SK2282002A3 - Integrin alpha'v'beta'3' inhibitors, process for the preparation and use thereof and pharmaceutical composition comprising same - 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

Technical field

The invention relates to novel compounds of the formula I

Xyzr ¹ -ch2-r ² (R ⁴ ) -ch ² -co-r ⁵ (I) wherein is

X h ₂ nc (= nh) -, h ₂ nc (= nh) ~ nh, AC (= NH) -NH-,

Het- ¹ · - or Het-NH-, wherein the primary amino groups are optionally protected with conventional amino protecting groups,

Y is - (CH ₂ ) _n - or

R ³ wherein one, two, three or four methylene groups may be replaced by N, O and / or S,

Z is absent or is oxygen, -NH-, -NA-,

-CH (OH) -, -CH (OA) -, -CHA-, -CA ₂ - or -S-,

R ^{1 is} a phenylene unsubstituted or monosubstituted, disubstituted or trisubstituted F, Cl, Br, OA, OCF ₃ or CN group,

R ² N, CH or CA,

R ³ is hydrogen, F, Cl, Br, A, OA or OCF ₃ ;

R _{4 is} phenyl, naphthyl or Het, each of which is unsubstituted, monosubstituted or polysubstituted with F, Cl, Br, A, Aryl, OA, SA, CO-A, COOA, CONH ₂ , CONHA CONA ₂ or NO ₂ ,

R ^{5 is} OH, OA, NH ₂ , NHA or NA ₂ ,

Ί

Het is a monocyclic or bicyclic heterocyclic ring having 1 to 4 N is unsubstituted or monosubstituted or disubstituted by _NH2, N

Het * an aromatic monocyclic or bicyclic heterocyclic group of 1 to 3 nitrogen, oxygen and / or sulfur unsubstituted or monosubstituted or disubstituted by F, Cl, Br, A, OA, SA, OCF ₃ -CO-A, CN, COOA, CONH ₂ , CONHA, CONA ₂ or NO ₂ ,

Aryl phenyl or naphthyl unsubstituted or monosubstituted or polysubstituted by Hal, A, OA, OH, -CO-A, CN, COOA, COOH, CONH ₂ , CONHA, CONA ₂ or NO ₂ ,

A is an alkyl group having 1 to 12 carbon atoms, n 1, 2, 3, 4, 5 or 6, m, o, in each case independently of one another 0, 1, 2, 3, 4, 5 or 6, but R ⁴ does not a phenyl or naphthyl group substituted with A or Aryl, and physiologically acceptable salts and solvates thereof.

SUMMARY OF THE INVENTION It is an object of the invention to provide novel compounds with valuable properties which are particularly suitable for the manufacture of medicaments.

BACKGROUND OF THE INVENTION

It has been found that the compounds of formula I and their salts have very valuable pharmacological properties with good tolerability. In particular, they act as integrin inhibitors and, in particular, inhibit the interaction of? 6 in integrin receptors with ligands. The compounds are particularly effective in the case of the integrins X v / v and α v v _δ . The compounds are particularly highly effective as adhesion receptor antagonists for the <RTIgt; This action can be demonstrated, for example, by the method of J. Smith et al. (J. Biol. Chem. 265, 11008-11013 and 12267-12271, 1990).

Inhibition of vitronection binding to the receptor at ₃ is experimentally demonstrated for 3- (4-fluorophenyl) -4- (4- (3-pyridin-2-ylamino) propoxy) phenyl] butyric acid.

B. Felding-Habermann and (Curr.Opin. Cell. Biol. 5, p. 864) as adhesion receptors to various

DACheresh describe 1993) the importance of integrins of phenomena and disease symptoms, especially taking into account nareceptor <X in /? ₃ .

Other integrin inhibitors are described in EP 0 820988. Vitronectin receptor antagonists are also described in WO 97/24124 and EP 0 820991.

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

P.C. Brooks, A.M. Montgomery, M. Rosenfeld, R.A. Reisfeld, T.-Hu. G. Klier and D.A. Cheresh (Cell 79, 1157-1164, 1994) have described the possibility of using inhibition of this interaction, thereby inducing apoptosis (programmed cell death) of angiogenic vascular cells by the action of a cyclic peptide.

Experimental evidence that the compounds of the invention also prevent the adhesion of living cells to the corresponding matrix proteins and accordingly the adhesion of tumor cells to the matrix proteins can be obtained by the cell adhesion assay as described by Mitjans F. et al.,

J. Cell Science 108, p. 2825-2838 (1995).

PC Brooks et al. (J. Clinn. Invest. 96: 1815-1822, 1995) discloses Zv antagonists ^{for the} treatment of cancer and for the treatment of tumor-induced agiogenic disorders.

Thus, the compounds of the formula I according to the invention can be used as therapeutically active compounds, in particular for the treatment of cancer, osteoporosis, osteolytic disorders and for suppressing angiogenesis.

Compounds of formula I that block the interaction of receptors and ligands, such as fibrinogen with the fibrinogen receptor (glycoprotein IIIbIIa), inhibit the dispersion of tumor cells by metastasis as GPIIb / IIIa antagonists. This is evidenced by the following knowledge: tumor cells spread from a localized tumor to the vascular system by the formation of microaggregates (micro-thrombi) by the interaction of tumor cells with platelets. Protected in microaggregates, tumor cells are shielded and are not recognized by cells of the immune system. These microaggregates can be deposited on the walls of blood vessels, thereby facilitating further penetration of tumor cells into the tissue. Since the formation of microthrombi is mediated by fibrinogen binding to fibrinogen receptors on activated platelets, GPIIb / IIIa antagonists can be considered as potent metastasis inhibitors.

In addition to the binding of fibrinogens, fibronectin and von Willebrand factor to the fibrinogen platelet receptor, the compounds of formula I also inhibit the binding of other adhesion proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on different cell types. In particular, they inhibit platelet thrombus formation and can therefore be used to treat thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis.

The properties of the compounds of the invention can be demonstrated by the methods described in EP-A1-0 462960. Inhibition of fibrinogen binding to the fibrinogen receptor can be demonstrated by the methods described in EP-A1-0 381033.

The inhibitory effect of platelet aggregation can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962). Inhibition of bone resorption by the compounds of the invention can be demonstrated by an osteoclast resorption assay similar to that described in WO 95/32710.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I as described above as an integrin inhibitor.

The invention thus relates to compounds of the formula I and / or their physiologically acceptable salts for the preparation of medicaments useful as integrin inhibitors. In particular, the invention relates to compounds of formula I and / or their physiologically acceptable salts for the preparation of medicaments for the treatment of pathologically angiogenic diseases, tumors, osteoporosis, inflammations and infections.

The compounds of the formula I can be used as active medicaments in human and veterinary medicine, in particular for the prophylaxis and / or treatment of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, cancer, osteolytic diseases such as osteoporosis, hypercalcemia. pathologically angiogenic diseases such as inflammation, ophthalmological diseases, diabetic retinopathy, corneal degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, for the treatment of rubeotic glaucoma, ulcerative colitis, angioplasty, lupus, atherosclerosis, atherosclerosis, Crohn's disease, Crohn's disease , bacterial infections, fungal infections, acute malfunctions, and wound healing and healing processes.

The compounds of the formula I can be used as antimicrobial agents in operations using biological cardiac stimulators, antiseptic. The efficacy of the material, implants, catheter or antimicrobial activity of these compounds can be demonstrated by the method of P. Valentin-Weigund et al.

(Infection and Immunity, 1988, 2851-2855).

The invention also relates to hydrates and solvates, for example alcoholates of the compounds of formula I.

The process according to the invention for the preparation of the compounds of the formula I, in which the individual symbols have the meaning given above, or their salts, consists in

(a) releasing a compound of formula (I) from its functional derivative by treatment with a solvolysis, reducing or hydrogenolysis agent; or,

(b) the group of symbols X and / or R ⁵ is converted to another group of symbols X and / or R ⁵ by:

(i) converting an amino group to a guanidino group by reaction with an amidating agent; (ii) saponifying the ester; (iii) converting hydroxiamidine to amidine by hydrogenation;

The compounds of formula I have at least one chiral center and can therefore be in several stereoisomeric forms. The invention includes all such forms (e.g. D- and L-forms) and mixtures thereof (e.g. DL-forms).

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

Abbreviations used have the following meanings:

Ac acetyl BOC tert-butoxycarbonyl CBz or Z - benzyloxycarbonyl DCCI dicyclohexylcarbodiimide DMF dimethylformamide EDCI N-Ethyl-N, N '- (dimethylaminopropyl) carbodiimide et ethyl Fmoc 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole HONSu N-hydroxysuccinimide Me methyl Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl OBu tert-butyl Oct octanoyl OEt ethyl OMe methyl ester POA phenoxyacetyl TFA trifluoroacetic acid Trt trityl (triphenylmethyl)

All groups that are present more than once in a compound, for example A, may be the same or different independently of one another.

In the above formulas, A is especially alkyl

group with carbon and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 atoms preferably A is methyl, ethyl, propyl,

isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, and 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-

lová a 1,1,2- or 1,2,2-trimethylpropyl, heptyl,

an octyl, nonyl, decyl, undecyl or dodecyl group. The hydrogen atom in the alkyl groups may be replaced by halogen atoms. Thus, A can be preferably trifluoromethyl.

X is preferably, for example, pyrimidin-2-yl amino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino, 2-aminoimidazole -5-ylamino, 2-amino-pyridin-6-ylamino, 2-amino-imidazol-5-yl or 2-amino-pyridin-6-yl.

Y is preferably, for example, an ethylene, propylene or butylene group.

Z is preferably, for example, an oxygen atom.

The symbol R ¹ is preferably, for example, 1,4-phenylene.

n

R is preferably, for example, CH or N, particularly preferably CH.

R @ ⁴ is preferably a monosubstituted or polysubstituted phenyl group.

The symbol ^R5 is preferably a hydroxyl group, for example.

Ί

Het is preferably unsubstituted or A, NHA and / or _NH2 monosubstituted or disubstituted with a group of 1-, 2- or 3-pyrrolyl, 1-, 2-, 4-, or

5-imidazolyl 1-, 3-, 4-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, further preferably preferably 1,2,3-triazole- 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-isoquinolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 1H- imidazof4,5-bj pyridin-2-yl or 1,8-naphthyridin-7-yl.

The heterocyclic groups may also be partially or partially hydrogenated. Het ^{1 may} therefore also be 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-dihydroimidazolo-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-quinols, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4- , -5-, -6-, -7- or -8-isoquinolyl or 1,2,3,4-tetrahydro-1,8-naphthyrdridin-7-yl. The hydrogenated or partially hydrogenated Het ¹ groups may additionally be substituted by = NH or carbonyloxy.

n

Preferably, Het is 2,3-, 2,4-, 2,5- or 3,410-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-pyridyls, 2,4-, 2,5-, 2,6-, 4,5- or 5-pyrimidines; 6-pyrimidinyl, each of which is unsubstituted or monosubstituted by fluorine, chlorine or bromine, A, OA or OCF ₃ ;

The index n is preferably 2, 3, 4, 5 or 6, hereinafter also

1, 3, 4 or 5.

The index m and o is preferably, independently of one another, 0, 1 or

2, but particularly preferably 0.

The term monosubstituted or polysubstituted means that the group has one, two, three or four specified substituents.

Aryl means unsubstituted, preferably, as indicated, substituted phenyl, particularly preferably m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o- , m- or pisopropylphenyl, o-, m- or p-tert-butylphenyl, o-, male- or p-cyanophenyl, o-, m- or p-methoxyphenyl, o-, male- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, male- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, male- or p-methylthiophenyl, o-, m- or p-methylsulfinyl phenyl, o-, m- or p-methylsulfonylphenyl , o-, m- or p-aminophenyl, o-, m- or p-methylaminophenyl, o-, p-dimethylaminophenyl, o-, m- or p-nitrophenyl, o-, m- or p-acetylphenyl, o -, m- or p-methoxycarbonylphenyl, o-, m- or p-aminocarbonylphenyl, further preferably 2,3-2,4-2,5-2,6-, 3,4-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or

3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methylphenyl, 2-chloro-4-methylphenyl , 2-chloro-5-methylphenyl, 2-chloro-6-methylphenyl, 2-methyl-3-chlorophenyl, 2-methyl-4-chlorophenyl, 2-methyl-5-chlorophenyl, 2-methyl-6-chlorophenyl, 3-chloro 4-methylphenyl 3-chloro-5-methylphenyl, 3-methyl-4-chlorophenyl,

2-bromo-3-methylphenyl, 2-bromo-4-methylphenyl, 2-bromo-5-methylphenyl, 2-bromo-6-methylphenyl, 2-methyl-3-bromophenyl,

2-methyl-4-bromophenyl, 2-methyl-5-bromophenyl, 2-methyl-6-bromophenyl, 3-bromo-4-methylphenyl, 3-bromo-5-methylphenyl,

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-triter-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 or 2,4,6-triisopropylphenyl.

The amino protecting group is preferably formyl, acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ (carbobenzyl, CBZ) FMOC, Mtr or benzyl.

In particular, the invention relates to compounds of the formula I in which at least one of the symbols has the above-mentioned preferred meaning. Some preferred groups of compounds of formula I are the following compounds of formulas Ia to Ia

Im, in which the symbols not specifically mentioned have the meaning given in the general formula I, in the general formula Ia)

Ib)

Ic)

Id)

X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino, 2-aminoimidazol-5-ylamino -amino-pyridin-6-ylamino 2-amino-imidazol-5-yl or 2-amino-pyridin-6-yl,

X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino,

Y - (CH ₂ ) _n -, n 2, 3 or 4,

X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino,

Y - (CH ₂ ) _n -, n 2,3 or 4,

X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino,

Y - (CH ₂ ) _n -, n 2, 3 or 4,

Z O,

Ie)

If) ig)

ih)

X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino,

Y - (CH ₂ ) _n -, n 2, 3 or 4,

Z 0,

R ² N or CH;

X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino,

Y - (CH ₂ ) _n -, n 2, 3 or 4,

Z 0,

R ² N or CH;

R ^{4 is} a monosubstituted or polysubstituted F, Cl, Br, OA, OCF ₃ , -CO-A, CN, COOA, CONH ₂ or NO ₂ ,

X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino,

Y - (CH ₂ ) _n -, n 2, 3 or 4,

Z N or CH,

R ^{4 is} a monosubstituted or polysubstituted F, Cl, Br, OA or OCF ₃ phenyl group,

R ⁵ OH or OA,

14-pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino,

Y - (CH ₂ ) _n -, n 2,3 or 4,

ZO,

R ² N or CH;

R ^{4 is} monosubstituted or polysubstituted F,

R ⁵ OH or OA,

(Ii) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino,

Y - (CH ₂ ) _n -, n 2, 3 or 4,

ZO,

R ² N or CH;

R ^{4 is} a monosubstituted or polysubstituted Hal, A or Aryl phenyl group,

R ^{5 is} OA or OH, but R ^{4 is} not A or Aryl monosubstituted phenyl or naphthyl:

Ik) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino,

Y - (CH ₂ ) _n -, n 2,3 or 4,

Z 0,

R ² N or CH;

R ⁴ phenyl substituted by Hal and Aryl,

R ^{5 is} OA or OH, but R ^{4 is} not A or Aryl monosubstituted phenyl or naphthyl, 11) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazole -2-ylamino, 4,5-dihydroimidazol-2-ylamino,

Y is ~ _{(CH2) n} -, n 2,3 or 4,

Z 0,

R ² N or CH;

R ⁴ phenyl substituted by Hal and Aryl,

R ⁵ OH or OA,

Aryl phenyl monosubstituted, disubstituted or trisubstituted by Hal, A, OA, CF ₃ , CN or NO ₂ , but where R ^{4 is} not A or Aryl monosubstituted phenyl or naphthyl, 1m) X pyrimidin-2-ylamino, pyridin-2- ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino, 2-aminoimidazol-5-ylamino, 2-amino-pyridin-6-ylamino, 2-amino-imidazol-2-ylamino -5-yl or 2-aminopyridin-6-yl,

Y - (CH ₂ ) _n -, n 2,3 or 4,

Z 0,

R ² N or CH;

R ^{4 is} a monosubstituted or polysubstituted Hal, A or Aryl phenyl group,

R ^{5 is} OA or OH, but R ^{4 is} not A or Aryl monosubstituted phenyl or naphthyl.

The compounds of formula I of the substance on them are described in the publications, and the starting preparation is prepared by known methods in the literature (e.g.

methoden

Verlag, Stuttgart), and for the aforementioned reactions to use the known ones closer here (such as Houben-Weyl, Chemie, Georg-Thieme conditions which are also possible in standard der organischen to be known and suitable for the reactions).

unspecified variants.

Alternatively, the starting materials may be formed in situ, i.e. they are not isolated from the reaction mixture, but are immediately used to prepare compounds of formula I.

The compounds of formula I can also be obtained by liberating from their functional derivatives by solvolysis, in particular by hydrolysis or hydrogenolysis.

Suitable starting materials for solvolysis or hydrogenolysis are compounds of the formula I which have, instead of one or more free amino and / or hydroxyl groups, the corresponding protected amino and / or hydroxyl groups, preferably compounds having an amino protecting group instead of a hydrogen atom bound to the hydrogen atom. a nitrogen atom, especially compounds having an R ^? -N, wherein R is an amino protecting group instead of HN and / or compounds having a hydroxyl protecting group instead of a hydroxyl group of a hydroxyl group, for example, compounds that correspond to the general formula I but have a -COOR ⁷ 'group where it is a protecting group hydroxyl instead of -COOH.

It is also possible that there are several identical or different amino-protecting groups and / or a hydroxyl group in the molecule of the starting material. If the protecting groups are different from each other, they can in many cases be selectively cleaved.

The term amino-protecting group is well known and are groups suitable for protecting (blocking) amino groups from chemical reactions, but which are readily removable if the desired reaction is carried out at the site of the molecule. Typical of such groups are unsubstituted or substituted acyl groups, since the reaction size of the aralkoxymethyl or amino protecting group, on other particularly the aryl groups, (or after the sequence of reactions) is removed is of critical importance.

acyl groups

It includes araliphatic, carboxyl or alkoxycarbonyl, aralkoxycarbonyl.

carbon and an acyl group

Especially preferred are 1 to 1 groups of aromatic aralkyl groups.

aryloxycarbonyl groups include, but are not limited to, the atoms in the broadest derived or sulfonic acids, aryloxycarbonyl groups. Examples are alkanoyl, acetyl, propionyl, butyryl phenylacetyl, aroyl groups with carbon. Aliphatic, heterocyclic as a separate group and especially such acyl groups such as formyl, aralkanenoyl such as benzoyl or up to 20 from toluyl, aryloxyalkanoyl such as phenoxyacetyl, alkoxycarbonyl such as methoxycarbonyl, 2,2-ethoxycarbonyl -trichloroethoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl, aralkyloxycarbonyl such as benzyloxycarbonyl (carbobenzoxy -CBZ), 4-methoxybenzyloxycarbonyl (MOZ), or 9-fluorenyl and 2-methoxycarbonyl (Foxy) methoxycarbonyl (FOS) 3,6-trimethylphenylsulfonyl (Mtr).

Preferred amino protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl, formyl and acetyl.

The cleavage of the amino protecting group is successful according to the protecting group used - for example, strong acids, preferably trifluoroacetic acid or chlorine, but also other inorganic inorganic acids such as hydrochloric or sulfuric acids, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids or p-toluenesulfone. The presence of an additional inert solvent is possible but not always necessary. Since inert solvents are suitable, for example, organic carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol, or isopropanol as well as water. Mixtures of these solvents are also contemplated. Trifluoroacetic acid is preferably used in excess without the addition of other solvents and

perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The reaction temperature for the cleavage is expediently about 0 to 50 ° C, preferably 15 to 30 ° C (room temperature).

For example, the BOC, OBut and Mtr groups may be conveniently cleaved with trifluoroacetic acid in dichloromethane, or using about 3-5% hydrochloric acid in dioxane at 15-30 ° C, the FMOC may be cleaved off with a 5 to 50% solution of secondary amines such as dimethylamine , diethylamine or piperidine in dimethylformamide at 15 to 30 ° C.

Hydrogenolytically removable protecting groups (e.g., CBZ or benzyl) may be removed, for example, by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, preferably on a support such as carbon). Suitable solvents are the abovementioned solvents, in particular, for example, alcohols such as methanol or ethanol or amides such as dimethylformamide. The hydrogenolysis is generally carried out at a temperature of about 0 to 100 ° C under a pressure of about 0.1 to 20 MPa, preferably at a temperature of 20 to 30 ° C under a pressure of about 0.1 to 1 MPa. Hydrogenolysis of the CBZ group is accomplished, for example, on 5-10% palladium on carbon in methanol or ammonium formate (instead of hydrogen) in the presence of palladium on carbon in a methanol / dimethylformamide system at 20-30 ° C.

Suitable inert solvents are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene, chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane or carbon tetrachloride, chloroform or dichloromethane, alcohols such as methanol, ethanol, isopropanol, n-propanol, n- butanol or tert-butanol, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane, glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether, ethylene glycol dimethyl ether (diglyme), ketones such as acetone or acetamide, dimethyl amide, dimethyl amide nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide (DMSO), carbon disulphide, organic carboxylic acids such as formic or acetic acid, nitro compounds such as nitromethane or nitrobenzene, esters such as ethyl acetate, water or mixtures of these solvents.

Compounds of formula I can also be obtained by saponifying an ester of a compound of formula I. Suitably this is done by solvolysis or hydrogenolysis as described above, for example using lithium hydroxide in methanol, sodium hydroxide or potassium hydroxide in a mixture of dioxane and water at a temperature of 0 to 60 °, preferably 10 to 40 ° C.

Conversion of the cyano group to the amidino group is accomplished by reaction with, for example, hydroxylamine and subsequent reduction of Nhydroxyamidine with hydrogen in the presence of a catalyst such as palladium on carbon.

In addition, a conventional amino-protecting group can be replaced by a hydrogen atom, whereby the protecting group as described above is cleaved solvolytically or by hydrogenolysis, or the conventional amino-protecting group is liberated by solvolysis or by hydrogenolysis.

For the preparation of compounds of formula I wherein X is H ₂ NC (= NH) -NH-, the corresponding amino compound can be treated with an amidating agent. A preferred amidating agent is 1-amidino-3,4-dimethylpyrazole (DPFN), which is used in particular as its nitrate. The treatment is preferably carried out with the addition of a base such as triethylamine or ethyldiisopropylamine in an inert solvent or solvent mixture, for example a mixture of water and dioxane, at a temperature of 0 to 120 ° C, preferably 60 to 120 ° C.

For the preparation of compounds of formula I wherein X is -C (NH) -NH ₂ , ammonia can be added to the nitrile of formula I (X is CN). The addition is preferably carried out in several known steps: a) converting the nitrile into a thioamide by treatment with hydrogen sulfide, which is converted with an alkylating agent, for example methyl iodide, to the corresponding S-alkylimidothioester, which is reacted with ammonia to give amidine; of an alcohol, for example ethanol in the presence of hydrogen chloride, to the corresponding imidoester, which is treated with ammonia; or c) reacting the nitrile with lithium bis (trimethylsilyl) amide and subsequently hydrolyzing the product obtained.

It is also possible to release the compounds of formula I from the oxidized precursor, for example, by reducing an oxyheterocyclic compound using a reducing agent such as phosphorus trichloride in an inert solvent.

The free amino groups may further be acylated in a known manner using an acid chloride or anhydride, or may be alkylated with an unsubstituted or substituted alkyl halide, preferably in an inert solvent such as dichloromethane or tetrahydrofuran, and / or in the presence of a base such as triethylamine or pyridine, at -60 to 30 ° C.

The base of formula (I) can be converted into the appropriate acid addition salt by acid, for example by reaction of an equivalent amount of base and acid in an inert solvent such as ethanol and subsequent evaporation of the solvent. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and organic acids, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic, mono- or non-polycarboxylic acids may be used, sulfonic or sulfuric acids such as formic, acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotonic, ethanesulfonic, ethanesulfonic, methanesulfonic 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, naphthalene monosulfonic acid, naphthalenedisulfonic acid and lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of formula I.

On the other hand, the compounds of formula I can be converted into their physiologically acceptable metal or ammonium salts by reaction with a base. Possible salts are, in particular, the sodium, potassium, magnesium, calcium and ammonium salts, further substituted ammonium salts, for example dimethylammonium, diethylammonium, diisopropylammonium, monoethanolammonium, diethanolammonium or diisopropylammonium, cyclohexylammonium dicyclohexylammonium dicyclohexylammonium dicyclohexylammonium dicyclohexylammonium dicyclohexylammonium dicyclohexylammonium dicyclohexylammonium dicyclohexylammonium dicyclohexylammonium;

The compounds of formula I may have one or more chiral centers and may therefore be in racemic or optically active form. Alternatively, the racemates obtained can be separated into their enantiomers mechanically or chemically by known methods. Preferably, diastereoisomers are formed from the racemate by reaction with an optically active resolving agent. Examples of such resolving agents are optically active acids such as the D and L forms of tartaric, diacetyltartaric, dibenzoyltartaric, mandelic, malic or lactic acid, or various optically active camphorsulfonic acids, such as β-camphorsulfonic acid. Also preferred is the resolution of enantiomers by columns packed with optically active resolving agents (e.g. dinitrobenzoyl phenylglycine), for example hexane / isopropanol / acetonitrile, for example in a 82: 15: 3 by volume ratio as suitable eluent.

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

The invention relates not only to the compounds of the formula I but also to mixtures and compositions which contain, in addition to the compounds according to the invention, other pharmacologically active ingredients and adjuvants which are capable of influencing the primary pharmacological action of the compounds according to the invention in the desired manner. They can be used as therapeutic agents, diagnostic agents and reagents. They can be administered to humans or animals locally or systemically, orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, transdermally, nasally, orally or by iontophoresis as suspending, emulsifying or as solutions, liposomes, ointments, pastes, biodegradable polymers or as nanoparticles, tablets, capsules or pills, granules or powders, such as aerosols for inhalation, such as intranasal drops or sprays. Combination of the novel compounds with other techniques such as surgery, radiation, diagnosis, radiotherapy, photodynamic therapy and gene therapy and other medicaments is also possible. Such medicaments may be derived from, for example, the cardiovascular system, the central nervous system, or oncology. They may be, for example, tumor agents such as angiogenesis inhibitors or cytostatics, chemotherapeutic agents selected from alkylating agents, antibiotics, antimetabolites, biological agents and immunomodulators, hormones and antagonists thereof, mustard gas derivatives and alkaloids, which may be low molecular weight and high molecular weight. . They may be lipids, carbohydrates or proteins. Also included are cytokines, toxins, fusion proteins, monoclonal antibodies and vaccines.

The invention thus relates to compounds of formula I as defined above, including their physiologically acceptable salts as drugs, diagnostic or reagents.

In particular, the invention relates to the corresponding medicaments as inhibitors for the treatment of diseases directly or indirectly dependent on expression of X, _{β 3} integrin receptor, i.e. pathologically angiogenic diseases, thromboses, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, inflammations, infections and to affect wound healing processes.

The invention therefore also relates to corresponding pharmaceutical compositions comprising at least one compound of the formula I, optionally carriers and / or auxiliary agents.

The invention further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the preparation of pharmaceutical compositions for the treatment of diseases directly or indirectly dependent on expression of novel receptor integrals, particularly pathologically angiogenic diseases, thromboses, heart attack, coronary heart disease, arteriosclerosis , tumors, osteoporosis, inflammations, infections, and to affect wound healing processes. The medicaments of the invention or pharmaceutical compositions containing them can be used in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (e.g. oral) or parenteral or topical administration or for administration in the form of inhalation sprays and compounds of the formula I, such as vegetable oils, benzyl alcohols which do not react with, for example, water , alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starches, magnesium stearate, talc and petrolatum. Especially suitable for oral use are tablets, pills, dragees, capsules, powders, granules, syrups, juices or drops, for rectal use lace, for parenteral use solutions, in particular oily or aqueous solutions, further suspensions, emulsions or implants, for topical use ointments, creams or powders. The compounds of the invention may also be lyophilized and the lyophilizates obtained, for example, used for the preparation of injectables. The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffers, coloring agents, flavoring agents and / or one or more other active ingredients. substances such as vitamins. For administration in the form of inhalation sprays, the active ingredient is dissolved or suspended in a propellant or propellant mixture (such as, for example, carbon dioxide or fluorocarbon). In this case, the active ingredient is used in micronized form, at least one physiologically compatible solvent, for example ethanol, being added. Inhalable solutions may be administered using known devices for this purpose.

As a rule, the compounds of the formula I according to the invention are used in similar doses to those known in the art, particularly similar to the compounds of US-A-4-472305, preferably at a dose of about 0.05 to 500 mg, in particular 0.5 to 500 mg. 100 mg per dosage unit. The daily dose is preferably about 0.01 to 20 mg / kg body weight. The dose for each individual depends on a variety of factors, such as the potency of a particular compound used, age, body weight, general health, sex, diet, moment and route of administration, rate of excretion, drug combination, and severity of the disease. . Parenteral administration is preferred.

The invention is illustrated by, but not limited to, the following examples. Temperatures are always given in degrees Celsius. The expression processing in the usual manner in the following examples of practical implementation means:

Optionally, water is added, or the pH is adjusted to 2-10 according to the constitution of the final product, the reaction mixture is extracted with ethyl acetate or dichloromethane, the organic phase is separated and dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography and / or crystallization .

HPLC (Rt retention time) analysis is performed using the following systems:

Silica Rod column with 210 second gradients from 20 to 100% water / acetonitrile / 0.1% trifluoroacetic acid, at a flow rate of 2.2 ml / min and detected at 220 nm.

Mass Spectrometry (MS): EI (electron impact-ionization)

M ⁺

FAB (fast atom bombardment) (M + H) ⁺

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 3- (4-fluorophenyl) -4- (4- [3- (pyridin-2-ylamino) propoxy] phenyl] butyric acid

835 mg of magnesium is suspended in 5 ml of absolute tetrahydrofuran. A solution of 2.0 g of 4-benzyloxybenzyl chloride in 5 ml of absolute tetrahydrofuran was added dropwise. When the addition is complete, the cloudy solution is stirred at room temperature for an additional hour, followed by the addition of a solution of 1.73 g of 2-cyano-3- (4-fluorophenyl) acrylic acid ethyl ester in 10 ml of absolute toluene and refluxing. 16 hours. The solvent was removed and conventional work-up gave 4- (4-benzyloxyphenyl) -2-cyano28.

-3- (4-fluorophenylbutyrate (AA)).

8.27 g of AA are suspended in a mixture of 80 ml of acetic acid and 80 ml of concentrated hydrochloric acid and the reaction mixture is refluxed for 16 hours. Conventional work-up gives 4- (4-hydroxyphenyl) -3- (4-fluorophenyl) butyric acid (AB).

A solution of 1.0 g AB in 10 ml absolute methanol was treated with 0.4 ml thionyl chloride and the reaction mixture was stirred at room temperature for 16 hours. Conventional work-up gives 4- (4-hydroxyphenyl) -3- (4-fluorophenyl) butyrate (AC).

pan-1-ol suspension load

0.4 g of AC, and 1.23 g of approximately mmol / g in the mixture are stirred with the solvent to obtain triphenylphosphine (ml absolute for an additional 16 hours. After the product is purified

0.62 ml of diethyl azadicarboxylate is added dropwise to the reaction mixture

0.5 g of 3- (1-oxypyridin-2-ylamino) -propolymer bound tetrahydrofuran and reaction filtration and removal by HPLC chromatography to give 3- (4-fluorophenyl-4- {4- [3- (1-oxypyridin-2-) ylamino) propoxy] phenyl} butyrate (AD).

A solution of 0.45 g of AD in 30 ml of chloroform is mixed with 0.59 g of phosphorus trichloride, and the reaction mixture is stirred at room temperature for two hours and refluxed for a further two hours. After the usual work-up, the residue in 15 ml of methanol is treated with 0.2 g of lithium hydroxide and the reaction mixture is stirred at room temperature for 16 hours. After removal of the solvent, 0.66 ml of trifluoroacetic acid is added and the product is purified by HPLC chromatography to give 3- (4-fluorophenyl) -4- [4- (3- (pyridin-2-ylamino) propoxy) phenyl] butyric acid trifluoroacetate.

Test results d € v / 3 ₃ inhibition of 3- (4-phenyl-4-4- £ 3- (pyridin-2-ylamino) propoxy phenyl] butyric acid

For the vitronectin binding assay, an IC ₅₀ value, i.e., a concentration in nmol / liter, that inhibits the binding of vitronectin to the corresponding isolated receptor by 50% (method described by Smith et al., J. Biol. Chem. 265, 12267-12271) 1990).

The IC _5Q CZV / S _3: 10

The pharmacological value confirms the? Receptor antagonist activity of the compound of the invention.

The following compounds are obtained in a similar manner to that described above.

3- (4-Fluoro-phenyl-4- [4- (2- (pyrimidin-2-ylamino) -ethoxy) -phenyl] -butyric acid, trifluoroacetate,

3- (4-Fluorophenyl-4- [4- (3- (pyrimidin-2-ylamino) propoxy] phenyl) butyric acid,

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) butoxyl phenyl] butyric acid, trifluoroacetate,

3- (4-Fluorophenyl-4- [4- (3- (imidazol-1-ylamino) propoxy) phenyl] butyric acid,

3- (4-Fluoro-phenyl-4- [4- (3- (4,5-dihydro-1H-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

Preparation of (4-Fluorophenyl-4- (3- (pyridin-2-ylamino) propoxy) benzyl} amino) acetic acid

Dissolve 40.0 g of 4-hydroxybenzaldehyde in 400 ml of absolute tetrahydrofuran under shielding gas, add 55.1 g of dihydropyran and 13.7 g of pyridinium p-toluenesulfonate and stir the reaction at room temperature overnight. The solvent was removed by rotary evaporation, and the residue was worked up in the usual manner to give 4- (tetrahydro-pyran-2-yloxy) -benzaldehyde (BA) as a colorless oil.

Aniline (1.17 g) was added to a solution of BA (2.0 g) in absolute methanol (20 ml) and the reaction mixture was stirred at 60 ° C for three hours. 0.79 g of sodium cyanoborohydride is added at room temperature and the reaction mixture is refluxed for 16 hours. The solvent was removed, the reaction mixture was worked up in the usual manner and purified by chromatography to give 4-fluorophenyl-4- (tetrahydropyran-2-yloxy) benzyl amine (BB) as a colorless liquid.

Dissolve 8.0 g of BB and 10.36 g of methyl bromoacetate in 100 ml of absolute tetrahydrofuran under nitrogen, add 12 g of potassium carbonate and reflux the reaction mixture for 16 hours.

The reaction mixture is worked up in the usual manner and purified by chromatography to give [E4-fluoro-phenyl] - {4- (tetrahydropyran-2-yloxy) -benzyl] -amino} -acetic acid methyl ester (BC) as a colorless solid.

2.76 ml of concentrated hydrochloric acid are added to a solution of 0.5 g of BC in 25 ml of methanol and 5 ml of dichloromethane, and the reaction mixture is stirred at room temperature for 5 minutes. The solvent is removed, the reaction mixture is worked up in the usual manner and the residue is dissolved in 16 ml of absolute tetrahydrofuran together with 0.47 g of 3- (1-oxypyridin-2-ylamino) propan-1-ol and then 1.17 g is added to the reaction mixture. bound triphenylphosphine polymer (loading about 3 mmol / g). 0.62 ml of diethyl azadicarboxylate is added dropwise. The resulting suspension was stirred for 16 hours at room temperature. After filtration and removal of the solvent, the product is purified by HPLC chromatography to give 4- [3- (1-oxypyridin-2-ylamino) propoxy-3-benzyl} - (4-fluorophenyl) amino acetic acid methyl ester (BD).

0.57 g of phosphorus trichloride is added to a solution of 0.44 g of BD in 30 ml of chloroform, and the reaction mixture is stirred for two hours at room temperature and refluxed for a further two hours. Working up in a known manner, 0.27 g of lithium hydroxide was added to the residue in 15 ml of methanol and the reaction mixture was stirred for 16 hours at room temperature. After removal of the solvent, 0.66 ml of trifluoroacetic acid is added and the product is purified by HPLC chromatography to give (4-fluorophenyl- {4- [3- (pyridin-2-ylamino) propoxy] benzy13-amino) -acetic acid as bistrifluoroacetate of formula

The following compounds are obtained in a similar manner:

((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-η 4 - [4- (pyrimidin-2-ylamino) butoxy7benzyl-amino) acetic acid, ((4-fluorophenyl-η 4 - [2- (pyridin-2-ylamino)) (ethoxy) benzyl] amino) acetic acid, ((4-fluorophenyl-4- (4- (pyridin-2-ylamino) butoxy) benzyl) amino) acetic acid, ((4-fluorophenyl) -? -? - (imidazole-1) (y-amino) propoxy] benzyl} amino) acetic acid, ((4-fluorophenyl- [4- (3- (4,5-dihydro-1H-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

In a similar manner to Example 1, the following compounds were obtained:

3- (3-chloro-4-phenyl) phenyl-4- [4- (3- (pyridin-2-ylamino) propoxy) phenyl] butyric acid,

Cl

OH

3- (2-Bromophenyl) -4- [4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid,

3- (3,4-Dichlorophenyl) -4- [4- (3- (pyridin-2-ylamino) propoxy) phenyl} butyric acid,

3- (4-Bromophenyl) -4- [4- (3- (pyridin-2-ylamino) propoxy) phenyl] butyric acid,

3- (2,3-Dichloro-phenyl) -4- [3- (pyridin-2-ylamino) -propoxy] -phenyl] -butyric acid

3- (2,4-Dichlorophenyl) -4- [4- (3- (pyridin-2-ylamino) propoxy) phenyl] butyric acid,

3- (3-bromophenyl) -4- [4- (3- (pyridin-2-ylamino) propoxy) phenyl} butyric acid,

3- (2,6-Difluorophenyl) -4- [4- (3- (pyridin-2-ylamino) propoxy) phenyl] butyric acid,

3- (3,5-Dichloro-phenyl) -4- [4- (3- (pyridin-2-ylamino) -propoxy] -phenyl} -butyric acid.

The following examples illustrate but do not limit the pharmaceutical compositions of the invention:

Example A. Injection ampoules

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 in 3 liters of double-distilled water is treated with 2 N hydrochloric acid to pH 6 5, sterile filtered, filled into injection ampoules, lyophilized under sterile conditions and sealed. Each vial contains 5 mg of active ingredient.

Example B. lace

A mixture of 20 g of 3- (4-fluorophenyl) -4- [4- (3- (pyridin-2-ylamino) propoxy) phenyl] butyric acid with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to solidify . Each suppository contains 20 mg of active ingredient.

Example C. Solution

A solution of 1 g of 3- (4-fluorophenyl) -4- [4- [1,3- (pyridin-2-ylamino) propoxy] phenyl] butyric acid and 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of sodium hydrogenphosphate with 10 water molecules and 0.10 g is prepared. 1 g of benzalkonium chloride in 940 ml of double-distilled water. The pH is adjusted to 6.8, made up to 1 liter and sterilized by irradiation. This solution can be used, for example, as eye drops.

Example D. Mast

500 mg of 3- (4-fluorophenyl) -4- (4- (1,3-pyridin-2-ylamino) propoxy) phenyl} butyric acid and 99.5 g of petroleum jelly under aseptic conditions are mixed.

Example E. Tablets

Mixture of 1 kg of 3- (4-fluorophenyl) -4- [4- [3- (pyridin-2-ylamino) propoxy] phenyl] butyric acid, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0 1 kg of magnesium stearate is compressed in known manner into tablets, each tablet containing 10 mg of the active compound of the formula I.

Example F. Coated tablets

Similar to Example E, tablets are compressed and coated in a manner known per se. sucrose, potato starch, talc, tragacanth and dye.

Example G. Capsules

2 kg of 3- (4-fluorophenyl) -4- [4- [3- (pyridin-2-ylamino) -propoxy] phenyl} butyric acid is filled into hard gelatin capsules, each capsule containing 20 mg of the active compound of the formula I.

Example H. Ampoules

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

Example I. Inhalation Spray

Dissolve 14 g of 3- (4-fluorophenyl) -4- [4- (3- (pyridin-2-ylamino) propoxy) phenyl} butyric acid in 10 l of isotonic sodium chloride solution and fill into conventional commercial spray canisters with a pump mechanism . The solution may be sprayed into the mouth and nose, corresponding to a dose of approximately

Each spray (approx

0.14 mg.

0.1 ml)

Industrial applicability of ceutical coronary treatments

Integrin inhibitors of compositions, diseases, diseases as in ₃ particularly suitable for are thromboses, heart, inflammation, farmosteoporosis, affecting fibrosis, wound healing processes. for the production of prophylaxis of heart attack, arteriosclerosis, tumors, infections, psoriasis and

Claims (10)

PATENT CLAIMS A compound of formula I XYZR ¹ -CH 2 -R ² (R ⁴ ) -ch ² -co-r ⁵ (I) wherein H ₂ NC (= NH) -, H ₂ NC (NH) -NH, AC (= NH) -NH, Het ¹ - or Het ¹ -NH-, wherein the primary amino groups commonly are optionally protected with amino protecting groups, - (CH ₂ ) _n or R ³ wherein the groups and / or sulfur, one, two, three or four methylene groups may be replaced by a nitrogen atom, an oxygen atom is absent or an oxygen atom, an -NH- group, -NA -, - CH (OH) -, -CH (OA) -, -CHA-, -CA ₂ - or -S-, R ^{1 is} a substituted, unsubstituted, disubstituted phenylene or F, Cl, Br, A, OA, OCF 8 or monotrisubstituted CN, R ² N, CH or CA, R ³ is H, F, Cl, Br, A, OA or _OCF3, R ^{4 is} phenyl, naphthyl or Het ² , wherein each group is unsubstituted, monosubstituted or polysubstituted with F, Cl, Br, A, Aryl, OA, SA, CO-A, CN, COOA, CONH ₂ , CONHA, CONA ₂ or NO ₂ , R ⁵ OH, OA, NH ₂ , NHA or NA ₂ Het ¹ a monocyclic or bicyclic heterocyclic group having 1 to 4 nitrogen atoms unsubstituted or monosubstituted or disubstituted with nh ₂ , Het ² aromatic monocyclic or bicyclic heterocyclic group of 1 to 3 nitrogen, oxygen and / or sulfur unsubstituted or monosubstituted or disubstituted by F, Cl, Br, A, OA, SA, OCF ₃ , -CO-A, CN, COOA, CONH ₂ , CONHA, CONA ₂ or NO ₂ , aryl unsubstituted or monosubstituted or polysubstituted phenyl or naphthyl, Hal, A, OA, OH, -CO-A, CN, COOA, COOH, CONH ₂ , CONHA, CONA ₂ or NO ₂ , A (C 1 -C 12) alkyl; n 1, 2, 3, 4, 5, or 6 m, o, each independently 0, 1, 2, 3, 4, 5 or 6, while however, R ^{4 is} not phenyl or naphthyl substituted with A or Aryl, and physiologically acceptable salts and solvates thereof. A compound of formula I according to claim 1 selected from the group consisting of (a) 3- (4-fluorophenyl) -4- (4-L3- (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 physiologically acceptable salts and solvates thereof. A process for the preparation of a compound of formula I, wherein the individual symbols are as defined in claim 1 and salts thereof according to claim 1, characterized in that (a) releasing a compound of formula (I) from its functional derivative by a solvolyzing, reducing or hydrogenolyzing agent; or (b) the group X and / or R ⁵ is converted to another group X and / or R ⁵ 'so that i) converting an amino group to a guanidino group by reaction with an amidating agent, ii) saponifying the ester, iii) converting hydroxyamidine to amidine by hydrogenation, and / or converting a base or acid of formula I to its salt. A compound of formula I according to claim 1 and a compound according to claim 2, and physiologically acceptable salts and solvates thereof as medicaments. 5. Medicament according to Claim 4 as integrin inhibitors for the treatment of diseases dependent on the expression and pathological function of the <^ v ^ ₃ integrin receptors. The medicament of claim 5 for the treatment of diseases such as thrombosis, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, fibrosis, inflammation, infection, psoriasis, and for influencing wound healing processes. Pharmaceutical composition, characterized in that it contains, as active ingredient, at least one medicament according to claim 5 and 6a, optionally carriers and / or auxiliaries and optionally other active ingredients. Use of the compounds of formula I according to claims 1 and 2, or of their physiologically acceptable salts, for the manufacture of a medicament for the treatment of diseases dependent on expression and pathological function at the ₃ integrin receptors. The ingestion of claim 8 for the manufacture of a medicament for the treatment of pathological processes which are maintained or spread by angiogenesis. Use according to claim 8 for the manufacture of a medicament for the treatment of diseases such as thromboses, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, fibrosis, inflammations, infections, psoriasis and to affect wound healing processes.