ZA200304191B - Methods and compositions for the treatment of diseases of the eye. - Google Patents
Methods and compositions for the treatment of diseases of the eye. Download PDFInfo
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- ZA200304191B ZA200304191B ZA200304191A ZA200304191A ZA200304191B ZA 200304191 B ZA200304191 B ZA 200304191B ZA 200304191 A ZA200304191 A ZA 200304191A ZA 200304191 A ZA200304191 A ZA 200304191A ZA 200304191 B ZA200304191 B ZA 200304191B
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Description
men -_— TT ——— « ow [™ - 1 -
Methods and compositions for the treatment of Diseases of the eye ) TECHNICAL FIELD ' 5 The present invention relates generally to the field of medicine, and relates specifically to methods and compositions for the treatment of diseases of the eye using antagonists of the integin receptors aps and/or avps. More specifically, the invention relates to methods and compositions for the treatment of diseases of the eye using antagonists of the integrin receptors af; and/or aps wherein the compositions are administered by injection into the sclera of the eye.
Integrins are a class of cellular receptors known to bind extracellular matrix proteins, and therefore mediate cell-cell and cell-extracellular matrix interactions, referred generally to as adhésion events. Integrins receptors constitute a family of proteins across membranes with shared structural characteristics heterodimeric glycoprotein complexes formed of a and p subunits.
One class of integrin receptors, the vitronectin receptor, named for its original : characteristic of preferential binding to vitronectin, is known to refer to three different integrins, designated. a4, awfs3 and ops. Horton, Int. J. Exp. Pathol., 71:741-759 (1990). owB4 binds fibronectin and vitronectin. a,Bs binds a large variety of ligands, } including fibrin, fibrinogen, laminin, thrombospondin, vitronectin, von Willebrand's factor, osteospontin and bone sialoprotein I. a.,Bs binds vitronectin. The specific cell adhesion roles these three integrins play in the many cellular interactions in tissues is : still under investigation, but it is clear that there are different integrins with different . biological functions. - 30 One important recognition site in the ligand for many integrins is the arginine-glycine- aspartic acid (RGD) tripeptide sequence. RGD is found in all of the ligands identified above for the vitronectin receptor integrins. This RGD recognition site can be mimicked by polypeptides ("peptides") that contain the RGD sequence, and such : ]
RGD peptides are known inhibitors of integrin function.
AMENDED SHEET
Integrin inhibitors containing the RGD sequence are disclosed, for example, in EP 0 770 622 A2. The compounds described inhibit in particular the interactions of Bs- ) and/or Bs-integrin receptors with ligands and. are particularly active in the case of the integrins ayPs, awPs and apPs, but also relative to a, B4, o/Be and ows receptors.
These actions can be demonstrated, for example, according to the method described by J. W. Smith et al. in J. Biol. Chem. 265, 12267-12271 (1990). In addition, the compounds possess anti-inflammatory effects.
On basis of integrin inhibitors containing the RGD sequence a multitude of antagonists without the RGD sequence have been made available. Those integrin inhibitors without RGD sequence are disclosed, for example, in WO 96/00730 Af,
WO 96/18602 A1, WO 97/37655 A1, WO 97/06791 A1, WO 97/45137 A1, WO 97/23451 A1, WO 97/23480 A1, WO 97/44333 A1, WO 98/00395 A1, WO 98/14192
A1, WO 98/30542 A1, WO 99/11626 A1, WO 99/15178 A1, WO 99/15508 A1, WO 99/26945 A1, WO 99/44994 A1, WO 99/45927 A1, WO 99/50249 A2, WO 00/03973
A1, WO 00/09143 A1, WO 00/09503 A1, WO 00/33838 Af.
DE 1970540 A1 disclose bicyclic aromatic amino acids acting as integrin inhibitors of : the ay integrin receptors, particulary of the integrins awps and ow Bs.. The compounds are very particularly active as adhesion receptor antagonists for the vitronectin receptor auPs. This effect can be demonstrated, for example, by the method described by J.W. Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990).
WO 00/26212 A1 discloses chromenone and chromanone derivatives acting as integrin inhibitors of the a, integrin receptors, particulary of the integrins a, 83 and avPs.. The compounds are also very particularly active as adhesion receptor ) antagonists for the vitronectin receptor of. ’ 30 Integrin inhibitors have been suggested as pharmaceutically active principle in “ human and veterinary medicine, in particular for the prophylaxis and treatment of various disorders. Specifically suggested have been their use for the treatment and prophylaxis of the circulation, thrombosis, cardiac infarction, arteriosclerosis, inflammations, apoplexy, angina pectoris, tumor disorders, osteolytic disorders,
especially osteoporosis, angiogenesis and disorders resulting from angiogenesis, for example diabetic retinopathy of the eye, macular degeneration, myopia, ocular ‘ histoplasmosis, rheumatic arthritis, osteoarthritis, rubeotic glaucoma, and also ulcerative colitis, Crohn's disease, multiple sclerosis, psoriasis and restenosis * 5 following angioplasty.
Eye diseases resulting from angiogenesis are the leading cause of visual loss in
America. While in case of the population of the age of over 65 visual loss is predominantly effected by age-related macular degeneration (AMD) in case of population of the age of less than 65 this is predominantly effected by diabetic retinopathy.
In Wall Street Journal from March 6 th, 2000 an overview about occurence and current therapies of AMD is given. According to this AMD currently afflicts some 12 million Americans. AMD progressively destroys the macula which is responsible for central vision and color vision. In some cases, deterioration of central vision to fuzzy blur can be rapid occuring in weeks or months. Two forms of the disease exists called atrophic" and exudative”. Although exudative AMD effects only 10% of the total AMD population, it accounts for 90% of all AMD-related blindness.
Until recently, the only treatment for exudative AMD consisted of directing a powerful laser beam at the harmful blood vessels to heat and coagulate them. However, only about 15% of patients with exudative AMD have been eligible for this laser surgery.
Other therapies are currently in experimental phase. In one approach, called photodynamic therapy, a low-power laser is combined with injection of light- absorbing dye. Another therapy is a more surgical approach and is called , limited retinal translocation”. In this therapy the leaky vessels are destroyed with a high- powered laser after separation and rotation of the retina from the outer wall of the eye. - 30
US 5,766,591 discribes the use of RGD-containing ap; antagonists for the treatment ; + of patients in which neovascularisation in the retinal tissue occurs. More specifically the use of said antagonists for the treatment of patients with diabetic retinopathy, macular degeneration and neovasular glaucoma is suggested. However, no examples with regard to this indications are presented. Concerning to the route of administration only general information are given. Specifically intravenous, ! intraperitoneal, intramuscular, intracavital and transdermal application is mentioned. in all cases oyBs antagonists are preferred exhibiting selectivity for aps over other integrins such as aps.
WO 97/06791 A1 discribes that ayBs antagonists can be used for inhibiting angiogenesis 100. Likewise as suggested for a,B3 antagonists in US 5,766,591 avBs antagonists are suggested for the treatment of a patient with diabetic retinopathy, macular degeneration and neovasular glaucoma. With regard to the route of administration intravenous, intraocular, intrasynovial, intramuscular, transdermal and oral application is specifically mentioned.
WO 00/07565 A1 discribes a method for application of pharmaceutically active substances to the eye via intrascleral injection into the scleral layer. The whole disclosure of WO 00/07565 A1 is incorporated to the present application by reference. As active substances a multitude of active substances is mentioned in WO 00/07565 A1 including integrin blockers. However, the term integrin blocker is silent with regard to the receptor type and refer to all substances acting as inhibitor on anyone of the large class of heterodimeric receptors formed from a and B subunits.
Moreover, no examples for integrin blockers are given.
It has been found that inhibitors of ayp3s and/or ows integrin receptors have particularly useful pharmacological and physicochemical properties combined with good tolerability, as, in particular, they can be used for prophylaxis and treatment of , diseases of the eye of a patient resulting from angiogenesis in the eye by injecting the inhibitor into the scleral layer of the eye.
Accordingly, the invention is directed to 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 scleral layer of the eye of said patient a composition comprising a therapeutically effective amount of an owf3 and/or a,fs inhibitor sufficient to inhibit angiogenesis of the eye whereby injecting occurs through the location of the exterior ) surface of the sclera that overlies retinal tissue.
A therapeutically effective amount is an amount of inhibitor sufficient to produce a measureable inhibition of angiogenesis in the tissue of the eye when injected into the scleral layer. In general, this is the case when the a,3 and/or as inhibitor is used in an amount from about 0.5 ug to about 5 mg.
The method of invention is especially usable for prophylaxis and/or treatment of diabetic retinopathy, macular degeneration, myopia and histoplasmosis.
In a preferred embodiment of the invention polypeptides containing the amino acid 165 sequence RGD are used as a3 and/or as inhibitors in the method for prophylaxis and/or treatment of eye diseases. As mentioned above, RGD is the peptide sequence Arg-Gly-Asp (arginine-glycine-aspartic acid) occuring in natural ligands of integrins like fibronectin or vitronectin. Solvable RGD containing linear or cyclic peptides are able to inhibit interactions of this integrins with their corresponding natural ligands.
The abbreviations for the amino acid residues used hereinafter are shown in the following table:
Ala A alanine
Arg R arginine
Asp D aspartic acid
D-homoPhe D-homo-phenylalanine
D-Nal D-3-(2-naphthyl)alanine
D-Phe D-phenylalanine , D-Phg D-phenylglycine
D-Trp D-tryptophan
D-Tyr D-tyrosine
Gly G glycine
4-Hal-Phe 4-halo-phenylalanine homoPhe homo-phenylalanine ) lie | isoleucine
Leu L leucine ’ 5 Nal 3-(2-naphthyl)alanine
Nie norleucine
Phe F phenylalanine
Phg phenyliglycine
Trp Ww tryptophan
Tyr Y tyrosine
Val Vv valine.
Particularly preferred as ayf3 and/or ays inhibitors to be used in the method for prophylaxis and/or treatment of eye diseases are compounds of formula cyclo-(Arg-Gly-Asp-D-(A)aE) 1, in which
D is D-Phe, Phe, D-Tmp, Trp, D-Tyr, Tyr, D-homoPhe, homoPhe, D-Nal, :
Nal, D-Phg, Phg or 4-Hal-Phe (D or L form), in which Hal is F, CI, Br, 1,
E is Val, Gly, Ala, Leu, lle or Nle,
A is alkyl having 1-18 carbon atoms and n isCor1 and also their physiologically acceptable salts.
Informula | alkyl is preferably methyl,ethyi, isopropyl, n-butyl, sec-butyl or tert-butyl.
More particular preferred polypeptides are used as oyB3 and/or a,fs inhibitors in the method of the invention that can be expressed by the subformula la, which otherwise corresponds to the formula | but in which :
Dis D-Phe and * Eis Gly, Ala, Val, Leu, lle or Nle.
Furthermore, particular preference is given to the use of all physiologically compatible salts of the compounds which come under the subformula la.
Most preferred as active compound in said method are cyclo-(Arg-Gly-Asp-DPhe-
Val) and cyclo-(Arg-Gly-Asp-DPhe-NMeVal).
This RGD-containing peptides described by formula | as well as the peptides specifically mentioned hereinbefore are disclosed in EP 0 770 622 A2, the disclosure of which is hereby incorporated to the present application by reference. Accordingly, the meaning of the substituents of formula | resp. subformula la are the same as defined for the substituents of subformula la resp. subformula Ib as disclosed on page 5, line 24 to line 32 resp. page 5, line 33 to line 41 in EP 0 770 662 A2.
It has been found that inhibitors of aB3 and/or ays integrin receptors which are no polypeptides and do not contain the RGD sequence can also be used for prophylaxis and treatment of diseases of the eye of a patient resulting from angiogenesis in the eye by injecting the inhibitor into the scleral layer of the eye.
Therefore, in one further preferred embodiment of the method of invention the awf3 and/or a,Bs inhibitors to be used in the method for prophylaxis or treatment of eye diseases are compounds of formula ll
R4 11
RA \X re —-pl : 8 wn OR 5 — ee
R>—W— (CHo)y—Z— (CH,),, R3 I wherein
R is H, alkyl having 1-6 C atoms or benzyl,
R? is R'®, CO-R", COOR®, COOR"?, SO;R® or SOR", . R® is H, Hal, OA, NHR, N(R), -NH-acyl, -O-acyl, CN, NO,, OR",
SR, R? or CONHR'?, : 5 R* is H, =0, =S, C4-Ce-alkyl or acyl,
R® is NHz, HoN-C(=NH) or HoN-(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™,
CO-R", COOR™ or SO,R",0r RS,
R’,R® are each independently of one another absent or H,
R” and R® together are also a bond,
XY are each independently of one another =N-, -N-, O, S, ~CH3- or =C-, with the proviso that at least one of the two definitions X,
Y is =N-,-N-, O or S,
Ww, Z are each independently of one another absent, O, S, NR, C(=0),
CONH, NHCO, C(=S)NH, NHC(=S), C(=S), SO2NH, NHSO or
CA=CA,
R® 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,, NO2, =NH or =0,
R® is H, Hal, OA, NHA, NAA’, NHacyl, Oacyl, CN, NO, SA, SOA,
SOA, SOAr or SOzH,
R'" is H, A, Ar or aralkyl having 7-14 C atoms,
RY is H or alkyl having 1-6 C atoms,
AA are each independently of one another H or unsubstituted or mono-, di- or tri-R%-substituted alkyl or cycloalkyl, each of which has 1-15 C atoms and in which one, two or three methylene groups ' 30 can be replaced by N, O and/or S,
Ar is unsubstituted or mono-, di- or tri-A- and/or R%-substituted mono- or binuclear aromatic ring system having 0, 1,2,3 or4 N,
O and/or S atoms,
Hal is F, Cl, Bror | and m,n are each independently of one another 0, 1, 2, 3 or 4, * and the physiologically acceptable salts thereof.
Particularly preferred aps and/or a, Bs inhibitors are used in the method of invention that can be expressed by the subformulae Ila to lig, which otherwise corresponds to the formula Il but in which inlla) R! is H or alkyl with 1-6 C atoms,
R?2 is R"®, CO-R%, COOR™ or SOR",
R3 is H,
R* is H or =O,
R® is HoN-C(=NH) or HzN-C(=NH)-NH,
Ww, Z are each independently of one another absent,
C(=0), NH, CONH or NHCO,
X is -NH-, O or -CHy-,
Y is NH or O, :
R10 is H, A or benzyl,
R" 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; inlib) R' is H or alkyl with 1-6 C atoms,
R? is R'®, CO-R'’, COOR™ or SORRY,
R® is H,
R* is H or =O,
R® is R®,
W,Z are each independently of one another absent,
C(=0), NH, CONH or NHCO,
X is -NH-, O or -CHz-,
Y is NH or O,
R® 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, CONHg, NO, =NH or =O,
R is H, A or benzyl,
R" is H,
A is unsubstituted alkyl or cycloalkyl with 1-16 C atoms and m, n are each independently of one another 0, 1 or 2; in He) R! is H or alkyl with 1-6 C atoms,
R? is R'%, CO-R'®, COOR" or SOR,
R® is H,
R* is H or =O,
R® is HoN-C(=NH) or HoN-C(=NH)-NH,
W,Z are each independently of one another absent,
C(=0), NH, CONH or NHCO,
X is -NH-, O or -CHo-,
Y is NH or O,
A is alkyl with 1-6 C atoms,
R" is H, alkyl with 1-6 C atoms, camphor-10-yi or benzyl,
R" is H, m,n are each independently of one another 0, 1 or 2; in 11d) R! is H or alkyl with 1-6 C atoms,
R? is R', CO-R"°, COOR™ or SO.R™,
R® is H,
R¢ is H or =O,
R® is R®,
W,2Z are each independently of one another absent, C(=0), NH, CONH or NHCO,
X is =NH-, O or -CHg-,
Y is NH or O,
R® 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,,
NO2, =NH or =O,
R'" is H, alkyl with 1-4 C atoms, camphor-10-yl or benzyl,
R" 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 lle) R! is H or alkyl with 1-6 C atoms,
R? is R'%, CO-R'%, COOR' or SOR",
R® is H,
R* is H or =O,
RS is R®,
W, Z are each independently of one another absent, C(=0), NH, CONH or NHCO,
X is -NH-, O or -CH2-,
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' is H, alkyl with 1-4 C atoms, camphor-10-yl or benzyl,
RM 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 11) R’ is H or alkyl with 1-6 C atoms,
R? is R'®, CO-R'?, COOR" or SOR",
R® is H,
rR is H or =0,
R® is HaN-C(=NH) or HoN-C(=NH)-NH, : W,Z are each independently of one another absent, C(=0), NH, CONH or NHCO, ’ 5 X is -NH-, O or ~-CH,-,
Y isNH or O,
RY is Ar,
R" 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 lg) R! is H or alkyl with 1-6 C atoms,
R? is R'%, CO-R™®, COOR™ or SOR",
R? is H,
R* is H or =O,
R® is R®,
W,Z are each independently of one another absent, C(=0), NH, CONH or NHCO,
X is -NH-, O or -CHz-,
Y is NH or O,
R® 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, CONHz,
NOg, =NH or =0,
R™ is Ar,
R™ is H,
A is unsubstituted alkyl or cycloalkyl with 1-15 C. ’ 30 atoms and m, n are each independently of one another 0, 1 or 2.
The compounds of formula Il and subformulae lla to lig have been disclosed in DE 197 05 450 A1, the whole disclosure of which is hereby incorporated to the present application by reference. Accordingly, the substituents of formula Il resp. subformulae lla to lig have the same meaning as defined for the substituents of formula | resp. ’ subformulae la to Ig as disclosed on page 2, lines 3 to 43 resp. page 5, line 58 to page 7, line 30 of DE 197 05 450 A1. The definitions for the substituents are given on ] 5 page 4, line 35 to page 5, line 56 of DE 197 05 450 A1.
More particularly preferred one of the following a3 and/or o,Bs inhibitors is used in the method of the present invention: (28)-2-[(R)-camphor-10-sulfonamido]-3-{3,4-dihydro-2-(3-guanidino-propyl)- (2R)-2H-1,4-benzoxazin-3-on-6-yl}propionic acid; (28)-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; (28)-2-benzyloxycarboxamido-3-(2-guanidinoacet-amidomethyi-1,4- benzodioxan-6-yl)propionic acid; (2S)-2-tert-butyloxycarboxamido-3-{3,4-dihydro-2-[N-(2-imidazolyl)- carbamoyimethyl}-2H-1,4-benzox-azin-3-on-6-yl)propionic acid; (2S)-2-tert-butyloxycarboxamido-3-{3,4-dihydro-2-[N-(2-benzimidazoiyl)- 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 acid; (2S)-2-[(R)-camphorsulfonamido]-3-{3,4-dihydro-2-[N-(2- benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-on-6-yl)propionic acid and their physiologically acceptable salts. © 30
Most preferred are (28)-2-(2,2-dimethylpropyloxycarboxamido)-3-{3,4-dihydro-2-[N-(2- imidazolyl)carbamoyl-ethyi]-(2S)-2H-1,4-benzoxazin-3-on-6-yi}propionic acid and
(2S)-2-[(R)-camphorsulfonamido}-3-{3,4-dihydro-2-[N-(2-benzimidazolyl}- carbamoylmethyl]-2H-1,4-benzoxazin-3-on-6-yl)propionic acid ’ 5 In one further preferred embodiment of the method of invention the on B3 and/or avs inhibitors to be used in the method for prophylaxis or treatment of eye diseases are compounds of formula lil
Re O R11
RY 1
HN 11]
Rf —(CH,)—2—(CH,), Re in which
R' is CH,0R™®, COOR'?, CONHR' or CON(R'?),,
R? is R'°, CO-R"’, CO-R®, COOR®, COOR™, SO,R?, SOR",
CONHR®, CON(R®),, CONHR™ or CON(R'2),,
R? is H, Hal, NHR’, N(R'?);, NH-acyl, -O-acyl, CN, NO, OR,
SR", SO;R', SO3R"°, COOR™, CONHR®, CON(R®),, CONHR™® or CON(R'2),,
R* is H, A, Ar or aralkylene having 7-14 C atoms,
R® is NH2, HoN-C(=NH) or HoN-(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°,
CO-R'™, COOR™ or SO;R", or RE-NH-,
RE is a mono- or binuclear heterocycle having 1 to 4 N, O and/or S : 25 atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OH, CN, COOH, COOA, CONH,, NO,, =NH or . -0,
R’, R® in each case independently of one another is absent or is H,
R’ and R® together are also a bond,
y4 is absent, O, S, NH, NR', C(=0), CONH, NHCO, C(=S)NH,
NHC(=S), C(=S), SO.NH, NHSO; or CA=CA’,
R® is H, Hal, OR", NH, NHR", N(R'?);, NHAcyl, OAcyl, CN, NO,
SR", SOR", SOR" or SO3H, :
RY is H, A, Ar or aralkylene having 7-14 C atoms,
RM is H or alkyl with 1-6 C atoms,
R' 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® 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®,
Hal is F, Cl, Brorl, m, n in each case independently of one another are 0, 1, 2, 3 or 4, and their physiologically acceptable salts and solvates.
In this embodiment of the method of the present invention particularly preferred aya and/or ows inhibitors are used that can be expressed by the subformulae Illa to lin, which otherwise correspond to formula lil but in which in Hla) R? is H; in lib) R® is H and
R? is COOR' or SOR"; in lic) R® is H,
C30 R? is COOR™ or SOR" and
RY is H, A, Ar or aralkylene having 7-14 C atoms; in lid) m is 0;
in lle) m is 0 and
R® is H; in 1If) R® is H,
R? is COOR" or SOR" and m is 0; in lig) R® is H,
R? is COOR™ or SOR" and
R" is H, A, Ar or aralkylene with 7-14 C atoms and m is 0; in 11th) R? is H,
R? is COOR" or SO,R" and
R10 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 111i) R® is a mono- or binuclear heterocycle having 1to 4 N atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OH, CN, COOH,
COOA, CONHgz, NO2, =NH or =0, in 11ij) R? isH,
R? is COOR™ or SOR" and
R10 is H, A, Ar or aralkylene having 7-14 C atoms and m is 0;
R® is a mono- or binuclear heterocycle having 1to 4 N atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OH, CN, COOH,
COOA, CONHz, NO2, =NH or =0;
in 1k) Z is absent; in 11) Z is absent and
R® is H; in [llm) y4 is absent,
R® is H and
R? is COOR™ or SOR, in liin) Z is absent,
R® is H,
R* is H,
R? is COOR" or SO,R™;
R10 is H, A, Ar or aralkylene having 7-14 C atoms,
R® 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, CONHz, NO, =NH or =O,
A is H or unsubstituted alkyl having 1-6 C atoms,
Ar is phenyl or naphthyl and m is 0.
The compounds of formula Ill and subformulae lila to llin have been disclosed in WO 00/26212 A1, the whole disclosure of which is incorporated to the present application by reference. Accordingly, the substituents of formula lI resp. subformulae Illa to llin have the same meaning as defined for the substituents of formula | resp. subformulae la to In as disclosed on page 1, line 5 to page 2, line 31 resp. page 13, line 20 to page 15, line 6 of WO 00/26212 A1. The definitions for the substituents are given on page 8, line 18 to page 13, line 10 of WO 00/26212 A1.
More particularly preferred one of the following aB3s and/or awBs inhibitors is used in this embodiment of the method of the present invention: (2S)-3-{2-(3-aminopropyl)-4-oxo-4H-chromen-6-yl]-2-(2,2-dimethylpropoxy-
carboxamido }-propionic acid; (28)-3-{2-[3-(1H-imidazol-2-ylamino)propyl}-4-oxo-4H-chromen-6-yl}-2-(2,2- dimethylpropoxycarboxamido)propionic acid; (28)-3-{2-[3-(1H-imidazol-2-ylamino)propyi]-4-oxochroman-6-yl}-2-(2,2-dimethyl- ‘ 5 propoxycarboxamido)propionic acid; (28)-3-{2-[3-(pyridin-2-ylamino)propyi]-4-oxo-4 H-chromen-6-yi}-2-(2,2-dimethyl- propoxycarboxamido)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-4 H-chromen-6-yl}-2-butyi- sulfonamidopropionic acid; (2S)-3-{2-[3-(pyridin-2-ylamino)propyi]-4-oxo-4 H-chromen-6-yl}-2-(2,4,6-trimethyl- phenyl)sulfonamidopropionic acid \ or their physiologically acceptable salts and solvates.
Most preferred are (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4 H-chromen-6-yl}-2- butylsuifonamidopropionic acid and (2S)-3-{2-[3-(pyridin-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,4,6- trimethylphenyl)sulfonamidopropionic acid. .
In one further preferred embodiment of the method of invention the ows and/or aps inhibitors to be used in the method for prophylaxis or treatment of eye diseases are compounds of formula IV
0 cx : OR!
RCH) -A-(CHy) 0 " V \
R2 wherein 5 AandB are each independently of one another O, S, NH, NR’, CO,
CONH, NHCO or directly bond,
X is alkylene having 1-2 C atoms, which is unsubstituted or monosubstituted by R* or R® or a direct bond,
R? is H, Z or -(CHz)o-Avr,
R2 is H, R” or -C(0)Z,
R3 is NHR, -NR®-C(=NR®)-NHR®, -C(=NR®)-NHR®, -NR®-C(=NR®)-
NHRS, -C(=NR®)-NHR® or Het",
R*orR® are each indipendently of one another H, oxo, R7, ~(CHz)o-Ar, ~-C(O)-(CHa)o-Ar, -C(O)-(CH2)o-R’, -C(O)-(CHa)o-Het, Het, NHRS,
NHAr, NH-Het, OR’, OAr, OR® or O-Het,
R® is H, ~C(O)R’, -C(0)-Ar, R7, COOR’, COO-(CH,)o-Ar, SO2-Ar,
SOR” or SO,-Het,
R? is alkyl having 1 to 10 C atoms or cycloalkyl having 1 to 10 C atoms,
R® is Hal, NO, CN, Z, (CHz)s-Ar, COOR', OR', CF3, OCF, SOR",
NHR’, N(R")z, NH-C(O)R', NHCOOR' or C(O)R!,
R® is CN or NO,
Z is alkyl having 1 to 6 C atoms, : Ar is aryl, which is unsubstituted or substituted by R®
Hal isF, Cl, Brorl, ) Het is unsaturated, 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 RS,
Het! 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’, OR’, CN, NHZ or NO», n is0,1o0r2 m is0,1,2,3,4,50r86, 0 is0,10r2 as well as their physiologically acceptable salts and solvates.
In this embodiment of the method of invention particularly preferred awB3 and/or ows inhibitors are used that can be expressed by the subformulae IVa to 1Vi, which otherwise correspond to formula IV but in which in IVa X is a direct bond 9” 0]
OR?
RS
R3-(CH,), -A<(CH,). - D IVa
N
\
R2 . in IVb X is a direct bond,
R? is H,
R® is H and
R* is Ar
Claims (46)
- What claimed is:: 1. Use of an aps and/or awBs inhibitor for the preparation of a medicament for prophylaxis and/or treatment of diseases of the eye of a patient resulting from angiogenesis in the eye, wherein the medicament is injected into the scleral layer of the eye of said patient through the location of the exterior surface of the sclera that overlies retinal tissue
- 2. Use according to Claim 1 wherein the awPs and/or ay Ps inhibitor is a RGD- containing polypeptide
- 3. Use according to Claim 2 wherein said polypeptide is a compound of formula cyclo-(Arg-Gly-Asp-D-(A)E) l, 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, lle or Nle and A is alkyl having 1-18 carbon atoms, n Oor1 and also their physiologically acceptable salts
- 4. Use according to Claim 2 wherein said polypeptide is a compound as expressed by subformula la, which otherwise correspond to formula | but in which D is D-Phe and E is Gly, Ala, Val, Leu, lle or Ne.
- 5. Use according to Claim 2 wherein said polypeptide is cyclo-(Arg-Gly-Asp-DPhe- Val)
- 6. Use according to Claim 2 wherein said polypeptide is cyclo-(Arg-Gly-Asp-DPhe- NMeVal)
- 7. Use according to Claim 2 wherein said therapeutically efective amount is from ‘ 5 about 0.5 pg to 5 mg
- 8. Use according to Claim 2 wherein said eye disease is diabetic retinopathy
- 9. Use according to Claim 2 wherein said eye disease is macular degeneration 10
- 10. Use according to Claim 2 wherein said eye disease is myopia
- 11. Use according to Claim 2 wherein said eye disease is ocular histoplasmosis 15 12. Use according to Claim 1 wherein the a3 and/or a. Bs inhibitor is a compound of formula Il RY R11 RA \X 0 pl 8 HN O-R R Y \ 2 —— R™~ W— (CH,) s—2— (CH), R3 i wherein R is H, alkyl having 1-6 C atoms or benzyl, R? is R', CO-R™, COOR?®, COOR'", SO,R® or SO.R™, R® is H, Hal, OA, NHR, N(R),, -NH-acyl, -O-acyl, CN, NO,, OR", : 25 SR’, RZ or CONHR", R* is H, =0, =8, C4-Ce-alkyl or acyl, : R® is NHz, H2N-C(=NH) or H,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, : CO-R", COOR™ or SO,R™,0r R?,
- R’ R® are each independently of one another absent or H, R’ and R® together are also a bond, : XY are each independently of one another =N-, -N-, O, S, -CH2- or =C-, ‘ 5 with the proviso that at least one of the two definitions X, Y is =N-, -N-, O or S, WwW, Z are each independently of one another absent, O, S, NR", C(=0), CONH, NHCO, C(=S)NH, NHC(=S), C(=S), SO.NH, NHSO- or CA=CA’, R® 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,, NO,, =NH or =, R® is H, Hal, OA, NHA, NAA’, NHacyl, Oacyl, CN, NO,, SA, SOA, SO2A, SOzAr or SO3H, R10 is H, A, Ar or aralkyl having 7-14 C atoms, R" is H or alkyl having 1-6 C atoms, AA are each independently of one another H or unsubstituted or mono-, di- or tri-R°-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®-substituted mono- or binuclear aromatic ring system having 0, 1,2, 3or4 N, O and/or S atoms, Hal is F, Cl, Brorl and m,n are each independently of one another 0, 1, 2, 3 or 4, or a the physiologically acceptable salts thereof
- 13. Use according to Claim 12 wherein the ayB3 and/or owPs inhibitor is selected from the group consisting of compounds of subformulae Ila to Ilg, which otherwise correspond to formula Il but in which in lla) R' is H or alkyl with 1-6 C atoms, RZ is R'%, CO-R™, COOR™ or SO,R™, : R® is H, R* is H or =0, RS is HoN-C(=NH) or HaN-C(=NH)-NH, W, Z are each independently of one another absent, C(=0), NH, CONH or NHCO, X is -NH-, O or -CH>-, Y is NH or O, R10 is H, A or benzyl, R" 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 lib) R? is H or alkyl with 1-6 C atoms, R? is R', CO-R", COOR™ or SO,R", Rr? is H, R* is H or =O, RS is R®, W, Z are each independently of one another absent, C(=0), NH, CONH or NHCO, X is -NH-, O or -CHg-, Y is NH or O, R® 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, CONHa, NO,, =NH or =0, R10 is H, A or benzyl, R" 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 llc) R? is H or alkyl with 1-6 C atoms, R? is R'%, CO-R'%, COOR™ or SOR", R® is H, R* is H or =O, R® is H2N-C(=NH) or HaN-C(=NH)-NH, W,Z are each independently of one another absent, C(=0), NH, CONH or NHCO, X is -NH-, O or -CHz-, Y is NH or Q, A is alkyl with 1-6 C atoms, R is H, alkyl with 1-6 C atoms, camphor-10-yl or benzyl, R" is H, m, n are each independently of one another 0, 1 or 2; in lid) R’ is H or alkyl with 1-6 C atoms, R? is R', CO-R", COOR" or SOR", R? is H, R* is H or =O, R® is RE, W,Z are each independently of one another absent, : C(=0), NH, CONH or NHCO, X is =NH-, O or -CHg-, Y is NHor Q, RS 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_, NO,, =NH or =O, R is H, alkyl with 1-4 C atoms, camphor-10-y! or benzyl, R" 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 lie) R’ is H or alkyl with 1-6 C atoms, R? is R', CO-R"™, COOR' or SO,R™, ‘ 5 R3 is H, R* is H or =O, : R® is RE,W,2Z are each independently of one another absent,C(=0), NH, CONH or NHCO, X is -NH-, O or -CH>-,Y is NHor 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'" is H, alkyl with 1-4 C atoms, camphor-10-yl or benzyl,R" 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 If) R’ is H or alkyl with 1-6 C atoms, R? is R", CO-R'®, COOR" or SOR, rR? is H, R* is H or =O,RS is HaN-C(=NH) or HoN-C(=NH)-NH,W,Z are each independently of one another absent, C(=0), NH, CONH or NHCO,X is -NH-, O or -CHz-, Y is NH or O, R™ is Ar, R" =~ isH, A is unsubstituted alkyl or cycloalkyl with 1-15 C i atoms and m,n are each independently of one another 0, 1 or 2; in lig) R' is H or alkyl with 1-6 C atoms, R? is R™®, CO-R™®, COOR® or SOR", R® is H, R* is H or =O, R° is R®, W, Z are each independently of one another absent, C(=0), NH, CONH or NHCO, X is -NH-, O or -CH>-, Y is NHor O, R® 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,, NO2, =NH or =O, R is Ar, R" 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. Use according to Claim 12 wherein the ay83 and/or ays inhibitor is a compound selected from the group consisting of (2S)-2-[(R)-camphor-10-sulfonamido}-3-{3,4-dihydro-2-(3-guanidino- propyl )-(2R)-2H-1,4-benzoxazin-3-on-6-yl}propionic acid; (2S)-2-benzyloxycarboxamido-3-(2-guanidinomethyi-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-benzo- dioxan-6-yl)propionic acid; : i i(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; (28)-2-(2,2-dimethylpropyloxycarboxamido)-3-{3,4-dihydro-2-[N-(2- imidazolyl)carbamoylethyl]-(2S)-2H-1,4-benzoxazin-3-on-6-yi}propionic acid; (28)-2-[(R)-camphorsulfonamido]-3-{3,4-dihydro-2-[N-(2-benzimidazolyl)- carbamoylimethyl]-2H-1,4-benzoxazin-3-on-6-yl)propionic acid and their physiologically acceptable salts
- 15. Use according to Claim 12 wherein the a, 3 and/or ous inhibitor is (28)-2-(2,2-dimethylpropyloxycarboxamido)-3-{3,4-dihydro-2-[N-(2- imidazolyl)carbamoylethyl]-(2S)-2H-1,4-benzoxazin-3-on-6-yl}propionic acid or (28)-2-[(R)-camphorsulfonamido]-3-{3,4-dihydro-2-[N-(2-benzimidazolyl)- carbamoylmethyl]-2H-1,4-benzoxazin-3-on-6-yl)propionic acid
- 16. Use according to Claim 12 wherein said amount is from about 0.5 pg to 5 mg
- 17.Use according to Claim 12 wherein said eye disease is diabetic retinopathy
- 18.Use according to Claim 12 wherein said eye disease is macular degeneration :
- 19.Use according to Claim 12 wherein said eye disease is myopia
- 20. Use according to Claim 12 wherein said eye disease is ocular histoplasmosis
- 21. Use according to Claim 1 wherein the ayB3 and/or ays inhibitor is a compound of formula HIRs O R11RT. 1 HN J] Ro — (CH,)—2Z— (CH,), Re in which R! is CH,OR'®, COOR'®, CONHR" or CON(R'?),, R? is R", COR", CO-R®, COOR®, COOR", SO.R®, SOR, CONHRS®, CON(R®),, CONHR or CON(R"?),, R® is H, Hal, NHR'®, N(R'?),, NH-acyl, -O-acyl, CN, NO», OR, SR’, SO,R, SOR", COOR™, CONHR®, CON(R®);, CONHR™" or CON(R'),, R* is H, A, Ar or aralkylene having 7-14 C atoms, R® is NHz, HoN-C(=NH) or HzN-(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®, CO-R', COOR" or SO;R™, or R%-NH-, R® 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,, NO, =NH or =0, R’, R® in each case independently of one another is absent or is H, R” and R® together are also a bond, Z is absent, O, S, NH, NR', C(=0), CONH, NHCO, C(=S)NH, NHC(=S), C(=S), SO,NH, NHSO, or CA=CA', R? is H, Hal, OR", NH,, NHR'?, N(R"), NHAcyl, OAcyl, CN, NO, SR", SOR", SO.R"? or SO3H, R10 is H, A, Ar or aralkylene having 7-14 C atoms, RM is H or alkyl with 1-6 C atoms, R'2 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® 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®, Hal isF, Cl,Bror], m,n in each case independently of one another are 0, 1, 2, 3 or 4, and their physiologically acceptable salts and solvates
- 22. Use according to Claim 21 wherein the a,f3 and/or o.fs inhibitor is selected from the group consisting of compounds of subformulae lla to llin, which otherwise correspond to formula lll but in which in lia) R® is H; in lib) R® is H and R? is COOR'" or SOR"; in llc) R® is H, R2 is COOR™ or SOR" and R10 is H, A, Ar or aralkylene having 7-14 C atoms; in ilid) m is 0; in lie) m is 0 and R is H; in 111f) R® is H, R? is COOR" or SOR" and m is 0;in lig) R3 is H, R? ~~ is COORYor SOR" and ’ R' is H, A, Ar or aralkylene with 7-14 C atoms and m is 0;in lh) R® is H, R? is COOR" or SO,R" and R' 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 II) R® 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,, NO2, =NH or =0; in lj) R® is H, R? is COOR" or SOR" and R10 is H, A, Ar or aralkylene having 7-14 C atoms and m is 0; R® 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, CONHz, NO2, =NH or =0; in (ilk) Z is absent; in 1111) Z is absent and R® is H; in flim) Z is absent, R® is H and Lo } oo 3 oo iR? is COOR™ or SOR; : in (lin) Z is absent, R® is H, R* is H, R? is COOR™ or SOR; R™ is H, A, Ar or aralkylene having 7-14 C atoms, R® is a mono- or binuclear heterocycle having 1to 4 N atoms, which can be unsubstituted or mono-, di- or trisubstituted by Hal, A, -CO-A, OH, CN, COOH, COOA, CONHaz, NO2, =NH or =0, A is H or unsubstituted alkyl having 1-6 C atoms, Ar is phenyl or naphthyl and m is0 :
- 23. Use according to Claim 21 wherein the a,B3 and/or ons inhibitor is a compound selected from the group consisting of (28)-3-[2-(3-aminopropyl)-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropoxy- carboxamido)-propionic acid; (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4 H-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; (28)-3-{2-[3-(pyridin-2-ylamino)propyi]-4-oxo-4 H-chromen-6-yi}-2-(2,2- dimethylpropoxycarboxamido)propionic acid; (2S)-3-{2-[3-(1H-benzimidazol-2-ylamino)propyl}-4-oxo-4 H-chromen-6-yi}-2- (2,2-dimethylpropoxycarboxamido)propionic acid; (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4 H-chromen-6-yi}-2- butylsulfonamidopropionic acid (2S)-3-{2-[3-(pyridin-2-ylamino)propyi]-4-oxo-4 H-chromen-6-yi}-2-(2,4,6- trimethylphenyl)sulfonamidopropionic acid §
- and their physiologically acceptable saits and solvates ‘ 24. Use according to Claim 21 wherein the aps and/or ays inhibitor is a compound selected from the group consisting of ' 5 (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl}-4-oxo-4 H-chromen-6-yl}-2- butylsulfonamidopropionic acid and (28)-3-{2-[3-(pyridin-2-ylamino)propyl]-4-oxo-4 H-chromen-6-yl}-2-(2,4,6- trimethylphenyl)sulfonamidopropionic acid
- 25. Use according to Claim 21 wherein said amount is from about 0.5 pg to 5 mg
- 26. Use according to Claim 21 wherein said eye disease is diabetic retinopathy
- 27.Use according to Claim 21 wherein said eye disease is macular degeneration
- 28. Use according to Claim 21 wherein said eye disease is myopia
- 29. Use according to Claim 21 wherein said eye disease is ocular histoplasmosis
- 30. Use according to Claim 1 wherein the a3 and/or ows inhibitor is a compound of formula IV 0 R¢ X — OR! Ny FR RE{CH,)-A-(CH,)or N v \ ' R2 wherein AandB are each independently of one another O, S, NH, NR’, CO,CONH, NHCO or directly bond,X is alkylene having 1-2 C atoms, which is unsubstituted or monosubstituted by R* or R® or a direct bond,R is H, Z or -(CHp)s"Arr,‘ 5 R? is H, R” or -C(0)Z,R? is NHR®, -NR®-C(=NR®)-NHR?, -C(=NR®)-NHR®, -NR®-C(=NR®)- NHRS®, -C(=NR®)-NHR® or Het’,R*or R® are each indipendently of one another H, oxo, R, -(CHy).-Ar, -C(O)-(CHz)o-Ar, -C(O)-(CHa)o-R’, -C(O)~(CHa)o-Het, Het, NHR®,NHAr, NH-Het, OR’, OAr, OR® or O-Het,R® is H, -C(O)R’, -C(0)-Ar, R’, COOR’, COO-(CHy)o-Ar, SOA, SOR’ or SO-Het,R’ is alkyl having 1 to 10 C atoms or cycloalkyl having 1 to 10 C atoms,R® is Hal, NO2, CN, Z, -(CHz),-Ar, COOR', OR", CF3, OCF3, SOR’, NHR’, N(R")2, NH-C(O)R', NHCOOR' or C(O)R’,R® is CN or NO3, Z is alkyl having 1 to 6 C atoms, Ar is aryl, which is unsubstituted or substituted by R®Hal isF, Cl, Brorl,Het is unsaturated, 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 RS,Het" 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, R7, OR?, CN, NHZ or NO,n is0,10r2 m is0,1,2,3,4,50r86, 0 is 0,10r2 as well as their physiologically acceptable salts and solvates
- 31. Use according to Claim 30 wherein the avs and/or aps inhibitor is selected of the group consisting of compounds of subformulae IVa to Vi, which otherwise correspond to formula IV but in which ) 5 in IVa X is a direct bond . 0 OR? Ny, FR R3-(CH,),-A~(CH,),- IVa N \R2 . in IVb X is a direct bond, R? is H, R® is H and R* is Ar 0 OR! A R3-(CH,),-A-(CH,)- y IVb \R2 . in Ve X is a direct bond, R® is H and R* is Ar or Het: in Ivd X is a direct bond, R® is H, B is O, A is NH,n is 0, m is 3or4, R3 is Het and R* is Ar ) 5 A 0 OR? Het-NH-(CH,), -O N vd N \R2 . in Ve X is a direct bond, R® is H, B is O, A is NH, n is 0, m is 3or4 and R3 is Het (9) . R$ OR! Het-NH-(CH,) -O h Ve N \R2 . in IVF X is methylene, which is unsubstituted or substituted ) by Ar, R? is H, R® is H oder Ar and R* is oxo(@) Q x OR!RS . R3-(CH,),-A-(CH,). - 0 IVE \R2 . in IVg =X is methylene, 0 ¢ OR! RS R&-(CHy)yrA-(CHy)B > Vo : N5 . R2 : in IVh X is methylene, R* is H or Ar, RS is H or Ar and R? is H; in IVi X is methylene, R* is H or Ar, R® is H or Ar, B is O, A is NH, n is 0, m is3or4 R® is Het and } 20 R2 is H0 > Het-NH-(CH,),_-O YR Vi N \ R2
- 32. Use according to Claim 30 wherein the o,B3 and/or os inhibitor is a compound selected from the group consisting of5 . 3-phenyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]-1H-indole-3-yl}-propionic acid; 3-phenyi-3-{6-[4-(pyridine-2-ylamino)-butoxyl-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]- 16 propionic acid or 3-phenyl-3-[6-(imidazole-2-yl-amidocarboxymethoxy)-indole-3-yl]-propionic acid as wel! as their physiologically acceptable salts and solvates
- 33. Use according to Claim 30 werein wherein the ofa and/or as inhibitor is 3-phenyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]-1H-indole-3-yl}-propionic acid
- 34. Use according to Claim 30 wherein said amount is from about 0.5 ug to 5 mg
- 35. Use according to Claim 30 wherein said eye disease is diabetic retinopathy
- 36. Use according to Claim 30 wherein said eye disease is macular degeneration :
- 37. Use according to Claim 30 wherein said eye disease is myopia : 5
- 38. Use according to Claim 30 wherein said eye disease is ocular histoplasmosis
- 39. Use of an awP3 and/or ous inhibitor for the preparation of a medicament for prophylaxis and/or treatment of diseases of the eye of a patient resulting from angiogenesis in the eye, wherein the medicament comprise nanoparticles containing a therapeutically effective amount of an a,p3 and/or a,Bs inhibitor sufficient to inhibit angiogenesis and is injected into the scleral layer of the eye of said patient through the location of the exterior surface of the sclera that overlies retinal tissue
- 40. Use according to Claim 39 characterized in that the nanoparticles contain a biocompatible polymer
- 41. Use according to Claim 39 characterized in that the nanoparticles contain a biodegradable polymer
- 42. Use according to 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. Use according to Claim 39 characterized in that the composition comprise a liquid medium wherein the nanoparticles are being dispersed thereby forming a colloidal suspension ” 30 }
- 44. Use according to Claim 39, characterized in that the nanoparticles have a diameter from about 10 nm to about 500 nm: R ! -51-
- 45. Use according to Claim 39 characterized in that the nanoparticles have a diameter from about 100 nm to about 200 nm }
- 46. Use according to Claim 39 characterized in that the nanoparticles have been ’ 5 prepared by solvent displacement process }
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