DE19654483A1 - Phenylalanine derivatives - 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

The invention relates to compounds of the formula I.

wherein
X is absent, alkylene, arylene, cycloalkylene with 4-8 C atoms or unsubstituted or mono-, di- or trisubstituted by A, oxo and / or R⁴-substituted heterocycloalkylene with 1 to 3 N, O and / or S atoms ,
Y, Z are each independently absent, alkylene, O, S, NH, C (= O), CONH, NHCO, C (= S), SO₂NH, NHSO₂, CA = CA 'or -C≡C-,
R¹ H₂N-C (= NH) or H₂N- (C = NH) -NH, where the primary amino groups can also be provided with conventional amino protecting groups, or can be substituted one, two or three times by A, Ar or R⁵, NH -CH₂-R⁶, NH-R⁶, NH-C (= NH) -NH-R⁶ or R⁶,
R² A, Ar or aralkylene,
R³ H or A,
R⁴ H, Hal, OA, NHA, NAA ′, -NH-acyl, -O-acyl, CN, NO₂, SA, SOA, SO₂A, SO₂Ar or SO₃H,
R⁵ alkanoyl or cycloalkanoyl with 1-18 C atoms, in which one, two or three methylene groups can be replaced by N, O and / or S, Ar-CO- or Ar-alkylene-CO-,
A, A 'each independently of one another H or unsubstituted or mono-, di- or trisubstituted by R⁴-substituted alkyl or cycloalkyl having 1-15 carbon atoms and in which one, two or three methylene groups can be replaced by N, O and / or S. can,
Ar unsubstituted or mono-, di- or trisubstituted by A and / or R⁴ mono- or dinuclear aromatic ring system with 0, 1, 2, 3 or 4 N, O and / or S atoms,
R⁸ is a mono- or dinuclear heterocycle with 1 to 4 N, O and / or S atoms which is unsubstituted or mono-, di- or triple by Hal, A, acyl, OH, CN, COOH, COOA, CONH₂, NO₂, = NH or = O can be substituted,
Hal F, Cl, Br or I
mean,
with the proviso that at least one element selected from the group X, Y, Z must be CH₂,
and their physiologically acceptable salts.

Similar connections are e.g. B. from EP 0478 363, EP 0478 328, WO 94/12181 and WO 95/32710.

The invention was based on the object, new compounds with valuable len properties to find, especially those that are used to manufacture of drugs can be used.

It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the α _v integrin receptors with ligands. The compounds show particular effectiveness in the case of the integrins α _v β₃ and α _v β₅. The compounds are particularly effective as adhesion receptor antagonists for the vitronectin receptor α _v β₃. This effect can e.g. B. can be detected by the method described by JW Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).

Inhibition of vitronectin binding to receptors has been reported for some representative compounds of formula I experimentally proven. The pharmacological test data are summarized in Tables I and II.

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

The dependence of the development of angiogenesis on the change effect between vascular integrins and extracellular matrix protein is from P.C. Brooks, R.A. Clark and D.A. Cheresh in Science 264, 569-71 (1994).

The possibility of inhibiting this interaction and thus to Initiation of apoptosis (programmed cell death) angiogenic vascular Cells by a cyclic peptide is from P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier and D.A. Cheresh in Cell 79 115764 (1994).

The experimental evidence that the verb the attachment of living cells to the corresponding Prevent matrix proteins and, accordingly, the attachment of Preventing tumor cells from matrix proteins can result in cell adhesion test can be performed, which is analogous to the method of F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995).

PC Brooks et al. describe in J. Clin. Invest 96 1815-1822 (1995) α _v β₃ antagonists for combating cancer and for treating tumor-induced angiogenic diseases.

The compounds of formula I according to the invention can therefore as Active pharmaceutical ingredients, in particular for the treatment of tumor cranes kung, osteoporosis, osteolytic diseases as well as under depression of angiogenesis.

Compounds of formula I, the interactions of integrin receptors and ligands, such as. B. from fibrinogen to the fibrinogen receptor (glycoprotein IIb / IIIa) prevent GPIIb / IIIa antagonists from spreading tumor cells through metastasis. This is evidenced by the following observations:
The spread of tumor cells from a local tumor into the vascular system occurs through the formation of microaggregates (micro thrombi) through the interaction of the tumor cells with platelets. The tumor cells are shielded by the protection in the micro-aggregate and are not recognized by the cells of the immune system.

The micro-aggregates can stick to the walls of the vessel, causing further penetration of tumor cells into the tissue is facilitated. Since the formation of the microthrombi by fibrinogen binding to the fibri nogenreceptors mediated on activated platelets, can GPIIa / IIIb antagonists regarded as effective metastasis inhibitors will.

Compounds of the formula I inhibit the binding of fibrinogen, Fibronectin and the Willebrand factor to the fibrinogen receptor Platelets also bind other adhesive proteins, such as Vitro nectin, collagen and laminin, to the appropriate receptors on the Surface of different cell types. In particular, they prevent that Formation of platelet thrombi and can therefore be used for treatment of thrombosis, apoplexy, heart attack, inflammation and arterio sclerosis can be used.

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

The experimental evidence that the verb inhibition of fibrinogen binding to the corresponding Blocking receptors has been shown for some representative compounds of the Formula I proven experimentally. The pharmacological test data are summarized in Table III.

The antiplatelet effect can be demonstrated in vitro the method of Born (Nature 4832, 927-929, 1962).

The invention accordingly relates to compounds of the formula I. according to claim 1 and / or their physiologically acceptable salts for Manufacture of a medicament for use as integrin inhibitors. The invention relates in particular to compounds of the formula I. according to claim 1 and / or their harmless salts, wherein R² is the Importance of camphor-10-yl has for the manufacture of a medicament for Combating pathologically angiogenic diseases, tumors, Osteoporosis, inflammation and infection.

The compounds of formula I can be used as active pharmaceutical ingredients in the Human and veterinary medicine are used for prophylaxis and / or Therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammation exercises, apoplexy, angina pectoris, tumor diseases, osteolytic Diseases such as osteoporosis, pathologically angiogenic diseases such as e.g. B. inflammation, ophthalmic diseases, diabetic Retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, ulcerative Colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angio plastic, viral infection, bacterial infection, fungal infection, in acute Kidney failure and wound healing to support healing processes.

The compounds of formula I can act as antimicrobial sub punches are used in operations where biomaterials, implan tate, catheter or pacemaker can be used. They work here antiseptic. The effectiveness of the antimicrobial activity can be  by P.Valentin-Weigund et al., in Infection and Immunity, 2851-2855 (1988) described methods can be detected.

The invention further relates to a method for producing Compounds of formula I according to claim 1 and their salts, thereby featured,

• a) that a compound of the formula I is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent,
  or
• b) that a compound of formula II wherein R¹, R³, R⁴, X, Y and Z have the meanings given in claim 1, with a compound of the formula IIIR²-SO₂-L IIIworin
  R² has the meaning given in claim 1 and L denotes Cl, Br, I, OH or a reactive esterified OH group,
  implements
  or
• c) that an ester of the formula I is saponified,
  or
• d) that one radical R¹ and / or R³ is converted into another radical R¹ and / or R³,
  and or
• e) that one by a basic or acidic compound of formula I. Treat with an acid or base in one of its salts transferred.

The compounds of formula I have at least one chiral center and can therefore occur in several stereoisomeric forms. All these forms (e.g. D and L forms) and their mixtures (e.g. the DL- Forms) are included in Formula I.

So-called prodrug- Including derivatives, i. H. with z. B. alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which in Organism quickly to the active compounds of the invention to be split.

The abbreviations listed above and below stand for:
Ac Acetyl
BOC tert-butoxycarbonyl
CBZ or Z benzyloxycarbonyl
DCCI dicyclohexylcarbodiimide
DMF dimethylformamide
EDCI N-ethyl-N, N ′ - (dimethylaminopropyl) carbodiimide
Et ethyl
Fmoc 9-fluorenylmethoxycarbonyl
HOBt 1-hydroxybenzotriazole
Me methyl
Mtr 4-methoxy-2,3,6-trimethylphenyl sulfonyl
HONSu N-hydroxysuccinimide
OBn benzyl ester
OBut tert-butyl ester
Oct octanoyl
OMe methyl ester
OEt ethyl ester
POA phenoxyacetyl
TBTU O- (benzotriazol-1-yl) -N, N, N, N-tetramethyluronium tetra fluoroborate
TFA trifluoroacetic acid
Trt trityl (triphenylmethyl).

For the entire invention applies that all residues, the multiple occur, such as B. A and A ', may be the same or different, d. H. are independent of each other.

In the above formulas, alkyl preferably represents methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and also also for pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1- Ethyl propyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-, 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl.

Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl or 3-menthyl. Cycloalkyl means in particular the rest of a bicyclic terpene, the most preferred is Camphor-10-yl rest.

Alkylene preferably means methylene, ethylene, propylene, butylene, Pentylene, also hexylene, heptylene, ocytylene, nonylene or decylene. Aralkylene preferably means alkylenephenyl and is e.g. B. preferably Benzyl or phenethyl.  

Cycloalkylene preferably means cyclopropylene, 1,2- or 1,3-cyclo butylene, 1,2- or 1,3-cyclopentylene, 1,2-, 1,3- or 1,4-cyclohexylene, also 1,2-, 1,3- or 1,4-cycloheptylene.

Alkanoyl preferably means formyl, acetyl, propionyl, butyryl, Pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, Undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, Hexadecanoyl, heptadecanoyl or octadecanoyl.

Acyl preferably means z. B. formyl, acetyl, propionyl, butyryl, Trifluoroacetyl or benzoyl.

Preferred substituents for alkyl, alkylene, cycloalkyl, cycloalkylene, Alkanoyl and cycloalkanoyl are e.g. B. Hal, OA, NHA, NAA ', CN, NO₂, SA, SOA, SO₂A, SO₂Ar and / or SO₃H, especially z. B. F, Cl, hydroxy, Methoxy, ethoxy, amino, dimethylamino, methylthio, methylsuifinyl, Methylsulfonyl or phenylsulfonyl.

Preferred substituents for Ar and arylene are e.g. B. A and / or Hal, OA, NHA, NAA ', CN, NO₂, SA, SOA, SO₂A, SO₂Ar and / or SO₃H, esp special z. B. F, Cl, hydroxy, methoxy, ethoxy, amino, dimethylamino, Methylthio, methylsulfinyl, methylsulfonyl or phenylsulfonyl.

In the residues alkyl, alkylene, cycloalkyl, cycloalkylene, alkanoyl and Cycloalkanoyl can each have one, two or three methylene groups be replaced by N, O and / or S.

Ar-CO is aroyl and preferably means benzoyl or naphthoyl.

Ar is unsubstituted, preferably - as indicated - monosubstituted phenyl, in particular preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o- , m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-cyanophenyl, o-, in- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl , o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, in- 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 ,
more preferably 2,3-, 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 methyl, 2-chloro-4-methyl, 2-chloro-5-methyl, 2-chloro-6-methyl, 2-methyl-3-chloro, 2-methyl-4-chloro, 2 -Methyl- 5-chloro, 2-methyl-6-chloro, 3-chloro-4-methyl, 3-chloro-5-methyl or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl -, 2-bromo-4-methyl, 2-bromo-5-methyl, 2-bromo-6-methyl, 2-methyl-3-bromo, 2-methyl-4-bromo, 2-methyl - 5-bromo, 2-methyl-6-bromo, 3-bromo-4-methyl, 3-bromo-5-methyl 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-tri-tert-butylphenyl, 2,5-dimethylphenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-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-Tr iisopropylphenyl, naphthyl, 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, benzothiadiazol-5-yl or benzoxadiazol-5-yl.

Ar furthermore preferably denotes 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-oxadi azol-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 4-4-H-thio pyranyl, 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 benzthiazolyl, 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-cinnolinyl, 2, 4, 5, 6, 7 or 8-quinazolinyl.  

Arylene has the same meanings as for Ar, with the Provided that a further bond from the aromatic system to next neighbor is knotted.

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-isox azolidinyl, 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- Piperazinyl, further preferably 1,2,3-tetrahydro-triazol-1,2- or 1,4-yl, 1,2,4-tetrahydro-triazol-1,2- or 3,5-yl, 1,2- or 2,5-tetrahydro tetrazolyl, 1,2,3-tetrahydro-oxadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,4- Tetrahydro-oxadiazol-2,3-, -3,4- or -4,5-yl, 1,3,4-tetrahydro-thiadiazol- 2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,4-tetrahydro-thiadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,3-thiadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 2,3- or 3,4- Morpholinyl, 2,3-, 3,4- or 2,4-thiomorpholinyl.

R⁶ 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 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- 4-H-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-benzo pyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisox azolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benziso thiazolyl, 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- Cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.

The heterocyclic radicals can also be partially or completely be hydrated.  

R⁶ can thus z. B. also mean 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5- Dihydro-2-, -3-, -4- or S4uryl, 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, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrole dinyl, 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-dioxan-2-, -4- or -5-yl, 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 preferably means acetyl, propionyl, butyryl, Phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("Carbo benzoxy "), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.

Accordingly, the invention relates in particular to those gene compounds of formula I in which at least one of the above Radicals has one of the preferred meanings given above. Some preferred groups of compounds can follow through the partial formulas Ia to Ii are expressed, which correspond to the formula I. and in which the radicals not specified are those in the formula have given meaning, but in what

in Ia)
R¹ H₂N-C (= NH),
X alkylene with 1-6 C atoms,
Y O,
R² A,
R³, R⁴ represent H;

in Ib)
R¹ H₂N- (C = NH) -NH,
X alkylene with 1-6 C atoms,
Y O,
R² A,
R³, R⁴ represent H;

in Ic)
X alkylene with 1-6 C atoms,
Y is missing
R³, R⁴ H and
R² is aryl;

in Id)
R¹ H₂N- (C = NH) -NH,
X alkylene with 1-6 C atoms,
Y CONH,
R³, R⁴ H and
R² is A;

in Ie)
X alkylene with 1-6 C atoms,
Y O or CO-NH,
Z is missing,
R² camphor-10-yl,
R³ H or A and
R⁴ mean H;

in if)
R¹ H₂N-C (= NH) or H₂N- (C = NH) -NH,
X is missing
Y alkylene with 1-6 C atoms,
Z O,
R² A,
R³, R⁴ represent H;

in Ig)
R¹ H₂N-C (= NH) or H₂N- (C = NH) -NH,
X is missing
Y alkylene with 1-6 C atoms,
Z O,
R² camphor-10-yl,
R³, R⁴ represent H;

in you)
R¹ NH-CH₂-R⁶, NH-R⁶ or R⁶,
X is missing
Y alkylene with 1-6 C atoms,
Z O,
R² camphor-10-yl,
R³, R⁴ represent H;

in II)
R¹ H₂N-C (= NH) or H₂N- (C = NH) -NH, where the primary amino groups can also be provided with conventional amino protecting groups, or can be substituted one, two or three times by A, Ar or R⁵, NH-CH₂-R⁶, NH-R⁶ or R⁶,
X is missing
Y alkylene with 1-6 C atoms,
Z O,
R² camphor-10-yl,
R³ H or A,
R⁴ H
R⁵ acetyl or benzyloxycarbonyl and
R⁶ is a mono- or dinuclear heterocycle with 1 to 4 N, O and / or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, acyl, OH, = NH or = O , mean.

The compounds of formula I and also the starting materials for their manufacture position are otherwise produced by methods known per se, as described in literature (e.g. in standard works such as Houben-Weyl, Methods of organic chemistry, Georg-Thieme-Verlag, Stuttgart;) are described, namely under reaction conditions for the ge mentioned implementations are known and suitable. You can also do that use of known variants not mentioned here do.  

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

Compounds of formula I can preferably be obtained by compounds of formula I from one of their functional derivatives by treatment with a solvolysing or hydrogenolysing Set the means free.

Preferred starting materials for solvolysis or hydrogenolysis are those that otherwise correspond to formula I, but instead of an or corresponding to several free amino and / or hydroxy groups contain protected amino and / or hydroxy groups, preferably those that, instead of an H atom connected to an N atom, carry an amino protecting group, especially those that replace one HN group carry an R'-N group, where R 'is an amino protecting group means, and / or those instead of the H atom of a hydroxy group carry a hydroxy protecting group, e.g. B. those of the formula I correspond, but instead of a group -COOH a group -COOR ′ ′ wear, wherein R '' is a hydroxy protecting group.

Several - identical or different - protected amino and / or hydroxyl groups present in the molecule of the starting material be. If the existing protecting groups are different from each other they can be split off selectively in many cases.

The term "amino protecting group" is well known and refers to on groups that are suitable, an amino group before chemical order to protect (block) settlements that are easily removable, after the desired chemical reaction elsewhere in the Molecule has been carried out. Typical of such groups are ins special unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting groups according to the desired Reaction (or sequence of reactions) to be removed is their type and size the rest not critical; however, preference is given to those with 1-20, in particular special 1-8 carbon atoms. The term "acyl group" is related  with the present procedure in the broadest sense. He around includes aliphatic, araliphatic, aromatic or hetero cyclic carboxylic acids or sulfonic acid derived acyl groups and in particular alkoxycarbonyl, aryloxycarbonyl and especially Aralkoxycarbonyl groups. Examples of such acyl groups are Alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl like Methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred Amino protecting groups are BOC and Mtr, also CBZ, Fmoc, Benzyl and Acetyl.

The separation of the amino protection group succeeds - depending on the one used Protecting group - e.g. B. with strong acids, suitably with TFA or Per chloric acid, but also with other strong inorganic acids such as Hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as Trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfone acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable as inert solvents preferably organic, for example carboxylic acids such as vinegar acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogen hydrocarbons such as dichloromethane, and also alcohols such as Methanol, ethanol or isopropanol, as well as water. Come further Mixtures of the aforementioned solvents in question. TFA is preferred use in excess without the addition of another solvent det, perchloric acid in the form of a mixture of acetic acid and 70% Perchloric acid in a 9: 1 ratio. The reaction temperatures for the spal tion are advantageously between about 0 and about 50 °, preferably one works between 15 and 300 (room temperature).

The groups BOC, OBut and Mtr can e.g. B. preferably with TFA in Di chloromethane or with about 3 to 5N HCl in dioxane at 15-30 ° be the FMOC group with an approximately 5 to 50% solution of Dimethylamine, diethylamine or piperidine in DMF at 15-30 °.  

Hydrogenolytically removable protective groups (e.g. CBZ or benzyl) can e.g. B. by treatment with hydrogen in the presence of a kata lysators (z. B. a noble metal catalyst such as palladium, appropriate on a carrier such as coal). As a solvent are the above, especially z. B. alcohols such as Methanol or ethanol or amides such as DMF. The hydrogenolysis is in usually at temperatures between about 0 and 100 ° and printing between about 1 and 200 bar, preferably at 20-30 ° and 1-10 bar guided. Hydrogenolysis of the CBZ group succeeds e.g. B. good at 5 to 10 % Pd / C in methanol or with ammonium formate (instead of Hydrogen) on Pd / C in methanol / DMF at 20-30 °.

Compounds of formula I can preferably be obtained by reacting compounds of formula II with compounds of formula III. The starting compounds of the formula II and III are generally new. she but can be prepared by methods known per se.

In the compounds of formula III, L is preferably Cl, Br, I or a reactively modified OH group such as alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl or p-tolylsulfonyloxy).

The compounds of the formula II are generally reacted in an inert solvent, in the presence of an acid-binding agent preferably an organic base such as triethylamine, dimethylaniline, Pyridine or quinoline.

Also the addition of an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or other salt of a weak acid Alkali or alkaline earth metals, preferably of potassium, sodium, Calcium or cesium can be beneficial.

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

Suitable inert solvents are, for. B. hydrocarbons such as hexane, Petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as  Trichlorethylene, 2-dichloroethane, carbon tetrachloride, chloroform or Dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methyl glycol or ethyl glycol), Ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Sulfur carbon; Carboxylic acids such as formic acid or acetic acid; Nitrover bonds such as nitromethane or nitrobenzene; Esters such as ethyl acetate, Water or mixtures of the solvents mentioned.

It is also possible to saponify an ester of the formula. This is expediently carried out by solvolysis or hydrogenolysis, as above specified, e.g. B. with NaOH or KOH in dioxane-water at temperatures between 0 and 60 ° C, preferably between 10 and 40 ° C.

It is also possible that a radical R¹ and / or R³ in one other R¹ and / or R³ converted.

In particular, a carboxylic acid can be converted into a carboxylic acid ester convert.

The conversion of a cyano group into an amidino group is carried out by Implementation with z. B. hydroxylamine and subsequent reduction of the N- Hydroxyamidine with hydrogen in the presence of a catalyst such as e.g. B. Pd / C.

It is also possible to use a conventional amino protecting group To replace hydrogen by the protecting group as described above is split off solvolytically or hydrogenolytically or that one amino group protected by a conventional protecting group Solvolysis or hydrogenolysis sets you free.

A base of formula I can with an acid in the associated acid addition salt can be transferred, for example by reaction equi valent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. For this implementation In particular acids are considered, the physiologically harmless  Deliver salts. So inorganic acids can be used, e.g. B. Sulfuric acid, nitric acid, hydrohalic acids such as chlorine hydrochloric acid or hydrobromic acid, phosphoric acids such as ortho phosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyc misch mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. B. Formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malein acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfone acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfone acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. B. Picrates, can be used to isolate and / or purify the compounds of formula I can be used.

On the other hand, an acid of the formula I can be reacted with a Base in one of their physiologically harmless metal or ammonium salts are transferred. The salts in particular come from Sodium, potassium, magnesium, calcium and ammonium salts in Consider further substituted ammonium salts, e.g. B. the dimethyl, diethyl or diisopropyl ammonium salts, monoethanol, diethanol or diiso propylammonium salts, cyclohexyl, dicyclohexylammonium salts, Di benzylethylenediammonium salts, further z. B. salts with arginine or Lysine.

The compounds of formula I contain one or more chiral centers and can therefore be in racemic or optically active form. Racemates obtained can be mecha by methods known per se nisch or chemically separated into the enantiomers. Preferably are from the racemic mixture by reaction with a optically active release agent diastereomers formed. Suitable as a release agent z. B. optically active acids, such as the D and L forms of tartaric acid Diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, milk acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Enantiomer separation is also advantageous  with the help of an optically active release agent (e.g. dinitrobenzoyl phenylglycine) filled column; as a solvent is z. B. a mixture Hexane / isopropanol / acetonitrile, e.g. B. in a volume ratio of 82: 15: 3.

Of course, it is also possible to use optically active compounds of the formula I. according to the methods described above, by choosing Aus used materials that are already optically active.

The test results of α _v β₃- and α _v β₅ inhibition by some 10 representative compounds of formula I are summarized in Tables I and II below. For the Vitronectin binding tests, the IC₅₀ values are given, ie the concentrations in nmoles / liter that inhibit 50% of the Vitronectin binding to the corresponding isolated receptor.

Table I

Table II

The pharmacological data prove the antagonistic activity of the compounds of the formula I according to the invention for the vitronectin receptors α _v β₃ and α _v β₅.

The results of GPllbllla inhibition are representative for some Compounds of formula I are in Table III below summarized. The IC₅₀ values are given, i. H. the concessions trations in nmoles / liter, which 50% of the fibrinogen binding to the inhibit corresponding isolated receptor.

Table III

The pharmacological data demonstrate the antagonistic activity of the Compounds of formula I according to the invention for the fibrinogen receptor GPIIbIIIa.  

The invention further relates to the use of the compounds of formula I and / or their physiologically acceptable salts Provision of pharmaceutical preparations, especially on non-chemical paths. Here you can use at least one fixed, liquid and / or semi-liquid carrier or auxiliary and given if in combination with one or more other active ingredients appropriate dosage form are brought.

The invention furthermore relates to pharmaceutical preparations, containing at least one compound of formula I and / or one of them physiologically acceptable salts.

These preparations can be used as medicinal products in human or veteri used in medicine. Organic or inorganic substances in question that are suitable for enteral (e.g. oral), parenteral, topical application or for an application in the form of a Inhalation sprays are suitable and do not react with the new compounds s, for example water, vegetable oils, benzyl alcohols, alkylene glycol kole, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as Lactose or starch, magnesium stearate, talc, petroleum jelly. For oral application tablets, pills, coated tablets, capsules, pul ver, granules, syrups, juices or drops, for rectal use Sup positions, for parenteral use solutions, preferably oily or aqueous solutions, also suspensions, emulsions or implan tate, for topical application of ointments, creams or powder. The new Compounds can also be lyophilized and the lyophilizates obtained e.g. B. can be used for the preparation of injectables. The on given preparations can be sterilized and / or auxiliary substances such as Lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers s, salts to influence the osmotic pressure, buffer substances, Contain color, taste and / or several other active ingredients, for. B. one or more vitamins.

Sprays can be used for application as an inhalation spray the one that has the active ingredient either dissolved or suspended in a propellant or propellant gas mixture (e.g. CO₂ or chlorofluorocarbons) ent hold. The active ingredient is expediently used in micronized form  Form, with one or more additional physiologically acceptable Solvents may be present, e.g. B. ethanol. Inhalation solutions can be administered using standard inhalers.

The compounds of formula I and their physiologically acceptable Salts can act as integrin inhibitors in fighting diseases, especially of pathologically angiogenic diseases, thrombosis, Heart attack, coronary heart disease, arteriosclerosis, tumors, Inflammation and infection are used.

Compounds of formula I according to claim 1 and / or their are preferred harmless salts, in which R² has the meaning camphor-10-yl, for Combating pathologically angiogenic diseases, tumors, Osteoporosis, inflammation and infection.

The substances according to the invention can generally be found in Ana logie zu other known, commercially available peptides, in particular but in analogy to the Ver. described in US-A-4,472,305 bonds are administered, preferably in doses between about 0.05 and 500 mg, especially between 0.5 and 100 mg each Dosage unit administered. The daily dosage is preferably between about 0.01 and 2 mg / kg body weight. The special dose for however, each patient depends on a variety of factors for example on the effectiveness of the special connection used, on age, body weight, general health, gender, of the food, the time and route of administration, the excretion application rate, drug combination and severity of each Disease to which the therapy applies. The parenteral application is prefers.

All temperatures above and below are given in ° C. In the examples below, "customary work-up" means: if necessary, water is added, and if necessary, depending on the constitution of the end product, the pH is adjusted to between 2 and 10, extracted with ethyl acetate or dichloromethane, separated off and dried the organic phase over sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.
Mass spectrometry (MS):
EI (electron impact ionization) M⁺
FAB (Fast Atom Bombardment) (M + H) ⁺

example 1

A solution of 25 g of benzyloxycarbonyl-L-tyrosine tert. -butyl ester, 29 ml 4-bromobutyric acid ethyl ester, 18.7 g potassium carbonate and 1.8 g 18-crown-6 in 300 ml of toluene is maintained at 85 ° for 12 hours Working up gives 25.3 g of (2S) -2-benzyloxycarboxamido-3- [4- (4- tert-butyl ethoxy-4-oxo-butyloxy) phenyl] propionate ("A") as colorless syrup; FAB 486.

A solution of 10 g "A" in 70 ml ethyl acetate, 20 ml methanol, 10 ml Water and 2 ml TFA are mixed with 1 g palladium 10% on activated carbon and hydrogenated with hydrogen for 4 hours at room temperature. After Separation of the catalyst and customary workup gives 8.8 g (2S) -2-Amino-3- [4- (4-ethoxy-4-oxo-butyloxy) phenyl] propionic acid ter-t.- butyl ester, trifluoroacetate ("B"); FAB 352.

A solution of 8.8 g "B" in 100 ml dichloromethane is added to the room temperature with 5.5 ml triethylamine and 3.9 ml 1-butanesulfonyl chloride added and stirred for 5 hours. After the usual work-up, 7.9 is obtained g (2S) -2-butylsulfonamido-3- [4- (4-ethoxy-4-oxo-butyloxy) phenyl] - tert-butyl propionate; FAB 472.

Analogously, by converting "B"
with (S) - (+) - camphor-10-sulfonyl chloride (2S) -2 - [(S) -campher-10-sulfonamido] -3- [4- (4-ethoxy-4-oxo-butyloxy) phenyl tert-butyl propionic acid; FAB 566
with 4-tolylsulfonyl chloride (2S) -2-tolylsulfonamido-3- [4- (4-ethoxy-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester; FAB 506.

A solution of 7.9 g of (2S) -2-butylsulfonamido-3- [4- (4-ethoxy-4-oxo tert-butyl butyloxy) phenyl] propionate and 10 ml of 2N sodium hydroxide solution  in 75 ml of methanol is stirred at room temperature for 12 hours. After The usual work-up gives (2S) -2-butylsulfonamido-3- [4- (3-carboxy tert-butyl propyloxy) phenyl] propionate as a colorless syrup; FAB 444.

Analogously, one obtains by cleaving the ethyl ester
from (2S) -2 - [(S) -campher-10-sulfonamido] -3- [4- (4-ethoxy-4-oxo-butyloxy) - phenyl] propionic acid tert-butyl ester (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (3-carboxypropyloxy) phenyl] propionic acid tert-butyl ester; FAB 538 and
from (2S) -2-tolylsulfonamido-3- [4- (4-ethoxy-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester (2S) -2-tolylsulfonamido-3- [4- (3rd -carboxy-propyloxy) -phenyl] - tert-butyl propionate; FAB 478.

A solution of 1.3 g of (2S) -2-butylsulfonamido-3- [4- (3-carboxypropyl oxy) phenyl] propionic acid tert-butyl ester in 15 ml DMF is mixed with 1.1 g 2- Chloro-1-methylpyridinium iodide, 3.9 ml of ethyldiisopropylamine and 2.8 g of Z- Guanidine was added and the mixture was stirred at room temperature for 12 hours. After usual work-up, 1.0 g of (2S) -2-butylsulfonamido-3- (4- (4-N- benzyloxycarbonyl-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid-ter-t.- butyl ester; FAB 619.

You get analog
from (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 guanidino-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester; FAB 713
and from (2S) -2-tolylsulfonamido-3- [4- (3-carboxypropyloxy) phenyl] - tert-butyl propionate (2S) -2-tolylsulfonamido-3- [4- (4-N- benzyloxycarbonyl-guanidino-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester; FAB 653.

Example 2

A solution of 1 g of (2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxy carbonyl-guanidino-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester in 18 ml of dioxane and 2 ml of water are mixed with 250 mg of palladium (10% Activated carbon) and hydrogenated for 3 hours at room temperature. After Removal of the catalyst and customary workup gives 0.78 g (2S) -2-butylsuifonamido-3- [4- (4-guanidino-4-oxo-butyloxy) phenyl] - tert-butyl propionate; FAB 485.

You get analog
from (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid tert-butyl ester ( 2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (4-guanidino-4-oxo-butyl oxy) phenyl] propionic acid tert-butyl ester; FAB 579
and from (2S) -2-tolylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester (2S) -2-tolylsulfonamido-3- [4- (4iuanidino-4-oxo-butyloxy) phenyl] tert-butyl propionate; FAB 519.

Example 3

A solution of 0.78 g (2S) -2-butylsulfonamido-3- [4- (4-guanidino-4-oxo butyloxy) phenyl] propionic acid tert-butyl ester in 20 ml dichloromethane mixed with 2 ml of TFA and stirred for 12 hours. After usual work-up and freeze drying, 0.87 g of (2S) -2-butylsuifonamido-3- [4- (4- guan idino-4-oxo-butyloxy) phenyl] propionic acid, trifluoroacetate, as white amorphous powder; FAB 429.

You get analog
from (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (4-guanidino-4-oxo-butyl oxy) -phenyl] propionic acid tert-butyl ester (2S) - 2 - [(S)-camphor-10-sulfonamido] -3- [4- (4-guanidino-4-oxo-butyl oxy) phenyl] propionic acid, trifluoroacetate; FAB 523
and from (2S) -2-tolylsulfonamido-3- [4- (4-guanidino-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester (2S) -2-tolylsulfonamido-3- [4- ( 4-guanidino-4-oxo-butyloxy) phenyl] propionic acid, trifluoroacetate; FAB 463.

Example 4

A solution of 50 mg (2S) -2-butylsulfonamido-3- [4- (4-guanidino-4-oxo butyloxy) phenyl] propionic acid, trifluoroacetate, in 5 ml pyridine at 0 ° mixed with 10 ul acetyl chloride and stirred for 2 hours. After usual Working up gives 0.027 g of (2S) -2-butylsulfonamido-3- [4- (4-N-acetyl guanidino-4-oxo-butyloxy) phenyl] propionic acid; FAB 471.

You get analog
from (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (4-guanidino-4-oxo-butyl oxy) -phenyl] propionic acid, trifluoroacetate (2S) -2- [ (S)-camphor-10-sulfonamido] -3- [4- (4-N-acetylguanidino-4-oxo-butyloxy) phenyl] propionic acid; FAB 565
and from (2S) -2-tolylsulfonamido-3- [4- (4-guanidino-4-oxo-butyloxy) phenyl] propionic acid, trifluoroacetate (2S) -2-tolylsulfonamido-3- [4- (4-N -acetyl-guanidino-4-oxo-butyloxy) phenyl] propionic acid; FAB 505.

Example 5

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

You get analog
from (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) -phenyl] -propionic acid tert-butyl ester ( 2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) phenyl] propionic acid; FAB 657
and from (2S) -2-tolylsulfonamido-3- [4- (4-N-benzyloxycarbonylguanidino-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester (2S) -2-tolylsulfonamido-3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butyloxy) phenyl] propionic acid; FAB 597.

Example 6

A solution of 0.1 g (2S) -2 - [(S) -campher-10-sulfonamido] -3- [4- (4- guanidino-4-oxo-butyloxy) phenyl] propionic acid, trifluoroacetate in 10 ml Ethanol is mixed with 5 mg of p-toluenesulfonic acid and 72 hours at Room temperature stirred. After working up and freezing drying gives 0.055 mg (2S) -2 - [(S) -campher-10-sulfonamido] -3- [4- (4-guanidino-4-oxo-butyloxy) phenyl] propionic acid ethyl ester; FAB 551.

You get analog
from (2S) -2-butylsulfonamido-3- [4- (4-guanidino-4-oxo-butyloxy) phenyl] propionic acid, trifluoroacetate (2S) -2-butylsulfonamido-3- [4- (4-guanidino- 4-oxo-butyloxy) phenyl] ethyl propionate; FAB 457
and from (2S) -2-tolylsulfonamido-3- [4- (4-guanidino-4-oxo-butyloxy) phenyl] propionic acid, trifluoroacetate (2S) -2-tolylsulfonamido-3- [4- (4-guanidino -4-oxo-butyloxy) phenyl] ethyl propionate; FAB 491.

Example 7

Analogously to Example 1, reaction of benzyloxycarbonyl-L- p-amino-phenylaIanine tert-butyl ester and 1-chloro-4-ethoxy-butanedione 1,4- the compound (2S) -2-benzyloxycarboxamido-3- [4- (3-ethoxy-3-oxo- propylcarboxamido) phenyl] propionic acid tert-butyl ester. By abspal The Z protecting group gives (2S) -2-amino-3- [4- (3-ethoxy-3-oxo- propylcarboxamido) phenyl] propionic acid tert-butyl ester ("C").

The following conversion of "C" gives
with 1-butanesulfonyl chloride (2S) -2-butylsulfonamido-3- [4- (3-ethoxy-3-oxo-propylcarboxamido) - phenyl] propionic acid tert-butyl ester,
with 4-tolylsulfonyl chloride (2S) -2-tolylsulfonamido-3- [4- (3-ethoxy-3-oxo-propylcarboxamido) phenyl] propionic acid tert-butyl ester
and with (S) - (+) - camphor-10-suifonyl chloride (2S) -2 - [(S) -campher-10-sulfonamido] -3- [4- (3-ethoxy-3-oxo-propylcarboxamido) - phenyl] propionic acid tert-butyl ester.

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

Analogously to Example 1, this is obtained by reaction with Z-guanidine
(2S) -2-butylsulfonamido-3- [4- (3-N-benzyloxycarbonyl-guanidino-3-oxo-propylcarboxamido) phenyl] propionic acid tert-butyl ester,
(2S) -2-Tolylsulfonamido-3- [4- (3-N-benzyloxycarbonyl-guanide ino-3-oxo-propylcarboxamido) -phenyl] -propionic acid tert-butyl ester
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (3-N-benzyloxycarbonyl guanidino-3-oxo-propylcarboxamido) phenyl] propionic acid tert-butyl ester .

The Z-protecting group is split off analogously to Example 2 and the following compounds are obtained
(2S) -2-butylsuifonamido-3- [4- (3-guanidino-3-oxo-propylcarboxamido) phenyl] propionic acid tert-butyl ester,
(2S) -2-Tolylsulfonamido-3- [4- (3-guanidino-3-oxo-propylcarboxamido) phenyl] propionic acid tert-butyl ester
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (3-guanidino-3-oxo-propylcarboxamido) -phenyl] propionic acid tert-butyl ester.

Analogously to Example 3, the tert-butyl ester is cleaved with TFA and is obtained
(2S) -2-butylsulfonamido-3- [4- (3iuanidino-3-oxo-propylcarboxamido) phenyl] propionic acid, trifluoroacetate,
(2S) -2-tolylsulfonamido-3- [4- (3-guanidino-3-oxo-propylcarboxamido) phenyl] propionic acid, trifluoroacetate
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (3-guanidino-3-oxo-propylcarboxamido) -phenyl] propionic acid, trifluoroacetate.

Analogously to Example 4, the following compounds are obtained therefrom by reaction with acetyl chloride
(2S) -2-butylsulfonamido-3- [4- (3-N-acetylguanidino-3-oxo-propylcarbox-x amido) phenyl] propionic acid,
(2S) -2-Tolylsulfonamido-3- [4- (3-N-acetyl-guanidino-3-oxo-propylcarbox-x amido) phenyl] propionic acid
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (3-N-acetylguanidino-3-oxo-propylcarboxamido) phenyl] propionic acid.

Analogously to Example 5, treatment is carried out with TFA
(2S) -2-butylsulfonamido-3- [4- (3-N-benzyloxycarbonyl-guanidino-3-oxo-propylcarboxamido) phenyl] propionic acid tert-butyl ester,
(2S) -2-Tolylsulfonamido-3- [4- (3-N-benzyloxycarbonyl-guanidino-3-oxo-propylcarboxamido) phenyl] propionic acid tert-butyl ester
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (3-N-benzyloxycarbonyl guanidino-3-oxo-propylcarboxamido) phenyl] propionic acid tert-butyl ester
the connections below
(2S) -2-butylsulfonamido-3- [4- (3-N-benzyloxycarbonyl-guanidino-3-oxo-propylcarboxamido) phenyl] propionic acid,
(2S) -2-Tolylsu Ifonamido-3- (4- (3-N-benzyloxycarbonyl-guanidino-3-oxo-propylcarboxamido) phenyl] propionic acid
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (3-N-benzyloxycarbonyl-guanidino-3-oxo-propylcarboxamido) phenyl] propionic acid.

Example 8

Analogously to Example 1, reaction of benzyloxycarbonyl-L- p-amino-phenylalanine tert-butyl ester and 1-chloro-5-ethoxy-pentanedione 1.5 the compound (2S) -2-benzyloxycarboxamido-3- [4- (4-ethoxy-4-oxo-  tert-butyl butylcarboxamido) phenyl] propionate. By Removal of the Z protective group gives (2S) -2-amino-3- (4- (4-ethoxy-4- oxo-butylcarboxamido) phenyl] propionic acid tert-butyl ester ("D").

The following implementation of "D"
with 1-butanesulfonyl chloride (2S) -2-butylsulfonamido-3- [4- (4-ethoxy-4-oxo-butylcarboxamido) phenyl] propionic acid tert-butyl ester,
with 4-tolylsulfonyl chloride (2S) -2-tolylsulfonamido-3- [4- (4-ethoxy-4-oxo-butylcarboxamido) phenyl] propionic acid tert-butyl ester
and with (S) - (+) - camphor-10-sulfonyl chloride (2S) -2 - [(S) -campher-10-sulfonamido] -3- [4- (4-ethoxy-4-oxo-butylcarboxamido) - phenyl] propionic acid tert-butyl ester.

Cleavage of the ethyl ester gives it
(2S) -2-butylsulfonamido-3- [4- (3-carboxypropylcarboxamido) phenyl] - tert-butyl propionate,
(2S) -2-Tolylsulfonamido-3- (4- (3-carboxypropylcarboxamido) phenyl] - tert-butyl propionate
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (3-carboxypropylcarboxamido) phenyl] propionic acid tert-butyl ester.

Analogously to Example 1, this is obtained by reaction with Z-guanidine
(2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butylcarboxamido) phenyl] propionic acid tert-butyl ester,
(2S) -2-Tolylsulfonamido-3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butylcarboxamido) phenyl] propionic acid tert-butyl ester
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butylcarboxamido) -phenyl] -propionic acid-tert.-butyles- ter.

The Z-protecting group is split off analogously to Example 2 and the following compounds are obtained
(2S) -2-butylsulfonamido-3- [4- (4-guanidino-4-oxo-butylcarboxamido) phenyl] propionic acid tert-butyl ester,
(2S) -2-Toylsulfonamido-3- [4- (4-guanidino-4-oxo-butylcarboxamido) phenyl] propionic acid tert-butyl ester
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (4-guanidino-4-oxobutylcarboxamido) phenyl] propionic acid tert-butyl ester.

Analogously to Example 3, the tert-butyl ester is cleaved with TFA and is obtained
(2S) -2-butylsulfonamido-3- [4- (4-guanidino-4-oxo-butylcarboxamido) phenyl] propionic acid, trifluoroacetate,
(2S) -2-tolylsulfonamido-3- [4- (4-guanidino-4-oxo-butylcarboxamido) phenyl] propionic acid, trifluoroacetate
and (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 therefrom by reaction with acetyl chloride
(2S) -2-butylsulfonamido-3- [4- (4-N-acetylguanidino-4-oxo-butylcarboxamido) phenyl] propionic acid,
(2S) -2-Tolylsulfonamido-3- [4- (4-N-acetylguanidino-4-oxo-butylcarboxamido) phenyl] propionic acid
and (2S) -2 - [(S) -campher-10-sulfonamido] -3- (4- (4-N-acetylguanidino-4-oxo-butylcarboxamido) phenyl] propionic acid.

Analogously to Example 5, treatment is carried out with TFA
(2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butylcarboxamido) phenyl] propionic acid tert-butyl ester,
(2S) -2-Tolylsulfonamido-3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butylcarboxamido) phenyl] propionic acid tert-butyl ester
and (2S) -2 - [(S)-camphor-1 0-sulfonamido] -3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butylcarboxamido) phenyl] propionic acid tert-butyl -ter
the connections below
(2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxycanbonyl-guanidino-4-oxo-butylcarboxamido) phenyl] propionic acid,
(2S) -2-Tolylsulfonamido-3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butylcarboxamido) phenyl] propionic acid
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (4-N-benzyloxycarbonyl-guanidino-4-oxo-butylcarboxamido) phenyl] propionic acid.

Example 9

Analogously to Example 1, reaction of benzyloxycarbonyl-L- p-Amino-phenylalanine tert-butyl ester and 1-chloro-3-ethoxypropanedione 1,3 the compound (2S) -2-benzyloxycarboxamido-3- (4- (2-ethoxy-2-oxo- ethyl carboxamido) phenyl] propionic acid tert-butyl ester. By abspal The Z protecting group gives (2S) -2-amino-3- [4- (2-ethoxy-2-oxo- butylcarboxamido) phenyl] propionic acid tert-butyl ester ("E").

The following implementation of "E" gives
with 1-butanesulfonyl chloride (2S) -2-butylsulfonamido-3- [4- (2-ethoxy-2-oxo-ethylcarboxamido) phenyl] propionic acid tert-butyl ester,
with 4-tolylsulfonyl chloride (2S) -2-tolylsulfonamido-3- [4- (2-ethoxy-2-oxo-ethylcarboxamido) phenyl] propionic acid tert-butyl ester
and with (S) - (+) - camphor-10-sulfonyl chloride (2S) -2 - [(S) -campher-10-sulfonamido] -3- [4- (2-ethoxy-2-oxoethylcarboxamido) - phenyl] propionic acid tert-butyl ester.

Cleavage of the ethyl ester gives it
(2S) -2-butylsulfonamido-3- [4- (carboxymethylcarboxamido) phenyl] - tert-butyl propionate,
(2S) -2-Tolylsulfonamido-3- [4- (carboxymethylcarboxamido) phenyl] propionic acid tert-butyl ester
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (carboxymethylcarboxamido) phenyl] propionic acid tert-butyl ester.

Analogously to Example 1, this is obtained by reaction with Z-guanidine
(2S) -2-butylsulfonamido-3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid tert-butyl ester,
(2S) -2-Tolylsuifonamido-3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid tert-butyl ester
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ethylcarboxamido) -phenyl] -propionic acid-tert.-butyles- ter.

The Z-protecting group is split off analogously to Example 2 and the following compounds are obtained
(2S) -2-butylsulfonamido-3- [4- (2-guanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid tert-butyl ester,
(2S) -2-Tolylsulfonamido-3- [4- (2-guanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid tert-butyl ester
and (2S) -2 - [(S) camphor-10-sulfonamido] -3- [4- (2-guanidino-2-oxoethylcarboxamido) phenyl] propionic acid tert-butyl ester.

Analogously to Example 3, the tert-butyl ester is cleaved with TFA and is obtained
(2S) -2-butylsulfonamido-3- [4- (2-guanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid, trifluoroacetate,
(2S) -2-tolylsulfonamido-3- [4- (2-guanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid, trifluoroacetate
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (2-guanidino-2-oxoethylcarboxamido) phenyl] propionic acid, trifluoroacetate.

Analogously to Example 4, standing compounds are obtained therefrom by reaction with acetyl chloride
(2S) -2-butylsulfonamido-3- [4- (2-N-acetylguanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid,
(2S) -2-tolylsulfonamido-3- [4- (2-N-acetylguanidino-2-oxoethylcarboxamido) phenyl] propionic acid
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (2-N-acetyl-guanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid.

Analogously to Example 5, treatment is carried out with TFA
(2S) -2-butylsulfonamido-3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid tert-butyl ester,
(2S) -2-Tolylsulfonamido-3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid tert-butyl ester
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (2-N-benzyloxycarbonyl guanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid tert-butyl ester
the connections below
(2S) -2-butylsulfonamido-3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid,
(2S) -2-Tolylsulfonamido-3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid
and (2S) -2 - ((S)-camphor-10-sulfonamido] -3- [4- (2-N-benzyloxycarbonyl-guanidino-2-oxo-ethylcarboxamido) phenyl] propionic acid.

Example 10

Analogously to Example 1, reaction of benzyloxycarbonyl-L- tyrosine tert. -butyl ester and 5-bromovaleric acid ethyl ester the compound (2S) -2-benzyloxycarboxamido-3- [4- (5-ethoxy-5-oxopentyloxy) phenyl] - tert-butyl propionate. By splitting off the Z protective group man (2S) -2-amino-3- [4- (5-ethoxy-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester ("F").

The following implementation of "F" gives
with 1-butanesulfonyl chloride (2S) -2-butylsulfonamido-3- [4- (5-ethoxy-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester,
with 4-tolylsulfonyl chloride (2S) -2-tolylsulfonamido-3- [4- (5-ethoxy-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester
and with (S) - (+) - camphor-10-sulfonyl chloride (2S) -2 - [(S) -campher-10-sulfonamido] -3- [4- (5-ethoxy-5-oxopentyloxy) - phenyl] propionic acid tert-butyl ester.

Cleavage of the ethyl ester gives it
(2S) -2-butylsulfonamido-3- [4- (4-carboxy-butyloxy) phenyl] propionic acid, tert-butyl ester,
(2S) -2-Tolylsuifonamido-3- [4- (4-carboxy-butyloxy) phenyl] propionic acid tert-butyl ester
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (4-carboxy-butyloxy) phenyl] propionic acid tert-butyl ester.

Analogously to Example 1, this is obtained by reaction with Z-guanidine
(2S) -2-butylsulfonamido-3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester,
(2S) -2-Tolylsulfonamido-3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester.

The Z-protecting group is split off analogously to Example 2 and standing compounds are obtained after
(2S) -2-butylsulfonamido-3- [4- (5-guanidino-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester,
(2S) -2-Tolylsulfonamido-3- [4- (5-guanidino-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (5-guanidino-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester.

Analogously to Example 3, the tert-butyl ester is cleaved with TFA and is obtained
(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
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (5-guanidino-5-oxopentyloxy) phenyl] propionic acid, trifluoroacetate; FAB 537.

Analogously to Example 4, the following compounds are obtained therefrom by reaction with acetyl chloride
(2S) -2-butylsulfonamido-3- [4- (5-N-acetylguanidino-5-oxopentyloxy) phenyl] propionic acid,
(2S) -2-tolylsulfonamido-3- [4- (2-N-acetylguanidino-2-oxoethylcarboxamido) phenyl] propionic acid
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (5-N-acetylguanidino-5-oxopentyloxy) phenyl] propionic acid.

Analogously to Example 5, treatment is carried out with TFA
(2S) -2-butylsuifonamido-3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxo-pentyloxy) phenyl] propionic acid tert-butyl ester,
(2S) -2-Tolylsulfonamido-3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester
and (2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxopentyloxy) phenyl] propionic acid tert-butyl ester
the connections below
(2S) -2-butylsulfonamido-3- [4- (5-N-benzyloxycarbonyl-guanidino-5-oxopentyloxy) phenyl] propionic acid; FAB 577
(2S) -2-Tolylsulfonamido-3- [4- (5-N-benzyloxycarbonyl-guanidino-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 the compound (2S) -2- Benzyloxycarboxamido-3- [4- (4-cyan-4-oxo-butyloxy) phenyl] propion acid tert-butyl ester.

By splitting off the Z protective group, the compound (2S) -2-amino- 3- [4- (4-cyan-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester ("G") receive.

Reaction of "G" with 1-butanesulfonyl chloride gives (2S) -2- Butylsulfonamido-3- [4- (4-cyan-4-oxo-butyloxy) phenyl] propionic acid t-ert. butyl ester ("H").

A solution of "H" and equimolar amounts of hydroxylamine hydrochloride and sodium hydrogen carbonate in isopropanol / water 6: 1 is heated under reflux for 12 hours. After usual work-up man (2S) -2-butylsulfonamido-3- [4- (5-amino-5-N-hydroxylimino-4-oxo pentyloxy) phenyl] propionic acid tert-butyl ester ("J").  

A solution of "J" in acetic acid is washed with palladium catalyst (10% on activated carbon) for 2 hours at room temperature and normal pressure. After separating off the catalyst and usual work-up, one obtains (2S) -2-butylsulfonamido-3- [4- (4-amidino-4oxo-butyloxy) phenyl] - propionic acid.

Example 12

Analogously to Example 1, reaction of N-benzyloxycarbonyl-N-ethyl-guanidine is obtained
with (2S) -2-butylsulfonamido-3- [4- (3-carboxypropyloxy) phenyl] tert-butyl propionate (2S) -2-butylsulfonamido-3- [4- (4-N-benzyloxycarbonyl -N-ethyl-guanidino-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester; FAB 647
with (2S) -2 - [(S) -campher-10-sulfonamido] -3- [4- (3-carboxypropyloxy) phenyl] propionic acid tert-butyl ester (2S) -2 - [(S ) Camphor-10-sulfonamido] -3- [4- (4-N-benzyloxycarbonyl-N-ethyl-guanidino-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester; FAB 741
and with (2S) -2-tolylsulfonamido-3- [4- (3-carboxypropyloxy) phenyl] - tert-butyl propionate (2S) -2-tolylsulfonamido-3- [4- (4-N- benzyloxycarbonyl-N-ethyl-guanidino-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester; FAB 681.

The Z-protecting group is split off analogously to Example 2 and the following compounds are obtained
(2S) -2-Butylsulfonamido-3- [4- (4-N-ethylguanidino-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester; FAB 513
(2S) -2 - [(S)-camphor-10-sulfonamido] -3- [4- (4-N-ethylguanidino-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester; FAB 607
and (2S) -2-tolylsulfonamido-3- [4- (4-N-ethyl-uanidino-4-oxo-butyloxy) phenyl] propionic acid tert-butyl ester; FAB 547.

Analogously to Example 3, the compounds are obtained by cleaving the tert-butyl ester with TFA
(2S) -2-butylsulfonamido-3- [4- (4-N-ethylguanidino-4-oxo-butyloxy) phenyl] propionic acid, trifluoroacetate; FAB 457
(2S) -2 - [(S) -campher-10-sulfonamido] -3- [4- (4-N-ethylguanidino-4-oxo-butyloxy) phenyl] propionic acid, trifluoroacetate; FAB 551
and (2S) -2-tolylsulfonamido-3- [4- (4-N-ethylguanidino-4-oxo-butyloxy) phenyl] propionic acid, trifluoroacetate; FAB 491.

Example 13

A solution of 3.5 g BOC-L-tyrosine benzyl ester, 5.5 g bromoacetic acid tert-butyl ester, 2.61 g of potassium carbonate and 250 mg of 18-crown-6 in 100 ml Toluene is stirred at 85 ° for 12 hours. After usual work-up 4.35 g of (2S) -2-tert-butoxycarboxamido-3- (4- (tert-butoxycarbonyl- benzyl methoxy) phenyl) propionate ("K"); FAB 486.

A solution of 4.3 g "K" in 20 ml dichloromethane and 100 ml 3n HCl in Diethyl ether is stirred for 6 hours at room temperature. After usual Working up gives 2.8 g of (2S) -2-amino-3- (4- (tert-butoxycarbonyl- benzyl methoxy) phenyl) propionate ("L"); FAB 386.

A solution of 2.8 g "L" in 50 ml dichloromethane is mixed with 3.7 g triethyl amine and 3.64 g of (R) camphor-10-sulfonic acid chloride are added and 2 Hours stirred. After usual work-up and chromatography on silica gel (toluene: acetone 10: 1), 3.8 g of (2S) -2 - ((R) -campher- 10-sulfonamido) -3- (4- (tert-butoxycarbonyl-methoxy) -phenyl) - benzyl propionate ("M"); FAB 600.  

2.5 g of "M" are dissolved in 5 ml of trifluoroacetic acid and stirred for 2 hours. The mixture is worked up in the customary manner and 1.9 g of (2S) -2 - ((R) -Campher-10- sulfonamido) -3- (4- (carboxymethoxy) phenyl) propionic acid benzyl ester ("N"); FAB 544.

A solution of 1 g "N", 270 mg 2-aminoimidazole sulfate, 770 mg TBTU, 85 mg HOBt and 1.3 g triethylamine in 30 ml DMF is added overnight Room temperature stirred. After the usual work-up, 1 g (2S) is obtained - 2 - ((R) -camher-10-sulfonamido) -3- (4- (N- (2-imidazolyl) carbamoyl benzyl methoxy) phenyl) propionate ("O"); FAB 609.

1 g of "O" is dissolved in 45 ml of dioxane and 5 ml of water and in the presence of 0.5 g palladium (10% on activated carbon) for 2 hours at room temperature hydrated. After removal of the catalyst and usual work-up is obtained after chromatography by preparative HPLC (RP-18; Elution gradient acetonitrile / water + 0.3% TFA 1:99 to 99: 1 in one Hour) and then freeze drying18o mg (2S) -2 - ((R) - Camphor-10-sulfonamido) -3- (4- (N- (2-imidazolyl) carbamoylmethoxy) - phenyl) propionic acid, trifluoroacetate; FAB 519.

Example 14

Analogously to the preparation of "O", tert-butyl ester is obtained starting from (2S) -2 - ((R) - camphor-10-sulfonamido) -3- (4- (3-carboxypropoxy) phenyl) propionic acid ("P") the compound by reaction with 2-aminobenzimidazole
(2S) -2 - ((R) -Campher-10-sulfonamido) -3- (4- (3- (N- (2-benzimidazolyl) carbamoyl) propoxy) phenyl) propionic acid tert.- butyleste-r.

By splitting the ester with TFA one obtains
(2S) -2 - ((R)-camphor-10-sulfonamido) -3- (4- (3- (N- (2-benzimidazolyl) carbamoyl) propoxy) phenyl) propionic acid, trifluoroacetate; FAB 597.

Analogously, by converting "P"
with 2-aminoimidazole and subsequent ester cleavage (2S) -2 - ((R) -campher-10-sulfonamido) -3- (4- (3- (N- (2-imidazolyl) carbamoyl) propoxy) phenyl) -propionic acid, trifluoroacetate; FAB 547;
with 5-aminotetrazole and subsequent ester cleavage (2S) -2 - ((R) -campher-10-sulfonamido) -3- (4- (3- (N- (5-tetrazolyl) carbamoyl) propoxy) phenyl) -propionic acid, trifluoroacetate; FAB 549;
with 3-aminoimidazole and subsequent ester cleavage (2S) -2 - ((R) -campher-10-sulfonamido) -3- (4- (3- (N- (3-imidazolyl) carbamoyl) propoxy) phenyl) -propionic acid, trifluoroacetate; FAB 547;
with 2-aminothiazole and subsequent ester cleavage (2S) -2 - ((R) -campher-10-suifonamido) -3- (4- (3- (N- (2-thiazolyl) carbamoyl) propoxy) phenyl) -propionic acid, trifluoroacetate; FAB 564 and
with 2-aminomethyl-benzimidazole and subsequent ester cleavage (2S) -2 - ((R) -campher-10-sulfonamido) -3- (4- (3- (N- (benzimidazol-2-ylmethyl) carbamoyl) propoxy ) -phenyl) -propionic acid, trifluoroacetate; FAB 583.

Example 15

A solution of 250 mg (2S) -2 - ((R) -campher-10-sulfonamido) -3- (4- (3- (N- (2-benzimidazolyl) carbamoyl) propoxy) phenyl) propionic acid and 25 mg of toluene-4-sulfonic acid in 25 ml of ethanol is 7 days at room temperature touched. After the usual work-up, 170 mg (2S) -2 - ((R) - Camphor-10-suifonamido) -3- (4- (3- (N- (2-benzimidazolyl) carbamoyl) - ethyl propoxy) phenyl) propionate; FAB 625.

Analogously, 2S) -2 - ((R) -campher-10-suifonamido) -3- (4- (3- (N- (2- imidazolyl) carbamoyl) propoxy) phenyl) propionic acid ethyl ester; FAB 575.  

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium Hydrogen phosphate is dissolved in 3 liters of double distilled water with 2N salt acid adjusted to pH 6.5, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Every In jection glass contains 5 mg of active ingredient.

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g soy lecithin and 1400 g cocoa butter, pour into molds and leave cool down. Each suppository contains 20 mg of active ingredient.

Example C: solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g NaH₂PO₄ · 2 H₂O, 28.48 g Na₂HPO₄ · 12 H₂O and 0.1 g benzalkonium chloride in 940 ml of double distilled water. Adjust to pH 6.8 makes up to 1 l and sterilized by radiation. This solution can be found in Form of eye drops can be used.

Example D: ointment

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

Example E: tablets

A mixture of 1 kg of active ingredient of formula I, 4 kg lactose, 1.2 kg kar Potato starch, 0.2 kg talc and 0.1 kg magnesium stearate are common Formed into tablets in such a way that each tablet contains 10 mg of active ingredient contains.  

Example F: coated tablets

Analogously to Example E, tablets are pressed, which are then made in the usual manner Wise with a coating of sucrose, potato starch, talc, tragacanth and dye are coated.

Example G: capsules

2 kg of active ingredient of formula I are in the usual way in hard gelatin capsules filled so that each capsule contains 20 mg of the active ingredient.

Example H: ampoules

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

Example I: Inhalation spray

14 g of active ingredient of the formula I are dissolved in 10 l of isotonic NaCl solution and fills the solution into commercially available spray vessels with a pump mechanism. The solution can be sprayed into the mouth or nose. A spray (about 0.1 ml) corresponds to a dose of about 0.14 mg.

Claims (12)

1. Compounds of formula I. wherein
X is absent, alkylene, arylene, cycloalkylene with 4-8 C atoms or unsubstituted or mono-, di- or trisubstituted by A, oxo and / or R⁴ hetero cycloalkylene with 1 to 3 N-, O- and / or S- Atoms,
Y, Z are each independently absent, alkylene, O, S, NH, C (= O), CONH, NHCO, C (= S), SO₂NH, NHSO₂, CA = CA 'or -C≡C-,
R¹ H₂N-C (= NH) or H₂N- (C = NH) -NH, where the primary amino groups can also be provided with conventional amino protective groups, or can be substituted one, two or three times by A, Ar or R⁵, NH-CH₂-R⁶, NH-R⁶, NH-C (= NH) -NH-R⁶ or R⁶,
R² A, Ar or aralkylene,
R³ H or A,
R⁴ H, Hal, OA, NHA, NAA ′, -NH-acyl, -O-acyl, CN, NO₂, SA, SOA, SO₂A, SO₂Ar or SO₃H,
R⁵ alkanoyl or cycloalkanoyl with 1-18 C atoms, in which one, two or three methylene groups can be replaced by N, O and / or S, Ar-CO- or Ar-alkylene-CO-,
A, A 'each independently of one another H or unsubstituted or mono-, di- or trisubstituted by R⁴-substituted alkyl or cycloalkyl having 1-15 C atoms and in which one, two or three methylene groups are replaced by N, O and / or S. could be,
Ar unsubstituted or mono-, di- or trisubstituted by A and / or R⁴ mono- or dinuclear aromatic ring system with 0, 1, 2, 3 or 4 N, O and / or S atoms,
R⁶ is a mono- or dinuclear heterocycle with 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or triple by Hal, A, -CO-A, OH, CN, COOH, COOA , CONH₂, NO₂, = NH or = O may be substituted,
Hal F, Cl, Br or I
mean,
with the proviso that at least one element selected from the group X, Y, Z must be CH₂,
and their physiologically acceptable salts. 2. Enantiomers or diastereomers of the compounds of the formula I. according to claim 1. 3. Compounds of formula I according to claim 1

• a) (2S) -2-butylsulfonamido-3- [4- (4-N-acetylguanidino-4-oxobutyloxy) phenyl] propionic acid;
• b) (2S) -2-butylsulfonamido-3- [4- (4-guanidino-4-oxo-butyloxy) 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-benzyloxycarbonyl guanidino-4-oxo-butyloxy) 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-oxo-butyl oxy) 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-suifonamido) -3- [4- (5-guanidino-5-oxopentyloxy) phenyl] propionic acid;
• j) (2S) -2- (camphor-10-sulfonamido) -3- [4- (3- (1 H -imidazol-2-ylcarbamoyl) propoxy) phenyl] propionic acid;
• k) (2S) -2- (camphor-10-sulfonamido) -3-4- (3- (1 H -benzimidazol-2-ylcarbamoyl) propoxy) phenyl] propionic acid;

and their physiologically acceptable salts.   4. A process for the preparation of compounds of the formula I as claimed in claim 1 and their salts, characterized in that

• a) that a compound of the formula I is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent,
  or
• b) that a compound of formula II wherein R¹, R³, R⁴, X, Y and Z have the meanings given in claim 1, with a compound of the formula IIIR²-SO₂-L IIIworin
  R² has the meaning given in claim 1 and L denotes Cl, Br, I, OH or a reactive esterified OH group,
  implements
  or
• c) that an ester of the formula I is saponified,
  or
• d) that one radical R¹ and / or R³ is converted into another radical R¹ and / or R³,
  and or
• e) that a basic or acidic compound of the formula I is converted into one of its salts by treatment with an acid or base.

5. Process for the preparation of a pharmaceutical preparation, because characterized in that a compound of formula I according to Claim 1 and / or one of their physiologically acceptable Salts together with at least one solid, liquid or semi liquid carrier or auxiliary in a suitable dosage form brings. 6. Pharmaceutical preparation, characterized by a content on at least one compound of the formula I according to claim 1 and / or one of their physiologically acceptable salts. 7. Compounds of formula I according to claim 1 and their physiological harmless salts to combat as GPIIb / IIIa antagonists of thrombosis, heart attack, coronary heart disease and Arteriosclerosis. 8. Compounds of formula I according to claim 1 and their physiologically acceptable salts as α _v integrin inhibitors for combating pathologically angiogenic diseases, thromboses, heart attack, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammation and infections. 9. Compounds of formula I according to claim 1 and their physiologically acceptable salts thereof, wherein R² has the meaning camphor-10-yl, diseases as A _v integrin inhibitors for controlling pathologically angio-related diseases, thromboses, cardiac infarction, coronary Herzer, arteriosclerosis, tumors , Osteoporosis, inflammation and infection. 10. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the preparation of a drug. 11. Compounds of formula I according to claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament for use as an α _v integrin inhibitor.