EP1311484A1

EP1311484A1 - Biphenyl derivatives and the use thereof as integrin inhibitors

Info

Publication number: EP1311484A1
Application number: EP01969486A
Authority: EP
Inventors: Wolfgang Staehle; Simon Goodman
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 2000-08-23
Filing date: 2001-07-24
Publication date: 2003-05-21
Also published as: HUP0302822A3; ZA200302253B; KR20030022419A; JP2004506717A; CZ2003670A3; CA2420205A1; CN1447795A; US20030187289A1; WO2002016323A1; DE10041428A1; NO20030812L; NO20030812D0; AU8973201A; MXPA03001556A; SK2952003A3; HUP0302822A2; BR0113373A; PL359154A1

Abstract

The invention relates to novel biphenyl derivatives of general formula (I) wherein Y, R, R<1>, R<2>, R<3>, R<4>, m, o and p have the designation cited in patent claim 1; and the physiologically tolerable salts or solvates thereof. Said derivatives are integrin inhibitors and can be used to combat thrombosis, infarction, coronary heart disease, arteriosclerosis, inflammation, tumours, osteoporosis, infection and restenosis after angioplasty, or in pathological processes which are maintained or spread by angiogenesis.

Description

BIPHENNYL DERIVATIVES AND THEIR USE AS INTIGRINE INHIBITORS

The invention relates to biphenyl derivatives of the formula

where Y NHR ⁷ , -NR ⁷ -C (= NR ⁷ ) -NHR ⁷ , -C (= NR ⁷ ) -NHR ⁷ , -NR ⁷ -C (= NR ⁸ ) -

NHR ⁷ , -C (= NR ⁸ ) -NHR ⁷ , Het ¹ -NH or Het ¹ ,

R ¹ OR or N (R) ₂ ,

R H, A, cycloalkyl, Ar, arylalkyl or Pol,

R ² , R ³ and R ⁴ each independently of one another H, A, Hai, NO ₂ , OR, N (R) ₂ ,

CN, CO-R, SO ₃ R, SO ₂ R, NH-C (O) A or SR,

R ^b H or A, R ⁶ shark or NO ₂ , R ⁷ H, -C (O) R ⁹ , -C (O) -Ar, R ⁹ , COOR ⁹ , COO- (CH ₂ ) ₀ -Ar, SO ₂ -Ar,

SO ₂ R ⁹ or SO ₂ -Het, R ⁸ CN or NO ₂ ,

R ⁹ alkyl with 1 to 10 carbon atoms or cycloalkyl with 3 to 15 carbon atoms

Atoms, A alkyl with 1 to 8 carbon atoms, where the alkyl groups can be substituted one or more times by R ⁶ and / or their

Alkyl carbon chain can be interrupted by -O-, Ar unsubstituted or one, two or three times substituted

Aryl, cycloalkyl cycloalkyl with 3 to 15 carbon atoms, Hal F, CI, Br or I,

Het a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical with 5 to 10 ring members, where 1 or 2 N and / or 1 or 2 S or O atoms may be present and the heterocyclic radical may be mono- or disubstituted by R ⁸ can be substituted,

Het ^{1 with} a mono- or bicyclic aromatic heterocycle

1 to 4 N atoms, which can be unsubstituted or mono- or disubstituted by shark, A, cycloalkyl, OA, O-cycloalkyl, CN, NHA, imino or NO ₂ ,

Pol is a solid phase without a terminal functional group, m 1, 2, 3 or 4, o 1, 2, 3 or 4, p 1, 2, 3, 4 or 5, and their physiologically acceptable salts and solvates.

Partially similar compounds are known from WO 95/32710.

The object of the invention was to find new compounds with valuable properties, in particular those which are used for the production of medicaments.

It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the αvß3 or αvß5 integrin receptors with ligands, such as, for example, the binding of vitronectin to the vß3 integrin receptor. Integrins are membrane-bound, heterodimeric glycoproteins that consist of an α subunit and a smaller β subunit. The relative affinity and specificity for ligand binding is determined by combining the various α and β subunits. The compounds according to the invention show particular activity in the case of the integrins αvßl, αvß3, αvßδ, αllbß3 and αvßδ and αvß8, preferably of αvß3, αvßδ and αvßδ. In particular, potent selective inhibitors of the integrin αvß3 were found. The αvß3 integrin is expressed on a number of cells, for example endothelial cells, cells of the smooth vascular muscles, for example the aorta, cells for breaking down bone matrix (osteoclasts) or tumor cells.

The action of the compounds according to the invention can e.g. detected using the method developed by J.W. Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271. The dependence of the development of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins is described by P.C. Brooks, R.A. Clark and D.A. Cheresh in Science 1994, 264, 569-571.

The possibility of inhibiting this interaction and thus inducing apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide has been discussed by P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T. Hu, G. Klier and D.A. Cheresh in Cell 1994, 79, 1157-1164. In it e.g. αvß3 antagonists or antibodies against αvß3 described that cause tumor shrinkage by inducing apoptosis.

The experimental proof that the compounds according to the invention also prevent the attachment of living cells to the corresponding matrix proteins and accordingly also prevent the attachment of tumor cells to matrix proteins can be carried out in a cell adhesion test can be provided, analogously to the method of F. Mitjans et al., J. Cell Science 1995, 108, 2825-2838.

The compounds of the formula I can inhibit the binding of metalloproteinases to integrins and thus prevent the cells from being able to use the enzymatic activity of the proteinase. An example can be found in the inhibibility of the binding of MMP-2- (matrix metallo-proteinase-2) to the vitronectin receptor αvß3 by a cyclo-RGD peptide, as described in P.C. Brooks et al., Cell 1996, 85, 683-693.

Compounds of the formula I which show the interaction of integrin receptors and ligands, e.g. from fibrinogen to the fibrinogen receptor (glycoprotein llb / llla), prevent the spread of tumor cells through metastasis as antagonists and can therefore be used as antimetastatic substances in operations in which tumors are surgically removed or attacked. 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 micro-aggregates (microthrombi) 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 attach themselves to the vessel walls, which facilitates further penetration of tumor cells into the tissue. Since the formation of the microthrombi is mediated by ligand binding to the corresponding integrin receptors, for example αvß3 or αllbß3, on activated platelets, the corresponding antagonists can be regarded as effective metastasis inhibitors. The effect of a compound on an αvßδ-innate receptor and thus the activity as an inhibitor can be demonstrated, for example, by the method described by JW Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271.

The compounds of formula I can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for the prophylaxis and / or therapy of diseases of the circulatory system, thrombosis, heart attack, arteriosclerosis, apoplexy, angina pectoris, tumor diseases such as tumor development or tumor metastasis, osteolytic diseases such as Osteoporosis, pathologically angiogenic diseases such as Inflammation, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angioplasty, infection, bile sclerosis, infection, biosclerotic infection, multiple infections, bile sclerosis, infection with bile sclerosis, infection with multiple sclerosis Kidney failure and wound healing to support the healing process.

αvß6 is a relatively rare integrin (Busk et al., 1992 J. Biol. Chem. 267 (9), 5790), which is increasingly formed in epithelial tissue during repair processes and preferentially binds the natural matrix molecules fibronectin and tenascin (Wang et al., 1996, Am. J. Respir. Cell Mol. Biol. 15 (δ), 664). The physiological and pathological functions of αvß6 are not yet exactly known, but it is believed that this integrin plays an important role in physiological processes and diseases (e.g. inflammation, wound healing, tumors) in which epithelial cells are involved. Thus, αvßδ is expressed on keratinocytes in wounds (Haapasalmi et al., 1996, J. Invest. Dermatol. 106 (1), 42), from which it can be assumed that in addition to wound healing processes and inflammation, other pathological events of the skin, such as, for example, B. psoriasis Agonists or antagonists of said integrin can be influenced. Furthermore, αvßδ plays a role in the respiratory epithelium (Weinacker et al., 199δ, Am. J. Respir. Cell Mol. Biol. 12 (δ), 547), so that corresponding agonists / antagonists of this integrin in respiratory diseases such as bronchitis, asthma, Lung fibrosis and respiratory tumors could be used successfully. Ultimately, it is known that αvßö also plays a role in the intestinal epithelium, so that corresponding integrin agonists / antagonists could be used in the treatment of inflammation, tumors and wounds of the gastrointestinal tract.

The effect of a compound on an αvßö integrin receptor and thus the activity as an inhibitor can e.g. detected using the method developed by J.W. Smith et al. in J. Biol. Chem. 1990, 265, 12267-12271.

The compounds of formula I can be used as antimicrobial substances in operations where biomaterials, implants, catheters or pacemakers are used. They have an antiseptic effect. The effectiveness of the antimicrobial activity can be determined by the P. Valentin-Weigund et al. methods described in Infection and Immunity, 1988, 2851-2855.

A measure of the absorption of an active pharmaceutical ingredient into an organism is its bioavailability.

Is the active ingredient in the form of a solution for injection

If the organism is added intravenously, its absolute bioavailability, i.e. the proportion of the drug that remains unchanged in the systemic blood, i.e. gets into the big cycle, at 100%.

When a therapeutic active ingredient is administered orally, the active ingredient is usually present as a solid in the formulation and must therefore first dissolve in order for it to overcome the entry barriers, for example the Gastrointestinal tract, the oral mucosa, nasal membranes or the skin, in particular the stratum corneum, can overcome or be absorbed by the body. Data on pharmacokinetics, ie on bioavailability, can be obtained analogously to the method of J. Shaffer et al, J. Pharm. Sciences, 1999, 88, 313-318. Another measure of the resorbability of a therapeutic agent is the logD value, because this value is a measure of the lipophilicity of a molecule.

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

So-called prodrug derivatives are also included in the compounds according to the invention, i.e. with e.g. Alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are quickly cleaved in the organism to the active compounds of the invention.

Furthermore, free amino groups or free hydroxyl groups as substituents of compounds of the formula I can be provided with corresponding protective groups.

Solvates of the compounds of the formula I are understood to mean the addition of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual attraction. Solvates are e.g. Mono- or dihydrates or addition compounds with alcohols, e.g. with methanol or ethanol.

The invention relates to the compounds of the formula I and their salts and solvates according to claim 1 and to a process for the preparation of compounds of formula I and their salts and solvates, characterized in that

(a) a compound of formula II

wherein R, R ¹ , R ² , R ³ , o and p have the meanings given in claim 1, but R ≠ H and in which free hydroxyl or amino groups are present as substituents R ² or R ³ protected by protective groups, with a compound of formula III

in which R, Y and m have the meanings given in claim 1 and optionally convert the radical R ≠ H into the radical R = H and split off the protective groups on R ² and / or R ³ , or (b) a compound of the formula IV 9 -

wherein R, R ¹ , R ² , R ³ , R ⁴ , o and p are those specified in claim 1

Have meanings, but R ≠ H, in which Q is Cl, Br or a reactive esterified OH group and in which free hydroxyl or amino groups are present as substituents R or R ³ protected by protective groups, with a compound of the formula V.

HO— (CH ₂ ) _m - YV

wherein Y and m have the meanings given in claim 1 and optionally convert the radical R ≠ H into the radical R = H and split off the protective groups on R ² and / or R ³ , or (c) in a compound of the formula I one or more radicals R, R ¹ ,

R ² , R ³ , R ⁴ and / or R ⁵ into one or more radicals R, R ¹ , R ² , R ³ ,

R ⁴ and / or R ⁵ converts, for example

) alkylated a hydroxy group, i) hydrolyzed an ester group to a carboxy group, ii) esterified a carboxy group, v) alkylated an amino group, v) an aryl bromide or iodide through a Suzuki coupling with

Converts boronic acids to the corresponding coupling products. Or vi) acylating an amino group, and / or converting a basic or acidic compound of the formula I into one of its salts or solvates by treatment with an acid or base.

In the above formulas, A means alkyl, is linear or branched, and has 1 to 8, preferably 1, 2, 3, 4, 5 or 6 carbon atoms. A is preferably methyl, furthermore ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or tert-butyl, further also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2 - or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2,2-, 2,3 - or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2- or 1, 2,2-trimethylpropyl, heptyl or octyl. Further preferred embodiments of A are the alkyl groups mentioned, but which can be substituted one or more times by shark or NO ₂ , preferably trifluoromethyl, 2,2,2-trifluoroethyl or 2-nitroethyl, or alkyl groups whose carbon chain is interrupted by -O- can be, preferably -CH ₂ -O-CH ₃ , -CH ₂ -O-CH ₂ -CH ₃ or -CH ₂ -CH ₂ -O-CH ₃ . Methyl and trifluoromethyl are particularly preferred for A.

Ar means unsubstituted or mono-, di- or trisubstituted by A, CF ₃ , OH, OA, OCF ₃ , CN, NO ₂ or shark, where aryl means phenyl, naphthyl, anthryl or biphenylyl. Ar is preferably phenyl or naphthyl which is unsubstituted or mono-, di- or trisubstituted by A, CF ₃ , OH, OA, OCF ₃ , CN, NO ₂ or shark. Ar is particularly preferred phenyl.

Arylalkyl also means - (CH ₂ ) _X -Ar, where Ar has one of the preferred meanings indicated above and where x can be 1, 2 or 3. Arylalkyl is preferably benzyl, phenylethyl or phenylpropyl; benzyl is particularly preferred for arylalkyl. Cycloalkyl with 3 to 15 carbon atoms preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Cycloalkyl also means mono- or bicyclic terpenes, preferably p-menthan, menthol, pinan, bornan or camphor, including any known stereoisomeric form or adamantyl. For campers, this means both L-campers and D-campers.

Shark is preferably F, Cl or bromine. Shark F or Cl is particularly preferred.

Het is preferably substituted or unsubstituted 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 3-, 4- or 5 -Pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or δ-isoxazolyl, 2-, 4- or δ-thiazolyl, 3-, 4- or δ-isothiazolyl, 2-, 3- or 4 -Pyridyl, 2-, 4-, δ- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-1-, -4- or -δ-yl, 1, 2,4-triazol-1-, - 4 or -δ-yl, 1- or δ-tetrazolyl, 1, 2,3-oxadiazol-4- or -δ-yl 1, 2,4-oxadiazol-3- or -δ-yl, 1, 3.4 -Thiadiazol-2- or -δ-yl, 1, 2,4-thiadiazol-3- or -δ-yl, 1, 2,3-thiadiazol-4- or -δ-yl, 2-, 3-, 4 -, δ- or 6- 2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, δ-, 6- or 7-benzofuryl , 2-, 3-, 4-, δ-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, δ-, 6- or 7-1 H-indolyl, 1-, 2- , 4- or δ- benzimidazolyl, 1-, 3-, 4-, δ-, 6- or 7-benzopyrazolyl, 2-, 4-, δ-, 6- or 7-benzoxazolyl, 3-, 4-, δ -, 6- or 7-benzisoxazole yl, 2-, 4-, δ-, 6- or 7-benzothiazolyl, 4- or δ-benzothiadiazolyl, 2-, 4-, δ-, 6- or 7-benzisothiazolyl, 4-, δ-, 6- or 7-Benz-2,1, 3-oxadiazolyl, 1-, 2-, 3-, 4-, δ-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, δ-, 6 -, 7- or 8-isoquinolinyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-, δ-, 6-, 7-, 8- or 9 -Acridinyl, 3-, 4-, δ-, 6-, 7- or 8-cinnolinyl, 2-, 4-, δ-, 6-, 7- or 8-quinazolinyl. The heterocyclic radicals can also be partially or completely hydrogenated. Het can also mean 2,3-dihydro-2-, -3-, -4- or -δ-furyl, 2, δ-dihydro-2-, -3-, -4- or -δ-furyl, tetrahydro -2- or -3-furyl, 1, 3- dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -δ-pyrrolyl, 2, δ-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -3-pyrollyl, tetrahydro-1-, -2- or 4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-, -δ-, -6-, -7 -1 H-indolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -δ-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, 2,3,6-tetrahydro-1-, -2-, -3, -4-, -δ- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 1- , 2-, 3- or 4-azepanyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1, 4-dioxanyl, 1, 3-dioxan-2-, -4- or -δ- yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -δ- pyrimidinyl, 1-, 2- or 3-piperazinyl , 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -δ-, -6-, -7- or -8-quinolinyl, 1, 2,3,4 -Tetrahydro-1-, -2-, -3-, -4-, -δ-, -6-, -7- or -8-isoquinolinyl.

Het is preferably substituted or unsubstituted 4-pyridyl or 4-benzothiadiazolyl.

Het ¹ is preferably substituted or unsubstituted 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or δ-imidazolyl, 3-, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, δ-, 6- or 7-1 H-indolyl, 1 -, 2-, 4- or δ-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7 - or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 1-, 4-, δ-, 6-, 7- or 8-phthalazinyl, 2-, 3-, δ-, 6-, 7- or 8-quinoxalinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl. The heterocyclic radicals can also be partially or completely hydrogenated. Het ¹ can also mean 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2, δ-dihydro-1-, -2-, -3-, - 4- or -δ-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -3-pyrollyl, tetrahydro-1-, -2- or 4-imidazolyl, 2,3-dihydro -1-, -2-, -3-, -4-, -5-, -6-, -7-1H-indolyl, 2,3-dihydro-1-, -2-, -3-, -4 - or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1, 5-dihydro-imidazol-4-one-2- or -5-yl, 1, 4-dihydro-1-, -2-, -3- or -4-pyridyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1, 2 , 3,6-tetrahydro-1 , -2-, -3, -4-, -δ- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-azepanyl, tetrahydro-2 -, -3- or -4-pyranyl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyτimidinyl, 1-, 2- or 3 - Piperazinyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8- quinolinyl, 1, 2,3 , 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8- isoquinolinyl.

The heterocyclic rings mentioned can also be substituted once or twice by = O, = NH or NHA.

Het ¹ particularly preferably denotes 2-pyridyl or 2-imino-pyridin-1-yl; very particularly preferably 2-imino-pyridin-1-yl.

Het ¹ -NH is preferably pyrrole-2 or pyrrole-3-ylamino, imidazole-2, imidazole-4 or imidazole-δ-ylamino, pyrazole-3, pyrazole-4 or pyrazole-δ-ylamino, pyridyl -2-, pyridyl-3- or pyridyl-4-ylamino, pyrimidin-2-, pyrimidin-4-, pyrimidin-δ- or pyrimidin-6-ylamino, pyridazin-3- or pyridazin-4-ylamino, pyrazin-2 - or Pyrazin-3-ylamino, where the heterocyclic rings mentioned can be substituted by preferably alkyl.

Particularly preferred for Het ¹ -NH is pyridyl-2-ylamino or 4-methyl-pyridin-2-ylamino, very particularly preferably pyridyl-2-ylamino.

Pol means a solid phase without a terminal functional group, as explained in more detail below. The term solid phase and resin is used synonymously in the following.

In the case of the biphenyl derivatives of the formula I, the second phenyl radical is preferably coupled in the 3- or 4-position to the first phenyl radical, particularly preferably to the 4-position of the first phenyl ring.

In the biphenyl derivatives of the formula I, the phenylene is preferably substituted in the 1- and 3-positions or in the 1- and 4-positions. Y preferably denotes Het ¹ or Het ¹ -NH.

R ^{1 represents} OR, N (R) ₂ , where R has one of the meanings below. R ¹ OH is particularly preferred.

R represents H, A, cycloalkyl, Ar, arylalkyl or Pol, where A, cycloalkyl, Ar and arylalkyl have one of the meanings described above and Pol has one of the meanings described below. R is particularly preferably Pol or H. R is particularly preferred.

R ² , R ³ and R ⁴ are each independently H, A, shark, NO ₂ , OR, N (R) ₂ , CN, CO-R, SO ₃ R, SO ₂ R, NH-C (O) A or SR, where A and R have one of the meanings described above. R ^{2 is} particularly preferred. R ³ is particularly preferred is shark, A, OA or CN; R ³ is very particularly preferably shark or A. R ⁴ is preferably H.

R ⁵ denotes H or A, where A has one of the meanings given above. R ⁵ is particularly preferred.

R ⁶ means shark or NO ₂ , where shark has one of the meanings given above. R ⁶ shark is particularly preferred.

R ⁷ is preferably H, -C (O) R ⁹ , -C (O) -Ar, R ⁵ , COOR ⁹ , COO- (CH ₂ ) ₀ -Ar, SO ₂ -Ar, SO ₂ R ⁹ or SO ₂ -Het, where Ar and Het have one of the meanings given above and R ^{9 is} alkyl with 1 to 10 C atoms or cycloalkyl with 3 to 10 C atoms. R ⁷ is preferably H, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl.

R ⁸ means CN or NO ₂ . m is 1, 2, 3 or 4. m is particularly preferably 2 or 3.

o means 1, 2, 3 or 4, particularly preferably 1. p means 1, 2, 3, 4 or 5, particularly preferably 1.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas la to le, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which

in la R 'OR means

in lb R ¹ OR and

R means H or A,

in Ic R ¹ OR,

R ² H,

R ⁴ H and m 2 or 3;

in Id R ¹ OR,

R ^ H, R ⁴ H,

Y Het ¹ and m 2 or 3;

R ² H,

R ⁴ H,

Y Het ¹ -NH and m 2 or 3.

The compounds of the formula I according to claim 1 and also the starting materials for their preparation are otherwise prepared by methods known per se, as described in the literature (for example in the standard works such as Houben-Weyl, methods of organic chemistry, Georg-Thieme-Verlag , Stuttgart) are described, namely under reaction conditions which are known and suitable for the reactions mentioned. Use can also be made of variants which are known per se and are not mentioned here in detail.

If desired, the starting materials can also be formed in situ, so that they are not isolated from the reaction mixture, but instead are immediately reacted further to give the compounds of the formula I according to claim 1.

Several - identical or different - protected amino and / or hydroxy groups can also be present in the molecule of the starting material. If the existing protective groups are different from one another, they can in many cases be split off selectively (cf .: TW Greene, PGM Wuts, Protective Groups in Organic Chemistry, 2nd ed., Wiley, New York 1991 or PJ Kocienski, Protecting Groups, 1st edition, Georg Thieme Verlag, Stuttgart - New York, 1994). The term "amino protecting group" is generally known and refers to groups which are suitable for protecting (blocking) an amino group against chemical reactions. Unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups are particularly typical of such groups. Since the amino protective groups are removed after the desired reaction (or reaction sequence), their type and size is otherwise not critical; however, preference is given to those having 1-20, in particular 1-8, carbon atoms. The term "acyl group" is to be understood in the broadest sense in connection with the present process. It encompasses acyl groups derived from aliphatic, araliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular alkoxycarbonyl, alkenyloxycarbonyl, 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 phenoxyacetyl; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; Alkenyloxycarbonyl such as allyloxycarbonyl (aloe), aralkyloxycarbonyl such as CBZ (synonymous with Z), 4-methoxybenzyloxycarbonyl (MOZ), 4-nitrobenzyloxycarbonyl or 9-fluorenylmethoxycarbonyl (Fmoc); 2- (phenylsulfonyl) ethoxycarbonyl; Trimethylsilylethoxycarbonyl (Teoc) or arylsulfonyl such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr). Preferred amino protecting groups are BOC, Fmoc and aloe, furthermore CBZ, benzyl and acetyl. Particularly preferred protective groups are BOC and Fmoc.

The term "hydroxyl protecting group" is also generally known and refers to groups which are suitable for protecting a hydroxyl group against chemical reactions. Typical of such groups are the unsubstituted or substituted aryl, aralkyl, aroyl or acyl groups mentioned above, furthermore also alkyl groups, alkyl, aryl or aralkylsilyl groups or O, O or O, S-acetals. The nature and size of the Hydroxy protective groups are not critical since they are removed again after the desired chemical reaction or reaction sequence; groups with 1-20, in particular 1-10, carbon atoms are preferred. Examples of hydroxy protecting groups include aralkyl groups such as benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, aroyl groups such as benzoyl or p-nitrobenzoyl, acyl groups such as acetyl or pivaloyl, p-toluenesulfonyl, alkyl groups such as methyl or tert-butyl, but also allyl, Alkylsilyl groups such as trimethylsilyl (TMS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS) or triethylsilyl, trimethylsilylethyl, aralkylsilyl groups such as tert.-butyldiphenylsilyl (TBDPS), cyclic acetals such as isopropylidene, cyclo -Methoxybenzyliden- or o, p-Dimethoxybenzy! Idenacetal, acyclic acetals such as tetrahydropyranyl (Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzyloxymethyl (BOM) or methylthiomethyl (MTM). Particularly preferred hydroxy protecting groups are benzyl, acetyl, tert-butyl or TBS.

The liberation of the compounds of the formula I from their functional derivatives is known from the literature for the protective group used in each case (for example TW Greene, PGM Wuts, Protective Groups in Organic Chemistry, 2nd edition, Wiley, New York 1991 or PJ Kocienski, Protecting Groups, 1st edition, Georg Thieme Verlag, Stuttgart - New York, 1994). Use can also be made of variants which are known per se and are not mentioned here in detail.

The groups BOC and O-tert-butyl can, for example, preferably be split off with TFA in dichloromethane or with about 3 to δN HCl in dioxane at 15-30 ° C., the Fmoc group with an about δ to 60% solution of Dimethylamine, diethylamine or piperidine in DMF at 15-30 ° C, the Aloe group can be split gently under precious metal catalysis in chloroform at 20-30 ° C. A preferred catalyst is tetrakis (triphenyl-phosphine) palladium (0). The starting compounds of the formula II to V and 1 to 6 are generally known. If they are new, they can be manufactured according to methods known per se.

The compounds of the formula I can also be synthesized on a solid phase, the bond to the solid phase being at R. When synthesized on a solid phase, R ^{1 also} means OPol, NHPol or NRPol, Pol meaning a solid phase without a terminal functional group. Pol stands for the polymeric carrier material as well as for all atoms of the anchor group of a solid phase, except for the terminal functional group. The anchor groups of a solid phase, also called linkers, are necessary for the connection of the connection to be functionalized to the solid phase. A summary of solid phase syntheses and the solid phases and / or linkers that can be used for this purpose is given, for example, in Novabiochem - The Combinatorial Chemistry Catalog, March 99, pages S1-S72.

Solid phases which are particularly suitable for the synthesis of the compounds according to the invention with R ¹ = OR are solid phases with a hydroxyl group as terminal functionality, for example the Wang resin or polystyrene A OH. Solid phases which are particularly suitable for the synthesis of the compounds according to the invention with R ¹ = N (R) ₂ are solid phases with an amino group as terminal functionality, for example Rink amide resin.

Compounds of the formula II with R ¹ = OL, where L is Pol or R and R ≠ H, are prepared, for example, according to the following reaction scheme 1, where SGi denotes an amino protective group, as described above. Reaction scheme 1:

The bromophenyl-substituted carboxylic acid 1 is activated in situ by known methods, for example by reaction with diisopropylcarbodiimide, and reacted with the alcohol HO-L, where L has the meaning given above. Subsequent coupling of compound 2 with a (R ³ ) -substituted phenylboronic acid under Suzuki compounds produces the biphenyl derivative 3. Elimination of the protective group SGi under known conditions releases a compound of the formula II. The Suzuki reaction is advantageously carried out in a palladium-mediated manner, preferably by adding Pd (PPh ₃ ), in the presence of a base such as potassium carbonate in an inert solvent or solvent mixture, for example DMF, at temperatures between 0 ° and 1δ0 °, preferably between 60 ° and 120 °. The reaction time is between a few minutes and several days depending on the conditions used. The boronic acid derivatives can be prepared by conventional methods or are commercially available. The reactions can be carried out analogously to those described in Suzuki et al., J. Am. Chem. Soc. 1989, 111, 314ff. and in Suzuki et al. Chem. Rev. 199δ, 9δ, 24δ7ff. specified methods are carried out.

The invention also relates to the reactive intermediates of the formula III

wherein

Y Het ¹ ,

Het ¹ 2-imino-pyridin-1-yl,

R ^{4 is} H, A, shark, NO ₂ , OR, N (F l) ₂ , CN, CO-R, S0 ₃ or SR, m 1, 2, 3 or 4, and their salts and solvates.

The reactive intermediates of the formula III according to claim 6, as defined above, can be prepared, for example, according to the following reaction scheme 2, where A in the formulas 3 to 6 has the meanings given above. Reaction scheme 2:

6

III

The hydroxybenzoate of the formula 4 is reacted in the presence of a base according to known reaction conditions for nucleophilic substitution with the dibromo compound Br- (CH ₂ ) _m -Br, where m has the meaning given in claim 6. The subsequent reaction with 2,2,2-trifluoropyridin-2-yl-acetamide in the presence of a base and the subsequent hydrolysis under the reaction conditions known to the person skilled in the art produces the reactive intermediates of the formula III according to the invention, where Y is Het ¹ and Het ¹ 2-Imino-pyridin-1-yl.

Preferred compounds of formula III according to claim 6 are the compounds a) 4- [2- (2-Imino-2H-pyridin-1-yl) ethoxy] benzoic acid and b) 3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] - benzoic acid.

Compounds of formula I are obtained by peptide-analog coupling of the compounds of formula II with a compound of formula III under standard conditions. The compounds of formula III can be prepared as in Reaction Scheme 2.

Compounds of the formula IV are obtained by peptide-analog coupling of a compound of the formula II with a corresponding Q-substituted benzoic acid under standard conditions, where Q is Cl, Br or a reactive esterified OH group.

Common methods of peptide synthesis are e.g. in Houben-Weyl, 1.c, Volume 15/11, 1974, pages 1 to 806.

The coupling reaction is preferably carried out in the presence of a dehydrating agent, for example a carbodiimide such as dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) or diisopropylcarbodiimide (DIC), and furthermore, for example, propanephosphonic anhydride (cf. Chem. 1980, 92, 129), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as tetrahydrofuran or dioxane, an amide such as DMF or Dimethylacetamide, a nitrile such as acetonitrile, in dimethyl sulfoxide or in the presence of these solvents, at temperatures between about -10 and 40, preferably between 0 and 30 °. The reaction time is between a few minutes and several days depending on the conditions used. The addition of the coupling reagent TBTU (0- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate) or 0- (benzotriazol-1-yl) -N has proven particularly advantageous. N, N ', N'-tetramethyl-uronium Hexafluorophosphate proved, since in the presence of one of these compounds, only a little racemization occurs and no cytotoxic by-products arise.

Instead of compounds of the formula III, derivatives of compounds of the formula III, preferably a preactivated carboxylic acid, or a carboxylic acid halide, a symmetrical or mixed anhydride or an active ester can also be used. Such residues for activating the carboxy group in typical acylation reactions are described in the literature (e.g. in the standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart). Activated esters are conveniently formed in situ, e.g. by adding HOBt (1-hydroxybenzotriazole) or N-hydroxysuccinimide.

The reaction is usually carried out in an inert solvent, when using a carboxylic acid halide in the presence of an acid-binding agent, preferably 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 another salt of a weak acid of the alkali metal or alkaline earth metal, preferably of potassium, sodium, calcium or cesium, can also be favorable.

The reaction conditions for nucleophilic substitutions, for example the reaction of a compound IV with a compound of the formula V, are sufficiently known to the person skilled in the art (Lit. Organikum, 17th edition, German Publishing House for Sciences, Berlin 1988).

A base of the formula I can be converted into the associated acid addition salt using an acid, for example by reacting equivalent amounts of the base and the acid in an inert manner Solvents such as ethanol and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. Thus, inorganic acids can be used, for example sulfuric acid, sulfurous acid, dithionic acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or poly-based carbon. , sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid , Isonicotinic acid, methane or ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantane carboxylic acid, p-toluenesulfonic acid, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, glyox ylic acid, palmitic acid, parachlorophenoxyisobutyric acid, cyclohexane carboxylic acid, glucose 1-phosphate, naphthalene mono- and disulfonic acids or laurylsulfuric acid Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of the formula I. On the other hand, compounds of the formula I with bases (for example sodium or potassium hydroxide or carbonate) can be converted into the corresponding metal, in particular alkali metal or alkaline earth metal or into the corresponding ammonium salts.

The invention also relates to the compounds of the formula I as claimed in claim 1 and their physiologically acceptable salts or solvates as active pharmaceutical ingredients. The invention furthermore relates to compounds of the formula I as claimed in claim 1 and their physiologically acceptable salts or solvates as integrin inhibitors.

The invention also relates to the compounds of the formula I as claimed in claim 1 and their physiologically acceptable salts or solvates for use in combating diseases.

The invention further relates to pharmaceutical preparations containing at least one compound of the formula I and / or one of its physiologically acceptable salts or solvates, which are prepared in particular by a non-chemical route. The compounds of the formula I can be brought into a suitable dosage form together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and, if appropriate, in combination with one or more further active compounds.

These preparations can be used as medicinal products in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral or topical application and do not react with the new compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petroleum jelly. Tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops are used for oral use, suppositories for rectal use, solutions, preferably oily or aqueous solutions, furthermore suspensions, emulsions or implants for topical use for parenteral use Ointments, creams or powder. The new compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injectables. The specified preparations can be sterilized and / or contain auxiliaries such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, coloring, taste and / or several other active ingredients, for example one or more vitamins.

For the application as an inhalation spray, sprays can be used which contain the active ingredient either dissolved or suspended in a propellant gas or propellant gas mixture (for example CO ₂ or chlorofluorocarbons). The active ingredient is expediently used in micronized form, it being possible for one or more additional physiologically compatible solvents to be present, for example ethanol. Inhalation solutions can be administered using standard inhalers.

The compounds of formula I and their physiologically acceptable salts or solvates can be used as integrin inhibitors in the control of diseases, in particular thromboses, heart attacks, coronary heart diseases, arterial sclerosis, tumors, osteoporosis, inflammations and infections.

The compounds of formula I according to claim 1 and / or their physiologically acceptable salts are also used in pathological processes which are maintained or propagated by angiogenesis, in particular in tumors, restenoses, diabetic retinopathy or rheumatoid arthritis.

The substances according to the invention are generally administered in analogy to the compounds described in WO 95/32710, preferably in doses between about 0.05 and 500 mg, in particular between 0.5 and 100 mg per dosage unit. The daily dosage is preferably between about 0.01 and 2 mg / kg body weight. However, the specific dose for each patient depends on a variety of factors, such as the effectiveness of the special connection used, on age, body weight, general health, gender, on the diet, on the time and route of administration, on the

Elimination rate, drug combination and severity of the disease to which the therapy applies. Parenteral administration is preferred.

Furthermore, the compounds of the formula I can be used as integrin ligands for the preparation of columns for affinity chromatography for the purification of integrins. The ligand, i.e. a compound of formula I is activated via an anchor function, e.g. the carboxy group, covalently coupled to a polymeric support.

Suitable polymeric carrier materials are the polymeric solid phases known per se in peptide chemistry with preferably hydrophilic properties, for example cross-linked poly sugars such as cellulose, Sepharose or Sephadex ^R , acrylamides, polyethylene glycol-based polymer or tentacle polymers ^R.

The materials for affinity chromatography for integrin purification are produced under conditions which are customary and known per se for the condensation of amino acids.

The compounds of the formula I contain one or more chiral centers and can therefore be present in racemic or in optically active form. Racemates obtained can be separated mechanically or chemically into the enantiomers by methods known per se. Diastereomers are preferably formed from the racemic mixture by reaction with an optically active release agent. Suitable release agents are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, Mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ß-camphorsulfonic acid. Enantiomer separation using a column filled with an optically active separating agent (for example dinitrobenzoyl-phenylglycine) is also advantageous; a mixture of hexane / isopropanol / acetonitrile, for example in a volume ratio of 82: 15: 3, is suitable as the mobile phase.

Of course, it is also possible to obtain optically active compounds of the formula I by the methods described above by using starting materials which are already optically active.

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

RT = retention time (in minutes) with HPLC in the following systems: Column: Lichrosorb RP Select B 250 x 4 mm ² .

Gradients of acetonitrile (B) with 0.08% TFA (trifluoroacetic acid) and water (A) with 0.1% TFA are used as eluents. The gradient is given in percent by volume of acetonitrile. Preferred gradient: linear, t = 0 min, A: B = 80:20, t = 15 min, A: B = 0: 100 (t = time).

Gradient (steep): linear t = 0, A: B = 80:20, t = 5-15min A: B = 0: 100 detection at 2δ4 nm. The compounds purified by preparative HPLC are isolated as trifluoroacetates.

Mass spectrometry (MS) using FAB (Fast Atom Bombardment): MS- FAB (M + H) ⁺ , El (M ⁺ ) or ESI (M + H) ⁺ .

Example 1 :

(1) 4.2 g of diisopropylcarbodiimide (DIC) and 14.1 g are added to a solution of 11.4 g of 3- (4-bromophenyl) -3-tert-butoxycarbonylamino-propionic acid in 100 ml of N, N-dimethylformamide Polystyrene A OH (Rapp, Art. No. HA 1 400 00) is added to the solid phase and 100 mg of dimethylaminopyridine (DMAP) is added. The reaction mixture is stirred at room temperature for 12 hours and then filtered off. The resin is washed three times with 1 δ0 ml DMF, dichloromethane and diethyl ether and dried. The resin-bound compound "AB" is obtained, where Pol is the solid phase polystyrene A OH, without the functional OH group.

(2) 2δ0 mg of tetrakis (triphenylphosphine) palladium (0) and 1.7 g of 4-chlorophenylboronic acid are added to a suspension of δ g of the compound "AB" in 40 g of ethylene glycol dimethyl ether under an inert gas atmosphere. The mixture is heated to boiling temperature for 12 h. After the reaction mixture has cooled, 100 ml of a 2δ% ammonium acetate solution are added and the resin is filtered off. The resin is then washed with 20 ml of the following solvents or acids: twice with dimethoxyethane (DME), once with Water, once with 0.2 N hydrochloric acid, twice with DME, twice with dichloromethane and twice with methanol. Resin-bound 3-tert-butoxycarbonylamino-3- (4'-chlorobiphenyl-4-yl) propionic acid "BC" is obtained,

(3) To a solution of 3 g of methyl 3-hydroxybenzoate, 3 g of 2- (3-hydroxypropylamino) pyridine-N-oxide and δ, 8 g of triphenylphosphine in 100 ml of dimethylformamide are added 3 ml of diethyl azodicarboxylate under inert gas conditions. The solution is stirred at room temperature for 60 hours. The solvent is then distilled off and worked up as usual. 3- [3- (1-Oxopyridin-2-ylamino) propoxy] benzoic acid methyl ester is obtained. HPLC: RT: 3.16 min (column Purospher Star RP-18e, 55mm x 4mm; gradient: linear t = 0, A: B = 80:20, t = 6 min, A: B = 0: 100. MS (ESI) : (M + H) ⁺ : 331.

(4) To a solution of 1.7 g of 3- [3- (1-hydroxy-pyridin-3-ylamino) propoxyj-benzoic acid methyl ester in 50 ml of chloroform are added 2 g of phosphorus trichloride and the solution is heated under reflux for 3 hours. After the usual work-up, methyl 3- [3- (pyridin-2-ylamino) propoxy] benzoate is obtained. HPLC: RT = 9.63 min (steep gradient) MS (EI): M ⁺ : 314.

(5) To a solution of 0.8 g of 3- [3- (pyridin-2-ylamino) propoxy] methyl benzoate in 20 ml of 1,4-dioxane, 6 ml of 1 N KOH added and stirred for 12 h at room temperature. The solution is then acidified with hydrochloric acid and worked up as usual. 3- [3- (Pyridin-2-ylamino) propoxy] benzoic acid is obtained; Rf: 0.62 (eluent: ethyl acetate (100%) (TLC plates: silica gel 60 (MerckKGaA)). MS (ESI): (M + H) ⁺ : 287.

(6) 2 ml of trifluoroacetic acid are added to a suspension of 250 mg of the solid phase "BC" in 2 ml of dichloromethane and the mixture is stirred for 30 minutes to split off the amino protecting group. The resin is filtered, washed with dichloromethane and then mixed with 10 ml of dimethylformamide (DMF). 0.4 g of DIC, 1 g of 3- [3- (pyridin-2-ylamino) propoxy] benzoic acid and a 20 mg of DMAP are added to this suspension and the mixture is stirred for 4-5 h. The resin is filtered off and washed with DMF, dichloromethane and methanol. Resin-bound 3- (4'-chlorobiphenyl-4-yl) -3- {3- [3- (pyridin-2-ylamino) propoxy] benzoylamino} propionic acid "CD" is obtained;

For cleavage, the resin "CD" is mixed with 0.5 ml of 4N NaOH, 1 ml of methanol and 4 ml of dioxane. The cleavage solution is neutralized and worked up as usual. 3- (4'-Chlorobiphenyl-4-yl) -3- {3- [3- (pyridin-2-ylamino) propoxy] benzoylamino} propionic acid is obtained. Preparative HPLC gives 3- (4'-chloro-biphenyl-4-yl) -3- {3- [3- (pyhdin-2-ylamino) propoxy] benzoylamino} propionic acid trifluoroacetate, RT 10.8 min, FAB -MS (M + H) ⁺ 531.

Example 2:

Analog to Example 1, the resin is "AB" with

2-fluorophenylboronic acid and then reacted with 3- [3- (pyridin-2-ylamino) propoxyj-benzoic acid. 3- (2'-Fluoro-biphenyl-4-yl) -3- is obtained.

{3- [3- (pyridin-2-ylamino) propoxy] -benzoylamino} -propionic acid.

Preparative HPLC gives 3- (2'-fluoro-biphenyl-4-yl) -3- {3- [3-

(pyhdin-2-ylamino) propoxy] benzoylamino} propionic acid trifluoroacetate, RT

10.2 min, FAB-MS (M + H) ⁺ 514.

Analog to Example 1, the resin is "AB" with

3-chlorophenylboronic acid and then reacted with 3- [3- (pyridin-2-ylamino) propoxyj-benzoic acid. 3- (3'-Chlorobiphenyl-4-yl) -3- is obtained.

{3- [3- (pyridin-2-ylamino) propoxy] -benzoylamino} -propionic acid.

Preparative HPLC gives 3- (3'-chlorobiphenyl-4-yl) -3- {3- [3-

(pyridin-2-ylamino) propoxy] benzoylamino} propionic acid trifluoroacetate, RT

10.75 min, FAB-MS (M + H) ⁺ 531.

Analog to Example 1, the resin is "AB" with

3-fluorophenylboronic acid and then reacted with 3- [3- (pyridin-2-ylamino) propoxyj-benzoic acid. 3- (3'-Fluoro-biphenyl-4-yl) -3- is obtained.

{3- [3- (pyridin-2-ylamino) propoxy] -benzoylamino} -propionic acid.

Preparative HPLC gives 3- (3'-fluoro-biphenyl-4-yl) -3- {3- [3-

(pyridin-2-ylamino) propoxy] benzoylamino} propionic acid trifluoroacetate, RT

10.27 min, FAB-MS (M + H) ⁺ 514.

Example 3:

Analog to Example 1, the resin is "AB" with 3-fluoro-phenylboronic acid and then with 4- [3- (pyridin-2-ylamino) propoxyj-benzoic acid [prepared analogously to Example 1 by reacting methyl 4-hydroxybenzoate with 2- (3-hydroxypropylamino) pyridine-N- oxide and reaction with phosphorus trichloride and KOH] implemented. 3- (3'-Fluoro-biphenyl-4-yl) -3- {4- [3- (pyridin-2-ylamino) propoxy] benzoylamino-propionic acid is obtained.

Preparative HPLC gives 3- (3'-fluoro-biphenyl-4-yl) -3- {4- [3- (pyridin-2-ylamino) propoxy] benzoylamino} propionic acid trifluoroacetate, RT 10.45 min, FAB -MS (M + H) ⁺ 514.

Analog to Example 1, the resin is "AB" with

2-fluorophenylboronic acid and then reacted with 4- [3- (pyridin-2-ylamino) propoxyj-benzoic acid. 3- (2'-F! Uor-biphenyl-4-yl) -3- is obtained.

{4- [3- (pyridin-2-ylamino) propoxy] -benzoylamino} -propionic acid.

Preparative HPLC gives 3- (2'-fluoro-biphenyl-4-yl) -3- {4- [3-

(pyridin-2-ylamino) propoxy] benzoylamino} propionic acid trifluoroacetate, RT

9.95 min, FAB-MS (M + H) ⁺ 514.

Example 4:

The resin "DE" (prepared by reaction of 3- (3-bromo-phenyl) -3-tert-butoxycarbonylamino-propionic acid with the solid phase polystyrene A OH (Rapp, Art. No. HA 1 400 00 )]

with 3-fluoro-phenylboronic acid and then with 4- [3- (pyridin-2-ylamino) propoxy] benzoic acid. 3- (3'-Fluoro-biphenyl-

3-yl) -3- {4- [3- (pyridin-2-ylamino) propoxy] -benzoylamino} -propionic acid. Preparative HPLC gives 3- (3'-fluoro-biphenyl-3-yl) -3- {4- [3- (pyridin-2-ylamino) propoxy] benzoylamino} propionic acid trifluoroacetate.

Analogous to example 1, the resin "DE" is added

2-fluorophenylboronic acid and then reacted with 4- [3- (pyridin-2-ylamino) propoxyj-benzoic acid. 3- (2'-Fluoro-biphenyl-3-yl) -3- {4- [3- (pyridin-2-ylamino) propoxy] benzoylamino} propionic acid is obtained. Preparative HPLC gives 3- (2'-fluoro-biphenyl-3-yl) -3- {4- [3- (pyridin-2-ylamino) propoxy] benzoylamino} propionic acid trifluoroacetate.

Example 5:

Analog to Example 1, the resin is "AB" with

4-ethoxyphenylboronic acid and then reacted with 3- [3- (pyridin-2-ylamino) propoxyj-benzoic acid. 3- (4'-Ethoxy-biphenyl-4-yl) -3- is obtained.

{3- [3- (pyridin-2-ylamino) propoxy] -benzoylamino} -propionic acid.

Preparative HPLC gives 3- (4'-ethoxy-biphenyl-4-yl) -3- {3- [3-

(pyridin-2-ylamino) propoxy] benzoylamino} propionic acid trifluoroacetate.

Analog to Example 1, the resin is "AB" with

3-cyano-phenylboronic acid and then reacted with 3- [3- (pyridin-2-ylamino) propoxyj-benzoic acid. 3- (3'-Cyano-biphenyl-4-yl) -3- is obtained.

{3- [3- (pyridin-2-ylamino) propoxy] -benzoylamino} -propionic acid.

Preparative HPLC gives 3- (3'-cyano-biphenyl-4-yl) -3- {3- [3-

(pyridin-2-ylamino) propoxy] benzoylamino} propionic acid trifluoroacetate.

Example 6:

(1) 4.2 g of diisopropylcarbodiimide (DIC) and 14.1 g are added to a solution of 11.4 g of 3- (4-bromophenyl) -3-tert-butoxycarbonylamino-propionic acid in 100 ml of N, N-dimethylformamide Polystyrene A OH (Rapp, Art. No. HA 1 400 00) is added to the solid phase and 100 mg of dimethylaminopyridine (DMAP) is added. The reaction mixture is stirred at room temperature for 12 hours and then filtered off. The resin will washed three times with 150 ml of DMF, dichloromethane and diethyl ether and dried. The resin-bound compound "AB" is obtained, where Pol is the solid phase polystyrene A OH, without the functional OH group.

(2) 260 mg of tetrakis (triphenylphosphine) palladium (0) and 1.7 g of 4-chlorophenylboronic acid are added to a suspension of 5 g of the compound "AB" in 40 g of ethylene glycol dimethyl ether under an inert gas atmosphere. The mixture is heated to boiling temperature for 12 h. After the reaction mixture has cooled, 100 ml of a 2δ% ammonium acetate solution are added and the resin is filtered off. The resin is then washed with 20 ml of the following solvents or acids: twice with dimethoxyethane (DME), once with water, once with 0.2 N hydrochloric acid, twice with DME, twice with dichloromethane and twice with methanol. Resin-bound 3-tert-butoxycarbonylamino-3- (4'-chlorobiphenyl-4-yl) propionic acid "BC" is obtained.

(3) To a solution of 18 g of methyl 4-hydroxybenzoate in 300 ml of dimethylformamide, 52 ml of 1,2-dibromoethane and 83 g of potassium carbonate are added under inert gas conditions. The solution is stirred under reflux for 16 h. The solution is then filtered, the solvent is distilled off and worked up as usual. 4- (2-Bromo-ethoxy) -benzoic acid methyl ester is obtained; RT = 12.91 min, MS (EI): (M + H) ⁺ : 258, 260

(4) 11 g of 2,2,2-trifluoro-N-pyridin-2-yl-acetamide and 8 g of potassium carbonate are added to a solution of 15.5 g of methyl 4- (2-bromo-ethoxy) benzoate in 300 ml of acetonitrile added and the solution heated under reflux for 16 h. The solution is filtered and worked up as usual. 4- {2- [2- (2,2,2-Trifluoro-acetylimino) -2H-pyridin-1-yl] ethoxy} benzoic acid methyl ester is obtained.

(5) To a solution of 2 g of 4- {2- [2- (2,2,2-trifluoro-acetylimino) -2H-pyridin-1-yl] ethoxy} benzoic acid methyl ester in 30 ml of ethylene glycol monoethyl ether, add 3 ml of NaOH (32%) was added and the mixture was stirred at room temperature for 12 h. The solvent is then distilled off and the residue is dissolved in water and washed with ethyl acetate. The aqueous phase is acidified to pH 4 with hydrochloric acid. The product is filtered off and 4- [2- (2-imino-2H- pyridin-1-yl) -ethoxy] -benzoic acid; RT: 0.46 min (column Chromolith Speed Rod, RP-18e, δOmm x 4.6mm; gradient: linear t = 0, A: B = 80:20, t = 3.5-4 min, A: B = 0: 100. MS (ESI): (M + H) ⁺ : 259.

(6) 2 ml of trifluoroacetic acid are added to a suspension of 250 mg of the solid phase "BC" in 2 ml of dichloromethane and the mixture is stirred for 30 minutes to split off the amino protecting group. The resin is filtered, washed with dichloromethane and then mixed with 10 ml of dimethylformamide (DMF). 0.4 g of DIC, 1 g of 4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoic acid and 20 mg of DMAP are added to this suspension and the mixture is stirred for 4-5 h. The resin is filtered off and washed with DMF, dichloromethane and methanol. Resin-bound 3- (4'-chlorobiphenyl-4-yl) -3- {4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid is obtained

EF ";

The resin "EF" is mixed with 0.5 ml of 4N NaOH, 1 ml of methanol and 4 ml of dioxane. The cleavage solution is neutralized and worked up as usual. 3- (4'-Chlorobiphenyl-4-yl) -3- {4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid is obtained. Preparative HPLC gives 3- (4'-chloro-biphenyl-4-yl) -3- {4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid trifluoroacetate , RT 8.8 min, FAB-MS (M + H) ⁺ 516.

Example 7:

Analogous to Example 6, the resin becomes "AB"

3-fluoro-phenylboronic acid and then reacted with 4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoic acid. 3- (3'-Fluoro-biphenyl-4-yl) -3- is obtained.

{4- [2- (2-imino-2H-pyridin-1-yl) -ethoxy] -benzoylamino} -propionic acid.

Preparative HPLC gives 3- (3'-fluoro-biphenyl-4-yl) -3- {4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid trifluoroacetate .

RT 8.3 min, FAB-MS (M + H) ⁺ 500.

Analogous to Example 6, the resin becomes "AB"

2-fluorophenylboronic acid and then reacted with 4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoic acid. 3- (2'-Fluoro-biphenyl-4-yl) -3- is obtained.

{4- [2- (2-imino-2H-pyridin-1-yl) -ethoxy] -benzoylamino} -propionic acid.

Preparative HPLC gives 3- (2'-fluoro-biphenyl-4-yl) -3- {4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid trifluoroacetate .

RT 8.2 min, FAB-MS (M + H) ⁺ 600.

Analogous to Example 6, the resin becomes "AB"

3-chlorophenylboronic acid and then with 4- [2- (2-imino-2H-pyridine-

1-yl) ethoxy] benzoic acid implemented. 3- (3'-Chlorobiphenyl-4-yl) -

3- {4- [2- (2-imino-2H-pyridin-1-yl) -ethoxy] -benzoylamino} -propionic acid.

Preparative HPLC gives 3- (3'-chlorobiphenyl-4-yl) -3- {4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid trifluoroacetate .

RT 8.9 min, FAB-MS (M + H) ⁺ 516.

Analogous to Example 6, the resin becomes "AB" 4-methyl-phenylboronic acid and then reacted with 4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoic acid. 3- (4'-Methyl-biphenyl-4-yl) -3- {4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid is obtained. Preparative HPLC gives 3- (4'-methyl-biphenyl-4-yl) -3- {4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid trifluoroacetate , RT 8.9 min, FAB-MS (M + H) ⁺ 496.

Analogous to Example 6, the resin becomes "AB"

4-trifluoromethyl-phenylboronic acid and then reacted with 4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoic acid. You get 3- (4'-

Trifluoromethyl-biphenyl-4-yl) -3- {4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid.

Preparative HPLC gives 3- (4'-trifluoromethyl-biphenyl-4-yl) -3- {4-

[2- (2-imino-2H-pyridin-1-yl) -ethoxy] -benzoylamino} -propionic acid

Trifluoroacetate, RT 9.2 min, FAB-MS (M + H) ⁺ 5δ0.

Example 8:

Analogous to Example 6, the resin becomes "AB"

3-fluoro-phenylboronic acid and then with 3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoic acid [prepared by reacting methyl 3-hydroxybenzoate with 1, 2-dibromoethane and reacting with 2,2,2-trifluoro-N-pyridin-2-yl-acetamide and NaOH]. 3- (3'-Fluorobiphenyl-4-yl) -3- {3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid is obtained.

Preparative HPLC gives 3- (3'-fluoro-biphenyl-4-yl) -3- {3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid trifluoroacetate .

RT 8.7 min, FAB-MS (M + H) ⁺ 600.

Analogous to Example 6, the resin becomes "AB"

2-fluorophenylboronic acid and then reacted with 3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoic acid. 3- (2'-Fluoro-biphenyl-4-yl) -3- is obtained.

{3- [2- (2-imino-2H-pyridin-1-yl) -ethoxy] -benzoylamino} -propionic acid. Preparative HPLC gives 3- (2'-fluoro-biphenyl-4-yl) -3- {3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid trifluoroacetate , RT 8.9 min, FAB-MS (M + H) ⁺ δOO.

Analogous to Example 6, the resin becomes "AB"

4-chlorophenylboronic acid and then with 3- [2- (2-imino-2H-pyridine-

1-yl) ethoxy] benzoic acid [prepared by reacting methyl 3-hydroxybenzoate with 1, 2-dibromoethane and reacting with 2,2,2-trifluoro-N-pyridin-2-yl-acetamide and NaOH]. 3- (4'-Chlorobiphenyl-4-yl) -3- {3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid is obtained.

Preparative HPLC gives 3- (4'-chlorobiphenyl-4-yl) -3- {3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid trifluoroacetate .

RT 9.04 min, FAB-MS (M + H) ⁺ 518.

Analogous to Example 6, the resin becomes "AB"

3-chlorophenylboronic acid and then with 3- [2- (2-imino-2H-pyridine-

1-yl) ethoxy] benzoic acid [prepared by reacting methyl 3-hydroxybenzoate with 1, 2-dibromoethane and reacting with 2,2,2-trifluoro-N-pyridin-2-yl-acetamide and NaOH]. 3- (3'-Chlorobiphenyl-4-yl) -3- {3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid is obtained.

Preparative HPLC gives 3- (3'-chloro-biphenyl-4-yl) -3- {3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid trifluoroacetate .

RT 8.96 min, FAB-MS (M + H) ⁺ 518.

Analogous to Example 6, the resin becomes "AB"

4-methyl-phenylboronic acid and then with 3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoic acid [prepared by reacting methyl 3-hydroxybenzoate with 1, 2-dibromoethane and reacting with 2,2,2-trifluoro-N-pyridin-2-yl-acetamide and NaOH]. 3- (4'-Methyl- biphenyl-4-yl) -3- {3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid.

Preparative HPLC gives 3- (4'-methyl-biphenyl-4-yl) -3- {3- [2- (2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid trifluoroacetate .

RT 8.8 min, FAB-MS (M + H) ⁺ 496.

Analogous to Example 6, the resin becomes "AB"

4-trifluoromethyl-phenylboronic acid and then reacted with 3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoic acid. You get 3- (4'-

Trifluoromethyl-biphenyl-4-yl) -3- {3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino-propionic acid.

Preparative HPLC gives 3- (4'-trifluoromethyl-biphenyl-4-yl) -3- {3-

[2- (2-imino-2H-pyridin-1-yl) -ethoxy] -benzoylamino} -propionic acid

Trifluoroacetate, RT 9.25 min, FAB-MS (M + H) ⁺ 5δ0.

Analogous to Example 6, the resin becomes "AB"

4-fluorophenylboronic acid and then reacted with 3- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoic acid. 3- (4'-Fluoro-biphenyl-4-yl) -3- is obtained.

{3- [2- (2-imino-2H-pyridin-1-yl) -ethoxy] -benzoylamino} -propionic acid.

Preparative HPLC gives 3- (4'-fluoro-biphenyl-4-yl) -3- {3- [2- (2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid trifluoroacetate .

RT 8.4δ min, FAB-MS (M + H) ⁺ δOO.

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 δ g of disodium hydrogenphosphate is adjusted to pH 6, δ in 3 l of double-distilled water with 2 N hydrochloric acid, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Each injection jar contains δ mg of active ingredient. Example B: Suppositories

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

Example C: solution

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

Example D: ointment

Mix δOO mg of an active ingredient of formula I with 99, δ g of petroleum jelly under aseptic conditions.

Example E: tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed into tablets in a conventional manner such that each tablet contains 10 mg of active ingredient.

Example F: coated tablets

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

Example G: capsules

2 kg of active ingredient of the formula I are filled into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient. Example H: ampoules

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

Example 1: Inhalation spray

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

Claims

claims

1. Compounds of formula I.

wherein

Y NHR ⁷ , -NR ⁷ -C (= NR ⁷ ) -NHR ⁷ , -C (= NR ⁷ ) -NHR ⁷ , -NR ⁷ -C (= NR ⁸ ) -

NHR ⁷ , -C (= NR ⁸ ) -NHR ⁷ , Het ¹ -NH or Het ¹ , R ¹ OR or N (R) ₂ ,

R H, A, cycloalkyl, Ar, arylalkyl or Pol,

CN, CO-R, SO ₃ R, SO ₂ R, NH-C (O) A or SR,

R ° H or A, R ⁶ shark or NO ₂ , R ⁷ H, -C (0) R ⁹ , -C (O) -Ar, R ⁹ , COOR ⁹ , COO- (CH ₂ ) ₀ -Ar, SO ₂ -Ar,

SO ₂ R ⁹ or SO ₂ -Het,

CN or NO ₂ ,

Alkyl with 1 to 10 carbon atoms or cycloalkyl with 3 to 15 carbon atoms

atoms,

A alkyl having 1 to 8 carbon atoms, where the alkyl groups can be substituted one or more times by R ⁶ and / or their

Alkyl carbon chain can be interrupted by -O-,

Ar unsubstituted or one, two or three times substituted

Aryl, cycloalkyl cycloalkyl with 3 to 15 carbon atoms, shark F, Cl, Br or I, Het a saturated, partially or completely unsaturated mono- or bicyclic heterocyclic radical with 5 to 10 ring members, where 1 or 2 N and / or 1 or 2 S or O atoms may be present and the heterocyclic radical may be mono- or disubstituted by R ⁸ can be substituted,

Het ^{1 with} a mono- or bicyclic aromatic heterocycle

Pol a solid phase without a terminal functional group, m 1, 2, 3 or 4,

0 1, 2, 3 or 4 and p 1, 2, 3, 4 or δ, and their physiologically acceptable salts and solvates.

2. Compounds according to claim 1 a) 3- (2'-fluoro-biphenyl-4-yl) -3- {3- [3- (pyridin-2-ylamino) propoxy] - benzoylamino} propionic acid, b) 3 - (3'-Fluoro-biphenyl-4-yl) -3- {4- [3- (pyridin-2-ylamino) propoxy] - benzoylaminoj-propionic acid, c) 3- (4'-chloro-biphenyl-4 -yl) -3- {4- [2- (2-imino-2H-pyridin-1-yl) ethoxy] benzoylamino} propionic acid and its physiologically acceptable salts and solvates.

3. A process for the preparation of the compounds of formula I according to claim

1 and their salts and solvates, characterized in that (a) a compound of formula II wherein R, R ¹ , R ² , R ³ , o and p have the meanings given in claim 1, but R ≠ H and in which free hydroxyl or amino groups are present as substituents R ² or R ³ protected by protective groups, with a compound of formula III

in which R, Y and m have the meanings given in claim 1 and, if appropriate, convert the radical R ≠ H into the radical R = H and split off the protective groups on R ² and / or R ³ , or

(b) a compound of formula IV

wherein R, R ¹ , R ² , R ³ , R ⁴ , o and p are those specified in claim 1

Have meanings, but R ≠ H, in which Q is Cl, Br or a reactive esterified OH group and in which free hydroxyl or amino groups are present as substituents R ² or R ³ protected by protective groups, with a compound of the formula V.

HO— (CH ₂ ) _m - YV

R ² , R ³ and / or R ^{4 are converted} into one or more radicals R, R ¹ , R ² , R ³ and / or R ⁴ , for example by vii) alkylating a hydroxy group, viii) hydrolyzing an ester group to a carboxy group, ix) esterifying a carboxy group, x) alkylating an amino group, xi) reacting an aryl bromide or iodide by Suzuki coupling with boronic acids to give the corresponding coupling products, or xii) acylating an amino group, and / or a basic or acidic compound of the formula I converted to one of its salts or solvates by treatment with an acid or base.

4. Compounds of formula I according to claim 1 and their physiologically acceptable salts or solvates as active pharmaceutical ingredients.

δ. Compounds of formula I according to claim 1 and their physiologically acceptable salts or solvates as integrin inhibitors.

6. Reactive intermediates of formula III

wherein

Y Het ¹ ,

Het ¹ 2-imino-pyridin-1-yl,

R ⁴ H, A, shark, NO ₂ , OR, N (R) ₂ , CN, CO-R, S0 ₃ R, SO ₂ R, NH-C (O) A or SR and m 1, 2, 3 or 4, and their salts and solvates.

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

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

9. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts or solvates for the manufacture of a medicament for combating thromboses, heart attack, coronary artery disease, arteriosclerosis, inflammation, tumors, osteoporosis, infections, rheumatoid arthritis, diabetic retinopathy and restenosis after angioplasty.

10. Use of compounds of formula I according to claim 1 and / or their physiologically acceptable salts or solvates in pathological processes which are maintained or propagated by angiogenesis.