EP1392654A1 - Integrin antagonists - Google Patents

Abstract

The invention relates to novel biphenyl derivatives of general formula (I) wherein A, X, R?1, R1', R1'', R2, R2', R2''¿ and n have the designations cited in patent claim 1. The stereoisomers and the physiologically acceptable salts or solvates of said derivatives are new inhibitors of integrin receptors, especially α¿v?β3, αvβ5 and/or αvβ6 integrin receptors. Said novel compounds can be used as pharmaceuticals.

Description

 integrin

The invention relates to new compounds of formula I.

wherein

A is NH ₂ , - (HN =) C-NH ₂ , -NH-C (= NH) -NH ₂ , A'-C (= NH) -NH-, Het ¹ - or Het ¹ -NH-, where the primary amino groups can also be provided with conventional amino protective groups,

B tetrazolyl or an alkylsulfonylaminocarbonyl group RH, A ', C ₃ -C ₄ -cycloalkyl, Cβ-Cio-aryl, C ₇ -C ₄ aralkyl, which can be substituted one or more times with R ³ and their

Alkyl carbon chain can be interrupted by O,

R ¹ , R ^r , R ^{1 "} independently of one another H, F, Cl, Br, J, NO ₂ , NH ₂ , NHR,

NRR, OH, OR, CO-R, SO ₃ R, SO ₂ R, SR,

R, R 2 ', _n R2 "independently of one another H, F, Cl, Br, J, NO ₂ , NH ₂ , NHR,

NRR, OH, OR, CO-R, SO ₃ R, SO ₂ R, SR,

R ^J F, Cl, Br, J, NO ₂ , CF ₃ , OH, CN, OCF ₃ , SCF ₃ , methoxy,

ethoxy,

Het ^{1 is} a mono- or dinuclear heterocycle with 1 to 4 N-

Atoms that are unsubstituted or single or double by A ',

NHA ', NA' ₂ and / or NH ₂ can be substituted, A 'alkyl with 1 to 8 carbon atoms

X nothing, O, NH or CH ₂ n 2, 3 or 4

means their stereoisomers and their physiologically acceptable salts and solvates.

Compounds with a partially similar structure are disclosed in WO96 / 22966 A1, WO 97/08145 A1 and WO 00/48996 A2, all of which

Compounds are effective as integrin receptor inhibitors. 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 different α and β subunits. According to the

Disclosure of the patent applications mentioned inhibit the compounds of WO 96/22966 A1 selectively the α ₄ β-integrin receptor and the compounds of WO 97/08145 A1 selectively inhibit the α _v β ₃ integrin receptor. The compounds of WO 00/48996 A2 primarily inhibit α _v β ₃ and α _v β _δ integrin receptors.

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, their stereoisomers and their salts have very valuable pharmacological properties with good tolerability. The compounds are particularly notable for their very high activity. They act as antagonists of integrin receptors, in particular the α _v β ₃ , α _v β and / or the α _v β ₆ integrin receptors. They also have octanol / water very favorable distribution coefficients in octctanol / water (logD values).

If an active ingredient is added to a mixture of octanol / water, it is distributed between the two phases at a given pH value according to its lipophilicity / hydrophilicity. The ratio of the distribution of the active substance between the octanol and water phase is called the distribution coefficient. Absorption of active ingredients requires that they both dissolve in aqueous media and penetrate the corresponding membranes. For the latter, there is a certain lipophilicity of the

Active ingredient required. The lipophilicity required results from the lipophilicity of the respective membrane. Absorption in the intestine requires a logD value> -1, 50 and passage through the blood-brain barrier requires a logD value> 0.5. (Lipinski C.A: Adv. Drug Del. Rev. 23 (1997), 3-25). A favorable logD value is an essential prerequisite for the absorption of an active ingredient.

The integrins have different physiological and pathological functions, which can be found in detail, for example, in the following review articles: Integrins and Signal transduction. Dedhar-S, Curr-Opin-Hematol. 1999 Jan; 6 (1): 37-43, Integrins take partners: cross-talk between integrins and other membrane receptors. Porter JC; Hogg-N, Trends Cell Biol. 1998 Oct; 8 (10): 390-6, Regulation of integrin-mediated adhesion during cell migration. Cox EA; Huttenlocher-A, Microsc-Res-Tech. 1998 Dec 1; 43 (5): 412-9, The role of integrins in the malignant phenotype ofgliomas. Uhm JH; Gladson-CL; Rao-JS, front biosci. 1999 Feb 15; 4: D 188-99, or Sperm disintegrins, egg integrins, and other cell adhesion molecules of mammalian gamete plasma membrane interactions. Evans-JP Front Biosci. 1999 Jan 15; 4: D114-31. The α _v integrins play an important role, such as in The role ofalpha v integrins in tumor progression and metastasis; Marshall JF; Hard IR Semin Cancer Biol. 1996 Jun; 7 (3): 129-38 or The role of alpha v-integrins during angiogenesis; Eliceiri-BP and Cheresh-DA Molecular Medicine 4: 741-750 (1998).

Among these integrins there are also α _v ß ₆ epithelial integrins. Sheppard-D bioessays. 1996 Aug; 18 (8): 655-60 and the two integrins α _v ß ₃ and αvßs, which represent known adhesion receptors, the biological meaning of which, for example, in JA Varner et al. Cell Adhesion and

Communication 3, 367-374 (1995) and in J. Samanen et al. Curr. Pharmaceutical Design, 3, 545-584 (1997).

ocvßβ is a relatively rare integrin (Busk et al., 1992 J. Biol. Chem. 267 (9), 5790), which is increasingly formed in repair processes in epithelial tissue and preferentially binds the natural matrix molecules fibronectin and tenascin (Wang et al., 1996, Am. J. Respir. Cell Mol. Biol. 15 (5), 664). The physiological and pathological functions of α _v ßβ are not yet exactly known, but it is suspected that this integrin is associated with physiological processes and diseases (e.g. inflammation,

Wound healing, tumors), in which epithelial cells are involved, plays an important role. Thus, α _v ßβ 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, _{v δ δ} plays a role in the respiratory epithelium (Weinacker et al., 1995, Am. J. Respir. Cell Mol. Biol. 12 (5), 547), so that corresponding agonists / antagonists of this integrin in respiratory diseases, such as bronchitis, Asthma, pulmonary fibrosis and respiratory tumors could be used successfully. Ultimately, it is known that α _v β _δ also in the intestinal epithelium Role plays, so that appropriate lnteghn agonists / antagonists could be used in the treatment of inflammation, tumors and wounds of the gastrointestinal tract. Microorganisms and viruses also have integrin receptors, in particular α _v β ₆ receptors. For example, α _v ß ₅ receptors are receptors for

Adenoviruses or α _v ß ₅ / _v ßs -receptors for HIV. The lnteghn antagonists / agoists could therefore also be used to treat infections, in particular viral infections.

The effect of a compound on an α _v β ₆ integrin 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.

In addition to the preferred inhibition of α _v β ₆ integrin receptors, the

Compounds also as inhibitors of the α _v ß ₃ or αvßs integrin receptors and as inhibitors of the glycoprotein llb / llla. The α _v ß ₃ integrin, for example, 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 effect of the compounds according to the invention on the various integrin receptors 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 PC Brooks, RA Clark and DA 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 is described by PC Brooks, AM Montgomery, M. Rosenfeld, RA Reisfeld, T. Hu, G. Klier and DA Cheresh in Cell 1994, 79, 1157-1164. For example, oc _v ß ₃ antagonists or

Antibodies against _v ß ₃ described that cause tumor shrinkage by inducing apoptosis.

The experimental proof that the compounds according to the invention also adhere living cells to the corresponding ones

Preventing matrix proteins and accordingly also preventing tumor cells from attaching to matrix proteins can be performed in a cell adhesion test, analogously to the method by 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 inhibition of the binding of MMP-2- (matrix-metallo-proteinase-2) to the vitronectin receptor α _v ß ₃ by a cyclo-RGD peptide, as in PC Brooks et al., Cell 1996, 85, 683-693.

Compounds of formula I which interact the integrin receptors and ligands, e.g. of fibrinogen to the fibrinogen receptor (glycoprotein llb / llla), prevent as antagonists

Spread of tumor cells through metastasis 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, eg α _v ß ₃ or αn _b ß ₃ , on activated platelets, the corresponding antagonists can be regarded as effective metastasis inhibitors.

The effect of a compound on an α _v β ₅ integrin 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 is described.

The compounds can be administered to humans or animals locally or systemically, orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, transdermally, nasally, buccally or iontophoretically.

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

If the active pharmaceutical ingredient is added intravenously to the organism in the form of a solution for injection, its absolute bioavailability lies, 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, especially 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. As described above, a measure of its resorbability can be a

Active ingredient whose logD value are used.

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-

Shapes) are included in the formula.

So-called prodrug dehvates 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 rapidly split into the active compounds according to the invention in the organism.

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 II

according to formula I, their salts and solvates and a process for the preparation of compounds of formula II and their salts and solvates, wherein A, X, R ¹ , R ¹ , R ¹ , R ² , R ² , R ² and n the in Formula I have the meanings given, characterized in that

(a) a compound of the formula

in which R ¹ , R ¹ , R ¹ , R ² , R ² , R ^{2 have} the meanings given in formula I and in the case where R ¹ , R ¹ , R ^{1 "} , R ² , R ² and / or R ^{2 has} free hydroxyl and / or amino groups which are protected by a protective group, with a compound of formula IV

in which A and n have the meanings given in formula I and X is nothing or - (CH ₂ ) - and in the case that A contains free amino groups, these are each protected by protective groups,

to a compound of general formula V

converts, wherein A, R ¹ , R ¹ , R ¹ , R ² , R ² , R ² , n, those specified in formula I.

Have meanings and X is - (CH ₂ ) -, and the compound of formula V obtained subsequently to one

Compound of formula II above, wherein R ¹ , R ¹ , R ^r , R ² ,

R ² , R ² , A and n have the meanings given there and X

- (CH ₂ ) - is implemented and optionally cleaves off the protective groups present on A, R, 1, R, R j 1 ", R, R and / or R,

or

(b) a compound of formula VI

in which R ¹ , R ¹ , R ^{1 "} , R ² , R ² , R ^{2 have} the meanings given in formula I and in the case where R ¹ , R ^r , R ^1" , R ² , R ² and / or R ^{2 has} free hydroxyl and / or amino groups which are protected by a protective group,

with a compound of formula VII

in which A, X and n have the meanings given in formula I and in which, if A contains free amino groups, these are each protected by protective groups, to a compound of the above general formula V, in which R ¹ , R ¹ , R ¹ , R ² , R ² , R ^{2 "} , A and n have the meanings given there and X has the meanings given in formula I, and the compound of formula V obtained subsequently to a compound of the above general formula II, wherein R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" , A, X and n have the meanings given there , and optionally cleaving off the protective groups present on A, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^2" ,

or

(c) in a compound of the formula II in which R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" , A, X and n have the meanings given there, one or more of the radicals R. ¹ , R ¹ , R ¹ , R ² , R ² and / or R ² into one or more radicals R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^2" by converting for example i) alkylated a hydroxy group or ii) alkylated an amino group

and / or converts a basic or acidic compound of the formula II into one of its salts or solvates by treatment with an acid or base. The invention further relates to the compounds of the formula VIII

according to formula I, their salts and solvates and a process for the preparation of compounds of formula VIII and their salts and solvates, wherein A, X, R, R ¹ , R ^r , R ^{1 "} , R ² , R ^{2 '} , R ^{2 "} and n have the meanings given in formula I, characterized in that

(a) a compound of formula IX

where n A, X, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" and n have the meanings given in formula I and in the case that A, R ¹ , R ¹ , R ^{1 '} , R ² , R ² and / or R ^{2 have} free hydroxyl or amino groups which are protected by a protective group,

with a compound of formula X

o. -s I: -R I -NH, X O

in which R has the meanings given in formula I, to a compound of the above-mentioned general formula VIII, in which A, X, R, R ¹ , R ¹ , R ^{1 "} , R ² , R ² , R ² and n are those given therein Have meanings, implement and optionally split off the protective groups present on A ', R ¹ , R ^1' , R ^{1 "} , R ² , R ^{2 '} and / or R ^2" ,

or

(b) one or more radicals R ¹ in a compound of the formula VIII,

R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^2" into one or more radicals R ¹ , R ^r ,

R ^{1 "} , R ² , R ^{2 '} and / or R ^{2" is} converted by, for example, i) alkylating a hydroxy group or ii) alkylating an amino group

and / or converts a basic or acidic compound of the formula VIII into one of its salts or solvates by treatment with an acid or base. It applies to the entire invention that all radicals which occur more than once, for example A ', R ¹ , R ¹ , R ^{1 "} , R ² , R ² , R ^{2, can be the} same or different, ie are independent of one another.

In the above formulas, A 'is 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, 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 ¹ are the alkyl groups mentioned, which, however, 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 -O- can be interrupted, preferably -CH ₂ -O-CH ₃ , -CH ₂ -O-CH ₂ -CH ₃ or -CH ₂ -CH ₂ -O-CH ₃ . Methyl or ethyl is particularly preferred for A '.

C ₃ -C ₄ cycloalkyl has 3 to 14 C atoms and preferably means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, particularly preferably cyclohexyl. 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.

C -C-Aralkyl is preferably benzyl, phenethyl, naphth-1-yl-methyl, naphth-2-yl-methyl, naphth-1-yl-ethyl, naphth-2-yl-ethyl, particularly preferred are benzyl and phenethyl. C ₆ -C ₁ -aryl is preferably unsubstituted or polysubstituted phenyl or naphthyl, in particular unsubstituted, mono-, di- or triple by A \ OH, OA ', NH ₂ , NHA', NA ' ₂ , NO ₂ , CF ₃ , CN, F, Cl, Br, J, CO-A ', SO ₃ A', SO ₂ A ', SA' substituted phenyl or naphthyl.

Het ¹ is an unsubstituted or substituted mono- or dinuclear aromatic heterocyclic ring system with 1, 2, 3 or 4, preferably 1 or 2 N atoms. Het ¹ is preferably unsubstituted or 1-, mono- or disubstituted by A ', NHA' NA ' ₂ and / or NH ₂ ,

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

3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably 1, 2,3-triazol-1-, -4- or -5-yl, 1, 2,4-triazoM- , -3- or 5-yl, 1- or 5-tetrazolyl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 3-, 4-, 5-,

6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or δ-cinnolinyl , 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 1 H-imidazo [4,5-b] pyhdin-2-yl or 1, 8-naphthyridin-7-yl. The heterocyclic radicals can also be partially or completely hydrogenated.

Het ¹ can, for. B. also mean 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, 4,5-dihydro-imidazol-2-yl, 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, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, - 2-, -4- or -5-pyrimidinyl, 1-, 2- or 3- piperazinyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- , -6-, -7- or -8-quinolyl, 1, 2,3,4-tetrahydro-1 -, - 2 -, - 3-, -4-, -5-, -6-, -7- or -8-isoquinolyl or 1, 2,3,4-tetrahydro-1, 8-naphthyhdin-7-yl.

Hydrogenated or partially hydrogenated Het ¹ radicals can additionally be substituted by = NH or carbonyl oxygen. Het ¹ is preferably present in A as Het ¹ -NH. It is particularly preferred

Pyhdin-2-ylamino is very particularly preferred.

R ¹ , R ^{1 '} , R ^{1 "} and R ² , R ^2' , R ^2" are preferably H, F, Cl, Br, I, NO ₂ , NH ₂ , NHA ', NA' ₂ , OA ', CO -A ', SO ₃ A', SO ₂ A ', SA'.

Amino protecting group preferably means formyl, acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.

B is preferably tetrazol-5-yl or alkylsulfonylaminocarbonyl, in which the alkyl group has the meanings given for A '. Methanesulfonylaminocarbonyl is particularly preferred.

n is preferably 2, 3 or 4, very particularly preferably n is 2 or 3.

"Multiple" substituted means one, two, three or four times substituted. 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.

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 Ig), which the

Formula I correspond and in which the radicals not specified have the meaning given for the formula I, but in

in la) A - (HN =) C-NH ₂ , -NH-C (= NH) -NH ₂ , A'-C (= NH) - NH-, Het ¹ , Het ¹ -NH-, with the primary

Amino groups can also be provided with conventional amino protecting groups, and in which Het ^{1 is} a mono- or dinuclear unsubstituted or mono- or disubstituted by A ', NHA', NH ₂ , and / or NA ' ₂ aromatic or partially or fully hydrogenated heterocyclic ring system Is 1 or 2 N atoms, in which, if a hydrogenated or partially hydrogenated heterocyclic ring system is present, this can additionally be substituted by = NH or carbonyl oxygen,

Ib) A - (HN =) C-NH ₂ , -NH-C (= NH) -NH ₂ , Het ¹ -NH-, the primary amino groups also having conventional amino protecting groups can be provided, and wherein Het ¹ -NH-

are,

Ic) A NH ₂ , - (HN =) C-NH ₂ , -NH-C (= NH) -NH ₂ , A'-

C (= NH) -NH-, Het ¹ - or Het ¹ -NH-, where the primary amino groups can also be provided with conventional amino protecting groups, B tetrazol-5-yl or one

Alkylsulfonylaminocarbonylgruppe RH, A ', C ₆ -C -cycloalkyl, C ₇ -d ₄ -aralkyl, which can be mono- or disubstituted with R ³ and whose alkyl carbon chain can be interrupted by O, R ¹ , R ¹ , R ¹ independently from each other H, F, Cl, Br, J, NO ₂ , NH ₂ , NHA ', NA' ₂ , OA ', CO-A', SO ₃ A ', SO ₂ A',

SA ', R ² , R ² , R ² independently of one another H, F, Cl, Br, J, NO ₂ ,

NH ₂ , NHA ', NA' ₂₎ OA ', CO-A', SO ₃ A ', SO ₂ A', SA ', R ³ F, Cl, Br, J, NO ₂ , CF ₃ , OH, CN , OCF ₃ , SCF ₃ ,

Methoxy, ethoxy, Het ¹ -NH-

A 'alkyl with 1 to 6 carbon atoms X nothing, O, NH or CH ₂ n 2, 3 or 4

Id) A - (HN =) C-NH ₂ , -NH-C (= NH) -NH ₂ , or Het ¹ - NH-, where the primary amino groups can also be provided with conventional amino protecting groups,

B tetrazol-5-yl or one

Alkylsulfonylaminocarbonyl group, wherein alkyl has 1, 2, 3, 4, 5 or 6 carbon atoms

R H, A ', cyclohexyl, benzyl, phenylethyl,

R ¹ , R ^{1 '} , R ^{1 "} independently of one another H, F, Cl, Br, J, NO ₂ , NHA', NA ' _2l OA',

R ² , R ² , R ² independently of one another H, F, Cl, Br, J, NO ₂ , NHA ', NA' ₂ , OA ',

Het ¹ -NH-

A alkyl with 1, 2, 3, 4, 5, 6 carbon atoms

X nothing, NH or CH ₂ n 2, 3 or 4

le) A Het ¹ -NH- with

H

KL _N 'H / ^N ^ ^NH _/ N ^ _/ NH _/ N ^^ NH

W //

B tetrazolyl or one

Alkylsulfonylaminocarbonyl group, R H, A ', cyclohexyl, benzyl, phenylethyl,

R ¹ , R ¹ , R ¹ independently of one another H, F, Cl, Br, J, NO ₂ ,

NR ₂ , OR, CO-R, R ² , R ^{2 '} , R ^{2 "} independently of one another H, F, Cl, Br, J, NO ₂ ,

NR ₂ , OR, CO-R, A "alkyl having 1 to 8 carbon atoms,

X nothing, O, NH or CH ₂ n 2, 3 or 4,

If) A Het ¹ -NH- with

N '

B tetrazol-5-yl or an alkylsulfonylaminocarbonyl group, wherein alkyl

1, 2, 3, 4, 5 or 6 carbon atoms R ¹ , R ¹ , R ¹ independently of one another H, F, Cl, Br, J, NO ₂ ,

NHA ', NA' ₂ , OA ', CO-A', R ² , R ² , R ² independently of one another H, F, Cl, Br, J, NO ₂ ,

NHA ', NA' ₂ , OA ', CO-A', A 'alkyl with 1 to 6 C atoms,

X nothing, O, NH or CH ₂ n 2, 3 or 4,

Ig) A Het ¹ -NH- with

B tetrazol-5-yl or one

Alkylsulfonylaminocarbonylgruppe, wherein alkyl has 1, 2, 3 or 4 carbon atoms

R ¹ , R \ R ^{1 "} independently of one another H, F, Cl, Br, J, NO ₂ ,

NHA ', NA' ₂ , OA ',

R ² , R ^{2 '} , R ^{2 "} independently of one another H, F, Cl, Br, J, NO ₂ ,

NHA ', NA' ₂ , OA ', A A''alkyl with 1 to 4 carbon atoms,

X nothing, O, NH or CH ₂ n 2, 3 or 4,

means.

The compounds of the general formula I mentioned below are particularly preferred / V- [1-Biphenyl-4-yl-2- (1 H-tetrazol-5-yl) ethyl] -2- [5- (pyridin-2-ylamino) pentanoylaminoj-acetamide

/ V- [1-Biphenyl-4-yl-2- (1 / - / - tetrazol-5-yl) ethyl] -2- {3- [3- (pyridin-2-ylamino) propyl ]ureido } -acetamide / V - [(1-biphenyl-4-yl-2- (methanesulfonylamino-carbonyl) -ethyl] -2- [5- (pyridin-2-ylamino) pentanoylamino] acetamide

The compounds of 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 (e.g. in the

Standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart) are described, under reaction conditions that 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 each other, they can be split off selectively in many cases (see: T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Chemistry, 2nd ed.,

Wiley, New York 1991 or P.J. Kocienski, Protecting Groups, 1st ed., Georg Thieme Verlag, Stuttgart - New York, 1994).

The term "amino protecting group" is well known and refers to groups which are suitable for replacing an amino group before chemical ones

Protect (block) implementations. Typical for such groups are in particular unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl 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 in

To be understood in connection with the present method in the broadest sense. 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, also 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 hydroxyl protective groups is 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 for 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, cyclopentylidene, cyclohexylidene, benzylidene, p-methoxybenzylidene or o, p-dimethoxy-tybenzylidene acetal (acetyl) acetal (acetyl) acetyl-acetyl-acetyl-acetyl-acetanyl-acetyl-acetyl-acetyl-acetyl-acetyl-acetyl-acetyl-acetyl-acetyl-acetyl-acetyl-acetyl-acetal ), 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 e.g. preferably with TFA in dichloromethane or with about 3 to 5 N HCl in dioxane at 15-30 ° C, the Fmoc group with an about 5 to 50%

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).

Some of the starting compounds of the formula III, IV, VI, VII, IX and X are known. For example, compounds of formula IX are produced as described in WO 0048996 A2. If they are new, they can be manufactured according to methods known per se.

Compounds of the formula V are obtained by peptide-analogous coupling of the compounds of the formula III with a compound of the formula IV or by peptide-analogous coupling of the compounds of the formula VI with a compound of the formula VII under standard conditions.

The reaction of the compounds V to the compounds of the formula II can be carried out, for example, using triethylammonium chloride and an azide, in particular sodium azide, under standard conditions. A suitable method is described, for example, in The Chemistry of Heterocycles, Georg Thieme Verlag, Stuttgart 1995.

Compounds of formula VIII are obtained by condensation of compounds of formula IX with compounds of formula X, preferably in the presence of a dehydrating agent, e.g. a carbodiimide such as dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethyl-carbodiimide hydrochloride (EDC) or

Diisopropylcarbodiimide (DIC), further e.g. Propanephosphonic.

Usual methods for the production of acylsulfonamides are described, for example, in Pelletier, J.C., Hesson, D.P., Synlett, 1995, 11, 1141-1142 or Barraclough, P., Caldwell, A.G., J. Chem. Soc, Perkin

Trans 1, 1989, 181

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), furthermore, for example, propanephosphonic anhydride (cf. Angew. Chem. 1980, 92, 129), diphenylphosphorylazide 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 (O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate) or O- (benzotriazol-1 -yl) -N has proven particularly advantageous. N, N ', N'-tetramethyl uronium hexafluorophosphate have been proven, since only a slight racemization occurs in the presence of one of these compounds and no cytotoxic by-products arise.

Instead of compounds of the formulas IV and / or VII, derivatives of compounds of the formula IV and / or VII, 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 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

Use of a carboxylic acid halide in the presence of a Acid-binding agent, preferably an organic base such as triethylamine, dimethylaniline, pyridine or quinoline.

Also the addition of an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid

Alkali or alkaline earth metals, preferably potassium, sodium, calcium or cesium, can be favorable.

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 solvent such as ethanol and subsequent evaporation. In particular, acids that provide physiologically acceptable salts are suitable for this implementation. So inorganic acids can be used, e.g. Sulfuric acid, sulfurous acid, dithionic acid,

Nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as e.g. Orthophosphoric acid, sulfamic acid, also organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid,

Acetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, hexadecanoic acid, octadecanoic acid, pivalic acid, diethyl acetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, isotonic acid or nicotinic acid, nicotinic acid

Ethanesulfonic acid, benzenesulfonic acid, trimethoxybenzoic acid, adamantane carboxylic acid, p-toluenesulfonic acid, glycolic acid, embonic acid, chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline, glyoxylic acid, palmitic acid, parachlorophenoxy isobutyric acid, cyclohexane carboxylic acid, glucose-1-phosphonic acid or naphthalenesulfonic acid, monophthalic acid or naphthalenesulfonic acid, monodisulfonic acid or naphthalenesulfonic acid, monophosphonic acid or naphthalenesulfonic acid, or monophthalic acid, Salts with physiologically not Safe acids, such as picrates, can be used to isolate and / or purify the compounds of 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, their stereoisomers and their physiologically acceptable salts or solvates as active pharmaceutical ingredients.

The invention furthermore relates to compounds of the formula I according to Claim 1, their stereoisomers and their physiologically acceptable salts or solvates as integrin receptor antagonists.

The invention also relates to the compounds of the formula I as claimed in claim 1, their stereoisomers 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, its stereoisomers and / or one of its physiologically acceptable salts or solvates. For this purpose, the compounds of formula I together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more others

Active ingredients are brought into a suitable dosage form.

The invention therefore also relates to the use of compounds of the formula I, their stereoisomers and / or their physiologically acceptable salts or solvates for the preparation of a

Drug. 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 (for example 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 in particular for oral use, suppositories for rectal use and for parenteral use

Solutions, preferably oily or aqueous solutions, also suspensions, emulsions or implants, for topical application of ointments, creams or powders. The new compounds can also be lyophilized and the resulting lyophilisates e.g. can be used for the production of injectables. The specified preparations can be sterilized and / or contain auxiliary substances 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 substances, e.g. 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, their stereoisomers and / or their physiologically acceptable salts can be used as active pharmaceutical ingredients in human and veterinary medicine, in particular for Prophylaxis and / or therapy of diseases of the circulatory system, pulmonary fibrosis, pulmonary embolism, thrombosis, in particular deep vein thrombosis, heart attack, arteriosclerosis, aneurysm dissecans, transient ischemic attacks, apoplexy, angina pectoris, in particular unstable angina pectoris, tumor diseases, such as

Tumor development or tumor metastasis, osteolytic diseases such as osteoporosis, hyperparathyroidism, Paget's disease, malignant hypercalcaemia, incompatible blood transfusion, pathologically angiogenic diseases such as e.g. Inflammation, ophthalmic diseases, diabetic retinopathy, macular degeneration, myopia,

Corneal transplantation, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis, especially after angioplasty, multiple sclerosis, pregnancy, absumptio placentaris, viral infection and bacterial infection, mucosal infection, bacterial infection, pelvic infection, pelvic infection, pelvic infection, pelvic infection, pelvic infection, pelvic infection, pelvic infection, pelvic infection, pelvic infection, bacterial infection, mucosal infection, bacterial infection, mucosal infection, bacterial infection, bacterial infection, mucosal infection, bacterial infection, bacterial infection, mucosal infection, bacterial infection, bacterial infection, finding of the bacterial infection, bacterial infection, bacterial infection, bacterial infection in acute kidney failure and in wound healing to support the healing process. The use for the treatment of tumor diseases, osteolytic diseases, in particular osteoporosis, and for the treatment of restenosis after angioplasty is particularly preferred.

The substances according to the invention are preferably administered 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, for example on the effectiveness of the particular compound used, on the age, body weight, general health, gender, on the diet, on the time and route of administration, on which

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

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 e.g. 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 (e.g. dinitrobenzoyl-phenylglycine) is also advantageous; a suitable solvent is e.g. a mixture of hexane / isopropanol / acetonitrile, e.g. in the volume ratio 82: 15: 3.

Of course, it is also possible to obtain optically active compounds of the formula I by the methods described above, by

Starting materials used that 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 to pH values between 2 and 10, extracted with ethyl acetate or dichloromethane, separated, dried, the organic phase over sodium sulfate, evaporated and purified by chromatography on silica gel, by preparative HPLC and / or by crystallization. The purified compounds are optionally freeze-dried. 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.

The HPLC analyzes (retention time RT) were carried out in the following

systems:

Column 3 μm silica rod with a 210-second gradient from 20 to 100

% Water / acetonitrile / 0.01% trifluoroacetic acid, at 2.2 ml / min flow and

Detection at 220 nm.

The compounds purified by preparative HPLC are isolated as trifluoroacetates.

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

The examples illustrate, but are not limited to, the invention.

Insofar as the compounds described as examples can exist as different stereoisomers and no information is given on the stereochemistry, mixtures of the stereoisomers are present in each case.

The logD values given above and below are distribution coefficients of the compounds in question in octanol / water at a pH of 7.4 (logD _(7.4) ).

Example 1 :

Preparation of Λ / - [1 -Biphenyl-4-yl-2- (1 H-tetrazol-5-yl) ethyl] -2- {3- [3- (pyridin-2-ylamino) propyl ]ureido } -acetamide

0.751 g of 3-biphenyl-4-yl-3-te / t-butoxycarbonylamino-propionic acid and 0.310 ml of triethylamine are placed in 20 ml of tetrahydrofuran (THF), 0.209 ml of ethyl chloroformate are added dropwise and the mixture is stirred for 20 minutes. Then 0.412 ml of 25% ammonia is added, cooled to room temperature and 20 min. stirred. The reaction product, which is in crystalline form, is filtered off with suction and dried in a vacuum drying cabinet. 3-Biphenyl-4-yl-3-te / f-butoxycarbonylamino-propionic acid amide is obtained.

b 0.700 g of 3-biphenyl-4-yl-3-tert-butoxycarbonylamino-propionic acid amide and 0.582 ml of triethylamine are placed in 20 ml of THF, 0.306 ml of trifluoroacetic anhydride are added dropwise with ice-cooling and the mixture is allowed to cool to room temperature. After 1 h, 2 ml of water are added, the mixture is evaporated to dryness, and the residue obtained in

Dissolved ethyl acetate and water, the aqueous phase washed twice with ethyl acetate. The combined organic phases are washed with 0.1 N HCl and 0.1 N NaOH, dried and concentrated to the residue. This gives (1-biphenyl-4-yl-2-cyano-ethyl) - carbamic acid te / butyl ester.

c 0.350 g (1-biphenyl-4-yl-2-cyano-ethyl) -carbamic acid ferf-butyl ester is dissolved in 10 ml dichloromethane (DCM), mixed with 5 ml trifluoroacetic acid (TFA), left to stand for 30 min and the residue concentrated. 3-Amino-3-biphenyl-4-yl-propionitrile is obtained.

d 0.233 g of 3-amino-3-biphenyl-4-yl-propionitrile, 267.4 mg of {3- [3- (pyridin-2-ylamino) propyl ]ureido} acetic acid, 15 ml of N, N-dimethylformamide , 0.340 g TBTU and 0.195 ml DIPEA are stirred as a mixture at room temperature overnight and then evaporated to dryness, the residue obtained on a silica gel column (Eluent: ethyl acetate / methanol 9: 1) purified. The substance was washed from the column with methanol and separated by preparative HPLC. A / - (1-biphenyl-4-yl-2-cyanoethyl) -2- {3- [3- (pyridin-2-ylamino) propyl ]ureido} acetamide is obtained.

20.0 mg Λ / - (1-biphenyl-4-yl-2-cyano-ethyl) -2- {3- [3- (pyridin-2-ylamino) propyl ]ureido} acetamide, 5.0 ml of N, N-dimethyformamide, 0.012 g of sodium azide and 0.025 triethylammonium chloride are stirred as a mixture at 80 ° C. for 6 h, suction filtered, concentrated to the residue and purified by preparative HPLC. This gives - / - [1-biphenyl-4-yl-2- (1H-tetrazol-5-yl) ethyl] -2- {3- [3- (pyridin-2-ylamino) propyl] -ureido} - acetamide, triflouracetate (EMD 387 890), RT 1, 058 min, logD _(7.4) + 6.19, FAB-MS (M + H) ⁺ 500.15.

Example 2:

Preparation of Λ / - [1 -Biphenyl-4-yl-2- (1 H-tetrazol-5-yl) ethyl] -2- [5- (pyridin-2-ylamino) pentanoylamino] acetamide

a 0.398 g of 3-biphenyl-4-yl-3- (2-fe / -butoxycarbonylamino-acetylamino) propionic acid and 0.139 ml of triethylamine are placed in 20 ml of tetrahydrofuran (THF), 0.095 ml of ethyl chloroformate are added dropwise and the mixture is stirred for 20 minutes. Then 0.082 ml of 25% ammonia is added, the mixture is cooled to room temperature and stirred for 3 h. The reaction product, which is in crystalline form, is filtered off with suction and dried in a vacuum drying cabinet. Obtaining [(1-biphenyl-4-yl-2-carbamoyl-ethylcarbamoyl) -methyl] -carbamic acid -f-butyl ester.

b 0.360 g of [(1-biphenyl-4-yl-2-carbamoyl-ethylcarbamoyl) methyl] tert-butyl carbamate and 0.277 ml of triethylamine are placed in 20 ml of THF, 0.139 ml of trifluoroacetic anhydride are added dropwise with ice-cooling and the mixture is allowed to cool to room temperature , After 1 h, 2 ml of water are added, the mixture is evaporated to dryness, the residue obtained is dissolved in ethyl acetate and water, and the aqueous phase is washed twice with ethyl acetate. The combined organic phases are washed with 0.1 N HCl and 0.1 N NaOH, dried and concentrated to the residue. N- (1-Biphenyl-4-yl-2-cyanoethyl) -2- (tert-butoxycarbonylamino) acetamide is obtained.

c 0.190 g of N- (1-biphenyl-4-yl-2-cyano-ethyl) -2- (terf-butoxy-carbonylamino) -acetamide is mixed 1: 1 in dichloromethane (DCM) trifluoroacetic acid (TFA), 15 min stirred and concentrated to the residue.

2-Amino- / V- (1-biphenyl-4-yl-2-cyano-ethyl) -acetamide is obtained.

d 0.190 g 2-amino-Λ / - (1-biphenyl-4-yl-2-cyano-ethyl) acetamide, 0.326 ml 5- (pyridin-2-ylamino) pentanoic acid, 2.5 ml N, N- Dimethylformamide, 2.5 ml 1, 2-dichloroethane 0.100 g 4- (diethylamino) pyridine and 0.365 g N-

Cyclohexylcarbodiimide, N'-methyl polystyrene HL are called Mixture stirred at room temperature overnight, mixed with 2.0 g of a strongly acidic ion exchanger, stirred for 2 h, suction filtered and separated by preparative HPLC. This gives Λ / - (1-biphenyl-4-yl-2-cyano-ethyl) -2- [5- (pyridin-2-ylamino) pentanoylamino] acetamide.

e 0.041 g Λ / - (1-biphenyl-4-yl-2-cyano-ethyl) -2- [5- (pyridin-2-ylamino) pentanoylaminoj-acetamide, 3.0 ml N, N-dimethyformamide, 0.059 g of sodium azide and 0.124 g of triethylammonium chloride are stirred as a mixture at 80 ° C. for 6 h, suction filtered, concentrated to the residue and purified by preparative HPLC. This gives Λ / - [1-biphenyl-4-yl-2- (1H-tetrazol-5-yl) ethyl] -2- [5- (pyridin-2-ylamino) pentanoylamino] acetamide, trifloroacetate (EMD 389 889), RT 1, 296 min, logD ₍₇ , ₄₎ + 6.52, FAB-MS (M + H) ⁺ 499.

Example 3:

Λ / - [(1-Biphenyl-4-yl-2- (methanesulfonylamino-carbonyl) ethyl] -2- [5- (pyridin-2-ylamino) pentanoylamino] acetamide

0.095 g of 3-biphenyl-4-yl-3- {2- [5- (pyridin-2-ylamino) pentanoylamino] acetylaminoj-propionic acid, 0.019 g of methanesulfonic acid amide, 0.115 g of N-cyclohexylcarbodiimide, N'-methyl-polystyrene HL , 0.080 g of 4- (dimethylamino) pyridine, 2.0 ml of 1, 2-dichloroethane and 2.0 ml of tert-butanol are stirred together at 50 ° C. for 24 h. Then 1.5 g of strongly acidic ion exchanger is added, the mixture is stirred for 2 h, suction filtered and concentrated to the residue. This gives Λ / - [(1-biphenyl-4-yl-2- (methanesulfonylaminocarbonyl) ethyl] -2- [5- (pyridin-2-ylamino) pentanoylamino] acetamide, trifluoroacetate (EMD 387 803) , RT 1, 298 min, logD _(7.4) - 0.38, FAB-MS (M + H) ⁺ 552.

The following examples relate to pharmaceutical preparations:

Example A: Injection glasses

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

Example B: Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g 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 of 1 g of an active ingredient is prepared of the formula I, 9.38 g of NaH ₂ PO ₄ • 2H ₂ O, 28.48 g Na ₂ HPO ₄ • 12 H 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

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

Example E: tablets

A mixture of 1 kg of active ingredient of formula I, 4 kg of lactose, 1, 2 kg

Potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate are pressed into tablets in the usual way, 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 I: Inhalation spray

14 g of active ingredient of the formula I are dissolved in 10 I of isotonic NaCl 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. A spray

(about 0.1 ml) corresponds to a dose of about 0.14 mg.

Claims

claims

1. Compounds of the formula

wherein

NH ₂ , - (HN =) C-NH ₂ , -NH-C (= NH) -NH ₂ , A'-C (= NH) -NH-, Het ¹ - or Het ¹ -NH-, where the primary amino groups can also be provided with conventional amino protective groups,

B tetrazolyl or an alkylsulfonylaminocarbonyl group RH, A ', C ₆ -C ₄ cycloalkyl, C _ö -Cio aryl, C ₇ -C ₄ aralkyl, which can be substituted one or more times with R ³ and whose alkyl carbon chain is interrupted by O. can be,

R ¹ , R ^{1 '} , R ^{1 "} independently of one another H, F, Cl, Br, J, NO ₂ , NH ₂ , NHR, NRR, OH, OR, CO-R, SO ₃ R, SO ₂ R, SR,

R ² , R ^{2 '} , R ^{2 "} independently of one another H, F, Cl, Br, J, NO ₂ , NH ₂ , NHR, NRR, OH, OR, CO-R, SO ₃ R, SO ₂ R, SR,

R ^J F, Cl, Br, J, NO ₂ , CF ₃ , OH, CN, OCF _3> SCF ₃ , methoxy, ethoxy, Het ^{1 is} a mono- or dinuclear heterocycle with 1 to 4 N-

Atoms which can be unsubstituted or mono- or disubstituted by A ', NHA', NA ' ₂ and / or NH ₂ ,

A 'alkyl with 1 to 8 carbon atoms X nothing, O, NH or CH ₂ n 2, 3 or 4

means their stereoisomers and their physiologically acceptable salts and solvates.

2. Compounds according to claim 1, characterized in that these

Λ / - [1-biphenyl-4-yl-2- (1H-tetrazol-5-yl) ethyl] -2- [5- (pyridin-2-ylamino) pentanoylaminoj-acetamide,

Λ / - [1-Biphenyl-4-yl-2- (1H-tetrazol-5-yl) ethyl] -2- {3- [3- (pyridin-2-ylamino) propyl ]ureido} acetamide .

A / - [(1-biphenyl-4-yl-2- (methanesulfonylamino-carbonyl) -ethyl] -2- [5-

(pyridin-2-ylamino) pentanoylamino] acetamide

3. Process for the preparation of the compounds of formula II

according to claim 1, their stereoisomers and their salts and solvates, wherein A, X, R ¹ , R ¹ , R ^r , R ² , R ² , R ² and n have the meanings given in formula I, characterized in that

(a) a compound of the formula

in which R ¹ , R ¹ , R ^{1 ″} , R ² , R ² , R ^{2 have} the meanings given in formula I and in the case that R ¹ , R ¹ , R ¹ , R ² , R ² and / or R ^{2 has} free hydroxyl and / or amino groups which are protected by a protective group, with a compound of formula IV

in which A and n have the meanings given in formula I and X is nothing or - (CH ₂ ) - and in the case where A contains amino groups, these are each protected by protective groups,

to a compound of general formula V

converts, wherein A, R ', R', R ', R ^, R ^* , R, n, those specified in formula I.

Have meanings and X is - (CH ₂ ) -, and the compound of formula V obtained subsequently to a compound of formula II above, wherein R ¹ , R ¹ ,

R ^{1 "} , R ² , R ² , R ^2" , A and n have the meanings given there and X - (CH ₂ ) - is implemented and optionally cleaves off the protective groups present on A, R ¹ , R ^r , R ^{1 "} , R ² , R ^{2 '} and / or R ^2" ,

or

(b) a compound of formula VI

in which R ¹ , R ¹ , R ¹ , R ² , R ² , R ^{2 have} the meanings given in formula I and in the case where R ¹ , R ¹ , R ^{1 "} , R ² , R ² and / or R ^{2 has} free hydroxyl and / or amino groups which are protected by a protective group,

with a compound of formula VII

in which A, X and n have the meanings given in formula I and in which, if A contains free amino groups, these are each protected by protective groups, to a compound of the above general formula V, wherein R ¹ , R ¹ , R ^{1 "} , R ² , R ² , R ^2" , A and n have the meanings given there and X has the meanings given in formula I. , and the compound of formula V obtained subsequently to a compound of the general formula II above, wherein R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ² , R ^2' , A, X and n have the meanings given there , and optionally cleaving off the protective groups present on A, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^2" ,

or

(c) in a compound of the formula II in which R ¹ , R ¹ , R ^{1 "} , R ² , R ² , R ² , A, X and n have the meanings given there, one or more of the radicals R ¹ , R ¹ , R ¹ , R ² , R ² and / or R ² into one or more radicals R ¹ , R ¹ , R ^{1 "} , R ² , R ² and / or R ^2" converted, for example by

i) alkylated a hydroxy group or ii) alkylated an amino group

and / or converts a basic or acidic compound of the formula II into one of its salts or solvates by treatment with an acid or base

Process for the preparation of compounds of formula VIII

according to formula I, their salts and solvates, wherein A, A ', X, R, R ¹ , R, R ^{1 "} , R ² , R ² , R ² and n have the meanings given in formula I, characterized in that you

(a) a compound of formula IX

wherein A, X, R ¹ , R ^r , R ^{1 "} , R ² , R ^{2 '} , R ^2" and n have the meanings given in formula I and wherein in the event that A, R ¹ , R ^r , R ^{1 "} , R ² , R ^{2 '} and / or R ^2" free hydroxyl or Have amino groups, these are protected by a protective group,

with a compound of formula X

O R

~ S; X

II ^• NH, O

wherein R has the meanings given in formula I to a compound of the above general formula VIII, wherein A, X, R, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" and n the have the meanings given there, and, if appropriate, split off the protective groups present on A, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^2" ,

or

(b) one or more radicals in a compound of the formula VIII

R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^2" into one or more radicals R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^{2 "} converted by, for example, i) alkylating a hydroxy group or ii) alkylating an amino group

and / or converts a basic or acidic compound of the formula VIII into one of its salts or solvates by treatment with an acid or base

5. Compounds of formula I according to claim 1 or 2, their stereoisomers and their physiologically acceptable salts or solvates as active pharmaceutical ingredients

6. Compounds of formula I according to claim 1 or 2, their stereoisomers and their physiologically acceptable salts or solvates as integrin receptor inhibitors

7. Compounds of formula I according to claim 1 or 2, their stereoisomers and their physiologically acceptable salts or solvates for

Application in fighting diseases

8. Medicament, characterized in that it contains at least one compound of formula I according to claim 1 or 2, its stereoisomers and / or one of its physiologically acceptable salts or solvates

9. Use of compounds of formula I according to claim 1 or 2, their stereoisomers and / or their physiologically acceptable salts or solvates for the manufacture of a medicament

10. Use of compounds of formula I according to claim 1 or 2, their stereoisomers and / or their physiologically acceptable salts or solvates for the manufacture of a medicament for the prophylaxis and / or therapy of circulatory diseases, pulmonary fibrosis,

Pulmonary embolism, thrombosis, in particular deep vein thrombosis, heart attack, arteriosclerosis, aneurysm dissecans, transient ischemic attacks, apoplexy, angina pectoris, especially unstable angina pectoris, tumor diseases such as tumor development or tumor metastasis, osteolytic diseases such as

Osteoporosis, hyperparathyroidism, Paget's disease, malignant hypercalcaemia, incompatible blood transfusion, pathologically angiogenic Diseases such as inflammation, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, corneal transplantation, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, uicerative colitis, Crohn's disease, atherosclerosis, psoriasis, angioplasty, angioplasty, restenosis, angioplasty, angioplasty, angioplasty, angioplasty, restenosis, angioplasty, restenosis, angioplasty, and restenosis, angioplasty , viral infection, bacterial infection, fungal infection, acute kidney failure and for wound healing