EP0879227A1

EP0879227A1 - Tyrosin-derivate as alpha-v-integrin inhibitors

Info

Publication number: EP0879227A1
Application number: EP96944578A
Authority: EP
Inventors: Beate Diefenbach; Claus Fittschen; Joachim Gante; Simon Goodman; Matthias Wiesner; Friedrich Rippmann
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1995-12-23
Filing date: 1996-12-16
Publication date: 1998-11-25
Also published as: CA2241149A1; WO1997023451A1; NO982907D0; DE19548709A1; HUP9903716A2; MX9804971A; CZ195198A3; SK78398A3; ZA9610725B; JP2000502664A; PL327185A1; BR9612201A; KR19990076676A; NO982907L; AU1301697A

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 -C C-; R1 represents H, CN, N¿3?, NH2, H2N-C(=NH) or H2N-(C=NH)-NH (the primary amino groups can also be provided with conventional amino protective groups); R?2, R3¿ each independently of one another represent H, A, A-SO¿2?-, 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 CH¿3?. Also disclosed are the physiologically tolerable salts of these compounds. The compounds and salts thereof can be used as αv-integrin inhibitors, in particular for treating tumours, osteoporoses, osteolytic disorders and for suppressing angiogenesis.

Description

TYROSIN DERIVATIVES AS ALPHA V INTEGRIN INHIBITORS

The invention relates to compounds of the formula

wherein

Alkylene with 1-6 C atoms or 1,4-piperidyl,

Y is missing, O, CONH or -C≡≡C-,

R ¹ H, CN, N ₃ , NH ₂ , H ₂ NC (= NH), H ₂ N- (C = NH) -NH, where the primary amino groups can also be provided with conventional amino protecting groups,

R ² , R ³ each independently of one another H, A, A-SO ₂ -, Ar-SO ₂ -, camphor-10-SO ₂ -, COOA or a conventional amino protecting group,

A, R each independently of one another H, alkyl having 1-10 C atoms or benzyl,

and

Ar unsubstituted or simply substituted by CH ₃ phenyl or benzyl,

mean,

and their physiologically acceptable salts. Similar connections are e.g. B. from EP 0 478 363 and EP 0 478 328.

The object of the invention was to find 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 α _v -integrin receptors with ligands. The compounds are particularly effective in the case of the integrins α _v ß3 and α _v ßs. The compounds are particularly effective as adhesion receptor antagonists for the vitronectin receptor α _v ß3. 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 receptors has been experimentally proven for some representative compounds of formula I. The pharmacological test data are summarized in Table I.

B. Felding-Habermann and DA Cheresh describe in Curr. Opin. Cell. Biol. 5, 864 (1993) the meanings of the integrins as adhesion receptors for the most varied phenomena and clinical pictures, especially in relation to the vitronectin receptor α _v β3.

The dependency of the development of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins is 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 prevent the attachment of living cells to the corresponding matrix proteins and accordingly also prevent the attachment of tumor cells to matrix proteins was provided in a cell adhesion test which, analogously to the method by F. Mitjans et al ., J. Cell Science 108, 2825-2838 (1995). The pharmacological data are listed in Table II.

pc Brooks et al. describe in J. Clin. Invest. 96, 1815-1822 (1995) σ. _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.

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 an αv-integrin inhibitor.

The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, for the prophylaxis and / or therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, tumor diseases, osteolytic

Diseases such as osteoporosis, 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, viral infection, viral infection in acute kidney failure and in wound healing to support the healing processes. 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 demonstrated by P.Valentin-Weigund et al., In Infection and

Immunity, 2851-2855 (1988).

The invention furthermore relates to a process for the preparation of compounds of the formula I according to claim 1,

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

R ¹ N ₃ , R ² H,

R ³ A-SO ₂ - or Ar-SO ₂ -,

X alkylene with 1-6 C atoms,

Y is absent, O or -C≡C- and R ^{4 is} alkyl with 1-10 C atoms or benzyl,

a compound which corresponds to the formula I per se, but in which

R ¹ N ₃ ,

R ² H,

X alkylene with 1-6 C atoms,

Y is missing, O or -C≡C-,

R ^{3 is} a conventional amino protecting group and R ^{4 is} alkyl with 1-10 C atoms or benzyl,

first treated with a solvolysing agent and then with a compound of formula II

R -L wherein

R ³ A-SO ₂ - or Ar-SO ₂ - and

L Cl, Br, I, OH or a reactive esterified OH

Group means

implements, or

b) that one saponifies an ester of formula I, or

c) that one radical R ¹ and / or R ^{2 is converted} into another radical R ¹ and / or R ² by

i) converting an azido group into an amino group by reduction,

ii) converts a cyano group into an amidino group,

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

iv) replacing a conventional amino protecting group with hydrogen by treatment with a solvolysing or hydrogenolysing agent, or one protected by a conventional protecting group

Sets amino group free,

v) releases an amidino group from its oxadiazole derivative by hydrogenolysis,

and or

d) converting a basic or acidic compound of formula I into one of its salts by treatment with an acid or base. The compounds of formula I have at least one 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.

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) carbodiimide

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).

In the above formulas, alkyl preferably represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also 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-methytρropyl, 1,1, 2-, 1, 2,2-trimethylpropyl, heptyl , Octyl, nonyl or decyl, also for the 3-menthyl radical. Alkylene preferably means methylene, ethylene, propylene, butylene, pentylene, and also hexylene.

Aryl is unsubstituted, preferably - as indicated - monosubstituted phenyl, in particular preferably phenyl, o-, m- or p-methylphenyl or benzyl.

Amino protecting group preferably means 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 form! 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 partial formulas Ia to Ie, 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) R ¹ NH ₂ ,

X alkylene with 1-6 C atoms,

Y O,

R ² H,

R ³ A-SO ₂ - and

R ^{4 is} H;

in b) R ¹ H ₂ NC (= NH),

X alkylene with 1-6 C atoms,

Y O,

R ² H,

R ³ A-SO ₂ - and

R ^{4 is} H;

in c) R ¹ H ₂ N- (C = NH) -NH,

X alkylene with 1-6 C atoms, Y 0,

R ² H,

R ³ A-SO ₂ - and

R ^{4 is} H;

in d) X alkylene with 1-6 C atoms,

Y is missing

R ² , R ⁴ H and

R ^{3 is} COOA;

in e) R ¹ H ₂ N- (C = NH) -NH,

X alkylene with 1-6 C atoms,

Y CONH,

R ² , R ⁴ H and

R ^{3 is} A-SO ₂ -;

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 that are known and suitable for the above-mentioned reactions. 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, wherein

R ¹ N ₃ ,

R ² H,

R ³ A-SO ₂ - or Ar-SO ₂ -,

X alkylene with 1 -6 carbon atoms

Y is missing, O or -C≡C-, and R ^{4 is} alkyl with 1-10 carbon atoms or benzyl, can preferably be obtained by using compounds of

Formula I.

woπn

R ^{3 is} a conventional amino protecting group,

R ⁴ alkyl with 1-10 C atoms or benzyl,

X alkylene with 1-6 C atoms,

Y is absent, O or -C≡C- means

first treated with a solvolysing agent, in particular a hydrolyzing or hydrogenolysing agent, and then reacted with a compound of the formula II.

The term "amino protecting group" is generally known and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions, but which are easily removable after the desired chemical reaction has been carried out at other locations 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 includes 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 acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl like Methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred amino protective groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl and acetyl.

The amino protective group is split off, depending on the protective group used, 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. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without the addition of another solvent, 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 or with about 3 to 5N HCl in dioxane at 15-30 °, the FMOC group with an about 5 to 50% solution of 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 °.

The compounds of the formula II are generally known. If they are not known, they can be produced by methods known per se.

The compounds of the formula II are generally reacted in an inert solvent, in the presence of an acid-binding agent, preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoin. Also the addition of an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid

Alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium, can be favorable.

Depending on the conditions used, the reaction time is between a few minutes and 14 days, the reaction temperature is between about -30 ° and 140 °, normally between -10 ° and 90 °, in particular between about 0 ° and about 70 °.

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); Sulfur carbon; 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 expediently carried out by solvolysis or hydrogenolysis, as indicated above, for example with NaOH or KOH in dioxane-water at temperatures between 0 and 60 ° C., preferably between 10 and 40 ° C.

It is also possible for one radical R ¹ and / or R ^{2 to be converted} into another radical R ¹ and / or R ² .

In particular one can use an azido group e.g. convert to an amino group by hydrogenolysis as indicated above or an amino group by reaction with an amidinating agent such as e.g.

Dimethylpyrazolformamidinium nitrate, convert into a guanidino group.

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 replace a conventional amino protecting group with hydrogen by removing the protective group as described above, solvolytically or hydrogenolytically, or by liberating an amino group protected by a conventional protecting group by solvolysis or hydrogenolysis.

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. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. Thus, 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, surfamic acid, and also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon atoms. , Sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimeic 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, for example 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 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 e.g. optically active acids, such as the D and L forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ß-camphorsurfonic acid. Enantiomer separation using a column filled with an optically active separating agent (e.g. dinitrobenzoylphenylglycine) is also advantageous; a suitable solvent is e.g. a mixture of hexane / isopropanol / acetonitrile, e.g. in the volume ratio 82: 15: 3.

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 test results of the α _v β ₃ and α _v β ₅ inhibition by some representative compounds of the formula I are summarized in Table I below. For the vitronectin binding tests are the IC ₅ o values are given, ie, the concentrations in nmol / liter which inhibit 50% of the Vitronectm binding to the corresponding isolated receptor.

Table I

IC 50 values (concentrations in nmoles / liter which inhibit 50% of the vitronectin binding to the isolated receptor) of representative compounds of the formula I which are analogous to the method by Smith et al., J. Biol. Chem. 265, 12267 -71 (1990) and the measured FAB values of the substances.

(1) = H ₂ NC (= NH) -NH-; (2) = H ₂ NC (= NH) -;

= Racemate; * = 2- (R) -isomer

The pharmacological data prove the antagonistic activity of the compounds of the formula I according to the invention for the vitronectin receptors α _v ßs and α _v ßs.

The results of the cell adhesion test for some representative compounds of the formula I are summarized in Table II below. The IC ₅₀ values are given, ie the concentrations at which 50% of the binding is achieved compared to the control without the substances. Table II

IC ₅₀ values (concentrations in μmol / liter) of representative compounds of the formula I which were obtained analogously to the method by F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995), and the measured FAB values of substances. Vitronectin served as the comparison matrix protein.

(1) = H ₂ NC (= NH) -NH-

The pharmacological data demonstrate the antagonistic activity of the compounds of the formula I according to the invention for the adhesion of tumor cells to tissue.

The invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular in a non-chemical way. They can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or Hirfstoff and optionally in combination with one or more other active ingredients. The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts.

These preparations can be used as pharmaceuticals in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (for example oral), parenteral, 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. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used in particular for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or for parenteral use Implants, for topical application of ointments, creams or powders. The new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables. The specified preparations can be sterilized and / or auxiliary substances such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, taste and / or several other active substances included, e.g. B. one or more vitamins. For application as an inhalation spray, sprays can be used which contain the active ingredient either dissolved or suspended in a propellant gas or propellant mixture (for example CO ₂ or chlorofluorocarbons). The active ingredient is expediently used in micronized form, it being possible for one or more additional physiologically acceptable solvents to be present, for. B. ethanol. Inhalation solutions can be administered using standard inhalers.

The compounds of the formula I and their physiologically acceptable salts can be used as integrin inhibitors in combating diseases, in particular pathologically angiogenic diseases, thromboses, Heart attack, coronary artery disease, arteriosclerosis, tumors, osteoporosis, inflammation and infection can be used.

The substances according to the invention can generally be administered in analogy to other known, commercially available peptides, but in particular in analogy to the compounds 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 administered. The daily dosage is preferably between about 0.01 and 2 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 special compound used, on the age, body weight, general health, sex, on the diet, on the time and route of administration, on the rate of elimination , Drug combination and severity of each

Disease to which the therapy applies. Parenteral administration is preferred.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, separated off, dries the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.

Mass spectrometry (MS): El (electron impact ionization) M ⁺

FAB (Fast Atom Bombardment) (M + H) ⁺

example 1

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

Analogously one obtains by reaction with sodium azide

(R) -3- [4- (4-bromobutoxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid benzyl ester,

(S) -3- [4- (5-bromopentyloxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid benzyl ester,

(R, S) -3- [4- (5-bromopentyloxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid benzyl ester,

(S) -3- [4- (3-bromopropoxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid benzyl ester and

(S) -3- [4- (6-bromohexyloxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid benzyl ester

the connections below

(R) -3- [4- (4-azidobutoxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid benzyl ester,

(S) -3- [4- (5-azidopentyloxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid benzyl ester,

(R, S) -3- [4- (5-azidopentyloxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid benzyl ester,

(S) -3- [4- (3-Azidopropoxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid benzyl ester and

(S) -3- [4- (6-Azidohexyloxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid benzyl ester. Example 2

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

Analogously one obtains by splitting off the BOC group with TFA

(S) -3- [4- (6-Azidohexyloxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid benzyl ester

the connections below

(R) -2-amino-3- [4- (4-azidobutoxy) phenyl] -2-propionic acid benzyl ester,

(S) -2-amino-3- [4- (5-azidopentyloxy) phenyl] propionic acid benzyl ester,

(R, S) -2-amino-3- [4- (5-azidopentyloxy) phenyl] propionic acid benzyl ester. (S) -2-Amino-3- [4- (3-azidopropoxy) phenyl] propionic acid benzyl ester and

(S) -2-Amino-3- [4- (6-azidohexyloxy) phenyl] propionic acid benzyl ester.

Example 3

A solution of 1.6 g of "A" in 20 ml of dichloromethane is mixed with 0.84 ml of butylsulfonyl chloride and 1.2 ml of triethylamine and stirred for 12 hours at room temperature. After customary working 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.

Analogously you get by implementing "A"

Propylsulfonyl chloride,

Benzylsurfonyl chloride,

Pentylsulfonyl chloride,

4-tolylsulfonyl chloride and

Camphor-10-sulfonyl chloride

the connections below

(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, (S) -2- (4-Tolylsulfonamido) -3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester and

(S) -2- (camphor-10-sulfonamido) -3- [4- (4-azidobutoxy) phenyl] - benzyl propionate.

Analogue one gets through implementation

of (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,

of (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] propionic acid benzyl ester,

of benzyl (S) -2-amino-3- [4- (3-azidopropoxy) phenyl] propionate with butyl sulfonyl chloride

(S) -2-butylsulfonamido-3- [4- (3-azidopropoxy) phenyl] propionic acid benzyl ester,

of benzyl (R) -2-amino-3- [4- (4-azidobutoxy) phenyl] propionate with butylsulfonyl chloride

(R) -2-butylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester and

of (S) -2-amino-3- [4- (6-azidohexyloxy) phenyl] propionic acid benzyl ester with butylsulfonyl chloride

(S) -2-butylsurfonamido-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) phenylj-propionic acid benzyl ester in 30 ml ethyl acetate / methanol / water in the ratio 5: 3: 1, 0.2 ml TFA and 0.1 g of palladium on activated carbon is hydrogenated for 3 hours at room temperature and normal pressure. After filtering off the catalyst and removing the solvents, freeze drying from acetonitrile / water gives 1.0 g of (S) -2-butylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid as an amorphous powder; FAB 373.

The same is obtained by hydrogenation

(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-butylsurfonamido-3- [4- (5-azidopentyloxy) phenyl] propionic acid benzyl ester,

(R) -2-butylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionic acid benzyl ester,

(S) -2-Butylsulfonamido-3- [4- (6-azidohexyloxy) pheny!] - benzyl propionate and (S) -2- (camphor-10-surfonamido) -3- [4- (4-azidobutoxy) phenyl] - benzyl propionate

the connections below

(S) -2-propylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid,

(S) -2-benzylsurfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid,

(S) -2-pentylsurfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid,

(R, S) -2-pentylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid,

(S) -2- (4-tolylsurfonamido) -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-butylsurfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid,

(S) -2-butylsurfonamido-3- [4- (6-aminohexyloxy) phenyl] propionic acid, FAB 387 and

(S) -2- (camphor-10-surfonamido) -3- [4- (4-aminobutoxy) phenyl] propionic acid.

Example 5

200 mg (S) -2-butylsurfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid and 170 mg 3,5-dimethylpyrazole-1-formamidinium nitrate (DPFN) are mixed with 150 μl triethylamine for 12 hours at 60 ° stirred. The solution is finally concentrated and the residue purified by HPLC (Lichrocart RP-18, gradient acetonitrile / water + 0.3% TFA, 99: 1 to 1:99 in 1 hour). After removal of the solvent, 50 mg of (S) -2-butylsulfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid are obtained as an amorphous powder; F. 70 °; FAB 415.

Similarly, one gets by implementing DPFN

(S) -2-propylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid,

(S) -2-benzylsurfonamido-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-butylsurfonamido-3- [4- (3-aminopropoxy) phenyl] propionic acid and

(S) -2- (camphor-10-sulfonamido) -3- [4- (4-aminobutoxy) phenyl] propionic acid

the connections below

(S) -2-Propylsurfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid, FAB 401

(S) -2-Benzylsulfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid, FAB 449

(S) -2-pentylsurfonamido-3- [4- (4-guanidinobutoxy) phenyl] propionic acid, FAB 429 (S) -2- (4-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-surfonamido) -3- [4- (4-guanidinobutoxy) phenyl] propionic acid, FAB 509.

Example 6

Analogously to Example 4, hydrogenation of 0.5 g of (S) -3- [4- (4-azidobutoxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid benzyl ester gives 370 mg (S) -3- [ 4- (4-aminobutoxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid ("B"); FAB 353. By reacting 105 mg "B" with DPFN analogously to Example 5, one obtains

160 mg (S) -3- [4- (4-guanidinobutoxy) phenyl] -2-N-tert-butoxycarbonylamino-propionic acid; FAB 395.

By splitting off the BOC group analogously to Example 2, (S) -2-amino-3- [4- (4-guanidinobutoxy) phenylJ-propionic acid, FAB 295 is obtained.

Example 7

A solution of 0.4 g of (S) -3- (4-aminophenyl) -2-butylsulfonamido-propionic acid ethyl ester, FAB 329 [obtainable by reacting (S) -3- (4-nitrophenyl) -2- Tert-butyloxycarbonylamino-propionic acid ethyl ester with TFA to (S) -3- (4-nitrophenyl) -2-amino-propionic acid ethyl ester, subsequent reaction with butylsulfonyl chloride to (S) -3- (4-nitrophenyl) -2-butylsulfone amido ethyl propionate, FAB 359, and reduction analogous to Example 4], 0.268 g of 4-BOC-aminobutyric acid, 0.5 g of O- (benzotriazol-1-yl) -N, N, N ', N' .- tetramethyluronium tetrafluoroborate (TBTU), 0.05 g HOBT, 260 μl N-

Methylmorpholine in 10 ml DMF is 12 hours at room temperature touched. The mixture is worked up in the customary manner and 0.62 g of (S) -3- [4- (4-tert-butyloxycarbonylamino-butyramido) phenyl] -2-butylsulfonamido-propionic acid ethyl ester is obtained; FAB 514.

Example 8

A solution of 0.62 g of (S) -3- [4- (4-tert-butyloxycarbonylamino-butyramido) phenyl] -2-butylsulfonamido-propionic acid ethyl ester in 5 ml of dioxane is mixed with 2.4 ml of 1N NaOH for 12 hours stirred at room temperature. The solution is then neutralized with TFA, concentrated and the residue is taken up in 2 ml of TFA. After stirring for 2 hours at room temperature, the mixture is worked up in the customary manner. (S) -3- [4- (4-Amino-butyramido) phenyl] -2-butylsulfonamido-propionic acid is obtained after freeze-drying from acetonitrile / water as a white amorphous powder; FAB 386.

Example 9

Analogously to Example 5, 0.160 g of (S) - is obtained by reacting 0.155 g of (S) -3- [4- (4-amino-butyramido) phenyl] -2-butylsulfonamido-propionic acid with 0.121 g of DPFN after freeze-drying as a white amorphous powder. 2-

Butylsulfonamido 3- [4- (4-guanidino-butyramido) phenyl3-propionic acid; F. 215-217 °; FAB 428.

Example 10

A solution of 2.65 g of benzyl 3- [4- (5- (4-methylphenylsuffonyloxy) pentyn-1-yl) phenyl] -2-butylsurfonamido-propionate, FAB 612 [obtainable by cleaving the BOC group from BOC- 4-iodophenylalanine benzyl ester with TFA and subsequent reaction with butylsulfonyl chloride to give benzyl 3- (4-iodophenyl) -2-butylsulfonamido-propionate, subsequent reaction with pentin-5-ol, 1-bis (triphenylphosphine) palladium- (II) - chloride and copper (I) iodide in diethylamine to give 3- [4- (5-hydroxypentin-1-yl) - phenyl] -2-butylsulfonamido-propionic acid benzyl ester, FAB 458, and reaction with toluenesulfonyl chloride in pyridine] and 1.4 g sodium azide in 25 ml DMF is stirred for 12 hours at room temperature. After the usual Working up gives 1.5 g of 3- [4- (5-azido-pentin-1-yl) phenyl] -2-butylsulfonamido-propionic acid benzyl ester as a colorless syrup; FAB 483.

Example 11

A solution of 0.2 g of 3- [4- (5-azido-pentin-1-yl) phenyl] -2-butylsulfonamido-propionic acid benzyl ester in 10 ml of pyridine / water 4: 1 is saturated with hydrogen sulfide for 30 minutes. After the solvent has been removed, the residue is dissolved in 10 ml of dioxane and mixed with 0.8 ml of 1N NaOH. After purification of the residue by HPLC analogously to Example 5, 0.066 g of 3- [4- (5-amino-pentin-1-yl) phenyl] -2-butylsulfonamido-propionic acid is obtained; FAB 367.

Analogously to Example 5, reaction of 0.05 g of 3- [4- (5-aminopentin-1-yl) -phenyl] -2-butylsurfonamido-propionic acid with 0.038 g of DPFN

0.044 g of 2-butylsulfonamido-3- [4- (5-guanidino-pentyn-1-yl) phenyl] propionic acid; Mp 147-150 °; FAB 409.

Example 12

Analogously to Example 4, from 0.5 g of 3- [4- (5-azido-pentin-1-yl) phenyl] -2-butylsurfonamido-propionic acid benzyl ester, after customary working up, 0.15 g of 3- [4- (5- Amino-pent-1-yl) phenyl] -2-butylsulfonamido-propionic acid; FAB 371.

Analogously to Example 5, reaction of 0.11 g of 3- [4- (5-amino-pent-1-yl) phenyl] -2-butylsulfonamido-propionic acid with 0.088 g of DPFN

0.06 g of 2-butylsulfonamido-3- [4- (5-guanidino-pent-1-yl) phenyl] propionic acid as a hygroscopic, deliquescent mass; FAB 413.

Example 13

A solution of benzyl (S) -2-butylsurfonamido-3- [4- (4-azidobutoxy) phenyl] propionate and 1.1 molar equivalent of NaH in THF is stirred for 1 hour under an inert gas atmosphere at room temperature. Then 2 molar equivalents of methyl iodide are added, working as usual after 1 hour and obtains (S) -2- (N-methylbutylsulfonamido) -3- [4- (4-azidobutoxy) phenylj-propionic acid benzyl ester.

Analogously to Example 4, reduction (S) -2- (N-methylbutylsulfonamido) -3- [4- (4-aminobutoxy) phenyl] propionic acid is obtained and reaction with DPFN analogously to Example 5 (S) -2 - (N-Methylbutylsulfonamido) -3- [4- (4-guanidinobutoxy) phenyl] propionic acid, FAB 429.

Example 14

Analogously to Example 1, benzyl ester is obtained starting from benzyl menthyloxycarbonylamino-propionate by reaction with 1,4-dibromobutane (S) -3- [4- (4-bromobutoxy) phenyl] -2-N-menthyloxycarbonylamino-propionic acid benzyl ester. By reaction with NaN ₃ and subsequent reduction analogously to Example 4, (S) -3- [4- (4-aminobutoxy) phenyl] -2-N-methyloxycarbonylamino-propionic acid is obtained, which with DPFN analogously to Example 5 in

(S) -2-N-menthyloxycarbonylamino-3- [4- (4-guanidinobutoxy) phenyl] propionic acid is converted, FAB 477.

Example 15

A solution of 2.3 g of (S) -3- [4- (5-bromopentyloxy) phenyl] -2-N-tert-butyl-oxycarbonyl-propionic acid benzyl ester, El 520 [obtainable by reacting 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-crown-6 in 50 ml of toluene], 1.6 g of KCN and 0.580 g of 18-crown-6 in 30 ml Acetonitrile is boiled under reflux for 12 hours. After customary working up, 1.97 g of (S) -3- [4- (5-cyano-pentyloxy) phenyl] -2-N-tert-butyloxycarbonyl-propionic acid benzyl ester, FAB 467, is obtained as an oily syrup.

Analogously, benzyl (S) -3- [4- (4-bromobutoxy) phenyl] -2-N-tert-butyl-oxycarbonyl-propionate is obtained

(S) -3- [4- (4-Cyanobutoxy) phenyl] -2-N-tert-butyloxycarbonyl-propionic acid benzyl ester.

Example 16 Analogously to Example 2 and Example 3, 1.97 g of (S) -3- [4- (5-cyanopentyloxy) phenyl] -2-N-tert-butyloxycarbonyl-propionic acid benzyl ester are obtained by treatment with TFA and subsequent reaction with Benzyl butylsulfonyl chloride 1.5 g (S) -2-butylsulfonamido-3- [4- (5-cyanopentyloxy) phenyl] propionate, FAB 487.

Analogously, benzyl (S) -3- [4- (4-cyanobutoxy) phenyf] -2-N-tert-butyl-oxycarbonyl-propionate is obtained

(S) -2-Butylsutfonamido-3- [4- (4-cyanobutoxy) phenyl] propionic acid benzyl ester.

Example 17

A solution of 1, 5 g of (S) -2-butylsutfonamido-3- [4- (5-Cyaπpentyloxy) - phenylj-propionic acid benzyl ester, 0.646 g of hydroxylamine hydrochloride and

0.780 sodium hydrogen carbonate in 50 ml isopropanol / water 6: 1 is heated under reflux for 12 hours. After customary working up, 1.6 g of (S) -2-butylsulfonamido-3- [4- (6-amino-6-N-hydroxylimino-hexyloxy) phenyl] propionic acid benzyl ester, FAB 520, is obtained as a colorless syrup.

Analogously, benzyl ester is obtained from (S) -2-butylsulfonamido-3- [4- (4-Cyanbtιtoxy) phenyl] propionic acid

(S) -2-butylsulfonamido-3- [4- (5-amino-5-N-hydroxylimino-pentyloxy) phenyl] propionic acid benzyl ester and

from (S) -3- [4- (4-cyanobutoxy) phenyl] -2-N-tert-butyloxycarbonyl-propionic acid benzyl ester

(S) -3- [4- (5-Amino-5-N-hydroxylimino-pentyloxy) phenyl] -2-N-tert-butyloxycarbonyl-propionic acid benzyl ester.

Example 18

A solution of 1, 6 g (S) -2-butylsulfonamido-3- [4- (6-amino-6-N-hydroxylimino-hexyloxy) phenyl] propionic acid benzyl ester in 30 ml acetic acid and 1 ml acetic anhydride is with 50 mg palladium - Catalyst (10% on activated carbon) hydrogenated for 2 hours at room temperature and normal pressure. After removal of the catalyst, customary work-up and purification by preparative HPLC analogously to Example 5, 0.24 g of (S) -2-butylsulfonamido-3- [4- (5-amidinopentyloxy) phenylj-propionic acid, FAB 414.

Analogously, (S) -2-butylsulfonamido-3- [4- (5-amino-5-N-hydroxylimino-pentyloxy) phenylj-propionic acid benzyl ester (S) -2-butylsulfonamido-3- [4- (4- Amidinobutoxy) phenyl] propionic acid, FAB 400 and

from (S) -3- [4- (5-amino-5-N-hydroxylimino-pentyloxy) phenyl] -2-N-tert-butyl-oxycarbonyl-propionic acid benzyl ester (S) -3- [4- (4- Amidinobutoxy) phenyl] -2-N-tert-butyloxycarbonyl-propionic acid, FAB 380.

Example 19

Analogously to Example 7, reaction of 0.4 g of (S) -3- (4-amonophenyO-2-butylsulfonamido-propionic acid ethyl ester, 0.3 g of N-BOC-piperidine-4-carboxylic acid, 0.05 g HOBt and 264 μl N-methylmorpholine in 10 ml DMF after conventional work-up 0.428 g (S) -2-butylsurfonamido-3- [4- (1- tert-butyloxycarbonyl-piperidine-4-carboxamido) phenyl] propionic acid ethyl ester , FAB 540.

Example 20

Analogously to Example 8, 0.42 g of (S) -2-butylsulfonamido-3- [4- (1-tert.-butyloxycarbonyl-piperidine-4-carboxamido) phenyl] propionic acid ethyl ester is obtained by ester hydrolysis with NaOH and cleavage of the BOC group with TFA 0.225 g of (S) -2-butylsulfonamido-3- [4- (piperidin-4-yl-carboxamido) phenyl] propionic acid, FAB 412.

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

Example 21

(S) -2-butylsulfonamido-3- [4- (5- (5-phenyl-1,2,4-oxadiazole) pentyloxy) phenylj-propionic acid [obtainable by reacting (S) -2-butylsulfonamido 3- [4- (6-Amino-6-N-hydroxylimino-hexyloxy) phenyl] propionic acid with 1.1 equivalents of benzoyl chloride and triethylamine] is analogous

Example 18 hydrogenated. After removal of the catalyst and usual work-up, (S) -2-butylsulfonamido-3- [4- (5-amidinopentyloxy) phenyl] propionic acid, FAB 414 is obtained.

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium hydrogenphosphate are adjusted to pH 6.5 in 3 l of double-distilled water with 2N hydrochloric acid, 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 an active ingredient of the formula I is melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH ₂ PO ₄ .2H ₂ O, 28.48 g of Na ₂ HPO ₄ .12H ₂ O and 0.1 g of benzalkonium chloride in 940 ml of double distilled water. Adjust to pH 6.8 makes up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment

500 mg of an active ingredient of the formula I are mixed with 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 into tablets in a conventional manner 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 active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

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

Example I: Inhalation spray 14 g of active ingredient of the formula I are dissolved in 10 I of isotonic NaCI 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.

wherein

X alkylene with 1-6 C atoms or 1,4-piperidyl,

Y is missing, O, CONH, or -C≡C-,

R ¹ H, CN, N ₃ , NH ₂ , H ₂ NC (= NH) or H ₂ N- (C = NH) -NH, where the primary amino groups can also be provided with conventional amino protective groups,

A, R ⁴ each independently of one another H, alkyl having 1-10 C atoms or benzyl,

and

Ar unsubstituted or simply substituted by CH ₃ phenyl or benzyl,

mean,

and their physiologically acceptable salts.

2. Enantiomers or diastereomers of the compounds of formula I according to claim 1.

3. (a) (S) -2-butylsurfonamido-3- [4- (4-guanidino-butoxy) phenyl] propionic acid;

(b) (S) -2-tert-butyloxycarbonylamino-3- [4- (4-guanidino-butoxy) phenyl] propionic acid;

(c) (S) -2-propylsulfonamido-3- [4- (4-guanidino-butoxy) phenyl] propionic acid;

(d) (S) -2-butylsurfonamido-3- [4- (3-guanidino-propoxy) phenyl] propionic acid;

(e) (S) -2-butylsurfonamido-3- [4- (4-guanidino-butyramido) phenyl] propionic acid;

(f) 2-butylsurfonamido-3- [4- (5-guanidino-pentyl) phenyl] propionic acid;

(g) 2-butylsulfonamido-3- [4- (5-guanidino-pentyn-1-yl) phenyl] propionic acid,

(h) (S) -2-butylsulfonamido-3- [4- (5-guanidino-pentyloxy) phenyl] propionic acid;

(i) (S) -2-benzylsurfonamido-3- [4- (4-guanidino-butoxy) phenyl] propionic acid;

(j) (S) -2-pentylsulfonamido-3- [4- (4-guanidino-butoxy) phenyl] propionic acid;

(k) (S) -2- (4-tolylsulfonamido) -3- [4- (4-guanidino-butoxy) phenyl] propionic acid; (I) (S) -2- (N-methylbutylsulfonamido) -3- [4- (4-guanidino-butoxy) phenyl] propionic acid;

(m) (S) -2-tert-butyloxycarbonylamino-3- [4- (4-amidino-butoxy) phenyl] propionic acid;

(n) (S) -2-butylsulfonamido-3- [4- (4-amidino-butoxy) phenyl] propionic acid;

(o) (R) -2-butylsuffonamido-3- [4- (4-guanidino-butoxy) phenyl] propionic acid;

(p) (S) -2- (camphor-10-sulfonamido) -3- [4- (4-guanidino-butoxy) phenyl] propionic acid;

as well as the physiologically acceptable acid addition salts of the compounds mentioned.

4. A process for the preparation of compounds of the formula I as claimed in claim 1,

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

R ¹ N ₃ , R ² H,

R ³ A-SO ₂ - or Ar-SO ₂ -

X alkylene with 1-6 C atoms,

Y is absent, O or -C≡C-, and R ^{4 is} alkyl with 1-10 C atoms or benzyl,

a compound which corresponds to the formula I per se, but in which

R ¹ N 3,

> 2nd

R "H, X alkylene with 1-6 C atoms,

Y is missing, O or -C≡C-,

R ^{3 is} a conventional amino protecting group and

R ⁴ denotes alkyl with 1-10 C atoms or benzyl,

first treated with a solvolysing agent and then with a compound of formula II

R ³ -L

wherein

A-SO ₂ - or Ar-SO ₂ - and

L denotes Cl, Br, I, OH or a reactive esterified OH group,

implements, or

b) that one saponifies an ester of formula I, or

i) converting an azido group into an amino group by reduction,

ii) converts a cyano group into an amidino group,

Sets amino group free, v) releases an amidino group from its oxadiazole derivative by hydrogenolysis,

and or

d) converting a basic or acidic compound of formula I into one of its salts by treatment with an acid or base.

5. A process for the preparation of a pharmaceutical preparation, characterized in that a compound of the formula I as claimed in claim 1 and / or one of its physiologically acceptable salts together with at least one solid, liquid or semi-liquid vehicle or hemp substance is suitable Dosage form brings.

6. Pharmaceutical preparation, characterized by a content of at least one compound of the formula I according to claim 1 and / or one of its physiologically acceptable salts.

7. Compounds of formula I according to claim 1 and their physiologically acceptable salts as integrin inhibitors for combating pathologically angiogenic diseases, thromboses, heart attacks, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammation and infections.

8. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament.

9. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts in the control of diseases.

10. Compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament for use as an α _v -integrin inhibitor.