EP2464359A2 - N-sulfierte oligosaccharide, die fgfs-rezeptoren aktivieren, ihre synthese und ihre therapeutische anwendung - Google Patents

N-sulfierte oligosaccharide, die fgfs-rezeptoren aktivieren, ihre synthese und ihre therapeutische anwendung

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Publication number
EP2464359A2
EP2464359A2 EP10761048A EP10761048A EP2464359A2 EP 2464359 A2 EP2464359 A2 EP 2464359A2 EP 10761048 A EP10761048 A EP 10761048A EP 10761048 A EP10761048 A EP 10761048A EP 2464359 A2 EP2464359 A2 EP 2464359A2
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EP
European Patent Office
Prior art keywords
sodium
sulfonato
deoxy
idopyranosyluronate
benzyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP10761048A
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English (en)
French (fr)
Inventor
Philippe Duchaussoy
Pierre Fons
Alexandre Froidbise
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Sanofi SA
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Sanofi SA
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Publication of EP2464359A2 publication Critical patent/EP2464359A2/de
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    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof

Definitions

  • the present invention relates to N-sulfated agonist oligosaccharides 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 receptor cell surface receptors associate as a dimer with a complex formed 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 studied in interactions with FGF receptors and showed their inhibitory effects on the binding of FGF-2 to its receptor on smooth muscle cells, with an IC50 of 16 ⁇ g / ml. mL, as well as an inhibition of the proliferation of these cells induced by FGF-2, with an IC50 of approximately 23 ⁇ g / mL (Tabeur et al., Bioorg. & Med. Chem., 1999, 7, 2003-2012, C. Noti et al., Chem Eur Eur, 2006, 12, 8664-8686).
  • the subject of the present invention is new oligosaccharide compounds corresponding to formula (I):
  • Ri represents a group -OSO 3 " or hydroxyl group
  • R 2 represents either an -O-alkyl group or a monosaccharide of formula (II), where R represents an alkyl group:
  • R 3 represents a disaccharide of formula
  • R 4 represents an -OSO 3 " group or a hydroxyl group
  • R 5 represents a disaccharide of formula (IV): in which :
  • - R 6 represents a group -OSO 3 " or a hydroxyl group
  • R 7 represents either a hydroxyl group or a disaccharide of formula (VI)
  • R 8 represents a group -OSO 3 " or a hydroxyl group
  • R 9 represents either a hydroxyl group, an -O-alkyl group or a disaccharide of formula (VII):
  • R 1 represents a -O-alkyl group
  • R 9 represents a hydroxyl group or a -O-alkyl group when R 2 represents a monosaccharide of formula (II) as defined above;
  • R 7 represents a disaccharide of formula (VI) as defined above when R 2 represents a -O-alkyl group; and
  • R 1 , R 4 , R 6 and R 8 do not simultaneously represent hydroxyl groups.
  • alkyl group means a saturated linear or branched aliphatic group comprising from 1 to 4 carbon atoms.
  • groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl are examples of groups methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.
  • the alkyl groups advantageously represent methyl groups, except for the substituents R 9 and R 10 , in which the alkyl radicals O-alkyl groups advantageously represent propyl groups.
  • the compounds according to the invention are synthetic oligosaccharides, that is to say that 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 oligosaccharides, 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 -COOH and -SO 3 H.
  • salt of the compounds of the invention is meant a compound in which one or more of -COO - and / or -SO 3 - functions 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 carbon 14 C.
  • radioactive isotope for example tritium or carbon 14 C.
  • the monosaccharide of formula (II) is bonded to the disaccharide unit represented in formula (I) by the oxygen atom located in position 4 of its uronic acid unit
  • the disaccharide of formula (III) is linked 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:
  • the compounds of formula (I) according to the invention may also be represented according to formula (I ') as follows, in which the iduronic units and the glucosamine units are successive and in which R 1 , R 2 , R 4 , R ⁇ and R 7 are as defined previously:
  • the oligosaccharides according to the invention may therefore comprise from 7 to 10 saccharide units.
  • the compounds of formula (I) / (I ') objects of the invention mention may be made of those in which:
  • R 1 , R 3 , R 4 , R 5 and R 6 are as defined above,
  • R 2 represents a monosaccharide of formula (II) as defined above, and
  • R 7 represents a hydroxyl group.
  • Such compounds are heptasaccharides. They correspond to the formula (1-1) below, in which R 7 represents a hydroxyl group and R, R 1 , R 4 and R 6 are as defined above, and are in acid form or in the form of any of their pharmaceutically acceptable salts.
  • Such compounds are octasaccharides or decasaccharides. They correspond to formula (I-2) below, in which R 1 , R 4 , R 6 , R 8 and R 9 are as defined above and R 2 represents a group -O-alkyl, and are present in acid form or in the form of any of their pharmaceutically acceptable salts.
  • R 2 represents a group -O-alkyl
  • R 7 represents a disaccharide of formula (VI) as defined above, in which R 9 represents a disaccharide of formula (VII) as defined above.
  • Such compounds are decasaccharides. They correspond to formula (I-3) below, in which R 1 , R 4 , R 6 , R 8 and R 10 are as defined above, and are in acid form or in the form of one any of their pharmaceutically acceptable salts.
  • formula (I) which are subjects of the invention, there may be mentioned a subgroup of compounds in which:
  • R 2 represents a group -O-alkyl
  • R 7 represents a disaccharide of formula (VI) as defined above, in which R 9 represents either a hydroxyl group or an -O-alkyl group.
  • Such compounds are octasaccharides and correspond to the formula (1-2) above, in which R 1, R 4 , R ⁇ and R 8 are as defined above, R 2 represents a -O-alkyl group and R 9 represents either a hydroxyl group or a -O-alkyl group.
  • the octasaccharides according to the invention are such that R 9 represents an -O-alkyl group.
  • Other subgroups of compounds according to the invention may have several of the characteristics stated above for each of the subgroups defined above.
  • the invention particularly relates to the following oligosaccharides:
  • the process for preparing the compounds according to the invention uses di- or oligosaccharide base synthons prepared as previously reported in the literature.
  • These synthons are then coupled to each other so as to provide a fully protected equivalent of a compound according to the invention.
  • This protected equivalent is then converted into a compound according to the invention.
  • a "donor" di- or oligosaccharide activated on its anomeric carbon, reacts with a "acceptor” di- or oligosaccharide having a free hydroxyl.
  • the present invention thus relates to a process for the preparation of the compounds of formula (I) / (I ') characterized in that: in a first phase, a completely protected equivalent of the desired compound (I) is synthesized,
  • 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. However, 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 groups Protectives are selected from, for example, acetyl, halomethyl, benzoyl, levulinyl, benzyl, allyl, tert-butyldiphenylsilyl (tBDPS).
  • Activator groups may also be used; these are those conventionally used in sugar chemistry, for example according to GJ. Boons, Tetrahedron (1996), 52, 1095-1121. These activating groups are chosen for example from imidates and 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 2OA below, in which 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 2OA in which Pg, Pg 'and Pg "respectively represent benzyl, allyl and acetyl groups,
  • Pg, Pg 'and Pg "respectively represent benzyl, allyl and acetyl groups
  • Rf Retardation factor (retention time measured on the TLC compared to the front of the migration solvent)
  • reaction medium is stirred for 2 hours at room temperature. After concentration, the residue is purified by flash column chromatography on silica gel (cyclohexane / ethyl acetate 5/6 v / v) to give 1.84 g of compound 23.
  • the reaction mixture is cooled to -20 ° C. and a 1M solution of tert-butyldimethylsilyl triflate in dichloromethane (250 ⁇ L) is added to the reaction medium. After 10 minutes, the reaction medium is neutralized by addition of solid sodium hydrogen carbonate.
  • the mixture containing hexasaccharide and octasaccharide 33 is treated according to the above conditions to give after size exclusion chromatography.
  • reaction medium After 1 hour at 0 ° C. and then 4 hours at room temperature, the reaction medium is neutralized with acetic acid and then left at -20 ° C. for 16 hours.
  • the reaction mixture was loaded onto a gel Sephadex ® LH20 eluted with methanol / water 4/1 v / v to give the compound 36 (38.9 mg).
  • a solution of compound 36 (40 mg, 10.8 ⁇ mol) in a 6/9 v / v tert-butanol / water mixture (1 mL) is treated under hydrogen pressure (11 bar) in the presence 10% palladium on carbon (80 mg, 2 x quantity of the compound to be reduced) at 40 ° C. for 4 hours. After filtration (Millipore ® filter LSWP 5 .mu.m), the solution is deposited on a resin column Chelex ® 100 (1 ml_) eluted with water and then concentrated to dryness. The crude compound thus obtained (27 mg) is used as such in the next step.
  • reaction mixture is cooled to -20 ° C. and a 1M solution of tert-butyldimethylsilyl triflate in dichloromethane (181 ⁇ L) is added. After 15 minutes, the middle The reaction is neutralized by addition of solid sodium hydrogen carbonate. After filtration and concentration, the residue obtained is purified by chromatography on a size exclusion column (Sephadex ® LH20, 190 x 3.2 cm, dichloromethane / ethanol 1/1 v / v) followed by chromatography on a gel column silica (toluene / ethyl acetate 1/1 v / v) to give 1.63 g of compound 42.
  • a size exclusion column (Sephadex ® LH20, 190 x 3.2 cm, dichloromethane / ethanol 1/1 v / v)
  • the resulting residue is dissolved in ⁇ -dimethylformanide (210 mL), and potassium hydrogen carbonate (17 g) and methyl iodide (21 mL) are added.
  • the reaction mixture is stirred at ambient temperature for 16 hours, then concentrated under vacuum.
  • 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.
  • reaction mixture is cooled to -20 ° C. and a 1M solution of tert-butyldimethylsilyl triflate in dichloromethane (27 ⁇ l) is added. After 1 hour, the reaction medium is neutralized by addition of solid sodium hydrogen carbonate. After filtration and concentration, the residue obtained is purified by size exclusion column chromatography (Sephadex ® LH20, 90 ⁇ 3 cm, dichloromethane / ethanol 1/1 v / v) followed by silica gel column chromatography. (toluene / ethyl acetate 2/1 v / v) to give compound 51 (212 mg).
  • the organic phase is washed successively with 10% aqueous potassium hydrogen sulfate solution, with water, with saturated sodium hydrogencarbonate solution and then with water, dried over sodium sulphate, filtered and then evaporated. dried up.
  • the residue is purified by flash chromatography on a silica gel column (cyclohexane / ethyl acetate 1/3) to give 57 (22.6 g).
  • Rf 0.37, silica gel, cyclohexane / ethyl acetate 1/3 v / v
  • Rf 0.23, silica gel, cyclohexane / ethyl acetate 1/3 v / v Methyl (methyl 2-O-acetyl-3-O-benzyl-4-O-levulinoyl- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) -3-O-benzyl-2-benzyloxycarbonylamino-6-O-fe / f-Butyldiphenylsilyl-2-deoxy- ⁇ -D-glucopyranoside (59)
  • Rf 0.42, silica gel, cyclohexane / ethyl acetate 2/1 v / v Methyl (methyl 2-O-acetyl-3-O-benzyl- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - 3-O-benzyl-2-benzyloxycarbonylamino-6-O-tert-butyldiphenylsilyl-2-deoxy- ⁇ -D-glucopyranoside (60)
  • Rf 0.40, silica gel, cyclohexane / ethyl acetate 2/1 v / v
  • Rf 0.34, silica gel, cyclohexane / ethyl acetate 2/1
  • Rf 0.46, silica gel, toluene / ethyl acetate 4/1 v / v
  • Rf 0.37, silica gel, cyclohexane / ethyl acetate 2/1 v / v
  • the resulting residue is dissolved in ⁇ -dimethylformanide (210 mL), and potassium hydrogen carbonate (17 g) and methyl iodide (21 mL) are added.
  • 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.
  • Rf 0.38, silica gel, cyclohexane / ethyl acetate 3/1 v / v
  • Diagram 17 Preparation of octasaccharides 80, 81, 82, 83, 84, 85, 86 and 87
  • reaction mixture is deposited on a column of Sephadex ® LH20 gel (120 ⁇ 3 cm) eluted with a 1/1 v / v dichloromethane / ethanol mixture followed by flash chromatography on a column of silica gel (toluene / acetone 100 / 0 ⁇ 85/15 v / v) to give compound 100 (193.2 mg).
  • the compound 103 (17.3 mg, 5.7 ⁇ mol) is treated according to the same procedure as that described for the preparation of the compound 91.
  • the crude compound 104 thus obtained, is again saponified.
  • a solution of the crude compound 104 in a 1/1 v / v tetrahydrofuran / methanol mixture (506 ⁇ l) is added, at 0 ° C., a 0.7 M solution of lithium hydroxide in water (202 ⁇ l, qs to have a final concentration of 0.2 M).
  • reaction mixture is chromatographed on a size exclusion column (Sephadex ® G 25 Fine, 95 x 2 cm, 0.2 M NaCl and then Sephadex ® G 25 Fine, 95 x 2 cm, water) to give compound 104 (6.5 mg).
  • Methyl (methyl 3,4-di-O-benzyl-2-O-triethylammonium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-azido-3-O-benzyl-2-deoxy-6) O-triethylammonium sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (methyl-3-O-benzyl-2-O-triethylammonium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2) azido-3-O-benzyl-6-O-te / f-
  • the reaction mixture is filtered (Millipore ® filter LSWP 5 .mu.m) and concentrated to dryness.
  • the residue is loaded onto a gel Sephadex ® G25- thin (95 x 2 cm) eluted with an aqueous solution of NaCl 0.2 M.
  • the fractions containing the expected compound are combined and loaded onto a gel Sephadex ® G-25-f (95 x 2 cm) eluted with water
  • the resulting crude product 111 (14.7 mg) was used as such in the next step.
  • EXAMPLE 1 sodium methyl (4-O-propyl-2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-6-O-sodium sulfonato-2-sodium (sulfonatoamino) ) - ⁇ -D-qlucopyranosyl) - (1 ⁇ 4H (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-6-O-sodium sulfonato-2) sodium (sulfonatoamino) - ⁇ -D-qlucopyranosyl- (1 ⁇ 4) -9- (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4)
  • EXAMPLE 2 sodium methyl (4-O-propyl-2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-6-O-sodium sulfonato-2-sodium (sulfonatoamino) ) - ⁇ -D-qlucopyranosyl) - (1 ⁇ 4H (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4H2-deoxy-6-O-sodium sulfonato-2-sodium (sulfonatoamino) - ⁇ -D-qlucopyranosyl- (1 ⁇ 4) i3- (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate H1 ⁇ 4) -2-deoxy
  • EXAMPLE 5 Sodium methyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2-sodium (sulfonatoamino) - ⁇ -D-glucopyranosyl) (4) - (2) Sodium-O-sodium sulfonato- ⁇ -L-idopyranosyluronate H1 ⁇ 4H2-deoxy-6-O-sodium sulfonato-2-sodium (sulfonatoamino) - ⁇ -D-glucopyranosyl-4H2-O-sodium sulfonate- ⁇ -L-idopyranosyluronate of sodiumH1 ⁇ 4H2-deoxy-2-sodium (sulfonatoamino) - ⁇ -D-
  • EXAMPLE 6 Sodium methyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-6-O-sodium sulfonato-2-sodium (sulfonatoamino) - ⁇ -D- glucopyranosyl) - (1 ⁇ 4) - (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2-sodium (sulfonatoamino) - ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2-sodium) - ⁇ -L-id
  • EXAMPLE 7 Sodium methyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-6-O-sodium sulfonato-2-sodium (sulfonatoamino) - ⁇ -D- glucopyranosyl) - (1 ⁇ 4) - (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-2-sodium (sulfonatoamino) - ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (sodium 2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4H2-deoxy-6-O-sodium sulfonato-2-s
  • EXAMPLE 8 sodium methyl (2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) - (1 ⁇ 4) - (2-deoxy-6-O-sodium sulfonato-2-sodium (sulfonatoamino) - ⁇ -D- sodium iucopyranosylHd ⁇ 4H2-O-sodium sulfonato- ⁇ -L-idopyranosyluronate) -
  • the compounds according to the invention have been the subject of pharmacological tests for determining their agonist effect of FGF receptors and their activity on angiogenesis, as well as on post-ischemic revascularization.
  • 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 .
  • FGF2 R & D Systems / 234-FSE-50
  • the compounds of the invention have a specific activity of between 10 -6 M and 10 -12 M.
  • Compounds Nos. 1 and 7 are active at 10 -6 M.
  • octasaccharide No. 8 according to the invention, heptasaccharide No. 3 and decasaccharide No. 2 are better activators of FGF-2 than their hexasaccharide analog (compound described by C. Tabeur et al in Bioorg & Med Chem, 1999, 7, 2003-2012).
  • 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.
  • 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)) .
  • 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
  • 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 1 and 7 are active at a concentration of 45 ng / site.
  • the compounds according to the invention have FGF receptor agonist activity and an activity on angiogenesis, as well as on post-ischemic revascularization. These compounds can therefore be used for the preparation of medicaments, especially medicaments useful for the treatment of diseases requiring activation of FGF receptors or drugs useful in pathologies requiring activation of angiogenesis and post-ischemic revascularization.
  • the invention therefore relates to medicaments which comprise a compound of formula (I) / (I ') or compound 10, or a pharmaceutically acceptable salt thereof. More generally, the subject of the invention is medicaments which comprise a compound of formula (I):
  • - R 1 represents a group -OSO 3 " or hydroxyl group
  • R 2 represents either an -O-alkyl group or a monosaccharide of formula (II), where R represents an alkyl group:
  • R 3 represents a disaccharide of formula
  • R 4 represents an -OSO 3 " group or a hydroxyl group
  • R 5 represents a disaccharide of formula (IV):
  • R 6 represents a group -OSO 3 " or a hydroxyl group
  • R 7 represents either a hydroxyl group, a monosaccharide of formula (V) below, or a disaccharide of formula (VI):
  • R 8 represents a group -OSO 3 " or a hydroxyl group
  • R 9 represents either a hydroxyl group, an -O-alkyl group or a disaccharide of formula (VII):
  • R 1 represents a -O-alkyl group
  • R 9 represents a hydroxyl group or a -O-alkyl group when R 2 represents a monosaccharide of formula (II) as defined above;
  • R 7 represents a disaccharide of formula (VI) as defined above when R 2 represents a -O-alkyl group; and
  • R 1 , R 4 , R 6 and R 8 do not simultaneously represent hydroxyl groups.
  • Such compounds include those of formula (I) / (I ') defined above, as well as the heptasaccharide 10 defined above, described in patent application US 2006/0079483 A1.
  • 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.
  • 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.
  • FGF family and in particular FGF-2 has 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.
  • 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 peripheral neuropathy.
  • Basic 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 post-operative nerve damage, in the repair of nerve deficits such as Parkinson's disease, Alzheimer's disease, Alzheimer's disease. prion, neuronal degeneration in the alcoholic or in cases of dementia.
  • VEGF vascular smooth muscle cells
  • 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 can preserve and perfuse tissues 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 is one of the factors most involved in the processes of angiogenesis during the healing phase.
  • 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 scarring 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 survival factors of photo receptors and as regulator of endothelial cells.
  • Pre-eclampsia is a pathology of the placenta associated with a lack of vascularization (Sherer, DM & 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 endothelial cell survival factors (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 pro-apoptotic activity against microvascular endothelial cells of the lungs (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 or a compound 10.
  • These pharmaceutical compositions contain an effective dose of at least one compound according to the invention or compound 10, 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 desired mode of administration, from the usual excipients which are known to those skilled in the art.
  • the subject of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising, as active principle, at least one compound of formula (I) in which:
  • Ri represents a group -OSO 3 " or hydroxyl group
  • R 2 represents either an -O-alkyl group or a monosaccharide of formula (II), where R represents an alkyl group:
  • R3 represents a disaccharide of formula
  • R 4 represents an -OSO 3 " group or a hydroxyl group
  • R 5 represents a disaccharide of formula (IV):
  • R 7 represents either a hydroxyl group, a monosaccharide of formula (V) below, or a disaccharide of formula (VI):
  • R 8 represents a group -OSO 3 " or a hydroxyl group
  • R 9 represents either a hydroxyl group, an -O-alkyl group or a disaccharide of formula (VII):
  • R 1 represents a -O-alkyl group
  • R 9 represents a hydroxyl group or a -O-alkyl group when R 2 represents a monosaccharide of formula (II) as defined above;
  • R 7 represents a disaccharide of formula (VI) as defined above when R 2 represents a -O-alkyl group; and
  • R 1 , R 4 , R 6 and R 8 do not simultaneously represent hydroxyl groups,
  • Such compounds include those of formula (I) / (I ') defined above, as well as the heptasaccharide 10 defined above, described in patent application US 2006/0079483 A1.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal the above active ingredient or its salt may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prevention or control of treatment of the disorders or diseases above.
  • 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 the use of a compound according to the invention or a compound 10, or a pharmaceutically acceptable salt thereof, for the treatment of the pathologies indicated above.
  • the subject of the invention is a compound of formula (I) in which:
  • - R 1 represents a group -OSO 3 " or hydroxyl group
  • R 2 represents either an -O-alkyl group or a monosaccharide of formula (II), where R represents an alkyl group:
  • R3 represents a disaccharide of formula
  • R 4 represents an -OSO 3 " group or a hydroxyl group
  • R 5 represents a disaccharide of formula (IV):
  • - R 6 represents a group -OSO 3 " or a hydroxyl group
  • R 7 represents either a hydroxyl group, a monosaccharide of formula (V) below, or a disaccharide of formula (VI):
  • R 8 represents a group -OSO 3 " or a hydroxyl group
  • R 9 represents either a hydroxyl group, an -O-alkyl group or a disaccharide of formula (VII):
  • R 10 is -O-alkyl
  • R 9 represents a hydroxyl group or a -O-alkyl group when R 2 represents a monosaccharide of formula (II) as defined above;
  • R 7 represents a disaccharide of formula (VI) as defined above when R 2 represents a -O-alkyl group; and
  • R 1 , R 4 , R 6 and R 8 do not simultaneously represent hydroxyl groups,
  • Such compounds include those of formula (I) / (I ') defined above, as well as the heptasaccharide 10 defined above, described in the patent application US 2006/0079483 A1.
  • 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 compound or a pharmaceutically acceptable salt thereof.
  • the drugs, pharmaceutical compositions and treatment method according to the invention may also relate to any one of the subgroups of compounds defined above.

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US20120202769A1 (en) 2012-08-09
CN102625704A (zh) 2012-08-01
MY160505A (en) 2017-03-15
JP2013501838A (ja) 2013-01-17
WO2011018587A3 (fr) 2011-07-07
FR2949115A1 (fr) 2011-02-18
MX2012001945A (es) 2012-06-27
CN102625704B (zh) 2015-05-06
KR20120059552A (ko) 2012-06-08
SG178406A1 (en) 2012-03-29
FR2949115B1 (fr) 2012-11-02
IL218069A (en) 2015-04-30
CN104945524A (zh) 2015-09-30
AU2010283613B2 (en) 2016-03-10
IL218069A0 (en) 2012-04-30
BR112012002980A2 (pt) 2016-04-19
WO2011018587A2 (fr) 2011-02-17
CA2771055C (fr) 2017-05-09
US9527930B2 (en) 2016-12-27
AR078093A1 (es) 2011-10-12
RU2012109572A (ru) 2013-09-20
RU2559629C2 (ru) 2015-08-10
CA2771055A1 (fr) 2011-02-17
JP5732460B2 (ja) 2015-06-10
AU2010283613A1 (en) 2012-03-08

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