl, phenyl, nitrophenyl and aminophenyl.

A preferred group of compounds of formula I comprises those wherein R 4 is hydrogen, alkyl, cycloalkyl, phenyl or pyridyl. Especially preferred are compounds of formula I wherein R 4 is hydrogen, alkyl, phenyl or pyridin-2-yl.

The group of preferred compounds of formula I also include those in which R5 and R6 are hydrogen or pyridyl, preferably hydrogen, and R7 and R8 are hydrogen or R5 and R are each hydrogen or pyridyl, preferably hydrogen, and R7. and R8 together with the N atoms to which they are attached form a ring of 5 or 6 members, especially a ring of imide zol idine or hexahydropyrimidine. Especially preferred are compounds of formula I wherein R7 and R8 together with the N atoms to which they are attached form an imide zol idine ring. Particularly preferred are those compounds of formula I wherein R5, Rd, R7 and R8 are hydrogen.

The group of compounds of formula I wherein R9 is hydrogen or cycloalkyl is also preferred. The compounds wherein R9 is hydrogen or cyclopropyl are especially preferred. Of these, compounds in which R9 is hydrogen are particularly preferred.

Preferred compounds of formula I are those in which R 10 is piperidyl, pyridyl, pyridyl, benzyl, alkyl, hydrogen or substituted or unsubstituted phenyl, the phenyl being substituted mono- or mu ti ti -substituted by halogen, alkoxy, alkoxycarbonyl , carboxyl or hydroxyl, or R10 is alkyl-0-CO-methyl, carboxymethyl, alkylsulfonyl, alkyl-CO-, benzyl-0-CO- or alkyl-0-CO-, whereby k is zero.

Furthermore, preferred compounds of formula I are those wherein R 10 is an alpha-amino acid linked via the amino group, where 1 is zero and k is 1, especially where R 10 is L-valine, L-phenylalanine, L-phenylglycine, L- leucine, L-isoleucine, L-serine, L-threonine, 3- (1-naphthyl) -L-alanine, 3 - (2 -naphthyl) -L-alanine, N-isopropyl-glycine, beta-ci cl ohexyl- L-alanine or L-proline, particularly L-valine or L-pheni glycine and being 1 zero and k being 1.

A preferred embodiment of the invention comprises compounds of formula I wherein A is carbonyl.

Another preferred embodiment of the invention comprises compounds of formula I wherein A is sulfonyl and R2 corresponds to the formula Via. Especially preferred are compounds of formula I wherein A is sulfonyl, R, 2 corresponds to the formula Via, d is 1 and It is zero.

Also preferred are compounds of the formula I wherein B is hydrogen or alkyl and especially those wherein B is hydrogen or methyl. In a particularly preferred embodiment B is hydrogen.

A group of preferred compounds of formula I comprises those wherein R e s R7HN-, H ^ C- NH- R8HN- = - RaN R2 is (CH) - (CHa), - COOH (C = Q) k (NH), (H), R is hydrogen, alkyl, cycloalkyl, aryl, aralkyl or heteroaryl, R4 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl, R5, R6, R7 and R8 are each, independently, hydrogen, alkyl or cycloalkyl or R7 and R8 together with the N atoms to which they are attached form a 5- to 8-membered erocyclic ring which may be mono- or substituted by alkyl, R 9 is hydrogen, alkyl or cycloalkyl, R 10 is aryl, aralkyl or heterocyclyl, R 10 is an alpha-amino acid linked via the amino group, where I is zero and k being 1, A is carbonyl or sulfonyl, aa 1 are zero or positive integers, being zero to 2, but not being zero when R1 is - NH2, where b is zero to 4, where c, d, f, g, ky 1 each, independently, zero or 1 and not being simultaneously the three c, f and g zero to 3, h is zero to 5, j is zero to 2 and the sum of e, h and j e s 2 to 7; and its pharmaceutical salts and esters.

Another preferred group of compounds of formula I comprises those wherein R 1 is R7HN R7HN ^ O RdHN • C-NH - aN * R is a substituent defined by formula III, IVa, IVb, V, Via, VIb, VIc or Vid, whereby in formulas VIb and VIc g is 1 when c is zero, R3 is hydrogen, alkyl, cycloalkyl, carboxyl, alkyl-O-CO- or substituted or unsubstituted phenyl, the phenyl being substituted mono- or muteinose by halogen, nitro and / or amino, R4 is hydrogen, alkenyl, cycloalkyl, phenyl or pi idilo, R5 and R6 are hydrogen or pyridyl, preferably hydrogen, and R7 and R8 are hydrogen, or R5 and R6 are each hydrogen or pyridyl and R7 and R8 together with the N atoms to which they are attached form a ring of 5 or 6 members, especially a zolidine or hexahydropyrimidine dimide ring, R9 is hydrogen or cycloalkyl, R10 is piperidyl, pyridyl, pyridyl, benzyl, alkyl, hydrogen or substituted or unsubstituted phenyl, the phenyl being substituted mono- or mu ti - its halogen, alkoxy, alkoxycarbonyl, carboxyl or hydroxyl, or R 10 is alkyl-O-CO-methyl, carboxymethyl, alkylsulfonyl, alkyl-CO-, benzyl-O-CO- or alkylo-O -CO-0, where k is zero, or R10 is an alpha-amino acid linked via the amino group, where i is zero and k is 1, and especially R10 is L-valine, L-phenylalanine, Lf enylglycine, L-leucine, L -isoleucine, L-serine, L-threonine, 3 - (1 -na ft i 1) -L-alanine, 3- (2-naphthyl) -L-alanine, N-isopropyl-glycine, be ta-ci c lohexyl-L-alanine or L-proline and 1 is zero and k is 1, B is hydrogen or alkyl and arylene means phenylene or substituted phenylene, the phenylene optionally being mono- or multi-substituted by alkoxy, alkoxy-alkoxy , halogen or aralkoxy.

A group of especially preferred compounds of formula I comprises those wherein R 1 is Rs O R6 R7HNV 4 I II 1 R7HN ^ R - (CH2) b- - C-N- ¿R8H ^ C- - C- NH- R8N * R is a substituent defined by formula III, IVa, IVb, V, Via, VIb, VIc or Vid, with which in formulas VIb and VIc g is 1 when c is zero, R3 is hydrogen, methyl, ethyl, propyl , isopropyl, butyl, tert-butyl, pentyl, cyclopentyl, me t -yl-O-CO-, carboxyl, phenyl, nitrophenyl or aminophenyl, R4 is hydrogen, alkyl, phenyl or pyridin-2-yl, R5, R6, R7 and R8 are hydrogen, R9 is hydrogen or cyclopropyl, R10 is piperidyl, pi, ridylmethyl, pyridyl, benzyl, algayl, hydrogen or substituted or unsubstituted phenyl, the phenyl being substituted mono- or mu ti ti-sus tu tuido by halogen, alkoxy, alkoxycarbonyl, carboxyl or hydroxy or R 10 is alkoyl-O-CO-methyl, carboxymethyl, alkylsulfonyl, alkyl-CO-, benzyl-O-CO- or alkyl-O-CO-, where k is zero or R 10 is L-valine or L-phenylglycine and where 1 is zero and 1 is B, hydrogen or methyl and arylene means meta- or para-phenylene or substituted meta- or para-phenylene, with the phenylene substituents previously given with the definition of R2 in the meta- or para-position and carrying the substituted phenylene on the ring an additional substituent selected from the group of alkoxyl, alkoxy-alkoxy, halogen and aralkoxy, A preferred replacement pattern on the thiazide ring comprises the above compounds wherein R2 is arranged in position 5 and R3 is disposed in position 4 of the thiazone rings. These are especially applicable when R2 represents a substituent of formula III, IVa, IVb, or V.

Examples of preferred compounds of formula I are: Ethyl 3- [3- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -propionyl-amino] -propionate, 3- [3- [(2-guanidino-4-) hydrochloride] methyl-thiazole-5-carbonyl) -amino] -propionylamino] -propionic 3- [3- [(2-guanidino-thiazole-4-carbonyl) -amino] -propionylamino] -propionic acid, ethyl hydrochloride 3- [ 3- [(2-guanidino-thiazole-4-carbonyl) -amino] -propionyl-amino] -propionic acid, 3- [3- [(2-guanidino-4-methyl-thiazole-5-carbonyl) - trifluoroacetate] amino] -benzoylamino] -propionic, rae 3- [3- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino] -3-phenyl-propionate ethyl, rae hydrochloride 3 - [3- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino] -3-phenyl-propionic, rae 3- [2- [(2-guanidi or -5-carbonyl- amino] -acetylamino] -3-phenyl-propionate, rae acid hydrochloride 3- [2- [(2-guanidino-thiazole-5-carbonyl) -amino] -acetylamino] -3-phenyl-propionic acid, rac- 6- { [2- (3-benzyl-urei or ) -thiazole- -carbonyl] -amino} - ethyl 3-phenyl-hexanoate, rac-6- acid. { (2- (3-benzyl-ureido) -thiazole-4-carbonyl] - • amino.} - 3-phenyl-hexanoic acid, rac-6 - [(2- ^ 3-guanidino-thiazole-4-carbonyl) amino )] -3-phenyl-hexanoate ethyl, rac-6- [(2-guanidino-thiazole-4-carbonyl) -amino] -3-phenyl-hexanoic acid, rac-3- [3- [(2-guanidino]] -thiazole-4-carbonyl] -amino] -benzoylamino.} - ethyl-3-phenylpropisnate, rac-3 { 3- [(2-guanidino-thiazol-4-carbonyl] -amino] - benzoylamino.). 3-phenyl-propionic acid, 3- [3- [(2-guanidino-thiazole-4-carbonyl] -amino] -benzoylamino] -propionic acid trifuoroacetate, 3-. {3- [3- (2-Guanidino-thiazole-4-carbonyl] -amino] -benzoylamino}.-Tert-butyl propionate, 1-N-phenyl-amide of (S) -N-2-. {2- (2 -guanidino-thiazole -carbonyl) -amino] -acetyl} -aspartic, rac-3- { 2- [(2-guanidino-thiazol-4-carbonyl] -amino] -acetylamino.} -3 ethyl-phenyl-propionate, rac-3- [2- [[2-guanidino-thiazole-4-carbonyl] -amino] -acetylamino] -3-phenyl-propionic acid hydrochloride, rac-3- [3- [(2-Guanidino-thiazol-4-carbonyl] -amino] -propionylamino] -3-phenyl-propionate, ethyl, rac-3- [3- [2-guanidino-thiazole-4-carbonyl] -amino] - propionylamino] -3-phenyl-propionic, rac-3- [3- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -propylamylamino] -3-enyl-propionic acid, rac-3- [3- [(2-guanidino-4-methyl-thiazole-5-carbo-nyl) amino] -propionylamino] -3-phenyl-propionic acid, [2-guanidino-thiazole-4-hydrochloride] carbonyl] -Gly-Asp- Val-OH, ethyl 3- [2- [(2-guanidino-thiazole-4-carbonyl] -amino] -acetylamino] -propionate, 3- [2- [(2-guanidino]] -thiazole-4-carbonyl) -amino] -acetylamino] -propionic acid, N- [4- (2-guanidino-4-methyl-thiazol-5-yl) -phenyl] -succinnamic acid monoamide, N-amino acid monoamide [3- (2-guanidino-4-methyl-thiazol-5-yl) -phenyl] -succinnamic acid, rae 4- [4- (2-guanidino-4-methyl-thiazol-5-yl) -phenylcarbamoyl] - 3-phenyl-butyric acid, 4- [3- (2-guanidino-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyric acid, 4- [4- (2-guanidino-4-) methyl-thiazol-5-yl) -phenylcarbamoyl] -pentanoate methyl, methyl 5- [3- (2-guanidino-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -pentanoate, 5- [4 -] (2-guanidino-4-methyl-thiazol-5-yl) -phenyl-carbamoyl] -pentanoic acid, 5- [3- (2-guanidino-4-methyl-thiazo l-5-yl) -phenylcarbamoyl] -pentanoic acid, rae 3- (4-chloro-phenyl) -4- [4- (2-gua idino-4-methyl-thiazol-5-yl) benzoylamino] -butyrate ethyl , rae 3- [4-Chloro-phenyl] -4- [3- (2-guanidino-4-methyl-thiazol-5-yl) -benzoylamino] -butyl-ethyl ester, rae 3- [4- (2-guanidino Ethyl 4-methyl-thiazol-5-yl) benzoylamino] -3-phenyl-propionate, 3- [3- (2-guanidino-4-methyl-thiazol-5-yl) -benzoylamino] -3-phenyl-propionate ethyl, 3-3- [4-chloro-phenyl] -4- [3- (2-guanadino-4-methyl-thiazol-5-yl) benzoylamino] -butyric acid, rae 3- [4-chloro-phenyl] acid ] -4- [3- (2-guanidino-4-methyl-thiazol-5-yl) -benzoylamino] -butyric acid, rae 3- [4- (2-guanidino-4-methyl-thiazol-5-yl)] -benzoylamino] -3-phenyl-propionic acid, rae 3- [3- (2-guanidino-4-methyl-thiazol-5-yl) -benzoylamino] -3-phenyl-propionic acid, rae hydrochloride 3- [2- [(2-guanidino-4-methyl-thiazol-5-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionate ethyl, rae 3- [2- [(2-guanidino-4-propyl-thiazole-5 -carbonyl) -amino] -acetylamino] Ethyl -3-phenyl-propionate, rae 3- [2- [. { ethyl-3-butyl-2-guanidino-thiazol-5-ylcarbo-nyl) -amino] -acetylamino] -3-phenyl-propionate, rae 3- [2- [(2-tert-butoxycarbonylamino-methyl) -thiazole] Ethyl 4-ylcarbonyl] -amino] -acetylamino] -3-phenyl-propionate, rae hydrochloride 3- [2- [(2-aminomethyl-thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenyl ethyl-propionate, rae hydrochloride 3- [2- [(2-guanidinomethyl-thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionate ethyl, rae 3- [2- [(2 -guanidino-4-methyl-thiazol-5-ylearbonyl) -α-ene] -acetylamino] -3-phenyl-propionic acid, rae 3- [2- [(2-guanidino-4-propyl-thiazol-5-ylcarbonyl)] -amino] -acetylamino] -3-phenyl-propionic acid, rae 3- [2- [(2-guanidino-4-phenyl-thiazol-5-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionic acid rae 3- [2- [(4-tert-Butyl-2-guanidino-thiazol-5-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionic acid, rae 3- [2- [(2-aminomethyl- thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionic acid, rae 3- [ 2- [(2-guanidinomethyl-thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionic acid, rae 3- [2- [(3-benzyl-ureido) -thiazole-4-ylenecarbonyl) -amino ] -acetylamino] -3-phenyl-propionate ethyl, rae 3- [3- [(4-tert-butyl-2-guanidino-thiazol-5-ylcarbo-nyl) -amino] -benzoylamino] -3-pyridine- Ethyl 3-yl-propionate, rae 3 - [3 - [(4-methyl-2- (3-methyl-butido) -thiazol-5-ylcarbonyl) -amino] -benzoylamino] -3-pyridin-3 ethyl-l-propionate, rae hydrochloride 3- [2- [cyclopropyl- (2-guanidino-4-methyl-thiazol-5-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionyl ethyl ester, (S ) -3- [2- [(2-Guanidino-4-methyl-thiazol-5-ylcarbonyl) -amino] -acetylamino] -oxo-4-piperidin-1-yl-butyrate of tert-butyl, 3- [ Ethyl 2- [(2-guanidino-4-methyl-thiazol-5-yl carbonyl) -amino] -acetylamino] -propionate, -acetic acid 3- [2- [(3-benzyl-ureido) -thiazole-4] -carbonyl) -amino] -acetylamino] -3-phenyl-propionic acid, rae 3- [3- [(4-tert-butyl-2-guanidino-thiazol-5-ylcarbonyl) -am] ino] -benzoylamino] -3-pyridin-3-yl-propionic acid, rae acid 3- [3- [(4-methyl-2- (3-methyl-ureido) -thiazol-5-ylcarbonyl] -amino] -benzoylamino] -3-pyridin-3-yl-propionic acid, rae 3 acid - [2- (cyclopropyl- (2-guanidino-4-methyl-thiazol-5-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionic acid, 3- [2- [(2-guanidino-4-methyl)] -thiazol-5-ylcarbonyl) -amino] -acetylamino] -propionic acid (S) -3- [2- [(2-guanidino-4-methyl-thiazol-5-ylcarbo-nyl) -amino] -acetylamino] -4-oxo-l-piperidin-l-yl-buty-rich, (S) -3- [2- [(2-guanidino-thiazol-4-ylenecarbonyl) -amino] -acetylamino] -4-oxo-4 -piperidin-l-yl-butylbutyric acid, (S) -3- [2- [(2-guanidino-thiazol-4-ylcarbonyl) -amino] -acetylamino] -4-oxo-4-? iperidin-l acid -yl-butyric, rae 3- [2- [(2-guanidino-4-methyl-thiazol-5-ylcarbonyl) -amino] -phenyl-sulfonylamino] -3-phenyl propionic acid rae 3- [3- [( 2-guanidino-4-methyl-thiazol-5-yl-carbonyl) -amino] -phenylsulfonylamino] -3-phenyl-propionic acid, rae 4- [3- (2-guanidino-thiazol-4-yl) - phenylcarbamoyl] -3-phenyl but irico, rae acid 3- [4-chloro-phenyl] -4- [3- (2-guanidino-thiazol-4-yl) -benzoylamino] -butyric acid, rae 4- [3- (2-guanidino-4- methyl-thiazol-5-yl) -phenylcarbamoyl] -3- (4-methoxyphenyl) -butyric acid, rac-3- [5- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -2 - ethyl (2-methoxyethoxy) -benzoylamino] -3-phenyl-propionate, rac-3- [5- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] hydrochloride] -2- (2-methoxy-etho i) -benzoylamino] -3-phenyl propionic, rac-3- (3- [(2-guanidino-thiazole-5-carbonyl) -amino] -benzoylamino) -3-phenyl-propionic acid , rac-3- (3- [(2-guanidino-thiazole-5-carbonyl) -amino] -benzoylamino) -3-phenylpropionic acid, rac-3- (3-benzyloxy-5- [(2-guanidino-4) ethyl-thiazole-5-carbonyl) -amino] -benzoylamino) -3-phenyl-propionate, rac-3- (3-benzyloxy-5- [(2-guanidino-4-methyl-thiazole-5- carbonyl) -amino] -benzoylamino) -3-phenyl-propionic, rac-7- ([2- (3-benzyl-ureido) -4-methyl-thiazole-5-carbonyl] -amino) -3-phenylheptanoate ethyl, rac-7- ([2- (3-benzyl-ureido) -4-methyl-thiazole-5-carbonyl] -amino) -3-phenyl-heptanoic acid, rac-3- (3- [(2- ethyl guanidino-4-methyl-thiazole-5-carbonyl) -amino] -4-methoxybenzoylamino) -3-phenyl-propionate, rac-3- (3- [(2-guanidino-4-methyl-thiazole) hydrochloride -5-carbonyl) -amino] -4-methoxybenzoylamino) -3-phenyl-propionic, rac-3- (2- [(2-guanidino-thiazole-4 -ca bonyl) -amino] -3-? Iridin-3 ethyl-l-propionate, rac-3- [2- [(2-guanidino-thiazol-4-carbonyl) -amino] -acetylamino) -3-pyridin-3-yl-propionic acid, rac-3- (3 - [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -4-methoxy-benzoylamino) -3-phenyl-propionyl ethyl, 6- ([2- (3-benzyl-ureido) -thiazole- 4-carbonyl] -amino) -5-oxo-hexanoate, 6- ([2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino) -5-oxo-hexanoic acid, rac-7 - ([2-guanidino-4-methyl-thiazole-5-carbonyl] -amino) -3-phenyl-heptanoate ethyl, rac-7- ([2-guanidino-4-methyl-thiazole-5-carbonyl]] -amino) -3-phenyl-heptan ico, (S) -3- (2- ([2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino) -acetylamino) -succinic acid 4-anilide-1-tert-butyl ester; - (S) -3- (2- ([2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino) -acetylamino) -succinic acid aniline, rae 4 - (3- [2- (3-benzyl-ureido) -4-methyl-thiazol-5-yl] -phenylcarbamoyl) -3-phenylbutyric ester, 4-anilide-1-tert-butyl ester of (S) -3- (2- ([2- rac 4- [3- (2-guanidi o-4-methyl-thiazol-5-yl) phenyl-carbamoyl] -3-pyridin-3-yl-butyrate, rae 4- [3- (2-guanidino-4 -methyl-thiazol-5-yl) phenylcarbamoyl] -3-pyridin-3-yl-butyric acid, rac-4- [3- (4-ethyl-2-guanidino-thiazol-5-yl) -phenylcarbamoyl] acetate] -3-phenylbutyric acid, rac-4 - [3-. { 2-guanidino-propyl-thiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyric acid, rac-4- [3- (4-butyl-2- guanidino-thiazol-5-yl) -phenylcarbamoyl] - 3-phenyl-butyric, rac-4- [3- (2-guanidino-4-pentyl-thiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyric acid, rac-3- (4-chloro-phenyl) acid ) -4- [3- (2-Guanidino-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -butyric acid, rac-4- [3- (2-guanidino-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -3-hydroxy-butyric acid, rac-4 - [3- (2-guanidino-4-methyl -thiazol-5-yl) -phenylcarbamoyl] -3-methyl-butyric acid, rac-3- (3-bromo-phenyl) -4 - [3- (2-guanidi or-4-methyl-thiazol-5-yl) ) -phenylcarbamoyl] -butyric acid, rac-3- (3,5-dichloro-2-hydroxy-phenyl) -4- [3- (2-gua-nidino-4-methyl-thiazol-5-yl) -phenylcarbamoyl acid ] -butyric, rac-4- [3- (2-guanidino-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -3- (3-methoxyphenyl) -butyric acid, rac-4- [4-chlor] acid -3- (2-guanidino-4-met-il-thiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyric acid, rac-4- [2-chloro-5- (2-guanidino-4-methyl- thiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyric acid (S) -2-butylsulphonylamino- [3- (2-guanidino-4-methyl-thiazol-5-yl) -benzoylamino] - hydrochloride] butyric, rac-3- [3- [3- (2-gua idino-4-methyl-thiazol-5-yl) -phenyl] -ureido] -3-phenylpropionate ethyl, rac-3- [3- [ 3- (2-guanidino-methyl-thiazol-5-yl) -phenyl] -ureido] -3-phenyl-propionic acid, rac-4- [3- (2-guanidino-4-methyl-thiazol-5-yl) -phenyl-carbamoyl] -3-phenyl-butyrate ethyl hydrochloride, rac-4- acid [[3- (2-guanidino-4-methyl-thiazol-5-yl) -phenyl] -methyl-carbamoyl] -3-phenyl-butyric acid, rac-4-benzyloxycarbonylamino-4 - [3- (2-guanidino- Methyl 4-methyl-thiazol-5-yl) -phenylcarbamoyl] -butyrate, rac-4-benzyloxycarboni lamino-4- [3- (2-guanidino-4-methyl-thiazol-5-yl) -phenylcarbamoyl] - butyric, rac-5- [3- (-carboxy-3-pheny-buty-ri-amino) -phenyl] -2-guanidino-thiazole-4-carboxylic acid methyl / rac-5- [3- (4-carboxylic acid)] 3-phenylbutyrylamino) -phenyl-2-guanidino-thiazole-4-carboxylic acid, rac-3- [2- [(2-guanidino-5-methyl-thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenyl ethyl-propionate, rac-3- [2- [(5-tert-butyl-2-guanidino-thiazol-4-ylcar-bonyl) -amino] -acetylamino] -3-phenyl-propionyl ethyl, rac-3 - [ethyl 2- [(2-guanidino-5-phenyl-thiazol-4-ylearbonyl) -amino] -acetylamino] -3-phenyl-propionate, rac-3- [2- [[2-guanidino-5] - (3-Nitro-phenyl) -thiazol-4-ylearbonyl] -amino] acetylamino] -3-phenyl-propionate, rac-3- [2- [(2-guanidino-5-methyl-thiazole-4)] -carbonyl) -amino] -acetylamino] -3-phenyl-propionic acid, rac-3- [2- [(5-tert-butyl-2-guanidino-thiazol-4-ylearbonyl) -amino] -acetylamino] -3 acid -phenyl-propionic acid, rac-3- [2- [(2-guanidino-5-phenyl-thiazol-4-ylearbonyl) -amino] -acetylamino] -3-phenyl-propionic acid, rac-3- acid [2 - [2-guanidino-5- (3-nitro-phenyl) -thiazol-4-ylcarbonyl] -amino] -acetylamino] -3-phenyl-propionic acid, rac-3- [2- [(5- (3-amino)] phenyl) -2-guanidino-thiazol-4-ylcarbonyl] -amino] -acetylamino] -3-phenyl-propionic, rac-3- [2- [(2- (3-benzyl-ureido) -5-methyl- thiazol-4-ylenecarbonyl] -amino] -acetylamino] -3-phenyl-propionate, rac-3- [2 - [(3-benzyl-ureido) -5-phenyl-thiazol-4-ylcar-bonyl] - amino] -acetylamino] -3-phenyl-propionic acid, rac-3- [2- (3-benzyl-ureido) -5-phenyl-thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenyl- propionic, rac-4- [3- [2- ( 3-benzyl-ureido) -5-methyl-1-thiazol-4-yl] -phenylcarbamoyl] -3-phenylbutyric acid, rac-4- [3- [2- (3-benzyl-ureido) -5-methyl-thiazole] -4-yl] -phenylmethyl-carbamoyl] -3-phenyl-butyric acid, rac-3-phenyl-3- [2 - [(2- (3-phenyl-ureido) -thiazol-4-ylcarbonyl] -amino] - ethyl acetylamino] -propionate, rac-3- [2 - [(2- (3-phenethyl-ureido) -thiazol-4-ylcarbonyl] -amino] -acetylamino] -3-phenyl-propionate, rac-3 - (ethyl 2- [[2- (3-butyl-ureido) -thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionate, rac-3-phenyl-3- [2- [ (2- (3-phenyl-ureido) -thiazol-4-ylcarbonyl) -amino] -acetylamino] -propionic acid, rac-3- [2- [[2- (3-phenethyl-ureido) -thiazole-4-acid] Ilearbonyl] -amino] -acetylamino] -3-phenyl-propionic acid, rac-3- (2- [[2- (3-butyl-ureido) -thiazol-4-ylearbonyl) -amino] -acetylamino] -3- acid phenyl-propionic, rac-3- [4- [[2- (3-benzyl-ureido) -thiazol-4-ylenecarbonyl] -amino] -phenyl] -3-tert-butoxycarbonylamino-propionate, rac-3- [4- [[2- (3-benzyl-urei o) -thiazol-4-ylcarb] onyl] -amino] -phenyl] -3-tert-butoxycarbonylamino-propionicrac-3-amino-3- [4- [[2- (3-benzyl-ureido) -thiazole-4-ylcarbonyl] -amino] -phenyl] -propionic acid, rac-3- [4- [[ 2- (3-benzyl-ureido) -thiazol-4-ylcarbonyl] -amino] -phenyl] -3-propionylamino-propionate, rac-3- [4- [[2- (3-benzyl-ureido)] thiazol-4-ylcarbonyl] -amino] -phenyl] -3-butyl-sulfonylamino-propionate, rac-3- [4 - [[2- (3-benzyl-ureido) -thiazole-4-ylearbonyl] - amino] -phenyl] -3-propynylamino-propionic acid, rac-3- [4- [[2- (3-benzyl-ureido) -thiazole-4-ylcarbonyl] -amino] -phenyl acid] -3-butyl-sulfonylamino-propionic, 3- [4- [4- [[2- (3-benzyl-ureido)] 3- [4- [[2- (3-benzyl-ureido) -thiazol-4-ylcarbonyl] -amino] -phenyl] glutarate] -thiazol-4-ylcarbonyl] -amino] -phenyl] -glutaric acid, rac-4- [3- [2- (N '-benzylguanidino) -4-methyl-thiazol-5-yl] -phenylcarbamoyl] - 3-phenyl-butyric, rac-3-phenyl-3- [2- ([2- (pyridin-2-ylamino) -thiazole-4-ylenecarbonyl] -amino] -acetylamino] -propionate ethyl, rac-3 acid -phenyl-3- [2 - [[2- (pyridin-2-ylamino) -thiazol--aryarbonyl] -amino] -acetylamino] -propionic, rac-3- [2- [[2- (3-benzyl)] -ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -3-pyridin-3-yl-propionate, rac-3- [2- [[2- (3-benzyl-ureido)] -thiazole-4-carbonyl] -amino] -acetylamino] -3-pyridin-3-yl-propionic acid, (S) -N-benzyl-3- [2- [[2- (3-benzyl-ureido) -thiazole] -4-carbonyl] -amino] -acetylamino] -succinato tert -butyl ester, '3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] - Ethyl propionate, Acid hydrochloride gone 3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -propionic, (S) -3- [2 - [[2- (3-benzyl) -ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -N- (3-methoxy-phenyl) -succinamate of tert-butyl, (S) -3- [2- [[2- (3-Benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -N- (3-methoxy-phenyl) -succinic acid, ( S) -2- [2- [2 - [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -3-tert-butoxycarbonyl-propionylamino-tert-butyl ester, acid (S) ) -2- [2- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbo-nyl] -amino] -acetylamino) -3-carboxy-propionylamino] -benzoic acid, 6- [[ 2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -hexanoate methyl, 6- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -hexanoic acid , (S) -3- [3- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino] -N-phenyl-tert-butyl-succionamate, (S) -trifluoroacetate 3- [3- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino] -N-phenyl-succinamic acid, (S) -2 - [(S) -2- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -3-tert-butoxycarbonyl-propionylamino] -3-methyl-tert-butyl butyrate, (S) -3- [(S) -2 - [[2- (3-benzyl-ureido) -thiazole -4 -carbonyl] -amino] - acetylamino] -N- (tert-butoxycarbonyl-phenyl-methyl) -succinamate of tert-butyl, acetate / trifluoroacetate of (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4] -carbonyl] -amino] -acetylamino] -N- [(S) -carboxy-pheny1-methy1-succinnamic, (S) -6- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] - amino] -2-tert-butoxy-carbonylamino-hexanoate methyl, (?) -6- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -2-tert-butoxy-carbonyl-amino acid -hexanoic, rac-3-benzylcarbamoy1-6- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -ethyl hexanoate, rac-3-benzylcarbamoyl-1- [2- acid (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -hexanoic acid, 5-0x0-6- [[2- (3-pyridin-2-ylmethyl-butido) -thiazole-4-carbonyl] -amino ] -ethyl hexanoate, 5-oxo-6- [[2- (3-pyridin-2-ylmethyl-ureido) -thiazole-4-carbonyl] -amino] -hexanoic acid hydrochloride, (S) -N-benzyl -3- [4- [2- (3-benzyl-ureido) -thiazol-4-yl] -butyryl-amino] -succinamate of tert-butyl, trifluoroacetate of acid (S) ) -N-benzyl-3- [4- [2- (3-benzyl-ureido) -thiazol-4-yl] -butyryl] -succinnamic acid, 3- [4- [[2- (3-benzyl-ureido ethyl) -thiazole-4-carbonyl] -amino] -phenyl] -propionate, 3- [4- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenyl] - propionic, rac-2- [3 - [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -2-oxo-propyl] -succinate, rac-2- [3- [[2- (3-benzyl-ureido) -thiazole-4-car-bonyl] -amino] -2-oxo-propyl] succinic, (S) -2- (2- [[2- (3-benzyl)] ureido) -thiazole-4-carbonyl] -amino] -acetylamino) -di-tert-butyl succinate, (S) -2- (2- [[2- (3-benzyl-ureido) -thiazole-trifluoroacetate] 4-carbonyl] -amino] -acetylamino] -succinic, (S) -3- [2 - [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -N-isobutyl -s-butyl succinate, (S) -3- [2 - [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -N-pyridin-2-ylmethyl-succinamate of tert-butyl, (S) -3- [2 - [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -a] -acetylamino] -N-pyridin-3-ylmethyl-succinamate tert-butyl ester, (S) -3- [2- [[2- (3-Benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -N-iridin-3-ylmethyl-succinamic acid trifluoroacetate, acid (S) ) -3- [4 - [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenyl] -2-tert-butoxy-carbonylamino-propionic acid, (R) -3- acid [4 - [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenyl] -N-tert-butoxycarbonylamino-propionic acid, (S) -N-pyridin-2-ylmethyl-3- (2- [[2- (3-pyridin-2-ylmethyl-ureido) -thiazole-4-carbonyl] -amino] -s-tert-butylsuccinamate, (S) -N-pridin-2-ylmethyl-3 acid - (2- [[2- (3-pyridin-2-ylmethyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino) -succinnamic, 3- (3- [[2- (3-benzyl-ureido ) -thiazole -carbonyl] -amino] -tert-butylpropnate, 3- (3- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -benzoylamino) - propionic, rac-3- (2- [[2- (imidazolidin-2-ylidenamino) -thiaz ol-4-carbonyl] -amino] -acetylamino] -3-pyridin-3-yl-propionate, 3- (2- [[2- (imidazolidin-2-ylidenamino) -thiazole-4-carbonyl] hydrochloride ] -amino] -acetylamino] -3-pyridin-3-yl-propionic acid, (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] acetate / trifluoroacetate] -amino] -acetylamino] -N- [(S) -carboxy-phenyl-methyl-succinamic, rac-7- [[4-methyl-2-. { ethyl tetrahydro-pyrimidin-2-yliddnamino) -thiazole-5-carbonyl] -amino] -3-phenyl-heptanoate and rac-7- [[4-methyl-2- (tetrahydro-pyrimidin-2-ylidenamino] hydrochloride] ) -thiazole-5-carbonyl] -amino] -3-phenyl-heptanoic.o acetate.Examples of especially preferred compounds of formula I are: Rae acid 3- [2- [[(2- (3-benzyl-ureido) -thiazol-4-ylearbonyl] -amino] -acetylamino] -3-phenyl-propionic acid, rae 4- [3- (2-guanidino -4-methyl-thiazol-5-yl] -phenylcarbamoyl) -3-phenyl-butyric acid, 3- [2- [(γ-guanidinomethyl-thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenylpropionic acid, Rae acid 3- [3- [(2-guanidino-4-methyl-thiazol-5-ylcarbonyl) -amino] -phenylsulfonylamino] -3-phenyl-propionic, rae hydrochloride 3- [3- [(2- guanidino-4-methyl-thiazole-5-carbonyl] -amino] -benzoylamino] -3-phenyl-propionic acid, rae 3- [3- [(4-tert-butyl-2-guanidino-thiazol-5-ylcarbonyl)] -amino] -benzoylamino] -3-pyridin-3-yl-propionic acid, [2-guanidino-thiazole-4-carbonyl] -Gly-asp-Val-OH hydrochloride, rae 3- (4-chloro-phenyl) acid -4- [3- (2-guanidino-4-methyl-thiazol-5-yl) -benzoylamino] -butyric acid, rac-3- [3- [(2-guanidino-4-methyl-thiazole-5-carbo -nil) -amino] -propionylamino] -3-phenyl-propionic acid, rae 4- [3- (2-guanidino-4-methyl-thiazol-5-yl] -phenylcarba moil) -3- (4-methoxyphenyl) -butyric acid, 4- [3- (2-guanidino-4-methyl-thiazol-5-yl] • phenylcarbamoyl) -3-pyridin-3-yl-butyric acid, acid 6- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -5-oxo-hexanoic acid, 4-anilide of (S) -3- (2- [[2- (3)] -benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino) -succinic acid, trifluoroacetate (S) -N-benzyl-3- [2- [[2- (3-benzyl-ureido) -thiazole] -4-carbonyl] -amino] -acetylamino] -succinnamic acid, (S) -2- [(S) -2- (2- [[2- (3-benzyl-ureido) -thiazole-) - acetate / trifluoroacetate carbonyl-amino] -acetylamino) -3-carboxy-propionylamino] -3-methyl-butyric acid, (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl trifluoroacetate] -amino] -acetylamino] -N-isobutyl-succinamic acid, and trifluoroacetate of the acid '(S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl-amino] -acetylamino) -N-pyridin-2-ylmethyl-succinamic acid.

Process for the preparation of compounds of formula I constitute an object of the present invention. The processes are preferably based on the reaction of a thiazole derivative, which represents the triazole base member, with a reactive agent, which represents the substituent R2 or a reactive part and / or its derivative.

For example, the following routes can be set forth for the preparation of the corresponding thiazolic base member, with the substituents and indices used in the following Schemes having the meaning indicated above unless otherwise indicated.

Suitable thiazolic base members can be prepared, for example, with the method set forth in Scheme la. In this one is reacted to the fa-bromo-ketone of formula VII, such as ethyl pyruvate, in a solvent, such as ethanol, with a thiourea derivative of formula VIII, such as 2-imino-4-t-iobiuret. , at elevated temperature (J. Med. Chem, 1991, 3_4_, 014). A subsequent saponification of the ester group by means of a base, such as aqueous NaOH or KOH, gives a thiazole-4-carboxylic acid of type X (scheme la).

In one variant of the process an optionally substituted thiourea of formula IX is used and, after cyclization to the thiazole, it is reacted with an isocyanate, such as benzyl isocyanate, in a solvent, such as DMF, at room temperature, followed by saponification of the ester as described above.

Scheme the 2) R4- (CH2) b NCO 3) LiOH or 'NaOH In an additional preparatory procedure (Scheme Ib) are used to the fa-halo-ce-tones, which analogously to the process described provides thiazole-5-carboxylic acid derivatives of type XIII (Drug 1989, 4_4_, 1011). The alpha-halo-ketones of formula XII are prepared from the corresponding beta-keto esters (formula XI), such as ethyl butyl acetate, ethyl ethyl acetate, etc., by halogenation with for example bromine in a solvent, such as water, conveniently at a temperature of 0-5 ° C (J. Chem. Soc. Perkin I 1982, 162).

It's burning Ib (Xla) (xp) X = Br, Cl (X? D R = Rent In another variant (Scheme I) the thiazole-based member is synthesized by reacting an optionally substituted N-protected amino acid thioamide at the amino nitrogen, such as N-Boc-glycine thioamide, with an alpha-halo-ketone of Formula VII or Xlb. A subsequent saponification of the ester group by means of a base, as described under the Scheme, provides thiazole carboxylic acid derivatives of formula XIV. After removal of the protecting group these can be further modified in accordance with Scheme 10.

When a radical ((CH2) e-NH- (protective group) is used in place of the radical COOR01 in the compound Xlb or XII, the amins-thiazole derivatives corresponding to XIII can be obtained.The analogous situation is also applicable to the Esguema la .

Scheme (Xlb) 2) NaOH In a variant of additional procedure (Scheme Id) a substituted benzaldehyde, such as 3-nitrobenzaldehyde, or methyl 3-formylbenzoate, is converted with a nitroalkane, such as nitroethane, in an appropriate solvent, such as acetic acid, with the addition of ammonium acetate , conveniently at elevated temperature, such as reflux temperature, in the corresponding nitro-olefin (Org Synth Coil IV, 573 or Synthesis, 19_94, 258). This is epoxidized by means of an oxidizing agent, such as hydrogen peroxide in an appropriate solvent, such as water, with the addition of aqueous hydroxide solution to give a nitro-epoxide of formula XV (Synthesis 1976, 53). Reaction of this nitroepoxide with a thiourea derivative, such as 2-imino-4-thiobiuret, at elevated temperature, such as the reflux temperature, gives arylthiazoles of formula XVI.

With the use of an alternative thiourea derivative in the above reaction and subsequent reaction with an isocyanate, such as benzyl isocyanate, in a solvent, such as DMF, arylthiazoles of formula XVII are obtained at room temperature, in which subsequently a additional substituent R5 with usual methods.

Scheme Id DR ^ / Os _? Y = -N02, (XV) -COOR03, -C .2) e-NH- (Protective group, for example Boc or Cbz) R03 = Rent (XVI) (XVH) R4- (CH2) b-NCO When it's used instead of a compound XV in Esguema Id, the compound corresponding to XVI and XVII is obtained, where, nevertheless, the arylene radical is linked in position 4 of the thiazole and R3 is linked in position 5 of the thiazole ring.

In order to prepare compounds XVI through XVII, where e is nonzero in accordance with formula (I), instead of the thiourea derivative used in Scheme Id, for example, the thioamide used as the starting material may be used. in the Scheme him.

The thiazolic base members obtainable according to the above procedures are converted to a subsequent reaction with reactive components and / or reactive derivatives of the substituent R2 to give the compound of general formula I in one or more reaction steps.

In cases where c equals 1, that is, an amide bond is present on the thiazole structure, a corresponding thiazolecarboxylic acid can be reacted with a corresponding amine to give a compound of formula I following known methods. In principle the following route can be exposed: In the following process variant (Scheme 2) by coupling a thiazolecarboxylic acid of formula XXXI with an amine of formula XXXVII with the use of BOP, HBTU or CDMT and with subsequent hydrolysis of the ester function, the desired thiazole I is prepared in this connection, see also ZJ Kaminski, Synthesis, 1987, 917.

It burns 2 Alkyl, aralkyl (XXXI) If necessary 2) hydrolysis of the ester function R03 and if necessary in R1Q (i) For example, when f is equal to zero and g is equal to 1 the following procedure can be used for the preparation of compounds of formula I: A zolcarboxylic acid of formula XXXI (Scheme 3) is coupled to an amine of formula XXXXII by means of a usual coupling reagent, such as HBTU CDMT, etc., in the presence of a base, such as N-methylmorpholine, in a solvent, such as DMF or THF. A subsequent hydrolysis by means of a strong base, such as NaOH in a solvent, such as water-ethanol gives the thiazolic acid XXXIV. This is reacted with amine XXXV in an additional coupling using HBTU or CDMT and subsequently hydrolysed to XXXVI by spherical cleavage using strong acid, such as trifluoroacetic acid in methylene chloride or aqueous hydrochloric acid, or using a strong base, such as NaOH .

"Scheme 3 HBTU, DMF, NMM, R9HN- (CH2) e-COOR03 (XXXI) (XXXHI) (xxxrv) R = Alkyl, aralkyl R10 The preparation of the corresponding amino components is carried out according to methods known per se. When g and f in the general formula I are not the same, the amide or sulfonamide linkage that is then produced can be obtained, for example, by reaction of the corresponding amine component with an acid component according to known methods.

The following procedure can be used, for example, for the preparation of the amine component: They are attached. N-protected amino acids XXI (Scheme 4) with an amino acid ester XXII by means of a coupling reagent, such as CDMT, in the presence of a base, such as N-methylmorpholin, in an appropriate solvent, such as THF. N-prot groups, such as BOC, are then dissociated with HCl in ethyl acetate or with trifluoroacetic acid and those such as Cbz are dissociated by catalytic hydrogenation, for example on Pd / C in a solvent, such as ethanol, to give compounds of type XXIII. • twenty E s qu ema 4 (XXII) CDMT, NMM, T? F R02- N M - (CH2) e- COOH (XXI) 2) HCl, AcOEt or H2, Pd-C (XXI?) R 02 B or c, Cb z 0 3 R alkyl, aralkyl R 0 6 H, aryl, heteroaryl For example, other amine components (formula XXV, Esschema 5a) can be prepared by coupling an optionally substituted N-protected aminobenzoic acid XXIV with an amino acid ester XXII using a coupling reagent, such as CDMT or BOP, in the presence of a base, such as NMM or N-ethyl-morpholine, in an appropriate solvent, such as DMF or THF at room temperature or, if necessary, elevated temperature and subsequent removal of the protecting groups as described in Example 4.

E s qu ema 5 a (xxn) Ros. - HCl. EtOAc. (R05 = Boc) R03 _ alkyl, aralkyl < % _ Other amino components can be prepared, for example as follows: Neither rosulchlorides (Scheme 5b) is reacted with an amine component XXII in the presence of the strong base, such as aqueous NaOH, in a solvent, such as ether. The esterification of the free carboxylic acids followed by a reduction of the nitro group according to usual methods, such as hydrogen in the presence of Raney nickel as the catalyst, gives the anilo-esters XXVI.

Scheme 5b 3) Nickel Raney H2, EtOH R03 = Alkyl, aralkyl R? 6 = (CO) - (NH) -R10 Other amino components can be prepared, for example as follows: XXX intermediates are prepared (Scheme 6a) by coupling an appropriate aspartic acid derivative, such as XXIX, with an amine HNRR 'using the methods already described.

Scheme 6a 1) CDMT, NMM, THF Cbz-Asp-OH H-Asp-NRR 'O-t-Bu 2) HNRR', NMM O-t-Bu 3) H "Pd / C (XXIX) (XXX) H. = H, alkyl X '= aryl, heteroaryl z R and R1 together with the N atom form a ring Compounds of formula XXXXII can be prepared as additional intermediates. For this, amine components of formula XXXXI, whose carboxylic acid function is appropriately protected as an ester, are reacted with an acid chloride, such as phosgene or sulfuryl chloride, in the presence of a base, such as, for example, toluene .

Scheme 6b (XXXXI) so2c ?. (xxxxp) R06 = "(CO) k (NH) r-R10 When f and g of the general formula are both equal to zero, the corresponding compound can be obtained (A is -C (O) -) following known methods for the preparation of ketones (such as, for example, Biochem. Med. 17.31- 44 (1977)).

When A is equal to S02, the corresponding sulfones are obtained by oxidation of the thioethers, which are prepared according to known methods, for example, by reaction of a thiazole with the corresponding alkyl halide.

When f and g are both equal to 1 the compounds are corresponding ureas or sulfonamides. The preparation is carried out when c is equal to zero by reaction of compound XXXXII with the compounds, for example, of formula XVI and XVII reduced to the amine. When c equals 1, the acid chloride of formula XXXXI I is reacted with a corresponding monoproteinated diamine, which after cleavage of the protective group is reacted with the azole-carboxylic acid of formula XXXI. Boc or Cbz is considered, for example, as the protective group. When d equals 1, ie arylene is present, a corresponding diamine is used where the arylene is already present.

~ Alternatively the above compounds of general formula I can also be obtained by reaction of a reactive fragment of the amine described in Scheme 2 and subsequent addition of the substituent portion of R2 which is still missing.

When the compounds of formula I are substances wherein c is equal to zero, it is possible to proceed analogously to Esguema 2 with the formation of an amide bond. When f is equal to 1 and g is equal to zero of is equal to zero and g is equal to 1, the corresponding compound of formula I can be prepared by reaction of an amino thiazole with an acid derivative (f equal to 1 and g equal to zero) .

For example, the following methods can be used: The reduction of the nitrile-polyols of formula XVI (Scheme 7a) with an appropriate reducing agent, such as hydrogen in the presence of an appropriate catalyst, such as Raney nickel, in a solvent, such as aqueous hydrochloric acid -methanol, or alternatively, tin-II chloride in aqueous hydrochloric acid, preferably at elevated temperatures, such as 50 ° C, gives the corresponding aniline derivative, this is reacted with a carboxylic acid anhydride, such as anhydride of succinic acid, glutaric acid anhydride, etc., in the presence of a base, such as 4-ethylhexamine, in a solvent, such as DMF, at room temperature and yields a guanidino-ar-thiazole of formula XVIII.

In a process variant the aniline derivative obtained after the reduction is reacted with a protected dicarboxylic acid such as the mono-ester, such as mono-methyl adipate, under the influence of a coupling reagent, such as BOP, and a base, such as 4-yl-morpholine, in a solvent, such as DMF, at room temperature, followed by ester hydrolysis by means of a strong base, such as lithium hydroxide, in a suitable solvent, such as water - trahydrofuran, preferably at room temperature.

When Y is - equal to - (CH2) e-NH- (protecting group), no reduction is required. The corresponding protecting group, for example Boc or Cbz, can be separated using customary methods (for example HCl in ethyl acetate).

Scheme 7a 4- ethylmorphine, DMF 0 HOOC - (CH ^ - ^ CH ^ CH ^ - COOR03 (C-O) k (N-H), R10 BOP, 4-ethylmorpholine followed by LiOH, H2O, THF Y = -NO2 - (CH2) e-NH-grupo protecting group) R0j = alkyl, aralkyl R? I2 = __ (CH2) f) _ ^ (CH ^ -ÍCHS), - COOH (C = 0) k (-H), R? O Analogously to Scheme 7a o-aryl thiazoles of formula XVII are converted in the corresponding ureido-aryl iazoles of formula XIX (Scheme 7b).

Also analogously to Scheme 7a, the corresponding 4 - (nor tro-aryl) -2-solid-thiazoles are reduced and acylated. Also here in the case where Y is equal to - (CH2) e_NH- (protective group) no reduction is required. When B is other than hydrogen the corresponding amines, as described for Scheme 7a, are alkylated before the acylation with an aldehyde in the presence of NaBH or NaCNBH3- E s qu ema 7 b R 1) see 7a) I) see 7a) (XVII) v _ = -NO, (XIX) - (CH2) e-NH- (protective group) - = - (CH2) h (CH), - (CHa), - COOH (C = 0) k (N-H), 'R10 As imi mo l s s c ompu t s of t i po they can be used analogously to Schemes 7a and 7b, although in this case the amino group must be protected with, for example, Boc or Cbz.

When f is equal to zero and g equals 1, the corresponding compounds of formula I can be obtained by reaction of a thiazolic acid derivative with an amine: The carboxyl esters of the arylthiazoles of formula XVI and XVII (Esguema Id) are hydrolyzed by means of a strong base, such as lithium hydroxide, in an appropriate solvent, such as water-tetrahydrofuran, preferably at room temperature (Scheme 8) . The coupling of the acids with an amine component, whose carboxylic acid function is appropriately protected with an ester, using a coupling reagent, such as BOP and a base, such as 4-ethylmorpholine, in a solvent, such as DMF, a room temperature, followed by ester hydrolysis using a strong base, such as lithium hydroxide, in an appropriate solvent, such as water trahydrofuran, preferably at room temperature, gives the. guanidino-ar i 1-thiazoles of formula XX. When R1 is amino, it must be present as an amino Boc- Cbz-prot.

The carboxylic acid esters of the 2-ureido-aryl-tiazoles of formula XVII are coupled and saponified analogously to Scheme 8. The corresponding 4- (hydroxycarbonylaryl) -thiazoles are reacted in an analogous manner.

Scheme 2) H2N-R012, BOP, - - ethylmorpholine followed by LiOH, H, O, THF R = alkyl, aralkyl The corresponding aminoaryl iazoles and carboxylaryl thiazoles are accessible, for example, by the reaction route set forth in Scheme Id. The amine derivatives (g equal to 1) or acid derivatives (f equal to 1) required for the generation of the substituent R 2 are obtainable according to methods known per se.

Compounds of the formula H 2 N-Ro 2 are commercially available or can be synthesized according to, for example, one of the following routes: when R 10 is an amino acid linked via the amino group and k is equal to 1 and 1 is equal to zero, the synthesis is carried out in accordance with usual methods and techniques of protecting groups as used in the synthesis of the peptides. When R.sub.10 is aryl, aralkyl, het, ethocyclyl, heterocyclyl, hydroxyl, hydrogen or alkyl, where 1 equals 1 and k being equal to 1, the same procedure can be used. When k is equal to zero 1 equals 1 and j equals 1, then the amine R 10 -NH 2 can be added to the corresponding carboxylic acid derivative alpha, bet a-unsaturated in the sense of a Michael addition. The primary amines obtained in this way can then be derivatized by reaction with chlorides or carboxylic acid anhydrides, esters of chloroformic acid or suifluorides according to conventional methods. When k is equal to zero, 1 is equal to 1 and j is equal to zero, the corresponding alpha-amino acids are commercially available or can be obtained in accordance with syntheses described in the literature. When k equals zero, 1 equals 1 and j equals 2, corresponding gamma-keto esters can be used and can be converted to the desired amines by reductive amination with R 10 -NH 2. When 1 is equal to zero and k is equal to 1, corresponding ketones can be prepared according to methods described by L.E. Fisher et al., Org. Prep. Proc. Int. 1990, 22, 399-484, or by K. Matsumoto et al., Chem. Pharm. Bull. 1986, 34, 4516. When R10 is hydroxyl, with 1 being equal to zero with k being equal to zero, but an ester of DL-4-amino-3-hydroxybutyric acid, which is commercially available, can be used, for example. . When R10 is carboxyalkyl the procedure described by 0. Tsuge et al. (Bull, Chem. Soc. Jpn 1986, 59, 2537-45).

The compounds of formula XXVII (scheme 9) can be reacted, for example, with an ittig-Horner reagent, such as triethyl phosphonoacetate, and a base, such as sodium alcoholate, in a solvent, such as ethanol, at room temperature. environment or elevated temperature. The unsaturated compounds thus obtained are hydrogenated on a catalyst, such as Pd / C, in a solvent, such as ethanol, and then converted to compounds XXVIII by removal of the protecting group.

Esguema 9 3) HCl ', AcOEt (XXVH) (xxvxp) R03 = alkyl, aralkyl In addition to the processes described above, the substituent R1 may vary within the scope of the definitions of the general formula I. In this process variant (Scheme 10), a thiazole derivative of the formula XXXVIII with intermediate protection of the acid functions in R2 and R3 can be guanidated (Tet Lett 29 3183-86, 1988). Compound XXVIII is reacted with an isocyanate for the preparation of the corresponding urea derivatives.

Compounds of type XXXVIII can be obtained, for example from compound XIV after reaction with the corresponding amine components and removal of the Boc protecting group. When a is equal to zero, the process is started from the corresponding thiazolic base compounds of Schemes la, Ib and Id.

E s qu ema 10 (xxxvpi) In the case where m equals zero and f and g are equal to zero and c equals 1 the compounds The corresponding one can be prepared according to Escher 2, wherein the substituent R 2 is introduced by forming an amide bond in the thiazole structure.

"The invention also includes intermediates of the formula s (XXXX) (XXXI) and their salts wherein R1, R3 and a have the meaning indicated above and wherein in the formula XXXI R3 is not hydrogen or methyl when R1 is H2N, H2N H2N- = N-IC-NH- HN * The especially preferred intermediates are: Ethyl 2-guanidino-4-propyl-thiazole-5-carboxylate bromide,. ethyl 2-guanidino-4-phenyl-thiazole-5-carboxylate hydrobromide, ethyl 4-tert-butyl-2-guanidino-thiazole-5-carboxylate hydrobromide, 4-cyclopentyl-2-guanidino-thiazole-hydrobromide Ethyl 5-carboxylate, ethyl 3- (3-amino-benzoylamino) -3-phenyl-propionate hydrochloride, rac-3- (2-benzyloxycarbonylamino-acetylamino) -3-phenyl-ethyl propionate, rac-6- ethyl-tert-5-carboxylamino-3-phenyl-hexanoate, ethyl rac-6-amino-3-phenyl-hexanoto hydrochloride, [(2-guanidino-thiazole-4-carbonyl) -amino] -ethyl acetate, acid [ (2-guanidino-t-azol-4-carbonyl) -amino] -acetic, 1-N-phenyl-amide of the 4-tert-butyl ester of Cbz- (L) -aspartic acid, 1-N-phenyl-amide 4-tert-butyl ester of (L) -aspartic acid, rac-3- (3-benzyloxycarbonylamino-propionylamino) -3-phenyl-propionate, rac-3- (3-amino-propionylamino) -3-phenyl -ethyl propionate, 2-guanidino-4-methyl-thiazole-5-carboxylic acid, 2-guanidino-4-propyl-thiazole-5-carboxylic acid hydrochloride, 2- acid guanidino-4-phenyl-thiazole-5-carboxylic acid, 4-tert-butyl-2-guanidino-thiazole-5-carboxylic acid hydrochloride, 4-cyclopentyl-2-guanidino-thiazole-5-carbamic acid hydrochloride boxyl, 2- (tert-butoxycarbonylamino-methyl) -4-methyl-thiazole-5-carboxylic acid, l-nitro-4- (2-nitro-propenyl) -benzene, N- [4-methyl-5- (4-nitro-phenyl) -thiazol-2-yl] -guanidine, N- [4-methyl-5- (3-nitro-phenyl) -thiazol-2-yl] -guanidine, 4- (2-guanidino-) Methyl 4-methyl-thiazol-5-yl) -benzoate, methyl 3- (2-guanidino-4-methyl-thiazol-5-yl) -benzoate, N- [5- (4-amino-phenyl) hydrochloride ) -4-methyl-thiazol-2-yl] -guanidine, N- [5- (3-amino-phenyl) -4-methyl-thiazol-2-yl] -guanidine clprhdirate, 4- (2-guanidino) -4-methyl-thiazol-5-yl) -benzoic acid, 3- (2-guanidino-4-methyl-thiazol-5-yl) -benzoic acid, 4-methyl-2- (3-methyl-ureido) - thiazole-5-carboxylic acid, 2- < 3-benzyl-ureido) -4-methyl-thiazole-5-carboxylic acid ethyl, 2- (3-benzyl-ureido) -4-methyl-thiazole-5-carboxylic acidEthyl 2- (3-benzyl-ureido) -thiazole-4-carboxylate 2- (3-benzyl-ureido) -thiazole-4-carboxylic acid 3- (3-tert-butoxycarbonylamino-benzoylamino) -3 ethyl-pyridin-3-yl-propionate, rae 3- (3-amino-benzoylamino) -3-pyridin-3-yl-propionate ethyl, rae 3- [2- (tert-butoxycarbonyl-cyclopropyl-nau.no ) -acetylamino] -3- ethyl phenylpropionate, rae hydrochloride 3- (2-cyclopropylamino-acetylamino) -3-phenylpropionate ethyl, 3- (3-nitro-phenylsulfonylamino) -3-phenyl-propionic acid, 3- (3-nitro-phenylsulphonylamino) -3-phenyl-propionate, ethyl 3- (3-amino-phenylsulfonylamino) -3-phenyl-propionate, rac-3- [5-amino-2- ( 2-methoxy-ethoxy) -benzoylamino] -3-phenyl-pro-ethyl pionate, rac-3- (3-amylo-5-benzyloxy-benzoylamino) -3-phenyl-propionyl ethyl propionate hydrochloride, rac-7- ethyl tert-butoxycarbonylamino-3-phenyl-heptanoate, ethyl rac-7-amino-3-phenyl-heptanoate hydrochloride, rac-3- (3-amino-4-methoxy-benzoylamino) -3-phenyl-propionate of ethyl, clo ethyl 6-amino-5-oxo-hexanoate hydrochloride, 4-methyl-5- (3-nitro-phenyl) -thiazol-2-yl-amine, l-benzyl-3- [4-methyl-5- ( 3-Nitro-phenyl) -thiazol-2-yl] -urea, 1- [5- (3-amino-phenyl) -4-methyl-thiazol-2-yl] -3-benzyl-urea, monoethyl ester of the acid rae 3-pyridin-3-yl-pentandicar-boxyl, [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetic acid ethyl ester [[2- (3-benzyl-ureido)] -thiazole-4-carbonyl] -amino] -acetic, (S) -N-benzyl-3-benzyloxycarbonylamino-succinamate of tert-butyl, (S) -3-amino-N-benzyl-succinamate of tert-butyl, (S) -3-benzyloxycarbonylamino-N- (3-methoxy-phenyl) -succinamate of tert-butyl, (S) -3-amino- N- (3-methoxy-phehyl) -succinamate of tert-butyl, (S) -2- (2-benzyloxycarbonylamino-3-tert-butoxycarbonyl-propionylamino) -benzoate of tert-butyl, (S) -2- (2 3-tert-butoxycarbonyl-propionylamino) -butyl tert-butyl ester, 3- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -ethylbenzoate, 3-tert-butyl-3-tert-butoxycarbonyl-propionylamino) -benzoate; - [(2-guanidino-4-methyl-thiazole-5-carbonyl) -anu.no] -benzoic acid, rac-3-tert-butoxycarbonylmethyl-2-oxo-piperidine-l-carboxylate of tert-butyl, rac-3 -benzylcarbamoyl-6-tert-butoxycarbonylamino-tert-butyl hexanote, ethyl rac-6-amino-3-benzylcarbamoyl-hexanoate hydrochloride, ethyl 2-phenoxycarbonylamino-thiazole-4-carboxylate, 2- (3-pyridine) Ethyl 2-ylmethyl-ureido) -thiazole-4-carboxylate, 2- (3-pyridin-2-ylmethyl-ureido) -thiazole-4-carboxylic acid, 4- [2- (3-benzyl-ureido) -thiazole -4-ethyl] -butyrate of ethyl, 4- [2- (3-benzyl-ureido) -thiazol-4-yl] -butyric acid, rac-2- (3-bromo-2-oxo-propyl) -succinate-diethyl ester, rac-2- (3-azido-2-oxo-propyl) -succinate-diethyl ester, rac-2- (3-amino-2-oxo-propyl) -succinate-diethyl, (S) -3-benzyloxycarbonylamino-N-pyridin-2-ylmethyl-succinamate-tert-butyl ester, (S) - 3-amino-N-pyridin-2-ylmethyl-succinamate tert-butyl ester, (S) -3-benzyloxycarbonylamino-N-pyridin-3-ylmethyl-succinamate tert-butyl ester, (S) -3-amino-N- tert-butyl pyridin-3-ylmethyl-succinamate, (S) -3- (2-benzyloxycarbonylamino-acetylamino) -N-pyridin-2-ylmethyl-succinamate tert-butyl ester, (S) -3- (2-amino) -acetylamino) -N-pyridin-2-ylmethyl-succinic acid tert-butyl ester, 2- (imidazolidinyl) -ylideneamino) -thiazole-4-carboxylic acid ethyl hydrobromide, 2- (imidazolidin-2-) ilidenamino) -thiazole-4-carboxylic acid, rac-3- (2-benzyloxycarbonylamino-acetylamino) -3-pyridin-3-yl-propionate, Ethyl 3- (2-amino-acetylamino) -3-pyridin-3-yl-propionate hydrochloride, ethyl 4-methyl-2- (tetrahydro-pyrimidin-2-ylidenamino) -thiazole-5-carboxylate hydrochloride and 4-methyl-2- (tetrahydro-pyrrr-L-ddin-2-ylidenamino) -thiazole-5-carboxylic acid.

The compounds of formula I described above for use as therapeutically active substances are another object of the invention.

The compounds described above for the production of medicaments for the prophylaxis and therapy of diseases that are caused by a poor function of the binding of adhesive proteins to vitronectin receptors also constitute an object of the invention.

Also, an object of the invention are pharmaceutical compositions containing a compound of formula I described above and a therapeutically inert carrier. The invention also relates to a pharmaceutical composition previously described, which additionally contains one or more compound of the general formula I or additionally one or more compounds selected from the group comprising anticagulants, fibrinolytic agents or medicaments for the prophylaxis and therapy of diseases that are caused by a bad function of the binding of adhesive proteins of vitronectin receptors.

An object of the invention is also the use of the compounds described above for the production of medicaments for the treatment or prophylaxis of diseases that are caused by a poor function of the binding of adhesive proteins of vitronectin receptors.

Another object of the invention is also the use of one of the compounds described above for the production of medicaments, for example for the treatment or prophylaxis of neoplasms, tumor metatasis, tumor development, osoporosis, Paget's disease, diabetic retinopathy, macular degeneration. restenosis after vascular intervention, psoriasis, arthritis, fibrosis, renal failure, as well as infections caused by viruses, bacteria or fungi.

Another object of the invention comprises compounds that can be prepared according to one of the methods described.

Also an object of the invention are methods for the treatment and prophylaxis of diseases that are caused by a poor function of the binding of adhesive proteins to vitronectin receptors and comprising the administration of an effective amount of a compound of formula I.

Another object of the invention is a method for the treatment and prophylaxis of neoplasms, tumor metatasis, tumor development, osteoporesis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis after vascular intervention, psoriasis, arthritis, fibrosis, renal insufficiency, as well as infections caused by viruses, bacteria or fungi, with which an effective amount of one of the compounds described above is administered.

Also an object of the invention are compounds described above for the treatment and prophylaxis of neoplasms, tumoral metastasis, tumor development, osoporosis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis after vascular intervention, psoriasis, arthritis, fibrosis, renal failure. , as well as infections caused by viruses, bacteria or fungi.

The conversion of a compound of formula I into a pharmaceutically usable salt can be carried out by treating such a compound with an inorganic acid, for example a hydrohalic acid, such as, for example, hydrochloric acid or hydrobromic acid, sulfuric acid , nitric acid, phosphoric acid, etc., or with an organic acid, such as, for example, acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, metasulfonic acid or p-toluenesulfonic acid.

The corresponding carboxylate salts can also be prepared from the compounds of formula I by treatment with physiologically compatible bases.

The conversion of a compound of formula I to a pharmaceutically usable ester can be carried out by treatment of a compound of this kind in the usual manner or as described in the examples. As previously indicated, the compounds of formula I and their pharmaceutically usable salts and esters especially inhibit the binding of various adhesive proteins such as fibrinogen, vitronectin, von Willebrand factor, fibronectin, rhombospondin and osteopontin to vitronectin receptors (such as , for example, avb3, avbs, avbß, avbs, etc.) on the surface of different cell types. Thus, the aforementioned compounds influence cell-cell and cell-matrix interactions. Because the receptors play a role, among others, in the spread of tumor cells,. in vascular regeneration, in the degradation of bone tissue, in the migration of smooth muscle cells in vascular walls and in the invasion of viral particles in target cells, said compounds can be used as receptor antagonists of vitronectin in the control or prevention of neoplasms , tumor metastasis, os teoporosis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis after vascular intervention, psoriasis, arthritis, fibrosis, kidney failure, as well as infections caused by viruses, bacteria, or fungi. Because the binding of the adhesive proteins to the fibrinogen receptor (alphapbeta3) on the surface of blood platelets is practically not inhibited, side effects such as, for example, hemorrhages can be suppressed with the therapeutic application of said compounds.

The inhibition of binding of adhesive proteins such as, for example, fibrinogen to vitronectin receptors (such as, for example, avb3, avb5, avbβ, avb8, etc.) by the compounds of the present invention can be determined as described by L Alig et al. (J. Med. Chem. 1992, 35, 4393-4407).

In detail, wells of microtiter plates (Nunc-Immunoplat and MaxiSorp) were coated overnight at 4 ° C with the vitronectin alfavbeta3 receptor (from human placenta, 100 μl / well) in a buffer system with 150 mmol / 1 NaCl, 1 mmol / CaCl2, 1 mmol / 1 MgCl2, 0.0005% Triton X-100 and 20 mmol / 1 Tris HCl, pH 7.4. Non-specific binding sites were blocked by incubation with 3.5% bovine serum albumin (Fluka BSA) at 20 ° C for at least 1 hour.

Before using the test the plates were washed in each case once with 150 mmol / 1 NaCl, 1 mmol / 1 CaCl 2, 1 mmol / l MgCl 2 and 20 mmol / l Tris HCl, pH 7.4 (buffer A). The plates thus coated can be stored for at least 2 months in the presence of 0.05% NaN3 (in buffer A) at 4 ° C in a humidity chamber without loss of binding activity. Fibrinogen (IMCO, free of fibronectin) was diluted to 1.5 μg / ml in buffer A in the presence of 1% BSA. The wells coated with the receptor were incubated with fibrinogen (100 μl / well) overnight at room temperature in the absence or in the presence of increasing concentrations of RGDS (as the reference substance) or the compounds to be measured. Unbound fibrinogen was separated by three washes with buffer A, detecting bound fibrinogen by an ELISA method. Rabbit antibodies directed against human firbinagen (Dakopatts, Denmark), diluted in buffer A in the presence of 0.1% BSA, were added at room temperature for 1 hour, followed by incubation with biotinylated antibodies directed against rabbit immunoglobulin (Amersham) for 30 minutes. By means of three washes with buffer A unbound antibodies were separated. Then, the pre-formed biotinylated peroxidase complex was added for 30 minutes (Amersham), again carrying out three "washes with buffer A. After the addition of the ABTS peroxidase substrate (acid 2, 2'-Azino-bis (3-eylbenzothiazolin-6-sulfonic acid), Boehringer Mannheim) enzyme activity was measured with a multichannel photometer (Uvmax, Molecular Devices). The difference between the total union activity (in the absence of a test substance) and non-specific binding activity (in the presence of 100 μM RGDS) is taken as the specific binding activity.

The concentration of a test substance that is required to inhibit the specific binding activity in 50% was defined as the IC50.

The isolation of the alfavbeta3 receptor used in the test can be carried out as follows: Human placenta is stored at -80 ° C immediately after its excision. In order to extract the recipient each placenta is thawed superficially and cut into narrow strips with a scarp. The pieces are washed twice with a buffer of 150 mmol / 1 NaCl, 1 mmol / l CaCl 2, 1 mmol / 1 MgCl 2 and 20 mmol / 1 Tris HCl (pH 7.4). The proteins are extracted at room temperature for one hour with a buffer solution of 1% Triton X-100, 150 mmol / 1 NaCl, 1 mmol / 1 CaCl 2, 1 mmol / 1 MgCl 2, 20 mmol / 1 Tris HCl, NaN 3 0.02%, 0.5 mmol / 1 phenylmethyl sulphide 1 fluoride, 1 mmol / 1 leupeptin and 2 mmol / 1 Ne t -malemaleimide (pH 7.4) and filtered through sterile gauze. The filtrate is centrifuged at 30000 g for 30 minutes at 4 ° C. First the glycoproteins are separated with the help of a concavalin A-Sepharose 4B column. Proteins bound to the column are eluted and then added to an Aeg-RGDS column. After repeated washing, the bound vitronectin receptor is eluted with 3 mmol / l RGDS in a buffer of 0.1% Triton X-100 150 mmol / 1 NaCl, 20 mmol / 1 Tris HCl, 1 _ mmol / l CaCl2, 1 mmol / 1 MgCl2, 0.05% NaN3 (pH 7.0).

Table 1 shows examples of compounds according to formula I, wherein these compounds have IC 50 values less than 1 μM. These results have been obtained using the preceding test.

Table Rae acid 3- [2- [I (2- (3-ber.-cyclo-ureic) -thiazol-4-ylcarbonyl] -amino] -acetylamino] -3-phenyl-prcpionic acid rae 4- [3- (2- guanidir.o-4-re-thiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyric acid rae 3- [2- [(2-guanidir.c ~ etiI-thiazol-4-ylcarbonyl) -amino] - acetylamino] -3-phenyl-prcpicr.o rae acid hydrochloride 3- [3- {; 2-g anidino-4-methyl-thia: .ol-5- -carbonyl) -amir.o! -benzollamino] -3-phenyl-propionic acid rae 3- (3- ((4-tert-butyl-2-g anidir.o-thiazol-5-ylcarbonyl) -amino] -ber.zoila.t.ino] - 3-pyridin-3-yl-prcpionic [2-guar.idir.o-tiaz.ol-4-carbcnyl] -Gly-Asp-Val-OH trifluoroacetate hydrochloride (S) -N-be.cil-3 2- ((2- (3-benzyl) -ureido) -thia- zol-4-carbcnil) -ainir.o) -acetylaptino) -succinanate Preferred compounds as described above have an IC50 that is less than 100 μM; Especially preferred compounds have a value of less than 10 μM, particularly preferred compounds have a value of less than 1 μM.

The compounds of the formula I and their pharmaceutically usable salts and esters can be used as medicaments (for example in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example in the form of nasal sprays) or rectally ( for example in the form of suppositories). However, the administration can also be carried out parenterally, such as intramuscularly or intravenously (for example in the form of injection solutions).

The compounds of formula I and their usable pharmaceutical salts and esters can be prepared with pharmaceutically inert inorganic or organic adjuvants for the production of tablets, coated tablets, dragees and hard gelatine capsules. As adjuvants for tablets, dragees and hard gelatin capsules, there can be used, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc.

Suitable adjuvants for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.

For the production of solutions and syrups, for example, water, polyols, sucrose, invert sugar, glucose, etc. are suitable.

Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquefied polyols, e t c.

In addition, pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, flavorings, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also still contain other therapeutically valuable substances.

According to the invention, the compounds of formula I and their pharmaceutically usable salts and esters can be used as antacysts of vitronectin receptors, especially for the prophylaxis of neoplasms, tumor metastasis, tumor development, osteoarthritis, Paget's disease, diabetic retinopathy, degeneration. macular, restenosis after vascular intervention, psoriasis, arthritis, fibrosis, renal failure, as well as infections caused by viruses, bacteria or fungi. The dose can vary within wide limits and will obviously conform to the individual requirements of each particular case. In general, in the case of oral administration, a daily dose of about 0.1 mg to 20 mg per kg of body weight, preferably about 0.5 mg to 4 mg per kg of body weight (per example about 300 mg per person), divided into, preferably, 1-3 individual doses, which may consist, for example, of the same amounts. However, it will be evident that the upper limit indicated above may be exceeded when considered appropriate.

The invention is illustrated below by means of examples that are not limiting in nature.

Example 1 13.9 ml of ethyl bromopyruvirate was added to a solution of 11.81 g of 2-imino-4-thiobiuret (Aldrich) in 100 of ethanol and the reaction mixture was heated to reflux for 3 hours (J. Me. Chem. 34, 914-918 (1991)). The mixture was then cooled to room temperature and the reaction product was precipitated by the addition of 550 ml of ethyl acetate and the precipitate was separated by filtration. 4.6 g of ethyl yellow 2-guanidin-thiazole-4-carboxylate bromohydrate, MS: 214 (M) +, were obtained.

Example 2 a) 1.62 ml of bromine was added dropwise, with stirring and cooling to 0-5 ° C in the range of 10 minutes, to a mixture of 2 phases of 5.06 ml of ethyl butyrylacetate and , 4 ml of water (J. Chem. Soc. Perkin I 1982, 162). The mixture was stirred at 0 ° C for a further 30 minutes and then the product was extracted with ether. After drying, 7.6 g of crude bromoketone were obtained, which was used immediately in Example 3. b) Analogously to the procedure of Example 2a, using ethyl benzoylacetate or ethyl pivaloylacetate or cyclopentyl-carbonyl-ethyl acetate instead of ethyl butylacetate, the corresponding bromoketone was prepared.

Example 3 Analogously to the procedure of Example 1, using the ethyl 2-chloroacetate or the bromo ketones prepared according to example 2, the following compounds were prepared in place of ethyl bromopyruvate: a) 2-guanidin-4-methyl-thiazole hydrochloride -5-ethyl carboxylate. MS: 228 (fcf). b) Ethyl 2-guanidin-4-propyl-thiazole-5-carboxylate bromohydrate. MS: 256 (M *). c) Ethyl 2-guanidin-4-propyl-thiazole-5-carboxylate bromohydrate. MS: 290 (M *). d) Ethyl 4-tert-butyl-2-guanidin-4-propyl-thiazole-5-carboxylate bromohydrate. MS: 271 (M + H) +. e) ethyl 4-cyclopentyl-2-guanidin-thiazole-5-carboxylate bromohydrate. MS: 283 (M + H) +.

Example 4 146 ml of 3N sodium hydroxide solution were added to 14.6 g of the ester obtained in example 1, and the reaction mixture was refluxed for 3 hours. (J. Med. Chem., 34, 914-918 (1991)). Then, the reaction mixture was cooled to RT, acidified with 73 ml of 6N hydrochloric acid and evaporated to volume. The precipitated material was separated by filtration and washed with water. After drying, 9.44 g of 2-guanidin-thiazole-4-carboxylic acid hydrochloride were obtained; MS: 186 (M *).

Example 5 220 mg of 2-guanidin-4-methyl-thiazole-5-carboxylic acid (example 29a), 225 mg of N-β-alanyl-β-alanine ethyl ester hydrochloride, 4 ml of DMF, 0.34 ml of N-methylmorpholine (NMM) and 445 mg of o- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), were stirred at room temperature under argon for 21 hours. hours. The reaction mixture was diluted with ethyl acetate and washed first with a dilute aqueous solution of sodium carbonate and sodium chloride, then with a dilute solution of sodium chloride, and finally with a saturated solution of chloride The organic phase was dried with sodium sulfate and evaporated in vacuo, chromatography on silica gel with ethyl acetate-ethanol 45: 1 gave 190 mg of 3- [3- [(2-guanidin-4-methyl)] ethyl thiazole-5-carbonyl) -amino] -prionylamino] -propionate, in the form of a pale yellow foam, MS: 371 (MfH) + Example 6 144 mg of 3- [3- [(2- ethyl guanidin-4-methyl-thiazole-5-carbonyl) -amino] -prionylamino] -propionate were allowed to stand with 2.9 ml of 25% hydrochloric acid for seven hours.The reaction mixture was evaporated in vacuo The residue was triturated in 2.5 ml of acetonitrile, filtered off with suction, washed with acetonitrile and dried in vacuo. 125 mg of 3- [3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -propionylamino] -propionic acid hydrochloride (1: 2) of m.p. 170 ° C MS: 343 (M + H) +.

Example 7 Analogously to the method described in example 5, from the sodium salt of 2-guanidin-thiazole-4-carboxylic acid and the ethylhydrochloride of the N-β-alanyl-β-alanine ethyl ester, the Ethyl 3- [3- [(2-guanidin-4-methyl-thiazole-4-carbonyl) -amino] -propionylamino] -propionate, p. F. 154-157 ° C, MS: 357 (M + H) +. Example 8 Analogously to Example 6, 3- [3- [(2-guanidin-thiazole-4-carbonyl) -amino] -propionylamino] -propionate ethyl was obtained, 3- [3- [3- [ (2-guanidin-thiazole-4-carbonyl) -amino] -propionylamino] -propionic acid (1: 1.35), m.p. 205-207 ° C, MS: 329 (M + H) +. Example 9 316 mg of tert-butyl 3- [3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino] -propionate, were stirred in 2.1 ml of methylene chloride and 2.1 ml of trifluoroacetic acid at RT for 2 hours. The solvents were evaporated and the residue obtained was triturated in MeCN. 311 mg of 3- [3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino] -propionic acid trifluoroacetate (1: 1.06), m.p. 212 ° C, MS: 391 (M + H) +. The starting material was prepared as follows: a) 3.14 g of .3-benzyloxycarbonylamino-benzoic acid, 2.02 g of CDMT, 34 ml of THF and 1.3 ml of NMM were stirred at RT for 2.5. hours. After the addition of 2.1 g of the β-alanine tert-butyl ester hydrochloride and 1.3 ml of NMM, the mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and washed successively with dilute hydrochloric acid cooled with ice, water, dilute sodium carbonate solution, water and saturated sodium chloride solution. After drying with sodium sulfate and evaporating the solvent and crystallizing with AcOEt, 3.83 g of 3- (3-benzyloxycarbonylamino-benzsil-amino) -propionate of tert-butyl, m.p. 62-163 ° C, MS: 399 (M + H) +. b) By means of catalytic hydrogenation with Pd / C in alcohol, the tert-butyl ester of N- (3-aminobenzoyl) -β-alanine was obtained therefrom, in the form of an oil, MS: 265 (MfH) -f- . c) This is coupled with 2-guanidin-4-methyl-thiazole-5-carboxylic acid, according to the method described in Example 5. Chromatography on silica gel with methylene chloride-alcohol provided the 3- [3 - [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino] -propionate tert -butyl in the form of a pale yellow foam, MS: 447 (M + H) +. Example 10 Analogously to example 5, from 2-guanidin-4-methyl-thiazole-5-carboxylic acid and ethyl rac-3- (3-amino-benzoylamino) -3-phenyl-propionate hydrochloride, the rac-3- [3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino] -3-phenyl-ethyl propionate, mp 177 ° C, MS: 495 (M + H) +. The starting material was prepared as follows: a) According to the method described in example 9a, from 3-tert-butoxycarbonylamino-benzoic acid and ethyl rac-3-amino-3-phenylpropionate hydrochloride , rac-3- (3-tert-butoxycarbonylamino-benzoylamino-3-phenyl-propionate ethyl, mp 130-131 ° C, MS 413 (M + H) +, b) 985 mg thereof, were dissolved in 4.5 ml of ethyl acetate, treated with 4.5 ml of 4N HCl in ethyl acetate and stirred at RT for 1 hour. After evaporation of the solvent in vacuo, ethyl rac-3- (3-amino-benzylamino) -3-phenylpropionate hydrochloride (1: 1.15) was obtained as a yellow foam, MS 313 (M + H) +. EXAMPLE 11 Approximately 100 mg of ethyl rac -3- [3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino] -3-phenyl-propionate was allowed to stand at 2 ° C. , 1 ml of 25 percent hydrochloric acid at RT for 6 hours. The solution was evaporated and the residue dissolved in water and evaporated again. The rac-3- [3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino] -3-phenyl-propionic acid hydrochloride (1: 1.27), m.p. 155-162 ° C, MS: 467 (M + H) +. Example 12 Analogously to Example 5, from 2-guanidin-thiazole-5-carboxylic acid and from rae 3- (2-amino-acetylamino) -3-phenyl-propionate ethyl ester, rae 3 was obtained. - [2- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -acetyl-amino] -3-phenyl-ethyl propionate, mp. 145 ° C, MS: 419 (M + H) +. The starting material was prepared as follows: a) Analogously to example 9a), coupling Z-glycine with ethyl 3-amino-3-phenyl-propionate hydrochloride, rae 3- [2-benzyloxycarbonyl- amino-acetylamino] -3-phenyl-propionate, MS: 385 (M + H) +. b) The latter was hydrogenated with - Pd / C in ethyl alcohol, the filtered solution was adjusted to pH 3 with ethanolic hydrogen chloride solution, and evaporated in vacuo. This gave the rae hydrochloride ethyl 3- (2-amino-acetylamino) -3-phenyl-propionate (1: 1) as a colorless foam, MS: 251 (M + H) +. Example 13 Analogously to Example 6, from rae 3- [2 - [(2-guanidin-thiazole-5-carbonyl) -amino] -acetylamino] -3-phenyl-propionate ethyl, rae hydrochloride was obtained 3- [2- [(2-guanidin-thiazole-5-carbonyl) -amino] -acetylamino] -3-phenyl-propionic acid (1: 1,15), m.p. 245 ° C, MS: 391 (M + H) +. Example 14 Analogously to the method described in example 9a, from 2- (3-benzyl-ureido) -thiazole-4-carboxylic acid and ethyl (RS) -6-amino-3-phenyl-hexanoate hydrochloride, After chromatography on silica gel with ethyl acetate / hexane and crystallization from ether, (RS) -6- was obtained. { (2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino.} - ethyl-3-phenyl-hexanoate, mp 93 ° C, MS: 495 (M + H) +. was prepared as follows: a) A solution of 1.725 g of sodium in 150 ml of ethanol was treated at RT with 15 ml of triethyl phosphonacetate and 13.17 g of (4-oxo-4-phenyl-butyl) -carbamate of tert-butyl, and stirred at 70 ° C for 6 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and washed successively with dilute hydrochloric acid, water and saturated sodium chloride solution. The ethyl acetate solutions were dried with sodium sulfate and evaporated. After chromatography on silica gel with acetone-hexane, a mixture of ethyl 6-tert.-butoxycarbonylamino-3-phenyl-hex-2-enoate and 6-tert-butoxycarbonylamino-3-phenyl-ex-3- was obtained. ethyl acetate, in the form of an oil, MS: 334 (M + H) +. b) By means of catalytic hydrogenation with Pd / C in ethanol, ethyl (RS) -6-tert-butoxycarbonyl-amino-3-phenyl-hexanoate was obtained therefrom, in the form of a colorless oil, MS 336 (M + H) +. c) Cleavage of the protecting group with HCl in ethyl acetate leads to ethyl (RS) -6-amino-3-phenyl-hexanoate hydrochloride, MS: 235 (M) +. Example 15 172 mg of (RS) -6-. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} Ethyl 3-phenyl-hexanoate in 3.5 ml of ethanol were treated with 0.52 ml of 1N NaCH and stirred at RT for 6 hours. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and washed with dilute hydrochloric acid, water and sodium chloride solution. The ethyl acetate solution was dried and evaporated in vacuo. Chromatography on silica gel with ethyl acetate and ethyl acetate / acetic acid 99: 1 gave 76 mg of (RS) -6- acid. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -3-phenyl-hexanoic acid, in the form of a white foam, MS: 467 (M + H) +. Example 16 The 2-guanidin-thiazole-4-carboxylic acid monohydrate was coupled to the ethyl (RS) -6-amino-3-phenyl-hexanoate, analogously to Example 5. Silica chromatography with CHCl2-MeOH provided the (RS) -6- [(2-Guanidinothiazole-4-carbonyl) -amino] -3-phenyl-hexanoate ethyl, in the form of a white foam, MS: 404 (M + H) +. 2-Guanidin-thiazole-4-carboxylic acid monohydrate (p.f. >); 270 ° C) was obtained from ethyl 2-guanidin-thiazole-4-carboxylate by saponification with sodium hydroxide solution in ethanol. After evaporation of the solvent the residue was dissolved in water and the product was precipitated with hydrochloric acid at pH 2. EXAMPLE 17 234 mg of (RS) -6- [(2-guanidin-thiazole-4-carbonyl) -amino] Ethyl 3-phenyl-hexanoate was stirred in 4.6 ml of 25% hydrochloric acid at RT for 28 hours. The solution was evaporated in vacuo, the residue dissolved in water and neutralized with ammonia. The precipitate obtained was filtered off with suction and triturated in ethanol for purification. 96 mg of (RS) -6 - [(2-guanidin-thiazole-4-carbonyl) -amino] -3-phenyl-hexanoic acid, p. F. 230 ° C, MS: 376 (M + H) +.

Example 18 306 mg. Of the 2-guanidin-thiazole-4-carboxylic acid monohydrate, 570 mg of HBTU, 6 ml of DMF and 0.51 ml of NMM, were stirred at RT for 40 minutes. After the addition of 531 mg of ethyl (RS) -3- (3-amino-benzoylamino) -3-phenyl-propionate hydrochloride, the mixture was stirred at RT overnight. Operating as described in Example 5, chromatography on silica gel with methylene chloride-EtOH 9: 1 and trituration of isopropyl ether gave 505 mg of (RS) -3-. { 3- [(2-guanidin-thiazole-4-carbonyl) -amino] -benzoylamino} Ethyl-3-phenyl-propionate, m.p. 117 ° C MS: 481 (M + H) +. Example 19 470 mg of (RS) -3-. { 3- [(2-guanidin-thiazole-4-carbonyl) -amino] -benzoylamino} 3-phenyl-propionate, 5 ml of acetic acid and 14.1 ml of 25% HCl were stirred at RT for 24 hours. The reaction mixture was evaporated to dryness in vacuo, the residue was dissolved in water, adjusted to pH 9 with ammonia and the solution was evaporated from. new. The residue obtained was triturated in water, filtered with suction and dried. 290 mg of (RS) -3- acid were obtained. { 3- [(2-guanidin-thiazole-4-carbonyl) -amino] -benzoylamino} -3-phenyl-propionic, of p.f. 235 ° C, MS: 453 (M + H) +. EXAMPLE 20 Analogously to Example 9, 3- [3- [(2-guanidin-thiazole-4-carbonyl) -amino] -benzoylamino] -propionate of tert-butyl was obtained from trifluoroacetate of 3- [3-] acid. [(2-guanidin-thiazole-4-carbonylo) -amino] -benzoylamino] -propionic acid (1: 1.05), m.p. 240 ° C, MS: 377 (M + H) +.

The 3- [3- [(2-guanidin-thiazole-4-carbonyl) -amino] -benzoylamino] -propionate of tert-butyl was obtained by analogy with example 5, from the sodium salt of the 2-acid. guanidin-thiazole-4-carboxylic acid and the tert-butyl ester of N- (3-aminobenzoyl) -β-alanine. Example 21 116 mg of 4-tert-butyl ester of (S) -N2- acid. { 2- [(2-guanidin-thiazole-4-carbonyl) -amino] -acetyl} Arctic 1-N-phenyl-amide was stirred in 0.7 ml of methylene chloride and 0.7 ml of TFA at RT for 3 hours. The reaction mixture was evaporated in vacuo, the residue dissolved in water and evaporated again. The residue was then adjusted in water to pH 8 with ammonia, triturated, filtered with suction, washed with water and dried. 86 mg of the N-phenyl-amide of (S) -N2- acid were obtained. { 2- [(2-guanidin-thiazole-4-carbonyl) -amino] -acetyl} aspartic, p.f. 192 ° C, MS: 434 (M + H) +. The starting material was obtained as follows: a) According to the method described in example 5, by coupling the sodium salt of 2-guanidin-thiazole-4-carboxylic acid with the hydrochloride of the glycine ethyl ester, ethyl [(2-guanidin-thiazole-4-carbonyl) -amino] acetate was obtained, mp 190 ° C. - b) By means of the saponification with NaOh in EtOh, [(2-guanidin-thiazole-4-carbonyl) -amino] -acetic acid, p.p. 230 ° C, MS: 244 (M + H) +. c) As described in example 12a, from 4-tert-butyl ester of (L) -aspartic and alanine, 1-N-phenyl-ami was obtained from the 4-tert-butyl acid ester Z- (L) -aspartic, pf 87-88 ° C, MS: 399 (M + H) +. d) By catalytic hydrogenation with Pd / C in EtOH, there was obtained the 1-N-phenyl-amide of the 4-tert-butyl ester of (L) -aspartic acid, m.p. 70-71 ° C, MS: 265 (M + H) +. e) As described in Example 5, starting from [(2-guanidin-thiazole-4-carbonyl) -amino] -acetic acid and the 1-N-phenyl-amide of the acid 4-tert-butyl ester of the acid ( L) - aspartic acid, the 1-N-phenyl-amide of the 4-tert-butyl ester of (S) -N2- acid was obtained. { 2- [(2-guanidin-thiazole-4-carbonyl) -amino] -acetyl} aspartic, p.f. 150 ° C, MS: 490 (M + H) + Example 22 Analogously to Example 5, from 2-guanidin-thiazolecarboxylic acid (J. Med. Chem. 1991, 34, 914-918) and the rac- Ethyl 3- (2-amino-acetylamino) -3-phenyl-propionate (see preparation in Example 12), after chromatography on silylated silica gel RP 18 (gradient water / ethanol) and trituration in diethyl ether, obtained ethyl rac-3- [2- [(2-guanidin-thiazole-4-carbonyl) -amino] -acetylamino] -3-phenyl-propionate, p.f. 177-178 ° C (decomp.), MS (ISP): 419 (M + H) +. Example 23 Starting from ethyl rac-3- [2- [(2-guanidin-thiazole-4-carbonyl) -amino] -acetylamino] -3-phenyl-propionate, by hydrolysis with concentrated aqueous sodium hydroxide solution / Ethanol 1:20 after 1 hour at 60 ° C, cooling to room temperature and addition of 2N hydrochloric acid to pH 3, gave rac-3- [2- [(2-guanidin-thiazole-4-carbonyl) acid) -amino] -acetylamino] -3-phenyl-propionic acid as a hydrochloride in the form of a colorless solid, mp 202-205 ° C, MS (ISP): 391 (M + H) +. Example 24 By the reaction of the N-succinimidyl ester of 2-guanidin-thiazole-4-carboxylic acid (J. Med. Chem. 1991, 34, 914-918) with rac-3- (amino-propionylamino) -3- Ethyl phenylpropionate in DMF in the presence of triethylamine at 60 ° C was obtained, after concentrating the reaction mixture and chromatographing on silica gel (dichloromethane / methanol 20: 1 to 10: 1), the rac-3 [3- [(2-guanidin-thiazole-4-carbonyl) -amino] -acetyl} ethyl -propionyl-amino] -3-phenyl-propionate, m.p. 85-87 ° C, MS (ISP): 433 (M + H) +. The starting material was prepared as follows: a) By reaction of Zb-Ala-Osu (Bachem) with ethyl rac-3-amino-3-phenylpropionate hydrochloride in DMF in the presence of triethylamine at 60 ° C was obtained after the usual operations, ethyl rac-3- (3-benzyloxycarbonyl-aminopropionylamino) -3-phenyl-propionate, mp 100-101 ° C, MS (SIP): 399 (M + H) +. b) By catalytic hydrogenation of the product of the previous step in ethanol in the presence of Pd-carbon at room temperature, it was obtained after the usual operations, and trituration of n-hexane, rac-3- (3-amino-propionylamino) - Ethyl 3-phenylpropionate, mp 163-165 ° C, MS (El): 264 (M) +.

Example 25 Starting from ethyl rac-3- [3- [(2-guanidin-thiazole-4-carbonyl) -amino] -propionylamino] -3-phenyl-propionate (example 24), was obtained by hydrolysis with LiOH in ethanol, subsequent neutralization with 2N hydrochloric acid, chromatography on silylated silica gel RP 18 (water / methanol gradient) and trituration in ethyl acetate, rac-3- [3- [(2-guanidin-thiazole-4-carbonyl ) -amino] -propionylamino] -3-phenyl-propionic, mp 105-107 ° C (dec. P.), MS (ISP): 405 (M + H) +. Example 26 By the reaction of ethyl rac-3- (3-amino-propionylamino) -3-phenylpropionate (example 24) with 2-guanidin-4-methyl-thiazole-5-carboxylic acid (example 29) in presence of BOP as described in example 44, was obtained after chromatography on silylated silica gel RP 18 (water / ethanol gradient) and trituration in acetone, rac-3- [3- [(2-guanidin-4) ethyl-thiazole-5-carbonyl) -amino] -propionylamino] -3-phenyl-ethyl propionate, mp 106-107 ° C, MS (ISP): 447 (M + H) +. Example 27 By hydrolysis of the product of Example 26 with 2N-ethane sodium hydroxide solution, it was obtained after chromatography on silylated silica gel RP 18 (gradient water / ethanol) and trituration in ethyl acetate, rac-3. [3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -propionylamino] -3-phenyl-propionate, mp 176-177 ° C, MS (ISP): 419 (M + H) +.

Example 28 By treatment of [2-guanidin-thiazole-4-carbonyl] -Gly-As (OtBu) -Val-OtBu, with HCl gas, dissolved in ethyl acetate, was obtained, after filtering the precipitate and crystallizing with ethyl acetate, -the [2-guanidin-thiazole-4-carbonyl] -Gly-Asp-Val-OH as hydrochloride, mp 93 ° C, MS (FAB): 458 (M + H) +. The starting material was prepared as follows: By the reaction of H-Gly-Asp (OtBu) -Val-OtBu (J. Med. Chem. 1992, 35, 4393-4407) with 2-guanidin-thiazole-4- acid carboxylic acid (J. Med. Chem. 1991, 34, 914-918) in the presence of HBTU and N-methylmorpholine in DMF analogously to example 5, was obtained after chromatography on silica gel (Ethyl methanol acetate 98: 2) and crystallization from ethyl acetate / hexane, [2-guanidin-thiazole-4-carbonyl] -Gly-Asp (OtBu) -Val-OtBU, m.p. 134-135 ° C, MS (FAB): 569 (M + H) +. Example 29 The following compounds were prepared analogously to the procedure of Example 4, from the esters obtained according to Example 3: a) 2-Guanidin-4-methyl-thiazole-5-carboxylic acid, MS: 200 ( M +), b) 2-Guanidin-4-propyl-thiazole-5-carboxylic acid hydrochloride, MS: 229 (M + H) +, c) 2-Guanidin-4-phenyl-thiazole-5-carboxylic acid, MS 263 (M + H) \ d) 4-tert-Butyl-2-guanidin-thiazole-5-carboxylic acid hydrochloride, MS: 243 (M + H) +. e) 4-Cyclopentyl-2-guanidin-thiazole-5-carboxylic acid hydrochloride, MS: 255 (M + H). EXAMPLE 30 A suspension of 15.1 g of Boc-glycine thioamide in 150 ml of ethanol was treated with 9.9 ml of ethyl bromopyruvate and stirred at RT overnight. Then, the reaction mixture was evaporated, the residue was dissolved in ethyl acetate and washed with water. After chromatography on silica gel with ethyl acetate-hexane, 5.1 g yellowish ethyl 2- (tert-butoxycarbonylamino-ethyl) -thiazole-4-carboxylate, MS 286 (M + H) were obtained. +. Example 31 a) A suspension of 9.0 g of thioamide of N-Boc-glycine in 90 ml of ethanol was treated with 7.0 ml of ethyl 2-chloroacetoacetate and stirred at 50 ° C for 4 hours. Then, the reaction mixture was evaporated, the residue was suspended in ethyl acetate, filtered and the filtrate, after evaporation, chromatographed on silica gel with ethyl acetate-hexane. Thus, 6.0 g of brownish ethyl 2- (tert-butoxy-carbonylamino-methyl-4-methyl-thiazole-5-carboxylate) ethyl ester, MS: 300 (M) + were obtained in this manner. EXAMPLE 32 The following compounds were prepared analogously to the procedure of Example 4 from the esters obtained according to examples% 30 and 31: a) 2- (tert-Butoxycarbonylamino-methyl-4-methyl-thiazole-4-carboxylic acid, MS: 257 (M + H) +. b) 2- (tert-Butoxycarbonylamino-methyl-4-methyl-thiazole-5-carboxylic acid, MS: 273 (M + H) + Example 33-a) A mixture of 15.1 g of 4-nitrobenzaldehyde, 90 ml of acetic acid, 9.15 g of ammonium acetate and 23 ml of nitroethane, was boiled under reflux for 2 hours. The yellow solution was cooled and poured over ice-water. The mixture was extracted twice with ethyl acetate and the organic phase was evaporated. After chromatography on silica gel with hexane-ethyl acetate, 12.5 g of crystalline, yellow 1-nitro-4- (2-nitro-propenyl) -benzene were obtained.; MS: 208 (M) +. b) A suspension of 12.2 g of the nitroolefin obtained according to example 33a) in 117 ml of methanol was treated by cooling to 3 ° C with 26.7 ml of hydrogen peroxide 35% and then with 14.7 g. ml of 2N sodium hydroxide solution. The reaction mixture was stirred at room temperature for a further 2 hours, then poured into ice-water, acidified to pH 1 with 2N hydrochloric acid and extracted twice with ether. The organic phases were washed successively with water, bicarbonate solution, iron sulfate solution acidified with 5% sulfuric acid and sodium chloride solution, dried and. It vanished. 9.88 g of yellow crystalline epoxide were obtained. This material was suspended in 370 ml of ethanol, treated with 5.21 g of imino-4-thiobiuret and boiled under reflux for 4.5 hours. The brown suspension was evaporated in half on a rotary evaporator and the precipitated material was removed by filtration. 5.95 g of crystalline, brown N- [4-methyl-5- (4-nitro-phenyl) -thiazol-2-yl] -guanidine were obtained in this way; MS: 278 (M + H) +. Example 34 The following compounds were prepared analogously to the procedure of Example 33, but using i) 3-nitrobenzaldehyde or ii) methyl 4-formylbenzoate or iii) methyl 3-formylbenzoate, in place of 4-nitrobenzaldehyde: ai) ( E) -l-nitro-3- (2-nitro-propenyl) -benzene, MS: 208 (M) +, aii) (E) -4- (2-nitro-o-pentyl) -methylbenzoate, MS: 221 (M) \ aiii) (E) -3- (2-nitro-propenyl) -benzoic acid methyl ester, MS: 221 (M) +, bi) N- [4-methyl-5- (3-nitro-phenyl) ) -thiazol-2-yl] -guanidine, MS: 278 (M + H) +, bii) methyl 4- (2-guanidin-4-methyl-thiazol-5-yl) -benzoate, MS: 290 (M ) \ biii) methyl 3- (2-guanidin-4-methyl-thiazol-5-yl) -benzoate, MS: 291 (M + H) +. Example 35 a) A solution of 1.0 g of the compound of Example 33b in 100 ml of methanol was treated with 7.22 ml of 1N hydrochloric acid and 3 g of Raney nickel and hydrogenated overnight. The reaction mixture was filtered to remove the catalyst, the filtrate was evaporated, the residue was azeotroped twice with ethanol and dried. 1.2 g of N- [5- (4-amino-phenyl) -4-methyl-thiazol-2-yl] -guanidine hydrochloride were obtained; MS: 248 (M + H) +. b) Analogously a), but using the nitro compound of example 34 bi), N- [5- (3-amino-phenyl) -4-methyl-thiazol-2-yl] -guanidine hydrochloride was obtained; MS: 248 (M + H) +. Example 36 A solution of 2.33 g of the ester of example 34 bii) in 23 ml of THF was treated with 24 ml of 1N lithium hydroxide and stirred at 50 ° C for 2.5 hours. After cooling, 24 ml of 1N hydrochloric acid were added and the precipitated acid was removed by filtration. After drying, 1.8 g of 4- (2-guanidin-4-methyl-thiazol-5-yl) -benzoic acid were obtained; MS 277 (M + H) +. Example 37 A solution of 2.9 g of the ester of example 34 biii) in 58 ml of THF was treated with 30 ml of 1N lithium hydroxide solution and stirred at room temperature overnight. Then, 30 ml of hydrochloric acid 1n were added thereto and the precipitated acid was removed by filtration. After drying, 2.3 g of 3- (2-guanidin-4-methyl-thiazol-5-yl) -benzoic acid were obtained; MS: 277 (M + H) +. Example 38 Ethyl 4-methyl-2- [[(methylamino) carbonyl] amino] -thiazole-5-carboxylate was hydrolyzed analogously to Example 4 in the corresponding 4-methyl-2- (3-methyl-ureido) - thiazole-5-carboxylic acid; MS 214 (M + H) +. Example 39 a) 4.05 mg of benzyl isocyanate was added to a solution of 5.0 g of ethyl 2-amino-4-methyl-thiazole-5-carboxylate in 50 ml of DMF. The reaction mixture was stirred at RT overnight, evaporated on a rotary evaporator where the residue was suspended in methylene chloride / methanol 1: 1. The insoluble material was separated by filtration and dried. 4.6 g of colorless ethyl 2- (3-benzyl-ureido) -4-methyl-thiazole-5-carboxylate were obtained; MS 320 (M + H) +. b) A suspension of 3.6 g of the ester obtained in a) in 36 ml of ethanol, treated with 68 ml of sodium hydroxide solution and boiled under reflux for 8 hours. Then, the reaction mixture was poured into 70 ml of 1N hydrochloric acid cooled with ice, and the solution was evaporated in half volume. After cooling, the precipitated crystals were filtered off and dried. In this way, 2.25 g of 2- (3-benzyl-ureido) -4-methyl-thiazole-5-carboxylic acid were obtained.; colorless; MS 292 (M + H) +. Example 40 a) Analogously to example 39a, but using ethyl 2-amino-thiazole-4-carboxylate in place of ethyl 2-amino-4-methyl-thiazole-5-carboxylate, 2- (3- benzylureido) -thiazole-4-carboxylate; MS: 305 (M) +. b) A suspension of 7.0 g of the ester obtained in a) in 140 ml of ethanol, treated with 79 ml of 1N sodium hydroxide solution and stirred at 50 ° C for 6 hours. The reaction mixture was cooled, 79 ml of 1N hydrochloric acid was added and the mixture was concentrated in a rotary evaporator to half the volume. After cooling, the precipitated crystals were separated by filtration and dried. 3.6 g of colorless 2- (3-benzyl-ureido) -thiazole-4-carboxylic acid were obtained in this manner; MS 277 (M) +. Example 41 a) 26.7 ml of 4-methylmorpholine, 13.5 g of ethyl beta-amino-3-pyridine propionate, and 18.7 g of BOP were added to a solution of 10.0 g of acid 3-tert-butoxy-carbonyl-amino-benzoic acid in 100 ml of DMF and the reaction mixture was stirred at RT overnight. The insoluble material was then separated by filtration and the filtrate was evaporated. The residue was dissolved in ethyl acetate, stirred once with a solution of 5% potassium hydrogen sulfate-10% potassium sulfate, and twice with water. The organic phase was dried, evaporated and the residue chromatographed on silica gel with hexane / ethyl acetate 4: 1. The product fractions were evaporated, the residue was redissolved in ethyl acetate, stirred once with ice-cold sodium carbonate solution and twice with sodium solution. After drying and evaporating the organic phase, 8.2 g of ethyl yellow 3- (3-tert-butoxycarbonylamino-benzoylamino) -3-pyridin-3-yl-pro-iolate was obtained; MS 414 (M + H) +. b) 7.3 g of the product of example 41a) were dissolved in 73 ml of ethyl acetate, cooled to 0 ° C. they were treated with 88 ml of 4N solution of HCl gas in ethyl acetate, and were stirred at room temperature for 5 hours. Then, the reaction mixture was evaporated, the residue was dissolved in ethyl acetate, stirred once with ice-cold solution and twice with sodium chloride solution. After drying and evaporating the organic phase, 3.9 g of ethyl 3- (3-amino-behzoylamino) -3-pyridin-3-yl-propionate were obtained; MS 314 (M + H) +. Example 42 A solution of 5.0 g of N-tert-butyl-N-cyclopropyl-glycine in 100 ml of methylene chloride was treated with 5.1 ml of 4-ethyl-morpholine, 3.87 of EDC, 0.25 g of 4-dimethyl-a-inopyridine and 5.1 of the ethyl ester hydrochloride of rae 3-phenyl-beta-alanine, and stirred at RT for 5 hours. The reaction mixture was treated with ethyl acetate, stirred once with 5% potassium hydrogen sulfate solution - 10% potassium sulfate, and twice with water. The organic phase was dried, evaporated and the residue chromatographed on silica gel with hexane-ethyl acetate 3: 1. Thus, 5.3 g of colorless ethyl rac-3- [2 (tert-butoxycarbonyl-cyclopropyl-amine) -acetyl-amino] -3-phenyl-propionate was isolated in this manner; MS 391 (M + H) +. b) 75.2 g of the product of example 42a, dissolved in 52 ml of methylene chloride, cooled to 0 ° C, treated with 66 ml of HCl 4n gas in ethyl acetate and stirred at room temperature for 5 hours. hours. Then, the reaction mixture was evaporated. 3.8 g of colorless ethyl rac-3- [2- (tert-butoxycarbonyl-cyclopropyl-amino) -acetylamino] -3-phenyl-propionate was obtained; MS: 391 (M + H) +. Example 43 a) A solution of 9.5 g of ZL-Asp (OtBu) -OH in 95 ml of methylene chloride was treated with 3.2 ml of piperidine, 5.64 g of EDC and 0.36 g of 4-dimethylamino-pyridine and stirred at RT for 5 hours. The reaction mixture was treated with ethyl acetate, stirred once with 5% potassium hydrogen sulfate solution - 10% potassium sulfate, and twice with water. The organic phase was dried, evaporated and the residue was chromatographed with hexane / ethyl acetate 3: 1. In this way, 9.9 g of colorless tert-butyl (S) -3-benzyloxycarbonylamino-4-oxo-4-piperidin-1-yl-butyrate were isolated; MS: 391 (M + H) + b) A solution of 4.0 g of the product obtained in a) was dissolved in 40 ml of ethanol, treated with 0.4 g of palladium on carbon and hydrogenated. The reaction mixture was filtered to remove the catalyst, and the filtrate was evaporated. The residue was dissolved 26 ml of methylene chloride, treated with 1.96 g of EDC and 0.12 g of 4-dimethylaminopyridine and 2.13 g of Z-glycine and stirred at RT for 5 hours. The reaction mixture was treated with ethyl acetate, stirred once with 5% potassium hydrogen sulfate solution - 10% potassium sulfate, and twice with water. The organic phase was dried, evaporated and the residue was chromatographed on silica gel with hexane / ethyl acetate 2: 1. In this way, 3.6 g of colorless (S) -3- (2-benzyloxycarbonylamino-acetylamino) -4-oxo-4-pi? Eridin-1-yl-butyrate tert-butyl ester were isolated; MS: 448 (M + H) +. c) A solution of 3.6 g of the product obtained in b) was dissolved in 36 ml of ethane, treated with 0.36 g of palladium on carbon and hydrogenated. The reaction mixture was separated from the catalyst by filtration and the filtrate was evaporated. In this way, 2.4 g of the free amine was obtained, which was used immediately. EXAMPLE 44 0.9 g of the ethyl ester hydrochloride of glycylbeta-alanine was dissolved in 10 ml of dimethylformamide, treated with 1.92 ml of 4-ethylmorpholine, 0.68 g of the acid of example 4, and 1, 34 g of benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP). The reaction was stirred at room temperature overnight, then the insoluble material was filtered off and the filtrate was evaporated on a rotary evaporator. The residue was chromatographed on a RP-18 column with a water-acetonitrile gradient. 0.7 g of crystalline ethyl 3- [2- [(2-guanidin-thiazol-4-ylcarbonyl) -amino] -acetylamino] -propionate were thus obtained; MS 343 (M + H) +.

Example 45 0.29 g of the ester obtained in example 44, were suspended in 3 ml of tetrahydrofuran and treated with 2.54 ml of a 3N aqueous solution of lithium hydroxide (sic). The reaction mixture was stirred at room temperature for 2 hours, neutralized by the addition of 2.54 ml of 1N hydrochloric acid, and evaporated on a rotary evaporator. After chromatography of the residue on a RP-18 column with a water-acetonitrile gradient, 0.1 g of 3- [2- [(2-guanidin-thiazol-4-ylcarbonyl) -amino] -acetylamino] was obtained] -propionic, crystalline, colorless; MS 315 (M + H) +. Example 46 a) 0.6 g of aniline compound obtained according to example 35a, were dissolved in 12 ml of DMF, treated with 1.2 ml of 4-ethylmorpholine and 0.23 g of succinic anhydride and stirred at RT overnight. After evaporation and chromatography on an RP-18 column with a water-acetonitrile gradient, 0.12 g of N- [4- (2-guanidin-4-methyl-thiazol-5-yl) - monoamide were obtained. phenyl] -succinnamic; MS 348 (M + H) +. b) Analogously to example a) but using the aniline compound of example 35b (instead of 13a), the N- [3- (2-guanidin-4-methyl-thiazol-5-yl) - monoamide was obtained phenyl] -succinnamic; MS 348 (M + H) +. Example 47 The following compounds were obtained analogously to example 46, but using the 3-phenylglutaric anhydride 3-anhydride. instead of succinic anhydride: a) rae 4- [4- (2-guanidin-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyric acid; MS 438 (M + H) +. b) 4- [3- (2-guanidin-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyric acid; MS 438 (M + H) +. Example 48 a) 0.8 g of the aniline compound obtained according to example 35a, were dissolved in 16 '. ml of DMF were treated with 1.6 ml of 4-ethylmorpholine and 0.44 ml of the monomethyl ester of adipic acid and 1.11 g of BOP and stirred at RT overnight. After evaporation and chromatography of the residue on an RP-18 column with a water-acetonitrile gradient, 0.21 g of 5- [4- (2-guanidin-4-methyl-thiazol-5-yl) -phenylcarbamoyl was obtained. ] -methyl pentanoate, orange; MS 390 (M + H) +. b) analogously to example a), but using the aniline compound of example 35b) in place of example 35a), 5- [3- (2-guanidin-4-methyl-thiazol-5-yl) -phenylcarba was obtained -moyl] -methyl pentanoate; MS 390 (M + H) +. Example 49 The following compounds were obtained analogously to the procedure described in example 45, but using the ester of 48a) and, respectively, example 48b): a) 5- [4- (2-guanidin-4-methyl-thiazole acid -5-yl) -phenyl-carbamoyl) -pentanoic acid; MS: 376 (M + H) +; b) 5- [3- (2-Guanidin-4-methyl-thiazol-5-yl) -phenyl-carbamoyl) -pentanoic acid; MS: 376 (M + H) +. Example 50 a) 0.6 g of the carboxylic acid obtained according to Example 36 was dissolved in 10 ml of DMF, treated with 0.82 ml of 4-ethylmorpholine and 0.72 g of rac-jS (aminomethyl) - 4- ethyl chlorophenylpropanecarboxylate and 0.96 g of BOP and • stirred at RT overnight. After evaporating and chromatographing the residue on a RP-18 column with a water-acetonitrile gradient, 0.76 of rac-3- (4-chloro-phenyl) -4- [4- (2-guanidin was obtained. Ethyl yellow -4-methyl-thiazol-5-yl) -benzoylamino] -butyrate; MS: 500 (M + H) *. b) Analogously to example a), but using the carboxylic acid of example 37 (instead of example 36) rac-3- (4-chloro-phenyl) -4- [3- (2-guanidin- - methyl-thiazol-5-yl) -benzoylamino] -butyrate of ethyl; MS: 500 (M + H) *. Example 51 The following products were obtained analogously to example 45, but using rae / 3-phenyl- / 3-alanine ethyl ester hydrochloride in place of ethyl β- (aminomethyl) -4-chlorophenyl-propionate hydrochloride: a) rac-3- [4- (2-guanidin-4-methyl-thiazol-5-yl) -benzoyl¬ • ethyl] -3-phenyl-propionate; MS: 452 (M + H) *; 20 b) ethyl rac-3- [3- (2-guanidin-4-methyl-thiazol-5-yl) -benzoylamino] -3-phenyl-propionate; MS: 452 (M + H) *. Example 52 The following products were obtained analogously to example 45, but using the esters of example 50 and, respectively, of example 51: a) Rae acid 3- (4-chloro-phenyl) -4- [4- (2- guanidin-4-methyl-thiazol-5-yl) -benzoylamino] -butyric acid; MS: 472 (M + H) *; b) Rae acid 3- (4-chloro-phenyl) -4- [3- (2-guanidin-4-methyl-thiazol-5-yl) -benzoylamino] -butyric acid; MS: 472 (M + H) *, - c) Rae acid 3- [4- (2-guanidin-4-methyl-thiazol-5-yl) -benzoylamino] -3-phenyl-propionic acid; MS: 424 (M + H) *; d) Rae 3- [3- (2-guanidin-4-methyl-thiazol-5-yl) -benzoylamino] -3-phenyl-propionic acid; MS: 424 (M + H) *. Example 53 The following compounds were obtained analogously to example 44, but using ethyl ester hydrochloride (RS) -glycyl-3-phenyl-beta-alanine in place of the ethyl ester hydrochloride of glycyl-beta-alanine, and with the acids of example 29a-d) and, respectively, of example 32a: a) Hydrochloride of 3- [ethyl 2- [(2-guanidin-4-methyl-thia-zol-5-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionate; MS: 433 (M + H) *; b) rae ethyl 3- [2- [(2-guanidin-4-propyl-thiazol-5-ylcarbo-nyl) -amino] -acetylamino] -3-phenyl-propionate, - MS: 461 (M + H) *; c) rae Ethyl 3- [2- [(2-guanidin-4-phenyl-thiazol-5-ylcarbo-nyl) -amino] -acetylamino] -3-phenyl-propionate; MS: 495 (M + H) *; d) rae ethyl 3- [2- [(4-tert-butyl) -2-guanidin-thiazol-5-yl-carbonyl) -amino] -acetylamino] -3-phenyl-propionate; MS: 475 (M + H) *; e) rae ethyl 3- [2- [[2- (tert-butoxycarbonylamino-methyl) -thia-zol-4-ylcarbonyl] -amino] -acetylamino] -3-phenyl-propionate; MS: 491 (M + H) *; Example 54 1.6 g of the product of example 53a were dissolved in 16 ml of methylene chloride, treated at 0 ° C with 16 ml of 4N gas HCl in ethyl acetate and stirred at room temperature for 5 hours. Then, the reaction mixture was evaporated and 1.6 g of the rae hydrochloride 3- [2- [(2-aminomethyl-thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionate were obtained. ethyl; MS: 391 (M + H) *. Example 55 1.35 ml of triethylamine and 0.41 g of formamidine sulfonic acid were added to a solution of 1.3 g of the product obtained in example 54 in 13 ml of DMF. The reaction mixture was stirred at RT overnight, then evaporated and the residue was chromatographed on an RP-18 column with a water-acetonitrile gradient. After evaporation of the product fractions and filtration of the residue through a Dowex column (Cl form), 0.65 g of the rae hydrochloride 3- [2- [(2-guanidin-methyl-thiazole- Ethyl 4-ylcar-bonyl) -amino] -acetylamino] -3-phenyl-propionate, in-color; MS: 433 (M + H) * .Emplo 56 The following products were obtained analogously to example 45, but using the esters of example 53a-d and respectively of example 54, and respectively, of example 55: a) Acid rae 3- [2- [(2-guanidin-4-methyl-thiazol-5-ylcar-bonyl) -amino] - acetylamino] -3-phenyl-propionic; MS: 405 (M + H) *, - b) Rae acid 3- [2- [(2-guanidin-4-propyl-thiazol-5-yl-carbonyl) -amino] -acetylamino] -3-phenyl-propionic, MS: 433 (M + H) *; c) Rae acid 3- [2- [(2-guanidin-4-phenyl-thiazol-5-yl-carbonyl) -amino] -acetylamino] -3-phenyl-propionic, MS: 467 (M + H) *; d) Rae acid 3- [2- [(4-tert-butyl-2-guanidin-thiazol-5-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionic; MS: 447 (M + H) *; e) Rae 3- [2- [(2-aminomethyl-thiazol-4-ylearbonyl) -amino] -acetylamino] -3-phenyl-propionic acid; MS: 363 (M + H) *; f) Rae acid 3- [2- [(2-guanidinmethyl-thiazol-4-ylcarbo-nyl) -amino] -acetylamino] -3-phenyl-propionic acid; MS: 405 (M + H) *. Example 57 Analogously to example 44, but using the hydrochloride of the ethyl ester of (RS) -glycyl-3-phenyl-beta-alanine, instead of the hydrochloride of the ethyl ester of glycyl-beta-alanine, and with the acid of example 40b), the following compound was obtained: rae 3- [2- [[(2- (3-benzyl-ureido) -thiazol-4-ylcarbonyl] -amino] -acetylamino] -3-phenyl-propionate of ethyl; MS: 510 (M + H) * Example 58 The following esters were obtained analogously to example 44, but using the amine of example 41b) in place of the glycyl beta-alanine ethyl ester hydrochloride, and the acids of example 29d) and, respectively, of the example 38 instead of the acid of example 4: a) rae 3- [3- [(4-tert-butyl-2-guanidin-thiazol-5-ylcar-bonyl) -amino] -benzoylamino] -3-pyridin-3 il-propionate of eti-l ?; MS: 538 (M + H) *; b) rae 3- [3- [[4-methyl-2- (3-methyl-ureido) -thiazol-5-yl-carbonyl] -amino] -benzoylamino] -3-pyridin-3-yl-propionate in ethyl; MS: 511 (M + H) *. Example 59 The following esters were obtained analogously to example 44, but using the amines of example 42b), respectively of example 43c), instead of the ethyl ester hydrochloride of glycyl-beta-alanine, and the acid of example 29 instead of the acid of Example 4: a) rae hydrochloride 3- [2- [Cyclopropyl- (2-guanidin-4-methyl-yiazol-5-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionate ethyl; MS: 473 (M + H) *; b) (S) -3- [2- [2-guanidin-4-methyl-thiazol-5-ylcarbonyl) -amino] -acetylamino] -4-oxo-piperidin-1-yl-butyl-tert-butyl ester; MS: 496 (M + H) *. Example 60 Analogously to example 44, but using the acid of example 29a instead of the acid of example 4, 3- [2- [(2-guanidin-4-methyl-thiazol-5-ylcarbonyl) -amino] - ethyl acetylamino] -propionate; MS: 357 (M + H) *. Example 61 The following products were obtained analogously to example 45, but using the esters of example 57, and respectively those of example 58, and respectively those of example 59, and respectively those of example 60: a) Acid rae 3- [2- [[(2- (3-benzyl-ureido) -thiazol-4-yl-carbonyl] -amino] -acetylamino] -3-phenyl-propionic; MS: 480 (MH) -; b) Rae 3- [3 - [(4-tert-Butyl-2-guanidin-thiazol-5-ylearbonyl) -amino] -benzoylamino] -3-pyridin-3-yl-propionic acid; MS: 510 (M + H) *; c) Rae acid 3- [3- [[4-methyl-2- (3-methyl-ureido) -thiazol-5-ylcarbonyl] -amino] -benzoylamino] -3-pyridin-3-yl-propionic acid; MS: 483 (M + H) *; d) Rae 3- [2- [cyclopropyl- (2-guanidin-4-methyl-thiazol-5-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionic acid; MS: 445 (M + H) *; e) 3- [2- [(2-Guanidin-4-methyl-thiazol-5-ylcarbo-nyl) -amino] -acetylamino] -propionic acid; MS: 329 (M + H) *. Example 62 0.6 g of the product of example 59b) were dissolved in 6 ml of methylene chloride, treated at 0 ° C with 6 ml of 4N HCl gas in ethyl acetate at room temperature for 2.5 hours. Then, the reaction mixture was evaporated and the residue was chromatographed on a RP-18 column with a water-acetonitrile gradient. 0.37 g of (S) -3- [2- [(2-guanidin-4-methyl-thiazol-5-ylcarbonyl) -amino] -acetylamino] -4-oxo-piperidin-1-yl- acid was obtained. butyric; MS: 440 (M + H) *. EXAMPLE 63 Analogously to Example 44, but using the amine of Example 43c in place of the ethyl ester hydrochloride of glycyl-beta-alanine, (S) -3- [2- [(2-guanidin-thia-zol -4-ylcarbonyl) -amino} -acetylamino] -4-oxo-4-piperidin-1-yl-butyrate of tert-butyl; MS: 482 (M + H) *. Example 64 Analogously to Example 62, but from the product of Example 63, (S) -3- [2- [(2-guanidin-thiazol-4-ylcarbonyl) -amino] -acetylamino] -4-oxo- acid was prepared. 4-piperidin-1-yl-butyric acid; MS: 426 (M + H) *. Example 65 Analogously to example 44, starting with 2-guani-din-4-methyl-thiazole-5-carboxylic acid (example 29a) and rae 3- (3-amino-phenylsulfonylamino) -3-phenyl-propionate ethyl, 3- [3- [(2-guanidin-4-methyl-thiazol-5-ylcarbonyl) -amino] -benzenesulfonylamino) -3-phenyl-propionic acid ethyl ester was obtained; MS: 531 (M + H) *. The starting material was prepared as follows: a) A solution of 3-nitrophenyl sulfochloride in 60 ml of ether was added dropwise in the range of 20 minutes at 20-25 ° C to a solution of 5.0 g of 3-amino-3-phenyl-propionic acid rae in 30 ml of 1N sodium hydroxide solution. 30 ml of sodium hydroxide solution were added thereto after 30 minutes, 1 hour and 2 hours stirring vigorously at room temperature. After stirring for a total of 6 hours, the precipitated material was filtered off and washed with ether. Then, the residue was suspended in water-ethyl acetate, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. 7.2 g of brownish-colored rac-3- (3-nitro-phenyl-sulfonylamino) -3-phenyl-propionic acid were obtained; MS: 349 (M-H). " b) A stream of hydrogen chloride gas was passed for 10 minutes, through a solution of the residue obtained in a) in 70 ml of ethanol at 0 ° C. Then, the reaction mixture was stirred at 0 ° C for a further 2 hours, then it was evaporated on a rotary evaporator and the residue was dried. 7.6 g of colorless ethyl rac-3- (3-nitro-phenyl-sulfonylamino) -3-phenylpropionate were obtained; MS: 379 (M + H) *. c) A solution of 1.9 g of the ester obtained in b) in 19 ml of ethanol, treated with 0.5 g of Raney nickel and hydrogenated for 25 hours under normal conditions. After filtering the catalyst and evaporating the filtrate, 1.8 g of colorless ethyl rac-3- (3-amino-phenylsulfonylamino) -3-phenylpropionate were obtained; MS: 349 (M + H) *. Example 56 Analogously to example 45, but using the ester of example 65, rae 3- [3- [(2-guanidin-4-methyl-thiazol-5-ylcarbonyl) -amino] -phenylsulfonylamino] -3- acid was obtained phenylpropionic; MS: 503 (M + H) *. Example 67 Analogously to the procedure described in example 46, but using the N- [4- (3-amino-phenyl) thiazol-2-yl] -guanidine hydrobromide (see preparation below) and the anhydride 3-phenylglutaric acid, 4- [3- (2-guanidin-thiazoI-4-yl) -phenylcarbamoyl] -3-phenyl-butyric acid was obtained; MS: 424 (M + H) *. Preparation of the educt: a) Analogously to the procedure of example 1, using 2-bromo-3'-nitro-acetophenone instead of ethyl bromopyruvate, the N- [4- (3-nitro-phenyl) -thiazol-2-yl] -guanidine hydrobromide was prepared, '. MS: 264 (M + H) *. b) A solution of 3.0 g of the product obtained in a) in 80 ml of methanol and 5 ml of water was treated with 3 g of palladium on carbon and hydrogenated for 4 hours. Then, the catalyst was removed by filtration and the filtrate was evaporated. There were thus obtained 2.7 g of N- [4- (3-amino-phenyl) -thiazol-2-yl] -guanidine hydrobromide, color-brown, MS: 234 (M + H) * . Example 68 Analogously to the procedure described in example 50, but using the hydrobromide of 3- (2-guanidin-iazol-4-11) -benzoic acid (see preparation below), instead of the carboxylic acid used there, the Rae acid. 3- (4-Chloro-phenyl) -4- [3- (2-guanidin-thiazol-4-yl) -benzoylamino] -butyric acid, MS: 458 (M + H) *. Preparation of the educt: Analogously to the procedure of Example 1, but using 3-bromoacetylbenzoic acid, instead of ethyl bromopyruvate, the hydrobromide of 3- (2-guanidin-thiazol-4-yl) -benzoic acid, MS was prepared: 263 (M + H) *. Example 69 Analogously to the procedure described in Example 46b, but using 3- (4-me oxy-phenyl) -glutaric acid anhydride, instead of succinic anhydride, the following was obtained: Rae 4- [3- (2- guanidin-4-methyl-thiazol-5-yl) -phenyl-carbamoyl] -3- (4-methoxy-phenyl) -butyric acid, MS: 468 (M + H) *. Example 70 Analogously to Example 18, from 2-guani-din-4-methyl-thiazole-5-carboxylic acid, and (RS) -3- [5-amino-2- (2-methoxy-ethoxy) - benzoylamino] -3-phenyl-propionate was obtained (RS) -3- [5- C (2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -2- (2-methoxy-ethoxy) ) -benzoylamino] -3-phenyl-propionate, in the form of a pale yellow foam. MS: 569 (M + H) *. Preparation of ethyl (RS) -3- [5-amino-2- (2-methoxy-ethoxy) -benzoylamino] -3-phenyl-propionate: a) 5-benzyloxycarbonyl-amino-2-hydroxy acid is reacted -benzoic acid (J. Med. Chem. (1993), 36 (26), 4201-7) with l-chloro-2-methoxy-ethane in DMF at 0 ° C in the presence of K2C03 and sodium iodide obtaining 5- 2-methoxyethyl benzyloxycarbonyl-amino-2- (2-methoxy-ethoxy) -benzoate. P.f. 104-105 ° C, MS: 404 (M + H) *. b) The latter is saponified with 2N NaOH in methanol to give 5-benzyloxycarbonylamino-2- (2-methoxy-ethoxy) -benzoic acid, m.p. 130-131 ° C, MS: 346 (M + H) *. c) The latter is coupled with ethyl (RS) -3-amino-3-phenyl-propionate hydrochloride, according to the method given in example 9a) to give the (RS) -3- [5-benzyloxycarbo- nyl-amino-2- (2-methoxy-ethoxy) -benzoylamino] -3-phenyl-propionate, mp 139-140 ° C, MS: 52L (M + H) *. d) By catalytic hydrogenation on Pd / C in ethanol, (RS) -3- [5-amino-2- (2-methoxy-ethoxy) -benzoylamino] -3-phenyl-propionate was obtained from the latter. , pf 105-106 ° C, MS: 387 (M + H) *. Example 71 197 mg of (RS) -3- [5- [(2-guanidin-4-methyl-thiazole-5-car-bonyl) -amino] -2- (2-methoxy-ethoxy) -benzoylamino] -3 Ethyl phenyl propionate was allowed to stand at RT for 23 hours in 2 ml of acetic acid and 4 ml of 25% hydrochloric acid. The reaction mixture was evaporated to dryness and (the residue) was dried in vacuo. The residue was lyophilized with acetic acid. 192 mg of (RS) -3- [5- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -2- (2-methoxy-ethoxy) -benzoyl-amino-hydrochloride were obtained ] -3-phenyl-propionic (1: 1) in the form of a white powder, MS: 451 (M + H) *. Example 72 In the same manner as described in Example 18, starting with 2-guanidin-thiazole-5-carboxylic acid and (RS) -3- (3-amino-benzoylamino) -3-phenyl- hydrochloride ethyl pro-pionate, (RS) -3- was obtained. { 3- [(2-guanidin-thiazole-5-carbonyl) -amino] -benzoylamino} Ethyl-3-phenyl-propionate, m.p. 149 ° C, MS: 481 (M + H) *. Example 73 Analogously to example 19, starting from (RS) -3-. { 3- [(2-guanidin-thiazole-5-carbonyl) -amino] -benzoylamino} Ethyl-3-phenylpropionate, (RS) -3- [3- [(2-guani-din-thiazol-5-carbonyl) -amino] -benzoylamino] -3-phenyl-propionic acid was obtained, pf 196 ° C, .MS: 453 (M + H) *.

Example 74 In a manner similar to that described in example 5, but at 70 ° C, from 2-guanidin-4-methyl-thiazole-5-carboxylic acid, and (RS) -3- hydrochloride ( 3-amino-5-benzyloxy-ben-zoylamino) -3-phenyl-ethyl propionate, (RS) -3- was obtained. { 3-benzyloxy-5- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino} Ethyl-3-phenylpropionate, m.p. 116 ° C, MS: 601 (M + H) *. The starting material was prepared as follows: a) 3-amino-5-hydroxy-benzoic acid (Tetrahedron (1983), 39 (24), 4189-92) was converted to t-BuOH / water with di-tere-butyl dicarbonate, and triethylamine, in 3-tert-butoxycarbonylamino-5-hydroxy-benzoic acid; p.f. 175 ° C, MS: 254 (M + H) *. b) The latter was converted at 56 ° C in acetone in the presence of K2C03 with benzyl bromide in benzyl 3-benzyloxy-5-tert-butoxycarbonylamino-benzoate; p.f. 130-131 ° C. MS: 433 (M) *. c) By saponification with sodium hydroxide solution in methanol at 40 ° C, 3-benzyloxy-5-tert-buto-xicarbonylamino-benzoic acid, m.p. 194 ° C, MS: 343 (M) *. d) The latter was coupled with the ethyl (RS) -3-amino-3-phenylpropionate hydrochloride obtained in Example 9a, obtaining (RS) -3- (3-benzyloxy-5-tere-butoxy ethyl -carbonyl-amino-benzoylamino) -3-phenyl-propionate, mp 115 ° C, MS: 519 (M + H) *. e) By treatment with HCl in ethyl acetate, the latter was obtained from ethyl (RS) -3- (3-amino-5-benzyloxy-benzoylamino) -3-phenyl-propionate hydrochloride, in the form of a foam white, MS: 418 (M) *. Example 75 7 Analogously to example 19, from (RS) -3-. { 3-benzyloxy-5- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino} Ethyl-3-phenylpropionate, (RS) -3- was obtained. { 3-benzyloxy-5- [(2-guanidin-4-methylthiazole-5-carbonyl) -amino] -benzoylamino} -3-phenyl-propionate, which was purified by trituration in acetone; p.f. 235 ° C, MS: 573 (M + H) *. Example 76 According to the method described in example 9a), from 2- (3-benzyl-ureido) -4-methyl-thiazole-5-carbo-xylic acid and (RS) -7-amino hydrochloride Ethyl-3-phenyl-heptanoate, (RS) -7- was obtained. { [Ethyl 2- (3-benzyl-ureido) -4-methyl-thiazole-5-carbonyl] -amino-3-phenyl-heptanoate, in the form of a white foam, MS: 523 (M + H) *. The starting material was prepared as follows: a) analogously to the method described in example 14, starting from tert-butyl (5-oxo-5-phenyl-pentyl) -carbamate (J. Org. Chem. (1989) , 54, 228-34), a mixture of ethyl 7-tert-butoxycarbonylamino-3-phenyl-hept-2-enoate and ethyl 7-tert-butoxycarbonylamino-3-phenyl-hept-3-enoate was obtained., in the form of an oil, MS: 348 (M + H) *. b) Catalytic hydrogenation with Pd / C in alcohol was obtained from the latter, ethyl (RS) -7-tert-butoxycarbonylamino-3-phenyl-heptanoate, in the form of a colorless oil, MS : 350 (M + H) * '. c) Cleavage of the protecting group with HCl in ethyl acetate afforded ethyl (RS) -7-amino-3-phenyl-heptanoate hydrochloride, MS: 250 (M + H) *. Example 77 Analogously to example 15, starting from (RS) -7-. { [2- (3-benzyl-ureido) -4-methyl-thiazole-5-carbonyl] -amino} Ethyl-3-phenylheptanoate, (RS) -7- acid was obtained. { [2- (3-benzyl-ureido) -4-methyl-thiazole-5-carbonyl] -amino} Ethyl-phenyl-heptanoic acid, in the form of a colorless foam, MS: 495 (M + H) *. Example-78 Analogously to example 18, but at 50-60 ° C, from 2-guanidin-4-methyl-thiazole-5-carboxylic acid and (RS) -3- (3-amino-4-methoxy) benzoylamino) -3-phenyl-propionate, the (RS) -3- was obtained. { 3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -4-methoxy-benzoylamino} Ethyl-3-phenyl-propionate, m.p. 123-126 ° C, MS: 525 (M + H) *. Ethyl (RS) -3- (3-amino-4-methoxy-benzoylamino) -3-phenyl-propionate was prepared according to the method described in Example 5 from 3-amino-4-methoxy acid. benzoic • and ethyl (RS) -3-amino-3-phenyl-propionate hydrochloride, mp 116-118 ° C, MS: 343 (M + H) *. Example 79 205 mg of (RS) -3-. { 3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -4-methoxy-benzoylamino} Ethyl-3-phenylpropionate, were stirred in 2 ml of ethyl acetate and 4 ml of 25% hydrochloric acid at RT. The precipitate of acid hydrochloride (RS) -3-. { 3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -4-methoxy-benzoylamino} -3-phenylpropionic acid (1: 1), was filtered off with suction, washed with water and dried; p.f. 176-179 ° C, MS: 497 (M + H) *.

Example 80 227 mg of [(2-guanidin-thiazole-4-carbonyl) -amino] -acetic acid, 249 mg of ethyl (RS) -3-amino-3-pyridin-3-yl-propionate dihydrochloride, ml of DMF, 0.41 ml of N-MM and 354 mg of HBTU were stirred at RT for 23 hours and at 50 ° C for 4 hours. The reaction mixture was diluted with ethyl acetate and washed first with a dilute aqueous solution of sodium carbonate and sodium chloride, then with dilute sodium chloride solution and finally with saturated sodium chloride solution. The organic phase was dried with sulphate and evaporated in vacuo. Chromatography on silica gel with methylene chloride-ethanol gave 101 mg of (RS) -3-. { 2- [(2-guanidin-thiazole-4-carbonyl) -amino] -acetylamino} Ethyl-3-pyridin-3-yl-propionate, m.p. 114 ° C, MS: 420 (M + H) *. [(2-Guanidin-thiazole-4-carbonyl) -amino] -acetic acid was prepared as follows: a) 2-Guanidin-thiazole-4-carboxylic acid was coupled according to the above described method, to give [(2-guanidin-thiazole-4-carbonyl) -amino] -ethyl acetate, mp 190 ° C. b) By saponification with NaOH in aqueous alcohol, after [evaporation of the solvent and acidification with dilute hydrochloric acid, [(2-guanidin-thiazole-4-carbonyl) -amino] -acetic acid, m.p. 230 ° C, MS: 244 (M + H) *. Example 81 84 mg of the (RS) -3-. { 2- [(2-guanidin-thiazole-4-carbonyl) -amino] -acetylamino} Ethyl 3-pyridin-3-yl-propionate were stirred at RT in 1 ral of acetic acid and 1.5 ml of 25% hydrochloric acid. After evaporating the solvent mixture in vacuo, the residue was neutralized with dilute ammonia and evaporated again to dryness. The residue was triturated in a small amount of water, filtered off with suction, purified by trituration in alcohol and dried. 55 mg of (RS) -3- acid were obtained. { 2- [(2-guanidin-thiazole-4-carbonyl) -amino] -acetylamino} -3-pyridine-3-yl-propionic, p. F. 186 ° C, MS: 392 (M + H) *. Example 82 Analogously to the method described in 9a, from 2- (3-benzyl-ureido) -thiazole-4-carboxylic acid and ethyl 6-amino-5-oxo-hexanoate hydrochloride, 6- was obtained. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -5-oxo-hexanoate of eti-lo, p. F. 135-136 ° C, MS: 433 (M + H) *. The hydrochloride of ethyl 6-amino-5-oxo-hexanoate (mp 74-76aC) was obtained from 6-amino-5-oxo-hexanoic acid (J. MacGee et al., Biochem. Med. 17, 31- 44 (1977)) by esterification in 5N HCl in EtOH. Emplo 83 According to the method described in example 15, from 6-. { [2- (2-benzyl-ureido) -thiazole-4-carbonyl] -amino} -5-ethyl hexanoate, the 6- acid was obtained. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -5-oxo-hexanoic acid, m.p. 169 ° C, MS: 405 (M + H) *. EXAMPLE 84 In the same manner as described in example 5, from 2-guanidin-4-methyl-thiazole-5-carboxylic acid and (RS) -7-amino-3-phenyl-heptanoate hydrochloride ethyl, ethyl (RS) -7- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -3-phenyl-heptanoate, mp. 138 ° C, MS: 432 (M + H) *. Example 85 Analogously to Example 19, from (RS) -7 - [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -3-phenyl-heptanoate ethyl, the acid was obtained (RS ) -7- [(2-guanidin-4-methyl-thia-zol-5-carbonyl) -amino] -3-phenyl-heptanoic acid, mp 125 ° C, MS: 404 (M + H) *. Example 86 Analogously to the method described in example 9a, from the acid. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -acetic and the 4-tert-butyl 1-anilide ester of (S) -aspartic acid, the 4-anilide-1-tert-butyl ester of (S) -3- (2- {2- [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino.}. -acetylamino) -succinic, mp. 133 ° C, MS: 581 (M + H) *. The starting material was obtained as follows: a) Analogously to the method described in example 9a, from [[2- (3-benzyl-ureido) -thiazole-4-carboxylic acid and glycine ethyl ester hydrochloride] , [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetate, mp was obtained 134 ° C, MS: 362 (M + H) *. b) By saponification with sodium hydroxide solution in ethanol, [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetic acid, mp185 ° was obtained from the latter. C, MS: 335 (M + H) *.

Example 87 240 mg of the (S) -3- (2 { [2- (3-benzylureido) -thiazole-4-carbonyl] -amino-4-anilide-l-tert-butyl ester. .-acetylamino) -succinic, was stirred in 2.4 ml of methylene chloride and 2.4 ml of trifluoroacetic acid at RT for 2 hours. The reaction mixture was evaporated in vacuo, the residue was dissolved in toluene and the solution was evaporated again. The residue was crystallized with acetonitrile, filtered off with suction and dried. 189 mg of the 4-anuide of (S) -3- acid were obtained. { [2- (3-benzyl-ureido) -thiazole-4-car-bonyl] -amino} -acetylamino) -succinic, m.p. 217 ° C, MS: (M + H) *. Example 88 Analogously to the procedure described in Example 46, starting with 1- [5- (3-amino-phenyl) -4-methyl-thiazol-2-yl] -3-benzyl urea and 3-phenylglutaric anhydride , the rae was obtained 4. { 3- [2- (3-benzyl-ureido) -4-methyl-thiazol-5-yl] -phenylcarbamoyl} - 3-feml-butyrate, MS: 529 (M + H) *. The starting material was prepared as follows: a) Analogously to example 38, but using thiourea instead of 2-imino-4-thiobiuret, 4-methyl-5- (3-nitro-phenyl) -thiazole-2 was obtained -il-amine, MS: 235 (M) *. b) Analogously to the procedure described in example 39a, starting from 4-methyl-5- (3-nitro-phenyl) -thiazol-2-yl-amine, l-benzyl-3 [4-methyl- 5- (3-Nitro-phenyl) -thia-zol-2-yl] -urea, MS: 369 (M + H) *. c) 2.0 g of tin (II) chloride dihydrate, were added in portions to a suspension of 1.0 g of the urea derivative prepared above in 9 ml of concentrated hydrochloric acid, and the mixture was stirred at 50 °. C. After 18 hours, an additional 0.5 g of tin (II) chloride dihydrate was added and after a further 6 hours, another 0.5 g of tin (II) chloride dihydrate was added. Then, the reaction mixture was poured onto ice-water, made basic with sodium hydroxide solution and extracted twice with methylene chloride. There were obtained 0.86 g of 1- [5- (3-amino-phenyl) -4-methyl-thiazol-2-yl] -3-benzyl urea, brownish, MS: 339 (M + H) * . Example 89 Analogously to the procedure described in example 48a, from N- [5- (3-amino-phenyl) -4-methyl-thiazol-2-yl] -guanidine hydrochloride and the monoethylester of rae 3- pyridin-3-yl-pentanedicarboxylic acid, 4- [3- (2-guanidin-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -3-pyridin-3-yl-butyrate ethyl ester, MS was obtained: 467 (M + H) *. The starting material was prepared as follows: 2.2 ml of piperidine were added to a mixture of 10.7 g of pyridine-3-carbaldehyde and 24.8 ml of ethyl acetoacetate and the mixture was stirred for 3 hours. Next, a solution of 22.7 g of sodium hydroxide in 114 ml of ethanol was added, diluted with 50 ml of ethanol and the reaction mixture was refluxed overnight. After cooling, 130 ml of ether were added and the precipitated residue was filtered off with suction. This was dissolved in water, the solution was adjusted to pH 5 and extracted with ethyl acetate. After evaporating the organic phase, 4.2 g of rae 3-pyridin-3-yl-pentanedicarboxylic monoethylester, MS: 236 (M-H) "were obtained.

Example 90 Analogously to the procedure described in Example 45, from the ester of Example 89, rae 4- [3- (2-guanidin-4-methyl-thiazol-5-yl) -phenyl-carbamoyl] - acid was obtained 3-pyridin-3-yl-butyric acid, MS: 439 (M + H) *. Example 91 By the reaction of N-5- (3-amino-phenyl) -4-ethyl-thiazol-2-yl] -guanidine with 3-phenyl-glutaric acid anhydride, as described in example 46, the acetate salt of rac-4- [3- (4-ethyl-2-guanidin-cyiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyric acid was obtained after crystallization with methanol / acetic acid. . P.f. 186-188 ° C; MS: 452 (M + H) *. The starting material was prepared as follows: a) By the reaction of 3-nitrobenzaldehyde with l-nitropropane, as described in example 33a), E / Zl-nitro-3- (2-nitro-butyl) was obtained -l-enyl) -benzene in the form of yellow crystals. P.f. 68-72QC; MS: 222 (M) *. b) By epoxidation of the E / Zl-nitro-3- (2-nitro-but-l-enyl) -benzene, and subsequent reaction of the product obtained with 2-imino-4-thiobiuret, as described in example 33b ), N- [4-ethyl-5- (3-nitro-phenyl) -thiazol-2-yl] -guanidine was obtained. P.f. 149-151 ° C; MS: 292 (M + H) *. c) By catalytic hydrogenation of N- [4-ethyl-5- (3-nitro-phenyl) -thiazol-2-yl] -guanidine in ethanol / 2N hydrochloric acid, 3: 1, in the presence of palladium / carbon 10%, it was obtained, after crystallizing with ethanol, the hydrochloride salt of N- [5- (3-amino-phenyl) -4-ethyl-thiazol-2-yl] -guanidine. P.f. greater than 250 ° C; MS: 262, (M + H) *.

Example 92 By the reaction of N- [5- (3-amino-phenyl) -4-propyl-thiazol-2-yl] -guanidine with 3-phenyl-glutaric acid anhydride, as described in Example 46 , rac-4- [3- (2-guanidin-4-propyl-thiazol-5-yl) -phenylcarba-moyl] -3-phenyl-butyric acid was obtained. P.f. 245-247 ° C (decomp.); MS: 466 (M + H) *. The starting material was prepared as follows: a) By reaction of the 3-nitrobenzaldehyde with 1-nitro-butane, as described in example 33 a), the E / Z-l-nitro-3- (2-nitro-pent-l-enyl) -benzene, in the form of yellow crystals. P.f. 45-47 ° C; MS: 236 (M) *. b) By epoxidation of the E / Zl-nitro-3- (2-nitro-pent-l-enyl) -benzene and subsequent reaction of the product obtained with 2-imino-4-thiobiuret, as described in Example 33 b) , N- [5- (3-nitro-phenyl) -4-propyl-thiazol-2-yl] -guanidine was obtained. P.f. 137-139 ° C; MS: 306 (M + H) *. c) By catalytic hydrogenation of N- [5- (3-nitro-phenyl) -4-propyl-thiazol-2-yl] -guanidine in ethanol / 2N 3: 1 hydrochloric acid, in the presence of platinum oxide, obtained the hydrochloride salt of N- [5- (3-amino-phenyl) -4-propyl-thiazol-2-yl] -guanidine. P. f. 247-249 ° C; MS: 276 (M + H) *. Example 93 By the reaction of N- [5- (3-amino-phenyl) -4-butyl-thiazol-2-yl] -guanidine, with 3-phenyl-glutaric acid anhydride, as described in Example 46, rac-4- [3- (4-butyl-2-guanidin-thiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyric acid, - was obtained. MS: 480 (M + H) *.

The starting material was prepared as follows: a) By the reaction of 3-nitrobenzaldehyde with 1-nitropentane, as described in Example 33 a), E / Zl-nitro-3- (2-nitropentane) was obtained. hex-l-enyl) -benzene in the form of an orange oil; MS: "250 (M) *. B) By epoxidation of E / Zl-nitro-3- (2-nitro-hex-l-enyl) -benzene and subsequent reaction of the product obtained with 2-imino-4-thiobiuret, as described in example 33 b), N- [4-butyl-5- (3-nitro-phenyl) -thiazol-2-yl] -guani-dine was obtained, mp 140-142 ° C; MS: 320 (M + H) *. C) By the catalytic hydrogenation of N- [4-butyl-5- (3-nitro-phenyl) -thiazol-2-yl] -guanidine in methanol / 2N 3: 1 hydrochloric acid in the presence of platinum, the hydrochloride salt of N- [5- (3-amino-phenyl) -4-butyl-thiazol-2-yl] -guanidine was obtained, mp 247-249 ° C, MS: 290 (M + H) * Example 94 By the reaction of N- [5- (3-amino-phenyl) -4-pentyl-thiazol-2-yl] -guanidine with 3-phenylglutaric acid anhydride, as described in Example 46, rac-4- [3- (2-guanidin-4-pentyl-thiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyric acid was obtained, mp 186-188 ° C (decomp. MS: 494 (M + H) * The starting material was prepared as follows: a) By reaction of 3-nitro benzaldehyde with 1-nitro-hexane, as described in example 33 a), E / Zl-nitro-3- (2-nitro-hept-l-enyl) -benzene was obtained in the form of an oil of Orange; MS: 264 (M) *. b) By epoxidation of the E / Zl-nitro-3- (2-nitro-hept-l-enyl) -benzene and subsequent reaction of the product obtained with 2-imino-4-thiobiuret, as described in example 33 b ), N- [5- (3-nitro-phenyl) -4-pentyl-thiazol-2-yl] -guanidine was obtained. P.f. 135-137 ° C; MS: 334 (M + H) *. c) By catalytic hydrogenation of N- [5- (3-nitro-phenyl) -4-pentyl-thiazol-2-yl] -guanidine in methanol / 2N hydrochloric acid 20: 1, in the presence of palladium / carbon at 10 %, the hydrochloride salt of N- [5- (3-amino-phenyl) -4-pentylthiazol-2-yl] -guanidine was obtained. P.f. 218-219 ° C; MS: 304 (M + H) *. Example 95 Analogously to example 46, but using the corresponding 3-substituted glutaric acid anhydride, there were obtained: a) rac-3- (4-chloro-phenyl) -4- [3- (2-guanidin-4-me acid -ethyl-thiazol-5-yl) -phenylcarbamoyl] -butyric acid; MS: 472 (M + H) *. b) rac-4- [3- (2-guanidin-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -3-hydroxy-butyric acid; MS: 378 (M + H) *. c) 4- [3- (2-Guanidin-4-methyl-thiazol-5-yl) -phenyl-carbamoyl] -butyric acid; MS: 362 (M + H) *. d) rac-4- [3- (2-guanidin-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -3-methyl-butyric acid; MS: 376 (M + H) *. Example 96 Analogously to example 46, using the 3-substituted glutaric acid anhydride described below, the following were obtained: a) rac-3- (3-bromo-phenyl) -4- [3- (2-guanidin-4-acid I-thiazol-5-yl) -phenylcarbamoyl] -butyric acid; MS: 516 (M + H) *. b) rac-3- (3,5-dichloro-2-hydroxy-phenyl) -4- [3- (2-guanidin-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -butyric acid; MS: 522 (M + H) *. c) rac-4- [3- (2-guanidin-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -3- (3-methoxy-phenyl) -butyric acid; MS: 468 (M + H) *. Preparation of 3-subsituted glutaric acid anhydride: ai) 0.23 ml of piperidine were added to a solution of 1.85 g of 3-bromobenzaldehyde in 2.53 ml of ethyl acetoacetate and the mixture was stirred at room temperature. environment for 5 hours. Then, 2.27 g of solid sodium hydroxide and 10 ml of ethanol were added thereto, and the mixture was stirred at 55 ° C for 18 hours. The cooled mixture was treated with 20 ml of ether, the precipitated material was separated by filtration, dissolved in water and acidified with concentrated hydrochloric acid. The mixture was extracted twice with ethyl acetate and 3.2 g of a brown oil, (RS) -3- (3-bromo-phenyl) -glutaric acid; were obtained from the organic phase; MS: 284 (M-H) -. The corresponding glutaric acids were obtained analogously to ai) from 3,5-dichloro-2-hydroxy-benzaldehyde and, respectively, 3-methoxy-benzaldehyde. b) The material obtained in a) was dissolved in 30 ml of methylene chloride and treated with a solution of 2.17 g of DCC in 14 ml of methylene chloride. The mixture was stirred at room temperature overnight, then treated with 30 ml of hexane and the precipitated material was removed by filtration. 1.2 g of a brown crystalline material, (RS) -3- (3-bromo-phenyl) -glutaric acid anhydride; MS: 270 (M + H) *.

The corresponding anhydrides of glutaric acid were obtained analogously to bi) from 3- (3,5-dichloro-2-hydroxy-phenyl) -glutaric acid and, respectively 3 - (3-methoxy-phenyl) - glutaric Example 97 - Analogously to example 46, but starting from N- [5- (5-amino-2-chloro-phenyl) -4-methyl-thiazol-2-yl] -guanidine, and respectively, N- [5 - (3-amino-4-chloro-phenyl) -4-methyl-thiazol-2-yl] -guanidine, by reaction with 3-phenylglutaric acid anhydride, were obtained: a) rac-4- [4-] acid chloro-3- (2-guanidin-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyric acid, - MS: 472 (M + H) *. b) rac-4- [2-chloro-5- (2-guanidin-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyric acid; MS: 472 (M + H) *. Preparation of the starting material: Analogously to example 33, but using 2-chloro-5-nitro-benzaldehyde and, respectively, 4-chloro-3-nitrobenzaldehyde, the following were obtained: ai) N- [5- (2-chloro-5- nitro-phenyl) -4-methyl-thiazol-2-yl] -guanidine; MS: 312 (M + H) *. bi) N- [5- (4-chloro-3-nitro-phenyl) -4-methyl-thiazol-2-yl] -guanidine; MS: 312 (M + H) *. Analogously to example 35, but using the products of ai) and bi), there were obtained: ci) N- [5- (5-amino-2-chloro-phenyl) -4-methyl-thiazol-2-yl] -guanidine; MS: 282 (M + H) *; di) N- [5- (3-amino-4-chloro-phenyl) -4-methyl-thiazol-2-yl] -guanidine; MS: 282 (M + H) *; Example 98 Analogously to example 50, by the reaction of the acid of example 37 with (S) -4-amino-2-butylsulfonyl-amino-butyric acid, (S) -2-butylsulfonylamino-4-hydrochloride was obtained [3- (2-guanidin-4-methyl-thiazol-5-yl) -benzoylamino] -butyric acid (1: 1); MS: 497 (M + H) *. Preparation of the educt: (S) -4-amino-2-butylsulfonylamino-butyric acid, MS: 239 (M + H) *, was obtained from L-glutamine by N-butylsulfonyl-L-glutamine [MS : 267 (M + H) *] analogously to a procedure described in J. Med. Chem. 40, 1779-88 (1997). Example 99 0.77 ml of 4-ethylmorpholine and a solution of 1.66 g of the activated carbamic acid ester in 8 ml of acetonitrile were added to a solution of 0.75 of the aniline compound of example 35b in 8. ml of acetonitrile The reaction mixture was stirred at room temperature overnight, then evaporated and the residue was chromatographed on a RP-18 column with a water-acetonitrile gradient, thus obtaining 0.23 g of rac- Ethyl 3- [3- [3- (2-guanidin-4-methyl-thiazol-5-yl) -phenyl] -ureido] -3-phenyl-propionate, orange: MS: 467 (M + H) * Preparation of the activated ester of carbamic acid: A solution of 4.0 g of ethyl rac-3-amino-3-phenylpropionate hydrochloride in 94 ml of acetonitrile was treated with 2.2 ml of 4- ethylmorpholine, cooled to 0 ° C and treated in portions with 5.35 g of DSC (di- (N-succinimidyl) -carbonate).

The reaction mixture was stirred at room temperature for 5 hours and then evaporated. The residue was dissolved in ethyl acetate, washed with sodium chloride solution and evaporated. 6.33 g of crude activated carbamate was obtained, which was used immediately. Example 100 Analogously to Example 45, rac-3- [3- [3- (2-guanidin-4-methyl-thiazol-5-yl) -phenyl] -ureido acid was prepared from the ester prepared in Example 99. ] -3-phenyl-propionic; MS: 439 (M + H) *. Example 101 Analogously to Example 48, from the aniline compound of Example 35b with the monoethyl ester of 3-phenylglutaric acid, the rac-4- [3- (2-guanidin-4-methyl-thiazole-5-hydrochloride was prepared -yl) -phenylcarbamoyl] -3-phenyl-butyrate ethyl (1: 1); MS: 466 (M + H) *. Example 102 Analogously to example 46, from the aniline compound prepared below with 3-phenylglutaric acid anhydride, rac-4- [[3- (2-guanidin-4-methyl-thiazol-5-yl was prepared ) -phenyl] -methyl-carbamoyl] -3-phenyl-butyrate MS: 452 (M + H) *. Preparation of the starting material: ai) 1.0 g of the aniline compound prepared in example 35b, dissolved in 9 ml of ethanol, treated with 0.48 g of succinimide and the reaction mixture was heated to 45 ° C. They were added to it0.39 ml of 35% formaldehyde solution and the mixture was refluxed for 1 hour. After cooling and evaporation, 1.66 g of N- [5- [3- [2, 5-di-oxo-pyrrolidin-1-ylmethyl) -amino] -phenyl] -4-methyl-thiazole-2 was obtained. -il] -guanidine, beige, MS: 359 (M + H) *. bi) 1.45 g of the material prepared according to ai) were dissolved in 10 ml of DMSO and treated with 0.15 g of sodium borohydride. The reaction mixture was stirred at 110 ° C for 15 minutes and, after cooling, poured into water / ice. The precipitated material was separated by filtration and chromatographed on an RP-18 column with a water-acetonitrile gradient. 0.28 g of N- [4-methyl-5- (3-methylamino-phenyl) -thiazol-2-yl] -guanidine, beige, MS: 262 (M + H) * was obtained. Example 103 Analogously to Example 48, from the aniline compound of Example 35b and the methyl D, LZ-glutamate, rac-4-benzyloxycarbonylamino-4- [3- (2-guanidin-4-methyl) was obtained methyl-thiazol-5-yl) -phenylcarbamoyl] -butyrate; MS: 525 (M + H) *. EXAMPLE 104 Analogously to Example 45, from the ester prepared in Example 103, rac-benzyloxy-carbonylamino-4 - [3- (2-guanidin-4-met-yl-yiazol-5-yl) - acid was prepared phenylcarbamoyl] -butyric; MS: 511 (M + H) *. EXAMPLE 105 Analogously to Example 46, from the aniline compound prepared below with 3-phenylglutaric acid anhydride, rac-5- [3- (4-carboxy-3-phenyl-butyrylamino) -phenyl] - Methyl 2-guanidin-thiazole-4-carboxylate; MS: 482 (M + H) *. .

Preparation of the aniline component: ai) A solution of 1.29 g of sodium in 22 ml of methanol was slowly added at 0 ° C to a solution of 10 g of 3-nitrobenzaldehyde and 7.43 ml of dichloroacetic acid in 22 g. ml of ether. The reaction mixture was stirred at room temperature for 1 hour, poured into water and extracted with ether. After evaporating the organic phase, 11.0 g of yellow crystalline chloroepsidium were obtained, which was reacted immediately. b) A suspension of 11 g of the chloroepoxide prepared in ai) in 100 ml of methanol was treated with 4.83 g of 2-imino-4-thiobiuret and boiled under reflux for 4 hours. The reaction mixture was cooled to room temperature, evaporated to 1/3 volume and the precipitated material was filtered off. After washing and drying, 9.45 g of the methyl 2-guanidin-5- (3-nitro-phenyl) -thiazole-4-carboxylate hydrochloride were obtained; MS: 322 (M + H) *. ci) 4.5 g of the nitro compound obtained in bi) were dissolved in 200 ml of methanol, treated with Raney nickel and hydrogenated. After filtration and evaporation, 3.68 g of the desired methyl 5- (3-amino-phenyl) -2-guanidin-thiazole-4-carboxylate hydrochloride (1: 1); MS: 292 (M + H) *. EXAMPLE 106 0.25 g of the latter prepared in example 105, were dissolved in 2.5 ml of 3N potassium hydroxide solution and boiled under reflux for 30 minutes. After cooling the reaction mixture was acidified with 3 ml of 6N hydrochloric acid and evaporated. After chromatography on an RP-18 column with a water-acetonitrile gradient, 0.09 g of rac-5- [3- (4-carboxy-3-phenyl-butyrylamino) -phenyl] -2-guanidin were isolated. -thiazole-4-carboxylic acid; MS: 466 (MH). "Example 10.7 The following compounds were prepared analogously to Example 41 from the acids described below and ethyl rac-3- (2-amino-acetylamino) -3-phenylpropionate ( see Example 12 for the preparation): a) rae ethyl 3- [2- [2-guanidin-5-methyl-thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionate; MS: 433 (M + H) *. B) ethyl rac-3- [2- [(5-tert-butyl-2-guanidin-thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionate; : 475 (M + H) *. C) rae Ethyl 3- [2- [(2-guanidin-5-phenyl-thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionate; MS: 495 (M + H) *. D) rae 3- [2- [[2-guanidin-5- (3-nitro-phenyl) -thiazole-4-ylenecarbonyl] -amino] -acetylamino] -3-phenyl -ethyl propionate, • MS: 540 (M + H) *. Preparation of the acid components: The following esters were prepared analogously to example 105ai) and 105bi), but using acetaldehyde, pivaldehyde and, respectively, benzaldehyde in place of nitrobenzaldehydc: ai) 2-guanidin-5-methyl-thiazole Methyl-4-carboxylate; MS: 214 (M) *. aii) methyl 5-tert-butyl-2-guanidin-thiazole-4-carboxylate, -MS: 257 (M + H) *. aiii) methyl 2-guanidin-5-phenyl-thiazole-4-carboxylate, -MS: 277 (M + H) *. The following acids were prepared analogously to Example 106 from products of example 107 ai), 107 aii), 107. aiii) and 107 bi): bi) 2-guanidin-5-methyl-thiazole-4-carboxylic acid; MS: 199 (M-H) ". Bii) 5-tert-butyl-2-guanidin-thiazole-4-carboxylic acid; MS: 243 (M + H) *. biii) 2-guanidin-5-phenyl-thiazole-4-carboxylic acid; MS: 263 (M + H) *. biv) 2-guanidin-5- (3-nitro-phenyl) -thiazyl-4-carbonyl-X-hydroxychloride (1: 1); MS: 306 (M-H) -. Example 108 The following acids were prepared analogously to Example 45 from the esters of Example 107: a) Rae 3- [2- [(2-guanidin-5-methyl-thiazol-4-ylcar-bonyl) -amino] acid] -acetylamino] -3-phenyl-propionic, - MS: 405 (M + H) *. b) Rae acid 3- [2- [(5-tert-butyl-2-guanidin-thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionic acid; MS: 447 (M + H) *. c) Rae acid 3- [2- [(2-guanidin-5-phenyl-thiazol-4-yl-carbonyl) -amino] -acetylamino] -3-phenyl-propionic acid; MS: 467 (M + H) *. d) Rae acid 3- [2- [2-guanidin-5- (3-nitro-phenyl) -thia-zol-4-ylcarbonyl] -amino] -acetylamino] -3-phenyl-propionic acid; S: 512 (M + E) *. Example 109 Analogously to the procedure described in example I05ci), the nitro compound of example I07d) was reduced to (RS) -3- [2- [[5- (3-Amino-phenyl) -2-guanidin-thiazole- 4-ylearbonyl] -amino] -acetylamino] -3-phenyl-propionic; MS: 482 (M + H) *. Example 110 The following compounds were prepared analogously to Example 41 from the acids described below and ethyl rac-3- (2-amino-acetylamino) -3-phenyl-propionate (see Example 12 for the preparation) -. a) rac-3- [2- [[2- (3-benzyl-ureido) -5-methyl-thiazol-4-ylcarbonyl] -amino] -acetylamino] -3-f ethyl-ethyl propionate, MS: 524 (M + H) *. b) rac-3- [2- [[2- (3-benzyl-ureido) -5-phenyl-thiazol-4-ylcarbonyl] -amino] -acetylamino] -3-phenyl-propionate ethyl, MS: 475 ( M + H) *. Preparation of the acid components: Analogously to Example 105ai), but using acetaldehyde in place of nitrobenzaldehyde, the corresponding chloroepoxide was obtained and thereafter according to the procedure described in example 105bi), but using thiourea instead of -imino-4-thiobiuret, the compound was obtained: ai) 2-amino-5-methyl-thiazole-4-carboxylic acid methyl ester; MS: 172 (M) *. Analogously to Example 39, starting from the product of ai) prepared above, the following compounds were prepared: bi) .2- (3-benzyl-ureido) -5-methyl-thiazole-4-carboxylic acid methyl ester; MS: 305 (M) *, and ci) 2- (3-Benzyl-ureido) -5-methyl-thiazole-4-carbo-XY1CO1 acid; MS: 291 (M) *. The following compound was prepared according to the procedure described in Example 39a from 2-amino-5-phenyl-thiazole-4-carboxylic acid: di) 2- (3-benzyl-ureido) -5-phenyl- acid thiazole-4-carbo-XY1CO; MS: 353 (M) *. Example 111 The following acids were prepared analogously to Example 45 from the esters of Example 110: a) rac-3- [2- [[2- (3-benzyl-ureido) -5-methyl-thiazole-4-acid] ylcarbonyl] -amino] -acetylamino] -3-phenyl-propionic acid; MS: 496 (M + H) *. b) rac-3- [2- [[2- (3-benzyl-ureido) -5-phenyl-thiazol-4-ylcarbonyl] -amino] -acetylamino] -3-phenyl-propionic acid; MS: 558 (M + H) *. Example 112 (RS) -4- [3- [2- (3-Benzyl-solid) -5-methyl-thiazol-4-yl] -phenylcarbamoyl] -3-phenyl-butyric acid, MS: 529 (M + H) *, was prepared analogously to example 47. Preparation of the starting material: a) Analogously to example 39a, from the hydrobromide of 2-amino-5-methyl-4- (m-nitrophenyl) -thiazole, the preparation was prepared 1-Benzyl-3- [5-methyl-4- (3-nitro-phenyl) -thiazol-2-yl] -urea, -MS: 368 (M) *. b) The product obtained in a) was reduced, analogously to example I05ci), to 1- [4- (3-amino-phenyl) -5-methyl-thiazol-2-yl] -3-benzyl-urea; MS: 339 (M + H) *. Example 113 The rac-4- [[3- [2- (3-benzyl-ureido) -5-methyl-thiazol-4-yl] -phenyl] -methyl-carbamoyl] -3-phenyl-butyric acid, MS: 543 (M + H) *, was prepared analogously to Example 46 from the aniline compound prepared below: Preparation of the starting material: a) Analogously to example 102ai, starting from the product of example 112b, the l-benzyl was prepared 3- [4- [3- [(2,5-dioxo-pyrrolidin-1-ylmethyl) -amino] -phenyl] -5-methyl-thiazol-2-yl] -urea; MS: 450 (M + H) *. b) Analogously to example 102bi, starting from the product obtained above, -l-benzyl-3- [5-methyl-4- [3-methylamino-phenyl) -thiazol-2-yl] -urea, - MS: 353 (M + H) *. Example 114 The following products were prepared analogously to example 39, but using the 2-amino-thiazole prepared below and the phenyl isocyanate, phenylethyl isocyanate and, respectively, butyl isocyanate: a) rac-3-phenyl-3- Ethyl [2- [[2- (3-phenyl-ureido) -thiazol-4-ylcarbonyl] -amino] -acetylamino] -propionate; MS: 496 (M + H) *. b) rac-3- [2- [[2- (3-phenethyl-ureido) -thiazol-4-ylcarbonyl] -amino] -acetylamino] -3-phenyl-propionyl ethyl ester; MS: 524 (M + H) *. c) rac-3- (2- [[2- (3-butyl-ureido) -thiazol-4-ylcarbonyl] -amino] -acetylamino) -3-phenyl-ethyl propionate, - MS: 476 (M + H ) *. Preparation of 2-amino-thiazole: Analogously to example 44, from 2-amino-thiazole-4-carboxylic acid and the ethyl ester hydrochloride of (RS) -glycyl-3-phenyl-beta-alanine, prepared the (RS) -3- [2- [(2-amino-thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenyl-propionyl ethyl ester; MS: 377 (M + H) *. EXAMPLE 115 The following acids were prepared analogously to Example 45 from the products of example 114a-c: a) rac-3-phenyl-3- [2- [[2- (3-phenyl-ureido) -thia) acid zol-4-ylcarbonyl] -amino] -acetylamino] -propionic; MS: 468 (M + H) *. b) rac-3- [2- [[2- (3-phenethyl-butido) -thiazol-4-yl-carbonyl] -amino] -acetylamino] -3-phenyl-propionic acid; MS: 496 (M + H) *. c) rac-3- (2- [[2- (3-Butyl-ureido) -thiazol-4-yl-carbonyl] -amino] -acetylamino) -3-phenyl-propionic acid; MS: 448 (M + H) *. Example 116 Analogously to Example 57, but using the amine components prepared below, instead of the ethyl ester hydrochloride of rac-glycyl-3-phenyl-beta-alanine, the (RS) -3- [ Ethyl 4- [[2- (3-benzyl-ureido) -thiazol-4-ylenecarbonyl] -amino] -phenyl] -3-tert-butoxycarbonylamino-propionate; MS: 568 (M + H) *.

Preparation of the amino component: a) 2.74 g of ethyl rac-3-amino-3- (4-nitro-phenyl) -propionate, dissolved in 50 ml of dioxane, treated with 2.40 g of sodium dicarbonate. di-tert-butyl, and 2.5 ml of 4-ethylmorpholine and stirred at room temperature overnight. The reaction mixture was dissolved in ethyl acetate and extracted once with 5% potassium hydrogen sulfate-10% potassium sulfate solution, and once with water. After evaporation of the organic phase and chromatography of the residue on silica gel with hexane-ethyl acetate 4: 1, 1.56 g of rac-3-tert-butoxycarbonyl-amino-3- (4-nitro) were obtained. ethyl phenyl) -propionate, colorless, - MS: 338 (M) *. b) The product obtained in a) was reduced, analogously to example 105ci), to ethyl rac-3- (4-amino-phenyl) -3-tert-butoxycarbonyl-propionate, - MS: 308 (M) * . Example 117 Analogously to example 45, from the product of example 116, rac-3- [4- [[2- (3-benzyl-ureido) -thiazol-4-ylcarbonyl] -amino] -phenyl acid was prepared] -3-tert-butoxycarbonylane-propionic acid; MS: 540 (M + H) *. Example 118 237 mg of the product prepared in example 117, were dissolved in 2 ml of dimethylformamide, treated with 6N hydrochloric acid and stirred at room temperature overnight. After evaporating and chromatographing the residue on a RP-18 column with a water-acetonitrile gradient, 75 mg of rac-3-amino-3 - [4- [[2- (3-benzyl-ureido) -thiazole acid were isolated. -4-ylcarbonyl] -amino] -phenyl] -propionic, colorless; MS: 438 (M-H). "Example 119 0.51 g of the educt prepared below, dissolved in 10 ml of DMF, treated with 0.4 ml of 4-ethylmorpholine and 0.21 ml of propionic anhydride, and stirred at room temperature overnight. The reaction mixture was evaporated and the residue was chromatographed on silica gel with ethyl acetate. This gave 0.42 g of rac-3- [4- [[2- (3-benzylidene) -thiazole-4-ylearbonyl] -amino] -phenyl] -3-propionylamino-propionate in ethyl. , pale yellow, - MS: 524 (M + H) *. Preparation of the educt: a) Analogously to the procedure described in example 54, from the product of example 116, rac-3-amino-3- [4- [[2- (3-benzyl-ureido) -thiazole was obtained Ethyl 4-ylcarbonyl] -amino] -phenyl] -propionate, -MS: 468 (M + H) *. Example 120 1.0 g of the educt prepared in example 119a, were dissolved in 4.4 ml of sodium hydroxide solution and 5 ml of dioxane and treated at 0 ° C in the range of 15 minutes with 0.4 ml of butyl sulfochloride and 2.4 ml of 1N sodium hydroxide solution. The reaction mixture was stirred at room temperature for 2.5 hours and then evaporated. The residue was treated with water, adjusted to pH 1 with concentrated hydrochloric acid and extracted twice with ethyl acetate. The organic phases were evaporated and the residue was chromatographed on silica gel with hexane-ethyl acetate 1: 2. 0.1 g of ethyl rac-3- [4- [[2- (3-benzyl-ureido) -thiazol-4-ylcarbonyl] -amino] -phenyl] -3-butylsulfonyl-amino-propionate was isolated from beige, -MS- 586 (MH). "Example 121 The following acids were prepared analogously to Example 45 from the esters of Examples 119 and 120: a) rac-3- [4- [[2- (3-benzyl-ureido) -thiazol-4-ylcar-bonyl] -amino] -phenyl] -3-propionylamino-propionic acid, - MS: 496 (M + H) *. b) rac-3- [4- [[2- (3-benzyl-solid) -thiazol-4-yl-carbonyl] -amino] -phenyl] -3-butylsulfonylamino-propionic acid; MS: 558 (MH). "Example 122 Analogously to Example 57, but using the amino component prepared below in place of the ethyl ester hydrochloride of rac-glycyl-3-phenyl-beta-alanine, 3- [ Diethyl 4- [[2- (3-benzyl-ureido) -thiazol-4-ylcarbonyl] -amino] -phenyl] -glutarate; MS: 539 (M + H) * Preparation of the amino component: a stream of hydrogen chloride during minutes at 0 ° C through a suspension of 3.0 g of 3- (4-nitro-phenyl) -glutaric acid in 30 ml of ethanol. The reaction mixture was stirred for 2 hours at 0 ° C, evaporated and the residue was chromatographed on silica gel with hexane-ethyl acetate 3: 1. 2.2 g of yellow diethyl 3- (4-nitro-phenyl) -glutarate were obtained in this way; MS: 309 (M) *. b) The product obtained in a) was reduced, analogously to example 105c), to diethyl 3- (4-amino phenyl) -glutarate; MS: 279 (M) *. Example 123 Analogously to example 45, a7 from the ester of example 122, but using 6 equivalents of 1N lithium hydroxide solution, it was prepared - 3- [4- [[2- (3-benzyl-ureido)] -thiazol-4-ylcarbonyl] -amino] -phenyl] -glutaric acid; MS: 483 (M + H) *. Example 124 Analogously to example 46, but using the aniline compound prepared below, and using 3-phenylglutaric anhydride in place of the succinic anhydride, rac-4- [3- [2- (N'-benzyl- guanidino) -4-methyl-thiazol-5-yl] -phenyl -carbamoyl] -3-phenyl-butyric acid; MS: 528 (M + H) *. Preparation of the aniline compound: a) Analogously to example 33b), but using the nitroolefin of example 34ai) and using 2, 4-dithiobiuret instead of 2-imino-4-thiobiure, [4-methyl-5 was obtained - (3-nitro-phenyl) -thiazol-2-yl] -thiourea; MS: 294 (M + H) *. b) 1.7 ml of methyl iodide were added to a suspension of 1.6 g of thiourea obtained in a) in 32 ml of acetone and the mixture was refluxed for 2 hours. The insoluble material was separated by filtration and the filtrate was evaporated to obtain 1.1 g of 2-methyl-l- [4-methyl-5- (3-nitro-phenyl) -thiazol-2-yl] -isothiourea hydroiodide ( 1: 1) brown, - MS: 309 (M + H) *. c) A solution of 1.1 g of the material obtained in b) in 7 ml of methanol was treated with 2.8 ml of benzylamine and boiled under reflux for 6 hours. The reaction mixture was evaporated and the residue was chromatographed on silica gel with hexane-ethyl acetate 1: 1. 0.23 g of orange N-benzyl-N '- [4-methyl-5- (3-nitro-phenyl) -thiazol-2-yl] -guanidine were isolated; MS: 368 (M + H) *. d) The product obtained in c) was reduced, analogously to example 105ci) to N- [5- (3-amino-phenyl) -4-methyl-thiazol-2-yl] -N'-benzyl-guanidine; MS: 338 (M + H) *. Example 125 Analogously to example 44, but using the acid component prepared below, and using the ethyl ester hydrochloride of rac-glycyl-3-phenyl-beta-alanine, in place of the glycyl beta-ethyl ester hydrochloride alanine, ethyl rac-3-phenyl-3- [2- [[2- (pyridin-2-ylamino) -thiazol-4-ylenecarbonyl] -amino] -acetylamino] -propionate, -MS: 454 ( M + H) *. Preparation of the acid component: a) Analogously to Example 1, but using pyridyl thiourea instead of 2-imino-4-thiobiuret, 2- (pyridin-2-ylamino) -thiazole-4-carboxylate was obtained from ethyl; MS: 250 (M + H) *. b) Analogously to Example 4, from the ester prepared above, 2- (pyridin-2-ylamino) -thiazole-4-carboxylic acid was obtained; MS: 222 (M + H) *. Example 126 Analogously to example 45, from the ester of example 125, rac-3-phenyl-3- [2- [[2- (pyridin-2-ylamino) -thiazole-4-ylearbonyl] -amino acid was obtained ] -acetylamino] -propionic; MS: 426 (M + H) *.

Example 127 Analogously to the method described in example 9a, from [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetic acid, and from rac-3-amino-3 hydrochloride ethyl-pyridin-3-yl-propionate, rac-3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -pyridin-3 was obtained ethyl-propionate, mp 194 ° C, MS: 511 (M + H) *. Example 128 208 mg of ethyl rac-3- [2- [[2- (3-benzyl-ureido) -thiazole-4-car-bonyl] -amino] -acetylamino] -3-pyridin-3-yl-propionate , were stirred at RT for 12 hours in 4.2 ml of 25 percent hydrochloric acid. After evaporating the hydrochloric acid in vacuo, the residue was dissolved in water, neutralized with ammonia and purified on silica gel 100 (reversed phase C18) with water-methanol (4: 1). The pure fractions were combined and the residue was lyophilized with acetic acid. 136 mg of rac-3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -3-pyridin-3-yl-propionic acid acetate were obtained ( 1: 1), p.f. 177 ° C, MS: 483 (M + H) *. Example 129 Analogously to the method described in example 9a, from [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetic acid, and (S) -3-amino-N - tert-butyl benzyl succinamate, (S) -N-benzyl-3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] - tert-butyl succinamate, mp 123 ° C, MS: 595 (M + H) *. Preparation of starting material. a) The 4-tert-butyl ester of the Z-aspartic acid, was coupled with benzylamine, obtaining the (S) -N-benzyl-3-benzyl-oxycarbonylamino-succinamate of tert-butyl, MS: 413 (M + H) *. b) By hydrogenation with Pd / C in ethanol, the latter was obtained from tert-butyl (S) -3-amino-N-benzyl-succinamate, MS: 279 (M + H) *. Example 130 Analogously to Example 87, starting from (S) -N-benzyl-3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -succinamate of t-butyl, (S) -N-benzyl-3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -succinnamic acid was obtained in the form of trifluoroacetate (1: 0.4), mp 193 ° C, MS: 539 (M + H) *. Example 131 Analogously to the method described in example 9a, from 2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetic acid and ethyl 3-aminopropionate, ethyl 3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -propionate was obtained, mp. 187 ° C, MS: 434 (M + H). "Example 132 236 mg of 3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -propionate of ethyl, were stirred in 4.7 ml of 25 percent hydrochloric acid, and 4 ml of acetic acid for 24 hours at 20 ° C. The reaction mixture was evaporated in vacuo and the residue was recrystallized from acetonitrile. 213 mg of 3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -propionic acid in the form of hydrochloride (1: 1), mp 174 ° C, MS: 406 (M + H) * Example 133 According to the same method as in Example 9a, from 2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] - of acetic acid and (S) -3-amino-N- (3-methoxy-phenyl) -succinamate of tert-butyl, the (S) -3- [2- [[2- (3-benzyl-ureido) was obtained -thiazole-4-carbonyl] -amino] -acetylamino] -N- (3-methoxy-phenyl) -succinamate tert-butyl, MS: 611 (M + H) * .The starting material was prepared as follows: a ) By copulation of the 4-tert-butyl ester of Z-aspartic acid with m-anisidine, the (S) -3-benzyloxy-carbonylamino-N- (3-methoxy-phenyl) -succinamate of tert-butyl, m.p. 68-69 ° C, MS: 429 (M + H) *. b) From the latter by hydrogenation over Pd / C in ethanol, the (S) -3-amino-N- (3-methoxy-phenyl) -succinamate of tert-butyl, MS: 295 (M + H) was obtained ) *. Example 134 Analogously to example 87, starting from (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -N- (3-methoxy) phenyl) -succinamate of tert-butyl, the (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -N- acid was obtained (3-methoxy-phenyl) -succinnamic, mp 185 ° C, MS: 555 (M + H) *. Example 135 According to the same method of example 9a, from 2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetic acid and (S) -2- ( 3-amino-3- tert -butoxycarbonyl-propionylamino) -benzoic acid tert -butyl ester, (S) -2- [2- [2- [[2- (3-benzyl-ureido) -thiazole-4- was obtained carbonyl] -amino] -acetylamino] -3-tert-butoxycarbonyl-propionylamino] -benzoate of tert-butyl, mp 116 ° C, MS: 681 (M + H) *.

The starting material was prepared as follows: a) By coupling the 4-tert-butyl ester of Z-aspartic acid with tert-butyl anthranilate, (S) -2- (2-benzyloxycarbonylamino-3-tert. tert-butyl-butoxycarbonyl-propionylamino) -benzoate, MS: 499 (M + H) *. b) From the latter by hydrogenation over Pd / C in ethanol, (S) -2- (2-amino-3-tert-butoxycarbonyl-propionylamino) -benzoic acid tert-butyl, m.p. 78 ° C, MS: 365 (M + H) *. Example 136 567 mg of (S) -2- [2- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -3-tere-butoxycarbonyl-propionylamino] tert-butylbenzoate, were stirred in 2.5 ml of methylene chloride and 2.5 of trifluoroacetic acid for 6 hours at RT. The solvent mixture was evaporated in vacuo and the residue dissolved in water and extracted with chloroform. After drying with sodium sulfate, the solution was evaporated. The residue was triturated successively with ethyl acetate and water and then dried. 307 mg of (S) -2- [2- (2- { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -acetylamino) -3-carboxylic acid were obtained. -propionylamino] -benzoic acid, pf 192 ° C, MS: 567 (M + H) *. Example 137 Using the method described in Example 9a, from 2- (3-benzyl-ureido) thiazole-4-carboxylic acid, and methyl 6-aminohexanoate, 6- was obtained. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} Methyl hexanoate, m.p. 140 ° C, MS: 405 (M + H) *.

Example 138 Analogously to example 15, from 6-. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} Methyl hexanoate, by saponification with NaOH in MeOH, the acid was obtained. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -hexanoic, p.f. 178 ° C, MS: 391 (M + H) *. Example 139 255 mg of HBTU was added to a suspension of 215 mg of 3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -benzoic acid, in 2 ml of DMF and 0, 15 ml of TEA. The mixture was stirred for one hour at RT, 177 mg of tert-butyl (S) -3-amino-N-phenyl-succinamate was added thereto, and the resulting mixture was stirred for 25 hours at RT. The remaining operations were carried out as described in example 5. After chromatography on silica gel with ethyl acetate-EtOH and methylene chloride-EtOH, 184 mg of (S) -3- [3- [(2)] were obtained. -guanidin-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino] -N-phenyl-succinic acid tert-butyl ester, in the form of a pale yellow foam, MS: 566 (M + H) *. The starting material was obtained as follows: a) According to the method described above, from 2-guanidin-4-methyl-thiazole-5-carboxylic acid and ethyl 3-aminobenzoate, 3 - [ (2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -benzoate, mp 149-152 ° C, 'MS: 348 (M + H) *. b) Saponification with sodium hydroxide solution in EtOH gave 3- [(2-guanidin-4-methyl-tlazole-5-carbonyl) -amino] -benzoic acid, p.

F. 260 ° C. Example 140 184 mg of (S) -3- [3- [(2-guanidin-4-methyl-thiazole-5-carbo-nyl) -amino] -benzoylamino] -N-phenyl-tert-butyl succinamate, were stirred in 1.3 ml of methylene chloride and 1.3 ml of TFA for 2.5 hours at RT. The solvent mixture was evaporated in vacuo and the residue was dried in vacuo. 215 mg of (S) -3- [3- [(2-guanidin-4-methyl-thia-zol-5-carbonyl) -amino] -benzoylamino] -N-phenyl-succinamic acid trifluoroacetate were obtained, : 510 (M + H) *. Example 141 Using the method described in example 9a, from [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetic acid and H-Asp (OtBu) -Val-OtBu, the (S) -2- [(S) -2- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -3-tere-butoxycarbonyl- was obtained tert-butyl propionylamino] -3-methyl-butyrate; p.f. 108-110 ° C, MS: 661 (M + H) *. Example 142 In the same manner as described in Example 140, and lyophilization of the crude product with acetic acid, it was obtained from (S) -2- [(S) -2- [2- [[2- ( 3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -3-tert-butoxycarbonyl-propionylamino] -3-methyl-butyrate of tert-butyl, the acid (S) -2- [(S ) -2- (2- {[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -acetylamino) -3-carboxy-propionylamino] -3-methyl-butyric acid, acetats / trifluoroacetate form, mp 93-98 ° C, MS: 549 (M + H) *.

Example 143 Using the method given in Example 9a, from [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetic acid and (S) -3-amino-N- [(S) -tert-butoxy-carbonyl-f-enyl-methyl] -succinamate of tert-butyl, the (S) -3- [(S) -2- [[2- (3-benzyl-solid) was obtained thiazole-4-carbonyl] -amino] -acetylamino] -N- (tert-butoxycarb-phenyl-methyl) -succinamate of tert-butyl, MS: 695 (M + H) *. Example 144 In the same manner as described in example 140 and lyophilization of the crude product with acetic acid, it was obtained from (S) -3 - [(S) -2 - [[2- (3-benzyl- ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -N- (tert-butoxycarbonyl-f-enylmethyl) -succinamate of tert -butyl, the acid (S) -3- [2- [[2- ( 3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -N- [(S) carboxy-f-enyl-methyl) -succinnamic, in the form of acetate / tri-fluoroacetate, mp 126-130 ° C, MS: 583 (M + H) *. Example 145 2- (3-Benzyl-ureido) -thiazole-4-carboxylic acid is coupled to the N-Boc-lysine methyl ester acetate, according to the method described in Example 9a, obtaining the (S) -6-. { [2- (3-benzyl-ureido) -thiazole-4-carbo-nyl] -amino} Methyl -2-tert-butoxycarbonylamino-hexanoate, m.p. 166 ° C, MS: 520 (M + H) *. Example 146 Analogously to example 15, starting from (S) -6-. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} Methyl 2-tert-butoxycarbonylaminohexanoate, by saponification with NaOH in MeOH, the (S) -6- acid was obtained. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -2-tert-butoxycarbonylaminohexanoic acid, m.p. 138 ° C, MS: 506 (M + H) *. Example 147 2- (3-Benzylureide) -thiazole-4-carboxylic acid is coupled to ethyl rac-6-amino-3-benzylcarbamoyl-hexanoate hydrochloride, according to the method described in the example 9a, obtaining rac-3-benzylcarbamsyl-6-. { [2- (3-benzyl-solid) -thiazole-4-carbonyl] -amino} Ethylhexanoate, "mp 128 ° C, MS: 552 (M + H) * .The starting material was obtained as follows: a) The 2-oxo-piperidin-l-carboxylate of tert-butyl in THF was deprotonated at -78 ° C with lithium diisopropylamide and alkylated at -50 ° C with tert-butyl bromoacetate.Rae-3-tert-butoxycarbonylmethyl-2-oxo-piperidin-1-carboxylate of tert-butyl was obtained, form of a pale yellow oil, MS: 314 (M + H) * b) Heating to 80 ° C with the equivalent amount of benzylamine, rac-3-benzylcarbamoyl-6-tert was obtained from the latter -butoxycarbonylamino-hexanoats of tert-butyl, mp 119 ° C, MS: 420 (M) * c) First, it is cleaved in methylene chloride with trifluoroacetic acid, and then converted with hydrogen chloride to ethanol, in the hydrochloride of rac-6-amino-3-benzyl-carbamoyl-hexanoate ethyl (1: 1), MS: 293 (M + H) *. Example 148 By saponification - with sodium hydroxide solution in alcohol, from (RS) -3-benzylcarbamoyl-6-. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -ethyl hexanoate, rac-3-benzylcarbamoyl-6 acid was obtained. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -hexanoic, MS: 524 (M + H) *. Example 149 Using the method described in Example 9a, from 2- (3-pyridin-2-ylmethyl-ureido) -thiazole-4-carboxylic acid and the hydrochloride of ethyl 6-amino-5-oxo-hexanoate, the 5-0x0-6- was obtained. { [2- (3-pyridin-2-ylmethyl-ureido) -thiazole-4-carbonyl] -amino} ethyl hexanoate, m.p. 110 ° C, MS: 434 (M + H) *. The starting material was prepared as follows: a) The hydrobromide of ethyl 2-amino-thiazole-4-carboxylate was reacted with phenyl chloroformate in the presence of pyridine in THF, yielding 2-phenoxycarbonyl-amino- ethyl thiazole-4-carboxylate, - pf 168 ° C, MS: 293 (M + H) *. b) from the latter with 2-aminomethylpyridine in DMSO, at RT, ethyl 2- (3-pyridin-2-ylmethyl-ureido) -thiazole-4-carboxylate, m.p. 190 ° C, MS: 306 (M) *. c) This was saponified with NaOH in EtOH, obtaining 2- (3-pyridin-2-ylmethyl-ureido) -thiazole-4-carboxylic acid, p.f. 2203C, MS: 279 (M + H) *. Example 150 In the same manner as described in Example 6, starting with 5-oxo-6-. { [2- (3-pyridin-2-ylmethyl-ureido) -thiazole-4-carbonyl] -amino} -ethyl hexanoate, 5-oxo-6- acid was obtained. { [2- (3-pyridin-2-ylmethyl-ureido) -thiazole-4-carbonyl] -amino} -hexanoic in the form of the hydrochloride, (1: 2), p.f. 199 ° C, MS: 406 (M + H) *. Example 151 Using the method described in example 9a, from 4- [2- (3-benzyl-ureido) -thiazol-4-yl] -butyric acid and from the (S) -3-amino-N-benzyl-succinamate of tert-butyl, the (S) -N-benzyl-3-. { 4- [2- (3-benzyl-ureido) -thiazol-4-yl] -butyrylamino} -succinamate, MS: 580 (M + H) *. The starting material was obtained as follows: a) The hydrobromide of ethyl 4- (2-amino-thiazol-4-yl) -butyrate was reacted with benzyl isocyanate in DMF in the presence of TEA, yielding 4- [ Ethyl 2- (3-benzyl-ureido) -thiazol-4-yl] -butyrate, - pf 157 ° C, MS: 347 (M) \ and b) Saponified with NaOH in EtOH obtaining the acid 4- [2- (3-benzyl-ureido) -thiazol-4-yl] -butyric, m.p. 191 ° C, MS: 318 (MH). "Example 152 281 mg of (S) -N-benzyl-3- { 4- [2- (3-benzyl-ureido) -thiazol-4-yl] - Butyrylamino, tert-butyl succinamoate were stirred in 2 ml of methylene chloride and 2 ml of trifluoroacetic acid for 2 hours at RT, after evaporating the solvent in vacuo, the acid trifluoroacetate was obtained with ethyl acetate. (S) -N-benzyl-3-. {-4- [2- (3-benzyl-ureido) -thiazol-4-yl] -butyrylamino] -succinic crystalline (1: 1), mp 159 ° C , MS: 524 (M + H) *. E'jus 153 Using the method described in example 9a, from 2- (3-benzyl-ureido) -thiazole-4-carboxylic acid and 3- (4 ethyl-amine-phenyl) -propionate, ethyl 3- [4 - [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenyl] -propionate was obtained, mp 194 ° C, MS: 453 (M + H) * Example 154 Analogously to example 15, starting with 3- [4- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenyl ] -ethyl propionate, 3- [4- [[2- (3-benzyl-u reido) -thia-zol-4-carbonyl] -amino] -phenyl] -propionic, m.p. 233 ° C, MS: 425 (M + H) *. Example 155 According to the method described in example 9a, 2- (3-benzyl-ureido) -thiazole-4-carboxylic acid was coupled to rac-2- (3-amino-2-oxo-propyl) - diethyl succinate, yielding rac-2- [3- [[2- (3-benzylureide) -thiazole-4-carbo-nyl] -amino] -2-oxo-propyl] -succinate diethyl, mp 126-129 ° C, MS: 505 (M + H) *. Preparation of starting material: a) By bromination of acetonylsuccinic acid in ethanol at 50 ° C, diethyl (RS) -2- (3-bromo-2-oxo-propyl) -succinate was obtained, MS: 309 (M + H) *. b) The latter is reacted with sodium azide in DMSO to obtain (RS) -2- (3-azido-2-oxo-propyl) -succinate of diethyl, MS: 226 (M-OEt) *. c) By catalytic hydrogenation with Pd / C in EtOH in the presence of hydrogen chloride, diethyl (RS) -2- (3-amino-2-oxo-propyl) -succinate hydrochloride was obtained from the latter. .

Example 156 Analogously to example 15, starting from (RS) -2- [3- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -2-oxo-propyl] -succinate of diethyl, it was obtained (RS) -2- [3- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -2-oxo-propyl] -succinic acid, MS: 447 ( MH) *. Example 157 According to the method described in example 9a, [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetic acid is coupled to di-tert-butyl ester of (S) -aspartic acid, yielding (S) -2- (2 { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino.}. -acetylamino) -succinate. di-tert-butyl, mp 111-114 ° C, MS: 562 (M + H) *. Example 158 Analogously to example 87 and crystallization with acetic acid, from (S) -2- (2 { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino. di-tert-butyl acetylamino) -succinate, (S) -2- (2 { [2- (3-benzyl-ureido) -thiazole-4-car-bonyl] -amino acid was obtained. -acetylamino) -succinic acid in the form of trifluoroacetate (1: 0.9), mp 183, MS: 450 (M + H) *. Example 159 According to the method described in Example 9a, [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetic acid, was coupled with (S) -3-amino -N-Isobutyl-succinamate of tert-butyl, obtaining (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -N-isobutyl -tert-butyl succinamate, MS: 561 (M + H) *.

Example 160 Analogously to example 87 and lyophilization with acetic acid, from (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -N -sobutyl-tert-butyl succinamate, (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -N-isobutyl-succinamate of tert-butyl in the form of trifluoroacetate (1: 0.3), MS: 505 (M + H) *. Example 161 According to the method described in Example 9a, the acid [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetic acid, was coupled with the (S) -3-amino- Tert-butyl N-pyridin-2-ylmethyl-succinamate, obtaining (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino ] -N-pyridin-2-methylmethyl succinamate tert-butyl, mp 108 ° C, MS: 596 (M + H) *. The (S) -3-amino-N-pyridin-2-ylmethyl-succinic acid tert-butyl ester was prepared as follows: a) The 4-tert-butyl ester of Z-aspartic acid was coupled with the 2-aminomethylpyridine, obtaining the (S) -3-benzyloxycarbonylamino-N-pyridin-2-ylmethyl-succinamate of tert-butyl, MS: 414 (M + H) *, and b) The latter is converted by catalytic hydrogenation to the (S) -3 -amino-N-pyridin-2-ylmethyl-succinic acid tert-butyl ester, MS: 280 (M + H) *. EXAMPLE 162 200 mg of (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbo-nyl] -amino] -acetylammo] -N-pyridin-2-ylmethyl-succinamate of tert-butyl, were stirred in 2 ml of methylene chloride and 2 ml of trifluoroacetic acid for 2 hours at RT. After evaporating the solvent in vacuo, (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] trifluoroacetate was obtained with ethyl acetate. -acetylamino] -N-pyridin-2-ylmethyl-succinamic acid (1: 1,16), crystalline, mp 114 ° C, MS: 540 (M + H) *. Example 163 According to the method described in example 9a, [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetic acid was coupled with (S) -3-amino -N-pyridin-3-ylmethyl-suc-cinnamate of tert-butyl, obtaining (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino ] -acetylamino] -N-pyridin-3-ylmethyl-succinamate tert-butyl, mp 185 ° C, MS: 596 (M + H) *. The (S) -3-amino-N-pyridin-3-ylmethyl-succinic acid tert-butyl ester was prepared as follows: a) The 4-tert-butyl ester of Z-aspartic acid was coupled with 3-aminomethylpyridine, obtaining (S) -3-benzyloxycarbonylamino-N-pyridin-3-ylmethyl-succinamate tert-butyl, MS: 414 (M + H) *, and b) The latter was converted by catalytic hydrogenation to (S) -3 -amino-N-pyridin-3-ylmethyl-succinic acid tert-butyl ester, MS: 280 (M + H) *. Example 164 In the same manner as described in Example 162, starting from (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbo-nyl] -amino] -acetylamino] -N-pyridin-3-ylmethyl-tert-butyl ester, the (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl acid was obtained ] -amino] -acetylamino] -N-pyridin-3-ylmethyl-succinamic acid in the form of trifluoroacetate (1: 1.2), mp 1353C, MS: 540 (M + H) *. Example 165 277 mg of 2- (3-benzyl-ureido) -thiazole-4-carboxylic acid, 175 mg of CDMT, 3 ml of THF and 0.12 ml of N-MM were stirred for 4 1/2. hours at RT, were treated with 280 mg of 3- (p-aminophenyl) -N- (tert-butoxycarbonyl) -L-alanine and 0.12 ml of N-MM and stirred for a further 20 hours at RT. Then, the mixture was diluted with ethyl acetate, washed with 0.1N hydrochloric acid and water, dried with sodium sulfate and evaporated in vacuo. Chromatography on silica gel with ethyl acetate-acetic acid 99: 1 and trituration in ethyl acetate gave 111 mg of (S) -3- [4- [[2- (3-benzyl-ureido) -thiazole-4-acid. -carbonyl] -amino] -phenyl] -2-tert-butoxycarbonylamino-propionic, mp 231 ° C, MS: 540 (M + H) *. Example 166 Similarly, 2- (3-benzyl-ureido) -thiazole-4-carboxylic acid and 3- (p-aminofenyl) -N- (tert-butoxycarbonyl) -D-alanine were obtained (R) -3 - [4- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenyl] -2-tert-butoxycarbonylamino-propionic acid, mp 232 ° C, MS: 540 (M + H) *. EXAMPLE 167 According to the method described in Example 9a, 2- (3-pyridin-2-ylmethyl-ureido) -iiazole-4-carboxylic acid was coupled with the (S) -3- (2-amino- acetylamino) -N-pyridin-2-ylmethyl-succinamate tert-butyl ester. For subsequent operationsThe mixture was diluted with ethyl acetate, washed with dilute sodium carbonate solution and water, dried and evaporated. Chromatography on silica gel with methylene chloride-ethanol gave (S) -N-pyridin-2-ylmethyl-3- (2 { [2- (3-pyridin-2-ylmethyl-ureido) - thiazole-4-carbonyl] -amino.}. -acetylamino] -succinamats of tert-butyl, mp 112 ° C, MS: 597 (M + H) * .The starting material was prepared as follows: a) By coupling Z-glycine with tert-butyl (S) -3-amino-N-pyridin-2-ylmethyl-succinamate, (S) -3- (2-benzyloxycarbonylamino-acetylamino) -N-pyridin-2 was obtained tert-butyl-methylmethyl-succinamate, MS: 471 (M + H) *. b) The latter was hydrogenated with Pd / C in alcohol, obtaining the (S) -3- (2-amino-acetylamino) -N-pyridin-2-yl-methyl-tert-butyl succinamate; MS: 337 (M + H) *. Example 168 394 mg of (S) -N-pyridin-2-ylmethyl-3 -2-. { [2- (3-pyridin-2-yl-methyl-ureido) -thiazole-4-carbonyl] -amino} -acetylamino) -succinamate of tert-butyl, were stirred in 1.5 ml of methylene chloride and 1.5 ml of TFA for 4 hours at RT. The solvents were evaporated in vacuo, the residue was dissolved in ethyl acetate and the solution was evaporated again. The residue was then dissolved in water, neutralized with ammonia and evaporated in vacuo. The residue was dissolved in ethanol and, after triturating, filtering with suction and drying, 254 mg of the acid (S) -N-pyridin-2-ylmethyl-3- (2-. {[2- (3- pyridin-2-yl-methyl-ureido) -thiazole-4-carbonyl] -amino.}. -acetylamino) -succinamic acid, mp. 164 ° C, MS: 541 (M + H) *.

Example 169 According to the method described in example 9a, 2- (3-benzyl-ureido) -thiazole-4-carbo-xylic acid was reacted with the tert-butyl ester. of N- (3-aminobenzoyl) -beta-alanine, obtaining 3- (3 { [2- (3-benzyl-ureido) -thia-zol-4-carbonyl] -amino.}. -benzoylamino ) -tert-butylpropionate. P.f. 212 ° C, MS: 524 (M + H) *. EXAMPLE 170 363 mg of tert-butyl 3- (3- {[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -benzoylamino) -propionate were stirred at 1.5 g. ~ ml of methylene chloride and 1.5 ml of TFA for 4 hours at RT. After evaporating the solution in vacuo, the residue was diluted with ethyl acetate, washed with water, dried and evaporated in vacuo. With acetone, there were obtained 145 mg of 3- (3 - { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -benzoylamino) -propionic acid, m.p. 157 ° C, MS: 468 (M + H) *. Example 171 Analogously to example 18, 2- (imidazolidin-2-ylidenamino) -thiazole-4-carboxylic acid was reacted with 3- (2-amino-acetylamino) -3-pyridin-3-yl-pro hydrochloride - ethylpionate. After chromatography on silica gel with ethyl acetate-ethanol and trituration in ether, (RS) -3- (2 { [2- (imidazolidin-2-ylidenamino) -thiazole-4-carbonyl] - ethyl.}. α-acetylamino) -3-pyridin-3-yl-propionate, mp 198-199 ° C, MS: 446 (M + H) * The starting materials were prepared as follows: a) The imidazolidin-2-ylidene thiourea was reacted in EtOH with ethyl bromopyrute to obtain the hydrobromide of 2- ( imidazolidin-2-ylidenamino) -thiazole-4-carboxylic acid ethyl ester. P.f. 207 ° C, MS: 241 (M + H) *. b) Saponification with sodium hydroxide solution in ethanol gave 2- (imidazolidin-2-ylidenamino) -thiazole-4-carboxylic acid, m.p. 260 ° C, MS: 212 (M) *. c) Z-glycine was coupled with ethyl (RS) -3-amino-3-pyridin-3-yl-propionate hydrochloride, obtaining rac-3- (2-benzyloxycarbonylamino-acetylamino) -3-pyridine Ethyl 3-yl-propionate; MS: 386 (M + H) *. d) By catalytic hydrogenation with Pd / C in ethanol in the presence of hydrogen chloride, ethyl 3- (2-amino-acetylamino) -3-pyridin-3-yl-propionate was obtained from the latter. hydrochloride, MS: 252 (M + H) *. Example 172 213 mg of rac-3- (2- { [2- (imidazolidin-2-ylidenamino) -thia-zol-4-carbonyl] -amino.} - acetylamino) -3-pyridin-3-yl ethylpropionate, were stirred for 10 hours at RT in 4 ml of 25% hydrochloric acid. The reaction mixture was evaporated in vacuo to dryness and the residue lyophilized with acetic acid. 241 mg of 3- (2-. {[[2- (imidazolidin-2-ylideneamino) -thiazole-4-carbonyl] -amino} -acetylamino) -3-pyridin-3-yl-hydrochloride were obtained. propionic (1: 2), mp 170-172 ° C, MS: 418 (M + H) *. Example 173 Analogously to example 18, the acid was reacted 4-methyl-2- (tetrahydro-pyrimidin-2-ylidenamino) -thiazole-5-carboxylic acid, with ethyl rac-7-amino-3-phenyl-heptanoate.

After chromatography on silica gel with ethyl acetate-alcohol and crystallization with alcohol, rac-7- [[4-methyl-2- (tetrahydro-pyrimidin-2-ylidenamino) -thiazole-5-carbonyl] - amino] -3-phenyl-heptanoate, mp 137-139 ° C, MS: 472 (M + H). "The starting material was prepared as follows: a) The (tetrahydro-pyrimidin-2-yl-den) -thiourea was reacted in 78 ° alcohol. C with ethyl chloroacetoacetate, obtaining the hydrochloride of ethyl 4-methyl-2- (tetrahydro-pyrimidin-2-ylideneamino) -thiazole-5-carboxylate (1: 1). Mp 224 ° C, MS: 269 (M + H) * 'b) By saponification with sodium hydroxide solution in ethanol, 4-methyl-2- (tetrahydro-pyrimidin-2-ylidenamino) -thiazole-5-carboxylic acid, mp was obtained from the latter. 198 ° C, MS-241 (M + H) * Example 174 437 mg of rac-7- [[4-methyl-2- (tetrahydro-pyrimidin-2-ylidenamino) -thiazole-5-carbonyl] -amino Ethyl] -3-phenyl-heptanoate was stirred for 22 hours at RT in 9 ml of 25% hydrochloric acid The reaction mixture was evaporated in vacuo to dryness and the residue was lyophilized with acetic acid 457 mg were obtained of rac-7- [[4-methyl-2- (tetrahydro-pyrimidin-) hydrochloride acetate 2-ylidenamino) -thiazole-5-carbonyl] -amino] -3-phenyl-heptanoic, p.f. 60-63 ° C, MS: 444 (M + H) *. Example A A compound of formula I can be used in a manner known per se as active substance for the production of tablets of the following composition: per tablet Active substance 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropyl methylcellulose 20 mg 425 mg Example B A compound of formula I can be used in a manner known per se, as an active substance for the production of capsules of the following composition: per capsule Active substance 100.0 mg Wheat starch 20.0 mg 15 Lactose 95.0 mg Talcum 4.5 mg magnesium stearate 0.5 mg 220, 0 mg twenty List of current abbreviations AcOEt Ethyl acetate AcOH Acetic acid Aeg-RGDS Aminoethylglycine-Arg-Gly-Asp-Ser-OH Boc tert-butoxycarbonyl BOP (Benzotriazol-1-yl-oxy) -tris- (dimethylamino) -phosphonium hexafluorophosphate BSA Bovine serum albumin Cbz Benzyloxycarbonyl 10 CDMT 2-chloro-4,6-dimethoxy-1,3,5-triazine DMF Dimethylformamide? DC N- (3-dimethylaminopropyl) N'-ethylcarbodiimide Hydrochloride The Impact of electrons 15 ELISA Enzyme immunoassay EtOH Ethanol FAB Bombardment with fast atoms HBTU 0- (Benzotriazol-1-yl) -N,, N ',' -tetramethyluronium ISP Spray ion (positively charged ions) MeCN Acetonitrile MeOH Metanol MS Mass spectroscopy 25 NMM N-methylmorpholine Pf Melting point RGDS H-Arg-Gly-Asp-Ser-OH RP Inverted phase TA Ambient temperature 30 t-BuOH tert-butanol TFA Trifluoroacetic acid THF Tetrahydrofuran It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (27)

1. Claims Some compounds of the formula I characterized because R1 e s ? R6 R ~ (CH ^ -N- C-Ñ RS GN - R "e s R3 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, carboxyl, alkyl-O-CO- or aralkyl-O-CO-; R 4 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl; R5 and R6 are each, independently, hydrogen, alkyl, cycloalkyl or heteroaryl; R7 and R8 are each, independently, hydrogen, alkyl, cycloalkyl or aralkyl or R7 and R8 together with the N atoms to which they are attached form a 5- to 8-membered heterocyclic ring which may be substituted by alkyl; R9 is hydrogen, alkenyl or cycloalkyl; R 10 is aryl, aralkyl, heterocyclic, thiocyclylalkyl, hydroxyl, hydrogen or alkyl, or R 10 is carboxyl, carboxyalkyl, alkyl-O-CO-, aralkui 1 oO-CO-, alkyl-CO-, aralkyl-CO- , heteroarylalkyl-CO-, alkylsulfonyl, ary1 sui foni lo or heteroarylsul fonyl and k is zero, or R10 is an alpha-amino acid linked via the amino group and 1 is zero and k is 1; A is carbonyl or sulfonyl; B is hydrogen, alkenyl or cycloalkyl; a to m are zero or positive integers, being zero to 2, but not being zero when R1 is - NH2; where b is zero to 4; being c, d, f, g, k, 1 and m each, independently, zero or 1, whereby c, f and g are not simultaneously zero and so m is not zero when f or g is 1; i is zero or 1, whereby k and 1 are also zero when i is zero; e is zero to 3; h is zero to 5; j is zero to 2; and the sum of e, h and j is 2 to 7; and its pharmaceutically usable salts and esters.
2. 2. The compounds, in accordance with the rei indication 1, characterized in that f and g are not both simultaneously 1.
3. 3. The compounds, according to claim 1, characterized in that R is and R9, R10, A, B, c and f a 1 have the meaning set forth in claim 1.
4. 4. The compounds according to any of claims 1 to 3, characterized in that R2 is and R10, A, B and f a 1 have the meaning stated in rei indication 1.
5. 5. The compounds, according to claim 1, characterized in that R2 is and R9, R10, A, d, e and h a 1 have the meaning set forth in claim 1.
6. 6. The compounds, according to claim 1, characterized in that R2 is and R- R 10 g and h 1 are as defined in claim 1, where c and g are not equal to zero simultaneously.
7. 7. The compounds according to any one of claims 1 to 5, characterized in that arylene is phenylene or substituted phenylene, the phenyl being substituted mono- or mu-i -substituted by alkoxy, aralkoxy, halogen or alkoxy-alkoxy.
8. 8. The compounds according to claim 7, characterized in that arylene is meta- or para-phenylene or meta- or substituted p-phenylene, the phenylene substituents being previously "given with the definition of R in meta-position". or para- and carrying a substituted phenylene with a further substituent on the ring selected from the group of alkoxy, alkoxy-alkoxy, halogen or aralkoxy.
9. 9. The compounds according to any of claims 1 to 8, characterized in that R3 is hydrogen, alkyl, cycloalkyl, alkyl-O-CO, carboxyl or unsubstituted or substituted phenyl, with the substituted phenyl being substituted by one or more substituents chosen from halogen, nitro and amino.
10. 10. The compounds according to any of claims 1 to 9, characterized in that R 4 is hydrogen, alkyl, cycloalkyl, phenyl or pyridyl.
11. 11. The compounds according to any of claims 1 to 10, characterized in that R5 and R6 are hydrogen or pyridyl and R7 and R8 are hydrogen or R5 and R6 are each hydrogen or pyridyl and R7 and R8 together with the N atoms to those that are joined form a pentagonal or hexagonal ring.
12. 12. The compounds, according to any of claims 1 to 11, characterized in that R10 is piperidyl, pyridylmethyl, pyridyl, benzyl, alkyl, hydrogen or substituted or unsubstituted phenyl, the phenyl being mono- or multi-substituted by halogen, alkoxy, alkoxycarbonyl, carboxyl or hydroxyl, or R10 is alkyl-0-CO -methyl, carboxymethyl, alkylsul fonyl, alkyl-CO-, benzyl-O-CO- or alkyl-O-CO-, where k is zero, or R10 is L-valine, L-phenylalanine, L-phenylglycine , L-leucine, Li-soleucine, L-serine, L-threonine, 3- (1-naphthyl) -L-alanine, 3 - (2 -naphthyl) -L-alanine, N-isopropyl-glycine, be t -cyclohexyl-L-alanine or L-proline, where k equals 1 and 1 equals zero.
13. 13. The compounds according to any of claims 1 to 12, characterized in that R9 is hydrogen or cycloalkyl or.
14. 14. The compounds according to any of claims 1 to 13, characterized in that R2 is linked in position 5 of the thiazide ring and R3 is linked in position 4 of the thiazole ring. -
15. 15. The compounds according to any one of claims 1 to 14, characterized in that they are selected from: 3- (2- [[(2- (3-benzyl-ureido) -thiazol-4-ylcarbonyl] -amino] acid] -acetylamino] -3-phenyl-propionic acid, rae 4- [3- (2-guanidins-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -3-phenyl-butyl ester, rae 3- [2 - [(2-guanidinoraetil-thiazol-4-ylcarbonyl) -amino] -acetylamino] -3-phenylpropionic rae 3- [3- [(2-guanidino-4-methyl-thiazol-5-ylcarbonyl) -amino] -feni lsulf oni lamino] -3-phenyl-propionic acid hydrochloride rae 3- [3- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -benzoylamino] -3-phenyl-propionic acid , rae acid 3- [3- [(4-tert-butyl-2-guanidino-thiazol-5-ylcarbonyl) -amino] -benzoylamino] -3-pyridin-3-yl-pro-ionic acid, hydrochloride of [2- guanidino-thiazole-4-carbonyl] -Gly-Asp-Val-OH, rae acid 3- (4-chloro-phenyl) -4- [3- (2-guanidino-4-methyl-thiazol-5-yl) - benzoylamino] -butyric acid, rac-3- [3- [(2-guanidino-4-methyl-thiazole-5-carbonyl)] -amino] -propionylamino] -3-f enyl-propionic acid rae 4- [3- (2-guanidino-4-methyl-thiazol-5-yl) phenylcarbamoyl] -3- (4-methoxyphenyl) butyric acid, Rae 4- [3- (2-guanidino-4-methyl-thiazol-5-yl) -phenylcarbamoyl] -3-pyridin-3-yl-butyric acid, 6- acid. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -5-oxo-hexanoic acid, (S) -3 (2- {[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -acetylamino) -succinic acid-4-anilide , trif luoroacetato of (S) -N-benzyl-3- [2- [[2- (3-benzyl- ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -succinamic acid acetate / trifluoroacetate acid (S) -2- [(S) -2- (2- { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino}. -acetylamino) -3-carboxy - propionylamino] -3-methyl-butyric acid, trifluoroacetate of (S) -3- [2- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -acetylamino] -N- isobutyl-succinamic acid and luoroacetato trif (S) -3- [2- [[2- (3-benzyl-ureido) - thiazole-4-carbonyl] -amino] -acetylamino] -N-pyridin-2-ylmethyl- succinamic
16. 16. A process for the preparation of a compound as defined in claim 1, characterized in that the process comprises reacting a compound of the formula (XXXI) with an amine of the formula wherein R1, R3, R9, R10, A, B and d to m have the meaning set forth in claim 1, c is equal to 1 and R, 03 is alkyl or aralkyl.
17. 17. Some compounds of the formulas (XXXI) characterized in that R1, R and a have the meaning set forth in claim 1 and wherein R3 is not hydrogen or methyl when R1 is H2N-. H2N. H2N- \ C-NH-HN1
18. 18. The compounds, according to any of claims 1 to 15, characterized in that they are for use as therapeutically active substances.
19. 19. The compounds according to any of claims 1-15, characterized in that they are for the production of medicaments for the prophylaxis and therapy of diseases that are caused by a poor function of the binding of adhesive proteins to vitronectin receptors.
20. 20. A pharmaceutical composition characterized in that it contains a compound according to any of claims 1-15 and a therapeutically inert carrier.
21. 21. A pharmaceutical composition according to claim 20, characterized in that it additionally contains one or more compounds selected from the group consisting of anticoagulants, fibrinolí ticos, compounds according to claim 1 as well as medicaments for the prophylaxis and therapy of diseases which are caused by a poor function of the binding of adhesive proteins of vitronectin receptors.
22. 22. The use of compounds, according to any of claims 1-15 for the production of drugs.
23. 23. The use of compounds, according to any of claims 1-15, for the production of medicaments for the treatment and prophylaxis of neoplasms, tumor metastasis, tumor development, osoporosis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis after vascular intervention, psoriasis, arthritis, fibrosis, renal failure, as well as infections caused by viruses, bacteria or fungi or for the production of corresponding medications.
24. 24. The compounds, according to any of claims 1-15, characterized in that they are prepared in accordance with claim 16
25. 25. A method for the treatment and prophylaxis of diseases that are caused by poor function of the binding of adhesive proteins of vitronectin receptors, characterized in that the method comprises administering an effective amount of a compound according to any of the rei indications 1-15.
26. 26. A method for the treatment and prophylaxis of neoplasms, tumor metastasis, tumor development, osoporosis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis after vascular intervention, psoriasis, arthritis, fibrosis, renal insufficiency, as well as infections caused by virus, bacteria or fungi, characterized in that the method comprises administering an effective amount of a compound according to any of claims 1-15.
27. 27. The invention as previously described.