EP1206455A1

EP1206455A1 - ALPHAvBETA3 INTEGRIN INHIBITORS

Info

Publication number: EP1206455A1
Application number: EP00958381A
Authority: EP
Inventors: Alfred Jonczyk; Oliver Schadt; Simon Goodman
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1999-08-24
Filing date: 2000-08-04
Publication date: 2002-05-22
Also published as: DE19939980A1; NO20020885L; HUP0203212A3; AU6992500A; AR034692A1; KR20020086849A; PL352987A1; SK2272002A3; CN1370146A; MXPA02001862A; CA2382561A1; CZ2002525A3; NO20020885D0; HK1049667A1; ZA200202284B; JP2003507457A; WO2001014337A1; US6645991B1; HUP0203212A2; BR0013502A

Abstract

The invention relates to novel compounds of formula (I) which are biologically active as αvβ3 integrin ligands X-Y-Z-R1-CH2-R?2(R4)-CH¿2-CO-R5, whereby X, Y, Z, R?1, R2, R4 and R5¿ have meanings cited in Claim (1). The invention also relates to the physiologically acceptable salts and solvates thereof.

Description

Inhibitors of the integrin α _v ß ₃

The invention relates to novel compounds of the formula I.

XYZR ¹ -CH ₂ -R ² (R ⁴ ) -CH ₂ -CO-R ⁵ I

wherein

XH ₂ NC (= NH) -, H ₂ NC (= NH) -NH-, AC (= NH) -NH-, Het ¹ - or Het ¹ -NH-, whereby the primary amino groups can also be provided with conventional amino protective groups .

Y - (CH ₂ ) _n -, - (CH 2,) m - (CH ₂ ) ₀

R3 in which one, two, three or four methylene groups can be replaced by N, O and / or S,

Z is missing, -0-, -NH-, -NA-, -CH (OH) -, -CH (OA) -, -CHA-, -CA ₂ - or -S-,

R ^{1 is} unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, A, OA, OCF ₃ or CN,

R ² N, CH or CA,

R ³ H, F, Cl, Br, A, OA or OCF ₃ ,

r> 4 phenyl, naphthyl or Het ² which is unsubstituted or mono- or polysubstituted by A, aryl or CF ₃ ,

R ⁵ OH, OA, NH ₂ , NHA or NA ₂ , Het ^{1 is} a mono- or dinuclear heterocycle with 1 to 4 N-

Atoms which may be unsubstituted or mono- or disubstituted by NH ₂ ,

Het ^{2 with} an aromatic mono- or dinuclear heterocycle

I to 3 N, O and / or S atoms which are unsubstituted or mono- or disubstituted by F, Cl, Br, A, OA, SA, OCF ₃ , -CO-A, CN, COOA, CONH ₂ , CONHA, CONA ₂ or N0 ₂ can be substituted,

Aryl phenyl which is unsubstituted or substituted once, twice or three times by shark, A or OA,

A alkyl with 1-12 C atoms,

n 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

m, o each independently of the other 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,

I I or 12,

mean,

and their physiologically acceptable salts and solvates.

The invention was based on the task of finding new compounds with valuable properties, in particular those which can be used for the production of medicaments.

It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the c_v integrin receptors with ligands. The compounds are particularly effective in the case of the integrins α _v ß ₃ and ctvß _δ . The compounds are particularly effective as adhesion receptor antagonists for the receptor _v ß ₃ • This effect can be demonstrated, for example, by the method described by JW Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990). The inhibition of vitronectin binding to the αvß ₃ receptor has been experimentally proven for 3-phenyl-4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid.

B. Felding-Habermann and DA Cheresh describe in Curr. Opin. Cell. Biol. 5, 864 (1993) the meanings of integrins as adhesion receptors for a wide variety of phenomena and clinical pictures, especially with regard to the receptor αvß _ß .

Other inhibitors of the integrin α _v β ₃ are described in EP 0820988. The compounds according to the invention are to be regarded as selection inventions in relation to the application mentioned. Vitronectin receptor antagonists are also described in WO 97/24124 and in EP 0820991.

The dependence of the development of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins has been described by P.C. Brooks, R.A. Clark and D.A. Cheresh in Science 264, 569-71 (1994).

The possibility of inhibiting this interaction and thus inducing apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide has been discussed by P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier and D.A. Cheresh in Cell 79, 1157-64 (1994).

The experimental proof that the compounds according to the invention also adhere living cells to the corresponding ones

Preventing matrix proteins and accordingly also preventing tumor cells from attaching to matrix proteins can be performed in a cell adhesion test which is carried out analogously to the method by F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995). PC Brooks et al. describe in J. Clin. Invest. 96, 1815-1822 (1995) α _v ß3 antagonists for combating cancer and for treating tumor-induced angiogenic diseases.

The compounds of the formula I according to the invention can therefore be used as active pharmaceutical ingredients, in particular for the treatment of tumor diseases, osteoporoses, osteolytic diseases and for suppressing angiogenesis.

Compounds of formula I, the interaction of integrin receptors and ligands, such as. B. from fibrinogen to the fibrinogen receptor (glycoprotein llb / llla) prevent GPIIb / llla antagonists from spreading tumor lines through metastasis. This is confirmed by the following observations: The spread of tumor cells from a local tumor into the vascular system occurs through the formation of micro-aggregates (microthrombi) through the interaction of the tumor cells with platelets. The tumor cells are shielded by the protection in the micro-aggregate and are not recognized by the cells of the immune system. The micro-aggregates can attach themselves to the vessel walls, which facilitates further penetration of tumor cells into the tissue.

Since the formation of the microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on activated platelets, the GPIIb / llla antagonists can be regarded as effective metastasis inhibitors.

In addition to the binding of fibrinogen, fibronectin and the Willebrand factor to the fibrinogen receptor of the platelets, compounds of the formula I also inhibit the binding of further adhesive proteins, such as vitonectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. In particular, they prevent that

Formation of platelet thrombi and can therefore be used to treat thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis.

The properties of the compounds can also be demonstrated by methods which are described in EP-A1-0 462 960. The Inhibition of fibrinogen binding to the fibrinogen receptor can be detected using the method specified in EP-A1-0 381 033.

The antiplatelet effect can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962). The bone resorption can be inhibited by the compounds according to the invention with the aid of an osteoclast absorption test analogous to WO 95/32710.

The invention accordingly relates to compounds of the formula I according to claim 1 and / or their physiologically acceptable salts for the preparation of a medicament for use as integrin inhibitors. The invention relates in particular to compounds of the formula I according to Claim 1 and / or their harmless salts for the production of a medicament for combating pathologically angiogenic diseases, tumors, osteoporosis, inflammation and infections.

The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, for prophylaxis and / or

Therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, tumor diseases, osteolytic diseases such as osteoporosis, hypercalcaemia, pathologically angiogenic diseases such as B. Inflammation, ophthalmic diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, infection, pilutectomy, acne infection, viral infection Kidney failure and wound healing to support the healing process.

The compounds of formula I can be used as antimicrobial substances in operations where biomaterials, implants, catheters or pacemakers are used. They have an antiseptic effect. The effectiveness of the antimicrobial activity can be by P.Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988).

The invention also relates to the hydrates and solvates, e.g. Alcoholates, these compounds.

The invention further relates to a process for the preparation of compounds of the formula I according to claim 1 and their salts, characterized in that

a) releases a compound of formula I from one of its functional derivatives by treatment with a solvolysing, reducing or hydrogenolysing agent, or

b) converts a radical X and / or R ⁵ into another radical X and / or R ⁵ ,

for example by

i) converting an amino group into a guanidino group by reaction with an amidifying agent, ii) saponifying an ester, iii) converting a hydroxyamidine into an amidine by hydrogenation,

and / or converts a base or acid of the formula I into one of its salts.

The compounds of formula I can have a chiral center and can therefore occur in several stereoisomeric forms. All of these forms (e.g. D and L forms) and their mixtures (e.g. the DL forms) are included in Formula I. So-called prodrug derivatives are also included in the compounds of the invention, ie with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I which in Organism can be quickly split into the active compounds of the invention.

The abbreviations listed above and below stand for:

Ac Acetyl

BOC tert-butoxycarbonyl

CBZ or Z benzyloxycarbonyl

DCCI dicyclohexylcarbodiimide

DMF dimethylformamide

EDCI N-ethyl-N, N '- (dimethylaminopropyl) carbodiirnide

Et ethyl

Fmoc 9-fluorenylmethoxycarbonyl

HOBt 1-hydroxybenzotriazole

Me methyl

Mtr 4-methoxy-2,3,6-trimethylphenyl sulfonyl

HONSu N-hydroxysuccinimide

OBut tert-butyl ester

Oct octanoyl

OMe methyl ester

OEt ethyl ester

POA phenoxyacetyl

TFA trifluoroacetic acid

Trt trityl (triphenylmethyl).

For the entire invention it applies that all residues that occur several times, such as A, may be the same or different, i.e. are independent of each other.

A is alkyl and has 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms and is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also for pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1 , 1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2 -methylpropyl, 1, 1, 2-, 1, 2,2-trimethylpropyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl. In the Alkyl radicals can also be substituted by halogen atoms. A therefore also means CF _3, for example.

X is preferably e.g. Pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1- y |, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydro-imidazol-2-ylamino, 2-amino-imidazole-5 -ylamino, 2-amino-pyridin-6-ylamino, 2-amino-imidazol-5-yl or 2-amino-pyridin-6-yl.

Y is preferably e.g. Ethylene, propylene or butylene.

Z is preferably, for example, O. R ¹ is preferably, for example, 1,4-phenylene.

R ² is preferably, for example, CH or N, very particularly preferably CH.

R ⁴ is preferably, for example, phenyl.

R ⁵ is preferably, for example, OH.

Het ¹ is preferably unsubstituted or mono- or disubstituted by A, NHA and / or NH ₂ 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazoM-, -4- or -5-yl, 1, 2,4- triazol-1-, -3- or 5-yl, 1- or 5-tetrazolyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 3-, 4-, 5- , 6-, 7- or 8- quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8- Cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 1 H-imidazo [4,5-b] pyridin-2-yl or 1, 8-naphthyridin-7-yl. The heterocyclic radicals can also be partially or completely hydrogenated.

Het ¹ can, for. B. also mean 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 4,5-dihydro-imidazol-2-yl, 2,3-dihydro- 1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4- pyrazolyl, 1, 4-dihydro-1-, -2-, -3- or -4-pyridyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4 -Piperidinyl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1, 2,3 , 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1, 2,3,4-tetrahydro-1-, -2 -, - 3-, -4-, -5-, -6-, -7- or -8-isoquinolyl or

1, 2,3,4-tetrahydro-1,8-naphthyridin-7-yl. Hydrogenated or partially hydrogenated Het ¹ radicals can additionally be substituted by = NH or carbonyl oxygen.

He _r2 • is preferably unsubstituted or simply substituted by F, Cl, Br, A, OA or OCF ₃ 2,3-, 2,4- 2,5- or 3,4-thienyl, 2,3-, 2,4 -, 2,5- or 3,4-pyrrolyl, 2,4-, 2,5- or 4,5-imidazolyl, 2,3-, 2,4-, 2,6- or 3,5-pyridyl, 2,4-, 2,5-, 2,6-, 4,5- or 5,6-pyrimidinyl.

n is preferably 2, 3, 4, 5 or 6, and also 1, 7 or 8; n very particularly preferably denotes 3, 4 or 5. m and 0 preferably, in each case independently of one another, 0.1 or 2, very particularly preferably they represent 0.

Amino protecting group preferably means formyl, acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl,

Ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas la to li, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which

in a) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydro-imidazol-2-ylamino, 2-amino- imidazol-5-ylamino, 2-amino-pyridin-6-ylamino, 2-amino-imidazol-5-yl or 2-amino-pyridin-6-yl; in b) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino,

Benzimidazol-2-ylamino or 4,5-dihydro-imidazol-2-ylamino,

Y is - (CH ₂ ) _n -, n is 2, 3 or 4;

in c) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yi, imidazol-2-ylamino,

Benzimidazol-2-ylamino or 4,5-dihydro-imidazol-2-ylamino,

Y is - (CH ₂ ) _n - n 2, 3 or 4;

in d) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydro-imidazol-2-ylamino,

Y - (<-_ π ₂ j _n - n 2, 3 or 4,

Z is O;

in e) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino,

Benzimidazol-2-ylamino or 4,5-dihydro imidazol-2-ylamino,

Y - (CH ₂ ) _π - n 2, 3 or 4,

Z 0,

R ^{2 is} N or CH; in f) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino,

Benzimidazol-2-ylamino or 4,5-dihydro imidazol-2-ylamino,

Y - (CH ₂ ) _n - n 2, 3 or 4,

Z 0,

R ² N or CH, phenyl which is unsubstituted or substituted by A, aryl or CF ₃ ;

in 9) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydro-imidazol-2-yiamino,

Y - L.π _{2 n} - n 2, 3 or 4,

Z 0,

R ² N or CH,

R ^{4 is} phenyl which is unsubstituted or substituted by A, aryl or CF ₃ ,

R ^{5 is} OA or OH;

in h) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino,

Benzimidazol-2-ylamino, 4,5-dihydro-imidazol-2-ylamino, 2-amino-imidazol-5-ylamino, 2-amino-pyridin-6-ylamino, 2-

Amino-imidazol-5-yl or 2-aminopyridin-6-yi.

Y - (CH ₂ ) _n - n 2, 3 or 4,

Z 0,

R ² N or CH, R ⁴ unsubstituted phenyl,

R ^{5 is} OA or OH;

in X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino,

Benzimidazol-2-ylamino or 4,5-dihydro imidazol-2-ylamino,

Y - (CH ₂ ) _n - n 2, 3 or 4,

Z 0,

R ² N or CH,

R ⁴ unsubstituted phenyl,

R ^{5 is} OA or OH;

The compounds of the formula I and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart; ) are described, namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I.

Compounds of formula I can preferably be obtained by liberating compounds of formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing agent. Preferred starting materials for solvolysis or hydrogenolysis are those which otherwise correspond to the formula I, but 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, which is connected to an N atom carry an amino protective group, in particular those which carry an R'-N group instead of an HN group, in which R 'represents an amino protective group, and / or those which have one instead of the H atom Hydroxy group carry a hydroxy protective group, for example those which correspond to the formula I, but instead of a group -COOH carry a group -COOR "in which R" denotes a hydroxy protective group.

Several - identical or different - protected amino and / or hydroxy groups can also be present in the molecule of the starting material. If the existing protective groups are different from one another, they can in many cases be split off selectively.

The term "amino protecting group" is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions, but which are easily removable after the desired chemical reaction has been carried out elsewhere in the molecule is. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as formyl or acetyl, propionyl, butyryl; Aralkanoyl such as phenyl acetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbo- benzoxy "), 4-methoxybenzyloxycarbonyl, FMOC; arylsulfonyl such as Mtr. Preferred amino protective groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl, formyl and acetyl.

The amino protective group can be split off, depending on the one used

Protecting group - e.g. B. with strong acids, suitably with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Come further

Mixtures of the aforementioned solvents in question. TFA is preferably used in excess without the addition of another solvent and / or small amounts of a scavenger such as water, a phenol or a thiol, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperatures for the cleavage are advantageously between about 0 and about 50 °, preferably between 15 and 30 ° (room temperature).

The groups BOC, OBut and Mtr can e.g. B. preferably with TFA in dichloromethane, TFA with about 3% water or with about 3 to 5n HCl in

Dioxane be split off at 15-30 °, the FMOC group with an approximately 5 to 50% solution of sec. Amines such as dimethylamine, diethylamine or piperidine in DMF at 15-30 °.

Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) can e.g. B. by treatment with hydrogen in the presence of a catalyst (z. B. a noble metal catalyst such as palladium, advantageously on a support such as coal). Suitable solvents are the above, especially z. B. alcohols such as methanol or ethanol or amides such as DMF. Hydrogenolysis is usually carried out at temperatures between about 0 and 100 ° and pressure between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar. Hydrogenolysis of the CBZ group succeeds e.g. B. good on 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) on Pd / C in methanol / DMF at 20-30 °.

Suitable inert solvents are e.g. Hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether,

Tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulphide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate, water or mixtures of the solvents mentioned.

It is also possible to saponify an ester of the formula I.

This is conveniently done by solvolysis or hydrogenolysis, as indicated above, e.g. with LiOH in methanol, NaOH or KOH in dioxane water at temperatures between 0 and 60 ° C, preferably between 10 and 40 ° C.

The conversion of a cyano group into an amidino group takes place by reaction with e.g. Hydroxylamine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as e.g. Pd / C. It is also possible to use a conventional amino protecting group

To replace hydrogen by splitting off the protective group as described above, solvolytically or hydrogenolytically, or by liberating an amino group protected by a conventional protective group by solvolysis or hydrogenolysis. To prepare compounds of the formula I in which XH _{2 is} NC (= NH) -NH-, a corresponding amino compound can be treated with an amidizing agent. Preferred amidinizing agent is 1-amidino-3,5-dimethylpyrazole (DPFN), which is used in particular in the form of its nitrate. It is advantageous to work with the addition of a base such as triethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, for example water / dioxane, at temperatures between 0 and 120 ° C., preferably between 60 and 120 ° C.

To produce an amidine of the formula I (X = -C (= NH) -NH ₂ ), ammonia can be added to a nitrile of the formula I (X = CN). The addition is preferably carried out in several stages by, in a manner known per se, a) converting the nitrile with H ₂ S into a thioamide, which is converted into the corresponding S-alkylimidothioester using an alkylating agent, for example CH ₃ I, which in turn, reacts with NH ₃ to form the amidine, b) converting the nitrile with an alcohol, for example ethanol in the presence of HCl, into the corresponding imidoester and treating it with ammonia, or c) reacting the nitrile with lithium bis (trimethylsilyl) amide and the product then hydrolyzed.

It is further preferred to release the compounds of the formula I from an oxidized precursor by, for example, an oxy heterocycle with a reducing agent such as e.g. Reduced phosphorus trichloride in an inert solvent.

Furthermore, free amino groups can be acylated in the usual way with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide, advantageously in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and + 30 °.

A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. For this implementation In particular, acids are considered which provide physiologically acceptable salts. So inorganic acids can be used, for example sulfuric acid, nitric acid, hydrohalic acids 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 heterocyclic mono- or polycarbonate, sulfonic or Sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid,

Ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-mono- and disulfonic acids, lauryl-sulfuric acid. Salts with physiologically unacceptable acids, e.g. Picrates can be used for the isolation and / or purification of the compounds of the formula I.

On the other hand, an acid of the formula I can be converted into one of its physiologically acceptable metal or ammonium salts by reaction with a base. Suitable salts here are in particular the sodium, potassium, magnesium, calcium and ammonium salts, and also substituted ammonium salts, e.g. B. the dimethyl, diethyl or diisopropyl ammonium salts, monoethanol, diethanol or diisopropylammonium salts, cyclohexyl, dicyclohexylammonium salts, dibenzylethylenediammonium salts, z. B. salts with arginine or lysine.

The compounds of the formula I contain one or more chiral centers and can therefore be present in racemic or in optically active form. Racemates obtained can be separated mechanically or chemically into the enantiomers by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent. Suitable release agents are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyi tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ß- Camphor sulfonic acid. Enantiomer separation using a column filled with an optically active separating agent (for example dinitrobenzoylphenylglycine) is also advantageous; a mixture of hexane / isopropanol / acetonitrile, for example in a volume ratio of 82: 15: 3, is suitable as the mobile phase.

Of course, it is also possible to obtain optically active compounds of the formula I by the methods described above by using starting materials which are already optically active.

The invention includes not only the compounds mentioned but also

Mixtures and preparations which, in addition to these compounds according to the invention, also contain other pharmacological active substances or adjuvants which can influence the primary pharmacological effect of the compounds according to the invention in a desired manner. These can be used as therapeutic agents, diagnostic agents or as reagents. They can be given to humans or animals locally or systemically, orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, transdermally, nasally, buccally, or iontophoretically, this includes formulations in suspensions, emulsions or solutions,

Liposomes, ointments, pastes, biodegradable polymers or as nanoparticles, tablets, capsules or pills, granules or powder, as an aerosol for inhalation, as intranasal drops or sprays. It is also possible to combine the new products with other technologies such as surgery, radiation, diagnosis, radiotherapy, photodynamic therapy and gene therapy, as well as with other medications. Such drugs can come from the fields of cardiovascular, central nervous system or oncology. They can be tumor agents, such as angiogenesis inhibitors or cytostatics, chemotherapeutics from the grouping alkylating agents, antibiotics, antimetabolites, biologicals and immunomodulators, hormones and their antagonists, mustard gas derivatives, alkaloids and others, whereby these substances can be low-molecular and high-molecular. It can Lipids, carbohydrates or proteins. This also includes cytokines, toxins, fusion proteins, monoclonal antibodies and vaccines.

The invention accordingly relates to compounds of the formulas defined above and below and in the claims, including their physiologically acceptable salts as medicaments, diagnostics or

Reagents.

The invention relates in particular to corresponding medicaments as inhibitors for combating diseases which are based directly or indirectly on expression of the α _v β3 integrin receptor, in particular in the case of pathologically angiogenic diseases, thrombosis, heart attack, coronary heart diseases, arteriosclerosis,

Tumors, osteoporosis, inflammation, infections and to influence wound healing processes.

Corresponding pharmaceutical preparations which contain at least one medicament of the formula I and, if appropriate, carriers and / or auxiliaries are also an object.

The invention furthermore relates to the use of the compounds and / or their physiologically acceptable salts according to the claims and the description for the manufacture of a medicament for combating diseases which are based directly or indirectly on expression of the α _v β ₃ integrin receptor, in particular therefore in pathologically angiogenic diseases, thrombosis, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, inflammation,

Infections and to influence wound healing processes. The pharmaceuticals according to the invention or pharmaceutical preparations containing them can be used in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral, suitable for topical application or for application in the form of an inhalation spray and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols,

Polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. In particular, tablets, pills, coated tablets, capsules, powders,

Granules, syrups, juices or drops, for rectal use suppositories, for parenteral use solutions, preferably oily or aqueous solutions, also suspensions, emulsions or implants, for topical use ointments, creams or powders. The new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables. The specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, flavoring and / or several other active substances, z. B. one or more vitamins.

For the application as an inhalation spray, sprays can be used which contain the active ingredient either dissolved or suspended in a propellant gas or propellant gas mixture (e.g. C0 ₂ or chlorofluorocarbons). The active ingredient is expediently used in micronized form, with one or more additional physiologically tolerable ones

Solvents may be present, e.g. B. ethanol. Inhalation solutions can be administered using standard inhalers.

The substances according to the invention can generally be administered in analogy to other known, commercially available preparations (for example described in US Pat. No. 4,472,305), preferably in doses between about 0.05 and 500 mg, in particular between 0.5 and 100 mg per dosage unit. The daily dosage is preferably between about 0.01 and 20 mg / kg body weight. However, the specific dose for each patient depends on a wide variety of factors, for example on the effectiveness of the specific ones used Connection, age, body weight, general state of health, gender, diet, time and route of administration, rate of excretion, drug combination and severity of the respective disease to which the therapy applies. Parenteral administration is preferred.

All temperatures above and below are given in ° C.

The HPLC analyzes (retention time Rt) were carried out in the following systems: column 3 μm silica rod with a 210-second gradient from 20 to

100% water / acetonitrile / 0.01% trifluoroacetic acid, at 2.2 ml / min flow and detection at 220 nm.

Mass spectrometry (MS): El (electron impact ionization) M ⁺ FAB (Fast Atom Bombardment) (M + H) ⁺

example 1

Synthesis of 3-phenyl-4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid

835 mg Mg are abs. In 5 ml. THF suspended. Then a solution of 2.0 g of 4-benzyloxybenzyl chloride in 5 ml of abs. Tetra hydrofuran ran added. When the addition is complete, the cloudy solution is stirred at room temperature for 1 hour, then one

Solution of 1.73 g of 2-cyano-3-phenyl-acrylic acid ethyl ester in 10 ml abs. Toluene added and refluxed for 16 hours. The solvent is removed and, after customary working up, 4- (4-benzyioxy-phenyl) -2-cyano-3-phenyl-butyric acid ethyl ester ("AA") is obtained.

8.27 g of "AA" are concentrated in a mixture of 80 ml of acetic acid and 80 ml. HCl suspended and then refluxed for 16 hours. After the usual work-up, 4- (4-hydroxyphenyl) -3-phenylbutyric acid ("AB") is obtained. A solution 1.0 g "AB" in 10 ml abs. 0.4 ml of thionyl chloride is added to methanol and the mixture is stirred at room temperature for 16 hours. After the usual work-up, methyl 4- (4-hydroxyphenyl) -3-phenylbutyrate ("AC") is obtained.

To a suspension of 0.4 g "AC", 0.5 g 3- (1-oxy-pyridin-2-ylamino) propan-1-ol and 1.23 g polymer-bound triphenylphosphine (loading approx. 3 mmol / g ) in 17 ml abs. THF is added dropwise to 0.62 ml of diethyl azadicarboxylate and stirring is continued for 16 hours. After filtration and removal of the solvent, it is purified by HPLC. 3-Phenyl-4- {4- [3- (1-oxypyridin-2-yiamino) propoxy] phenyl} butyric acid methyl ester ("AD") is obtained.

A solution of 0.45 g of "AD" in 30 ml of chloroform is mixed with 0.59 g of phosphorus trichloride, stirred for 2 hours at room temperature and for a further 2 hours under reflux. After the usual workup, the

The residue in 15 ml of methanol is mixed with 0.2 g of lithium hydroxide and stirred at room temperature for 16 hours. After removal of the solvent, 0.66 ml of trifluoroacetic acid is added and the mixture is purified by HPLC. 3-Phenyl-4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid, trifluoroacetate, Rt 1, 209, FAB 391, 1 are obtained

Test result of the inhibition of yr by 3-phenyl-4-f4-r3- (pyridin-2-ylamino) -propoxyl-phenyl) -butyric acid

The IC 50 value is given for the vitronectin binding test, ie the concentration in nmoles / liter which inhibits 50% of the vitronectin binding to the corresponding isolated receptor (method of Smith et al., J. Biol. Chem. 265, 12267 -71, 1990). The pharmacological data demonstrate the antagonistic activity of the compound according to the invention for the receptor αvß ₃ -

The following compounds are obtained analogously to the synthesis scheme described above

3-phenyl-4- {4- [2- (pyrimidin-2-ylamino) ethoxy] phenyl} butyric acid, trifluoroacetate, Rt 1, 680, FAB 377.9;

3-phenyl-4- {4- [3- (pyrimidin-2-ylamino) propoxy] phenyl} butyric acid,

Trifluoroacetate, Rt 1, 701, FAB 391, 6;

3-phenyl-4- {4- [4- (pyrimidin-2-ylamino) butoxy] phenyl} butyric acid, trifluoroacetate, Rt 1, 751, FAB 406.0;

3-phenyl-4- {4- [2- (pyridin-2-ylamino) ethoxy] phenyl} butyric acid, trifluoroacetate, Rt 1, 144, FAB 377.1;

3-phenyl-4- {4- [4- (pyridin-2-ylamino) butoxy] phenyl} butyric acid, trifluoroacetate, Rt 1, 248, FAB 405.2;

3-phenyl-4- {4- [3- (imidazol-1-yl) propoxy] phenyl} -butyric acid;

3-phenyl-4- {4- [3- (4,5-dihydro-1H-imidazol-2-ylamino) propoxy] phenyl} butyric acid;

3-phenyl-4- {4- [3- (imidazol-2-ylamino) propoxy] phenyl} -butyric acid;

3-phenyl-4- {4- [3- (benzimidazol-2-ylamino) propoxy] -phenyl} -butyric acid;

3-phenyl-4- {4- [3- (2-aminopyridin-6-ylamino) propoxy] phenyl} butyric acid,

3-phenyl-4- {4- [3- (2-aminoimidazol-5-yi-amino) propoxy] phenyl} butyric acid. Example 2

Synthesis of (phenyl- {4- [3- (pyridin-2-ylamino) propoxy] benzyl} amino) - acetic acid 40.0 g of 4-hydroxybenzaldehyde are treated in a protective gas atmosphere in 400 ml of abs. THF dissolved, mixed with 55.1 g dihydropyran and 13.7 g pyridinium p-toluenesulfonate and stirred overnight at room temperature. The solvent is removed on a rotary evaporator, the residue is worked up as usual and 4- (tetrahydro-pyran-2-yloxy) benzaldehyde ("BA") is obtained as a colorless oil.

A solution of 2.0 g "BA" in 20 ml abs. Methanol is mixed with 1.17 g of aniline and stirred at 60 ° for 3 hours. 0.79 g of sodium cyanoborohydride are added at room temperature and the reaction solution is refluxed for 16 hours. After removing the solvent, more common

Working up and purification by chromatography gives phenyl- [4- (tetrahydro-pyran-2-yloxy) benzyl] amine ("BB") as a colorless liquid.

8.0 "BB" g and 10.36 g of methyl bromoacetate are N ₂ - abs ml atmosphere in 100th THF dissolved, mixed with 12.0 g of potassium carbonate and boiled under reflux for 16 hours. After removal of the solvent, customary work-up and purification by chromatography, {phenyl- [4- (tetrahydro-pyran-2-yloxy) benzyl] amino} acetic acid methyl ester ("BC") is obtained as a colorless solid.

A solution of 0.5 g "BC" in 25 ml methanol and 5 ml dichloromethane is concentrated with 2.76 ml. HCI added and stirred for 5 minutes at room temperature. After removal of the solvent and usual work-up, the residue together with 0.47 g of 3- (1-oxypyridin-2-ylamino) propan-1-ol in 16 ml of abs. THF dissolved and then with 1.17 g of polymer

Triphenylphosphine (loading approx. 3 mmol / g) was added. Then 0.62 ml of diethyl azadicarboxylate are added dropwise. The suspension is then stirred for 16 hours at room temperature. After filtration and removal of the solvent, it is purified by HPLC. This gives ({4- [3- (1-oxy-pyridin-2-ylamino) propoxy] benzyl} phenylamino) acetic acid methyl ester ("BD"). A solution of 0.44 g of "BD" in 30 ml of chloroform is mixed with 0.57 g of phosphorus trichloride, stirred for 2 hours at room temperature and for a further 2 hours under reflux. After the usual working up, the residue in 15 ml of methanol is mixed with 0.27 g of lithium hydroxide and stirred for 16 hours at room temperature. After removal of the solvent, 0.66 ml of trifluoroacetic acid is added and the mixture is purified by HPLC. This gives (phenyl- {4- [3- (pyridin-2-ylamino) propoxy] benzyl} amino) acetic acid, bistrifluoroacetate

The following compounds are obtained analogously

(Phenyl {4- [2- (pyrimidin-2-ylamino) ethoxy] benzyl} -amino) acetic acid,

(Phenyl- {4- [3- (pyrimidin-2-ylamino) propoxy] benzyl} amino) acetic acid, Rt 1, 517, FAB 392.8;

(Phenyl {4- [4- (pyrimidin-2-ylamino) butoxy] benzyl} -amino) acetic acid,

(Phenyl {4- [2- (pyridin-2-ylamino) ethoxy] benzyl} -amino) acetic acid,

(Phenyl- {4- [4- (pyridin-2-ylamino) butoxy] benzyl} amino) acetic acid, Rt 1, 336, FAB 406.1;

(Phenyl {4- [3- (imidazol-1-yl) propoxy] benzyl} -amino) acetic acid,

(Phenyl- {4- [3- (4,5-dihydro-1H-imidazol-2-ylamino) propoxy] benzyl} amino) acetic acid, (Phenyl {4- [3- (imidazol-2-ylamino) propoxy] benzyl} -amino) acetic acid,

(Phenyl- {4- [3- (benzimidazol-2-ylamino) propoxy] benzyl} amino) acetic acid.

Example 3

The following compounds are obtained analogously to Example 1

3- (biphenyl-4-yl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid,

3- (4'-chlorobiphenyl-4-yl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid,

3- (naphth-2-yl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid,

3- (Thien-2-yl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid,

3- (4'-chlorobiphenyl-3-yl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid,

3- (biphenyl-3-yl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} -butyric acid.

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of 3-phenyl-4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid and 5 g of disodium hydrogenphosphate is brought to pH 6 in 3 l of double-distilled water with 2N hydrochloric acid , 5 adjusted, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of 3-phenyl-4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid is melted with 100 g of soy lecithin and 1400 g

Cocoa butter, pour into molds and let cool. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution is prepared from 1 g of 3-phenyl-4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid, 9.38 g of NaH ₂ PO ₄ • 2 H ₂ 0, 28 , 48 g Na ₂ HP0 ₄ 12 H ₂ 0 and 0.1 g benzalkonium chloride in 940 ml double-distilled water. It is adjusted to pH 6.8, made up to 1 I and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

500 mg of 3-phenyl-4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E: tablets

A mixture of 1 kg of 3-phenyl-4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid, 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 tablets in the usual way, such that each tablet contains 10 mg of active ingredient.

Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G: capsules

2 kg of 3-phenyl-4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid are filled in hard gelatin capsules in a customary manner, so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

A solution of 1 kg of 3-phenyl-4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid in 60 l of double-distilled water is sterile filtered, filled into ampoules and lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Example I: Inhalation spray

14 g of 3-phenyl-4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid are dissolved in 10 l of isotonic NaCl solution and the solution is filled into commercially available spray vessels with a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Claims

claims

1. Compounds of formula I.

XYZR ¹ -CH ₂ -R ² (R ⁴ ) -CH ₂ -CO-R ^e

wherein

XH ₂ NC (= NH) -, H ₂ NC (= NH) -NH-, AC (= NH) -NH-, Het ¹ - or HetλNH-, whereby the primary amino groups can also be provided with conventional amino protecting groups,

in which one, two, three or four methylene groups can be replaced by N, O and / or S,

Z is missing, -O-, -NH-, -NA-, -CH (OH) -, -CH (OA) -, -CHA-,

-CA ₂ - or -S-,

R ^{1 is} unsubstituted or one, two or three times by F,

Cl, Br, A, OA, OCF ₃ or CN substituted phenylene,

R ² N, CH or CA,

R ³ H, F, Cl, Br, A, OA or OCF ₃ ,

R ^{4 is} phenyl, naphthyl or Het ² which is unsubstituted or mono- or polysubstituted by A, aryl or CF ₃ ,

R ⁵ OH, OA, NH ₂ , NHA or NA ₂ , Het ^{1 is} a mono- or dinuclear heterocycle with 1 to 4

N atoms, which can be unsubstituted or substituted once or twice by NH ₂ ,

Het ^{2 is} an aromatic mono- or dinuclear heterocycle with 1 to 3 N, O and / or S atoms, which is unsubstituted or mono- or disubstituted by F, Cl, Br, A, OA, SA, OCF ₃ , -CO -A, CN, COOA, CONH ₂ , CONHA, CONA ₂ or N0 ₂ can be substituted,

Aryl unsubstituted or single, double or triple through

Shark, A or OA substituted phenyl,

A alkyl with 1-12 C atoms,

n 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

m, o each independently 0, 1,

2,

3, 4, 5, 6, 7, 8, 9, 10, 11 or 12,

mean,

and their physiologically acceptable salts and solvates.

Compounds according to claim 1

a) 3-phenyl-4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid; b) 3-phenyl-4- {4- [3- (2-aminopyridin-6-ylamino) propoxy] phenyl} butyric acid; c) 3-Phenyl-4- {4- [3- (2-aminoimidazol-5-ylamino) propoxy] phenylj-butyric acid.

and their physiologically acceptable salts and solvates.

, A process for the preparation of compounds of formula I according to claim 1 and their salts, characterized in that

b) converts a radical X and / or R ⁵ into another radical X and / or R ⁵ ,

for example by

i) converting an amino group into a guanidino group by reaction with an amidinizing agent,

ii) saponifying an ester,

iii) converting a hydroxyamidine into an amidine by hydrogenation,

and / or converts a base or acid of the formula I into one of its salts.

4. Compounds of formula I according to claim 1 and the compounds according to claim 2 and their physiologically acceptable salts and solvates as medicaments.

Medicament according to claim 4 as an inhibitor for combating diseases which are based on expression and pathological function of α _v ß ₃ integrin receptors.

, Medicament according to claim 5 for combating thrombosis, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, fibrosis, inflammation, infection, psoriasis and for influencing wound healing processes.

7. Pharmaceutical preparation containing at least one medicament according to one of claims 5 to 6 and optionally carriers and / or auxiliaries and optionally other active substances.

8. Use of compounds according to claims 1 to 2 and / or their physiologically acceptable salts for the manufacture of a medicament for combating diseases which are based on the expression and pathological function of α _v β ₃ integrin receptors.

9. Use according to claim 8 for the manufacture of a medicament for combating pathological processes which are maintained or propagated by angiogenesis.

10. Use according to claim 8 for the manufacture of a medicament for combating thromboses, heart attacks, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, fibroses,

Inflammation, infections, psoriasis and to influence wound healing processes.