DE19937394A1 - Fluorene derivatives - 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 compounds of the formula I.

wherein
R ¹ OR ⁷ , NHR ⁷ or NA " ₂ ,
R ² H, CO-R ⁷ , CO-OR ⁷ , CONHR ⁷ , CONA " ₂ or SO ₂ R ⁷ ,
R ⁴ , R ⁵ each independently of one another 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 is} unsubstituted or simply substituted by -COA, -COOA, -OH or by a conventional amino protecting group NH ₂ , -C (= NH) -NH ₂ , -NH-C (= NH) -NH ₂ or -C (= O ) - N = C (NH ₂ ) ₂ ,

or R ⁶ -NH-,
R ^{6 is} a mono- or dinuclear heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or triple by Hal, A ", -CO-A ', OA', CN , COOA ', CONH ₂ , NO ₂ , = NH or = O can be substituted,
R ⁷ H, A, Ar or Aralk,
A is unsubstituted or mono-, di- or trisubstituted by R ⁸ substituted alkyl with 1-15 C- or cycloalkyl with 3-15 C atoms and in which one, two or three methylene groups can be replaced by N, O and / or S,
R ⁸ Hal, NO ₂ , NHA ', NA " ₂ , OA', phenoxy, CO-A ', SO ₃ A', CN, NHCOA ', COOA', CONA ' ₂ or SO ₂ A',
A 'H or alkyl with 1-6 C atoms,
A "alkyl with 1-6 C atoms,
Ar unsubstituted or mono-, di- or trisubstituted by alkyl with 1-6 C atoms and / or R ⁸ mono- or dinuclear aromatic ring system with 0, 1, 2, 3 or 4 N-, O- and / or S -Atoms,
Aralk unsubstituted or mono-, di- or trisubstituted by R ⁸ aralkylene with 7-14 carbon atoms and in which one, two or three methylene groups can be replaced by N, O and / or S,
Hal F, Cl, Br or I,
m, n each independently of one another 0, 1, 2, 3 or 4
mean,
and their physiologically acceptable salts and solvates.

Other vitronectin antagonists are known from WO 97/24124. Bicyclic fibrinogen antagonists are e.g. B. in WO 96/18602 described.

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

It has been found that the compounds of the formula I and their salts and solvates have very valuable pharmacological properties with good tolerability. Above all, they act as integrin inhibitors, in particular inhibiting the interactions of the α _v integrin receptors with ligands. The compounds are particularly effective in the case of integrins a _v β ₃ and α _v β ₅ . The compounds are particularly effective as adhesion receptor antagonists for the receptor α _v β ₃ . This effect can e.g. B. can be detected by the method described by JW Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).

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

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

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

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

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

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

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

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

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

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

The antiplatelet effect can be demonstrated in vitro the method of Born (Nature 4832, 927-929, 1962).

The invention accordingly relates to the compounds of the formula I. and their physiologically acceptable salts and solvates as Drug.

The invention furthermore relates to said medicaments as inhibitors for combating diseases which are based on the expression and pathological function of α _v β ₃ and α _v β ₅ integrin receptors. The invention also relates to medicaments as GPIIb / IIIa antagonists for combating thromboses, heart attacks, coronary heart diseases and arteriosclerosis, and the medicaments as α _v - integrin inhibitors for combating pathologically angiogenic diseases, thromboses, heart attacks, coronary heart diseases, arteriosclerosis, tumors, Osteoporosis and Rheumatoid Arthritis.

The compounds of formula I can be used as active pharmaceutical ingredients in the Human and veterinary medicine are used for prophylaxis and / or Therapy of thrombosis, myocardial infarction, arteriosclerosis, inflammation exercises, apoplexy, angina pectoris, tumor diseases, osteolytic Diseases such as osteoporosis, pathologically angiogenic diseases such as e.g. B. inflammation, ophthalmic diseases, diabetic Retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, ulcerative Colitis, Crohn's disease, atherosclerosis, psoriasis, restenosis after angio plastic, viral infection, bacterial infection, fungal infection, in acute Kidney failure and wound healing to support healing processes.  

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

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

• a) that a compound of formula I from one of its functional Derivatives by treatment with a solvolysing or sets hydrogenolysing agents free, or
• b) that one radical R ¹ , R ² and / or R ^{3 is converted} into another radical R ¹ , R ² and / or R ³ ,
  for example by
  • a) converting an amino group into a guanidino group by reaction with an amidinizing agent,
  • b) saponifying an ester,
  • c) converting a hydroxyamidine into an amidine by hydrogenation

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

The invention further relates to a process for the preparation of compounds of the formula I according to claim 1, in which R ¹ OH and R ² , R ³ , R ⁴ , R ⁵ , m and n have the meanings given in claim 1, and their salts and Solvates, characterized in that a compound of formula II

wherein R ^{1 is} O-alkyl having 1-6 C atoms and R ² , R ³ , R ⁴ , R ⁵ , m and n have the meanings given in claim 1, saponified and then decarboxylated.

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

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

Solvates of the verb are also in the compounds according to the invention included. Among them are addition compounds with z. B. Understand water (hydrates) or alcohols such as methanol or ethanol.

The abbreviations listed above and below stand for:
Ac Acetyl
BOC tert-butoxycarbonyl
CBZ or Z benzyloxycarbonyl
DCCI dicyclohexylcarbodiimide
DBU 1,8-diazabicyclo [5,4,0] undec-7-ene
DMF dimethylformamide
DOPA (3,4-dihydroxyphenyl) alanine
DPFN 3,5-dimethylpyrazole-1-formamidinium nitrate
DMAP dimethylaminopyridine
EDCI N-ethyl-N, N '- (dimethylaminopropyl) carbodiimide
Et ethyl
Fmoc 9-fluorenylmethoxycarbonyl
HOBt 1-hydroxybenzotriazole
Me methyl
MTB ether methyl tert-butyl ether
Mtr 4-methoxy-2,3,6-trimethylphenyl sulfonyl
HONSu N-hydroxysuccinimide
Np neopentyl
OBn benzyl ester
OBut tert-butyl ester
Oct octanoyl
OMe methyl ester
OEt ethyl ester
Orn ornithine
POA phenoxyacetyl
TBTU O- (benzotriazol-1-yl) -N, N, N, N-tetramethyluronium tetra fluoroborate
TFA trifluoroacetic acid
pTSS salt para-toluenesulfonic acid salt
Trt trityl (triphenylmethyl)
Z or CBZ benzyloxycarbonyl.

For the entire invention applies that all residues, the multiple occur, may be the same or different, d. H. independently are from each other.

Preferred compounds of the formula I are those in which the radical - (CH ₂ ) _n -R ^{3 is in} the 2-position and the radical - (CH ₂ ) _m -CH (NHR ² ) -COR ^{1 in} the 7-position of the fluorene- Ring system substituted.

Alkyl preferably means methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl or tert-butyl, also for pentyl, 1-, 2- or 3- Methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3- Dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2- methylpropyl, 1,1,2-, 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or Decyl, and z. B. trifluoromethyl or pentafluoroethyl.

A 'preferably denotes H, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.

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

Cycloalkyl preferably means cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, adamantyl or 3-menthyl.

Alkylene preferably means methylene, ethylene, propylene, butylene, Pentylene, also hexylene, heptylene, ocytylene, nonylene or decylene.

Aralk is aralkylene and preferably means alkylenephenyl and is e.g. B. preferably benzyl or phenethyl.

A very particularly preferably denotes methyl, ethyl, propyl, isopropyl, Butyl or tert-butyl. CO-A 'is alkanoyl or cycloalkanoyl and preferably means formyl, Acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, Nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, Tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl or Octadecanoyl.

Preferred substituents R ⁸ for alkyl, Ar, cycloalkyl and aralk are preferably, for. Hal, NO ₂ , NH ₂ , NHA ", such as methylamino, NA" ₂ , such as. B. dimethylamino, methoxy, phenoxy, acyl such as. B. formyl or acetyl, CN, NHCOA ', such as. B. acetamido, COOA ', such as. B. COOH or methoxycarbonyl, CONA ' ₂ or SO ₂ A', especially z. B. F, Cl, hydroxy, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methylsulfonyl or phenylsulfonyl.

In the alkyl, alkylene and cycloalkyl radicals, one or two can be used or three methylene groups can be replaced by N, O and / or S.

Ar-CO is aroyl and preferably means benzoyl or naphthoyl.

Ar is unsubstituted, preferably - as indicated - monosubstituted Phenyl, in particular preferably phenyl, o-, m- or p-tolyl, o-, m- or p- Ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-cyanphenyl, 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-methyl thiophenyl, o-, m- or p-methylsulfinylphenyl, o-, m- or p-methylsulfone ylphenyl, o-, m- or p-aminophenyl, o-, m- or p-methylaminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p-nitrophenyl, further before adds 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-dibromo phenyl, 2-chloro-3-methyl, 2-chloro-4-methyl, 2-chloro-5-methyl, 2-chloro-6- methyl, 2-methyl-3-chloro, 2-methyl-4-chloro, 2-methyl-5-chloro, 2-methyl-6- chloro, 3-chloro-4-methyl, 3-chloro-5-methyl or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl, 2-bromo-4-methyl, 2-bromo-5-methyl, 2-bromo-6-methyl, 2-methyl-3-bromo, 2-methyl-4-bromo, 2-methyl-5-bromo, 2-methyl-6-bromo, 3-bromo-4-methyl-, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-tri-tert-butylphenyl, 2,5-di methylphenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3,5-dimethyl phenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 2,4-dichloro-5- methylphenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2- Methoxy-5-methylphenyl, 2,4,6-triisopropylphenyl, naphthyl, 1,3-benzo dioxol-5-yl, 1,4-benzodioxan-6-yl, benzothiadiazol-5-yl or benzoxa diazol-5-yl.

Ar furthermore preferably denotes 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 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- 4-H-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-benzo pyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzis oxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benziso thiazolyl, 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- Cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.

R ⁶ is a mono- or dinuclear heterocycle, 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, further 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 4-4-H-thiopyranyl, 3- or 4-pyridazinyl, pyr azinyl, 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 -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, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.

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

R ⁵ can, for. B. also mean 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-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5 -pyrrol yl, 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.

The heterocyclic rings mentioned can also be substituted one, two or three times by Hal, A, -CO-A, OH, CN, COOH, COOA, CONH ₂ , NO ₂ , = NH or = O.

R ⁶ very particularly preferably denotes 1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-2-yl, 5-oxo-4, 5-dihydro-1H-imidazol-2-yl, thiazol-2- yl, 1H-benz imidazol-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-imino-imidazolidin-4-one-5-yl, 1-alkyl-1,5-dihydro -imidazol-4-one-2-yl, pyridin-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydro-pyrimidin-2-yl.

R ¹ means in particular z. B. Hydroxy, methoxy, ethoxy, NH ₂ , NHMe, NHEt, NMe ₂ or NEt ₂ .

R ¹ very particularly preferably denotes OH or OEt.

R ² preferably means z. B. H, acetyl, propionyl, aminocarbonyl, N, N-dimethylaminocarbonyl, alkoxycarbonyl such as. B. pentyloxycarbonyl, alkylsulfonyl such as. B. methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, iso-butylsulfonyl, 2,2-dimethylpropylsulfonyl, phenylsulfonyl or benzylsulfonyl.

R ² very particularly preferably denotes 2,2-dimethylpropoxycarbonyl or butylsulfonyl.

R ³ preferably means z. B. 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-imino-imidazolidin-4-one-5-ylamino, 1-methyl-1,5- dihydro imidazol-4-one-2-ylamino, pyridin-2-ylamino, pyrimidin-2-ylamino or 1,4,5,6-tetrahydro-pyrimidin-2-ylamino.

R ⁴ and R ⁵ very particularly preferably denote H.

Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings indicated above. Some preferred groups of compounds can be expressed by the following sub-formulas Ia to Ih, which correspond to the formula I and in which the radicals not specified have the meaning given for the formula I, but in which
in Ia)
R ^{1 represents} OH;
in Ib)
R ¹ OH and
R ^{2 is} CO-OR ⁷ or SO ₂ R ⁷ ;
in Ic)
R ¹ OH,
R ² CO-OR ⁷ or SO ₂ R ⁷ and
R ³ 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-benz imidazol-2-ylamino, 2H-pyrazol-2-ylamino, 2-imino-imidazolidin-4-one-5-ylamino, 1-methyl-1,5 - mean dihydro-imidazol-4-one-2-ylamino, pyridin-2-ylamino, pyrimidin-2-ylamino or 1,4,5,6-tetrahydro-pyrimidin-2-ylamino;
in Id)
m represents 1;
in Ie)
m 1 and
R ^{1 represents} OH;
in if)
R ¹ OH,
R ² CO-OR ⁷ or SO ₂ R ⁷ and
m is 1;
in Ig)
R ¹ OH,
R ² CO-OR ⁷ or SO ₂ R ⁷ and
R ⁷ alkyl with 1-6 C atoms and
m is 1;
in you)
R ¹ OH,
R ² CO-OR ⁷ or SO ₂ R ⁷ ,
R ⁷ alkyl with 1-6 C atoms,
R ³ 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-benz imidazol-2-ylamino, 2H-pyrazol-2-ylamino, 2-imino-imidazolidin-4-one-5-ylamino, 1-methyl-1,5 - mean dihydro-imidazol-4-one-2-ylamino, pyridin-2-ylamino, pyrimidin-2-ylamino or 1,4,5,6-tetrahydro-pyrimidin-2-ylamino;
R ⁴ _, R ⁵ H,
m 1 and
n is 2, 3 or 4;
and their physiologically acceptable salts and solvates.

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

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

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

Preferred starting materials for solvolysis or hydrogenolysis are Those which otherwise correspond to formula I, but instead of one or more erer free amino and / or hydroxyl groups correspondingly protected Contain amino and / or hydroxyl groups, preferably those which instead of an H atom connected to an N atom, an amino wear a protective group, especially those that replace an HN group carry an R'-N group, in which R 'represents an amino protecting group, and / or those which have a hydroxy instead of the H atom of a hydroxy group wear protective group, e.g. B. those corresponding to formula I, however place a group -COOH a group -COOR ", where R" is a Hydroxy protecting group means.

Preferred starting materials are also the oxadiazole derivatives, which are in the corresponding amidino compounds can be transferred.

The release of the amidino group from its oxadiazole derivative can e.g. B. by treatment with hydrogen in the presence of a catalyst (e.g. Raney nickel) can be split off. The solvents are suitable specified below, in particular alcohols such as methanol or Ethanol, organic acids such as acetic acid or propionic acid or Mixtures of these. Hydrogenolysis is usually done with Temperatures between about 0 and 100 ° and pressures between about 1 and 200 bar, preferably at 20-30 ° (room temperature) and 1-10 bar carried out.

The introduction of the oxadiazole group succeeds, for. B. by implementing the Cyano compounds with hydroxylamine and reaction with phosgene, Dialkyl carbonate, chloroformate, N, N'-carbonyldiimidazole or Acetic anhydride.

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

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

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

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

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

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

It is also possible to convert a radical R ¹ , R ² and / or R ³ into another radical R ¹ , R ² and / or R ³ .

In particular, one can convert a carboxylic acid ester into a carboxylic acid convert.

It is thus possible to saponify an ester of the formula I. Appropriately this is done by solvolysis or hydrogenolysis, as indicated above, e.g. B. with NaOH or KOH in dioxane-water at temperatures between 0 and 60 ° C, preferably between 10 and 40 ° C.

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

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

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

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

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

A base of formula I can with an acid in the associated acid addition salt can be transferred, for example by reaction equi valent amounts of the base and the acid in an inert solvent such as ethanol and subsequent evaporation. For this implementation In particular acids are considered, the physiologically harmless Deliver salts. 5o inorganic acids can be used, e.g. B. Sulfuric acid, nitric acid, hydrohalic acids such as chlorine hydrochloric acid or hydrobromic acid, phosphoric acids such as ortho phosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. B. Formic acid, acetic acid, propionic acid, pivalic acid, diethyl acetic acid, Malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, Lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, Ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfone acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfone acid, p-toluenesulfonic acid, naphthalene mono- and disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. B. Picrates, can be used to isolate and / or purify the compounds of formula I can be used.

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

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

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

The invention further relates to the use of the compounds of formula I and / or their physiologically acceptable salts provision of pharmaceutical preparations, in particular on non-chemical paths. You can do this together with at least one solid, liquid and / or semi-liquid carrier or auxiliary and optionally in combination with one or more others Active ingredients are brought into a suitable dosage form.

The invention furthermore relates to pharmaceutical preparations, containing at least one drug containing at least one Compound of formula I and / or one of its physiologically acceptable Lichen salts, and optionally carriers and / or auxiliaries and optionally other active ingredients.  

These preparations can be used in human or veterinary medicine be used. Organic or anor are used as carriers ganic substances in question, which are suitable for enteral (e.g. oral) teral, topical application or for an application in the form of a Inhalation sprays are suitable and do not react with the new compounds s, for example water, vegetable oils, benzyl alcohols, alkylene glycol kole, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as Lactose or starch, magnesium stearate, talc, petroleum jelly. For oral application tablets, pills, coated tablets, capsules, pul ver, granules, syrups, juices or drops, for rectal use Sup positions, for parenteral use solutions, preferably oily or aqueous solutions, also suspensions, emulsions or implan tate, for topical application of ointments, creams or powder. The new Compounds can also be lyophilized and the lyophilizates obtained e.g. B. can be used for the production of injectables. The on given preparations can be sterilized and / or auxiliary substances such as Lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, Salts for influencing the osmotic pressure, buffer substances, Contain color, taste and / or several other active ingredients, for. B. one or more vitamins.

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

The invention thus also relates to the use of compounds of the formula I and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for combating diseases which are based on the expression and pathological function of α _v β ₃ and α _v β ₅ integrin receptors .

The invention furthermore relates to the use of compounds of the formula I and / or their physiologically acceptable salts and Solvate for the manufacture of a medicament for combating pathologically angiogenic diseases, thrombosis, heart attack, coronary heart disease, arteriosclerosis, tumors, osteoporosis, rheumatic arthritis, restenosis, and diabetic retinopathy. The substances according to the invention can generally be found in Ana logic to other known, commercially available integrin inhibitors, but in particular in analogy to that described in US-A-4,472,305 ben compounds are administered, preferably in dosages between approximately 0.05 and 500 mg, in particular between 0.5 and 100 mg administered per dosage unit. The daily dosage is preferred between about 0.01 and 2 mg / kg body weight. The special dose for each patient, however, depends on a variety of factors, for example on the effectiveness of the special verb used dung, age, body weight, general health, Gender, the diet, the time and route of administration, the Elimination rate, drug combination and severity of respective disease to which the therapy applies. The parenteral Application is preferred.

All temperatures above and below are given in ° C. In the The following examples mean "customary workup": If there is required to add water, if necessary, depending on the constitution of the End product to pH between 2 and 10, extracted with ethyl acetate or dichloromethane, separates, the organic phase dries over Sodium sulfate, evaporates and purifies by chromatography on silica gel and / or by crystallization.

Mass SpectroIonization) M ⁺
FAB (Fast Atom Bombardment) (M + H) ⁺
ES / MS (electron spray MS) (M + H) ⁺

The stated R _f values were determined by thin layer chromatography using TLC films, silica gel 60 F ₂₅₄ .

example 1 3- {7- [2- (4,5-Dihydro-1H-imidazol-2-ylamino) ethyl] -9H-fluoren-2-yl} -2- (2,2-dimethylpropoxycarbonylamino) 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 potassium carbonate in 300 ml of acetonitrile is at 90 ° for 4 hours and stirred 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 2- (7-bromomethyl-9H-fluoren-2-ylmethyl) -2- (2,2-dimethyl-propoxycarbonylamino) malonate ("AB"), R _f 0.45, are obtained.

A solution of 5.1 g of "AB" and 0.8 g of sodium cyanide in 30 ml of DMF is stirred at 90 ° for 1 hour. After customary working up, 4.1 g of diethyl 2- (7- cyanomethyl-9H-fluoren-2-ylmethyl) -2- (2,2-dimethyl-propoxycarbonylamino) -malonate ("AC"), R _f 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 mixed with 1.05 g of cobalt (II) chloride. With stirring and cooling, 3.06 g of sodium borohydride are added and the mixture is stirred for 16 hours. The mixture is worked up in the customary manner, chromatographed on silica gel (ethyl acetate / 11ethanol 4: 1) and 2.0 g of 2- (7-aminoethyl-9H-fluoren-2-ylmethyl) -2- (2,2-dimethyl-propoxycarbonylamino) are obtained. -malonic acid diethyl ester ("AD"), R _f 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 DMF is stirred at 100 ° for 16 hours. After removal of the solvent and purification by HPLC, 220 mg of 2- {7- [2- (4,5-dihydro-1H-imidazol-2-ylamino) ethyl] -9H-fluoren-2-ylmethyl} -2- (2,2-dimethyl-propoxycarbonylamino) - diethyl malonate ("AE"), R _f 0.69 (ethyl acetate / methanol 1: 1)

A solution of 0.22 g of "AE" and 50 mg of potassium hydroxide in 20 ml of ethylene glycol monoethyl ether is stirred for 4 days at room temperature. After removal of the solvent, the residue is dissolved in 20 ml of 1N HCl and 5 ml of acetonitrile and stirred at 100 ° for 2 days. After removing the solvents, the residue is purified by HPLC. 100 mg of 3- {7- [2- (4,5-dihydro-1H-imidazol-2-ylamino) ethyl] -9H-fluoren-2-yl} -2- (2,2-dimethylpropoxycarbonylamino) - are obtained. propionic acid

The following compounds are obtained analogously
3- {7- [2- (Benzimidazol-2-ylamino) ethyl] -9H-fluoren-2-yl} -2- (2,2-dimethylpropoxycarbonylamino) propionic acid, ES / MS 527;
3- {7- [2- (4,5-dihydro-1H-imidazol-2-ylamino) ethyl] -9H-fluoren-2-yl} -2-butylsulfonamido-propionic acid,
3- {7- [2- (Benzimidazol-2-ylamino) ethyl] -9H-fluoren-2-yl} -2-butylsulfonamidopropionic acid.

The following examples relate to pharmaceutical preparations:

Example A Injection glasses

A solution of 100 g of an active ingredient of the formula I and 5 g of disodium Hydrogen phosphate is dissolved in 3 liters of double distilled water with 2N salt acid adjusted to pH 6.5, sterile filtered, filled into injection glasses, lyophilized under sterile conditions and sealed sterile. Every In jection glass contains 5 mg of active ingredient.

Example B Suppositories

A mixture of 20 g of an active ingredient of the formula I is melted with 100 g soy lecithin and 1400 g cocoa butter, pour into molds and leave cool down. Each suppository contains 20 mg of active ingredient.

Example C solution

A solution is prepared from 1 g of an active ingredient of the formula I, 9.38 g of NaH ₂ PO ₄ .2 H ₂ O, 28.48 g of Na ₂ HPO ₄ .12 H ₂ O and 0.1 g of benzalkonium chloride in 940 ml double distilled water. It is adjusted to pH 6.8, made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D ointment

500 mg of an active ingredient 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 formula I, 4 kg lactose, 1.2 kg kar Potato starch, 0.2 kg talc and 0.1 kg magnesium stearate are common Formed into tablets in such a way that each tablet contains 10 mg of active ingredient contains.  

Example F Dragees

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

Example G Capsules

2 kg of active ingredient of formula I are in the usual way in hard gelatin capsules filled so that each capsule contains 20 mg of the active ingredient.

Example H Ampoules

A solution of 1 kg of active ingredient of formula I in 60 l of double distilled Water is sterile filtered, filled into ampoules, under sterile conditions lyophilized and sealed sterile. Each ampoule contains 10 mg Active ingredient.

Example I Inhalation spray

14 g of active ingredient of the formula I are dissolved in 10 l of isotonic NaCl solution and fills the solution into commercially available spray vessels with a pump mechanism. The solution can be sprayed into the mouth or nose. A spray (about 0.1 ml) corresponds to a dose of about 0.14 mg.

Claims (12)

1. Compounds of formula I.
wherein
R ¹ , OR ⁷ NHR ⁷ or NA " ₂ ,
R ² H, CO-R ⁷ , CO-OR ⁷ , CONHR ⁷ , CONA " ₂ or SO ₂ R ⁷ ,
R ⁴ , R ⁵ each independently of one another 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 is} unsubstituted or simply substituted by -COA, -COOA, -OH or by a conventional amino protecting group NH ₂ , -C (= NH) -NH ₂ , -NH-C (= NH) -NH ₂ or -C (= O ) -N = C (NH ₂ ) ₂ ,
or R ⁶ -NH-,
R ^{6 is} a mono- or dinuclear heterocycle having 1 to 4 N, O and / or S atoms, which is unsubstituted or mono-, di- or triple by Hal, A ", -CO-A ', OA', CN , COOA ', CONH ₂ , NO ₂ , = NH or = O can be substituted,
R ⁷ H, A, Ar or Aralk,
A unsubstituted or mono-, di- or trisubstituted by R ⁸ substituted alkyl with 1-15 C or cycloalkyl with 3-15 C atoms and in which one, two or three methylene groups can be replaced by N, O and / or S. ,
R ⁸ Hal, NO ₂ , NHA ', NA " ₂ , OA', phenoxy, CO-A ', SO ₃ A', CN, NHCOA ', COOA', CONA ' ₂ or SO ₂ A',
A 'H or alkyl with 1-6 C atoms,
A "alkyl with 1-6 C atoms,
Ar unsubstituted or mono-, di- or trisubstituted by alkyl with 1-6 C atoms and / or R ⁸ mono- or dinuclear aromatic ring system with 0, 1, 2, 3 or 4 N-, O- and / or S -Atoms,
Aralk unsubstituted or mono-, di- or trisubstituted by R ⁸ substituted aralkylene with 7-14 C atoms and in which one, two or three methylene groups can be replaced by N, O and / or S,
Hal F, Cl, Br or I,
m, n each independently of one another 0, 1, 2, 3 or 4
mean,
and their physiologically acceptable salts and solvates. 2. Enantiomers or diastereomers of the compounds of the formula I. according to claim 1. 3. Compounds of formula I according to claim 1

• a) 3- {7- [2- (4,5-Dihydro-1H-imidazol-2-ylamino) ethyl] -9H-fluoren-2-yl} -2- (2,2-dimethylpropoxycarbonylamino) propionic acid;
• b) 3- {7- [2- (4,5-Dihydro-1H-imidazol-2-ylamino) ethyl] -9H-fluoren-2-yl} -2-butylsulfonamido-propionic acid;

and their physiologically acceptable salts and solvates. 4. A process for the preparation of compounds of formula I according to claim 1 and their salts and solvates, characterized in that

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

or

• a) converts a radical R ¹ , R ² and / or R ³ into another radical R ¹ , R ² and / or R ³ ,
  for example by
  • a) converting an amino group into a guanidino group by reaction with an amidinizing agent,
  • b) saponifying an ester,
  • c) converting a hydroxyamidine into an amidine by hydrogenation

and / or converts a base or acid of the formula I into one of its salts. 5. A process for the preparation of compounds of formula I according to claim 1, wherein R ¹ OH and R ² , R ³ , R ⁴ , R ⁵ , m and n have the meanings given in claim 1, and their salts and solvates, characterized that a compound of formula II
wherein R ^{1 is} O-alkyl having 1-6 C atoms and R ² , R ³ , R ⁴ , R ⁵ , m and n have the meanings given in claim 1, saponified and then decarboxylated. 6. Compounds of formula I according to claims 1-2 and the Compounds according to claim 3 and their physiological harmless salts and solvates as medicines. 7. Medicament according to claim 6 as an inhibitor for combating diseases which are based on an expression and pathological function of α _v β ₃ and α _v β ₅ integrin receptors. 8. Medicament according to claim 6 as GPIIb / IIIa antagonists Combating thrombosis, heart attack, coronary heart disease and atherosclerosis. 9. Medicament according to claim 7 as α _v integrin inhibitors for combating pathologically angiogenic diseases, thrombosis, heart attack, coronary heart diseases, arteriosclerosis, tumors, osteoporosis and rheumatic arthritis. 10. Pharmaceutical preparation containing at least one medicament agent according to one of claims 7 to 9 and optionally Carriers and / or auxiliary substances and optionally other active substances.   11. Use of compounds according to claims 1 to 3 and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for combating diseases which are based on the expression and pathological function of α _v β ₃ and α _v β ₅ integrin receptors . 12. Use of compounds according to claims 1 to 3 and / or their physiologically acceptable salts and solvates for Manufacture of a drug to combat pathological angiogenic diseases, thrombosis, heart attack, coronary artery Heart disease, arteriosclerosis, tumors, osteoporosis, rheumatoid arthritis, restenosis, and diabetic retinopathy.