Integrin inhibitors for the treatment of eye diseases

Abstract

Methods and compositions for prophylaxis and/or treatment of diseases of the eye using antagonists of the integin receptors α v β 3 and/or α v 62 5 . The compositions can be nanoparticles and are administered to the eye by injection into the vitreous body of the eye.

What claimed is:  
     
         1 . A method for prophylaxis and/or treatment of diseases of the eye of a patient resulting from angiogenesis in the eye comprising injecting into the vitreous body of the eye of said patient a composition comprising a therapeutically effective amount of an α v β 3  and/or α v β 5  inhibitor sufficient to inhibit angiogenesis of the eye  
     
     
         2 . A method of  claim 1  wherein the α v β 3  and/or α v β 5  inhibitor is a RGD-containing polypeptide  
     
     
         3 . A method of  claim 2  wherein said polypeptide is a compound of formula I  
       cyclo-(Arg-Gly-Asp-D-(A) n E)   I,  
       in which 
 D is D-Phe, Phe, D-Trp, Trp, D-Tyr, Tyr, D-homoPhe, homoPhe, D-Nal, Nal, D-Phg, Phg or 4-Hal-Phe (D or L form),  
 E is Val, Gly, Ala, Leu, Ile or Nle and  
 A is alkyl having 1-18 carbon atoms,  
 n 0 or 1  
 and also their physiologically acceptable salts  
 
     
     
         4 . A method of  claim 2  wherein said polypeptide is a compound as expressed by subformula la, which otherwise correspond to formula I but in which 
 D is D-Phe and  
 E is Gly, Ala, Val, Leu, Ile or Nle.  
 
     
     
         5 . A method of  claim 2  wherein said polypeptide is cyclo-(Arg-Gly-Asp-DPhe-Val)  
     
     
         6 . A method of  claim 2  wherein said polypeptide is cyclo-(Arg-Gly-Asp-DPhe-NMeVal)  
     
     
         7 . A method of  claim 2  wherein said therapeutically efective amount is from about 0.5 μg to 5 mg  
     
     
         8 . A method of  claim 2  wherein said eye disease is diabetic retinopathy  
     
     
         9 . A method of  claim 2  wherein said eye disease is macular degeneration  
     
     
         10 . A method of  claim 2  wherein said eye disease is myopia  
     
     
         11 . A method of  claim 2  wherein said eye disease is ocular histoplasmosis  
     
     
         12 . A method of  claim 1  wherein the α v β 3  and/or α v β 5  inhibitor is a compound of formula II  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is H, alkyl having 1-6 C atoms or benzyl,  
 R 2  is R 10 , CO—R 10 , COOR 6 , COOR 10 , SO 2 R 6  or SO 2 R 10 ,  
 R 3  is H, Hal, OA, NHR 10 , N(R 10 ) 2 , —NH-acyl, —O-acyl, CN, NO 2 , OR 10 , SR 10 , R 2  or CONHR 10 ,  
 R 4  is H, ═O, ═S, C 1 -C 6 -alkyl or acyl,  
 R 5  is NH 2 , H 2 N—C(═NH) or H 2 N—(C═NH)—NH, where the primary amino groups can also be provided with conventional amino protective groups or can be mono-, di- or trisubstituted by R 10 , CO—R 10 , COOR 10  or SO 2 R 10 , or R 6 ,  
 R 7 , R 8  are each independently of one another absent or H,  
 R 7  and R 8  together are also a bond,  
 X, Y are each independently of one another ═N—, —N—, O, S, —CH 2 — or ═C—, 
 with the proviso that at least one of the two definitions X, Y is ═N—, —N—, O or S,  
 
 W, Z are each independently of one another absent, O, S, NR 1 , C(═O), CONH, NHCO, C(═S)NH, NHC(═S), C(═S), SO 2 NH, NHSO 2  or CA═CA′,  
 R 6  is a mono- or binuclear heterocycle which has 1 to 4 N, O and/or S atoms and can be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH 2 , NO 2 , ═NH or ═O,  
 R 9  is H, Hal, OA, NHA, NAA′, NHacyl, Oacyl, CN, NO 2 , SA, SOA, SO 2 A, SO 2 Ar or SO 3 H,  
 R 10  is H, A, Ar or aralkyl having 7-14 C atoms,  
 R 11  is H or alkyl having 1-6 C atoms,  
 A, A′ are each independently of one another H or unsubstituted or mono-, di- or tri-R 9 -substituted alkyl or cycloalkyl, each of which has 1-15 C atoms and in which one, two or three methylene groups can be replaced by N, O and/or S,  
 Ar is unsubstituted or mono-, di- or tri-A- and/or R 9 -substituted mono- or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N, O and/or S atoms,  
 Hal is F, Cl, Br or I and  
 m, n are each independently of one another 0, 1, 2, 3 or 4,  
 or a the physiologically acceptable salts thereof  
 
     
     
         13 . A method of  claim 12  wherein the α v β 3  and/or α v β 5  inhibitor is selected from the group consisting of compounds of subformulae IIa to IIg, which otherwise correspond to formula II but in which 
 in IIa) R 1  is H or alkyl with 1-6 C atoms, 
 R 2  is R 10 , CO—R 10 , COOR 10  or SO 2 R 10 ,  
 R 3  is H,  
 R 4  is H or ═O,  
 R 5  is H 2 N—C(═NH) or H 2 N—C(═NH)—NH,  
 W, Z are each independently of one another absent, C(═O), NH, CONH or NHCO,  
 X is —NH—, O or —CH 2 —,  
 Y is NH or O,  
 R 10  is H, A or benzyl,  
 R 11  is H,  
 A is unsubstituted alkyl or cycloalkyl with 1-15 C atoms and  
 m, n are each independently of one another 0, 1 or 2;  
 
 in IIb) R 1  is H or alkyl with 1-6 C atoms, 
 R 2  is R 10 , CO—R 10 , COOR 10  or SO 2 R 10 ,  
 R 3  is H,  
 R 4  is H or ═O,  
 R 5  is R 6 ,  
 W, Z are each independently of one another absent, C(═O), NH, CONH or NHCO,  
 X is —NH—, O or —CH 2 —,  
 Y is NH or O,  
 R 6  is a mono- or binuclear heterocycle which has 1-4 N, O and/or S atoms and which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH 2 , NO 2 , ═NH or ═O,  
 R 10  is H, A or benzyl,  
 R 11  is H,  
 A is unsubstituted alkyl or cycloalkyl with 1-15 C atoms and  
 m, n are each independently of one another 0, 1 or 2;  
 
 in IIc) R 1  is H or alkyl with 1-6 C atoms, 
 R 2  is R 10 , CO—R 10 , COOR 10  or SO 2 R 10 ,  
 R 3  is H,  
 R 4  is H or ═O,  
 R 5  is H 2 N—C(═NH) or H 2 N—C(═NH)—NH,  
 W, Z are each independently of one another absent, C(═O), NH, CONH or NHCO,  
 X is —NH—, O or —CH 2 —,  
 Y is NH or O,  
 A is alkyl with 1-6 C atoms,  
 R 10  is H, alkyl with 1-6 C atoms, camphor-10-yl or benzyl,  
 R 11  is H,  
 m, n are each independently of one another 0, 1 or 2;  
 
 in IId) R 1  is H or alkyl with 1-6 C atoms, 
 R 2  is R 10 , CO—R 10 , COOR 10  or SO 2 R 10 ,  
 R 3  is H,  
 R 4  is H or ═O,  
 R 5  is R 6 ,  
 W, Z are each independently of one another absent, C(═O), NH, CONH or NHCO,  
 X is ═NH—, O or —CH 2 —,  
 Y is NH or O,  
 R 6  is a mono- or binuclear heterocycle which has 1-4 N, O and/or S atoms and which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH 2 , NO 2 , ═NH or ═O,  
 R 10  is H, alkyl with 1-6 C atoms, camphor-10-yl or benzyl,  
 R 11  is H,  
 A is unsubstituted alkyl with 1-6 C atoms and  
 m, n are each independently of one another 0, 1 or 2;  
 
 in IIe) R 1  is H or alkyl with 1-6 C atoms, 
 R 2  is R 10 , CO—R 10 , COOR 10  or SO 2 R 10 ,  
 R 3  is H,  
 R 4  is H or ═O,  
 R 5  is R 6 ,  
 W, Z are each independently of one another absent, C(═O), NH, CONH or NHCO,  
 X is —NH—, O or —CH 2 —,  
 Y is NH or O,  
 R is 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-imino-imidazolidin-4-on-5-yl, 1-A-1,5-dihydro-imidazol-4-on-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydro-pyrimidin-2-yl,  
 R 10  is H, alkyl with 1-6 C atoms, camphor-10-yl or benzyl,  
 R 11  is H,  
 A is unsubstituted alkyl with 1-6 C atoms and  
 m, n are each independently of one another 0, 1 or 2;  
 
 in IIf) R 1  is H or alkyl with 1-6 C atoms, 
 R 2  is R 10 , CO—R 10 , COOR 10  or SO 2 R 10 ,  
 R 3  is H,  
 R 4  is H or ═O,  
 R 5  is H 2 N—C(═NH) or H 2 N—C(═NH)—NH,  
 W, Z are each independently of one another absent, C(═O), NH, CONH or NHCO,  
 X is —NH—, O or —CH 2 —,  
 Y is NH or O,  
 R 10  is Ar,  
 R 11  is H,  
 A is unsubstituted alkyl or cycloalkyl with 1-15 C atoms and  
 m, n are each independently of one another 0, 1 or 2;  
 
 in IIg) R 1  is H or alkyl with 1-6 C atoms, 
 R 2  is R 10 , CO—R 10 , COOR 10  or SO 2 R 10 ,  
 R 3  is H,  
 R 4  is H or ═O,  
 R 5  is R 6 ,  
 W, Z are each independently of one another absent, C(═O), NH, CONH or NHCO,  
 X is —NH—, O or —CH 2 —,  
 Y is NH or O,  
 R 6  is a mono- or binuclear heterocycle which has 1-4 N, O and/or S atoms and which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH 2 , NO 2 , ═NH or ═O,  
 R 10  is Ar,  
 R 11  is H,  
 A is unsubstituted alkyl or cycloalkyl with 1-15 C. atoms and  
 m, n are each independently of one another 0, 1 or 2  
 
 in IIh) R 1  is H or alkyl with 1-6 C atoms, 
 R 2  is R 10 , CO—R 10 , COOR 10  or SO 2 R 10 ,  
 R 3  is H,  
 R 4  is H or ═O,  
 R 5  is H 2 N—C(═NH), H 2 N—C(═NH)—NH, a mono- or binuclear heterocycle which has 1-4 N, O and/or S atoms and which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH 2 , NO 2 , ═NH or ═O,  
 W, Z are each independently of one another absent, C(═O), NH, CONH or NHCO,  
 X is —CH 2 —,  
 Y is NH or O,  
 R 7 , R 8  is H  
 R 10  is A, Ar, aralkyl or Het,  
 R 11  is H,  
 A is unsubstituted alkyl or cycloalkyl with 1-15 C atoms and  
 m,n are each independently of one another 0, 1 or 2;  
 
 
     
     
         14 . A method according to  claim 12  wherein the α v β 3  and/or α v β 5  inhibitor is a compound selected from the group consisting of 
 (2S)-2-[(R)-camphor-10-sulfonamido]-3-{3,4-dihydro-2-(3-guanidinopropyl)-(2H-1,4-benzoxazin-3-on-6-yl}propionic acid;  
 (2S)-2-benzyloxycarboxamido-3-(2-guanidinomethyl-1,4-benzodioxan-6-yl)propionic acid;  
 (2S)-2-tert-butyloxycarboxamido-3-[3,4-dihydro-2-(2-guanidino-2-oxoethyl)-2H-1,4-benzoxazin-3-on-6-yl]propionic acid;  
 (2S)-2-benzyloxycarboxamido-3-(2-guanidinoacet-amidomethyl-1,4-benzodioxan-6-yl)propionic acid;  
 (2S)-2-tert-butyloxycarboxamido-3-{3,4-dihydro-2-[N-(2-imidazolyl)carbamoylmethyl]-2H-1,4-benzox-azin-3-on-6-yl)propionic acid;  
 (2S)-2-tert-butyloxycarboxamido-3-{3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-on-6-yl)propionic acid;  
 (2S)-2-tert-butyloxycarboxamido-3-{3,4-dihydro-2-[2-(2-imino-4-oxoimidazolidin-5-yl)ethyl]-2H-1,4-benzoxazin-3-on-6-yl}propionic acid;  
 (2S)-2-(2,2-dimethylpropyloxycarboxamido)-3-{3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl]-(2S)-2H-1,4-benzoxazin-3-on-6-yl}propionic;  
 (2S)-2-[(R)-camphorsulfonamido]-3-{3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-on-6-yl)propionic acid  
 (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(2,2-dimethylpropoxycarboxamido)propionic acid;  
 (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(butylsulfonamido)-propionic acid;  
 (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(4-fluorphenylsulfonamido)-propionic acid;  
 (2S)-3-{2-[3-(pyridin-2-ylamino)propyl]-chroman-6-yl}-2-(2,4,6-trimetylphenylsulfonamido)propionic acid;  
 (2S)-3-{2-[3-(pyridin-2-ylamino)propyl]-chroman-6-yl}-2-(2,2-dimethylpropoxycarboxamido)propionic acid;  
 (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(tert.butyloxycarboxamido)-propionic acid;  
 (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(diphenylmethylsulfonamido)-propionic acid;  
 and their physiologically acceptable salts  
 
     
     
         15 . A method according to  claim 12  wherein the α v β 3  and/or α v β 5  inhibitor is 
 (2S)-2-(2,2-dimethylpropyloxycarboxamido)-3-{3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl]-(2S)-2H-1,4-benzoxazin-3-on-6-yl}propionic acid  
 (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(2,2-dimethylpropoxycarboxamido)propionic acid;  
 (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(butylsulfonamido)-propionic acid; or  
 (2S)-2-[(R)-camphorsulfonamido]-3-{3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-on-6-yl)propionic acid  
 
     
     
         16 . A method of  claim 12  wherein said amount is from about 0.5 μg to 5 mg  
     
     
         17 . A method of  claim 12  wherein said eye disease is diabetic retinopathy  
     
     
         18 . A method of  claim 12  wherein said eye disease is macular degeneration  
     
     
         19 . A method of  claim 12  wherein said eye disease is myopia  
     
     
         20 . A method of  claim 12  wherein said eye disease is ocular histoplasmosis  
     
     
         21 . A method of  claim 1  wherein the α v β 3  and/or α v β 5  inhibitor is a compound of formula III  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  is CH 2 OR 10 , COOR 10 , CONHR 10  or CON(R 12 ) 2 ,  
 R 2  is R 10 , CO—R 10 , CO—R 6 , COOR 6 , COOR 10 , SO 2 R 6 , SO 2 R 10 , CONHR 6 , CON(R 6 ) 2 , CONHR 10  or CON(R 12 ) 2 ,  
 R 3  is H, Hal, NHR 10 , N(R 12 ) 2 , NH-acyl, —O-acyl, CN, NO 2 , OR 10 , SR 10 , SO 2 R 10 , SO 3 R 10 , COOR 10 , CONHR 6 , CON(R 6 ) 2 , CONHR 10  or CON(R 12 ) 2 ,  
 R 4  is H, A, Ar or aralkylene having 7-14 C atoms,  
 R 5  is NH 2 , H 2 N—C(═NH) or H 2 N—(C═NH)—NH, where the primary amino groups can also be provided with conventional amino protective groups, or can be mono- di- or trisubstituted by R 10 , CO—R 10 , COOR 10  or SO 2 R 10 , or R 6 —NH—,  
 R 6  is a mono- or binuclear heterocycle having 1 to 4 N, O and/or S atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH 2 , NO 2 , ═NH or ═O,  
 R 7 , R 8  in each case independently of one another is absent or is H,  
 R 7  and R 8  together are also a bond,  
 Z is absent, O, S, NH, NR 1 , C(═O), CONH, NHCO, C(═S)NH, NHC(═S), C(═S), SO 2 NH, NHSO 2  or CA═CA′,  
 R 9  is H, Hal, OR 11 , NH 2 , NHR 12 , N(R 12 ) 2 , NHAcyl, OAcyl, CN,  
 NO 2 , SR 11 , SOR 12 , SO 2 R 12  or SO 3 H,  
 R 10  is H, A, Ar or aralkylene having 7-14 C atoms,  
 R 11  is H or alkyl with 1-6 C atoms,  
 R 12  is alkyl having 1-6 C atoms,  
 A is H or alkyl having 1-15 C atoms or cycloalkyl having 3-15 C atoms, which is unsubstituted or is mono-, di- or trisubstituted by R 9  and in which one, two or three methylene groups can also be replaced by N, O and/or S,  
 Ar is a mono- or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N, O and/or S atoms, which is unsubstituted or mono-, di- or trisubstituted by A and/or R 9 ,  
 Hal is F, Cl, Br or O,  
 m, n in each case independently of one another are 0, 1, 2, 3 or 4,  
 and their physiologically acceptable salts and solvates  
 
     
     
         22 . A method of  claim 21  wherein the α v β 3  and/or α v β 5  inhibitor is selected from the group consisting of compounds of subformulae IIIa to IIIn, which otherwise correspond to formula III but in which 
 in IIIa) R 3  is H;  
 in IIIb) R 3  is H and 
 R 2  is COOR 10  or SO 2 R 10 ;  
 
 in IIIc) R 3  is H, 
 R 2  is COOR 10  or SO 2 R 10  and  
 R 10  is H, A, Ar or aralkylene having 7-14 C atoms;  
 
 in IIId) m is 0;  
 in IIIe) m is 0 and 
 R 3  is H;  
 
 in IIIf) R 3  is H, 
 R 2  is COOR 10  or SO 2 R 10  and  
 m is 0;  
 
 in IIIg) R 3  is H, 
 R 2  is COOR 10  or SO 2 R 10  and  
 R 10  is H, A, Ar or aralkylene with 7-14 C atoms and  
 m is 0;  
 
 in IIIh) R 3  is H, 
 R 2  is COOR 10  or SO 2 R 10  and  
 R 10  is H, A, Ar or aralkylene having 7-14 C atoms and  
 A is H or unsubstituted alkyl having 1-15 C atoms or cycloalkyl having 3-15 C atoms,  
 Ar is phenyl or naphthyl and  
 m is 0;  
 
 in IIIi) R 6  is a mono- or binuclear heterocycle having 1 to 4 N atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH 2 , NO 2 , ═NH or ═O;  
 in IIIj) R 3  is H, 
 R 2  is COOR 10  or SO 2 R 10  and  
 R 10  is H, A, Ar or aralkylene having 7-14 C atoms and  
 m is 0;  
 R 6  is a mono- or binuclear heterocycle having 1 to 4 N atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH 2 , NO 2 , ═NH or ═O;  
 
 in IIIk) Z is absent;  
 in IIIl) Z is absent and 
 R 3  is H;  
 
 in IIIm) Z is absent, 
 R 3  is H and  
 R 2  is COOR 10  or SO 2 R 10 ;  
 
 in IIIn) Z is absent, 
 R 3  is H,  
 R 4  is H,  
 R 2  is COOR 10  or SO 2 R 10 ;  
 R 10  is H, A, Ar or aralkylene having 7-14 C atoms,  
 R 6  is a mono- or binuclear heterocycle having 1 to 4 N atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH 2 , NO 2 , ═NH or ═O,  
 A is H or unsubstituted alkyl having 1-6 C atoms,  
 Ar is phenyl or naphthyl and  
 m is 0  
 
 
     
     
         23 . A method according to  claim 21  wherein the α v β 3  and/or α v β 5  inhibitor is a compound selected from the group consisting of 
 (2S)-3-[2-(3-aminopropyl)-4-oxo-4H-chromen-6-yl]-2-(2,2-dimethylpropoxycarboxamido)-propionic acid;  
 (2S)-3-[2-(3-guanidinopropyl)-4-oxo-4H-chromen-6-yl]-2-(2,2-dimethylpropoxycarboxamido)-propionic acid;  
 (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropoxycarboxamido)propionic acid;  
 (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxochroman-6-yl}-2-(2,2-dimethylpropoxycarboxamido)propionic acid;  
 (2S)-3-{2-[3-(pyridin-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropoxycarboxamido)propionic acid;  
 (2S)-3-{2-[3-(1H-benzimidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropoxycarboxamido)propionic acid;  
 (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-butylsulfonamidopropionic acid  
 (2S)-3-{2-[3-(pyridin-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,4,6-trimethylphenyl)sulfonamidopropionic acid  
 and their physiologically acceptable salts and solvates  
 
     
     
         24 . A method according to  claim 21  wherein the α v β 3  and/or α v β 5  inhibitor is a compound selected from the group consisting of 
 (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-butylsulfonamidopropionic acid and  
 (2S)-3-{2-[3-(pyridin-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,4,6-trimethylphenyl)sulfonamidopropionic acid  
 2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropoxycarboxamido)propionic acid;  
 
     
     
         25 . A method of  claim 21  wherein said amount is from about 0.5 μg to 5 mg  
     
     
         26 . A method of  claim 21  wherein said eye disease is diabetic retinopathy  
     
     
         27 . A method of  claim 21  wherein said eye disease is macular degeneration  
     
     
         28 . A method of  claim 21  wherein said eye disease is myopia  
     
     
         29 . A method of  claim 21  wherein said eye disease is ocular histoplasmosis  
     
     
         30 . A method of  claim 1  wherein the α v β 3  and/or α a β 5  inhibitor is a compound of formula IV  
       
         
           
           
               
               
           
         
       
       wherein 
 A and B are each independently of one another O, S, NH, NR 7 , CO, CONH, NHCO or directly bond,  
 X is alkylene having 1-2 C atoms, which is unsubstituted or monosubstituted by R 4  or R 5  or a direct bond,  
 R 1  is H, Z or —(CH 2 ) o —Ar,  
 R 2  is H, R 7  or —C(O)Z,  
 R 3  is NHR 6 , —NR 6 —C(═NR 6 )—NHR 6 , —C(═NR 6 )—NHR 6 , —NR 6 —C(═NR 9 )—NHR 6 , —C(═NR 9 )—NHR 6  or Het 1 ,  
 R 4 or R 5  are each indipendently of one another H, oxo, R 7 , —(CH 2 ) o —Ar, —C(O)—(CH 2 ) o —Ar, —C(O)—(CH 2 ) o —R 7 , —C(O)—(CH 2 ) o -Het, Het, NHR 6 , NHAr, NH-Het, OR 7 , OAr, OR 6  or O-Het,  
 R 6  is H, —C(O)R 7 , —C(O)—Ar, R 7 , COOR 7 , COO—(CH 2 ) o —Ar, SO 2 —Ar, SO 2 R 7  or SO 2 -Het,  
 R 7  is alkyl having 1 to 10 C atoms or cycloalkyl having 1 to 10 C atoms,  
 R 8  is Hal, NO 2 , CN, Z, —(CH 2 ) o —Ar, COOR 1 , OR 1 , CF 3 , OCF 3 , SO 2 R 1 , NHR 1 , N(R 1 ) 2 , NH—C(O)R 1 , NHCOOR 1  or C(O)R 1 ,  
 R 9  is CN or NO 2 ,  
 Z is alkyl having 1 to 6 C atoms,  
 Ar is aryl, which is unsubstituted or substituted by R 8,    
 Hal is F, Cl, Br or I,  
 Het is saturated, partly of fully saturated mono- or bicyclic heterocyclic ring system having 5 to 10 atoms, which can contain 1 or 2 N atoms and/or 1 or 2 S or O atoms and wherein the heterocyclic ring system can be mono or disubstituted by R 8 ,  
 Het 1  is a mono or bicyclic aromatic heterocyclic ring system having 1 to 4 N atoms, which can be unsubstituted or mono or disubstituted by Hal, R 7 , OR 7 , CN, NHZ or NO 2 ,  
 n is 0, 1 or 2  
 m is 0, 1, 2, 3, 4, 5 or 6,  
 o is 0, 1 or 2  
 as well as their physiologically acceptable salts and solvates  
 
     
     
         31 . A method according to  claim 30  wherein the α v β 3  and/or α v β 5  inhibitor is selected of the group consisting of compounds of subformulae IVa to IVi, which otherwise correspond to formula IV but in which 
 in IVa x is a direct bond  
                     
 in IVb X is a direct bond, 
 R 2  is H,  
 R 5  is H and  
 R 4  is Ar  
                     
 
 in IVc X is a direct bond, 
 R 5  is H and  
 R 4  is Ar or Het;  
 
 in IVd X is a direct bond, 
 R 5  is H,  
 B is O,  
 A is NH,  
 n is 0,  
 m is 3 or 4,  
 R 3  is Het and  
 R 4  is Ar  
                     
 
 in IVe X is a direct bond, 
 R 5  is H,  
 B is O,  
 A is NH,  
 n is 0,  
 m is 3 or 4 and  
 R 3  is Het  
                     
 
 in IVf X is methylene, which is unsubstituted or substituted by Ar, 
 R 2  is H,  
 R 5  is H oder Ar and  
 R 4  is oxo  
                     
 
 in IVg X is methylene,  
                     
 in IVh X is methylene, 
 R 4  is H or Ar,  
 R 5  is H or Ar and  
 R 2  is H;  
 
 in IVi X is methylene, 
 R 4  is H or Ar,  
 R 5  is H or Ar,  
 B is O,  
 A is NH,  
 n is 0,  
 m is 3 or 4  
 R 3  is Het and  
 R 2  is H  
                     
 
 
     
     
         32 . A method according to  claim 30  wherein the α v β 3  and/or α v β 5  inhibitor is a compound selected from the group consisting of 
 3-phenyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]-1H-indole-3-yl}-propionic acid;  
 3-phenyl-3-{6-[4-(pyridine-2-ylamino)-butoxy]-1H-indole-3-yl}-propionic acid;  
 3-phenyl-3-{5-[4-(pyridine-2-ylamino)-butoxy]-1H-indole-3-yl}-propionic acid;  
 3-phenyl-3-{5-[3-(pyridine-2-ylamino)-propoxy]-1H-indole-3-yl}-propionic acid;  
 3-phenyl-3-[6-(pyridine-2-yl-amidocarboxymethoxy)-indole-3-yl]-propionic acid;  
 3-phenyl-3-[6-(benzimidazole-2-yl-amidocarboxymethoxy)-indole-3-yl]-propionic acid;  
 3-phenyl-3-[6-(imidazole-2-yl-amidocarboxymethoxy)-indole-3-yl]-propionic acid or  
 3-Benzo[1,2,5]thiadiazol-5-yl-3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-1H-indol-3-yl}-propionic acid  
 as well as their physiologically acceptable salts and solvates  
 
     
     
         33 . A method of  claim 30  werein wherein the α v β 3  and/or α v β 5  inhibitor is 
 3-phenyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]-1H-indole-3-yl}-propionic acid or  
 3-Benzo[1,2,5]thiadiazol-5-yl-3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-1H-indol-3-yl}-propionic acid  
 
     
     
         34 . A method of  claim 30  wherein said amount is from about 0.5 μg to 5 mg  
     
     
         35 . A method of  claim 30  wherein said eye disease is diabetic retinopathy  
     
     
         36 . A method of  claim 30  wherein said eye disease is macular degeneration  
     
     
         37 . A method of  claim 30  wherein said eye disease is myopia  
     
     
         38 . A method of  claim 30  wherein said eye disease is ocular histoplasmosis  
     
     
         39 . A method for prophylaxis and/or treatment of diseases of the eye of a patient resulting from angiogenesis in the eye comprising injecting into the vitreous body of the eye of said patient a composition comprising nanoparticles containing a therapeutically effective amount of an α v β 3  and/or α v β 5  inhibitor sufficient to inhibit angiogenesis of the eye  
     
     
         40 . A method of  claim 39  characterized in that the nanoparticles contain a biocompatible polymer  
     
     
         41 . A method of  claim 39  characterized in that the nanoparticles contain a biodegradable polymer  
     
     
         42 . A method of  claim 41  characterized in that the polymer is poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polycaprolactone (PCL), a copolymer of lactic acid and glycolic acid (PLGA), a copolymer of lactic acid and caprolactone, polyepsilon caprolactone, polyhyroxy butyric acid, a poly(ortho)ester, a polyurethane, a polyanhydride, a polyacetal, a polydihydropyran or a polycyanoacrylate  
     
     
         43 . A method of  claim 39  characterized in that the composition comprise a liquid medium wherein the nanoparticles are being dispersed thereby forming a colloidal suspension  
     
     
         44 . A method of  claim 39 , characterized in that the nanoparticles have a diameter from about 10 nm to about 500 nm  
     
     
         45 . A method of  claim 39  characterized in that the nanoparticles have a diameter from about 100 nm to about 200 nm  
     
     
         46 . A method of  claim 39  characterized in that the nanoparticles have been prepared by solvent displacement