AU6263000A - Inhibitors of the integrin alphavbeta6 - Google Patents

Description

WO 01/00660 PCT/EPOO/05404 -1 Inhibitors of the integrin a46 The invention relates to novel peptides of the formula I which, as ligands of the integrin aip 6 , are 5 biologically active Ac-Arg-X -Asp-X2X3 -X -X-X -X NH 2 I in which 10 Ac is acetyl, X1 is Ser, Gly, Thr, Asp, Arg, Val, Tyr, His or Ala, X 2 is Leu, Ile, Nle, Val or Phe, X 3 is Asp, Glu, Lys, Phe, Aib, Nal, Gly, Ala, Bgl or Phg, 15 X 4 is Gly, Ala, Ser, 1-Ala or (o-Abu, X 5 is Leu, Ile, Nle, Val or Phe, X 6 is Arg, Har, Lys, Leu, Orn, Phe, Ala, Tyr, Gly, Ser or Asp, 20 where the amino acids mentioned can also be derivatized, the amino acid residues are linked to one another in peptide fashion via the ax-amino and a-carboxyl groups, the D and the L forms of the optically active amino 25 acid residues are included, and their physiologically acceptable salts, and where Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Arg-NH2 is excluded. 30 The invention is based on the object of finding novel compounds having valuable properties, in particular those which can be used for the production of medicaments. 35 It has been found that the compounds according to the invention and their salts have valuable pharmacological properties together with good tolerability.

- 2 The peptides according to the invention can be employed as efficacious inhibitors of the aO3P 6 integrin receptor and thus for the treatment of various diseases and pathological findings. 5 Other inhibitors of the integrin Ca1P6 are described in DE 19858857 and by S. Kraft et al. in J. Biol. Chem. 274, 1979-85 (1999). The compounds according to the invention are to be considered as a selection invention 10 with respect to the application mentioned. Integrins belong to the family of heterodimers of Class I - transmembrane receptors which play an important role in numerous cell-matrix or cell-cell adhesion 15 processes (Tuckwell et al., 1996, Symp. Soc. Exp. Biol. 47). They can be roughly divided into three classes: the P1 integrins, which are receptors for the extracellular matrix, the $2 integrins, which are activatable on leucocytes and are "triggered" during 20 inflammatory processes, and the av integrins, which influence the cell response during wound-healing and other pathological processes (Marshall and Hart, 1996, Semin. Cancer Biol. 7, 191). 25 The integrins a$ 5 1 , cX11$b3, aL 8 pi, a41, ap 3 , ays 5 , a4 8 and avf 6 all bind to the Arg-Gly-Asp (RGD) peptide sequence in natural ligands, such as, for example, fibronectin or vitronectin. Soluble RGD-containing peptides are able to inhibit the interaction of each of these 30 integrins with the corresponding natural ligands. a4 6 is a relatively rare integrin (Busk et al., 1992 J. Biol. Chem. 267(9), 5790), which is formed to an increased extent in repair processes in epithelial tissue and preferably binds the natural matrix 35 molecules fibronectin and tenascin (Want et al., 1996, Am. J. Respir. Cell Mol. Biol. 15(5), 664). The physiological and pathological functions of a0 6 are still not precisely known; it is suspected, however, that this integrin plays an important role in - 3 physiological processes and disorders (e.g. inflammation, wound healing, tumours) in which epithelial cells are involved. Thus c$ 6 is expressed on keratinocytes in wounds (Haapasalmi et al., 1996, J. 5 Invest. Dermatol. 106(1), 42), from which it is to be assumed that in addition to wound-healing processes and inflammation other pathological skin events, such as, for example, psoriasis, can also be influenced by agonists or antagonists of the said integrin. c$ 6 10 furthermore plays a role in the respiratory tract epithelium (Weinacker et al., 1995, Am. J. Respir. Cell Mol. Biol. 12(5), 547), so that appropriate agonists/antagonists of this integrin could be successfully employed in respiratory tract disorders, 15 such as bronchitis, asthma, pulmonary fibrosis and respiratory tract tumours. Finally, it is known that 0$ 6 also plays a role in the intestinal epithelium, so that appropriate integrin agonists/antagonists could be used in the treatment of inflammation, tumours and 20 wounds of the stomach/intestinal tract. The dependence of the formation of angiogenesis on the interaction between vascular integrins and extra cellular matrix proteins is described by P.C. Brooks, 25 R.A. Clark and D.A. Cheresh in Science 264, 569-71 (1994). The object was therefore, in addition to the previously known natural high molecular weight ligands and 30 antibodies, which are therapeutically and diagnos tically difficult to handle, to find potent, specific and selective low molecular weight ligands for c $P 6 , preferably peptides, which can be used for the therapeutic areas mentioned, but also as diagnostic or 35 reagent. It has been found that the peptide compounds according to the invention and their salts, as soluble molecules, exert an effect on cells which carry the said receptor, - 4 or if they are bound to surfaces, are artificial ligands for 43-mediated cell adhesion. Above all, they act as $36 integrin inhibitors, where they particularly inhibit the interactions of the receptor with other 5 ligands, such as, for example, the binding of fibro nectin. This action can be detected, for example, by the method which is described by J.W. Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990). 10 It has furthermore been found that the novel substances have very valuable pharmacological properties together with good tolerability and can be employed as medicaments. This is described more precisely further below. 15 The peptide compounds according to the invention can furthermore be used in vivo as diagnostics for the detection and localization of pathological conditions in the epithelial system, if they are equipped with 20 appropriate markers (e.g. the biotinyl radical) according to the prior art. The invention also comprises combinations with at least one other active compound and/or conjugates with other active compounds, such as cytotoxic active compounds 25 and conjugates with radiolabels for X-ray therapy or PET diagnosis, but also fusion proteins with marker proteins such as GFP or antibodies, or therapeutic proteins such as IL-2. 30 Some preferred groups of compounds can be expressed by the following subformulae Ia to If, which correspond to the formula I and in which the radicals not designated in greater detail have the meaning indicated in the formula I, but in which 35 in a) X' is Ser, Gly or Thr; in b) X' is Ser, Gly or Thr, X2 is Leu; - 5 in C) X 1 is Ser, Gly or Thr, X2 is Leu, X 3 is Asp or D-Asp; 5 in d) X is Ser, Gly or Thr, X2 is Leu, X 3 is Asp or D-Asp, X 4 is Gly, Ala or Ser; 10 in e) X is Ser, Gly or Thr, X2 is Leu, X 3 is Asp or D-Asp, X 4 is Gly, Ala or Ser, X 5 is Leu; 15 in f) X is Ser, Gly or Thr, X2 is Leu, X 3 is Asp or D-Asp, X 4 is Gly, Ala or Ser, 20 X5 is Leu, X is Arg; and their salts. The invention relates in particular to peptide 25 compounds selected from the group consisting of Ac-Arg-Gly-Asp-Leu-D-Asp-Ser-Leu-Arg-NH 2 , Ac-Arg-Gly-Asp-Leu-Asp-Ser-Leu-Arg-NH 2 , Ac-Arg-Ser-Asp-Leu-Asp-Ser-Leu-Arg-NH 2 , 30 Ac-Arg-Asp-Asp-Leu-Asp-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Ala-NH 2 , Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-D-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-D-Asp-Ser-Leu-Arg-NH 2 , Ac-D-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Arg-NH 2 , 35 Ac-Arg-Thr-Asp-Leu-D-Ala-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-Aib-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-D-Nal-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-Gly-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-Ala-Ser-Leu-Arg-NH 2

,

- 6 Ac-Arg-Thr-Asp-Nle-D-Asp-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Ile-D-Asp-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-Asp-D-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-Asp-Ala-Leu-Arg-NH 2 , 5 Ac-Arg-Thr-Asp-Leu-Asp-Gly-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Har-NH 2 , Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Lys-NH 2 , Ac-Arg-Thr-Asp-Leu-D-Asp-D-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-D-Asp-Ser-Leu-Ala-NH 2 , 10 Ac-Arg-Thr-Asp-Leu-D-Asp-Gly-Leu-Arg-NH 2 , and their physiologically acceptable salts. The abbreviations of amino acid residues mentioned above and below stand for the radicals of the following 15 amino acids: Abu 4-aminobutyric acid Aha 6-aminohexanoic acid, 6-aminocaproic acid Aib a-aminoisobutyric acid 20 Ala alanine Asn asparagine Asp aspartic acid Arg arginine Bgl C-alpha-tert-butylglycine 25 Cys cysteine Dab 2,4-diaminobutyric acid Dap 2,3-diaminopropionic acid Gln glutamine Glp pyroglutamic acid 30 Glu glutamic acid Gly glycine Har homoarginine His histidine homo-Phe homo-phenylalanine 35 Ile isoleucine Leu leucine Lys lysine Met methionine Nal naphth-2-ylalanine -7 Nle norleucine Orn ornithine Phe phenylalanine Phg phenylglycine 5 4-Hal-Phe 4-halophenylalanine Pro proline Ser serine Thr threonine Trp tryptophan 10 Tyr tyrosine Val valine. In addition, the following have the meanings below: 15 Ac acetyl BOC tert-butoxycarbonyl BSA bovine serum albumin CBZ or Z benzyloxycarbonyl DCCl dicyclohexylcarbodiimide 20 DMF dimethylformamide EDCl N-ethyl-N,N' - (dimethylaminopropyl) carbodiimide Et ethyl FCA fluoresceincarboxylic acid 25 FITC fluorescein isothiocyanate Fmoc 9-fluorenylmethoxycarbonyl FTH fluoresceinthiourea HOBt 1-hydroxybenzotriazole Me methyl 30 MBHA 4-methylbenzhydrylamine Mtr 4-methoxy-2, 3, 6-trimethylphenylsulfonyl HONSu N-hydroxysuccinimide OBut tert-butyl ester Oct octanoyl 35 OMe methyl ester OEt ethyl ester Pbf 2,2,4,6, 7-pentamethyldihydrobenzofuran-5 sulfonyl Pmc 2,2,5,7, 8-pentamethylchroman-6-sulfonyl - 8 POA phenoxyacetyl Sal salicyloyl TBS++ tris buffered saline with divalent cations TBSA TBS + BSA 5 TBTU 2-(1H-benzotriazol-1-yl)-1,1,3 tetramethyluronium tetrafluoroborate TFA trifluoroacetic acid Trt trityl (triphenylmethyl). 10 If the abovementioned amino acids can occur in two or more enantiomeric forms, all these forms and their mixtures (for example the DL forms) are included above and below. In addition, the amino acids can be provided with appropriate protective groups which are known per 15 se. So-called prodrug derivatives are included in the compounds according to the invention, that is compounds modified with, for example, alkyl or acyl groups, 20 sugars or oligopeptides, which are cleaved rapidly in the body to give the active compounds according to the invention. These also include biodegradable polymer derivatives of the compounds according to the invention, as is described, for example, in Int. J. 25 Pharm. 115, 61-67 (1995). The amino acids and amino acid residues mentioned, such as, for example, the NH functions or alternatively the C-terminal amide function, can also be derivatized, the 30 N-methyl, N-ethyl, N-propyl, N-benzyl or Ca-methyl derivatives being preferred. Derivatives which are additionally preferred are those of Asp and Glu, in particular the methyl, ethyl, propyl, butyl, tert butyl, neopentyl or benzyl esters of the side chain 35 carboxyl groups, and in addition also derivatives of Arg, which can be substituted on the -NH-C(=NH)-NH 2 group by an acetyl, benzoyl, methoxycarbonyl or ethoxycarbonyl radical.

- 9 In the compounds according to the invention, in addition to the compounds of the formula I which carry an acetyl group N-terminally, those compounds are also included in which Ac is replaced by another acyl 5 function, such as, for example, propionyl, butyryl or alternatively benzoyl. Furthermore, derivatives additionally included in the compounds according to the invention are those which 10 consist of the actual peptides according to the invention and known marker compounds which make it possible to detect the peptides easily. Examples of such derivatives are radiolabelled, biotinylated or fluorescence-labelled peptides. 15 A fluorescent dye radical is preferably 7-acetoxy coumarin-3-yl, fluorescein-5- (and/or 6-)yl, 2' ,7 dichlorofluorescein-5- (and 6-)yl, dihydrotetramethyl rosamin-4-yl, tetramethylrhodamin-5- (and 6-)yl, 4,4 20 difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3 ethyl or 4,4-difluoro-5,7-diphenyl-4-bora-3a,4a-diaza s-indacene-3-ethyl. Suitable functionalized fluorescent dye radicals which 25 can serve as reagents for the preparation of the compounds of the formula I according to the invention are described, for example, in "Handbook of Fluorescent Probes and Research Chemicals, 5 th Edition, 1992-1994, by R.P. Haughland, Molecular Probes, Inc.". 30 In general, the peptides according to the invention are linear, but they can also be cyclized [sic]. The invention comprises not only the peptides mentioned but also mixtures and preparations which, in addition to 35 these compounds according to the invention, also contain other pharmacological active compounds or adjuvants which can desirably influence the primary pharmacological action of the peptides according to the invention.

- 10 The compounds according to the invention and also the starting substances for their preparation are otherwise prepared by methods which are known per se and frequently employed, such as are described in the 5 literature (e.g. in the standard works such as Houben Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Georg-Thieme Verlag, Stuttgart) namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be 10 made in this case of variants which are known per se. Preferably, the peptides according to the invention can be prepared by means of solid-phase synthesis and subsequent removal and purification, as was described, 15 for example, by Jonczyk und Meienhofer (Peptides, Proc. 8 th Am. Pept. Symp., Eds. V. Hruby and D.H. Rich, Pierce Comp. III, pp. 73-77, 1983, or Angew. Chem. 104, 1992, 375) or according to Merrifield (J. Am. Chem. Soc. 94, 1972, 3102). 20 The peptides according to the invention can be prepared on a solid phase (manually or in an automated synthesizer) in an Fmoc strategy using acid-labile side protective groups and purified by means of RP-HPLC. The peak homogeneity can be measured by RP-HPLC and the 25 substance identity by means of FAB-MS. Otherwise, the peptides can be prepared by customary methods of amino acid and peptide synthesis, such as is known, for example, from Novabiochem - 1999 Catalog & 30 Peptide Synthesis Handbook of Calbiochem-Novabiochem GmbH, D-65796 Bad Soden, from numerous standard works and published patent applications. Stepwise couplings and fragment condensations can be utilized. Different N-terminal, C-terminal and side 35 protection groups can be used, which are preferably selected to be orthogonally cleavable. Coupling steps can be carried out using different condensing reagents such as carbodiimides, carbodiimidazole, those of the uronium type such as TBTU, mixed anhydride methods, and - 11 acid halide or active ester methods. Activated esters are expediently formed in situ, for example by addition of HOBt or N-hydroxysuccinimide. A cyclization of a linear precursor molecule having 5 side protective groups can likewise be carried out using such condensation reactions, as is described, for example, in DE 43 10 643 or in Houben-Weyl, l.c., Volume 15/11, pages 1 to 806 (1974). 10 Different resins and anchor functions can be utilized in the solid-phase peptide synthesis. Resins can be based, for example, on polystyrene or polyacrylamide, anchor functions such as Wang, o-chlorotrityl are utilizable for the preparation of peptide acids, 15 aminoxanthenoxy anchors, for example for the preparation of paptide [sic] amides. Biotinylated or fluorescence-labelled peptides/proteins can likewise be prepared by standard methods. (for 20 example E.A. Bayer and M. Wilchek in Methods of Biochemical Analysis Vol. 26 The Use of the Avidin Biotin Complex as a Tool in Molecular Biology; and Handbook of Fluorescent Probes and Research Chemicals, 6 t Edition, 1996, by R.P. Haugland, Molecular Probes, 25 Inc.; or alternatively WO 97/14716) Of course, the peptides according to the invention can also be liberated by solvolysis, in particular hydrolysis, or by hydrogenolysis of their functional 30 derivatives. Preferred starting substances for the solvolysis or hydrogenolysis are those which, instead of one or more free amino and/or hydroxyl groups, contain corresponding protected amino and/or hydroxyl groups, preferably those which, instead of an H atom 35 which is connected to an N atom, carry an amino protective group or which, instead of the H atom of a hydroxyl group, carry a hydroxyl protective group. The same applies to carboxylic acids which can be protected - 12 by substitution of their -CO-OH hydroxyl function by means of a protective group, for example as an ester. The expression "amino protective group" is generally 5 known and relates to groups which are suitable for protecting (or blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the molecule. The expression "hydroxyl 10 protective group" is likewise generally known and relates to groups which are suitable for protecting a hydroxyl group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other positions in the 15 molecule. The liberation of the compounds from their functional derivatives takes place - depending on the protective group utilized - for example using strong acids, expediently using TFA or perchloric acid, but also using other strong inorganic acids such as 20 hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluenesulfonic acid. Hydrogenolytically removable protective groups (for example CBZ or benzyl) can be removed, for 25 example, by treating with hydrogen in the presence of a catalyst (for example of a noble metal catalyst such as palladium, expediently on a support such as carbon). Typical protective groups for N termini and for side 30 position amino groups are Z, BOC, Fmoc, those for C termini or the Asp or Glu side chains are 0-prim-alkyl (for example OMe or OEt), 0-tert-alkyl (for example OBut) or Obenzyl. Z, BOC, NO 2 , Mtr, Pmc or Pbf, for example, is suitable for the guanidino function of the 35 Arg. Alcoholic functions can be protected by tert-alkyl radicals or trityl groups. The groups BOC, OBut and Mtr can preferably be removed, for example, using TFA in dichloromethane or using - 13 approximately 3 to 5 N HCl in dioxane at 15-300, the Fmoc group using an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15 30O. 5 The trityl group is employed, for example, for the protection of the amino acids histidine, asparagine, glutamine and cysteine. Removal is carried out, depending on the desired final product, using TFA/10% 10 thiophenol, the trityl group being removed from all amino acids mentioned, when using TFA/anisole or TFA/thioanisole only the trityl group of His, Asn and Gln is removed, whereas that on the Cys side chain remains. 15 Hydrogenolytically removable protective groups (for example CBZ or benzyl) can be removed, for example, by treating with hydrogen in the presence of a catalyst (for example of a noble metal catalyst such as 20 palladium, expediently on a support such as carbon). Suitable solvents in this case are those indicated above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. As a rule, the hydrogenolysis is carried out at temperatures 25 between approximately 0 and 100O and pressures between approximately 1 and 200 bar, preferably at 20-300 and 1-10 bar. Hydrogenolysis of the CBZ group takes place readily, for example, on 5 to 10% Pd/C in methanol or using ammonium formate (instead of hydrogen) on Pd/C in 30 methanol/DMF at 20-300. As already mentioned, the peptides according to the invention include their physiologically acceptable salts, which can likewise be prepared by standard 35 methods. Thus a base of a compound according to the invention can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent - 14 evaporation. Acids which are suitable for this reaction are in particular those which yield physiologically acceptable salts. Thus inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids 5 such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or hetero cyclic mono- or polybasic carboxylic, sulfonic or 10 sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, 15 nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2 hydroxyethanesulfonic acid, benzenesulfonic acid, p toluenesulfonic acid, naphthalenemono- and -disulfonic acids, laurylsulfuric acid. Salts with physiologically 20 unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds according to the invention. On the other hand, an acid of the compounds according to the invention can be converted into one of its physiologically acceptable 25 metal or ammonium salts by reaction with a base. Possible salts in this case are in particular the sodium, potassium, magnesium, calcium and ammonium salts, furthermore substituted ammonium salts, for example the dimethyl-, diethyl- or diisopropylammonium 30 salts, monoethanol-, diethanol- or diisopropylammonium salts, cyclohexyl- or dicyclohexylammonium salts, dibenzylethylenediammonium salts, furthermore, for example, salts with arginine or lysine. 35 The peptide compounds according to the invention can be employed, as already mentioned, as pharmaceutical active compounds in human and veterinary medicine, in particular for the prophylaxis and/or therapy of disorders in which epithelial cells are involved.

- 15 Particularly to be emphasized in this context are disorders or inflammations or wound-healing processes of the skin, the respiratory tract organs and the stomach and intestinal region, thus, for example, 5 apoplexy, angina pectoris, oncoses, osteolytic diseases such as osteoporosis, pathological angiogenic diseases such as, for example, inflammation, pulmonary fibrosis, opthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid 10 arthritis, osteoarthritis, rubeotic glaucoma, ulcer ative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, in acute kidney failure, nephritis, microbial infections and multiple sclerosis. 15 The invention accordingly relates to peptide compounds of the formulae defined above and below and in the claims including their physiologically acceptable salts as medicaments, diagnostics or reagents. 20 The invention in particular relates to appropriate medicaments as inhibitors for the control of disorders which are indirectly or directly based on expression of the avI 6 integrin receptor, thus in particular in 25 pathological angiogenic disorders, thromboses, cardiac infarct, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, inflammation, infections and for influencing wound-healing processes. 30 The invention also relates to appropriate pharmaceutical preparations, which contain at least one medicament of the formula I and, if appropriate, vehicles and/or excipients. The invention furthermore relates to the use of the 35 peptide compounds and/or their physiologically acceptable salts according to the claims and the description for producing a medicament for the control of disorders which are based indirectly or directly on expression of the O4$6 integrin receptor, thus in - 16 particular in pathological angiogenic disorders, thromboses, cardiac infarct, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, inflammation, infections and for influencing wound-healing processes. 5 The medicaments according to the invention or pharmaceutical preparations comprising them can be used in human or veterinary medicine. Possible vehicles are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral administration, or 10 topical application or for administration in the form of an inhalation spray and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as 15 lactose or starch, magnesium stearate, talc, petroleum jelly. In particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops are used for oral administration, suppositories are used for rectal administration, solutions, preferably 20 oily or aqueous solutions, furthermore suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained can 25 be used, for example, for the production of injection preparations. The preparations indicated can be sterilized and/or can contain excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic 30 pressure, buffer substances, colorants, flavourings and/or one or more further active compounds, e.g. one or more vitamins. For administration as an inhalation spray, sprays can be used which contain the active compound either in 35 dissolved form or suspended in a propellant or propellant mixture (for example CO 2 or fluoro chlorohydrocarbons) . The active compound is expediently used in this case in micronized form, where one or more additional physiologically tolerable solvents can be - 17 present, e.g. ethanol. Inhalation solutions can be administered with the aid of customary inhalers. As a rule, the substances according to the invention 5 can be administered in analogy to other known, commercially available peptides (for example described in US-A-4 472 305), preferably in doses between approximately 0.05 and 500 mg, in particular between 0.5 and 100 mg, per dose unit. The daily dose is 10 preferably between approximately 0.01 and 20 mg/kg of body weight. The specific dose for each patient depends, however, on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health and sex, 15 on the diet, on the time and route of administration, and on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy relates. Parenteral administration is preferred. 20 Furthermore, the novel compounds of the formula I can be used in analytical biology and molecular biology. The novel compounds of the formula I, where X is a fluorescent dye radical linked via a -CONH, -COO, -NH 25 C(=S)-NH, -NH-C(=O)-NH, -SO 2 NH or -NHCO bond, can be used as diagnostic markers in the FACS (Fluorescence Activated Cell Sorter) technique and fluorescence microscopy. 30 The use of labelled compounds in fluorescence microscopy is described, for example, by Y.-L. Wang and D.L. Taylor in "Fluorescence Microscopy of Living Cells in Culture, parts A + B, Academic Press, Inc. 1989". 35 The novel compounds according to the invention can also be used as integrin ligands for the preparation of columns for affinity chromatography for the preparation of integrins in pure form. The complex of an avidin derivatized support material, e.g. Sepharose, and the - 18 novel compounds is formed by methods known per se (for example E.A. Bayer and M. Wilchek in Methods of Biochemical Analysis Vol 26 The Use of the Avidin Biotin Complex as a Tool in Molecular Biology). 5 Suitable polymeric support materials here are the polymeric solid phases having preferably hydrophilic properties and known per se in peptide chemistry, for example crosslinked polysugars such as cellulose, Sepharose or Sephadex@, acrylamides, polymers based on 10 polyethylene glycol or Tentakel polymers. The invention finally also includes recombinant DNA sequences which contain sections which code for peptide regions which have the peptide structural motifs 15 according to the invention. DNA of this type can be transferred to cells by particles, as is described in Ch. Andree et al. Proc. Natl. Acad. Sci. 91, 12188-12192 (1994), or the 20 transfer to cells can be increased by other excipients, such as liposomes (A.I. Aronsohn and J.A. Hughes J. Drug Targeting, 5, 163-169 (1997)) The transfer of a DNA of this type could accordingly be 25 utilized in yeasts, by means of bacculoviruses or in mammalian cells for the production of the peptide substances of this invention. If an animal or human body is infected with a 30 recombinant DNA of this type, the peptides according to the invention finally themselves formed by the infected cells can immediately bind to the Ca4, integrin receptor, for example of tumour cells, and block it. Corresponding recombinant DNA, which can be prepared by 35 known and customary techniques, can, for example, however also be present in the form of virus DNA which contains sections which code for the virus coat protein. By infection of a host organism with recombinant, preferably non-pathogenic viruses of this - 19 type, host cells which express the integrin v46 can preferably be attacked (targeting). Suitable viruses are, for example, adenoviral types 5 which have been used a number of times already as vectors for foreign genes in mammalian cells. A number of properties make them into good candidates for gene therapy, as can be seen from S.J. Watkins et al. Gene Therapy 4, 1004-1012 (1997) (see also J. Engelhardt et 10 al. Hum. Gene Ther. 4, 759-769 (1993)). As can be found in A. Fasbender et al. J. Clin. Invest. 102, 184-193 (1998), a common problem in gene therapy by means of viral and non-viral vectors is the limited efficiency of the gene transfer. Using the additional 15 ligand sequence for OCi6 integrin described above the coat protein of the adenoviruses, an improvement in the transfer, for example, of cystic fibrosis transmembrane conductance regulator (CFTR) cDNA can be achieved. 20 In a manner similar to that in the work of T. Tanaka et al. Cancer Research 58, 3362-3369 (1998), instead of the DNA for angiostatin the DNA for the sequences of this invention can also be utilized for cell transfections by means of retroviral or adenoviral 25 vectors. The peptides according to the invention can also be employed within a liposome complex of lipid/peptide/DNA for a transfection of cell cultures together with a 30 liposome complex consisting of lipid/DNA (without peptide) for use in gene therapy in man. The preparation of a liposome complex from lipid/DNA/peptide is described, for example, in Hart S.L. et al. 1998: Lipid-Mediated Enhancement of 35 Transfection by a Non-Viral Integrin-Targeting Vector. Human Gene Therapy 9, 575-585. A liposome complex of lipid/peptide/DNA can be prepared, for example, from the following stock solutions: 1 pg/pl of lipofectin (equimolar mixture of - 20 DOTMA (= N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethyl ammonium chloride) and DOPE (dioleyl phosphatidyl ethanolamine) ), 10 pLg/ml of plasmid DNA and 100 pg/ml of peptide. For this, both DNA and peptide are 5 dissolved in cell culture medium. The liposome complex is prepared by mixing the three components in a specific weight ratio (lipid : DNA : peptide, for example 0.75:1:4). Liposomal DNA complexes for gene therapy in man have already been described 10 (Caplen N.J. et al. 1995: Liposome-mediated CFTR gene transfer to the nasal epithelium of patients with cystic fibrosis Nature Medicine 1, 39-46). The invention thus also relates to the use of 15 accordingly modified recombinant DNA of gene-releasing systems, in particular virus DNA, for the control of diseases which are based indirectly or directly on expression of av 6 6 integrin receptors, thus in particular in pathological angiogenic disorders, 20 thromboses, cardiac infarct, coronary heart disorders, arteriosclerosis, tumours, osteoporosis, inflammations, infections and for influencing wound-healing processes. Above and below, all temperatures are indicated in OC. 25 The HPLC analyses (retention time Rt) were carried out in the following systems: Column 5 jm LichroSpher 60 RP-Select B (250-4), with a 50-minute gradient from 0 to 80% 2-propanol in 30 water/0.3% trifluoroacetic acid, at 1 ml/min flow and detection at 215 nm. Mass spectrometry (MS): EI (electron impact ionization) M' 35 FAB (fast atom bombardment)

(M+H)+

- 21 Example 1 Preparation and purification of peptides according to the invention: 5 In principle, the preparation and purification was carried out by means of Fmoc strategy with protection of acid-labile side chains on acid-labile resins using a commercially obtainable "continuous flow" peptide synthesizer according to Haubner et al. (J. Am. Chem. 10 Soc. 118, 1996, 17703). Ac-Arg-Gly-Asp-Leu-D-Asp-Ser-Leu-Arg-NH 2 2 g of aminoxanthenyloxypolystyrene resin (Novabiochem 15 0.37 mmol/g) were subjected twice in succession to a coupling step in a double coupling technique using 0.50 g of TBTU, 0.53 ml of ethyldiisopropylamine and Fmoc amino acid in DMF each time in a commercial synthesis apparatus and a typical procedure (apparatus and TM 20 handbook Milligen 9050 PepSynthesizer , 1987), for 30 minutes in each case. Washing steps were carried out in DMF for 10 minutes, cleavage steps in piperidine/DMF (1:4 vol) for 5 minutes, and N-terminal acetylations (capping) were carried out with acetic 25 anhydride/pyridine/DMF (2:3:15 vol) for 15 minutes. The amino acids Fmoc-Arg(Pmc), then Fmoc-Leu, then Fmoc-Ser (But), then Fmoc-D-Asp (OBut), then Fmoc-Leu, then Fmoc-Asp(OBut), then Fmoc-Gly and finally Fmoc-Arg(Pmc) were used. After removal of the Fmoc 30 protective group from the Fmoc-Arg(Pmc)-Gly Asp(OBut) -Leu-D-Asp(OBut) -Ser(But) -Leu-Arg(Pmc) -amino xanthenyloxypolystyrene resin, acetylation was again carried out. After washing with DMF and isopropanol and subsequent drying in vacuo at room temperature, 2.8 g 35 of Ac-Arg(Pmc) -Gly-Asp(OBut) -Leu-D-Asp (OBut) -Ser(But) Leu-Arg(Pmc) -aminoxanthenyloxypolystyrene resin were obtained. By treatment of this peptidyl resin with 20 ml of trifluoroacetic acid/water/TIS (94:3:3 vol) for 2 hours - 22 at room temperature, filtration, concentration in vacuo and trituration with diethyl ether, 0.47 g of Ac-Arg Gly-Asp-Leu-D-Asp-Ser-Leu-Arg-NH2 (code EMD 272974) was obtained. 5 Purification of the product was carried out by RP-HPLC on Lichrosorb RP 18 (250 - 25, 7 pim, Merck KGaA) in 0.3% TFA using a gradient of 4% to 24% 2-propanol in one hour at 10 ml/min and assessment of the eluate by 10 means of a UV flow-through photometer at 215 and 254 nm. 168 mg of product were obtained; Rt [sic] 15.5 min; FAB 973. The following products were prepared analogously: 15 Code Sequence MW FAB Rt (EMD) (g/mol) [sic} 271277 Ac-RADLDSLR-NH 2 986.1 986.6 18.18 271315 Ac-RGDLdsLR-NH 2 972.1 972.6 15.7 272973 Ac-RaDLDSLR-NH 2 986.1 986.6 16.39 271294 Ac-RSDLDSLR-NH 2 1002.1 1002 18.28 271296 Ac-RVDLDSLR-NH 2 1014.2 1014 19.68 271295 Ac-RYDLDSLR-NH 2 1078.2 1078.6 19.58 271297 Ac-RGDLDSLR-NH 2 972.1 972 16.83 271298 Ac-RHDLDSLR-NH 2 1052.2 1052 17.10 271299 Ac-RRDLDSLR-NH 2 1071.2 1071 16.50 271300 Ac-RDDLDSLR-NH 2 1030.1 1030 16.95 Ac-RGDLdGLR-NH 2 Ac-RGDLdALR-NH 2 271293 Ac-RTDLDSLR-NH 2 1016.1 1017 17.67 271265 Ac-RTDLDSLA-NH 2 931.0 931.6 18.15 271266 Ac-RTDLDSAR-NH 2 974.0 974.6 14.43 271267 Ac-RTDLDALR-NH 2 1000.1 1000.6 18.64 271268 Ac-RTDLASLR-NH 2 972.1 972.6 18.42 271270 Ac-RTDADSLR-NH 2 974.0 974.6 14.95 271273 Ac-RTALDSLR-NH 2 972.1 972.6 18.95 271277 Ac-RADLDSLR-NH 2 986.1 986.6 18.18 - 23 271283 Ac-ATDLDSLR-NH 2 931.0 931.5 18.75 271285 Ac-RTDLDSLr-NH 2 1016.1 1017 17.38 271286 Ac-RTDLDS1R-NH 2 1016.1 1017 17.22 271287 Ac-RTDLDsLR-NH 2 1016.1 1017 16.98 271288 Ac-RTDLdSLR-NH 2 1016.1 1017 17.70 271289 Ac-RTDlLDSLR-NH 2 1016.1 1017 17.31 271290 Ac-RTdLDSLR-NH 2 1016.1 1017 17.72 271291 Ac-RtDLDSLR-NH 2 1016.1 1017 16.84 271292 Ac-rTDLDSLR-NH 2 1016.1 1017 18.07 271577 Ac-RTELDSLR-NH 2 1030.2 1030.6 17.27 271309 Ac-RTDLaSLR-NH 2 972.1 973 17.03 271317 Ac-RTDL-(D-Phg)-SLR-NH 2 1034.2 1034.7 19.86 271318 Ac-RTDLfSLR-NH 2 1048.2 1049 22.66 271319 Ac-RTDL-(D-Nal)-SLR-NH 2 1098.3 1099 26.38 271320 Ac-RTDLGSLR-NH 2 958.1 958.6 16.74 271321 Ac-RTDL-Aib-SLR-NH 2 986.1 986 19.63 271322 Ac-RTDLpSLR-NH 2 998.2 998.6 18.23 271575 Ac-RTDLPSLR-NH 2 998.2 998.5 17.30 271576 Ac-RTDL-(D-Bgl)-SLR-NH 2 1014.2 1014.6 20.06 271310 Ac-RTDLdSLA-NH 2 931.0 931.5 18.20 271311 Ac-RTDLdSAR-NH 2 974.0 974.6 14.59 271547 Ac-RTDLdSPR-NH 2 1000.1 1000.4 13.26 271573 Ac-RTDLdSFR-NH 2 1050.1 1050.5 16.82 271574 Ac-RTDLdSlR-NH 2 1016.1 1016.5 15.99 249381 Ac-RTDFdSLR-NH 2 1050.1 1050.5 17.04 249383 Ac-RTDldSLR-NH 2 1016.1 1016.5 16.22 249385 Ac-RTD-Nle-dSLR-NH 2 1016.1 1016.5 17.03 271314 Ac-RTDLdsLR-NH 2 1016.1 1016.8 15.4 271303 Ac-Orn-RDLDSLR-NH 2 974.1 974 16.26 271308 Ac-Har-TDLDSLR-NH 2 1030.1 1030 17.66 271302 Ac-HTDLDSLR-NH 2 997.1 997 17.28 271301 Ac-KTDLDSLR-NH 2 988.1 988 16.46 271323 Ac-RTDLdLR-NH 2 929.1 929 15.95 271324 Ac-RTDLdGLR-NH 2 986.1 986 16.66 271325 Ac-RTDLd-Ala-LR-NH 2 1000.1 1000 15.92 271327 Ac-RTDLd-Abu-LR-NH 2 1014.1 1014 16.43 272975 Ac-RTDLDSLG-NH 2 916.9 917 16.19 271329 Ac-RTDLDSLF-NH 2 1007.1 1007 24.23 - 24 271332 Ac-RTDLDSLD-NH 2 975.0 975 16.40 271336 Ac-RTDLDSLL-NH 2 973.1 973 23.51 271339 Ac-RTDLDSLS-NH 2 947.0 947 16.54 271343 Ac-RTDLDSLK-NH 2 988.1 988 16.36 271346 Ac-RTDLDSLY-NH 2 1023.1 1023 18.98 271350 Ac-RTDLDSL-Orn-NH 2 974.1 974 15.84 271355 Ac-RTDLDSL-Har-NH 2 1030.1 1030 17.55 271316 Ac-RTDLDGLR-NH 2 986.1 986.7 17.55 Ac-RTDLdALR-NH 2 272974 Ac-RGDLdSLR-NH 2 972.1 973 16.4 Nomenclature for amino acids according to Eur. J. Biochem. 138, 9-37 (1984) lower case letter = D-amino acid 5 Example 2: aI8 6 / fibronectin receptor binding test: The prepared peptides according to the invention were bonded to the immobilized $3 6 receptor together with 10 competitively acting fibronectin in solution and the Q value was determined as a measure of the selectivity of the binding of the peptide to be tested to cx$3 6 . The Q value is calculated here from the quotient of the IC 50 values of test peptide and a standard. The standard 15 used was the linear Ac-RTDLDSLR-NH 2 (Code EMD 271293) (ref./patent cf. Pytela et al. Science 231, 1559, (1986) ). The binding test was carried out in detail as follows: The immobilization of soluble C43 6 receptor on 20 microtitre plates was carried out by dilution of the protein solution in TBS++ and subsequent incubation overnight at 4 0 C (100 pl/hollow). Non-specific binding sites were blocked by incubation (2 h, 37 0 C) with 3% (w/v) BSA in TBS++ (200 pl/hollow). Excess BSA was 25 removed by washing three times with TBSA++. Peptides were diluted serially (1:10) in TBSA++ and incubated with the immobilized integrin (50 gl of peptide + 50 pl of ligand per hollow; 2 h; 37 0 C) together with - 25 biotinylated fibronectin (2 gg/ml). Unbound fibronectin and peptides were removed by washing three times with TBSA++. The bound fibronectin was detected by incubation (1 h; 37oC) with an alkaline phosphatase 5 coupled anti-biotin antibody (Biorad) (1:20,000 in TBSA++; 100 pl/hollow). After washing three times with TBSA++, colorimetric detection was carried out by incubation (10-15 min; 25oC, in the dark) with substrate solution (5 mg of nitrophenyl phosphate, 1 ml 10 of ethanolamine, 4 ml of H 2 0; 100 p1/hollow). The enzyme reaction was stopped by addition of 0.4 M NaOH (100 p1/hollow). The colour intensity was determined at 405 nm in an ELISA measuring apparatus and made equal to the zero value. Hollows which were not coated with 15 receptor served as a zero value. Ac-RTDLDSLR-NH 2 was employed as a standard. The IC 50 values for the peptides tested were read off from a graph and from this, together with the IC 50 value of the standard peptide, the Q value of the peptide according to the invention 20 was determined. Q value = IC 50 test peptide / IC 50 standard Q values were calculated as means from repeat experiments. 25 The results of the test described are summarized in the Table 1 which follows: Table 1 30 Results of the ci06 / fibronectin receptor binding test Code (EMD) Sequence Q value = IC 50 test peptide /

IC

50 EMD 271293 271293 Ac-RTDLDSLR-NH 2 1.00 (=75 nM) 272974 Ac-RGDLdSLR-NH 2 0.15 271297 Ac-RGDLDSLR-NH 2 0.22 271294 Ac-RSDLDSLR-NH 2 3.2 - 26 1 271300 Ac-RDDLDSLR-NH 2 14 271299 Ac-RRDLDSLR-NH 2 15 271296 Ac-RVDLDSLR-NH 2 16 271291 Ac-RtDLDSLR-NH 2 20 271295 Ac-RYDLDSLR-NH 2 30 271298 Ac-RHDLDSLR-NH 2 30 271277 Ac-RADLDSLR-NH 2 31 272973 Ac-RaDLDSLR-NH 2 98 271265 Ac-RTDLDSLA-NH 2 7 271266 Ac-RTDLDSAR-NH 2 60 271270 Ac-RTDADSLR-NH 2 60 271285 Ac-RTDLDSLr-NH 2 1 271286 Ac-RTDLDS-(D-Leu)-R-NH 2 10 271288 Ac-RTDLdSLR-NH 2 0.08 271289 Ac-RTD-(D-Leu)-DSLR-NH 2 40 271290 Ac-RTdLDSLR-NH 2 15 271292 Ac-rTDLDSLR-NH 2 7 271308 Ac-Har-TDLDSLR-NH 2 20 271302 Ac-HTDLDSLR-NH 2 70 271301 Ac-KTDLDSLR-NH 2 110 271303 Ac-Orn-TDLDSLR-NH 2 190 271309 Ac-RTDLaSLR-NH 2 0.16 271321 Ac-RTDL-Aib-SLR-NH 2 0.4 271319 Ac-RTDL-(D-Nal)-SLR-NH 2 0.7 271320 Ac-TRDLGSLR-NH 2 1 271268 Ac-RTDLASLR-NH 2 1 271318 Ac-RTDLfSLR-NH 2 1.6 271317 Ac-RTDL-(D-Phg)-SLR-NH 2 3.6 271576 Ac-RTDL-(D-Bgl)-SLR-NH 2 71 271575 Ac-RTDLPSLR-NH 2 157 271322 Ac-RTDLpSLR-NH 2 182 249385 Ac-RTD-Nle-dSLR-NH 2 0.15 249383 Ac-RTD1dSLR-NH 2 0.6 249381 Ac-RTDFdSLR-NH 2 7.1 271287 Ac-RTDLDsLR-NH 2 0.45 271267 Ac-RTDLDALR-NH 2 0.8 271316 Ac-RTDLDGLR-NH 2 0.95 - 27 271323 Ac-RTDLdLR-NH 2 273 271355 Ac-RTDLDSL-Har-NH 2 1.8 271343 Ac-RTDLDSLK-NH 2 2.2 271336 Ac-RTDLDSLL-NH 2 4.4 271350 Ac-RTDLDSL-Orn-NH 2 4.5 271329 Ac-RTDLDSLF-NH 2 5.5 271265 Ac-RTDLDSLA-NH 2 7 271346 Ac-RTDLDSLY-NH 2 8.5 272975 Ac-RTDLDSLG-NH 2 12 271339 Ac-RTDLDSLS-NH 2 13 271332 Ac-RTDLDSLD-NH 2 51 271314 Ac-RTDLdsLR-NH 2 0.26 271310 Ac-RTDLdSLA-NH 2 0.47 271324 Ac-RTDLdGLR-NH 2 1 - 1 271574 Ac-RTDLdSlR-NH 2 1.4 271573 Ac-RTDLdSFR-NH 2 2.4 271311 Ac-RTDLdSAR-NH 2 13 271325 Ac-RTDLd-SAla-LR-NH 2 18 271327 Ac-RTDLd-Abu-LR-NH 2 33 The following examples relate to pharmaceutical preparations: 5 Example A: injection vials A solution of 100 g of Ac-RGDLdSLR-NH 2 and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 1 10 of double-distilled water using 2 N hydrochloric acid, sterile-filtered, dispensed into injection vials, lyophilized under sterile conditions and aseptically sealed. Each injection vial contains 5 mg of active compound. 15 - 28 Example B: suppositories A mixture of 20 g of Ac-RGDLdSLR-NH 2 is fused with 100 g of soya lecithin and 1400 g of cocoa butter, 5 poured into moulds and allowed to cool. Each suppository contains 20 mg of active compound. Example C: solution 10 A solution is prepared from 1 g of Ac-RGDLdSLR-NH 2 , 9.38 g of NaH 2

PO

4 - 2H 2 0, 28.48 g of Na 2

HPO

4 - 12H20 and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. The mixture is adjusted to pH 6.8, made up to 1 1 and sterilized by irradiation. This 15 solution can be used in the form of eye drops. Example D: ointment 500 mg of Ac-RGDLdSLR-NH 2 are mixed with 99.5 g of 20 petroleum jelly under aseptic conditions. Example E: tablets A mixture of 1 kg of Ac-RGDLdSLR-NH 2 , 4 kg of lactose, 25 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a customary manner to give tablets in such a way that each tablet contains 10 mg of active compound. 30 Example F: coated tablets Analogously to Example E, tablets are pressed and are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colorant. 35 - 29 Example G: capsules 2 kg of Ac-RGDLdSLR-NH 2 are dispensed into hard gelatin capsules in a customary manner such that each capsule 5 contains 20 mg of the active compound. Example H: ampoules A solution of 1 kg of Ac-RGDLdSLR-NH 2 in 60 1 of 10 double-distilled water is sterile-filtered, dispensed into ampoules, lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of active compound. 15 Example I: inhalation spray 14 g of Ac-RGDLdSLR-NH 2 are dissolved in 10 1 of isotonic NaCl solution and the solution is dispensed into commercially available spray containers having a 20 pump mechanism. The solution can be sprayed into the mouth or nose. One burst of spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Claims (8)

1. Peptide compounds of the formula I 5 Ac-Arg-X -Asp-X2-X3 X 4X 5-X -NH

2 I in which Ac is acetyl, X1 is Ser, Gly, Thr, Asp, Arg, Val, Tyr, His or 10 Ala, X2 is Leu, Ile, Nle, Val or Phe, X 3 is Asp, Glu, Lys, Phe, Aib, Nal, Gly, Ala, Bgl or Phg, X 4 is Gly, Ala, Ser, O-Ala or (o-Abu, 15 X 5 is Leu, Ile, Nle, Val or Phe, X 6 is Arg, Har, Lys, Leu, Orn, Phe, Ala, Tyr, Gly, Ser or Asp, where the amino acids mentioned can also be 20 derivatized, the amino acid residues are linked to one another in peptide fashion via the a-amino and x-carboxyl groups, the D and the L forms of the optically active 25 amino acid residues are included, and their salts, and where Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Arg-NH 2 is excluded. 30 2. Peptide compounds according to Claim 1 selected from the group consisting of Ac-Arg-Gly-Asp-Leu-D-Asp-Ser-Leu-Arg-NH 2 , Ac-Arg-Gly-Asp-Leu-Asp-Ser-Leu-Arg-NH 2 , 35 Ac-Arg-Ser-Asp-Leu-Asp-Ser-Leu-Arg-NH 2 , Ac-Arg-Asp-Asp-Leu-Asp-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Ala-NH 2 , - 31 Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-D-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-D-Asp-Ser-Leu-Arg-NH 2 , Ac-D-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-D-Ala-Ser-Leu-Arg-NH2, 5 Ac-Arg-Thr-Asp-Leu-Aib-Ser-Leu-Arg-NH2, Ac-Arg-Thr-Asp-Leu-D-Nal-Ser-Leu-Arg-NH2, Ac-Arg-Thr-Asp-Leu-Gly-Ser-Leu-Arg-NH2, Ac-Arg-Thr-Asp-Leu-Ala-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Nle-D-Asp-Ser-Leu-Arg-NH 2 , 10 Ac-Arg-Thr-Asp-Ile-D-Asp-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-Asp-D-Ser-Leu-Arg-NH2, Ac-Arg-Thr-Asp-Leu-Asp-Ala-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-Asp-Gly-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Har-NH 2 , 15 Ac-Arg-Thr-Asp-Leu-Asp-Ser-Leu-Lys-NH2, Ac-Arg-Thr-Asp-Leu-D-Asp-D-Ser-Leu-Arg-NH 2 , Ac-Arg-Thr-Asp-Leu-D-Asp-Ser-Leu-Ala-NH2, Ac-Arg-Thr-Asp-Leu-D-Asp-Gly-Leu-Arg-NH 2 , 20 and their physiologically acceptable salts.

3. Peptide compounds of the formula I according to Claim 1 and the compounds according to Claim 2, and their physiologically acceptable salts as 25 medicaments.

4. Medicament according to Claim 3 as an inhibitor for the control of disorders which are based on an expression and pathological function of CC-a43 30 integrin receptors.

5. Medicament according to Claim 4 for the control of thromboses, cardiac infarct, coronary heart disorders, arteriosclerosis, tumours, osteo 35 porosis, fibroses, inflammation, infections, psoriasis and for influencing wound-healing processes. - 32

6. Pharmaceutical preparation, comprising at least one medicament according to one of Claims 4 and 5 and, if appropriate, vehicles and/or excipients and, if appropriate, other active compounds. 5

7. Use of peptide compounds according to Claims 1 and 2 and/or their physiologically acceptable salts for producing a medicament for the control of disorders which are based on expression and 10 pathological function of L0 6 integrin receptors.

8. Use according to Claim 7 for producing a medicament for the control of thromboses, cardiac infarct, coronary heart disorders, arterio 15 sclerosis, tumours, osteoporosis, fibroses, inflammation, infections, psoriasis and for influencing wound-healing processes.