Inhibitors of integrin for treating ocular diseases

FIELD: medicine, ophthalmology.

SUBSTANCE: the present innovation deals with applying a composition that contains antagonists of integrin αvβ3 and/or αvβ5 receptors for manufacturing the medicinal preparation indicated for treating angioproliferative ocular diseases. The compositions mentioned could be presented as nanoparticles. Application of the declared compositions provides the chance for intravitreous introduction.

EFFECT: higher efficiency of therapy.

46 cl, 1 ex, 1 tbl

 

The technical field

The present invention relates to the field of medicine and more specifically relates to methods and compositions for the prevention and/or treatment of eye diseases, which are antagonists of the integrin receptors αvβ3and/or αvβ5. In particular, the invention relates to methods and compositions for the prevention and/or treatment of eye diseases, which are antagonists of the integrin receptors αvβ3and/or αvβ5and songs are introduced by injection into the vitreous body of the eye.

Background of invention

Integrins are a class of cellular receptors known to bind extracellular matrix proteins and thus mediate interactions between cells and between cells and the extracellular matrix, resulting in adhesion. The integrin receptors are a family of transmembrane proteins with common structural features, namely non-covalent heterodimeric glycoprotein complex formed α and β subunits.

For one of the classes of integrin receptors, namely the vitronectin receptor, named so due to the fact that it preferably is initially associated with vitronectin, you know, h is about him are three different integrin, marked as αvβ1that αvβ3αvβ5. Horton, Int. J.Exp. Pathol., 71: 741-759 (1990). αvβ1binds fibronectin and vitronectin. αvβ3binds many ligands, including fibrin, fibrinogen, laminin, thrombospondin, vitronectin, von Willebrand factor, osteopontin and bone sialoprotein. αvβ5binds vitronectin. Processes specific adhesion of cells occurring with the participation of these three integrins play an important role in many cell-cell interactions in tissues, are currently being explored, but it is clear that different integrins have different biological functions.

One important part of recognition ligand for many integrins is Tripeptide sequence arginine-glycine-aspartic acid (RGD). RGD was detected in all the ligands mentioned above, for integrins vitronectin receptor. This RGD site recognition can be simulated by polypeptides ("peptides"), which include the RGD sequence, and such RGD peptides known as inhibitors of the action of the integrin.

Inhibitors of integrin containing the RGD sequence is described, for example, in application EP 0770622 A2. The described connections, in particular, inhibit the interaction of receptors β3and/or β 5-integrins to ligands and especially active for integrins αvβ3that αvβ5and αIIβ3but also relatively receptors αvβ1that αvβ6and αvβ8. Their action can be demonstrated, for example, in accordance with the method described J.W.Smith and others in J.Biol. Chem. 265. 12267-12271 (1990). In addition, the compounds possess anti-inflammatory actions.

Based inhibitors of integrin containing the RGD sequence found many antagonists without RGD-sequence. Such inhibitors of integrin without RGD sequences are described, for example, in applications WO 96/00730 A1, 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 A1 00/33838.

In the application DE 1970540 A1 describes bicyclic aromatic amino acids having activity as inhibitors of integrin receptors αvintegrin, in particular αvβ3and αvβ5-integrins. The most active compounds found in as antagonists of the adhesion receptor for vitronectin receptor αvβ3. This action can be demonstrated, such as the er, using the method described J.W.Smith and others in J.Biol. Chem. 265. 11008-11013 and 12267-12271 (1990).

In the application WO 00/26212 A1 describes derivatives chromanone and chromanone, which are inhibitors of integrin receptor αvintegrin, in particular integrins αvβ3and αvβ5. Connections are extremely active as antagonists of the adhesion receptor for vitronectin receptor αvβ3.

Inhibitors of integrin serves as a pharmaceutically active component in the treatment of human and veterinary medicine, in particular for the prevention and treatment of various diseases. Most preferably they are available for use for the treatment and prevention of circulatory disorders, thrombosis, myocardial infarction, arteriosclerosis, inflammation, apoplexy, angina, malignant diseases, diseases, destructive bone, especially osteoporosis, development of blood vessels and diseases that arise due to the development of blood vessels, for example, diabetic retinopathy, eye, macular degeneration, myopia, histoplasmosis of the eye, rheumatoid arthritis, osteoarthritis, robotically glaucoma and also ulcerative colitis, Crohn's disease, multiple sclerosis, psoriasis and restenosis after plastic surgery suck on the Ah.

Diseases of the eye, resulting from the development of blood vessels are the main cause of vision loss in America. While for people older than 65 years, the vision loss was mainly due to age-related macular degeneration (AMD), but for people under the age of 65 years, the main reason that causes vision loss, is diabetic retinopathy.

In the Wall Street Journal, March 6, 2000, presents an overview of research on the occurrence and treatment of AMD. According to this study from AMD currently affects about 12 million Americans. When AMD gradual destruction of the yellow spot, which is responsible for Central and color vision. In some cases, the deterioration of Central vision to "veil before eyes" can occur quickly, within weeks or months. Two existing form of the disease called "atrophic and exudative". Although the exudative form of AMD occurs only in 10% of cases of AMD, it causes about 90% of all cases of AMD-related blindness.

Until recently, the treatment of the exudative form of AMD was only in the direction of action of a powerful laser beam on a dangerous blood vessels, causing them to heat and coagulate. However, only about 15% of patients with the exudative form of AMD can be subjected to the s of this laser surgery. Other methods of treatment are currently in the experimental stages. According to one proposed approach, called photodynamic therapy, laser low power combined with the introduction of light-absorbing dye. Another method of treatment involves additional surgical approach and is called "limited movement of the retina. When such treatment is loosely connected vessels destroyed by a high power laser after detachment and rotation of the retina from the outer wall of the eye.

In the patent US 5766591 describes the use of RGD-containing antagonists αvβ3for the treatment of patients which is the formation of new blood vessels in the retinal tissue. In particular, these antagonists were invited to apply for the treatment of patients with diabetic retinopathy, macular degeneration and neovascular glaucoma. However, it was not given any examples for these indications. Was presented only General information about route of administration. When this was mentioned, in particular, intravenous, intraperitoneal, intramuscular, intra-and percutaneous introduction. In all cases, antagonists αvβ3discover the preferred selectivity for αvβ3on sravnenie the other integrins, such as αvβ5.

In the application WO 97/06791 A1 describes that antagonists αvβ5can also be used for inhibiting the development of blood vessels. As shown in the patent US 5766591 the instructions for antagonists αvβ3antagonists αvβ5was supposed to be used for the treatment of patients with diabetic retinopathy, macular degeneration and neovascular glaucoma. In the way of introduction, in particular, were mentioned intravenous, intraocular, intraarticular, intramuscular, percutaneous and oral administration.

The invention

It was found that inhibitors of integrin receptors αvβ3and/or αvβ5possess extremely useful pharmacological and physico-chemical properties combined with good tolerability, and therefore they can be applied, in particular, for the prevention and treatment of eye diseases in a patient, which is a consequence of the development of ocular blood vessels, by introducing the inhibitor into the vitreous body of the eye.

Thus, the invention relates to a method of prevention and/or treatment of eye diseases in a patient, which is a consequence of the development of eye blood vessels, which provides for the introduction into the vitreous body Glazounov patient composition, containing a therapeutically effective amount of an inhibitor αvβ3and/or αvβ5sufficient for inhibiting the development of blood vessels in the eye.

The vitreous body is located in the back of the eye and takes about 4/5 of the cavity of the eyeball behind the lens. The vitreous body is formed of a gelatinous substance known as the liquid part of the vitreous body. The liquid part of the vitreous body of the eye in norm consists of about 99% water and 1% of macromolecules, including collagen, hyaluronic acid, soluble glycoproteins, sugars and other low molecular weight metabolites.

For the introduction of drugs into the vitreous body of the inhibitor αvβ3and/or αvβ5in sufficient amount to inhibit the development of blood vessels of the eye can directly be introduced into the vitreous body by the insertion of the needle through the pars plana.

Therapeutically effective amount is an amount of inhibitor sufficient to provide significant inhibition of the development of blood vessels in the eye tissues when injected into the vitreous body. In General inhibitor αvβ3and/or αvβ5used amount is from about 0.5 μg to about 5 mg

The method according to the invention is particularly useful for the prevention and/or treatment of diabetic retinopathy, macular degeneration, myopia and histoplasmosis.

In a preferred embodiment of the invention the polypeptide containing the amino acid sequence RGD, are used as inhibitors αvβ3and/or αvβ5in the method of prevention and/or treatment of eye diseases. As stated above, the RGD is a peptide sequence Arg-Gly-Asp (RGD (arginine-glycine-aspartic acid), which occurs in natural integrin ligands, such as fibronectin or vitronectin. Soluble RGD-containing linear or cyclic peptides capable of inhibiting the interaction of these integrins with their respective natural ligands.

Abbreviations for amino acid residues that are further described in the following table:

AlaAalanine
ArgRarginine
AspDaspartic acid
D-PheD-homophenylalanine
D-NalD-3-(2-naphthyl)alanine
D-Phe D-phenylalanine
D-PhgD-phenylglycine
D-TrpD-tryptophan
D-TyrD-tyrosine
GlyGglycine
4-Hal-Phe4-halogenallanes
Phehomophenylalanine
IleIisoleucine
LeuLleucine
Nal3-(2-naphthyl)alanine
Nlenorleucine
PheFphenylalanine
Phgphenylglycine
TrpWtryptophan
TyrYtyrosine
ValVvaline.

More preferred as inhibitors αvβ3and/or αvβ5used in the method of prevention and/or treatment of diseases of the eye, are the compounds of formula I

in which

D represents D-Phe, Phe, D-Trp, Trp, D-Tyr, Tyr, D-Phe, Phe, D-Na, Nal, D-Phg, Phg or 4-Hal-Phe - (D or L form), where Hal represents F, Cl, Br, I,

E is Val, Gly, Ala, Leu, lIe or Nle,

And represents alkyl which has 1 to 18 carbon atoms, and

n represents 0 or 1,

and also their physiological acceptable salt.

In formula I, the alkyl preferably represents methyl, ethyl, isopropyl, n-butyl, sec-butyl or tert-butyl.

The most preferred polypeptides that are used as inhibitors αvβ3and/or αvβ5in the method according to the invention, can be represented by dogformulas Ia, which otherwise corresponds to the formula I but in which

D represents D-Phe, and

E represents Gly, Ala, Val, Leu, lIe or Nle.

In addition, more preferable is the use of all physiologically compatible salts of the compounds which fall under podporou Ia.

Most preferred as the active compound in a specific way are cyclo-(Arg-Gly-Asp-DPhe-Val), cyclo-(Arg-Gly-Asp-DPhe-NMeVal).

These RGD-containing peptides, which are described by formula I, as well as polypeptides that specifically referred to in the present invention previously described in the application EP 0770622 A2, which is therefore fully included in the present description by reference. Accordingly, the values of the substituents in the formula I, respectively in podfarm the Le Ia, are what is specified for Deputy in Podgornoe Ia, respectively Podgornoe Ib, as described on page 5, lines 24-32 ACC. page 5, lines 33-41 in the application EP 0770662 A2.

It was found that inhibitors of integrin receptors αvβ3and/or αvβ5which are not polypeptides and do not contain the RGD sequence, can also be used for the prevention and treatment of eye diseases in a patient, which is a consequence of the development of ocular blood vessels, by introducing the inhibitor into the vitreous body of the eye.

Therefore, in another preferred embodiment of the method according to the invention the inhibitors αvβ3and/or αvβ5used in a method of prevention or treatment of diseases of the eye, are compounds of formula II

in which

R1represents H, alkyl which has 1 to 6 carbon atoms, or benzyl,

R2is an R10, CO-R10, COOR6, COOR10, SO2R6or SO2R10,

R3represents H, Hal, OA, other10N(R10)2, -NH-acyl, -O-acyl, CN, NO2, OR10, SR10, R2or CONHR10,

R4represents H, =O, =S, C1-C6-alkyl or acyl,

R5PR is dstanley a NH 2H2N-C(=NH) or H2N-(C=NH)-NH, where the primary amino group can also be protected by the usual aminosidine groups or can be mono-, di - or tizamidine R10, CO-R10, COOR10or SO2R10or R6,

R7, R8each independently from each other, is absent or represents H,

R7and R8together represent a bond,

X, Y each independently from each other represents =N-, -N-, O, S, -CH2- or =C-, provided that at least one of the two values of X, Y is =N-, -N-, O or S,

W, Z are each independently from each other, is absent or represents O, S, NR1With(=O), CONH, NHCO, C(=S)NH, NHC(=S), C(=S), SO2NH, NHSO2or SA=SA′,

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atoms N, O and/or S and can be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, cooa, CONH2, NO2, =NH or =O,

R9represents H, Hal, OA, NHA, NAA′, NH, Oezil, CN, NO2, SA, SOA, SO2A, SO2Ar or SO3N

R10represents H, A, Ar or aralkyl, which has 7 to 14 carbon atoms,

R11represents H or alkyl which has 1 to 6 carbon atoms,

And And′ each independently of the other represents H or unsubstituted or mono-, di - or tri-R9-substituted alkyl or cycloalkyl, each of which has 1-15 carbon atoms and in which one, two or three methylene groups may be replaced by N, O and/or S,

Ar represents an unsubstituted or mono-, di -, or three-And - and/or R9-substituted mono - or bicyclic aromatic ring system which has 0, 1, 2, 3 or 4 atoms N, O and/or S,

Hal represents F, Cl, Br or I and

m, n are each independently from each other represents 0, 1, 2, 3,or 4

and their physiologically acceptable salts.

The preferred inhibitors αvβ3and/or αvβ5used in the method according to the invention, are compounds in accordance with the subformulas lla-llg, which otherwise correspond to formula II, but in which

in IIa) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SCO2R10,

R3represents H,

R4represents H or a =O,

R5represents H2N-C(=NH) or H2N-C(=NH)-NH,

W, Z are each independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

R10represents H, or benzyl,

R11represents H,

But nezamedin the th alkyl or cycloalkyl with 1-15 carbon atoms and

m, n are each independently from each other represents 0, 1 or 2;

in IIb) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5is an R6,

W, Z are each independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atoms N, O and/or S and which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, COOA, CONH2, NO2, =NH or =O,

R10represents H, or benzyl,

R11represents H,

But is an unsubstituted alkyl or cycloalkyl with 1-15 carbon atoms and

m, n are each independently from each other represents 0, 1 or 2;

in IIc) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5represents H2N-C(=NH) or H2N-C(=NH)-NH,

W, Z are each independently from each other without the duty to regulate or represents C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

And represents alkyl with 1-6 carbon atoms,

R10represents H, alkyl with 1-6 carbon atoms, camphor-10-yl or benzyl,

R11represents H,

m, n are each independently from each other represents 0, 1 or 2;

in IId) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5is an R6,

W, Z are each independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X is a =NH-, or-CH2-,

Y represents NH or O,

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atoms N, O and/or S and which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, COOA, CONH2, NO2, =NH or =O,

R10represents H, alkyl with 1-6 carbon atoms, camphor-10-yl or benzyl,

R11represents H,

And represents unsubstituted alkyl with 1-6 carbon atoms, and

m, n are each independently from each other represents 0, 1 or 2;

in IIe) R1represents H or alkyl with 1-6 at the Mami carbon

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5is an R6,

W, Z are each independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

R6represents 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazole-2-yl, 2H-pyrazole-2-yl, 1H-tetrazol-5-yl, 2-imino-imidazolidin-4-one-5-yl, 1-A-1,5-dihydro-imidazol-4-one-2-yl, pyrimidine-2-yl or 1,4,5,6-tetrahydro-pyrimidine-2-yl,

R10represents H, alkyl with 1-6 carbon atoms, camphor-10-yl or benzyl,

R11represents H,

And represents unsubstituted alkyl with 1-6 carbon atoms, and

m, n are each independently from each other represents 0, 1 or 2;

in IIf) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5represents H2N-C(=NH) or H2N-C(=NH)-NH,

W, Z are each independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents Soboh is NH or O,

R10represents Ar,

R11represents H,

But is an unsubstituted alkyl or cycloalkyl with 1-15 carbon atoms and

m, n are each independently from each other represents 0, 1 or 2;

in IIg) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5is an R6,

W, Z are each independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atoms N, O and/or S and which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, COOA, CONH2, NO2, =NH or =O,

R10represents Ar,

R11represents H,

But is an unsubstituted alkyl or cycloalkyl with 1-15 carbon atoms and

m, n are each independently from each other represents 0, 1 or 2.

in IIh) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4

R5represents H2N-C(=NH), H2N-C(=NH)-NH, mono - or bicyclic a heterocycle, which has 1 to 4 atoms N, O and/or S and which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, COOA, CONH2, NO2, =NH or =O,

W, Z are each independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X represents-CH2-,

Y represents NH or O,

R7, R8represents N

R10represents A, Ar, aralkyl or Het,

R11represents H,

But is an unsubstituted alkyl or cycloalkyl with 1-15 carbon atoms and

m, n are each independently from each other represents 0, 1 or 2;

The compounds of formula II and subformulas IIa-IIg described in the application DE 19705450 A1, which is fully incorporated into the present description by reference. Thus, the substituents in formula II, respectively subformulas IIa-IIg have the same value, which is specified for the substituents in formula I, respectively in the subformulas Ia-Ig, as described on page 2, line 3-43, ACC. page 5, line 58 - page 7, line 30 application DE 19705450 A1. Definitions of the substituents listed on page 4, line 35 to page 5, line 56 application DE 19705450 A1.

More preferred of these inhibitors αvβ3and/or αvβ5used in the method is according to the invention, are these connections:

(2S)-2-[(R)-camphor-10-sulfonamide]-3-{3,4-dihydro-2-(3-guanidinopropionic)-()-2H-1,4-benzoxazin-3-one-6-yl}propionic acid;

(2S)-2-benzyloxycarbonylamino-3-(2-guanidinate-1,4-benzodioxan-6-yl)propionic acid;

(2S)-2-tert-butyloxycarbonyl-3-[3,4-dihydro-2-(2-guanidino-2-oxoethyl)-2H-1,4-benzoxazin-3-one-6-yl]propionic acid;

(2S)-2-benzyloxycarbonylamino-3-(2-guanidinoacetic-aminomethyl-1,4-benzodioxan-6-yl)propionic acid;

(2S)-2-tert-butyloxycarbonyl-3-{3,4-dihydro-2-[N-(2-imidazolyl)-carbamoylmethyl]-2H-1,4-benzoxazin-3-one-6-yl)propionic acid;

(2S)-2-tert-butyloxycarbonyl-3-{3,4-dihydro-2-[N-(2-benzimidazolyl)-carbamoylmethyl]-2H-1,4-benzoxazin-3-one-6-yl)propionic acid;

(2S)-2-tert-butyloxycarbonyl-3-{3,4-dihydro-2-[2-(2-imino-4-Oxymetazoline-5-yl)ethyl]-2H-1,4-benzoxazin-3-one-6-yl}propionic acid;

(2S)-2-(2,2-dimethylpolysiloxane)-3-(3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl]-(2S)-2H-1,4-benzoxazin-3-one-6-yl}propionic acid;

(2S)-2-[(R)-camphorsulfonic]-3-{3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-one-6-yl)propionic acid

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(butylsulfonyl)-propionic acid;

(S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(4-torpedoshaped)-propionic acid;

(2S)-3-{2-[3-(pyridine-2-ylamino)propyl]-chroman-6-yl}-2-(2,4,6-trimethylphenylsulfonyl)propionic acid;

(2S)-3-{2-[3-(pyridine-2-ylamino)propyl]-chroman-6-yl}-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(trebouxiophyceae)-propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(diphenylmethylene)-propionic acid;

and their physiological acceptable salt.

Most preferred are

(2S)-2-(2,2-dimethylpolysiloxane)-3-{3,4-dihydro-2-[N-(2-imidazolyl)carbarnoyl-ethyl]-(2S)-2H-1,4-benzoxazin-3-one-6-yl}propionic acid

(2S)-2-(2,2-dimethylpolysiloxane)-3-{3,4-dihydro-2-[N-(2-imidazolyl)carbarnoyl-ethyl]-(2R)-2H-1,4-benzoxazin-3-one-6-yl}propionic acid

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(butylsulfonyl)propionic acid;

and

(2S)-2-[(R)-camphorsulfonic]-3-{3,4-dihydro-2-[N-(2-benzimidazolyl)-carbamoylmethyl]-2H-1,4-benzoxazin-3-one-6-yl)propionic acid.

In another preferred embodiment of the method according to the invention the inhibitors αvβ3and/or αvβ5used in a method of prevention or treatment of Zabol is the eyes, are the compounds of formula III

in which

R1represents CH2OR10, COOR10, CONHR10or CON(R12)2,

R2is an R10, CO-R10, CO-R6, COOR6, COOR10, SO2R6, SO2R10, CONHR6, CON(R6)2, CONHR10or CON(R12)2,

R3represents H, Hal, other10N(R12)2, NH-acyl, -O-acyl, CN, NO2, OR10, SR10, SO2R10, SO2R10, COOR10, CONHR6, CON(R6)2, CONHR10or CON(R12)2,

R4represents H, A, Ar or kalkeren, which has 7 to 14 carbon atoms,

R5represents NH2H2N-C(=NH) or H2N-(C=NH)-NH, where the primary amino group can also be protected by the usual aminosidine groups, or may be mono -, di - or tizamidine R10, CO-R10, COOR10or SO2R10or R6-NH-,

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atoms N, O and/or S, which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, cooa, CONH2, NO2, =NH or =O,

R7, R8in each case, independently from each other, is absent or represents H,

R7and R 8together represent a bond,

Z is absent or represents O, S, NH, NR1With(=O), CONH, NHCO, C(=S)NH, NHC(=S), C(=S), SO2NH, NHSO2or CA=CA′,

R9represents H, Hal, OR11, NH2, Other12N(R12)2, NH, Oezil, CN, NO2, SR11, SOR12, SO2R12or SO3N

R10represents H, A, Ar or kalkeren, which has 7 to 14 carbon atoms,

R11represents H or alkyl with 1-6 carbon atoms,

R12represents alkyl which has 1 to 6 carbon atoms,

And represents H or alkyl which has 1 to 15 carbon atoms, or cycloalkyl, which has 3 to 15 carbon atoms, which is unsubstituted or mono-, di - or tizamidine R9and in which one, two or three methylene groups can be replaced by atoms of N, O and/or S,

Ar represents a mono - or bicyclic aromatic ring system which has 0, 1, 2, 3 or 4 atoms N, O and/or S, which is unsubstituted or mono-, di - or tizamidine a and/or R9,

Hal represents F, Cl, Br or I,

m, n in each case independently of one another represent 0, 1, 2, 3,or 4

and their physiological acceptable salt and solvate,

In this embodiment of the method according to the present invention is more preferably used which are inhibitors α vβ3and/or αvβ5who are compounds of subformulas IIIa-IIIn, which otherwise correspond to formula III but in which

in IIIa) R3represents N;

in IIIb) R3represents H and

R2represents COOR10or SO2R10;

in IIIc) R3represents H,

R2represents COOR10or SO2R10and

R10represents H, A, Ar or kalkeren, which has 7 to 14 carbon atoms;

in IIId) m is 0;

in IIIe) m represents 0 and

R3represents N;

in IIIf) R3represents H,

R2represents COOR10or SO2R10and

m represents 0;

in IIIg) R3represents H,

R2represents COOR10or SO2R10and

R10represents H, A, Ar or kalkeren with 7-14 carbon atoms, and

m represents 0;

in IIIh) R3represents H,

R2represents COOR10or SO2R10and

R10represents H, A, Ar or kalkeren, which has 7 to 14 carbon atoms, and

And represents H or unsubstituted alkyl which has 1 to 15 carbon atoms, or cycloalkyl, which has 3 to 15 carbon atoms;

Ar represents Enel or naphthyl and

m represents 0;

in IIIi) R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atom N, which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, cooa, CONH2, NO2, =NH or =O,

in IIIj) R3represents H,

R2represents COOR10or SO2R10and

R10represents H, A, Ar or kalkeren, which has 7 to 14 carbon atoms, and

m represents 0;

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atom N, which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, cooa, CONH2, NO2, -NH or =O;

in IIIk) Z is absent;

in IIIl) Z is absent and the

R3represents N;

in IIIm) Z is absent,

R3represents h, R represents a COOR10or SO2R10;

in IIIn) Z is absent,

R3represents H,

R4represents H,

R2represents COOR10or SO2R10;

R10represents H, A, Ar or kalkeren, which has 7 to 14 carbon atoms,

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atom N, which may be unsubstituted or mono-or tizamidine Hal, A, -CO-AND, HE, CN, COOH, COOA, CONH2O 2, =NH or =O,

And represents H or unsubstituted alkyl which has 1 to 6 carbon atoms,

Ar represents phenyl or naphthyl, and

m is 0.

The compounds of formula III and subformulas IIIa-IIIn described in the application WO 00/26212 A1, which is fully incorporated into the present description by reference. Thus, the substituents in formula III, respectively subformulas IIIa-IIIn have the same value, which is specified for the substituents in formula I, respectively in the subformulas Ia-In, as described on page 1, line 5 to page 2, line 31 ACC. page 13, line 20 to page 15, line 6 application WO 00/26212 A1. Definitions of the substituents listed on page 8, line 18 to page 13, line 10 of the application WO 00/26212 A1.

More preferred of these inhibitors αvβ3and/or αvβ5that are used in this embodiment of the method according to the invention are such compounds are:

(2S)-3-[2-(3-aminopropyl)-4-oxo-4H-chromen-6-yl]-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-[2-(3-guanidinopropionic)-4-oxo-4H-chromen-6-yl]-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-exogamy-6-yl}-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(pyridine-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(1H-benzimidazole-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-butylcyclopentadienyl acid;

(2S)-3-{2-[3-(pyridine-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,4,6-trimetilfenil)sulfhemoglobinemia acid

or a physiological acceptable salt and solvate.

Most preferred are

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-butylcyclopentadienyl acid

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropanamide)propionic acid

and (2S)-3-{2-[3-(pyridine-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,4,6-trimetilfenil)sulfhemoglobinemia acid.

In another preferred embodiment of the method according to the invention inhibitors (αvβ3and/or αvβ5) used in the method of prevention or treatment of diseases of the eye, are the compounds of formula IV

in which

A and b each independently of one another represents O, S, NH, NR7, CO, CONH, NHCO, or a direct link,

X represents alkyl is n, which has 1 to 2 carbon atoms, which is unsubstituted or monosubstituted R4or R5or a direct link,

R1represents N, Z or -(CH2)o-Ar,

R2represents H, R7or-C(O)Z,

R3represents other6, -NR6-C(=NR6)-Other6, -C(=NR6)-Other6, -NR6-C(=NR9)-Other6, -C(=NR9)-Other6or Het1,

R4or R5each independently of the other represents H, oxo, R7, -(CH2)o-Ar, -C(O)-(CH2)o-Ar, -C(O)-(CH2)o-R7-C(O)- (CH2)o-Het, Het, other6, NHAr, NH-Het, OR7, OAr, OR6or O-Het,

R6represents H, -C(O)R7, -C(O)-Ar, R7, COOR7, COO-(CH2)o-Ar, SO2-Ar, SO2R7or SO2-Het,

R7represents alkyl which has 1 to 10 carbon atoms, or cycloalkyl, which has 1-10 carbon atoms,

R8represents Hal, NO2CN, Z, -(CH2)about-Ar, COOR1, OR1, CF3, OCF3, SO2R1, Other1N(R1)2, NH-C(O)R1, NHCOOR1or C(O)R1,

R9represents CN or NO2,

Z represents alkyl which has 1 to 6 carbon atoms,

Ar represents aryl, which is unsubstituted or substituted R8,

Hl represents F, Cl, Br or I,

Het is a saturated, partially or fully saturated mono - or bicyclic ring system which has 5 to 10 atoms that can contain 1 or 2 N atom and/or 1 or 2 atoms S or O and where the heterocyclic ring system may be mono - or disubstituted R8,

Het1represents a mono - or bicyclic aromatic ring system which has from 1 to 4 atom N, which may be unsubstituted or mono - or disubstituted by Hal, R7, OR7CN, NHZ or NO2,

n represents 0, 1 or 2

m represents 0, 1, 2, 3, 4, 5 or 6,

o represents 0, 1 or 2,

as well as their physiological acceptable salt and solvate.

In this embodiment of the method according to the present invention is more preferably used inhibitors αvβ3and/or αvβ5who are compounds of subformulas IVa-IVi, which otherwise correspond to formula IV, in which

in IVa X represents a direct bond

in IVb X represents a direct bond,

R2is,

R5represents H and

R4represents Ar

in IVc X represents a direct bond,

R5represents H and

R 4represents an Ar or Het;

in IVd X represents a direct bond,

R5represents H,

In represents Oh,

And represents NH,

n represents 0,

m represents 3 or 4,

R represents Het and

R4represents Ar

IVe X represents a direct bond,

R5represents H,

In represents Oh,

And represents NH,

n represents 0,

m represents 3 or 4 and

R3represents Het

in IVf, X represents a methylene which is unsubstituted or substituted by Ar,

R2represents H,

R5represents H or Ar, and

R4represents oxo

in IVg X represents a methylene

in IVh X represents methylene,

R4represents H or Ar,

R5represents H or Ar, and

R2represents N;

IVi X represents methylene,

R4represents H or Ar,

R5represents H or Ar,

In represents Oh,

And represents NH,

n represents 0,

m represents 3 or 4

R3is the Wallpaper Het and

R2represents N

The preferred inhibitors αvβ3and/or αvβ5in accordance with the formula IV which are used in the method according to the present invention, are:

3-phenyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]-1H-indol-3-yl}-propionic acid;

3-phenyl-3-{6-[4-(pyridine-2-ylamino)-butoxy]-1H-indol-3-yl}-propionic acid;

3-phenyl-3-{5-[4-(pyridine-2-ylamino)-butoxy]-1H-indol-3-yl}-propionic acid;

3-phenyl-3-{5-[3-(pyridine-2-ylamino)-propoxy]-1H-indol-3-yl}-propionic acid;

3-phenyl-3-[6-(pyridin-2-yl-aminocarboxylate)-indol-3-yl]-propionic acid;

3-phenyl-3-[6-(benzimidazole-2-yl-aminocarboxylate)-indol-3-yl]-propionic acid

3-phenyl-3-[6-(imidazol-2-yl-aminocarboxylate)-indol-3-yl]-propionic acid, or

3-Benzo[1,2,5]thiadiazole-5-yl-3-{6-[2-(6-methylamino-pyridine-2-yl)-ethoxy]-1H-indol-3-yl}-propionic acid,

as well as their physiological acceptable salt and solvate.

The most preferred inhibitors αvβ3and/or αvβ5in accordance with the formula IV which are used in the method according to the present invention, are

3-phenyl-3-(6-[3-(pyridine-2-ylamino)-propoxy]-1H-indol-3-yl}-propionic acid, or

3-Benzo[1,2,5]thiadiazole-5-yl-3-{6-[2-(6-METI the amino-pyridine-2-yl)-ethoxy]-1H-indol-3-yl}-propionic acid.

These compounds, and the compounds of formula IV and subformulas IVa-IVi described in the parallel patent application DE 10006139.7, which is fully incorporated into the present description by reference. Thus, the substituents in the formula IV and the subformulas IVa-IVi have the same value, which is specified for the substituents in formula I, respectively the subformulas Ia-Ii, as described on page 1, line 3 - page 2, line 13 ACC. page 17, line 4 - p.20, line 9 of the application for patent in Germany, No..10006139.7. Definitions of the substituents refer to page 9, line 6 - page 16, line 28 patent application DE 10006139.7.

Particularly suitable compounds described above for use in the treatment of diseases of the eye was exposed to research on some specific connections.

Inhibition of the development of blood vessels after injection into the vitreous body of the compounds can be demonstrated by quantifying the formation of new blood vessels in the eye after stimulation of development of new blood vessels and subsequent injection into the vitreous body of the inhibitor αvβ3and/or αvβ5. One of the models that is appropriate to confirm the inhibitory effect of the inhibitor αvβ3and/or αvβ5on the development of blood vessels is, for example, the model microcarbon of the cornea in rabbits, describe the Naya R.W. Shaffer and others, in: Molecular, Cellular, and Clinical Aspects of Angiogenesis, Maragoudakis, E. (ed). Plenum Press, New York, 241 ff. (1996). In this model, the development of blood vessels is stimulated by implantation of hydronomic balls that contain a cytokine that stimulates the development of blood vessels, such as, for example, fibroblast growth factor (FGF) or growth factor vascular endothelial (VEGF) in the cornea. After implantation test active compound is transferred through paralambano injection into the vitreous body. The effect on the formation of new blood vessels was measured after certain time intervals by visual examination in the microscope, pictures and quantification using computer analysis of images.

Alternatively, the introduction of cytokines stimulating the development of new blood vessels can also be performed by laser photocoagulation, as described, for example, Murata T. other, IOVS, 41, 2309 ff. (2000).

In addition, an object of the present invention is a composition suitable for the method for the prevention and treatment of eye diseases in a patient, which is a consequence of the development of ocular blood vessels, providing for the introduction into the vitreous body of the eye of the specified patient a composition containing a therapeutically effective amount of an inhibitor αvβ3and/or αv; 5sufficient for inhibiting the development of blood vessels in the eye.

The drug is used for the introduction of compounds into the vitreous body of the eye, may be in any form suitable for injection into the vitreous body using a cannula with a small diameter, suitable for injection into the vitreous body. Examples of input forms by injection are solutions, suspensions or colloidal suspension.

Compositions suitable for injection into the vitreous body, contain a physiologically tolerable carrier together with a suitable tool, as described in the present invention, soluble or dispersed therein as an active ingredient. The term "pharmaceutically suitable"as used in the present invention refers to compositions, carriers, solvents and reagents, which are substances that do not cause adverse physiological effects when injected into the vitreous body of the mammal. Preparation of pharmaceutical compositions for injection that contains the active ingredients dissolved or dispergirovannom, it is clear in the art and should not be limited on the basis of the composition. The composition can also be emulsified. The active ingredient may be mixed with fillers, which are pharmaceutical is appropriate and compatible with the active component, and in amounts suitable for use in therapeutic methods described in this invention. Suitable fillers are, for example, water, saline solution, sorbitol, glycerol and the like and combinations thereof. In addition, if necessary, the composition may include minor amounts of auxiliary substances such as wetting or emulsifying agents, buffering agents and the like which enhance the effectiveness of the active ingredient. The composition may also include substances that increase the viscosity, such as hyaluronic acid. therapeutic composition according to the present invention can include pharmaceutically acceptable salts of its components. Pharmaceutically acceptable salts include acid additive salts which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acid, or such organic acids as acetic, tartaric, almond and such. Salts formed free carboxyl group, can also be derived inorganic bases, such as, for example, hydroxides of sodium, potassium, ammonium, calcium or iron, and such organic bases as Isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine and the like, More preferred are salts with HCl.

Physiologically the Ki tolerant carriers are well known in the art. Examples of liquid carriers are sterile aqueous solutions that do not contain other substances in addition to the active ingredients and water, or contain a buffer such as sodium phosphate at physiological pH value, physiological saline or both, such as phosphate buffer and saline. In addition, water carriers may include more than one buffer salt, as well as salts such as the chlorides of sodium and potassium, sorbitol and other dissolved substances.

Depending on the form of the introduction of the active connection can be allocated in a free state from the intermediate product, or by sustained release. Compositions with delayed release are preferred due to the reduced frequency of administration.

One of the possibilities to achieve the kinetics of slow release is the introduction or conclusion of the active component in the nanoparticles. The nanoparticles may be introduced in the form of a powder, in the form of powder mixed with additional excipients, or in the form of suspensions. Colloidal suspensions of nanoparticles are preferred because they can easily be entered using the small diameter cannula.

Nanoparticles are particles having a diameter from about 5 nm to about 1000 nm. The term "nanoparticles", as the on used in the present invention, refers to particles formed by a polymer matrix in which is dispersed active component, which is also known as "nanospheres", and also refers to the nanoparticles consisting of a core containing the active compound, which is surrounded by a polymeric membrane, which is also known as "nanocapsules". For injection into the vitreous body of the eye preferably, the nanoparticles have a diameter from about 50 nm to about 500 nm, in particular from approximately 100 nm to approximately 200 nm.

Nanoparticles can be obtained in situ by polymerization of dispersed monomers or by applying pre-formed polymers. As derived in situ polymers are often not biodegradable and/or contain significantly toxic by-products, nanoparticles of pre-formed polymers are preferred. The nanoparticles of the pre-formed polymers can be prepared using different technologies, for example by emulsion evaporation, solvent displacement, vysalivaniya and emulsified by diffusion.

Evaporation of the emulsion is a classic way to obtain the nanoparticles of the pre-formed polymers. In accordance with this method, the polymer and the active compound is dissolved in immiscible with water, an organic solvent, which is mullerova in aqueous solution. Then the crude emulsion is exposed to high-energy source, such as an ultrasonic device, or passed through the homogenizer, high pressure, or micropedia to reduce the particle size. Then the organic solvent is removed by heating and/or vacuum, obtaining nanoparticles with a diameter of approximately 100 nm to approximately 300 nm. Usually, the organic solvent used methylenchlorid and chloroform, as they are insoluble in water, have good solvent properties, easily emulsified and are highly volatile. However, these solvents are hazardous because of their physiological tolerance. In addition, a significant shear force needed to reduce the size of particles that can damage the polymer and/or active connection.

The way that the displacement of the solvent was first described in the application EP 0274961 A1. In this way the active compound and the polymer are dissolved in an organic solvent which is miscible with water in all proportions. This solution will contribute in an aqueous solution containing a stabilizer, with weak stirring, the result is the spontaneous formation of nanoparticles. Examples of acceptable organic solvent and stabilizer are acetone or ethanol, the meet is but polyvinyl alcohol. This can be avoided favorable chlorinated solvents and voltage shift. The mechanism of formation of nanoparticles can be explained interfacial turbulence arising from the displacement of solvent (Fessi H. etc.. Int. J.Pharm. 55, (1989) R1-R4). Recently, the method of displacement of the solvent described in the application WO 97/03657 A1, in which an organic solvent containing the active compound and the polymer, bring in an aqueous solution without stirring.

For the first time how vysalivaniya was described in the application WO 88/08011 A1. According to this method, a solution of water-insoluble polymer and the active compounds in water-soluble organic solvent, preferably in acetone, mixed with a concentrated aqueous viscous solution or gel containing a colloidal stabilizer and wasalive agent. To the resulting emulsion oil-in-water, water is added in sufficient quantity to diffusion in the aqueous phase and to cause rapid diffusion of the organic solvent in the aqueous phase, which leads to interfacial turbulence and the formation of nanoparticles. Remaining in suspension of nanoparticles of organic solvent and wasalive agent is then removed by repeated washing with water. Alternative solvent and wasalive agent can be removed by filtering with a cross over.

When the method emulsified the second diffusion polymer is dissolved in a water-saturated partially water-soluble organic solvent. This solution is mixed with an aqueous solution containing a stabilizer, receiving the emulsion oil-in-water. To this emulsion was added water, which causes the diffusion of the solvent in the surface of an aqueous phase and leads to the formation of nanoparticles. During the formation of particles in each droplet of the emulsion leads to the formation of several nanoparticles. Since this phenomenon cannot be fully explained by convective action caused by interfacial turbulence, it has been suggested that the diffusion of the organic solvent from the droplets of crude suspension, load-bearing molecules active compound and the polymer phase in the aqueous phase leads to the formation of supersaturated local areas from which the polymer is combined with the formation of nanoparticles (Quintanar-Guerrero D. and other Colloid. Polym. Sci. 275 (1997) 640-647). As the organic solvents preferably can be used pharmaceutically acceptable solvents such as propylene carbonate or acetate.

Using the methods described above can be formed nanoparticles from different types of polymers. For use in the method according to the present invention, which provides for the introduction of drugs into the vitreous body of the eye, are preferred nanoparticles that are biocompatible polymers. The term "biocompatible" refers to ve is estu, which, after introduction into a biological environment does not cause any significant impacts on the biological environment. From biocompatible polymers particularly preferred is a polymer, which also bioresource. The term "biodegradable" refers to a substance which upon introduction into a biological environment enzymatic or chemically decomposed into smaller molecules, which can then be removed.

Biodegradable polymers are well known to the person skilled in the art. Examples are prilojenie esters of hydroxycarboxylic acids, such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polycaprolactone (PCL), and copolymers of lactic acid and glycolic acid (PLGC), copolymers of lactic acid and caprolactone, polietilen caprolacton, Polyoxymethylene acid and poly(ortho)esters, polyurethanes, polyanhydrides, Polyacetals, policyidreference, polycyanoacrylate, natural polymers such as alginate and other polysaccharides including dextran and cellulose, collagen and albumin.

Liposomes represent an additional delivery system of the medicinal product, which is easily introduced. Thus, in the method according to the invention active compound can also be introduced into the vitreous body of the eye using liposomes as a delivery system. Liposomes x is well known to a person skilled in the art. Liposomes can be formed from different phospholipids, such as cholesterol, stearylamine of phosphatidylcholine. Liposomes that can be used in the method according to the invention include all types of liposomes, including, but not limited to, small single-layer vesicles, large single bubbles and multi-layered vesicles.

Example

The effect of the inhibitor αvβ3and/or αvβ5when injected into the vitreous body was studied on the model microcarbon of the cornea in rabbits, as described R.W. Shaffer (see above). As an example of an inhibitor αvβ3and/or αvβ5the experiment used a 2-(2,2-dimethylpolysiloxane)-3-{3,4-dihydro-2-[N-(2-imidazolyl)-carbamoylethyl]-2H-1,4-benzoxazin-3-one-6-yl}propionic acid. To encourage the development of blood vessels used geronova balls containing basic fibroblast growth factor (bFGF). Getting implants containing bFGF, was carried out by using the distribution of Gerona [poly(hydroxyethyl)methacrylate] in a specially prepared Teflon pins that have a 2.5 mm cores drilled on their surfaces. Approximately 12 μl of distributed material were placed in each post and polymerizable overnight in sterile cabinets and then sterilized by irradiation ultravio is this.

The experiment was performed on 10 animals; in each eye animals implanted one individual ball, thus surgically creating a "pocket" in the middle of the corneal stroma of the rabbit. The surgical procedure was performed under sterile conditions using a surgical microscope Moeller-Wedel Microflex (Company Haag-Streit, Germany), equipped with a beam splitter and camera photographic records of individual corneas. To create a 3-5 mm of the pocket to a depth of half the thickness of the cornea used the knife 69 Beaver. Stroma was cut perifericheskie using a spatula, and implanted the ball perifericheskie at least 2 mm from the edge. Directly after implantation of hydronomic balls containing bFGF, 5-and 10 animals in each eye was injected with 100 μl of a solution of a medicinal product containing 2.0 mg/ml of 2-(2,2-dimethylpolysiloxane)-3-{3,4-dihydro-2-[N-(2-imidazolyl)-carbamoylethyl]-2H-1,4-benzoxazin-3-one-6-yl}propionic acid, dissolved in saline solution for injection into the vitreous body. For comparison the same procedure was carried out for the other 5 animals, using only saline. After implantation of the eye photographed and measured the areas of the formation of new blood vessels through certain time intervals. Summary of the results obtained on the 5th, 7th, 10th and 14th days of postimplantation, presented in the table.

Effect of a single (day 0) injection into the vitreous body 2-(2,2-dimethylpolysiloxane)-3-{3,4-dihydro-2-[N-(2-imidazolyl)-carbamoylethyl]-2H-1,4-benzoxazin-3-one-6-yl}propionic acid on the development of blood vessels in the cornea, stimulated by bFGF, 5, 7, 10, 14 days after implantation

to 1.86
Once (day 0) introduction to the vitreous body, 100 μl, 20 mg/ml of the medicinal product = 2 mg/eye
days after implantation571014
inhibition [%]56,3 p<0,00513,4 p<0,23345,8 p<0,00240,0 p<0,005
ControlDosageControlDosageControlDosageControlDosage
The average lot size [mm2]3,911,71lower than the 5.374,659,415,1016,569,94
The standard deviation1,841,292,112,97of 2.26of 5.403,31
The coefficient of variation, %47,0675,4434,6445,3831,5644,3132,6133,30
n109109109107

The obtained results clearly show the positive effect of the present invention. Although the inhibitor αvβ3and/or αvβ5introduced only in a single dose and dosage form represented only solution, observed a significant inhibition of the formation of new vessels for many days.

1. The use of a composition containing inhibitors αvβ3and/or αvβ5to obtain medicines for the treatment of eye diseases in a patient, which is a consequence of the development of ocular blood vessels, by injection into the vitreous body.

2. The use according to claim 1, in which the inhibitor αvβ3and/or αvβ5is an RGD-containing polypeptide.

3. The method according to claim 2, wherein said polypeptide is a connection is their formula I

in which D represents D-Phe, Phe, D-Trp, Trp, D-Tyr, Tyr, D-Phe, Phe, D-Nal, Nal, D-Phg, Phg or 4-Hal-Phe - (D or L form)

E is Val, Gly, Ala, Leu, lle, or Nle and

And represents alkyl which has 1 to 18 carbon atoms,

n represents 0 or 1

and also their physiologically acceptable salts.

4. The use according to claim 2, wherein said polypeptide is a compound as represented by dogformulas Ia, which otherwise corresponds to the formula I but in which

D represents D-Phe, and

represents Gly, Ala, Val, Leu, lle, or Nle.

5. The use according to claim 2, wherein said polypeptide is a cyclo-(Arg-Gly-Asp-DPhe-Val).

6. The use according to claim 2, wherein said polypeptide is a cyclo-(Arg-Gly-Asp-DPhe-NMeVal).

7. The use according to claim 2, in which the specified therapeutically effective amount of the drug is 0.5 mg to 5 mg

8. The use according to claim 2, in which the specified eye disease is a diabetic retinopathy.

9. The use according to claim 2, in which the disease of the eye is a macular degeneration.

10. The use according to claim 2, in which the disease of the eye is a myopia.

11. The use according to claim 2, in which the specified eye disease isone histoplasmosis of the eye.

12. The use according to claim 1, in which the inhibitor αvβ3and/or αvβ5is a compound of formula II

in which R1represents H, alkyl which has 1 to 6 carbon atoms, or benzyl,

R2is an R10, CO-R10, COOR6, COOR10, SO2R6or SO2R10,

R3represents H, Hal, OA, other10N(R)2, -NH-acyl, -O-acyl, CN, NO2, OR10, SR10, R2or CONHR10,

R4represents H, =O, =S, C1-C6-alkyl or acyl,

R5represents NH2H2N-C(=NH) or H2N-(C=NH)-NH, where the primary amino group can also be protected by the usual aminosidine groups or can be mono-, di - or tizamidine R10WITH-R10, COOR10or SO2R10or R6,

R7, R8each, independently from each other, is absent or represents H,

R7and R8together represent a bond,

X, Y each, independently of one another, represents =N-, -N-, O, S, -CH2- or =C-, provided that at least one of the two values of X, Y is =N-, -N-, O or S,

W, Z each, independently from each other, is absent or presented yet themselves About, S, NR1C(=O), CONH, NHCO, C(=S)NH, NHC(=S), C(=S), SO2NH, NHSO2or CA=CA',

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atoms N, O and/or S and can be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, cooa, CONH2, NO2, =NH or =O,

R9represents H, Hal, OA, NHA, NAA', NH, Oezil, CN, NO2, SA, SOA, SO2A, SO2Ar or SO3N

R10represents H, A, Ar or aralkyl, which has 7 to 14 carbon atoms,

R11represents H or alkyl which has 1 to 6 carbon atoms,

A, a' each, independently of one another, represent H or unsubstituted or mono-, di - or tri-R9-substituted alkyl or cycloalkyl, each of which has 1-15 carbon atoms, and in which one, two or three methylene groups may be replaced by atoms N, O and/or S,

Ar represents an unsubstituted or mono-, di -, or three-And - and/or R9-substituted mono - or bicyclic aromatic ring system which has 0, 1, 2, 3 or 4 atoms N, O and/or S,

Hal represents F, Cl, Br or I and

m, n each, independently of one another represents 0, 1, 2, 3,or 4

or their physiologically acceptable salts.

13. The application indicated in paragraph 12, in which the inhibitor αvβ3and/or αv² 5selected from the group comprising compounds of subformulas IIa-IIg, which otherwise correspond to formula II, but in which

in IIa) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5represents H2N-C(=NH) or H2N-C(=NH)-NH,

W, Z each, independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

R10represents H, or benzyl,

R11represents H,

But is an unsubstituted alkyl or cycloalkyl with 1-15 carbon atoms and

m, n each, independently of one another represents 0, 1 or 2;

in IIb) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5is an R6,

W, Z each, independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X before the hat is-NH-, Oh or-CH2-,

Y represents NH or O,

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atoms N, O and/or S and which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, COOA, CONH2, NO2, =NH or =O,

R10represents H, or benzyl,

R11represents H,

But is an unsubstituted alkyl or cycloalkyl with 1-15 carbon atoms and

m, n each, independently of one another represents 0, 1 or 2;

in IIc) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5represents H2N-C(=NH) or H2N-C(=NH)-NH,

W, Z each, independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

And represents alkyl with 1-6 carbon atoms,

R10represents H, alkyl with 1-6 carbon atoms, camphor-10-yl or benzyl,

R11represents H,

m, n each, independently of one another represents 0 or 2;

in IId) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5is an R6,

W, Z each, independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X is a =NH-, or-CH2-,

Y represents NH or O,

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atoms N, O and/or S, and which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, COOA, CONH2, NO2, =NH or =O,

R10represents H, alkyl with 1-6 carbon atoms, camphor-10-yl or benzyl,

R11represents H,

And represents unsubstituted alkyl with 1-6 carbon atoms, and

m, n each, independently of one another represents 0, 1 or 2,

in IIe) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5is an R6,

W, each independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

R6represents 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazole-2-yl, 2H-pyrazole-2-yl, 1H-tetrazol-5-yl, 2-imino-imidazolidin-4-one-5-yl, 1-A-1,5-dihydro-imidazol-4-one-2-yl, pyrimidine-2-yl or 1,4,5,6-tetrahydro-pyrimidine-2-yl,

R10represents H, alkyl with 1-6 carbon atoms, camphor-10-yl or benzyl,

R11represents H,

And represents unsubstituted alkyl with 1-6 carbon atoms, and

m, n each, independently of one another represents 0, 1 or 2;

in IIf) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5represents H2N-C(=NH) or H2N-C(=NH)-NH,

W, Z each, independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

R10represents Ar,

R11represents H,

But nezamedin the th alkyl or cycloalkyl with 1-15 carbon atoms and

m, n each, independently of one another represents 0, 1 or 2;

in IIg) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5is an R6,

W, Z each, independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X represents-NH-, or-CH2-,

Y represents NH or O,

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atoms N, O and/or S, and which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, COOA, CONH2, NO2, =NH or =O,

R10represents Ar,

R11represents H,

But is an unsubstituted alkyl or cycloalkyl with 1-15 carbon atoms and

m, n each, independently of one another represents 0, 1 or 2

in IIh) R1represents H or alkyl with 1-6 carbon atoms,

R2is an R10, CO-R10, COOR10or SO2R10,

R3represents H,

R4represents H or a =O,

R5depict is to place an H 2N-C(=NH), H2N-C(=NH)-NH, mono - or bicyclic a heterocycle, which has 1 to 4 atoms N, O and/or S, and which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-A, HE, CN, COOH, cooa, CONH2, NO2, =NH or =O,

W, Z each, independently from each other, is absent or represents C(=O), NH, CONH or NHCO,

X represents-CH2-,

Y represents NH or O,

R7, R8represents H,

R10represents A, Ar, aralkyl or Het,

R11represents H,

But is an unsubstituted alkyl or cycloalkyl with 1-15 carbon atoms and

m, n each, independently of one another represents 0, 1 or 2.

14. The application indicated in paragraph 12, in which the inhibitor αvβ3and/or αvβ5is a compound selected from the group including

(2S)-2-[(R)-camphor-10-sulfonamide]-3-{3,4-dihydro-2-(3-guanidinopropionic)-(2H-1,4-benzoxazin-3-one-6-yl}propionic acid;

(2S)-2-benzyloxycarbonylamino-3-(2-guanidinate-1,4-benzodioxan-6-yl)propionic acid;

(2S)-2-tert-butyloxycarbonyl-3-[3,4-dihydro-2-(2-guanidino-2-oxoethyl)-2H-1,4-benzoxazin-3-one-6-yl]propionic acid;

(2S)-2-benzyloxycarbonylamino-3-(2-guanidinoacetic-aminomethyl-1,4-benzodioxan-6-yl)propionic KIS the GTC;

(2S)-2-tert-butyloxycarbonyl-3-{3,4-dihydro-2-[N-(2-imidazolyl)-carbamoylmethyl]-2H-1,4-benzoxazin-3-one-6-yl)propionic acid;

(2S)-2-tert-butyloxycarbonyl-3-{3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-one-6-yl)propionic acid;

(2S)-2-tertbutyloxycarbonyl-3-{3,4-dihydro-2-[2-(2-imino-4-Oxymetazoline-5-yl)ethyl]-2H-1,4-benzoxazin-3-one-6-yl}propionic acid;

(2S)-2-(2,2-dimethylpolysiloxane)-3-{3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl]-(2S)-2H-1,4-benzoxazin-3-one-6-yl}propionic acid;

(2S)-2-[(R)-camphorsulfonic]-3-{3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-one-6-yl)propionic acid

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(butylsulfonyl)-propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(4-torpedoshaped)-propionic acid;

(2S)-3-{2-[3-(pyridine-2-ylamino)propyl]-chroman-6-yl}-2-(2,4,6-trimethylphenylsulfonyl)propionic acid;

(2S)-3-{2-[3-(pyridine-2-ylamino)propyl]-chroman-6-yl}-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(trebouxiophyceae)-propio the OIC acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(diphenylmethylene)-propionic acid;

and their physiological acceptable salt.

15. The application indicated in paragraph 12, in which the inhibitor αvβ3and/or αvβ5represents a

(2S)-2-(2,2-dimethylpolysiloxane)-3-{3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl]-(2S)-2H-1,4-benzoxazin-3-one-6-yl}propionic acid

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-chroman-6-yl}-2-(butylsulfonyl)-propionic acid;

or (2S)-2-[(R)-camphorsulfonic]-3-{3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-one-6-yl)propionic acid.

16. The application indicated in paragraph 12, in which the specified amount is from 0.5 mg to 5 mg

17. The application indicated in paragraph 12, in which the specified eye disease is a diabetic retinopathy.

18. The application indicated in paragraph 12, in which the disease of the eye is a macular degeneration.

19. The application indicated in paragraph 12, in which the disease of the eye is a myopia.

20. The application indicated in paragraph 12, in which the disease of the eye represents the histoplasmosis of the eye.

21. The use according to claim 1, in which the inhibitorα vβ3and/or αvβ5is a compound of formula III

in which R1represents CH2OR10, COOR10, CONHR10or CON(R12)2,

R2is an R10, CO-R10, CO-R6, COOR6, COOR10, SO2R6, SO2R10, CONHR6, CON(R6)2, CONHR10or CON(R12)2,

R3represents H, Hal, other10N(R12)2, NH-acyl, -O-acyl, CN, NO2, OR10, SR10, SO2R10, SO3R10, COOR10, CONHR6, CON(R6)2, CONHR10or CON(R12)12,

R4represents H, A, Ar or kalkeren, which has 7 to 14 carbon atoms,

R5represents NH2H2N-C(=NH) or H2N-(C=NH)-NH, where the primary amino group can also be protected by the usual aminosidine groups, or may be mono -, di - or tizamidine R10WITH-R10, COOR10or SO2R10or R6-NH-,

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atoms N, O and/or S, which may be nesnesinin or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, cooa, CONH2, NO2, =NH or =O,

R7, R8in ka is the case, independently from each other, is absent or represents H,

R7and R8together represent a bond,

Z is absent or represents O, S, NH, NR1C(=O), CONH, NHCO, C(=S)NH, NHC(=S), C(=S), SO2NH, NHSO2or SA=SA',

R9represents H, Hal, OR11, NH2, Other12N(R12)2, NH, Oezil, CN, NO2, SR11, SOR12, SO2R12or SO3H,

R10represents H, A, Ar or kalkeren, which has 7 to 14 carbon atoms,

R11represents H or alkyl with 1-6 carbon atoms,

R12represents alkyl which has 1 to 6 carbon atoms,

And represents H or alkyl which has 1 to 15 carbon atoms, or cycloalkyl, which has 3 to 15 carbon atoms, which is unsubstituted or mono-, di - or tizamidine R9and in which one, two or three methylene groups may be replaced by atoms N, O and/or S,

Ar represents a mono - or bicyclic aromatic ring system which has 0, 1, 2, 3 or 4 atoms N, O and/or S, which may be unsubstituted or mono-, di - or tizamidine a and/or R9,

Hal represents F, Cl, Br or I,

m, n in each case independently of one another, represent 0, 1, 2, 3,or 4

and their physio is logicheskie acceptable salt and solvate.

22. Use item 21, in which the inhibitor αvβ3and/or αvβ5selected from the group comprising compounds of subformulas IIIa-IIIn, which otherwise correspond to formula III but in which

in IIIa) R3represents H;

in IIIb) R3represents H and

R2represents COOR10or SO2R10;

in IIIc) R3represents H,

R2represents COOR10or SO2R10and

R10represents H, A, Ar or kalkeren, which has 7 to 14 carbon atoms;

in IIId) m is 0;

in IIIe) m represents 0 and

R3represents N;

in IIIf) R3represents H,

R2represents COOR10or SO2R10and

m represents 0;

in IIIg) R3represents H,

R2represents COOR10or SO3R10and

R10represents H, A, Ar or kalkeren with 7-14 carbon atoms, and

m represents 0;

in IIIh) R3represents H,

R2represents COOR10or SO2R10and

R10represents H, A, Ar or kalkeren, which has 7-14

carbon atoms, and

And represents H or unsubstituted alkyl which has 1 to 15 carbon atoms, or cycloalkyl, which has 3 to 15 carbon atoms,

Ar represents phenyl or naphthyl, and

m represents 0;

in IIIi) R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atom N, which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, COOA, CONH2, NO2,=NH or =O;

in IIIj) R3represents H,

R2represents COOR10or SO2R10and

R10represents H, A, Ar or kalkeren, which has 7 to 14 carbon atoms, and

m represents 0;

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atom N, which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, COOA, CONH2, NO2, =NH or =O;

in IIIk) Z is absent;

in IIIl) Z is absent and the

R3represents N;

in IIIm) Z is absent,

R3represents H and

R2represents COOR10or SO2R10;

in IIIn) Z is absent,

R3represents H,

R4represents H,

R2represents COOR10or SO2 10;

R10represents H, A, Ar or kalkeren, which has 7 to 14 carbon atoms,

R6represents a mono - or bicyclic a heterocycle, which has 1 to 4 atom N, which may be unsubstituted or mono-, di - or tizamidine Hal, A, -CO-AND, HE, CN, COOH, COOA, CONH2, NO2, =NH or =O,

And represents H or unsubstituted alkyl which has 1 to 6 carbon atoms,

Ar represents phenyl or naphthyl, and

m is 0.

23. Use item 21, in which the inhibitor αvβ3and/or αvβ5is a compound selected from the group including

(2S)-3-[2-(3-aminopropyl)-4-oxo-4H-chromen-6-yl]-2-(2,2-dimethylpropanamide)-propionic acid;

(2S)-3-[2-(3-guanidinopropionic)-4-oxo-4H-chromen-6-yl]-2-(2,2-dimethylpropanamide)-propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-exogamy-6-yl}-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(pyridine-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropanamide)propionic acid;

(2S)-3-{2-[3-(1H-benzimidazole-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-DIMETHYLPROPANE is carboxamido)propionic acid;

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-butylcyclopentadienyl acid

(2S)-3-{2-[3-(pyridine-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,4,6-trimetilfenil)alphameprodine acid

and their physiological acceptable salt and solvate.

24. Use item 21, in which the inhibitor αvβ3and/or αvβ5is a compound selected from the group including

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-butylcyclopentadienyl acid and

(2S)-3-{2-[3-(pyridine-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,4,6-trimetilfenil)alphameprodine acid

(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropanamide)propionic acid.

25. Use item 21, in which the specified amount is from 0.5 mg to 5 mg

26. Use item 21, in which the specified eye disease is a diabetic retinopathy.

27. Use item 21, in which the disease of the eye is a macular degeneration.

28. Use item 21, in which the eye disease is a myopia.

29. Use item 21, in which the disease of the eye represents the histoplasmosis of the eye.

30. The use according to claim 1, in cat the rum inhibitor α vβ3and/or αvβ5is a compound of formula IV

in which a and b each, independently of one another represents O, S, NH, NR7, CO, CONH, NHCO, or a direct link,

X represents alkylene that has 1-2 carbon atoms, which is unsubstituted or monogamist R4or R5or represents a direct bond,

R1represents N, Z or -(CH2)about-Ar,

R2represents H, R7or-C(O)Z,

R3represents other6, -NR6-C(=NR6)-Other6, -C(=NR6)-Other6, -NR6-C(=NR9)-Other6, -C(=NR9)-Other6or Het1,

R4or R5each, independently of one another, represent H, oxo, R7, -(CH2)about-Ar, -C(O)-(CH2)o-Ar, -C(O)-(CH2)o-R7, -C(O)-(CH2)o-Het, Het, other6, NHAr, NH-Het, OR7, OAr, OR6or O-Het.

R6represents H, -C(O)R7, -C(O)-Ar, R7, COOR7, COO-(CH2)o-Ar, SO2-Ar, SO2R7or SO2-Het,

R7represents alkyl which has 1 to 10 carbon atoms, or cycloalkyl, which has 1-10 carbon atoms,

R8represents Hal, NO2CN, Z, -(CH 2)about-Ar, COOR1, OR1, CF3, OCF3, SO2R1, Other1N(R1)2, NH-C(O)R1, NHCOOR1or C(O)R1,

R9represents CN or NO2,

Z represents alkyl which has 1 to 6 carbon atoms,

Ar represents aryl, which is unsubstituted or substituted R8,

Hal represents F, Cl, Br or I,

Het is a saturated, partially or fully saturated mono - or bicyclic heterocyclic aromatic system which has 5 to 10 atoms that can contain 1 or 2 N atom and/or 1 or 2 atoms S or O and where the heterocyclic ring system may be mono - or disubstituted R8,

Het1represents a mono - or bicyclic aromatic heterocyclic ring system which has from 1 to 4 atom N, which may be unsubstituted or mono or disubstituted by Hal, R7, OR7CN, NHZ or NO2,

n represents 0, 1 or 2

m represents 0, 1, 2, 3, 4, 5 or 6,

o represents 0, 1 or 2,

as well as their physiological acceptable salt and solvate.

31. The application of article 30, in which the inhibitor αvβ3and/or αvβ5selected from the group comprising compounds of subformulas IVa-IVi to the e otherwise correspond to the formula IV, but

in IVa X represents a direct bond

in IVb X represents a direct bond,

R2represents H,

R5represents H and

R4represents Ar

in IVc X represents a direct bond,

R5represents N and R4represents an Ar or Het;

in IVd X represents a direct bond,

R5represents H,

In represents Oh,

And represents NH,

n represents Oh,

m represents 3 or 4,

R3represents Het and

R4represents Ar

IVe X represents a direct bond,

R5represents H,

In represents Oh,

And represents NH,

n represents Oh,

m represents 3 or 4 and

R3represents Het

in IVf, X represents a methylene which is unsubstituted or substituted by Ar,

R2represents H,

R5represents H or Ar, and

R4represents oxo

in IVg X represents methylene;

in IVh X represents methylene,

R4represents H or Ar,

R5represents H or Ar, and

R2represents N;

IVi X represents methylene,

R4represents H or Ar,

R5represents H or Ar,

In represents Oh,

And represents NH,

n represents Oh,

m represents 3 or 4

R3represents Het and

R2represents N

32. The application of article 30, in which the inhibitor αvβ3and/or αvβ5is a compound selected from the group including

3-phenyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]-1H-indol-3-yl}-propionic acid;

3-phenyl-3-{6-[4-(pyridine-2-ylamino)-butoxy]-1H-indol-3-yl}-propionic acid;

3-phenyl-3-{5-[4-(pyridine-2-ylamino)-butoxy]-1H-indol-3-yl}-propionic acid;

3-phenyl-3-{5-[3-(pyridine-2-ylamino)-propoxy]-1H-indol-3-yl}-propionic acid;

3-phenyl-3-[6-(pyridin-2-yl-aminocarboxylate)-indol-3-yl]-propionic acid;

3-phenyl-3-[6-(benzimidazole-2-yl-aminocarboxylate)-indol--yl]-propionic acid;

3-phenyl-3-[6-(imidazol-2-yl-aminocarboxylate)-indol-3-yl]-propionic acid, or

3-Benzo[1,2,5]thiadiazole-5-yl-3-{6-[2-(6-methylamino-pyridine-2-yl)-ethoxy]-1H-indol-3-yl}-propionic acid

as well as their physiological acceptable salt and solvate.

33. The application of article 30, in which the inhibitor αvβ3and/or αvβ5represents a

3-phenyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]-1H-indol-3-yl}-propionic acid, or

3-Benzo[1,2,5]thiadiazole-5-yl-3-{6-[2-(6-methylamino-pyridine-2-yl)-ethoxy]-1H-indol-3-yl}-propionic acid.

34. The application of article 30, in which the specified amount is from 0.5 mg to 5 mg

35. The application of article 30, in which the specified eye disease is a diabetic retinopathy.

36. The application of article 30, in which the disease of the eye is a macular degeneration.

37. The application of article 30, in which the eye disease is a myopia.

38. The application of article 30, in which the disease of the eye represents the histoplasmosis of the eye.

39. The use of a composition comprising nanoparticles containing inhibitors αvβ3and/or αvβ5to obtain medicines for the treatment of eye diseases in a patient, resulting again in the development of eye blood vessels, by injection into the vitreous body.

40. The application of § 39, characterized in that the nanoparticles contain a biocompatible polymer.

41. The application of § 39, characterized in that the nanoparticles contain a biodegradable polymer.

42. The application of paragraph 41, wherein the polymer is a poly(lactic acid) (PLA), poly(glycolic acid) (PGA), polycaprolactone (PCL), a copolymer of lactic acid and glycolic acid (PLGC), a copolymer of lactic acid and caprolactone, polietilen caprolacton, Polyoxymethylene acid, poly(ortho)esters, polyurethanes, polyanhydrides, Polyacetals, politicization or polycyanoacrylate.

43. The application of § 39, wherein the composition includes a liquid medium in which the dispersed nanoparticles, forming a colloidal suspension.

44. The application of § 39, characterized in that the nanoparticles have a diameter from about 10 nm to about 500 nm.

45. The application of § 39, characterized in that the nanoparticles have a diameter from about 100 nm to about 200 nm.

46. The application of § 39, characterized in that the nanoparticles obtained by the displacement of solvent.



 

Same patents:

FIELD: medicine, ophthalmology.

SUBSTANCE: it is necessary to introduce parabulbarly per about 0.3-0.5 ml perfluoran once daily for 10 d. Moreover, one should prescribe intravenous laser blood irradiation that enables to shorten terms of therapy, exclude side effects and maximally decrease the number of relapses.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: since the 1st d of prescribing corticosteroids onto the skin of the upper and the lower eyelid it is necessary to apply "gel Relict 0.5" twice daily without rubbing it in. The gel mentioned should be applied and spread steadily with a layer of about 2-3 mm thickness, not les; the duration of therapy for every patients corresponds to the duration of the conducted corticosteroid therapy. The innovation provides prophylactics of local immunosuppression.

EFFECT: higher efficiency.

3 ex, 1 tbl

FIELD: medicine, ophthalmology.

SUBSTANCE: invention proposes a solution used in treatment of cornea injuries that comprises sulfated glycosaminoglycans, cellulose water-soluble derivatives and a saline solution wherein chondroitin sulfate is used as sulfated glycosaminoglycans, hydroxyethylcellulose is used as cellulose water-soluble derivatives, and balanced saline solution is used as a saline solution wherein these components are taken in the definite ratio, g/100.0 ml. Invention provides improving rheological and viscous properties of the solution that allows obtaining anti-inflammatory and anti-edematous effect of the preparation and to accelerate the cornea tissue reparation processes.

EFFECT: improved and valuable medicinal properties of solution.

1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: method involves intravenously dripping Cytoflavin at a dose of 0.5 ml per 1 year of life. Cytoflavin is introduced during the first 2-3 days from transcutaneous electrostimulation onset in equalizing parabiosis phase and during the first 4-5 days in paradoxical phase and during the first 6-8 days in inhibitory phase. Current intensity of 15-200 mcA of frequency not exceeding 30 Hz is applied in performing the electrostimulation. An electrode is first set over nasal upper eyelid point and then, 30 s later, on temporal upper eyelid point. The total transcutaneous electrostimulation treatment course is 10 days long, giving four treatment series on the eyes every day.

EFFECT: improved vision function recovery; increased optic nerve conductivity.

1 tbl

FIELD: medicine.

SUBSTANCE: method involves introducing 1 ml of combined 2% hydrogel Chytosane ascorbate solution of 94-98% deacetylation degree as single dose into Tennon space to posterior eye pole. Molecular mass is equal to 100-700 kDa. 1 l of the solution contains 200 mg of hyaluronic acid, 2 g of chondroitin sulfuric acid, 110-440 mcg of cattle serum growth factor and 50 mg of heparin.

EFFECT: enhanced effectiveness of treatment; substituting hydrogel with proper connective tissue reach in newly formed blood vessels.

1 tbl

FIELD: medicine, ophthalmology.

SUBSTANCE: one should apply biopolymer into Tenon's space towards posterior ocular pole followed by conventional antiphlogistic therapy, moreover, as biopolymer one should once introduce a sponge at area up to 2 sq. cm consisted of chitosan ascorbate at deacetylation degree being 98%, molecular weight of 1000 kDa that contains in 1 sq. mm: 28×10-9 g hyaluronic acid, 27.8×10-8 g chondroitin-sulfuric acid, 3.06×10-8 g cattle serumal growth factor, 7×10-9 g heparin, 25×10-6 g collagen. The innovation enables to increase and stabilize ocular visual functions due to improved tissue trophics of posterior ocular segment.

EFFECT: higher efficiency of therapy.

1 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: method involves applying corticosteroid preparation instillations into conjunctival cavity. Cyclosporin is per os introduced in addition at a daily dose of 2.0-2.5 mg/kg twice a day.

EFFECT: enhanced effectiveness interrupting inflammatory eye tissue changes cascade in early postoperative period.

2 cl

FIELD: medicine.

SUBSTANCE: method involves administering Panavir preparation slowly introduced in jet mode at a dose of 5 ml every other day in a three injections long treatment course.

EFFECT: enhanced effectiveness of treatment.

FIELD: medicine.

SUBSTANCE: method involves administering palm-oil CAROTINO phonophoresis in eye-baths mode. The phonophoresis is applied to eye region in continuous generation mode at frequency of 880 Hz, insonation intensity of 0.2-0.4 W/cm2 daily or every other day during 5 min. The total treatment course is 10-15 procedures long.

EFFECT: enhanced effectiveness of epithelialization and inflammatory infiltrate absorption; prevented degenerative processes occurrence in cornea.

1 tbl

FIELD: medicine.

SUBSTANCE: method involves carrying out lensectomy. Retrobulbar catheterization is next applied using irrigation system to introduce Dexazon, Riboflavin, Dicinon, Actipol, Emoxipin at a dose of 0.4 ml during 10 days. The preparations are introduced fractionally in arbitrary sequence with 2 h long pauses. Laserpleoptic treatment with SPECLE apparatus operating at wavelength of 0.63 mcm and sequential magnetic treatment of four zones on head, that is, frontal, temporal, parietal auriculo-temporal and occipital ones. Optic nerve light stimulation is concurrently carried out using Medopotica MS-11 apparatus operating at pulsation frequency growing from 20 to 50 Hz in narrow spectral zone of 660 nm and magnetic field intensity of 300 mTesla units during 5 min one session per day during 10 days. Ginkgo biloba preparations and MILGAMMA in capsules are administered in age-specific doses as outpatient procedure during 1 month, after having finished stationary treatment course.

EFFECT: improved vision functions; improved connective tissue trophism.

FIELD: medicine, pharmaceuticals.

SUBSTANCE: disclosed is application of dipeptidyl peptidase inhibitors (DPIV-inhibitors) particularly isoleucyl-tiazolidine as active ingredient of pharmaceutical hypotensive composition for mammalian suffering from diabetes. Disclosed is stabilizing of systolic blood pressure in diabetic fats and lowering levels thereof from 170 mmHg (control animals without isoleucyl-tiazolidine) to 150 mmHg.

EFFECT: new dipeptidyl peptidase inhibitors useful in pharmaceutical hypotensive composition.

9 cl, 9 dwg, 11 tbl, 20 ex

FIELD: biotechnology, medicine, oncology.

SUBSTANCE: invention proposes peptide of the structure Tyr-Ser-Leu and a pharmaceutical composition based on thereof that is used for stimulating antitumor immune response. Also, invention proposes methods for treatment of mammal and for modulation of the immune response. Proposed inventions expand assortment of agents used in treatment of cancer diseases.

EFFECT: valuable medicinal properties of peptide and pharmaceutical composition.

20 cl, 48 tbl

FIELD: chemistry of peptides, medicine, pharmacology.

SUBSTANCE: invention relates to using the combination of bioactive regions SYSMEHFRWGKPV and YGGFM in pro-opiomelanocortine in manufacturing a medicine used in treatment of inflammatory, degenerative and autoimmune diseases, traumas, infections and burns. Also, invention relates to using polypeptide chosen from group: YGGFMSYSMEHFRWGKPVYGGEM, YGGFMSYSMEHFRWGKPV, SYSMEHFRWGKPVYGGFM and compositions eliciting cytoprotective properties. Invention provides enhancing in peptides effect.

EFFECT: valuable medicinal properties of peptides.

9 cl, 1 tbl, 1 dwg

FIELD: medicine, gynecology.

SUBSTANCE: before operation it is necessary to sample patient's blood to divide it into plasma and blood cells. Blood plasma should be divided into three parts and frozen. After operation one should intravenously reinfuse by drops erythrocytic mass incubated for 30 min at 37° C with 2 g lendacyn followed by further lendacyn injection per 1g intramuscularly during the next 6 d. Blood plasma should be portionally defrosted, incubated at 37° C with: 10000 U trasilol, 0.15 g lisozyme, 0.02 g novocain, after incubation it is necessary to add 100 ml gelatinol to be reinfused for a patient on the 2nd, 4th and 6th d against the onset of therapy course through microirrigator withdrawn out of posterior arch during operation. The innovation provides combined impact of antibiotics upon pathological focus biotransformed with erythrocytic mass and local immunomodulating and resolving effect and, thus, decreased formation of adhesions, fistulas and cicatrices.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: virology.

SUBSTANCE: invention proposes different compositions able to induce production of antibodies against Tat HIV-1 that can inhibit multiplication of HIV-1. Also, invention proposes a method for induction of antibodies raised against Tat HIV-1, in vitro method for assay of the presence of antibodies and their titer values, a method for reducing HIV-1 virus levels, sequence of synthetic nucleic acid and synthetic molecule. Proposed group of inventions can be used for inhibition of multiplication of HIV-1 in infected patients and for attenuation of HIV-1 multiplication after the primary infection in early infected persons.

EFFECT: valuable methods and compositions.

39 cl, 7 dwg, 9 tbl, 5 ex

Caspase inhibitors // 2274642

FIELD: medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds that represent inhibitors of caspases, in particular, inhibitors of interleukin-1β-converting enzyme and their pharmaceutical compositions. Proposed compounds can be used successfully as agents directed against diseases mediated by interleukin-1, apoptosis and factor inducing interferon-γ or by interferon-γ.

EFFECT: valuable medicinal and biochemical inhibitors.

35 cl

FIELD: medicine.

SUBSTANCE: method involves applying peptide containing amino acid sequence of Thr-R1-Lue-Ile-Asp-Asn-Asn-Ala-Thr-Glu-Glu-Ile-Leu-Tyr, where R1 is the D-alanine (SEQ ID N:2) for treating patients for neurodegenerative disorder or myelinogenesis disorder by introducing effective dose of this peptide. Given disorders for which the medicament has proved to be useful are polyneuropathy, mononeuropathy, neuroma, nerve compression, nerve injury, contusion, tumor or incomplete spinal cord transection, infarction or injury of brain stem cells, thalamus or cerebral cortex, compression, rupture or inflammation of dorsal ganglia roots, postpoliosyndrome, traumatic or ischemic injury of central or peripheral nervous system, disseminated sclerosis.

EFFECT: enhanced effectiveness of treatment.

6 cl, 3 dwg, 6 tbl

FIELD: biotechnology, medicine, oncology, peptides.

SUBSTANCE: invention relates to a method based on phage display for preparing peptides interacting specifically with mammary Ehrlich tumor and can be used in therapy and diagnosis of malignant neoplasm. Peptides are prepared by affinity selection from phage peptide libraries comprising ten millions of different peptides of size 15 amino acid residues, the group of nine peptides wherein each peptide shows ability for accumulation in Ehrlich tumor. For practice using mimetic-peptides selected by such manner can be prepared by chemical synthesis and to use for preparing conjugates on their basis with the known cytotoxic preparations, radioactive isotopes and they can be incorporated in the composition of liposomal preparations for visualization of tumor neoplasm also.

EFFECT: valuable medicinal properties of peptides.

2 dwg, 2 ex

The invention relates to medicine, surgery and anesthesia, and can be used for endolymphatic treatment

The invention relates to medicine, in particular to a gastroenterologist

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (IA) or (IB) given in the invention description wherein R1 means hydrogen atom, (C1-C7)-alkyl, -(CH2)n-OH, -(CH2)n-N(R6)2; R2 means (C1-C7)-alkyl, -(CH2)n-N(R6)2, -NR6C(O)C(O)O-(C1-C7)-alkyl, -NR6-(CH2)n-OH, -NR6C(O)-(C1-C7)-alkyl, -NH-benzyl; R3 means hydrogen atom or amine; or R2 and R3 in common with carbon atoms to which they are bound mean the group -N(R6)-CH2-O-CH2-; R4 means hydrogen atom or (C1-C7)-alkyl; R5 means hydrogen atom; R6 means independently of one another hydrogen atom or (C1-C7)-alkyl; R' means hydrogen atom or (C1-C7)-alkyl; n = 0, 1, 2 or 3. Also, invention relates to a medicinal agent possessing the selective blocking activity with respect of subspecies of NMDA-receptors and containing one or more compounds of the formula (IA) or (IB) or their pharmaceutically acceptable acid-additive salt or inert carrier. Invention provides preparing novel compounds possessing the high affinity to NMDA-receptors that can be used as components of a medicinal agent for treatment of diseases mediated by these receptors.

EFFECT: valuable medicinal properties of compounds and drug.

13 cl, 35 ex

Up!