SK78398A3 - Tyrosin-derivate as alpha-v-integrin inhibitors, method for the preparation thereof and pharmaceutical compositon containing same - Google Patents

Abstract

Disclosed are compounds of formula (I) in which X represents alkylene with 1-6 C atoms or 1,4-piperidyl; Y is absent or represents O, CONH or -CC-; R<1> represents H, CN, N3, NH2, H2N-C(=NH) or H2N-(C=NH)-NH (the primary amino groups can also be provided with conventional amino protective groups); R<2>, R<3> each independently of one another represent H, A, A-SO2-, Ar-SO2, campher-10-SO2-, COOA or a conventional amino protective group; A, R<4> each independently of one another represent H or alkyl with 1-10 C atoms; and Ar represents phenyl or benzyl which is unsubstituted or single-substituted with CH3. Also disclosed are the physiologically tolerable salts of these compounds. The compounds and salts thereof can be used as alpha v-integrin inhibitors, in particular for treating tumours, osteoporoses, osteolytic disorders and for suppressing angiogenesis.

Description

Technical field

The invention relates to a tyrosine derivative as an alpha inhibitor _in integrin, to a process for its preparation and to a pharmaceutical composition containing it. The compounds of the invention are useful in the treatment of, for example, cancer, osteoporosis, osteolytic diseases, and the suppression of angiogenesis.

BACKGROUND OF THE INVENTION

EP 0 478363 and EP 0 478328 disclose similar compounds to those of the invention. SUMMARY OF THE INVENTION It is an object of the invention to provide novel compounds having valuable properties which are particularly suitable for the manufacture of medicaments.

SUMMARY OF THE INVENTION

The present invention provides a tyrosine derivative of the general formula

(I) where it is C 1 -C 6 alkylene or 1,4-piperidyl, is absent or O, CONH or

-C? C-,

X

- 2 R ¹ is hydrogen, cyano, N ₃ , amino, H ₂ NC (= NH), H ₂ NC (= NH) -NH, the primary amino group optionally having a known protecting group,

R ² and R ^3, independently of one another, H, A, _{A-SO2-, Ar-SO2} -, camphor-10-S0 _2, COOA or a conventional amino protective group,

A and R ⁴ independently of one another are hydrogen, C 1 -C 10 alkyl or benzyl; and

Ar is an unsubstituted or one methyl-substituted phenyl or benzyl group, and their physiologically acceptable salts.

It has been found that the compounds of the formula I and their salts have very good pharmacological properties, with good tolerability. They act especially as integrin inhibitors, and in particular inhibit the interactions of _the alpha -integrínových receptors with ligands. A particularly high efficiency of the compounds of formula I for the integrin alpha _v beta ₃ and alpha _v beta ₅ · compounds are very particularly active as adhesion receptor antagonists for the vitronectin receptor alpha _v beta _third This action can be demonstrated, for example, by the method of JW Smith et al. (J. Biol. Chem. 265, 11008-11013 and 12267-12271, 1990).

Inhibition of vitronectin binding to receptors has been experimentally demonstrated for some compounds of Formula I. The results of the pharmacological tests are shown in Table I.

B. Felding-Habermann and DA Cheresh (Curr. Opin. Cell. Biol. 5, p. 864, 1993) described the importance of the integrins as adhesion PTORA river for different events and disease, particularly with respect to the vitronectin receptor _alpha beta _3.

The dependence of angiogenesis on the interaction of vascular integrin and extracellular matrix proteins has been described by P.C. Brooks, R.A. Clark and D.A. Cheresh (Science 264: 569-571, 1994).

The possibility of inhibiting this interaction and thereby inducing apoptosis (programmed cell death) of angiogenic vascular cells by the action of the cyclic peptide has been described by P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier, and D.A. Cheresh (Cell 79, 1157-1164, 1994).

Experimental evidence that such compounds of the general formula

According to the invention, they prevent the adhesion of living cells to the corresponding matrix proteins and thus also the adhesion of the tumor cells to the matrix proteins, based on the cell adhesion assay carried out as described by F. Mithans et al. (J. Cell Science 108: 2825-2838, 1995). The pharmacological values are shown in Table II.

PC Brooks et al. (J. Clin. Invest. 96: 1815-1822, 1995) have described alpha _in beta ₃ antagonists for combating cancer and for treating tumor-inducing angiogenic diseases.

The compounds of the formula I according to the invention can therefore be used as active substances of medicaments for the treatment of cancer, osteoporosis, osteolytic diseases and for the inhibition of angiogenesis.

The invention therefore relates to compounds of the formula I and / or their physiologically acceptable salts for the manufacture of pharmaceutical compositions used as alpha _- integrin inhibitors.

The compounds of formula I can be used as medicaments in human and veterinary medicine for the prophylaxis and / or treatment of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, cancer, osteolytic diseases such as osteoporosis, pathological angiogenic diseases such as inflammation, ophthalmic diseases, diabetic retinopathy, muscle degeneration, myopathy, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, viral infection, restenosis after angioplasty, restenosis after angioplasty acute renal failure and to promote wound healing.

The compounds of the formula I can be used as antimicrobial agents in operations using biological materials, implants, catheters or cardiac stimulators. These compounds have an antiseptic effect. The efficacy of antimicrobial activity can be demonstrated by the method of P. Valentin-Weigund et al. (Infection and Immunity, 1988, 2851-2855).

The process for the preparation of a tyrosine derivative of the general formula I, in which the individual symbols have the meaning given above, consists in

(a) for the preparation of compounds of formula (I), wherein

R ¹ N ₃ ,

R ² is H,

R ³ a-SO ₂ -, Ar-so ₂ -,

X is an alkylene group having 1 to 6 carbon atoms

Y is absent or represents an oxygen atom or a -C ,C- group, an alkyl group having 1 to 10 carbon atoms or a benzyl group, and

A and Ar are as defined above, but the compound of formula (I) is treated

R ¹ N ₃ ,

R ² is H,

^R3 conventional amino protective group,

X is an alkylene group having 1 to 6 carbon atoms

Y is absent or represents an oxygen atom or a -C ,C-, R4 alkyl group having 1 to 10 carbon atoms or a benzyl group.

A and Ar are as defined above, first with a solvolysing agent and then reacted with a compound of formula II

R ³ -L (II) wherein is

R ³ A-SC 2 -, Ar-SC 2 -a

L is a chlorine, bromine, iodine, hydroxyl or reactive esterified hydroxyl group, or

(b) saponification of an ester of formula I; or

Ί 9

(c) transforming the group R and / or R into another group of R ¹ and / or R ² by

i) the azido group is reduced to the amino group, ii) the cyano group is converted to the amidino group, iii) the amino group is converted to the guanidino group by reaction with the amidating agent, iv) the conventional amino-protecting group is replaced with or removed from the solvolysis or hydrogenolysis reagent amino,

v) releasing the amidino group from its oxadiazole derivative by hydrogenolysis and / or

d) converting the basic or acidic compound of the formula I into an acid or base treatment into its salt.

The compounds of formula I have at least one chiral center and can therefore be in several stereoisomeric forms. The invention includes all such forms (e.g. D- and L-forms) and mixtures thereof (e.g. DL-forms).

The abbreviations used have the following meanings:

Ac acetyl BOC tert-butoxycarbonyl CBZ or Z - benzyloxycarbonyl DCC1 dicyklohexylkarodiimid DMF dimethylformamide EDC1 N-ethyl-N, N '- (dimethylaminopropyl) carbodiimide et ethyl Fmoc 9-fluórenylmetoxykarbony1 HOBt 1-hydroxybenzotriazole Me methyl Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl HONSu N-hydroxysuccinimide OBu tert-butyl Oct octanoyl OMe methyl ester OEt ethyl POA phenoxyacetyl

TFA

Trt trifluoroacetic acid trityl (triphenylmethyl)

Alkyl groups are, in particular, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl or tert-butyl, and also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2-methyl. , 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2- or 3-methylpentyl, 1,1-,

1,2-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl,

1,1.2- or 1,2,2-trimethylpropyl, heptyl, octyl, rionyl or decyl and furthermore also 3-methyl.

Alkylene is preferably understood to mean methylene, ethylene, propylene, butylene, pentylene or hexylene.

By aryl is meant unsubstituted, especially monosubstituted phenyl, preferably phenyl, o-, m- or p-methylphenyl or benzyl.

Amino-protecting group is preferably acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, phenoxyacetyl (POA), methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl (BOC), CBZ (carbobenzoxy), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FOMC), 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr) or benzyl.

In particular, the invention relates to compounds of formula I, wherein at least one of the symbols has the above-mentioned preferred meaning. Preferred groups of compounds have the general formulas Ia to Ie, which fall under the formula I and wherein the individually undefined symbols have the meaning given in the formula I:

Ia)

Ib)

Ic)

Id)

Ie)

R ¹

Y

R ² ,

R ³

R ¹

Y

R ² ,

R ³

R ¹

Y

R ² ,

R ³

Y

R ² ,

R ³

R ¹

Y

R ² ,

R ³

R ⁴

R ⁴

R ⁴

R ⁴

R ⁴ nh ₂ , alkylene oxygen atom, hydrogen atom and α-so ₂ nh ₂ -c (= nh), alkylene oxygen atom, hydrogen atom and α-so ₂ nh ₂ -c (= nh) -nh, alkylene an oxygen atom, a hydrogen atom, and an α- ₂ alkylene group lacking a hydrogen atom; and

CODA

NH ₂ -C (= NH) -NH, CONH alkylene, hydrogen and α-so ₂ of formula

The compounds for their preparation are, moreover, prepared up to as far as possible also by carbon atoms carbon atoms carbon atoms carbon starting materials by known methods as described in the literature (e.g. Houben-Weyl, Methoden der organischen Chemie, Georg Thieme-Verlag, Stuttgart) ) under reaction conditions known and suitable for the above reactions. It is also possible to use non-described variations of such methods.

The starting materials are optionally prepared in situ so that they are not isolated from the reaction mixture, but the reaction mixtures are immediately used to prepare the compounds of formula I.

Compounds of formula (I) wherein

R ¹ N ₃ ,

R ² is H,

R ³ A-SO ₂ "or Ar-SO ₂ -,

X is an alkylene group having 1 to 6 carbon atoms

Y is absent or is oxygen or -C = C- a

An R ⁴ alkyl group having 1 to 10 carbon atoms or benzyl may be prepared by reacting a compound of formula I

where it means

R ³ amino protecting group,

X is an alkylene group having 1 to 6 carbon atoms

Y is absent or is oxygen or -C = C- a

R ^{4 is} a C 1 -C 10 alkyl or benzyl group first with a solvolysing agent, in particular a hydrolyzing or hydrogenolysing agent, and then with a compound of formula II.

The term amino protecting group is well known and refers to groups which are suitable for protecting (blocking) the amino group from chemical reactions, but which are readily removable when the desired reaction elsewhere in the molecule is carried out. Typically, such groups are unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino-protecting groups are removed after the desired reaction (or reaction sequence), their type and size are not critical. However, groups having 1 to 20, and in particular 1 to 8, carbon atoms are preferred. The term acyl group is always used herein in the broadest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups include alkanoyl groups such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; aralkoxycarbonyl such as the benzyloxycarbonyl (CBZ), 4-methoxybenzyloxycarbonyl and 9-fluorenylmethoxycarbonyl (FMOC) groups. Preferred amino protecting groups are BOC and Mtr, CBZ, Fmoc, benzyl and acetyl.

Deprotection of the amino protecting group proceeds according to the protecting group used - for example, strong acids, preferably trifluoroacetic acid or perchloric acid, but also other strong inorganic acids such as hydrochloric or sulfuric acids, strong carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzenesulfonic acid or p-sulfenesulfonic acid. . The presence of an additional inert solvent is possible but not always necessary. Suitable inert solvents are, in particular, organic, for example, carboxylic acids such as acetic acid, ethers such as tetrahydrofuran (THF) or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, alcohols such as methanol, ethanol, isopropanol and water. . Mixtures of the solvents mentioned may also be used. Trifluoroacetic acid is preferably used in excess without the addition of additional solvents, perchloric acid as a mixture with acetic acid and 70% perchloric acid in a ratio of 9: 1. The cleavage reaction temperature is suitably about 0 to about 50 ° C; it is preferably carried out at a temperature of 15 to 30 ° C (room temperature).

For example, the BOC group, OBut group, and Mtr group can be conveniently cleaved with trifluoroacetic acid in dichloromethane or with about 3 to 5 n hydrochloric acid in dioxane at 15 to 60 ° C, FMOC group with 5 to 50% dimethylamine, diethylamine or piperidine solution in dimethylformamide at 15 to 50 ° C.

Hydrogenolytically removable protecting groups (e.g. BOM, CBZ or benzyl groups) can be removed, for example, by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, preferably on a support such as carbon). Suitable solvents are the abovementioned solvents, in particular, for example, alcohols such as methanol or ethanol or amides such as dimethylformamide. The hydrogenolysis is generally carried out at a temperature of about 0 to 100 ° C, at a pressure of about 0.1 to 20 MPa, preferably at a temperature of 20 to 30 ° C, at a pressure of about 0.1 to 1 MPa. Hydrogenolysis of CBZ groups, for example, performs well on 5 to 10% palladium on carbon in methanol at 20 to 30 ° C.

The compounds of formula II are generally known. If they are not known, they can be prepared by known methods.

The reaction of the compounds of formula II is generally carried out in an inert solvent, in the presence of an acid binding agent, preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline. The addition of alkali and alkaline earth metal hydroxides, carbonates or bicarbonates or other salts of weak acids and alkali and alkaline earth metals, preferably potassium, sodium, calcium or cesium salts, may also be beneficial. The reaction time is, depending on the reaction conditions, a few minutes to 14 days, a reaction temperature of -30 to + 140 ° C, generally -10 to + 90 ° C, in particular 0 to 70 ° C.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethane, 1,2-dichloroethane or 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 or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulphide; organic carboxylic acids such as formic or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate. Mixtures of these solvents are also suitable.

In addition, the ester of the formula I can be saponified. The saponification is conveniently carried out by solvolysis or hydrogenolysis as described above, for example sodium hydroxide or potassium hydroxide in a dioxane / water system at a temperature of 0 to 60, preferably 10 to 40 ° C.

Furthermore, the group R ¹ and / or R ^{2 can be} converted to another group R ¹ and / or R ² .

In particular, an azido group can be converted to an amino group by, for example, hydrogenolysis as described above, or the amino group can be converted to a guanidino group by reaction with an amidating agent, for example dimethylpyrazolformamidine nitrate. Conversion of the cyano group to the amidino group is accomplished by reaction with, for example, hydroxylamine and subsequent reduction of hydroxylamidine with hydrogen in the presence of a catalyst, for example palladium on carbon.

In addition, it is possible to replace the conventional amino protecting group with hydrogen, whereby the protecting group as described above is solvolytically or hydrogenolytically cleaved, or the conventional amino-protected amino group is liberated by solvolysis or hydrogenolysis.

The base of formula (I) may be converted by an acid into the appropriate acid addition salt, for example by reaction of an equivalent amount of base and acid in an inert solvent such as ethanol and subsequent evaporation. Acids which give physiologically acceptable salts are suitable for this reaction. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, acid and sulfamic acid and organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monohydric acids or not can be used carboxylic acids, sulfonic or sulfuric acids, such as formic, acetic, propionic, pivalic, diethyl, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, nicotinic, nicotinic, nicotinic, nicotinic, nicotinic, nicotinic, ethanesulfonic, ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene monosulfonic and naphthalenedisulfonic and laurylsulfonic acids. Salts with physiologically unacceptable acids, for example picrates, are used for the isolation and / or purification of the compounds of formula I.

On the other hand, the acids of the formula I can be converted into physiologically acceptable metal or ammonium salts by reaction with a base. Suitable salts are, in particular, the sodium, potassium, magnesium, calcium and ammonium salts, further substituted ammonium salts, e.g. lysine.

The compounds of formula I may have one or more chiral centers and may therefore be in racemic or optically active form. Alternatively, the racemates obtained can be separated into their enantiomers mechanically or chemically by known methods. Preferably, diastereoisomers are formed from the racemate by reaction with an optically active resolving agent. Examples of such resolving agents are optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid or lactic acid, or various camphorsulfonic acids such as beta-camphorsulfonic acid. Separation of enantiomers by columns filled with optically active resolving agents (e.g. dibenzoylphenylglycine) is also preferred. Hexane / isopropanol / acetonitrile is suitable, for example, in a ratio of 82: 15: 3.

It is also possible to prepare optically active compounds of the formula I according to the methods described above using starting materials which are already optically active.

The following Table I shows the results of alpha _in beta ₃ and alpha _in beta ₅ inhibition by several representative compounds of Formula I. For vitronectin binding assays, IC ₅₀ values, i.e., concentration in nmol / liter, that inhibit 50% of vitronectin binding to the corresponding isolated receptor.

Table I

IC ₅₀ values (concentration in nmol / liter that inhibits 50% of vitronectin binding to the isolated receptor) of representative compounds of formula I are obtained in a similar manner to that described by Smith et al. (J. Biol. Chem. 265, 12267-12271, 1990) and the measured FAB values of the compounds.

R ² '? ICáctvfó ' ΓΟδοίίνβδ 0) H Butyl! SO ₂ . butylene 0 415 0.4 216 · (1) H BOC butylene 0. 395 · 3.5 60 0) H Propyl-SO ₂ butylene 0 401 8.9 1000 (1) H Butyl _2-SO pentylene 0 429 0.45 970 (1) H Butyl _2-SO propylene CON 428 2.0 1120 0) H Benzyl-SO2 butylene 0 449 4.4

R R ² R ³ X \ y / ' FAB ' G $ q ctv $ 3 · // · »· · · · · · · · · · · · · · · ·; ICsG ClvOsí 0) H _Pentyl-SO2 butylene 0 429 5.5 0) H _4-tolyl-2 S0 butylene 0 ¹ 449 6.6 0) H Butyl-SO ₂ propylene 0 401 20 0) * H Butyl _2-SO propylene JA) 409 15 0) ch ₃ Butyl-SO ₂ butylene 0 429 17 0) * H Butyl-SO ₂ pentylene a mistake 413 30 ( ² ) H BOC butylene 0 380 36 (2) H Butyl _2-SO butylene 0 400 66 (1) * H Butyl _2-SO butylene 0 415 229 (2) ’ H Butyl _2-SO (B) CON 454 540 ŇH ₂ - H Butyl-SO ₂ butylene 0 373 140 ňh ₂ . H Butyl-SO ₂ pentylene a mistake 371 2400 (2) H Butyl-SO ₂ pentylene 0 414 2700 (1) H H butylene 0 295 · 3700 ‘ • nh ₂ * H Butyl _2-SO propylene JA) 367 3900 nh ₂ * H Butyl _2-SO pentylene ABOUT 373 700 N H, H Butyl-SO ₂ hexylene 0 387 2900 · 0) H Camphor - .10-SO ₂ butylene 0 509 0.6 H H? Butyl-SO 2 (B) CONH. 412 ' 9180

(1) = H ₂ NC (= NH) -NH-; (2) = H ₂ N-J (= NH) -j

- Racemate, 4 '= 2- (R) -isomer

The pharmacological values demonstrate the antagonistic activity of the compounds of the formula I for vitronectin receptors alpha _in beta ₃ and alpha _in beta _5.

Table II shows the results of a cell adhesion assay for several representative compounds of Formula I of the invention. IC ₅₀ values, i.e. the concentration at which 50% binding is achieved compared to the control without test compound, are given.

Table II

IC ₅₀ values (concentration in gmol / L) of representative compounds of formula I obtained in a similar manner to that described by Mitjans et al. (J. Cell Science 108: 2825-2838, 1990) and the FAB values of the compounds. Vitronectin was used as reference matrix protein.

·, ··. ·. · W; .. · ♦. · R ¹ X ' icfc ?. H Butyl-SO ₂ butylene 0 415 1 · ID H BOC · butylene 0 395 0,5 ' (Ώ H Propyl-SO ₂ butylene 0 401 2.7 (1) H ’ Butyl-SO ₂ pentylene about 429 4 (1) H Butyl _2-SO propylene CON 428 2.7 H ' _Pentyl-SO2 butylene 0 429 2.1

(1) = H ₂ NC (= NH) -NH The pharmacological values demonstrate the antagonistic activity of the compounds of the formula I according to the invention for the adhesion of tumor cells to tissue.

The compounds of the formula I and their physiologically acceptable salts can be used for the production of pharmaceutical compositions, in particular by a non-chemical route. For this purpose, they can be converted into a suitable dosage form with at least one solid or liquid and / or semi-liquid carrier or excipient and optionally in admixture with one or more other active substances.

The invention therefore also relates to compositions, pharmaceutical compositions comprising at least one compound of the formula I according to the invention and / or a physiologically acceptable salt thereof.

The compositions of the invention may be used as medicaments in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteric (e.g. oral) or parenteral or topical administration or for administration in the form of inhalation sprays and which do not react with compounds of the formula I, such as water, vegetable oils, benzyl alcohols , polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starches, magnesium stearate, talc, lanolin and petrolatum. Especially suitable for oral use are tablets, dragees, capsules, syrups, juices or drops, for rectal use suppositories, for parenteral use solutions, in particular oily or aqueous solutions, further suspensions, emulsions or implants, for topical use ointments, creams or powders. The compounds of the invention may also be lyophilized and the resulting lyophilisates used, for example, for the preparation of injectables. The compositions may be sterilized and / or may contain adjuvants such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffers, coloring agents, flavoring agents and / or flavoring agents. Alternatively, they may contain one or more other active substances, such as vitamins.

For application in the form of inhalation sprays, sprays may be used which contain the active ingredient dissolved or suspended in a propellant or propellant mixture (e.g. carbon dioxide or fluorocarbon). For this purpose, the active ingredient in micronized form is expediently used, and at least one physiologically acceptable solvent, for example ethanol, may be added. Inhalable solutions may be administered using conventional inhalation devices.

The compounds of formula I and their physiologically acceptable salts can be used as integrin inhibitors for the treatment of diseases, in particular pathological angiogenic diseases, thromboses, heart attacks, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations and infections.

The compounds of the formula I according to the invention are generally administered in doses similar to known peptides, in particular similar to those described in UA-A-4 472305, preferably in an amount of 0.05 to 500 mg, in particular in an amount of 0, 5 to 100 mg per dosage unit. The daily dose is preferably about 0.01 to 2 mg / kg body weight. The dose for each individual patient will depend on a variety of factors, such as the efficacy of the particular compound used, age, body weight, general health, sex, diet, time and route of administration, elimination rate, drug combination and severity of the disease. . Oral administration is preferred.

The invention is illustrated by the following non-limiting examples. Temperatures are always given in ’C. The general treatment in the following practical examples means: Optionally water is added, the reaction mixture is optionally adjusted to a pH of 2 to 10 according to the constitution of the final product, extracted with ethyl acetate or dichloromethane, the product is separated, the organic phases are dried over sodium sulfate, evaporated and purified by silica gel chromatography and / or crystallization.

Mass spectrometry (MS): EI (electron beam ionization) M ⁺ (FAB (fast atom bombardment (M + H) ⁺ )

Examples

Example 1

A solution of 2.5 g of (S) -3- [4- (4-bromobutoxy) phenyl] 2-N-tert-butoxycarbonylaminopropionic acid benzyl ester (obtainable by reacting 2 g of BOC-L-tyrosine benzyl ester with 1.9 ml of 1,4- of dibromobutane in the presence of 5 g of potassium carbonate, 0.1 g of 18 Krone-6 in 20 ml of toluene at 80 ° C) in 20 ml of dimethylformamide and 1.6 g of sodium azide are stirred for 12 hours. After usual work-up, (S) -3- [4- (4-azidobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid benzyl ester is obtained as a colorless syrup; FAB 469.

Similarly, they are obtained by reaction with sodium azide using (R) -3- [4- (4-bromobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid benzyl ester, (S) -3- [4- (5-bromopentyloxy) benzyl ester (phenyl) -2-N-tert-butoxycarbonylaminopropionic acid, (R, S) -3- [4- (5-bromopentyloxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid benzyl ester, (S) -3- [ 4- (3-bromopropoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid and (S) -3- [4- (6-bromohexyloxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid benzyl ester the following benzyl ester compounds (R) ) -3- [4- (4-azidobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid, (S) -3- [4- (5-azidopentyloxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid benzyl ester acids, (R, S) -3- [4- (5-azidopentyloxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid benzyl ester, (S) -3- [4- (3-azidopropoxy) phenyl] -2-benzyl ester - N - tert -butoxycarbonylaminopropionic acid and (S) -3- [4- (6-azidohexyloxy) phenyl] benzyl ester nyl] -2-N-tert-butoxycarbonylaminopropionic acid.

Example 2

A solution of 2.0 g of (S) -3- [4- (4-azidobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid benzyl ester and 2 ml of trifluoroacetic acid was stirred at room temperature for three hours. After removal of trifluoroacetic acid, (S) -2-amino-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester (A) is obtained as a colorless syrup.

Similarly, they are obtained by cleaving the BOC group with trifluoroacetic acid using (R) -3- [4- (4-azidobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid benzyl ester, (S) -3- [4- ( 5-azidopentyloxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid, (R, S) -3- [4- (5-azidopentyloxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid benzyl ester, (S) -3 benzyl ester - [4- (3-azidopropoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid and (S) -3- [4- (6-azidohexyloxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid benzyl ester the following benzyl ester compounds (R) -2-amino-3- [4- (4-azidobutoxy) phenyl] propionic acid, (S) -2-amino-3- [4- (5-azidopentyloxy) phenyl] propionic acid benzyl ester, benzyl ester (R) (S) -2-amino-3- [4- (5-azidopentyloxy) phenyl] propionic acid, (S) -2-amino-3- [4- (3-azidopropoxy) phenyl] propionic acid benzyl ester, and benzyl ester (S) -2-amino-3- [4- (6-azidohexyloxy) phenyl] propionic acid.

Example 3

A solution of 1.6 g of compound A in 20 ml of dichloromethane is treated with 0.84 ml of butylsulfonyl chloride and 1.2 ml of triethylamine and stirred at room temperature for 12 hours. After usual work-up, 1.4 g of (S) -2-butylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester is obtained as a colorless syrup;

FAB 489.

Similarly, by reacting compound A and propylsulfonyl chloride, benzylsulfonyl chloride, pentylsulfonyl chloride, 4-tolylsulfonyl chloride and camphor-10-sulfonyl chloride, the following compounds (S) -2-propylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester, benzyl ester (benzyl ester) S) -2-benzylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid, (S) -2-pentylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester, (S) -2- ( 4-tolylsulfonamido) -3- [4- (4-azidobutoxy) phenyl] propionic acid and (S) -2- (camphor-10-sulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester.

Similarly obtained by reacting (S) -2-amino-3- [4- (5-azidopentyloxy) phenyl] propionic acid benzyl ester with butylsulfonyl chloride (S) -2-butylsulfonamido-3- [4- (5-azidopentyloxy) phenyl] propionic acid benzyl ester (R, S) -2-Amino-3- [4- (5-azidopentyloxy) phenyl] propionic acid benzyl ester with butylsulfonyl chloride (R, S) -2-butylsulfonamido-3- [4- (5-azidopentyloxy) phenyl] benzyl ester ] (S) -2-Amino-3- [4- (3-azidopropoxy) phenyl] propionic acid benzyl ester with butylsulfonyl chloride (S) -2-butylsulfonamido-3- [4- (3-azidopropoxy) phenyl] benzyl ester propionic acid and (R) -2-amino-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester with butylsulfonyl chloride (R) -2-butylsulfonamido-3- [4- (4-azibutoxy) phenyl] propionic acid benzyl ester (S) -2-amino-3- [4- (6-azidohexyloxy) phenyl] propionic acid benzyl ester with butylsulfonyl chloride (S) -2-butylsulfonamido-3- [4- (6-azidohexyloxy) phenyl] propionic acid benzyl ester .

Example 4

A solution of 1.3 g of (S) -2-butylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester in 30 mL of 5: 3: 1.0 ethyl acetate / methanol / water and 0.2 mL trifluoroacetic acid and 0.1 g of palladium on charcoal are hydrogenated at room temperature for three hours at ambient pressure. After filtering off the catalyst and removing the solvent, freeze drying from acetonitrile / water yielded 1.0 g of (S) -2-butylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid as an amorphous powder; FAB 373.

Similarly, they are obtained by hydrogenating (S) -2-propylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester, (S) -2-benzylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester (S) -2-Pentylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester, (R, S) -2-Pentylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester (S) -2- (4-Tolylsulfonamido) -3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester, (S) -2-Butylsulfonamido-3- [4- (5-azidopentyloxy) phenyl benzyl ester propionic acid, (S) -2-butylsulfonamido-3- [4- (3-azidopropoxy) phenyl] propionic acid benzyl ester, (R) -2-butylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester (S) -2-Butylsulfonamido-3- [4- (6-azidohexyloxy) phenyl] propionic acid benzyl ester and (S) -2- (Camphor-10-sulfonamido) -3- [4- (4-azidobutoxy) benzyl ester Phenyl] propionic acid the following compounds (S) -2-propylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid onic acid, (S) -2-benzylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid, (S) -2-pentylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid, (R) (S) -2-pentylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid, (S) -2- (4-tolylsulfonamido) -3- [4- (4-aminobutoxy) phenyl] propionic acid (S) -2-butylsulfonamido-3- [4- (5-aminopentyloxy) phenyl] propionic acid, (S) -2-butylsulfonamido-3- [4- (3-aminopropoxy) phenyl] propionic acid, ( R) -2-butylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid, (S) -2-butylsulfonamido-3- [4- (6-aminohexyloxy) phenyl] propionic acid; FAB 387 and (S) -2- (Camphor-10-sulfonamido) -3- (4- (4-aminobutoxy) phenyl) propionic acid.

Example 5

Stir 200 mg of (S) -2-butylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid and 170 mg of 3,5-dimethylpyrazole-1-formamidinium nitrate (DPFN) with 150 μΐ of triethylamine for 12 hours at 60 ° C. . The solution was concentrated and the residue was purified by HPLC chromatography (Lichrocart RP-18, gradient acetonitrile / water + 0.3% TFA, 99: 1 to 1: 99 over 1 hour). Removal of the solvent gave 50 mg of (S) -2-butylsulfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid as an amorphous powder, m.p. 70 ° C; FAB 415.

Similarly, they are obtained by the reaction of DPFN and (s) -2-propylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid, (S) -2-benzylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid, (S). ) -2-pentylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid, (S) -2- (4-tolylsulfonamido) -3- [4- (4-aminobutoxy) phenyl] propionic acid, ( (s) -2-butylsulfonamido-3- [4- (5-aminopentyloxy) phenyl] propionic acid, (S) -2-butylsulfonamido-3- [4- (3-aminopropoxy) phenyl] propionic acid, and (S) - 2- (camphor-10-sulfonamido) -3- [4- (4-aminobutoxy) phenyl] propionic acid the following compound (S) -2-propylsulfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid; FAB 401, (s) -2-benzylsulfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid; FAB 449, (S) -2-Pentylsulfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid; FAB 429, (S) -2-tolylsulfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid; FAB 449, (S) -2-Butylsulfonamido-3- [4- (5-guanidinopentyloxy) phenyl] propionic acid; FAB 429, (S) -2-Butylsulfonamido-3- [4- (3-guanidinopropoxy) phenyl] propionic acid; FAB 401 and (S) -2- (Camphor-10-sulfonamido) -3- [4- (4-guanidinobutoxy) phenyl] propionic acid; FAB 509.

Example 6

Similar to Example 4, by hydrogenation of 0.5 g of (S) -3- [4- (4-azidobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid benzyl ester, 370 mg of (S) 3- [4- (4-benzyl) ester was obtained. (4-aminobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid (B); FAB 353.

Treatment of 150 mg of B with DPFN similar to Example 5 afforded 160 mg of (S) -3- (4- (4-guanidinobutoxy) phenyl) -2-N-tert-butoxycarbonylaminopropionic acid; FAB 395.

Cleavage of the BOC group as in Example 2 affords (S) -2-amino-3- [4- (4-guanidinobutoxy) phenyl] propionic acid; FAB 295.

Example 7

A solution of 0.4 g of (S) -3- (4-aminophenyl) -2-butylsulfonamidopropionate, FAB 329 (obtainable by reaction of (S) -3- (4-nitrophenyl) -2-tert-butyloxycarbonylaminopropionic acid ethyl ester with trifluoroacetic acid) acid to give (S) -3- (4-nitrophenyl) -2-aminopropionic acid ethyl ester, which is reacted with butylsulfonyl chloride to give (S) -3- (4-nitrophenyl) -2-butylsulfonamidopropionic acid ethyl ester, FAB 359, which was reduced by the method of Example 4) 0.268 g 4-BOC-aminobutyric acid, 0.5 g O- (benztriazol-1-yl) -N, N, N'N'-tetramethyluronium tetrafluoroborate (TBTU), 0.05 g HOBT, 260 μΐ of N-methylmorpholine in 10 ml of dimethylformamide is stirred for 12 hours at room temperature. The reaction mixture was worked up in the usual manner to give 0.62 g of (S) -3- [4- (4-tert-butoxycarbonylaminobutyramido) phenyl] -2-butylsulfonamidopropionate; FAB 514.

Example 8

A solution of 0.62 g of (S) -3- [4- (4-tert-butoxycarbonylaminobutyramido) phenyl] -2-butylsulfonamidopropionic acid ethyl ester in 5 ml of dioxane is stirred with 2.4 ml of 1N sodium hydroxide solution for 12 hours at a temperature of rooms. The solution is neutralized with trifluoroacetic acid, concentrated and the residue is taken up in 2 ml of trifluoroacetic acid. After stirring at room temperature for 2 hours, it is worked up in the usual manner. There was obtained (S) -3- [4- (4-aminobutyramido) phenyl] -2-butylsulfonamidopropionic acid after freeze-drying from acetonitrile / water as a white amorphous powder; FAB 386.

Example 9

Similar to Example 5, 0.155 g of (S) -3- [4- (4-aminobutyramido) phenyl] -2-butylsulfonamidopropionic acid with 0.121 g of DPFN is obtained after freeze-drying of 160 g of (S) -2-butylsulfonamido-3- [ 4- (4-guanidinobutyramido) phenyl] propionic acid as a white amorphous powder, m.p. 215-217 ° C; FAB 428.

Example 10

A solution of 2,65 g of 3- [4- (5- (4-methylphenylsulfonyloxy) pentin-1-yl) phenyl] -2-butylsulfonamidopropionic acid benzyl ester,

FAB 612 (obtainable by cleavage of the BOC group from BOC-4-lodphenylalanine benzyl ester with trifluoroacetic acid and subsequent reaction with butylsulfonyl chloride to give benzyl ester of 3 (4-lodphenyl) -2-butylsulfonamidopropionic acid, followed by reaction with bis-5-ol-pentanediol) - (triphenylphosphine) palladium (II) and cuprous iodide in diethylamine to give 3- [4- (5-hydroxypentin-1-yl) phenyl] -2-butylsulfonamidopropionic acid benzyl ester, FAB 458, and reaction with toluenesulfonyl chloride in pyridine) and 1.4 g sodium azide in DMF (25 mL) was stirred at room temperature for 12 h. Conventional work-up gave 1.5 g of 3- [4- (5-azidopentin-1-yl) -phenyl] -2-butylsulfonamidopropionic acid benzyl ester as a colorless syrup; FAB 483.

Example 11

A solution of 0.2 g of 3- [4- (5-azidopentin-1-yl) phenyl] -, benzyl ester -

Of 2-butylsulfonamidopropionic acid in 10 mL of 4: 1 pyridine / water was saturated with hydrogen sulfide for 30 min. After removal of the solvent, the residue is dissolved in 10 ml of dioxane and treated with 0.8 ml of 1N sodium hydroxide solution. The residue was purified by HPLC chromatography similar to Example 5 to give 0.066 g of 3- [4- (5-aminopentin-1-yl) phenyl] -2-butylsulfonamidopropionic acid; FAB 367.

Analogously to Example 5, 0.05 g is obtained by reaction

3- [4- (5-aminopentin-1-yl) phenyl] -2-butylsulfonamidopropionic acid with 0.038 g DPFN 0.044 g of 2-butylsulfonamido-3- [4- (5-guanidinopentin-1-yl) phenyl] propionic acid, m.p. 147-150 ° C; FAB 409.

Example 12

Similar to Example 4, 0.165 g of 3- [4- (5-aminopent-1-yl) phenyl] -2-butylsulfonamido propionic acid is obtained from 0.5 g of benzyl ester of 3- [4- (5-azidopentin-1-yl) phenyl] -2-butylsulfonamido. -yl) phenyl] -2-butylsulfonamidopropionic acid; FAB 371.

Similar to Example 5, by reaction of 0.11 g of 3- [4- (5-aminopent-1-yl) phenyl] -2-butylsulfonamidopropionic acid with 0.088 g of DPFN is 0.06 g of 2-butylsulfonamido-3- [4]. - (5guanidinopent-1-yl) phenyl] propionic acid in the form of a hygroscopic melting mass; FAB 413.

Example 13

A solution of (S) -2-butylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester and 1.1 mol equivalents of sodium hydride in tetrahydrofuran is stirred for one hour in an inert atmosphere at room temperature. Methyl iodide (2 mol equivalents) was added, treated in the usual manner for one hour to give (S) -2- (N-methylbutylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester.

Similar to Example 4, it is obtained by reducing (S) -2- (N-methylbutylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid benzyl ester and reacting with DPFN similarly to Example 5 ^: (S) -2. - (N-methylbutylsulfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid; FAB 429.

Example 14

Analogously to Example 1, (S) -3- [4- (4-bromobutoxy) phenyl] -2-N-methyloxycarbonylaminopropionic acid benzyl ester is obtained from methyloxycarbonylaminopropionic acid benzyl ester by treatment with 1,4-dibromobutane. Treatment with sodium azide followed by reduction according to the method of Example 4 gives (S) -3- [4- (4-aminobutoxy) phenyl] -2-N-methyloxycarbonylaminopropionic acid and with DPFN similar to that of Example 5 for (S) - 2-N-methyloxycarbonylamino-3- [4- (4-guanidinobutoxy) phenylpropionic acid; FAB 477.

Example 15

A solution of 2.3 g of (S) -3- [4- (5-bromopentyloxy) phenyl] 2-N-tert-butyloxycarbonylpropionic acid benzyl ester, EI 520 (obtainable by reaction of 2.0 g of BOC-L-tyrosine benzyl ester with 2, 2 ml of 1,5-dibromopentane, 0.815 g of potassium carbonate and 0.132 g of 18 Krone-6 in 50 ml of toluene), 1.6 g of potassium cyanide and 0.580 g of 18-Krone-6 in 30 ml of acetonitrile are refluxed for 12 hours. . Conventional work-up gives 1.97 g of (S) -3- [4- (5-cyanopentyloxy) phenyl] -2-N-tert-butyloxycarbonylpropionic acid benzyl ester as an oily syrup;

FAB 467.

Similarly obtained from (S) -3- [4- (4-bromobutoxy) phenyl] -2-N-tert-butyloxycarbonylpropionic acid benzyl ester, (S) -3- [4- (4-cyanobutoxy) phenyl] - 2-N-tert-butyloxycarbonylzpropionic acid.

Example 16

Similar to Examples 2 and 3, 1.97 g of (S) -3- [4- (5-cyanopentyloxy) phenyl] -2-N-tert-butyloxycarbonylpropionic acid benzyl ester was obtained by treatment with trifluoroacetic acid followed by reaction with butylsulfonyl chloride 1. 5 g of (S) -2-butylsulfonamido-3- [4- (5-cyanopentyloxy) phenyl] propionic acid benzyl ester; FAB 487.

Similarly obtained from (S) -3- [4- (4-cyanobutoxy) phenyl] -2-N-tert-butyloxycarbonylpropionic acid benzyl ester, (S) -2-butylsulfonamido-3- [4- (4-cyanobutoxy) benzyl ester Phenyl] propionic acid.

Example 17

A solution of 1.5 g of (S) -2-butylsulfonamido-3- [4- (5-cyanopentyloxy) phenyl] propionic acid benzyl ester, 0.646 g of hydroxylamine hydrochloride and 0.780 g of sodium bicarbonate in 50 ml of isopropanol / water 6: 1 was heated to reflux. for 12 hours. After usual work-up, 1.6 g of (S) -2-butylsulfonamido-3- [4- (6-amino-6-N-hydroxyliminohexyloxy) phenyl] propionic acid benzyl ester is obtained as a colorless syrup; FAB 520.

Similarly, obtained by reacting (S) -2-butylsulfonamido-3- [4- (4-cyanobutoxy) phenyl] propionic acid benzyl ester (S) -2-butylsulfonamido-3- [4- (5-amino-5-N-) benzyl ester hydroxyliminopentyloxy) phenyl] propionic acid and (S) -3- [4- (4-cyanobutoxy) phenyl] -2-N-tert-butylcarbonylpropionic acid benzyl ester (S) -3- [4- (5-amino-5) benzyl ester N-hydroxyliminopentyloxy) phenyl] -2-N-tert-butyloxycarbonylpropionic acid.

Example 18

A solution of 1.6 g of (S) -2-butylsulfonamido-3- [4- (6-amino-6-N-hydroxyliminohexyloxy) phenyl] propionic acid benzyl ester in 30 ml of acetic acid and 1 ml of acetic anhydride is hydrogenated in the presence of 50 mg. of palladium (10% on activated carbon) as catalyst for two hours at room temperature and ambient pressure. After separation of the catalyst, 0.24 g of (S) -2-butylsulfonamido-3- [4- (5-aminopentyloxy) phenyl] propionic acid was obtained by conventional work-up and purification by preparative HPLC according to Example 5; FAB 414.

Similarly, (S) -2-butylsulfonamido-3- [4- (5-amino-5-N-hydroxyliminopentyloxy) phenyl] propionic acid benzyl ester (S) -2-butylsulfonamido-3- [4- (4-amidinobutoxy) phenyl] propionic acid benzyl ester acid; FAB 400 and (S) -3- [4- (5-amino-5-N-hydroxyliminopentyloxy) phenyl] -2-N-tert-butyloxycarbonylpropionic acid benzyl ester (S) -3- [4- (4-amidinobutoxy) phenyl] -2-N-tert-butyloxycarbonylpropionic acid; FAB 380.

Example 19

Similar to Example 7, 0.4 g of (S) -3- (4-aminophenyl) -2-butylsulfonamidopropionic acid ethyl ester, 0.3 g of N-BOC-piperidine-4-carboxylic acid, 0.05 g of HOBt are obtained by reaction. and 264 μΐ of N-methylmorpholine in 10 ml of dimethylformamide after usual treatment with 0.428 g of (S) -2-butylsulfonamido-3- [4- (1-tert-butyloxycarbonylpiperidine-4-carboxamido) phenyl] propionic acid ethyl ester; FAB 540.

Example 20

Similar to Example 8, 0.4 g of (S) -2-butylsulfonamido-3- [4- (1-tert-butyloxycarbonylpiperidine-4-carboxamido) phenyl] propionic acid ethyl ester is obtained by hydrolysis of the ester with sodium hydroxide and cleavage of the BOC group. trifluoroacetic acid 0.225 g of (S) -2-butylsulfonamido-3- [4 (piperidin-4-ylcarboxamido) phenyl] propionic acid; FAB 412.

Similar to Example 5, 0.16 g of (S) 2-butylsulfonamido-3- [4- (piperidin-4-yl-carboxamido) phenyl] propionic acid is obtained with 0.115 g of DPFN, 105 μΐ of triethylamine in 5 ml of DMF 0.085. g (S) -2-butylsulfonamido-3- [4- (1-amidinopiperidine-4-carboxymido) phenyl] propionic acid; FAB 454.

Example 21 (S) -2-Butylsulfonamido-3- [4- (5- (5-phenyl-1,2,4-oxadiazole) pentyloxy) phenyl] propionic acid (obtainable by reaction of (S) butylsulfonamido-3- [4- (6)) -amino-6-N-hydroxylimino-hexyloxy) -phenyl] -propionic acid with 1.1 equivalents of benzoyl chloride and triethylamine) was hydrogenated similarly to Example 18. After separation of the catalyst and usual work-up, (S) -2-butylsulfonamido-3- [4- ( 5-amidinopentyloxy) phenyl] propionic acid; FAB 414.

The following examples illustrate but do not limit the pharmaceutical compositions of the invention.

Example A

Injection ampoules

A solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogen phosphate in 3 liters of double-distilled water is adjusted to pH 6.5 with 2 n hydrochloric acid, sterile filtered, filled into injection vials, lyophilized under sterile conditions and sealed . Each ampoule contains 5 mg of active ingredient.

Example B

suppository

A mixture of 20 g of an active compound of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to solidify. Each suppository contains 20 mg of active ingredient.

Example C Solution

A solution of 1 g of an active compound of the formula I and 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of dihydrogen phosphate with 12 water molecules and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. The pH is adjusted to 6.8, made up to 1 liter and sterilized by irradiation. This solution can be used, for example, in the form of eye drops.

Example D

ointment

500 mg of an active compound of the formula I are mixed

99.5 g of petroleum jelly under aseptic conditions.

Example E

tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in known manner into tablets, each tablet containing 10 mg of the active compound of the formula I .

Example F

dragee

Similar to Example E, tablets are compressed and coated in a known manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G

The capsules kg of the active ingredient of the formula I are filled into hard gelatin capsules, each capsule containing 20 mg of the active ingredient of the formula I.

Example H

ampoules

A solution of 1 kg of active compound of the formula I in 60 liters of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed. Each ampoule contains 10 mg of active ingredient.

Example I

Inhalation spray

Dissolve 14 g of an active compound of the formula I in 10 l of isotonic sodium chloride solution and fill in conventional commercial spray cans with a pump mechanism. The solution may be sprayed into the mouth or nose. Each spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Industrial usability

Tyrosine derivative as an alpha _v -integrin inhibitor suitable for the manufacture of pharmaceutical compositions for the treatment of, for example, cancer, osteoporosis, osteolytic diseases and for the suppression of angiogenesis.

Claims (10)

PATENT CLAIMS A tyrosine derivative of the general formula I (I) wherein is X is (C 1 -C 6) alkylene or 1,4-piperidyl, Y is absent or represents an oxygen atom, a CONH group, or &quot; C = C &quot; R ^X is hydrogen, cyano, N ₃ , amino, H ₂ NC (= NH), H ₂ NC (= NH) -NH, wherein the primary amino group contains an optionally known protecting group, R and R independently of one another, H, A, _{A-SO2-, Ar-SO2-,} camphor-10-S0 _2, COOA or a conventional amino protective group, A and R ⁴ are independently hydrogen, C 1 -C 10 alkyl or benzyl; and Ar is an unsubstituted or one methyl-substituted phenyl or benzyl group, and their physiologically acceptable salts. A tyrosine derivative of the formula I as an enantiomer or a diastereomer according to claim 1. The tyrosine derivative of the general formula I according to claim 1, characterized in that it is: (a) (S) -2-Butylsulfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid; (b) (S) -2-tert-butoxycarbonylamino-3- [4- (4-guanidinobutoxy) phenyl] propionic acid, (c) (S) -2-propylsulfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid; (d) (S) -2-butylsulfonamido-3- [4- (4-guanidinopropoxy) phenyl] propionic acid; (e) (S) -2-butylsulfonamido-3- [4- (4-guanidinobutyramido) phenyl] propionic acid; (f) 2-butylsulfonamido-3- [4- (5-guanidinopentyl) phenyl] propionic acid; (g) 2-butylsulfonamido-3- [4- (5-guanidinopentin-1-yl) phenyl] propionic acid; (h) (S) -2-butylsulfonamido-3- [4- (5-guanidinopentyloxy) phenyl] propionic acid; (i) (S) -2-benzylsulfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid; (j) (S) -2-pentylsulfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid; (k) (S) -2- (4-tolylsulfonamido) -3- [4- (4-guanidinobutoxy) phenyl] propionic acid; (l) (S) -2- (N-methylbutylsulphonamido) -3- (4- (4-guanidinobutoxy) phenyl) propionic acid; (m) (S) -2-tert-butyloxycarbonylamino-3- [4- (4-amidinobutoxy) phenyl] propionic acid; (n) (S) -2-butylsulfonamido-3- [4- (4-amidinobutoxy) phenyl] propionic acid; o) (R) -2-Butylsulfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid; p) (S) -2- (Camphor-10-sulfonamido) -3- (4- (4-guanidinobutoxy) phenyl) propionic acid and their physiologically acceptable salts. 4. A process for the preparation of a tyrosine derivative of the general formula According to claim 1, characterized in that: (a) for the preparation of compounds of formula (I), wherein R ¹ N ₃ , R ² is H, R ³ A-SO ₂ ', Ar-S0 ₂ , X is (C 1 -C 6) alkylene, Y is absent or is oxygen or -C = C-, R ^{4 is} C 1 -C 10 alkyl or benzyl; A and Ar are as defined above, but the compound of formula I is treated R ¹ n ₃ , R ² is H, ^R3 conventional amino protective group, X is an alkylene group having 1 to 6 carbon atoms Y is absent or is oxygen or -C = C-, R ^{4 is} C 1 -C 10 alkyl or benzyl; A and Ar are as defined above, first with a solvolysing agent and then reacted with a compound of formula II R ³ -L (II) wherein is R ³ A-SO ₂ ', Ar-SO ₂ - a L is a chlorine, bromine, iodine, hydroxyl or reactive esterified hydroxyl group, or (b) saponification of an ester of formula I; or (c) transform the group of symbols R ¹ and / or R ² into another group of symbols R ¹ and / or R ² by: (i) the azido group is reduced to an amino group, (ii) the cyano group is converted to an amidino group, (iii) the amino group is converted to a guanidino group by reaction with an amidating agent, (iv) amino, v) liberating the amidino group from its oxadiazole derivative by hydrogenolysis, and / or d) the basic or acidic compound of formula I is converted into its salt by treatment with an acid or base. A process for the preparation of a pharmaceutical composition, characterized in that the tyrosine derivative of the formula I or a physiologically acceptable salt thereof according to claim 1 is formulated in a dosage form with at least one solid, liquid or semi-solid carrier or excipient. Pharmaceutical composition, characterized in that it contains, as active ingredient, a tyrosine derivative of the formula I or a physiologically acceptable salt thereof according to claim 1. A tyrosine derivative of the formula I or a physiologically acceptable salt thereof according to claim 1 as an integrin inhibitor for combating pathological angiogenic diseases, thromboses, heart attacks, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations and infections. Use of a tyrosine derivative of the formula I or a physiologically acceptable salt thereof according to claim 1 for the manufacture of a medicament. Use of a tyrosine derivative of the formula I or a physiologically acceptable salt thereof according to claim 1 for the treatment of diseases. »Λ 10. A compound of formula I, a tyrosine, or a physiologically acceptable salt thereof according to claim 1 for the manufacture of a medicament for use as an inhibitor _of alpha -integrínu.