MXPA01008424A

MXPA01008424A - &bgr;-ALANINE DERIVATIVES

Info

Publication number: MXPA01008424A
Application number: MXPA/A/2001/008424A
Authority: MX
Inventors: Gunter Holzemann; Simon Goodman; Alfred Jonczyk; Wolfgang Stahle
Original assignee: Merck Patent Gesellschaft Mit Beschrankter Haftung
Priority date: 1999-02-20
Filing date: 2001-08-20
Publication date: 2002-06-05

Abstract

The invention relates to novel&bgr;-alanine derivatives of general formula (I), wherein Q1, Q2, Q3, Q4, R1, R2, R3, R4, R5, R6 and n have the meaning cited in patent claim 1 and to their physiologically acceptable salts or solvates. Said substances are integrin inhibitors and can be used in the treatment of thrombosis, heart infarct, coronary heart diseases, arteriosclerosis, inflammations, tumors, osteoporosis, infections and restenosis after angioplasty or in pathological processes induced or propagated by angiogenesis.

Description

DERIVATIVES OF THE BETA-ALA INA DESCRIPTION OF THE INVENTION The invention relates to the derivatives of the β-alanine of formula I where Q3 or Q4 independently represent CH or N, R represents H, A, Ar, Hal, OH, OA, CF3 or OCF .., R- represents H or A, R represents R "and R = represents independentlymeiite H, A, Hal, OH, OA, CF3, OCF, CN, NH :, NHA, NA, or NH-C (OJA, Rd represents H, A, - (CH) - OH , - (CH) p-0-C (O) A or - (CH 2) r-Ar, A represents alkyl of 1 to 6 carbon atoms, Ar represents unsubstituted or mono, di or trisubstituted aryl, REF: 131307 Hal represents F, Cl, Br or I, n is 2, 3, 4, 5 or 6, m is 1, 2, 3 or 4, and its salts acceptable from the physiological point of view and its solvates. In World Patent Nos. 97/26250 and 97/24124, there are disclosed compounds that are similar in part. The aim of the invention was to develop new compounds with valuable properties, in particular compounds that can be used in the manufacture of medicines. It was found that the compounds of formula I and their salts possess very valuable pharmacological properties and are well tolerated. First of all, they act as inhibitors of mtegrin, in particular, by inhibiting the interaction of the mtegrma receptors with ß_ or ß- with the ligands, such as, for example, the binding of vitronectm to the αβ integrin receptor. The mtegpnas are glycoproteins bound to the membrane and constitute heterodimers. They are composed of a subunit a and a subunit β smaller. The relative affinity and specificity for a binding with the ligand is determined by the combination of the different subunits a and β. The compounds of the invention have a particular effect in the case of integrins a, .β :, vß3, aβ5, a:; Dβ3 and also a.β.sub.a, ß =, preferably in the case of av.sub.3 and a.β ? In particular, potent selective inhibitors of integrin, β3 have been discovered. The avß3 integrin is expressed on a series of cells, for example, endothelial cells, smooth vascular muscle cells such as, for example, the aorta, cells that degrade bone tissue (osteoclasts) or tumor cells. The effect of the compounds of the invention can be checked, for example, according to the method described by J.W. Smith et al. in J. Biol. Chem. 1990, 265, p. 12267 to 12271. P.C. Brooks, R.A. Clark and D.A. Cheresh describes in Science 1994 264, pgs. 569-71, the dependence of the beginning of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins. The possibility of inhibiting this exchange and thus introducing apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide is described in Cell 1994 79, pp. 1157-64, by P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T. -Hu, G. Klier and D.A. Cheresh Here we describe, for example, the antagonists of avß3 or the antibodies that, when introducing apoptosis, produce a reduction of the tumors. The experimental verification that the compounds of the invention also prevent living cells from being fixed on the corresponding matrix proteins and, therefore, also that the tumor cells are fixed on the matrix proteins, was carried out by a test cell adhesion similar to the method employed by F. Mitjans et al. in J. Cell. Science 1995, 108, pgs. 2825-2838. The compounds of formula I can inhibit the binding of metalloproteinases to the integrins and thus prevent the cells from taking advantage of the enzymatic activity of the proteinase. As an example, one can name the ability of a RGD cyclic peptide to inhibit the binding of MMP-2- (matrix metallo-proteinase-2) to the avr3 vitronectin receptor, as described by P.C. Brooks et al. in Cell 1996, 85, pgs. 683-693. The compounds of formula I that block the interaction of integrin receptors with ligands such as, for example, the binding of fibrinogen to the fibrinogen receptor (glycoprotein Ilb / IIIa), act as antagonists and prevent the proliferation of tumor cells by metastasis, so they can be used as substances with an antimestastatic effect in operations in which tumors are removed or surgically treated. This concept is supported by the following observations: the spread of tumor cells from a local tumor to the vascular system occurs through the formation of microaggregates (microthrombi) by the interaction of tumor cells with platelets. The tumor cells are protected and camouflaged in the microaggregate and are not recognized by the cells of the immune system. The microaggregates can be fixed to the walls of the vessels, which facilitates the internalization of the tumor cells in the tissue. Since the formation of microthrombi is facilitated by the binding of the ligands to the respective integrin receptors, for example avß3 or (Xnbßj on activated platelets, the corresponding antagonists can be considered effective inhibitors of the metastasis. employees in medicine and veterinary medicine as active substances in medicines, in particular for the prophylaxis and / or therapy of diseases of the circulatory system, thrombosis, myocardial infarction, arteriosclerosis, stroke, angina, diseases tumors, the development or metastasis of tumors, osteolytic diseases such as osteoporosis, pathological angiogenic diseases such as inflammations, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatic arthritis, osteoarthritis, rubeopathic glaucoma, colitis u Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, multiple sclerosis, viral infection, bacterial infection, fungal infection, acute renal insufficiency and wound healing to help healing processes. The compounds of formula I can be used as substances with an antimicrobial effect in operations in which biological materials, implants, a catheter or a pacemaker are used. In these cases they act as antiseptic substances. The effect of the antimicrobial activity can be checked according to the procedure described by P.Valentin-Weigund et al. in "Infection and Immunity," 1988, p. 2851 to 2855. Among the compounds of formula I are selected, in particular, the selective inhibitors of integrin receptors ..- ß and ayß5. Among the compounds of formula I, in particular, selective inhibitors of the integrin receptors a.ßs and a.β- are selected. Among the compounds of formula I are selected, in particular, the selective inhibitors of the integrin avβ3 receptors and aß = yo. The effect of a compound on an a.β integrin receptor and, therefore, the activity as an inhibitor can be checked, for example, according to the method described by J.W. Smith et al. in J. Biol. Chem. 1990, 265, pgs. 12267 to 12271. The effect of a compound on an integrin receptor aYß6 and, consequently, the activity as an inhibitor can be checked, for example, according to the method described by J.W. Smith et al. in J. Biol. Chem. 1990, 265, p. 12267 to 12271. These selected compounds are particularly suitable for therapy or for combating the pathological processes that can be influenced by the integrin. -ß3 and / or aß = and a-.ße- Among the angiogenic pathologies are, for example, skin diseases such as psoriasis, pemphigus bullosa, dermatitis and erythema, and also pulmonary fibrosis, cystic fibrosis, endometriosis, liver cirrhosis or periodontitis, diseases that can be influenced by aß3 inhibitors and / or avß5, and among which particularly the carcinomas such as skin diseases and pulmonary fibrosis, which were mentioned above, are also pathologies of the epithelial cells that can be influenced by means of avß6 inhibitors. Healy DL et al., Hum. Reprod. Update 1998, 4 (5), pp. 736-40; Creamer D. Y. col., Br.J. Dermatol., 1997, 137 pp. 851-5; Norrby K., APMIS, 1997, 105, pp. 41 7-37; Creamer D. Y col., Br. J. Dermatol. 1997, 136, pgs. 859-65; Polverini P.J., Crit. Rev. Oral. Biol. Med. 1995, 6, pgs. 230-47; Brown L.F. et al., J. Invest. Dermatol. 1995, 104, p. 744-9; Hoyt D.G. et al., Am. J. Physiol. 1997, 273, L612-7; Pilewski J.M. and col. ibid 1997, 273, L256-63 or Goldman M. Y. col., Gene. Ther. 1996, 3, pgs. 811-8). A preferred application of these selected compounds is intended for cancer therapy. New advances in cancer therapy are usually focused on combating a partial area, a compartment, in the development of a solid tumor. By compartments are understood, among other things,. the development of the tumor itself or the blood vessels that grow into the tumor and that are responsible for the nutri-mental supply of the tumor. As soon as the arrival of nutrients in the tumor is localized, the activators of transcription unleash the production and secretion of polypeptide growth factors, using mostly hypoxic or hypoglycemic promoters. These growth factors activate the growth of blood vessels. In order for the endothelial cells of the blood vessel to divide, anti-apoptotic signals are needed that are released from the integrin family receptors, which are located on the cell surface. The aß3 and avßs integrin receptors are the main responsible for this release (Lit .: PC Brooks, Eur. J. Cancer, 1996, 32A, pp. 2423-2429, PC Brooks et al., Cell, 1994, 79, p. 1157-1164).

An inhibition of these integrin receptors to ß .. and / or a-'ß =, in particular of -ß3, induces the apoptosis of the activated endothelial cells of the blood vessel that grows into the tumor, while the normal vascular bed at rest it remains intact. The tumor loses its entry of nutrients, which stops its development. However, by applying this therapy, the tumor itself is not affected, that is, degenerated cancer cells are not affected, so that upon suspending treatment the tumor growth can be reinitiated. Integrin receptors located on the surface of tumor cells are significantly distinguished from those that are expressed on normal tissue. For example, on many carcinomas there is a high de novo expression of the integrin avße which is not very abundant, whereas avß3 is a good marker for malignant melanomas in progress. It is also known that the avenue intervenes in the mechanisms of tumor development itself and in the mechanisms of invasion of healthy tissue by degenerated cells, that is, metastasis. So far, only one combination therapy has been described, which aims simultaneously at the angiogenesis of the tumor tissue and at combating the tumor tissue., and it is about the combined use of inhibitors of mtegrin to ß-with cytotoxic substances (chemotherapy) or irradiation (radiotherapy). It was surprisingly discovered that the use of selective inhibitors of mtegpna and selective inhibitors of mtegrin to ßc to prepare a medicament is appropriate for such a combination therapy. A smergic effect is observed. Due to the high selectivity of the inhibition of the mtegrin and a.ße receptor, the inhibition of other mtegrins, such as a ^ ß, does not occur. or a; Dß., Which perform, for example, important and critical functions in normal tissue. It was also found that the use of selective inhibitors of integpna to β-, and of selective inhibitors of mtegrin auß6 to prepare a medicament is also appropriate for a combined therapy of this type. The same happens with the use of selective inhibitors of the integlomerate at ß., At ßs and at ßt. In each case a smérgico effect is observed. The compounds of formula I have at least one chiral center and, therefore, can have various este-re-isomeric forms. Formula I covers all of these forms (for example, forms D and L) and their mixtures (for example, DL forms). Among the compounds of the invention of claim 1 are also included the so-called "prerogatives", that is, the compounds of formula I that have been modified, for example, with alkyl or acyl groups, with sugars or oligopeptides, which are cleaved rapidly within the body thereby releasing the active compounds of the invention. Likewise, free amino groups or free hydroxyl groups which are found as substituents in the compounds of formula I can be protected with corresponding protecting groups. Solvates of the compounds of formula I are understood to be the additions of inert solvent molecules to the compounds of formula I which are produced due to their mutual attraction power. Solvates include, for example, mono- or dihydrates or addition compounds with alcohols, such as, for example, with methanol or ethanol. The invention relates to the compounds of formula I and their salts and solvates according to claim 1, and also to a process for preparing the compounds of formula I and their salts and solvates, characterized in that (a) a compound is reacted of formula II wherein Q :, Q;, Q3, Q4, R: and n have the meanings indicated in claim 1, with a compound of formula III wherein R-, R ', R ", RD and R ° have the meanings indicated in claim 1, and optionally the residue R6? H is converted to the radical R6 = H, or (b) a compound of formula IV wherein Q_, Q2, Q3 Q ,, R ~, R ~ and n have the meanings indicated in claim 1, with a compound of formula V wherein RJ, R4, R = and R6 have the meanings indicated in claim 1, and eventually the remainder R ° is transformed? H in the rest R6 = H, or (c) in a compound of formula I one or more residues R ~, R ?, R ", R and / or R" are transformed into one or several residues R ", R2, R3 , X and / or R 'different either, for example, i) alkylating a hydroxyl group, 11 hydrolyzing an ester group to a carboxyl group, iii) esterifying a carboxyl group iv) alkylating an amino group v) acylating an amino group, and / or a basic compound or acid of formula I is transformed into one of its salts or in one of its solvates by treatment with an acid or a base In the formulas indicated above, A represents straight chain alkyl or branched and from 1 to 6, preferably 1, 2, 3, 4, 5 or 6 carbon atoms. A preferably represents methyl, then ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tertbutyl, then also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2, 2-dimethylpropyl, 1-ethyl-propyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- 2-ethylbutyl, 1-ethyl-1-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl. Particularly preferred meanings of A are methyl, ethyl, isopropyl, n-propyl, n-butyl or tert-butyl. Ar represents unsubstituted aryl or mono, di or trisusituted with A, CF3, OH, OA, OCF, CN, N02 or Hal, the meaning of aryl being phenyl, naphthyl, anthryl or biphenyl. Ar preferably means phenyl or naphthyl mono, di or trisubstituted with A, CF3, OH, OA, OCF3, CN, N02 or Hal.

Therefore, Ar preferably represents phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-pro-pylphenyl, o-, m- or p-isopropylphenyl , o-, m- or p-terbuylphenyl, o-, m- or p-hydroxyphenyl, o-, - or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p- (trifluoromethyl) phenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, then preferably 2,3-, 2,4-, 2,5 -, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2 , 3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3, 5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,3-, 2,4 -, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl or 3-chloro-4-fluorophenyl, 4-fluoro-2-hydroxyphenyl, naphthalene-1-yl, naphthalene-2-yl or 2-, 3-, 4-, 5-, 6-, 7- or 8-methyl-naphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7-or 8-ethyl -naphthalene-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-chloro-naphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-fluoro-naphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-bromo-naphthalen-1-yl, 2-, 3-, 4-, 5-, 6-, 7- or 8-hydroxy-naphthalene-1-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-methyl-naphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7-or 8-ethyl- naphthalene-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-chloro-naphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7 - or 8-fluoro-naphthalen-2-yl, 1-, 3-, 4-, 5-, 6-, 7- or 8-bromo-naphthalen-2-yl, 1-, 3-, 4-, 5 -, 6-, 7- or 8-hydroxy-naphthalen-2-yl. Particularly preferred meanings of Ar are that of phenyl, o-, m- or p-fluorophenyl, m- or p-chlorophenium, p-methylphenyl, p-trifluoromethylphenyl, 3-chloro-4-fluorophenyl, 4-fluoro-2- hydroxyphenyl, naphthalen-1-yl or naphthalen-2-yl. In - (CH2) r_Ar, Ar has one of the preferred meanings stated above and m can be 1 or 2. The particularly preferred meaning for - (CH ^ -A is benzyl. En - (CH2) .- OH, m can is 1, 2, 3 or 4. Preferred meanings for - (CH;) - OH are hydroxymethyl, hydroxyethyl, hydroxypropyl or hydroxybutyl, with hydroxyethyl being the particularly preferred meaning In - (CH :) AOC (O) A A has one of the preferred meanings indicated above and m can be 1 or 2. The particularly preferred meaning of A is that of terbutyl and the preferred value of m is 1. Hal preferably represents F, Cl or bromine. , 3, 4, 5 or 6, in particular, preferably 3, 4 or 5. preferentially means 3-trifluoromethoxy) phenyl or 4- (trifluoromethoxy) phenyl. preferably it means biphenyl-4-yl, '-fluorobiphenyl-4-yl, 4' -fluorobiphenyl-3-yl, 3'-fluorobiphenyl-4-yl, 2'-fluorobiphenyl-4-yl, 4'-chlorobiphenyl-4- ilo, 3 '-chlorobiphenyl-4-yl, 4' -methylbiphenyl-4-yl, 4 '- (trifluoromethyl) biphenyl-4-yl, 3'-chloro-' -fluoro-biphenyl-4-yl, 4 '- fluoro-2-hydroxy-biphenyl-4-yl, 4'-fluoro-2'-hydroxy-biphenyl-4-yl, 4'-fluoro-2'-hydroxy-biphenyl-3-yl, naphthalene-1-yl- phenyl-4-yl, naphthalen-2-yl-phenyl-4-yl or naphthalen-1-yl- (3-hydroxyphenyl) -4-yl. preferably it means 2-, 3- or 4-nitrophenyl, 4-methyl-3-nitrophenyl, 4-chloro-3-nitrophenyl, 3-nitro-2-hydroxyphenyl or 3-bromo-6-hydroxy-5-nitrophenyl. Q :, 0.2 / Q3 or Q4 independently represent CH or N. The preferred meaning of Q: is CH or N, that of Q: is CH, that of Q3 is CH and that of Q4 is CH. The particularly preferred meaning for Q :, Q, Q3 and Q- is CH. R: represents H, A, Ar, Hal, OH, OA, CF_, or 0CF3, wherein A, Ar or Hal have the preferred or particularly preferred meanings indicated above. The particularly preferred meaning of R is H or A. Preferred positions of the substituent R 'are the 4 or 6 position. In particular, the 4-position of the ring is preferred. R2 preferably represents H or A, in particular, preferably H. RJ represents wherein R4 and R "independently represent H, A, Hal, OH, OA, CF3, OCFj, CN, NHr, NHA, NA or NH-C (0) A and Ar has one of the meanings indicated above. preferred for R4 is H, A, OH or Hal.

The particularly preferred meaning for Rr is H u u OH. In particular, R 4 and R preferably represent H in In particular, R 4 preferably represents H or OH, and Ar preferably represents phenyl unsubstituted or disubstituted with Hal, A or CF 3 or unsubstituted naphthyl in In particular, R "preferably represents H, A or Hal and R preferably represents H or OH in R represents preferably 2-, 3- or 4-trifluoromethoxy-phenyl, 2-, 3- or 4-nitrophenyl, biphenyl-3-yl, biphenyl-4-yl, 3-methyl-, 4-methyl-, 5-methyl - or 6-methyl-2- (trifluorome-tox?) phenol, 3-et? l-, 4-et? l-, 5-et? l- or 6-et? l-2- (trifluoromethoxy) phenyl, 2-met? l-, 4-met? I-, 5-met? l- or 6-met? l-3- (trifluoromethoxy) phenyl, 2-et? l-, 4-et? l-, 5-et? L- or 6-et? L-3- (trifluoromethoxy) phenyl, 2-met? L-, 3-met? L-, 5-methyl- or 6-met? L-4- (trifluoromethoxy) phenyl, 2-et? i-, 3-et? l-, 5-et? l- or 6-et? l-4- (trifluoromethoxy) femlo, 3-met? l-, 4-methyl-, 5- Metho- or 6-met? l-2-n? trophene, 3-et? l-, 4-et? l-, 5-et? l- or 6-et? l-2-n? trofen? It, 2-met? l-, 4-met? l-, 5-met? l-ó 6-met? l-3-n? trophelo, 2-et? l-, 4-et? l-, 5 -et? l- or 6-et? l-3-n? trophin, 2-met? l-, 3-met? l-, 5-met? l- or 6-met? l-4-nitrophenyl , 2-et? L-, 3-et? L-, 5-et? L- or 6-et? L-4-nu: trophenyl, 3-chloro-, 4'doro-, 5-chloro- or -chloro-2-nu: trofenil, 2-chloro-, 4-chloro-, 5-chloro- or 6-chloro-3-nitrophenyl, 2-chloro-, 3-chloro-, 5-chloro- or 6-chloro -4-nitrophenyl or, 3-n? tro-2-h? drox? phenyl, 3-bromo-6-h? drox? -5-nitrophenyl, 4 '-fluorob? phen? l-4? lo, 4' -fluorobifen? l-3-? lo, 3 '-fluorob? phen? l-4? lo, 2' -fluorobifen? l-4? lo, 4'-chloro? phen? l-4? lo, 3 '- chlorobiphen? l-4? lo, 4 '-methylbifemyl-4? lo, 4' - (trifluoromethyl) bifen? l-4? lo, 3 '-chloro-4' fluoro-b? phen? l-4 -? lo, 4 '-fluoro-2-h? drox? -b? phen? l-4-? lo, 4'-fluoro-2' -h? drox? -b? fen? l-4-? lo , 4 '-fluoro-2' -hydroxy-biphen-l-3-yl, naphthalene-l-? L-fem-4-? Lo, naphthalene-2-? L-phen? L-4-? Lo or naphthalene -1-? L- (3-h? Drox? Phenyl) -4-? Lo.

Particularly preferred meanings of R ~ "are 4- (trifluoromethoxy) phenyl, 3- (trifluoromethoxy) phenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, biphenyl-4- lo, 4-methyl-3-nitrophenyl, -fluoro-2-hydroxyphenyl or 4-doro-3-nitrophenyl, 4'-fluorobiphenyl-4-yl, '-fluorobiphenyl-3-yl, 3'-fluorobiphenyl-4-yl, 2'-fluorobiphenyl-4-yl, 4'-chlorobiphenyl-4-yl, 3'-chlorobiphenyl-4-yl, 4 '-methylbiphenyl-4-yl, 4' - (trifluoromethyl) biphenyl-4-yl, 3'-chloro- '-fluorobiphenyl-4- ilo, 4 '-fluoro-2-hydroxy-biphenyl-4-yl, 4'-fluoro-2'-hydroxy-biphenyl-4-yl, 4' -fluoro-2'-hydroxy-biphenyl-3-yl, naphthalene-1 -yl-phenyl-4-yl, naphthalen-2-yl-phenyl-4-yl or naphthalen-1-yl- (3-hydroxyphenyl) -4-yl or 3-bromo-6-hydroxy-5-nitrophenyl. R6 represents H, A, - (CH2) r-OH, - (CHJ ~ -0-C (O) A or - (CHJ ^ -Ar, where A, - (CH2) - OH, - (CH - -0-C (O) A and - (CH2) -Ar have one of the preferred or particularly preferred meanings indicated above The compounds of formula I, in which R6 represents preferably A, - (CHJ -OH, - (CH2) ,, - OC (O) A or- (CH2) m-Ar, and their solvates constitute the so-called prerogs, that is, they are inactive in the in-vitro assays since their biologically active carboxyl group is found However, the prerogatives are metabolically meta-transformed in the body in the biologically active form.The corresponding free acid, which responds to a compound of formula I with Rs = H, and its salts and solvates is active in-vitro. Accordingly, a particular object of the invention are those compounds of formula I in which at least one of the mentioned moieties has one of the preferred meanings indicated above. Preferred compounds can be represented by the sub-formula I a, which are indicated below, which correspond to formula I and in which the radicals which are not explicitly stated have the meaning indicated for formula I, namely: R ~ represents in Ib R represents in le R "reoresenta in Id the residues Q, Q3, Q3 and Q4 of the formula I represent CH. in the Q: represents N and QZl Q and Q .; of the formula I represent CH. in If RJ represents H or A and R "3 represents in Ig R- represents H or A, R- is And Q: represents N and Q;, Q3 and Q - of the formula I represent CH. in Ih R 'represents H or A, Q:, Q t Q- * and Q4 of the formula I represent CH and R3 represents in Ii R "represents H or A and R represents in Ik R- represents H or A and R- represents Particularly preferred compounds of formula la are 3- (2- [4- (4-methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino] -3- (4-trifluoromethoxy-phenyl) -propionic acid, acid 3-. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic, acid 3-. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic or 3- (2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino] -3- (3-trifluoromethoxy-phenyl) -propionic acid, and its salts acceptable from the point of view physiological and its solvates Particularly preferred compounds of formula Ib are 3- (4-methyl-3-nitro-phenyl) -3- (2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic, 3- (4-methy1-3-nitro-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, 3- (4-methyl-3-nitro-phenyl) -3- (2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic acid, 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic, 3- (2-Nitro-phenyl) -3- (2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic acid, acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (2-nitrophenyl) -propionic, acid 3-. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (2-nitrophenyl) -propionic, 3- (2-nitro-phenyl) -3- (2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic acid, 3- (3-nitro-phenyl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic, 3- (3-nitro-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [4- (6-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic, 3- (4-Methyl-3-nitro-phenyl) -3- (2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionate methyl; 3- (4-Methyl-3-nitro-phenyl) -3- (2- [5- (6-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic acid, 3- (4-chloro-3-nitro-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [4- (pyrimidin-2-ylamido-no) -butyrylamino] -acetylamino} -propionic or 3- (4-methyl-3-nitro-phenyl) -3- (2- [5- (pyrimidin-2-ylamino) -pentanoylamino] -acetylamino} -propionic acid and its salts Physiologically acceptable and their solvates Particularly preferred compounds of the formula are 3- [{2- [4- (4-methyl-pyridin-2-ylamino) -butyrylamino] -acetylamine acid} . -3- (4-biphenyl) -propionic, acid 3-. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-biphenyl) -propionic, 3- acid. { 2- [5- (pyrimidin-2-ylamino) -pentanoylamino] -acetylamine} -3- (4-biphenyl) -propionic, acid 3-. { 2- [4- (pyrimidin-2-ylamino) -butyrylamino] -aceti-1-amino} -3- (4-biphenyl) -propionic, acid 3-. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -aceti-1-amino} -3- (4-biphenyl) -propionic or acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-biphenyl) -propionic, and its physiologically acceptable salts and solvates. Particularly preferred compounds of formula Id are 3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic, acid 3-. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (-trifluoromethoxy-phenyl) -propionic, acid 3-. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic, acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic, 3- (4-methyl-3-nitro-phenol) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic, 3- (4-methyl-3-nitro-phenol) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic, 3- (2-nitro-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, 3- (2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino] -3- (2-nitro-phenyl) -propionic acid, acid 3-. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (2-nitro-phenyl) -propionic, 3- (2-Nitro-phenyl) -3- (2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic acid, 3- (3-nitrophenyl) -3- acid {. 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino}. -propionic, 3- (3-nitro-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, 3- (4-Methyl-3-nitro-phenyl) -3- (2- [4- (6-methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic acid, 3- (4-methyl-3-nitro-phenyl) -3-. { 2- [5- (-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -Methyl propionate, 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (6-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, 3- (4-chloro-3-nitro-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-biphenyl) -propionic, acid 3-. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-biphenyl) -propionic, acid 3-. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-biphenyl) -propionic or acid 3-. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-biphenyl) -propionic, and its physiologically acceptable salts and solvates. Preferred compounds of formula I are 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [4- (pyrim? Din-2-ylamino) -butyrylamino] -acetylamino} -propionic, 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (pyrimidin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, acid 3-. { 2- [5- (Pyrimidin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-biphenyl) -propionic or acid 3-. { 2- [4- (Pyrimidin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-biphenyl) -propionic, and its physiologically acceptable salts and solvates. Preferred compounds of formula If are acid 3-. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-biphenyl) -propionic, acid 3-. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-biphenyl) -propionic, 3- (2- [5- (Pyridin-2-ylamino) -pentanoylamino] -acetyl-mino} -3- (4-biphenyl) -propionic acid or acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-biphenyl) -propionic, and its physiologically acceptable salts and solvates. In general, both the compounds of formula I, according to claim 1, and the starting materials for their preparation are prepared according to known methods, such as those described in the literature (for example, in standard works such as those of Houben-Weyl, "Methoden der organischen Chemie" (Methods of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart) and under reaction conditions that are known and suitable for the reactions mentioned. You can also make use of known variants of these methods that are not detailed in this text. If desired, the starting materials can also be prepared in situ, but in such a way that instead of isolating them from the reaction mixture they are reacted immediately to form the compounds of formula I, according to claim 1. In the substance molecule there can also be several groups, identical or different, of protected amino and / or hydroxyl. If the protective groups present are different from each other, then they can be removed selectively in many cases [see for this: T.W. Greene, P.G.M. Wuts, Protecti sees Groups in Organi c Chemi stry (Protective Groups in Organic Chemistry), 2"edition, Wiley, New York 1991 or PJ Kociensky, Protecting Groups (Protective Groups), 1st edition, Georg Thieme Verlag, Stuttgart-New York , 1994, H.Kunz, H.Waldmann in Comprehensi ve Organi c Synthesi s (Extensive Organic Synthesis), vol 6 (editors: BMTrost, I. Flemming, E. Winterfeldt), Pergamon, Oxford, 1991, pp. 631 a 701] The expression "amino-protecting group" is known and refers to groups that are adapted to protect (block) an amino group from chemical reactions Typical examples of these groups are, in particular, non-amino groups. Substituted or substituted of acyl, aryl, aralkoxymethyl or aralkyl Since the amino protecting groups are removed after the desired reaction (or the sequence of reactions) has elapsed, the type and size thereof is not a critical point; however, those groups from 1 to 20, in particular from 1 to 8, C atoms are preferred. In the context of the process of the present invention, the expression "acyl group" has a very broad interpretation. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids such as, in particular, the alkoxycarbonyl, alkenyloxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl groups such as acetyl, propionyl and butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; alkenyloxycarbonyl such as ali-loxycarbonyl (Aloe); aralkyloxycarbonyl such as CBZ (synonym of Z), 4-methoxybenzyloxycarbonyl (MOZ), 4-nitro-benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc); 2- (phenylsulfonyl) ethoxycarbonyl; trimethylsilylethoxycarbonyl (Teoc) or arylsulfonyl such as 4-methoxy-2,3,6-trimethyl-phenyl-sulfonyl (Mtr). Preferred amino protecting groups are BOC, Fmoc and Aloe, then CBZ, benzyl and acetyl. The term "hydroxyl protecting group" is also known and refers to groups that are suitable to protect a hydroxyl group from chemical reactions. Typical examples of these groups are the substituted or unsubstituted groups of aryl, aralkyl, aroyl or acyl mentioned above, and also the alkyl, alkylsilyl, arylsilyl or aralkylsilyl groups or the acetals 0.0 or 0, S. The nature and size of the hydroxyl protecting groups do not constitute a critical point, since these are removed once the chemical reaction or the desired chemical reaction sequence has been completed; however, groups from 1 to 20, in particular from 1 to 10, atoms are preferred. Examples of hydroxyl protecting groups are, inter alia, aralkyl groups such as benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl , aroyl groups such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluenesulfonyl, alkyl groups such as methyl or tertbutyl, and also allyl, alkylsilyl groups such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylethyl, aralkylsilyl groups such as tert-butyldiphenylsilyl (TBDPS), cyclic acetals such as isopropylidenacetal, cyclopentylidene acetal, cyclohexylidenacetal, benzylidene acetal, p -methoxybenzylidene acetal, p-dimethoxybenzylidenacetal, acyclic acetals such as tetrahydropyranyl (Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzyloxymethyl (BOM) or methylthiomethyl (MTM). Particularly preferred hydroxyl protecting groups are benzyl, acetyl, tertiary butyl or TBS. The release of the compounds of formula I from their functional derivatives is described in the literature for each protective group employed (for example, TW Greene, PGM Wuts, Protective Groups in Organi c Chemi stry (Protective Groups in Organic Chemistry), 2nd edition, Wiley, New York 1991 or PJ Kociensky, Protecting Groups (Protective Groups), 1st edition, Georg Thieme Verlag, Stuttgart-New York, 1994). It is also possible to apply variants known per se that are not described here in detail. The BOC and O-terButyl groups can be removed preferably with, for example, TFA in dichloromethane or with HCl ca. 3N to 5N in dioxane, at a temperature between 15 and 30 ° C; The Fmoc group can be removed using a solution of approximately 5-50% dimethylamine, diethylamine or piperidine in DMF, at a temperature between 15 and 30 ° C. The Aloe group can be carefully cleaved with catalysis of a noble metal in chloroform and at a temperature of 20-30 ° C. A preferred catalyst is tetrakis (triphenylphosphine) palladium (0). The starting compounds of formulas II to V are usually known. If they are new, then they can be prepared according to methods known per se. The compounds of formula II are obtained, for example, by coupling the corresponding 2-amino compound of the heterocycle, wherein Q :, Q3, Q? or Q4 have the meaning indicated in claim 1, with the corresponding esters of the n-bromocarboxylic acid (Br- [CH2]., - COOSG ", where SG" represents a hydroxyl group as described above), in the presence of a base, and then by cleavage of the protecting group under standard conditions. The compounds of formula IV are obtained by means of a coupling of the peptide type of the compounds of formula II with a glycine derivative H3N-CH-COOSG2, where SG ^ represents a hydroxyl protecting group as described above, in standard conditions. The compounds of formula V (β-amino acids) can be prepared analogously to that described by Skinner et al., J. Org. Chem. 1960, 25, 1756. By reaction of the corresponding aldehyde R3-CH0 with malonic acid and ammonium acetate in a suitable solvent, preferably in alcohols such as, for example, ethanol, the β-amino acid of formula V is obtained in the which R represents H. By esterification of this free acid of formula V under standard conditions the compounds of formula V are obtained in which R ° represents A or - (CHJ ~ -Ar. amino acids of formula V protected in their acid function, either with a corresponding protecting group or when R ° represents A, - (CHJ --OH, - (CHJ r-0-C (0) A or - (CHJ-Ar , with a glycine derivative SG'-NH-CH-C00H The substituent SG3 of the glycine derivative SG '; -NH-CH; -C00H represents an amino protecting group as described above, which is then cleaved. The usual methods of peptide synthesis are described, for example, in Houben-Weyl, le, vol. 15/11, 1974, p. 1 to 806. The compounds of formula I can be prepared by reaction of a compound of formula II with a compound of formula III and then by cleavage of a protecting group or by transformation of the radical R6, which represents A, - (CHJm- OH, - (CH2) m-0-C (0) A or - (CHzJ.-Ar, in the rest R6 = H.

The compounds of formula I can also be prepared by reaction of a compound of formula IV with a compound of formula V and then by cleavage of a protecting group or by transformation to the radical R ", which represents A, - (CHJ- -0H, - (CHJ.-OC (0) A or - (CHJ-Ar, in the remainder Rd = H. The coupling reaction is preferably carried out in the presence of a dehydrating agent, such as, for example, a carbodumid such as dicloclohexyl-caroodiimide (DCC), N- (3-d? meth? la-mmopropyl) -N'-ethyl-carbodumide hydrochloride (EDC) or dusopropylcarbodumide (DIC), then also, for example , propanophosphonic anhydride (see Angew. Chem. 1980, 92, 129), diphenylphospholazide or 2-ethoxy? -N-ethoxycarbon? ll, 2-d? h? -droquinoline, in an inert solvent such as, for example, example, a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or dimethylacetamide, a nitro such as acetonitoplo, in dimethylsulfoxide or in the presence of these solvents, at temperatures between about -10 and 40, preferably between 0 and 30 °. The reaction times are, depending on the conditions used, between a few minutes and several days.

As a coupling reagent, TBTU ((O- (benzotrolol-1-yl) -N, N, N ', N' -bis- (tetramethylene) -uronium trifluoroborate) or O- hexafluorophosphate ( benzotriazol-1-yl) -N, N, N ', N' -bis- (tetramethylene) -uronium, since in the presence of one of these compounds the racemization is low and no cytotoxic side products are formed. of the compounds of formula II and / or IV it is also possible to use derivatives of the compounds of formula II and / or IV, preferably a pre-activated carboxylic acid, or an acid halide, a symmetrical or mixed anhydride or an active ester. of this type serve to activate the carboxyl group in typical acylation reactions and are described in the literature (for example, in standard works such as Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme- Verlag, Stuttgart) Activated esters are conveniently prepared in situ u, for example, by adding HOBt (1-hydroxybenzotriazole) or N-hydroxy succinimide. In general, the reaction is carried out in an inert solvent, using an acid halide and in the presence of an acid trapping agent, preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline. The addition of an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, or the addition of another salt of weak acid and alkali metal or alkaline earth metal, preferably a salt of potassium, sodium, calcium or cesium may also be appropriate. A base of formula I can be converted into its salt by the addition of an acid, for example, by reaction of equivalent amounts of the base and the acid in an inert solvent such as ethanol and then by subsequent evaporation. Acids which form physiologically acceptable salts are particularly suitable for this reaction. Therefore, inorganic acids can be used, such as, for example, sulfuric, sulfuric, dithionic, nitric acid, hydrocides such as hydrochloric or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, then also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulphonic or sulfuric acids such as, for example, formic, acetic, propionic, hexanoic, octanoic, decanoic, hexadecanoic, octadecanoic, pivalic acids , diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, methanesulfonic or ethanesulfonic, benzenesulfonic, trimethoxybenzenesulfonic, adamantanecarboxylic, p-toluenesulfonic, glycolic, embonic, chlorophenoxyacetic, aspartic, glutamic, proline, glyoxylic, palmitic, parachlorophenoxyisobutyric, cyclohexanecarboxylic, glucose-1-phosphate, naphthalene-sulfonic acid, naphthalene-disulfonic acid and lauryl-sulphonic acid. Salts of physiologically unacceptable acids, for example picrates, can be used to isolate and / or purify the compounds of formula I. The compounds of formula I can also be converted into their respective metal salts, in particular of alkali metal or alkaline earth metal, by treatment with bases (for example, sodium or potassium hydroxide or carbonate), or in their respective ammonium salts. Another object of the invention are the compounds of formula I, according to claim 1, and physiologically acceptable salts thereof or their solvates which act as active substances of medicaments. Also object of the invention are the compounds of formula I, according to claim 1, and their physiologically acceptable salts or their solvates acting as integrin inhibitors. Also object of the invention are the compounds of formula I, according to claim 1, and their physiologically acceptable salts or their solvates which are used to combat diseases. Another object of the invention is the use of a combination of selective integrin inhibitors, which are selected from the group of selective integrin inhibitors combined with selective inhibitors of the integrin aß & amp; amp; amp;;, of the selective inhibitors of integrin a.β. combined with selective inhibitors of integrin a.ße or of the selective inhibitors of the integrin avß combined with selective inhibitors of the integrin avßs and combined with selective inhibitors of the integrin vñ6 l to prepare a medicament destined to combat the pathological processes influenced by the integrins avß3 and / or avß = and a-.ße. The object of the invention is the use of a combination of selective inhibitors of integrin, which are selected from the group of selective inhibitors of the integrin avß3 combined with selective inhibitors of integpna a -.- ß,., Of selective inhibitors of the α-β β integrin. combined with selective inhibitors of integrin a, β. or of the selective inhibitors of the integrin, β-. combined with selective aß integrin inhibitors; and combined with selective inhibitors of integrin o.β0, to prepare a medicament for cancer therapy, whereby, on the one hand, the angiogenesis of the blood vessels that grow into the tumor is prevented by inhibition of the receptor. integrin a > ß3 and / or the integrin receptor or..β: and, on the other hand, the development of the tumor by inhibition of the a.β integrin receptor is prevented. The object of the invention is the use of a combination of selective inhibitors of the integrin avß3 and / or selective inhibitors of the integrin α-ββ = and selective inhibitors of the integrin v β 6, to prepare a drug intended to combat the diseases associated with cancer such as the metastasis of solid tumors, angiofibromatosis, fibroplasia retrolental, hemangioma or Kaposi's sarcoma.

The selected compounds of formula I listed below are, in particular, selective inhibitors of the aß3 integrins and aβ: a) trifluoroacetate. { 2- [5- (-methyl-pyrid? N-2-ylamino) -pentanoylamino] -acetylamino} -3- (-chloro-3-nitro-phenyl) -propionic; b) 3- (4-Methyl-3-nitro-phenyl) -3- (2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic acid trifluoroacetate; ) 3- (4-methyl-3-nitro-phenyl) -3- acid trifluoroacetate. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; d) 3- acid trifluoroacetate. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic or e) trifluoroacetate of 3- (biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic The selected compounds of formula I which are indicated below are, in particular, selective inhibitors of the integrins a-.β .. and a -β6: a) trifluoroacetate of the 3-acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3- (trifluoromethoxy-phenyl) -propionic or) 3- (3-nitro-phenyl) -3- (2- [5- (4-methyl-pyridin-2-ylamino) -pentanoyiamino] - trifluoroacetate acetylamino] -propionic The selected compounds of formula I listed below are, in particular, selective inhibitors of the avß3 integrins, and a -.β.s: a) trifluoroacetate of the 3-acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-methyl-3-nitro-phenyl) -propionic; b) 3- (3-nitro-phenyl) -3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic, c) 3- (2- [4- (-methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic acid trifluoroacetate; d) trifluoroacetate of the acid 3-. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} 3- (3-trifluoromethyl) -3- (2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -3- (3-trifluoromethoxy-phenyl) -propionic acid oe) hydrochloride] - acetylamino.} -propionic.

The inhibitors of integrins which may be used in a particularly appropriate manner for preparing a medicament for therapy or for combating the pathological processes which may be influenced by the integrins a.β3 and / or a-.β_ and ßc, are indicated below. particular, intended for cancer therapy as described above: a) trifluoroacetate of 3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-chloro-3-ni tro-phenyl) -propionic; b) 3- (4-Methyl-3-nitro-phenyl) -3- (2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic acid trifluoroacetate; ) 3- (4-methyl-3-nitro-phenyl) -3- acid trifluoroacetate. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; d) 3- (2- [5- (4-Methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino] -3- (4-trifluoromethoxy-phenyl) -propionic acid o (e) trifluoroacetate acid trifluoroacetate 3- (biphenyl-4-yl) -3-. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic f) 3- acid trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic or g) trifluoroacetate of 3- (3-nitro-phenyl) -3- acid. { 2- [5- (4- met? L-p? R? Dm-2-? Lam? No) -pentanoiiammo] -aceti lammo} -prc-pionic. h) 3- acid trifluoroacetate. { 2- [4- (4-met? L-p? Ndm-2-ylamino) -butyr lammo] -acetylamm} -3- (4-met? L-3-n? Tro-fe-nil) -propionic; i) 3- (3-n-tro-phenyl) -3- trifluoroacetate. { 2- [- (-met? L-p? R? Dm-2-? Lamino) -butyrylammo] -acetylamino} -propionic, j) 3- acid tpfluoroacetate. { 2- [4- (4-met? L-p? R? Dm-2-ylammo) -butyrylammo] -acetylammon} -3- (4-tr? Fluoromethoxy-phenyl) -propionic; k) acid trifluoroacetate 3-. { 2- [5- (4-met? L-p? R? Dm-2-ylamino) -phenylamino] -acetylamine} -3- (3-tr? Fluoromethoxy-phenyl) -propionic or 1) 3- (3-n-tro-phenyl) -3- hydrochloride. { 2- [5- (4-met? L-p? R? D? N-2-? Lammo) -pentanoylamm] -acetylamm} -propionic Another object of the invention is the use of selective inhibitors of the mtegrmas, which are selected from the group consisting of a) trifluoroacetate of the acid 3-. { 2- [5- (4-met? L-p? Rid? N-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-chloro-3-nitro-phenyl) -propionic; b) 3- (4-met? l-3-n? tro-phenyl) -3- trifluoroacetate. { 2- [5- (4-met? I-p? R? D? N-2-? Lammo) -pentanoylamm] -acetylamino} -propionic; c) 3- (4-met l-3-n? tro-phenyl) -3- trifluoroacetate. { 2- [4- (p? R? Dm-2-? Lamino) -butip lamino] -aceti lamino} -propionic; d) 3- acid trifluoroacetate. { 2- [5- (4-met? L-p? R? Dm-2-ylamino) -phenylamino] -acetylamine} -3- (4-tr? Uoromethoxy-phenyl) -propionic or e) tp? Uoroacetate of 3- (bifen? L-4-? L) -3- acid. { 2- [5- (p? R? Dm-2? -lamino) -pentanoylamino] -aceti lamino} -propionic f) 3- acid trifluoroacetate. { 2- [4- (4-met? L-p? R? Dm-2-yla mo) -butiri lamino] -acet? Lam? No} -3- (3-trifluoromethoxy-phenyl) -propionic or g) 3- (3-n-tro-phenyl) -3- trifluoroacetate. { 2- [5- (4-met? L-p? R? Dm-2-? Lamino) -pentanoi lamino] -aceti lamino} -propionic h) 3- acid tpfluoroacetate. { 2- [4- (4-met? L-p? Ridm-2-ylammo) -butyrylammo] -acetylammon} -3- (4-met? L-3-n? Tro-phenyl) -propionic; i) 3- (3-n-tro-phenyl) -3- trifluoroacetate. { 2- [4- (4-met? L-p? R? D? N-2-? Lammo) -butiri lamino] -aceti lamino} -propionic, j) 3- acid tpfluoroacetate. { 2- [4- (4-met? L-p? R? D? N-2-ylamino) -butyrylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic; k) 3- acid trifluoroacetate. { 2- [5- (4-Methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic or 1) 3- (3-nitro-phenyl) -3- hydrochloride. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, to prepare a drug designed to combat pathological processes influenced by ß3 integrins The object of the invention is the use of selective integrin inhibitors, which are selected from the group consisting of a) trifluoroacetate of 3-acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-chloro-3-nitro-phenyl) -propionic; b) 3- (4-methyl-3-nitro-phenyl) -3- trifluoroacetate. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; c) 3- (methyl-3-nitro-phenyl) -3- trifluoroacetate. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; d) 3- acid trifluoroacetate. { 2- [5- (4-met? L-p? R? Dm-2-1lamino) -phenylamino] -acetyiammo} -3- (4-tr? Uoromethoxy-phenyl) -propionic or e) trifluoroacetate of 3- (or phen? I-4? I) -3- acid. { 2- [5- (p? Pd? N-2-? Lamino) -pentanoylamino] -acetylamm} -propionic. f) 3- acid trifluoroacetate. { 2- [4- (4-met? L-p? Pdm-2-ylamino) -butyrylammo] -acetylamino} 3- (3-n-tro-phenyl) -3- (2- [5- (4-met? Lp? R? Dm-) 3- (3-tr? Uoromethoxy-phenyl) -propionic og) trifluoroacetate 2-? Lamino) -pentanoi lamino] -aceti lamino.}. -propionic. H) 3- trifluoroacetate. { 2- [4- (4-met? L-p? R? D? N-2-ylamino) -butyral lamino] -acetylamino} -3- (4-met? L-3-n? Tro-fe-nil) -propionic; i) 3- (3-n-tro-phenyl) -3- trifluoroacetate. { 2- [4- (4-met? L-p? R? D? N-2-? Lam? No) -butylamino] -acetylamino} -pro-pionic, j) 3-acid tpfluoroacetate. { 2- [4- (4-met? L-p? R? Dm-2- l amyl) -butyrylamm] -acetyl mo} -3- (4-tr? Fluoromethoxy-fe-mi) -propionic; k) 3- acid tpfluoroacetate. { 2- [5- (4-met? L-p? R? Dm-2-ylamino) -pentanoylamm] -acetylamm} -3- (3-tr? Fluoromethoxy-phenyl) -propionic or 1) 3- (3-nitrc-phenyl) -3- hydrochloride. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, to prepare a drug for cancer therapy, by which, on the one hand, the angiogenesis of blood vessels that grow into the tumor is prevented by inhibition of integrin receptor a.β3 and / or receptor of integrin avß3 and, on the other hand, the development of the tumor is prevented 'by inhibition of the aβ6 integrin receptor. The object of the invention is the use of selective inhibitors of integrin α, β and / or selective inhibitors of integrin α, β _. and selective inhibitors of integrin a & amp;, which are selected from the group consisting of a) trifluoroacetate of 3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (-chloro-3-nitro-phenyl) -propionic; b) 3- (4-methyl-3-nitro-phenyl) -3- trifluoroacetate. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; c) 3- (methyl-3-nitro-phenyl) -3- (2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic acid trifluoroacetate; d) 3- (2- [5- (4-Methyl-pipd-n-2-ylamino) -pentanoylamino] -acetylamino] -3- (4-trifluoromethoxy-phenyl) -propionic acid o-trifluoroacetate trifluoroacetate 3- (biphenyl-4-ii) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic f) 3- acid trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic or g) trifluoroacetate of 3- (3-nitro-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -pro-pionic. h) 3- (2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino] -3- (4-methyl-3-nitro-phenyl) -propionic acid trifluoroacetate; i) 3- (3-nitro-phenyl) -3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic, j) 3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic; k) 3- acid trifluoroacetate. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic or 1) 3- (3-nitro-phenyl) -3- hydrochloride. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acet-lamino} -proponic, to prepare a drug intended to combat diseases associated with cancer such as metastases from solid tumors, angiofibromatosis, retrolental fibroplasia, hemangioma or Kaposi's sarcoma. The ß-alanine derivatives listed below are particularly suitable for use in the manufacture of a medicament for the therapy of cancer, whereby, on the one hand, the angiogenesis of the blood vessels growing to the side is prevented. within the tumor by inhibition of the β-integrin receptor and, on the other hand, tumor development is prevented by inhibition of the integrin receptor a >; ß .: a) trifluoroacetate of 3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-chloro-3-nitro-phenyl) -propionic; b) 3- (4-Methyl-3-nitro-phenyl) -3- (2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic acid trifluoroacetate; ) 3- (4-methyl-3-nitro-phenyl) -3- acid trifluoroacetate. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; d) 3- (2- [5- (4-Methy-pyridin-2-yl) yl) -pentanoylamino] -acetylamino] -3- (4-trifluoromethoxy-phenyl) -propionic acid trifluoroacetate acid trifluoroacetate 3- (biphenyl-4-yl) -3- (2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic acid The following ß-alanine derivatives are particularly suitable for use in the development of a drug for cancer therapy, whereby, on the one hand, the angiogenesis of blood vessels growing in the tumor is prevented by inhibition of the integrin receptor a.-β- and, on the other hand, the development of the tumor is prevented by inhibition of the integrin receptor ayßfc: a) trifluoroacetate of the 3-acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic or b) trifluoroacetate of 3- (3-nitro-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic The ß-alanine derivatives listed below are particularly suitable for use in the preparation of a medicament for cancer therapy, whereby, by a laao, the angiogenesis of blood vessels is prevented from occurring. Growth is born within the tumor by inhibiting the mtegrin receptor at ß_ and ß3 and, on the other hand, tumor development is prevented by inhibition of the integrin receptor at ß: a) 3-acid tpfluoroacetate. { 2- [4- (4-met? L-p? Pd? N-2-ylamino) -butyrylamino] -acetylamino} -3- (4-met? L-3-n? Tro-phenyl) -propionic; b) 3- (3-n-tro-phenyl) -3- trifluoroacetate. { 2- [- (4-met? L-p? R? D? N-2-? Lammo) -butyrylamm] -acetylamm} -propionic, c) 3- (2- [4- (4-met? lp? r? d? n-2-ylammo) -butyrylammo] -acetylammon. -3- (4-tr? fluoromethoxy) acid tpfluoroacetate. -phenyl) -propionic; d) trifluoroacetate of 3- acid. { 2- [5- (4-met? L-p? R? D? N-2-ylammo) -pentanoylammo] -acetylamm} -3- (3-tr? Fluoromethoxy-phenyl) -propionic or e) 3- (3-n? Tro-feml) -3- acid hydrochloride. { 2- [5- (4-met? L-p? R? D? N-2-? Lammo) -pentanoylamino] -acetylamino} -propionic Along with the use of selective inhibitors of the mtegrins as described by the invention as an internal combination therapy of at least two inhibitors of mtegrins, other combinations with usual therapies such as radiotherapy, vaccination against the tumor can also be applied. , immunotherapy or chemotherapy. This internal and external combination therapy should further increase the effectiveness of the treatment and, above all, reduce the dose of the toxic therapeutic compounds, thereby also reducing the side effects associated with the dose. Also the subject of the invention are pharmaceutical compositions containing at least one compound of formula I and / or one of its physiologically acceptable salts or one of its solvates, which are prepared, in particular, by a non-chemical route . For these purposes, the compounds can be brought into a suitable dosage form, together with at least one solid, liquid and / or semi-liquid auxiliary excipient or auxiliary product and, optionally, in combination with one or more additional active substances. These compositions can be used in medicine and veterinary medicine as a medicine. Among the excipients there may be mentioned organic or inorganic substances which are suitable for enteral (for example, oral), parenteral or topical application, and which do not react with the new compounds. Examples of these excipients are water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petrolatum. For oral administration, in particular, tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used, for the rectal application of suppositories, for the parenteral administration of the solutions, preferably the oily solutions. or aqueous, and also suspensions, emulsions or implants, and for topical application ointments, creams or powders. The new compounds can also be lyophilised and the resulting lyophilized products can be used, for example, for the preparation of injectable preparations. The mentioned compositions can be sterilized and / or contain auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifying agents, salts for influencing the osmotic pressure, pH regulating substances, dyes, flavor correction substances and / or various additional active substances such as, for example, one or several vitamins.

For the application in the form of aerosol inhaling solution, aerosols can be used which contain the active substance either dissolved or suspended in a carrier gas or in a mixture of gases (for example, C03 or chlorofluorocarbons). The particles of active substance are usually conveniently micronized, and one or more additional solvents which are physiologically acceptable can also be added, such as, for example, ethanol. Inhalant solutions can be administered using conventional inhalers. The compounds of formula I and their physiologically acceptable salts or solvates thereof can be used as integrin inhibitors to combat diseases, in particular thrombosis, myocardial infarction, coronary diseases, arteriosclerosis, tumors, osteoporosis, inflammations and infections. The compounds of formula I, according to claim 1, and / or their physiologically acceptable salts can also be used in the pathological processes that are propagated or maintained by angiogenesis, in particular, in the case of tumors or rheumatoid arthritis As mentioned above, the selected compounds of formula I and / or their solvates can be used to combat the pathological processes that are influenced by the α3 and / or αβ integrins and α-ββ., in particular for cancer therapy, since, on the one hand, they prevent the angiogenesis of blood vessels that grow into the tumor by inhibiting the avß3 integrin receptor and / or the α3 integrin receptor and, on the other hand, they prevent the development of the tumor by inhibition of the a.β- integrin receptor. For these treatments, the substances of the invention are generally administered analogously to the compounds described in the world patents No. 97/26250 and 97 / 24124, preferably in doses between approximately 0.05 and 500 mg, in particular between 0.5 and 100 mg per dosage unit. The daily dose is preferably comprised between ca. 0.01 and 2 mg / kg of body weight. However, the particular dose for each patient depends on a wide variety of factors, for example, the effectiveness of the particular compound used, age, body weight, general state of health, sex, diet , of the time and method of administration, of the rate of excretion, of the combination of drugs and of the severity of the particular disease to which the therapy is applied. Parenteral administration is preferred. The new compounds of formula I can also be used as integrin ligands in the preparation of columns for affinity chromatography in order to obtain integrins at the pure state. To do this, the ligand - that is, a compound of formula I - is covalently bound to a polymeric support via a binding function, such as, for example, the carboxyl group. As the polymeric support materials, the fixed phases based on polymers having preferably hydrophilic properties and which are known and customary in the chemistry of peptides can be used. Examples of these fixed phases are crosslinked polyazuccans such as cellulose, Sepharose or Sephadex®, acrylamides, polymers based on polyethylene glycol or TentakeU polymers Preparation of materials for affinity chromatography, intended for purification of integrins , it is carried out under the known and usual conditions of amino acid condensation. The compounds of formula I have one or several chiral centers, whereby they can be obtained as racemates c in their optically active forms. The obtained racemates can be separated into their enantiomers by known chemical or mechanical methods. The diastereomers are formed from the racemic mixture, preferably by reaction with an optically active separation agent. Examples of suitable separation agents are optically active acids such as the D and L forms of tartaric, diacetyltartaric, dibenzoyltartaric, mandelic, malic, lactic acids, or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. It is also convenient to separate the enantiomers through a column filled with an optically active separation agent (eg dinitrobenzoyl-phenyl-glycine); As the mobile phase, for example, a hexane / isopropanol / acetonitrile mixture can be used in a volume ratio of, for example, 82: 15: 3. Of course, it is also possible to obtain optically active formula I compounds by applying the methods described above and using starting substances that are already optically active. All temperatures of the present text are given in ° C. In the examples that follow, the expression "is worked (or treated) in a usual manner" means the following: if necessary, water is added, if necessary the pH is adjusted between 2 and 10 according to the constitution of the final product, it is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulphate, concentrated by evaporation and purified by chromatography on silica gel, by HPLC on a prepartial scale and / or by recrystallization. The pure compounds can also be lyophilized. TR = retention time (minutes) on HPLC and under the following conditions: Column: Lichrosorb RP-18 (5 um) 250 x 4 mm; Lichrosorb RP-18 (15 um) 250 x 50 mm. As gradients, gradients of acetonitrile (B) with TFA (trifluoroacetic acid) 0.1? Were used. and water (A) with 0.1 TFA; > . The gradient is indicated in percent by volume of acetonitrile. Preferred gradient: 5 min. at 20. B and 55 min. to 90? > B. Detection at 225 nm. The retention times indicated with * were measured with a gradient of 5 min. 5?. B and 40 min. up to 80% B. The compounds purified by HPLC on a prepartial scale are isolated as trifluoroacetates.

Mass spectrometry (MS) by FAB (fast atom bombardment): MS-FAB (M + H) " Example 1 (1) During 10 hours, 10.5 g of 4- (trifluoroethoxy) -benzaldehyde, 5.72 g of malonic acid, 8.5 g of ammonium acetate and 40 ml of ethanol are heated to reflux and the mixture is stirred. overnight at room temperature. After cooling, the reaction mixture is filtered with suction, washed with ethanol and ether and allowed to air dry. 3-Amino-3- (4-trifluoromethoxy-phenyl) -propionic acid, m.p. 258-260 °. 7.5 g of 3-amino-3- (4-trifluoromethoxy-phenyl) -propionic acid are activated with thionyl chloride (1.2 equivalents) and esterified with methanol at boiling temperature and under standard conditions. After working the mixture in the usual way, 3-amino-3- (4-tri-fluoromethoxyphenyl) -propionate methyl, FAB-MS (M + H) + 263 is obtained. (2) 0.364 g of [4- (pyridin-2-ylamino) -butyrylamino] -acetic acid [obtained by peptide coupling of 4- (pyridin-2-ylamino) -butyric acid with the glycine methyl ester in presence of HOBT / TBTU and then by saponification of the methyl ester, carrying out each of these reactions under standard conditions] in 30 ml of DMF, 0.3 g of 3-amino-3- (-trifluoromethoxy-phenyl) -propionate are added. of methyl and cooled to 30 °. After adding 0.321 g of TBTU and 0.045 g of HOBT it is neutralized with 0.22 ml of N-methylmorpholine (NMM). The reaction mixture is stirred for 2 days at room temperature. After distilling off the solvent, the residue is taken up in ethyl acetate, washed with NaHCO and saturated NaCl solution and the mixture is continued to be treated in the usual manner. Thirty-methyl 3- (2- [4- (4-methyl-pyridin-2-ylamino) butyrylamino] -acetylamino] -3- (4-tri-fluoromethoxy-phenyl) -propionate, FAB-MS ( M + H) * 497. (3) 280 mg of 3- are dissolved. { 2- [- (4-Methyl-pyridin-2-ylamino) butyrylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionate methyl (raw material) in 30 ml of dioxane and 0.61 ml of NaOH (2 mol / l) are added. After stirring overnight at room temperature, the solvent is distilled off and the mixture is worked up in the usual manner. You get the 3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) butyrylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic. If you work with an excess of NaOH, then you get the sodium salt of acid 3-. { 2- [- (4-Methyl-pyridin-2-ylamino) butyrylamino] -acetylamino} -3- (-trifluoromethoxy-phenyl) -propionic. By means of HPLC on a preparative scale, trifluoroacetate of 3- acid is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) butyrylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic, RT 24.93 min., FAB-MS (M + H) "483.

Example 2 (1) During 8 hours, 0.06 mol of 2-nitro-benzaldehyde, 5.72 g of malonic acid, 8.5 g of ammonium acetate and 40 ml of ethanol are heated to reflux and the mixture is stirred throughout the night at room temperature. After cooling, the reaction mixture is filtered with suction, washed with ethanol and ether and allowed to air dry. 3-Amino-3- (2-nitro-phenyl) -propionic acid, m.p. 222 °. The esterification is then carried out by activation with thionyl chloride and reaction with methanol under standard conditions, thus obtaining methyl 3-amino-3- (2-nitro-phenyl) -propionate. (2) The methyl 3-amino-3- (2-nitro-phenyl) -propionate is reacted with the BOC-protected glycine (BOC-Gli-OH) analogously to that described in Example 1 (2) . After cleaving the BOC amino protecting group under standard conditions, the 3- (2-amino-acetylamino) -3- (2-nitro-phenyl) -propionate methyl chlorohydrate FAB-MS (M + H) * 317 is obtained. . (3) 360 mg of methyl 3- (2-amino-acetylamino) -3- (2-nitro-phenyl) -propionate hydrochloride is dissolved in 35 ml of DMF and 190 mg of 4- (4-) acid are added. methyl-pyridin-2-ylamino) -butyric acid. After cooling to 0 °, 450 mg of TBTU and 63 mg of HOBt are added to the reaction mixture. It is neutralized with 0.15 ml of N-methylmorpholine and stirred overnight at room temperature. The solvent is distilled, the residue is mixed with 30 ml of ethyl acetate, washed with a half-concentrated bicarbonate solution and saturated sodium chloride solution and the mixture is continued to work in the usual manner. There is obtained methyl (3- {2- [4- (4-methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (2-nitro-phenyl) -propionate. (4) 280 mg of (3- {2- [4-; 4-met l-p? R? D n-2-ylamino) -butyrylammo] -acetylamm is dissolved} -3- (2-n? Tro-feml) -prc-methyl pionate (raw material) in 30 ml of dioxane and add 0.61 ml of NaOH (2 mol / l). After stirring overnight at room temperature, the solvent is distilled off and the mixture is worked up in the usual manner. The acid is obtained (3-. {2- 2- [4- (4-met? Lp? R? D? N-2-? Lammo) -butiplammo] -acet? Lammo.}. -3- (2-n) If you work with an excess of NaOH, you get the sodium salt of the acid (3- {{{2- {4- (4-met? lp? r? d? n-2-? lammo) -buty-ryamino] -acetylamino.} -3- (2-n? trc-phen? l) -propionic acid. By means of preparative HPLC, the acid trifluoroacetate (3- (2- [4]) is obtained. - (4-met? Lp? R? Dm-2-ylammo) -butyrylamino] -acetylamm.}. -3- (2-n? Tro-phenyl) -propiomco, RT 16.14 mm., FAB-MS ( M + H) 444.

EXAMPLE 3 Proceeding analogously to that described in example 2 and by reaction of 4- (4-met? L-p? R? Dm-2-ylamino) -butyric acid "AB" with methyl 3- (2-ammo-acet? lam? no) -3- (3-trifluoromethoxy-phenyl) -propionate hydrochloride, 3- is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionate methyl; with methyl 3- (2-amino-acetylamino) -3- (4-methyl-3-nitro-phenyl) -propionate hydrochloride, 3- (4-methyl-3-nitro-phenyl) -3- is obtained. . { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (3-nitro-phenyl) -propionate hydrochloride, 3- (3-nitrophenyl) -3- is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} Methylpropionate, after preparative-scale HPLC analysis, 3- (3-nitro-phenyl) -3- trifluoroacetate is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -Methyl propionate, RT * 19.09, FAB-MS (M + H) 4 458 or with methyl 3- (2-amino-acetylamino) -3- (4-biphenyl) -propionate hydrochloride, 3- is obtained. { 2- [4- (-methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-biphenyl) -propionate methyl.

Example 4 After saponifying the methyl esters of the compounds of Example 3 in a manner analogous to that described in Example 2 (5), 3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic; the sodium salt of acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic; 3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic; RT 24.40 min, FAB-MS (M + H) + 483; 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (4-methyl-3-nitro-phenyl) -3- acid trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; RT 19.18 min, FAB-MS (M + H) + 458; 3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic; the sodium salt of acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic; 3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic; RT 17.68 min, FAB-MS (M + H) * 444; or the acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-biphenyl) -propionic; the sodium salt of acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-biphenyl) -propionic; 3- trifluoroacetate. { 2- [4- (-methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-biphenyl) -propionic; RT 25.65 min, FAB-MS (M + H) 4"475.

Example 5 Proceeding analogously to that described in example 2 and by reaction of 5- (4-methyl-pyridin-2-ylamino) -pentanoic acid "BC" with methyl 3- (2-amino-acetylamino) -3- (4-trifluoromethoxy-phenyl) -propionate hydrochloride, 3- is obtained. { 2- [5- (-methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionate methyl; with methyl 3- (2-amino-acetylamino) -3- (3-trifluoromethoxy-phenyl) -propionate hydrochloride, 3- is obtained. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionate methyl; with methyl 3- (2-amino-acetylamino) -3- (4-methyl-3-nitro-phenyl) -propionate hydrochloride, 3- (4-methyl-3-nitro-phenyl) -3- is obtained. . { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; HPLC yields 3- (4-methyl-3-nitro-phenyl) -3- trifluoroacetate. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate, RT 23.81 min, FAB-MS (M + H) "486. with methyl 3- (2-amino-acetylamino) -3- (2-nitro-phenyl) -propionate hydrochloride, 3- is obtained. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -3- (2-Nitro-phenyl) -propionate methyl; with the 3- (2-amino-acetylamino) -3- (3-nitrophenyl) -propionate hydrochloride, 3- (3-nitro-phenyl) -3- is obtained. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4-methyl-3-nitro-phenyl) -propionate hydrochloride, 3- (4-methyl-3-nitro-phenyl) -3- is obtained. . { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4-naphthalen-2-yl-phenyl) -propionate hydrochloride, 3- (4-naphthalen-2-yl-phenyl) -3- is obtained. . { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4-chloro-3-nitro-phenyl) -propionate hydrochloride, 3- (4-chloro-3-nitro-phenyl) -3- is obtained. . { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -Methyl propionate or with methyl 3- (2-amino-acetylamino) -3- (4-biphenyl) -propionate hydrochloride, 3-biphenyl-4-yl-3- is obtained. { 2- [5- (4-methyl-pyrid? N-2-ylam? -no) pentanoylamino] -acetylamino} methylpropionate, by preparative-scale HPLC, 3-biphenyl-4-yl-3-trifluoroacetate is obtained. { 2- [5- (4-methyl-pyridin-2-ylamino) pentanoylamino] -acetylamm} methyl-propionate, RT 30.13 min, FAB-MS (M + H) + 503.

Example 6 After saponifying the methyl esters of the compounds of Example 5 in a manner analogous to that described in example 2 (5), 3- acid. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic; the sodium salt of acid 3-. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic; 3- (2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino] -3- (4-trifluoromethoxy-phenyl) -propionic acid trifluoroacetate: RT 24.88 min, FAB -MS (M + H) + 497; 3- acid. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic; the sodium salt of 3- (2- [5- (4-methyl-pyridm-2-ylamino) -pentanoylamino] -acetylamino] -3- (3-trifluoromethoxy-phenyl) -propionic acid; trifluoroacetate of 3 - { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino.} - 3 - (3-trifluoromethoxy-phenyl) -propionic; RT 24.61 min, FAB-MS ( M + H) * 497; 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (4-methyl-3-nitro-phenyl) -3- acid trifluoroacetate. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; RT 22.13 min, FAB-MS (M + H) + 472; 3- acid. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -3- (2-nitro-phenyl) -propionic; the sodium salt of 3- [2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino acid} -3- (2-nitro-phenyl) -propionic; 3- trifluoroacetate. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -3- (2-nitro-phenyl) -propionic; RT 16.98 min, FAB-MS (M + H) * 458; the 3- (3-nitro-phenyl) -3- acid. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (3-nitro-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (3-nitro-phenyl) -3- acid trifluoroacetate. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; RT 17.29 min, FAB-MS (M + H) + 458; 3- (4-naphthalen-2-yl-phenyl) -3- [2- [5- (4-methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino acid} -propionic; the sodium salt of 3- (4-naphthalen-2-yl-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (4-naphthalen-2-yl-phenyl) -3- acid trifluoroacetate. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the 3- (4-chloro-3-nitro-phenyl) -3- acid. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4-chloro-3-nitro-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (4-chloro-3-nitro-phenyl) -3- (2- [5- (4-methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino] -propionic acid trifluoroacetate; RT 22, 34 min, FAB-MS (M + H) * 492 or 3-biphenyl-4-yl-3- acid. { 2- [5- (4-methyl-pyrid? N-2-ylam-no) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3-biphenyl-4-yl-3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3-biphenyl-4-yl-3-trifluoroacetate. { 2- [5- (4-Methyl-pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; RT 27.09 min, FAB-MS (M + H) * 489.

Example 7 Proceeding in a manner analogous to that described in example 2 and by reacting 4- (pyridin-2-ylamino) -butyric acid "CD" with 3- (2-amino-acetylamino) -3- hydrochloride ( Methyl 4-methyl-3-nitro-phenyl) -propionate is obtained 3- (4-methyl-3-nitro-phenyl) -3-. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (2-nitro-phenyl) -propionate hydrochloride, 3- (2-nitro-phenyl) -3- is obtained. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -Methyl propionate or with methyl 3- (2-amino-acetylamino) -3- (4-biphenyl) -propionate hydrochloride, 3- is obtained. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-biphenyl) -propionate methyl.

EXAMPLE 8 After saponification of the methyl esters of the compounds of Example 7 in a manner analogous to that described in Example 2 (5), 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (4-methyl-3-nitro-phenyl) -3- (2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic acid, the trifluoroacetate of the acid 3 - (4-Methyl-3-nitro-phenyl) -3- { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic acid, RT 19.12 min, FAB-MS (M + H) + 444; the 3- (2-nitro-phenyl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionx; the sodium salt of 3- (2-nitro-phenyl) -3- acid. { 2- [4- (pyridiri-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (2-nitro-phenyl) -3- acid trifluoroacetate. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; RT 12.42 min, FAB-MS (M + H) * 430 or 3-biphenyl-4-yl-3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3-biphenyl-4-yl-3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3-biphenyl-4-yl-3- (2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic acid trifluoroacetate; RT, 25.20 min, FAB-MS (M + H) 4"461.

Example 9 Proceeding analogously to that described in example 2 and by reaction of 5- (pyridin-2-ylamino) -pentanoic acid "DE" with methyl 3- (2-am? no-acetylamino) -3- (4-methyl-3-nitro-phenyl) -propionate hydrochloride, 3- (4-methyl-3-nitro-phenyl) - 3-. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (2-nitro-phenyl) -propionate hydrochloride, 3- (2-nitro-phenyl) -3- (2- [5- (pyridine Methyl-2-ylamino) pentanoylamino] -acetylamino.]. Propionate; with methyl 3- (2-amino-acetylamine) -3- (4-biphenyl) -propionate hydrochloride, 3-biphenyl-4-yl-3- is obtained. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} methylpropionate, by preparative-scale HPLC, 3-biphenyl-4-yl-3-trifluoroacetate is obtained. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} methyl-propionate, RT 28.88 min, FAB-MS (M + H) * 489.

EXAMPLE 10 After saponification of the methyl esters of the compounds of Example 9 in a manner analogous to that described in example 2 (5), 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (4-methyl-3-n? tro-phenyl) -3- trifluoroacetate. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; RT 19.78 min, FAB-MS (M + H) * 458; the 3- (2-nitro-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (2-nitro-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (2-nitro-phenyl) -3- acid trifluoroacetate. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; RT 12.80 min, FAB-MS (M + H) * 444 or 3-biphenyl-4-yl-3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3-biphenyl-4-yl-3- (2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic acid, 3-biphenyl-4-yl trifluoroacetate -3- { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino}. -propionic, RT 25.84 min, FAB-MS (M + H) + 475.

Example 11 Proceeding analogously to that described in example 2 and by reaction of 4- (6-methyl-pyridin-2-ylamino) -butyric acid "EF" with methyl 3- (2-amino-acetylamino) -3- (4-methyl-3-nitro-phenyl) -propionate hydrochloride, 3- (4-methyl-3-nitro-phenyl) -3- is obtained. . { 2- [4- (6-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -Methyl propionate.

Proceeding in a manner analogous to that described in example 2 and by reaction of 5- (6-methyl-pyridin-2-ylamino) -pentanoic acid "FG" with methyl 3- (2-amino-acetylamino) -3- (4-methyl-3-nitro-phenyl) -propionate hydrochloride, 3- (4-methyl-3-nitro-phenyl) -3- is obtained. . { 2- [5- (6-Methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -Methyl propionate.

EXAMPLE 12 After saponification of the methyl esters of the compounds of Example 11 in a manner analogous to that described in example 2 (5), 3- (4-methyl-3-nitro-phenyl) -3- (2- [4- (6-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino] -propionic acid, the sodium salt of 3- (4-methyl-3-nitro-phenyl) -3-. {2 - [4- (6-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino] -propionic acid, 3- (4-methyl-3-nitro-phenyl) -3-. {2} trifluoroacetate. - [4- (6-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino.] -propionic or 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (6-Methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (6-Methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (4-methyl-3-nitro-phenyl) -3- acid trifluoroacetate. { 2- [5- (6-Methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic Example 13 Proceeding analogously to that described in Example 2 and by reaction of 4- (pyrimidin-2-ylamino) -butyric acid "GH" with 3- (2-ammo-acetylamino) -3- (4-hydrochloride methyl-3-nitro-phenyl) -propionate is obtained 3- (4-methyl-3-nitro-phenol) -3-. { 2- [4- (pyrimidm-2-ylamino) -butyrylamino] -acetylamino} -Methyl propionate or with methyl 3- (2-amino-acetylamino) -3- (4-biphenyl) -propionate hydrochloride, 3- is obtained. { 2- [4- (pyrimidin-2-ylamino) -butyrylamino] -acetylamine} -3- (4-biphenyl) -propionate methyl.

Proceeding in a manner analogous to that described in example 2 and by reaction of 5- (pyrimidin-2-ylamino) -pentanoic acid "HK" with methyl 3- (2-amino-acetylamino) -3- (4-methyl-3-nitro-phenyl) -propionate hydrochloride, 3- (4-ethyl-3-nitrophenyl) -3- is obtained. . { 2- [5- (pyrimidin-2-ylamino) -pentanoylamino] -acetylamino} -Methyl propionate or with methyl 3- (2-amino-acetylamino) -3- (4-biphenyl) -propionate hydrochloride, 3- is obtained. { 2- [5- (pyrimidin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-biphenyl) -propionate methyl.

Example 14 After saponifying the methyl esters of the compounds of Example 13 in a manner analogous to that described in example 2 (5), 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [4- (Pyrimidin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (methyl-3-nitro-phenyl) -3- acid. { 2- [4- (Pyrimidin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (4-Methyl-3-nitro-phenyl) -3- (2- [4- (pyrimidin-2-ylamino) -butyrylamino] -acetylamino] -propionic acid trifluoroacetate: RT 16.33 min, FAB-MS (M + H) 4 445; 3-biphenyl-4-yl-3- acid. { 2- [4- (Pyrimidin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3-biphenyl-4-yl-3- acid. { 2- [4- (Pyrimidin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3-biphenyl-4-yl-3-trifluoroacetate. { 2- [4- (Pyrimidin-2-ylamino) -butyrylamino] -acetylamino} -propionic; RT 24.45 min, FAB-MS (M + H) + 462; 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (pyrimidin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (pyrimidin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (4-methyl-3-nitro-phenyl) -3- acid trifluoroacetate. { 2- [5- (pyrimidin-2-ylamino) -pentanoylamino] -acetylamino} -propionic or 3-biphenyl-4-yl-3- acid. { 2- [5- (pyrimidin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; the sodium salt of 3-biphenyl-4-yl-3- acid. { 2- [5- (pyrimidin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3-biphenyl-4-yl-3-trifluoroacetate. { 2- [5- (pi-rimidin-2-ylamino) -pentanoylamino] -acetylamino} -propionic Example 15 Proceeding in a manner analogous to that described in example 2 and by reaction of 4- (6-methyl-pyridin-2-ylamino) -butyric acid "HK" with methyl 3- (2-amino-acetylamino) -3- (4-methyl-3-nitro-phenyl) -propionate hydrochloride, 3- (4-methyl-3-nitro-phenyl) -3- is obtained. . { 2- [4- (6-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylaminoj-methyl propionate.

After saponifying the methyl ester in a manner analogous to that described in example 2 (5), 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [4- (6-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [4- (6-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (methyl-3-nitro-phenyl) -3- trifluoroacetate. { 2- [4- (6-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; RT 20.10 min, FAB-MS (M + H) + 458.

Example 16 Proceeding analogously to that described in example 2 and by reaction of 6- (4-methyl-pyridin-2-ylamino) -hexanoic acid "KL" with methyl 3- (2-amino-acetylamino) -3- (4-methyl-3-nitro-phenyl) -propionate hydrochloride, 3- (4-methyl-3-nitro-phenyl) -3- is obtained. . { 2- [6- (4-Methyl-pyridin-2-ylamino) -hexanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (3-nitro-phenyl) -propionate hydrochloride, 3- is obtained. { 2- [6- (4-Methyl-pyridin-2-ylamino) -hexanoylamino] -acetylamino} -3- (3-Nitro-phenyl) -propionate methyl or with methyl 3- (2-amino-acetylamino) -3- (4-chloro-3-nitro-phenyl) -propionate hydrochloride, 3- (4-chloro-3-nitro-phenyl) -3- is obtained. . { 2- [6- (4-Methyl-pyridin-2-ylamino) -hexanoylamino] -acetylamino} -Methyl propionate.

After saponification of the methyl esters described above analogously to that described in Example 2 (5), 3- (4-methyl-3-nitro-phenyl) -3- acid is obtained. { 2- [6- (4-Methyl-pyridin-2-ylamino) -hexanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [6- (4-Methyl-pyridin-2-ylamino) -hexanoylamino] -acetylamino} -propionic; 3- (4-methyl-3-nitro-phenyl) -3- acid trifluoroacetate. { 2- [6- (4-Methyl-pyridin-2-ylamino) -hexanoylamino] -acetylamino} -propionic; RT 22.10 min, FAB-MS (M + H) t 468; 3- acid. { 2- [6- (4-Methyl-pyridin-2-ylamino) -hexanoylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic; the sodium salt of acid 3-. { 2- [6- (4-Methyl-pyridin-2-ylamino) -hexanoylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic; 3- trifluoroacetate. { 2- [6- (4-Methyl-pyridin-2-ylamino) -hexanoylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic; RT 18.27 min, FAB-MS (M + H) * 472 or the 3- (4-chloro-3-nitro-phenyl) -3- acid. { 2- [6- (4-Methyl-pyridin-2-ylamino) -hexanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4-chloro-3-nitro-phenyl) -3- acid. { 2- [6- (4-methy1-pyridin-2-ylamino) -hexanoylamino] -acetylamino} -propionic; 3- (4-chloro-3-nitro-phenyl) -3- trifluoroacetate. { 2- [6- (4-Methyl-pyridin-2-ylamino) -hexanoylamino] -acetylamino} -propionic; RT 23.33 min, FAB-MS (M + H) + 506.

Example 17 Proceeding analogously to that described in example 2 and by reaction of 7- (4-methyl-pyridin-2-ylamino) -heptanoic acid "LM" with methyl 3- (2-amino-acetylamino) -3- (3-nitro-phenyl) -propionate hydrochloride, 3- is obtained. { 2- [7- (4-Methyl-pyridin-2-ylamino) -heptaoylamino] -acetylamino} -3- (3-nitro-phenyl) -propionate methyl. After saponifying the ester in a manner analogous to that described in example 2 (5), 3- acid. { 2- [7- (4-methyl-pyridin-2-ylamino) -heptanoylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic; the sodium salt of acid 3-. { 2- [7- (4-methyl-pyridin-2-ylamino) -heptanoylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic; 3- trifluoroacetate. { 2- [7- (4-methyl-pyridin-2-ylamino) -heptanoylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic; RT 20.98 min, FAB-MS (M + H) * 486.

Example 18 Proceeding analogously to that described in Example 2 and by reaction of 5- (pyridin-2-ylamino) -pentanoic acid "DE" with methyl 3- (2-amino-acetylamino) -3- (3-nitro-phenyl) -propionate hydrochloride, 3- (3-nitro-phenyl) -3- is obtained. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4-chloro-3-nitro-phenyl) -propionate hydrochloride, 3- (4-chloro-3-nitro-phenyl) -3- is obtained. . { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4'-fluorobiphenyl-4-yl) -propionate hydrochloride, 3- (4'-fluoro-biphenyl-4-yl) -3- is obtained. . { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4'-fluorobiphenyl-3-yl) -propionate hydrochloride, 3- (4'-fluoro-biphenyl-3-yl) -3- is obtained. . { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (3'-fluorobiphenyl-4-yl) -propionate hydrochloride, 3- (3'-fluoro-biphenyl-4-yl) -3- is obtained. . { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (2'-fluorobiphenyl-4-yl) -propionate hydrochloride, 3- (2'-fluoro-biphenyl-4-yl) -3- is obtained. . { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (1-chlorobiphenyl-4-yl) -propionate hydrochloride, 3- (4'-chloro-biphenyl-4-yl) -3- is obtained. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (3'-chlorobiphenyl-4-yl) -propionate hydrochloride, 3- (3'-chloro-biphenyl-4-yl) -3- is obtained. . { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4'-methyl-biphenyl-4-yl) -propionate hydrochloride, 3- (4'-methyl-biphenyl-4-yl) - 3-. { 2- [5- (pyridin-2-ylamido-no) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3 - [(4'-trifluoromethyl) -biphenyl-4-yl] -propionate hydrochloride, 3- [(4'-trifluoromethyl) -biphenyl-4 is obtained -il] -3-. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (3'-chloro-4'-fluoro-biphenyl-4-yl) -propionate hydrochloride, 3- (3'-chloro-4 'is obtained -fluoro-biphenyl-4-yl) -3-. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4-naphthalen-1-yl-phenyl) -propionate hydrochloride, 3- (4-naphthalene-1-yl-phenyl) -3- is obtained. . { 2- [5- (pyridin-2-ylamido-no) pentanoylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4-naphthalen-2-yl-phenyl) -propionate hydrochloride, 3- (4-naphthalen-2-yl-phenyl) -3- is obtained. . { 2- [5- (pyridin-2-yla-mino) pentanoylamino] -acetylamino} -Methyl propionate or with methyl 3- (2-amino-acetylamino) -3- (4'-fluoro-2-hydroxy-biphenyl-4-yl) -propionate hydrochloride, 3- (4'-fluoro-2-hydroxy) is obtained -biphenyl-4-yl) -3-. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -Methyl propionate.

Example 19 After saponification of the methyl esters of the compounds of Example 18 in a manner analogous to that described in example 2 (5), the 3- (3-nitro-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (3-nitro-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (3-nitro-phenyl) -3- acid trifluoroacetate. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; RT * 16.07 min, FAB-MS (M + H) * 444; the 3- (4-chloro-3-nitro-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4-chloro-3-nitro-phenyl) -3- acid. { -2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (4-chloro-3-nitro-phenyl) -3- trifluoroacetate. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; RT * 18.67 min, FAB-MS (M + H) 4 478; 3- (4'-Fluoro-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4'-fluoro-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (4 '-fluoro-biphenyl-4-? l) -3- acid trifluoroacetate. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; RT 24.66 min, FAB-MS (M + H) * 493; 3- (4'-Fluoro-biphenyl-3-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- ('-fluoro-biphenyl-3-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (4'-Fluoro-biphenyl-3-yl) -3- acid trifluoroacetate. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; RT 25.36 min, FAB-MS (M + H) 4"493; 3- (3'-Fluoro-biphenyl-4-yl) -3- (2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic acid, the sodium salt of 3- ( 3 '-fluoro-biphenyl-4-yl) -3- { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino}. -propionic acid trifluoroacetate 3- (3' - fluoro-biphenyl-4-yl) -3- { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino}. -propionic; FAB-MS (M + H) * 493; 3- (2'-Fluoro-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (2'-fluoro-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (2'-Fluoro-biphenyl-4-yl) -3- acid trifluoroacetate. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; FAB-MS (M + H) "493; 3- (4'-chloro-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4'-chloro-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (4'-chloro-biphenyl-4-yl) -3- acid trifluoroacetate. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; FAB-MS (M + H) * 510; 3- (3'-chloro-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (3'-chloro-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (3'-chloro-biphenyl-4-yl) -3- acid trifluoroacetate. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; FAB-MS (M + H) 4 510; 3- (4 '-methyl-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4 '-methyl-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionized; 3- (4 '-methyl-biphenyl-4-yl) -3- acid trifluoroacetate. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; FAB-MS (M + H) * 489; 3- [(4'-trifluoromethyl) -biphenyl-4-yl] -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- [(4'-trifluoromethyl) -biphenyl-4-yl] -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- [(4'-trifluoromethyl) -biphenyl-4-yl] -3- (2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino] -propionic acid trifluoroacetate; FAB-MS ( M + H) * 543; 3- (3'-chloro-4'-fluoro-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (3'-chloro-4 '-fluoro-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (3'-chloro-4 '-fluoro-biphenyl-4-yl) -3- acid trifluoroacetate. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylaminoj-propionic; FAB-MS (M + H) + 527; 3- (naphthalen-1-yl-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4-naphthalen-1-yl-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (4-naphthalen-1-yl-phenyl) -3- (2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic acid trifluoroacetate; RT * 24.91 min. , FAB-MS (M + H) + 525; 3- (4-naphthalen-2-yl-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4-naphthalen-2-yl-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (4-naphthalen-2-yl-phenyl) -3- acid trifluoroacetate. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic or 3- (4'-fluoro-2-hydroxy-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic; the sodium salt of 3- (4'-fluoro-2-hydroxy-biphenyl-4-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; 3- (4'-Fluoro-2-hydroxy-biphenyl-4-yl) -3- acid trifluoroacetate. { 2- [5- (pyridin-2-ylamino) pentanoylamino] -acetylamino} -propionic EXAMPLE 20 Proceeding in a manner analogous to that described in example 2 and by reaction of 4- (pyridin-2-ylamino) -butyric acid "CD" with methyl 3- (2-amino-acetylamino) -3- (3-nitro-phenyl) -propionate hydrochloride, 3- (3-nitro-phenyl) -3- is obtained. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4-chloro-3-nitro-phenyl) -propionate hydrochloride, 3- (4-chloro-3-nitro-phenyl) -3- is obtained. . { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4'-fluoro-biphenyl-4-yl) -propionate hydrochloride, 3- (4'-fluoro-bipheni-4-yl) - 3- . { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamine) -3- (4'-fluorobiphenyl-3-yl) -propionate hydrochloride, 3- (4'-fluoro-biphenyl-3-yl) - 3-. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} methyl-propionate; with the 3- (2-amino-acetylamino) -3- (4-naphthalen-1-yl-phenyl) -propionate hydrochloride, 3- (4-naphthalen-1-yl-phenyl) -3- is obtained. . { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylaminoj-methyl propionate; with the 3- (2-amino-acetylamino) -3- (2-hydroxy-4-naphthalen-1-yl-phenyl) -propionate hydrochloride, 3- (4-naphthalene-1-yl-2 is obtained -hydroxy-phenyl) -3-. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -Methyl propionate or with methyl 3- (2-amino-acetylamino) -3- (2-hydroxy-biphen-l-4-yl) -propionate hydrochloride, 3- (2-hydroxy-biphenyl-4-yl) - 3-. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -Methyl propionate.

Example 21 After saponifying the methyl esters of the compounds of Example 20 in a manner analogous to that described in example 2 (5), the 3- (3-nitro-phenyl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (3-nitro-phenyl) -3- acid. { 2- [- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (3-nitro-phenyl) -3- acid trifluoroacetate. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; RT * 15.50 min, FAB-MS (M + H) + 430; the 3- (4-chloro-3-nitro-phenyl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (4-chloro-3-nitro-phenyl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (4-chloro-3-nitro-phenyl) -3- acid trifluoroacetate. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; RT * 18.31 min, FAB-MS (M + H) * 464; 3- (4'-Fluoro-biphenyl-4-yl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (4'-fluoro-biphenyl-4-yl) -3- (2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino] -propionic acid; 3- ('-fluoro-biphenyl-4-yl) -3- acid trifluoroacetate. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; RT 24.53 min, FAB-MS (M + H) * 479; 3- (4'-Fluoro-biphenyl-3-yl) -3- (2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino] -propionic acid; (4 '-fluoro-biphenyl-3-yl) -3- { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic acid trifluoroacetate 3- (4') -fluoro-biphenyl-3-yl) -3- { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic acid, RT 25.06 min, FAB-MS (M + H) * 479; 3- (4-naphthalen-1-yl-phenyl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (4-naphthalen-1-yl-phenyl) -3- acid. { 2- [- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (4-naphthalen-1-yl-phenyl) -3- trifluoroacetate. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; RT * 24.80 min., FAB-MS (M + H) * 511; 3- (4-naphthalen-1-yl-2-hydroxy-phenyl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (4-naphthalen-1-yl-2-hydroxy-phenyl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (4-naphthalen-1-yl-2-hydroxyphenyl) -3- acid trifluoroacetate. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic or the 3- (2-hydroxy-biphenyl-4-yl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (2-hydroxy-biphenyl-4-yl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (2-hydroxy-biphenyl-4-yl) -3- acid trifluoroacetate. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic Example 22 Proceeding analogously to that described in example 2 and by reaction of 4- (4-methyl-pyridin-2-ylamino) -butyric acid "AB" 3- (2- [4- (4-Methyl-pyridin-2-ylamino) - is obtained with methyl 3- (2-amino-acetylamino) -3- (4-nitro-phenyl) -propionate hydrochloride. butyrylamino] -acetylamino.} - .3- (4-nitro-phenyl) -propionate methyl; with methyl 3- (2-amino-acetylamino) -3- (3-nitro-2-hydroxy-phenyl) -propionate hydrochloride, 3- is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-2-hydroxy-phenyl) -propionate methyl; with methyl 3- (2-amino-acetylamino) -3- (4-chloro-3-nitro-phenyl) -propionate hydrochloride, 3- is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-chloro-3-nitro-phenyl) -propionate methyl; with methyl 3- (2-amino-acetylamino) -3- (4'-fluorobiphenyl-3-yl) -propionate hydrochloride, 3- (4'-fluoro-biphenyl-3-yl) -3- is obtained. . { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4'-fluorobiphenyl-4-yl) -propionate hydrochloride, 3- (4'-fluoro-biphenyl-4-? l) -3 is obtained. -. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4-naphthalen-1-yl-phenyl) -propionate hydrochloride, 3- is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} - Methyl (4-naphthalen-1-yl-phenyl) -propionate; with the 3- (2-amino-acetylamino) -3- (4-naphthalen-l-yl-2-hydroxy-phenyl) -propionate hydrochloride, the 3- is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-naphthalen-1-yl-2-hydroxy-phenyl) -propionate methyl; with the 3- (2-amino-acetylamino) -3- (5-bromo-2-hydroxy-3-nitro-phenyl) -propionate methyl chloride, 3- is obtained. { 2- [4- (4-methy1-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (Methyl 5-bromo-2-hydroxy-3-nitro-phenyl) -propionate; with methyl 3- (2-amino-acetylamino) -3- (4-naphthalen-2-yl-phenyl) -propionate hydrochloride, 3- is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} - Methyl (4-naphthalen-2-yl-phenyl) -propionate; with methyl 3- (2-amino-acetylamino) -3- (4'-fluoro-2'-hydroxy-biphenyl-4-yl) -propionate hydrochloride, 3- (4'-fluoro-2 'is obtained -hydroxy-biphenyl-4-yl) -3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} methyl-propionate; with methyl 3- (2-amino-acetylamino) -3- (4'-fluoro-2'-hydroxy-biphenyl-3-yl) -propionate hydrochloride, 3- (4'-fluoro-2 'is obtained -hydrox? -biphenyl-3-? l) -3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -Methyl propionate or with methyl 3- (2-amino-acetylamino) -3- (2-hydroxy-biphenyl-4-yl) -propionate hydrochloride, 3- (2-hydroxy-biphenyl-4-yl) -3- is obtained. . { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -Methyl propionate.

Example 23 After saponifying the methyl esters of the compounds of Example 22 in a manner analogous to that described in example 2 (5), 3- (2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-nitro-phenyl) -propionic acid, the sodium salt of 3- acid {2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-nitro-phenyl) -propionic acid trifluoroacetate 3- (2- [4 - (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino.} - 3 - (4-nitro-phenyl) -. propionic; 3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-2-hydroxy-phenyl) -propionic; the sodium salt of acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-2-hydroxy-phenyl) -propionic; 3- trifluoroacetate. { 2- [- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-2-hydroxy-phenyl) -propionic; 3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-chloro-3-nitro-phenyl) -propionic; the sodium salt of acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-chloro-3-nitro-phenyl) -propionic; 3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-chloro-3-nitro-phenyl) -propionic, RT 21.44 min, FAB-MS (M + H) * 478; 3- (4'-Fluoro-biphenyl-3-yl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (4'-fluoro-biphenyl-3-yl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- ('-fluoro-biphenyl-3-yl) -3- acid trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; RT 26.32 min, FAB-MS (M + H) * 493; 3- (4'-Fluoro-biphenyl-4-yl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (4'-fluoro-biphenyl-4-yl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (4'-Fluoro-biphenyl-4-yl) -3- (2- [4- (4-methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic acid trifluoroacetate; 3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-naphthalen-1-yl-phenyl) -propionic; the sodium salt of acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (-naphthalen-1-yl-phenyl) -propionic; 3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-naphthalen-1-yl-phenyl) -propionic, RT * 25.44 min, FAB-MS (M + H) * 525; 3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-naphthalen-1-yl-2-hydroxy-phenyl) -propionic acid; the sodium salt of acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-naphthalen-1-yl-2-hydroxy-phenyl) -propionic acid; 3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-naphthalene-l-yl-2-hydroxy-phenyl) -propionic; 3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (5-bromo-2-hydroxy-3-nitro-phenyl) -propionic; the sodium salt of 3- (2- [4- (4-methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino] -3- (5-bromo-2-hydroxy-3-nitro-phenyl) acid -propionic, the trifluoroacetate of 3- {2- [4- (-methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (5-bromo-2-hydroxy-3-nitro) phenyl) -propionic; 3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-naphthalen-2-yl-phenyl) -propionic; the sodium salt of acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-naphthalen-2-yl-phenyl) -propionic; 3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-naphthalen-2-yl-phenyl) -propionic; 3- (4'-Fluoro-2'-hydroxy-biphenyl-4-yl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (4 '-fluoro-2' -hydroxy-biphenyl-4-yl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (4 '-Fluoro-2' -hydroxy-biphenyl-4-yl) -3- acid trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (4'-Fluoro-2'-hydroxy-biphenyl-3-yl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (4 '-fluoro-2' -hydroxy-biphenyl-3-yl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (4 '-Fluoro-2' -hydroxy-biphenyl-3-yl) -3- acid trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic or the 3- (2-hydroxy-biphenyl-3-yl) -3- acid. { 2- [- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; the sodium salt of 3- (2-hydroxy-biphenyl-3-yl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; 3- (2-hydroxy-biphenyl-3-yl) -3- acid trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyryl] -acetylamino} -propionic Example 24 1. Hydrochlorides 1 mmol of 3- (3-nitro-phenyl) -3- trifluoroacetate is dissolved. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic of example 6 in 10 ml of water and 0.1% HCl solution is added dropwise. The solution is lyophilized. The procedure is repeated several times. The 3- (3-nitro-phenyl) -3- acid hydrochloride is obtained. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, RT * 17.53 min., FAB-MS (M + H) + 458.

By analogous reaction of trifluoroacetate of 3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic of example 4 gives the hydrochloride of 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic, RT 15.13 min., FAB-MS (M + H) * 444. 2. 2vtitterio-.es According to the corresponding addition of sodium hydroxide, carried out analogously to that described in example 2 (5), Zwitterion can also precipitate. The Zwitterion corresponding to 3- (3-nitro-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic responds to the following analytical data: RT * 17.53 min., FAB-MS (M + H) * 458, p.f. 221-222 °. The Zwitterion corresponding to the acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic responds to the following analytical data: RT * 17.01 min., FAB-MS (M + H) * 444, p.f. 212-213 °. 3. Methanesulfonate 1 mmol of 3- (3-nitro-phenyl) -3- trifluoroacetate is dissolved. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic of example 6 in 10 ml of water and methanesulfonic acid is added dropwise. The solution is lyophilized. The methanesulfonate of 3- (3-nitro-phenyl) -3- acid is obtained. { 2- [5- (4-Methyl-pyr? Din-2-ylamino) -pentanoylamino] -acetylamino} -propionic By analogous reaction of trifluoroacetate of 3- acid. { 2- [4- (4-Methyl-pyridm-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic of example 4 gives the methanesulfonate of 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic, RT * 17.07 min., FAB-MS (M + H) * 444.

Example 25 (1) For 8 hours, 0.06 mol of 3-nitro-benzaldehyde, 5.72 g of malonic acid, 8.5 g of ammonium acetate and 40 ml of ethanol are heated to reflux and the mixture is stirred for overnight at room temperature. After cooling, the reaction mixture is filtered with suction, washed with ethanol and ether and allowed to air dry. 3-Amino-3- (3-nitro-phenyl) -propionic acid is obtained.

The N-acylation is then carried out with phenylacetyl chloride under standard conditions and 3- (3-nitro-phenyl) -3-phenylacetylamino-propionic acid is obtained. This racemate is dissolved in 40 ml of water and the pH of the solution is adjusted to 7.5 with potassium hydroxide. The ezima penicillin amidase is added and vigorously shaken for 3 days. After separating the enzyme by filtration and working the reaction mixture in a usual manner, the (R) -3-amino-3- (3-nitro-phenyl) -propionic acid and the (S) -3- (3 -nitro-phenyl) -3-phenylacetylamino-propionic acid. By proceeding analogously to example 2, (R) -3-amino-3- (3-nitro-phenyl) -propionic acid is esterified by activation with thionyl chloride and reaction with methanol under standard conditions, thus obtaining 3-amino -3- (3-nitro-phenyl) -propionate methyl, which is reacted with BOC-Gli-OH and with 4- (4-methyl-pyridin-2-ylamino) -butyric acid. After cleaving the ester, the acid (R) -3- is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic. If you work with an excess of NaOH, you get the sodium salt of (R) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic. By means of HPLC on a preparative scale, the trifluoroacetate of (R) -3- acid is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-Nitro-phenyl) -propionic, RT * 16.89 min., FAB-MS (M + H) * 444.

The (S) -3- (3-nitro-phenyl) -3-phenylacetylamino-propionic acid is treated with 10 ml of 6N HCl solution. The (S) -3-amino-3- (3-nitro-phenyl) -propionic acid obtained is obtained in a manner analogous to that of the (R) -enantiomer. The (S) -3- acid is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic acid, the sodium salt of (S) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenol) -propionic, the trifluoroacetate of (S) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionic, RT * 16.89 min., FAB-MS (M + H) * 444.

Example 26: Pre-drugs 1. Esterifying the acid 3- (4-chloro-3-nitro-phenyl) -3-. { 2- [5- (4-Methyl-pyridm-2-ylamino) -pentanoylamino] -acetylamino} -propionic by activation with thionyl chloride and reaction with ethanol under standard conditions, the 3- (4-chloro-3-nitro-phenyl) -3- hydrochloride is obtained. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -ethyl propionate, RT 27.95, FAB-MS (M + H) "520. By analogous esterification and subsequent analysis by preparative scale HPLC of 3- (4-chloro-3-nitro-phenyl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino '} -propionic is obtained 3- (4-chloro-3-nitro-phenyl) -3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} Ethylpropionate, RT 27.57, FAB-MS (M + H) * 506; of 3- (4-chloro-3-nitro-phenyl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic is obtained trifluoroacetato of ethyl 3- (4-chloro-3-nitro-phenyl) -3- (2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino]. -propionate, RT * 15.29, FAB-MS (M + H) * 492; of the (R) -3- (3-nitro-phenyl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic is obtained the trifluoroacetate of (R) -3- (3-nitro-phenyl) -3-. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} Ethylpropionate, RT * 20.61, FAB-MS (M + H) * 472; of the (S) -3- (3-nitro-phenyl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic is obtained the trifluoroacetato of (S) -3- (3-nitro-phenyl) -3-. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} Ethylpropionate, RT * 20.61, FAB-MS (M + H) * 472; of 3- (4-chloro-3-nitro-phenyl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic is obtained 3- (4-chloro-3-nitro-phenyl) -3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} Ethylpropionate, RT * 20.77, FAB-MS (M + H) * 472 or of 3- ('-fluoro-biphenyl-3-yl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic is obtained 3- (4 '-fluoro-biphenyl-3-yl) -3- trifluoroacetate. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} Ethylpropionate, RT 30.26, FAB-MS (M + H) * 521. 2. Esterifying the 3- (3-nitro-phenyl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic by activation with thionyl chloride and reaction with terbutanol under standard conditions and after analysis by HPLC on a preparative scale, the trifluoroacetate of 3- (3-nitro-phenyl) -3- is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -Terbutylpropionate, RT 27.20, FAB-MS (M + H) * 500. By analogous esterification with propanol, 3- (3-nitro-phenyl) -3- trifluoroacetate is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} propylpropionate, RT * 22.24, FAB-MS (M + H) t 486; with isopropanol, 3- (3-nitro-phenyl) -3- trifluoroacetate is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionate isopropyl, RT * 22.03, FAB-MS (M + H) * 486 or with butanol, 3- (3-nitro-phenyl) -3- trifluoroacetate is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -butylpropionate, RT * 24.00, FAB-MS (M + H) "500. 3. By reaction of 3- (3-nitro-phenyl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic with chloromethyl 2, 2-dimethylpropionate under standard conditions and by subsequent HPLC analysis on a preparative scale, the trifluoroacetate of 2, 2-dimethyl-propionate of 3- is obtained. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionyloxymethyl, RT 69.68, FAB-MS (M + H) * 558. 4. By reaction of 3- (3-nitro-phenyl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic with diethylene glycol under standard conditions and after preparative HPLC, 3- trifluoroacetate is obtained. { 2- [4- (4-methy1-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-nitro-phenyl) -propionate glycol.

. By reaction of 3- (3-nitro-phenyl) -3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic with benzyl alcohol under standard conditions and after preparative HPLC, 3- (2- [4- (4-methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino trifluoroacetate is obtained. -3- Benzyl (3-nitro-phenyl) -propionate.

Example 27: Assays Angiogenic blood vessels exhibit avß3 integrin in a conspicuous manner and, therefore, can be localized voluntarily by means of avß3-specific inhibitors. With the help of an analysis process, cell lines could be identified that could be obtained from human tumors that had the avß6 integrin, but not the avß3 integirna, for example Detroit 562, HT-29 and UCLA-P3, or that They had both avß3 and avßd integrins, for example Calu-3 and Capan 2. (Analysis method: immunoprecipitation and fluorescence-activated cell sortin analysis) These identified cell lines grow in immunodeficient rodents (for example, in mice nu / nu) as subcutaneous tumors.

As described above, avß3 integrin receptor inhibitors block tumor growth such that blood vessels growing into the tumor are exposed to apoptotic signals and die due to programmed cell death (apoptosis).

(Lit: P.C. Brooks, Eur. J. Cancer 1996, 32A, pp. 2423-2429, P.C. Brooks et al., Cell 1994, 79, p. 1157-1164 or S.

Stomblad et al., J. Clin. Invest. 1996, 98 pages. 426-433).

Inhibitors of aβ6 integrin directly affect tumor development. The synergistic effect of the combination therapy of the invention is documented through the sequence of tests indicated below and which is similar to the test systems of Mitjans et al, J. Cell. Sci. 1995, 108, p. 2825-2838: Tumor cells expressing the aße are implanted subcutaneously in, for example, nu / nu mice. In the same way as with the M21 cell line of Mitjans et al. The growth of these tumor cells in mice and their dependence on integrin inhibitors is observed. After implanting the tumor cells, the mice are separated, prepared in the manner described above, and divided into groups of 10 mice each. According to the invention, the mice are treated daily with the corresponding integrin inhibitors, which are administered by an intraperitoneal injection, and the growth of the tumors is observed. The control group receives injections of sterile and pyrogen-free saline solution. The size of the tumor is measured twice a week and the corresponding volume of the tumor is calculated.

The following examples relate to pharmaceutical compositions.

Example A: vials for injections The pH of a solution of 100 g of an active substance of formula I and 5 g of disodium hydrogen phosphate in 3 1 of bidistilled water is adjusted to 6.5 with 2N hydrochloric acid, then filtered in sterile conditions, this solution is introduced into the bottles, lyophilized and finally the bottles are closed in sterile conditions.

Each bottle for injection contains 5 mg of the active substance. Example B: suppositories A mixture composed of 20 g of an active substance of formula I, 100 g of soy lecithin and 1400 g of cocoa butter, pour the melt into the molds and let it cool. Each suppository contains 20 mg of active substance. Example C: solution A solution is prepared with 1 g of active substance of formula I, 9.38 g of NaH2P04 x 2 H20, 28.48 g of Na2HP04 x 12 H20, 0.1 g of benzalkonium chloride and 940 ml of bidistilled water. The pH is adjusted to 6.8, brought to a volume of 1 1 and sterilized by irradiation. This solution can be used in the form of eye drops. Example D: ointment Under aseptic conditions 500 mg of an active substance of formula I are mixed with 99, 5 g of Vaseline. Example E: Tablets A mixture composed of 1 kg of an active substance of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablet form, such that each tablet contains 10 mg of the active substance. Example F: Dragees The tablets are formed analogously to that described in Example E and then coated in the usual manner with a bath of sucrose, potato starch, talc, tragacanth and dye. Example G: capsules With 2 kg of an active substance of formula I, hard gelatine capsules are filled, so that each capsule contains 20 mg of the active substance. Example H: ampoules A solution of 1 kg of an active substance of formula I in 60 1 of bidistilled water is filtered under sterile conditions. The ampoules are filled with this solution and then lyophilized and closed under sterile conditions. Each ampoule contains 10 mg of the active substance. Example I: aerosol inhalant solution 14 g of an active substance of formula I are dissolved in 10 1 of isotonic NaCl solution. With this solution, commercial containers that have a vaporizing mechanism are filled. The solution can be inhaled through the mouth or nose. Each spray (approximately 0.1 ml) corresponds to a dose of approx. 0.14 mg.

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.

Claims

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

1. Compounds of formula I characterized because Q or Q4 independently represent CH or N, R1 represents H, A, Ar, Hal, OH, OA, CF3 or OCF3, R¿ represents H or A, R "represents R4 and R5 represents' independently H, A, Hal, OH, OA, CF3, OCF3, CN, NH2, NHA, NA? Or NH-C (O) A, R6 represents H, A, - (CH2) rr-OH, - (CHJ m-0-C (O) A or - (CHJm-Ar, A represents alkyl of 1 to 6 carbon atoms, Ar represents unsubstituted or mono, di or trisubstituted aryl, Hal represents F, Cl, Br or I, n is 2, 3, 4, 5 or 6, m is 1, 2, 3 or 4, and their salts acceptable from the physiological point of view and their solvates.

2. - Compounds according to claim 1, (a) 3- (methyl-3-nitro-phenyl) -3- acid. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic, (b) 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, (c) 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, (d) 3- (2-nitro-phenyl) -3- acid. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, (e) acid 3-. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (2-nitro-phenyl) -propionic, (f) 3- (2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (2- nitro-phenyl) -propionic, (g) 3- {2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl)} -propionic, (h) 3- {2- [5- (4-Methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic acid, (i) 3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic, (j) 3- acid. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (biphenyl) -propionic, (k) 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (6-Methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, (1) 3- (4-Chloro-3-nitro-phenyl) -3- acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic or (m) 3- (4-methyl-3-nitro-phenyl) -3- acid. { 2- [5- (pyrimidin-2-ylamino) -pentanoylamino] -acetylamino} -propionic

3. - Process for preparing the compounds of formula I, according to claim 1, and their salts and solvates, characterized in that (a) a compound of formula II is reacted wherein Qi, Q2, Q3, Q,, R1 and n have the meanings indicated in claim 1, with a compound of formula III wherein R, R, R, R and R have the meanings indicated in claim 1, and eventually the remainder R6 is transformed? H in the rest R6 = H, or [b) a compound of formula IV is reacted wherein Qi, Q2, Q3, Q, R, R2 and n have the meanings indicated in claim 1, with a compound of formula V wherein R3, R4, R5 and R6 have the meanings indicated in claim 1, and eventually the radical R ° is transformed? H in the rest R6 = H, or (c) in a compound of formula I one or more residues R1, R2, Rj R4 and / or R5 are transformed into one or several residues R1, R2, R3, R4 and / or RD different, eg, vi) alkylating a hydroxyl group, vii) hydrolyzing an ester group to a carboxyl group, HIV, esterifying a carboxyl group IX by alkylating an amino group xi by acylating an amino group, and / or a basic compound or acid of formula I is converted into one of its salts or into one of its solvates by treatment with an acid or a base.

4. - Compounds of formula I, according to claim 1, and their physiologically acceptable salts or their solvates as drug active substances.

5. - Compounds of formula I, according to claim 1, and their physiologically acceptable salts or their solvates as integrin inhibitors.

6. - Pharmaceutical composition, characterized in that it contains at least one compound of formula I, according to claim 1, and / or one of its salts acceptable from the physiological point of view or one of its solvates.

7. Use of the compounds of formula I, according to claim 1, and / or their physiologically acceptable salts or solvates thereof to prepare a medicament.

8. Use of the compounds of formula I, according to claim 1, and / or of their physiologically acceptable salts or solvates thereof, for preparing a medicament for the control of thrombosis, myocardial infarction, coronary diseases , arteriosclerosis, inflammation, tumors, osteoporosis, infections and restenosis after angioplasty.

9. Use of the compounds of formula I, according to claim 1, and / or of their physiologically acceptable salts or solvates thereof, in the pathological processes that are propagated or maintained by angiogenesis.

10. - Use of the selective integrin inhibitors that are chosen from the group consisting of a) trifluoroacetate of 3- acid. { 2- [5- (4-Methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-chloro-3-nitro-phenyl) -propionic; b) 3- (methyl-3-nitro-phenyl) -3- trifluoroacetate. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; c) 3- (4-methyl-3-nitro-phenyl) -3- (2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino] -propionic acid trifluoroacetate; d) trifluoroacetate acid 3-. { 2- [5- (4-Methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic; e) 3- (biphenyl-4-yl) -3- trifluoroacetate. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; f) 3- acid trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic; g) 3- (3-nitro-phenyl) -3- trifluoroacetate. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; h) 3- acid trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-methyl-3-nitro-phenyl) -propionic; i) 3- (3-nitro-phenyl) -3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic, j) 3- (2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic acid trifluoroacetate; k) 3- acid trifluoroacetate. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic or 1) 3- (3-nitro-phenyl) -3- hydrochloride. { 2- [5- (4-Methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, to prepare a drug designed to combat the pathological processes influenced by the integrins avß3 and / or avß5 and avß6.

11.- Use of selective inhibitors of integrins that are chosen from the group consisting of a) trifluoroacetate of 3-acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-chloro-3-nitro-phenyl) -propionic; b) 3- (4-methyl-3-nitro-phenyl) -3- trifluoroacetate. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; c) 3- (4-methyl-3-nitro-phenyl) -3- trifluoroacetate. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; d) 3- acid trifluoroacetate. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic; e) 3- (biphenyl-4-yl) -3- trifluoroacetate. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; f) 3- acid trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} 3- (3-trifluoromethoxy-phenyl) -propionic; g) 3- (3-nitro-phenyl) -3- (2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic acid trifluoroacetate; h) 3- acid trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-methyl-3-nitro-phenyl) -propionic; i) 3- (3-nitro-phenyl) -3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic, j) 3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic; k) 3- (2- [5- (4-Methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino] -3- (3-trifluoromethoxy-phenyl) -propionic acid trifluoroacetate or 1) hydrochloride of acid 3- (3-nitro-phenyl) -3-. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, to prepare a drug for cancer therapy, by which, on the one hand, the angiogenesis of blood vessels that grow into the tumor is prevented by inhibition of the integrin receptor avß3 and / or the integrin receptor avß5 and, on the other hand, tumor development is prevented by inhibition of the avß6 integrin receptor.

12. - Use of selective inhibitors of the integrin avß3 and / or selective inhibitors of integrin avßs and selective inhibitors of the aβ6 integrin, which are chosen from the group consisting of a) trifluoroacetate of 3-acid. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-chloro-3-nitro-phenyl) -propionic; b) 3- (4-Methyl-3-nitro-phenyl) -3- (2- [5- (-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic acid trifluoroacetate; c) 3- (4-methyl-3-nitro-phenyl) -3- acid trifluoroacetate. { 2- [4- (pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic; d) 3- acid trifluoroacetate. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic; e) 3- (biphenyl-4-yl) -3- trifluoroacetate. { 2- [5- (pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; f) 3- acid trifluoroacetate. { 2- [4- (-methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic; g) 3- (3-nitro-phenyl) -3- trifluoroacetate. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic; h) 3- acid trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-methyl-3-nitro-phenyl) -propionic; i) 3- (3-nitro-phenyl) -3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -propionic, j) 3- trifluoroacetate. { 2- [4- (4-Methyl-pyridin-2-ylamino) -butyrylamino] -acetylamino} -3- (4-trifluoromethoxy-phenyl) -propionic; k) 3- acid trifluoroacetate. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -3- (3-trifluoromethoxy-phenyl) -propionic or 1) 3- (3-nitro-phenyl) -3- hydrochloride. { 2- [5- (4-methyl-pyridin-2-ylamino) -pentanoylamino] -acetylamino} -propionic, to prepare a drug intended to combat diseases associated with cancer such as metastases from solid tumors, angiofibromatosis, retrolental fibroplasia, hemangioma or Kaposi's sarcoma.