WO2003014088A1

WO2003014088A1 - Biphenyl thioamides serving as integrin receptor antagonists

Info

Publication number: WO2003014088A1
Application number: PCT/EP2002/007797
Authority: WO
Inventors: Wolfgang Stähle; Alfred Jonczyk; Oliver Schadt; Simon Goodman
Original assignee: Merck Patent Gmbh
Priority date: 2001-08-08
Filing date: 2002-07-12
Publication date: 2003-02-20
Also published as: DE10139059A1

Abstract

The invention relates to novel biphenyl derivatives of general formula (I), wherein A, B, X, Y, Z, R?1, R1', R1', R2, R2', R2'¿ and n have the meanings as cited in Patent Claim No. 1. The stereoisomers and physiologically safe salts or solvates of these compounds are novel antagonists of integrin receptors, particularly of the α¿v?β3, αvβ5, and/or αvβ6 integrin receptors. The novel compounds can be used as medicaments.

Description

BIPHENYLTHIOAMIDES AS INTEGRINE RECEPTOR TAGONISTS

The invention relates to new compounds of formula I.

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 OR or NRR can be RH, A ', C ₃ -C ₄ cycloalkyl, C ₆ -C ₀ aryl, C ₇ -Cu aralkyl, which can be substituted one or more times with R ³ and their

Alkyl carbon chain can be interrupted by O,

1"

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

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

R ^ύ F, Cl, Br, J, N0 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 are unsubstituted or one or more times by A ',

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

X and Y are O and / or S, where if X = O is Y = S and if

X = S is Y = O or S can be Z - (CH ₂ ) - or O n 1, 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 compounds being active as integrin receptor antagonists. 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, the compounds of WO 96/22966 A1 selectively inhibit the α ₄ integrin receptor and the compounds of WO 97/08145 A1 selectively inhibit the _v ₃ integrin receptor.

The compounds of WO 00/48996 A2 primarily inhibit α _v β ₃ and α β β integrin receptors.

The invention was based on the task of finding new compounds with valuable properties, in particular those which

Manufacture of drugs can be used.

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 work here as antagonists of integrin receptors, especially the α _v ß3, oc _v ß5 and / or the α _v ß ₆ integrin receptors. They also have very favorable distribution coefficients in octanol 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. The absorption of active ingredients requires that they dissolve in aqueous media as well as the corresponding ones

Penetrate membranes. For the latter, a certain lipophilicity of the active ingredient is 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, the following for example in detail

Reviews can be found: 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 penetration cell migration. Cox EA;

Huttenlocher-A, Microsc-Res-Tech. 1998 Dec 1; 43 (5): 412-9, The ro / e of integrins in the malignant phenotype ofgliomas. Uhm JH; Gladson-CL; Rao-JS, front biosci. 1999 Feb 15; 4: D188-99, 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 in this, 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 ofalpha v-integrins during angiogenesis; Eliceiri-BP and Cheresh-DA Molecular

Medicine 4: 741-750 (1998).

Among these integrins there are also α _v ß _θ epithelial integrins. Sheppard-D bioessays. 1996 Aug; 18 (8): 655-60 and the two integrins α _v ß ₃ and α _v ßs, 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).

ctvß _δ 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 ßδ 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 plays. Thus α _v ß _{6 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 z. B. psoriasis, can be influenced by agonists or antagonists of said integrin. Furthermore, α _v esse 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 successfully used could become. Ultimately, it is known that _v ßβ also plays a role in the intestinal epithelium, so that appropriate integrin agonists could find / antagonists in the treatment of inflammation, tumors and wounds of the stomach / intestinal tract using. Microorganisms and viruses also have integrin receptors, in particular _v β _δ receptors. For example, _v ßs receptors are adenovirus or α _v ßs / _v ßs receptors for HIV. The integrin antagonists / agoists could therefore also be used to treat infections, in particular viral infections.

The effect of a compound on an α _v ß 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 act as inhibitors of the α _v β ₃ or α _v β ₅ integrin receptors and as inhibitors of glycoprotein IIb / IIla. 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 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 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, _v ß ₃ antagonists or antibodies against α _v ß _{3 were} described which cause tumors to shrink by inducing apoptosis.

The experimental evidence that the invention

Compounds preventing the attachment of living cells to the corresponding matrix proteins and accordingly also preventing the attachment of tumor cells 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- 2838th

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. One example is the inhibibility of the binding of MMP-2- (matrix metallo-proteinase-2) to the vitronectin

To find receptor α _v β ₃ by a cyclo-RGD peptide, as described 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) block, as antagonists prevent the 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 ßs 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 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 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, B, X, Y, Z, R ¹ , R ^{1 '} , R ^{1 "} , 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 B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^{2" have} the meanings given in formula I and X = O and in the case that B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^{2" have} free hydroxyl and / or amino groups which are protected by a protective group, either

(i) to a compound of the general formula IV

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

and the compound IV obtained either

(aa) with a compound of formula V

in which A and n have the meanings given in formula I and Y = O and Z = - (CH ₂ ) - and in the case that A contains free amino groups, these are each protected by protective groups, converts to a compound of formula II,

wherein A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" and n have the meanings given in formula I and X = S, Y = O and Z = - (CH ₂ ) - and optionally cleaves off the protective groups present on A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^2" ,

or

(bb) with thiophosgene to a compound of formula VI

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

reacted, and the compound obtained with a compound of

Formula VII AX ² VII

in which A and n have the meanings given in formula I and Z = O and in which, if A contains free amino groups, these are each protected by protective groups,

converts to a compound of formula II,

wherein A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" and n have the meanings given in formula I and X = S, Y = S and Z = O and optionally splits off the protective groups present on A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ² ,

or

(ii) reacted with thiophosgene to give a compound of the formula VI, in which B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^{2" are} those given in formula I.

Have meanings and differing from the meanings given above for the formula IV, X = O and in which in the event that B, R ¹ , R, R ^{1 "} , R ² , R ^{2 '} and / or R ^{2" are} free hydroxyl and / or have amino groups which are protected by a protective group,

and the compound obtained with a compound of the formula VII, in which A, n and Z have the meanings given above for formula VII and in the case where A is free

Contains amino groups, each by protective groups are protected, converted to a compound of formula II,

wherein A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" and n have the meanings given in formula I and X = O, Y = S and Z =

Is O and optionally cleaves off the protective groups present on A, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^{2 '} ,

or

(b) a compound of formula VIII

in which B, R, R, R, R, R, R ^{2 "have} the meanings given in formula I and in the case where B, 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 IX

in which A and n have the meanings given in formula I, X = O, Y = S and Z = - (CH ₂ ) -, in which, if A contains free amino groups, these are each protected by protective groups,

to a compound of the above general formula II, wherein R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" , A, B and n have the meanings given there and X = O, Y = S and Z = - (CH ₂ ) - is reacted and optionally cleaves off the protective groups present on A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^2" ,

or

(c) a compound of the formula II in which A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" and n have the meanings given in formula I, X and Y are each O and Z = - (CH ₂ ) -, and in the case that A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^{2 are} free hydroxyl and / or have amino groups which are protected by a protective group, converted to a compound of the formula II in which A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" and n are those in the formula I have the meanings indicated, X = S, Y = S and Z = - (CH ₂ ) -, and optionally those on A, B, R ¹ , R, R ^{1 "} , R ² , R ^{2 '} and / or R. ^{2 "} contained protective groups, or

(d) in a compound of the formula II in which R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" , A, B, X, Y, Z and n have the meanings given there, one or more of the radicals B, R ¹ , R, R ^{1 "} , R ² , R ^{2 '} and / or R ^2" into one or more radicals B, R ¹ , R ^1' , R ^{1 '} , R ² , R ^{2 '} and / or R ^{2 "} 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 II 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, such as A \ R, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" , R ^{3 can be the} same or different, ie are independent of each other.

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, furthermore 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, 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 -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, pinane,

Bornan or camphor, including any known stereoisomeric form, or adamantyl. For campers, this means both L-campers and D-campers.

C ₇ -Cu-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 -Cιo-aryl is preferably unsubstituted or poly-substituted

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 ', S0 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-triazol-1-, -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 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 1 H-imidazo [ 4,5-b] pyridin-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-pyrrolyI, 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-isochinoIyl or 1, 2,3,4-tetrahydro-1, 8-naphthyridin-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

Pyridin-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 ', S0 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, BOG, 2-iodoethoxycarbonyl, CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl.

B is preferably OR with R = H, A 'or C -C -aralkyl. B is particularly preferably H, methoxy, ethoxy or benzyloxy, of which in particular H.

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

NH-, Het ¹ , Het ¹ -NH-, where 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 completely hydrogenated heterocyclic ring system with 1 or 2 N-

Is 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 , HetλNH-, where the primary amino groups can also be provided with conventional amino protecting groups, and in which 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 OR or NRR RH, A \ C ₆ -Ci ₄ -cycloalkyl, C ₇ -C ₁₄ -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 of one another H, F, Cl, Br, J, NO ₂ ,

NH ₂ , NHA ', NA' ₂ , OA ', CO-A', SO ₃ A ', S0 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 having 1 to 6 carbon atoms 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 OR or NRR

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

NHA ', NA' ₂ , OA ',

HetλNH-

I

/ NH -NH ^ ^ N ^ NH '% r

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

le) A Het ¹ -NH- with

B OR or NRR, 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, n 2, 3 or 4, If) A Het ¹ -NH- with

B OR or NRR

R H or A '

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

R ² , R ^{2 '} , R ^{2 "} independently of one another H, F, Cl, Br, J, NO ₂ , NHA', NA ' ₂ , OA', CO-A ', A A" alkyl with 1 to 6 C. Atoms, n 2, 3 or 4,

Ig) A Het ¹ -NH- with

B OR or NRR

R H or A '

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 'alkyl with 1 to 4 carbon atoms,

X p

YO n 2, 3 or 4, means.

The compounds of the general formula I mentioned below are particularly preferred

3-biphenyl-4-yl-3- {2- [2- (pyridin-2ylamino) ethoxycarbonylamino] - ethanthioylaminoj-propionic acid and

3- (3'-Chloro-4'-flourobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] ethanthhioylamino} propionic acid.

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 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 above-mentioned unsubstituted or substituted aryl, aralkyl,

Aroyl or acyl groups, also also alkyl groups, alkyl, aryl or aralkyl silyl groups or 0, 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,

Cyelopentylidene, cyclohexylidene, benzylidene, p-methoxybenzylidene or o, p-dimethoxybenzylidene acetal, acyclic acetals such as tetrahydropyranyl (Thp), methoxymethyl (MOM), methoxyethoxymethyl (MEM), benzyloxymethyl (BOM) or methylthiomethyl. Particularly preferred hydroxyl 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 (e.g. 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). 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 gently analyzed using precious metal catalysis

Split chloroform at 20-30 ° C. A preferred catalyst is tetrakis (triphenyl-phosphine) palladium (0). Acid amides are converted into the corresponding thioamides by methods known per se, for example by reaction with Lawesson reagent, with P4S10 (Link, A .; Zaharevitz, DW; Kunick, C; Pharmazie 1999, 54 (3), 163-166) , with Heimgartner's reagent

(Heimgartner, H., Helv. Chim. Acta, 1987, 70, 1001) or with H ₂ S (Charette, AB; Chua, P .; Tetrahedron Lett 1998, 39 (3), 245-248). The reaction is preferably carried out with 2,4-bis (4-methoxyphenyl) -2,4-dithioxo-1, 2,3,4-dithiaphospethane (Lawesson reagent) in a suitable solvent, such as, for example, toulol.

Some of the starting compounds of the formula III, V and VII are known. The same applies to compounds of the formula II which are used as starting materials in accordance with (c). These can be produced, for example, as described in WO 0048996 A2. Are the

Reconnect them, but they can be made according to methods known per se.

The thioamides of the formulas IV and IX can be prepared from the corresponding acid amides as described above. In case of

Thioamide compounds of the formula IV are used here compounds of the formula III.

Compounds of the formula II, such as those prepared in reaction path (b), are obtained by peptide-analogous coupling of the compounds of

Formula VIII and IX obtained.

Compounds of the formula VI are used inter alia. obtained by reacting compounds of the formula IV with thiophosgene under suitable reaction conditions, as described, for example, by Garcia

Fernandez, JM et al. in J. Org. Chem. 1994, 59 (19) 5565-5572. Usual methods of peptide synthesis are described, for example, 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, e.g. a carbodiimide such as dicyclohexylcarbodiimide (DCC), N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC) or diisopropylcarbodiimide (DIC), further e.g. Propanephosphonic anhydride (see Angew. Chem. 1980, 92, 129), diphenylphosphorylazide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, e.g. 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 ^, -tetramethyl-uronium-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 V and / or IX, too

Derivatives of compounds of formula V and / or IX, preferably a preactivated carboxylic acid, or a carboxylic acid halide, a symmetrical or mixed anhydride or an active ester can be used. Such residues for activating the carboxy group in typical aeylation reactions are in the literature (e.g. in the standard works such as

Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart). Activated esters are expediently formed in situ, eg 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.

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, 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 isolation and / or

Purification of the compounds of formula I can be used. On the other hand, compounds of formula I with bases (e.g. 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 compounds of the formula I can also be synthesized on a solid phase, the binding to the solid phase being effected via OH of the carboxyl group. When synthesized on a solid phase, the carboxyl group is substituted with OPol, where Pol means 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

A summary of solid phase syntheses and the solid phases and / or linkers that can be used for this 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 are solid phases with a hydroxyl group as terminal functionality, for example the Wang resin or polystyrene A OH. 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 according to claim 1, their stereoisomers and their physiologically acceptable

Salts or solvates for the therapy and prophylaxis of 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 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.

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 production of a medicament.

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, Vaseline. 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 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 fluorocarbon hydrocarbons). 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 inflammation, ophthalmological diseases, diabetic retinopathy, macular degeneration, myopia, corneal transplantation, ocular histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, morbidity

Atherosclerosis, psoriasis, restenosis, especially after angioplasty, multiple sclerosis, pregnancy, abscentptio placentaris, viral infection, bacterial infection, fungal infection, foot and mouth disease, acute kidney failure and wound healing to support the healing process. The use for is particularly preferred

Treatment of tumor diseases, osteolytic diseases, especially osteoporosis and for the treatment of restenosis after angioplasty.

The substances according to the invention are preferably in

Dosages between about 0.05 and 500 mg, in particular between 0.5 and 100 mg administered 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, sex, on the diet, on the time and route of administration, on the rate of elimination, combination of drugs and severity the respective disease to which the therapy applies. The parenteral

Application 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. The racemic mixture is preferably reacted formed with an optically active release agent diastereomers. Suitable release agents are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyl tartaric acid, dibenzoyl tartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphor sulfonic acids such as β-camphor sulfonic 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, evaporated and purified by chromatography

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 volume percent acetonitrile.

The HPLC analyzes (retention time RT) were carried out in the following systems: Column LiChrosorb RP Select B, 250 x 4 mm ² from Merck with a linear gradient t = 0 min, A: B = 80:20, t = 15 min A: B = 0: 100, at 2.2 ml / min flow and detection at 220 nm.

The compounds purified by preparative HPLC are called

Trifluoroacetate isolated.

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

Chromolith SpeedROD column, 50 x 4.6 mm ² from Merck with a linear gradient t = 0 min, A: B = 80:20, t = 3 to t = 3.5 min, A: B = 0: 100.

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.

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 3- (3'-chloro-4'-flourobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] ethanthhioylamino} propionic acid

a 0.20 g of 3- (3'-chloro-4'-fluorobiphenyl-4-yl) -3- [2- (9 / - -flourene-9-ylmethoxycarbonylamino) acetylamino-propionic acid bound to resin via oxygen "A", 0.600 g of 2,4-bis (4-methoxyphenyl) -2,4-dithioxo-1,2,3,4-dithiaphosphethane in 10 ml of toluene are stirred at 60 ° C. for 6 hours. The solvent is removed and the product washed with toluene, dimethylformamide (DMF), dichloromethane and methanol. 0.21 g of "B" is obtained.

b 0.20 g "B" is incubated with 5 ml piperidine / DMF for 30 min, the product is separated and washed with DMF. Then 0.16 mg

5- (pyridin-2-ylamino) pentanoic acid, 0.26 g O- (benzotriazol-l-yl) - N, N, N \ N'-tetramethyl uronium tetrafluoroborate (TBTU), 0.28 ml N, N, - Diisopropyl-N-ethyl-amine (DIPEA) added and stirred overnight. The product is washed and purified by preparative HPLC. 18.0 mg of 3- (3'-chloro-4'-flourobiphenyl-4-yl) are obtained -

3- {2- [5- (pyridin-2-ylamino) pentanoylamino] ethanthioylamino} - propionic acid, trifloroacetate, RT 1.058 min, logD _{(7 | 4)} + 0.820, FAB-MS (M + H) ⁺ 500.15.

Example 2:

Preparation of 3-biphenyl-4-yl-3- {2- [2- (pyridin-2ylamino) ethoxycarbonylaminoj-ethanthioylaminoj-propionic acid

0.100 g resin-bound 3-biphenyl-4-yl-3- {2- [2- (pyridin-2ylamino) ethoxycarbonylaminoj-ethanoylaminoj-propionic acid and 0.300 g 2,4-bis (4-methoxyphenyl) -2,4-dithioxo- 1, 2,3,4-dithiaphosphethane in 10.0 ml of toluene are first stirred at 60 ° C for 10 hours, then at 90 ° C for 8 hours. The solvent is removed and the product is worked up as usual and purified by preparative HPLC. 3-Biphenyl-4-yl-3- {2- [2- (pyridin-2ylamino) ethoxycarbonylamino] ethanthioylamino] - propionic acid, trifloroacetate, RT 1, 434 min, logD ₍₇ , ₄₎ -0.250, FAB are obtained -MS (M + H) ⁺ 479.

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, filled into injection glasses, 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 0 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 the formula I, 4 kg of laetose, 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 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. One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Claims

claims

1. The invention relates to new compounds of the formula

wherein

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 protective groups,

Alkyl carbon chain can be interrupted by O,

R ¹ , R ^{1 '} , R ^{1 "} independently of one another H, F, Cl, Br, J, N0 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, N0 ₂₎ NH ₂ , NHR,

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

R ^ό 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 substituted one or more times by A ', NHA', NA ' ₂ and / or NH ₂ ,

A 'alkyl having 1 to 8 carbon atoms X and Y are O and / or S, where if X = O is Y = S and if X = S is Y = O or S.

Z - (CH ₂ ) - or O n 1, 2, 3 or 4

means their stereoisomers and their physiologically acceptable salts and solvates.

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

3-biphenyl-4-yl-3- {2- [2- (pyridin-2ylamino) ethoxycarbonylamino] ethanthioylaminoj-propionic acid or

3- (3'-Chloro-4'-flourobiphenyl-4-yl) -3- {2- [5- (pyridin-2-ylamino) pentanoylamino] ethanthioylamino} propionic acid

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

(a) a compound of formula III

in which B, R ¹ , R ¹ ', R ¹ ", R ² , R ² , R ^{2" have} the meanings given in formula I and X = O and in the case that B, R ¹ , R ^1' , R ^{1 "} , R ² , R ² 'and / or R ² " free hydroxyl and / or Have amino groups, these are protected by a protecting group, either

(i) to a compound of the general formula IV

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

and the compound IV obtained either

(aa) with a compound of formula V

in which A and n have the meanings given in formula I and Y = O and Z = - (CH ₂ ) - and in the event that A contains free amino groups, these are each protected by protective groups,

converts to a compound of formula II,

wherein A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" and n have the meanings given in the formula and X = S, Y = O and Z = - (CH ₂ ) - and optionally cleaves off the protective groups present on A, B, R ¹ , R, R ^{1 "} , R ² , R ^{2 '} and / or R ^2" ,

or

(bb) with thiophosgene to a compound of formula VI

in which B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^{2" have} the meanings given in formula I and X = S and in which in the event that B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^{2 have} free hydroxyl and / or amino groups which are protected by a protective group, and the compound obtained with a compound of formula VII

^A f VII

converts to a compound of formula II,

wherein A, B, R ¹ , R ^' , R ^{1 "} , R ² , R ^2' , R ^2" and n have the meanings given in formula I and X = S, Y = S and Z = O and optionally the splits off protective groups contained on A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^2" ,

or

(ii) reacted with thiophosgene to give a compound of the formula VI in which B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^{2" have} the meanings given in formula I and differ from those for the meanings of the formula IV are X = O and in the case that B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^{2" are} free

Have hydroxyl and / or amino groups, these are protected by a protective group,

and the compound obtained with a compound of formula VII wherein A, n and Z are those given for formula VII Have meanings and in which, if A contains free amino groups, these are each protected by protective groups, are converted into a compound of the formula II,

or

(b) a compound of formula VIII

in which B, R> 1, r R.1 ', R πl ", R, R - _> 2', π R2" have the meanings given in formula I and in the case that B, R ¹ , R ^{1 '} "R ^1" , R ² , R ² and / or R ^{2 "have} free hydroxyl and / or amino groups which are protected by a protective group,

with a compound of formula IX

wherein A and n have the meanings given in formula I, X = O, Y = S and Z = - (CH ₂ ) -, in which, if A contains free amino groups, these are each protected by protective groups, to one Compound of the above general formula II, wherein R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" , A, B and n have the meanings given there and X = O, Y = S and Z = - (CH ₂ ) - is reacted and optionally cleaves off the protective groups present on A, B, R ¹ , R ^{1 '} , R ¹ ", R ² , R ^2' and / or R ^2" ,

or

(c) a compound of the formula II in which A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" and n have the meanings given in formula I, X and Y are each O are and Z = - (CH ₂ ) -, and in the case that A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^{2" are} free hydroxyl and / or have amino groups, these are protected by a protective group, converted to a compound of the formula II in which A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ^2" and n the in Formula I have the meanings given, X = S, Y = S and Z = - (CH ₂ ) -, and optionally those on A, B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^{2 "} contains protective groups, or

(d) in a compound of the formula II in which R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' , R ² , A, B, X, Y, Z and n have the meanings given there or more of the radicals B, R ¹ , R ^{1 '} , R ^{1 "} , R ² , R ^2' and / or R ^2" into one or more radicals B, R ¹ , R ^{1 '} , 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

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

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

Integrinrezeptorenantagonisten

6. Compounds of formula I according to claim 1 or 2, their stereoisomers and their physiologically acceptable salts or solvates for the therapy and prophylaxis of diseases

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

8. 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

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 for the prophylaxis and / or therapy of circulatory diseases, pulmonary fibrosis, pulmonary embolism, thrombosis, in particular deep , angiogenic vein thrombosis, myocardial infarction, arteriosclerosis, dissecting aneurysm, 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

Diseases such as Inflammation, ophthalmic diseases, diabetic retinopathy, macular degeneration, myopia, comea transplantation, ocular histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis, especially after angioplasty, especially after angioplasty

Multiple sclerosis, abscentptio placentaris, viral infection, bacterial infection, fungal infection, acute kidney failure and for wound healing