DE19724793A1 - New peptides inhibit vascular endothelial cell growth factor - Google Patents

Abstract

Peptides of formula (I) in which at least one amino acid is a D-amino acid are new. R1-(X)n-(Y)m-(Lys)p-(Y)m-(X)n-(R2)r (I) R1, R2 = peptides with the sequence R3-Z; R3 = peptide with the sequence Q; X, Y = any L- or D-amino acids; Z = sequence of up to 12 amino acids; Q = sequence of 3-10 amino acids; and n, m, p and r = 0 or 1.

Description

The invention relates to D-mutant peptides with VEGF blocking properties and their use in the manufacture of medicaments for the treatment of various diseases.

Persistent angiogenesis can cause various diseases such as Psoriasis, rheumatoid arthritis, hemangioma, angiofibroma, diabetic retinopathy and neovascular glaucoma, or to make it worse Lead diseases.

An inhibitor with VEGF receptor blocker properties can be used for treatment such diseases and other VEGF-induced pathological angiogenesis and vascular permeable conditions such as tumor vascularization will.

VEGF is a growth factor protein with a size of 42000 daltons that in almost all cells are produced under hypoxic conditions. Receptors for this Factors are VEGFRI and VEGFRII, both on endothelial cells in wound healing, in tumors and during cell proliferation of the menstrual cycle in ovaries and be found in the uterus. You cannot by immunohistochemical techniques be found on resting endothelial cells. The factor induces the Endothelial cell proliferation and migration.

Growing tumors need a constantly expanding vascular network, which it allows newly formed tumor cells to be supplied with sufficient food. It were experiments with VEGF-blocking antibodies on tumor nude mice carried out. The result was a suppression of tumor growth.

It is known that by soluble receptors and antibodies against VEGF that Growth of tumors can be inhibited.

In WO 94/21679 vascular endothelial cell growth factor (VEGF) are Inhibitors described that are of natural origin or recombinantly produced represent soluble forms. It is also described that the soluble forms of the receptor to the growth factor with high affinity and not to Lead signal transduction. Such soluble forms of the receptor bind VEGF and inhibit its function.

A disadvantage of the known inhibitors is that they consist of high molecular weight peptides exist, their isolation or manufacture, characterization and cleaning with a lot of work is involved. Such high molecular weight can also be used Compounds usually do not formulate drugs without problems and then apply as a medication.

Furthermore, the shelf life of such preparations is lower than that of low-molecular ones Peptides.  

There have now been D-mutated peptides of the general formula I

R ¹ - (X) _n - (Y) _m - (Lys) p- (Y) m- (X) _n - (R ² ) _r (I),

in the
R ¹ and R ^{2 are} a peptide of the sequence R ³ -Z,
R ^{3 is} a peptide of the sequence Q,
X and Y independently of one another any L or D amino acid,
Z can represent a peptide sequence with up to 12 amino acids which are the same or different and can be contained one or more times,
Q for a peptide sequence with 3-10 amino acids, which may be contained one or more times, the same or different, wherein the complete peptide sequence contains at least one D-amino acid and
n, m, p and r are independently 0 or 1, found, which have better properties than the known compounds.

Preferred peptides of the general formula I are those in which
R ¹ and R ^{2 are} a peptide of the sequence R ³ -Z,
R ^{3 is} a peptide of the sequence Q,
X and Y independently of one another any L or D amino acid,
Z can stand for a peptide sequence with up to 12 amino acids which are the same or different and can be contained one or more times and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are,
Q for a peptide sequence with 3-10 amino acids, which are the same or different and can be contained one or more times and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr , Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are where at least one D-amino acid is contained in the complete peptide sequence and
n, m, p and r are independently 0 or 1.

Preferred peptides of the general formula I are also those in which
R ¹ and R ^{2 are} a peptide of the sequence R ³ -Z,
R ^{3 is} a peptide of the sequence Q,
X and Y independently of one another for Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit, each have the L or D shape,
Z can stand for a peptide sequence with up to 12 amino acids, which are the same or different and can be contained one or more times and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys , Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are,
Q for a peptide sequence with 3-10 amino acids, which are the same or different and can be contained one or more times and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr , Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are wherein the complete peptide sequence contains at least one D-amino acid and
n, m, p and r are independently 0 or 1.

Those peptides of the general formula I in which
R ¹ and R ^{2 are} a peptide of the sequence R ³ -Z,
R ^{3 is} a peptide of the sequence Q,
X for Ala,
Y for Ser,
Z can stand for a peptide sequence with up to 12 amino acids, which are the same or different and can be contained one or more times and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys , Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are,
Q for a peptide sequence with 3-10 amino acids, which are the same or different and can be contained one or more times and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr , Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are wherein the complete peptide sequence contains at least one D-amino acid and
n, m, p and r are independently 0 or 1.

Those peptides of the general formula I in which
R ¹ and R ^{2 are} a peptide of the sequence R ³ -Z,
R ^{3 is} a peptide of the sequence Q,
X for Ala,
Y for Ser,
Z can stand for a peptide sequence with up to 8 amino acids, which are identical or different and can be contained one or more times and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys , Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are,
Q for a peptide sequence with 5-7 amino acids, which are the same or different and can be contained one or more times, and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr , Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are wherein the complete peptide sequence contains at least one D-amino acid and
n, m, p and r are independently 0 or 1.

Those peptides of the general formula I in which
R ¹ and R ² a peptide of the sequence R ³ -Ile-Asp-Phe-Asn-Trp-Glu-Tyr-Pro, R ³ -Ser-Asp-Phe-Asn-Trp-Glu-Tyr-Pro, R ³ -Ser-Asp-Phe-Asn-Trp-Glu-Thr-Pro, R ³ -Ser-Asp- Phe-Asn-Trp-Asp-Thr-Pro, R ³ -Ser-Asp-Phe-Gln- Trp-Asp-Thr-pro-, R ³ -Phe-Asn-Trp-Glu-Tyr-pro-, R ³ -Phe-Asn-Trp-Glu-Tyr-Asp, R ³ - Phe-Asp-Trp Glu-Tyr-Asp-, R ³ -Phe-Asp-Phe-Glu-Tyr-Asp-, R ³ -Tyr- Asp-Tyr-Asp-Tyr-Asp-, R ³ -Tyr-Asp-Tyr-Asp- Tyr-, R ³ -Tyr-Asp-Tyr- Asp-, R ³ -Tyr-Asp-Tyr-, R ³ -Tyr-Asp-, R ³ -Tyr-, R ³ -Trp-Asp-Trp-Asp- Trp-Asp-, R ³ -Phe-Asp-Phe-Asp-Phe-Asp- or R ³ -Tyr-Glu-Tyr-Glu- Tyr-Glu- and
R ^{3 is} a peptide of the sequence Glu-Leu-Asn-Val-Gly-Phe-Asp-, Asn-Leu-Asp-Val-Gly-Phe-Asp-, Asn-Leu-Asp-Ile-Gly-Phe-Asp- , Asp- Tyr-Asp-Tyr-Asp-Tyr-Asp-, Asp-Trp-Asp-Trp-Asp-Trp-Asp-, Asp- Phe-Asp-Phe-Asp-Phe-Asp-, Glu-Tyr- Glu-Tyr-Glu-Tyr-Glu- or Glu-Phe-Ala-Tyr-Leu- is and
X Ala,
Y Ser is
wherein at least one D-amino acid is contained in the complete peptide sequence and
n, m, p and r are independently 0 or 1.

The particularly preferred peptides include peptides of the general formula I with the sequence

meant.

The peptides according to the invention come as active pharmaceutical ingredients Application and can be used alone or in the form of a pharmaceutical Composition containing one or more compounds of general formula I contains, together with pharmaceutically suitable solutions, carriers and Additives are applied.

The peptides according to the invention can be used alone, as a mixture or as Composition together with pharmaceutically suitable solutions, carriers and Additives applied enterally, parenterally, intravenously, subcutaneously, orally or transdermally will.

The peptides according to the invention and their compositions and mixtures can be used to manufacture a drug for the treatment of diseases such as Psoriasis, Kaposi's sarcoma, blood vessel growth in joints and bones Rheumatoid Arthritis, Hemangioma, Angiofribroma, Diabetic Retinopathy and Neovascular glaucoma and other VEGF-induced pathological angiogenesis, VEGF-related vascular permeabilization, edema, stroke, and vascular permeable conditions such as tumor vascularization can be used.  

In particular, the compounds according to the invention can be used to prepare a Medicinal product used to inhibit the growth of tumors and metastases will.

The compounds according to the invention, their compositions and mixtures, can also be used to manufacture a medicinal product for the treatment of gynecological Diseases with an angiogenic background such as endometriosis, adenomyosis, Dysfunctional uterine bleeding, choriocarcinoma, ectopic pregnancy and Diseases of the ovary can be used.

The peptides according to the invention can also be used in combination with locally applicable Vascular growth stimulators such as VEGF, FGF are used.

The active pharmaceutical ingredients in their composition or mixtures and their uses are also the subject of the present invention.

Suitable compositions can be prepared by methods known per se are, all for a formulation of the compounds of general formula I in solutions, carriers and additives that can be used in pharmacy are used can (Remington's Pharmaceutical Science, 15th Ed. Mack Publishing Company, East Pennsylvania, 1980).

Different doses of the invention come for therapeutic use Peptides in question. So the dose that can be applied depends on the compound in question Individual, the type of application (enteral, parenteral, intravenous, subcutaneous, oral, transdermal) and the severity of the disease to be treated.  

Description of the abbreviations

Ala = alanine
Val = valine
Leu = leucine
Ile = isoleucine
Pro = proline
Phe = phenylalanine
Trp = tryptophan
Met = methionine
Gly = glycine
Ser = serine
Thr = threonine
Cys = cysteine
Tyr = tyrosine
Asn = asparagine
Gln = glutamine
Asp = aspartic acid
Glu = glutamic acid
Lys = lysine
Arg = arginine
His = histidine
Orn = ornithine
Cit = citrulline.

The following examples explain the preliminary investigations and the production of the Peptides according to the invention without restricting them to the examples.

example 1 Synthesis of peptide libraries

Cellulose-bound and cleavable peptide sets were automatically compared Standard point synthesis protocols (PepSpots, Jerini Bio Tools GmbH, Berlin, Germany) using a point synthesizer (Abimed GmbH Langenfeld, Germany). Cleavable peptides were identified as amides by the Cellulose carriers removed using ammonia vapor (Bray et al.). Then filter disks with adsorbed peptides were removed from the microplates punched out. After desorption from the cellulose matrix, using Buffer, the peptide solution was used directly for the test system. To the generation The sequence fragments used a software that is customary for this.

Example 6 Synthesis of the peptides

The peptides according to the invention were in mg amounts in one Multiple peptide synthesizer according to the standard Fmoc machine protocol (Abimed GmbH, Langenfeld, Germany), using TentaGel S RAM resin (50 mmol / g; Rapp Polymer, Tübingen, Germany) and PyBOP activation. All peptides were HPLC on a reversed C18 column using a 5% to 60% acetonitrile / water gradient (0.05% TFA) over a period of Analyzed for 20 minutes at a flow rate of 1.2 ml / min (detection at 214 nm wavelength) and by means of laser desorption in a time-of-flight mass spectrometer meter using α-cyano-4-hydroxy-cinnamic acid as a matrix.

The following peptides were produced in an analogous procedure:

The following application examples show the application of the Peptides according to the invention without restricting them to the examples.

Application example 1 Human umbilical vein endothelial cell cultures

Human umbilical cords are cannulated with a conical device and washed with sterile PBS buffer containing calcium, magnesium and penicillin / streptomycin to remove blood cells. The veins are then filled with PBS buffer containing chymotrypsin (0.1%) and incubated at room temperature for 25 minutes. After a gentle manual massage of the umbilical cords, the cell suspension is placed in a vessel that contains 2 ml of fetal calf serum. After dilution with buffer, the cells are collected by centrifugation, washed once with buffer and seeded in two 25 cm ² culture bottles per umbilical cord. The bottles are coated with 10 µg / ml collagen, possibly with 1 µg / ml fibronectin. The culture media contain M 199, 10% fetal calf serum (FCS), 10% human serum (HS), glutamine or Glutamax (2 mM), penicillin (50 U / ml), streptomycin (100 U / ml), ascorbic acid (0.00127 mM), pyruvic acid (1 mM) and 1% non-essential amino acids, 10 µg / ml endothelial cell growth factor from bovine brain and 7.5 µg / ml heparin. 3 hours after plating, the adherent cells are washed twice with PBS buffer containing magnesium and calcium ions. The cells are then cultivated under standard conditions in the medium described above. The cells are then subjected to trypsin digestion (0.02% trypsin, 0.01% EDTA in phosphate-buffered saline without divalent ions), sown in microtiter plates with a density of 1.6 × 104 cells / well and then cultured for 3 to 7 days.

Example of use 2 Receptor binding assay (HUVEC binding)

300,000 HUVEC were sown in each well of a 48 well plate. The cells were then cultured in a complete medium for two days then washed with phosphate buffered saline, the calcium and Contains magnesium chloride. Then 100 .mu.l medium M 199 were without at 4 ° C. Additives but with 0.1% bovine serum albumin added. Then were 10 μl each of a solution of the peptides according to the invention were added. The whole  was dissolved in DMSO and then diluted. Then 40 ul 125l-VEGF added. After 2 hours of incubation at 4 ° C, the medium was suctioned off and washed 3 times with 500 ul PBS. The cells were then treated with 100 µl 0.5% Sodium dodecyl sulfate solution lysed with constant shaking. The solution was placed in a counter tube for measuring the y radiation. The result results from the concentration that reduces the specific binding by 50%.

The effect of the D-mutants according to the invention is shown in Table I below Peptides shown as VEGF blockers.

Example of use 3 Solid phase binding assay

Peptide libraries that are covalently bound to cellulose filter paper have been published in TRIS-Cl buffered saline containing 0.05% Tween 20 (TBS / Tween) incubated. After two washes with buffer, the paper was incubated for 60 minutes stopped at 4 ° C in TBS / Tween containing 5% milk powder. This solution became 125l VEGF added up to a concentration of 0.1 mCi / ml. The incubation was continued for five minutes before the cellulose libraries in three baths, containing TBS / Tween. The cellulose sheets were left overnight placed on an autoradiography film and left to act. Then the Film developed. Binding peptides are detected as strong black dots.

Example of use 4 Receptor autophosphorylation

100,000 HUVEC were clad in 12 corrugated sheets. After 48 hours, the cells put on ice and fresh medium was added with the solvent control, VEGF or VEGF plus peptides in ice-cold medium M199, with 0.1% BSA. The Incubation was continued for 1 hour. The medium was then removed and ice-cold RIPA buffer (50 mM HEPES pH 7.2.10 mM EDTA; 0.1% SDS; 1% NP- 40; 0.5% deoxycholate; 50 mM Na pyrophosphate; 100 mM NaF; 2mM ortho vanadate; 1 mM zinc acetate; 1.25 mM PMSF; 10 µg / ml aprotinin) added. The DNA was removed via Millipore filtration (0.65 mM). 50 µl wheat germ agglutinin Sepharose was then added to the filtrate and the mixture was added under incubated for 1 hour at 4 ° C. The Sepharose was centrifuged separated, the supernatant was discarded and 25 µl of a doubly concentrated SDS Electrophoresis buffers according to Laemmli were added and boiled for 5 minutes. Proteins were separated on a 6% SDS gel according to their size. The Proteins were applied to a PVDF membrane by semi-dry electroblotting transfer. The membrane was coated with 0.25% Tween in PBS, the Magnesium and Contains calcium chloride, canceled. After three 15 minute washes with 0.05% Horseradish-coupled antiphosphotyrosine were tweened in the same buffer monoclonal antibodies in a concentration of 1: 1000, that of a concentration of 250 ng / ml (again in a buffer containing 0.05% Tween), added. After every three 1 5-minute washes, the blot with one Amplifier chemiluminescence system developed.

The results of the study are shown in Table II below.  

Inhibition of VEGFR II receptor autophosphorylation

Claims (16)

1. D-mutated peptides of the general formula I
R ¹ - (X) _n - (Y) _m - (Lys) _p - (Y) _m - (X) _n - (R ² ) _r (I),
in the
R ¹ and R ^{2 are} a peptide of the sequence R ³ -Z,
R ^{3 is} a peptide of the sequence Q,
X and Y independently of one another any L or D amino acid,
Z can stand for a peptide sequence with up to 12 amino acids, which are the same or different and can be contained one or more times,
Q for a peptide sequence with 3-10 amino acids, which may be contained one or more times, the same or different, the complete peptide sequence containing at least one D-amino acid and
n, m, p and r are independently 0 or 1. 2. peptides of the general formula I, according to claim 1, in the
R ¹ and R ^{2 are} a peptide of the sequence R ³ -Z,
R ^{3 is} a peptide of the sequence Q,
X and Y independently of one another any L or D amino acid,
Z for a peptide sequence with up to 12 amino acids, which are the same or different and can be contained one or more times, and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr , Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are,
Q for a peptide sequence with 3-10 amino acids, which are the same or different and can be contained one or more times and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr , Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are,
wherein at least one D-amino acid is contained in the complete peptide sequence and
n, m, p and r are independently 0 or 1. 3. peptides of the general formula I, according to claims 1 and 2, in the
R ¹ and R ^{2 are} a peptide of the sequence R ³ -Z,
R ^{3 is} a peptide of the sequence Q,
X and Y independently of one another for Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit, are each in the L or D shape,
Z can stand for a peptide sequence with up to 12 amino acids, which are the same or different and can be contained one or more times and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys , Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are,
Q for a peptide sequence with 3-10 amino acids, which are the same or different and can be contained one or more times and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr , Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are,
wherein at least one D-amino acid is contained in the complete peptide sequence and
n, m, p and r are independently 0 or 1. 4. peptides of the general formula I, according to claims 1-3, in the
R ¹ and R ^{2 are} a peptide of the sequence R ³ -Z,
R ^{3 is} a peptide of the sequence Q,
X for Ala,
Y for Ser,
Z can stand for a peptide sequence with up to 12 amino acids, which are the same or different and can be contained one or more times and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys , Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are,
Q for a peptide sequence with 3-10 amino acids, which are the same or different and can be contained one or more times and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr , Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are,
wherein at least one D-amino acid is contained in the complete peptide sequence and
n, m, p and r are independently 0 or 1. 5. Peptides of the general formula I, according to claims 1-4, in the
R ¹ and R ^{2 are} a peptide of the sequence R ³ -Z,
R ^{3 is} a peptide of the sequence Q,
X for Ala,
Y for Ser,
Z can stand for a peptide sequence with up to 8 amino acids, which are identical or different and can be contained one or more times and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys , Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are,
Q for a peptide sequence with 5-7 amino acids, which are the same or different and can be contained one or more times, and Ala, Val, Leu, Ile, Pro, Phe, Trp, Met, Gly, Ser, Thr, Cys, Tyr , Asn, Gln, Asp, Glu, Lys, Arg, His, Orn and Cit are,
wherein at least one D-amino acid is contained in the complete peptide sequence and
n, m, p and r are independently 0 or 1. 6. peptides of the general formula I, according to claims 1-5, in the
R ¹ and R ^{2 are} a peptide of the sequence
R ³ -Ile-Asp-Phe-Asn-Trp-Glu-Tyr-Pro, R ³ -Ser-Asp-Phe- Asn-Trp-Glu-Tyr-Pro R ³ -Ser-Asp-Phe-Asn- Trp-Glu-Thr- Pro, R ³ -Ser-Asp-Phe-Asn-Trp-Asp-Thr-Pro, R ³ -Ser-Asp-Phe-Gln-Trp-Asp-Thr-Pro, R ³ -Phe-Asn-Trp-Glu-Tyr-Pro-, R ³ -Phe-Asn-Trp-Glu-Tyr-Asp-, R ³ -Phe-Asp-Trp-Glu-Tyr- Asp-, R ³ - Phe-Asp-Phe-Glu-Tyr-Asp-, R ³ -Tyr-Asp-Tyr-Asp- Tyr-Asp-, R ³ -Tyr-Asp-Tyr-Asp-Tyr-, R ³ -Tyr-Asp- Tyr-Asp-, R ³ -Tyr-Asp-Tyr-, R ³ -Tyr-Asp-, R ³ -Tyr-, R ³ -Trp-Asp-Trp-Asp- Trp-Asp-, R ³ -Phe- Asp-Phe-Asp-Phe-Asp or R ³ -Tyr-Glu-Tyr-Glu-Tyr-Glu is and
R ^{3 is} a peptide of the sequence Glu-Leu-Asn-Val-Gly-Phe-Asp-, Asn-Leu-Asp-Val-Gly-Phe-Asp-, Asn-Leu-Asp-Ile-Gly-Phe-Asp- , Asp-Tyr-Asp-Tyr-Asp-Tyr-Asp-, Asp-Trp-Asp-Trp-Asp-Trp- Asp-, Asp-Phe-Asp-Phe-Asp-Phe-Asp-, Glu-Tyr- Glu-Tyr-Glu- Tyr-Glu- or Glu-Phe-Ala-Tyr-Leu- is and
X Ala,
Y Ser is
wherein at least one D-amino acid is contained in the complete peptide sequence and
n, m, p and r are independently 0 or 1. 7. peptides of the general formula I, according to claims 1-6, with the sequence
8. peptides of the general formula I, according to one of claims 1-7, as active pharmaceutical ingredients. 9. A pharmaceutical composition containing one or more peptides of general formula I, according to claims 1-7, together with contains pharmaceutically suitable solutions, carriers and additives. 10. An enteral, parenteral, intravenous, subcutaneous, oral, or transdermal Applicable composition containing one or more of the peptides general formula I, according to claims 1-7, together with contains pharmaceutically suitable solutions, carriers and additives. 11. Use of the peptides according to claims 1-7 and their Compositions according to claims 9 and 10 or mixtures thereof, for the manufacture of a medicament for the treatment of psoriasis, kaposi Sarcoma, blood vessel growth in joints and bones, rheumatoid Arthritis, hemangioma, angiofribroma, diabetic retinopathy and Neovascular glaucoma. 12. Use of the peptides according to claims 1-7 and their Compositions according to claims 9 and 10 or mixtures thereof, for the manufacture of a medicament for the treatment of VEGF-induced pathological angiogenesis, VEGF-related vascular permeabilization, edema and stroke. 13. Use of the peptides according to claims 1-7 and their combination settlements according to claims 9 and 10 or mixtures thereof Production of a drug for inhibiting the growth of tumors and metastases. 14. Use of the peptides according to claims 1-7 and their Compositions according to claims 9 and 10 or mixtures thereof, for the manufacture of a medicament for the treatment of gynecological Diseases with an angiogenic background such as endometriosis, adenomyosis, Dysfunctional uterine bleeding, choriocarcinoma, ectopic pregnant shaft and diseases of the ovary.   15. Use of the peptides according to claims 1-7 and their Compositions according to claims 9 and 10 or mixtures thereof, in combination with locally applicable vascular growth stimulators. 16. Use of the peptides according to claim 15, characterized in that the VEGF and FGF is vascular growth stimulator.