FR2957597A1 - SYNTHETIC CYCLOPEPTIDES, PROCESS FOR PREPARATION AND USES - Google Patents

Abstract

The present invention relates to novel synthetic cyclopeptides, their method of preparation and their uses in the prevention or treatment of a disease associated with angiogenesis. The invention also relates to a pharmaceutical composition comprising a cyclopeptide according to the invention.

Description

SYNTHETIC CYCLOPEPTIDES PREPARATION METHOD AND USES

TECHNICAL FIELD The present invention relates to novel synthetic cyclopeptides, their methods of preparation and their uses in the prevention or treatment of a disease associated with angiogenesis. The invention also relates to a pharmaceutical composition comprising a cyclopeptide according to the invention. In the description below, references in brackets [] refer to the list of references at the end of the text. STATE OF THE ART Vasculogenesis and angiogenesis are processes responsible for the formation of the circulatory system, the first functional unit during the development of the embryo. Unlike vasculogenesis, angiogenesis involves the growth of new vessels from preexisting vessels. Angiogenesis is an indispensable process for the establishment of the vascular system in the embryo, the healing and the development of the uterine endometrium. In contrast, angiogenesis under pathophysiological conditions participates in the development of rheumatoid arthritis, adult macular degeneration, tumor growth, and metastatic spread. In the pathological context, angiogenesis plays a preponderant role in neovascularization of tumors. The tumor cells are able to invade the surrounding normal tissue, remolding it, and migrate remotely to form metastases. Moreover, the tumor vasculature being abnormal and tortuous, it reduces the distribution of therapeutic molecules and / or the tissue oxygenation necessary for radiotherapy. Angiogenesis is regulated by pro- and anti-angiogenic factors. Among the pro-angiogenic factors are the vascular endothelial growth factor (VEGF), which is a potent mitogen for endothelial cells, fibroblast growth factor 1 or FGF-1 ( Fibroblast Growth Factor 1 in English) and the growth factor of fibroblasts 2 or FGF-2 (Fibroblast Growth Factor 2). VEGF activity is often markedly increased in a wide range of tumor cells, including kidney, breast, ovarian, stomach, lung, bladder, tumors of head and neck, and in the glioblastoma. The currently marketed anti-angiogenic agents target the production of endothelial mitogens, the mitogens themselves, their receptors, or the signaling pathways associated with these agents and the cell adhesion molecules, such as integrins. There are a large number of monoclonal antibodies used in the context of tumor vascularization inhibition. In general, each monoclonal antibody is specific for a given cancer, that is, the organ and the cause of tumor formation. The main monoclonal antibodies are bevacizumab (Avastin®), cetuximab (Erbitux®), rituximab (Mabthéra®) and trastuzumab (Herceptin®). These current anti-angiogenic therapies have undesirable effects such as pulmonary hypertension, hypersensitivity, cardiac toxicity and gastrointestinal perforation. Therefore, research and development of structurally simpler new molecules than these antibodies, with better profiles of routes of administration, bioavailabilities, side effects, cost of production remain relevant. In the particular case of breast cancer, estrogens are considered hormones involved in the formation and growth of tumors of the mammary gland. Of all the compounds that have been evaluated, many phytoestrogens such as genistein (flavonoid) have shown in vitro, estrogenic and / or antiangiogenic properties according to their class. These compounds bind to the estrogenic receptors of breast, ovarian or endometrial cells, for example, contributing to the regulation of cellular reproduction mechanisms by initiation of an estrogen-dependent transcription. Likewise, it has been observed that estrogen analogues or compounds with cestrogenic properties also possess pro or antiangiogenic activity. Thus, 2-methoxyestradiol is an estrogen derivative capable of preventing the formation of new vessels. The estrogenic properties of other phytoestrogen analogues called segetalin, extracted from the seeds of Vaccaria segetalis, have also been studied. Recent advances in scientific knowledge of tumor angiogenesis demonstrate that anti-angiogenic treatment would provide a new modality for controlling tumor growth in cancer patients. Among all the molecular actors involved in the activation of angiogenesis, VEGF has proved its effectiveness in almost all experimental models of activity measurement of angiogenesis. Thus, there is a real need for new anti-angiogenic molecules, having at least one of the following characteristics: - not having the deleterious effects on the physiological endothelial function observed with the current molecules; structurally simpler than already existing molecules such as antibodies; - able to bind to VEGF; having greater efficacy compared to existing anti-angiogenic molecules; presenting better profiles at the level of routes of administration, bioavailability and / or side effects; - having an easy implementation, reproducible and low cost; capable of normalizing the tumor vascularization and of facilitating the access of the therapeutic molecules to the tumor, before completely destroying the tumor vascular network; Capable of inhibiting the growth of hormone-dependent tumors such as breast cancers; can be used in the treatment of a large number of tumors of different types; and / or - allowing the establishment of a treatment to make the tumor regress in conditions less drastic than those related to current treatments. DESCRIPTION OF THE INVENTION The present invention is specifically intended to meet these needs by providing cyclopeptides of formula (I): ## STR2 ## in which Ala represents alanine; ^ Gly represents glycine; Val represents valine; n = 0.1.2; M = 0.1.2; X, Y, Z represent, independently of one another, a compound of formula (II) and / or a compound of formula (III) ## STR2 ## wherein -q = 0.1; R 1 and R 2 represent, independently of one another, a hydrogen atom, a C 1 -C 10 alkyl group optionally substituted by one or more groups selected from the group consisting of: • a carboxyl group a group -COOR3, a group -COR3, a hydroxyl group, a C1-C4 alkoxy group, -CONR3R4, -NR3-CO-R4, -NR3R4, ùSR3, ùSeR3, a halogen atom, a guanidine group; A 5- or 6-membered heterocycle chosen from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, pyrrolidine, piperazine, tetrahydrofuran, pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of a C 1 -C 6 alkyl group, a carboxyl group, a COOR3 group, a COR3 group, a hydroxyl group, a C1-C4 alkoxy group, CONR3R4, -NR3-CO-R4, -NR3R4, SiR3, SiR3, a halogen atom, a guanidine group; A phenyl group optionally substituted by one or more groups selected from the group consisting of a C 1 -C 6 alkyl group, a carboxyl group, a COOR 3 group, a CORS group, a hydroxyl group, a C 1 -C 4 alkoxy group, or CONR 3 R 4, -NR3-CO-R4, -NR3R4, -SR3, -SeR3, a halogen atom, a guanidine group; or - R2 and NH2 together form a 5- or 6-membered heterocycle chosen from pyrrolidine, piperidine, piperazine, pyrrole, pyridine, 1-pyrroline, 2-pyrroline and 3-pyrroline, said heterocycle optionally being substituted with one or more C1-C6 alkyl groups; R5, R6, R7, R8 represent, independently of one another, a hydrogen atom, an oxygen atom, a sulfur atom, a C1-C10 alkyl group, a C2-C10 alkene group, a C 6 -C 18 aryl group, said alkyl, alkene and aryl groups being optionally substituted by one or more groups selected from the group consisting of: • a C 1 -C 6 alkyl group, a carboxyl group, a group - COOR 3, a group - COR 3 hydroxyl group, C 1 -C 4 alkoxy group, CONR 3 R 4, -NR 3 -CO-R 4, -NR 3 R 4, SiR 3, SiR 3, a halogen atom, a guanidine group; A 5- or 6-membered heterocycle chosen from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine, tetrahydrofuran, pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group, a carboxyl group, a group -COOR3 a hydroxyl group, a C1-C4 alkoxy group, -CONR3R4, -NR3-CO-R4, -NR3R4, -SR3, ùSeR3, a halogen atom, a guanidine group; A phenyl group optionally substituted with one or more groups selected from the group consisting of a C 1 -C 6 alkyl group, a carboxyl group, a COOR 3 group, a COR 3 group, a hydroxyl group, a C 1 -C 4 alkoxy group, or CONR 3 R 4 , -NR3-CO-R4, -NR3R4, ùSR3, ùSeR3. a halogen atom, a guanidine group; R3 and R4 represent, independently of one another, a hydrogen atom, a C1-C6 alkyl group, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine, pyrrolidine; said alkyl group, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine being optionally substituted by a carboxyl group, a group ùCOOR3, a group ùCOR3 a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, a halogen atom; or a pharmaceutically acceptable salt thereof; with the proviso that when n = 0, m = 1 and X is a compound of formula (II) wherein R1 is hydrogen and R2 is indole, Y is not a compound of formula ( II) wherein R1 is a hydrogen atom and R2 is a methyl group; when n = 0, m = 1 and X is a compound of formula (II) wherein R1 is a hydrogen atom and R2 is a parahydroxybenzyl group, Y is not a compound of formula (II) wherein R1 is a hydrogen atom and R2 a group - (CH2) 4 -NH2, and when n = 1, m = 1, Z is a compound of formula (II) in which R1 is a hydrogen atom and R2 is pyrrolidine and X is a compound of formula (II) wherein R1 is hydrogen and R2 is indole, Y is not a compound of formula (II) wherein R1 is hydrogen and R2 is iso-propyl group. The cyclopeptides according to the invention have the advantage of being easily accessible and of having a strong anti-angiogenic activity. Quite unexpectedly, it has been observed that depending on the nature of X, Y and / or Z, the cyclopeptides according to the invention may exhibit direct or indirect anti-angiogenic action (differentiation and migration of endothelial cells). Moreover, it has been observed that the anti-angiogenic activity of the cyclopeptides according to the invention makes it possible to control the formation of new vessels and to eliminate the risk of tumor propagation. The tumors are thus preserved in a state of dormancy. For the purposes of the present invention, the term "alkyl" means a linear, branched or cyclic, saturated or unsaturated, optionally substituted carbon group comprising 1 to 10 carbon atoms, for example 1 to 6 carbon atoms, for example 1 at 4 carbon atoms. As an indication, mention may be made of methyl, ethyl, propyl, iso-propyl, n-butyl, sec-butyl isobutyl, tert-butyl, cyclobutyl, pentyl (or amyl), sec-pentyl, iso-pentyl, neopentyl, hexyl, isohexyl, tert-hexyl, neohexyl, heptyl, octyl, nonyl, decyl and their branched and / or cyclic isomers. For the purposes of the present invention, the term "alkene" means a linear or branched, cyclic or acyclic unsaturated hydrocarbon group comprising at least one carbon-carbon double bond. The alkene group can comprise, for example, from 2 to 10 carbon atoms, more particularly from 2 to 8 carbon atoms, even more particularly from 2 to 6 carbon atoms. For example, an alkene group may be an allyl, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl or similar groups.

The term "aryl" generally refers to a cyclic aromatic substituent having from 6 to 18 carbon atoms. In the context of the invention, the aryl group may be optionally substituted mono- or polycyclic. In this respect, mention may in particular be made of phenyl. For the purpose of the present invention, the term "heterocycle" means a system comprising at least one saturated or initiated aromatic ring comprising at least one heteroatom chosen from the group comprising sulfur, oxygen, nitrogen and phosphorus. In the context of the invention, the heterocycles may comprise from 3 to 20 carbon atoms. The heterocycles may be substituted. By way of example of a heterocycle, mention may be made of pyrrolidine, pyrazoline, pyrazolidine, imidazole, imidazolidine, piperidine, piperazine, oxazolidine, isoxazolidine, morpholine, thiazolidine, and the like. isothiazolidine, tetrahydrofuran, pyridine, pyrazine, pyrimidine, pyrrole, pyrazole, imidazoline, thiazoline, oxazoline, isooxazoline, thiadiazoline, oxadiazoline, thiophenyl, furan, quinoline, isoquinoline, benzopyrrole, benzofuran, benzothiophene and the like. For the purposes of the present invention, the term "alkoxy" means an alkyl group bonded to an oxygen atom. For example, an alkoxy radical may be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy, n-hexoxy, or a similar radical. For the purposes of the invention, the halogen atom may be chosen from the group comprising fluorine, chlorine, bromine and iodine. In the context of the present invention, the term "pharmaceutically acceptable salts" includes salts prepared with non-toxic acids or bases, depending on the substituents present on the compounds. When the compounds of the invention comprise acid functions, the corresponding salts may be obtained by addition of an organic or inorganic base to the compound in the presence of a preferably inert solvent. Examples of a base addition salt may be sodium, potassium, calcium, ammonium, amino (organic), or magnesium salts. When the compounds of the invention comprise basic functions, the corresponding salts may be obtained by addition of an organic or inorganic acid optionally in a solvent which is preferably inert. Examples of inorganic acid addition salts may be the hydrochloric (or hydrochloride), hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, hydroiodic monohydrogenosulfuric salts. Examples of salts of organic acid additions may be the acetic, propionic, isobutyric, maleic (or maleate), malonic, benzoic, oxalic (or oxalate), glucuronic (or glucuronate), succinic, suberic, fumaric (or fumarate) salts. ), lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic. The term "substituted" denotes, for example, the replacement of a hydrogen atom in a given structure with a group as defined above. When more than one position may be substituted, the substituents may be the same or different at each position. According to a first variant of the invention, the cyclopeptide is of formula (I) in which: Ala represents alanine; ^ Gly represents glycine; Val represents valine; N = 0.1.2; m = 0.1.2; X, Y and Z represent, independently of one another, a compound of formula (II) and / or a compound of formula (III) in which - q = 1; R1 is a hydrogen atom; R2 represents a hydrogen atom, a C1-C10 alkyl group optionally substituted with one or more groups selected from the group consisting of: a carboxyl group, a COOR3 group, a CORS group, a hydroxyl group, a Cl- group, C4 alkoxy, -CONR3R4, -NR3-CO-R4, -NR3R4, ùSR3, ùSeR3, a halogen atom, a guanidine group; A 5- or 6-membered heterocycle chosen from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperazine, piperidine, tetrahydrofuran, pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group, a carboxyl group, a group -COOR3, a group COR3, a hydroxyl group, a C1-C4 alkoxy group, CONR3R4, -NR3-CO-R4, -NR3R4, -SR3, SeR3, a halogen atom, a guanidine group; A phenyl group optionally substituted with one or more groups selected from the group consisting of a C 1 -C 6 alkyl group, a carboxyl group, a COOR 3 group, a CORS group, a hydroxyl group, a C 1 -C 4 alkoxy group, or CONR 3 R 4 -NR3-CO-R4, -NR3R4, -SR3, -SeR3 a halogen atom, a guanidine group; or - R2 and NH2 together form a 5- or 6-membered heterocycle selected from pyrrolidine, piperazine, piperidine, pyrrole, pyridine, 1-pyrroline, 2-pyrroline, 3-pyrroline, said heterocycle being optionally substituted with one or more C1-C6 alkyl groups; - R8 represents an oxygen atom, a sulfur atom; R5, R6, R7 represent, independently of each other, a hydrogen atom, a C1-C10 alkyl group, a C2-C10 alkene group, a C6-C18 aryl group, the said alkyl groups, alkene groups; and aryl being optionally substituted with one or more groups selected from the group consisting of: • C1-C6 alkyl group, carboxyl group, COOR3 group, -COR3 group, hydroxyl group, C1-C4 alkoxy group; , -CONR3R4, -NR3-CO-R4, -NR3R4, ùSR3, ùSeR3, a halogen atom, a guanidine group; A 5- or 6-membered heterocycle chosen from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine, tetrahydrofuran, pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group, a carboxyl group, a group -COOR3 hydroxyl group, C1-C4 alkoxy group, -CONR3R4, -NR3-CO-R4, -NR3R4, ùSR3, ùSeR3, a halogen atom (Cl, Br, I, F), a guanidine group; A phenyl group optionally substituted with one or more groups selected from the group consisting of C1-C6 alkyl group, carboxyl group, COOR3 group, -COR3 group, hydroxyl group, C1-C4 alkoxy group, CONR3R4 group; , -NR3-CO-R4, -NR3R4, -SR3, -SeR3, a halogen atom, a guanidine group; R3 and R4 represent, independently of one another, a hydrogen atom, a C1-C6 alkyl group, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole or thiophene; furan, piperidine, piperazine, pyrrolidine; said alkyl group, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine being optionally substituted by a carboxyl group, a group -ORCO3, a group -COR3, a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, a halogen atom; Or a pharmaceutically acceptable salt thereof. According to a second variant of the invention, the cyclopeptide is of formula (I), in which: Ala represents alanine; ^ Gly represents glycine; Val represents valine; n = 0.1.2; m = 0.1.2; X, Y and Z represent, independently of each other, a compound of formula (II) and / or a compound of formula (III), said compound (II) being an amino acid selected from the group comprising alanine, arginine, asparagine, aspartate, citrulline, cysteine, glutamate, glutamine, glycine, histidine, homocysteine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine, valine, or a pharmaceutically acceptable salt thereof, it being understood that when n = 0, m = 1 and X is tryptophan, Y is not alanine, when n = 0, m = 1 and X is tyrosine, Y is not lysine; and when n = 1, m = 1 and X is tryptophan, Z is proline, Y is not valine; said compound (III) is a compound in which - q = 1; R8 represents an oxygen atom, a sulfur atom; - R5, R6, R7 represent, independently of each other, a hydrogen atom, a C1-C10 alkyl group, a C2-C10 alkene group, a C6-C18 aryl group, said alkyl, alkenyl and wherein ayl is optionally substituted with one or more groups selected from the group consisting of: • C 1 -C 6 alkyl group, carboxyl group, COOR 3 group, COR 3 group, hydroxyl group, C 1 -C 4 alkoxy group, CONR 3 R 4 , -NR3-CO-R4, -NR3R4, a halogen atom, a guanidine group; A 5- or 6-membered heterocycle chosen from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine and tetrahydrofuran, pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of a C 1 -C 6 alkyl group, a carboxyl group, a COOR3, a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, a halogen atom, a guanidine group; A phenyl group optionally substituted by one or more groups selected from the group consisting of a C 1 -C 6 alkyl group, a carboxyl group, a -COOR 3 group, a -COR 3 group, a hydroxyl group or a C 1 -C 4 alkoxy group; NR3R4, a halogen atom (Cl, Br, I, F), a guanidine group; R3 and R4 represent, independently of each other, a hydrogen atom, a C1-C6 alkyl group, the piperazine, said alkyl group and piperazine being optionally substituted by a carboxyl group; COOR 3, a group -COR 3, a hydroxyl group, a Cl-C 4 alkoxy group, -NR 3 R 4, a halogen atom; or a pharmaceutically acceptable salt thereof. According to a third variant of the invention, the cyclopeptide is of formula (I), in which: Ala represents alanine; ^ Gly represents glycine; Val represents valine; n = 0; m = 1; X, Y represent, independently of one another, a compound of formula (II) and / or a compound of formula (III), said compound (II) being an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartate, citrulline, cysteine, glutamate, glutamine, glycine, histidine, homocysteine, isoleucine, leucine, lysine, methionine ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine, valine, it being understood that when X is tryptophan, Y is not the same as alanine; and when X is tyrosine, Y is not lysine; said compound (III) is a compound in which - q = 1; R8 represents an oxygen atom; R5, R6, R7 represent, independently of one another, a hydrogen atom, a C1-C10 alkyl group, a C2-C10 alkene group, a C6-C18 aryl group, the said alkyl, alkene and aryl being optionally substituted with one or more groups selected from the group consisting of: • a C1-C6 alkyl group, a carboxyl group, a group-COOR3, a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, an atom halogen; A 5- or 6-membered heterocycle chosen from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine and tetrahydrofuran; , pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group, a carboxyl group, a COOR3 group, hydroxyl group, C1-C4 alkoxy group, -NR3R4, halogen atom; A phenyl group optionally substituted with one or more groups selected from the group consisting of a C 1 -C 6 alkyl group, a carboxyl group, a COOR 3 group, a hydroxyl group, a C 1 -C 4 alkoxy group, -NR 3 R 4, a halogen; R3 and R4 represent, independently of each other, a hydrogen atom, a C1-C6 alkyl group, the piperazine, said alkyl group and piperazine being optionally substituted by a carboxyl group, a COOR3 group; a group -COR3, a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, a halogen atom; or a pharmaceutically acceptable salt thereof. According to a fourth variant of the invention, the cyclopeptide is of formula (I), in which: Ala represents alanine; ^ Gly represents glycine; Val represents valine; n = 1; m = 0; Y and Z represent, independently of each other, a compound of formula (II) and / or a compound of formula (III), said compound (II) being an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartate, citrulline, cysteine, glutamate, glutamine, glycine, histidine, homocysteine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine, valine, it being understood that when Y is tryptophan, Z is not alanine ; and when Y is tyrosine, Z is not lysine; said compound (III) is a compound in which - q = 1; R8 represents an oxygen atom; R5, R6, R7 represent, independently of one another, a hydrogen atom, a C1-C10 alkyl group, a C2-C10 alkene group, a C6-C18 aryl group, the said alkyl, alkene and wherein aryl is optionally substituted with one or more groups selected from the group consisting of: • a C1-C6 alkyl group, a carboxyl group, a -COOR3 group, a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, an atom halogen; A 5- or 6-membered heterocycle selected from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine and tetrahydrofuran; , pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group, a carboxyl group, a group -COOR3, a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, a halogen atom; A phenyl group optionally substituted with one or more groups selected from the group consisting of a C 1 -C 6 alkyl group, a carboxyl group, a -COOR 3 group, a hydroxyl group, a C 1 -C 4 alkoxy group, -NR 3 R 4, a halogen; R3 and R4 represent, independently of each other, a hydrogen atom, a C1-C6 alkyl group, the piperazine, said alkyl group and piperazine being optionally substituted with a carboxyl group, a -COOR3 group; a -COR 3 group, a hydroxyl group, a C 1 -C 4 alkoxy group, -NR 3 R 4, a halogen atom; or a pharmaceutically acceptable salt thereof. Cyclopeptides according to the invention with anti-angiogenic activity, may offer several advantages over conventional anticancer therapies, in particular antitumor specificity of action, easier target accessibility, lower risk of resistance, efficacy in combination therapy with conventional anticancer drugs, and the possibility of chemoprophylaxis. The invention also relates to the process for the preparation of a cyclopeptide of formula (I), in which: a) a compound of formula (IV) or (V) is cyclized: Pr Pr (Z) n (X) ## STR1 ## wherein Pr (V) m Gly (Z) n H \ Y / \ Ala / \ Va / \ OH Pr (V) in which Ala, Gly , Val, X, Y, Z, n, m are as previously described, and Pr is a protecting group selected from the group consisting of acetamidomethyl (Acm), allyloxycarbonyl (Alloc), t-butyloxycarbonyl (Boc ), benzyloxymethyl (Bom), 2- (4-biphenylyl) propyl (2) oxycarbonyl (Bpoc), 2-bromobenzyloxycarbonyl (Br-Z), butoxymethyl (Bum), benzoic acid (Bz), benzyl (Bzl), dichlorobenzyl (Cl2Bzl), 2-chlorobenzyloxycarbonyl (CIZ), N- [1- (4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl] (Dde), dithia-succinyl (Dts) ), 4-methoxybenzyl (Mbzl), 4 methylbenzyl (MeBzl), methoxybenzyl (Mob), 4-methoxy-2,3,6-trimethylbenzene sulfonyl (Mtr), mesitylene ne-2-sulfonyl (Mts), 2-nitro-phenylsulfenyl (Nps), benzyl ester (OBzl), tert-butyl ester (O-tBu), 2,2,4,6,7-pentamethyldihydrobenzofuran-5 sulfonyl (Pbf), 2,2,5,7,8-pentamethyl-chroman-6-sulfonyl (Pmc), tert-butyl (tBu), 2,4,6-trimethoxybenzyl (Tmob), triphenylmethyl (trityl or trt), in the presence of a cyclization agent. b) the protecting groups of the different compounds X, Y, Z are cleaved to recover the starting compounds X, Y, Z. By "protecting group" is meant a group introduced into a molecule to prevent side reactions from occurring in the course of the synthesis and / or to obtain some chemo-selectivity. The protecting groups are, in general, inert under the chosen reaction conditions. Once the reaction (s) carried out in the presence of the protecting groups, the latter are removed to return to the starting molecules (deprotection). In the context of the present invention, the term "cyclization agent" is intended to mean a compound that allows the formation of a cyclic organic compound by creating a bond between the organic molecules, providing the constituent elements of this cycle. In the present invention, the cyclizing agent allows the formation of a peptide bond between the C-terminus of glycine and the N-terminus of valine present in the linear compound of formula (IV), and between the C-terminus of compound Z and the N-terminus of compound Y present in the linear compound of formula (V), to yield the cyclopeptide of formula (I).

The choice of the experimental conditions, in particular the nature of the cyclization agent, its concentration and the choice of the two amino acids involved in the cyclization, are important in order to avoid the racemization of the constituent molecules of the compounds of formulas (IV) and (V). ), and the formation of dimers from the compound of formula (IV) or (V). The choice of the aforementioned experimental conditions makes it possible, moreover, to obtain a regioselective cyclization. Phosphorylated azides have been shown to be particularly useful cyclization agents. For example, diphenylphosphoryl azide (DPPA), bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP), O-benzotriazole-N, N, N ', N' tetramethyl-uronium-hexafluorophosphate (HBTU) may be mentioned. benzotriazol-1-yl-oxytris- (dimethylamino) -phosphonium hexafluorophosphate (BOP), N, N'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 3- (diethoxyphosphoryloxy) -3H-benzo [d] [1,2,3] triazin-4-one (DEPBT), N, N'-diisopropylcarbodiimide (DIC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl) ), methanaminium 2- (1H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyl uronium hexafluorophosphate (HIGH), anhydrous N-hydroxybenzotriazole (HOBt), 3,4-hydroxybenzene 4-Dihydro-4-oxo-1,2,3-benzotriazine (HOOBt), 1H-benzotriazolium 1- [bis (dimethylamino) methylene] -5-chloro-hexafluorophosphate (1 -), 3-oxide (HCTU), 6-chloro-1-hydroxybenzotriazole (CI-HOBt), O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetraf luoroborate (TBTU), 4,5-dicyanoimidazole. As indicated, the concentration of the cyclizing agent is an important parameter in the cyclization reaction. For example, in the case of the cyclization of a compound of formula (IV), it has been observed that a concentration between 2.10-4 and 10-4M leads to the cyclopeptide of formula (I), with very low concentrations even zero of the corresponding dimer. The cyclization reaction can take place in an aprotic organic solvent. As such, there may be mentioned for example acetonitrile, dichloromethane or dimethylformamide. The compound of formula (I) can be obtained at the end of step b), after cleavage of the protective groups Pr of the compounds (IV) or (V). The cleavage or cleavage can be done under various acidic and / or basic conditions known to those skilled in the art. The deprotection reaction of step b) may optionally be followed by a washing and / or purification step.

The compounds (IV) and (V) can be obtained respectively from the compounds of formula (VI) and (VII):

Pr Pr Pr Pr Pri (Z) n (X) m Gly Pr (X) m Gly (Z) n \ Val / \ Y / \ Ala \ Rs 1Y / \ Ala / \ Va / l \ Rs Pr Pr (VI) (VII) in which: Ala, Gly, Val, X, Y, Z, n, m, are as defined above; Pr, Pr 1 are protective groups selected independently of each other from the group consisting of acetamidomethyl (Acm), allyloxycarbonyl (Alloc), t-butyloxycarbonyl (Boc), benzyloxymethyl (Bom ), 2- (4-biphenylyl) propyl (2) oxycarbonyl (Bpoc), 2-bromobenzyloxycarbonyl (Br-Z), butoxymethyl (Bum), benzoic acid (Bz), benzyl (Bzl), dichlorobenzyl (Cl2Bzl), 2-chlorobenzyloxycarbonyl (CIZ), N- [1- (4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl] (Dde), dithia-succinyl (Dts), fluorenylmethyloxycarbonyl (Fmoc), 4-methoxybenzyl (Mbzl), 4-methylbenzyl (MeBzl), methoxybenzyl (Mob), 4-methoxy-2,3,6-trimethylbenzene sulfonyl (Mtr), mesitylene-2-sulfonyl (Mts), 2-nitro-phenylsulfenyl (Nps), benzyl ester (OBzl), tert-butyl ester (O-tBu), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) ), 2,2,5,7,8, -pentamethyl-chroman-6-sulfonyl (Pmc), tert-butyl (tBu), 2,4,6-trimethoxybenzyl (Tmob), triphenylmethyl (trityl or trt); Rs is a resin selected from the group consisting of SASRIN resin (marketed by Bachem), SASRIN ™ 2-pyridylthiocarbonate (SASRIN-TOPCAT [1]), WANG resin (marketed by Matrix-Innovation), resin 2 chlorotrityl (sold by Iris Biotech GmbH), TENTAGEL resin (marketed by Sigma-Aldrich), WANG-TENTAGEL resin (marketed by Iris Biotech GmbH), Wang-PEG resin (marketed by the company). Sigma Watanabe Chemical Industries), benzhydrylamine resin (BHA-resin, sold by ChemPep Inc.), polystyrene-NH2 resin (sold by Iris Biotech GmbH), Merrifield resin (marketed by Matrix-Innovation) 4-methylbenzhydrylamine resin (MBHA-resin, PAL-MBHA-resin) (marketed by the company Matrix-Innovation), the resin 4-hydroxymethylbenzylamide-synbeads [2], the resi 4-hydroxymethylphenoxyacetylamidomethylpolystyrene (HMPA-resin) (marketed by Matrix-Innovation); after cleavage of the protecting group Pr1 and the resin Rs. The protecting group Pr1 which is generally bonded to the N-terminus of the valine and the compound Y, and the resin Rs which is generally bonded to the end C-terminal glycine and compound Z, may be successively for example under different operating conditions. In one variant of the invention, the compounds (IV) and (V) are obtained after successive cleavages of the protective group Pr1 and the resin Rs of the compounds of formulas (VI) and (VII), respectively. By "resin" is meant a (co) polymeric support used in solid phase synthesis. In general, they are functionalized crosslinked (co) polymers insoluble but capable of swelling in the solvents used. By way of example, the cleavage or cleavage of the Gly-Rs or (Z) n-Rs bond, after cleavage or cleavage of the Pr1-Val bond or of the Pr1-Y bond, makes it possible to release the compound of formula (VI) or (VII) of its synthesis support. The compound resulting from this cleavage is recovered in the filtrate. Cleavage or cleavage can be in mild acidic and / or basic conditions. As an example of mild acidic conditions, mention may be made of the use of 1% trifluoroacetic acid (TFA) (cleavage or cleavage of the Gly ù Rs or (Z) n-Rs bond). Cleavage under mild basic conditions can be done, for example, in the presence of a primary and secondary amine such as piperidine (cleavage or cleavage of the Pr1-Val bond or the Pri-Y bond). In turn, the compounds (VI) and (VII) can be prepared by successive couplings.

Thus, compound (VI) can be prepared by the successive coupling between a compound of formula (VIII): ## STR1 ## and Ala-Pr1, (Pr-X) m-Pri, (Pr-Y) -Pri, (Pr-Z) ) n-Pri, Val-Pr1 respectively, and the compound (VII) by the successive coupling between a compound of formula (IX): Pr 15 and Val-Pr1, Gly-Pr1, Ala-Pr1, (Pr-X) m -Pri, (Pr-Y) -Pri, respectively, where Ala, Gly, Val, X, Y, Z, n, m, Pr and P1 are as previously defined in the presence of a coupling agent. The use of an Rs resin in the compounds (VIII) and (IX) allows the synthesis of the compounds of the formula (VI) and (VII) respectively on a solid support according to the methods already published [2]. Solid support synthesis involves a carrier consisting of an insoluble (co) polymer (resin), inert under the conditions of synthesis. On the other hand, these polymers (resins) have the particularity of swelling in the solvents used, which ensures a good diffusion of the reagents. In the present invention, Gly or (Pr-Z) n are attached to the resin, advantageously, by a covalent bond. Ala-Pr1, (Pr-X) m-Pri, (Pr-Y) -Pri, (Pr-Z) n-Pri, Val-Pr1 in the case of (VI), and Val-Pr1, Gly- Pr1, Ala-Pr1, (Pr-X) m-Pri, (Pr-Y) -Pri in the case of (VII), are added in solution, often in large excess, to the resin. After each addition, the synthesized compound remains bound to the insoluble (co) polymer (resin) and can be easily separated from the excess reagents (s) and solvents for example by simple filtration. The group Pr1 is then cleaved. This process can be repeated as many times as necessary until compounds (VI) and (VII) are synthesized. The bond which binds these compounds (VI) and (VII) to the (co) polymer (resin) as well as the protective group Pr1 are then cleaved and the reaction product is recovered in the filtrate. The coupling agent may be chosen from the group comprising, for example, bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP), O-benzotriazole-N, N, N ', N'tetramethyl-uronium-hexafluorophosphate (HBTU). , benzotriazol-1-yl-oxy-tris (dimethylamino) -phosphonium hexafluorophosphate (BOP), N, N'-carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), 3- (diethoxy-phosphoryloxy) -3H- benzo [d] [1,2,3] triazin-4-one (DEPBT), N, N'diisopropylcarbodiimide (DIC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC. HCl), methanaminium 2- (1 H-7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyl uronium hexafluorophosphate (HIGH), anhydrous N-hydroxybenzotriazole (HOBt), hydroxy-3 4-Dihydro-4-oxo-1,2,3-benzotriazine (HOOBt), 1H-benzotriazolium 1- [bis (dimethylamino) methylene] -5chloro-, hexafluorophosphate (1 -), 3-oxide (HCTU) 6-chloro-1-hydroxybenzotriazole (CI-HOBt), O- (benzotriazol-1-yl) -N, N, N ', N'tetramethyluronium, and rafluoroborate (TBTU), 4,5-dicyanoimidazole. The cyclopeptides according to the invention can be used directly or in the form of a pharmaceutical composition containing them, for their use as a medicament. The subject of the invention is therefore medicaments comprising a cyclopeptide according to the invention. Another object of the present invention is a pharmaceutical composition comprising a cyclopeptide as defined above and optionally one or more pharmaceutically acceptable excipient (s). Excipients are usually non-therapeutic elements that are part of a drug or are used in its manufacture. The purpose of the excipient is to improve the appearance or taste, to ensure the preservation, to facilitate the shaping and the administration of the medicament. It is also used to convey the active ingredient to its site of action and to control its absorption by the body. Depending on the desired dosage form and mode of administration, different excipients may be used. Those skilled in the art are able to select the appropriate excipients according to the desired dosage form and mode of administration. The pharmaceutical compositions according to the invention can be prepared by known methods. The amount of cyclopeptide directly administered or included in the pharmaceutical compositions is a therapeutically effective amount. Effective amount or therapeutically effective amount means an amount of cyclopeptide as is or included in a pharmaceutical composition, which leads to the desired prophylactic or therapeutic effect. Said effective amount can be determined experimentally by standard pharmaceutical procedures. In order to obtain the desired prophylactic or therapeutic effect, the dose of active principle may vary between 0.1 μg and 200 mg per kg of body weight per day. Although these assays are examples of average conditions, there may be special cases where higher or lower dosages are more appropriate. Such assays are part of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient. Modes of administration may include, for example, the oral, sublingual, rectal, topical, nasal, pulmonary, ocular, intestinal and parenteral routes. Parenteral administration may include, for example, intravenous, intramuscular, subcutaneous, intraperitoneal, intraarterial, intra-articular, intracisternal, intradermal, intra-lesional, intraocular, intrapleural, intrathecal, intrauterine administration, and intraventricular. The therapeutic indication to be treated as well as the physicochemical and biological properties of the composition make it possible to determine the most appropriate route of administration and formulation. Different formulations and delivery systems are described in the state of the art.

The pharmaceutical compositions may be in the form of instant release, controlled release, or delayed release. The most commonly used formulations are, for example, solutions, suspensions, (micro) emulsions, ointments, gels, patches, tablets, dragees, soft and hard capsules, implants, amorphous powders or crystalline, and lyophilized formulations. The appropriate formulation depends on the chosen mode of administration. For example, for parenteral administration by injection, the compositions are usually sterile and may be presented in unit dosage form such as, for example, ampoules, syringes, injection pens, or multiple dose vials. The compositions may be in the form of suspensions, solutions or emulsions in an aqueous or fatty vehicle and contain physiologically compatible buffers such as, for example, phosphate, histidine, or citrate to adjust the pH of the formulation, tonicity agents such as sodium chloride or dextrose, viscosity agents, suspending agents, dispersing agents, surfactants, antioxidants, biocompatible polymers, chelating agents, preservatives. Depending on the injection site, the vehicle may contain water, vegetable or synthetic oil and / or organic cosolvents. In some cases, such as in the case of a lyophilized product or a concentrate, the parenteral formulation can be reconstituted or diluted prior to its administration. In the case of injectable formulations with a delayed effect, the composition according to the invention may be in the form of suspension of nano / micro particles with polymers as matrix. Other delay formulations may be in the form of implants or pumps. For transmucosal or nasal administration, solid, semi-solid or patch formulations may be preferred. For oral administration, the composition may be formulated in liquid or solid form and as an instant-release or controlled-release formulation, especially in the form of granules, tablets, dragees, soft and hard capsules, liquids. , gels, suspensions and emulsions.

The cyclopeptide as defined above, can be used for the manufacture of a medicament for the prevention or treatment of a disease associated with angiogenesis. An object of the invention relates to the cyclopeptides according to the invention or a pharmaceutical composition as defined above, for the prevention or treatment of a disease associated with angiogenesis. More particularly, the invention relates to the cyclopeptides according to the invention or the pharmaceutical composition as defined above, for the prevention or the treatment of a disease associated with angiogenesis selected from the group comprising tumor growth (colon tumor , breast, liver, kidney and prostate), metastatic dissemination (colon tumor, breast, liver, kidney and prostate), hemangiomas, rheumatoid arthritis, endometriosis, atherosclerosis, diabetic retinopathy and macular degeneration. The invention relates more particularly to the cyclopeptides according to the invention or the pharmaceutical composition as defined above, for the prevention or treatment of tumor growth (colon, breast, liver, kidney and prostate). The administration of the cyclopeptides of the invention first makes it possible to normalize the tumor vascularization and to facilitate the access of the therapeutic molecules to the tumor and then to completely destroy the tumor vascular network. The cyclopeptides of the invention can be used in therapy, especially oncotherapy, in the mammal and in particular in humans. The term "mammal" refers to any mammal. By way of example, mention may be made of domestic animals such as dogs and cats; farm animals such as hogs, cattle, sheep and goats; animals such as mice and rats; primates like monkeys, chimpanzees; and the man. The present invention, according to another of its aspects, also relates to a method of preventing or treating the pathologies indicated above which comprises the administration of a cyclopeptide according to the invention or of a pharmaceutical composition comprising it. Brief Description of the Figures - Figure 1 shows the high-resolution mass spectrum of the SA compound (sevelin A). High Resolution Mass: Calculated for C31H43N7NaO6: 632.3173. Found: 632.3157 - Figure 2 shows the high-resolution mass spectrum of the SPI compound. High resolution mass calculated for C25H42N6NaO6 545.3064. Found: 545.3069 - Figure 3 shows the high-resolution mass spectrum of the SP2 compound. High Resolution Mass: Calculated for C22H34N6NaO7: 517.2387. Found: 517,2401 - Figures 4A and 4B show the effect of conditioned media (MC) on endothelial cell proliferation. HUVEC cells were treated for 48 hours with MCs prepared from culture supernatants of MCF7 cells (FIG. 4A) or with MC 20 prepared from culture supernatants of MDA-MB-231 cells (FIG. 4B), previously treated for 48 hours by SA and SPI (10-12 to 10-5 M). The inhibitory potential of SA and SPI on cell proliferation was evaluated against the condition of 10% fetal bovine serum (FBS). Untreated cells were used as basal control. The white bars represent the rate of cell proliferation in response to MCs treated with different concentrations of SPI. The black bars represent the rate of cell proliferation in response to MC treated with different concentrations of SA. The dotted line delineates the cell proliferation rate relative to the basal control. The results are expressed as a change in optical density (OD), read at 450 and 570 nm. The values correspond to the average OD ± SEM of each concentration tested (n = 3) * p <0.05, ** p <0.01 *** p <0.001 versus control. Figure 5A shows the phosphorylation analysis of signaling pathways involved in cell migration and survival (AKT-1) in human umbilical cord endothelial cells (HUVEC), in response to MC obtained from MCF7 cells. .

The HUVEC cells in culture are treated with the MCs prepared from the supernatants of the MCF7 cells, cells previously treated with different concentrations of SA and SPI (10-11 to 10-5 M). The HUVEC cells are then recovered and lysed at 5 min of treatment. The histograms displayed represent the result normalized by the ratio P-Akt / t-Akt. The data is expressed in arbitrary units. p-Akt (Akt phospho), t-Akt (total Akt), TO (basal control). The results are expressed as a function of the concentrations and the values correspond to the average ± SEM of each concentration tested (n = 3) * p <0.05, ** p <0.01 *** p <0.001, versus control. Figure 5B shows the phosphorylation analysis of signaling pathways involved in cell migration and survival (AKT-1) in human umbilical cord endothelial cells (HUVEC), in response to MC obtained from the cells. MDA-MB-231. HUVEC cells in culture are treated with MC prepared from supernatants of MDA-MB-231 cells, cells previously treated with different concentrations of SA and SPI (10-11 to 10-5 M). The HUVEC cells are then recovered and lysed at 5 min of treatment. The histograms displayed represent the result normalized by the ratio p-Akt / t-Akt. The data is expressed in arbitrary units. p-Akt (Akt phospho), t-Akt (total Akt), TO (basal control). The results are expressed as a function of the concentrations and the values correspond to the average ± SEM of each concentration tested (n = 3) * p <0.05, ** p <0.01 *** p <0.001, versus control. Figure 5C shows the phosphorylation analysis of signaling pathways involved in proliferation (ERK112) in human umbilical cord endothelial cells (HUVEC), in response to MC obtained from MCF7 cells. HUVEC cells in culture are treated with MC prepared from cell supernatants MCF7 cells previously treated with different concentrations of SA and SPI (10-11 to 10-5 M). The HUVEC cells are then recovered and lysed at 5 min of treatment. The histograms displayed represent the result normalized by the ratio p-Erk / t-Erk. The data is expressed in arbitrary units. p-Akt (phospho Erk), t-Akt (total Erk), TO (basal control). The results are expressed as a function of the concentrations and the values correspond to the average ± SEM of each concentration tested (n = 3) * p <0.05, ** p <0.01 *** p <0.001, versus control. Figure 5D shows phosphorylation analysis of signaling pathways involved in proliferation (ERK112) in human umbilical cord endothelial cells (HUVEC), in response to MC obtained from MDA-MB-231 cells. The HUVEC cells in culture are treated with the MCs prepared from the supernatants of the MDA-MB-231 cells cells previously treated with different concentrations of SA and SPI (10-11 to 10-5 M). HUVEC cells are then recovered and lysed at 5 min of treatment. The histograms displayed represent the result normalized by the ratio p-Erk / t-Erk. The data is expressed in arbitrary units. p-Akt (phospho Erk), t-Akt (total Erk), TO (basal control). The results are expressed as a function of the concentrations and the values correspond to the mean ± SEM of each concentration tested (n = 3) * p <0.05, ** p <0.01 *** p <0.001, versus control. FIG. 6A represents the effect of the cyclopeptides SPI and SA on the secretion of VEGFA by the MCF7 cells. The cells were treated for 48 h with different concentrations of SA or SPI (10-12 to 10-5 M). Untreated cells represent the basal control whereas cells treated with different concentrations of E2 (10-5 to 10-12 M), the positive control. The curve connecting the diamonds (top line) represents the different VEGFA concentrations of the cells treated with E2. The curve connecting the squares (mean line) corresponds to the different VEGFA concentrations of the cells treated with SPI. The curve connecting the triangles (lower line) corresponds to the different VEGFA concentrations of the cells treated with SA. The dashed line represents the level of the secretion rate of VEGFA by the cells treated with the culture medium alone (basal control). The results are expressed as a function of the concentrations and the values correspond to the average ± SEM of each concentration tested (n = 3) p <0.05, ** p <0.01 *** p <0.001, versus control. FIG. 6B shows the effect of the cyclopeptides SPI and SA on the secretion of VEGFA by MDA-MB-231 cells.

The cells were treated for 48 h with different concentrations of SA or SPI (10-12 to 10-5 M). The untreated cells represent the basal control while the cells treated with different concentrations of E2 (10-5 to 10-12 M), the positive control. The curve connecting the diamonds (top line) represents the different VEGFA concentrations of the cells treated with E2. The curve connecting the squares (mean line) corresponds to the different VEGFA concentrations of the cells treated with SPI. The curve connecting the triangles (lower line) corresponds to the different VEGFA concentrations of the cells treated with SA. The dotted line represents the level of secretion rate of VEGFA by the cells treated with the culture medium alone (basal control). The results are expressed as a function of the concentrations and the values correspond to the average ± SEM of each concentration tested (n = 3) p <0.05, ** p <0.01 *** p <0.001, versus control. FIG. 6C represents the inhibitory effect of SA and SPI cyclopeptides on the secretion of VEGFA by MCF-7 cells, in the presence of E2. Cells were treated for 48 h with different concentrations of SA or SPI (10-12 to 10-5 M). Cells treated with different concentrations of E2 only (10-5 to 10-12 M), represents the positive control. The white bars represent the different VEGFA concentrations of the cells treated with E2. The gray bars represent the different VEGFA concentrations of the SPI treated cells. The black bars represent the different VEGFA concentrations of the cells treated with SA. The results are expressed as a function of the concentrations (E2, SPI and SA) and the values correspond to the mean ± SEM of each observed VEGF concentration (n = 3) * p <0.05, ** p <0.01 *** p < 0.001 versus control. (E2: 17 R, 30 estradiol). FIG. 6D represents the inhibitory effect of SA and SPI cyclopeptides on the secretion of VEGFA by MDA-MB-231 cells, in the presence of E2.

The cells were treated for 48 h with different concentrations of SA or SPI (10-12 to 10-5 M). Cells treated with different concentrations of E2 only (10-5 to 10-12 M), represents the positive control. The white bars represent the different VEGFA concentrations of the cells treated with E2. The gray bars represent the different VEGFA concentrations of the SPI treated cells. The black bars represent the different VEGFA concentrations of the cells treated with SA. The results are expressed as a function of the concentrations (E2, SPI and SA) and the values correspond to the mean ± SEM of each concentration of VEGF io observed (n = 3) * p <0.05, ** p <0.01 *** p <0.001 versus control. (E2: 17 R estradiol). Figure 7A shows analysis of VEGF121, VEGF165 and VEGF189 mRNA expression in MCF-7 cells in response to SA and SPI treatment. Cells were treated for 6 h with SA and SPI (10-5 M). Untreated cells represent basal control (0) while cells treated with E2 (10-9 M) represent positive control. The white bars characterize the level of mRNA expression of the VEGF121 isoform, the gray bars the mRNA expression level of the VEGF165 isoform and the black bars the mRNA expression level. of the VEGF189 isoform. The results are expressed as a function of the treatments (E2, SPI and SA) and correspond to the average ± SEM of the relative level of expression of the mRNA of the different isoforms of VEGFA, (n = 3) * p <0.05, ** p <0.01 *** p <0.001 versus control. Figure 7B shows the analysis of VEGF121 mRNA expression, VEGF165 and VEGF189 in MCF-7 cells in response to SA and SPI treatment. The cells were treated for 6 h with SA and SPI (10-5 M). Untreated cells represent basal control (0) while cells treated with E2 (10-9 M) represent positive control. The white bars characterize the level of expression of the VEGF121 isoform mRNA, the gray bars the VEGF165 isoform mRNA expression level and the black bars the mRNA expression level. of the VEGF189 isoform. The results are expressed as a function of the treatments (E2, SPI and SA) and correspond to the average ± SEM of the relative level of expression of the mRNA of the different isoforms of VEGFA, (n = 3) * p <0.05, ** p <0.01 *** p <0.001 versus control. FIG. 8A represents the HUVEC differentiation test in Matrigel®. The cells were treated for 16 hours by different concentrations of SA and SPI (10-6 to 10-5 M). Two controls were used: genistein at 30 μg / mL, inhibitor of HUVEC differentiation in Matrigel® and HUVEC migration, and EGF at 50 ng / mL, an activator of HUVEC differentiation in Matrigel® and of HUVEC migration. Untreated cells were used as basal control (cells cultured in culture medium supplemented with 10% FBS alone). Gen means genistein and EGF stands for Endothelial Growth Factor. FIG. 8B represents the evaluation of the anti-angiogenic activity of the SA and S1 cyclopeptides by the HUVEC migration test. The cells were treated for 16 hours by different concentrations of SA and SPI (10-6 to 10-5 M). Two controls were used: genistein at 30 μg / mL, inhibitor of HUVEC differentiation in Matrigel® and HUVEC migration, and EGF at 50 ng / mL, an activator of HUVEC differentiation in Matrigel® and of HUVEC migration. Untreated cells were used as a basal control (cells cultured in culture medium supplemented with 10% FBS alone). (Gen means genistein, EGF means epidermal growth factor).

EXAMPLES Solvents and Reagents The Fmoc-Gly-Sasrin and Fmoc-Pro-Sasrin resins used in the examples are marketed by Bachem. Peptide synthesis was carried out on a solid support on an Applied Biosystem 433A peptide synthesizer marketed by the company Applied Biosystem. The mixture of O-benzotriazole-N, N, N ', N' tetramethyl-uronium-hexafluorophosphate (HBTU) and anhydrous N-hydroxybenzotriazole (HOBt), in solution in dimethylformamide (DMF) is marketed by the company Applied Biosystem . The amino acids Fmoc-Ala-OH, Fmoc-Trp (Boc) -OH, Fmoc-Val-OH, Fmoc-Pro-OH, Fmoc-Gly-OH used in the examples come from the companies Bachem and Iris Biotech. N, N-diisopropylethylamine (DIEA) in N-methylpyrrolidinone (NMP), NMP originates from Applied Biosystem. Piperidine, trifluoroacetic acid (TFA), dichloromethane (DCM) and acetonitrile are marketed by the companies Acros and Applied Biosystem. Diphenylphosphoryl azide azide (DPPA), DIEA, diethyl ether, methanol and palladium on carbon are marketed by Sigma and Acros.

Nuclear Magnetic Resonance (NMR) The 1H and 13C spectra were made on a Bruker Avance 500 instrument. The chemical proton shifts (at ppm) were calibrated against tetramethylsilane. The coupling constants are given in Hertz. The spectra are carried out in deuterated solvents from the Aldrich and SDS or Eurisotop suppliers.

Mass Spectrometry Mass spectra were recorded on a Micromass-Waters QiFOF Ultima spectrometer in "Analytical" grade solvents.

Chromatography High performance liquid chromatography (HPLC) analyzes were performed on a Shimadzu chain with a C18 prosphere 100A analytical column (4.6 x 250mm 5p: flow rate 1 ml / min) marketed by Alltech-Grace with a UV detector (220 nm). A gradient of two solvents A (water / TFA: 100 / 0.1) and B (acetonitrile / water / TFA: 80/20 / 0.1) was used. The purifications by high performance liquid chromatography (HPLC), were performed on a semi-preparative C18 column (prosphere 100A 10 x 250mm 5p: flow rate 2-3 ml / min) marketed by Alltech-Grace with a UV detector. (220 nm). Example 1 Preparation of Segalin A (Cyclopeptide SA) Trp Val / Ala Pro Gly Val

The linear peptide H2N-Val-Pro-Val-Trp (boc) -Ala-Gly-OH is synthesized from Fmoc-Gly-Sasrin, according to the peptide synthesis methods on a solid support on an Applied peptide synthesizer. Biosystem 433A (1 equivalent, 0.1 mM) [3]. After activating the acid function with HBTU and 0.5M HOBt dissolved in DMF, ten equivalents of Fmoc-Ala-OH, Fmoc-Trp (Boc) -OH amino-acid, Fmoc-Val-OH, Fmoc-Pro-OH and Fmoc-Val-OH are successively added to Fmoc-Gly-Sasrin in the presence of N, N-diisopropylethylamine (DIEA) in N-methylpyrrolidinone (NMP). After each peptide coupling, the Fmoc group located at the N-terminus of the last amino acid coupled to the resin is cleaved with a solution of 20% Piperidine NMP. 125 mg of resin-peptide (HO-Val-Pro-Val-Trp (boc) -Ala-Gly-Sasrin) were obtained. The linear peptide thus obtained is cleaved from the Sasrin resin using a 1% solution of trifluoroacetic acid (TFA) in dichloromethane for 45 minutes at room temperature (20 ° C). After filtration of the resin, the linear peptide is recovered in the filtrate. After removal of the solvent under vacuum, 41.6 mg of protected peptide are obtained in the form of a colorless oil. The linear peptide is cyclized at a concentration of 2.10-4 M in acetonitrile in the presence of 34 equivalents (eq) of DIEA and 3 eq of DPPA, under argon, until complete disappearance of the linear peptide (48h) at room temperature (20 ° C). The reaction is monitored by High Performance Liquid Chromatography (Shimadzu, analytical column C18 prosphere 100A 4.6 x 250mm 5p (Alltech-Grace), with a solvent gradient (A: water / TFA: 100 / 0.1; B: acetonitrile). / water / TFA: 80/20 / 0.1).

After removing the solvent in vacuo, the protected cyclic peptide is obtained. The Boc group of the tryptophan chain of the cyclic peptide is cleaved with a solution of 50% TFA in dichloromethane. After vacuum removal of the solvent, the cyclic peptide is filtered after addition of diethyl ether.

A pasty product is obtained. HPLC purification is finally carried out on a semi-preparative C18 prosphere 100A 10 x 250mm 5p column (Alltech-Grace). After lyophilization, the segetalin A is obtained in the form of a white powder. Mass: 10.1 mg; Yield: 29%.

High Resolution Mass. Calc'd for C31H43N7NaO6: 632.3173. Found: 632.3157 (SA = 632.3157 ± 2.5 ppm, FIG. 1). 1H NMR (500 MHz, [2H6] -DMSO, 8 ppm relative to tetramethylsilane, J (Hz)): GIy1, 3.32 (1H, H, m), 3.66 (1H, Ha, m), 7, 44 (1H, HNH, m). Val2, 0.82 (3H, Hy, d, 6.8), 0.95 (3H, Hy, d, 6.7), 2.11 (1H, H [3, m], 4.51 (1H , Ha, dd, 8.7, 4.9), 7.42 (1H, HNH, m). Pro3, 1.68 (1H, Hy, m), 1.91 (1H, Hy, m), 1.94 (1H, H [3, m], 2.05 (1H, H [3, m], 3.57 (1H, H8, m), 3.59 (1H, H8, m), 4.35 (1H, Ha, d, 8.0). Val4, 0.75 (3H, Hy, d, 6.2), 0.77 (3H, Hy, d, 6.2), 2.05 (1H, H [3, m], 4.13 (1H , Ha, t, 9.8), 7.31 (1H, HNH, d, 9.8). Trp5, 3.10 (1H, H [3, dd, 16.5, 7.7), 3.12 (1H, H [3, dd, 16.5, 7.7), 4.26 (1H, H 1, m), 6.98 (1H, H 6, t, 7.8), 7.07 (1H, H 5, t, 7.8), 7.14 (1H, H 2, s), 7.34 ( 1H, H7, d, 7.8), 7.55 (1H, H4, d, 7.8), 8.49 (1H, HNH, d, 5.7), 10.88 (1H, H1-NH , s). Ala6, 1.14 (3H, H (3, d, 7.0), 3.69 (1H, Ha, m), 8.92 (1H, HNH, d, 6.3) 13C NMR (125 MHz , [2H6] -DMSO, 8 ppm relative to tetramethylsilane): GIy1, 43.6 (Ca), 169.3 (CO) Val2, 56.0 (Ca), 30.5 (C [3), 18, 2 and 20.3 (Cy), 171.6 (CO), Pro3, 61.1 (Ca), 32.1 (C [3), 22.2 (Cy), 47.66 (C8), 172, 3 (CO) Val4, 60.1 (Ca), 30.8 (C [3), 19.4 and 20.0 (Cy), 173.4 (CO) .Trp5, 56.4 (Ca), 26.8 (C [3), 122.2, 110.0, 119.2, 121.9, 119.2, 112.1, 136.9 and 127.9 (aromatic C), 173.7 (CO Ala6, 50.9 (Ca), 16.2 (C8), 171.9 (CO).

EXAMPLE 2 Preparation of the cyclopeptide of formula (I) with X = Val, Y = Val, Z = Pro, m = n = 1 (cyclopeptide SPI)

The linear H2N-Val-Pro-Val-Val-Ala-Gly-OH peptide is synthesized, from Fmoc-Gly-Sasrin, according to the peptide synthesis methods on a solid support on a Applied Biosystem 433A peptide synthesizer (1 equivalent, 0.1 mM) [3]. After activation of the acid function with HBTU and 0.5M HOBt dissolved in DMF, ten equivalents of amino acids Fmoc-Ala-OH, Fmoc-Val-OH, Fmoc-Val- OH, Fmoc-Pro-OH and Fmoc-Val-OH are successively added to Fmoc-Gly-Sasrin in the presence of DIEA in N-methylpyrrolidinone (NMP). After each peptide coupling, the Fmoc group located at the N-terminus of the last amino acid coupled to the resin is cleaved with a solution of 20% Piperidine NMP. 148 mg of peptide-resin are obtained. The Sasrin resin is then cleaved from the linear peptide thus obtained with a solution of 1% trifluoroacetic acid in dichloromethane for 45 minutes at room temperature (20 ° C.). After filtration and removal of the resin, the linear peptide is obtained as a colorless oil after vacuum removal of the solvent. The linear peptide (49 mg) is cyclized at a concentration of 2.10-4 M in acetonitrile in the presence of 34 eq of DIEA and 3 eq of DPPA, under argon, until complete disappearance of the linear peptide (48h) at ambient temperature. The reaction is monitored by High Performance Liquid Chromatography (Shimadzu, analytical column C18 prosphere 100A 4.6x250mm 5p (Alltech-Grace), with a solvent gradient (A: water / TFA: 100 / 0.1; acetonitrile / water / TFA: 80/20 / 0.1) After removal of the solvent in vacuo, 60 mg of impure cyclic peptide are obtained after precipitation with diethyl ether and filtration, a pasty product is obtained. Finally, by HPLC, a preparative C18 prosphere column 100A 10x250 mm 5p (Alltech-Grace) was prepared.After lyophilization, the cyclopeptide SPI was obtained in the form of a white powder Mass: 22.7 mg; : 49%.

High Resolution Mass. Calc'd for C25H42N6NaO6: 545.3064. Found: 545.3069 (SPI = 545.3069 ± 1.1 ppm, FIG. 2). Example 3 Preparation of the cyclopeptide of formula (I) with n = 1, m = O, Z = Pro, Y = compound of formula (III) with q = 1, R8 = O, R6 = R7 = H, R5 = OH Z = Pro (cyclopeptide SP2) The linear peptide H2N-Ala-Gly-Val-Pro-OH is synthesized from Fmoc-Pro-Sasrin according to the solid support peptide synthesis methods on a synthesis synthesizer. Applied Biosystem 433A peptide (1 equivalent, 0.1 mM) [3]. Ten equivalents of the Fmoc-Val-OH, Fmoc-Gly-OH and Fmoc-Ala-OH amino-acids are successively added to the H2N-Pro-resin in the presence of DIEA in N-methylpyrrolidinone, after activation of the acid function. using an HBTU mixture and 0.5M HOBt dissolved in DMF. After each peptide coupling, the Fmoc group located at the N-terminus of the last amino acid coupled to the resin is cleaved with a solution of NMP 20% piperidine. 161 mg of peptide-resin are obtained.

The linear peptide H2N-piperazinone-Ala-Gly-Val-Pro-OH is obtained by coupling two equivalents of piperazinone [4] with a compound of formula (III) in which q = 1, R8 = O, R6 = R7 = H, R5 = Ph-CH2O, with one equivalent of the H2N-Ala-Gly-Val-Pro-OH peptide-resin, at a concentration of 7.10-3M, in acetonitrile, in the presence of 34 equivalents of DIEA and 3 equivalents of DPPA in solid phase. The solution is stirred at ambient temperature (20 ° C.) under an argon atmosphere for 48 hours. After removal of the solvent under vacuum, the deprotection of the Boc group and the cleavage of the resin are carried out simultaneously with a 50/50 mixture of TFA / DCM for 2 hours. After filtration of the resin and removal under reduced pressure of the solvents, the cyclization of the linear peptide H2N-piperazinone-Ala-Gly-Val-Pro-OH is carried out at a concentration of 2.10-4 M in acetonitrile in the presence of Equivalents of DIEA and 3 equivalents of DPPA, under argon, until complete disappearance of the linear peptide (48h) at room temperature (20 ° C). The reaction is monitored by High Performance Liquid Chromatography (Shimadzu, analytical column C18 prosphere 100A 4.6 x 250mm 5p (Alltech-Grace), with a solvent gradient (A: water / TFA: 100 / 0.1; B: acetonitrile). / water / TFA: 80/20 / 0.1) After removal of the solvent in vacuo, the crude is directly purified by HPLC on a semi-preparative C18 prosphere 100A 10 x 250mm 5p column (Alltech-Grace). the protected cyclopeptide SP2 (15.2 mg) is obtained in the form of an oil Finally, the deprotection of the benzyl group is carried out by hydrogenolysis in methanol in the presence of 10% of palladium on charcoal After filtration and elimination under After evaporation of the solvent, a yellow oil is obtained, Mass: 12.5 mg, Yield: 18%.

High Resolution Mass. Calc'd for C22H34N6NaO7: 517.2387. Found: 517.2401 (SP2 = 517.2401 ± 2.7 ppm, Figure 3). EXAMPLE 4 Biological Tests The tests relate to the cyclopeptides SPI and SA and are intended to compare the angiogenic activity of SPI and SA. The cyclopeptide SPI has demonstrated significant resistance to acid hydrolysis. The latter solubilized, at a concentration of 10-3M, in a solution of 0.5 M hydrochloric acid, at room temperature (20 ° C), is found unchanged at 72% after 7 days, against 98% in the same conditions in aqueous solution only.

Cyclopeptides Used The tests were carried out on the cyclopeptides SPI and SA and more particularly with the aim of comparing the anti-angiogenic activity of the synthetic cyclopeptide SPI with that of the natural cyclopeptide SA. The cyclopeptide SPI has demonstrated significant resistance to acid hydrolysis. The latter solubilized, at a concentration of 10 -3 M, in a solution of 0.5 M hydrochloric acid, at room temperature (20 ° C.), is found unchanged at 72% after 7 days, as against 98% under the same conditions in aqueous solution only.

Cells Used The two peptides, after solubilization in water at a concentration of 10-3M, were tested at concentrations ranging from 10-12 to 10-5M on different types of cell cultures: (i) endothelial cells, human umbilical cord (HUVEC), and (ii) human mammary adenocarcinoma cells: MCF7 and MDAMB231. The cords were obtained in the Department of Gynecology Obstetrics and Reproductive Medicine of the Center of Obstetric Gynecology of Amiens (CGO). HUVECs are cultured in complete M199 medium (Eurobio, France) which is an M199 medium supplemented with 30 - 20% fetal bovine serum (FBS, Abcys, France), 1% of 200 mM stabilized glutamine (GIBCO, France), 1% penicillin / streptomycin (final concentrations of 100 IU / ml and 100 μg / ml, respectively) (Invitrogen, France), and 2 ml of Endothelial Cell Growth Supplement (ECGS, PromoCell, France). MFC7 are hormone-dependent human breast adenocarcinoma cells that express both estrogen receptors (ERa + and ERf3 +). These cells have a low metastatic power. MDAMB231 cells, which are non-hormonally dependent, are highly metastatic cells that express only one estrogen receptor, the f3 receptor (ERα and ERf3 +). MCF7 and MDA-MB231 are from the American Type Culture Collection (ATCC). Proliferation, Cellular Cytotoxicity and Measurement of VEGF Concentration Synthesized HUVECs cells were used to evaluate the antiangiogenic activity of the cyclopeptides SPI and SA by studying their direct effects on proliferation, differentiation and migration. of these cells in a first step and to compare the activity of the cyclopeptide SPI with that of SA in a second time. The MCF7 and MDA-MB-231 cells were used to evaluate the indirect anti-angiogenic activity of the cyclopeptides SPI and SA by studying, on the one hand, their direct effect on the cell proliferation of these cells and, on the other hand, their indirect effect on endothelial cells by targeting more specifically VEGFA. VEGFA is a proangiogenic growth factor synthesized and secreted by these two cell lines MCF7 and MDA-MB231. To test the direct effect on cell proliferation and cytotoxicity, two experimental conditions were used: (i) at 0% fetal bovine serum (FBS): this condition makes it possible to evaluate the activating effect of the cyclopeptides SPI and SA on cell proliferation. (ii) 10% bovine fetal serum (FBS): this condition makes it possible to evaluate the inhibitory effect of cyclopeptides SPI and SA on cell proliferation. It appears that neither SPI nor SA modifies the proliferation of HUVECs, MCF7 and MDA-MB-231 (proliferation tests in normal medium).

The secreted VEGF assay was performed on the cell cultures (MCF7 or MDA-MB-231), after synchronization of the G1 phase cell cycle for 24h and treatment for 48h with the different concentrations of the cyclopeptides SPI and SA (10-12 to 10-5 M) prepared extemporaneously in DMEM (Dulbecco's Modified Eagle's Medium) culture medium without phenol red (Invitrogen, France) and supplemented with 10% fetal bovine serum (FBS, Abcys, France). Each concentration of cyclopeptide SPI and SA is tested three times. The 17-R-estradiol (E2), used as a positive control [5] (Sigma, France), induces the secretion of VEGFA by the MCF7 cells and the MDA-MB-231 cells (FIGS. 6A and 6B). SPI and SA have IC50s between 10.8 and 10-9 M. The MCF7 and MDA-MB-231 cells were treated with different concentrations of SA and SPI (10-12 to 10-5 M) for 48 hours. The supernatants of these cultures are recovered and called conditioned media (MC). A proliferation test on the HUVEC cells treated with these conditioned media was carried out under the same conditions as the cell proliferation test in a normal culture medium (FIG. 4). Untreated HUVEC cells were used as basal control. The inhibitory effect of SPI and SA on VEGF secretion previously induced by E2 was also evaluated (Figures 6C-6D). Thus, the cells (MCF7 and MDA-MB-231) were treated for 48h with fixed concentrations of SPI and SA (10-6 or 10-5M) in the presence of varying concentrations of E2 (10-12 to 10-5). M). The level of secreted VEGFA was then assayed with the Quantikine® ELISA kit for detection of human VEGF (RaD, France). The analysis of PI3K / AKT and ERK1 / 2 signaling pathways was performed by Western Blot. AKT-1 and ERK1 / 2 are over-activated serine / threonine kinases in many human cancers [6], [7]. The PI3K / AKT and ERK1 / 2 signaling pathways are signaling pathways involved in proliferation (ERK112), migration, and cell survival (PI3K / AKT) [8], [9]. To analyze the phosphorylation of AKT-1 and ERK1 / 2 (FIGS. 5A to 5D), the HUVEC cells cultured in M199 medium (Eurobio, France) without phenol red, were deprived of serum for one hour in order to dephosphorylate Akt. -1 and ERK112. The HUVEC cells for 5, 15 and 30 minutes in MCs composed of the red-free M199 were then treated phenol supplemented with 10% FBS and 20% culture supernatant of MCF7 or MDA-MB-231 previously treated with cyclopeptides. SPI and SA (10-12 to 10-5 M). These culture supernatants are called conditioned media. 10% fetal bovine serum (FBS). Untreated HUVEC cells were used as basal control. In parallel, a proliferation test on these HUVEC cells treated with these conditioned media was carried out under the same conditions, the cell proliferation test in a normal culture medium (FIG. 4).

Analysis of the activity of the cyclopeptides SPI and SA on the expression of transcripts of VEGFA and its isoforms The analysis of the activity of the cyclopeptides SPI and SA on the expression of the three isoforms of VEGFA (VEGF121, VEGF165 and VEGF189 ) was also performed by quantitative RT-PCR reaction. The cells (MCF7 and MDA-MB231) are treated with 10-5 M cylopeptides SPI and SA for 6, 8, 12, 16, or 20 h (Figures 7A and 7B). 17-R-Estradiol (E2) is used as a positive control and untreated cells as basal control. The RNAs are extracted using the "TriPure Isolation Reagent" kit (Eurobio, France). The cDNA is synthesized using the "AB Applied Biosystems" kit according to the supplier's instructions. The cDNAs are then stored at -80 ° C until use. To quantify the expression of the mRNA encoding the three major VEGFA isoforms (VEGF121, VEGF165 and VEGF189), the ABI PRISM 7009 HT thermocycler (Applied Biosystems) was used. The specific amplification of each sequence was carried out exclusively with specific primers of each isoform. The VEGFA primers (Fisher Bioblock, Invitrogen, France) have already been validated [10], [11]. The 32-microglobulin primers were used as an internal control. Cell Differentiation Assays The differentiation of endothelial cells to form vessels can be induced in vitro by culturing endothelial cells in the presence of different components of the extracellular matrix, such as bi- or tri-dimensional collagen I or fibrin gels, or Matrigel®. Endothelial cells cultured on Matrigel® (Basement Membrane Matrix, BD, USA) can form capillary-like structures in just 6 hours, making this test suitable for finding antiangiogenic molecules [12]. These cell differentiation tests were performed on HUVECs (FIG. 8A). The cells are immediately treated in 500 μl of Matrigel® containing different concentrations of the cyclopeptides SPI and SA (10-12 to 10-5 M), two "control" conditions were carried out with 50 ng / ml of EGF (Endothelial Growth). Factor in English), and 30 μg / mL of genistein (Figure 8A) [13]. The formation of tubes is quantified by image analysis techniques, making it possible in particular to measure the number and the length of the tubes or the area covered by the capillary network [14].

Endothelial cell migration assays Finally, endothelial cell migration assays (HUVEC cells) were performed in order to establish the chemoattractant potential of the SPI and SA cyclopeptides. Migration to a proangiogenic factor is a key step in the process of angiogenesis. The in vitro migration test or injury test is used to estimate the effect of a molecule on endothelial cell migration. The principle of this test relies on the removal of a thin band of confluent endothelial cells from the culture dish and the enumeration of the cells that migrate into the space released by the wound. The cells are seeded in 500 μl of complete M199 medium at a rate of 5.105 cells per well in 24-well plates. The plate is incubated 24h in a thermostatted oven at 37 ° C in a humid atmosphere with 5% CO2. After 24h, the 100% confluent cells are washed once with phosphate buffered saline (PBS from phosphate buffered saline). The injury is then performed. The photos are taken before and after the injury. The cells are then treated with 250 μl of the different concentrations of SA and SPI cyclopeptides (10-12 to 10-5 M) prepared extemporaneously in M199 medium without phenol red supplemented with 10% FBS. Each concentration is tested three times. The plate is incubated for 24 hours, under the same conditions as on the first day. The photos are shot at the x4 lens after 8am, 4pm and 24h using a JVC Ky-F50 video camera connected to the VisioL software and mounted on a Leica microscope (France) (Figure 8B). In control, we used the same controls as during the Matigel® test, 50ng / mL of EGF (migration activator) and 30 μg / mL of genistein (cell migration inhibitor), the untreated cells were used as basal control [13].

Results of the anti-angiogenic activity of the cyclopeptides according to the invention 1) Whatever the concentration tested (10-12 to 10-5 M), the cyclopeptides SPI and SA do not affect the proliferation of the three cell types tested ( HUVEC, MCF7, MDA-MB-231). This demonstrates the absence of cytotoxic activity by lack of direct effect on the proliferation of endothelial cells as well as on cancer cells, for cyclopeptides SPI and SA. This result is very interesting because unlike current anti-angiogenic treatments which exhibit cytotoxicity on endothelial cells that may lead to adverse effects such as pulmonary hypertension, hypersensitivity, cardiac toxicity and gastrointestinal perforation, cyclopeptides SPI and SA do not exhibit direct cytotoxic activity on the proliferation of endothelial cells. With regard to the proliferation of endothelial cells in conditioned media (MC), it appears that the MCs obtained from the MCF7 and MDA-MB231 cells treated with the cyclopeptides SPI and SA exhibit an inhibitory activity on the proliferation of HUVECs compared to MCs obtained from untreated MCF7 and MDA-MB231 cells. At concentrations between 10-8 and 10-5M, SPI and SA inhibit the proliferation of HUVECs in the presence of MC from MDA-MB-231 or MCF7 cell cultures by 20 to 26% (approximately 26% for MDA-MB-231 and 20% for MCF7 cells). This activity suggests an effect of cyclopeptides on the production of proangiogenic growth factors secreted by both cell types (MCF7 and MDA-MB-231). Inhibition of the production of these proangiogenic factors may explain the indirect activity of SPI and SA on the proliferation of HUVECs. 2) Among these inhibited factors, VEGFA is a target of choice. This study shows that MCs were able to inhibit the activation of the PI3K / AKT pathway (FIGS. 5A-5D) involved in cell survival and the ERK 1/2 pathway involved in endothelial cell proliferation (HUVEC). The analysis of the results indicates a significant reduction in phosphorylation of Akt-1 io and Erk 1/2 in HUVEC by MC for concentrations of 10-7 to 10-5M. In this study, cyclopeptides demonstrated an inhibitory potential on phosphorylation of AKT-1 and ERK 1/2, similar to tyrosine kinase inhibitors. This inhibitory effect is very fast. 3) An angiogenic growth factor secreted by cancer cells (MCF7 and MDA-MB-231) which induces proliferation of endothelial cells by the PI3K / Akt and Erk1 / 2 signaling pathways has been well described in the literature: this is VEGFA. The efficacy of SPI and SA on the secretion, synthesis and transcription of VEGFA has been studied. It has thus been demonstrated that the cyclopeptides SPI and SA also have an excellent inhibitory potential on the transcription of VEGFA mRNA in mammary adenocarcinoma cells. The inhibitory effects of SPI and SA on the transcription of VEGFA mRNA are characterized by a significant reduction in VEGFA secretion (FIGS. 6A to 6D). 4) In addition, the cyclopeptides SPI and SA significantly inhibit, in MCF7 cells, the transcription of the mRNA of the diffusible isoforms VEGF121 and VEGF165 and not the transcription of the isoform anchored in the plasma membrane: the VEGF189 isoform . In MDA-MB-231 cells, the cyclopeptides SPI and SA were found to be active on the inhibition of the three major VEGFA isoforms (VEGF121, VEGF165 and VEGF169) (Figures 7A and 7B).

This is an important result because the VEGF121 isoform is considered one of the most tumorigenic factors in breast cancer and is the preponderant isoform in tumor progression. The reduction of VEGFA secretion in MCF7 cells only affects VEGF121 and VEGF165 isoforms, in contrast to MDA-MB-231 cells where the three isoforms are concerned. This inhibition was observed with the cyclopeptides SPI and SA for relatively high concentrations with significant IC50. 5) A direct and specific anti-angiogenic activity of the cyclopeptide io SPI has been demonstrated. It has been demonstrated that the SPI cyclopeptide at concentrations of 10-6 to 10-5M is able to directly impede cell migration and formation of endothelial cell capillary tubes in contrast to sevelin A (Figures 8A and 8B). This result is comparable to that described in the literature with genistein but at higher concentrations (30 μg / ml) [15]. The SA however, unlike SP1 showed no significant effect on capillary tube formation and endothelial cell migration.

Conclusion The various anti-angiogenic results obtained on the SPI and SA cyclopeptides according to the invention clearly demonstrate the presence of an indirect anti-angiogenic effect which involves a decrease in the synthesis of VEGFA mRNA. SPI and SA have IC50s between 10-8 and 10-9 M for the secretion of VEGFA. The results show that the cyclopeptides SPI and SA 25 according to the invention have no cytotoxic effect on the endothelial cells. These cyclopeptides are relatively stable to hydrolysis, which may make it possible to envisage a sufficiently long pharmacological action. In contrast to SA, synthetic cyclopeptide SPI also has direct anti-angiogenic action on cell migration and formation of capillary endothelial cells. Therefore, the synthetic cyclopeptides according to the invention such as SPI are therefore simple and easy to access. They possess strong direct and indirect anti-angiogenic activity without endothelial toxicity. Controlling their synthesis makes it possible, depending on the components introduced, to have molecules having an indirect and / or direct action on angiogenesis, which opens up interesting therapeutic perspectives, particularly in the treatment of diseases associated with angiogenesis. references [1] P. Zhao et al., Tetrhedron Letters, vol. 49, Issue 18, pp. 2951-2955, 2008. [2] I.W. James, Tetrahedron, vol 55, Issue 16, pp. 4855-4946, 1999. [3] P. Sonnet et al, Tetrahedron Letters, vol. 42, pp. 1681-1683, 2001; P.

Sonnet et al, Tetrahedron Letters, 44, pp. 3293-3296, 2003. [4] N. Franceschini, P. Sonnet, D. Guillaume, Org. Biomol. Chem., 2005, 3 (5), 787-793. [5] Buteau-Lozano, H., M. Ancelin, et al. (2002). "Transcriptional regulation of vascular endothelial growth factor by estradiol and tamoxifen in breast cancer cells: a complex interplay between estrogen receptors alpha and beta." Cancer Res 62 (17): 4977-84. [6] Sun, M., J. E. Paciga, et al. (2001). Phosphatidylinositol-3-OH Kinase (PI3K) / AKT2, activated in breast cancer, regulates and is induced by estrogen receptor alpha (ERalpha) via interaction between ERalpha and PI3K. Cancer Res 61 (16): 5985-91. [7] Sun, M., G. Wang, et al. (2001). "AKT1 / PKBalpha kinase is frequently elevated in human cancers and its constitutive activation is required for oncogenic transformation in NIH3T3 cells." Am J Pathol 159 (2): 431-7. [8] Nurcombe, V., C.E. Smart, et al. (2000). "The proliferative and migratory activities of breast cancer cells can be differentially regulated by heparan sulfates." J Biol Chem 275 (39): 30009-18. [9] Vercoutter-Edouart, A., Lemoine J, et al. (2000). "The mitogenic signaling pathway for fibroblast growth factor-2 involves the tyrosine phosphorylation of cyclin D2 in MCF-7 human breast cancer cells." FEBS Lett 478 (3): 209-15. [10] Kellouche, S., S. Mourah, et al. (2007). "Platelets, thrombospondin-1 and human dermal fibroblasts cooperate for endothelial cell stimulation tubulogenesis through VEGF and PAI-1 regulation." Exp Oeil Res 313 (3): 486-99. [Il] Wellmann, S., T. Taube, et al. (2001). "Specific reverse transcription-PCR quantification of vascular endothelial growth factor (VEGF) splice variants by LightCycler technology." Clin Chem 47 (4): 654-60. [12] Benelli, R. and A. Albini (1999). "In vitro models of angiogenesis: the use 5 of Matrigel." Int J Biol Markers 14 (4): 243-6. [13] Zilberberg, L., S. Shinkaruk, et al. (2003). "Structure and inhibitory effects on angiogenesis and tumor development of a new vascular endothelial growth inhibitor." J Biol Chem 278 (37): 35564-73. [14] Taraboletti, G. and R. Giavazzi (2004). "Modeling approaches for io angiogenesis." Eur J Cancer 40 (6): 881-9. [15] Fotsis, T., M. Pepper, et al. (1993). "Genistein, a dietary-derived inhibitor of in vitro angiogenesis." Proc Natl Acad Sci U S A 90 (7): 2690-4.

Claims (13)

REVENDICATIONS1. Cyclopeptide of formula (I): embedded image in which Ala represents alanine; ^ Gly represents glycine; Val represents valine; ^ N = 0,1,2; m = 0.1.2; X, Y, Z represent, independently of one another, a compound of formula (II) and / or a compound of formula (III) R5 / CO2H ........ R7 NHN (R8) q R6 in which -q = 0.1; R 1 and R 2 represent, independently of one another, a hydrogen atom, a C 1 -C 10 alkyl group optionally substituted with one or more groups chosen from the group comprising: a carboxyl group, a -COOR 3 group a -COR3 group, a hydroxyl group, a C1-C4 alkoxy group, -CONR3R4, -NR3-CO-R4, -NR3R4, ùSR3, ùSeR3, a halogen atom, a guanidine group; A 5- or 6-membered heterocycle chosen from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, the 3-pyrroline, imidazole, thiophene, furan, piperidine, pyrrolidine, piperazine, tetrahydrofuran, pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of C 1 -C 6 alkyl, carboxyl, COOR 3, COR 3, hydroxyl, C 1 -C 4 alkoxy, CONR 3 R 4, -NR 3 -CO -R4, -NR3R4, ùSR3, ùSeR3, a halogen atom, a guanidine group; A phenyl group optionally substituted by one or more groups selected from the group consisting of a C 1 -C 6 alkyl group, a carboxyl group, a COOR 3 group, a CORS group, a hydroxyl group, a C 1 -C 4 alkoxy group, or CONR 3 R 4, -NR3-CO-R4, -NR3R4, -SR3, -SeR3, a halogen atom, a guanidine group; or R2 and NH2 together form a 5- or 6-membered heterocycle selected from pyrrolidine, piperidine, piperazine, pyrrole, pyridine, 1-pyrroline, 2-pyrroline, 3-pyrroline, said heterocycle being optionally substituted with one or more C1-C6 alkyl groups; R5, R6, R7, R8 represent, independently of one another, a hydrogen atom, an oxygen atom, a sulfur atom, a C1-C10 alkyl group, a C2-C10 alkene group, a C 6 -C 18 aryl group, said alkyl, alkene and aryl groups being optionally substituted by one or more groups selected from the group consisting of: • a C 1 -C 6 alkyl group, a carboxyl group, a COOR 3 group, a group C 1 -C 3, hydroxyl, C 1 -C 4 alkoxy, CONR 3 R 4, -NR 3 -CO-R 4, -NR 3 R 4, SiR 3, SiR 3, a halogen atom, a guanidine group; A 5- or 6-membered heterocycle chosen from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine, tetrahydrofuran, pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group, a carboxyl group, a group -COOR3 a hydroxyl group, a C1-C4 alkoxy group, -CONR3R4, -NR3-CO-R4, -NR3R4, -SR3, ùSeR3, a halogen atom, a guanidine group; A phenyl group optionally substituted with one or more groups selected from the group consisting of C 1 -C 6 alkyl, carboxyl group, COOR 3 group, COR 3 group, hydroxyl group, C 1 -C 4 alkoxy group, CONR 3 R 4, -NR3-CO-R4, -NR3R4, -SR3, -SeR3, a halogen atom, a guanidine group; R 3 and R 4 represent, independently of one another, a hydrogen atom, a C 1 -C 6 alkyl group, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine, pyrrolidine; said alkyl group, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine being optionally substituted with a carboxyl group, a group ùCOOR3, a group ùCOR3 a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, a halogen atom; or a pharmaceutically acceptable salt thereof; with the proviso that when n = 0, m = 1 and X is a compound of formula (II) wherein R1 is hydrogen and R2 is indole, Y is not a compound of formula (II) wherein R1 is a hydrogen atom and R2 is a methyl group; when n = 0, m = 1 and X is a compound of formula (II) wherein R1 is hydrogen and R2 is hydroxybenzyl, Y is not a compound of formula (II) wherein R1 is a hydrogen atom and R2 a group (CH2) 4 -NH2; and when n = 1, m = 1, Z is a compound of formula (II) wherein R1 is a hydrogen atom and R2 is pyrrolidine and X is a compound of formula (II) wherein R1 is a hydrogen atom. and R2 is indole, Y is not a compound of formula (II) wherein R1 is hydrogen and R2 is isopropyl. 2. Cyclopeptide according to claim 1, of formula (I) wherein: Ala represents alanine; ^ Gly represents glycine; Val represents valine; n = 0.1.2; m = 0.1.2; X, Y and Z represent, independently of one another, a compound of formula (II) and / or a compound of formula (III) in which - q = 1; - R1 is a hydrogen atom; R2 represents a hydrogen atom, a C1-C10 alkyl group optionally substituted with one or more groups selected from the group consisting of: a carboxyl group, a COOR3 group, a CORS group, a hydroxyl group, a C1 group -C4 alkoxy, -CONR3R4, -NR3-CO-R4, -NR3R4, ùSR3, ùSeR3, a halogen atom, a guanidine group; A 5- or 6-membered heterocycle chosen from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperazine, piperidine, tetrahydrofuran, pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group, a carboxyl group, a group -COOR3 a group CORS, a hydroxyl group, a Cl-C4 alkoxy group, CONR3R4, -NR3-CO-R4, -NR3R4, -SR3, SeR3, a halogen atom, a guanidine group; A phenyl group optionally substituted by one or more groups selected from the group consisting of a C 1 -C 6 alkyl group, a carboxyl group, a COOR 3 group, a CORS group, a hydroxyl group, a C 1 -C 4 alkoxy group, or CONR 3 R 4, -NR3-CO-R4, -NR3R4, -SR3, -SeR3 a halogen atom, a guanidine group; or - R2 and NH2 together form a 5- or 6-membered heterocycle chosen from pyrrolidine, piperazine, piperidine, pyrrole, pyridine, 1-pyrroline, 2-pyrroline and 3-pyrroline, said heterocycle optionally being substituted with one or more C1-C6 alkyl groups; - R8 represents an oxygen atom, a sulfur atom; - R5, R6, R7 represent, independently of each other, a hydrogen atom, a C1-C10 alkyl group, a C2-C10 alkene group, a C6-C18 aryl group, said alkyl, alkene and wherein aryl is optionally substituted with one or more groups selected from the group consisting of: • a C1-C6 alkyl group, a carboxyl group, a -COOR3 group, a -COR3 group, a hydroxyl group, a C1-C4 alkoxy group, -CONR3R4, -NR3-CO-R4, -NR3R4, -SR3, -SeR3, a halogen atom, a guanidine group; A 5- or 6-membered heterocycle chosen from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine, tetrahydrofuran, pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group, a carboxyl group, a group -COOR3, a hydroxyl group, a C1-C4 alkoxy group, a -CONR3R4 group, -NR3-CO-R4 group, -NR3R4 group, a RS1 group, a (C1, Br, I, F) halogen atom, a guanidine group; A phenyl group optionally substituted with one or more groups selected from the group consisting of C 1 -C 6 alkyl, carboxyl group, COOR 3 group, COR 3 group, hydroxyl group, C 1 -C 4 alkoxy group, CONR 3 R 4, -NR3-CO-R4, -NR3R4, -SR3, -SeR3, a halogen atom, a guanidine group; R 3 and R 4 represent, independently of one another, a hydrogen atom, a C 1 -C 6 alkyl group, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine pyrrolidine; said alkyl group, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine being optionally substituted with a carboxyl group, a group --COOR3, a group --COR3 a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, a halogen atom; or a pharmaceutically acceptable salt thereof. 3. Cyclopeptide according to one of claims 1 or 2, of formula (I) wherein: Ala is alanine; ^ Gly represents glycine; Val represents valine; n = 0.1.2; M = 0.1.2; X, Y and Z represent, independently of each other, a compound of formula (II) and / or a compound of formula (III), said compound (II) being an amino acid selected from the group comprising alanine, arginine, asparagine, aspartate, citrulline, cysteine, glutamate, glutamine, glycine, histidine, homocysteine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine, valine, or a pharmaceutically acceptable salt thereof, it being understood that when n = 0, m = 1 and X is tryptophan, Y is not alanine, when n = 0, m = 1 and X is tyrosine, Y is not lysine; and when n = 1, m = 1 and X is tryptophan, Z is proline, Y is not valine; said compound (III) is a compound in which - q = 1; - R8 represents an oxygen atom, a sulfur atom; R5, R6, R7 represent, independently of each other, a hydrogen atom, a C1-C10 alkyl group, a C2-C10 alkene group, a C6-C18 aryl group, said alkyl, alkenyl groups; and ayl being optionally substituted by one or more groups selected from the group consisting of: • a C1-C6 alkyl group, a carboxyl group, a group-COOR3, a group -OR03, a hydroxyl group, a C1-C4 alkoxy group, -CONR3R4 , -NR3-CO-R4, -NR3R4, a halogen atom, a guanidine group; A 5- or 6-membered heterocycle chosen from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine, tetrahydrofuran, pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group, a carboxyl group, a group -COOR3, a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, a halogen atom, a guanidine group; A phenyl group optionally substituted by one or more groups selected from the group consisting of a C 1 -C 6 alkyl group, a carboxyl group, a COOR 3 group, a COR 3 group, a hydroxyl group, a C 1 -C 4 alkoxy group, - NR 3 R 4, a halogen atom (Cl, Br, I, F), a guanidine group; R3 and R4 represents, independently of one another, a hydrogen atom, a C1-C6 alkyl group, piperazine said alkyl group and piperazine being optionally substituted with a carboxyl group, a -COOR3 group, a -COR3 group, a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, a halogen atom; or a pharmaceutically acceptable salt thereof. 4. A cyclopeptide according to any one of claims 1 to 3 of formula (I): wherein Ala is alanine; ^ Gly represents glycine; Val represents valine; n = 0; M = 1; X, Y represent, independently of one another, a compound of formula (II) and / or a compound of formula (III), said compound (II) being an amino acid selected from the group comprising alanine arginine, asparagine, aspartate, citrulline, cysteine, glutamate, glutamine, glycine, histidine, homocysteine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine, valine, it being understood that when X is tryptophan, Y is not alanine; and when X is tyrosine, Y is not lysine; said compound (III) is a compound in which - q = 1; R8 represents an oxygen atom; R5, R6, R7 represent, independently of each other, a hydrogen atom, a C1-C10 alkyl group, a C2-C10 alkene group, a C6-C18 aryl group, the said alkyl groups, alkene groups; and aryl being optionally substituted by one or more groups selected from the group consisting of: • a C1-C6 alkyl group, a carboxyl group, a -COOR3 group, a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, an atom halogen; A 5- or 6-membered heterocycle chosen from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine, tetrahydrofuran, pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group, a carboxyl group, a group -COOR3 a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, a halogen atom; A phenyl group optionally substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group, a carboxyl group, a COOR3 group, a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, an atom of halogen; R3 and R4 represent, independently of each other, a hydrogen atom, a C1-C6 alkyl group, the piperazine, said alkyl group and piperazine being optionally substituted by a carboxyl group, a COOR3 group; a group -COR3, a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, a halogen atom; or a pharmaceutically acceptable salt thereof. 25 5. A cyclopeptide according to any one of claims 1 to 3, of formula (I): in which ^ Ala represents alanine; Gly represents glycine; Val represents valine; n = 1; m = 0; Y and Z represent, independently of one another, a compound of formula (II) and / or a compound of formula (III), said compound (II) being an amino acid selected from the group consisting of alanine, arginine, asparagine, aspartate, citrulline, cysteine, glutamate, glutamine, glycine, histidine, homocysteine, isoleucine, leucine, lysine, methionine , ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, threonine, tryptophan, tyrosine, valine, it being understood that when Y is tryptophan, Z is not alanine ; and when Y is tyrosine, Z is not lysine; said compound (III) is a compound in which - q = 1; R8 represents an oxygen atom; R5, R6, R7 represent, independently of one another, a hydrogen atom, a C1-C10 alkyl group, a C2-C10 alkene group, a C6-C18 aryl group, the said alkyl groups, alkene groups; and aryl being optionally substituted by one or more groups selected from the group consisting of: • a C1-C6 alkyl group, a carboxyl group, a group-COOR3, a hydroxyl group, a C1-C4 alkoxy group, -NR3R4, a halogen atom; A 5- or 6-membered heterocycle selected from pyrrolidine, pyrrole, 1-pyrroline, 2-pyrroline, 3-pyrroline, imidazole, thiophene, furan, piperidine, piperazine and tetrahydrofuran, pyridine, indole, quinoline, benzofuran, benzopyrrole, benzothiophene, said heterocycle being optionally substituted by one or more groups selected from the group consisting of a C1-C6 alkyl group, a carboxyl group, a group COOR 3, a hydroxyl group, a C 1 -C 4 alkoxy group, -NR 3 R 4, a halogen atom; A phenyl group optionally substituted with one or more groups selected from the group consisting of a C 1 -C 6 alkyl group, a carboxyl group, a COOR 3 group, a hydroxyl group, a C 1 -C 4 alkoxy group, -NR 3 R 4, a halogen atom; ; R3 and R4 represent, independently of one another, a hydrogen atom or a C1-C6 alkyl group, the piperazine, said alkyl group and piperazine being optionally substituted with a carboxyl group; COOR 3, a group -COR 3, a hydroxyl group, a Cl-C 4 alkoxy group, -NR 3 R 4, a halogen atom; or a pharmaceutically acceptable salt thereof. 10 6. Process for the preparation of a cyclopeptide of formula (I) according to any one of claims 1 to 5, in which: a) a compound of formula (IV) or (V) is cyclized; Z) n (X) m Gly H \ Val / \ Y / \ AI \ OH Pr (IV) Pr Pr (X) m Gly (Z) n H \ Y / \ Ala / \ Va / \ OH Pr (V) wherein Ala, Gly, Val, X, Y, Z, n, m are as described in any one of Claims 1 to 5, and selected. Pr is a protecting group in the group consisting of acetamidomethyl (Acm) ), allyloxycarbonyl (Alloc), t-butyloxycarbonyl (Boc), benzyloxymethyl (Bom), 2- (4-biphenylyl) propyl (2) oxycarbonyl (Bpoc), 2-bromobenzyloxycarbonyl (Br-Z), butoxymethyl (Bum), benzoic acid (Bz), benzyl (Bzl), dichlorobenzyl (Cl2Bzl), 2-chlorobenzyloxycarbonyl (CIZ), N- [1- (4,4-dimethyl-2), 6-dioxocyclohexylidene) ethyl] (Dde), dithia-succinyl (Dts), 4-methoxybenzyl (Mbzl), 4-methylbenzyl (MeBzl), methoxybenzyl (Mob), 4-methoxy-2,3,6- t trimethylbenzene sulfonyl (Mtr), mesitylene-2-sulfonyl (Mts), 2-nitro-phenylsulfenyl (Nps), benzyl ester (OBzl), tert-butyl ester (O-tBu), 2,2,4,6 , 7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), 2,2,5,7,8-pentamethyl-chroman-6-sulfonyl (Pmc), tert-butyl (tBu), trimethoxybenzyl (Tmob), triphenylmethyl (trityl or trt), in the presence of a cyclization agent; b) the protecting groups of the different compounds X, Y, Z are cleaved to recover the starting compounds X, Y, Z. 7. Preparation process according to claim 6, wherein the compounds (IV) and (V) respectively, from the compounds of formula (VI) and (VII): Pr1 Pr Pr Pr1 (Z) n (X) m Gly \ Val / \ Y / \ AI / \ Rs PrPr Pr (X) m Gly (Z) n ~ Y / / \ / \ Va / l \ Rs Pr where: • Ala, Gly, Val, X, Y , Z, n, m, are as defined in any one of claims 1 to 5; Pr, Pr1 are protective groups chosen, independently of one another, from the group comprising acetamidomethyl (Acm), allyloxycarbonyl (Alloc), t-butyloxycarbonyl (Boc), benzyloxymethyl (Bom) , 2- (4-biphenylyl) propyl (2) oxycarbonyl (Bpoc), 2-bromobenzyloxycarbonyl (Br-Z), butoxymethyl (Bum), benzoic acid (Bz), benzyl (Bzl), dichlorobenzyl (Cl2Bzl), 2-chlorobenzyloxycarbonyl (CIZ), N- [1- (4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl] (Dde), dithia-succinyl (Dts), fluorenylmethyloxycarbonyl chloride ( Fmoc), 4-methoxybenzyl (Mbzl), 4-methylbenzyl (MeBzl), methoxybenzyl (Mob), 4-methoxy-2,3,6-trimethylbenzene sulfonyl (Mtr), mesitylene-2-sulfonyl (Mts) , 2-nitro-phenylsulfenyl (Nps), benzyl ester (OBzl), tert-butyl ester (O-tBu), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), 2 , 2,5,7,8-pentamethyl-chroman-6-sulfonyl (Pmc), tert-butyl (tBu), 2,4,6- trimethoxybenzyl (Tmob), triphenylmethyl (trityl or trt); Rs is a resin selected from the group consisting of SASRIN, SASRIN-2-pyridylthiocarbonate resin, WANG resin, 2-chlorotrityl resin, TENTAGEL resin, WANG-TENTAGEL resin, Wang-PEG resin, benzhydrylamine resin, polystyrene-NH2 resin, Merrifield resin, 4-methylbenzhydrylamine resin (MBHA-resin, PAL-MBHA-resin), 4-hydroxymethylbenzylamide-synbeads resin, 4-hydroxymethylphenoxyacetylamidomethylpolystyrene resin (HMPA-resin); after cleavage of the protective group Pr1 and the resin Rs. 8. Preparation process according to claim 7, wherein the compound (VI) is prepared by the successive coupling between a compound of formula (VIII): and Ala-Pr1, (Pr-X) m-Pr1, (Pr- Y) -Pr1, (Pr-Z) n-Pr1, Val-Pr) respectively, and the compound (VII) by the successive coupling between a compound of formula (IX): Pr and Val-Pr1, Gly-Pr1 , Ala-Pr1, (Pr-X) m-Pri, (Pr-Y) -Pri, respectively, where Ala, Gly, Val, X, Y, Z, n, m, Pr and PI are as defined at any one of claims 1 to 7, in the presence of a coupling agent. 9. A pharmaceutical composition comprising a cyclopeptide according to any one of claims 1 to 5, and optionally one or more pharmaceutically acceptable excipient (s). 10. A cyclopeptide according to any of claims 1 to 5 or a composition according to claim 9 for use as a medicament. Cyclopeptide according to any of claims 1 to 5 or the composition of claim 9 for the prevention or treatment of a disease associated with angiogenesis. The cyclopeptide of any one of claims 1 to 5 or the composition of claim 9 for the prevention or treatment of a disease associated with angiogenesis selected from the group consisting of tumor growth (colon tumor, breast liver, kidney and prostate), metastatic dissemination (colon tumor, breast, liver, kidney and prostate), hemangiomas, rheumatoid arthritis, endometriosis, atherosclerosis, diabetic retinopathy and macular degeneration. 13. Cyclopeptide according to any one of claims 1 to 5 or composition according to claim 9 for the prevention or treatment of tumor growth (colon, breast, liver, kidney and prostate). 25