SK107199A3 - Bicyclic aromatic amino acids - Google Patents

Abstract

The invention relates to compounds of formula (I), wherein X, Y, Z, R<1>, R<2>, R<3>, R<4>, R<5>, R<7>, R<8>, R<11>, m and n have the meaning cited in Claim 1, and to their physiologically acceptable salts. Said compounds can be used as integrin inhibitors, specially for prophylaxis and treatment of circulatory diseases, thrombosis, infarcts, coronary heart diseases, arteriosclerosis, osteoporosis, pathological symptoms sustained or propagated by angiogenesis and in tumor therapy.

Description

Bicyclic aromatic amino acids

The invention relates to compounds of formula I

where it means

R ( ¹⁾ is hydrogen, (C1-C6) -alkyl or benzyl,

R ² R ¹⁰ , CO-R ¹⁰ , COOR ⁶ , COOR ¹⁰ , SO ² R ⁶ or SO ² R ¹⁰ ,

R ³ H, Hal, OA, NHR ¹⁰ , N (R ¹⁰ ) ₂ , -NH-acyl, -O-acyl, CN,

NO ₂ , OR ¹⁰ , SR ¹⁰ , R ² or CONHR ¹⁰ ,

R ⁴ H, = 0, = S, C ₁ _ ₆ alkyl, or acyl,

R ⁵ NH 2, H 2 N-C (= NH) or H 2 N-C (= NH) -NH, wherein the primary amino groups are optionally protected with a conventional amino protecting group or optionally substituted with one, two or three groups R ¹⁰ , CO- R ¹⁰ , COOR ¹⁰ or SO ² R ¹⁰ , or is R ⁶ ,

R ⁷ , R ⁸ independently of one another are absent or a hydrogen atom, or

R ⁷ and R ⁸ together bond,

X, Y independently = N-, -N-, O, S, -CH ₂ - or = C-, wherein at least one of X and Y is = N -, -N-, o or S,

W, Z independently of each other are absent or O, S, NR ¹ ,

C (= O), CONH, NHCO, C (= S) NH, NHC (= S), C (= S), SO ₂ NH, NHSO ₂ , or CA = CA ',

R ^{6 is a} heterocycle having one or two rings of 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur, unsubstituted or substituted by one, two or three groups selected from Hal, A, -CO-A, OH, CN , COOH, COOA, CONH ₂ , NO ₂ , = NH or = O,

R ⁹ H, Hal, OA, NHA, NAA, NHacyl, Oacyl, CN, NO ₂ , SA,

SOA, SO ₂ Ä, SO ₂ Ar or SO ₃ H,

R H, A, Ar or C 7 -C 14 aralkylene,

R H or C 1 -C 6 alkyl,

A, A ', independently of one another, are hydrogen or alkyl or cycloalkyl of up to 15 carbon atoms or substituted or R ⁹ substituted once, twice or three times, whereby one, two or three methylene groups are optionally replaced by nitrogen, oxygen and / or or sulfur,

Ar a single ring or two-ring aromatic ring system is unsubstituted or A and / or R ⁹ is mono-, di-, or trisubstituted with zero, one two, three or four nitrogen, oxygen and / or sulfur,

Hal is a fluorine, chlorine, bromine or iodine atom and m, n are independently 0, 1, 2, 3 or 4, and physiologically acceptable salts thereof.

Similar compounds to the invention are known, for example, from WO 94/29273, WO 96/00730 and WO 96/18602.

SUMMARY OF THE INVENTION It is an object of the present invention to provide novel compounds having valuable properties, particularly useful in the manufacture of medicaments.

It has been found that the compounds of the formula I and their salts possess particularly valuable pharmacological properties when well tolerated. In particular, they are integrin inhibitors, in particular inhibiting the interaction of the α-integrin receptors with the ligands. The compounds of the invention have particular activity in the case of integrxins and _y P ₃ and α _γ β ₅ . The compounds according to the invention show a very special activity as antagonists of the adhesion receptors for the vitronectin receptor α _ν β _3. This action can be demonstrated, for example, by the test described by

JW Smith et al. (J. Biol. Chem. 265, 11008-11013 and 12267-12271, 1990). B. Felding-Habermann and DA Cheresh (Curr. Opin. Cell. Biol., 5, p. 864, 1993) described the importance of integrxnov as adhesion receptors for a variety of events and pathogens, in particular in view of the vitronektxnový receptor _α ν β _third

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

The possibility of inhibiting the interaction and thus inducing apoptosis (programmed cell death) of angiogenic vascular cells with 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 prevent the attachment of viable cells to the corresponding matrix proteins, and accordingly the attachment of tumor cells to the matrix proteins, can be obtained in a cell adhesion assay, which is carried out similarly 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 the fight against cancer and for the treatment of tumor-inducing 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.

The compounds according to the invention of the formula I which block the interaction of integrin receptors and ligands, for example fibrinogen, on fibrinogen receptors (glycoprotein IIb / IIIa) prevent, as GPIIb / IIIa antagonists, the spread of cancer cells by metastasis. This fact is supported by the following observations:

The dissemination of tumor cells from a local tumor to the vascular system is accomplished by the formation of microaggregates (micro-thrombi) by the interaction of tumor cells and platelets. Tumor cells are shielded by microaggregates and are not recognized by cells of the immune system.

Microaggregates can be deposited on the walls of veins, thereby facilitating further penetration of tumor cells into tissues. Since the formation of microthrombi is mediated by the binding of fibrinogen to fibrinogen receptors on activated platelets, GPIIa / IIIb antagonists can be considered as active metastasis inhibiting agents.

In addition to the formation of fibrinogen, fibronectin and Willebrand factor at the fibrinogen platelet receptor, the compounds of formula I also inhibit the binding of other adhesive proteins such as vitronectin, collagen and laminin to the corresponding cell surface receptors of different types. In particular, they prevent the formation of platelet thrombi and can therefore be 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 fibrinogen binding to the fibrinogen receptor can be demonstrated by the method described in EP-A1-0 381033.

The inhibition of platelet aggregation can be demonstrated in vitro as described by Born (Nature 4832, 927-929, 1962).

Accordingly, the present invention provides a compound of formula I according to claim 1 and / or a physiologically acceptable salt thereof for the manufacture of a pharmaceutical composition useful as an integrin inhibitor. In particular, the present invention relates to compounds of the formula I according to claim 1 and / or their physiologically acceptable salts, wherein R ^{2 represents a} camphor-10-sulfonyl group, for the manufacture of pharmaceutical compositions for controlling pathological angiogenic diseases, tumors, osteoporosis, inflammations and infections.

The compounds of the formula I can be used as active ingredients of medicaments in human and veterinary medicine for the prophylaxis and / or therapy of diseases such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, cancer, osteolytic diseases such as osteoporosis, pathological angiogenic diseases such as inflammation, ophthalmological diseases, diabetic retinopathy, xnacular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, angioplasty, psoriasis disease, psoriasis disease, psoriasis disease, psoriasis disease, psoriasis disease, psoriasis, , bacterial infection, fungal infection, acute renal failure and wound healing to support the healing process.

The compounds of formula (I) may be used as antibacterial agents in operations involving the use of biological materials, implants, catheters or heart stimulators. In this case, they act antiseptic. The efficacy of antimicrobial activity can be demonstrated by the method of P. Valentin-Weigund et al. (Infection and Immunity, 1988, 2851-2855).

The process for the preparation of the compounds of the formula I and their salts according to the invention is characterized in that:

(a) the compound of formula (I) is released from its functional derivative by treatment with a solvolyzing or hydrogenolysing agent; or

b) reacting a compound of formula II

wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁷ , R ⁸ , R ³ - * - W, X, Y, Z, m and n are as defined above, with a compound of formula III (III) wherein R has and L is a chlorine, bromine, iodine, hydroxyl or reactive esterified hydroxyl group, or

c) saponifying the ester of the formula I, and / or

d) R ¹ and / or R is converted into another radical R ¹ and / or R ^5, and / or

(e) converting a basic or acidic compound of formula (I) treated with an acid or base into its salt.

The compounds of formula (I) may have one or more chiral centers and may therefore be in several stereoisomeric forms. The invention includes all such forms (e.g. D- and L-forms) and mixtures thereof (e.g. DL-forms).

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

Abbreviations used have the following meanings:

Ac acetyl

BOC tert-butoxycarbonyl

CBZ or Z benzyloxycarbonyl DCC1 dicyclohexylcarbodiimide dimethylformamide dimethylformamide

DOPA

DPFN

EDC1 (3,4-dihydroxyphenyl) alanine

3,5-Dimethylpyrazole-1-formamidinium nitrate N-ethyl-N, N '- (dimethylaminopropyl) carbodiimide

et ethyl Fmoc 9-fluórenylmetoxykarbony1 HOBt 1-hydroxybenzotriazole Me methyl Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl HONSu N-hydroxysuccinimide OBn benzyl OBu tert-butyl Oct octanoyl OMe methyl ester OEt ethyl Om ornithine POA phenoxyacetyl TBTU 0- (benzotriazol-l-yl) -N, N, N, N-tetramethyluronium tetrafluoroborate TFA trifluoroacetic acid Trt trityl (triphenylmethyl) Z or CBZ benzyloxycarbonyl.

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

In the general formulas, alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and also pentyl, 1-, 2- or 3-methylbutyl; -, 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 a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or 3-menthyl group. By cycloalkyl is meant quite particularly the remainder of the bicyclic terpenes, in particular the camphor-10-yl group.

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

Cycloalkylene means preferably cyclopropylene, 1,2- or 1,3-cyclobutylene, 1,2 or 1,3-cyclopentylene, 1,2-, 1,3- or 1,4-cyclohexylene and furthermore 1,2 group -, 1,3- or 1,4-cycloheptylene.

The CO-A group is an alkanoyl or cycloalkanoyl group, preferably a formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, pentadecanecadecanoyl, tetradecanecadecanoyl, tetradecanecadecanoyl group.

Acyl is understood to mean an acyl group having 1 to 7 carbon atoms having 1, 2, 3, 4, 5, 6 or 7 carbon atoms, preferably, for example, a formyl, acetyl, propionyl, butyryl, trifluoroacetyl or benzyl group.

Preferred substituents of the alkyl, alkylene, cycloalkyl, cycloalkylene, alkanoyl and cycloalkanoyl substituents are, for example, Hal, OA, NHA, NAA ¹ , CN, NO ₂ , SA, SOA, SO ₂ A, SO ₂ Ar and / or SO ₃ H, in particular F, Cl, hydroxy, methoxy, ethoxy, amino, di10 methylamino, methylthio, methylsulfinyl, nylsulfonyl 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 Cl, hydroxy, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methylsulfonyl or phenylsulfonyl.

In the alkyl, alkylene, cycloalkyl, cycloalkylene, alkanoyl and cycloalkanoyl group, one, two or three methylene 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-, m- or p-propylphenyl, o -, m- or p-isopropylphenyl, o-, m- or p-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-, male or p-methylaminophenyl, o-, m- or p-dimethylaminophenyl o-, m- or p-nitrophenyl groups, further preferably a group

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-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-methylphenyl, 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- or 3,4,5 trichlorophenyl, 2,4,6- 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-triisopropylphenyl, naphthyl, 1,3-benzodioxol-5-yl 1,4-benzodioxan-6-yl, benzothiadiazol-5-yl or benzoxadiazol-5-yl.

Furthermore, Ar 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-pyrazo- zolyl, 2-, 4- or 5-oxazolyl, 3. 4- or 5-izoxa- zolyl, 2-, 4- or 5-thiazolyl, 3. 4- or 5-izoti- azolyl, 2-, 3- - or 4-pyridyl, 2. 4-, 5- or 6-py-

a rimidinyl, preferably 1,2,3-triazol-1-, -4 or -5-yl, 1,2,4-triazol-1-, 3- or -5-yl, 1- or 5-yl group;

5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxa diazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5 -yl, 1,2,3,4-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-, 4-, 5-, 6-, 7- or 8-quinazolinyl.

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

Heterocycloarylene 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-,

A 2,3-, 3,4, or 1,4-piperidinyl, 1,4- or 1,2-piperazinyl group, further preferably a 1,2,3-tetrahydrotriazol-1,2- or 1,4-yl group, 1,2 , 4-tetrahydrotriazole-1,2- or -3,5-yl, 1,2- or 2,5-tetrahydrotetrazolyl, 1,2,3-tetrahydro-oxadiazole-2,3-, -3,4-, -4,5 - or 1,5-yl, 1,2,4-tetrahydrooxadiazol-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-tetrahydrothiadiazol-2,3-, -3,4-, -4,5- or 1,5-yl, 1,2, 3-thiadiazole-2,3-3,4-, -4,5- or 1,5-yl, 2,3- or 3,4-morpholinyl, 2,3

3.4- or 2,4-thiomorpholinyl.

The symbol R ⁶ is a heterocycle having one or two rings, preferably a 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 a 1,2,3-triazole group -1-, -4- or -5-yl, 1,2,4-triazol-1-, 3- or -5-yl, 1- or 513 tetrazolyl, 1,2,3-oxadiazole-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- 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-yl; -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-, 4-, 5-, 6-, 7- or 8-quinazolinyl.

The heterocyclic groups may also be partially or fully hydrogenated.

The symbol R ⁶ may also represent a group such as 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-dioxolane-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-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-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; 2,3,4-tetrahydro14

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

The heterocyclic rings may also have one, two or three substituents selected from the group consisting of halogen, A, -CO-A, OH, CN, COOH, COOA, CONH 3, NO ₂ , = NH or = O.

R &lt; ⁶ & gt ^; very particularly preferably is 1H-imidazolyl-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl, 2-H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2- iminoimidazolidin-4-one-5-yl, 1-alkyl-1,5-dihydroimidazol-4-one-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl.

The symbol R ¹¹ is H or alkyl having 1 to 6 carbon atoms, preferably a hydrogen atom.

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 (Ig), wherein not particularly indicated symbols have the meanings given in formula (I), wherein in formula (Ia), R ^{1 is}

R '

R ^J

W, Z

X

Y

R

R

H or (C 1 -C 6) alkyl, R ¹⁰ , CO-R ¹⁰ , COOR ¹⁰ or SO ₂ R ¹⁰ ,

H /

H or = O,

H ₂ NC (= NH) or H ₂ NC (= NH) -NH, each independently absent or C (= O), NH, CONH or NHCO,

-NH-, O or -CH ₂ -,

NH or O,

H, A or benzyl,

H,

A unsubstituted alkyl or cycloalkyl group

m, n fishing with up to 15 carbon atoms, independently of each other 0, 1 or 2, Ib) R ¹ H or (C 1 -C 6) -alkyl, R ² R ¹⁰ , CO-R ¹⁰ , COOR ¹⁰ or SO ₂ R ¹⁰ R ³ H, R ⁴ H or = O, R ⁵ R ⁶ W, Z is absent or C (= O), NH, CONH or NHCO, x -NH-, O or -CH ₂ -, Y NH or 0,

R ^{6 is a} heterocycle with one or two rings of 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur, unsubstituted or with one, two or three substituents from the group consisting of Hal, A, -CO-A, OH, CN, COOH, COOA, CONH ₂ , NO ₂ , = NH and = O,

R ¹⁰ H, A or benzyl,

R ¹¹ H,

A is unsubstituted alkyl or cycloalkyl having up to 15 carbon atoms, m, n each, independently of one another 0, 1 or 2, c) R ¹ is H or alkyl having 1 to 6 carbon atoms,

R ² R ¹⁰ , CO-R ¹⁰ , COOR ¹⁰ or SO, R ¹⁰

R ³ H,

R ⁴ H or = O,

R ⁵ H ₂ NC (= NH) or H ₂ NC (= NH) -NH,

W, Z are each independently absent or C (= O),

NH, CONH or NHCO,

X -NH-, O or -CH ₂ -,

Y NH or O,

A (C1-C6) alkyl,

R ¹⁰ H, (C 1 -C 6) alkyl, camphor-10-yl or benzyl,

R ¹¹ H / m, n each independently 0, 1 or 2, (ld) R ¹ R ² R ³ R ⁴ R ⁵ H or an alkyl group having 1 to 6 carbon atoms, R ¹⁰ , CO-R ¹⁰ , COOR ¹⁰ or SO ₂ R ¹⁰ , H · H or = O, R ⁶ , W, Z is absent or C (= O), NH, CONH or NHCO, X -NH-, O or -CH ₂ -, Y R ⁶ NH or O, a single or two-ring heterocycle of 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur, unsubstituted or with one, two or three substituents selected from the group consisting of Hal, A, -CO-A, OH, CN, COOH, COOA, CONH ₂ , NO ₂ , = NH and = O, R ¹⁰ H, (C 1 -C 4) alkyl, camphor-10-yl or benzyl, R ¹¹ H, A unsubstituted (C1-C6) -alkyl, m, n independently of each other 0, 1 or 2, (le) R ¹ R ² R ³ R ⁴ R ⁵ H or (C 1 -C 6) alkyl, R ¹⁰ , CO-R ¹⁰ , COOR ¹⁰ or SO ₂ R ¹⁰ , H, H or = O, R ⁶ , W, Z is absent or C (= O) independently NH, CONH or NHCO, x -NH-, O or -CH ₂ -, Y R ⁶ NH or 0, 1H-imidazolyl-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl, 2-H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on-5-yl .

R ¹⁰

R ¹¹

A 1-A-1,5-dihydroimidazol-4-one-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl,

H, (C 1 -C 4) alkyl, camphor-10-yl or benzyl,

H, unsubstituted C 1 -C 6 alkyl, m, n are each independently 0, 1 or 2, (1f) R ¹ H or C 1 -C 6 alkyl,

R ² R ¹⁰ , CO-R ¹⁰ , COOR ¹⁰ or SO ₂ R ¹⁰

R ³ H,

R ⁴ H or = O,

R ⁵ H ₂ NC (= NH) or H ₂ NC (= NH) -NH,

W, Z are each independently absent or C (= O),

NH, CONH or NHCO,

X -NH-, O or -CH ₂ -,

Y NH or O,

R ¹⁰ Ar,

R ¹¹ H,

A is unsubstituted alkyl or cycloalkyl having up to 15 carbon atoms, m, n each, independently of one another 0, 1 or 2, g) R ¹ is H or alkyl having 1 to 6 carbon atoms,

R ² R ¹⁰ , CO-R ¹⁰ , COOR ¹⁰ or SO ₂ R ¹⁰

R ³ H,

R ⁴ H or = O,

R ⁵ R ⁶

W, Z are each independently absent or C (= O),

NH, CONH or NHCO,

X -NH-, O or -CH ₂ -,

Y NH or O,

R (R) heterocycle with one or two rings of 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur, unsubstituted or with one, two or three

R ¹⁰

R ¹¹

A m, n substituents from the group consisting of Hal, A, -CO-A, OH, CN, COOH, COOA, CONH ₂ , NO ₂ , = NH and = O,

Ar,

H, unsubstituted alkyl or cycloalkyl having up to 15 carbon atoms, independently of one another being 0, 1 or 2.

The compounds of 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 above reactions. It is also possible to use known variants which are 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 instead have free amino or hydroxyl groups corresponding to protected amino or hydroxy groups, preferably compounds which have a protecting group instead of a hydrogen atom which is bonded to a nitrogen atom. amino, in particular 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, e.g. -COOR, wherein R is a hydroxyl protecting group.

Several of the same or different amino protecting groups and / or hydroxyl 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 aralkyl 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 group is always meant in the broadest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, such as, in particular, alkoxycarbonyl, aryloxycarbonyl and, in particular, 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 such as carbobenzoxy (CBZ), 4-methoxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC) and arylsulfonyl such as Mtr. Preferred amino protecting groups are BOC and Mtr, further CBZ, Fmoc, benzyl and acetyl.

The cleavage of the amino protecting group is successful, depending on the protecting group used, for example with strong acids, preferably 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 sulfenesulfonic acids 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 addition of additional solvents, perchloric acid in the form of a 9: 1 mixture of acetic acid and 70% perchloric acid. The reaction temperature for the cleavage is expediently about 0 to about 50 ° C, preferably 15 to 30 ° C (room temperature).

The BOC, O-but and Mtr groups can, for example, preferably using TFA in dichloromethane or in details, 3 to 5N HCl in dioxane at 15-30 ^and C, the Fmoc group using 5 to 50% solution of dimethylamine, diethylamine not or piperidine in DMF at 15 to 30 ° C.

Hydrogenolytically removable protecting groups (e.g., CBZ or benzyl) can be removed, for example, by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, preferably on a support such as coal). Suitable solvents are the abovementioned solvents, in particular, for example, alcohols such as methanol or ethanol or amides such as dimethylformamide. Hydrogenolysis is generally carried out at a temperature of about 0 to about 0 ° C

100'C, at a pressure of about 0.1 to 20 MPa, preferably at 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, compounds of formula I may be prepared by reacting compounds of formula II with compounds of formula III, wherein the symbols are 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 group (preferably methylsulfonyloxy) or a C 6 -C 10 arylsulfonyloxy group (preferably phenylsulfonyloxy) or ponyl 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.

The 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, a few minutes to 14 days, the reaction temperature being about -30 to about 14 days

140'C, generally -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.

The 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 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 ⁵ into another group of R ¹ and / or R ⁵ . In particular, the carboxylic acid can be converted to a carboxylic acid ester.

Conversion of the cyano group to an amidino group is accomplished by reaction with, for example, hydroxylamine and subsequent reduction of N-hydroxyamidine with hydrogen in the presence of a catalyst such as 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 released by solvolysis or hydrogenolysis.

The base of formula (I) can be converted by acid into the appropriate acid addition salt, for example by reacting an equivalent amount of base and acid in an inert solvent such as ethanol and then evaporating 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-polyhydric 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 acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene monosulfonic acid, naphthalenedisulfonic acid and lauryl sulfuric acid. 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 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. lysine.

The compounds of formula I may have one or more chiral centers and may therefore be in racemic or optically active form. Alternatively, the racemates obtained can be separated into their enantiomers mechanically or chemically by known methods. Preferably, 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); a suitable eluent is, for example, hexane / isopropanol / acetonitrile, for example in a 82: 15: 3 by volume ratio.

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 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), 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, glycerol 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, in particular oily or aqueous solutions, further suspensions, emulsions or implants, for topical use ointments, creams or powders. The compounds of the invention may also be lyophilized and the resulting lyophilisates used, for example, for the preparation of injectables. The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, stabilizing agents 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 in the form of inhalation sprays, the active ingredient is dissolved or suspended in a propellant or propellant mixture (such as, for example, carbon dioxide or fluorocarbon). In this case, the active ingredient is used in micronized form, and at least one physiologically compatible solvent, for example ethanol, can be 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 compounds of the formula I and / or physiologically acceptable salts thereof, wherein R ² is camphor-10-yl, for combating pathologically angiogenic diseases, tumors, osteoporosis, inflammations and infections.

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 recipient will depend on a variety of factors, such as the efficacy of the particular compound employed, 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 by the following non-limiting examples. Temperatures are always given in degrees Celsius. In the following examples, the term "conventional 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 (electron impact ionization) M ⁺ FAB (fast atom bombardment) (M + H) ⁺

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A solution of 12 g of BOC-3-nitro-L-tyrosine benzyl ester (1) is hydrogenated under ambient pressure for six hours in the presence of 1 g of Raney-nickel. The catalyst was separated and after usual work-up, 11.7 g of BOC-3-amino-L-tyrosine benzyl ester (2), FAB 387, were obtained.

A solution of 9.3 g of 2, 2.36 g of maleic anhydride and 3.3 ml of triethylamine in 150 ml of dimethylformamide is heated to 80 DEG C. and stirred for a further 12 hours. The solvent was removed and the residue was chromatographed on silica gel using dichloromethane / methanol 20: 1 to 10: 1 as eluent. 5.1 g of (2S) -2-tert-butyloxycarboxyamido-3- (3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid benzyl ester is obtained as a mixture. diastereomers (3), FAB 485.

A solution of 1 g of 3 and 0.79 g of 2-chloro-1-methylpyridinium iodide in 20 ml of dimethylformamide was treated with 1 g of Z-guanidine and 1.75 ml of ethyldiisopropylamine and stirred for 12 hours at room temperature. After customary work-up, silica gel chromatography (eluting with toluene / methanol 10: 1) gave 0.2 g of (2S) -2-tert-butyloxycarboxamido-3- [3,4-dihydro-2- ( 2-Benzyloxycarbonylguanidino-2-oxoethyl) -2H-1,4-benzoxazin-3-one-6-yl) propionic acid (4), FAB 660.

A solution of 200 mg of 4 and 3 ml of water / 3 ml of dioxane is hydrogenated under ambient pressure and at room temperature in the presence of 100 mg of palladium (10% on charcoal). The pH is maintained at 4-5 by addition of 1N hydrochloric acid. The catalyst and solvent were removed. The residue was purified by preparative HPLC (RP-18 using acetonitrile / water + gradient as eluent for one hour).

0.3% TFA 1:80 to 99: 1) to give 40 mg of (2S) -2-tert-trifluoroacetate. -butyloxycarboxamido-3- [3,4-dihydro-2- (2-guanidino-2-oxoethyl) -2H-1,4-benzoxazin-3-one-6-yl) propionic acid (5), FAB 660.

Example 2

A solution of 6 g of Z-L-DOPA-ethyl ester (6), 25 ml of ethanol and 25 ml of water is reacted with 2.3 g of potassium carbonate in a shielding gas medium. The reaction mixture is heated to 60 DEG C., 4.5 ml of epibromohydrin are added and heated to 90 DEG C. The reaction mixture is stirred for two hours, worked up in the usual manner and the crude product is purified on silica gel. 5.6 g of a mixture of (8) positional isomeric diastereomeric pairs are obtained which cannot be separated:

(2S) -2-Benzyloxycarboxamido-3- (3- (3R, 3S) -hydroxymethyl-1,4-benzodioxan-6-yl) propionic acid ethyl ester (7a) and (2S) -2-Benzyloxycarboxamido-3 ethyl ester - (2- (2R, 2S) -Hydroxymethyl-1,4-benzodioxan-6-yl) propionic acid (7b), FAB 416.

A solution of 2 g of 8 in 30 ml of pyridine at 0 DEG C. is mixed with 0.413 ml of methanesulfonyl chloride, stirred for two hours and worked up in the usual manner. 2.2 g of (2S) -2-benzyloxycarboxamido-2- (2,3-methylsulfonyloxymethyl-1,4-benzodioxan-6-yl) propionic acid ethyl ester (9) are obtained, FAB 494.

A solution of 1.6 g of 9.1.6 g of sodium azide and 30 ml of dimethylformamide is stirred at 75 ° C for 12 hours. After usual work-up, (2S) -2-benzyloxycarboxamido-329 (2/3-azidomethyl-1,4-benzodioxan-6-yl) -propionic acid ethyl ester (10), FAB 441, is obtained.

A solution of 1.25 g of 10 and 25 ml of methanol is mixed with 3.4 ml of 1 N sodium hydroxide solution and the mixture is stirred for 12 hours at room temperature. Work up in the usual way yielded 1.3 g of (2S) -2-benzyloxycarboxamido-3- (2,3-azidomethyl-1,4-benzodioxan-6-yl) propionic acid (11), FAB 413.

To a solution of 1.3 g of 11 in 40 ml of pyridine and 20 ml of water is added hydrogen sulfide at room temperature for 30 minutes and the mixture is allowed to stand for 12 hours. After removal of the solvent, 1.5 g of (2S) -2-benzyloxycarboxamido-3- (2,3-aminomethyl-1,4-benzodioxan-6-yl) propionic acid (12) is obtained, FAB 387.

A solution of 0.3 g of 12, 0.23 g of DPFN and 0.22 ml of triethylamine in 10 ml of dimethylformamide is stirred at 60 ° C for 12 hours. After the usual workup, preparative HPLC (under conditions similar to Example 1 for purification 5) affords the separation of the 2-guanidinomethyl compounds from the 3-guanidinomethyl compounds. Yield 80 mg of (2S) 2-benzyloxycarboxamido-3- (2- (2R, S) -guanidinomethyl-1,4-benzodioxan-6-yl) propionic acid (13), FAB 429.

Example 3

A solution of 0.95 g of BOC-glycine and 0.96 g of carbonyldiimidazole in 20 ml of tetrahydrofuran was stirred for two hours. Add 0.7 g of 12 and stir for a further twelve hours. After usual work-up, 0.66 g of (2S) -2-benzyloxycarboxamido-3- (2/3-tert-butyloxycarboxamidoacetamidomethyl-1,4-benzodioxan-6-yl) propionic acid (14) is obtained, FAB 544.

Treat 0.15 g (14) in 5 mL of dichloromethane with 0.5 mL of trifluoroacetic acid and stir for eight hours. After removal of the solvent, 10 ml of dimethylformamide, 80 mg of DPFN and 70 μΐ of triethylamine are added successively. The mixture is heated to 80 ° C and stirred for twelve hours.

Purification and isolation of 2/3 isomers was performed by preparative HPLC as in Example 1. 42 mg of (2S) -2-benzyloxycarboxamido-3- (2-guanidinoacetamidomethyl-1,4-benzodioxan-6-yl) propionic acid (15) was obtained. FAB 486.

Example 4

Hydrogen was bubbled through a solution of 0.45 g of 14 in 10 ml of dioxane and 5 ml of water in the presence of 0.2 g of palladium (10% on carbon) for two hours. After removal of the catalyst and usual work-up, 0.28 g of (2S) -2-amino-3- (2,3-tert-butyloxycarboxamidoacetamidomethyl-1,4-benzodioxan-6-yl) propionic acid (16) is obtained, FAB 410 .

To a solution of 0.28 g of 16 in 5 ml of acetonitrile is added 430 μΐ of N, O-bis- (trimethylsilyl) trifluoroacetamide (BSTFA), and then the mixture is refluxed for three hours. 66 μΐ of pyridine and 0.188 g of R-camphor-10-sulfonic acid chloride are added and stirred for three hours at 70 ° C. After usual work-up, 0.26 g of (2S) -2- (R) -phosphorsulfonamidoamido-3- (2/3 tert-butyloxycarboxamidoacetamidomethyl-1,4-benzodioxan-6-yl) propionic acid (17) is obtained, FAB 624 .

Analogous to Preparation (15), after cleavage of the BOC group and guanylation, 0.25 g of 17 58 mg of (2S) 2- (R) -phosphorosulfonamido-3- (2-guanidinoacetamidomethyl-1,4-benzodioxan-6-yl) is obtained. propionic acid (18), FAB 566.

Similarly, by reaction of 16 with butyl (2S) -2-butylsulphonamido-3- (2/3-tert-butyloxycarboxamidoacetamidomethyl-1,4-benzodioxan-6-yl) propionic acid with 4-tolylsulphonyl chloride (2S) -2- (4 -tolylsulfonamido-3- (2/3-tert-butyloxycarboxamidoacetamidomethyl-1,4-benzodioxan-6-yl) Propionic acid with benzylsulfonyl chloride (2S) -2-benzylsulfonamido-3- (2,3-tert-butyloxycarboxamidoacetamidomethyl) 4-Benzodioxan-6-yl-propionic acid with phenylsulfonyl chloride (2S) -2-phenylsulfonamido-3- (2,3-tert-butyloxycarboxamidoacetamidomethyl-1,4-benzodioxan-6-yl) propionic acid with 2-naphthylsulfonyl chloride (2S) - 2- (2-naphthylsulfonamido) -3- (2,3-tert-butyloxycarboxamido acetamidomethyl-1,4-benzodioxan-6-yl) propionic acid with cyclohexylsulfonyl chloride (2S) -2-cyclohexylsulfonamido-3- (2/3-tert. butyloxycarboxamido acetamidomethyl-1,4-benzodioxan-6-yl) propionic acid

Cleavage of the BOC group and guanylation affords (2S) -2-butylsulfonamido-3- (2-guanidinoacetamidomethyl-1,4-benzodioxan-6-yl) propionic acid (2S) -2- (4-tolylsulfonamido-3- (2-guanidinoacetamidomethyl) -1). (2S) -2-Benzylsulphonamido-3- (2-guanidinoacetamidomethyl-1,4-benzodioxan-6-yl) propionic acid (2S) -2-phenylsulphonamido-3- (2- (4-benzodioxan-6-yl) propionic acid) (2S) -2- (2-naphthylsulfonamido) -3- (2-guanidinoacetamidomethyl-1,4-benzodioxan-6-yl) propionic acid (2S) -2-cyclohexylsulfonamido guanidinoacetamidomethyl-1,4-benzodioxan-6-yl -3- (2-guanidinoacetamidomethyl-1,4-benzodioxan-6-yl) propionic acid.

Example 5

A solution of 0.3 g (3) and 0.248 g of 2-aminobenzimidazole (A) in 10 ml of dimethylformamide is mixed with 0.26 g of TBTU, 26 mg of HOBT and 0.34 ml of N-methylmorpholine and stirred for 12 hours at room temperature. After usual work-up, 0.14 g of (2S) - (2-tert-butyloxycarboxamido-3- (3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl) -2H-1,4-benzoxa) benzyl ester is obtained. trans-3- (6-yl) propionic acid (19).

Analogously to Example 1, 60 mg of (2S) -2-tert-butyloxycarboxamido-3- (3,4-dihydro-2 [N- (2-benzimidazolyl) carbamoylmethyl) -2H-1,4-benzoxazine] was obtained by hydrogenation of 19. -3-on-6-yl) propionic acid (22), FAB 510.

Similarly, by reaction of 3 with 2-aminoimidazole (B) (2S) -2-tert-butyloxycarboxamido-3- {3,4-dihydro-2- [N- (2-imidazolyl) carbamoylmethyl] -2H-1, benzyl ester, 4-benzoxazin-3-one-6-yl) propionic acid (20) followed by cleavage of (2S) -2-tert-butyloxycarboxamido-3- {3,4-dihydro-2- [N- (2-imidazolyl) carbamoylmethyl] benzyl ester -2H-1,4-benzoxazin-3-one-6-yl) propionic acid (23), FAB 460, and 2-aminomethylbenzimidazole (C) benzyl ester (2S) -2-tert-butyloxycarboxamido-3- {3 4-dihydro-2- [N- (2-benzimidazolyl) methylcarbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl) propionic acid (21) followed by cleavage of (2S) -2-tert-benzyl ester .-butyloxycarboxamido-3- {3,4-dihydro-2- [N- (2-benzimidazolyl) methylcarbamoylmethyl] -2H-1,4-benzoxa-3-one-6-yl} propionic acid ( 24), FAB 524.

Example 6

A solution of 2 g of 3 is reacted with 50 ml of dichloromethane with 5 ml of trifluoroacetic acid and stirred at room temperature for one hour. After removal of the solvent, 2 g of (2S) -amino-3- {3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl} -propionic acid benzyl ester is obtained. Trifluoroacetate (25), FAB 385.

To a solution of 1 g of 25 and 0.3 ml of triethylamine in 25 ml of acetonitrile is added 1.2 ml of BSTFA and the mixture is refluxed for two hours. At 40C, 0.19 ml of pyridine and 0.55 g of (R) -camphor-10-sulfonic acid chloride are added and stirred at 70 ° C for 12 hours. After usual work-up, 0.41 g of (2S) -2 - [(R) -phosphorosulfonamido] -3- (3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-one) benzyl ester is obtained. -propionic acid (26). FAB 599.

Similarly, (2S) -2-butylsulfonamido-3- (3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) -propionic acid benzyl ester with 4- tolylsulfonyl chloride (2S) -2- (4-tolylsulfonamido) -3- (3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid benzyl ester with benzylsulfonyl chloride benzyl ester (2S) - 2-Benzylsulfonamido) -3- (3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid with phenylsulfonyl chloride (2S) -2-phenylsulfonamido) -3 - (3,4-Dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid with (2S) -2- (2-naphthylsulfonamido) -3- (3, 2-naphthylsulfonyl chloride) benzyl ester 4-Dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid and with cyclohexylsulfonyl chloride (2S) -2-cyclohexylsulfonamido) -3- (3,4-dihydro-2-carboxymethyl-2H-1) benzyl ester 4-benzoxazin-3-one-6-yl) propionic acid

Analogously to Example 5, it is obtained by reaction of 26

(2S) -2 - [(R) -Gaphosphorsulfonamido] -3- {3,4-dihydro-2- [N (2-benzimidazolylcarbamoylmethyl) -2H-1,4-benzoxazin-3-one-6-yl] benzyl ester } propionic acid (27), FAB 714, with (2S) -2 - [(R) -phosphorosulfonamido) -3- {3,4-dihydro-2- [N (2-imidazolylcarbamoylmethyl) -2H-1 benzyl ester], 4-Benzoxazin-3-one-6-yl} propionic acid, with (2S) -2 - [(R) -phosphorosulfonamido] -3- {3,4-dihydro-2- [N (2-benzimidazolylmethyl) carbamoylmethyl] benzyl ester 1 H-1,4-Benzoxazin-3-one 6-yl} -propionic acid (29).

Cleavage of the benzyl ester by hydrogenation gives 27 (2S) -2 - [(R) -phosphorosulfonamido] -3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzoxazine- 3-on-6-yl-propionic acid (28), FAB 624, az 29 (2S) -2 - [(R) -phosphorosulfonamido] -3- {3,4-dihydro-2- [N- (2-benzimide) zolyimethyl) carbamoylimethyl] -2H-1,4-benzoxazolin-3-one-6-yl} propionic acid (30), FAB 638.

Similarly, it is obtained by reacting:

(2S) -2-Butylsulfonamido-3- (3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) -propionic acid benzyl ester with A (2S) -2-Butylsulfonamido-3 benzyl ester - {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, with B (2S) -2 benzyl ester -butylsulfonamido-3- {3,4-dihydro-2- [N- (2imidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, with (2S) -2 benzyl ester -butylsulfonamido-3- {3,4-dihydro-2- [N- (2-imidazolylmethyl) carbamoylimethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, from benzyl ester (2S) -2- (4-tolylsulfonamido-3- (3,4-dihydro-2-carboxymethyl) -2H-1,4-benzoxazin-3-one-6-yl) propionic acid with (2S) -2- (4-) - 4-benzyl ester tolylsulfonamido-3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, with B (2S) -2- benzyl ester (4-Tolylsulfonamido-3- {3,4-dihydro-2- [N- (2imidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, with C benzyl ester r (2S) -2- (4-Tolylsulfonamido-3- {3,4-dihydro-2- [N- (2-benzimidazolylmethyl) carbamoylmethyl] -2H-1,4-benzoxazol-3-yl-6-yl) propionic acid, from (2S) -2-benzylsulfonamido) -3- (3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid benzyl ester with A benzyl ester (2S) -2-benzylsulfonamido) -3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl-2H-1,4-benzoxazin-3-one-6-yl} propionic acid with B benzyl ester (2S) -2-benzylsulfonamido) -3- {3,4-dihydro-2- [N- (2imidazolyl) carbamoylmethyl-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, with C (2S) -2-Benzylsulfonamido) -3- {3,4-dihydro-2- [N- (2-benzimidazolylmethyl) carbamoylmethyl-2H-1,4-benzoxazin-3-one6-yl) propionic acid benzyl ester, z (2S) -2-Phenylsulfonamido) -3- (3,4-dihydro-2-carboxymethyl) -2H-1,4-benzoxazin-3-one-6-yl) propionic acid benzyl ester with A (2S) -2-phenylsulfonamido benzyl ester ) -3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid , (2S) -2-phenylsulfonamido) -3- {3,4-dihydro-2- [N - (2-imidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-benzyl ester -yl} propionic acid, with (2S) -2-phenylsulfonamido) -3- {3,4-dihydro-2- [N- (237-benzimidazolylmethyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one benzyl ester -yl} propionic acid, from (2S) -2- (2-naphthylsulfonamido) -3- (3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid benzyl ester with (2S) -2- (2-Naphthylsulfonamido) -3- {3,4-dihydro-2 [N- (2-benzimidazolyl) carbamoylmethyl) -2H-1,4-benzoxazin-3-one6-yl} propionic acid benzyl ester with B (2S) -2- (2-naphthylsulfonamido) -3- {3,4-dihydro-2 [N- (2-imidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6 benzyl ester (2S) -2- (2-naphthylsulfonamido) -3- {3,4-dihydro-2- [N- (2-benzimidazolylmethyl) carbamoylmethyl] -2H-1,4-benzoxazine-3-yl} propionic acid benzyl ester on-6-yl} propionic acid, from (2S) -2-cyclohexylsulfonamido) -3- (3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazine benzyl ester) n-3-one-6-yl) propionic acid with (2S) -2-cyclohexylsulfonamido) -3- {3,4-dihydro-2 [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzyl ester -benzoxazin-3-one-6-yl) propionic acid, with (2S) -2-cyclohexylsulfonamido) -3- {3,4-dihydro-2 [N- (2-imidazolyl) carbamoylmethyl] -2H-1,4 benzyl ester -benzoxazin-3-one-6-yl} propionic acid, with (2S) -2-cyclohexylsulfonamido) -3- {3,4-dihydro-2 [N - (2-benzimidazolylmethyl) carbamoylmethyl] -2H-1,4 benzyl ester -benzoxazin-3-one-6-yl} propionic acid.

Similarly, the following compounds are obtained by cleavage of the benzyl ester by hydrogenation:

(2S) -2-Butylsulfonamido-3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, ( 2S) -2-butylsulfonamido-3- {3,4-dihydro-2- [N- (2-imidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, (2S) -2-Butylsulfonamido-3- {3,4-dihydro-2- [N- (2-benzimidazolyl) methylcarbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, (2S) -2 - (4-tolylsulfonamido) -3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, (2S ) -2- (4-Tolylsulfonamido) -3- {3,4-dihydro-2-1 N- (2-imidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (2S) -2- (4-tolylsulfonamido) -3- {3,4-dihydro-2- [N- (2-benzimidazolylmethyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl propionic acid, (2S) -2-benzylsulfonamido-3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzoxa-3-one- 6-yl} propionic acid, (2S) -2-benzylsulfonamido-3- {3,4-dihydro-2- [N- (2-imida) zolyl) carbamoylmethyl-2H-1,4-benzoxazin-3-one-6-yl} propionic acid, (2S) -2-benzylsulfonamido-3- (3,4-dihydro-2- [N- (2-benzimidazolylmethyl)) carbamoylmethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid, (2S) -2-phenylsulfonamido) -3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl] Propionic acid, (2S) -2-phenylsulfonamido-3- {3,4-dihydro-2- [N- (2-imidazolyl) carbamoylmethyl] -2H -1,4-benzoxazin-3-one-6-yl] Propionic acid, (2S) -2-phenylsulfonamido-3- {3,4-dihydro-2- [N- (2-benzimidazolylmethyl) carbamoylmethyl] -2H -1,4-benzoxazin-3-one-6-yl] Propionic acid, (2S) -2- (2-naphthylsulfonamido) -3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl-propionic acid, (2S) -2- (2-naphthylsulfonamido) -3- {3,4-dihydro-2- [N- (2- imidazolyl) carbamoylmethyl] -2H-1,4-benzoxolin-3-one-6-ylpropionic acid, (2S) -2- (2-naphthylsulfonamido) -3- (3,4-dihydro) -2- [N- (2-benzimidazolylmethyl) carbamate moylmethyl] -2H-1,4-benzoxazin-3-one-6-yl-propionic acid, (2S) -2-cyclohexylsulfonamido-3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] ] -2H-1,4-Benzoxazin-3-one-6-yl] Propionic acid, (2S) -2-cyclohexylsulfonamido-3- {3,4-dihydro-2- [N- (2-imidazolyl) carbamoylmethyl] -2H-1,4-benzoxolin-3-one-6-yl-propionic acid, (2S) -2-cyclohexylsulfonamido-3- {3,4-dihydro-2- [N- (2- benzimidazolylmethyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl] propionic acid.

Example 7

Cleavage of the BOC group with trifluoroacetic acid in dichloromethane yields:

from 19 (2S) - (- 2-Amino-3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzoxa-2-yl ester) on-6-yl) propionic acid (31a), FAB 500, z 20 (2S) -2-amino-3- {3,4-dihydro-2- [N- (2-imidazolyl) carbamoylmethyl] benzyl ester -2H-1,4-benzoxazin-3-on-6-yl] propionic acid (31b), from 21 (2S) -2-amino-3- {3,4-dihydro-2- [N- (2-benzimidazoles) benzyl ester methyl 1) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl} propionic acid (31c).

Mix a solution of 0.13 g of 31a in 15 ml of dichloromethane with 22 ml of butylsulfonic acid chloride (D) and 71 μΐ of triethylamine and stir for 30 hours. After the usual work-up, the crude product is hydrogenated according to Example 1. After purification by preparative HPLC, 13 mg of (2S) -2-butylsulfonamido-3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] is obtained. -2H-1,4-benzoxazin-3-one-6-yl-propionic acid (32a), FAB 530.

Similarly, obtained by reaction D followed by hydrogenation with 31b (2S) -2-butylsulfonamido-3- {3,4-dihydro-2- [N- (2-imidazolyl) carbamoylmethyl] -2H-1,4-benzoxazine-3 -on-6-yl} propionic acid (32b) and 31c (2S) -2-butylsulfonamido-3- {3,4-dihydro-2- [N- (2-benzimidazolylmethyl) carbamoylmethyl] -2H-1,4- benzoxazin-3-one-6-yl} propionic acid (32c).

Example 8

A solution of 2.1 g of 1, 3.7 g of 2,4-dibromo-adipic acid diester, 1.4 g of potassium carbonate and 0.137 g of 18-Krone-6 in 100 ml of toluene is stirred at 80 ° C for two hours. After usual work-up, 1.8 g of (2S) -2-tert-butyloxycarboxamido-3- [3-nitro-4- (1,4-bis- (ethoxycarbonyl) -4-bromobutyloxy) phenyl] propionic acid benzyl ester is obtained ( 34) as a colorless syrup, FAB 696.

A solution of 1.5 g of 34 and 0.7 g of sodium azide in 60 ml of dimethylformamide is stirred for 12 hours at 60 DEG C. After the usual work-up, 1.3 g of (2S) -2-tert-butyloxycarboxamido-3- [3- [3-] is obtained. nitro-4- (1,4-bis- (ethoxycarbonyl) -4azidobutyloxy) phenyl] propionic acid (35), FAB 658.

1.1 g of 35 are dissolved in 50 ml of methanol, mixed with 5.9 ml of 1N sodium hydroxide solution and stirred for 5 hours. After usual work-up, 0.85 g of (2S) -2-tert-butyloxycarboxamido-3- [3-nitro-4- (1,4-bis-carboxyl-4-azidobutyloxy) phenyl] propionic acid (36) is obtained. FAB 512.

A solution of 0.5 g of 36 in 10 ml of dioxane and 5 ml of water was hydrogenated for six hours in the presence of 0.1 palladium (10% on charcoal). The pH is maintained with 4 to 6 N hydrochloric acid. Removal of the solvent affords 0.21 g of (2S) -2-tert. -butyloxycarboxamido-3- [3,4-dihydro-2,3-amino-3-carboxypropyl) -2H- (1,4-benzoxazin-3-one-6-yl) propionic acid (37), FAB 456.

The crude product 37 (0.2 g) was dissolved in 10 ml of dimethylformamide, 2 ml of ethanol and 1 ml of water and guanylated for 24 hours with 0.354 g of DPFN in the presence of 0.5 ml of triethylamine at 60 ° C. After usual work-up, 0.1 g of (2S) -2-tert-butyloxycarboxamido-3- [3,4-dihydro-2- (3-guanidino-3-carbonylpropyl) -2H-1,4-benzoxazin-3-one-6 is obtained. -yl] propionic acid (38), FAB 480.

A solution of 50 mg of 38 (trifluoroacetate) in 2 ml of dimethylformamide is mixed with 32 mg of 2-chloro-1-methylpyridinium iodide and 60 μΐ of ethyldiisopropylamine and stirred for 12 hours. After usual work-up, 22 mg of (2S) -2-tert-butyloxycarboxamido-3- [3,4-dihydro-2- [3- (2-imino-4-oxoimidazolidin-5-yl) propyl] -2H1,4 is obtained. -benzoxazin-3-one-6-yl] propionic acid (39).

Example 9

A solution of (2S) -2-butylsulfonamido-3- {3-hydroxymethyl-1,4-benzodioxan-6-yl} propionic acid benzyl ester in dimethylformamide was treated with an equimolar amount of tert-butyl bromoacetate and sodium hydride.

The mixture was stirred for two hours to give 2-butylsulfonamido-3- (2- tert -butoxycarbonylmethoxymethyl-2,3-dihydrobenzo [1,4] dioxin-6-yl} propionic acid benzyl ester) as usual.

Similarly, it is obtained after subsequent cleavage of the BOC-group with trifluoroacetic acid, treatment with 2-aminobenzimidazole and cleavage of the benzyl ester by the hydrogenation of (2S) -2-butylsulfonamido-3- {2 - [(1H-imidazol-2-ylcarbamoyl) methoxymethyl] -2,3-dihydrobenzo [1,4] dioxin-6-yl) propionic acid.

Similarly, 2- (4-tolylsulfonamido-3- {2 - [(1H-imidazol-2-ylcarbamoyl) methoxymethyl] -2,3-dihydrobenzo [1,4] dioxin-6-yl} propionic acid is obtained.

Example 10

Treatment of 25 with 2,2,2-trichloro-1,1-dimethylethyl chloroformate followed by cleavage of the benzyl ester by hydrogenation affords (2S) -2 - {[(2,2,2-trichloro-1,1-dimethyl) ethyl] carboxamido} -3- (3,4-dihydro-2-carboxymethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid (40).

Similarly, reaction of 40 with A gives (2S) -2 - {[(2,2,2-trichloro-1,1-dimethyl) ethyloxy] carboxamido} trifluoroacetate -3 (3,4-dihydro-2- [N- (2 (benzimidazoyl) carbamoylmethyl-2H-1,4-benzoxazin-3-one-6-yl) propionic acid, FAB 726.

Similarly, (2S) -2 - {[(neopentyloxy) ethyl] carboxamido} -3- (3,4-dihydro-2- [N- (2-benzimidazoyl) carbamoylmethyl-2H1,4-benzoxazine-3-) is obtained. on-6-yl) propionic acid, FAB 524.

Example 11

Reaction of BOC-3-amino-L-tyrosine ethyl ester with (2S) -bromopentanedioic acid 5-benzyl ester [obtainable by reaction of L-glutamic acid gamabenzyl ester with sodium nitrite and potassium bromide in sulfuric acid] and EDC1 in dichloromethane at room temperature for 1 hr. and after usual treatment with (4S) -4-bromo-4- (5 - ((2S) 2-tert-butyloxycarbonylamino-2-ethoxycarbonylethyl) -2-hydroxyphenylcarbamoyl) butyric acid benzyl ester, FAB 608.

Maintaining for 12 hours with DBU (diazabicycloundec-7-ene) in toluene at 100 ° C gives, after usual work-up, (2S) -3 - [(2R) -2- (2-benzyloxycarbonylethyl) -3-ΟΧΟ-3,4 ethyl ester -dihydro-2H-benzo [1,4] oxazin-6-yl] -2-tert. butoxycarbonylaminopropionic acid, FAB 527. Hydrogenation in the presence of palladium on carbon gives (2S) -2-tert-butoxycarbonylamino-3 - [(2R) -2- (2-carboxyethyl) -3-oxo-3,4-dihydro 2H ethyl ester. -benzo [1,4] oxazin-6-yl] propionic acid (41), FAB 437.

Analogously to Example 5, (2S) -2-tert-butyloxycarboxamido-3- {3,4-dihydro-2 [N- (2-benzimidazolyl) carbamoylethyl] - (2R) -2H- ethyl ester was obtained by reaction of 41 with A. 1,4-benzoxazin-3-yl-6-yl} -propionic acid (42) and (2S) -2-tert-butyloxycarboxamido-3- {3,4-dihydro-2 [N- (2-imidazole) ethyl ester B 1) carbamoylmethyl] - (2R) -2H-1,4-benzoxazin-3-on-6-yl} propionic acid (43), FAB 502.

Cleavage of the ethyl ester in 42 and 43 with aqueous sodium hydroxide solution affords (2S) -2-tert-butyloxycarboxamido-3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylethyl] - (2R) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 524 and (2S) -2-tert-butyloxycarboxamido-3- {3,4-dihydro-2- [N- (2 (imidazolyl) carbamoylethyl] - (2R) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 474.

Similarly, (2S) -2-tert-butyloxycarboxamido-3- {3,4-dihydro-2- [N- (2-imidazolyl) carbamoylethyl] - (2S) -2H-1,4-benzoxazine-3 was obtained. -on-6-yl} propionic acid, FAB 474.

Example 12

Cleavage of the BOC group with trifluoroacetic acid in dichloromethane affords the following compounds from 42 and 43:

(2S) -2-Amino-3- (3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylethyl] - (2R) -2H-1,4-benzoxazin-3-one-6-yl] propionate ethyl ester acid (44) and (2S) -2-amino-3- (3,4-dihydro-2- [N- (2-imidazolylcarbamoylethyl) - (2R) -2H-1,4-benzoxazin-3-one-, ethyl ester) 6-yl} propionic acid (45), FAB 402.

Analogously to Example 6, by reaction of 44 with 2,3,5,6-tetramethylphenylsulfonyl chloride (2S) -2- (2,3,5,6-tetramethylphenylsulfonamido) -3 (3,4-dihydro-2- [N] -, ethyl ester. - (2-benzimidazolyl) carbamoylethyl] - (2R) 2H-1,4-benzoxazin-3-one-6-yl] propionic acid and, by cleavage of (2S) -2- (2,3,5,6-tetramethylphenylsulfonamido) ester, 3- (3,4-Dihydro-2 [N- (2-benzimidazolyl) carbamoylethyl] - (2R) -2H-1,4-benzoxazin-3-one-6-yl) propionic acid, FAB 620.

Similarly, (2S) -2- (3-chloro-6-methoxyphenylsulfonamido) -3- (3,4-dihydro-2- [N- (2-imidazolylcarbamoylethyl)] - is obtained by reaction of 45 with 3-chloro-6-methoxyphenylsulfonyl chloride - (2R) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, (2S) -2- (1-naphthylsulfonamido) -3- (3,4-dihydro) 1-naphthylsulfonyl chloride -2- [N (2-imidazolylcarbamoylethyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, with 2,3,5,6-tetramethylphenylsulfonyl chloride (2S) -2- ( 2,3,5,6-tetramethylphenylsulfonamido-3- (3,4-dihydro-2- [N- (2-imidazolylcarbamoylethyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid) Acids, with (R)-Camphor-10-sulfonyl chloride (2S) -2 - [(R)-Camphor-10-sulfonamido) -3- (3,4-dihydro-2 [N- (2-imidazolylcarbamoylethyl)] - (2R) -2H-1,4-benzoxazin-3-one-6-yl} -propionic acid, with (2S) -2- (butylsulfonamido) -3- (3,4-dihydro-2- [N- ( 2imidazolylcarbamoylethyl] - (2R) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, with propyl chloro ester (2S) -2-isopropoxycarboxamido-3- (3,4-dihydro-2- [N (2-imidazolylcarbamoylethyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid ethyl formate , with butyl chloroformate ethyl (2S) -2-isobutoxycarboxamido-3- (3,4-dihydro-2- [N- (2-imidazolylcarbamoyl) 1] - (2R) -2H-1,4-benzoxazole 4-Amino-3-one-6-yl} -propionic acid, with (2S) -2-neopentyloxycarboxamido-3- (3,4-dihydro-2 [N- (2-imidazolylcarbamoylethyl) - (2R) -2H) pentyl chloroformate -1,4-benzoxazin-3-one-6-yl) propionic acid, with benzyl chloroformate ethyl (2S) -2-benzyloxycarboxamido-3- (3,4-dihydro-2- [N- (2imidazolylcarbamoylethyl)] - (2R) -2H-1,4-benzoxazin-3-on-6-yl} propionic acid, with benzylsulfonyl chloride (2S) -2-benzylsulfonamido-3- (3,4-dihydro-2- (N- (2-imidazolylcarbamoy) ethyl) flights 1] - (2R) -2H-1,4-benzoxin-3-one-6-yl} propionic acid, with (2S) -2-benzolsulfonamido-3- (3,4-dihydro-2) -benzenesulfonyl chloride - [N- (2im idazolylcarbamoylethyl] - (2R) -2H-1,4-benzoxazin-3-one-6-yl) propionic acid, and cleaving the ester with the following propionic acid derivatives (2S) -2- (3-chloro-6-methoxyphenylsulfonamido) -3 - (3,4-dihydro-2 [N- (2-imidazolylcarbamoylethyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl) propionic acid, FAB 578, (2S) -2- (1) -naphthylsulfonamido) -3- (3,4-dihydro-2- [N- (2-imidazolylcarbamoylethyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 564 (2S) -2- (2,3,5,6-tetramethylphenylsulfonamido-3- (3,4-dihydro-2- [N- (2-imidazolylcarbamoylethyl) - (2R) -2H-1,4-benzoxazin-3-one) 6-yl) propionic acid, FAB 570, (2S) -2 - [(R)-Camphor-10-sulfonamido) -3- (3,4-dihydro-2- [N- (2-imide and zolylcarbamoylethyl)] - (2R) -2H-1,4-benzoxazin-3-yl-6-yl) propionic acid, FAB 588, (2S) -2- (butylsulfonamido) -3- (3,4-dihydro- 2- [N- (2-imidazolylcarbamoylethyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl] propionic acid, FAB 494, (2S) -2-isopropoxycarboxamido-3- (3,4) -dihydro-2- [N- (2-imidazole) ylcarbamoylethyl] - (2R) -2H-1,4-benzoxazin-3-one-6-yl] propionic acid, FAB 460, (2S) -2-isobutoxycarboxamido-3- (3,4-dihydro-2- [N- ( 2-imidazolylcarbamoylethyl] - (2R) -2H-1,4-benzoxazin-3-one-6-yl] propionic acid, FAB 474, (2S) -2-neopentyloxycarboxamido-3- (3,4-dihydro-2- [ N- (2-imidazolylcarbamoylethyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 488, (2S) -2-benzyloxycarboxamido-3- (3,4-dihydro -2- [N- (2-imidazolylcarbamoylethyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl} -propionic acid, FAB 508, (2S) -2-benzylsulfonamido-3- ( 3,4-dihydro-2- [N- (2-imidazolylcarbamoylethyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl) propionic acid, FAB 528, (2S) -2-benzolsulfon Onamido-3- (3,4-dihydro-2- [N- (2-imidazolylcarbamoylethyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl) -propionic acid, FAB 514.

Similarly, (2S) -2- (1,1-dimethyl-2,2,2-trichlorethyloxycarboxamido-3- (3,4-dihydro-2- [N- (2-imidazolylcarbamoylethyl) - (2R) -2H-) was obtained. 1,4-benzoxazin-3-one-6-yl] propionic acid, FAB 578.

Example 13

In 300 ml of 2.5 N sulfuric acid was dissolved 25 g of L-0 m (N ^ ^^ ^{e and} Z) with 37 g of potassium bromide and mixed at O'C te49 fence with 9.7 g nátriumnitritu. The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. After usual work-up, 11 g of (2S) -2-bromo-4-benzyloxycarbonylaminobutyric acid are obtained in the form of an oil, El 330.

Subsequent reaction with BOC-3-amino-L-tyrosine ethyl ester and EDC1 in dichloromethane afforded the ethyl ester after stirring for 12 hours at room temperature and usual work-up followed by reaction of the product with DBU (diazabicycloundec-7-ene) in toluene at 100 ° C. (2S) -3 - [(2R) -2- (3-Benzyloxycarbonylamino-propyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-6-yl] -2-tert- butoxycarbonylaminopropionic acid (46), FAB 556.

Hydrolysis of the ester with aqueous sodium hydroxide solution followed by cleavage of the Z-group by hydrogenation (in the presence of palladium on carbon) in dioxane / water gives (2S) -3 - [(2R) 2- (3-aminopropyl) -3-oxo-3 4-dihydro-2H-benzo [1,4] oxazin-6-yl] -2-tert-butoxycarbonylaminopropionic acid, FAB 394.

Analogously to Example 3, DPFN (2S) -3 - [(2R) -2- (3-guanidinopropyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazine- 6-yl] -2-tert. butoxycarbonylaminopropionic acid, FAB 436.

Cleavage of the BOC group with trifluoroacetic acid in dichloromethane yields from 46 (2S) -2-amino-3 - [(2R) 2- (3-benzyloxycarbonylaminopropyl) -3-oxo-3,4-dihydro-2H-benzo [1] ethyl ester 4] oxazin-6-yl] propionic acid (47), trifluoroacetate, FAB 456.

Analogously to Example 6, (2S) -2- (2,3,5,6-tetramethylphenylsulfonamido) -3- {3,4-dihydro-2- (3-) - is obtained by reaction of 47 with 2,3,5,6-tetramethylphenylsulfonyl chloride. benzyloxycarbonylaminopropyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, with (2S) -2- (3-chloro-6-) 3-chloro-6-methoxyphenylsulfonyl chloride ethyl ester methoxyphenylsulfonamido) -3- (3,4-dihydro-2- (3-benzyloxycarbonylaminopropyl) - (2R) -2H-1,4-benzoxa-3-one-6-yl} -propionic acid, with naphthylsulfonyl chloride ethyl ester (2S) ) -2- (1-naphthylsulfonamido) -3- {3,4-dihydro-2- (3-benzyloxycarbonylaminopropyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl) propionic acid, s 2, 3,5,6-tetramethylphenylsulfonyl chloride (2S) -2- (2,3,5,6-tetramethylphenylsulfonamido) -3- (3,4-dihydro-2- (3-benzyloxycarbonylaminopropyl) - (2R) -2H-1,4 ethyl ester) -benzoxazin-3-on-6-yl} propionic acid, with (R) -camphor-10-sulfonyl chloride (2S) -2 - ((R) -camphor-10-ylsulfonamido) -3- (3,4- dihydro2- (3-benzyloxycarbonylaminopropyl) - (2 R) -2 H -1,4-benzoxazin-3 trans-6-yl) propionic acid, with (2S) -2- (butylsulfonamido-3- {3,4-dihydro-2- (3-benzyloxycarbonylaminopropyl) - (2R) -2H-1,4-benzoxazine ethyl ester (2S) -2- (butylsulfonamido) - 3-on-6-yl} propionic acid, FAB 576, with propyl chloroformate ethyl (2S) -2-isopropoxycarboxamido-3- {3,4-dihydro-2- (3-benzyloxycarbonylaminopropyl) - (2R) -2H-1, ethyl ester, 4-Benzoxazin-3-one-6-yl} propionic acid, with isobutyl chloroformate ethyl (2S) -2-isobutoxycarboxamido-3- {3,4-dihydro-2- (3-benzyloxycarbonylaminopropyl) - (2R) -2H-1,4 ethyl ester -benzoxazin-3-one-6-yl] propionic acid, with (2S) -2-neopentyloxycarboxamido-3- (3,4-dihydro-2- (3-benzyloxycarbonylaminopropyl) - (2R) -2H-1,4-benzoxazine, ethyl pentylester) -on-6-yl-propionic acid, FAB 570, with benzyl chloroformate ethyl (2S) -2-benzyloxycarboxamido-3- (3,4-dihydro-2- (3-benzyloxycarbonylaminopropyl) - (2R) -2H-1,4-benzoxazine) -3-one-6-yl] propionic acid, with ethyl benzylsulfonyl chloride (2S) -2-Benzylsulfonamido-3- (3,4-dihydro-2- (3-benzyloxycarbonylaminopropyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl) propionic acid, with benzolsulfonyl chloride (2S) -2-Benzenesulfonamido-3- (3,4-dihydro-2- (3-benzyloxycarbonylaminopropyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl) -propionic acid ethyl ester,

The following compounds are obtained from the above-mentioned Z-protected propionic esters with ester cleavage and hydrogenation:

(2S) -2- (2,3,5,6-tetramethylphenylsulfonamido) -3- {3,4-dihydro-2- (3-aminopropyl) - (2R) -2H-1,4-benzoxazine-3 (2S) -2- (3-chloro-6-methoxyphenylsulfonamido) -3- {3,4-dihydro-2- (3-aminopropyl) - (2R) - 2H-1,4-benzoxazin-3-one-6-yl-propionic acid, (2S) -2- (1-naphthylsulfonamido) -3- {3,4-dihydro-2- (3-aminopropyl) (2R) -2H-1,4-benzoxazin-3-one-6-yl] propionic acid, (2S) -2- (2,3,5,6-tetramethylphenylsulfonamido) -3- {3,4-dihydro-2 ( 3-Aminopropyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl] propionic acid, (2S) -2 - ((R)-Camphor-10-ylsulfonamido) -3- {3,4 -dihydro-2- (3-aminopropyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl] propionic acid, (2S) -2- (butylsulfonamido-3- {3,4-a] -dihydro-2- (3-aminopropyl) (2R) -2H-1,4-benzoxazin-3-one-6-yl] propionic acid, (2S) -2-isopropoxycarboxamido-3- {3,4-dihydro- 2- (3-Aminopropyl) (2R) -2H-1,4-benzoxazin-3-one-6-yl] propionic acid, (2S) -2-isobutoxycarboxamido-3- {3,4-dihydro-2- (3-aminopropyl) (2 R) -2 H -1,4-benzoxazine 3-on-6-yl-propionic acid, (2S) -2-neopentyloxycarboxamido-3- {3,4-dihydro-2- (3-aminopropyl) - (2R) -2H-1,4-benzoxazin-3-one -6-yl-propionic acid,

FAB 408, (2S) -2-benzyloxycarboxamido-3- {3,4-dihydro-2- (3-aminopropyl) (2R) -2H-1,4-benzoxazolin-3-one-6-yl] propionic acid (2S) -2-Benzylsulfonamido-3- {3,4-dihydro-2- (3-aminopropyl) (2R) -2H-1,4-benzoxazin-3-one-6-yl propionic acid, (2S) -2-benzolsulfonamido-3- {3,4-dihydro-2- (3-aminopropyl) (2R) -2H-1,4-benzoxazin-3-one-6-yl] propionic acid.

Analogously to Example 3, the following compounds are obtained from the above propionic acids by reaction with DPFN:

(2 S) -2- (2,3,5,6-tetramethylphenylsulfonamido) -3- (3,4-dihydro2- (3-guanidinopropyl) - (2R) -2H-1,4-benzoxazin-3-on-6 -yl} -propionic acid, (2S) -2- (3-chloro-6-methoxyphenylsulfonamido) -3- (3,4-dihydro-2- (3-guanidinopropyl) - (2R) -2H-1,4-benzoxazine) -3-On-6-yl-propionic acid, (2S) -2- (1-naphthylsulfonamido) -3- {3,4-dihydro-2- (3-guanidinopropyl) - (2R) -2H-1,4- benzoxazin-3-one-6-yl-propionic acid, (2S) -2- (2,3,5,6-tetramethylphenylsulfonamido) -3- {3,4-dihydro-2- (3-guanidinopropyl) - (2R) -2H -1,4-Benzoxazin-3-yl-6-yl-propionic acid, (2S) -2 - ((R)-Camphor-10-ylsulfonamido) -3- {3,4-dihydro-2- (3-guanidinopropyl) - (2R) -2H-1,4-benzoxazin-3-one-6-yl] propionic acid, (2S) -2- (butylsulfonamido-3- {3,4-dihydro-2- (3-guanidinopropyl) (2R) ) -2H-1,4-benzoxazin-3-one-6-yl} propionic acid, FAB 456, (2S) -2-isopropoxycarboxamido-3- {3,4-dihydro-2- (3-guanidinopropyl) - ( 2R) -2H-1,4-benzoxazin-3-one-6-yl] propionic acid, (2S) -2-isobutoxycarboxamido-3- {3,4-dihydro-2- (3-guanidinopropyl) - (2R) -2H -1 4-Benzoxazin-3-one-6-yl} propionic acid, (2S) -2-neopentyloxycarboxamido-3- {3,4-dihydro-2- (3-guanidinopropyl) - (2R) -2H-1,4 -benzoxazin-3-one-6-yl-propionic acid, FAB.450, (2S) -2-benzyloxycarboxamido-3- {3,4-dihydro-2- (3-guanidinopropyl) - (2R) -2H-1,4 (2S) -2-benzylsulphonamido-3- {3,4-dihydro-2- (3-guanidinopropyl) (2R) -2H-1,4-benzoxazoxin-3-benzoxazin-3-one-6-yl] -propionic acid -on-6-yl-propionic acid, (2S) -2-benzenesulfonamido-3- {3,4-dihydro-2- (3-guanidinopropyl) (2R) -2H-1,4-benzoxazin-3-one-6- yl] propionic acid.

The following examples illustrate the composition of the 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 injection vials, lyophilized under sterile conditions and sealed. Each ampoule contains 5 mg of active ingredient.

Example B Suppositories

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

Example C Solution

A solution of 1 g of an active compound of the formula I and 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of 12-molar sodium hydrogen phosphate dihydrate and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. The pH is adjusted to 6.8, made up to 1 liter and sterilized by irradiation.

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

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 magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of the active ingredient.

Example F Dragees

Similar to Example E, tablets are compressed to which a coating of sucrose, potato starch, talc, tragacanth and dye is applied in a known manner.

EXAMPLE G Capsules kg of active ingredient of the formula I are filled into hard gelatine capsules in a conventional manner such that each capsule contains 20 mg of active ingredient.

Example H Ampoules

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

Example I Inhalation Spray

Dissolve 14 g of an active compound of the formula I in 10 l of isotonic sodium chloride solution and fill in conventional commercial spray cans with a pump mechanism.

The solution may be sprayed into the mouth or nose. Each spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Technical usability

Bicyclic aromatic amino acids useful as GPIIb / IIa-antagonists and as inhibitors and α _- integrin for the manufacture of pharmaceutical compositions for the control of, for example, pathological angiogenic diseases, thromboses, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, inflammation and infections.

Claims (11)

PATENT CLAIMS CLAIMS 1. Compounds of formula (I) EMI3.0 wherein is R ( ¹⁾ is hydrogen, (C1-C6) -alkyl or benzyl, R ² R ¹⁰ , CO-R ¹⁰ , COOR ⁶ , COOR ¹⁰ , SO ² R ⁶ or SO ² R ¹⁰ , R ³ H, Hal, OA, NHR ¹⁰ , N (R ¹⁰ ) ₂ , -NH-acyl, -O-acyl, CN, NO ₂ , OR ¹⁰ , SR ¹⁰ , R ² or CONHR ¹⁰ , R ⁴ H, = 0, = S, C ₁ _ ₆ alkyl, or acyl, R ⁵ NH ₂ , H ₂ NC (= NH) or H ₂ NC (= NH) -NH, wherein the primary amino groups are optionally protected with a conventional amino protecting group or optionally substituted with one, two or three groups from the group consisting of R ¹⁰ , CO -R ¹⁰ , COOR ¹⁰ or SO ₂ R ¹⁰ , or is R ⁶ , R ⁷ , R ⁸ independently of one another are absent or a hydrogen atom, or R ⁷ and R ⁸ together bond, X, Y independently = N-, -N-, O, S, -CH ₂ - or = C-, wherein at least one of X and Y is = N-, -N-, o or S, W, Z are independently absent or are 0, S, NR ¹ , C (= O), CONH, NHCO, C (= S) NH, NHC (= S), C (= S), SO ₂ NH, NHSO ₂ , or CA = CA ', g R is a heterocycle having one or two rings of 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur, unsubstituted or substituted by one, two or three groups selected from Hal, A, -CO-A, OH, CN, COOH, COOA, CONH ₂ , NO ₂ , = NH or = O, R ⁹ H, Hal, OA, NHA, NAA ', NHacyl, Oacyl, CN, NO ₂ , SA, SOA, SO ₂ A, SO ₂ Ar or SO 3 H, TO * * R H, A, Ar or C 7 -C 14 aralkylene, R ( ¹¹⁾ H or alkyl of 1 to 6 carbon atoms, A, A ', independently of one another, a hydrogen atom or an alkyl or cycloalkyl group of up to 15 carbon atoms unsubstituted or R ^9, mono- or triple-substituted, whereby one, two or three methyl groups are optionally replaced by nitrogen, oxygen and / or S, Ar a single ring or two-ring aromatic ring system is unsubstituted or A and / or R ⁹ is mono-, di-, or trisubstituted with zero, one two, three or four nitrogen, oxygen and / or sulfur, Hal is a fluorine, chlorine, bromine or iodine atom and m, n are independently 0, 1, 2, 3 or 4, and physiologically acceptable salts thereof. Enantiomers or stereomers of the compounds of formula I according to claim 1. Compounds according to claim 1 which are (a) (2S) -2-Benzyloxycarboxamido-3- (2-guanidinomethyl-1,4-benzodioxan-6-yl) propionic acid; b) (2S) -2-tert-Butyloxycarboxamido-3- [3,4-dihydro-2- (2-guanidino-2-oxoethyl) -2H-1,4-benzoxazin-3-one-6-yl] propionic acid acid, (c) (2S) -2-benzyloxycarboxamido-3- (2-guanidinoacetamidomethyl-1,4-benzodioxan-6-yl) propionic acid; d) (2S) -2-tert-Butyloxycarboxamido-3- {3,4-dihydro-2- [N- (2imidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one-6-yl] propionic acid acid, e) (2S) -2-tert-Butyloxycarboxamido-3- {3,4-dihydro-2- [N- (2-benzimidazolyl) carbamoylmethyl] -2H-1,4-benzoxazin-3-one - on-6-yl-propionic acid, f) (2S) -2-tert. -butyloxycarboxamido-3- {3,4-dihydro-2- [2- (2-imino-4-oxoimidazolidin-5-yl) ethyl] -2H-1,4-benzoxazin-3-one6-yl] propionic acid, and their physiologically acceptable salt. 4. A process for the preparation of the compounds of the formula I and their salts, characterized in that: (a) the compound of formula I is released from its functional derivative by treatment with a solvolysis or hydrogenolysis agent; or b) reacting a compound of formula II wherein R ¹ , R ³ , R ⁴ , R ^{5 *} , R ⁷ , R ⁸ , R ¹¹ W, X, Y, Z, m and m are as defined above with a compound of formula III R ² - L (III) wherein R ² is as defined above and L is Cl, Br, I, OH or a reactive esterified OH group, or c) saponifying the ester of the formula I, and / or (d) the group R ¹ and / or R ⁵ is converted into another group R ¹ and / or R ⁵ and / or (e) converting a basic or acidic compound of formula (I) by treatment with an acid or base into its salt. 5. A process for the preparation of pharmaceutical compositions, characterized in that the compound of the formula I and / or its physiologically acceptable salt together with at least one solid, liquid and / or semi-liquid carrier or excipient are brought into a suitable dosage form. A pharmaceutical composition comprising at least one compound according to claim 1 or 2 and / or one physiologically acceptable salt thereof. Compounds of formula I according to claim 1 and their physiologically acceptable salts as GPIIb / IIa-antagonists for the treatment of thromboses, heart attack, coronary heart disease and arteriosclerosis. 8. Compounds of formula I according to Claim 1 and their physiologically acceptable salts as inhibitors _of -integrínu and the treatment of pathological angiogenic disorders, thromboses, cardiac infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations and infections. Compounds of formula I wherein R ^{2 is} camphor- 10-yl claim 1 and their physiologically acceptable salts as inhibitors _in the treatment -integrínu pathologically angiogenic disorders, thromboses, cardiac infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations and infections _e. b * ’10. The use of the compounds of formula I according to the invention - claim 1 and / or their physiologically acceptable salts for the manufacture of a medicament. Use of the compounds of the formula I according to claim 1 and / or their physiologically acceptable salts as inhibitors and α _- integrin for the manufacture of a medicament.