MXPA01004000A - Thiazole-derivatives - Google Patents

Abstract

Compounds of formula (I) as well as pharmaceutically usable salts and esters thereof, wherein R1, R2 and R3 have the significance given in claim 1, inhibit the binding of adhesive proteins to the surface of different types of cell and accordingly influence cell-cell and cell-matrix interactions. They can be used in the form of pharmaceutical preparations in the control or prevention of neoplasms, tumour metastasizing, tumour growth, osteoporosis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis following vascular intervention, psoriasis, arthritis, fibrosis, kidney failure as well as infections caused by viruses, bacteria or fungi.

Description

DERIVATIVES OF TIAZOL DESCRIPTION OF THE INVENTION The present invention relates to new thiazole derivatives. These derivatives inhibit the binding of adhesive proteins to the surface of different cell types by the influence they exert on cell-cell and cell-matrix interactions. The present invention relates especially to thiazole derivatives of formula (I) where R1 is R2 is REF: 128272 R3 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, carboxyl, alkyl-0-CO- or aralkyl-0-CO-; R 4 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl; R5 and R6 independently of one another are hydrogen, alkyl, cycloalkyl or heteroaryl; R7 and R8 independently of each other, are hydrogen, alkyl, cycloalkyl or heteroaryl or R7 and R8 together with the N atoms to which they are attached, form a 5- to 8-membered heterocyclic ring, which can carry one or more alkyl substituents; R9 is hydrogen, alkyl or cycloalkyl; R10 is hydrogen, aryl, aralkyl, heteroaryl, heterocyclylalkyl, carboxyalkyl, alkyl, cycloalkyl, alkyl-O-CO-, aralkyl-O-CO-, alkyl-CO-, alkylsulfonyl, arylsulfonyl or Heteroarylsulfonyl; A is oxygen, sulfur, -CH = CH- or "ssaferi- ,. from a to f are zero or are positive integers, with a being from zero to 2; b being from zero to 4; c and d being zero or 1, with the proviso that c and d are not both simultaneously zero; e is from zero to 5, with the proviso that e is non-zero when d is zero and e is from zero to 3 when A equals -CH = CH-; and f is from zero to 3, with the proviso that f is not zero when A is oxygen, sulfur or and its pharmaceutically acceptable salts and esters. The compounds of formula I and their pharmaceutically acceptable salts and esters are new and have valuable pharmaceutical properties. In particular, they inhibit the union. of the adhesive proteins such as fibrinogen, vitronectin, illebrand factor, fibronectin, thrombospondin and osteopontin to the vitronectin receptors (such as for example avß3, avß5 / otvßdf civßs etc.) on the surface of different cell types. These compounds therefore influence cell-cell and cell-matrix interactions, and can be used in the treatment and prophylaxis of diseases based on dysfunction. - «k * of the binding of the adhesive proteins to the vitronectin receptors. In particular, they can be used as antagonists of the vitronectin receptor in the prophylaxis or treatment of neoplasms, metastasis of 5 tumors, tumor growth, osteoporosis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis after a vascular intervention, psoriasis, arthritis , fibrosis, renal deficiency, as well as infections caused by viruses, bacteria or fungi.

The subject of the present invention are the compounds of formula I and their salts and esters mentioned above, by themselves and their use as therapeutically active substances, a process for obtaining said compounds, intermediates, pharmaceutical compositions, medicaments containing said compounds, their salts or esters, the use of said compounds, solvates and salts for the prophylaxis and / or therapy of diseases, especially in the treatment or prophylaxis of, for example, neoplasms, tumor metastases, tumor growth, osteoporosis, 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, and the use of qfa. » -. . *? *** ~ »** ~~ * ¿. .x X u ^ t &zsi, said compounds and salts for the preparation of medicaments for the treatment or prophylaxis of, for example, neoplasms, tumor metastasis, tumor growth, osteoporosis, 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. 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 4 carbon atoms. Examples of straight chain alkyl groups or Branched chain, with 1 to 8 carbon atoms, are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, isomeric pentyls, isomeric hexyl, isomeric heptyls and isomeric octyls, preferably methyl, ethyl, isopropyl and butyl tertiary 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 cycloalkyl of 3 to 8 carbon atoms are the ^ É¿ £ & * - ~ fc ~ a & i, «,. '* 3' 3?, .- * jet. cyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethylcyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopentyl and particularly cyclopentyl. The term "alkoxy", alone or in combination, means an alkyl ether group in which the term "alkyl" has the meaning given above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy; sec.butoxy and terebutoxy, preferably methoxy and ethoxy. The term "aryl", alone or in combination, means a phenyl or naphthyl group, which bears 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.butoxyphenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl. Alkoxy phenyls and chlorophenyls are preferred, especially phenyl and ortho-, meta- and para-monochlorophenyls, especially para- and meta-chlorophenyl and para- and meta-methoxy-phenyl. Phenyl is particularly preferred.

The term "aryloxy", alone or in combination, means a group of formula -O-aryl in which the term "aryl" has the meaning given above. The term "aralkyl", alone or in combination, means an alkyl or cycloalkyl group as defined above in which a hydrogen atom is replaced by an aryl group as defined above, such as, for example, benzyl, 2-phenylethyl and the like, preferably benzyl. The term "aralkoxy", alone or in combination, means an aralkyl group as defined above in which a hydrogen atom of the alkyl part is replaced by an oxygen atom bearing the free valence. Benzyloxy is the preferred one. The term "arylene", alone or in combination, means a phenylene or naphthylene group, which optionally bears one or more substituents selected from alkyl, cycloalkyl, halogen, Hydroxyl, amino, nitro, aryloxy, aralkoxy, alkoxy-alkoxy and preferably alkoxy, carboxyl and -CO-0-CH2-CO-0-alkyl. Examples are ortho-, meta- or para-phenylene, toluenes, methoxyphenylenes, tere-butoxyphenylenes, fluorophenylenes, chlorophenylenes, hydroxyphenylenes, naphthylenes, benzyloxyphenylenes, etc.

Preferred are the meta- and para-phenylenes, with the phenylene substituents indicated above in the definition of R2 in meta position or for each other, and wherein in addition one or more substituents selected from alkyl, cycloalkyl, halogen, hydroxyl, amino , aryloxy and alkoxy-alkoxy and preferably alkoxy, carboxyl and -CO-0-CH2-CO-0-alkyl may be present on the arylene ring. Especially preferred are meta- and para-phenylene which carry one of the above-mentioned substituents on the phenylene ring and in this case the methoxy and para-phenylenes which are methoxy are the most particularly preferred., carboxy or -CO-0-CH2-CO-0-ethyl on the phenylene ring. The meta- and para-phenylene are particularly preferred. The term "heterocyclyl", alone or in combination, means a saturated, partially unsaturated or aromatic heterocycle of 5 to 10 members, containing one or more heteroatoms selected from nitrogen, oxygen and sulfur. If desired, it can be substituted on one or more carbon atoms with halogen, alkyl, alkoxy, oxo, etc. and / or on a secondary nitrogen atom (i.e., -NH-) with alkyl, cycloalkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl, preferred on a tertiary nitrogen atom (ie = N-) with oxide, halogen, alkyl, cycloalkyl and alkoxy. Examples of said heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyrrolyl, imidazolyl (for example imidazol-4-yl, l-benzyloxycarbonylimidazol-4-yl), pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, hexahydropyrimidinyl. , furyl, thienyl, thiazolyl, oxazolyl, thiazolyl, indolyl (for example 2-indolyl), quinolyl (for example 2-quinolyl, 3-quinolyl, 1-oxide-2-quinolyl), isoquinolyl (for example 1-isoquinolyl, isoquinolyl), tetrahydroquinolyl (for example 1, 2, 3, -tetrahydro-2-quinolyl), 1,2,3,4-tetrahydroisoquinolyl (for example 1, 2, 3, 4-tetrahydro-1-oxoisoquinolyl) and quinoxalinyl . Preferred are 5 or 6 membered rings, especially piperidyl and pyridyl. The term "heteroaryl", alone or in combination, means the aromatic compounds which fall within the definition of "heterocyclyl" and which can carry the substituents described therein. Preferred are 5 and 6 membered rings, especially pyridyl. The term "amino", alone or in combination, means a primary, secondary or is tertiary, linked via the nitrogen atom with the secondary amino group carrying an alkyl or cycloalkyl substituent and its tertiary amino group carrying two similar or different alkyl or cycloalkyl substituents, or the two nitrogenous substituents forming together a ring, such as -NH2 - methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino, etc., preferably amino, dimethylamino and diethylamino, particularly primary amino. The term "halogen" means fluorine, chlorine, bromine or iodine, preferably chlorine. The term "alkyl-O-CO-" means an alkyl ester group in which the alkyl is as previously defined. In this case, the methyl ester, ethyl ester, isomeric propyl ester and isomeric butyl ester groups are preferred. The methyl ester and ethyl ester groups are especially preferred. The term "aralkyl-O-CO-" means an aralkyl ester group, in which aralkyl is as previously defined. In this case, the benzyl ester group is preferred. The term "heterocyclylalkyl" means an alkyl group as previously defined, in the .aaajáift? sa & -. tf & amp; - * '. - ^ ¡? 0ÍISßB? 6 ^ & ^ ^ A ^ - Brs * '' ^ afo. ^^^^ Jarifra which a hydrogen atom has been replaced with a heterocyclyl group. Pyridylmethyl, 1-pyridylethyl and 2-pyridylethyl are examples of said heterocyclylalkys. The term "alkylsulfonyl" means a O Alquilo-S « group in which the alkyl is as defined above. Preferred "alkylsulfonyls" are methylsulfonyl, ethylsulfonyl, isomeric propylsulfonyl and isomeric butylsulfonyl. The term "arylsulfonyl" means a Or Aril < 1 8 group in which the aryl is as defined above. Preferred arylsulfonyls are phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and 2-mesitylenesulfonyl. The term "heteroarylsulfonyl" means a group in which the heteroaryl is as defined above. The preferred heteroarylsulfonyls are 2-thiophenesulfonyl and 3,5-dimethylisoxazole-4-sulphonyl. The term "alkyl-CO-" means an alkylcarbonyl group in which the alkyl is as defined above. Methyl- and ethylcarbonyl are the preferred examples. Examples of physiologically usable salts of the compounds of formula I are salts with physiologically compatible mineral acids such as sulfuric acid, phosphoric acid or preferably hydrochloric acid; or with organic acids such as methanesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The compounds of formula I having a free carboxyl group can also form salts with physiologically compatible bases. Examples of such salts are the alkali metal salts, alkaline earth metal, ammonium and alkylammonium salts such as the Na, K, Ca or tetramethylammonium salt. The compounds of formula I may also exist in the form of amphoteric ions. In the nomenclature used in the present descrin, the ring atoms of the thiazole ring are numbered as follows: the substituent R1 being attached to the 2-position, the substituents R2 being attached to the 4-position, and R3 being attached to the 5-position. or R2 being attached to the 5-position, and R3 to the 4-position, of the thiazole ring: The invention expressly includes pharmaceutically suitable derivatives of the compounds of formula I. For example, the COOH groups of R2 can be esterified. Examples of suitable esters are the alkyl and aralkyl esters. Preferred esters are the methyl, ethyl, propyl, butyl, benzyl and (R / S) -1- (isopropoxy-carbonyl) -oxy) -ethyl ester. Ethyl esters and isomeric butyl esters are especially preferred. The compounds of formula I can also be solvated, for example hydrated. The hydration may be carried out in the course of the production process or may take place, for example, as a consequence of the hygroscopic properties of an initially anhydrous compound of formula I (hydration). The compounds of formula I can contain several asymmetric centers and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as for example racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates. Examples of preferred compounds of formula (I) are those in which R2 is (lll) Also preferred are the above compounds of formula (I) in which R2 is Equally preferred compounds of formula (I) are those in which R2 is R9 CO- - arylene - A-f-CHr] - COOH (V) For the preferred compounds also belong those in which R2 is aa¡ * • -i- 1, ^?. & • * • ^ 4 - «ü".-.--? • j-tar. TaiítSBKa! Í 8Etea¿-Ait? - - * -ife¿ »j •! *. < £. A .ea -, «- ^. > a K The compounds of formula (I) in which A 'is oxygen or -CH = CH- are preferred. Oxygen is especially preferred. The preferred compounds described above also belong to those in which R1 is In addition, preferred compounds of formula (I) are those in which the arylene is phenylene or substituted phenylene, with the substituted phenylene carrying one or more substituents, preferably one, aralkoxy, halogen, alkoxy-alkoxy and especially alkoxy, carboxyl or - CO-0-CH2-CO-0-alkyl. Especially preferred are the above compounds of formula (I) in which the arylene is meta- or para-phenylene or substituted meta- or para-phenylene, with the phenylene substituents given above in the definition of R2 with said substituents in the meta- or para- position, and with the substituted phenylene carrying an additional substituent, selected from the group consisting of alkoxy, carboxyl or -CO-0-CH2-CO-0-alkyl and particularly of the group formed by methoxyl, carboxyl and -CO-0-CH2-CO-0-ethylol on the ring. Very particularly preferred are the above compounds of formula (I) in which the arylene is unsubstituted phenylene and especially unsubstituted meta- or para-phenylene. A group of preferred compounds of formula (I) comprises those in which R3 is hydrogen, alkyl, cycloalkyl or phenyl. Of these, the especially preferred compounds are those in which R3 is hydrogen or alkyl. Another group of preferred compounds of formula (I) comprises those in which R4 is hydrogen, alkyl, cycloalkyl or phenyl, with those in which R4 is hydrogen or phenyl being particularly preferred. The above compounds are also preferred Of formula (I) in which R5, R6, R7 and R8 are hydrogen or R5 and R6 are both hydrogen and R7 and R8 together with the N atoms to which they are attached, form a ring of 5 to 6 members. Of these, those in which R5, R6, R7 and R8 are hydrogen.

Another group of preferred compounds of formula (I) comprises those in which Rs is hydrogen or cycloalkyl. Those in which R9 is hydrogen are particularly preferred. Preferred compounds of formula (I) in which A is are those in which R10 is alkyl or cycloalkyl and especially those in which R10 is hydrogen. Particularly preferred are those compounds in which R 10 is phenyl. Preferred compounds are compounds of formula (I) in which R2 is attached to the 4-position and R3 is attached to the 5-position of the thiazole ring. Of these, those in which R2 is attached to the 4-position and R3 is attached to the 5-position of the thiazole ring and R1 are especially preferred are Equally preferred are the compounds of formula (I) in which a is equal to 1. Those in which a is zero, are especially preferred. Also preferred are compounds of formula (I) in which b is from zero to 2 and especially those in which b is equal to 1. In addition, compounds of formula (I) in which e is from zero to 4. Those in which e is equal to 3 and d equals zero are especially preferred. Also especially preferred are compounds according to formula (I) in which e is equal to zero and d equals 1. Another group of preferred compounds of formula (I) comprises those in which f is equal to 1 and A is, equal to oxygen, sulfur or and particularly those in which A is oxygen. Equally preferred are compounds of formula (I) in which f is equal to zero and A is -CH = CH-. In addition, compounds of formula (I) in which A is R10 -JL. R10 is phenyl, c is 1 and e is zero. Examples of preferred compounds of formula I are: { 3- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -propoxy} -acetate of butilo; [3- [(2-Guanidino-4-methylthiazole-5-carbonyl) -amino] -propoxy] -acetic acid hydrochloride; . { 4- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -phenoxy} -ethyl acetate; [4- [(2-Guanidino-4-methylthiazole-5-carbonyl) -amino] -phenoxy] -acetic acid hydrochloride; . { 3- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -phenoxy} -acetate of butilo; [3- [(2-guanidino-4-methyl-thiazole-5-carbonyl) -amino] -phenoxy] -acetic acid; . { 4- [(2-guanidino-thiazole -carbonyl) -amino] -phenoxy} ethyl acetate; [4- [(2-Guanidino-thiazole-4-carbonyl) -amino] -phenoxy] -acetic acid hydrochloride; . { 4- [(2-guanidino-thiazole-5-carbonyl) -amino] -phenoxy} -ethyl acetate; [4- [(2-Guanidino-thiazole-5-carbonyl) -amino] -phenoxy] -acetic acid hydrochloride; (4- {[2- (3-benzyl-ureido) -1-yiazole-4-carbonyl] -amino} -phenoxy) -acetic acid ethyl ester; [4- [[2- (3-Benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenoxy] -acetic acid; (4- {[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -2-methoxy-phenoxy) -acetic acid ethyl ester; (4- {[[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -2-methoxy-phenoxy) -acetic acid; 5- . { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} Ethoxycarbonylmethyl-2-ethoxycarbonylmethoxybenzoate; Acid 5-. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -2-carboxymethoxy-benzoic; (E) -3- [4 - [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenyl] -ethyl acrylate; (E) -3- [4- [2- (3-Benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenyl] -acrylic acid; and [(4- {[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} - phenyl) -phenyl-amino] -acetic acid methyl ester. The following compounds are preferred examples thereof: v » (4- {[2- (3-benzyl-ureido) -thiazole-carbonyl] -amino} -phenoxy) -acetic acid ethyl ester; [4- [[2- (3-Benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenoxy] -acetic acid; (4- {[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -2-methoxy-phenoxy) -acetic acid ethyl ester; (4- {[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -2-methoxy-phenoxy) -acetic acid; 5- . { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} Ethoxycarbonylmethyl-2-ethoxycarbonylmethoxybenzoate; Acid 5-. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -2-carboxymethoxy-benzoic; (E) -3- [4 - [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenyl] -ethyl acrylate; (E) -3- [4- [2- (3-Benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenyl] -acrylic acid. The processes for obtaining the compounds of formula I are also an object of the invention. The methods are based in each case on the reaction of a thiazole derivative, representing the basic thiazole structure, with a reactive compound, which represents the substituent R2 or a reactive component and / or derivative thereof.

The following routes can be followed for the preparation of the corresponding basic thiazole structure, with the substituents and indices used in the following schemes, having the meanings given above, unless otherwise indicated. Suitable basic thiazole structures can be prepared, for example, by the method indicated in the scheme la. In this, an a-bromo ketone of formula VII, such as ethyl pyruvate, is reacted in a solvent such as ethanol, with a thiourea derivative of formula VIII, such as 2-imino-4-thiobiuret, at elevated temperature (J. Med. Chem. 1991, 3_4, 914). A subsequent saponification of the ester group by a base, such as an aqueous NaOH or KOH, yields a thiazole-4-carboxylic acid derivative of type X (reaction scheme la). In one variant of the process, an optionally substituted thiourea of formula IX is used, which, after cyclization of the thiazole, is reacted with an isocyanate, such as benzyl isocyanate, in a solvent, such as DMF, at room temperature. environment, followed by saponification of the ester as described above.

Reaction scheme or 3) LiOH or NaOH In another preparative process (Reaction Scheme Ib) a-halo-ketones are used, which analogously to the process described above, provide thiazole-5-carboxylic acid derivatives of type XIII (Drug 1989, 44, 1011). The α-halo-ketones of formula XII are prepared from the corresponding β-ketoesters (formula XI), such as ethyl butyrylacetate, ethyl pivaloylacetate, etc., by halogenation with for example bromine in a solvent, such as water, conveniently to a temperature of 0-5 ° C (J. Chem. Soc. Perkin I, 1982, 162). Reaction scheme Ib (Xla) (Xp) (XIII) 10 X = Br, Cl R10 = Alkyl In another variant (reaction scheme c), the basic structure of the thiazole is synthesized by the reaction of an N-protected amino acid thioamide, Optionally substituted on the amino nitrogen, such as N-Boc-glycine thioamide, with an α-halo-ketone of formula VII or Xlb. A subsequent saponification of the ester group by means of a base, as described in the reaction scheme la, provides derivatives of the thiazolecarboxylic acid of formula XIV. After removing the protective group these can be subsequently modified, for example according to the reaction scheme 7. When a residue ((CH2) e ~ NH- (group protector)) instead of the COOR01 residue of the compound Xlb or XII, then the aminothiazole derivatives corresponding to XIII can be obtained. The same is also true for the reaction scheme.

Diagram of reaction R01 = alkyl 15 (Xlb) 2) NaOH In a further variant of the process (reaction scheme Id), a substituted benzaldehyde, such as 3-nitrobenzaldehyde, such as 3- 20 nitrobenzaldehyde, or methyl 3-formylbenzoate, is converted with a nitroalkane, such as nitroethane , in a suitable solvent, such as acetic acid, with addition of ammonium acetate, conveniently at elevated temperature, such as at reflux temperature, in the corresponding nitro-olefin (Org. Synth. Coil.

IV, 573 or Synthesis 1994, 258). This is epoxidized by an oxidizing agent such as hydrogen peroxide, in a suitable solvent such as water, with the addition of an aqueous solution of sodium hydroxide to give a nitro-epoxide of formula XV (Synthesis 1976, 53). Reaction of said nitroepoxide with a derivative of thiourea, such as 2-imino-4-thiobiuret, at elevated temperature, such as the reflux temperature, provides arylthiazoles of formula XVI. Using an alternative derivative of thiourea in the above reaction, and subsequent reaction with an isocyanate, such as benzyl isocyanate, in a solvent such as DMF, at room temperature, arylthiazoles of formula XVII have been obtained in which an additional R5 substituent by conventional methods.

Reaction scheme Id 1) R ^^ NO,? v AcÓH. NRjOAc N ° to full) - > "or; 2) H2O2, NaOH (art leno) (XV) Y = -NO 2. - - "-? - *". "z * .r z ^.

-COOR03, - (CH2) e-NH- (protecting group for example Boc or Cbz) 03 R = Al qui lo (XVI) When it is used instead of compound XV in the reaction scheme Id, the compound corresponding to XVI and XVII is obtained, but with the arylene residue attached in the 4-position, and RJ bound in the 5-position of the thiazole ring. In order to prepare compounds analogous to XVI and XVII, being at non-zero according to formula (I), the thioamide used as the starting material in the reaction scheme may be used, for example, instead of the derivative of thiourea employed in the reaction scheme Id. The basic thiazole structures obtainable according to the above procedures are converted into a subsequent reaction with a reactive component and / or a reactive derivative of the substituent R2 to give a compound of general formula I in one or more reaction steps. When c equals 1, that is, when there is an amide bond in the thiazole structure, a corresponding thiazolecarboxylic acid can be reacted, according to the methods already known, with a corresponding amine, to give a compound of formula I. In principle, the following route can be followed: In the variant of the following procedure (reaction scheme 2), the desired thiazole I is obtained by coupling a thiazolecarboxylic acid of formula . * ^ • ^^ ^ ^ Z aáS & * - XVIII with an amine of formula XIX by means of BOP, HBTU or CDMT and then hydrolyzing the ester function. In this regard, see also Z.J. Kaminski, Synthesis, 1987, 917.

Reaction scheme 2 (i) When A is equal to -NH-, this amine function has to be protected with the usual protection groups, for example Boc. In particular, a thiazolecarboxylic acid XVIII is coupled with an amine of formula XIX by a conventional 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. The free compounds of formula I are formed in a subsequent cleavage of the ester by means of a strong acid, such as trifluoroacetic acid in methylene chloride or aqueous hydrochloric acid, or by a strong base, such as NaOH. Alternatively, the above compounds of general formula I can also be obtained by reaction of a reactive partial component of amine XIX and subsequent addition of the R2 component still absent. When c is equal to zero, that is, when the thiazole ring does not carry an amide bond and d is 1, the following procedure is used for the synthesis of the compounds of formula I: When e is also equal to zero, the basic structure of thiazole is prepared analogously to reaction scheme Id, with Y being equal to -O-benzyl (see reaction scheme 3). Reaction scheme 3 (XXI) The benzyl group is cleaved by hydrogenolysis and, when A is oxygen, the resulting alcohol is reacted with the halide of formula XXIII.

Br-H COO-tert Bu ilo (XXIII) When c is equal to zero, d is equal to, e equals zero, and A is sulfur, the following procedure is employed: The thiazole-arylene halide XXIV is reacted with the corresponding thiolate XXV for example in the presence of a Cu or Pd catalyst in DMF or DMSO. + 5- L JLC ?? - tert-But? Lc (XXIV) The halogenated arylene XXIV is prepared according to the reaction scheme Id, where Y is bromine, chlorine or iodine.

When c is equal to zero, d is equal to, e is nonzero and A is sulfur, the products of reaction scheme 3 are used. After the hydrogenolysis cleavage of the benzyl group (H2, Pd / C) the alcohol thus obtained it is converted into the corresponding mesylate or tosylate with for example methanesulfonyl chloride or p-toluenesulfonyl chloride. It is then reacted with the corresponding thiols or thiolates in the presence of a non-nucleophilic base, for example diisopropylethylamine. When c is equal to zero, d is equal to l, e is equal to zero and A is equal to -NR10-, the corresponding basic thiazole structures are prepared according to the reaction scheme Id, where Y is equal to N02. The corresponding amine is obtained after reduction with hydrogen and a Pd / C or Raney nickel catalyst in alcohol. When R10 is aralkyl, alkyl, cycloalkyl, heterocyclylalkyl or carboxyalkyl, these are obtained by reductive amination with the corresponding aldehydes in the presence of borohydrides and catalytic hydrogenation (see for example G. Verardo et al., Synthesis 1993, 121). When R10 is aryl or heteroaryl, the basic structure of the thiazole of reaction scheme Id is used, where Y is equal to -NH2. This is reacted with the corresponding heteroaryl halide or aryl halide (see J. P. Wolfe et al., Tetrahedron Letters, 1997, 38, 6367; S.L. Buchwald et al., Tetrahedron Letters, 1997, 38, 6359; S.L. Buchwald et al., J. Org. Chem., 1997, 62, 6066; D. Ma et al., Tetrahedron Asymm., 1998, 9, 1137). The amines thus obtained are reacted with the corresponding halides of formula R11 = alkyl, aralkyl under the conditions of a nucleophilic substitution reaction. The esters thus obtained are cleaved under basic conditions, as mentioned in the reaction scheme la. When R10 is acyl or sulfonyl, the following procedure can be employed: When d is zero, a protected amine of the following formula Protective group R11 = alkyl, aralkyl Protective group: for example Boc or Cbz (see for example L. Christensen et al., Nucleic Acids Res., 1998, 26, 2735) is acylated on the free nitrogen atom with a carboxylic acid chloride or carboxylic acid anhydride or sulfone with a sulfonic acid chloride (see for example IS eitz et al., J. Org. Chem. 1997, 62, 2527 or PHH Eermkens et al., Tetrahedron, 1988, 44, 1991). After cleavage of the protecting group the resulting amine can be coupled with a thiazolecarboxylic acid of formula X or XIII according to conventional methods and, after hydrolysis of the ester function, converted into the corresponding derivatives of formula I. When d is 1 , a compound of formula NOz ari lßpo CH2 - N-f- CH2-j- COOR11 11 R alkyl, aralkyl (see J. Kihlberg et al., Acta Chem. Scand., Ser B. 1983, B37, 911 and AG Katopodis et al., Biochemistry, 1990, 29, 4541), can be acylated or sulfonylated at the free nitrogen atom of the way described above. The compounds thus obtained are then reduce to give the corresponding amines of formula > 10 Nhfe ari leno - CH2 - tt - CH2-j- COOR11 R10 = acyl, sulfonyl R11 = alkyl, aralkyl When R9 means alkyl or cycloalkyl, the amine thus obtained is reacted with the corresponding aldehyde under conditions of reductive amination (procedure for reductive amination for example see the case where c equals zero, d equals to 1, e is equal to zero and A is equal to -NR10-). The corresponding derivatives of formula I can be obtained by coupling these amines with the thiazolecarboxylic acids of formula X or XIII and subsequent hydrolysis of the ester function. 20 When c is equal to zero, d is equal to, e is different from zero and A is equal to -NR-, the compound corresponding to the reaction scheme Id with Y equal to O-benzyl, is converted by hydrogenation into the corresponding alcohol [and] then it is done react with for example methanesulfonyl chloride or paratoluenesulfonyl chloride to give the corresponding mesylate or tosylate. The subsequent reaction takes place with the corresponding amine components under the conditions of a nucleophilic substitution reaction. The process of Reaction Scheme 4 is used for the preparation of thiazole XXVI derivatives of Formula I, with c equal to zero, d equal to 1, and equal to zero and A equal to -CH = CH-: Reaction scheme 4 ? is equal to Br or I ZX (arylene) I CH CH2 - o- -group protector (XXV? D "• -> e-l 1) removal of the protection group (eg benzyl, by catalytic hydrogenation) 2) oxidation to aldehyde (eg Tetrahedron Lett, 1992, 33, 5029) The corresponding thiazole / arylene bromide or arylene XXIV is converted in the conditions of the Heck reaction in the presence of Pd / C in for example DMF at about 80 ° C to 100 ° C with the corresponding alkene (see for example SG Davies et al., J. Chem. Soc. Perkin 1, 1987, 2597). When c is equal to zero, d equals l, e is 1 to 3 and A is -CH = CH-, the following procedure is used: the procedure is followed as in the reaction scheme Id using the following aldehyde XXVII: (protective group for example benzyl) The thiazole derivative (XXVIII) thus obtained is then processed further, according to reaction scheme 5. The benzyl protecting group is removed by catalytic hydrogenation. The alcohol obtained by reduction is finally oxidized to aldehyde according to the usual conditions (for example Tetrahedron Lett, 1992, 33, 5029).

Reaction scheme 5 jnfíC (arylene) CHa - O- -protective group 10 (XXVHI) Hafct 1) removal of the protection group (eg benzyl, by catalytic hydrogenation) 2) oxidation to aldehyde (eg Tetrahedron Lett, 1992, 33, 5029) The aldehyde thus obtained XX IX is made react according to the reaction burn or in »Aa -.

Wittig conditions (or a variant thereof) with a phosphonium halide with formation of a double bond. The free acid of the desired compound is obtained by cleavage of the ester, for example with LiOH / THF / H20.

Reaction scheme 6 alkyl sodium anode) In addition to the procedures described above, the substituent R1 can be varied in the frame of the definitions of the general formula I. For example, the Boc protection group of the compound (XIV) can be cleaved for the preparation of the corresponding compounds of the formula: The resulting amine is reacted with the corresponding amidation reagent for example amidinosulfonic acid, to give the corresponding guanidine derivatives (R7 and R8 are hydrogen). When R7 and R8 are other than hydrogen, the amidation process corresponding to M.A. Poss et al., Tetrahedron Letters, 1992, 33, 5933-36. In a variant of the process (reaction scheme 7), a thiazole derivative of formula XXXI can be guanidated (Tet Lett 29, 3183-86, 1998) with the intermediate protection of the acid functions contained in R2 and R3.

Reaction scheme 7 (XXXJI) Compound XXXI is reacted with an isocyanate to obtain the corresponding urea derivatives. Alternatively, the amine XXXI can also be treated with equimolar amounts of phosgene in the presence of a base, for example triethylamine and this can be reacted with the corresponding amine of the formula RJ -N-H R * tf When R6 is other than hydrogen, after cleavage of the Boc protecting group, of the compound (XIV), alkylation takes place by reductive amination with the corresponding aldehyde. Compounds of type XXXI can be obtained, for example, from compounds XIV by removal of the Boc protecting group under acidic conditions, for example trifluoroacetic acid. Alternatively, the amine thus obtained can be converted stepwise into the corresponding monoalkylamines by reductive amination with the corresponding aldehydes for example in the presence of borohydrides or H2 / PdC. In order to obtain the corresponding heteroaryl derivatives of the compound (XIV), the thiourea derivatives corresponding to the reaction scheme le, which have been substituted on the nitrogen, have been used with heteroaryl. These are reacted with the compound (VII) or (Xlb).

When a is equal to zero, the process starts from the corresponding basic thiazole compounds of the reaction schemes Ia, Ib and Id. The amine XIX used in the reaction scheme 2 can be prepared according to generally known processes. For example, the following procedure can be employed when A is oxygen. The present ether linkage can be obtained by reaction of a hydroxyl function with the corresponding halide. At the same time, other reactive groups such as for example the amino function must be inactivated using the known technology of the protecting groups. When A is sulfur, the thioether group can be prepared, for example, by the reaction of a halide with the corresponding thiolate in DMF or DMSO. The thiolate used is obtained from the corresponding thiol by separating a proton by means of a base. In a variant, the desired thioether compound can be obtained by the reaction of a thiolate with the corresponding mesylate or tosylate.

This mesylate or tosylate can be obtained, for example, from the corresponding alcohols by reaction with methanesulfonyl chloride or paratoluenesulfonyl chloride.

When A is -NR10- the desired nitrogen-carbon bond can be obtained according to the same principles described above (see c equal to zero and A equal to -NR10-). When A is -CH = CH-, the amine used in the reaction scheme 2 can be obtained by analogy with the processes described above (see reaction scheme 4, reaction scheme 5 and reaction scheme 6). Thus, for example analogously to the reaction scheme 4, the corresponding aminobromoarylene or the palladium-catalyzed amino-iodoarylene can be reacted with the corresponding alkene. In this case, the amino group can carry a BOC protecting group. Alternatively, the process can start from the corresponding nitrobromoarylene, which, after palladium catalyzed coupling, is reduced with tin dichloride dihydrate in ethanol with the retention of the double bond. Likewise, the corresponding nitroarylene can be used analogously to the reaction scheme 5. After oxidation in aldehyde and after carrying out the Wittig reaction, the nitro group can be reduced to tin amine (II) as described above. The amine in which d is equal to zero, necessary for the reaction scheme 2, can be prepared starting from the corresponding protected aminoalcohol. After oxidation to obtain the aldehyde (see reaction scheme 5), the desired amine is then obtained by a Wittig reaction. The invention also encompasses intermediate products of formula (XXXIII) Y (XVIII) and its salts, with R1, R3 and a having the meanings given previously, and R3 of the formula XVIII not being hydrogen or methyl when R1 is l r-¡? Especially preferred intermediates are; Butyl (3-tert-butoxycarbonylamino-propoxy) -acetate; Butyl (3-amino-propoxy) -acetate hydrochloride; 5-Benzyloxycarbonylamino-2-ethoxycarbonylmethoxybenzoate of ethoxycarbonylmethyl; Etoxycarbonylmethyl 5-amino-2-ethoxycarbonylmethoxybenzoate. Other objects of the invention are the compounds of formula (I) described above for use as therapeutically active substances. Also the object of the invention are the compounds of formula (I) described above for the preparation of medicaments for the prophylaxis and therapy of diseases that are based on a dysfunction of the binding of the adhesive proteins to the vitronectin receptors. Likewise, the subject of the invention is the pharmaceutical compositions containing a compound of formula (I) described above and a therapeutically inert carrier. The invention also relates to a pharmaceutical composition as previously described which additionally contains one or more compounds of general formula (I) or additionally one or more compounds selected from the group comprising anticoagulants, fibrinolytics as well as medicaments for prophylaxis and therapy of diseases that are based on a dysfunction of the binding of the adhesive proteins to the vitronectin receptors. The object of the invention is also the use of the compounds of formula (I) described above for the preparation of medicaments for the treatment or prophylaxis of diseases that are based on a dysfunction of the binding of the adhesive proteins to the vitronectin receptors . Another object of the invention is the use of one of the compounds of formula (I) described above for the preparation of medicaments, for example for the treatment or prophylaxis of neoplasms, tumor metastasis, tumor growth, osteoporosis, Paget's disease, retinopathy diabetic, macular degeneration, restenosis subsequent to a vascular intervention, psoriasis, arthritis, fibrosis, kidney failure, as well as infections caused by viruses, bacteria or fungi. Another object of the invention comprises the compounds of formula (I), which can be prepared according to one of the methods described. It is also the object of the invention methods for the treatment and prophylaxis of diseases that are based on a dysfunction of the binding of the adhesive proteins to the vitronectin receptors, and which comprises the administration of an effective amount of a compound of formula (I). An object of the invention is furthermore a method for the treatment and prophylaxis of neoplasms, tumor metastasis, tumor growth, osteoporosis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis subsequent to a vascular intervention, psoriasis, arthritis, fibrosis, insufficiency kidney, as well as infections caused by viruses, bacteria or fungi, wherein the method comprises administering an effective amount of a compound of formula (I) described above. Also the object of the invention is the compounds of formula (I) described above, for the treatment and prophylaxis of neoplasms, tumor metastasis, tumor growth, osteoporosis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis subsequent to a vascular intervention, psoriasis, arthritis, fibrosis, kidney failure, as well as infections caused by viruses, bacteria or fungi. The conversion of a compound of formula (I) into a pharmaceutically acceptable salt can be effected by treating said compound with an inorganic acid, for example a hydrocidal 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, methanesulfonic acid or p-toluenesulfonic acid. The corresponding carboxylate salts of the compounds of formula (I) can also be prepared by treatment with physiologically compatible bases. The conversion of a compound of formula (I) to a pharmaceutically acceptable ester can be effected by treatment of said compound in the usual manner or as described in the examples. As mentioned above, the compounds of formula I and their salts and esters pharmaceutically acceptable inhibitors especially the binding of various adhesive proteins such as fibrinogen, vitronectin, von Willebrand factor, fibronectin, thrombospondin and osteopontin to the vitronectin receptors (such as for example avß3 / avßs, ocvßes, avßs, etc.) on the surface of various cell types. Said compounds therefore exert an influence on cell-cell and cell-matrix interactions. Since the recipients of the Vitronectin plays a role, among others, in the dissemination of tumor cells, in the growth of new vascular tissue, in the degradation of bone tissue, in the migration of smooth muscle cells in the vascular walls, and in the penetration of virus particles in the target cells, said compounds can be used as antagonists of the vitronectin receptor in the control or prevention of neoplasms, tumor metastasis, osteoporosis, Paget's disease, diabetic retinopathy, degeneration macular, restenosis subsequent to a vascular intervention, psoriasis, arthritis, renal failure, as well as infections caused by viruses, bacteria or fungi. Since the binding of the adhesive proteins to the fibrinogen receptor (anbß3) on the surface of blood platelets, is practically not inhibited, The undesirable side effects, such as hemorrhage, can be suppressed with the therapeutic application of said compounds. The inhibition of the binding of proteins adhesives such as for example fibrinogen to the vitronectin receptors (such as avß3 / ctvßs, avß6, otvßs, etc.), or to the fibrinogen receptor (oiiißß) by compounds of formula (I), can be determined as it has been described by L. Alig et al., (J.

Med. Chem. 1992, 35, 4393-4407). In detail, this was done: wells of microtiter plates (Nunc immunoplates, MaxiSorp) were coated overnight at 4 ° C with the avr3 vitronectin receptor (human placenta, 100 μl / well) in a buffer or buffer system with 150 mmole / liter of NaCl, 1 mmole / liter of CaCl 2, 1 mmole / liter of MgCl 2, 0.0005% Triton X-100 and 20 mmole / liter of Tris HCl, pH 7.4. The non-specific binding sites were blocked by incubation with 3.5% bovine serum albumin (BSA from Fluka) at 20 ° C for at least 1 hour. Before the beginning of the test, the plates were washed in each case once, with 150 mmoles / liter of NaCl, 1 mmole / liter of CaCl 2, 1 mmole / liter of MgCl 2 and 20 mmoles / liter of Tris HCl, pH 7.4 (buffer A). The plates thus coated can Store 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. The fibrinogen (IMCO, free of fibronectin) was diluted at 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 of, or in the presence of, increasing concentrations of RGDS (as a reference substance) or the compounds to be measured. Unbound fibrinogen was washed out three times with buffer A, and bound fibrinogen was detected by ELISA analysis. Rabbit antibodies induced against human fibrinogen (Dakopatts, Denmark), diluted in buffer A in the presence of 0.1% BSA, were added at room temperature for 1 hour, followed by an incubation with biotinylated antibodies induced against rabbit immunoglobulin (Amersham) during 30 minutes. Unbound antibodies were washed out, three times, with buffer A. Then, the streptavidin-biotinylated peroxidase complex was added.

(Amersham), prepared previously, for 30 minutes.

A wash was carried out again, three times, with buffer A.

After the addition of ABTS peroxidase substrate (2, 2 '-azino-bis (3-ethyl-benzothiazoline-6-sulfonic acid), *, • & > , ** ^^ - ^ - T ^^^ iftW-lM11 ** ^^ ^ ¿^ «fe-A» - ^ ^ A fcvA¿ ^ a (Boehringer Mannheim), the enzymatic activity was measured with a multichannel photometer ( Uvmax, Molecular Devices). The difference between the total binding activity (in the absence of the test substance) and the non-specific binding activity (in the presence of 100 μM of RGDS) is taken as the specific binding activity. The concentration of a test substance, necessary to inhibit the specific binding activity by 50% was defined as IC5o The isolation of the avb3 receptor, used in the assay, was carried out as follows: Human placenta was stored at -80 ° C immediately after its split. In order to extract the receptor, each placenta was thawed superficially and cut into narrow strips with a scalpel. The pieces were washed twice with a buffer of 150 mmol / liter of NaCl, 1 mmol / liter of CaCl2, 1 mmol / liter of MgCl2 and 20 mmol / liter of Tris HCl, (pH 7.4). The protein was extracted at room temperature for one hour with a buffer solution of 1% Triton X-100, 150 mmol / liter of NaCl, 1 mmol / liter of CaCl2, 1 mmol / liter of MgCl2, 20 mmol / liter of Tris HCl, 0.02% NaN3, 0.5 mmol / liter of phenylmethanesulfonyl fluoride, 1 mmol / liter of leupeptin and 2 mmol / liter of N-ethylmaleimide (pH 7.4) and filtered through gauze 'A ^ ^ ^' * ^ s iik? 3Í íiStih, sterile. The filtrate was centrifuged at 30000 g for 30 minutes at 4 ° C. The glycoprotein was first separated with the aid of a concavalin A-sepharose 4B column. The proteins bound to the column were eluted and then added to a column of Aeg-RGDS. After repeated washing of the vitronectin receptor, it was eluted by 3 mmole / liter of RGDS in a 0.1% Triton X-100 buffer, 150 mmol / l NaCl, 20 mmol / l Tris HCl, 2 mmol / l. liter of 10 CaCl2. 1 mmol / l of MgCl2, 0.05% of NaN3 (pH 7.0). The results obtained in the previous test employing representative compounds of formula I as the test compound are summarized in the following table. 15 Table 1 VNR substance IC50 [nM] Acid (4-. {[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -2-methoxy-phenoxy) -acetic acid 0.2 Acid 5- . { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -2-carboxymethoxy-benzoic acid 1.3 (4- ((2- (3-benzyl-ureido) -thiazole-4-carbonyl) -amino) -phenoxy) -acetic acid 1.0 25 Preferred compounds have an IC50 value less than 100 nM; especially preferred compounds have a value less than 10 nM. Particularly preferred compounds have an IC50 value of less than 2 nM. The compounds of formula I and their pharmaceutically acceptable salts and esters can be used as medicaments (for example in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered both internally and orally (for example in the form of tablets, coated or coated tablets, dragees, soft and hard gelatine capsules, solutions, emulsions or suspensions), nasally (for example in the form of sprays or nasal sprays) or rectally (for example in the form of suppositories). The administration can, however, be carried out parenterally, for example intramuscularly or intravenously (for example in the form of injection solutions). The compounds of formula I and their pharmaceutically acceptable salts or esters can be processed with pharmaceutically inert, inorganic or organic excipients for the preparation of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, stearic acid or its salts, etc., for example, as such excipients for tablets, dragees and hard gelatine capsules. Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc. They are suitable excipients for the preparation of solutions and syrups, for example, water, polyols, sucrose, invert sugar, glucose, etc. Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerin, vegetable oils, etc. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid polyols or liquid polyols, etc. In addition, the pharmaceutical preparations may contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

According to the invention, the compounds of formula I and their pharmaceutically acceptable salts and esters can be used as antagonists of the vitronectin receptor, especially for the treatment or prophylaxis of neoplasms, tumor metastasis, tumor growth, osteoporosis, Paget's disease. , diabetic retinopathy, macular degeneration, restenosis after a vascular intervention, psoriasis, arthritis, fibrosis, renal deficiency, as well as infections caused by viruses, bacteria or fungi. The dosage can vary between wide limits and will of course be adjusted to the individual needs of each particular case. 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 about 4 mg per kg of body weight (for example about 300 mg per person) will generally be adequate. ), preferably divided into 1-3 individual doses, which may consist, for example, of the same amounts. It is clear, however, that the upper limit cited above may be exceeded when it is stated that it is indicated.

The invention is illustrated below by the Examples, which do not presuppose any limits to the invention. * Example 1 175 mg of 2-guanid? N-4-methyl-thiazole-5-carboxylic acid, 2.6 ml of DMF, 0.29 ml of N-MM and 332 of HBTU were stirred at room temperature for one hour, treated with 197 mg of butyl (3-amino-propoxy) -acetate hydrochloride and stirred at room temperature for a further 18 hours. For final processing, the mixture was diluted with ethyl acetate, washed with dilute sodium carbonate solution, dilute sodium chloride solution and saturated sodium chloride solution, dried and evaporated in vacuo. Chromatography on silica gel with methylene chloride-alcohol gave 162 mg of. { 3- [(2-guanidin-4-methylthiazole-5-carbonyl) -amino] -propoxy} -butyl acetate, MS: 372 (M + H) +. The butyl (3-amino-propoxy) -acetate hydrochloride can be prepared as follows: a) Butyl 2-cyano-ethoxyacetate was hydrogenated in the presence of Pd / C in acetic acid and then reacted in tert-butanol and triethylamine with di-tert-butyl dicarbonate obtaining butyl (3-tert-butoxycarbonylamino-propoxy) -acetate and purified by chromatography; MS: 290 (M + H) +. b) By treatment with 4N HCl in ethyl acetate, there was obtained therefrom the butyl (3-amino-propoxy) -acetate hydrochloride, m.p. 36-36 ° C, MS: 190 (M + H) +.

Example 2 151 mg of. { 3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) amino] -propoxy} butyl acetate, were stirred for 5 hours in 3 ml of 25% hydrochloric acid. The reaction mixture was evaporated to dryness in vacuo and the residue lyophilized from acetic acid. 144 mg of [3 - [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -propoxy] -acetic acid hydrochloride (1: 1), m.p. 48-51 ° C, MS: 316 (M + H) +.

Example 3 400 mg of 2-guanidin-4-methyl-thiazole-5-carboxylic acid, 463 mg of ethyl 4-amino-phenyloxyacetate hydrochloride, 6 ml of DMF, 0.67 ml of N-MM and 759 mg of HBTU, they were stirred at room temperature for 22 hours. The final processing and purification were carried out as described in example 1. The crystallization with MeCN provided 368 mg of. { 4 - [(2-guanidin-4-methyl-thiazole-5-carbonyl) amino] -phenoxy} ethyl acetate, m.p. 223 ° C, MS: 378 (M + s) +.

Example 4 330 mg of. { - [(2-guanidin-4-methyl-thiazole-5-carbonyl) amino] -phenoxy} ethyl acetate, were stirred at room temperature for 11 hours in 6 ml of 25% hydrochloric acid. The reaction mixture was evaporated to dryness in vacuo and the residue was triturated in MeCN. 293 mg of [4 - [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -phenoxy] -acetic acid hydrochloride (1: 1); p.f. 273 ° C, MS: 350 (M + H) +.

Example 5 2-Guanidin-4-methyl-thiazole-5-carboxylic acid was reacted with tere-butyl (3-amino-phenoxy) -acetate in the same manner as in Example 3. Chromatography on silica gel with chloride of methylene-ethyl acetate methylene chloride-alcohol yielded 176 mg of. { 3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) -amino] -phenoxy} tere-butyl acetate, m.p. 204 ° C, MS: 406 (M + H) +.

S + útSSrjit ti viA. "i * -.

Example 6 142 mg of. { 3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) amino] -phenoxy} Tere-butyl acetate, were stirred in 1.1 ml of methylene chloride and 1.1 ml of TFA for 2 hours at room temperature. The reaction mixture was evaporated in vacuo, the residue was dissolved in water and the solution was evaporated to dryness. The solid was suspended in water, adjusted to pH 8 with ammonia IN, stirring, filtered off by suction, washed with water and dried. 101 mg of [3- [(2-guanidin-4-methyl-thiazole-5-carbonyl) amino] -phenoxy] -acetic acid, m.p. 284 ° C, MS: 350 (M + H) +.

Example 7 In the same manner as described in Example 3, starting with 2-guanidin-thiazole-4-carboxylic acid and ethyl 4-amino-phenyloxyacetate hydrochloride, it was obtained. { 4- [(2-guanidin-thiazole-4-carbonyl) -amino] -phenoxy} ethyl acetate, m.p. 206 ° C, MS: 364 (M + H) +.

Example 8 227 mg of. { 4- [(2-guanidin-thiazole-4-carbonyl) -amino] -phenoxy} ethyl acetate, were stirred for 3 days at room temperature in 25% hydrochloric acid.

The precipitate was filtered off by suction, washed with water, triturated in methanol, filtered off by suction and dried. 165 mg of [4 - [(2-guanidin-thiazole-4-carbonyl) -amino] -phenoxy] -acetic acid hydrochloride (1: 1); p.f. 278 ° C, MS: 336 (M + H) +.

Example 9 In the same manner as described in Example 3, and crystallization with MeOH, from 2-guanidynthiazole-5-carboxylic acid and ethyl 4-amino-phenyloxyacetate hydrochloride, was obtained. { 4 - [(2- guanidin-thiazole-5-carbonyl) -amino] -phenoxy} ethyl acetate, m.p. 218 ° C, MS: 364 (M + H) +.

Example 10 239 mg of. { 4- [(2-guanidin-thiazole-5-carbonyl) -amino] phenoxy} ethyl acetate, were stirred for 27 hours in 4.8 ml of 25% hydrochloric acid. The precipitate was filtered off by suction, washed with water and dried. 222 mg of [4 - [(2-guanidin-thiazole-5-carbonyl) -amino] -phenoxy] -acetic acid hydrochloride (1: 1), m.p. 336 ° C, MS: 364 (M + H) +.

Example 11 419 mg of 2- (3-benzyl-ureido) -thiazole-4-carboxylic acid, 265 mg of CDMT, 4.5 ml of THF and 0.18 ml of N-MM were mixed for 4.5 hours at room temperature. After the addition of 350 mg of ethyl 4-amino-phenyloxyacetate hydrochloride, and 0.18 ml of N-MM, the mixture was stirred for a further 20 hours at room temperature. During the final processing, the mixture was diluted with ethyl acetate and washed successively with dilute hydrochloric acid, water, dilute sodium carbonate solution, water and saturated sodium chloride solution, dried with sodium sulfate and evaporated at room temperature. empty. Chromatography on silica gel with methylene chloride-alcohol 99: 1 and crystallization with ether gave 350 mg of (4- {[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino.} - phenoxy) -ethyl acetate, mp 173 ° C, MS: 455 (M + H) +.

Example 12 243 mg of (4- {[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -ammo} -phenoxy) -acetic acid ethyl ester were stirred in 4.3 ml of ethanol and 0.8 ml of IN NaOH for 4.5 hours at room temperature. During the final processing, the mixture was stirred in dilute ethyl acetate / hydrochloric acid, the organic phase was separated, washed with water and sodium chloride solution, dried with sodium sulfate and evaporated in vacuo. Crystallization with ether propoated 208 mg of [4- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenoxy] -acetic acid, m.p. 208 ° C, MS: 427 (M + H) +.

Example 13 Analogously to Example 11, from 2- (3-benzyl-ureido) -thiazole-4-carboxylic acid and (4-amino-2-methoxy-phenoxy) -acetate, (4- { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -2-methoxy-phenoxy) -acetic acid ethyl ester, mp. 197-198 ° C, MS 485 (M + H) +.

Example 14 In the same manner as described in Example 12 and crystallization with acetonitrile, from (4- {[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino}. -2-methoxy-phenoxy) ethyl acetate, 4-acid was obtained. { [2- (3-benzyl-ureido) -thiazole-4-carboni 1] -amino} -2-methoxy-phenoxy) -acetic, m.p. 210 ° C, MS: 457. (M-t-H) +.

Example 15 Analogously to example 11, from 2- (3-benzyl-ureido) -thiazole-4-carboxylic acid and 5-amino-2-ethoxycarbonylmethoxy-benzoate of ethoxycarbonylmethyl, 5- was obtained. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} Etoxycarbonyl-methoxybenzoate of ethoxycarbonylmethyl, m.p. 125-127 ° C (with ethyl acetate), MS: 585 (M + H) +. The starting material can be prepared as follows: a) 5-benzyloxycarbonylamino-2-hydroxy-benzoic acid is reacted under reflux in acetone with ethyl bromoacetate in the presence of potassium carbonate to give 5-benzyloxycarbonylamino-2-ethoxycarbonylmethoxy -ethoxycarbonylmethylbenzoate, mp 77-78 ° C. MS: 460 (M + H) +. b) Catalytic hydrogenation in the presence of Pd / C in EtOH yields 5-amino-2-ethoxycarbonylmethoxybenzoate of ethoxycarbonylmethyl, MS: 326 (M + H) +.

Example 16 378 mg of 5-. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} Ethoxycarbonylmethyl-2-ethoxycarbonylmethoxybenzoate, 6.5 ml of ethanol and 1.29 ml of 2N sodium hydroxide solution were stirred for 5 hours at room temperature. After the addition of 3 ml of acetic acid and 2 ml of water, the mixture was heated to a homogeneous solution. After cooling the precipitate was filtered off by suction, washed with acetic acid-water 1: 1 and dried. 290 mg of 5- ([2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -2-carboxymethoxy-benzoic acid, mp 219 ° C, MS: 471 (M + H) were obtained. ) + Example 17 2- (3-Benzyl-ureido) -thiazole-4-carboxylic acid is coupled to (E) -3- (4-amino-phenyl) -ethyl acrylate by analogy with Example 11. After the Chromatography on silica gel with methylene chloride-ethanol 98: 2 and crystallization with ether gave (E) -3- [4- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] phenyl] ethyl acrylate, mp 207 ° C, MS: 451 (M + H) +.

Example 18 235 mg of (E) -3- [4- [[2- (3-benzyl-ureido) -t? Azol-4-carbonyl] -amino] -phenyl] -ethyl acrylate, 4.7 ml of ethanol and 1 ml of 2N NaOH, were stirred for 6 hours at room temperature. The reaction mixture was diluted with 4.7 ml of water and adjusted to pH 2 with 2 ml of IN hydrochloric acid. The precipitate was filtered off by suction, washed with water, triturated in ethanol, filtered off by suction and dried. 164 mg of (E) -3- [4- [[2- (3-benzyl-urej-do) -thiazole-4-carbonyl] -amino] phenyl] -acrylic acid, m.p. 264 ° C, MS: 423 (M + H) +.

Example 19 A solution of 1.1 g (4 mmoles) of 2- (3-benzylureido) -thiazole-4-carboxylic acid, 1.05 g (4 mmol) of [(4-amino-phenyl) -phenyl-amino] -acetate of methyl, 1.7 g (4.4 mmol) of HTBU and 0.6 ml (6 mmol) of NMM in 50 ml of DMF were stirred at room temperature overnight. After processing as usual followed by chromatography (silica gel, dichloromethane / methanol 30: 1) 1.2 g of [4-. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} methyl-phenyl) -phenyl-amino] -acetate, in the form of an amorphous powder. MS: 516 (M + 1). The starting material can be prepared as follows: a) The 4-nitro-diphenylamine is reacted (Aldrich) with methyl bromoacetate in the presence of potassium carbonate in DMF at 70 ° C to give methyl [(4-nitro-phenyl) -phenyl-amino] -acetate (brown oil). MS: 287 (M + 1). b) Catalytic hydrogenation of methyl [(4-nitrophenyl) -phenyl-amino] -acetate in methanol in the presence of palladium / carbon (lOg) resulted, after filtration and solvent removal, of [(4-amino- phenyl) -phenyl-amino] -acetic acid methyl ester in the form of a brown oil MS: 256 (M +).

Example A A compound of formula I can be used in a manner known per se as active substance for the preparation of tablets of the following composition: per tablet Active substance 200 mg 10 Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg 15 Example B A compound of formula I can be used in a manner known per se as active substance, for the preparation of capsules of the following composition: per capsule Active substance 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talcum 4.5 mg Magnesium stearate 0.5 mg 25 220.0 mg List of common abbreviations AcOEt Ethyl acetate AcOH Acetic acid Aeg-RGDS Aminoethylglycine-Arg-Gly-Asp-Ser-OH Boc tert-butoxycarbonyl BOP (Benzotriazol-1-yloxy) -tris- (dimethylamino) -phosphonium bisphosphonate BSA Albumin bovine serum Cbz Benzyloxycarbonyl CDMT 2-chloro-4,6-dimethoxy-1,3,5-triazine DMF dimethylformamide EDC N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride The Impact of ELISA electrons Enzyme immunoassay EtOH Ethanol FAB Bombardment with fast atoms HBTU O- (benzotriazol-l-yl) -N hexafluorophosphate N, N ', N' -tetramethyluronium ISP Ion spray (positively charged ions) MeCN Acetonitrile MeOH Methanol MS NMM mass spectrometry N-methylmorpholine < A »3gJg &« 8 »¿&A ^ RGDS H-Arg-Gly-Asp-Ser-OH RP Inverted phase p.f. Melting point 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 the conventional one for the manufacture of the objects or products to which it refers.

Claims (26)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. The compounds of formula (I) 10 where R1 is R "e s 15 RJ is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, carboxyl, alkyl-0-CO- or aralkyl-0-CO-; R 4 is hydrogen, alkyl, cycloalkyl, aryl or heteroaryl; R5 and R6 independently of one another are hydrogen, alkyl, cycloalkyl or heteroaryl; R7 and R8 independently of each other, are hydrogen, alkyl, cycloalkyl or heteroaryl or R7 and R8 together with the N atoms to which they are attached, form a 5- to 8-membered heterocyclic ring, which may carry one or more alkyl substituents; R9 is hydrogen, alkyl or cycloalkyl; R10 is hydrogen, aryl, aralkyl, heteroaryl, heterocyclylalkyl, carboxyalkyl, alkyl, cycloalkyl, alkyl-O-CO-, aralkyl-O-CO-, alkyl-CO-, alkylsulfonyl, arylsulfonyl or heteroarylsulfonyl; A is oxygen, sulfur, -CH = CH- O a to f are zero or positive integers, with a being from zero to 2; b being from zero to 4; c and d being zero or 1, with the proviso that c and d are not both simultaneously zero; e is zero to 5, with the proviso that e is non-zero when d is zero and e is zero to 3 when A equals -CH = CH-; and f is zero to 3, with the proviso that f is not zero when A is oxygen, sulfur or and its pharmaceutically acceptable salts and esters.

2. The compounds according to claim 1, characterized in that R2 is (lll) 0 and R, A, d to f are as defined in claim 1. 5

3. The compounds according to claim 1 or 2, characterized in that R¿ is and R, A, e and f are as defined in claim 1.

4. The compounds according to claim 1 to 3, characterized in that R2 is and R, A, e and f are as defined in the claim 1.

5. The compounds according to claim 1 6 2, characterized in that R2 is e is 1 to 5 and R9, A, and f are as defined in claim 1.

6. The compounds according to any of claims 1 to 5, characterized in that A is oxygen or -CH = CH-.

7. The compounds according to any of claims 1 to 6, characterized in that R1 is

8. The compounds according to any of claims 1 to 7, characterized in that the arylene is phenylene or substituted phenylene, with the substituted phenylene one or two alkyl, aralkyl, halogen, alkoxy-alkoxy, carboxy or

-CO-O-CH2-CO-O-alkyl substituents »< * $ 9. The compounds according to claim 8, characterized in that the arylene is meta- or para-phenylene or meta- or substituted paraphenylene, with the phenylene substituents given above by R2 being in the meta- or para- position yes and with the substituted phenylene carrying in the ring an additional substituent selected from the group consisting of alkoxy, carboxyl or 10 - CO - 0 - CH2 - CO - O - alkyl.

10. The compounds according to any of claims 1 to 9, characterized in that R3 is hydrogen, alkyl, cycloalkyl or phenyl.

11. The compounds according to any of claims 1 to 10, characterized in that Rq is hydrogen, alkyl, cycloalkyl or phenyl.

12. The compounds according to any of claims 1 to 11, characterized in that R5, R6, R7 and R8 are hydrogen or R5 and R6 are both hydrogen, and R7 and R8 together with the atoms 25 * g * ^ g? && i: ^ a ^^ a @ ^^! ^ »^^^^ aeg ^ - t ^? M ^^? J ^ k ^^^^^^^ j ^ i of N to which they are attached form a ring of 5 to 6 members.

13. The compounds according to any of claims 1 to 12, characterized in that R9 is hydrogen or cycloalkyl.

14. The compounds according to any of claims 1 to 13, 10 characterized in that R2 is attached to the 4-position and R3 is attached at the 5-position of the thiazole ring.

15. The compounds according to any one of claims 1 to 14, selected from: (4- {[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -phenoxy) -acetate of ethyl; [4- [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino] -phenoxy] -acetic acid; 20 (4-. {[[2- (3-benzyl-ureido) -thiazole-4-carbonyl-1] -amino) -2-methoxy-phenoxy) -acetic acid ethyl ester; (4- {[[2- (3-benzylideido) -thiazole-4-carbonyl] -amino} -2-methoxy-phenoxy) -acetic acid; 25 ,.;, .. 5- . { [2- (3-benzyl-ureido) -thiazole -carbonyl] -amino} Ethoxycarbonylmethyl-2-ethoxycarbonylmethoxybenzoate; 5- acid. { [2- (3-benzyl-ureido) -thiazole-4-carbonyl] -amino} -2-carboxymethoxy-benzoic; (E) -3- [4 - [[2- (3-benzyl-ureido) -thiazole-4-carbonyl] -ammo] -phenyl] -ethyl acrylate; (E) -3- [4- [2- (3-Benzyl-ureido) -thiazole-4-carbonyl] -ammo] -phenyl] -acrylic acid;

16. A process for obtaining a compound of formula I, characterized in that the process comprises the reaction of a compound of the formula (XVII I) 20 with an amine of formula N- (ari leno) d- ["CH2 j- A-i- CH24- COOR11 (XIX) 25 ** 4 «É? Taitt & teu» &-2 **? (.. wherein R1, R3, R9, a and d to f have the meanings given in claim 1, c is equal to 1 and R11 is alkyl or aralkyl.

17. The compounds according to any of claims 1 to 15, characterized in that they are used as therapeutically active substances.

18. The compounds according to any of claims 1 to 15, characterized by the preparation of medicaments for the prophylaxis and treatment of diseases based on a dysfunction of the binding of the adhesive proteins to the vitronectin receptors.

19. A pharmaceutical preparation characterized in that it contains a compound according to any of claims 1 to 15, and a therapeutically inert carrier.

20. A pharmaceutical preparation according to claim 19, characterized in that it additionally contains one or more compounds selected from the group formed by Maií? Iil & anticoagulants, fibrinolytics, compounds according to claim 1, as well as medicaments for the prophylaxis and therapy of diseases based on a dysfunction of the binding of the adhesive proteins to the vitronectin receptors.

21. The use of compounds according to any of claims 1 to 15, characterized by the preparation of medicaments.

22. The use of compounds according to any of claims 1 to 15, characterized by the preparation of medicaments for the treatment and prophylaxis of neoplasms, tumor metastasis, tumor growth, osteoporosis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis after of a vascular intervention, psoriasis, arthritis, fibrosis, renal deficiency, as well as infections caused by viruses, bacteria or fungi, and respectively for the preparation of the corresponding medicines.

23. The compounds according to any of claims 1 to 15, rS & i ^ ríX ^? ~ &< 4 > characterized in that they are prepared according to the process described in claim 16.

24. A method for the treatment and prophylaxis of diseases based on a dysfunction of the binding of the adhesive proteins to the vitronectin receptors, characterized in that an effective amount of a compound according to any of claims 1 to 15 is administered.

25. A method for the treatment and prophylaxis of neoplasms, tumor metastasis, tumor growth, osteoporosis, Paget's disease, diabetic retinopathy, macular degeneration, restenosis after vascular intervention, psoriasis, arthritis, fibrosis, renal deficiency, as well as infections caused by virus, bacteria or fungi, characterized in that it comprises the administration of an effective amount of a compound according to any of claims 1 to 15.

26. The invention of compliance as described herein. h * fi «lltta > lfrAligfrfodBi