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Definitions

• the present invention relates to N-acylated agonist octasaccharides of the FGFs / FGFRs system, to their preparation and to their therapeutic application.
• Angiogenesis is a process of generating new capillaries. When obstruction of a blood vessel, angiogenesis, associated with arteriogenesis (dilation of capillaries), improves revascularization of the obstructed area. It has been shown in vitro and in vivo that several growth factors, such as Fibroblast Growth Factors (FGFs), stimulate the process of neovascularization.
• FGFs Fibroblast Growth Factors
• FGF2 (or basic FGF) is an 18 kDa protein. FGF2 induces at the endothelial cells in culture their proliferation, their migration and the production of proteases. In vivo, FGF2 promotes neovascularization phenomena. FGF2 interacts with endothelial cells via two classes of receptors, high affinity receptors with tyrosine kinase activity (FGFRs) and low affinity heparan sulfate proteoglycan (HSPG) receptors.
• FGFRs tyrosine kinase activity
• HSPG heparan sulfate proteoglycan
• tyrosine kinase cell surface receptors associate as a dimer with a complex of two ligand molecules and a heparan sulfate molecule. The formation of this complex triggers a cascade of intracellular signals leading to the activation of proliferation and cell migration, two key processes involved in angiogenesis.
• FGF2 and its receptors represent highly relevant targets for therapies aimed at activating or inhibiting angiogenesis processes.
• Synthetic oligosaccharides have also been the subject of interaction studies with FGF receptors (C. Tabeur et al., Bioorg et al., Chem., 1999, 7, 2003-2012, C. Noti et al. J. Chem., 2006, 12, 8664-8686).
• novel synthetic oligosaccharide compounds capable of facilitating the formation of the FGF / FGFRs complex and thus promoting the survival of endothelial cells in vitro and increasing the formation of neovessels in vitro and in vivo.
• the present invention relates to novel octasaccharide compounds corresponding to formula (I):
• the wavy line denotes a bond situated either below or above the plane of the pyranosic ring of the glucosamine unit
• R 1 represents an O-alkyl group, in which said alkyl group comprises from 1 to 16 carbon atoms and is optionally substituted by one or more (for example 1 or 2) groups, identical or different, chosen from aryl and cycloalkyl groups; ,
• R 2 represents either a 3 " OSO group or a hydroxyl group
• R 3 represents an alkyl, cycloalkyl or alkyl-cycloalkyl group
• R 4 represents a disaccharide of formula (II):
• R 3 is as defined above
• R 5 represents either a 3 " OSO group or a hydroxyl group
• R 3 is as defined above
• R 7 represents either a 3 " OSO group or a hydroxyl group
• R 3 represents a disaccharide of formula (IV):
• R 3 is as defined above
• R 9 represents either a 3 " OSO group or a hydroxyl group.
• alkyl group a saturated linear or branched aliphatic group. Unless otherwise indicated in the text, such an alkyl group advantageously comprises between 1 and 6 carbon atoms.
• alkyl group advantageously comprises between 1 and 6 carbon atoms.
• cycloalkyl group a cyclic alkyl group comprising from 3 to 6 carbon atoms, for example a cyclopentyl or cyclohexyl group;
• alkyl-cycloalkyl group an alkyl group itself substituted with a cycloalkyl group, said alkyl and cycloalkyl groups being as defined above;
• aryl group a cyclic aromatic group comprising between 5 and 10 carbon atoms, such as a phenyl group. Such an aryl group is optionally substituted with one or more groups such as halogen atoms and alkyl, alkoxy, thioalkyl, trifluoromethyl and phenyl groups.
• the octasaccharides according to the invention are synthetic oligosaccharides, that is to say they are compounds obtained by total synthesis from intermediate synthons, as will be described in detail in the following. In this respect, they differ from oligosaccharides obtained by depolymerization or isolation from complex mixtures of polysaccharides, of heparin or heparin type of low molecular weight.
• the compounds according to the invention have a well-defined structure resulting from their chemical synthesis and are in the form of pure octasaccharides, that is to say free of other oligosaccharide species.
• the invention encompasses compounds of formula (I) in acid form or in the form of any of their pharmaceutically acceptable salts.
• the -COO " and -SO 3 " functions are respectively in the form of -COOH and -SO 3 H.
• pharmaceutically acceptable salt means compounds of the invention, a compound in which one or more of the functions - COO " or / and -SO 3 " are ionically bonded to a pharmaceutically acceptable cation.
• the preferred salts according to the invention are those whose cation is chosen from alkali metal cations, in particular the Na + cation.
• the compounds of formula (I) according to the invention also include those in which one or more hydrogen or carbon atoms have been replaced by their radioactive isotope, for example tritium or C 14 carbon.
• radioactive isotope for example tritium or C 14 carbon.
• the disaccharide of formula (II) is bonded to the disaccharide unit represented in formula (I) by the oxygen atom located in position 1 of its glucosamine unit,
• glucosamine unit is understood to mean the monosaccharide unit of the following formula:
• the other type of saccharide unit present in the compounds according to the invention is a uronic acid, more specifically an iduronic acid, corresponding to the following formula:
• a uronic acid more specifically an iduronic acid
• the compounds of formula (I) according to the invention which are octasaccharides, can also be represented according to the formula (I ') as follows, in which the iduronic units and the glucosamine units follow one another and in which Ri, R 2, R3, Rs, R 7 and R 9 are as defined previously:
• alkyl group comprises from 5 to 16 carbon atoms, advantageously from 5 to 12 carbon atoms (for example a -O-pentyl, -O-undecyl or 2-propyl-pentyl group; )
• alkyl group contains from 1 to 8 carbon atoms, advantageously from 3 to 6 carbon atoms (for example a -O-propyl or -O-pentyl group), and is substituted by 1 or 2 groups, identical or different, chosen from aryl and cycloalkyl groups (for example phenyl and cycloalkyl groups, such as cyclohexyl).
• R 3 represents either an alkyl group comprising from 2 to 6 carbon atoms (for example a propyl or pentyl group), a cycloalkyl group (for example a cyclopentyl group).
• alkyl group comprises from 5 to 16 carbon atoms, advantageously from 5 to 12 carbon atoms (for example a -O-pentyl, -O-undecyl or 2-propyl-pentyl group) ,
• alkyl group contains from 1 to 8 carbon atoms, advantageously from 3 to 6 carbon atoms (for example a -O-propyl or -O-pentyl group), and is substituted with 1 or 2 groups, identical or different, chosen from aryl and cycloalkyl groups (for example phenyl and cycloalkyl groups, such as cyclohexyl),
• R 3 represents either an alkyl group comprising from 2 to 6 carbon atoms (for example a propyl or pentyl group), or a cycloalkyl group (for example a cyclopentyl group), and
• At least one of the groups R 2 , R 5 , R 7 and R 9 represents a hydroxyl group.
• the compounds of the invention there may be mentioned the following octasaccharides:
• the process for preparing the compounds according to the invention uses di- or oligosaccharide base synthons prepared as previously reported in the literature. Reference is made in particular to patents or patent applications EP 0 300 099, EP 0 529 715, EP 0 621 282 and EP 0 649 854, as well as the publication of C. Van Boeckel and M. Petitou published in Angew. Chem. Int. Ed. Engl., 1993, 32, 1671-1690. These synthons are then coupled to each other so as to provide a fully protected equivalent of an octasaccharide according to the invention. This protected equivalent is then converted into a compound according to the invention. In the coupling reactions mentioned above, a "donor" di- or oligosaccharide, activated on its anomeric carbon, reacts with a "acceptor” di- or oligosaccharide having a free hydroxyl.
• the present invention therefore relates to a process for the preparation of the octasaccharides of formula (I) / (I '), characterized in that:
• the N-acyl groups are introduced (introduction of the R 3 -CO- groups).
• the synthesis of the completely protected equivalent of the desired octasaccharide (I) is carried out according to reactions well known to those skilled in the art, using the methods for the synthesis of oligosaccharides (for example GJ, Boons, Tetrahedron (1996), 52, 1095-1121 and patent applications WO 98/03554 and WO 99/36443), wherein a glycosidic link donor oligosaccharide is coupled with a glycosidic link acceptor oligosaccharide to lead to another oligosaccharide whose size is equal to the sum of the sizes of the two reactive species. This sequence is repeated until the compound of formula (I) is obtained, optionally in protected form.
• oligosaccharides for example GJ, Boons, Tetrahedron (1996), 52, 1095-1121 and patent applications WO 98/03554 and WO 99/36443
• the nature and the charge profile of the desired final compound determine the nature of the chemical entities used in the various steps of the synthesis, according to the rules well known to those skilled in the art.
• the compounds of the invention can naturally be prepared using various strategies known to those skilled in the art of oligosaccharide synthesis. The process described above is the preferred method of the invention.
• the compounds of formula (I) / (I ') can be prepared by other well known methods of the chemistry of sugars, described for example in “Monosaccharides, Their chemistry and their roles in natural products", PM Collins and RJ. Ferrier, J. Wiley & Sons (1995) and by GJ. Boons in Tetrahedron (1996), 52, 1095-1 121.
• the protective groups used in the process for the preparation of the compounds of formula (I) / (I ') are those which make it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, d on the other hand, to regenerate the intact reactive function at the end of synthesis.
• the protective groups commonly used in the chemistry of sugars as described for example in "Protective Groups in Organic Synthesis", Green et al., 3 rd Edition (John Wiley & Sons, Inc., New York).
• the protecting groups are chosen, for example, from acetyl, methyl, pentenyl, benzoyl, levulinyl, benzyl, substituted benzyl, azides, benzyl carbamate, tert-butyldimethylsilyl (tBDMS) or tert-butyldiphenylsilyl (tBDPS) groups.
• Activator groups may also be used; these are those conventionally used in sugar chemistry, for example according to GJ. Boons, Tetrahedron (1996), 52, 1095-121. These activating groups are chosen for example from imidates or thioglycosides.
• the process described above makes it possible to obtain the compounds of the invention in the form of salts, advantageously in the form of the sodium salt.
• the compounds of the invention in the form of salts can be contacted with a cation exchange resin in acid form.
• the compounds of the invention in the form of acids can then be neutralized with a base to obtain the desired salt.
• any mineral or organic base giving, with the compounds of formula (I) / (I') pharmaceutically acceptable salts may be used.
• the subject of the invention is also the compounds of formula (V) below, in which Alk represents an alkyl group, Ri is as defined previously in with the compounds of formula (I) / (I '), bet Pg, Pg' and Pg ", which are identical to or different from one another, represent protective groups:
• Such compounds are useful as synthesis intermediates for the compounds of formula (I) / (I ').
• the subject of the invention is the compounds (V) in which Alk represents a methyl group and Pg, Pg 'and Pg "respectively represent benzyl, tBDPS and acetyl groups, More particularly from these compounds of formula (V), the invention is directed to those wherein R 1 is selected from the following groups: -O-methyl, -O- (CH 2 ) 5 -phenyl, -O-CH 2 -CH (C 3 H 7 ) 2, -O- (CH 2 ) SC 6 H 11 and -O- (CH 2 ) 2 -CH (phenyl) 2 .
• Such compounds correspond to the disaccharides 58, 131, 132, 133 and 134 illustrated in the following synthetic schemes, which are useful for the synthesis of compounds 10, 11 and 14 to 19 according to the invention, such as will be detailed in the following.
• the subject of the invention is also the compounds of formula (VI) below, in which Alk represents an alkyl group and Pg, Pg 'and Pg ", which are identical or different from one another, represent protective groups:
• Such compounds are useful as synthesis intermediates for the compounds of formula (I) / (I).
• the subject of the invention is the compound (VI) in which Alk represents a methyl group and Pg, Pg 'and Pg "respectively represent benzyl, levulinyl and acetyl groups,
• Such a compound corresponds to the disaccharide 24 illustrated in the diagrams Synthesis which follows, which is useful for the synthesis of compounds 1 to 4 according to the invention, as will be detailed in the following.
• Rf Retardation factor (retention time measured on the TLC compared to the front of the migration solvent)
• reaction mixture is diluted with ethyl acetate, washed with water, dried (Na 2 SO 4 ), filtered and concentrated, then purified on silica gel (acetone-cyclohexane) to lead to 21 (15.8 g, 76%).
• reaction mixture After 10 min of magnetic stirring at 0 ° C., then 1 h 45 at room temperature, the reaction mixture is diluted with dichloromethane, then successively washed with a 10% aqueous solution of potassium hydrogen sulphate, with water, and then with organic phase is dried (Na 2 SO 4 ), filtered and concentrated.
• the resulting residue is dissolved in ⁇ - / -dimethylformamide (210 mL), and potassium hydrogen carbonate (17 g, 5 molar equivalents) as well as methyl iodide (21 mL, 10 molar equivalents). are added together.
• the reaction mixture is stirred at ambient temperature for 16 hours and then concentrated in vacuo.
• the residue is diluted with ethyl acetate and then washed with water, with a saturated aqueous solution of sodium thiosulfate, with a saturated aqueous sodium chloride solution, then dried (Na 2 SO 4 ), filtered and concentrated.
• the compound obtained is engaged in the next step without purification.
• a solution of tert-butyldimethylsilyl triflate in dichloromethane (1 M, 0.1 mole per mole of imidate) is added, under argon, at -15 ° C, to a solution of imidate 38 (2.61 g 2.92 mmol) and glycosyl acceptor 31 (4.78 g, 2.25 mmol) in dichloromethane (146 ml) in the presence of 4 ⁇ molecular sieve (1.99 g).
• imidate 38 is again added at intervals of between 15 and 30 min, until the maximum consumption of the acceptor 31 is reached.
• reaction mixture After filtration and partial concentration, the reaction mixture is purified on LH-20 exclusion column using a 1: 1 methanol / dichloromethane mixture as eluent, then after collecting the fractions containing the product and concentration in vacuo, the residue is purified on silica gel with dichloromethane / ethyl acetate / ethanol to provide compound 40 (185 mg, 69%).
• Triethylamine / sulfur trioxide complex (513 mg, 5 moles per hydroxyl function) is added to a solution in ⁇ /, ⁇ -dimethylformamide (6.3 ml, 90 L / mol) of compound 40 (178 mg, 70.8 ⁇ mol). .
• methanol is added at 0 ° C. and after 0.5 h of stirring at 0 ° C. and 0.5 h at room temperature, the reaction medium is purified. using an LH-20 column using a 9: 1 methanol / ⁇ /, ⁇ / -dimethylformamide mixture as eluent.
• the product-containing fractions are then concentrated under high vacuum to yield the desired compound 41 (241 mg, 87%).
• reaction mixture After filtration and partial concentration, the reaction mixture is purified on LH-20 exclusion column using a 1: 1 methanol / dichloromethane mixture as eluent, then after collecting the fractions containing the product and concentration in vacuo, the residue is purified on silica gel with toluene / acetone / ethyl acetate / ethanol to provide 46 (83 mg, 61%).
• reaction mixture After filtration and partial concentration, the reaction mixture is purified on LH-20 exclusion column using a 1: 1 methanol / dichloromethane mixture as eluent, then after collecting the fractions containing the product and concentration in vacuo, the residue is purified on silica gel with dichloromethane / ethyl acetate / ethanol to provide compound 47 (141 mg, 69%).
• Triethylamine / sulfur trioxide complex (225 mg, 5 moles per hydroxyl function) was added to a solution in ⁇ -dimethylformamide (2.8 ml, 90 L / mol) of compound 46 (81 mg, 31 ⁇ mol). . After 16 hours of magnetic stirring at 50 ° C. in the absence of light, methanol (0.2 ml) is added at 0 ° C. and after stirring for 35 minutes at room temperature.
• reaction mixture is purified using an LH-20 column using a 1: 1: 0.1 methanol / dichloromethane / ⁇ /, ⁇ / - dimethylformamide as the eluent. Fractions containing the product are then concentrated under high vacuum to yield the desired compound 48 (122 mg, 99%).
• Triethylamine / sulfur trioxide complex (385 mg, 5 moles per hydroxyl function) was added to a solution in ⁇ -dimethylformamide (4.7 ml, 90 L / mol) of compound 47 (138 mg, 53 ⁇ mol). .
• methanol (0.35 ml) is added at 0 ° C. and after stirring for 30 minutes at 0 ° C. and then for 1 hour at room temperature, The reaction medium is purified using an LH-20 column using a mixture of 1: 1: 0.1 methanol / dichloromethane / N, N-dimethylformamide as eluent. Fractions containing the product are then concentrated under high vacuum to yield the desired compound 49 (194 mg, 92%).
• Rf 0.37, silica gel, cyclohexane / ethyl acetate 1/3
• Rf 0.23, silica gel, cyclohexane / ethyl acetate 1/3
• Rf 0.42, silica gel, cyclohexane / ethyl acetate 2/1
• Rf 0.40, silica gel, cyclohexane / ethyl acetate 2/1.
• Rf 0.30, silica gel, cyclohexane / ethyl acetate 2/1
• Rf 0.34, silica gel, cyclohexane / ethyl acetate 2/1
• reaction mixture After stirring for 8 hours at room temperature, the reaction mixture is placed at -18 ° C. for 16 h and then again for 2.5 h at room temperature. The medium is then diluted with ethyl acetate and then neutralized with 1N HCl in cold (0-4 ° C.), washed with water, dried (Na 2 SO 4 ), filtered and concentrated. and purified on silica gel (ethyl acetate - cyclohexane 15/85) to yield 70 (3.83 g, 91%).
• Rf 0.26, silica gel, ethyl acetate / pyridine / acetic acid / water 28/16 / 3.8 / 9.
• a mixture of the glycosyl acceptor 65 (1.82 g, 1.00 mmol), imidate 27 (1.35 g, 1.50 mmol), and 4 ⁇ molecular sieve powder (1, 12 g) in dichloromethane (52 ml) is stirred under argon for 1 hour at 25 ° C.
• the reaction mixture is cooled to -20 ° C. and then a 1M solution of tert-butyldimethylsilyl triflate in dichloromethane (224 ⁇ l) is added. After 50 minutes, the reaction medium is neutralized by addition of sodium hydrogencarbonate solid. After filtration through Celite ®, the reaction mixture is diluted with dichloromethane (500 ml_).
• Compound 80 (820 mg, 0.257 mmol) is saponified according to the method used for the preparation of compound 73 to give octasaccharide 81 (593.8 mg) after flash chromatography on silica gel column (toluene / acetone 1/0 ⁇ 0/1).
• reaction mixture is deposited on a Sephadex ® LH20 (120 x 3 cm, dichloromethane / ethanol 1/1) followed by flash chromatography on silica gel column (methanol / water 95/5) to give compound 83 (62.7 mg).
• Rf 0.27, silica gel, ethyl acetate / pyridine / acetic acid / water 17/9 / 2.2 / 5.
• Rf 0.37, silica gel, ethyl acetate / pyridine / acetic acid / water 17/9 / 2.2 / 5.
• Rf 0.25, silica gel, ethyl acetate / pyridine / acetic acid / water 17/9 / 2.2 / 5.
• Triethylamine / sulfur trioxide complex (761 mg, 5 moles per hydroxyl function) is added to a solution in ⁇ -dimethylformamide (11 ml, 90 L / mol) of compound 96 (324 mg, 120 ⁇ mol). ). After 17 hours of magnetic stirring at 55 ° C. in the dark, methanol is added at 0 ° C. and after 0.5 h of stirring at 0 ° C.
• the reaction medium is diluted with methanol and then purified using an LH-20 column using a 1: 1 methanol / dichloromethane mixture as eluent.
• the fractions containing the product are then concentrated under high vacuum and, if necessary, reactivated under the same conditions.
• the compound obtained 97 is then directly engaged in the next step.
• Rf 0.5 (AcOEt-pyridine-AcOH-H 2 O 1 1/7 / 1.6 / 4).
• Triethylamine / sulfur trioxide complex (376 mg, 5 moles per hydroxyl function) is added to a solution in ⁇ -dimethylformamide (5.3 ml, 90 L / mol) of compound 101 (160 mg, 59 ⁇ mol). .
• methanol is added at 0 ° C. and after 0.5 h of stirring at 0 ° C. and then 0.5 h at room temperature, the reaction medium is diluted. by methanol and then purified using an LH-20 column using a 1: 1 ethanol / dichloromethane mixture as eluent. The fractions containing the product are then concentrated under high vacuum. The compound obtained is then directly engaged in the next step.
• Rf 0.24 (cyclohexane - acetone 7/3).
• Triethylamine / sulfur trioxide complex (267 mg, 5 moles hydroxyl function) to a solution in ⁇ /, ⁇ -dimethylformamide (4.4 ml, 90 L / mol) of compound 109 (144 mg, 49 ⁇ mol).
• methanol is added at 0 ° C. and after 0.5 h of stirring at 0 ° C. and 0.5 h at room temperature, the reaction medium is diluted. with methanol and then purified using an LH-20 column using a 1: 1 methanol / dichloromethane mixture as eluent. The fractions containing the product are then concentrated under high vacuum. The compound obtained is then directly engaged in the next step.
• Triethylamine / sulfur trioxide complex (317 mg, 5 moles per hydroxyl function) is added to a solution in ⁇ /, ⁇ -dimethylformamide (4.5 ml, 90 L / mol) of compound 114 (135 mg, 50 ⁇ mol). .
• methanol is added at 0 ° C. and after 0.5 h of stirring at 0 ° C. and 0.5 h at room temperature, the reaction medium is diluted. by methanol and then purified using an LH-20 column using a 1: 1 ethanol / dichloromethane mixture as eluent. The fractions containing the product are then concentrated under high vacuum. Compound 115 (168 mg, 86%) is then obtained.
• Compound 122 (0.844 g, 0.80 mmol) is treated according to a protocol similar to that described for the synthesis of 124. In case of non completion of the reaction, the same amount of reagent may optionally be added. After treatment, the compound 126 is directly engaged in the next step.
• Rf 0.41 (cyclohexane-acetone 3/2).
• the compound 123 obtained above is dissolved in dichloromethane (173 ml). At 0 ° C. and under argon, triethylamine (7.6 ml, 2.5 molar equivalents), 4-dimethylaminopyridine (1.3 g, 0.5 molar equivalents) and tert-butyldiphenylsilyl chloride (1.2 ml.sup.3) are added successively. 2 molar equivalents). After 5.5 h of magnetic stirring, the reaction medium is diluted with dichloromethane, washed with an aqueous solution of potassium hydrogen sulfate at 10%, with a saturated aqueous solution of sodium chloride, dried
• Rf 0.46 (cyclohexane-acetone 3/2).
• Rf 0.42 (cyclohexane-acetone 7/3).
• glycosyl donor 63 (0.63 g, 0.57 mmol) and the glycosyl acceptor 133 (1.03 g, 0.95 mmol) are treated according to a protocol similar to that described for the synthesis of 136 to provide the compound 137 (716 mg, 62 mg). %).
• Rf 0.20 (cyclohexane-acetone 3/1).
• glycosyl donor 63 (0.63 g, 0.57 mmol) and the glycosyl acceptor 134 (0.83 g, 0.72 mmol) are treated according to a protocol similar to that described for the synthesis of 136 to provide compound 138.
• Rf 0.34 (cyclohexane-acetone 7/3).
• Rf 0.21 (cyclohexane-ethyl acetate 3/2).
• Rf 0.38 (cyclohexane-ethyl acetate 3/2).
• Rf 0.32 (cyclohexane-acetone 7/3).
• glycosyl donor 151 (0.56 g, 0.36 mmol) and the glycosyl acceptor
• Rf 0.36 (cyclohexane-acetone 3/2).
• glycosyl donor 151 (0.51 g, 0.33 mmol) and the glycosyl acceptor
• Rf 0.25 (cyclohexane-acetone 7/3).
• R (CH 2 J 3 Ph 2 Preparation of 5-phenylpentyl (methyl 3,4-di-O-benzyl- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-azido-3-O-benzyl-2-deoxy- ⁇ -D) -glucopyranosyl) - (1 ⁇ 4) - (methyl 3-O-benzyl- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-azido-3-O-benzyl-2-deoxy- ⁇ -D- glucopyranosyl) - (1 ⁇ 4) - (methyl 3-O-benzyl- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-azido-3-O-benzyl-6-O-tert-butyldiphenylsilyl) -2-deoxy- ⁇ -D-glucopy
• Rf 0.20 (cyclohexane-acetone 7/3).
• Triethylamine / sulfur trioxide complex (775 mg, 5 moles per hydroxyl function) is added to a solution in ⁇ /, ⁇ -dimethylformamide (12.8 ml, 90 L / mol) of compound 155 (438 mg, 142 ⁇ mol). .
• methanol is added at 0 ° C. and after 0.5 h of stirring at 0 ° C. and then at ambient temperature for 1 h, the reaction medium is diluted. by methanol and then purified using an LH-20 column using a 9: 1 methanol / N, N-dimethylformamide mixture as eluent.
• the product-containing fractions are then concentrated under high vacuum to yield the desired compound 159 (571 mg, 96%).
• Compound 156 (178 mg, 0.054 mmol) is treated according to a protocol similar to that described for the synthesis of 159 to provide 160 (196 mg, 75%).
• the product-containing fractions are then partially concentrated and then the residue is purified using an LH-20 column using a 9: 1 methanol / N-dimethylformamide mixture as eluent.
• the product-containing fractions are then concentrated under high vacuum to afford 163 (295 mg, 74%).
• Compound 168 is treated according to a protocol similar to that described for the synthesis of 171 to provide compound 172 (47 mg, 74% (2 steps)).
• EXAMPLE 1 Sodium pentyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate H1 ⁇ 4H2-acetamido-2-deoxy-6-O-sodium sulfonato- ⁇ -D-glucopyranosyl)
• Pentyl (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2- (1-oxobutyl) amino-6-O-sodium sulfonato- ⁇ - D-glucopyranosyl) - (1 ⁇ 4H 2 -O-sodium sulfonato- ⁇ -L-idopyranosyluronate sodium) - (1 ⁇ 4) - (2-deoxy-2- (1-oxobutyl) amino-6-O-sodium sulfonato - ⁇ -D-glucopyranosyl) -
• N-dimethylformamide / water 2.9 ml
• diisopropylethylamine 33 ⁇ l, 17 equivalents
• molar in solution in N, N-dimethylformamide (100 ⁇ l), as well as N-hydroxysuccinimide butyrate (27.4 mg,
• reaction medium is deposited on top of a Sephadex ® G-25 eluted with 0.2M sodium chloride was concentrated fractions containing product and desalified using the same column eluted by water. The product-containing fractions are then concentrated under high vacuum to yield the desired compound 2 (26 mg, 89%).
• EXAMPLE 3 Pentyl (sodium 2-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2- (1-oxohexyl) amino-6-O-sodium sulfonato- ⁇ - D-glucopyranosyl) - (1 ⁇ 4H 2 -O-sodium sulfonato- ⁇ -L-idopyranosyluronate sodium) -
• reaction medium is then deposited on top of a Sephadex ® G-25 eluted with 0.2M sodium chloride was concentrated fractions containing product and desalified using the same column eluted with water. The product-containing fractions are then concentrated under high vacuum to yield the desired compound 3 (4 mg, 34%).
• EXAMPLE 4 Pentyl (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2 - [(cyclopentylcarbonyl) amino] -2-deoxy-6-O-sodium sulfonato- ⁇ -D - glucopyranosyl) - (1 ⁇ 4H 2 -O-sodium sulfonato- ⁇ -L-idopyranosyluronate sodium) -
• the reaction medium is deposited on top of a Sephadex ® G-25 eluted with 0.2M sodium chloride was concentrated fractions containing product and desalted using the same column eluted by water. The fractions containing the product are then concentrated under high vacuum to yield the desired compound 4 (5.6 mg, 55%). In case of incomplete reaction, the product obtained can be re-engaged under the same conditions.
• EXAMPLE 6 sodium 5-phenylpentyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-acetamido-2-deoxy-6-O-sodium sulfonato- ⁇ -D) -glucopyranosyl) -
• EXAMPLE 7 sodium methyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-acetamido-2-deoxy-6-O-sodium sulfonato- ⁇ -D-glucopyranosyl) r (1 ⁇ 4) - (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-acetamido-2-deoxy-6-O-sodium sulfonato- ⁇ -D- glucopyranosyl) 1?
• EXAMPLE 8 Sodium Methyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate H1 ⁇ 4H2-acetamido-2-deoxy-6-O-sodium sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (2) Sodium ⁇ -Sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4H 2 -acetamido-2-deoxy-6-O-sodium sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (2-O) sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-acetamido-2-deoxy- ⁇ -D-glucopyranosyl) - (1 ⁇ 4H 2 -O-s
• EXAMPLE 10 Sodium Methyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate H1 ⁇ 4H2-acetamido-2-deoxy- ⁇ -D-glucopyranosyl) - (1 ⁇ 4H2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate of sodium) - (1 ⁇ 4) - (2-acetamido-2-deoxy-6-O-sodium sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (2-O-sodium sulfonato- ⁇ -L) - sodium idopyranosyluronate) - (1 ⁇ 4H2-acetamido-2-deoxy-6-O-sodium sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4H2-O-
• EXAMPLE 1 1 Sodium methyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-acetamido-2-deoxy- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (Sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-acetamido-2-deoxy-6-O-sodium sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) Sodium (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-acetamido-2-deoxy-6-O-sodium sulfonato- ⁇ -D-glucopyranosyl) - (1) ⁇
• EXAMPLE 12 Sodium methyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-acetamido-2-deoxy-6-O-sodium sulfonato- ⁇ -D-glucopyranosyl)
• EXAMPLE 13 Sodium methyl-2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate H1 ⁇ 4H2-acetamido-2-deoxy-6-O-sodium sulfonato- ⁇ -D-glucopyranosyl (1 ⁇ 4) - (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-acetamido-2-deoxy- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) Sodium (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-acetamido-2-deoxy-6-O-sodium sulfonate- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (sodium
• EXAMPLE 14 sodium 5-phenylpentyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2- (1-oxobutyl) amino-6-O-sodium sodium sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4H2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2- (1-oxobutyl) amino-6- O-sodium sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2-)
• reaction medium is deposited on top of a Sephadex ® G-25 eluted with 0.2M sodium chloride was concentrated fractions containing product and desalted using the same column eluted by water. Fractions containing the product are then concentrated under high vacuum to yield the desired compound 14 (133 mg, 93%).
• EXAMPLE 15 sodium 2-propyl-pentyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2- (1-oxobutyl) amino-6-O-sodium sodium sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4H 2 -O-sodium sulfonato- ⁇ -L-idopyranosyluronate) -
• EXAMPLE 16 3-Cyclohexyl-propyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate sodium) -d ⁇ 4) - (2-deoxy-2-acetamido-6-O-sodium sulfonate- ⁇ -D- sodium glucopyranosyl) - (1 ⁇ 4H2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4H2-deoxy-2-acetamido-6-O-sodium sulfonato- ⁇ -D-glucopyranosyl-d ⁇ 4) Sodium (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) -d ⁇ 4) - (2-deoxy-2-acetamido- ⁇ -D-glucopyranosyl) -d ⁇
• EXAMPLE 17 3-Cyclohexyl-propyl (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2- (1-oxobutyl) amino-6-O-sodium sodium sulfonato- ⁇ -D-glucopyranosylH1 ⁇ 4) - (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2- (1-oxobutyl) amino-6- O-sodium sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2- (1)
• EXAMPLE 18 Sodium 3,3-diphenylpropyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2- (1-oxobutyl) amino-6-O) -sodium sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4H 2 -O-sodium sulfonato- ⁇ -L-idopyranosyluronate sodium) - (1 ⁇ 4) - (2-deoxy-2- (1-oxobutyl) amino) Sodium 6-O-sodium sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2-) (1-
• N-dimethylformamide / water 4.8 mL
• diisopropylethylamine 63 ⁇ L, 15 molar equivalents
• N-dimethylformamide (43 ⁇ l) in solution in N, N-dimethylformamide (43 ⁇ l), as well as N-hydroxysuccinimide butyrate (49 mg, 11 molar equivalents) in solution in ⁇ /, ⁇ -dimethylformamide (43 ⁇ l).
• Stirring is maintained at room temperature for 3 hours, then the same amount of reagent is added under the same conditions three times.
• reaction medium is deposited on top of a Sephadex ® G-25 eluted with 0.2M sodium chloride was concentrated fractions containing product and desalted using the same column eluted by water. Fractions containing the product are then concentrated under high vacuum to yield the desired compound 18 (6 mg, 98%).
• EXAMPLE 19 sodium 5-phenylpentyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2- (3-methyl-1-oxobutyl) amino-6 Sodium ⁇ -sodium sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) -
• the in vitro angiogenesis model corresponds to a rearrangement of human venous endothelial cells on a biological matrix.
• the matrix is formed by dispensing into each well of a 96 well plate (Becton Dickinson 353872), 60 .mu.l of Matrigel ® diluted 1/3 (Growth Factor Reduced Matrigel ®: Becton Dickinson 356230) in collagen (Rat Tail collagen, type I: Becton Dickinson 354249).
• the biological matrix cures after 1 hour at 37 ° C.
• Human venous endothelial cells (HUVEC ref: C-12200 - Promocell) seeded on the biological matrix at 7800 cells / well in 120 ⁇ l of EBM ® medium (Endothelial Basal Medium, Lonza C3121) + 2% FCS (fetal calf serum - Lonza) + hEGF (Recombinant Human Epidermal Growth Factor - Lonza) 10 ⁇ g / ml.
• the cells are stimulated with FGF2 (R & D Systems / 234-FSE-50) 10 ng / ml or with the products of the invention for 18 hours at 37 ° C in the presence of 5% CO 2 . After 24 hours, the cells are observed under a microscope (objective X4) and the analysis of the length of the pseudo-tubules is performed using an image software (BIOCOM-software Visiolab 2000).
• the compounds of the invention have a specific activity of between 10 -6 M and 10 -12 M.
• Compounds Nos. 1 and 2 are active at 10-11 M.
• This model is an adaptation of the model described by Andrade et al.
• Animals (white mice BALB / c inbred J) are anesthetized with Xylazine mixture (Rompun ®, 10 mg / kg) / Ketamine (Imalgene ® 1000, 100 mg / kg) intraperitoneally. The back of the animal is shaved and disinfected with Hexomedine ® . A pocket of air is created subcutaneously on the back of the mouse by injecting 5 ml of sterile air. An incision of about 2 cm, on the upper back of the animal is performed to introduce a sterile cellulose implant (disc 1 cm in diameter, 2 mm thick, Cellspon ® ref 0501) impregnated with 50 ⁇ l of sterile solution containing the product to be tested. The incision is then sutured and cleaned with Hexomedine ® .
• mice can receive in the implant the product by an injection through the skin (50 ⁇ l / implant / day) under gas anesthesia (Isoflurane 5% (Aerrane ® , Baxter)) .
• gas anesthesia Isoflurane 5% (Aerrane ® , Baxter)
• mice Seven days after laying the sponge, the mice are sacrificed by a lethal dose of Pentobarbital Sodium (CEVA Animal Health) administered intraperitoneally. The skin is then cut, about 1 cm around the sponge avoiding the scar to clear the skin and the sponge. The sponge is then cut into several pieces and placed in a Ribolyser ® tube containing 1 ml of lysis buffer (CeII Death Detection ELISA, Roche). The tubes are shaken 4 consecutive times, for 20 seconds, force 4, with the cell grinder (FastPrep ® FP 120). The tubes are then centrifuged for 10 minutes at 2000 g at 20 ° C. and the supernatants are frozen at -20 ° C. while waiting for the determination of hemoglobin.
• CeII Death Detection ELISA Roche
• the tubes are again centrifuged after thawing and the hemoglobin concentration is measured with Drabkin's reagent (Sigma, volume to volume) by spectrophotometer reading at 405 nm against a standard range of bovine hemoglobin (Sigma ).
• the concentration of hemoglobin in each sample is expressed in mg / ml according to the polynomial regression performed from the range. The results are expressed in mean value ( ⁇ sem) for each group. Differences between the groups are tested with ANOVA followed by a Dunnett test on the square root of the values.
• the compounds of the invention have demonstrated a specific activity of between 5 and 45 ng / site.
• Compounds No. 1 and 2 are active at 45 ng / site
• Compound No. 7 is active at 15 ng / site.
• compound No. 7 By way of comparison with a compound analogous to compound No. 7 according to the invention, but in which all the -NH-acyl groups are replaced by -NH-SO 3 - groups, compound No. 7 according to In this test, the present invention has an activity that is 21% higher than that of the fully sulfated analogue, which shows the importance of the N-acyl groups in the compounds according to the invention.
• pharmacokinetics The pharmacokinetic profile of the compounds according to the invention is evaluated after subcutaneous administration, in OF1 or C57 / BL6 mice, at a concentration of 30 mg / kg. The systemic exposure of the compounds is evaluated after single administration in the animal previously anesthetized with pentobarbital. The blood is removed from the vena cava and transferred to plastic tubes containing lithium heparin. After centrifugation (2000 g for 10 minutes at 8 ° C), the concentration of the compounds in the plasma is quantified by LC / MS-MS.
• the tested compounds show an improved pharmacokinetic profile (in particular AUC and higher plasma concentration, longer half-life times) compared to completely sulphated analogous compounds (replacement of N-acyl groups by groups).
• NH-SO 3 - the pharmacokinetic parameters of compounds 1, 6 and 7 according to the invention are described in the following table, in comparison with a fully sulfated analog No. 175 of the following formula:
• AUC Area Under the Curve between 0
• the invention therefore relates to medicaments which comprise a compound of formula (I) / (I ') according to the invention, or a pharmaceutically acceptable salt thereof.
• ischemia cardiac ischemia, arterial ischemia of the lower limbs
• diseases associated with a narrowing or obstruction of the arteries or arteritis the treatment of angina pectoris.
• treatment of thromboangiitis obliterans treatment of atherosclerosis, treatment of inhibition of restenosis after angioplasty or endoarterectomy, treatment of scarring, treatment for muscle regeneration, treatment for survival of myoblasts , treatment of peripheral neuropathy, treatment of postoperative nerve damage, treatment of nerve disorders such as Parkinson's disease, Alzheimer's disease, prion disease and neuronal degeneration in alcoholics, treatment of dementia, the treatment for improving the survival of the pancrofan bioartificial sheaves in the diabetic patient, the treatment of the improvement of graft revascularization and graft survival, the treatment of retinal degeneration, the treatment of retinitis pigmentosa, the treatment of osteoarthritis, the treatment of the pre - eclampsia or treatment of vascular lesions and acute respiratory distress syndrome, treatment for cartilage repair, treatment for bone repair and protection, treatment for repair and protection of hair follicles and for the protection and the regulation of capillary growth.
• Ischemia is a decrease in the arterial circulation in an organ resulting in a decrease in the oxygen concentration in the injured tissues.
• angiogenesis is the process of generating new capillaries from pre-existing vessels.
• Arteriogenesis contributes to the development (increase in size and caliber) of collateral vessels around the ischemic or avascular zone.
• FGF2 and in particular FGF-2 have been most widely described (Post, MJ, Laham, R., Sellke, FW & Simons, M. Therapeutic angiogenesis in cardiology using protein formulations, Cardiovasc Res 49, 522-31, 2001).
• FGF2 and its receptors represent highly relevant targets for therapies aimed at inducing the processes of angiogenesis and arteriogenesis (Khurana, R. & Simons, M. Insights from angiogenesis trials using fibroblast growth factor for advanced arteriosclerotic disease. Trends Cardiovasc Med 13, 1 16-22, 2003).
• One of the applications of the compounds of the invention is post-ischemic treatment after occlusion at the cardiac or peripheral arteries.
• cardiac ischemia one of the most promising clinical trials is a clinical trial in which FGF-2 was sequestered in microspheres of alginate in the presence of heparin (Laham, RJ et al. Local perivascular delivery of basic fibroblast growth factor in undergoing coronary bypass surgery patients: results of a phase I randomized, double-blind, placebo-controlled trial, Circulation 100, 1865-71, 1999).
• These micro-spheres were implanted near the ischemic focus at the level of the myocardium. After 90 days, all FGF2-treated patients had no ischemic heart symptoms.
• FGF2-mimicking compounds may be a therapy of choice for treating the consequences of cardiac ischemia.
• the compounds described in the invention may find an application in the treatment of diseases associated with a narrowing of the coronary arteries and in particular in the treatment of angina pectoris.
• Buerger's disease or thromboangiitis obliterans affects distal vascular structures and is characterized by distal arteritis of the legs with pain and ulceration.
• induction of angiogenesis and vasculogenesis would be a therapy for this pathology.
• the compounds of the present invention represent a therapy of choice for thromboangiitis obliterans.
• Peripheral neuropathy is an axonal or demyelinating lesion of the motor and / or sensory peripheral nerve that causes desensitization of the distal limbs.
• One of the major secondary complications of diabetes is the chronic development of peripheral neuropathy.
• FGF2 induces axonal regeneration which could be a therapy of choice in the treatment of peripheral nerve injury and thus in neuropathy.
• Peripheral fibroblast growth factor isoforms promote axonal elongation and branching of adult sensory neurons in vitro, Klimaschewski L, Nindl W, Feurle J, Kavakebi P, Kostron H. Neuroscience, 2004, 126 (2): 347-53). Because of the FGF receptor agonist activity, the compounds of said invention would be a treatment of choice in peripheral neuropathy in healthy or diabetic patients.
• FGF2 is an activator of nerve cells during development. Recent results suggest that FGF2 would also be a pivotal factor in promoting neuronal regeneration in adults (Sapieha PS, Peltier M, Rendahl KG, WC Manning, Di Polo A., Fibroblast growth factor-2 gene delivery stimulates axon growth by adult retinal ganglion cells after acute optic nerve injury Mol CeII Neurosci 2003 Nov; 24 (3): 656-72.
• the compounds of said invention would be a therapy of choice in the repair of postoperative nervous damage, in the repair of nerve deficits such as Parkinson's disease, Alzheimer's disease, prion disease , neuronal degeneration in the alcoholic or in cases of dementia.
• vascular smooth muscle cells contribute to intimal hypertrophy of the arteries and thus play a prominent role in atherosclerosis and restenosis after angioplasty and endoarterectomy.
• An angiogenic factor, VEGF has been shown to significantly reduce intimal thickening by accelerating re-endothelialization (Van Belle, E., Maillard, L., Tio, FO & Isner, JM Accelerated endothelialization by local delivery of recombinant human vascular endothelial growth factor reduces in-stent intimal formation Biochem Biophys Res Commun 235, 31 1-6, 1997).
• the compounds of the present invention possessing pro-angiogenic activity may be useful in the treatment of atherosclerosis and in the inhibition of restenosis after angioplasty or endoarterectomy.
• the vascular network is essential for tissue development and preservation. By promoting the delivery of nutrients, oxygen and cells, blood vessels help maintain the functional and structural integrity of tissues.
• angiogenesis and vasculogenesis help to preserve and infuse tissue after ischemia.
• Angiogenic growth factors such as VEGF and FGF2 thus promote revascularization for tissue regeneration.
• the compounds presented in the invention could represent a treatment of choice in the treatment for the regeneration of muscles.
• the processes of muscle regeneration on dystrophic or normal muscles depend on the supply of cytokines and angiogenic growth factors at the local level (Fibbi, G., D'Alessio, S., Pucci, M., Cerletti, M. & Dei Rosso, M. Growth factor-dependent proliferation and invasion of muscle satellite cells require the cell-associated fibrinolytic system, Biol Chem 383, 127-36, 2002). It has been proposed that the FGF system is a critical system for muscle regeneration, survival and proliferation of myoblasts (Neuhaus, P.
• FGF fibroblast growth factor
• Angiogenesis is an essential phenomenon during cutaneous healing.
• the newly formed vessels provide the oxygen and nutrients needed for tissue repair.
• scarring is a slow and difficult process with angiogenesis defects.
• FGFS are among the growth factors most involved in angiogenesis processes during the healing phase.
• Some FGFs are highly over-regulated in dermal cells after a skin injury. By their FGF receptor agonist activities, the compounds of said invention would be a therapy of choice for the treatment of wound healing in healthy or diabetic patients.
• the compounds of said invention represent a therapy of choice in improving the survival of the bioartificial pancreas graft in the diabetic patient and more generally in the improvement of graft revascularization. and therefore in the survival of grafts.
• Retinitis pigmentosa is a pathology involving progressive degeneration of the retina characterized by degeneration of photoreceptors and obliteration of the retinal vessels.
• Lahdenranta et al. (An anti-angiogenic state in mice and humans with retinal photoreceptor cell degeneration, Proc Natl Acad Sci USA 98, 10368-73, 2001) have proposed that angiogenic growth factors regulate neural coordination and associated retinal vascularization by functioning. simultaneously as photoreceptor survival factors and as regulator of endothelial cells.
• Pre-eclampsia is a pathology of the placenta associated with a lack of vascularization (Sherer, D. M. & Abulafia, O. Angiogenesis during implantation, and placental and early embryonic development, Placenta 22, 1-13, 2001). These defects of vascularization would be due to a defect of angiogenesis and would cause disturbances in the placenta which could lead to the death of the fetus.
• the compounds of the invention could be a treatment of choice to overcome a lack of angiogenesis in pre-eclamptic placentas.
• VEGF vascular endothelial growth factor
• FGF2 growth factors
• the intrinsic signaling pathway is activated by mitochondria in response to stress such as DNA deprivation or damage
• the extrinsic signaling pathway is induced by proapoptotic factor binding such as TNF- ⁇ or Fas.
• VEGF and FGF2 are two cell survival factors Endothelial (RoIe of Raf in Vascular Protection from Distinct Apoptotic Stimuli: A Alavi, JD Hood, R.
• Acute Respiratory Distress Syndrome is characterized by cardiovascular and neuropsychiatric problems.
• cardiovascular problems patients have significant vascular lesions and in particular an induction of apoptosis of endothelial cells high. Recently, Harnacher & al.
• bronchoalveolar lavage fluids from ARDS patients exhibited proapoptotic activity against microvascular lung endothelial cells (Tumor necrosis factor-alpha and angiostatin are mediators of endothelial cytotoxicity in bronchoalveolar washes of patients with acute respiratory distress syndrome Am J Respir Crit Care Med 2002 Sep 1; 166 (5): 651-6: Harnacher J, Lucas R, Lijnen HR, Buschke S, Dunant Y, Wendel A, Grau GE, Suter PM, Ricou B. ).
• the products of the invention could present a treatment of choice in the vascular improvement of patients with vascular lesions and in particular patients with ARDS.
• FGF7 or KGF
• FGF18 Is Highly Expressed in Hair Follicles and Capable of Inducing Anagen from Telogen Hair Follicles Stage: Mitsuko Kawano, Akiko Komi-Kuramochi, Masahiro Asada, Masashi Suzuki, Junko Oki, Ju Jiang and Toru Imamura).
• the compounds of said invention could present a treatment of choice for the repair and protection of hair follicles and in the protection and regulation of hair growth.
• the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
• These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt of said compound, as well as at least one pharmaceutically acceptable excipient.
• Said excipients are chosen according to the pharmaceutical form and the mode desired administration, among the usual excipients which are known to those skilled in the art.
• compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration the active ingredient of formula (I) ) above or its salt may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prevention or treatment of the above disorders or diseases.
• Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal forms of administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants.
• oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions
• sublingual, oral, intratracheal intraocular, intranasal forms of administration by inhalation
• topical, transdermal, subcutaneous, intramuscular or intravenous administration forms rectal administration forms and implants.
• the compounds according to the invention can be used in creams, gels, ointments or lotions.
• Injectable administration forms are particularly advantageous, comprising conventionally the active compound dissolved in water for injection, in the presence of sodium chloride.
• the unit dose of active compound must be adapted to the desired therapeutic effect; it may be for example between 0.1 and 100 mg of active ingredient.
• the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention or a pharmaceutically acceptable salt thereof acceptable.

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