KR19990076676A - Tyrosine derivatives used as alpha-V-integrin inhibitors - Google Patents

Abstract

The compounds of formula (I) and their physiologically acceptable salts can be used for the treatment of? _V -integrin inhibitors, in particular, for the treatment of tumorigenesis, osteoporosis, keloid diseases and inhibition of angiogenesis.

Formula I

[In the above formula,

X is alkylene having 1 to 6 carbon atoms or 1,4-piperidyl,

Y is absent, O, CONH or -C? C-,

R ¹ is H, CN, N ₃ , NH ₂ , H ₂ NC (═NH), H ₂ N- (C═NH) -NH wherein the primary amino group can also be protected with conventional amino protecting groups In addition,

R ² and R ³ are each independently H, A, A-SO ₂ -, Ar-SO ₂ -, camphor-10-SO ₂ -, COOA or a common amino protecting group,

A and R < ⁴ > are each independently H, alkyl having 1-10 carbon atoms or benzyl,

Ar is optionally substituted, respectively, is one substituted phenyl or benzyl with CH _3.]

Description

Tyrosine derivatives used as alpha-V-integrin inhibitors

Similar compounds are disclosed, for example, in EP 0 478 365 and EP 0 478 328.

The present invention relates to compounds of formula (I) and physiologically acceptable salts thereof.

[In the above formula,

X is alkylene having 1 to 6 carbon atoms or 1,4-piperidyl,

Y is absent, O, CONH or -C? C-,

R ¹ is H, CN, N ₃ , NH ₂ , H ₂ NC (═NH), H ₂ N- (C═NH) -NH wherein the primary amino group can also be protected with conventional amino protecting groups In addition,

R ² and R ³ are each independently H, A, A-SO ₂ -, Ar-SO ₂ -, camphor-10-SO ₂ -, COOA or a common amino protecting group,

A and R < ⁴ > are each independently H, alkyl having 1-10 carbon atoms or benzyl,

Ar is optionally substituted, respectively, is one substituted phenyl or benzyl with CH _3.]

The object of the present invention is to find novel compounds which have useful properties and which can be produced in particular as pharmaceuticals.

The compounds of formula I and their salts have very useful pharmacological properties and excellent resistance. They are particularly active as integrin inhibitors, particularly inhibiting the interaction of the ligand with the? _V -integrin receptor. These compounds exhibit specific activity in the case of integrin [alpha] _{v [} beta] ₃ and [alpha] _{v [} beta] ₅ . These compounds are particularly active as adhesion receptor antagonists to the vitronectin receptor [alpha] _{v [} beta] ₃ . This action is described, for example, in JW Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).

It has been experimentally confirmed that some representative compounds of formula I inhibit binding of bitronectin to the receptor. The pharmacy test data is shown in Table I.

[B. Felding-Habermann and in Cheresh in Curr. Opin. Cell. Biol. 5, 864 (1993) describes the importance of integrins as adherent receptors in various phenomena and syndromes, in particular the bitonectin receptor? _V ? ₃ .

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

The possibility of inhibiting this interaction by the cyclopeptide and initiating apoptosis of angiogenic vascular cells (planned cell death) is described in 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).

Experimental evidence that compounds according to the present invention prevent live cells from attaching to the corresponding substrate proteins and thus prevent tumor cells from attaching to the substrate proteins is described in F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995)]. The pharmacological data are shown in Table II.

PC Brooks et al. Clin. Invest. 96, 1815-1822 (1995)) and describes an < RTI ID = 0.0 > _v < / RTI > ₃ antagonist to treat tumor-induced angiogenic diseases.

Accordingly, the compounds of formula (I) according to the invention can be used as pharmaceutically active compounds, particularly for the treatment of tumorigenesis, osteoporosis, keloid diseases and inhibition of angiogenesis.

Accordingly, the present invention relates to a compound of formula I according to claim 1 and / or a physiologically acceptable salt thereof, which can be produced as a medicament for an? _V -integrin inhibitor.

The compounds of formula I can be used in the treatment of osteoinductive diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, stroke, angina pectoris, tumorigenesis, osteoporosis and the like such as inflammatory diseases, eye diseases, diabetic retinopathy, A prophylactic and / or therapeutic agent for the prevention and / or treatment of recurrent stenosis, viral infections, bacterial infections, fungal infections after psoriasis, angioplasty, atherosclerosis, ulcerative colitis, Crohn ' s disease, atherosclerosis, rheumatoid arthritis, osteoarthritis, Or as pharmaceutically active compounds in human and veterinary medicine to aid in the healing process during treatment and acute renal failure and wound healing.

The compounds of formula I can be used as antimicrobial agents during surgery where biocompatible materials, implants, catheters or cardiac pacemakers are used. In these cases, these compounds have side effects. [P. The effect of antimicrobial activity can be demonstrated by the method described by Valentin-Weigund et al., In Infection and Immunity, 2851-2855 (1988).

The present invention also

a) R < ¹ > is N < ₃ &

R < ² > is H,

R ³ is A-SO ₂ - or Ar-SO ₂ -

X is alkylene having 1 to 6 carbon atoms,

Y is absent, O or -C? C-,

In order to prepare the compounds of formula I wherein R < ⁴ > is alkyl of 1-10 carbon atoms or benzyl,

R ¹ is N ₃ ,

R < ² > is H,

X is alkylene having 1 to 6 carbon atoms,

Y is absent, O or -C? C-,

R < ³ > is a normal amino protecting group,

The compound corresponding to formula (I) in which R < ⁴ > is alkyl of 1 to 10 carbon atoms or benzyl is first treated with solubilization to give a compound of formula

R ³ -L

[In the above formula,

R ³ is A-SO ₂ - or Ar-SO ₂ -

L is Cl, Br, I, OH or an esterified reactive OH group.

≪ / RTI > or

b) hydrolyzing the ester of formula (I); or

c) i) converting the azido group to an amino group,

ii) conversion of a cyano group to an amidino group,

iii) converting the amino group into an guanidino group by reacting with an aminating agent,

iv) deprotection of the amino group protected by a common protecting group, or deprotection of an amino group protected by an ordinary protecting group,

v) hydrolyzing the oxadiazole derivative to liberate the amidino group, thereby converting the radicals R ¹ and / or R ² to other radicals R ¹ and / or R ² ; And / or

d) treating a compound of formula I, which is basic or acid, with an acid or base to convert it to one of its salts.

Since compounds of formula I have one or more chiral centers, several stereoisomers can be produced. Such stereoisomers (e. G. D- and L-form) and mixtures thereof (e. G., DL-form) are all included in formula I.

Abbreviations mentioned above and below indicate the following.

Ac Acetyl

BOC tert-butoxycarbonyl

CBZ or Z benzyloxycarbonyl

DCCI dicyclohexylcarbodiimide

DMF dimethylformamide

ECDI N-ethyl-N, N '- (dimethylaminopropyl) -carbodiimide

Ethyl ethyl

Fmoc 9-fluorenylmethoxycarbonyl

HOBt 1-hydroxybenzotriazole

Me methyl

Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl

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, the alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tertiary butyl and also preferably pentyl, 1-, 2- or 3- 1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, Ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-tetramethylbutyl, Or 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl are more preferable, and a 3-methyl radical is more preferable.

The alkylene is preferably methylene, ethylene, propylene, butylene or pentylene, and more preferably hexylene.

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

The amino protecting group is selected from the group consisting of acetyl, propionyl, butyryl, phenylacetyl, benzoyl, tolyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2- trichloroethoxycarbonyl, Ethoxycarbonyl, CBZ (" carbobenzoxy "), 4-methoxybenzyloxycarbonyl, Fmoc, Mtr or benzyl are preferred.

Accordingly, the present invention relates especially to compounds of formula I wherein at least one of said radicals has at least one of the above preferred definitions. Some preferred groups of compounds may be represented by the following formulas Ia-Ie. These correspond to the general formula (I), and the radicals not shown in detail other than those shown below are as defined in the formula (I).

In a), R ¹ is NH ₂ ,

X is alkylene having 1 to 6 carbon atoms,

Y is O,

R ² is H,

R ³ is A-SO ₂ -

R ⁴ is H;

b), R ¹ is H ₂ NC (═NH)

X is alkylene having 1 to 6 carbon atoms,

Y is O,

R ² is H,

R ³ is A-SO ₂ -

R ⁴ is H;

c), R ¹ is H ₂ N- (C = NH) -NH,

X is alkylene having 1 to 6 carbon atoms,

Y is O,

R ² is H,

R ³ is A-SO ₂ -

R ⁴ is H;

d), X is alkylene having 1 to 6 carbon atoms,

Y is absent,

R ² and R ⁴ are H,

R ³ is COOA;

e) R ¹ is H ₂ N- (C = NH) -NH,

X is alkylene having 1 to 6 carbon atoms,

Y is CONH,

R ² and R ⁴ are H,

R ³ is A-SO ₂ -.

Alternatively, the compounds of formula I and also the starting materials for their preparation are prepared by known methods as described in the literature (for example, in the authoritative book Houben-Wely, Methoden der Organischen Chemie, Georg-Thieme-Verlag, Stuttgart, , That is, under known reaction conditions suitable for the above reaction. In this case, various known modifications may occur, but are not described in detail herein.

If necessary, the starting materials may be formed in the same reactor without separation in the reaction mixture and reacted immediately to give the compounds of formula (I).

R ¹ is N ₃ ,

R < ² > is H,

R ³ is A-SO ₂ - or Ar-SO ₂ -

X is alkylene having 1 to 6 carbon atoms,

Y is absent, O or -C? C-,

Compounds of formula (I) wherein R < ⁴ > is alkyl of 1-10 carbon atoms or benzyl are preferably obtained by first reacting the compound of formula (I) with a solubilizing agent, .

[In the above formula,

R ³ is a conventional amino protecting group,

R < ⁴ > is alkyl of 1 to 10 carbon atoms or benzyl,

X is alkylene having 1 to 6 carbon atoms,

Y is absent or O or -C? C-.]

The term " amino protecting group " is generally known and relates to a group that is suitable for protecting (or shielding) an amino group from a chemical reaction and which can be easily removed at the other site of the molecule after the desired chemical reaction is over. Typical groups of this type include, in particular, substituted or unsubstituted acyl, aryl, aralkoxymethyl or aralkyl groups. Alternatively, since the amino protecting groups are removed after the desired reaction (or reaction sequence), their nature and size are not important; However, it is preferable to have 1-20 carbon atoms, especially 1-8 carbon atoms. The term " acyl group " should be interpreted broadly in the context of the present process. The term includes alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups as well as acyl groups derived from aliphatic, aromatic aliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids. Examples of such an acyl group include alkanoyl such as acetyl, propionyl, butyryl and the like; Aralkanoyl such as phenyl acetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl and the like; Aralkyloxycarbonyl such as CBZ (" carbobenzoxy "), 4-methoxybenzyloxycarbonyl, Fmoc and the like; Mtr and the like. BOC and Mtr are preferred as amino protecting groups, and CBZ, Fmoc, benzyl and acetyl are also preferred.

The amino protecting group may be removed, for example, using strong acids, for convenience TFA or perchloric acid, depending on the protecting group used, but other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid, -Sulfonic acid such as toluenesulfonic acid. In addition, inert solvents may be used but are not always necessary. Suitable inert solvents include organic solvents, for example, carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and methanol, Alcohol and water such as isopropanol are also preferred. Mixtures of the above solvents are also suitable. It is preferable to use TFA in an excess amount without adding any other solvent, and it is preferable to use perchloric acid in the form of a mixture of acetic acid and perchloric acid at a concentration of 70% at a ratio of 9: 1. The reaction temperature for the decomposition is conveniently in the range of about 0 ° to 50 °, and the reaction is preferably carried out at 15 ° to 30 ° (room temperature).

BOC, OBut, and Mtr may be removed, for example, preferably using TFA in dichloromethane, or may be removed using about 3-5N HCl in dioxane at 15-30 [deg.], Is preferably removed using a solution of dimethylamine, diethylamine or piperidine at a concentration of about 5-50% in DMF.

The protecting group (e.g., CBZ or benzyl) that can be removed by the hydrogenolysis reaction can be removed by treatment with hydrogen in the presence of, for example, a catalyst (for example a noble metal catalyst such as palladium on a support such as carbon for convenience) Can be removed. Suitable solvents in such cases are as described above, for example, alcohols such as methanol or ethanol, or amides such as DMF are particularly suitable. The hydrogenolysis reaction is generally carried out at a temperature of about 0-100 ° and a pressure of 1-200 bar, preferably 20-30 °, 1-10 bar. Hydrogenolysis of the CBZ group can be carried out using, for example, ammonium formate (instead of hydrogen) on Pd / C at a concentration of 5-10% in methanol or Pd / C in methanol / DMF at 20-30 ° When the reaction occurs well.

The compounds of formula (II) are generally known and can be prepared by known methods, if not known.

The reaction of the compound of formula (II) is generally carried out in an inert solvent in the presence of an acid-coupling agent, preferably in the presence of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline.

It may be advantageous to add alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates or to add other salts of alkali metal or alkylitomic metals, preferably potassium, sodium, calcium or cesium.

The reaction time is between several minutes and 14 days, depending on the conditions used, and the reaction temperature is about -30 to 140, generally -10 to 90, and preferably about 0 to about 70.

Suitable inert solvents include, for example, 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 monoether ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate; Water or a mixture of these solvents.

In addition, esters of formula (I) can be hydrolyzed. Conveniently, the hydrolysis is carried out as described above, for example, by means of an aqueous solution of NaOH or KOH in dioxane-water at a temperature of from 0 to 60 DEG C, preferably from 10 to 40 DEG C, .

Further, it is possible to convert a radical R ¹ and / or R ² into another radical R ¹ deionized and / or R ^2. In particular, the azido group may be converted into an amino group by, for example, the above-described hydrolysis reaction, or an amino group may be converted into a guanidino group by an amineating agent such as dimethylpyrazole formamidinium nitrate . The cyano group is converted into an amidino group by, for example, reaction using hydroxylamine and subsequent reaction of N-hydroxyamidine with hydrogen in the presence of a catalyst such as Pd / C. Further, as described above, the protecting group can be removed by solvolysis or hydrolysis, or the amino group protected by a common protecting group can be deprotected by solvolysis or hydrolysis to replace the usual amino protecting group with hydrogen.

The base of formula (I) can be converted to the corresponding acid addition salt using an acid, for example, by reacting an equivalent amount of base with an acid in an inert solvent such as ethanol and then evaporating. Acids suitable for such reactions are those which provide particularly physiologically acceptable salts. Therefore, the use of inorganic acids such as hydrohalic acids such as sulfuric acid, nitric acid, hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acids and organic acids, especially aliphatic, alicyclic, aromatic aliphatic, aromatic or heterocyclic mono- or poly For example, carboxylic acid, sulfonic acid or sulfuric acid such as formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimetic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Methane- or ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono-and disulfonic acid and laurylsulfuric acid may be used. Salts with physiologically acceptable acids, e. G., Picrates, can be used in the separation and / or purification of the compounds of formula (I).

On the other hand, an acid of formula (I) may be converted into one of its physiologically acceptable metal or ammonium salts by reaction with a salt. Possible salts in this case are, in particular, salts with sodium, potassium, magnesium, calcium and ammonium salts, also with substituted ammonium salts such as dimethyl-, diethyl- or diisopropylammonium salts, monoethanol, diethanol or diisopropylammonium salts , Cyclohexyl- or dicyclohexylammonium salts, dibenzylethylenediammonium salts, and also salts of, for example, arginine or lysine.

The compounds of formula I may have one or more chiral centers and thus may have a racemic or optically active form. The obtained racemate can be mechanically or chemically separated into enantiomers by known methods. It is preferred to form the diastereomer from the racemic mixture by reaction using an optically active resolving agent. Suitable resolving agents include, for example, various optically active camphorsulfonic acids such as D-type and L-type tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, It is an acid. Partitioning of enantiomers using columns packed with an optically active resolving agent (e. G., Dinitrobenzoylphenylglycine) is also advantageous, and suitable eluents are, for example, hexane / isopropanol mixed in a volume ratio of 82: / Acetonitrile mixture.

Of course, it is possible to obtain the optically active compounds of formula I by the above-mentioned method using already optically active starting materials.

The results of the inhibition of α _v β ₃ - and α _v β ₅ by several representative compounds of formula I are summarized in the following Table I. For the vitronectin binding test, the IC ₅₀ value, i.e. the concentration at which 50% of bitonectin is inhibited from binding to the corresponding glass receptor (nmol / l) is shown.

Smith et al., J. Biol. Chem. 265, 12267-71 (1990)], IC ₅₀ values of some representative compounds of formula I obtained in a manner analogous to that of the method of the present invention, in which 50% of the bitternetin, as expressed in nmol / ) And the FAB value of the measured substance R ¹ R ² R ³ X Y FAB IC ₅₀ ? _V ? ₃ IC ₅₀ ? _V ? ₅ (One) H Butyl-SO ₂ Butylene O 415 0.4 216 (One) H BOC Butylene O 395 3.5 60 (One) H Propyl-SO ₂ Butylene O 401 8.9 1000 (One) H Butyl-SO ₂ Pentylene O 429 0.45 970 (One) H Butyl-SO ₂ Propylene CONH 428 2.0 1120 (One) H Benzyl-SO ₂ Butylene O 449 4.4 (One) H Pentyl-SO ₂ Butylene O 429 5.5 (One) H 4-tolyl-SO ₂ Butylene O 449 6.6

R ¹ R ² R ³ X Y FAB IC ₅₀ ? _V ? ₃ IC ₅₀ ? _V ? ₅ (One) H Butyl-SO ₂ Propylene O 401 20 (1) ^* H Butyl-SO ₂ Propylene (A) 409 15 (One) CH ₃ Butyl-SO ₂ Butylene O 429 17 (1) ^* H Butyl-SO ₂ Pentylene absence 413 30 (2) H BOC Butylene O 380 36 (2) H Butyl-SO ₂ Butylene O 400 66 (1) ♣ H Butyl-SO ₂ Butylene O 415 229 (2) H Butyl-SO ₂ (B) CONH 454 540 NH ₂ H Butyl-SO ₂ Butylene O 373 140 NH ₂ H Butyl-SO ₂ Pentylene absence 371 2400 (2) H Butyl-SO ₂ Pentylene O 414 2700 (One) H H Butylene O 295 3700 NH ₂ ^* H Butyl-SO ₂ Propylene (A) 367 3900 NH ₂ ^* H Butyl-SO ₂ Pentylene O 373 700 NH ₂ H Butyl-SO ₂ Hexylene O 387 2900 (One) H Camphor-10-SO ₂ Butylene O 509 0.6 H H Butyl-SO ₂ (B) CONH 412 9180 _{(1) = H 2 NC (} = NH) -NH-; (2) = H ₂ NC (= NH) -; (A) = -C? C-; (B) = * = Racemate; ♣ = 2- (R) -isomer

From the pharmacological data, it has been confirmed that the compounds of formula I according to the invention exhibit antagonistic activity against the vitronectin receptors α _v β ₃ and α _v β ₅ .

The results of the cell adhesion test for some representative compounds of formula I are summarized in Table II. The IC ₅₀ value, i.e., the concentration at which 50% binding was achieved compared to the control without the material was indicated.

F. The IC ₅₀ value (μmol / l) and the FAB value of the measured substance (comparative substrate protein (μmol / l)) of a representative compound of formula I obtained by a method similar to that of Mitjans et al., J. Cell Science 108, 2825-2838 Was used. R ¹ R ² R ³ X Y FAB IC ₅₀ (One) H Butyl-SO ₂ Butylene O 415 One (One) H BOC Butylene O 395 0.5 (One) H Propyl-SO ₂ Butylene O 401 2.7 (One) H Butyl-SO ₂ Pentylene O 429 4 (One) H Butyl-SO ₂ Propylene CONH 428 2.7 (One) H Pentyl-SO ₂ Butylene O 429 2.1 _{(1) = H 2 NC (} = NH) -NH

From the pharmacological data, it has been confirmed that the compounds of formula I according to the invention exhibit antagonistic activity against the adherence of the tumor cells to the tissues.

The present invention also relates to the use of a compound of formula I and / or a physiologically acceptable salt thereof, in a particularly non-chemical way, for the production of pharmaceutical preparations. In this regard, they may be in admixture with one or more solid, liquid and / or semi-liquid excipients or adjuvants and, where appropriate, in combination with other active compounds, in a suitable dosage form.

The present invention also relates to pharmaceutical preparations comprising at least one compound of formula I and / or a physiologically acceptable salt thereof.

Such pharmaceutical preparations can be used as pharmaceutical preparations in human medicine or veterinary medicine. Possible excipients are organic or inorganic substances which are suitable for enteral (e.g. oral) or parenteral or local application, or for administration in the form of an inhaler spray, and which do not react with the novel compounds, for example water , Vegetable oil, benzyl alcohol, alkylene glycols, polyethylene glycols, glycerol triacetate, carbohydrates such as gelatin, lactose or starch, magnesium stearate, talc and petrolatum. In particular, suppositories are used in rectal administration in the form of solutions, preferably oily or aqueous solutions and suspensions, emulsions, suspensions, solutions, suspensions and the like, in the form of tablets, pills, pills, capsules, powders, granules, syrups, Or implants are used for parenteral administration, and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophiles obtained can be used, for example, for the production of injectables.

The pharmaceutical preparations described above may be sterilized and may be sterilized and used in the form of lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts affecting osmotic pressure, buffering substances, coloring agents, flavoring agents and / or one or more other active compounds, , Vitamins and the like. For administration by inhalation spray, a spray containing the active compound dissolved or suspended in a propellant or propellant mixture (e. G., CO ₂ or chlorofluorohydrocarbons) may be used. In this case, the active compound is conveniently used in a finely divided form, so that one or more physiologically acceptable solvents (e. G., Ethanol) may be added. The inhalant solution may be administered using a conventional inhaler.

The compounds of formula I and their physiologically acceptable salts can be used as integrin inhibitors in the control of diseases, in particular angioplasty diseases, thrombosis, myocardial infarction, coronary heart disease, arteriosclerosis, tumors, osteoporosis, inflammation and infection .

In this case, the substances according to the invention are generally used in analogous manner to the other known commercially available peptides, in particular the compounds described in US-A-4 472 305, preferably at a dosage of about 0.05 to 500 mg per dosage unit , More preferably 0.5 to 100 mg, per day. A daily dose of about 0.01 to 2 mg / kg body weight is preferred. However, the specific dose for each patient will depend upon a variety of factors, including, for example, the effectiveness of the particular compound employed, age, weight, general condition of health, sex, diet, time and route of administration, And the severity of the particular disease to which the treatment is applied. Parenteral administration is preferred.

In the above and below, all temperatures are expressed in ° C. In the following examples, the term " conventional operation " means: adding water if necessary, adjusting the pH of the mixture to between 2 and 10, extracting with ethyl acetate or dichloromethane according to the configuration of the final product, Separation, drying with sodium sulfate, evaporation, and purification of the residue by chromatography and / or recrystallization on silica gel.

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

FAB (fast atom impact) (M + H) ⁺

Example 1

To a solution of benzyl (S) -3- [4- (4-bromobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate [BOC- Dibromobutane in 80 ml of toluene in the presence of 5 g of potassium carbonate and 0.1 g of 18-crown-6 in 20 ml of toluene] was added to a solution of 2.5 g of the compound dissolved in 20 ml of DMF and sodium azide Was stirred for 12 hours. After the usual work-up, lyophilization gave benzyl (S) -3- [4- (4-azidobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate as colorless syrup; FAB 469.

Similarly,

Benzyl (R) -3- [4- (4-bromobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate,

Benzyl (S) -3- [4- (5-bromopentyloxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate,

Benzyl (R, S) -3- [4- (5-bromopentyloxy) phenyl] -2-N- tert -butoxycarbonylaminopropionate,

Benzyl (S) -3- [4- (3-bromopropoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate and

Benzyl (S) -3- [4- (6-bromohexyloxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate was reacted with sodium azide,

Benzyl (R) -3- [4- (4-azidobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate,

Benzyl (S) -3- [4- (5-azidopentyloxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate,

Benzyl (R, S) -3- [4- (5-azidopentyloxy) phenyl] -2-N- tert -butoxycarbonylaminopropionate,

Benzyl (S) -3- [4- (3-azidopropoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate and

Benzyl (S) -3- [4- (6-azidecyloxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate was obtained.

Example 2

A solution of 2.0 g of benzyl (S) -3- [4- (4-azidobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate and 2 ml of trifluoroacetic acid was stirred at room temperature for 3 hours Lt; / RTI > After removal of the TFA, benzyl (S) -2-amino-3- [4- (4-azidobutoxy) phenyl] propionate ("A") was obtained as colorless syrup.

Similarly, using TFA,

Benzyl (R) -3- [4- (4-azidobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate,

Benzyl (S) -3- [4- (5-azidopentyloxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate,

Benzyl (R, S) -3- [4- (5-azidopentyloxy) phenyl] -2-N- tert -butoxycarbonylaminopropionate,

Benzyl (S) -3- [4- (3-azidopropoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate and

Removal of the BOC group from benzyl (S) -3- [4- (6-azidecyloxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate gave

Benzyl (R) -2-amino-3- [4- (4-azidobutoxy) phenyl] propionate,

Benzyl (S) -2-amino-3- [4- (5-azidopentyloxy) phenyl] propionate,

Benzyl (R, S) -2-amino-3- [4- (5-azidopentyloxy) phenyl] propionate,

Benzyl (S) -2-amino-3- [4- (3-azidopropoxy) phenyl] propionate and

Benzyl (S) -2-amino-3- [4- (6-azidecyloxy) phenyl] propionate.

Example 3

A solution of 1.6 g of "A" in 20 ml of dichloromethane was treated with 0.84 ml of butylsulfonyl chloride and 1.2 ml of triethylamine, and the mixture was stirred at room temperature for 12 hours. After usual workup, 1.4 g of benzyl (S) -2-butylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionate was obtained as colorless syrup; FAB 489.

Similarly, " A "

Propylsulfonyl chloride,

Benzylsulfonyl chloride,

Pentylsulfonyl chloride,

4-Tolylsulfonyl chloride and

Lt; RTI ID = 0.0 > camphor-10-sulfonyl <

Benzyl (S) -2-propylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionate,

Benzyl (S) -2-benzylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionate,

Benzyl (S) -2-pentylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionate,

Benzyl (S) -2-4-tolylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionate,

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

Similarly,

Benzyl (S) -2-amino-3- [4- (5-azidopentyloxy) phenyl] propionate with butylsulfonyl chloride to give benzyl (S) [4- (5-azidopentyloxy) phenyl] propionate,

(R, S) -2-amino-3- [4- (5-azidopentyloxy) phenyl] propionate was reacted with butylsulfonyl chloride to give benzyl -3- [4- (5-azidopentyloxy) phenyl] propionate,

Benzyl (S) -2-amino-3- [4- (3-azidopropoxy) phenyl] propionate was reacted with butylsulfonyl chloride to give benzyl (S) [4- (3-azidopropoxy) phenyl] propionate,

Benzyl (R) -2-amino-3- [4- (4-azidobutoxy) phenyl] propionate was reacted with butylsulfonyl chloride to give benzyl (R) 4- (4-azidobutoxy) phenyl] propionate,

(S) -2-amino-3- [4- (6-azidecyloxy) phenyl] propionate was reacted with butylsulfonyl chloride to give benzyl - [4- (6-azidecyloxy) phenyl] propionate.

Example 4

1.3 g of benzyl (S) -2-butylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionate was dissolved in 30 ml of a 5: 3: 1 mixture of ethyl acetate / methanol / And 0.2 ml of TFA and 1.0 g of palladium on activated carbon were added thereto, followed by hydrogenolysis at room temperature under a constant pressure for 3 hours. (S) -2-butylsulfonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid as a non-crystalline powder was obtained as a white solid from the crude product after filtering off the catalyst and freeze-drying from acetonitrile / water. ; FAB 373.

Similarly,

Benzyl (S) -2-propylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionate,

Benzyl (S) -2-benzylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionate,

Benzyl (S) -2-pentylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionate,

Benzyl (R, S) -2-pentylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionate,

Benzyl (S) -2- (4-tolylsulfonamido) -3- [4- (4-azidobutoxy) phenyl] propionate,

Benzyl (S) -2-butylsulfonamido-3- [4- (5-azidopentyloxy) phenyl] propionate,

Benzyl (S) -2-butylsulfonamido-3- [4- (3-azidopropoxy) phenyl] propionate,

Benzyl (R) -2-butylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionate,

Benzyl (S) -2-butylsulfonamido-3- [4- (6-azidecyloxy) phenyl] propionate and

Benzyl (S) -2- (camphor-10-sulfonamido) -3- [4- (4-azidobutoxy) phenyl] propionate was hydrolyzed,

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

(S) -2-benzylsulfonamido-3- [4- (4-aminobutoxy) phenyl]

(S) -2-pentylsulfonamido-3- [4- (4-aminobutoxy) phenyl]

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

(S) -2- (4-tolylsulfonamido) -3- [4- (4-aminobutoxy) phenyl]

(S) -2-butylsulfonamido-3- [4- (5-aminopentyloxy) phenyl]

(S) -2-butylsulfonamido-3- [4- (3-aminopropoxy) phenyl]

(R) -2-butylsulfonamido-3- [4- (4-aminobutoxy) phenyl]

(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

(S) -2-butylsulphonamido-3- [4- (4-aminobutoxy) phenyl] propionic acid and 170 mg of 3,5-di-methylpyrazole-1-formamidinium nitrate Was stirred with 150 占 퐇 of triethylamine at 60 占 폚 for 12 hours. The solution was then concentrated and the residue was purified by HPLC (Lichrocart RP-18, acetonitrile / water + 0.3% TFA, 99: 1 to 1:99 concentration gradient 1 h). After removing the solvent, 50 mg of (S) -2-butylsulfonamido-3- [4- (4-guanidino butoxy) phenyl] propionic acid was obtained as a non-crystalline powder; m.p. 70 °; FAB 415.

Similarly,

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

(S) -2-benzylsulfonamido-3- [4- (4-aminobutoxy) phenyl]

(S) -2-pentylsulfonamido-3- [4- (4-aminobutoxy) phenyl]

(S) -2- (4-tolylsulfonamido) -3- [4- (4-aminobutoxy) phenyl]

(S) -2-butylsulfonamido-3- [4- (5-aminopentyloxy) phenyl]

(S) -2-butylsulfonamido-3- [4- (3-aminopropoxy) phenyl]

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

(S) -2-propylsulfonamido-3- [4- (4-guanidino butoxy) phenyl]

(S) -2-benzylsulfonamido-3- [4- (4-guanidino butoxy) phenyl] propionic acid,

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

(S) -2- (4-tolylsulfonamido) -3- [4- (4-guanidinobutoxy) phenyl]

(S) -2-butylsulfonamido-3- [4- (5-guanidinopentyloxy) phenyl]

(S) -2-butylsulfonamido-3- [4- (3-guanidinopropoxy) phenyl]

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

Example 6

0.5 g of benzyl (S) -3- [4- (4-azidobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionate was hydrolyzed in a similar manner to Example 4, 370 mg of (S) -3- [4- (4-aminobutoxy) phenyl] -2-N-tert-butoxycarbonylaminopropionic acid ("B"); FAB 353. In analogy to example 5, 105 mg of "B" was reacted with DPFN to give (S) -3- [4- (4-guanidino butoxy) phenyl] -2-N-tert-butoxycar / RTI > FAB 395. Removal of the BOC analogously to Example 2 provided (S) -2-amino-3- [4- (4-guanidinobutoxy) phenyl] propionic acid, FAB 295.

Example 7

Ethyl (S) -3- (4-nitrophenyl) -2,3-tert-butoxycarboxylic acid ethyl ester (FAB 329) (S) -3- (4-nitrophenyl) -2-aminopropionate was obtained by reacting 4- (4-nitrophenyl) -2-aminopropionate with TFA and then reacting with butylsulfonyl chloride to obtain ethyl -Butylsulfonamidopropionate (FAB 359) and obtained by reduction in the same manner as in Example 4], 0.268 g of 4-BOC-aminobutyric acid, 0.25 g of O- (benzotriazole- A solution of 0.5 g of N, N, N'N'-tetramethyluronium tetrafluoroborate (TBTU), 0.05 g of HOBT and 260 μl of N-methylmorpholine in 10 ml of DMF was stirred at room temperature Lt; / RTI > for 12 hours. The mixture was treated in a conventional manner to give ethyl (S) -3- [4- (tert-butoxycarbonylaminobutyramido) phenyl] -2-butylsulfonamidopropionate ; FAB 514.

Example 8

A solution of 0.62 g of ethyl (S) -3- [4- (tert-butoxycarbonylaminobutyramido) phenyl] -2-butylsulfonamidopropionate in 5 ml of dioxane was treated with 1N NaOH < / RTI > at room temperature for 12 hours. The solution was then neutralized with TFA, concentrated, and the residue was dissolved in 2 ml of TFA. After stirring at room temperature for 2 hours, the reaction mixture was treated in a usual manner. After freeze-drying from acetonitrile / water, (S) -3- [4- (4-aminobutyrimido) phenyl] -2-butylsulfonamidopropionic acid was obtained as a white amorphous powder; FAB 386.

Example 9

Similarly to Example 5, 0.155 g of (S) -3- [4- (4-aminobutyramido) phenyl] -2-butylsulfonamidopropionic acid was reacted with 0.121 g of DPFN, 0.160 g of (S) -2-butylsulfonamido-3- [4- (4-guanidinobutyrylamido) phenyl] propionic acid was obtained as a crystalline powder; m.p. 215-217 [deg.]; FAB 428.

Example 10

Benzyl 3- [4- (5- (4-methylphenylsulphonyloxy) pentyn-1-yl) phenyl] -2-butylsulfonamidopropionate (FAB 612) [treated with TFA to give BOC- Phenylalanine benzyl ester, followed by reaction with butylsulfonyl chloride to obtain benzyl 3- (4-iodophenyl) -2-butylsulfonamidopropionate, followed by pentyn-5-ol, 1 (I) in bis (triphenylphosphine) palladium (II) chloride and diethylamine to give benzyl 3- [4- (5-hydroxypentin-1-yl) phenyl] (Obtained by reacting amide propionate (FAB 458) with toluenesulfonyl chloride in pyridine] and 1.4 g of sodium azide in 25 ml of DMF was stirred at room temperature for 12 hours. After usual workup, 1.5 g of benzyl 3- [4- (5-azidopentin-1-yl) phenyl] -2-butylsulfonamidopropionate was obtained as colorless syrup; FAB 483.

Example 11

A solution of 0.2 g of benzyl 3- [4- (5-azidopentn-1-yl) phenyl] -2-butylsulfonamidopropionate in 10 ml of pyridine / water 4: 1 was saturated with hydrogen sulphide for 30 minutes . After removal of the solvent, the residue was dissolved in 10 ml of dioxane and treated with 0.8 ml of 1N NaOH. Similar to Example 5, the residue was purified by HPLC to give 0.066 g of 3- [4- (5-aminopentin-1-yl) phenyl] -2-butylsulfonamidopropionate; FAB 367.

Similar to Example 5, 3- [4- (5-aminopentin-1-yl) phenyl] -2-butylsulfonamidopropionate was reacted with 0.038 g of DPFN to give 2-butylsulfonamido- - [4- (5-guanidinopentin-1-yl) phenyl] propionic acid; m.p. 147-150 DEG; FAB 409.

Example 12

In analogy to Example 4, from 0.5 g of benzyl 3- [4- (5-azidopentin-1-yl) phenyl] -2-butylsulfonamidopropionate, (5-aminopentin-1-yl) phenyl] -2-butylsulfonamidopropionic acid was obtained; FAB 371.

Similarly to Example 5, 0.11 g of 3- [4- (5-aminopentin-1-yl) phenyl] -2-butylsulfonamidopropionic acid was reacted with 0.088 g of DPFN to obtain 2-butylsulfoneimide 3- [4- (5-guanidino-penten-1-yl) phenyl] propionic acid was obtained; FAB 413.

Example 13

Benzyl (S) -2-butylsulfonamido-3- [4- (4-azidobutoxy) phenyl] propionate and 1.1 molar equivalent of NaH in THF was treated under inert gas atmosphere at room temperature for 1 hour Lt; / RTI > Then, 2 mol equivalent of methyl iodide was added, and after 1 hour, the mixture was treated in a usual manner to give benzyl (S) -2- (N-methylbutylsulfonamido) -3- [4- Phenyl] propionate.

(S) -2- (N-methylbutylsulfonamido) -3- [4- (4-aminobutoxy) phenyl] propionate was obtained in analogy to example 4, To give (S) -2- (N-methylbutylsulfonamido) -3- [4- (4-guanidinobutoxy) phenyl] propionate; FAB 429.

Example 14

Benzyl menthyloxycarbonylaminopropionate was reacted with 1,4-dibromobutane to obtain (S) -3- [4 - ((4-bromobutoxy) phenyl] -2 -N-menthyloxycarbonylaminopropionate was reacted with NaN ₃ and then reduced in a similar manner to Example 4 to give (S) -3- [4- (4-aminobutoxy) phenyl] -2 (S) -2-N-menthyloxycarbonylamino-3- [4- (4-guanidino-butoxy) -phenyl] -N-menthyloxycarbonylaminopropionic acid was obtained in the same manner as in Example 5, Phenyl] propionic acid, FAB 477.

Example 15

Benzyl (S) -3- [4- (5-bromopentyloxy) phenyl] -2-N-tert-butoxycarbonylpropionate (EI 520) [BOC-L-tyrosine benzyl ester 2.0 2.3 g of KCN, 1.6 g of KCN and 0.580 g of 18-crown-6 were dissolved in 30 ml of acetonitrile Was boiled while refluxing for 12 hours. After usual workup, benzyl (S) -3- [4- (5-cyanopentyloxy) phenyl] -2-N-tert-butoxycarbonyl propionate was obtained as an oil syrup, FAB 467.

Similarly, a solution of benzyl (S) -3- [4- (4-fluorophenyl) -2-methoxy- 4-cyanobutoxy) phenyl] -2-N-tert-butoxycarbonyl propionate was obtained.

Example 16

1.97 g of benzyl (S) -3- [4- (5-cyanopentyloxy) phenyl] -2-N-tert-butoxycarbonyl propionate were dissolved in TFA And then reacted with butyl sulfonyl chloride to obtain 1.5 g of benzyl (S) -2-butylsulfonamido-3- [4- (5-cyanopentyloxy) phenyl] propionate. FAB 487.

Similarly, from benzyl (S) -2-butylsulfonamido-benzyl (S) -3- [4- (4-cyanobutoxy) phenyl] 3- [4- (4-cyanobutoxy) phenyl] propionate.

Example 17

1.5 g of benzyl (S) -2-butylsulfonamido-3- [4- (5-cyanopentyloxy) phenyl] propionate, 0.646 g of hydroxylamine hydrochloride and 0.780 g of sodium hydrogencarbonate were dissolved in isopropanol / water 6: 1 (50 ml) was heated under reflux for 12 hours. After the usual workup, benzyl (S) -2-butylsulfonamido-3- [4- (6-amino-6-N-hydroxyliminohexyloxy) phenyl] propionate was obtained as colorless syrup, FAB 520.

Similarly,

Benzyl (S) -2-butylsulphonamido-3- [4- (5-tert-butoxycarbonylamino) -Amino-5-N-hydroxyliminopentyloxy) phenyl] propionate was obtained,

Benzyl (S) -3- [4- (5-amino-benzyl) -2-methylpropionic acid ethyl ester was prepared from benzyl (S) -3- [4- (4-cyanobutoxy) -5-N-hydroxyliminopentyloxy) phenyl] -2-N-tert-butoxycarbonyl propionate.

Example 18

Benzyl (S) -2-butylsulfonamido To a solution of 1.6 g of 3- [4- (6-amino-6-N-hydroxyliminohexyloxy) phenyl] propionate in 30 ml of acetic acid and 1 ml of acetic anhydride The dissolved solution was hydrolyzed with 50 mg of palladium catalyst (10% on activated carbon) at room temperature under a constant pressure for 2 hours. The catalyst was isolated, treated by conventional workup and purified by preparative HPLC analogously to example 5 to give (S) -2-butylsulfonamido-3- [4- (5-amidinopentyloxy) phenyl] 0.24 g of propionic acid was obtained, FAB 414.

Similarly,

Benzyl (S) -2-butylsulfonamido-3- [4- (5-amino-5-N-hydroxyliminopentyloxy) phenyl] -3- [4- (4-amidinobutoxy) phenyl] propionic acid (FAB 400)

Benzyl (S) -3- (4-chloro-phenyl) -2-N-tert-butoxycarbonylpropionate was obtained from benzyl (S) -3- [4- To obtain [4- (4-amidinobutoxy) phenyl] -2-N-tert-butoxycarbonylpropionic acid (FAB 380).

Example 19

(S) -3- (4-aminophenyl) -2-butylsulfonamidopropionate, 0.3 g of N-BOC-piperidine-4-carboxylic acid and 0.05 g of HOBt, And 264 [mu] L of N-methylmorpholine were reacted in 10 ml of DMF and after the usual work, ethyl (S) -2-butylsulphonamido-3- [4- (1- tert -butoxycarbonylpiperidine -4-carboxamido) phenyl] propionate, FAB 540.

Example 20

(S) -2-butylsulfonamido-3- [4- (1-3-butoxycarbonylpiperidine-4-carboximido) phenyl] propionate 0.42 g was hydrolyzed with NaOH and the BOC group was removed with 0.225 g of TFA to give (S) -2-butylsulfonamido-3- [4- (piperidin-4- ylcarboxamide) phenyl] 0.225 g was obtained, FAB 412.

0.16 g of (S) -2-butylsulfonamido-3- [4- (piperidin-4-ylcarboxamide) phenyl] propionic acid were added to a solution of 0.115 g of DPFN in 5 ml of DMF, Amine to give (S) -2-butylsulfonamido-3- [4- (1-amidinopiperidine-4-carboximido) phenyl] propionic acid. FAB 454.

Example 21

(S) -2-butylsulfonamido-3- [4- (5- (5-phenyl-1,2,4-oxadiazole) pentyloxy) phenyl] Can be obtained by reacting 3- [4- (6-amino-6-N-hydroxyliminohexyloxy) phenyl] propionic acid with 1.1 equivalents of benzyl chloride and triethylamine. Hydrogen was decomposed. The catalyst was removed and treated in a conventional manner to give (S) -2-butylsulfonamido-3- [4- (5-amidinopentyloxy) phenyl] propionic acid. FAB 414.

The following examples relate to pharmaceutical formulations.

Example A: Vial for injection

A solution obtained by dissolving 100 g of the active compound of formula (I) and 5 g of sodium periodate in 3 l of secondary distilled water was adjusted to pH 6.5 using 2N hydrochloric acid, sterilized and filtered, and lyophilized under sterilization conditions and sealed . Each injection vial containing 5 mg of the active compound was obtained.

Example B: Suppositories

A mixture of 20 g of the active compound of the formula I and 100 g of soya lecithin and 1400 g of cocoa butter was poured into the mold and allowed to cool. Suppositories each containing 20 mg of the active compound were obtained.

Example C: Solution

1 g of the active compound 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 were dissolved in 940 ml of distilled water. The solution was adjusted to pH 6.8, adjusted to 1 liter, and sterilized by radiation to prepare a liquid agent which can be used in eye drops form.

Example D: ointment preparation

500 mg of the active compound of the formula I was mixed with 99.5 g of vaseline under sterile conditions to prepare an ointment.

Example E: Purification

A mixture of 1 kg of the active compound 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 was compressed by a conventional method to prepare tablets each containing 10 mg of the active compound.

Example F:

Similar to Example E, the tablets were pressed and then the suppositories were prepared by a conventional method using a skin comprising sucrose, potato starch, talc, tragacanth and a coloring agent.

Example G: Capsules

2 kg of the active compound of the formula (I) was filled in a hard gelatine capsule in a conventional manner to prepare a capsule containing 20 mg of the active compound, respectively.

Example H: Ampoules

A solution obtained by dissolving 1 kg of the active compound of the formula (I) in 60 l of secondary distilled water was sterilized and filtered, and the ampoule was lyophilized under sterilization conditions and sealed. An ampoule containing 10 mg of each active compound was prepared.

Example I: Inhalant spray

14 g of the active compound of the formula (I) are dissolved in 10 l of an isotonic NaCl solution and the solution is filled into a spray container equipped with a pump as is commonly used. The solution can be inhaled into the mouth or nose. One spray (about 0.1 ml) corresponds to a dose of about 0.14 mg.

Claims (10)

Claims 1. Compounds of the general formula < RTI ID = 0.0 > (I) < / RTI > [In the above formula, X is alkylene having 1 to 6 carbon atoms or 1,4-piperidyl, Y is absent, O, CONH or -C? C-, R ¹ is H, CN, N ₃ , NH ₂ , H ₂ NC (═NH), H ₂ N- (C═NH) -NH wherein the primary amino group can also be protected with conventional amino protecting groups In addition, R ² and R ³ are each independently H, A, A-SO ₂ -, Ar-SO ₂ -, camphor-10-SO ₂ -, COOA or a common amino protecting group, A and R < ⁴ > are each independently H, alkyl having 1-10 carbon atoms or benzyl, Ar is optionally substituted, respectively, is one substituted phenyl or benzyl with CH _3.] Or an enantiomer or diastereomer of a compound of formula (I) according to claim 1. The following compounds and their physiologically acceptable acid addition salts. (a) (S) -2-Butylsulfonamido-3- [4- (4-guanidino butoxy) 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- (3-guanidinopropoxy) phenyl] propionic acid; (e) (S) -2-Butylsulfonamido-3- [4- (4-guanidinobutyrylamido) phenyl] (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-guanidino butoxy) phenyl] propionic acid; (k) (S) -2- (4-Tolylsulfonamido) -3- [4- (4-guanidino butoxy) phenyl] propionic acid; (1) (S) -2- (N-Methylbutylsulfonamido) -3- [4- (4-guanidinobutoxy) phenyl] propionic acid; (m) (S) -2-tert-Butoxycarbonylamino-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-guanidino butoxy) phenyl] propionic acid; (p) (S) -2- (Camphor-10-sulfonamido) -3- [4- (4-guanidino butoxy) phenyl] propionic acid. A process for the preparation of a compound of formula (I) according to claim 1, a) R < ¹ > is N < ₃ & R < ² > is H, R ³ is A-SO ₂ - or Ar-SO ₂ - X is alkylene having 1 to 6 carbon atoms, Y is absent, O or -C? C-, In order to prepare the compounds of formula I wherein R < ⁴ > is alkyl of 1-10 carbon atoms or benzyl, R ¹ is N ₃ , R < ² > is H, X is alkylene having 1 to 6 carbon atoms, Y is absent, O or -C? C-, R < ³ > is a normal amino protecting group, The compound corresponding to formula (I) in which R < ⁴ > is alkyl of 1 to 10 carbon atoms or benzyl is first treated with solubilization to give a compound of formula (II) R ³ -L [In the above formula, R ³ is A-SO ₂ - or Ar-SO ₂ - L is Cl, Br, I, OH or an esterified reactive OH group. ≪ / RTI > or b) hydrolyzing the ester of formula (I); or c) i) converting the azido group to an amino group, ii) conversion of a cyano group to an amidino group, iii) converting the amino group into an guanidino group by reacting with an aminating agent, iv) deprotection of the amino group protected by a common protecting group, or deprotection of an amino group protected by an ordinary protecting group, v) hydrolyzing the oxadiazole derivative to liberate the amidino group, thereby converting the radicals R ¹ and / or R ² to other radicals R ¹ and / or R ² ; And / or d) converting a compound of formula (I), which is basic or acid, to an acid or base and converting it into one of its salts. Characterized in that one of the compounds of formula (I) according to claim 1 and / or physiologically acceptable salts thereof is formulated in a suitable dosage form together with one or more solid, liquid or semi-liquid excipients or adjuvants. Way. A pharmaceutical preparation characterized by containing at least one of the compound of formula (I) according to claim 1 and / or a physiologically acceptable salt thereof. A compound of formula (I) according to claim 1 as an integrin inhibitor for the control of angiogenic diseases, thrombosis, myocardial infarction, coronary heart disease, arteriosclerosis, tumor, osteoporosis, inflammation and infection and a physiologically acceptable salt thereof. A compound of formula I according to claim 1, or a physiologically acceptable salt thereof, for use in the manufacture of a medicament. A compound of formula I according to claim 1, or a physiologically acceptable salt thereof, for use in the control of disease. A compound of formula I according to claim 1, or a physiologically acceptable salt thereof, for use in the manufacture of a medicament for an? _v -integrin inhibitor.