CZ2002523A3 - Inhibitors of integrin alpha in beta 3 - 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 present invention relates to novel compounds of formula I

XYZR ¹ -CH ₂ -R ² (R ⁴ ) -CH 2 -CO-R ⁵ Cl) where iX is H ₂ N-CC = NH) -, H ₂ N-CC = NH) -NH, A-CC = NH) -NH-, Het ¹ -, or Het ¹ -NH-, wherein the primary amino groups are optionally protected with conventional amino protecting groups.

Y is -CCH ₂₎ n or

- (CH ₂ )

ch ₂ ) ₀ wherein one, two, three or four methylene groups may be replaced by nitrogen, oxygen and / or sulfur,

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

-CHCOH) -, -CHCOA) -, -CHA-, -CA ₂ - or -S-, /

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

R ² is N, CH or CA,

AND.

4 4

4494 4 · 9494

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

R ⁴ is phenyl, naphthyl or Het ² , each of which 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, _NH2, NHA or NA 2,

Het ¹ monocyclic or bicyclic heterocyclic group having 1 to 4 nitrogen atoms unsubstituted or monosubstituted or disubstituted NH2,

Het ^{2 is an} aromatic monocyclic or bicyclic heterocyclic group having 1 to 3 nitrogen, oxygen and / or sulfur atoms unsubstituted or monosubstituted or disubstituted with F, Cl, Br, A, OA, SA, OCF 3, -CO-A, CN, COOA, CONH2, CONHA, CONA2 or NO ₂ ,

Aryl phenyl or naphthyl unsubstituted or monosubstituted or polysubstituted by Hal, A, OA, OH, -CO-A, CN, COOA, COOH, COH ₂ , CONHA, CONA2 or NO2,

A is an alkyl group having 1 to 12 carbon atoms, n, 2, 3, 4, 5 or 6, m, o, independently of each other 0, 1, 2, 3, 4,5 or 6, but R ⁴ does not 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 present invention to provide novel compounds having valuable properties which are particularly suitable for the manufacture of medicaments.

• • •

BACKGROUND OF THE INVENTION

It has been found that the compounds of the 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 αv integrin receptors with ligands. The compounds are particularly effective in the case of αv β 33 and α v β 3 integrins. The compounds are very particularly effective as adhesion receptor antagonists for the α v β 3 receptor. This action can be demonstrated, for example, by the method described by J.W. Smith et al. (J. Biol-Chem. 265, 11008-11013 and 12267-12271, 1990).

Inhibition of vitronection binding to the α 1 receptor is experimentally demonstrated for 3- (4-fluorophenyl) -4- <4- [3- (pyridin-2-ylamino) propoxy] phenylbutyric acid.

B. Felding-Habermann and D.A. Cheresh (Curr. Opin. Cell. Biol. 5, p. 864, 1993) describe the importance of integrins as adhesion receptors for various phenomena and symptoms of diseases, particularly with respect to the receptor (33). Other acv @ 3 integrin inhibitors are described in European patent specification. Vitronectin receptor antagonists are also described in WO 97/24124 and EP 0 820991.

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, p. 1157 to • «44 44» »« 44 »· · · · · · · · · · · · · · · ·

444 4 ·· 4 · · 4 4 · 4 44 4444 44 4444 4 · 4444

1164 (1994) described the possibility of using inhibition of this interaction and 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 2825-2838 (1995).

P..Crooks et al. <J. Clin. Invest. 96, pp. 1815-1822 (1995) discloses ββ3 antagonists for the treatment of cancer and for the treatment of tumor-induced angiogenic disorders. F

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 the suppression of angiogenesis.

Compounds of formula I that block the interaction of iritegrin receptors and ligands, such as fibrinogen with the fibrinogen receptor (glycoprotein IIIbIIa), inhibit, as GPIIb / IIIa antagonists, tumor cell scattering by metastasis. This is evidenced by the following findings:

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 settle on the walls of blood vessels, thereby facilitating further penetration of tumor cells into the tissue. Since microtromb formation is mediated by fibrinogen binding to fibrinogen receptors on activated platelets, GPIIb / IIIa antagonists can be considered as potent metastasis inhibitors.

• ·

4 4 4 • · 44 4 «4444

In addition to the binding of fibrinogens, fibronectin and von Willebrand factor to the platelet fibrinogen receptor, the compounds of formula I also inhibit the binding of other adhesive 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 thromboses, apoplexy, heart attack, inflammation and arteriosclerosis.

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

The inhibitory effect of platelet aggregation can be demonstrated in vitro by the method described by Born (488: 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 an integrin inhibitor as described above.

The invention therefore relates to compounds of 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 formula (I) may be used as active medicaments in human and veterinary medicine, in particular for the preparation of a medicament

phylaxis and / or for the treatment of thromboses, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina pectoris, cancer, osteolytic diseases such as osteoporosis, hypercalcemia, pathologically angiogenic diseases such as inflammation, corneal ophthalmologic diseases, diabetic diabetic diseases , myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rhubeotic glaucoma, ulcerative colitis, Crohn's disease, atherosclerosis, psoriasis, angioplasty restenosis, viral infections, bacterial infections, fungal infections and acute renal failure, and acute renal failure and acute renal failure of healing processes.

The compounds of the formula I can be used as arithicrobial agents in operations using biological material, implants, catheter or cardiac stimulators. These compounds are antiseptic. The efficacy of antimicrobial activity can be demonstrated by the method of P. Valentin-Veigund et al. (Infection and Immunity, 1988, 2851-2855).

The invention also relates to hydrates and solvates, for example alcoholates of 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 are as defined above, or their salts, is characterized in that:

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

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

(i) converting an amino group to a guanidino group by reaction with an amidating agent, · · ♦ gu gu gu gu gu gu gu gu gu gu gu gu gu gu gu gu gu (ii) saponification of the ester, (iii) conversion of hydroxyamidine to amidine by hydrogenation, and / or or the base or acid of formula I is converted to its sf11.

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 invention also include so-called prodrug derivatives, i.e., alkyl or acyl groups, sugars or oligopeptides of a compound of the formula I which are rapidly cleaved into the active compounds of the invention.

Abbreviations used have the following meanings:

ftc acetyl BOC tert-butoxycarbones CBz or From benzyloxycarbonyl DCCI dicyclohexylcarbodiimide DMF dimethylformamide EDCI , N-ethyl-N, N (dimethylaminopropyl) carbodiimide Et ethyl Fmoc 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazo1 HONSu N-hydroxysuccinimide Me methyl Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl Obut tert-butyl ester Oct octanoyl OEt ethyl ester About me methyl ester POft f enoxyacety1

TFA trifluoroacetic acid

Trt trityl (triphenylmethyl)

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

In the above formulas, A is especially alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms and preferably A is methyl, ethyl, propyl, isopropyl, butyl , isobutyl, sec-butyl or tert-butyl, also pentyl, 1-, 2- or 3-methylbutyl,

1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-,

2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and 1,1,2 or 1,2,2-trimethylpropyl, a heptyl, octyl, nonyl, decyl, undecyl or dodecyl group. The hydrogen atom in the alkyl groups may be replaced by halogen atoms. Thus, A may be preferably trifluoromethyl.

X is preferably, for example, 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-aminopyridin-6-ylamino, 2-aminoimidazol-5-yl or 2-aminopyridin-6-yl.

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

Z is preferably, for example, an oxygen atom.

R @ ¹ is preferably, for example, 1,4-phenylene.

• In '»' · * ·». · '♦ »>>>>>>>>>>> · · · · · · · ·

R @ ² is preferably, for example CH or N, particularly preferably CH.

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

R @ ⁵ is preferably, for example, hydroxyl group.

Preferably, Het ^{1 is} unsubstituted or A, NHA and / or NH 2 monosubstituted or disubstituted 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 being 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-isoquinolyl ,

3-, 4-, 5-, 6-, 7- or 8-cinnolinyl or 2-, 4-, 5-, 6-,

7- or 8-quinazolinyl, 1H-imidazo [4,5-b] pyridin-2-yl or 1,8-naphthyridin-7-yl.

The heterocyclic groups may also be partially or fully 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

4 4 4 4 ’4 '· 4 4 4 4 4 4 4

piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or 8-ehinolyl. 1,2,3,4-Tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolinyl or 1,2,3,4- tetrahydro-1,8-naphthyridin-7-yl. Hydrogenated or partially hydrogenated Het ¹ groups can be additionally substituted with = NH or carbonyloxy. Preferably, Het ^{2 is} 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, 2,4-, 2,5, - 2,6-, 4,5 - or 5,6-pyrimidinyl, each of which is unsubstituted or monosubstituted by fluorine, chlorine or bromine, A, OA or OCF _3; n is preferably 2, 3, 4, 5 or 6, furthermore 1, 3, 4 or 5.

The index m and o are preferably independently of one another □, 1 or 2 and most preferably 0.

The term monosubstituted or polysubstituted means that the group has one, two, three or four specified substituents. The symbol Aryl means a substituted, preferably, as indicated, substituted phenyl group, particularly preferably an o-, m- or p-tolyl group, 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, ο-, o m- or p-methylthiophenyl, o-, m- or p-methylsulfinylphenyl, o-, m- or p-methylsulfonylphenyl, o-, m- or p-aminophenyl, ο-, n- or p-methylamino-phenyl, o-, m- or p-dimethylaminophenyl. o-, ra- or p-nitrophenyl, o-, m- or p-acetylphenyl, o-, m- or p-methoxycarbonylphenyl, o-.

2.3-, 2.4-,

2,4-, 2,5-, ra- or p-aminocarbonylphenyl, further preferably

2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-,

2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-,

3,4- or 3,5-dibroraphenyl, 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-chlorophenyl -met-hy 1 female,

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.

Preferably, the amino protecting group is form 1, acetyl, proplonyl, butyryl, phenylacetyl, benzoyl, toluyl, POft, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl, CBZ, methoxybenzyloxycarbonyl, 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 12

Φ · φ · · · · • · • · • · • · • ·

Φ Φφφφ Φφφφ φ

I are the following compounds of the formulas Ia to Im, wherein the symbols not particularly indicated have the meanings given in formula I, wherein in the formula Ia) X is pyrimidin-2-ylamino, pyridine 2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino, 2-aminoimidazol-5-ylamino, 2- aminopyridin-6-ylamino, 2-aminoimidazol-5-yl or 2-aminopyridin-6-yl:

1b) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazole -2-ylamino,

Y is -CCH2) n-, π 2, 3 or 4;

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

Y is - (CH 2) n ^- , n 2,3 or 4;

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

Y is - (CH 2) n -, n 2, 3 or 4,.

Z O:

le) X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, φ · »· φ ·» · φ · « · · 99 ··· ig)

(Lh) benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino,

Y is - (CH 2) n -, n 2,3 or 4,

Z O,

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 is - (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, COH ₂ or NO ₂ phenyl group;

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

Y is -CCH2) n-, n 2, 3 or 4,

Z O,

R ² N or CH,

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

^R5 OA or OH;

X pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-ylamino, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino, 44 4 »·· ·· '4 4 4 ·' 4 '4 4 4' 9 4 4

4 4 4 '·. '4 4 .4 ·' 4 »'4 4 4 4 (444> 4444 <4444 44 4444 ·· li)

Ik)

Y is -CCH 2) n -, n 2, 3 or 4,

Z O,

R ² N or CH.

R ^{4 is} a monosubstituted or polysubstituted phenyl group.

R ⁵ OH or OA.

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

Y is -CCH2) n-.

n 2, 3 or 4

Z O.

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:

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

Y is - (CH 2) n -, n 2, 3 or 4,

Z 0,

R ² N or CH,

R ^{4 is a} phenyl group substituted with Hal and Aryl,

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

II) X pyrimidin-2-ylamino, pyridin-2-ylamino,

imidazol-2-yl-amino, imidazol-2-yl-amino, benzimidazol-2-ylamino, 4,5-dihydroimidazol-2-ylamino,

Y is - (CH 2) n -, n 2, 3 or 4,

Z O,

R ² N or CH.

R ^{4 is a} phenyl group substituted with Hal and Aryl,

R ⁵ OH or OA.

Aryl is phenyl which is monosubstituted, disubstituted or trisubstituted by Hal, OA, A, CF 3, CN or N0 _2, provided that R ⁴ is not a group A, or aryl monosubstituted tuovanou phenyl or naphthyl group;

Im) 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-aminopyridin-6-ylamino, 2-aminoimidazol-5-yl or 2-aminopyridin-6-yl;

Y is - (CH 2) n -, n 2, 3 or 4,

Z O,

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 is a monosubstituted phenyl or naphthyl group.

The compounds of formula (I) and the starting materials for their preparation are prepared by methods known per se, as described in the literature (for example, in standard publications such as Houben-Veyl, Methoden der organischen Chemie, Georg-Thieme).

4 «49 99 ·· 49 · · 9 '9 4 · 4 4 4 4

4 '9 9>' 9 9 9 '> 4 4 4.4 9 9 4 4', 4 4 4 <· ♦ · ‘49 4449 44 4444

Verlag, Stuttgart) under reaction conditions which are known and suitable for the above reactions. It is also possible to use variants which are known per se, not described here in greater detail.

The starting materials can optionally be formed in situ, i.e. they are not isolated from the reaction mixture, but are immediately used for the preparation of the compounds of formula I.

Λ

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

For solvolysis or hydrogenolysis, the compounds of the formula I which have corresponding protected amino and / or hydroxyl groups in place of one or more free amino and / or hydroxyl groups, preferably compounds having an amino protecting group in place of a hydrogen atom bonded, are suitable as starting materials. on a nitrogen atom, especially compounds having an R'-N group, wherein R 'is an amino protecting group instead of an HN group and / or compounds having a hydroxyl protecting group instead of a hydrogen atom of a hydroxyl group, for example compounds of formula I but have the group -COOR '* where R' 'is a hydroxyl protecting group instead of -COOH.

It is also possible that there are several identical or different amino and / or hydroxyl protecting groups 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 generally known and refers to groups which are suitable for protecting (to block) the amino group from chemical reactions but which are readily removable when a reaction elsewhere on the molecule is desired

Υ7 · Φ · · · · · · · φ ·> · · φ ':::::::: · · · φ φ φ'φ φφφφ φφ φφφφ φ φ · ¹ ·· φφ made. Typically, such groups are unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protecting groups are removed after the desired reaction (or sequence of reactions), their type and size are not critical. Preferred are, however, groups having 1 to 20 carbon atoms and especially 1 to 8 carbon atoms. The term acyl is always meant in the broadest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, and in particular alkoxycarbonyl, aryloxycarbonyl and, in particular, aralkoxycarbonyl groups. Examples of such acyl groups include alkanoyl groups such as formyl, acetyl, propionyl, butyryl: aralkanoyl groups such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl (BOC), 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as the benzyloxycarbonyl (carbobenzoxy-CBZ), 4-methoxybenzyloxycarbonyl (MOZ), or 9-fluorenylmethoxycarbonyl (Fmoc) group; and arylsulfonyl such as 4-methoxy-2,3,6-trimethylphenylsulfonyl (Mtr). Preferred amino protecting groups are BOC, and Mtr, and also CBZ, Fmoc, benzyl, formyl and acetyl.

Depending on the protecting group used, cleavage of the amino protecting group is successful, for example with strong acids, preferably trifluoroacetic acid or perchloric acid, but also with other strong inorganic acids such as hydrochloric or sulfuric acids, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzenesulfonic acid or -toluenesulfonovou. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are, for example, 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. mixtures of these solvents may also be suitable, such as methanol, ethanol or isopropanol, as well as water, and trifluoroacetic acid is preferably used in excess without the addition of other solvents;

perchloric acid in the form of a mixture of acetic acid and 70¾ perchloric acid in a ratio of 9 = 1

it is suitably about 0 to about 50 ° C, preferably 15 to 30 ° C

C (room temperature) The BOC, OBut, and Mtr groups may, for example, be advantageously cleaved with trifluoroacetic acid in dichloromethane, or by using approximately 3 to 5n hydrochloric acid in dioxane at a temperature of 15 to 30 ° C; , for example dimethylamine, diethylamine or piperidine in dimethylformamide at 15 to 30 ° C.

Hydrogenolytically removable protecting groups (e.g., CBZ or benzyl) may be cleaved, 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 coal). 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, at a pressure of about 0.1 to 20 MPa, preferably at a temperature of about 20 to 30 C, at a pressure of about 0.1 to 10 MPa. Hydrogenolysis of the CBZ group is successful, for example, on 5 to 10¾ palladium on carbon in methanol or with 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 tetrachloroethane, 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 butanone; amides such as acetamide, dimethyl acetamide, dimethylformamide (DMF): 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. Conveniently, this is accomplished 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 ° C, preferably 10 to 40 ° C.

Conversion of the cyano group to an amidino group is accomplished by reaction with, for example, hydroxylamine and subsequent reduction of N-hydroxyamidine with hydrogen in the presence of a catalyst such as palladium on carbon. In addition, the conventional amino-protecting group can be replaced by a hydrogen atom. hydrogenolytically or a conventional amino-protecting group is liberated by solvolysis or hydrogenolysis. For the preparation of compounds of formula I wherein X is

4 «. 4 '-4 · 4> to' 4 '4 to 4 · this · 4' 4 fto · 4 · 4 · 4 to 4 4 4 to 4 4 4 to 4 4 4 The 4444 H2 group NC (= NH) -NH-, the corresponding amide may be treated with an amidating agent. A preferred amidinating agent is 1-amidino-3,5-dimethylpyrazole (CDPFN), which is especially used in the form of its nitrate. The treatment is preferably carried out with an additive of a base, such as triethylamine or ethyldiisopropylamine, in an inert solvent or solvent mixture, for example in a mixture of water and dioxane, at a temperature of 0 to 120 ° C, preferably 60 to 120 ° C. 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 a multi-stage manner known per se: (a) converting the nitrile with hydrogen sulfide to a thioamide which is converted with an alkylating agent, for example methyl iodide, to the corresponding S-alkylimidothioester which is reacted as such with ammonia to obtain amidine; 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 the oxyheterocyclic compound using a reducing agent such as phosphorus trichloride in an inert solvent.

The free amino groups may further be acylated in a manner known per se 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 a temperature of -60 to 30 ° C.

The base of formula (I) can be converted into an acid by converting it to an acid of &quot; -4 &quot;

4 4 4 4 4 4 4 4 4 ', · 4 4 4 4 · 4 · 4 · 4 · 4 4 · 4 ·

4, 4444 4, 4444 .44 · 4 · 4 an appropriate acid addition film, for example by reacting an equivalent amount of a base and an acid in an inert solvent such as ethanol and subsequently evaporating the solvent.

Particularly suitable acids for this reaction are 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 ogranic acids may be used, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polyhydric carboxylic, sulfonic acids or sulfuric acids such as formic, acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, methanesulfonic, ethanesulfonic, ethanesulfonic, ethanesulfonic, ethanesulfonic -hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene monosulfonic and naphthalenedisulfonic and lauryl sulfuric acids. Salts with physiologically unacceptable acids, for example picrate, 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 to 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 of further substituted ammonium salts, for example dimethylammonium, diethylammonium, diisopropylammonium, monoethanolammonium, diethanolammonium, or diisopropylammonium, cyclohexylammonium, dicyclohexyl ammonium, dibasyl ammonium, dibenzylammonium, .

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 may be separated mechanically or chemically into their enantiomers by methods known per se.

44 44 Φφ • '· · · Φ · »φ

Φ Φ 4 · · φ

Φ 4 Φ 4 Φ φ

ΦΦΦ .ΦΦφ

ΦΦΦΦ'Φ.ΦΦ · Φ ΦΦΦΦ thiomers. Preferably, diastereomers 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. Separation of enantiomers is also preferred. using columns filled with optically active resolving agents (e.g. dinitrobenzoylphenylglycine); as eluent, for example, a hexane / isopropanol / acetonitrile mixture, e.g. in a volume ratio of 82-15-3, is suitable.

It is also possible to obtain optically active compounds of the formula I according to 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 a desired manner. They can be used as therapeutic agents, diagnostic agents and as reagents. They can be administered to humans or animals locally or systemically, orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, transdermally, nasally, by mouth or iontophoretically as suspension, emulsion or solution formulations, 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 new compounds with other techniques such as surgery, radiation, diagnosis, radiotherapy, photodynamic therapy and gene therapy and with other medicaments is also possible. Such medicaments may come from, for example, the cardiovascular system, the central nervous system, or oncology. They may be, for example, tumor agents such as 9 9 9 9

9 9 9 9 9 9

9 9 9 9 9

9 9 9 9 9 9

99.9 .9999 99 9 999 99 999 9 angiogenesis inhibitors or cytostatics, chemotherapeutic agents from the group consisting of 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 the formula I as defined above, including their physiologically acceptable salts as medicaments, diagnostic or reagents.

The invention particularly relates to corresponding medicaments as inhibitors for the treatment of diseases directly or indirectly dependent on the expression of the _α ν β3 integrin receptor, i.e. in particular of pathologically angiogenic diseases, thromboses, cardiac infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammation, infections and for influencing wound healing processes.

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

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 ββ3 integrin receptors, particularly pathologically angiogenic diseases, thromboses, heart attack, coronary heart disease. arteriosclerosis, tumors, osteoporosis, inflammation, 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 use

(E.g. oral) or for parenteral or topical administration or for administration in the form of inhaled sprays and which do not react with the compounds of formula I, such as water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerin triacetate, gelatin, carbohydrates such as lactose or starches, magnesium stearate, talc and vaseline. In particular, tablets, dragee pills, capsules,

X in I powders, granules, syrups, juices or drops, for rectal use suppositories, 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 resulting lyophilisates used, for example, for the preparation of injectables. The compositions may be sterilized and / or contain adjuvants such as glidants, preservatives, stabilizing agents and / or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffers, coloring agents, flavoring agents and / or one or more more active ingredients 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 carbon dioxide or fluorinated hydrocarbons). In this case, the active ingredient is used in micronized form, and at least one physiologically compatible solvent, for example ethanol, can be added. Inhalation solutions can be administered using devices known in the art for this purpose.

The compounds of the formula I according to the invention are generally employed in doses similar to those known in the art, particularly analogously to the compounds of U.S. Pat. No. 4,447,305, 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 particular dose for each individual depends on a variety of factors, such as the efficacy of the particular one used

Also compounds, on age, body weight, general health, sex, diet, at the time and route of administration, on the rate of excretion, on the combination of drugs and on the severity of a particular disease. Parenteral administration is preferred.

The invention is illustrated by the following examples. Temperatures are always given in degrees Celsius. The expression processing in the usual manner in the following examples illustrates:

If necessary, 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 and / or crystal chromatography isolation.

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

Silica Rod column with 210 second gradients from 20 to 100% water / acetonitrile / 0.01% trifluoroacetic acid, at a flow rate of 2.2 ml / min and detected at 220 nm.

Mass spectrometry (MS): EI (electron impact-ionization) M ⁺

FflB (fast atom bombardment) (M + H) ⁺

DETAILED DESCRIPTION OF THE INVENTION

Example 1.

Preparation of 3- (4-fluorophenyl) -4- (4-C3- (pyridin-2-ylamino) propoxylphenyl) 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 is 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. After 16 hours, the solvent was removed and the usual work-up gave 4- (4-benzyloxyphenyl) -2-cyano-3- (4-fluorophenylbutyrate (ΑΆ)).

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 of AB in 10 ml of absolute methanol was treated with 0.4 ml of 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).

0.62 ml of diethyl azadicarboxylate is added dropwise to a suspension of 0.4 g of AC, 0.5 g of 3- (1-oxypyridin-2-ylamino) propan-1-ol and 1.23 g of polymer-bound triphenylphosphine (loading approximately 3 mmol / g) in 17 ml of absolute tetrahydrofuran and the reaction mixture was stirred for an additional 16 hours. After filtration and removal of the solvent, the product was purified by HPLC to give 3- (4-fluorophenyl-4- (4-13- (1-oxypyridin-2-ylamino) propoxylphenylbutyrate (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 mixed with 0.2 g of lithium hydroxide and the reaction mixture is stirred at room temperature for 16 hours. After27 • ·

by removing 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) propoxylphenyl] butyric acid trifluoroacetate

Results of ανβ3 Inhibition of 3- (4-Fluorophenyl-4- (4- [3- (pyridin-2-ylamino) propoxy] phenyl) butyric acid inhibition test

The IC 50 value is given for the vitronectin binding assay. this is the concentration in nmol / liter that 50¾ inhibits the binding of vitronectin to the corresponding isolated receptor (the method described by Smith et al., J. Biol. Chem. 265, 12267-12271, 1990).

IC50 value νβ3 ^: 10

The pharmacological value confirms the? 3 receptor antagonist activity of the compound of the invention. The following compounds are obtained similarly to the method described above.

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

- (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-ylamino) propoxy) phenylbutyric acid;

3- (4-fluorophenyl) -4- (4- [3- (4,5-dihydro-1H-imidazol-2-ylamino) propoxy] phenyl) butyric acid;

- (4-fluorophenyl) -4- (4- [3- (imidazol-2-ylamino) propoxyl phenyl) butyric acid;

3- (4-fluorophenyl) -4- (4- [3- (benzimidazol-2-ylamino) propoxylphenylbutyric acid);

3- (4-fluorophenyl) -4- (4- [3- (2-aminopyridin-6-ylamino) propoxy) phenylbutyric acid;

3- (4-Fluorophenyl-4- (4-C 3- (2-aminoimidazol-5-ylamino) propoxy) phenylbutyric acid).

Example 2

Preparation of (4-Fluorophenyl- (4- [3- (pyridin-2-ylamino) propoxylbenzylamino) acetic acid

40.0 g of 4-hydroxybenzaldehyde are dissolved in 400 ml of absolute tetrahydrofuran in a protective gas medium, 55.1 g of dihydropyran and 13.7 g of pyridinium p-toluenesulfonate are added and the reaction mixture is stirred overnight at room temperature. The solvent was removed by rotary evaporation, and the residue was worked up in the usual manner to give 4- (tetrahydropyran-2-yloxylbenzaldehyde (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-tetrahydro-pyran-2-yloxyl-benzyl] -amine (BB) as a colorless liquid.

8.0 g of BB and 10.36 g of bromoacetic acid methyl ester are dissolved in 100 ml of absolute tetrahydrofuran under nitrogen, 12 g of potassium carbonate are added 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 (14-fluorophenyl-14- (tetrahydropyran-2-yloxy) benzyl] aminocetic acid methyl ester (BC) as a colorless solid.

2.76 ml of concentrated hydrochloric acid was added to a solution of 0.5 g of BC in 25 ml of methanol and 5 ml of dichloromethane and the reaction mixture was 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, followed by 1.17 g of triphenylphosphine bound polymer (loading about 3 mmol / g). 0.62 ml of diethyl azadicarboxylate was added dropwise. The resulting suspension was stirred for 16 hours at room temperature. After filtration and removal of the solvent, the product was purified by HPLC to give ((4-13- (1-oxypyridin-2-ylamino) propoxy) 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 another two hours. It is worked up in the usual way, added

0.27 g of lithium hydroxide to a residue in 15 ml of methanol is added and the reaction mixture is 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 to give (4- Fluorophenyl) - (4-13- (pyridin-2-ylamino) propoxy] benzyl) amino) acetic acid in the form of bistrifluoroacetate of formula

F

The following compounds are obtained in a similar manner:

((4-Fluorophenyl) - (4-12- (pyrimidin-2-ylamino) ethoxy] benzyl) amino) acetic acid:

((4-Fluorophenyl 1- (4- 13- (pyrimidin-2-ylamino) propoxy) benzyl) amino) acetic acid:

((4-Fluorophenyl 1- (4-14- (pyrimidin-2-ylamino) butoxy] benzyl) amino) acetic acid:

((4-Fluorophenyl 1- (4-12- (pyridin-2-ylamino) ethoxy] benzyl) amino) acetic acid:

((4-fluorophenyl- (4- [4- (pyridin-2-ylamino) butoxy] benzyl) amino) acetic acid;

((4-fluorophenyl 1- (4-13- (imidazol-1-ylamino) propoxy) benzyl) amino) acetic acid;

<(4-fluorophenyl-1,4-1- (4,5-dihydro-1H-imidazol-2-ylamino) propoxy] benzylamino) acetic acid;

((4-Fluorophenyl-4- [3- (imidazol-2-ylamino) propoxy] benzylamino) 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;

3- (2-bromophenyl) -4- (4- [3- (pyridin-2-ylamino) propoxy] phenyl) butyric acid;

3- (3,4-Dichlorophenyl) -4- (4-13- (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- {4-13- (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- (4-13- (pyridin-2-ylamino) propoxylphenyl) butyric acid;

3- (2,6-Difluorophenyl) -4- (4-13- (pyridin-2-ylamino) propoxy] phenyl) butyric acid;

3- (3,5-dichlorophenyl) -4- (4-13- (pyridin-2-ylamino) propoxy] phenyl) butyric acid.

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

Example A. Injection ampoules

A solution of 100 g of 3- (4-fluorophenyl) -4- (4-13- (pyridin-2-ylamino) propoxy) phenylbutyric acid and 5 g of disodium hydrogen phosphate is adjusted to pH 6 in 3 liters of double-distilled water with 2 N hydrochloric acid, 5, sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed, each ampoule containing 5 mg of active ingredient.

Example B. Suppositories

A mixture of 20 g of 3- (4-fluorophenyl) -4- <4- [3- (pyridin-2-ylamino) propoxy] phenylbutyric acid is melted with 100 g of soybean and 1400 g of cocoa butter, poured into molds and let it solidify. Each suppository contains 20 mg of active ingredient.

Example C. Solution

A solution of 1 g of 3- (4-fluorophenyl) -4- <4- [3- (pyridin-2-ylamino) propoxy] phenylbutyric acid and 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of 12-molecule disodium hydrogen phosphate, is prepared. water and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water. The pH is adjusted to 6.8, made up to one 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- [3- (pyridin-2-ylaminolpropoxy) phenylbutyric acid] and 99.5 g of vaseline under aseptic conditions are mixed.

Example E. Tablets

A mixture of 1 kg of 3- (4-fluorophenyl) -4- <4- [3- (pyridin-2-ylamino) propoxy] phenylbutyric 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 a manner known per se 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 known manner with a coating of sucrose, potato starch, talc, tragacanth and colorant.

Example G. Capsules

Fill 2 kg of 3- (4-fluorophenyl) -4- <4- [3- (pyridin-2-ylamino) propoxy] phenylbutyric acid into hard gelatin capsules. Each capsule contains 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] phenylbutyric acid in 60 liters of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions. It is sterilized and sealed. Each ampoule contains 10 mg of the active substance.

Example I. Inhalation Spray

Dissolve 14 g of 3- (4-fluorophenyl) -4- (4- [3- (pyridin-2-ylamino) propoxy] phenylbutyric 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 or nose. Each spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

Industrial applicability

Integrin inhibitors are useful for the manufacture of pharmaceutical compositions, particularly for the prophylaxis and treatment of diseases such as thrombosis, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, fibroses, inflammations, infections, psoriasis, and to affect wound healing processes.

Claims (10)

A compound of formula I XYZR ¹ -CH ₂ -R ² (R ¹ -Cl ¹ -CO-R ⁵ (I) wherein H _{2 is} NC (= NH) -, H ₂ N-CC = NH) -NH, A-CC = NH -NH-, Het ¹ -, or Het ¹ -NH-, wherein the primary amino groups are optionally protected with conventional amino protecting groups, -CCH ₂ ) n - or (CH ₂ ) _o wherein one, two, three or four methylene groups can be replaced by nitrogen, oxygen and / or sulfur, Z is absent or is oxygen, -NH-, -NA-, -CHCOH) -, -CH (OA) -, -CHA-, -CA ₂ - or -S-, R ^{1 is} a phenylene unsubstituted or monosubstituted, disubstituted or trisubstituted F, Cl, Br, A, OA, OCF 3 or CN group, R ² is N, CH or CA, R ³ is hydrogen, F, Cl, Br, A, OA or OCF 3, R ⁴ is phenyl, naphthyl or Het ² , each of which is unsubstituted, monosubstituted or polysubstituted with F, Cl, Br, A, Aryl, OA, SA, CO-A, CN, COOA, COH ₂ , CONHA CO ₂ or N0 ₂ , R ⁵ OH, OA, NH2, NHA or NA 2, Het ¹ monocyclic or bicyclic heterocyclic group having 1 to 4 nitrogen atoms unsubstituted or monosubstituted or disubstituted NH2, Het ^{2 an} aromatic monocyclic or bicyclic heterocyclic group having 1 to 3 nitrogen, oxygen and / or sulfur atoms unsubstituted or monosubstituted or disubstituted by F, Cl, Br, A, OA, SA, OCF 3, -CO-A, CN, COOA , CONH2, CONHA, CONA2 or NO2, Aryl phenyl or naphthyl unsubstituted or monosubstituted or polysubstituted by Hal, A, OA, OH, -CO-A, CN, COOA, COOH, CONH2, CONHA, COŇA2 or NO2, A is an alkyl group having 1 to 12 carbon atoms, n 1, 2, 3, 4, 5 or 6, m, o, independently of each other 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. A compound of formula I according to claim 1 selected from the group consisting of (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] phenylbutyric 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 a compound of formula (I), wherein each symbol is as defined in claim 1 and a salt thereof according to claim 1, characterized in that: (a) releasing a compound of formula (I) from its functional derivative by treatment with a solvolysing, reducing or hydrogenolysing agent; or (b) the group X and / or R ⁵ * is converted to another X and / or R ^{5 group} by: (i) converting an amino group into a guanidino group by reaction with an amidating agent; 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. The medicament of claim 4 as an integrin inhibitor for the treatment of diseases dependent on the expression and pathological function of the vβ3 integrin receptors. A medicament according to claim 5 for the treatment of diseases such as thrombosis, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, fibroses, inflammations, infections, psoriasis and for influencing wound healing processes. Pharmaceutical composition, characterized in that it contains at least one medicament as active substance. 4 4 4 4 4 4 4 4 4 4 4 4444 according to claims 5 and 6 and optionally carriers and / or auxiliaries and optionally other active ingredients. Use of the compounds of the 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 the expression and pathological function of the ββ3 integrin receptors. Use according to claim 8 for the manufacture of a medicament for the treatment of pathological processes which maintain or spread angiogenesis. Use according to claim 8 for the manufacture of a medicament for the treatment of diseases such as thrombosis, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, fibrosis, inflammation, infection, psoriasis and for influencing healing processes