DE19939981A1 - New inhibitors of the integrin alphavß3 - Google Patents

Abstract

The invention relates to novel compounds of formula (I) which are biologically active when present as ligands of the integrin alpha v beta 3: X-Y-Z-R<1>-CH2-R<2>(R<4>)-CH2-CO-R<5> wherein the meaning of X, Y, Z, R<1>, R<2>, R<4> and R<5> is given in Claim 1. The invention also relates to the physiologically acceptable salts and solvates of said compounds.

Description

The invention relates to novel compounds of the formula I.

XYZR ¹ -CH ₂ -R ² (R ⁴ ) -CH ₂ -CO-R ⁵ I

wherein
XH ₂ NC (= NH) -, H ₂ NC (= NH) -NH-, AC (= NH) -NH-, Het ¹ - or Het ¹ -NH-,
the primary amino groups can also be provided with conventional amino protective groups,

in which one, two, three or four methylene groups can be replaced by N, O and / or S,
Z is missing, -O-, -NH-, -NA-, -CH (OH) -, -CH (OA) -, -CHA-, -CA ₂ - or -S-,
R ^{1 is} phenylene which is unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, A, OA, OCF ₃ or CN,
R ² N, CH or CA,
R ³ H, F, Cl, Br, A, OA or OCF ₃ ,
Mono- or polysubstituted by R ⁴ F, Cl, Br, A, aryl, OA, SA, CO-A, CN, COOA, CONH _2, CONHA, CONA ₂ or NO ₂ substituted phenyl, naphthyl, or Het ^2,
R ⁵ OH, OA, NH ₂ , NHA or NA ₂ ,
Het ^{1 is} a mono- or dinuclear heterocycle with 1 to 4 N atoms, which can be unsubstituted or mono- or disubstituted by NH ₂ ,
Het ^{2 is} an aromatic mono- or dinuclear heterocycle with 1 to 3 N, O and / or S atoms, which is unsubstituted or mono- or disubstituted by F, Cl, Br, A, OA, SA, OCF ₃ , -CO -A, CN, COOA, CONH ₂ , CONHA, CONA ₂ or NO ₂ can be substituted,
Aryl unsubstituted or mono- or polysubstituted by Hal, A, OA, OH, CO-A, CN, COOA, COOH, CONH ₂ , CONHA, CONA ₂ or NO ₂ .
A alkyl with 1-12 C atoms,
n 1, 2, 3, 4, 5 or 6
m, o each independently of one another 0, 1, 2, 3, 4, 5 or 6,
mean,
with the proviso that R ⁴ ≠ is a phenyl or naphthyl radical which is simply substituted by A or aryl,
and their physiologically acceptable salts and solvates.

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

It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the α _v integrin receptors with ligands. The compounds are particularly effective in the case of integrins a _v β ₃ and α _v β ₅ . The compounds are particularly effective as adhesion receptor antagonists for the receptor α _v β ₃ .

This effect can e.g. B. can be detected by the method that by J.W. Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267- 12271 (1990).

The inhibition of vitronectin binding to the receptor α _v β ₃ has been experimentally proven for 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid.

B. Felding-Habermann and DA Cheresh describe in Curr. Opin. Cell. Biol. 5, 864 (1993) the meanings of the integrins as adhesion receptors for a wide variety of phenomena and clinical pictures, especially with regard to the receptor α _v β ₃ .

Other inhibitors of the integrin α _v β ₃ are described in EP 0820988. Vitronectin receptor antagonists are also described in WO 97/24124 and in EP 0820991.

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

The possibility of inhibiting this interaction and thus to Initiation of apoptosis (programmed cell death) angiogenic vascular Cells by a cyclic peptide is from P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T.-Hu, G. Klier and D.A. Cheresh in Cell 79, 1157-64 (1994).

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

PC Brooks et al. describe in J. Clin. Invest. 96, 1815-1822 (1995) α _v β ₃ antagonists for combating cancer and for treating tumor-induced angiogenic diseases.

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

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

The micro-aggregates can stick to the walls of the vessel, causing further penetration of tumor cells into the tissue is facilitated. Since the formation of the microthrombi by fibrinogen binding to the fibrino gene receptors mediated on activated platelets can GPIIb / IIIa antagonists regarded as effective metastasis inhibitors become.

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

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

The antiplatelet effect can be demonstrated in vitro the method of Born (Nature 4832, 927-929, 1962). The Inhibition of bone resorption by the verbin according to the invention with an osteoclast absorption test analogous to WO 95/32710 respectively.

The invention accordingly relates to compounds of the formula I. according to claim 1 and / or their physiologically acceptable salts for Manufacture of a medicament for use as integrin inhibitors. The invention relates in particular to compounds of the formula I. according to claim 1 and / or their safe salts for the preparation a drug to fight pathologically angiogenic Diseases, tumors, osteoporosis, inflammation and infections.

The compounds of formula I can be used as active pharmaceutical ingredients in the Human and veterinary medicine are used for prophylaxis and / or Therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammation exercises, apoplexy, angina pectoris, tumor diseases, osteolytic Diseases such as osteoporosis, hypercalcaemia, pathologically angiogenic Diseases such as B. inflammation, ophthalmic diseases, diabetic retinopathy, macular degeneration, myopia, ocular Histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic Glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, Restenosis after angioplasty, viral infection, bacterial infection, Fungal infection, acute kidney failure and wound healing Support the healing processes.

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

The invention also relates to the hydrates and solvates, for. B. Alcoholates, these compounds.

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

• a) a compound of formula I from one of its functional Derivatives by treatment with a solvolysing, releases reducing or hydrogenolysing agents,

or

• a) converts a radical X and / or R ⁵ into another radical X and / or R ⁵ ,

for example by

• a) an amino group by reaction with a converts amidinating agents into a guanidino group,
• b) saponifying an ester,
• c) a hydroxyamidine by hydrogenation in an amidine convicted,

and / or a base or acid of the formula I in one of its salts converts.

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

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

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

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

A is alkyl and has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms and is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.- Butyl or tert-butyl, also for 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-, 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl, undecyl or dodecyl. A also means alkyl substituted by halogen, preferably CF ₃ .

X is preferably z. B. pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydro-imidazol-2-ylamino, 2-amino-imidazole 5-ylamino, 2-amino-pyridin-6-ylamino, 2-amino-imidazol-5-yl or 2-amino-pyridin-6-yl.
Y is preferably z. B. ethylene, propylene or butylene.
Z is preferably z. BO
R ¹ is preferably z. B. 1,4-phenylene.
R ² is preferably z. B. CH or N, very particularly preferably CH.
R ⁴ is preferably z. B. phenyl substituted one or more times by F.
R ⁵ is preferably z. B. OH.

Het ¹ is preferably unsubstituted or mono- or disubstituted by A, NHA and / or NH ₂ 1-, 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, 1H-imidazo [4,5-b] pyridin-2-yl or 1,8-naphthyridin-7-yl.

The heterocyclic radicals can also be partially or completely hydrogenated his.

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-naphthyridin-7-yl.

Hydrogenated or partially hydrogenated Het ¹ radicals can additionally be substituted by = NH or carbonyl oxygen.

Het ² is preferably unsubstituted or simply substituted by F, Cl, Br, A, OA or OCF ₃ 2,3-, 2,4-2,5- or 3,4-thienyl, 2,3-, 2,4- , 2,5- or 3,4-pyrrolyl, 2,4-, 2,5- or 4,5-imidazolyl, 2,3-, 2,4-, 2,6- or 3,5-pyridyl, 2nd , 4-, 2,5-, 2,6-, 4,5- or 5,6-pyrimidinyl.

n is preferably 2, 3, 4, 5 or 6, very particularly preferably n means 3, 4 or 5.

m and o are preferably, independently of one another, 0.1 or 2, very particularly preferably they mean 0.

"Multiple" substituted means one, two, three or four times substituted. Aryl is unsubstituted, preferably - as indicated - monosubstituted phenyl, in particular preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o- , m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl , o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methylthiophenyl, o-, m- or p-methylsulfinylphenyl , o-, m- or p- methylsulfonylphenyl, o-, m- or p-aminophenyl, o-, m- or p-methyl aminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p- Nitro phenyl, o-, m- or p-acetylphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-aminocarbonylphenyl,
more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2, 6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3 methyl, 2-chloro-4-methyl, 2-chloro-5-methyl, 2-chloro-6-methyl, 2-methyl-3-chloro, 2-methyl-4-chloro, 2 -Methyl- 5-chloro, 2-methyl-6-chloro, 3-chloro-4-methyl, 3-chloro-5-methyl or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl -, 2-bromo-4-methyl, 2-bromo-5-methyl, 2-bromo-6-methyl, 2-methyl-3-bromo, 2-methyl-4-bromo, 2-methyl - 5-bromo, 2-methyl-6-bromo, 3-bromo-4-methyl, 3-bromo-5-methyl or 3-methyl-4-bromophenyl, 2,4- or 2,5- Dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-tri-tert-butylphenyl, 2,5-dimethylphenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2, 5-difluoro-4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2-methoxy-5-methylphenyl, 2,4,6-Tr iisopropylphenyl.

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.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Im, 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 a)
X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydro imidazol-2-ylamino, 2-amino-imidazol-5- ylamino, 2-amino-pyridin-6-ylamino, 2-amino-imidazol-5-yl or 2-amino-pyridin-6-yl
means;
in b)
X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydro imidazol-2-ylamino,
Y - (CH ₂ ) _n -,
n 2, 3, or 4
mean;
in c)
X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydro imidazol-2-ylamino,
Y - (CH ₂ ) _n -
n 2, 3 or 4
mean;
in d)
X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydro imidazol-2-ylamino,
Y - (CH ₂ ) _n -
n 2, 3 or 4,
ZO
mean;
in e)
X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydro imidazol-2-ylamino,
Y - (CH ₂ ) _n -
n 2, 3 or 4,
ZO,
R ² N or CH
mean;
in f)
X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazoi-2-ylamino or 4,5-dihydro imidazol-2-ylamino,
Y (CH ₂ ) _n -
n 2, 3 or 4,
ZO,
R ² N or CH,
R ^{4 is} mono- or polysubstituted by F, Cl, Br, OA, OCF ₃ , -CO-A, CN, COOA, CONH ₂ or NO ₂
mean;
in g)
X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydro imidazol-2-ylamino,
Y - (CH ₂ ) _n -
n 2, 3 or 4,
ZO,
R ² N or CH,
R ^{4 is} phenyl substituted one or more times by F, Cl, Br, OA or OCF ₃ ,
R ⁵ OA or OH
mean;
in h)
X pyrimidin-2-ytamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydroimidazol-2-ylamino,
Y - (CH ₂ ) _n -
n 2, 3 or 4,
ZO,
R ² N or CH,
R ⁴ phenyl which is substituted once or several times by F,
R ⁵ OA or OH
mean;
in i)
X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydro imidazol-2-ylamino,
Y (CH ₂ ) _n -
n 2, 3 or 4,
ZO,
R ² N or CH,
R ⁴ substituted one or more times by Hal, A or aryl, substituted phenyl,
R ⁵ OA or OH
mean
with the proviso that R ⁴ ≠ is a phenyl or naphthyl radical which is monosubstituted by A or aryl;
in k)
X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydro imidazol-2-ylamino,
Y (CH ₂ ) _n -
n 2, 3 or 4,
ZO,
R ² N or CH,
R ⁴ phenyl substituted by Hal and aryl,
R ⁵ OA or OH
mean
with the proviso that R ⁴ ≠ is a phenyl or naphthyl radical which is monosubstituted by A or aryl;
in l)
X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydro imidazol-2-ylamino,
Y - (CH ₂ ) _n -
n 2, 3 or 4,
ZO,
R ² N or CH,
R ⁴ phenyl substituted by Hal and aryl,
R ⁵ OA or OH,
Aryl phenyl substituted once, twice or three times by Hal, A, OA, CF ₃ , CN or NO ₂
mean
with the proviso that R ⁴ ≠ is a phenyl or naphthyl radical which is monosubstituted by A or aryl;
in m)
X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydro imidazol-2-ylamino, 2-amino-imidazol-5- ylamino, 2-amino-pyridin-6-ylamino, 2-amino-imidazol-5-yl or 2-amino-pyridin-6-yl,
y - (CH ₂ ) _n -
n 2, 3 or 4,
ZO,
R ² N or CH,
R ⁴ substituted one or more times by Hal, A or aryl, substituted phenyl,
R ⁵ OA or OH
mean
with the proviso that R ⁴ ≠ is a phenyl or naphthyl radical which is simply substituted by A or aryl.

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

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

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

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

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

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

The amino protective group can be split off, depending on the one used Protecting group - e.g. B. with strong acids, suitably with TFA or Per chloric acid, but also with other strong inorganic acids such as Hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as Trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfone acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable as inert solvents preferably organic, for example carboxylic acids such as vinegar acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogen hydrocarbons such as dichloromethane, and also alcohols such as Methanol, ethanol or isopropanol, as well as water. Come further Mixtures of the aforementioned solvents in question. TFA is preferred use in excess without the addition of another solvent det, perchloric acid in the form of a mixture of acetic acid and 70% Perchloric acid in a 9: 1 ratio. The reaction temperatures for the spal tion are advantageously between about 0 and about 50 °, preferably one works between 15 and 30 ° (room temperature).

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

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

Suitable inert solvents are, for. B. hydrocarbons such as hexane, Petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as Trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or Dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol mono methyl or monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles like Acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds like Nitromethane or nitrobenzene; Esters such as ethyl acetate, water or Mixtures of the solvents mentioned.

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

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

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

To prepare compounds of the formula I in which XH _{2 is} NC (= NH) -NH-, a corresponding amino compound can be treated with an amidizing agent. Preferred amidinizing agent is 1-amidino-3,5-dimethylpyrazole (DPFN), which is used in particular in the form of its nitrate. It is convenient to work with the addition of a base such as triethylamine or ethyl diisopropylamine in an inert solvent or solvent mixture, for. B. water / dioxane at temperatures between 0 and 120 ° C, preferably between 60 and 120 ° C.

To produce an amidine of the formula I (X = -C (= NH) -NH ₂ ), ammonia can be added to a nitrile of the formula I (X = CN). The addition is preferably carried out in several stages by a) converting the nitrile with H ₂ S into a thioamide in a manner known per se, the medium with an alkylating agent, for. B. CH ₃ l, is converted into the corresponding S-alkyl imidothioester, which in turn reacts with NH ₃ to give the amidine, b) the nitrile with an alcohol, for. B. ethanol in the presence of HCl in the corresponding imido ester and treated with ammonia, or c) reacting the nitrile with lithium bis (trimethylsilyl) amide and then hydrolyzing the product.

The release of the compounds of the formula I from is also preferred an oxidized precursor by e.g. B. with an oxy heterocycle a reducing agent such. B. phosphorus trichloride in an inert Reduced solvent.

You can also free amino groups in the usual way with an acid chloride or anhydride or with an unsubstituted or Alkylate substituted alkyl halide, advantageously in an inert Solvents such as dichloromethane or THF and / or in the presence of one Base such as triethylamine or pyridine at temperatures between -60 and + 30 °.  

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

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

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

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

The invention includes not only the compounds mentioned but also Mixtures and preparations, which besides these fiction compounds according to other pharmacological agents or Adjuvants contain the primary pharmacological effects of the Influencing compounds of the invention in a desired manner can. These can be used as therapeutic agents, diagnostic agents or as reagents Find use. They can be local to humans or animals systemic, oral, intravenous, intraperitoneal, intramuscular, subcutaneous, transdermal, nasal, buccal, or iontophoretic, the includes formulations in suspensions, emulsions or solutions, Liposomes, ointments, pastes, biodegradable polymers or as Nanoparticles, tablets, capsules or pills, granules or powder, as Inhaled aerosol, as intranasal drops or sprays. Also a combination of new products with other techniques, such as Surgery, radiation, diagnosis, radiotherapy, photodynamic Therapy and gene therapy, as well as with other drugs is possible. Such drugs can e.g. B. from the areas of cardiovascular, Central nervous system or oncology. It can Tumor agents, such as angiogenesis inhibitors or cytostatics, Chemotherapeutics of the groups alkylating agents, antibiotics,  Antimetabolites, biologicals and immunomodulators, hormones and their Antagonists, mustard gas derivatives, alkaloids and others, these Substances can be low molecular weight and high molecular weight. It can Lipids, carbohydrates or proteins. This includes cytokines, Toxins, fusion proteins, monoclonal antibodies and vaccines.

The invention accordingly relates to compounds of the above and formulas defined below and in the claims including their physiologically acceptable salts as medicines, diagnostics or Reagents.

The invention relates in particular to corresponding medicaments as inhibitors for combating diseases which are based, directly or indirectly, on expression of the α _v β ₃ integrin receptor, in particular in the case of pathologically angiogenic diseases, thromboses, heart attack, coronary heart diseases, arteriosclerosis, tumors, osteoporosis , Inflammation, infections and to influence wound healing processes.

Appropriate pharmaceutical preparations are also a subject of the invention, which at least one drug of formula I and optionally Contain carrier and / or auxiliary substances.

The invention furthermore relates to the use of the compounds and / or their physiologically acceptable salts according to the claims and the description for the manufacture of a medicament for combating diseases which are based directly or indirectly on expression of the α _v β ₃ integrin receptor, in particular, therefore, in pathologically angiogenic diseases, thromboses, heart attacks, coronary heart diseases, arteriosclerosis, tumors; Osteoporosis, inflammation, infections and to influence wound healing processes. The pharmaceuticals according to the invention or pharmaceutical preparations containing them can be used in human or veterinary medicine. Suitable carriers are organic or inorganic substances which are suitable for enteral (e.g. oral), parenteral, topical application or for application in the form of an inhalation spray 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. For oral use in particular tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops, for rectal use suppositories, for parenteral use solutions, preferably oily or aqueous solutions, also suspensions, emulsions or implants, for topical use Use ointments, creams or powder. The new connec tions can also be lyophilized and the resulting lyophilizates z. B. can be used for the preparation 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, colors, flavors and / or several other active substances, e.g. . B. one or more vitamins.

For application as an inhalation spray, sprays can be used which contain the active ingredient either dissolved or suspended in a propellant gas or propellant mixture (e.g. CO ₂ or chlorofluorocarbons). The active ingredient is expediently used in micronized form, with one or more additional ones physiologically acceptable solvents may be present, e.g. B. ethanol. Inhalation solutions can be administered using standard inhalers.

The substances according to the invention can generally be analogous to other known, commercially available preparations (e.g. described in US-A-4,472,305), preferably in dosages between approximately 0.05 and 500 mg, in particular between 0.5 and 100 mg administered per dosage unit. The daily dosage is preferred  Way between about 0.01 and 20 mg / kg body weight. The special one However, dose for each patient depends on various factors depending, for example, on the effectiveness of the special Connection, age, body weight, general health, Gender, the diet, the time and route of administration, the Elimination rate, drug combination and severity of respective disease to which the therapy applies. The parenteral Application is preferred.

All temperatures above and below are given in ° C.

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.
Mass spectrometry (MS): EI (electron impact ionization) M ⁺
FAB (Fast Atom Bombardment) (M + H) ⁺

example 1 Synthesis of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] - phenyl} butyric acid

835 mg Mg are abs. In 5 ml. THF suspended. Then will dropwise a solution of 2.0 g of 4-benzyloxybenzyl chloride in 5 ml of abs. Tetrahydrofuran added. When the addition is complete, the cloudy Solution stirred for 1 hour at room temperature, then one Solution of 1.73 g of 2-cyano-3- (4-fluorophenyl) acrylic acid ethyl ester in 10 ml Section. Toluene added and refluxed for 16 hours. The Solvent is removed and after the usual work-up, 4- (4-Benzyloxyphenyl) -2-cyano-3- (4-fluorophenyl) butyric acid ethyl ester ("AA").  

8.27 g of "AA" are in a mixture of 80 ml of acetic acid and 80 ml conc. HCl suspended and then under reflux for 16 hours cooked. After the usual work-up, 4- (4-hydroxyphenyl) -3- (4- fluorophenyl) butyric acid ("AB").

A solution of 1.0 g "AB" in 10 ml abs. Methanol is mixed with 0.4 ml of thionyl chloride added and stirred for 16 hours at room temperature. To Normal work-up gives 4- (4-hydroxyphenyl) -3- (4-fluorophenyl) - methyl butyrate ("AC").

To a suspension of 0.4 g "AC", 0.5 g 3- (1-oxy-pyridin-2-ylamino) - propan-1-ol and 1.23 g polymer-bound triphenylphosphine (loading approx. 3 mmol / g) in 17 ml abs. THF is added dropwise to 0.62 ml of diethyl azadicarboxylate and stir for 16 hours. After filtration and removal of the solution is cleaned by HPLC. 3- (4-Fluorophenyl) -4- {4- [3- (1- oxypyridin-2-ylamino) propoxy] phenyl} butyric acid methyl ester ("AD").

A solution of 0.45 g of "AD" in 30 ml of chloroform is mixed with 0.59 g of phosphorus trichloride, stirred for 2 hours at room temperature and for a further 2 hours under reflux. After the usual workup, the residue in 15 ml of methanol is mixed with 0.2 g of lithium hydroxide and stirred at room temperature for 16 hours. After the solvent has been removed, 0.66 ml of trifluoroacetic acid is added and the mixture is purified by HPLC. This gives 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid, trifluoroacetate

Test result of α _v β ₃ inhibition by 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid

The IC ₅₀ value is given for the vitronectin binding test, ie the concentration in nmoles / liter which inhibits 50% of the vitronectin binding to the corresponding isolated receptor (method of Smith et al., J. Biol. Chem. 265, 12267-71, 1990).
IC ₅₀ α _v β _3: 10th

The pharmacological data demonstrate the antagonistic activity of the compound according to the invention for the receptor α _v β ₃ .

The following compounds are obtained analogously to the synthesis scheme described above
3- (4-fluorophenyl) -4- {4- [2- (pyrimidin-2-ylamino) ethoxy] phenyl} butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4- {4- [3- (pyrimidin-2-ylamino) propoxy] phenyl} butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4- {4- (4- (pyrimidin-2-ylamino) butoxy] phenyl} butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4- {4- [2- (pyridin-2-ylamino) ethoxy] phenyl} butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4- {4- [4- (pyridin-2-ylamino) butoxy] phenyl} butyric acid, trifluoroacetate;
3- (4-fluorophenyl) -4- {4- [3- (imidazol-1-yl) propoxy] phenyl} butyric acid;
3- (4-fluorophenyl) -4- {4- [3- (4,5-dihydro-1 H -imidazol-2-ylamino) propoxy] phenyl} butyric acid;
3- (4-fluorophenyl) -4- {4- [3- (imidazol-2-ylamino) propoxy] phenyl} butyric acid;
3- (4-fluorophenyl) -4- {4- [3- (benzimidazol-2-ylamino) propoxy] phenyl} butyric acid;
3- (4-fluorophenyl) -4- {4- [3- (2-aminopyridin-6-ylamino) propoxy] phenyl} butyric acid,
3- (4-fluorophenyl) -4- {4- [3- (2-aminoimidazol-5-ylamino) propoxy] phenyl} butyric acid.

Example 2 Synthesis of (4-fluorophenyl- {4- [3- (pyridin-2-ylamino) propoxy] benzyl} - amino) acetic acid

40.0 g of 4-hydroxybenzaldehyde are placed in a protective gas atmosphere in 400 ml Section. THF dissolved, with 55.1 g dihydropyran and 13.7 g pyridinium-p- added toluenesulfonate and stirred overnight at room temperature. The Solvent is removed on a rotary evaporator, the residue as worked up in the usual way and 4- (tetrahydro-pyran-2-yloxy) is obtained - benzaldehyde ("BA") as a colorless oil.

A solution of 2.0 g "BA" in 20 m (absolute methanol is mixed with 1.17 g 4- Fluoraniline were added and the mixture was stirred at 60 ° for 3 hours. At room temperature 0.79 g of sodium cyanoborohydride are added and the reaction solution boiled under reflux for 16 hours. After removing the Solvent, usual processing and cleaning by Chromato graphy is obtained 4-fluorophenyl- [4- (tetrahydro-pyran-2-yloxy) benzyl] - amine ("BB") as a colorless liquid.

8.0 "BB" g and 10.36 g of methyl bromoacetate are N ₂ - abs ml atmosphere in 100th THF dissolved, mixed with 12.0 g of potassium carbonate and boiled under reflux for 16 hours. After removal of the solution by means of customary work-up and purification by chromatography, {[4-fluorophenyl] - [4- (tetrahydro-pyran-2-yloxy) benzyl] amino] - methyl acetate ("BC") is obtained as a colorless solid.

A solution of 0.5 g "BC" in 25 ml methanol and 5 ml dichloromethane is concentrated with 2.76 ml. HCl added and 5 minutes at room temperature touched. After removal of the solvent and usual workup the residue together with 0.47 g of 3- (1-oxypyridin-2-ylamino) propane-1- ol in 16 ml abs. THF dissolved and then with 1.17 g of polymer Triphenylphosphine (loading approx. 3 mmol / g) was added. Subsequently 0.62 ml of diethyl azadicarboxylate are added dropwise. The suspension will then stirred for 16 hours at room temperature. After filtration and Removal of the solvent is purified by HPLC. You get ({4- [3- (1-oxy-pyridin-2-ylamino) propoxy] benzyl} - (4-fluorophenyl) amino) - methyl acetate ("BD").

A solution of 0.44 g of "BD" in 30 ml of chloroform is mixed with 0.57 g of phosphorus trichloride, stirred for 2 hours at room temperature and for a further 2 hours under reflux. After the usual work-up, the residue in 15 ml of methanol is mixed with 0.27 g of lithium hydroxide and stirred at room temperature for 16 hours. After the solvent has been removed, 0.66 ml of trifluoroacetic acid is added and the mixture is purified by HPLC. This gives ((4-fluorophenyl) - {4- [3- (pyridin-2-ylamino) propoxy] - benzyl} amino) acetic acid, bistrifluoroacetate

The following compounds are obtained analogously
((4-fluorophenyl) - {4- [2- (pyrimidin-2-ylamino) ethoxy] benzyl} amino) - acetic acid,
((4-fluorophenyl) - {4- [3- (pyrimidin-2-ylamino) propoxy] benzyl} amino) - acetic acid,
((4-fluorophenyl) - {4- [4- (pyrimidin-2-ylamino) butoxy] benzyl} amino) - acetic acid,
((4-fluorophenyl) - {4- [2- (pyridin-2-ylamino) ethoxy] benzyl} amino) - acetic acid,
((4-fluorophenyl) - {4- [4- (pyridin-2-ylamino) butoxy] benzyl} amino) - acetic acid,
((4-fluorophenyl) - {4- [3- (imidazol-1-yl) propoxy] benzyl} amino) acetic acid,
((4-fluorophenyl) - {4- [3- (4,5-dihydro-1 H -imidazol-2-ylamino) propoxy] benzyl} amino) acetic acid,
((4-fluorophenyl) - {4- [3- (imidazol-2-ylamino) propoxy] benzyl} amino) - acetic acid,
((4-fluorophenyl) - {4- [3- (benzimidazol-2-ylamino) propoxy] benzyl} amino) - acetic acid.

Example 3

Analogously to Example 1, the following compound is obtained
This gives 3- (3-chloro-4-phenyl) phenyl) -4- {4- (3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid,

The following examples relate to pharmaceutical preparations:

Example A Injection glasses

A solution of 100 g of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) - propoxy] -phenyl} -butyric acid and 5 g of disodium hydrogen phosphate is in 3 l of double-distilled water adjusted to pH 6.5 with 2 N hydrochloric acid, sterile filtered, filled into injection glasses, under sterile conditions lyophilized and sealed sterile. Each injection jar contains 5 mg Active ingredient.

Example B Suppositories

A mixture of 20 g of 3- (4-fluorophenyl) -4- {4- [3- (pyridine-2- ylamino) propoxy] phenyl} butyric acid with 100 g soy lecithin and 1400 g Cocoa butter, pour into molds and let cool. Any suppository contains 20 mg of active ingredient.

Example C solution

A solution is prepared from 1 g of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid, 9.38 g of NaH ₂ PO ₄ .2 H ₂ O, 28.48 g Na ₂ HPO ₄ .12 H ₂ O and 0.1 g benzalkonium chloride in 940 ml double-distilled water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D ointment

Mix 500 mg of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] - phenyl} -butyric acid with 99.5 g petroleum jelly under aseptic conditions.

Example E Tablets

A mixture of 1 kg of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) - propoxy] phenyl} butyric acid, 4 kg lactose, 1.2 kg potato starch, 0.2 kg  Talc and 0.1 kg of magnesium stearate become tablets in the usual way pressed in such a way that each tablet contains 10 mg of active ingredient.

Example F Dragees

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

Example G Capsules

2 kg of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} - Butyric acid are filled in hard gelatin capsules in the usual way that each capsule contains 20 mg of the active ingredient.

Example H Ampoules

A solution of 1 kg of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) - propoxy] -phenyl} -butyric acid in 60 l of double distilled water sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each ampoule contains 10 mg of active ingredient.

Example I Inhalation spray

14 g of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] - are dissolved phenyl} -butyric acid in 10 l isotonic NaCl solution and fill the solution in standard spray jars with pump mechanism. The solution can be sprayed into the mouth or nose. One spray (about 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Claims (10)

1. Compounds of formula I.
XYZR ¹ -CH ₂ -R ² (R ⁴ ) -CH ₂ -CO-R ⁵ I
wherein
XH ₂ NC (= NH) -, H ₂ NC (= NH) -NH-, AC (= NH) -NH-, Het ¹ - or Het ¹ -NH-,
the primary amino groups can also be provided with conventional amino protective groups,
in which one, two, three or four methylene groups can be replaced by N, O and / or S,
Z is missing, -O-, -NH-, -NA-, -CH (OH) -, -CH (OA) -, -CHA-, -CA ₂ - or -S-,
R ^{1 is} phenylene which is unsubstituted or mono-, di- or trisubstituted by F, Cl, Br, A, OA, OCF ₃ or CN,
R ² N, CH or CA,
R ³ H, F, Cl, Br, A, OA or OCF ₃ ,
Mono- or polysubstituted by R ⁴ F, Cl, Br, A, aryl, OA, SA, CO-A, CN, COOA, CONH _2, CONHA, CONA ₂ or NO ₂ substituted phenyl, naphthyl, or Het ^2,
R ⁵ OH, OA, NH ₂ , NHA or NA ₂ ,
Het ^{1 is} a mono- or dinuclear heterocycle with 1 to 4 N atoms, which can be unsubstituted or mono- or disubstituted by NH ₂ ,
Het ^{2 is} an aromatic mono- or dinuclear heterocycle with 1 to 3 N, O and / or S atoms, which is unsubstituted or mono- or disubstituted by F, Cl, Br, A, OA, SA, OCF ₃ , - CO-A, CN, COOA, CONH ₂ , CONHA, CONA ₂ or NO ₂ can be substituted,
Aryl unsubstituted or mono- or polysubstituted by Hal, A, OA, OH, CO-A, CN, COOA, COOH, CONH ₂ , CONHA, CONA ₂ or NO ₂ ,
A alkyl with 1-12 C atoms,
n 1, 2, 3, 4, 5 or 6
m, o each independently of one another 0, 1, 2, 3, 4, 5 or 6,
mean,
with the proviso that R ⁴ ≠ is a phenyl or naphthyl radical which is simply substituted by A or aryl,
and their physiologically acceptable salts and solvates. 2. Compounds according to claim 1

• a) 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid;
• b) 3- (4-fluorophenyl) -4- {4- [3- (2-aminopyridin-6-ylamino) propoxy] phenyl} butyric acid,
• c) 3- (4-fluorophenyl) -4- {4- [3- (2-aminoimidazol-5-ylamino) propoxy] phenyl} butyric acid,

and their physiologically acceptable salts and solvates. 3. A process for the preparation of compounds of formula I according to claim 1 and their salts, characterized in that

• a) liberates a compound of formula I from one of its functional derivatives by treatment with a solvolysing, reducing or hydrogenolysing agent,

or

• a) converts a radical X and / or R ⁵ into another radical X and / or R ⁵ ,
  for example by
  • a) converting an amino group into a guanidino group by reaction with an amidinizing agent,
  • b) saponifying an ester,
  • c) converting a hydroxyamidine into an amidine by hydrogenation,

and / or converts a base or acid of the formula I into one of its salts. 4. Compounds of formula I according to claim 1 and the compounds according to claim 2 and their physiologically acceptable salts and Solvate as a medicine.   5. Medicament according to claim 4 as an inhibitor for combating diseases which are based on an expression and pathological function of α _v β ₃ integrin receptors. 6. Medicament according to claim 5 for combating thrombosis, Heart attack, coronary heart disease, arteriosclerosis, tumors, Osteoporosis, fibrosis, inflammation, infection, psoriasis as well for influencing wound healing processes. 7. Pharmaceutical preparation containing at least one medicament agent according to one of claims 5 to 6 and optionally Carriers and / or auxiliary substances and optionally other active substances. 8. Use of compounds according to claims 1 to 2 and / or their physiologically acceptable salts for the manufacture of a medicament for combating diseases which are based on the expression and pathological function of α _v β ₃ integrin receptors. 9. Use according to claim 8 for the manufacture of a medicament to combat pathological processes caused by angiogenesis entertained or propagated. 10. Use according to claim 8 for the manufacture of a medicament to fight thrombosis, heart attack, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, fibrosis, Inflammation, infections, psoriasis and for influencing Wound healing processes.