SK1402002A3 - Fluorene derivative, process for the preparation thereof and pharmaceutical composition comprising same - Google Patents

Abstract

The invention relates to compounds of formula (I) wherein R<1>, R<2>, R<3>, R<4>, R<5>, m and n have the meaning given in Claim 1, and to their physiologically acceptable salts and solvates, which can be used as integrin inhibitors, especially for the prophylaxis and treatment of blood circulation disorders, thrombosis, myocardial infarction, coronary disorders, arteriosclerosis, osteoporosis, pathological processes which are maintained or propagated through angiogenesis, as well as in tumour therapy.

Description

The invention relates to a fluorene derivative. of formula T

where it means.

R ^{1 is} OR ⁷ , NHR ⁷ or NA ₂ ,

R ² is H, CO-R ^7, CO-OR ^7, CONHR ^7, CONA ₂ or S0 ₂ R ^7,

R ⁴ , R ^{5 are} each independently H, Hal, NO 2, NHR ⁷ , NA 2,

OR ⁷ , -CO-R ⁷ , SO ³ R ⁷ , SO ² R ⁷ or SR ⁷ ,

R ³ NH ₂ , -C (= NH) -NH ₂ , -NH-C (= NH) -NH ₂ , -C (= O) -N = C (NH ₂ ) _2, or

N.

<t í \ l ‘m.

CH.

which is unsubstituted or annually substituted.

-COA, -COOA, -OH or a conventional amino-protecting group or R ^S -NH-,

R ^{6 is a} monocyclic or bicyclic heterocyclic group having 1 to 4 nitrogen, oxygen and / or sulfur atoms which is unsubstituted or is monosubstituted, disubstituted or trisubstituted by Hal, A, -CO A ', OA', CN, COQA ', CONH ₂ , NO ₂ , = NH or = O,

R ⁷ is H, A, Ar or aralk,

A is alkyl having 1 to 15 carbon atoms or cycloalkyl having 3 to 15 carbon atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by ^R8 and in which one, two or three methylene groups are optionally replaced by N, O and / or sulfur,

R ⁸ Hal, NO ₂ , NHA ', NA ₂ , OA', phenoxy, CO-A ', SO ₃ A',

CN, NHCOA ', COOA', C0NA ' ₂ or SO ₂ A',

A H H or C 1 -C 6 alkyl,

A '(C 1 -C 6) -alkyl,

Ar mono- or bicyclic aromatic group having O, 1, 2, 3, or 4 N, O and / or S atoms which is unsubstituted or monosubstituted, disubstituted or trisubstituted by alkyl of 1 to 6 carbon atoms and / or the group R ⁸ .

A C 7 -C 14 aralkylene group which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R ⁸ and wherein one, two or three methylene moieties are optionally replaced by nitrogen, oxygen and / or sulfur,

Hal is F, Cl, Br or J, m, n independently of one another 0, 1, 2, 3, or 4 and physiologically acceptable salts and solvates thereof.

BACKGROUND OF THE INVENTION

Other vitconectin antagonists are described in WO 97/24124. Bicyclic fibrinogen antagonists are described, for example, in WO 96/18602.

The invention is based on the discovery of novel compounds having valuable properties, in particular properties which can be used for the manufacture of medicaments.

It has been found that the compounds of the formula I and their salts and solvates have very valuable pharmacological properties with good tolerability. In particular, they act as integrin inhibitors, in particular they inhibit the interaction of α _in integrin receptors with ligands. The compounds are particularly effective in the case of integrins α _ν β ₃ aa _v 3s. The compounds are very particularly effective as adhesion receptor antagonists for. σ. _ν , β ₃ receptor. This action can be demonstrated, for example, by the method described by JW Smith et al. (J. Biol. Chem. 265, p. 6).

11008-11013 and 12267-12271 (1990).

B. Felding-Habermann and DA-Cheresh describe (Curr. Opia. Cell. B.iol. 5, p. 864, .993) the importance of integrins as adhesion receptors for various phenomena and symptoms of diseases, especially with regard to the α _ν β3 receptor.

The dependence 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. Hlier and P, A. Cheresh (Cell 79, pp. 1157 to 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. C. Brooks et al., (J. Clin. Invest. 96, pp. 1815-1822,

1995) describes antagonists of α _ν β3 for the treatment of cancer and for the treatment of tumor-induced angiogenic disorders.

Thus, the compounds of the formula I according to the invention can be used as therapeutically active compounds, in particular for the treatment of neoplastic diseases, osteoporosis, osteoporotic disorders and for the control of angiogenesis.

Compounds of formula I that block the interaction of integrin receptors and ligands, such as fibrinogen with the fibrinogen receptor (glycoprotein IIIbIIa), inhibit the dispersion of tumor cells by metastasis as GPIIb / IIIa antagonists. This is evidenced by the following knowledge: tumor cells spread from a localized tumor to the vascular system by the formation of microaggregates (micro-thrombi) by the interaction of tumor cells with platelets. Protected in microaggregates, tumor cells are shielded and are not recognized by cells of the immune system. These microaggregates can 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.

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

The properties of the compounds of the invention may be exemplified by the methods described in EP-A1-0 462960. Inhibition of fibrinogen binding to the fibrinogen receptor may be exemplified by the methods described in European Patent Publication No. ΕΡ-Ά1-0 381033.

The inhibitory effect of platelet aggregation can be demonstrated in vitro by the method described by Born (Nature 4832, 927-929, 1962).

SUMMARY OF THE INVENTION

The present invention provides a compound of formula (I) as defined above and its physiologically acceptable salts and solvates as medicaments.

The invention further relates to said medicaments as inhibitors for the treatment of disorders based on the expression and pathological function of α _ν β3 and α _ν β5 integrin receptors. The invention also relates to medicaments such as GPIIb / IIIa antagonists for the treatment of thromboses, heart attack, coronary heart disease and arteriosclerosis and medicaments such as or _in integrin inhibitors for the treatment of pathological angiogenic diseases such as thrombosis, heart attack, coronary heart disease, arteriosclerosis, arteriosclerosis osteoporosis and rheumatoid arthritis.

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

r r

The compounds of formula (I) may be used as antimicrobial agents in operations using biological material, implants, catheters or cardiac stimulators. These compounds have an antiseptic effect. The efficacy of antimicrobial activity can be demonstrated as described by P. Valerrtin-Weigund et al. (Infection and Immunity, 1988, 2851-2855).

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

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

or (b) a group of R ¹ , R ² and / or R ³ of R ¹ , R ² and / or R ³ such that:

i) converting an amino group into an amidating agent ii) hydrolyzing the ester iii) converting hydroxyamidine into another guanidino group by reaction with an amidine by hydrogenation and / or converting a base or acid of formula I to its salt.

The invention also relates to a process for the preparation of compounds of the formula I wherein R ^{@ 1 represents a} hydroxyl group and R ^{@ 2} , R ^{@ 3} , R ^{@ 4} , R ^{@ 5} , m and n are as defined hereinbefore and their salts and solvates. of formula II

Γ f • ο

wherein R ¹ is 0-alkyl of 1 to 6 carbon atoms and R ² R ^3, R ^4, R ^5, m and n are as defined in, hydrolyzed and subsequently decarboxylated much.

The compounds of the formula I have at least one chiral center and can therefore be present 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 according to the invention also include so-called prodrug derivatives, i.e., alkyl or acyl groups, sugars or oligopeptides-modified compounds of the formula I which are rapidly cleaved in the body into active compounds according to the invention.

The invention also includes solvates of the compounds of formula (I). Solvates are addition compounds with, for example, water (hydrates) or alcohols, for example, methanol or ethanol.

Ac

BOC

CBz or

DCCI

DBU

Abbreviations used have the following meanings: acetyl tert-butoxycarbonyl

From benzyloxycarbonyl dicyclohexylcarbodiimide

1,8-diazahicyclo [5.4.0] undec-7-ene rt

DMF d imety1formami d DOPA (3,4-dihydroxyphenyl) alanine DPFN 3.5 - d e t ery 1 p y r o z 1 - i -'f o r mam i d i n art DMAP dimethylaminopyridine EDCI N-ethyl-N. N'- (dimethylaminopropyl) carbodiimide et ethyl Fmoc 9-fluorenylmethylaxy and ronyl HQBt 1-Hydroxybenzoate triazole HONSu N-hydr o x y with ukc in imi d Me methyl mtb ether methyl tert-butyl ether Mtr 4-methoxy-2,3,6-triroethylphenylsulfonyl np neopentyl OBn benzyl DBut tert-butyl ester. Oct octanoyl OEt ethyl OMe methyl ester Orn ornithine POA • fenoxvacetyl TBTU O- (benzotriazol-1-yl) -N, N, N, N-tetramethyl- ur ón i ui i t et r af u uor borate TFA trifluoroacetic acid pTSS sol para-toluenesulfonic acid Trt trityl (triphenylmethyl) Z or CBZ ben / zyloxycarbonyl

All groups that are contained in a compound more than once may independently be the same or different.

Preferred are compounds of formula I having the - (CH ₂ ) _n -R ^{3 group} at the 2-position and the - (CH ₂ ) _m -CK (NHR ² ) -COR ^{1 group} at the 7-position of the fluorene ring system.

e f

Alkyl is, in particular, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl. 1-, 2-, 3- or 4-methylpentyl, 1,1, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1- ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and 1,1,2- or 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl, as well as, for example, trifluoromethyl or pentafluoroethyl.

Preferably, A 'represents a hydrogen atom, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, pentyl or hexyl group.

A is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, pentyl or hexyl.

The cycloalkyl group is preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl or 3-menthyl group.

The alkylene group is preferably methylene, ethylene, propylene, butylene, pentylene, preferably hexylene, heptylene, octylene, nonylene or decylene.

Aralk represents an arylalkylene group and preferably an alkylenephenyl group and, for example, preferably a benzyl group. or phenethyl.

In particular, A is methyl, ethyl, propyl, isopropyl, butyl or tert-butyl.

e λ

Π

CO-A 'is an alkanoyl or cycloalkanoyl group, and is preferably a formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, hexadecanoyl, pentadecanecanoyl, hexadecanoyl, pentadecanecanoyl, pentadecanoyl, group.

Preferred R ⁸ substituents for alkyl, Ar, cycloalkyl and aralk include, for example, Hal, NO ₂ , NH ₂ , NHA such as methylamino, NA ₂ such as dimethylamino, methoxy, phenoxy, acyl such as formyl or acetyl, CN, NHCOA 'such as acetamido, COOA' such as COOH or methoxycarbonyl. CDNA * ₂ or SO ₂ A ', in particular, for example, fluorine, chlorine, hydroxyl, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methylsulfonyl or phenylsulfonyl.

In the alkyl, alkylene and cycloalkyl group, one, two or three methylene moieties may be replaced by a nitrogen, oxygen and / or sulfur atom.

Ar-CO represents an aroyl group and preferably a benzoyl or naphthoyl group.

I

Ar is unsubstituted, preferably if the indicated monosubstituted phenyl group, 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-, κ or p-cyanophenyl, o-, m- or p-methoxyphenyl, o-, male or p-ethoxyphenyl, O- , m- or p-fluorophenyl, O-, mr or p-bromophenyl, ο-, m- or p-chlorophenyl, o-, male- or p-methylthiophenyl, o-, m- or p-methylsulfinylphenyl, o-, ra- or p-methylsulfonylphenyl, o-, ra- or paminophenyl, o-, m- or p-methylaminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p-nitrophenyl, further 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-methylphenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl , 2-chloro-6-methylphenyl, 2-methyl-3-chlorophenyl, 2-methyl-4-chlorophenyl, 2-methyl-5-chlorophenyl, 2-methyl-6-chlorophenyl, 3-chloro-4-methylphenyl, 3-chloro-5 -raethylphenyl, 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-diethylphenyl, 3-bromo-5-methylphenyl, 3-methyl-4-bromophenyl, 2,4-, 2,5-dinitrophenyl, 2,5-, 3,4-diaethoxyphenyl, 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-ethyl-phenyl, 2,4,6-triisopropyl-phenyl, naphthyl, 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, benzothiadiazol-5-yl or benzoxadiazol-5-yl.

Ar is furthermore preferably 2- or 3-furyl, 2 or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4 or 5-imidazolyl, 1-, 3-, 4- or 5- pyrazolyl, 2-, 4 or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4 or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3 or 4-pyridyl, 2-, 4 -, 5- or 6-pyrrolidinyl, further preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazole-1-, -3- or -5 -yl, 1- or 5-tetrazolyl,

1,2.3-o-xadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or 5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2 , 4-thiadiazol-3 or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl,

3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6 or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2- , 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4 or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2- , 4-, 5-, 6- or 7-benzaxazolyl, 3-, 4-, 5, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzthiazolyl, 2-, 4- , 5-, 6- or 7-benzisothiazolyl, 4-, 5, 6- or 7-benz-2,1,3-oxadiazolyl, 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-quinolinyl or 2-,

A 4-, 5-, 6-, 7- or 8-quinazolinyl group.

The symbol R ⁶ is a monocyclic or bicyclic heterocyclic ring, preferably 2- or 3-furyl,

2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4 or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4 or 5-oxazolyl, 3 -, 4- or 5-isoxazolyl, 2-, 4 or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3 or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, hereinafter referred to as s, preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl,

1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or 5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4 -thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-,

4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4Hthiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl,

1-, 7.-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or

7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl,

3-, 4-, 5-, 6-, or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or

7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl,

4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-,

6-, 7- or 8-quinolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 1-, 3-, 4-, 5-, 6-, Ί- or 8- a quinolinyl or 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl group.

The heterocyclic groups may also optionally be partially or fully hydrogenated.

Thus, for example, R &lt; ⁵ &gt; is also 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolane-4-yl, tetrahydro-2- or -3-thienyl, 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, 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, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl,

1,3-dioxan-2-, -4- or -5-yl, 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.

Heterocyclic rings may also be monosubstituted, disubstituted or trisubstituted with Hal, A, -CO-A, OH, CN, COOH, COOA, CONH ₂ , NO ₂ , = NH or = O.

The symbol R ⁶ is particularly preferably imidazol-2vlovú group, _f 4 5-dihydro-imidazol-2-yl, 5-oxo-4,5-dihydro-imidazol-2-yl, thiazol-2-yl, H -benzimidazol-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-yl-5-yl, 1-alkyl-1,5-dihydroimidazol-4-one-2-yl, pyridine2 -yl, pyrimidin-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl.

The symbol R ¹ represents a particular example, hydroxyl, methoxy, ethoxy, NH _2, NHMe, NHEt, NMe, or .NET. In particular, ^R1 is OH or OEt ·

R ^{@ 1} is preferably, for example, hydrogen, acetyl, propionyl, aminocarbonyl, N, N-dimethylaminocarbonyl, alkoxycarbonyl, such as pentyloxycarbonyl, alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, isobutylsulfonyl, propylsulfonyl, propylsulfonyl, propylsulfonyl dimethylpropylsulfonyl, phenylsulfonyl or benzylsulfonyl. R @ ² is, in particular, 2,2-dimethylpropylcarbonyl or butylsulfonyl.

R ³ is preferably, for example, H ₂ NC (= NH), H ₂ N -C (= NH) -NH, 1H-imidazol-2-ylamino, 4,5-dihydro-1H-imidazol-2-ylamino 5-oxo-4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino, 2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4-one-5-ylamino, 1-methyl- 1,5-dihydroimidazol-4-one-2-ylamino, pyridin-2-ylamino, pyrimidin-2-yl-amino or 1,4,5,6-tetrahydro-pyrimidin-2-ylamino.

R @ ⁴ and R @ ⁵ are particularly hydrogen.

* r * e k

In particular, the invention relates to compounds of the formula I in which at least one of the symbols has the above-mentioned preferred meaning. Some preferred groups of compounds of formula I are the following compounds of formulas Ia to Ih, wherein not particularly indicated are as defined in formula I, wherein in formula Ia, R ^{1 is} OH;

Ib) R ¹ OH, and

R ² CO-OR ⁷ or SO ₂ R ⁷ ;

c) R ¹ OH, and

R ² CO-OR ⁷ or SO ₂ R ⁷

R ^{3 is} H ₂ NC (= NH), H ₂ N -C (= NH) -NH, 1H-imidazol-2-ylamino, 4,5-dihydro-1H-imidazol-2-ylamino, 5-OXO- 4,5-dihydro-1H-imidazol-2-ylamino, 1H-benzimidazol-2-ylamino, 2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4-one-5-ylamino 1-methyl-1, 5-dihydroimidazol-4-one-2-ylamino, pyridin-2-ylamino, pyrimidin-2-ylamino or 1,4,5,6-tetrahydropyrimidin-2-ylamino;

(ld) m 1;

le) m la

R ¹ OH;

If) R ¹ OH, and

R ² CO-OR ⁷ or SO ₂ R ⁷ and m 1;

g) R ¹ OH, and

R ² CO-OR ⁷ or SO ₂ R ⁷ ,

R ^{7 is} C 1 -C 6 alkyl, m 1:

Ih) R ¹ OH, and

R ² CO-OR ⁷ or SO ₂ R ⁷

R ^{7 is} C 1 -C 6 alkyl,

R ^{3 is} H ₂ NC (= NH), H ₂ N -C (= NH) -NH, 1H-imidazol-2-ylamino, 4,5-dihydro-1H-imidazol-2-ylamino, 5-OXO-4 5-dibydro-1H-imidazol-2-ylamino

1H-benzimidazol-2-ylamino, 2H-pyrazol-2-ylamino, 2-iminoimidazolidin-4-one-5-ylamino, 1-methyl-1,5-dihydroimidazol-4-one-2-ylamino, pyridin-2- ylamino, pyrimidin-2-ylamino or 1,4,5,6-tetrahydropyrimidin-2-ylamino;

R ⁴ , R ⁵ H, m and n 2, 3 or 4;

and physiologically acceptable salts and solvates thereof.

The compounds of the 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-Weyl, Methoden der organischen Chemie, Georg-Thieme 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 and are 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, and the reaction mixture is immediately used for the preparation of the compounds of the formula I.

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

For solvolysis or for hydrogenolysis. Suitable starting materials are compounds of the formula I which have, instead of one or more free amino and / or hydroxyl groups corresponding to the protected amino and / or hydroxyl group, preferably compounds having an amino protecting group instead of a hydrogen atom bound to the atom. nitrogen compounds, 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 hydroxyl group of a hydroxyl group, for example compounds which correspond to formula I but they have a -COOR group where R is a hydroxyl protecting group instead of a -COOH group.

Also preferred are oxadiazole derivatives which can be converted to the corresponding amidino compounds.

The amidino group can be liberated from its oxadiazole derivatives, for example, by treatment with hydrogen in the presence of a catalyst (e.g. Raney nickel). Suitable solvents for this reaction are the solvents listed below, in particular alcohols such as methanol or ethanol, organic acids such as acetic or propionic acid, or mixtures thereof. As a rule, the hydrogenolysis is carried out at a temperature of about 0 to 100 ° C and at a pressure of 0.1 to 20 MPA, preferably at a temperature of 20 to 30 ° C and at a pressure of 0.1 to 2 MPA.

Introduction of the oxadiazole group is possible, for example, by reaction of cyano compounds with hydroxylamine and reaction with phosgene, dialkyl carbonate [sic], chloroformic acid esters, with N, N'-carbonyldiimidazole or acetic anhydride.

r c 5 5 f r r r c t- u. f e r

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

The term amino protecting group is generally known and refers to groups which are suitable for protecting (blocking) the amino group from chemical reactions but which are readily removable when the desired reaction is carried out elsewhere in the molecule. Typically such groups are especially 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 group ”is always meant in the broadest sense. It includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups include alkanoyl groups such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as phenoxyacetyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 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-2,3,620 trimethylphenylsulfonyl (Mtr). Preferred amino protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, benzyl, formyl and acetyl.

The cleavage of the amino protecting group proceeds according to the protecting group used, 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. The presence of an additional inert solvent is possible but not always necessary. Suitable inert solvents are, for example, organic carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as dimethylformamide (DMF), halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol. as well as water. Mixtures of these solvents may also be suitable. Trifluoroacetic acid is preferably used in excess without addition of additional solvents and perchloric acid in the form of a 9: 1 mixture of acetic acid and 70% perchloric acid. The reaction temperature for the cleavage is suitably about 0 to about 50 ° C, preferably 15 to 30 ° C (room temperature).

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

Hydrogenolytically removable protecting groups (e.g., CBZ or benzyl) can be removed, for example, by treatment with hydrogen in the presence of a catalyst (e.g., a noble metal catalyst such as palladium, preferably on a support such as charcoal). 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 20 to 30 ° C, at a pressure of about 0.1 to 1 MPa. Hydrogenolysis of the CBZ group, for example, performs well on 5-10% palladium on carbon in methanol or on ammonium formate (instead of hydrogen) in the presence of palladium on carbon in a methanol / dimethylformamide system at 20-30 ° C.

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

It is also possible to convert R ¹ , R ² and / or R ³ groups to other R ¹ , R ² and / or R ³ groups. In particular, the carboxylic acid ester can be converted to a carboxylic acid.

It is. Suitably, such an operation is carried out by solvolysis or hydrogenolysis as described above, for example using sodium or potassium hydroxide in a dioxane / water system at a temperature of 0 to 60 ° C, preferably 10 to 40 ° C.

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

It is also possible to replace the conventional amino protecting group with hydrogen by removing the protecting group, as described above, by solvolysis or hydrogenolysis or by releasing, the amino group protected by the conventional protecting group by solvolysis or hydrogenolysis.

For the preparation of compounds of formula I wherein R ^{3 is} H ₂ NC (= NH) -NH-, the corresponding amino compound can be treated with an amidating agent. A preferred amidating agent is 1-amidino-3,5-dimethylprazole (DPFN), which is used in particular as its nitrate. The treatment is preferably carried out with the addition of a base such as triethylamine or ethyldiisopropylamine in an inert solvent or in a solvent mixture, for example a mixture of water and dioxane, at a temperature of 0 to 120 ° C, preferably 60 to 120 ° C.

For the preparation of an amidine of the formula I (where R ^{3 is} -C (= NH) -NH ₂₎ , ammonia can be added to the nitrile of the formula I (R ³ is CN). The reaction is preferably carried out in several steps 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 Salkylimidothioester, which as such is reacted with ammonia to obtain an amidine; or c) reacting the nitrile with lithium bis (trimethylsilyl) amide and subsequently hydrolyzing the obtained product.

The free amino groups may further be acylated in a manner known per se using chloride or acid 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 the appropriate acid addition salt by acid, for example by reacting an equivalent amount of base and acid in an inert solvent such as ethanol and then evaporating the solvent. Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts. Inorganic acids such as sulfuric, nitric, hydrohalic acids such as hydrochloric or hydrobromic acids, phosphoric acids such as orthophosphoric acid, sulfamic acid and organic acids may be used, especially aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic acids or sulfuric acids such as formic, acetic, propionic, pivalic, diethyl acetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic, citric, gluconic, ascorbic, nicotinic, isonicotinic, ethanesulfonic, methanesulfonic, methanesulfonic -hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene monosulphonic acid and naphthalenedisulfonic acid and lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for the isolation and / or purification of the compounds of formula I.

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

The compounds of formula I may have one or more chiral centers and may therefore be in racemic or optically active form. Alternatively, the racemates obtained can be separated into their enantiomers mechanically or chemically by methods known per se. 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 the enantiomers by means of columns filled with optically active resolving agents (e.g. dinitrobenzoylphenylglycine) is also advantageous: hexane / isopropanol / acetonitrile, for example, in a volume ratio of 82: 15: 3 is suitable as the eluent.

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

The invention is. it further relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the production of pharmaceutical preparations, in particular non-chemical. way. For this purpose, they are converted into a suitable dosage form together with at least one solid, semi-solid or liquid carrier or excipient and, if appropriate, in combination with one or more other active substances.

The invention therefore also relates to pharmaceutical compositions comprising at least one medicament comprising at least one compound of the formula I and / or a physiologically acceptable salt thereof and optionally a carrier and / or excipients and optionally other active substances.

These compositions can be used in human and veterinary medicine. Suitable carriers are inorganic or organic substances which are suitable for enteral (e.g. oral) or for parenteral or topical administration or for administration in the form of inhalation sprays and which do not react with compounds of the 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 petrolatum. Especially suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suppositories for rectal use, solutions for parenteral use, especially oily or aqueous solutions, further suspensions, emulsions or implants, for topical use use ointments, creams or powders. The compounds of the invention may also be lyophilized and the lyophilizates obtained, for example, used for the preparation of injectables. The compositions may be sterilized and / or may contain adjuvants such as glidants, preservatives, 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 fluorochlorinated hydrocarbons). In this case, the active ingredient is used in micronized form, at least one physiologically compatible solvent, for example ethanol, being added. Inhalable solutions may be administered using known devices for this purpose.

The invention also relates to the use of the compounds of formula I and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of diseases which are based on expression and pathological function (βνββ and α _ν β5 integrin receptors).

The invention further relates to the use of the compounds of formula I and / or their physiologically acceptable salts and solvates for the manufacture of medicaments for the treatment of pathologically angiogenic diseases, thromboses, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, rheumatic and arthritis restenosis and diabetic retinopathy.

The compounds of the formula I according to the invention are generally used in doses similar to those known in the art, in particular analogously to commercially available integrin inhibitors, but in particular US-A-4 472305, preferably at a dose of approximately 0.05 to 500 mg. in particular 0.5 to 100 mg per dosage unit. The daily dose is preferably about 0.01 to 2 mg / kg body weight. The dose for each individual depends on a variety of factors, such as the efficacy of the particular compound used, age, body weight, general health, sex, diet, time and route of administration, elimination rate, drug combination and the severity of the disease. . Parenteral administration is preferred.

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

If necessary, water is added or, depending on the constitution of the final product, the pH is adjusted to 2 to 10, the reaction mixture is extracted with ethyl acetate or dichloromethane, separation of the organic phase and drying over sodium sulfate, and evaporation and purification of the residue by silica gel chromatography and / or crystallization.

Mass Spectrometry (MS):

EI (electron impact ionization) M ⁺

FAB (fast atom bombardment) (M + H) ⁺

EM / MS (electron spray MS) (M + H) ⁺

Rf values reported are determined by thin layer chromatography using TLC films, silica gel 60 F 254.

Examples

Example 1

3- {7- [2- (4,5-Dihydro-1H-imidazol-2-ylamino) -ethyl] -9H-fluoren-2-yl} -2- (2,2-dimethyl-propoxycarbonylamino) -propionic acid

A solution of 19.8 g of 2,7-di (bromomethyl) fluorene, 16.3 g of diethyl 2 (2,2-dimethylpropoxycarbonylamino) malonate and 15.6 g of carbonate »

- t 9 »<* r t 9

- f R L · _R .b, carbonate in 300 ml of acetonitrile was stirred for four hours at 90 DEG C. and for 16 hours at room temperature. After filtration and removal of the solvent, the crude product is chromatographed on silica gel (petroleum ether / dichloromethane 4: 1). 5.1 g of diethyl 2- (7-bromomethyl-9H-fluoren-2-ylmethyl) -2- (2,2-dimethylpropoxycarbonylamino) malonate (AB) having an Rf value of 0.45 is obtained.

A solution of 5.1 g of AB and 0.8 g of sodium cyanide in 30 ml of dimethylformamide is stirred for one hour at 90 ° C. Conventional work-up gives 4.1 g of diethyl 2- (7-cyanomethyl-9H-fluoren-2-ylmethyl) -2- (2,2-dimethylpropoxycarbonylamino) malonate (AC) of Rf 0.18 (petroleum ether / ethyl acetate 4): 1).

A solution of 4.1 g of AC in 50 ml of methanol and 4.6 ml of glacial acetic acid is treated with 1.05 g of cobalt chloride,

3.06 g of sodium borohydride [sic] is added under stirring and cooling, and the mixture is subsequently stirred for 16 hours.

Work up as usual and chromatograph on silica gel (ethyl acetate / methanol 4: 1). There was thus obtained 2.0 g of diethyl 2- (7-aminoethyl-9H-fluoren-2-ylmethyl) -2- (2,2-dimethylpropoxycarbonylamino) malonate (AD) having an Rf value of 0.14 (methanol).

A solution of 0.6 g of AD, 1 g of 2- (3,5-dimethylpyrazolyl) -4,5-dihydroimidazole and 1 ml of triethylamine in 30 ml of dimethylformamide is stirred for 16 hours at 100 ° C. Removal of the solvent and purification by HPLC chromatography gave 220 mg of diethyl-2- {7- [2- (4,5-dihydro-1H-imidazol-2-ylamino) ethyl] -9H-fluoren-2-ylmethyl} -2- ( 2,2-dimethylpropoxycarbonylamino) malonate (AE) Rf 0.69 (ethyl acetate / methanol 1: 1).

A solution of 0.22 g of EA and 50 mg of hydroxide. of potassium potassium in 20 ml of ethylene glycol monoethyl ether is stirred for four days at room temperature. After removal of the solvent, the residue was dissolved in 20 ml of 1N hydrochloric acid and 5 ml of acetonitrile and stirred for two days at 100 ° C. Removal of the solvent and purification by HPLC chromatography gave 100 mg of 3- (7- [2- (4,5-dihydro-1H-imidazol-2-ylamino) ethyl] 9H-fluoren-2-yl} -2- (2 (2-dimethylpropoxycarbonylamino) propionic acid.

ES / MS 479.3.

The following compounds are obtained in a similar manner:

3- {7- [2- (benzenidazol-2-ylamino) ethyl] -9H-fluoren-2-yl)} -2 (2,2-dimethylpropoxycarbonylamino) propionic acid,

EM / MS 527;

3- {7- [2- (4,5-dihydro-1H-imidazol-2-ylamino) ethyl] -9H-fluoren-2-yl} -2-butylsulfonamidopropionic acid;

3- {7- [2- (benzimidazol-2-ylamino) ethyl] -9H-fluoren-2-yl} -2-butylsulfonamidopropionic 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 an active compound of the formula I and 5 g of aine sodium hydrogen phosphate in 3 liters of double-distilled water is adjusted to pH 6.5 with 2 N hydrochloric acid, sterile filtered, filled into injection ampoules, lyophilized under sterile conditions and sealed . Each vial contains 5 mg of active ingredient.

Example B

suppository

A mixture of 20 g of an active compound of the formula I with 100 g of soya lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to solidify. Each suppository contains 20 mg of active ingredient.

Example C

solution

A solution of 1 g 'of the active compound of the formula I and 9.38 g of sodium dihydrogen phosphate dihydrate, 28.48 g of dihydrogen phosphate with 12 water molecules and 0.1 g of benzalkonium chloride in 940 ml of double-distilled water is prepared. The pH is adjusted to 6.8, made up to 1 liter and sterilized by irradiation.

This solution can be used, for example, as eye drops.

Example D

ointment

500 mg of an active compound of the formula I are mixed with 99.5 g of petroleum jelly under aseptic conditions.

Example E

tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg of 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 general formula Formula I.

Example F

Film-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

The capsules

2 kg of active compound of the formula I are filled into hard gelatin capsules, each capsule containing 20 mg of active compound of the formula I.

Example H

ampoules

A solution of 1 kg of active compound of the formula I in 60 liters of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Example I

Inhalation spray

Dissolve 14 g of the active ingredient 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 (about 0.1 ml) corresponds to a dose of about 0.14 mg.

Industrial Applicability

The fluorene derivative is suitable for the manufacture of pharmaceutical compositions for the treatment of diseases based on the expression and pathological function of α _ν β ₃ and α _ν βδ integrin receptors.

Claims (12)

PATENT CLAIMS A fluorene derivative of the formula I cn PPM -0λ where means R ^{1 is} OR ⁷ , NHR ⁷ or NA 2, R ² is H, CO-R ^7, CO-OR ^7, CONHR ^7, CONA 2 or S0 ₂ R ^7, R ⁴ , R ^{5 are} each independently H, Hal, NO 2, NHR ⁷ , NA 12, OR ⁷ , -CO-R ⁷ , SO ³ R ⁷ , SO ² R ⁷ or SR ⁷ , R ³ NH ₂ , -C (= NH) -NH ₂ , -NH-C (= NH) -NH _{2 from} -C (= O) -N = C (NH ₂ ) ₂ or "S" Any is unsubstituted or monosubstituted Λ Γ -COA, -coqa, -OH or a conventional amino protecting group or R ^S -NH-, R is ^a monocyclic or bicyclic heterocyclic group having 1 to 4 nitrogen, oxygen and / or sulfur atoms which is unsubstituted or is monosubstituted, disubstituted or trisubstituted by Hal, A, -CO A ', OA', CN, COOA ', CONH ₂ , NO ₂ , = NH or = O, H, A, Ar or aralk, A is alkyl having 1 to 15 carbon atoms or cycloalkyl having 3 to 15 carbon atoms, which is unsubstituted or monosubstituted, disubstituted or trisubstituted by ^R8 and in which one, two or three methylene groups are optionally replaced by N, O and / or sulfur, R ^with Hal, NO ₂ , NHA ', NA ₂ , OA', phenoxy, CO-A ', SO ₃ A', CN, NHCOA ', COOA' / C0NA ' ₂ or SO ₂ A', A 'H or C 1 -C 6 alkyl, A '(C 1 -C 6) -alkyl, Ar mono- or bicyclic automatic account group having 0, 1, 2, 3, or 4 N, O and / or S atoms which is unsubstituted or monosubstituted, disubstituted or trisubstituted by alkyl of 1 to 6 carbon atoms and / or groups ^R a (C 7 -C 14) aralkylene group which is unsubstituted or monosubstituted, disubstituted or trisubstituted by R ⁸ and wherein one, two or three methylene moieties are optionally replaced by nitrogen, oxygen and / or sulfur, Hal is F, Cl, Br or J, m, n independently of one another 0, 1, 2, 3, or 4. and physiologically acceptable salts and solvates thereof. Enantiomers or diastereomers of the compounds of formula I according to claim 1. A compound of the formula I according to claim 1 selected from the group consisting of (a) 3- {7- [2- (4,5-dihydro-1H-iridazol-2-ylamino) ethyl] -9H-fluoren-2-yl} -2- (2,2-dimethylpropoxycarbonylamino) for pionic acid, b) 3- {7- [2- (4,5-dihydro-1H-imidazol-2-ylamino) ethyl] -9H-fluoren-2-yl} -2-butylsulfonamidopropionic acid and its physiologically acceptable salts and solvates. 4. A process for the preparation of a compound of formula (I) wherein the individual symbols are as defined in claim 1 or a salt thereof according to claim 1, wherein: (a) releasing a compound of formula (I) from its functional derivative by treatment with a solvolysis, reduction or hydrogenolysis agent; or. b) P symbol group? , R ² and / or R ³ is converted to another group of R ¹ , R ² and / or R ³ by i) converting an amino group to a guanidino group by reaction with an amidating agent, ii) hydrolyzing the ester, iii) converting hydroxyamidine to amidine by hydrogenation, and / or converting a base or acid of formula I to its salt. A process for the preparation of compounds according to claim 1, wherein R ^{1 is a} hydroxyl group and R ² , R ³ , R ⁴ , R ^{5 and} m are as defined in claim 1, and salts and solvates thereof, characterized in that the compound is of the formula II wherein R ¹ is 0-alkyl of 1 to 6 carbon atoms and R ^2, R ^3, R ^4, R ^5, m and n have the meanings defined in claim 1, is hydrolysed and then decarboxylated much. Compounds of formula I according to claims 1 to 3 or physiologically acceptable salts or solvates thereof as medicaments. The medicament of claim 6 as an inhibitor for the treatment of disorders based on the expression and pathological function of α _{v at} β 3 and integrin receptor cyps. The medicament according to claim 6 as an GPIIb / IIIa antagonist for the treatment of thromboses, heart attack, coronary heart disease and arteriosclerosis. 9. The medicament of claim 7 as an inhibitor _of integrin receptors and for the treatment of pathologically angiogenic diseases, thromboses, cardiac infarct, coronary heart disorders, arteriosclerosis, tumors, osteoporosis and rheumatoid arthritis. Pharmaceutical composition, characterized in that it contains, as active ingredient, at least one medicament according to claims 7 to 9 and optionally a carrier and / or excipients and optionally other active compounds. 11. The method of claim 1 to 3 and / or physiologically acceptable salts and solvates for the preparation of a medicament for the treatment of disorders which are based on expression and pathological function of _α ν β3 3s and on _the integrin receptors. Use of the compounds according to claims 1 to 3 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment of pathologically angiogenic diseases, thromboses, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, rheumatoid arthritis, restenosis and diabetic retinopathy.