SK176898A3 - Phenylalamine derivatives as integrin inhibitors - Google Patents

Abstract

Compounds of formula (I) wherein X, Y, Z, R<1>, R<2>, R<3> and R<4> have the meaning stated in claim 1, with the proviso that at least one element chosen from the group X, Y, Z must be CH2, as well as their physiologically harmless salts, can be used as integrin inhibitors, particularly for prophylaxis and treatment of circulatory diseases, in case of thrombosis, heart infarct, coronary heart diseases, arteriosclerosis, osteoporosis, in pathological processes which are maintained or propagated by angiogenesis, and in tumor therapy.

Description

X is absent or represents an alkylene, arylene, cycloalkylene group having 4 to 8 carbon atoms or unsubstituted or one, two or three times a group A, oxo and / or R ⁴ substituted heterocycloalkylene group having 1 to 3 nitrogen, oxygen and / or sulfur atoms,

Y and Z are each independently absent or oxygen, sulfur, NH, C (= O), CONH, NHCO, C (= S), SO ₂ NH, NHSO ₂ , CA = CA 'or -C = C-

R ^{1 is} H 2 N-C (= NH) or H 2 N- (C = NH) -NH, wherein the amino group also has optionally conventional protecting groups or is optionally substituted one, two or three times with A, Ar or R ⁵ , NH-CH 2 - R ⁶ , NH-R ⁶ ,

NH-C (= NH) -NH-R ^6, or R ⁶

R is A, Ar or aralkylene,

R ^{3 2} is H or A,

R ⁴ is hydrogen, Hal, OA, NHA, NAA ', -NH-acyl,

-O-acyl, CN, NO ₂ , SA, SOA, SO ₂ A, SO ₂ Ar or SO ₃ H, an alkanoyl or cycloalkanoyl group having 1 to 18 carbon atoms, optionally substituted by one, two or three methylene groups nitrogen, oxygen and / or sulfur, Ar-CO- or Ar-alkylene-CO-,

A, A 'are independently a hydrogen atom or an unsubstituted or mono-, di- or trisubstituted by R ⁴ substituted alkyl or cycloalkyl of 1 to 15 carbon atoms, in which one, two or three methylene groups are optionally replaced by N, O and / or S,

Ar unsubstituted or mono-, di- or trisubstituted by A and / or R ⁴ substituted by a monocyclic or two-nuclear aromatic ring system having 0, 1, 2, 3 or 4 N, O and / or S,

R ^{6 is a} mononuclear or bi-core heterocyclic system having 1 to 4 nitrogen, oxygen and / or sulfur atoms which is unsubstituted or once, twice or three times by Hal, A, acyl, OH, CN, COOH, COOA, CONH ₂ , NO ₂ , = NH or = O substituted,

Hal F, Cl, Br or J, with the proviso that at least one of X, Y, Z must be ch ₂ , and physiologically acceptable salts thereof.

Similar compounds are known, for example, from EP 0 478363, EP 0 478328, WO 94/12181 and WO 95/32710.

SUMMARY OF THE INVENTION It is an object of the present invention to provide novel compounds with valuable properties, particularly those suitable for the manufacture of medicaments.

It has been found that the compounds of the formula I and their salts have very good pharmacological properties with good tolerability. They act especially as integrin inhibitors, in particular inhibiting the interactions _of a -integrínových receptors with ligands. Particular efficacy is exhibited poor) substituting Compound for the integrin _α ν β ₃ and _α ν β ₅ · Fully particularly, the active compounds as adhesion receptor antagonists for the vitronectin receptor _α ν β ₃ · This action can be demonstrated, for example, described by JW Smith et al . (J. Biol. Chem. 265, 11008-11013 and 12267-12271, 1990).

Inhibition of vitronectin binding to receptors has been experimentally demonstrated for some representative compounds of formula (I). The pharmacological values of the assays are summarized in Tables I and II.

, B. Felding-Habermann and D.A. Cheresh described (Curr. Opin.

Cell. Biol. 5, p. 864, 1993) The importance of integrins as adhesion receptors for various phenomena and disease agents, particularly in connection with the vitronectin receptor α _ν β ₃ ·

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

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

Experimental evidence that the compounds of the invention also prevent living cells from binding to the corresponding matrix proteins and thus also prevent the binding of tumor cells to the matrix proteins can also be derived from a cell adhesion assay performed in a similar manner to that described by F. Mitjans et al.

(J. Cell Science 108: 2825-2838, 1995).

PC Brooks et al. (J. Clin. Invest. 96, pp. 1815-1822, 1995) have described α _ν β ₃ -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 substances of medicaments, in particular for the treatment of cancer, osteoporosis, osteolytic diseases, as well as for the suppression of angiogenesis.

Compounds of formula I that block the interaction of integrin receptors and ligands such as fibrinogen at the fibrinogen receptor (glycoprotein IIb / IIIa) prevent GPIIb / IIIa antagonists from spreading tumor cells through metastasis. This observation is supported by the following observations:

The proliferation of tumor cells from one local tumor to the vascular system is effected by the binding of microaggregates (micro-thrombi) by the interaction of tumor cells and platelets. Tumor cells are shielded in microaggregates by shielding and are not recognized by cells of the immune system.

The microaggregates can be firmly attached to the vessel walls, thereby facilitating further penetration of tumor cells into the tissue. Since the binding of microthrombi by fibrinogen binding to fibrinogen receptors is mediated on activated platelets, GPIIa / IIIb-antagonists can be considered to be an effective brake on metastasis.

In addition to the binding of fibrinogen, fibronectin and Willebrand factor to the fibrinogen platelet receptors, the compounds of the formula I also inhibit the binding of other adhesive proteins such as vitronectin, collagen and laminin to the corresponding receptors on different cell types. used for the treatment of thromboses, apoplexy, heart attack, inflammation and arteriosclerosis.

The properties of the compounds can also be demonstrated by the methods described in EP-A1-0 462960. The inhibition of the binding of filbrinogen to fibrinogen receptors can also be demonstrated by the method described in EP-A1-0 381033.

Experimental evidence that compounds of the invention of formula I inhibit the binding of fibrinogen to the corresponding receptors has been performed for some representative compounds of formula I. The pharmacological values of the assays are shown in Table III.

Thrombocyte aggregation inhibiting action can be detected in vitro by the method of Born (Nature 4832, 927-929, 1962).

Accordingly, the present invention provides a compound of formula I as claimed in claim 1 and / or a physiologically acceptable salt thereof for the manufacture of pharmaceutical compositions useful as integrin inhibitors. In particular, the present invention provides compounds of the formula I according to claim 1 and / or their physiologically acceptable salts, wherein R ^{2 is a} camphor-10-yl group, for the manufacture of pharmaceutical compositions for combating pathologically angiogenic diseases, tumors, osteoporosis, inflammations and infections.

The compounds of the formula I according to the invention can be used as active substances in human and veterinary medicine in the prophylaxis and / or treatment of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, cancer, osteolytic diseases such as osteoporosis, pathological angiogenic diseases such as inflammation, ophthalmological diseases, diabetic retinopathy, muscle degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, tumor colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after infection, angioplasty, viral infection, viral infection, viral infection , in acute renal failure and wound healing to support the healing process.

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

According to the invention, the process for the preparation of the compounds of the formula I, in which the individual symbols are as defined above, is characterized in that:

a) the compound of formula I is released from its functional derivative by treatment with a solvolytic or hydrogenolytic agent

b) reacting a compound of formula II

(II) wherein R ¹ , R ³ , R ⁴ , X, Y and Z are as defined in claim 1, with a compound of formula III

R ² -SO ₂ -L (III) wherein R is as defined in claim 1, and L is Cl, Br, J, OH or a reactive esterified hydroxyl group, or

c) saponification of the ester of the formula I, or even η

d) converting the group R and / or R into another group ^{J and} R and / or R ³ and / or

e) the basic or acidic compound of formula I is converted into its salt by treatment with an acid or base.

The compounds of formula I have at least one chiral center and can therefore be in several stereomeric forms. All of these forms (e.g., D- and L-forms) and mixtures thereof (e.g., DL-forms) include Formula I.

The invention also includes so-called prodrug derivatives, i.e. compounds of formula I which are altered with alkyl or acyl groups, sugars or oligopeptides which are rapidly cleaved in the body to release the active compound of formula I according to the invention.

Abbreviations used have the following meanings: Ac acetyl

BOC tert-butoxycarbonyl

CBZ or Z benzyloxycarbonyl

DCC1

DMF

EDC1

Et dicyclohexylcarbodiimide dimethylformamide

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

Fmoc 9 fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole Me methyl Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl HONSu N-hydroxysuccinimide OBn benzyl OBu tert-butyl Oct octanoyl OMe methyl ester OEt ethyl POA phenoxyacetyl TBTU 0- (benzotriazol-l-yl) -N, N, N, N-tetramethyluronium tetrafluoroborate TFA trifluoroacetic acid Trt trityl (triphenylmethyl)

When some residues in the compound occur several times, for example, A and A ', these residues are the same or different, i.e., they are independent of each other.

In formula (I), alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and also pentyl, 1-, 2- or 3-methylbutyl; 1-,

1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,

1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3 or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, heptyl, octyl nonyl or decyl

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or 3-methyl. Cycloalkyl is understood in particular to mean a residue of a bicyclic terpene, in particular a camphor-10-yl group.

Alkylene is preferably methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene or decylene. Aralkylene is preferably understood to mean alkylenephenyl, for example, in particular benzyl or phenethyl.

Cycloalkylene is preferably understood to mean cyclopropylene, 1,2- or 1,3-cyclobutylene, 1,2- or cycloalkylene.

1,3-cyclopentylene, 1,2-, 1,3- or 1,4-cyclohexylene and further 1,2-, 1,3- or 1,4-cycloheptylene.

Alkanoyl is preferably a formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl, hexadecanoyl

Acyl is preferably understood to mean, for example, a formyl, acetyl, propionyl, butyryl, trifluoroacetyl or benzoyl group.

Preferred substituents of the alkyl, alkylene, cycloalkyl, cycloalkylene, alkanoyl and cycloalkanoyl substituents are, for example, Hal, OA, NHA, NAA ', CN, NO ₂ , SA, SOA, SO ₂ A, SO ₂ Ar and / or SO ₃ H, in particular F, Cl, hydroxy, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methylsulfonyl or phenylsulfonyl.

Preferred Ar and arylene substituents are, for example, A and / or Hal, OA, NHA, NAA ', CN, NO ₂ , SA, SOA, SO ₂ A, SO ₂ Ar and / or SO ₃ H, in particular F C1-hydroxy, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, nylsulfonyl or phenylsulfonyl.

In the alkyl, alkylene, cycloalkyl, cycloalkylene, alkanoyl and cycloalkanoyl group, one, two or three methyl groups may each be replaced by a nitrogen, oxygen and / or sulfur atom.

Ar-CO represents an aroyl group, preferably a benzoyl or naphthoyl group.

Ar is unsubstituted preferably as mentioned above monosubstituted phenyl group, preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, male- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methylthiophenyl, o-, m- or p-methylsulfinylphenyl, o-, m- or p-methylsulfonylphenyl, o-, m- or p-aminophenyl, o-, m- or p-methylaminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p-nitrophenyl group further preferably a 2,3- group,

2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-,

2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-,

2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methylphenyl,

2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl, 2-chloro-6-methylphenyl, 2-methyl-3-chlorophenyl, 2-methyl-4-chlorophenyl, 2-methyl-5-chlorophenyl, 2-methyl- 6-chlorophenyl, 3-chloro-4-methylphenyl, 3-chloro-5-methylphenyl or 3-methyl-4-chlorophenyl, 2-bromo-3-methylphenyl, 2-bromo-4-methylphenyl, 2-bromo-5-methylphenyl, 2- bromo-6-methylphenyl, 2-methyl-3-bromophenyl, 2-methyl-4-bromophenyl, 2-methyl-5-bromophenyl, 2-methyl-6-bromophenyl, 3-bromo-4-methyl-11 phenyl, 3-bromo-5 -methylphenyl or 3-methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or

3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or

3,4.5-Trichlorophenyl, 2,4,6-tert-butylphenyl, 2,5-dimethylphenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 4fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2 5-difluoro-4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2-methoxy-5-methylphenyl,

2.4.6- triisopropylphenyl, naphthyl, 1,3-benzodioxol-5-yl,

1,4-benzodioxan-6-yl, benzothiadiazol-5-yl or benzoxadiazol-5-yl.

Furthermore, Ar is preferably a 2- or 3-furyl group,

2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4 or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-,

4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4 or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3 or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, further preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, 3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,

1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3 -, 4-, 5 or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl,

3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6 or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2- , 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4 or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4 -, 5-, 6- or 7-benzoxazolyl, 3-, 4-,

5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-,

5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-,

7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinolinyl, 2-,

A 4-, 5-, 6-, 7- or 8-quinazolinyl group.

Arylene has the same meaning as Ar, but is bound to the adjacent group by another bond of the aromatic system.

Heterocycloalkylene is preferably 1,2-, 2,3- or 1,3-pyrrolidinyl, 1,2-, 2,4-, 4,5- or 1,5-imidazolidinyl, 1,2-, 2,3- or 1,3-pyrazolidinyl, 2,3-, 3,4,

4,5- or 2,5-oxazolidinyl, 1,2-, 2,3-, 3,4, or 1,4-isoxazolidinyl, 2,3-, 3,4, 4,5- or 2,5-thiazolidinyl,

2,3-, 3,4, 4,5- or 2,5-isothiazolidinyl, 1,2-, 2,3-, 3,4-, or 1,4-piperidinyl, 1,4- or 1,2 a piperazinyl group, further preferably a 1,2,3-tetrahydrotriazole-1,2-or 1,4-yl, 1,2,4-tetrahydrotriazol-1,2-or 3,5-yl, 1,2-

2,5-tetrahydrotetrazolyl, 1,2,3-tetrahydrooxadiazole-2,3-, -3,4-, -4,5- or 1,5-yl, 1,2,4-tetrahydrooxadiazole-2,3-, -3 , 4- or -4,5-yl, 1,3,4-tetrahydrothiadiazole-2,3-, -3,4-, -4,5- or 1,5-yl, 1,2,4-tetrahydrothiadiazole- 2,3-, -3,4-, -4,5- or 1,5-yl, 1,2,3-thiadiazole-2,3-, -3,4-, -4,5 or 1,5- an alkyl, 2,3- or 3,4-morpholinyl, 2,3-, 3,4 or 2,4-thiomorpholinyl group.

The symbol R ⁶ is preferably 2- or 3-furyl,

2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4 or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-,

4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4 or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3 or 4-pyridyl, 2-, 4-, 5 - or 6-pyrimidinyl, further preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, 3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,

1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2- , 3-, 4-, 5 or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl,

3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6 or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl 13, 1, 2 -, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4 or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2- , 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-,

5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-,

5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-,

7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 2- .

A 4-, 5-, 6-, 7- or 8-quinazolinyl group.

R1 may also be, for example, 2,3-dihydro-2-, -3-, -4- or 5-furyl, 2,5-dihydro-2-, -3-, -4- or 5-furyl, tetrahydro- 2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1-, 2-, -3-, -4- or 5-pyrrolyl; , 5-dihydro-1-, 2-, -3-, -4- or 5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or 4-imidazolyl, 2,3- dihydro-1-, -2-, 3-, -4- or 5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or 4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-,

3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or 4-pyranyl, 1,4-dioxanyl, 1,3-dioxane, 2-, -4- or -5- hexyl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4- tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or 8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl.

Amino-protecting group is preferably acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBT (carbobenzenzenzyl) , FMOC, Mtr or benzyl

Accordingly, the invention relates in particular to compounds of the formula I in which at least one of the symbols has the above-mentioned preferred meaning. Some preferred groups of compounds of formula (I) are the following compounds of formulas (Ia) to (Ii), wherein not particularly indicated symbols have the meanings given in formula (I) and in the formula

Ia) R ¹ X Y R ² R ³ R ⁴ h ₂ nc (= nh), alkylene of 1 to 6 carbon atoms, O, A and hydrogen; Ib) R ¹ h ₂ nc (= nh) -nh X alkylene having 1 to 10 carbon atoms; 6 carbon alkyl, Y 0 R ² And a R ³ , R ⁴ a hydrogen atom; ic) X alkylene having 1 to 10 carbon atoms; 6 carbon alkyl, Y a mistake, R ³ , R ⁴ hydrogen atom; and R ² aryl; Id) R ¹ h ₂ nc (= nh) -nh X alkylene having 1 to 10 carbon atoms; 6 carbon alkyl, Y CO-NH, R ³ , R ⁴ hydrogen atom; and R ² A; Ie) X alkylene having 1 to 10 carbon atoms; 6 carbon alkyl, Y 0 or CO-NH, FROM a mistake R ² camphor-10-yl,

R ³ is hydrogen or A a

R ⁴ is hydrogen;

If) R ¹ H ₂ NC (= NH) or H ₂ NC (= NH) -NH,

X is missing

Y alkylene of 1 to 6 carbon atoms,

Z O,

R ² A a

R ³ , R ^{4 are} hydrogen;

Ig) R ¹ H ₂ NC (= NH) or H ₂ NC (= NH) -NH,

X is missing

Y alkylene of 1 to 6 carbon atoms,

Z 0,

R ² camphor-10-yl a

R ³ , R ^{4 are} hydrogen;

Ih) R ¹ NH-CH ₂ -R ⁶ , NH-R ⁶ or R ⁶ ,

X is missing

Y alkylene of 1 to 6 carbon atoms,

Z 0,

R ² camphor-10-yl a

R ³ , R ^{4 are} hydrogen;

(Ii) R ^{1 is} H 2 N-C (= NH) or H 2 N-C (= NH) -NH, wherein the primary amino groups are optionally protected with common amino protecting groups or substituted one, two or three times with group A, Ar or R ⁵ , NH-CH 2 -R ⁶ , NH-R ⁶ or R ⁶

X is missing

Y alkylene of 1 to 6 carbon atoms,

Z 0,

R ² camphor-10-yl a

R, hydrogen or A,

R ⁴ is hydrogen

R is acetyl or benzyloxycarbonyl; and

R is a mono- or bi-core heterocyclic group having 1 to 4 nitrogen, oxygen and / or sulfur atoms, unsubstituted or substituted one, two or three times with Hal, A, acyl, hydroxyl, = NH or = O.

The compounds of the formula I and the starting materials for their preparation are prepared by known methods described in the literature (for example, in standard publications such as Houben-Weyl, Methoden der Organischen Chemie, Georg-Thieme Verlag, Stuttgart) under reaction conditions, which are known and suitable for the reactions mentioned. It is also possible to use known variants not described here in greater detail.

The starting materials may optionally be formed in situ, i.e. they are not isolated from the reaction mixture, but the reaction mixture is immediately used to prepare compounds of formula I.

The compounds of formula (I) may be prepared by liberating from their functional derivatives by solvolysis, in particular hydrolyzing or hydrogenolyzing agents.

The starting materials for solvolysis or hydrogenolysis are compounds which otherwise correspond to the above formulas, but have corresponding amino or hydroxyl groups instead of free amino or hydroxyl groups, preferably compounds which have a protecting group instead of a hydrogen atom which is bonded to a nitrogen atom. amino, especially compounds having an R'-N group instead of the HN group, wherein R 'is an amino protecting group, and / or compounds having a hydroxyl protecting group instead of a hydrogen atom in a hydroxyl group, for example compounds having a -COOH group instead a -COOR group wherein R is a hydroxyl protecting group.

Several of the same or different amino and / or hydroxyl protecting groups may be present in the molecule of the starting material. If the protecting groups are different from each other, they can in many cases be selectively cleaved.

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

4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC) and arylsulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, CBZ, Fmoc, benzyl and acetyl.

The cleavage of the amino protecting group proceeds according to the protecting group used, for example with strong acids, preferably with trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric or sulfuric acids, strong organic carboxylic acids such as trichloroacetic acid or sulfonic sulfones such as benzenesulfonic acid. The presence of an additional inert solvent is possible but not always necessary. Suitable inert solvents are organic, for example, carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol as well as water. Mixtures of these solvents may also be suitable. Trifluoroacetic acid is preferably used in excess without the addition of other solvents, perchloric acid in the form of a 9: 1 mixture of acetic acid and 70% perchloric acid. ° C (room temperature).

For example, the BOC, OBut, and Mtr groups may be conveniently cleaved with trifluoroacetic acid in dichloromethane or about 3-5% hydrochloric acid in dioxane at 15 to 30 ° C, FMOC with a 5 to 50% solution of dimethylamine, diethylamine or piperidine in dimethylformamide at 15 ° C. to 30 ° C.

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

Preferably, the compounds of formula (I) may be prepared by reacting compounds of formula (II) with compounds of formula (III), the symbols being as defined above. The compounds of formula II and III are generally novel. However, they can be prepared by known methods.

In the compounds of formula III, L is preferably a chlorine, bromine, iodine or reactively modified hydroxyl group such as a C 1 -C 6 alkylsulfonyloxy (preferably methylsulfonyloxy) or a C 6 -C 10 arylsulfonyloxy (preferably phenylsulfonyloxy or tolyl) alkoxy group . The reaction of the compound of formula II with the compounds of formula III is generally carried out in an inert organic solvent in the presence of an acid binding agent, preferably in the presence of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline. Addition of an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or other weak alkali metal or alkaline earth metal salt, preferably potassium, sodium calcium or cesium, may be favorable. The reaction time is, depending on the reaction conditions, from a few minutes to 14 days, the reaction temperature being about -30 to 140'C, typically -10 to 90'C, and especially about 0 to about 70'C.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane or carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulphide; organic carboxylic acids such as formic or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate; water or mixtures of these solvents.

Compounds of formula I can also be obtained by saponifying an ester of a compound of formula I. Suitably this is accomplished by solvolysis or hydrogenolysis as described above, for example using sodium hydroxide or potassium hydroxide in a mixture of dioxane and water at a temperature of 0 to 60 ° C, preferably 10 to 40 ° C.

Furthermore, it is possible to convert a group of R ¹ and / or R ³ into another group of R ¹ and / or R ³ . In particular, the carboxylic acid can be converted to a carboxylic acid ester.

The conversion of the cyano group to the amidino group is carried out by reaction with, for example, hydroxylamine and subsequent reduction of N-hydroxyamidine with hydrogen in the presence of a catalyst, for example palladium on carbon.

In addition, the conventional amino-protecting group can be replaced by a hydrogen atom, whereby the protecting group as described above is cleaved solvolytically or hydrogenolytically or the conventional amino-protecting group is liberated by sololysis or hydrogenolysis.

The base of formula (I) may be converted by an acid into the appropriate acid addition salt, for example by reaction of an equivalent amount of base and acid in an inert solvent such as ethanol and subsequent evaporation of the solvent.

Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monohydric or non-polybasic carboxylic, sulfonic acids may be used. or sulfuric acids such as formic, acetic, propionic, pivalic, diethyl acetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, ethanesulfonic, methanesulfonic, methanesulfonic -hydroxyethanesulfonic, benzenesulfonic, ptoluenesulfonic, naphthalene-monosulfonic and naphthalenedisulfonic and laurylsulfuric acids. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of formula I.

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

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

It is of course also possible to obtain the optically active compounds of the formula I by one of the abovementioned processes, starting from optically active substances.

The results of the α _ν β ₃ - and α _ν β ₅ - inhibition tests for some representative compounds of formula I are shown in Tables I and II below. For the vitronectin binding assay, IC ₅₀ values, i.e., the concentration in nmol / L, are reported to inhibit 50% of vitronectin binding to the corresponding isolated receptor.

Table I

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

R ⁵ R ² R ³ Y FAb ^IC 50 ^and vP3 ^IC 50 ^and V 5 5 (D butyl H propylene 471 6.50 55,00 H butyl H propylene 429 1.10 2.10 (2) butyl H propylene 563 92.00 (2) (A) H propylene 657 61.00 136.00 H (A) H propylene 523 0.13 0.16 H (A) H propylene 551 16,00 13,00 ethyl butyl H propylene 457 0.81 (2) (A) H butylene 671 252.00 H 4-tolyl H butylene 477 4.60 (2) butyl H butylene 443 6.20 H (A) H butylene 537 0.45

(1) = acetyl (2) = benzyloxycarbonyl (A) = (S) -camphor-10-yl

Table II

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

R ¹ R ² R ³ X Y FROM FAb ^{1 <3} 50 ^and V ^ 3 (D (A) H - CH ₂ 0 569 6.9 (D (A) H - propylene 0 597 7.0 (2) (B) H - propylene 0 564 82.0 (3) (B) H - propylene 0 547 33.0 (D (B) H - ^ch 2 0 583 25.0 (4) (B) H - propylene 0 547 0.5 (5) (B) H propylene 0 577 970.0

R ¹ R ² R ³ X Y FROM FAb ^IC 50 ^and V 3 3 (6) (B) H - propylene 0 639 61 (4) (B) ethyl - propylene 0 575 100 (D (B) ethyl - propylene 0 625 98 (7) (B) H ch ₂ -ch ₂ - CON - 549 45 (4) (B) H - ch ₂ 0 519 55

(A) = (S)-Camphor-10-yl (B) = (R)-Camphor-10-yl

The pharmacological values demonstrate the antagonistic action of the compounds of the formula I for the vitronectin receptors α _ν β ₃ and α _ν β _5.

The results of GPIIbIIa-inhibition for some representative compounds of Formula I are shown in Table III below. IC ₅₀ values, i.e. the concentration in nmol / L, are reported to inhibit 50% of fibrinogen binding to the corresponding isolated receptor.

Table III

IC ₅₀ values (concentration in nmol / l that inhibits 50% of fibrinogen binding to the isolated receptor) of representative compounds of formula I and measured FAB values of compounds of formula I

R ⁵ R ² R ³ Y FROM FAb IC _5Q GPIIblIIa (D butyl H propylene 0 471 1,860.0 H butyl H propylene 0 429 16.0 (2) butyl H propylene 0 563 5,600.0 (2) (A) H propylene 0 657 167.0

R ⁵ R ² R ³ Y FROM FAb IC _5Q GPIIblIIa H (A) H propylene 0 523 1.3 H (A) ethyl propylene 0 551 78.0 (D = acetyl (2) = benzyloxycarbonyl

(A) = (S)-Camphor-10-yl

The pharmacological values demonstrate the antagonistic action of the compounds of the formula I according to the invention for the fibrinogen receptors GPIIblIa.

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

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

The compositions of the invention may be used as medicaments in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (e.g. oral) or parenteral or topical administration or for administration in the form of inhalation sprays and which do not react with compounds of the formula I, such as water, vegetable oils, benzyl alcohols , alkylene glycols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starches, magnesium stearate, talc and petrolatum. Especially suitable for oral use are tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops, suppositories for rectal use, solutions for parenteral use, especially oily or aqueous solutions, further suspensions, emulsions or implants, for topical use ointments, creams or powders. The compounds of the invention may also be lyophilized and the lyophilizates obtained, for example, used for the preparation of injectables. The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffers, coloring agents, flavoring agents and / or one or more others. other active ingredients such as vitamins. For administration as inhalation sprays, the active ingredient is dissolved or suspended in a propellant or propellant mixture (such as carbon dioxide or fluorocarbon). In this case, the active ingredient is used in micronized form, at least one physiologically compatible solvent, for example ethanol, being added. Inhalable solutions may be administered using known devices for this purpose.

The compounds of formula I and their physiologically acceptable salts can be administered as integrin inhibitors in the fight against diseases, such as, in particular, pathological angiogenic diseases, thrombosis, heart attack, coronary heart disease, arteriosclerosis, tumors, inflammations and infections.

Preferred are compounds of formula I and / or n

physiologically acceptable salts, wherein R is a camphor-10-yl group to combat pathological angiogenic diseases, tumors, osteoporosis, inflammation, and infection.

As a rule, the compounds of the formula I according to the invention are used in doses similar to commercially known peptides, in particular analogously to the compounds of U.S. Pat. No. 4,472,305, preferably at a dose of about 0.05 to 500 mg, in particular 0.5 to 100 mg per dosage. unit. The daily dose is preferably about 0.01 to 2 mg / kg body weight. The dose for each individual depends on a variety of factors, such as the efficacy of the particular compound used, age, body weight, general health, sex, diet, time and route of administration, elimination rate, drug combination and severity of the disease. . Parenteral administration is preferred.

The invention is illustrated, but not limited, by the following examples. Temperatures are always given in degrees Celsius. The term conventional processing in the following examples of practical processing means:

Optionally, water is added or, depending on the constitution of the final product, the pH is adjusted to 2-10, the reaction mixture is extracted with ethyl acetate or dichloromethane, separated, dried over the organic phase with sodium sulfate, evaporated and purified by silica gel chromatography and / or crystallization.

Mass Spectrometry (MS): EI (single electron ionization) M ⁺ FAB (fast atom bombardment) (M + H) ⁺

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A solution of 25 g of benzyloxycarbonyl-L-tyrosine-tert-butyl ester, 29 ml of 4-bromobutyric acid ethyl ester, 18.7 g of potassium carbonate and 1.8 g of 18-Krone-6 in 300 ml of toluene is stirred at 85C for 12 hours. After usual work-up, 25.3 g of (2S) -2-benzyloxycarboxamino-3- [4- (4-ethoxy-4-oxobutyloxy) phenyl] -propionic acid tert-butyl ester (A) are obtained in the form of a colorless syrup; FAB 486.

A solution of 10 g (A) in 70 ml of ethyl acetate, 20 ml of methanol, ml of water and 2 ml of TFA is treated with 1 g of 10% palladium on charcoal and hydrogenated for 4 hours at room temperature. .8 g of propionic acid (2S) -2-amino-3- [4- (4-ethoxy-4-oxobutyloxy) phenyl] tert -butyl ester trifluoroacetate (B); FAB 352. A solution of 8.8 g (B) in 100 ml of dichloromethane was treated at room temperature with 5.5 ml of triethylamine and 3.9 ml of 1-butanesulfonyl chloride, and the mixture was stirred for 5 hours. After usual work-up, 7.9 g of (2S) -2-butylsulfonamido-3- [4- (4-ethoxy-4-oxobutyloxy) phenyl] t-butyl propionate are obtained; FAB 472.

Similarly, it is obtained by reaction of B with (S) - (+) - camphor-10-sulfonyl chloride (2S) -2 - [(S) camphor-10-sulfonamido] -3- [4- (4-ethoxy-4-oxobutyloxy) phenyl] Propionic acid tert-butyl ester; FAB 566 with (2S) -2-tolylsulfonamido-3- [4- (4-ethoxy-4-oxobutyloxy) phenyl] propionic acid tert-butyl ester 4-tolylsulfonyl chloride; FAB 506.

A solution of 7.9 g of (2S) -2-butylsulfonamido-3- [4- (4-ethoxy-4-oxobutyloxy) phenyl] -propionic acid tert-butyl ester and 10 ml of 2N sodium hydroxide solution in 75 ml of methanol is stirred for 12 hours. at room temperature. After usual work-up, (2S) -2-butylsulfonamido-3- [4- (3-carboxypropyloxy) phenyl] tert. propionic acid butyl ester as a colorless syrup;

FAB 444.

Similarly, it is obtained by cleaving the ethyl ester from (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-ethoxy-4-oxobutyloxy) phenyl] propionic acid tert-butyl ester (2S) - Propionic acid 2 - [(S)-Camphor-10-sulfonamido] -3- [4- (3-carboxypropyloxy) phenyl] tert-butyl ester; FAB 538 (2S) -2-Tolylsulfonamido-3- [4- (4-ethoxy-4-oxobutyloxy) phenyl] propionic acid tert-butyl ester (2S) -2-tolylsulfonamido-3- [4- (3-carboxypropyloxy) phenyl] tert-butyl propionate; FAB 478.

A solution of 1.3 g of (2S) -2-butylsulfonamido-3- [4- (3-carboxypropyloxy) phenyl] -propionic acid tert-butyl ester in 15 ml of dimethylformamide is treated with 1.1 g of 2-chloro-1-methylpyridinium iodide. , with 3.9 ml of ethyldiisopropylamine and 2.8 g of Zguanidine and stirred at room temperature for 12 hours. After usual work-up, 1.0 g of (2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutyloxy) phenyl] tert-butyl ester of propionic acid is obtained; FAB 619.

Similarly obtained from (2S) -2 - [(S) - camphor-10-sulfonamido] -3- [4- (3-carboxypropyloxy) phenyl] tert-butyl ester (2S) -2 - [(S) - Camphor-10-sulfonamido] -3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutyloxy) phenyl] tert-butyl ester of propionic acid; FAB 713 (2S) -2-tolylsulfonamido-3- [4- (4-carboxypropyloxy) phenyl] tert-butyl ester of (2S) -2-tolylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-) - oxobutyloxy) phenyl] propionic acid tert-butyl ester; FAB 653.

Example 2

A solution of 1 g of (2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutyloxy) phenyl] propionic acid tert-butyl ester in 18 ml of dioxane and 2 ml of water is treated with 250 mg of palladium (10% on charcoal) and hydrogenated at room temperature for three hours. After separation of the catalyst and customary work-up, 0.78 g of (2S) -2-butylsulfonamido-3- [4- (4-guanidino-4-oxobutyloxy) phenyl] tert-butyl ester is obtained. -butyl propionate; FAB 485.

Similarly, from (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4N-benzyloxycarbonylguanidino-4-oxobutyloxy) phenyl] tert. (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-guanidino-4-oxobutyloxy) phenyl] tert -butyl propionate; -butyl propionate; FAB 579 and from (2S) -2-tolylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutyloxy) phenyl] tert. Butyl propionate gave (2S) -2-tolylsulfonamido-3- [4- (4-guanidino-4-oxobutyloxy) phenyl] tert. -butyl propionate; FAB 519.

Example 3

A solution of 0.78 g of (2S) -2-butylsulfonamido-3- [4- (4-guanidino-4-oxobutyloxy) phenyl] -propionic acid tert-butyl ester in 20 ml of dichloromethane was treated with 2 ml of TFA and stirred for 12 hours. After usual working-up and freeze-drying, 0.87 g of (2S) -2-butylsulfonamido-3- [4- (4-guanidino-4-oxobutyloxy) phenyl] propionic acid trifluoroacetate is obtained in the form of a white amorphous powder; FAB 429.

Similarly, propionic acid tert-butyl ester (2S) -2- [- (S) -2 - [(S) -phosphor-10-sulfonamido] -3- [4- (4-guanidino-4-oxobutyloxy) phenyl] tert-butyl ester is obtained. (S)-Camphor-10-sulfonamido] -3- [4- (4-guanidino-4-oxobutyloxy) phenyl] propionic acid; FAB 523 from (2S) -2-tolylsulfonamido-3- [4- (4-guanidino-4-oxobutyloxy) phenyl] tert -butyl ester of propionic acid gives (2S) -2-tolylsulfonamido-3- [4 '(4 -guanidino 4-oxobutyloxy) phenyl] propionic acid; FAB 463.

Example 4

A solution of 50 mg of (2S) -2-butylsulfonamido-3- [4- (4-guanidino-4-oxobutyloxy) phenyl] propionic acid trifluoroacetate in 5 ml of pyridine was treated at 10 ° C with 10 μchlor of acetyl chloride and stirred for two hours. . After usual work-up, 0.027 g of (2S) -2-butylsulfonamido-3- [4- (4-N-acetylguanidino-4-oxobutyloxy) phenyl] propionic acid is obtained; FAB 471.

Similarly, (2S) -2 - [((S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-guanidino-4-oxobutyloxy) phenyl] propionic acid trifluoroacetate gives (2S) -2 - [( S)-Camphor-10-sulfonamido] -3- [4- (4-N-acetylguanidino-4-oxobutyloxy) phenylpropionic acid; FAB 565: (2S) -2-tolylsulfonamido-3- [4- (4-guanidino-4-oxobutyloxy) phenyl] propionic acid trifluoroacetate gives (2S) -2-tolylsulfonamido-3- [4- (4-N-N-) trifluoroacetate. acetylguanidino (4-oxobutyloxy) phenyl] propionic acid; FAB 505.

Example 5

A solution of 0.05 g of (2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester in 5 ml of dichloromethane is treated with 1 ml of TFA and stirred. at room temperature for 12 hours. After the usual work-up, 0.045 g of (2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxo-butyloxy) phenyl] propionic acid is obtained; FAB 563.

Similarly, (2S) - (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutyloxy) phenyl] propionic acid is obtained from (2S) -2 - [(S) -phosphoric-10-sulfonamido] - 2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutyloxy) phenyl] propionic acid; FAB 657 and (2S) -2-tolylsulfonamido34 was obtained from (2S) -2-tolylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutyloxy) phenyl] propionic acid tert-butyl ester34

3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutyloxy) phenyl] propionic acid; FAB 597.

Example 6

To a solution of (2S) -2 - [(S) -phosphor-10sulfonamido] -3- [4- (4-guanidino-4-oxobutyloxy) phenylpropionic acid trifluoroacetate (0.1 g) in ethanol (10 ml) was added 5 mg of ethanol. toluene sulfonic acid and stirred at room temperature for 72 hours. After usual working-up and freeze-drying, 0.055 mg of (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-guanidino-4-oxobutyloxy) phenyl] propionic acid ethyl ester is obtained; FAB 551.

Similarly, (2S) -2-butylsulfonamido-3- [4- (4-guanidino-4-oxo-butyloxy) phenyl] propionic acid trifluoroacetate gives (2S) -2-butylsulfonamido-3- [4- (4-guanidino-4) -ethyl ester. oxabutyloxy) phenyl] propionic acid, FAB 457, and (2S) -2-tolylsulphonamido-3- [4- (4-guanidino-4-oxobutyloxy) phenylpropionic acid trifluoroacetate gives (2S) -2-tolylsulphonamido-3- [4 (4-guanidino-4-oxobutyloxy) phenylpropionate. - (4-guanidino-4-oxobutyloxy) phenyl] propionic acid; FAB 491.

Example 7

Analogously to Example 1, reaction of benzyloxycarbonyl-1β-aminophenylalanine tert-butyl ester and 1-chloro-4-ethoxybutanedione affords (2S) - (2) -benzyloxycarboxamido-3- [4- (3-ethoxy- 3-Oxopropylcarboxamido) phenyl] propionic acid. Cleavage of the Z-protecting group gives the tert-butyl ester (2S).

2-Amino-3- [4- (3-ethoxy-3-oxopropylcarboxamido) phenyl] -propionic acid (C).

Treatment of compound C with 1-butanesulfonyl chloride affords (2S) -2-butylsulfonamido-3- [4- (3-ethoxy-3-propylcarboxamido) phenyl] propionic acid tert-butyl ester with 4-tolylsulfonyl chloride to give tert. (2Sj-2-tolylsulfonamido-3- [4- (3-ethoxy-3-oxopropylcarboxamido) phenyl] propionic acid-butyl ester and (S) - (+) - camphor-10-sulfonyl chloride affords tert-butyl ester (2S) 1 - 2 - [(S)-Camphor-10-sulfonamido] -3- [4- (3-ethoxy-3-oxopropylcarboxamido) phenyl] propionic acid.

Cleavage of the ethyl ester yields (2S) -2-butylsulfonamido-3- [4- (2-carboxyethylcarboxamido) phenyl] propionic acid tert-butyl ester, tert. (2S) -2-Tolylsulfonamido-3- [4- (2-carboxyethylcarboxamido) phenyl] propionic acid-butyl ester and (2S) -2 - [(S)-Camphor-10-sulfonamido] -3-tert-butyl ester - [4- (2-carboxyethylcarboxamido) phenyl] propionic acid.

Analogously to Example 1, reaction with Z-guanidine affords tert. (2S) -2-Butylsulfonamido-3- [4- (3-N-benzyloxycarbonylguanidino-3-oxopropylcarboxamido) phenyl] propionic acid tert-butyl ester (2S) -2-tolylsulfonamido-3- [4- ( 3-N-benzyloxycarbonylguanidino-3-oxopropylcarboxamido) phenyl] propionic acid and (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (3N-benzyloxycarbonylguanidino-3-) - tert -butyl ester oxopropylcarboxamido) phenyl] propionic acid.

Cleavage of the Z-protecting group analogously to Example 2 gives the following compounds:

(2S) -2-Butylsulfonamido-3- [4- (3-guanidino-3-oxopropylcarboxamido) phenyl] propionic acid tert-butyl ester, (2S) -2-Tolylsulfonamido-3- [4- (3-guanidino-3-oxopropylcarboxamido) tert-butyl ester and (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (3-guanidino-3-oxopropylcarboxamido) phenyl] propionic acid tert-butyl ester.

Analogously to Example 3, the tert-butyl ester is cleaved by TFA to give (2S) -2-butylsulfonamido-3- [4- (3-guanidino-3-oxopropylcarboxamido) phenyl] propionic acid trifluoroacetate, (2S) -2-tolylsulfonamido-3- trifluoroacetate. [4- (3-guanidino-3-oxopropylcarboxamido) phenyl] propionic acid and (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (3-guanidino-3-oxopropylcarboxamido) phenyl] propionic acid trifluoroacetate.

Analogously to Example 4, the following compounds are obtained by treatment with acetyl chloride:

(2S) -2-butylsulfonamido-3- [4- (3-N-acetylguanidino-3-oxopropylcarboxamido) phenyl] propionic acid, (2S) -2-tolylsulfonamido-3- [4- (3-N-acetylguanidino-3-oxopropylcarboxamido) (phenyl) propionic acid and (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (3-N-acetylguanidino-3-propylcarboxamido) phenyl] propionic acid.

Analogously to Example 5, treatment with (2S) -2-butylsulfonamido-3- [4- (3-N-benzyloxycarbonylguanidino-3-oxopropylcarboxamido) phenyl] propionic acid (2S) -2 tert-butyl ester TFA tolylsulfonamido-3- [4- (3-N-benzyloxycarbonylguanidino-3-oxopropylcarboxamido) phenyl] propionic acid and (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4-tert-butyl ester] - (3N-Benzyloxycarbonylguanidino-3-oxopropylcarboxamido) phenyl] propionic acid gives the following compounds:

(2S) -2-butylsulfonamido-3- [4- (3-N-benzyloxycarbonylguanidino-3-oxopropylcarboxamido) phenyl] propionic acid, (2S) -2-tolylsulfonamido-3- [4- (3-N-benzyloxycarbonylguanidino-3-propylcarboxamido) phenyl propionic acid; and (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (3-N-benzyloxycarbonylguanidino-3-oxopropylcarboxamido) phenyl] propionic acid.

Example 8

Analogously to Example 1, reaction of benzyloxycarbonyl-Lp-aminophenylalanine tert-butyl ester and 1-chloro-5-ethoxypentanedione-1,5 affords (2S) - (2) -benzyloxycarboxamido-3- [4- (4) -butyl ester. -ethoxy-4-oxobutylcarboxamido) phenylpropionic acid. Cleavage of the Z-protecting group affords (2S) -2-amino-3- [4- (4-ethoxy-4-oxobutylcarboxamido) phenyl] propionic acid tert-butyl38 ester (D).

Subsequent reaction of (D) with 1-butanesulfonyl chloride affords (2S) -2-butylsulfonamido-3- [4- (4-ethoxy-4-oxobutylcarboxamido) phenyl] propionic acid tert-butyl ester, with 4-tolylsulfonyl chloride to give tert-butyl ester (2S) -2-tolylsulfonamido-3- [4- (4-ethoxy-4-oxobutylcarboxamido) phenyl] propionic acid, and (S) - (+) - camphor-10-sulfonyl chloride affords (2S) -2 tert-butyl ester - [(S)-Camphor-10-sulfonamido] -3- [4- (4-ethoxy-4-oxobutylcarboxamido) phenyl] propionic acid.

Cleavage of the ethyl ester yields (2S) -2-butylsulphonamido-3- [4- (3-carboxypropylcarboxamido) phenyl] propionic acid tert-butyl ester, (2S) -2-tolylsulphonamido-3- [4- (3-carboxypropylcarboxamido) phenyl] propionate. (3-carboxypropylcarboxamido) phenyl] carboxamido) phenyl] propionic acid, (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (3-carboxypropylcarboxamido) phenyl] propionic acid tert-butyl ester.

By reaction with Z-guanidine, they are obtained analogously to Example 1:

(2S) -2-Butylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutylcarboxamido) phenyl] propionic acid tert-butyl ester (2S) -2-tolylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutylcarboxamido) phenyl] propionic acid, (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-N-benzyloxycarbonylguanidino) - tert -butyl ester 4-oxobutylcarboxamido) phenyl] propionic acid.

The cleavage of the protecting group Z proceeds as in Example 2 to give the following compounds:

(2S) -2-Butylsulfonamido-3- [4- (4-guanidino-4-oxobutylcarboxamido) phenyl] propionic acid tert-butyl ester, (2S) -2-Tolylsulfonamido-3- [4- (4-guanidino4) -butyl ester (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-guanidino-4-oxobutylcarboxamido) phenyl] propionic acid-oxobutylcarboxamido) phenyl] propionic acid,

Analogously to Example 3, the tert-butyl ester is cleaved by TFA to give:

(2S) -2-Butylsulfonamido-3- [4- (4-guanidino-4-oxobutylcarboxamido) phenyl] propionic acid trifluoroacetate, (2S) -2-Tolylsulfonamido-3- [4- (4-guanidino-4-oxobutylcarboxamido) phenyl] propionic acid trifluoroacetate (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-guanidino-4-oxobutylcarboxamido) phenyl] propionic acid trifluoroacetate.

Analogously to Example 4, the following compounds are obtained by reaction with acetyl chloride:

(2S) -2-butylsulphonamido-3- [4- (4-N-acetylguanidino-4-oxobutylcarboxamido) phenyl] propionic acid, (2S) -2-tolylsulphonamido-3- [4- (4-N-acetylguanidino-4) (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-N-acetylguanidino-4-oxobutylcarboxamido) phenyl] propionic acid -oxobutylcarboxamido) phenyl] propionic acid

Analogously to Example 5, they are obtained by treating TFA from (2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutylcarboxamido) phenyl] propionic acid tert-butyl ester, from tert-butyl ester (2S) -2-tolylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutylcarboxamido) phenyl] propionic acid, from (2S) -2 - [(S)-Camphor-10- sulfonamido] -3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutylcarboxamido) phenyl] propionic acid, the following compounds:

(2S) -2-Butylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutylcarboxamido) phenyl] propionic acid (2S) -2-tolylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino4-oxobutylcarboxamido) phenyl] propionic acid (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-N-benzyloxycarbonyl guanidino-4-oxobutylcarboxamido) phenyl] propionic acid.

Example 9

Analogously to Example 1, reaction of benzyloxycarbonyl Lp-aminophenylalanine-tert-butyl ester and 1-chloro-3-ethoxypropanedione-1,3 gives (2S) -2-benzyloxycarboxamido-3- [4- (2-ethoxy) tert-butyl ester -2-oxoethylcarboxamido) phenyl] propionic acid. Cleavage of the Z-protecting group gives (2S) -2-amino-3- [4- (2-ethoxy-2-oxobutylcarboxamido) phenyl] propionic acid tert-butyl ester (E).

Subsequent reaction of (E) with 1-butanesulfonyl chloride affords (2S) -2-butylsulfonamido-3- [4- (2-ethoxy-2-oxoethylcarboxamido) phenyl] propionic acid tert-butyl ester, with 4-tolylsulfonyl chloride, to give 4-tolylsulfonyl chloride. (2S) -2-Tolylsulfonamido-3- [4- (2-ethoxy-2-oxoethylcarboxamido) phenyl] propionic acid tert-butyl ester, with (S) - (+) - camphor-10-sulfonyl chloride to obtain tert- (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (2-ethoxy-2-oxoethylcarboxamido) phenyl] propionic acid butyl ester.

Cleavage of the ethyl ester yields (2S) -2-butylsulphonamido-3- [4- (carboxymethylcarboxamido) phenyl] propionic acid tert-butyl ester, (2S) -2-tolylsulphonamido-3- [4- (carboxymethylcarboxamido) tert-butyl ester (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4-carboxymethylcarboxamido) phenyl] propionic acid tert-butyl ester.

Analogously to Example 1, reaction with Z-guanidine affords (2S) -2-butylsulfonamido-3- [4- (2-N-benzyloxycarbonylguanidino-2-oxoethylcarboxamido) phenyl] propionic acid tert-butyl ester, tert-butyl ester (2S) -2-Tolylsulfonamido-3- [4- (2-N-benzyloxycarbonylguanidino-2-oxoethylcarboxamido) phenyl] propionic acid, (2S) -2 - [(S)-Camphor-10-sulfonamido] tert -butyl ester -3- [4- (2-N-benzyloxycarbonylguanidino-2-oxoethylcarboxamido) phenyl propionic acid.

The cleavage of the Z-protecting group is carried out analogously to Example 2 to give the following compounds:

(2S) -2-Butylsulfonamido-3- [4- (2-guanidino-2-oxoethylcarboxamido) phenyl] propionic acid tert-butyl ester, (2S) -2-Tolylsulfonamido-3- [4- (2-guanidino2) -butyl ester (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (2-guanidino-2-oxoethylcarboxamido) phenyl] propionic acid tert-butyl ester (2-oxoethylcarboxamido) phenyl] propionic acid.

Analogously to Example 3, the tert-butyl ester was cleaved by TFA to give (2S) -2-butylsulfonamido-3- [4- (2-guanidino-2-oxoethylcarboxamido) phenyl] propionic acid trifluoroacetate, (2S) -2-tolylsulfonamido trifluoroacetate. 3- [4- (2-guanidino-2-oxoethylcarboxamido) phenyl] propionic acid, (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (2-guanidino-2-oxoethylcarboxamido) trifluoroacetate] phenylpropionic acid.

In analogy to Example 4, the following compounds were reacted with acetyl chloride to give (2S) -2-butylsulfonamido-3- [4- (2-N-acetylguanidino-2-oxoethylcarboxamido) phenyl] propionic acid, (2S) -2-tolylsulfonamido- 3- [4- (2-N-acetylguanidino-2-oxoethylcarboxamido) phenyl] propionic acid, (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (2-N-acetylguanidino-2-oxoethylcarboxamido) Phenyl] propionic acid.

Analogously to Example 5, TFA treatment affords (2S) -2-butylsulfonamido-3- [4- (2-N-benzyloxycarbonylguanidino-2-oxoethylcarboxamido) phenyl] propionic acid tert-butyl ester, from (2S) - 2-Tolylsulfonamido-3- [4- (2-N-benzyloxycarbonylguanidino-2-oxoethylcarboxamido) phenyl] propionic acid and (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4 (2) -butyl ester] The following compounds are N-benzyloxycarbonylguanidino-2-oxoethylcarboxamido) phenyl] propionic acid:

(2S) -2-butylsulfonamido-3- [4- (2-N-benzyloxycarbonylguanidino-2-oxoethylcarboxamido) phenyl] propionic acid, (2S) -2-tolylsulfonamido-3- [4- (2-N-benzyloxycarbonylguanidino-2-oxoethylcarboxamido) phenyl] phenyl] propionic acid (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (2-N-benzyloxycarbonyl guanidino-2-oxoethylcarboxamido) phenyl] propionic acid.

Example 10

Analogously to Example 1, (2S) -2-benzyloxycarboxamido-3- [4- (5-ethoxy-5-oxopentyloxy) -benzyloxycarbonyl-L-tyrosine-tert-butyl ester and 5-bromovaleric acid ethyl ester was obtained by reaction of benzyloxy. phenyl] propionic acid. Cleavage by protecting the Z-group yields (2S) -2-amino-3- [4- (5-ethoxy-5-oxopentyloxyphenyloxy) phenyl] propionic acid tert-butyl ester (F).

Subsequent reaction of (F) with 1-butanesulfonyl chloride affords (2S) -2-butylsulfonamido-3- [4- (5-ethoxy-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester, with 4-tolylsulfonyl chloride to give tert. (2S) -Tolylsulfonamido-3- [4- (5-ethoxy-5-oxopentyloxy) phenyl] propionic acid-butyl ester with (S) - (+) - camphor-10-sulfonyl chloride to give tert-butyl ester (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (5-ethoxy-5-oxopentyloxy) phenyl] propionic acid.

Cleavage of ethyl ester yields:

(2S) -2-Butylsulfonamido-3- [4- (4-carboxybutyloxy) phenyl] propionic acid tert-butyl ester, (2S) -2-Tolylsulfonamido-3- [4- (4-carboxybutyloxy) phenyl] propionic acid tert-butyl ester (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-carboxybutyloxy) phenyl] propionic acid tert-butyl ester.

In analogy to Example 1, the following compounds are obtained by reaction with Z-guanidine:

(2S) -2-Butylsulfonamido-3- [4- (5-N-benzyloxycarbonylguanidino-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester, tert. (2S) -2-Tolylsulfonamido-3- [4- (5-N-benzyloxycarbonylguanidino-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester, tert. (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (5-N-benzyloxycarbonylguanidino-5-oxopentyloxy) phenyl] propionic acid -butyl ester.

Following the cleavage of the Z-protecting group according to Example 2, the following compounds are obtained:

t. (2S) -2-Butylsulfonamido-3- [4- (5-guanidino-5-oxopentyloxy) phenyl] propionic acid butyl ester, tert. (2S) -2-Tolylsulfonamido-3- [4- (5-guanidino-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester (2S) -2 - [(S)-Camphor-10-sulfonamido] - 3- [4- (5-guanidino-5-oxopentyloxy) phenyl] propionic acid.

In analogy to Example 3, the tert-butyl ester is cleaved by TFA to give:

(2S) -2-Butylsulfonamido-3- [4- (5-guanidino-5-oxopentyloxy) phenyl] propionic acid trifluoroacetate; FAB 443, (2S) -2-Tolylsulfonamido-3- [4- (5-guanidino-5-oxopentyloxy) phenyl] propionic acid trifluoroacetate; FAB 477, (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (5-guanidino-5-oxopentyloxy) phenyl] propionic acid trifluoroacetate; FAB 537.

Analogously to Example 4, reaction with acetyl chloride affords:

(2S) -2-butylsulphonamido-3- [4- (5-N-acetylguanidino-5-oxopentyloxy) phenyl] propionic acid, (2S) -2-tolylsulphonamido-3- [4- (5-N-acetylguanidino-5-oxopentyloxy) (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (5-N-acetylguanidino-5-oxopentyloxy) phenyl] propionic acid.

Analogously to Example 5, treatment of TFA from (2S) -2-butylsulfonamido-3- [4- (5-N-benzyloxycarbonylguanidino-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester, from (2S) - 2-tolylsulfonamido-3- [4- (5-N-benzyloxycarbonylguanidino-5-oxopentyloxy) phenyl] propionic acid and (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-) - tert -butyl ester (5N-Benzyloxycarbonylguanidino-5-oxopentyloxy) phenyl] propionic acid gives the following compounds:

47 (2S) -2-butylsulfonamido-3- [4- (5-N-benzyloxycarbonylguanidino-5-oxopentyloxy) phenyl] propionic acid; FAB 577 (2S) -2-Tolylsulfonamido-3- [4- (5-N-benzyloxycarbonylguanidino-5-oxopentyloxy) phenyl) propionic acid and (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [ 4- (5-N-benzyloxycarbonyl guanidino-5-oxopentyloxy) phenyl] propionic acid; FAB 671.

Example 11

Analogously to Example 1, reaction of benzyloxycarbonyl L-tyrosine-tert-butyl ester with 5-bromo-2-oxo-valeronitrile affords (2S) -2-benzyloxycarboxamido-3- [4- (4-cyano-4) -butyl ester. (oxo butyloxy) phenyl) propionic acid.

Cleavage of the Z-protecting group gives (2S) -2-amino-3- [4- (4-cyano-4-oxobutyloxy) phenyl] propionic acid tert-butyl ester (G).

Treatment of (G) with 1-butanesulfonyl chloride affords (2S) -2-butylsulfonamido-3- [4- (4-cyano-4-oxobutyloxy) phenyl] propionic acid tert-butyl ester (H).

Solution (H) and an equimolar amount of hydroxylamine and sodium bicarbonate in isopropanol / water 6: 1 were heated at reflux for 12 hours. After usual work-up, (2S) -2-butylsulfonamido-3- [4- (5-amino-5-N-hydroxylimino-4-oxopentyloxy) phenyl] propionic acid tert-butyl ester (J) is obtained.

The solution (J) in acetic acid was hydrogenated at ambient pressure for two hours at room temperature using palladium catalyst (10% on activated carbon). After separation of the catalyst and usual work-up, (2S) -2-butylsulfonamido-3- (4- (4-amidino-4-oxobutyloxy) phenyl) propionic acid is obtained.

Example 12

In a similar manner to Example 1, the reaction of N-benzyloxycarbonyl-N-ethylguanidine with (2S) -2-butylsulfonamido-3- [4- (3-carboxypropyloxy) phenyl] propionic acid tert-butyl ester (2S) is obtained. -2-butylsulfonamido-3- [4- (4-N-benzyloxycarbonyl-N-ethylguanidino-4-oxobutyloxy) phenyl] propionic acid; FAB 647, with (2S) -2 - ((S)-Camphor-10-sulfonamido) -3- [4- (3-carboxypropyloxy) phenyl] propionic acid tert-butyl ester (2S) -2- [ (S)-Camphor-10-sulfonamido] -3- [4- (4-N-benzyloxycarbonyl-N-ethylguanidino-4-oxobutyloxy) phenyl] propionic acid FAB 741, with (2S) -2-tolylsulfonamido- tert -butyl ester 3- [4- (3-carboxypropyloxy) phenyl] propionic acid (2S) -2-tolylsulfonamido-3- [4- (4-N-benzyloxycarbonyl-N-ethylguanidino-4-oxobutyloxy) phenyl] propionic acid tert-butyl ester FAB 681.

By cleavage of the Z-protecting group analogously to Example 2, the following compounds are obtained:

(2S) -2-Butylsulfonamido-3- [4- (4-N-ethylguanidino-4-oxobutyloxy) phenyl] propionic acid tert-butyl ester; FAB 513 (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-methyl-guanidino-4-oxobutyloxy) -phenyl] -propionic acid tert-butyl ester; FAB 607 terc. (2S) -2-Tolylsulfonamido-3- [4- (4-N-ethylguanidino-4-oxobutyloxy) phenyl] propionic acid butyl ester; FAB 547.

Analogously to Example 3, cleavage of the tert-butyl ester with TFA gave the following compounds:

(2S) -2-Butylsulfonamido-3- [4- (4-N-ethylguanidino-4-oxobutyloxy) phenyl] propionic acid trifluoroacetate; FAB 457 (2S) -2 - [(S)-Camphor-10-sulfonamido] -3- [4- (4-methylguanidino-4-oxobutyloxy) phenyl] propionic acid trifluoroacetate; FAB 551 (2S) -2-Tolylsulfonamido-3- [4- (4-N-ethylguanidino-4-oxobutyloxy) phenyl] propionic acid trifluoroacetate; FAB 491.

Example 13

A solution of 3.5 g of BOC-L-tyrosine benzyl ester, 5.5 g of tert-butyl bromoacetate, 2.61 g of potassium carbonate and 250 mg of Krone-6 in 100 ml of toluene was stirred at 85 ° C for 12 hours. After usual work-up, 4.35 g of (2S) -2-tert-butoxycarboxamido-3- (4- (tert-butoxycarbonylmethoxy) phenyl) propionic acid benzyl ester (K); FAB 486 are obtained.

A solution of 4.3 g (K) in 20 ml of dichloromethane and 100 ml of 3N hydrochloric acid in diethyl ether was stirred at room temperature for 6 hours. After usual work-up, 2.8 g of (2S) -2-amino-3- (4- (tert-butoxycarbonylmethoxy) phenyl) propionic acid benzyl ester (L) is obtained; FAB 386.

A solution of 2.8 g of (L) in 50 ml of dichloromethane was treated with 3.7 g of triethylamine and 3.64 g of (R) -phosphoric-10-sulfonic acid chloride and stirred for 2 hours. After usual work-up and chromatography on silica gel (toluene: acetone 10: 1), it is obtained

3.8 g of (2S) -2- (R)-Camphor-10-sulfonamido) -3- (4- (tert-butoxycarbonylmethoxy) phenyl) propionic acid benzyl ester (M); FAB 600.

Dissolve 2.5 g (M) in 5 ml of trifluoroacetic acid and stir for 2 hours. After usual work-up, 1.9 g of (2S) -2- (R) -phosphor-10-sulfonamido) -3- (4- (carboxymethoxy) phenyl) propionic acid benzyl ester (N) are obtained; FAB 544.

A solution of 1 g of N, 270 mg of 2-aminoimidazole sulphate, 770 mg of TBTU, 85 mg of HOBt and 1.3 g of triethylamine in 30 ml of DMF is stirred overnight at room temperature. After customary work-up, 1 g of (2S) -2 - ((R)-Camphor-10-sulfonamido) -3- (4-N- (2-imidazolyl) - (carbamoylmethoxy) phenyl) propionic acid benzyl ester (O) is obtained;

FAB 609.

1 g of O is dissolved in 45 ml of dioxane and 5 ml of water and hydrogenated at room temperature for 2 hours in the presence of 0.5 g of palladium (10% on charcoal). After separation of the catalyst and usual work-up, preparative HPLC (RP-18; acetonitrile / water gradient + 0.3% TFA 1) is obtained after chromatography:

to 99: 1 within one hour) and then freeze-drying (180 mg of (2S) -2- ((R) -phosphor-10-sulfonamido) -3- (4-N- (2-imidazolyl) - (carbamoylmethoxy) trifluoroacetate) trifluoroacetate) phenyl) propionic acid; FAB 519.

Example 14

As in Preparation 0, (2S) -2 - ((R)-Camphor-10-sulfonamido) -3- (4- (3-carboxypropoxy) phenyl) propionic acid (P) is obtained as the starting material. (2S) -2 - ((R)-Camphor-1051 sulfonamido) -3- (4- (3- (N- (2-benzimidazolyl) carbamoyl) propoxy) phenyl) propionic acid tert-butyl ester acid.

Cleavage of the TFA ester gives (2S) -2 - ((R) camphor-10-sulfonamido) -3- (4- (3- (N- (2-benzimidazolyl) carbamoyl) propoxy) phenyl) propionic acid trifluoroacetate; FAB 597.

Similarly, P is reacted with 2-aminoimidazole followed by cleavage of (2S) -2 - ((R) camphor-10-sulfonamido) trifluoroacetate ester -3- (4- (3- (N (2-benzimidazolyl) carbamoyl) propoxy) phenyl) propionic acid; FAB 547, with 5-aminotetrazole followed by cleavage of (2S) -2 - ((R)-Camphor-10-sulfonamido) trifluoroacetate ester -3- (4-3- (N (5-tetrazolyl) carbamoyl) propoxy) phenyl) propionic acid;

FAB 549, with 3-aminoimidazole followed by cleavage of (2S) -2 - ((R) -phosphor-10-sulfonamido) trifluoroacetate ester -3- (4- (3- (N (3-imidazolyl) carbamoyl) propoxy) phenyl) propionic acid;

FAB 547, with 2-aminothiazole followed by cleavage of (2S) -2 - ((R) -camphor-10-sulfonamido) trifluoroacetate ester -3- (4- (3- (N (2-thiazolyl) carbamoyl) propoxy) phenyl) phenyl propionic acid;

FAB 564 with 2-aminomethylbenzimidazole followed by cleavage of (2S) -2 - ((R) camphor-10-sulfonamido) trifluoroacetate ester -3- (4- (3- (N (benzimidazol-2-ylmethyl) carbamoyl) propoxy) phenyl) propionic acid; FAB 583.

Example 15

A solution of 250 mg of (2S) -2 - ((R) -phosphor-10-sulfonamido) -3- (4- (3 (N- (2-benzimidazolyl) carbamoyl) propoxy) phenyl) propionic acid and 25 mg of toluenesulfonic acid in 25 ml of ethanol are stirred at room temperature for 7 days. After usual work-up, 170 mg of (2S) -2 - ((R) -camphor-10-sulfonamido) -3- (4- (3 (N- (2-benzimidazolyl) carbamoyl) propoxy) phenyl) propionic acid ethyl ester) FAB are obtained. 625th

Similarly, (2S) -2 - ((R)-Camphor-10-sulfonamido) -3- (4- (3- (N- (2-imidazolyl) carbamoyl) propoxy) phenyl) propionic acid ethyl ester is obtained; FAB 575.

The following examples illustrate pharmaceutical compositions:

Example A Injection ampoules

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

Example B Suppositories

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

Example C Solution

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

Example D Ointment

500 mg of an active compound of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E Tablets

Tablets are compressed in a conventional manner from 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 such that each tablet contains 10 mg of the active ingredient.

Example F Dragees

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

Example G Capsules

In a known manner, 2 kg of active ingredient of the formula I are filled into hard gelatin capsules such that each capsule contains 20 mg of active ingredient.

Example H Ampoules

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

Example I Inhalation Spray

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

Industrial usability

The phenylalamine derivative and its pharmaceutically acceptable salts are useful as integrin inhibitors for the manufacture of pharmaceutical compositions.

Claims (11)

PATENT CLAIMS Compounds of general formula I wherein X is absent or represents an alkylene, arylene, cycloalkylene group having 4 to 8 carbon atoms or unsubstituted or one, two or three times a group A, oxo and / or R ⁴ substituted heterocycloalkylene group having 1 to 3 nitrogen, oxygen and / or sulfur atoms, Y and Z are each independently absent or O, S, NH, C (= O), CONH, NHCO, C (= S), SO ₂ NH, NHSO ₂ , CA = CA 'or -c = c-, R ^{1 is} H 2 N-C (= NH) or H 2 N- (C = NH) -NH, wherein the amino group also has optionally conventional protecting groups or is optionally substituted one, two or three times with A, Ar or R ⁵ , NH-CH 2 - R ⁶ , NH-R ⁶ , NH-C (= NH) -NH-R ^6, or R ⁶ N R is A, Ar or aralkylene, R ³ is H or A, R ⁴ is hydrogen, Hal, OA, NHA, NAA ', -NH-acyl, -O-acyl, CN, _NO2, SA, SOA, SO ₂ A, SO ₂ Ar or SO ₃ H, R ^{5 is} an alkanoyl or cycloalkanoyl group having 1 to 18 carbon atoms, wherein one, two or three methylene groups are optionally replaced by nitrogen, oxygen and / or sulfur, Ar-CO- or Ar-alkylene-CO-, A, A 'are independently hydrogen or an unsubstituted or mono-, di- or trisubstituted by R ⁴ substituted alkyl or cycloalkyl of 1 to 15 carbon atoms, in which one, two or three methylene groups are optionally replaced by N, O and / or S, Ar is unsubstituted or mono- or bi-core aromatic ring system having 0, 1, 2, 3 or 4 nitrogen, oxygen and / or sulfur atoms substituted by A and / or R ^4, unsubstituted or singly or twice; R ^{6 is a} mononuclear or bi-core heterocyclic system having 1 to 4 nitrogen, oxygen and / or sulfur atoms which is unsubstituted or once, twice or three times by Hal, A, acyl, OH, CN, COOH, COOA, CONH ₂ , NO ₂ , = NH or = O substituted, Hal F, Cl, Br or J, with the proviso that at least one element must be selected from X, Y, Za CH ₂ , and physiologically acceptable salts thereof. 2. Enantiomers and diastereomers of compounds of general formula I according to claim 1. Compounds of formula (I) according to claim 1 which are (a) (2S) -2-Butylsulfonamido-3- [4- (4-N-acetylguanidino-4-oxobutyloxy) phenyl] propionic acid; (b) (2S) -2-Butylsulfonamido-3- [4- (4-guanidino-4-oxobutyloxy) phenyl] propionic acid; (c) (2S) -2- (camphor-10-sulfonamido-3- [4- (4-N-ethylguanidino-4-oxobutyloxy) phenyl] propionic acid, (d) (2S) -2- (camphor-10-sulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxobutyloxy) phenyl] propionic acid, (e) (2S) -2- (Camphor-10-sulfonamido-3- [4- (4-guanidino-4-oxobutyloxy) phenyl] propionic acid; (f) (2S) -2- (Camphor-10-sulfonamido-3- [4- (4-guanidino-4-oxobutyloxy) phenyl] propionic acid ethyl ester; (g) (2S) -2-Butylsulfonamido-3- [4- (4-N-ethylguanidino-4-oxobutyloxy) phenyl] propionic acid; (h) (2S) -2-Butylsulfonamido-3- [4- (5-guanidino-5-oxopentyloxy) phenyl] propionic acid; (i) (2S) -2- (camphor-10-sulfonamido) -3- [4- (5-guanidino-5-oxopentyloxy) phenyl] propionic acid; j) (2S) -2- (Camphor-10-sulfonamido) -3- [4- (3- (1H-imidazol-2-ylcarbamoyl) propoxy) phenyl] propionic acid k) (2S) -2- (camphor-10-sulfonamido) -3- [4- (3- (1H-benzimidazol-2-ylcarbamoyl) propoxy) phenyl] propionic acid as well as their physiologically acceptable salts. A process for the preparation of compounds of formula I, wherein the individual symbols are as defined in claim 1, according to claim 1, characterized in that: (a) the compound of formula (I) is released from its functional derivative by treatment with a solvolytic or hydrogenolytic agent; b) reacting a compound of formula II (II) wherein R ¹ , R ³ , R ⁴ , X, Y and Z are as defined in claim 1 with a compound of formula III r ² -so ₂ -1 (m) wherein ^R2 is as given in claim 1 and L is Cl, Br, I, OH or a reactive esterified OH group, or (c) saponification of an ester of formula I, or (d) the group R ¹ and / or R ³ is transformed into another R ¹ and / or R ^{3 group} and / or e) the basic or acidic compound of formula I is converted into its salt by treatment with an acid or base. Process for the preparation of a pharmaceutical composition, characterized in that a compound of the formula I, wherein the individual symbols are as defined in claim 1 and / or their physiologically acceptable salts with at least one solid, liquid or semi-liquid carrier or excipient, is processed into a suitable the dosage form. Pharmaceutical composition, characterized in that it contains as active ingredient at least one compound according to claim 1 of the general formula I, in which the individual symbols have the meaning given in claim 1 and / or a physiologically acceptable salt thereof. Compounds according to claim 1 of formula I, wherein the individual symbols are as defined in claim 1, and their physiologically acceptable salt as GPIIb / IIIa-antagonists for the treatment of thromboses, heart attack, coronary heart disease and arteriosclerosis. Compounds according to claim 1, wherein the individual symbols are as defined in claim 1 and their physiologically acceptable salts as α _v -integrin inhibitors for the treatment of pathological angiogenic diseases, thromboses, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, inflammation and infections. 9. The compound of claim 1 of formula I, wherein R ² is camphor-10-yl group, and other symbols are of Claim 1 above, and the physiologically acceptable salts, and as _the -integrínové inhibitors for the treatment of pathological angiogenic disorders, thromboses, myocardial myocardial infarction, coronary heart disease, arteriosclerosis, tumors, osteoporosis, inflammation and infections. Use of the compounds according to claim 1 of the general formula I, wherein the individual symbols have the meaning given in claim 1 and / or their physiologically acceptable salts for the manufacture of medicaments. Compounds according to claim 1 of the general formula I, wherein the individual symbols are as defined in claim 1, and / or their physiologically acceptable salts for the manufacture of medicaments suitable as α _v integrin inhibitors.