KR20020016651A - NOVEL INTEGRIN αvβ3 INHIBITORS - Google Patents

Abstract

The present invention relates to novel compounds of formula (I) which are biologically active when present as α _Ｖ β ₃ integrin ligands:

[Formula I]

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

(Wherein X, Y, Z, R ¹ , R ² , R ⁴ and R ⁵ are the meanings in claim 1). The invention also relates to physiologically acceptable salts thereof and solvates thereof.

Description

Novel INTEGRIN αｖβ3 INHIBITORS

The present invention is a novel compound of formula (I):

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

(Wherein,

X is H ₂ NC (= NH)-, H ₂ NC (= NH) -NH-, AC (= NH) -NH-, Het ¹ -or Het ¹ -NH-, which is a common amino protecting group for primary amino groups Can be provided,

Y is Wherein one, two, three or four methylene groups may be substituted with N, O and / or S,

Z is absent or is -O-, -NH-, -NA-, -CH (OH)-, -CH (OA)-, -CHA-, -CA ₂ -or -S-,

R ¹ is unsubstituted or mono-, di- or trisubstituted phenylene with F, Cl, Br, A, OA, OCF ₃ or CN,

R ² is N, CH or CA,

R ³ is H, F, Cl, Br, A, OA or OCF ₃ ,

R ⁴ is phenyl, naphthyl or Het ² mono- or polysubstituted with F, Cl, Br, A, aryl, OA, SA, CO-A, CN, COOA, CONH ₂ , CONHA, CONA ₂ or NO ₂ ,

R ⁵ is OH, OA, NH ₂ , NHA or NA ₂ ,

Het ¹ is a mono- or dinuclear heterocycle having 1 to 4 N atoms, which may be unsubstituted or mono- or disubstituted with NH ₂ ,

Het ² is an N, O and / or S aromatic mono- or dinuclear heterocycle having 1 to 3 atoms, which may be unsubstituted or substituted with F, Cl, Br, A, OA, SA, OCF ₃ , -CO-A, CN, May be mono- or disubstituted with COOA, CONH ₂ , CONHA, CONA ₂ or NO ₂ ,

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

A is alkyl having 1 to 12 carbon atoms,

n is 1, 2, 3, 4, 5 or 6,

m, o are each independently 0, 1, 2, 3, 4, 5 or 6,

With the proviso that R ⁴ is not a monophenyl or naphthyl radical monosubstituted with A or aryl),

Physiologically acceptable salts and solvates thereof.

It is an object of the present invention to find novel compounds with good properties, in particular compounds which can be used for the preparation of a medicament.

It has been found that the compounds of formula (I) and salts thereof have very good physiological characteristics and good resistance. In particular, they act as integrin inhibitors which in particular inhibit the interaction of the α _V integrin receptor with the ligand. This compound has special activity on integrins α _v β ₃ and α _v β ₅ . This compound is particularly excellent in activity as an adhesion receptor antagonist of receptor α _v β ₃ . Such actions are described, for example, in JW Smith et al., J. Biol. Chem. 265 , 11008-11013 and 12267 and 12271 (1990).

For 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid experimentally confirmed inhibition of vitronectin binding to receptor α _v β ₃ It became.

Curr. Opin. Cell. Biol. 5 , 864 (1993), B. Felding-Habermann and DA Cheresh, disclose the importance of integrins as adhesion receptors, in particular with respect to receptor α _v β ₃ , in a variety of symptoms and signs.

Another inhibitor of integrin α _v β ₃ is disclosed in EP 0820988. Vitronectin receptor antagonists are also disclosed in WO 97/24124 and EP 0820991.

The dependence of the onset of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins is disclosed in PC Brooks, RA Clark and DA Cheresh, Science 264 569-71 (1994).

In PCBrooks, AM Montgomery, M. Rosenfeld, RA Reisfeld, T.-Hu, G. Klier and DA Cheresh, Cell 79 , 1157-64 (1994), cyclic peptides are used to inhibit such interactions. The possibility of initiating apoptosis (planned cell death) of vasculature-derived vascular cells is disclosed.

The compounds according to the invention can also inhibit the attachment of living cells to the corresponding matrix protein, and therefore can also inhibit the attachment of tumor cells to the matrix protein. Mitjans et al., J. Cell Science 108 , 2825-2838 (1995)], can be demonstrated experimentally.

J. Clin. Invest. 96 , 1815-1822 (1995), PC Brooks et al., Describe α _v β ₃ antagonists for cancer inhibition and for treating tumor-induced vasculature-derived diseases.

Thus, the compounds of formula (I) according to the invention can be used, in particular, as pharmaceutically active compounds for the treatment of tumor diseases, osteoporosis and osteolytic diseases and for inhibition of angiogenesis.

Compounds of formula (I) that block the interaction of integrin receptors with ligands (eg fibrinogen to fibrinogen receptors (glycoprotein IIb / IIIa)) are GPIIb / IIIa antagonists that inhibit the spread of tumor cells through metastasis. This is confirmed through the following observations:

Tumor cells, as a result of the interaction of platelets and tumor cells, form microaggregates (fine thrombosis), which diffuse from the local tumor into the vascular system. Tumor cells are shielded by microaggregates, so that immune system cells cannot recognize them. The microaggregates attach to the blood vessel walls, allowing tumor cells to more easily penetrate tissue. GPIIb / IIIa antagonists can be regarded as effective metastasis inhibitors, because fibrinogen binds to fibrinogen receptors on activated platelets to mediate the formation of microthrombosis.

Compounds of formula (I) also inhibit the binding of fibrinogen, fibronectin and von Willebrand factor to fibrinogen receptors on platelets, as well as other adhesion proteins such as vitronectin, collagen and laminin of various cell types. It also inhibits binding to the corresponding receptor on the surface. They especially inhibit the formation of platelet thrombi and can therefore be used for the treatment of thrombosis, stroke, myocardial infarction, inflammation and atherosclerosis.

The properties of such compounds can also be confirmed by the method of EP-A1-0 462 960. Inhibition of the binding of fibrinogen to the fibrinogen receptor can be confirmed by the method of EP-A1-0 381 033.

Platelet aggregation-inhibitory action can be confirmed in vitro using the method of Bonn (Nature 4832, 927-929, 1962). Inhibition of bone resorption by the compounds of the present invention can be confirmed through osteoclast resorption, similar to WO 95/32710.

The present invention therefore relates to a compound of formula (I) according to claim 1 and / or a physiologically acceptable salt thereof for the preparation of a medicament for use as an integrin inhibitor. The invention relates in particular to the compounds of formula (I) and / or acceptable salts thereof according to claim 1 for the preparation of a medicament for inhibiting pathological vasculature-associated diseases, tumors, osteoporosis, inflammation and infection.

Compounds of formula (I) include thrombosis, myocardial infarction, arteriosclerosis, inflammation, stroke, angina pectoris, tumor diseases, osteolytic diseases such as osteoporosis, pathologically vascular diseases such as calcium hyperemia, inflammation, ophthalmic diseases, diabetic retinopathy, Macular degeneration, myopia, an histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn's disease, arteriosclerosis, psoriasis, stenosis after angioplasty, viral infection, bacterial infection In human or animal medicaments for the prophylaxis and / or treatment of fungal infections, it may be used as a pharmaceutically active compound in acute renal failure and in the healing of wounds to aid the healing process.

Compounds of formula (I) can be used as antimicrobial actives when operating with biocompatible materials, implants, catheters or pacemakers. At this time, a bactericidal effect is exhibited. The antimicrobial activity can be confirmed by the method of P. Valentin-Weigund et al., Infection and Immunity, 2851-2855 (1988).

The present invention also relates to solvates and hydrates such as alcoholates of these compounds.

The invention also relates to a process for the preparation of a compound of formula (I) and salts thereof according to claim 1, which method

a) treating the functional derivative of the compound of formula (I) with a solubilizer, reducing agent or hydrogenolysis agent to liberate the compound of formula (I), or

b) for example,

i) converting an amino group with amidinating agent to convert to a guanidino group,

ii) hydrolyzing esters,

iii) converting radicals X and / or R ⁵ to other radicals X and / or R ⁵ by hydrogenating hydroxyamidine to conversion into amidine,

And / or convert the base or acid of formula (I) to one of its salts.

Since the compound of formula (I) has one chiral center, various stereoisomeric forms may occur. All of these forms (eg Forms D and L) and mixtures thereof (eg Form DL) are included in Formula (I).

So-called prodrug derivatives (i.e. compounds of formula (I), for example modified with alkyl or acyl groups, sugars or oligopeptides, which are rapidly degraded in the body to form the active compounds according to the invention) are also compounds according to the invention Included in

The above and following abbreviations 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

Me methyl

Mtr 4-methoxy-2,3,6-trimethylphenylsulfonyl

HONSu N-hydroxysuccinimide

OBut tert-butyl ester

Oct Octanoyl

OMe Methyl Ester

OEt ethyl ester

POA phenoxyacetyl

TFA trifluoroacetic acid

Trt trityl (triphenylmethyl)

All radicals mentioned several times, for example A, may be the same or different (ie, independent of one another) for the whole invention.

A is alkyl, having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-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 Preference is given to -1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl. A is also alkyl substituted with halogen, preferably CF ₃ .

X is for example pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imi Dazol-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 is preferred.

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

Z is preferably O, for example.

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

R ² is preferably CH or N, for example, and CH is particularly very preferred.

R ⁴ is preferably phenyl mono- or polysubstituted with F, for example.

R ⁵ is preferably OH, for example.

Het ¹ is 1-, 2- or 3-pyrroylyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3 unsubstituted or mono- or di-substituted with A, NHA and / or NH ₂ . -, 4- or 5-pyrazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl are preferred, and 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, pyrazine 1, 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-shinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl , 1H-imidazo [4,5-b] pyridin-2-yl or 1,8-naphthyridin-7-yl is preferred.

Heterocyclic radicals may also be partially or wholly hydrogenated.

Thus, Het ¹ is for example 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrroyl, 2,5-dihydro-l, -2-, -3-,-4- or -5-pyrroylyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 4,5-dihydroimide Dazol-2-yl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-l, -3- or -4-pyrazolyl, 1,4-dihydro-1-,-2-,-3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-,-2-,-3-,-4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2 -, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4- , -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-,-2-,-3-,-4-, -5-,- 6-, -7- or -8-isoquinolyl or 1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl.

Hydrogenated or partially hydrogenated Het ¹ radicals may be further substituted with = NH or carbonyl oxygen.

Het ² is 2,3-, 2,4-, 2,5- or 3,4-thienyl, 2,3-, 2 unsubstituted or monosubstituted with F, Cl, Br, A, OA or OCF ₃ , 4-, 2,5- or 3,4-pyrroyl, 2,4-, 2,5- or 4,5-imidazolyl, 2,3-, 2,4-, 2,6- or 3 Preference is given to, 5-pyridyl, 2,4-, 2,5-, 2,6-, 4,5- or 5,6-pyrimidinyl.

n is preferably 2, 3, 4, 5 or 6, with 3, 4 or 5 being particularly preferred.

m and o are each independently preferably 0, 1 or 2, with 0 being particularly preferred.

By "one or several" substitutions is meant one-, two-, three- or tetrasubstituted.

Aryl is unsubstituted phenyl, preferably as indicated-monosubstituted phenyl, particularly preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-cyanophenyl, o-, m Or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methylthiophenyl, o-, m- or p-methylsulfinylphenyl, o-, m- or p-methylsulfonylphenyl, o-, m- or p -Aminophenyl, o-, m- or p-methylaminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p-nitrophenyl, o-, m- or p-acetylphenyl, o-, m- or p-methoxycarbonylphenyl, o-, m- or p-aminocarbonylphenyl, also preferably 2,3- 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3- 2,4-, 2,5-, 2,6-, 3,4- or 3, 5-dichlorophenyl, 2,3- 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methyl-, 2-chloro -4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-5-chloro- , 2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl- or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl-, 2-bro Parent-4-methyl-, 2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-methyl-4-bromo-, 2-methyl -5-Bromo-, 2-methyl-6-bromo-, 3-bromo-4-methyl-, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,4 Or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- Or 3,4,5-trichlorophenyl, 2,4,6-tri-tert-butylphenyl, 2,5-dimethylphenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 4- Fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3- Homes is 6-methoxy-phenyl, 3-chloro-6-methoxyphenyl, 2-methoxy-5-methylphenyl, 2,4,6-tri-isopropylphenyl.

Aminoprotecting groups are formyl, acetyl, propionyl, butyryl, phenylacetyl, benzoyl, toluyl, POA, methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2 -Iodoethoxycarbonyl, CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC, Mtr or benzyl are preferred.

The present invention therefore relates in particular to compounds of formula (I) in which one or more radicals have one of the above preferred meanings. Some preferred groups of compounds, which correspond to formula (I) and which are not mentioned in more detail, can be represented by the formulas (Ia) to (I) to (I) having the meanings given in formula (I). At this time,

in a),

X is pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazole- 2-ylamino, 2-aminoimidazol-5-ylamino, 2-aminopyridin-6-ylamino, 2-aminoimidazol-5-yl or 2-aminopyridin-6-yl,

in b),

X is pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydroimidazole- 2-ylamino,

Y is-(CH ₂ ) _n- ,

n is 2, 3 or 4;

in c),

X is pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydroimidazole- 2-ylamino,

Y is-(CH ₂ ) _n- ,

n is 2, 3 or 4;

in d),

X is pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydroimidazole- 2-ylamino,

Y is-(CH ₂ ) _n- ,

n is 2, 3 or 4

Z is O;

e),

X is pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydroimidazole- 2-ylamino,

Y is-(CH ₂ ) _n- ,

n is 2, 3 or 4

Z is O,

R ² is N or CH;

f),

X is pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydroimidazole- 2-ylamino,

Y is-(CH ₂ ) _n- ,

n is 2, 3 or 4,

Z is O,

R ² is N or CH,

R ⁴ is phenyl mono- or polysubstituted with F, Cl, Br, OA, OCF ₃ , -CO-A, CN, COOA, CONH ₂ or NO ₂ ;

g),

X is pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydroimidazole- 2-ylamino,

Y is-(CH ₂ ) _n- ,

n is 2, 3 or 4,

Z is O,

R ² is N or CH,

R ⁴ is phenyl mono- or polysubstituted with F, Cl, Br, OA, OCF ₃ ,

R ⁵ is OA or OH;

h),

X is pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydroimidazole- 2-ylamino,

Y is-(CH ₂ ) _n- ,

n is 2, 3 or 4,

Z is O,

R ² is N or CH,

R ⁴ is mono- or polysubstituted phenyl by F,

R ⁵ is OA or OH;

in i),

X is pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydroimidazole- 2-ylamino,

Y is-(CH ₂ ) _n- ,

n is 2, 3 or 4,

Z is O,

R ² is N or CH,

R ⁴ is phenyl mono- or polysubstituted by Hal, A or aryl,

R ⁵ is OA or OH,

Provided that R ⁴ is not monosubstituted phenyl or naphthyl radical with A or aryl;

in k),

X is pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydroimidazole- 2-ylamino,

Y is-(CH ₂ ) _n- ,

n is 2, 3 or 4,

Z is O,

R ² is N or CH,

R ⁴ is phenyl substituted with Hal and aryl,

R ⁵ is OA or OH,

Provided that R ⁴ is not monosubstituted phenyl or naphthyl radical with A or aryl;

in l),

X is pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino or 4,5-dihydroimidazole- 2-ylamino,

Y is-(CH ₂ ) _n- ,

n is 2, 3 or 4,

Z is O,

R ² is N or CH,

R ⁴ is phenyl substituted with Hal and aryl,

R ⁵ is OA or OH,

Aryl is phenyl mono-, di- or trisubstituted with A, OA, CF ₃ , CN or NO ₂ ,

Provided that R ⁴ is not monosubstituted phenyl or naphthyl radical with A or aryl;

m),

X is pyrimidin-2-ylamino, pyridin-2-ylamino, imidazol-1-yl, imidazol-2-ylamino, benzimidazol-2-ylamino, 4,5-dihydroimidazole- 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 is 2, 3 or 4,

Z is O,

R ² is N or CH,

R ⁴ is phenyl mono- or polysubstituted by Hal, A or aryl,

R ⁵ is OA or OH,

With the proviso that R ⁴ is not a monophenyl or naphthyl radical monosubstituted with A or aryl.

Compounds of formula (I) and starting materials for preparing them are described in, for example, standard workbooks such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart). It is prepared by known methods, ie under known reaction conditions suitable for the above reaction. It is also possible to use known modified methods which are not mentioned here in detail.

If necessary, the starting material may be formed in situ so that the reaction is continued immediately without separation from the reaction mixture so that the compound of formula I is produced.

Compounds of formula (I) can be obtained by treating one of the corresponding functional derivatives with a solubilizer or a hydrogenolytic agent to liberate the compound of formula (I).

Starting materials that can be used for solvolysis or hydrogenolysis include those corresponding to formula (I), except that they have corresponding protected amino and / or hydroxyl groups in place of one or more free amino and / or hydroxyl groups. Preferred, in particular starting materials having amino protecting groups in place of H atoms bonded to nitrogen atoms, in particular starting materials having R'N groups (R 'being amino protecting groups) in place of NH groups and / or H of hydroxyl groups Preferred are starting materials having hydroxyl protecting groups in place of atoms (for example, substances corresponding to formula (I) having a —COOR ″ group in which R ″ is a hydroxyl protecting group in place of —COOH groups).

Within the molecule of the starting material there may be several (identical or different) protected amino and / or hydroxyl groups. If the protecting groups present are different, most of them can be selectively removed.

The term "amino protecting group" is generally known and refers to a group which is suitable for protecting (blocking) an amino group from a chemical reaction, but which can be easily removed after carrying out the desired chemical reaction in another part of the molecule. Typical examples are unsubstituted or substituted acyl, aryl, alkoxymethyl or aralkyl groups. Since the amino protecting group is removed after the desired reaction (or series of reactions), its nature and size are not critical; However, it is preferable that they are C1-C20, especially C1-C8. The term "acyl group" may be interpreted in the broadest sense with respect to the method of the invention. Acyl groups include acyl groups derived from aliphatic, aromatic aliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids, and in particular, alkoxycarbonyl groups, aryloxycarbonyl groups and aralkoxycarbonyl groups. Examples of this form of acyl group include formyl or alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC and 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ (“carbenzoxy”), 4-methoxybenzyloxycarbonyl and FMOC; Aryl sulfonyl like Mtr is mentioned. Preferred amino protecting groups are BOC and Mtr, with CBZ, Fmoc, benzyl, formyl and acetyl also preferred.

Depending on the protecting group used, for example, strong acids, preferably TFA or perchloric acid, or other inorganic strong acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or benzenesulfonic acid or p-toluenesulfonic acid The same sulfonic acid is used to remove the amino protecting group. In addition, it is also possible to use inert solvents, but this is not necessary. Suitable inert solvents are, for example, organic solvents such as carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and the like. Alcohols such as isopropanol or water are also preferred. Also mixtures of the above solvents are possible. TFA is preferably used in excess without further use of other solvents, and perchloric acid is preferably used in a mixture of acetic acid and 70% perchloric acid in a ratio of 9: 1. The decomposition reaction is suitably carried out in the temperature range of about 0 to about 50 °; In particular, it is preferable to perform reaction in the temperature range (room temperature) of 15-30 degrees.

The BOC, OBut and Mtr groups are preferably removed using, for example, TFA in dichloromethane or about 3 to 5 N HCl in dioxane at a temperature of 15 to 30 °, while FMOC groups are DMF at a temperature of 15 to 30 °. It can be removed using a solution of about 5-50% of a secondary amine such as dimethylamine, diethylamine or piperidine.

Protective groups (eg CBZ or benzyl) that can be removed by hydrogenolysis can be removed, for example, by treatment with hydrogen in the presence of a catalyst (eg a noble metal catalyst such as palladium on a support such as carbon). . Suitable solvents for this may be those solvents, in particular alcohols such as methanol, ethanol or amides such as DMF. Hydrolysis is generally carried out at a temperature of about 0 to 100 ° and a pressure of about 1 to 200 bar, with 20 to 30 ° and 1 to 10 bar being preferred. For example, CBZ groups can be readily hydrolyzed using, for example, ammonium formate (instead of hydrogen) on 5-10% Pd / C in methanol or on Pd / C in methanol / DMF at 20-30 °. Can be.

Suitable inert solvents include, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; Chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); Nitriles such as acetonitrile; Sulfoxides such as dimethyl sulfoxide (DMSO); Carbon disulfide; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate, water or mixtures of these solvents.

It is also possible to hydrolyze esters of formula (I). This can be done by solvolysis or hydrogenolysis at temperatures ranging from 0 to 60 ° C., preferably from 10 to 40 ° C., using, for example, LiOH in methanol, NaOH or KOH in dioxane / water. It is preferable to carry out.

The cyano group is reacted, for example with hydroxyamine, and then reduced to hydrogen with N-hydroxyamidine in the presence of a catalyst such as Pd / C.

As described above, the conventional amino protecting group may be replaced with hydrogen by solvolysis or hydrogenolysis to remove the protecting group, or by solvolysis or hydrogenolysis to free the amino group protected with the conventional protecting group.

To prepare a compound of formula (I) wherein X is H ₂ NC (═NH) —NH—, the appropriate amino compound may be treated with an amidating agent. Suitable amidating agents are in particular 1-amidino-3,5-dimethylpyrazole (DPFN), which is used in nitrate form. This reaction is carried out at a temperature of 0 to 120 ° C., preferably 60 to 120 ° C. in an inert solvent or a solvent mixture such as for example water / dioxane by adding a base such as triethylamine or ethyldiisopropylamine. It is preferable.

To prepare amidine (X = -C (= NH) -NH ₂ ) of formula (I), ammonia can be added to the nitrile (X = CN) of formula (I). The addition comprises: a) converting the nitrile to thioamide in a known manner using H ₂ S and converting it to the corresponding S-alkyl-imidothioester using an alkylating agent such as CH ₃ I, a portion of which is Reacting with NH ₃ to produce amidine, or b) converting the nitrile to the corresponding imidoester in the presence of HCl using an alcohol such as ethanol and treating it with ammonia, or c) nitrile to lithium bis (trimethylsilyl) amide The reaction is preferably carried out in several stages of hydrolysis of the product.

For example, it is also preferred to obtain the compound of formula I from an oxidized precursor by reducing the oxy-heterocycle using a reducing agent such as phosphorus trichloride in an inert solvent.

In addition, the free amino groups are preferably used unsubstituted or substituted alkyl halides at temperatures from -60 to + 30 ° in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine. Alkylation or acylation using acid chlorides or anhydrides in conventional manner.

Bases of formula (I) can be converted to the relevant acid addition salts using an acid, for example by reacting an equivalent of the base with the acid in an inert solvent such as ethanol and then evaporating. This reaction uses, in particular, acids from which physiologically acceptable salts can be obtained. For example, inorganic acids such as hydrochloric acid such as sulfuric acid, nitric acid, hydrochloric acid or hydrobromic acid, phosphoric acid such as orthophosphoric acid, sulfamic acid, and also formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid , Succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isnicotinic acid, methane- or ethane-sulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid aliphatic, cycloaliphatic, aromatic aliphatic, aromatic or heterocyclic monobases such as p-toluenesulfonic acid, naphthalene mono- and disulfonic acid or lauryl sulfate, or organic acids such as polybasic carboxylic acid, sulfonic acid or sulfuric acid can be used. Can be. Salts of physiologically unacceptable acids, such as picric acid salts, can be used to isolate and / or purify the compound of formula (I).

On the other hand, the acid of formula (I) can be converted to either a physiologically acceptable metal or ammonium salt by reaction with a base. Suitable salts are in particular sodium, potassium, magnesium, calcium and ammonium salts and for example dimethyl-, diethyl- or diisopropylammonium salts, monoethanol-, diethanol- or diisopropylammonium salts, cyclohexyl-, dicyclo Substituted ammonium salts such as hexyl ammonium salts, dibenzylethylenediammonium salts, arginine or salts with lysine.

Compounds of formula (I) contain one or more chiral centers and may therefore exist in racemic or optically active form. The racemates obtained can be separated into enantiomers by known mechanically or chemically. Preferably the diastereomers are obtained by reacting the racemic mixture with an optically active splitting agent. Examples of suitable splitting agents include optically active acids such as D and L forms of other optically active camphorsulfonic acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or β-camphorsulfonic acid. have. It is also advantageous to separate enantiomers using a column filled with an optically active splitting agent (eg dinitrobenzoylphenylglycine); Suitable eluents are, for example, hexane / isopropanol / acetonitrile mixtures (eg volume ratios of 82: 15: 3).

According to this method it is of course also possible to obtain optically active compounds of the formula (I) using starting compounds which are already optically active.

The present invention comprises not only the above-mentioned compounds but also mixtures and auxiliaries which, in addition to these compounds according to the invention, can influence in any desired manner the primary pharmacological action of other pharmacologically active compounds or compounds according to the invention Formulations. These can be used as therapeutics, diagnostics or reagents. They may be applied locally or systemically to humans or animals, orally, intravenously, intraperitoneally, intramuscularly, subcutaneously, skin permeable, nasal, oral, or iontophoretic and may be nanoparticles, tablets, capsules or pills, granules or Powders, inhalation sprays, nasal drops or suspensions as sprays, emulsions or solutions, liposomes, ointments, pastes, biodegradable polymer compositions. It is also possible to combine new products with other technologies, such as surgery, investigation, diagnosis, radiation therapy, photodynamic therapy and gene therapy, and to combine with other drugs. Such agents may be derived from, for example, the cardiovascular, central nervous system, or oncology fields. These can be angiogenesis inhibitors or cell growth inhibitors, chemotherapeutic agents of the alkylating agent group, antibiotics, metabolic inhibitors, biological agents and immunomodulators, hormones and antagonists thereof, ipherite derivatives, alkaloids and the like. Both low and high molecular weights are possible. These may be lipids, carbohydrates or proteins. These include cytokines, toxins, fusion proteins, monoclonal antibodies and vaccines.

Accordingly, the present invention relates to compounds having a composition in the claims as described above and below as a medicament, diagnostic agent or reagent, including physiologically acceptable salts thereof.

The present invention is particularly useful in the case of pathological vasculature-associated diseases, thrombosis, myocardial infarction, coronary heart disease, arteriosclerosis, tumors, osteoporosis, inflammation, infection, especially diseases based on the expression of the α _v β ₃ integrin receptor directly or indirectly. It relates to a corresponding agent as an inhibitor that inhibits and affects the wound-healing process.

The invention also relates to corresponding pharmaceutical preparations which contain at least one medicament of formula (I) and, where appropriate, the vehicle and / or excipients.

The invention also relates to diseases based on the expression of α _v β ₃ integrin receptors, directly or indirectly, especially in the case of pathological vasculature-associated diseases, thrombosis, myocardial infarction, coronary heart disease, arteriosclerosis, tumors, osteoporosis, inflammation, infection The invention relates to the use of a compound and / or a physiologically acceptable salt thereof according to the claims and the description for the manufacture of a medicament that inhibits and affects the wound-healing process.

The medicament according to the present invention or the pharmaceutical preparation comprising the same may be used as a medicament in human or animal medicine. Suitable vehicles are organic or inorganic substances suitable for enteral (eg oral), parenteral or topical administration, or suitable for administration in the form of inhalation sprays, which do not react with the new compounds, for example water, vegetables Oils, benzyl alcohol, alkylene glycols, polyethylene glycols, glycerol triacetate, carbohydrates such as gelatin, lactose or starch, magnesium stearate, talc or petrolatum. Tablets, pills, tablets, capsules, powders, granules, syrups, juices or drops are used for oral administration, in particular suppositories for rectal administration, solutions, preferably oily or aqueous solutions and suspensions, emulsions or Implants are used for parenteral administration, and ointments, creams or powders are used for topical application. The novel compounds may also be lyophilized and the resulting lyophilisate may be used, for example, in the preparation of injectables. Such formulations may be sterilized and / or lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts that affect osmotic pressure, buffers, colorants, flavoring agents and / or additional active compounds (eg 1 Excipients such as vitamins).

When administered by inhalation spray, sprays containing the active compound dissolved or suspended in a propellant gas or a propellant gas mixture (eg CO ₂ or chlorofluorohydrocarbons) can be used. In this case, the active compound is preferably in the form of a fine powder in which one or more other physiologically acceptable solvents (eg ethanol) may be present. Inhalation solutions are administered using conventional inhalers.

In general, the compounds according to the invention are similar to other commercially available formulations (for example, those described in US-A-4 472 305), preferably with a dosage of about 0.05 to 500 mg, in particular 0.5 to 100 mg per dosage unit. Can be administered. The daily dose is preferably in the range of about 0.01 to 20 mg / kg body weight. However, the specific dosage of each patient may vary depending on a variety of factors, such as the activity, age, weight, general health, sex, diet, time and route of administration, and rate of excretion, pharmaceutical combination and specific treatment to be administered. It depends on the severity of the disease. Parenteral administration is preferred.

All temperatures above and below are in degrees Celsius.

HPLC analysis (hold time Rt) was performed as follows:

A 210 second gradient of 20-100% water / acetonitrile / 0.01% trifluoroacetic acid was loaded on a 3 μm column silica rod column at a flow rate of 2.2 ml / min and detected at 220 nm.

Mass spectrometry (MS): EI (electron collision ionization) M ⁺

Accelerated Atomic Impact (FAB) (M + H) ⁺

Example 1

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

835 mg of Mg is suspended in 5 ml of pure THF. Then a solution of 2.0 g of 4-benzyloxybenzyl chloride dissolved in 5 ml of pure tetrahydrofuran was added dropwise. After completion of the dropwise addition, the turbid solution was stirred at room temperature for 1 hour, and then a solution obtained by dissolving 1.73 g of ethyl 2-cyano-3- (4-fluorophenyl) acrylate in 10 ml of pure toluene was added. The mixture is refluxed for 16 hours. After removing the solvent, normal reaction is completed to give ethyl 4- (4-benzyloxyphenyl) -2-cyano-3- (4-fluorophenyl) butyrate ("AA").

8.27 g of "AA" is suspended in 80 ml of acetic acid and 80 ml of concentrated HCl mixture and then the mixture is refluxed for 16 hours. After usual reaction completion, 4- (4-hydroxyphenyl) -3- (4-fluorophenyl) butyric acid ("AB") is obtained.

A solution of 1.0 g of "AB" dissolved in 10 ml of pure methanol is treated with 0.4 ml of thionyl chloride and stirred at room temperature for 16 hours. After usual reaction completion, methyl 4- (4-hydroxyphenyl) -3- (4-fluorophenyl) butyrate ("AC") is obtained.

0.62 ml of diethyl azodicarboxylate was added to 0.4 g of "AC", 0.5 g of 3- (1-oxypyridin-2-ylamino) propan-1-ol and 1.23 g of polymer-linked triphenylforce Fin (approximately 3 mmol / g loading) is added dropwise to the suspension suspended in 17 ml of pure THF, and the mixture is stirred for 16 hours. After filtration the solvent is removed and the residue is purified by HPLC. Methyl 3- (4-fluorophenyl) -4- {4- [3- (1-oxypyridin-2-ylamino) propoxy] phenyl} butyrate ("AD") is obtained.

A solution of 0.45 g of "AD" in 30 ml of chloroform is treated with 0.59 g of phosphorus trichloride, stirred at room temperature for 2 hours and further under reflux for 2 hours. After usual reaction completion, the residue was treated with 15 ml of methanol containing 0.2 g of lithium hydroxide and stirred at room temperature for 16 hours. After removal of the solvent, the residue is treated with 0.66 ml of trifluoroacetic acid and purified by HPLC. 3- (4-fluorophenyl) -4- {4- [3-pyridin-2-ylaminopropoxy] phenyl} butyric acid and trifluoroacetate are obtained.

Α using 3- (4-fluorophenyl) -4- {4- [3-pyridin-2-ylamino) propoxy] phenyl} butyric acid _v β ₃ Suppression test results

In the Vitronectin binding test, an IC ₅₀ value is given, i.e. a concentration (nmol / L) that inhibits 50% of Vitronectin binding to the corresponding isolated receptor (Smith et al., J. Biol. Chem. 265 , 12267-71, 1990).

IC ₅₀ α _v β ₃ : 10.

The pharmacological data confirms the antagonistic action of the receptor α _v β ₃ of the compounds according to the invention.

Similar to the above synthesis method, the following compounds were obtained.

3- (4-fluorophenyl) -4- {4- [2- (pyrimidin-2-ylamino) ethoxy] phenyl} butyric acid, trifluoroacetate;

3- (4-fluorophenyl) -4- {4- [3- (pyrimidin-2-ylamino) propoxy] phenyl} butyric acid, trifluoroacetate;

3- (4-fluorophenyl) -4- {4- [4- (pyrimidin-2-ylamino) butoxy] phenyl} butyric acid, trifluoroacetate;

3- (4-fluorophenyl) -4- {4- [2- (pyridin-2-ylamino) ethoxy] phenyl} butyric acid, trifluoroacetate;

3- (4-fluorophenyl) -4- {4- [4- (pyridin-2-ylamino) butoxy] phenyl} butyric acid, trifluoroacetate;

3- (4-fluorophenyl) -4- {4- [3- (imidazol-1-yl) propoxy] phenyl} butyric acid;

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

3- (4-fluorophenyl) -4- {4- [3- (imidazol-2-ylamino) propoxy] phenyl} butyric acid;

3- (4-fluorophenyl) -4- {4- [3- (benzimidazol-1-ylamino) propoxy] phenyl} butyric acid;

3- (4-fluorophenyl) -4- {4- [3- (2-aminopyridin-6-ylamino) propoxy] phenyl} butyric acid;

3- (4-fluorophenyl) -4- {4- [3- (2-aminoimidazol-5-ylamino) propoxy] phenyl} butyric acid.

Example 2

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

40.0 g of 4-hydroxybenzaldehyde is dissolved in 400 ml of pure THF under protective gas atmosphere, the solution is treated with 55.1 g of dihydropyran and 13.7 g of pyridinium p-toluenesulfonate and stirred at room temperature overnight. . The solvent is removed on a rotary evaporator and the residue is subjected to a conventional reaction finish to give 4- (tetrahydropyran-2-yloxy) benzaldehyde ("BA") as a colorless oil.

A solution of 2.0 g of "BA" dissolved in 20 ml of pure methanol is treated with 1.17 g of 4-fluoroaniline and stirred at 60 ° for 3 hours. 0.79 g sodium cyanoborohydride is added dropwise at room temperature and the reaction solution is refluxed for 16 hours. After solvent removal, conventional reaction finishing and chromatographic purification, 4-fluorophenyl- [4- (tetrahydropyran-2-yloxy) benzyl] amine (“BB”) is obtained as a colorless liquid.

8.0 g of "BB" and 10.36 g of methyl bromoacetate are dissolved in 100 ml of pure THF under N ₂ atmosphere, treated with 12.0 g of potassium carbonate and refluxed for 16 hours. After solvent removal, conventional reaction finish and chromatographic purification, methyl {[4-fluorophenyl]-[4- (tetrahydropyran-2-yloxy) benzyl] amino} acetate ("BC") as colorless solid was obtained. Get

A solution of 0.5 g of "BC" dissolved in 25 ml of methanol and 5 ml of dichloromethane is treated with 2.76 ml of concentrated HCl and stirred at room temperature for 5 minutes. After solvent removal and normal reaction finish, the residue was dissolved with 0.47 g of 3- (1-oxypyridin-2-ylamino) propan-1-ol in 16 ml of pure THF followed by 1.17 g of polymer triphenylphosphine (Approximately 3 mmol / g loading). Then 0.62 ml of diethyl azodicarboxylate is added dropwise. This suspension is then stirred for 16 hours at room temperature. After filtration and solvent removal, the residue is purified by HPLC. Methyl {4- [3- (1-oxypyridin-2-ylamino) propoxy] benzyl}-(4-fluorophenyl) amino) acetate ("BD") is obtained.

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

The following compounds are similarly obtained.

((4-fluorophenyl)-{4- [2- (pyrimidin-2-ylamino) ethoxy] benzyl} amino) acetic acid,

((4-fluorophenyl)-{4- [3- (pyrimidin-2-ylamino) propoxy] benzyl} amino) acetic acid,

((4-fluorophenyl)-{4- [4- (pyrimidin-2-ylamino) butoxy] benzyl} amino) acetic acid,

((4-fluorophenyl)-{4- [2- (pyridin-2-ylamino) ethoxy] benzyl} amino) acetic acid,

((4-fluorophenyl)-{4- [4- (pyridin-2-ylamino) butoxy] benzyl} amino) acetic acid,

((4-fluorophenyl)-{4- [3- (imidazol-1-yl) propoxy] benzyl} amino) acetic acid,

((4-fluorophenyl)-{4- [3- (4,5-dihydro-1 H -imidazol-2-ylamino) propoxy] benzyl} amino) acetic acid,

((4-fluorophenyl)-{4- [3- (imidazol-2-ylamino) propoxy] benzyl} amino) acetic acid,

((4-fluorophenyl)-{4- [3- (benzimidazol-2-ylamino) propoxy] benzyl} amino) acetic acid.

Example 3

Similar to Example 1, the following compounds are obtained.

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

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

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

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

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

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

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

3- (2,6-difluoro-phenyl) -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 relate to pharmaceutical formulations.

Example A: Vials for Injection

A solution of 100 g of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid and 5 g of sodium diphosphate in 3 liters of secondary distilled water was dissolved in 2N. Adjust to pH 6.5 with hydrochloric acid, filter sterilized by injection into vials, lyophilize under sterile conditions and seal aseptically. Injectable vials containing 5 mg of active compound are obtained.

Example B: Suppositories

A mixture of 20 g of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid was melted together with 100 g of soy lecithin and 1400 g of cocoa butter, poured into a mold. Cool. Suppositories containing 20 mg of the active compound are obtained.

Example C: Liquid

3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid 1 g, NaH ₂ PO ₄ .2H ₂ O 9.38 g, Na ₂ HPO ₄ 28.48 g of 12H ₂ O and 0.1 g of benzalkonium chloride were dissolved in 940 mL of secondary distilled water to prepare a liquid. The liquid is adjusted to pH 6.8, adjusted to 1 l, and sterilized by radiation to prepare a liquid. This solution can be used in the form of eye drops.

Example D: Ointment

An ointment is prepared by mixing 500 mg of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid with 99.5 g of petrolatum under aseptic conditions.

Example E: Tablets

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 mg of magnesium stearate The kg mixture is compressed in a conventional manner to produce tablets in which each tablet contains 10 mg of the active compound.

Example F: Tablets

Similar to Example E, tablets are compressed and then coated by conventional methods using a coating consisting of sucrose, potato starch, talc, tragacanth and a colorant to prepare a coated tablet.

Example G: Capsule

2 kg of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid, hard gelatin in a conventional manner so that each capsule contains 20 mg of the active compound Fill in capsules.

Example H: Ampoules

A solution of 1 kg of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid dissolved in 60 l of secondary distilled water was sterilized by filtration and filled into an ampoule. Lyophilized under sterile conditions and sealed aseptically. An ampoule containing 10 mg of the active compound is obtained.

Example I: Inhalation Spray

A conventional spray having a pump mechanism is a solution in which 14 g of 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) propoxy] phenyl} butyric acid is dissolved in 10 l of an isotonic NaCl solution. Fill the container. This solution can be sprayed into the mouth or nose. One spray (about 0.1 ml) corresponds to about 0.14 mg administration.

Claims (10)

Compound of Formula (I): [Formula I] XYZR ¹ -CH ₂ -R ² (R ⁴ ) -CH ₂ -CO-R ⁵ (Wherein, X is H ₂ NC (= NH)-, H ₂ NC (= NH) -NH-, AC (= NH) -NH-, Het ¹ -or Het ¹ -NH-, which is a common amino protecting group for primary amino groups Can be provided, Y is Wherein one, two, three or four methylene groups may be substituted with N, O and / or S, Z is absent or is -O-, -NH-, -NA-, -CH (OH)-, -CH (OA)-, -CHA-, -CA ₂ -or -S-, R ¹ is unsubstituted or mono-, di- or trisubstituted phenylene with F, Cl, Br, A, OA, OCF ₃ or CN, R ² is N, CH or CA, R ³ is H, F, Cl, Br, A, OA or OCF ₃ , R ⁴ is phenyl, naphthyl or Het ² mono- or polysubstituted with F, Cl, Br, A, aryl, OA, SA, CO-A, CN, COOA, CONH ₂ , CONHA, CONA ₂ or NO ₂ , R ⁵ is OH, OA, NH ₂ , NHA or NA ₂ , Het ¹ is a mono- or dinuclear heterocycle having 1 to 4 N atoms, which may be unsubstituted or mono- or disubstituted with NH ₂ , Het ² is an N, O and / or S aromatic mono- or dinuclear heterocycle having 1 to 3 atoms, which may be unsubstituted or substituted with F, Cl, Br, A, OA, SA, OCF ₃ , -CO-A, CN, May be mono- or disubstituted with COOA, CONH ₂ , CONHA, CONA ₂ or NO ₂ , Aryl is phenyl or naphthyl unsubstituted or mono- or polysubstituted with Hal, A, OA, OH, CO-A, CN, COOA, COOH, CONH ₂ , CONHA, CONA ₂ or NO ₂ , A is alkyl having 1 to 12 carbon atoms, n is 1, 2, 3, 4, 5 or 6, m, o are each independently 0, 1, 2, 3, 4, 5 or 6, With the proviso that R ⁴ is not a monophenyl or naphthyl radical monosubstituted with A or aryl), Physiologically acceptable salts and solvates thereof. The method of claim 1, Compound represented by the following formula: a) 3- (4-fluorophenyl) -4- {4- [3- (pyridin-2-ylamino) -propoxy] phenyl} butyric acid, b) 3- (4-fluorophenyl) -4- {4- [3- (2-aminopyridin-6-ylamino) propoxy] phenyl} butyric acid, c) 3- (4-fluorophenyl) -4- {4- [3- (2-aminoimidazol-2-ylamino) propoxy] phenyl} butyric acid, And physiologically acceptable salts and solvates thereof. a) treating the functional derivative of the compound of formula (I) with a solubilizer, reducing agent or hydrogenolysis agent to liberate the compound of formula (I), or b) for example, i) converting an amino group with amidinating agent to convert to a guanidino group, ii) hydrolyzing esters, iii) converting radicals X and / or R ⁵ to other radicals X and / or R ⁵ by hydrogenating hydroxyamidine to conversion into amidine, And / or converting a base or an acid of formula (I) into one of its salts. A compound of formula I according to claim 1, a compound according to claim 2, and a physiologically acceptable salt and solvent compound thereof. A pharmaceutical according to claim 4 as an inhibitor for controlling a disease based on the expression and pathological function of the α _v β ₃ integrin receptor. The method of claim 5, The agent is for controlling thrombosis, myocardial infarction, coronary heart disease, atherosclerosis, tumors, osteoporosis, fibrosis, inflammation, infection, psoriasis and affect the wound-healing process. A pharmaceutical formulation comprising at least one medicament according to claim 5 or 6, with a vehicle and / or excipients as appropriate, and other active compounds as appropriate. Use of a compound according to claim 1 and / or a physiologically acceptable salt thereof for the manufacture of a medicament for inhibiting disease based on the expression and pathological function of the α _v β ₃ integrin receptor. The method of claim 8, Said use is for the manufacture of a medicament for inhibiting pathological progression, which is maintained or propagated by angiogenesis. The method of claim 8, Said use is for the manufacture of a medicament that inhibits thrombosis, myocardial infarction, coronary heart disease, arteriosclerosis, tumors, osteoporosis, fibrosis, inflammation, infection, psoriasis and affects the wound-healing process.