EP2328935A1 - Polysaccharides with antithrombotic activity, including a covalent bond and an amino chain - Google Patents
Polysaccharides with antithrombotic activity, including a covalent bond and an amino chainInfo
- Publication number
- EP2328935A1 EP2328935A1 EP09737025A EP09737025A EP2328935A1 EP 2328935 A1 EP2328935 A1 EP 2328935A1 EP 09737025 A EP09737025 A EP 09737025A EP 09737025 A EP09737025 A EP 09737025A EP 2328935 A1 EP2328935 A1 EP 2328935A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- formula
- oso
- polysaccharides
- pharmaceutically acceptable
- 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.)
- Withdrawn
Links
- 150000004676 glycans Chemical class 0.000 title claims abstract description 46
- 229920001282 polysaccharide Polymers 0.000 title claims abstract description 45
- 239000005017 polysaccharide Substances 0.000 title claims abstract description 45
- 230000002785 anti-thrombosis Effects 0.000 title claims abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims description 24
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- -1 desoxy sugars Chemical class 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 239000004480 active ingredient Substances 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 150000001721 carbon Chemical group 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
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- 239000003146 anticoagulant agent Substances 0.000 description 4
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- 230000000144 pharmacologic effect Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- YGNAPHHZSGNZRX-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 6-(phenylmethoxycarbonylamino)hexanoate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCNC(=O)OCC1=CC=CC=C1 YGNAPHHZSGNZRX-UHFFFAOYSA-N 0.000 description 3
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
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- 125000004429 atom Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
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- 238000001228 spectrum Methods 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
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- 150000008266 deoxy sugars Chemical class 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960002768 dipyridamole Drugs 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002454 idoses Chemical class 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 150000003949 imides Chemical class 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000005524 levulinyl group Chemical group 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003569 thioglycosides Chemical class 0.000 description 1
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000012991 xanthate Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to novel synthetic oligomers and polysaccharides having at least one covalent linkage with an amino chain and having the anticoagulant and antithrombotic pharmacological activities of heparin.
- the patent application WO 02/24754 describes synthetic polysaccharides which have a covalent bond with biotin (hexahydro-2-oxo-7H-thieno [3,4-d] imidazole-4-pentanoic acid) or with a derivative of biotin.
- biotin hexahydro-2-oxo-7H-thieno [3,4-d] imidazole-4-pentanoic acid
- Such polysaccharides have antithrombotic activity which makes them usable as anticoagulants and have, in addition, the advantage of being able to be quickly neutralized by a specific antidote, in an emergency situation.
- This specific antidote is avidin (The Merck Index, Twelfth edition, 1996, MN 920, pages 151-152) or streptavidin, two tetrameric proteins of respective masses equal to about 66,000 and 60,000 Da, which possess a very strong affinity for biotin.
- the invention therefore relates to synthetic polysaccharides with antithrombotic activity having at least one covalent bond with an amino chain of formula -NH-CO- (CH 2 ) 5 -NH 2 .
- the subject of the present invention is the polysaccharides of formula (I):
- the wavy line designates a link situated either below or above the plane of the pyranosic cycle
- h 1 or 2
- n is an integer and can take any value from 0 to 25,
- R 1 represents a group -NH-CO- (CH 2 ) S -NH 2 , a group (C 1 -C 6 JaClOXy) or a group -OSO 3 " ,
- R 2 represents a group -NH-CO- (CH 2 ) 5 -NH 2 , a group (C 1 -C 6 JaClOXy) or a group -OSO 3 '
- R 3 represents a group -NH-CO- (CH 2 ) S -NH 2 or a group (C 1 -C 6 JaClOXy
- R 4 represents a group -NH-CO- (CH 2 ) 5 -NH 2 , a group (C 1 -C 6 JaClOXy) or a group -OSO 3 " or else R 4 constitutes a bridge -O-CH 2 -, the group -CH 2 - being bonded to the carbon atom carrying the carboxylic function on the same ring, it being understood that at least one of the substituents R 1 , R 2 , R 3 or R 4 represents a group -NH -CO- (CH 2 ) 5 -NH 2 ,
- - W represents an oxygen atom or a methylene group, and their pharmaceutically acceptable salts.
- a wavy line designates a link located either below or above the plane of the pyranosic cycle.
- the monosaccharides contained in Po may be identical or different from one another, the interglycosidic bonds may be of the ⁇ or ⁇ type.
- the polysaccharide portion Po may consist of from 0 to 25 monosaccharide units alkylated and di- or trisulfated.
- the polysaccharide part Po may also consist of from 0 to 25 monosaccharide mono- saccharide units and mono- or disulfated.
- the polysaccharide portion Po may consist of from 0 to 25 unloaded and / or partially charged and / or fully charged alkylated monosaccharide units.
- the charged or uncharged units may be dispersed throughout the chain or they may instead be grouped into charged or uncharged saccharide domains.
- the links between the units can be 1, 2; 1, 3; 1, 4; 1, 5; 1, 6; and of the ⁇ or ⁇ type.
- L-iduronic acid may be 1 C 4 2 S 0 or 4 C 1 conformation.
- the invention relates to the polysaccharides of formula (1.1):
- the groups R 1 are as defined for (I) and, for the same monosaccharide, may be identical or different, the monosaccharide contained in [] m is repeated m times, the monosaccharide contained in [] t is repeated t times , the monosaccharide contained in [] p is repeated p times, m is an integer varying from 1 to 5, t is an integer varying from 0 to 24 and p is an integer varying from 0 to 24, provided that 1 ⁇ m + 1 + p ⁇ 25, as well as their pharmaceutically acceptable salts.
- polysaccharides of formula (1.1) polysaccharides in which only one of the substituents R 1 , R 2 , R 3 or R 4 represents a group -NH-CO- (CH 2 ) S -NH 2 , as well as their pharmaceutically acceptable salts acceptable, constitute a subgroup of the invention.
- the invention relates to hexadecasaccharides of formula (1.2):
- - T represents a group -NH-CO- (CH 2 ) 5 -NH 2
- - Pe represents a pentasaccharide of structure:
- R 1 represents a group (C 1 -C 6 JaClOXy or a group -OSO 3 " ,
- R 2 represents a group (C 1 -C 6 JaClOXy or a group -OSO 3 " ,
- R 3 represents a group (C r C 6 ) alkoxy
- R 4 represents a group (CrC 6 ) alkoxy or a group -OSO 3 " , or R 4 constitutes a bridge -O-CH 2 -, the group -CH 2 - being bonded to the carbon atom carrying the carboxylic function on the same cycle,
- W represents an oxygen atom or a methylene group, as well as their pharmaceutically acceptable salts.
- the invention relates to the pentasaccharides of formula (1.3):
- R 1 , R 2 , R 3 , R 4 and W are as defined for (I), as well as their pharmaceutically acceptable salts.
- pentasaccharides of formula (1.3) pentasaccharides in which only one of the substituents R 1 , R 2 , R 3 or R 4 represents a group -NH-CO- (CH 2 ) 5 -NH 2 , as well as their pharmaceutically acceptable salts acceptable, constitute a subgroup of the invention.
- pentasaccharides of formula (1.3) the subject of the invention is also the pentasaccharides of formula (1.4):
- T represents a group -NH-CO- (CH 2 ) 5 -NH 2 ,
- R 1 represents a group (C 1 -C 6 JaClOXy or a group -OSO 3 " ,
- R 2 represents a group (C 1 -C 6 JaClOXy) or a group -OSO 3 '
- - R 3 represents a group (C 1 -C 6 ) BlCOXy
- - R 4 represents a group (C 1 -C 6 JaClOXy) or a group -OSO 3 '
- R 4 constitutes a bridge -O-CH 2 -, the group -CH 2 - being bonded to the carrier carbon atom of the carboxylic function on the same cycle
- - W represents an oxygen atom or a methylene group, and their pharmaceutically acceptable salts.
- the invention relates to the following polysaccharide: Methyl (2- [N- (6-aminohexanoyl)] - 2-deoxy-3,4-di-O-methyl-6-O-sulfonato- ⁇ -D-glucopyranosyl) - (1 - ⁇ 4) - (2,3-di-O-methyl- ⁇ -D-glucopyranosyluronic acid) - (1 ⁇ 4) - (2,3,6-tri-O-sulfonato) - ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (2,3-di-O-methyl- ⁇ -L-idopyranosyluronic acid) - (1 ⁇ 4) -2,3,6-tri-O- sulfonato- ⁇ -D-glucopyranoside, sodium salt.
- the invention includes polysaccharides in their 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.
- salt polysaccharides of the invention, a polysaccharide 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 and more preferably still those whose cation is Na + or K + .
- the compounds of formula (I) above 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. Such labeled compounds are useful in research, metabolism or pharmacokinetics, in biochemical assays as ligands.
- 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 polysaccharide according to the invention. This protected equivalent is then converted into a compound according to the invention.
- One of the basic synthons mentioned above contains a particular protected function allowing the subsequent introduction of the group -CO- (CH 2 ) S -NH 2 (so as to form the chain -NH-CO- (CH 2 ) 5 -NH 2 on the polysaccharide), for example a latent amine function in the form of an azido group or protected in the form of N-phthalimido.
- a "donor" di- or oligosaccharide activated on its anomeric carbon, reacts with a "acceptor” di- or oligosaccharide having a free hydroxyl.
- the present invention relates to a process for the preparation of compounds of formula (I) characterized in that: in a first step, a completely protected equivalent of the desired polysaccharide (I), containing a protected precursor of the domain Pe extended at its non-reducing end by a protected precursor of the sulphated polysaccharide Po is synthesized, one of these precursors containing in particular a suitably protected amino function for the subsequent introduction of the -CO- (CH 2 ) 5 -NH 2 group , itself suitably protected; in a second step, the negatively charged groups are introduced and / or unmasked; in a third step, the amine function is deprotected on the polysaccharide and then the -CO- (CH 2 ) 5 -NH 2 protected group is introduced; in a fourth step, the NH 2 terminal group is unmasked.
- the synthesis of Pe is carried out according to the methods described in particular in the patent applications published under the numbers WO 98/03554 and WO 99/36443, as well as
- the synthesis of the polysaccharide precursor part of Po is carried out according to reactions well known to those skilled in the art, using the methods of oligosaccharide synthesis (GJ Boons, Tetrahedron, 1996, 52, 1095-1121, WO 98/03554 and WO 99/36443).
- a glycosidic link donor oligosaccharide is coupled with a glycosidic link acceptor oligosaccharide to yield another oligosaccharide the size of which is equal to the sum of the sizes of the two reactive species. This sequence is repeated until the desired compound of formula (I) is obtained.
- 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 are obtained from their completely protected polysaccharide precursors using the following sequence of reactions:
- the alcohol functions to be converted into an O-sulpho group and the carboxylic acids are deprotected by the elimination of the protective groups used during the development of the skeleton,
- the suitably protected -CO- (CH 2 ) 5 -NH 2 group is introduced by a conventional amino / acid coupling reaction, and then
- 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) 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 in GJ. Boons, Tetrahedron, 1996, 52, 1095-1121.
- the pentasaccharides Pe can thus be obtained from disaccharide synthons in the manner described in the publication by C. van Boeckel, M. Petitou, Angew. Chem. Int. Ed. Engl., 1993, 32, 1671-1690.
- the protecting groups used in the process for the preparation of compounds (I) are those commonly used in the chemistry of sugars, as described, for example, in Protective Groups in Organic Synthesis, TW Greene, John Wiley & Son, New York, 1981.
- the protecting groups may for example be selected from acetyl, halomethyl, benzoyl, levulinyl, benzyl, substituted benzyl, optionally substituted trityl, tetrahydropyranyl, allyl, pentenyl, tert-butyldimethylsilyl (tBDMS) or trimethylsilylethyl groups.
- Activator groups are those conventionally used in sugar chemistry according to GJ for example.
- the introduction of the -CO- (CH 2 ) S -NH 2 group onto the free amine function of the polysaccharide can be carried out using an Act-CO type reagent.
- Act represents an activating group of an acid function (such as an imide, for example a succinimide derivative, or a mixed anhydride, or any other agent known activator in peptide chemistry for amino / acid coupling reactions) and
- Pg represents an amine protecting group (such as a benzyloxycarbonyl group).
- the process described above makes it possible to obtain the compounds of the invention in the form of salts.
- the compounds of the invention in the form of salts are 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 inorganic or organic base can be used, giving with the compounds of formula (I), pharmaceutically acceptable salts.
- Sodium, potassium, potassium hydroxide is preferably used as the base. calcium or magnesium.
- the sodium and calcium salts of the compounds of formula (I) are the preferred salts.
- the grafting of the amino chain is carried out on pentasaccharide 44, or methyl (2-amino-2-deoxy-3,4-di-O-methyl-6-O-sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (2,3-di-O-methyl- ⁇ -D-glucopyranosyluronic acid) - (1-> 4) - (2,3,6-tri-O-sulfonato- ⁇ -D-glucopyranosyl) - (1 ⁇ 4) - (2,3-di-O-methyl- ⁇ -L-idopyranosyl-uronic acid) - (1 ⁇ 4) - 2,3,6-tri-O-sulfonemono- ⁇ - D-glucopyranoside, sodium salt, the preparation of which is described in patent application WO 02/24754:
- the solid residue is triturated with 2-propanol (10 mL) and the suspension centrifuged for 5 minutes at 2500 rpm.
- the alcohol phase is withdrawn and replaced by 2-propanol (10 mL) and the centrifugation is repeated. After withdrawing the solvent, the crude product is dried under vacuum.
- Proton NMR at 200 MHz in deuterated water The structure of the expected product is confirmed, since the spectrum obtained is identical to that produced on a product synthesized according to Example 5 of patent application WO 02/24754. , without the signals due to the atoms of the biotin part but with signals from 7.4 to 7.5 ppm due to the benzyloxy group.
- the product obtained after the previous step (399 mg) is dissolved in deuterated water (10 mL).
- the solution is treated with 10% palladium on carbon (25 mg) and the solution is stirred for 20 hours in the presence of hydrogen at atmospheric pressure.
- the mixture is diluted with water (15 mL), the catalyst is filtered and the solution is washed with chloroform (2 x 15 mL) and evaporated to dryness under reduced pressure.
- An aliquot (98 mg on 320 mg) of this product is purified on a column of Sephadex G-25 gel (2.5 x 50 cm) with water as eluent to give 25 mg of compound 1.
- the compounds according to the invention have been the subject of biochemical and pharmacological studies.
- IC 50 1.69 ⁇ 10 -2 ⁇ g / ml (IC 50: dose allowing a 50% inhibition).
- the oligosaccharides of the present invention constitute very interesting drugs. Their toxicity is perfectly compatible with this use. They are also very stable and are therefore particularly suitable for constituting the active principle of pharmaceutical specialties.
- thromboembolic disorders associated with atherosclerosis and diabetes such as unstable angina, cerebral attack, restenosis after angioplasty, endarterectomy, placement of endovascular prostheses; or thromboembolic disorders associated with rethrombosis after thrombolysis, infarction, dementia of ischemic origin, peripheral arterial diseases, hemodialysis, atrial fibrillation, or the use of aortic bypass graft vascular prostheses. -coronariens.
- These products can also be used for the treatment or prevention of venous thromboembolic pathologies, such as pulmonary embolism and deep vein thrombosis. They can be used or to prevent or treat thrombotic complications observed for example as a result of surgical operations, tumor development or disruption of coagulation, induced by bacterial, viral or enzymatic activators.
- the compounds of the present invention can cover prostheses and thus make them hemocompatible.
- they can be attached to intravascular prostheses (stents).
- they may optionally be chemically modified by introduction to the non-reducing or reducing end of a suitable arm, as described in EP 649854.
- the compounds of the present invention may also be used as adjuvants during endarterectomy performed with porous balloons.
- the compounds of the invention may be used for the preparation of medicaments for treating or preventing the above diseases.
- the subject of the present invention is therefore a pharmaceutical composition containing, as active ingredient, a synthetic polysaccharide according to the invention or a pharmaceutically acceptable salt thereof, optionally in combination with one or more inert excipients. and appropriate.
- Said excipients are chosen according to the desired pharmaceutical form and mode of administration: oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, transmucosal, local or rectal.
- the active ingredient may also be presented in the form of a complex with a cyclodextrin, for example ⁇ , ⁇ or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
- the active ingredient can also be released by a balloon containing it or by an endovascular stent introduced into the blood vessels. The pharmacological effectiveness of the active ingredient is thus not affected.
- each dosage unit the active ingredient is present in the appropriate amounts in order to obtain the desired prophylactic or therapeutic effect.
- Each dosage unit may contain from 0.1 to 100 mg of active ingredient, preferably 0.5 to 50 mg, more preferably 2.5 to 3.0 mg.
- the compounds according to the invention may also be used in combination with one or more other active ingredients that are useful for the desired therapy, such as, for example, antithrombotics, anticoagulants, antiplatelet agents such as, for example, dipyridamole, aspirin or ticlopidine. , clopidogrel or antagonists of the glycoprotein Ilb / IIIa complex.
Abstract
The present invention relates to novel synthetic polysaccharides with antithrombotic activity, having at least one covalent bond with an amino chain, and to the preparation method thereof and to the therapeutic use thereof.
Description
POLYSACCHARIDES A ACTIVITE ANTITHROMBOTIQUE COMPRENANT UNE LIAISON COVALENTE AVEC UNE CHAINE AMINE POLYSACCHARIDES WITH ANTITHROMBOTIC ACTIVITY COMPRISING A COVALENT BINDING WITH AN AMINO CHAIN
La présente invention concerne des nouveaux oligo - et polysaccharides de synthèse présentant au moins une liaison covalente avec une chaîne aminé et possédant les activités pharmacologiques anticoagulante et antithrombotique de l'héparine.The present invention relates to novel synthetic oligomers and polysaccharides having at least one covalent linkage with an amino chain and having the anticoagulant and antithrombotic pharmacological activities of heparin.
La demande de brevet WO 02/24754 décrit des polysaccharides de synthèse qui présentent une liaison covalente avec la biotine (acide hexahydro-2-oxo-7H-thiéno[3,4- d]imidazole-4-pentanoïque) ou avec un dérivé de la biotine. De tels polysaccharides ont une activité antithrombotique qui les rend utilisables en tant qu'agents anticoagulants et possèdent, en outre, l'avantage de pouvoir être rapidement neutralisés par un antidote spécifique, en situation d'urgence. Cet antidote spécifique est l'avidine (The Merck Index, Twelfth édition, 1996, M. N. 920, pages 151-152) ou la streptavidine, deux protéines tétramériques de masses respectives égale à environ 66 000 et 60 000 Da, qui possèdent une très forte affinité pour la biotine.The patent application WO 02/24754 describes synthetic polysaccharides which have a covalent bond with biotin (hexahydro-2-oxo-7H-thieno [3,4-d] imidazole-4-pentanoic acid) or with a derivative of biotin. Such polysaccharides have antithrombotic activity which makes them usable as anticoagulants and have, in addition, the advantage of being able to be quickly neutralized by a specific antidote, in an emergency situation. This specific antidote is avidin (The Merck Index, Twelfth edition, 1996, MN 920, pages 151-152) or streptavidin, two tetrameric proteins of respective masses equal to about 66,000 and 60,000 Da, which possess a very strong affinity for biotin.
On a maintenant identifié de nouveaux polysaccharides de structures analogues à ceux décrits dans la demande de brevet WO 02/24754 mais qui, à la place de la liaison covalente avec la biotine, présentent une chaîne aminé. Ces nouveaux polysaccharides, de façon avantageuse, possèdent des propriétés antithrombotiques comparables à ceux décrits dans la demande de brevet sus-mentionnée.We have now identified new polysaccharides of structures similar to those described in patent application WO 02/24754 but which, instead of the covalent bond with biotin, have an amino chain. These new polysaccharides, advantageously, have antithrombotic properties comparable to those described in the aforementioned patent application.
D'une manière générale, l'invention concerne donc des polysaccharides synthétiques à activité antithrombotique présentant au moins une liaison covalente avec une chaîne aminé de formule -NH-CO-(CH2)5-NH2.In general, the invention therefore relates to synthetic polysaccharides with antithrombotic activity having at least one covalent bond with an amino chain of formula -NH-CO- (CH 2 ) 5 -NH 2 .
En particulier, la présente invention a pour objet les polysaccharides de formule (I) :In particular, the subject of the present invention is the polysaccharides of formula (I):
dans laquelle :
- le trait ondulé désigne une liaison située soit au-dessous soit au-dessus du plan du cycle pyranosique,in which : the wavy line designates a link situated either below or above the plane of the pyranosic cycle,
- la formule :- the formula :
désigne un polysaccharide contenant n unités monosaccharidiques identiques ou différentes, lié par son carbone anomère à Pe, - la formule :denotes a polysaccharide containing n identical or different monosaccharide units, linked by its anomeric carbon to Pe, - the formula:
est une représentation schématique d'une unité monosaccharidique à structure pyranosique choisie parmi les hexoses, les pentoses et les sucres desoxy correspondants, cette unité étant liée par son carbone anomère à une autre unité monosaccharidique, et les groupes hydroxy de cette unité étant substitués par des groupes R1 identiques ou différents, R1 étant tel que défini ci-dessous, - Pe représente un pentasaccharide de structure :is a schematic representation of a monosaccharide unit with a pyranosic structure chosen from hexoses, pentoses and corresponding desoxy sugars, this unit being linked by its anomeric carbon to another monosaccharide unit, and the hydroxyl groups of this unit being substituted by identical or different groups R 1 , R 1 being as defined below, - Pe represents a pentasaccharide of structure:
- h est égal à 1 ou 2,h is 1 or 2,
- n est un entier et peut prendre toute valeur de O à 25,n is an integer and can take any value from 0 to 25,
- R1 représente un groupe -NH-CO-(CH2)S-NH2, un groupe (C1-C6JaIcOXy ou un groupe -OSO3 ",R 1 represents a group -NH-CO- (CH 2 ) S -NH 2 , a group (C 1 -C 6 JaClOXy) or a group -OSO 3 " ,
- R2 représente un groupe -NH-CO-(CH2)5-NH2, un groupe (C1-C6JaIcOXy ou un groupe -OSO3 ',
- R3 représente un groupe -NH-CO-(CH2)S-NH2 ou un groupe (C1-C6JaIcOXy,R 2 represents a group -NH-CO- (CH 2 ) 5 -NH 2 , a group (C 1 -C 6 JaClOXy) or a group -OSO 3 ' , R 3 represents a group -NH-CO- (CH 2 ) S -NH 2 or a group (C 1 -C 6 JaClOXy,
- R4 représente un groupe -NH-CO-(CH2)5-NH2, un groupe (C1-C6JaIcOXy ou un groupe -OSO3 " ou bien R4 constitue un pont -0-CH2-, le groupe -CH2- étant lié à l'atome de carbone porteur de la fonction carboxylique sur le même cycle ; étant entendu que l'un au moins des substituants R1, R2, R3 ou R4 représente un groupe -NH-CO-(CH2)5-NH2,R 4 represents a group -NH-CO- (CH 2 ) 5 -NH 2 , a group (C 1 -C 6 JaClOXy) or a group -OSO 3 " or else R 4 constitutes a bridge -O-CH 2 -, the group -CH 2 - being bonded to the carbon atom carrying the carboxylic function on the same ring, it being understood that at least one of the substituents R 1 , R 2 , R 3 or R 4 represents a group -NH -CO- (CH 2 ) 5 -NH 2 ,
- W représente un atome d'oxygène ou un groupe méthylène, ainsi que leurs sels pharmaceutiquement acceptables.- W represents an oxygen atom or a methylene group, and their pharmaceutically acceptable salts.
Comme indiqué précédemment, on notera que de façon générale dans la présente description un trait ondulé désigne une liaison située soit au-dessous, soit au-dessus du plan du cycle pyranosique.As indicated above, it will be noted that generally in the present description a wavy line designates a link located either below or above the plane of the pyranosic cycle.
Les monosaccharides contenus dans Po peuvent être identiques ou différents les uns des autres, les liaisons interglycosidiques peuvent être du type α ou β.The monosaccharides contained in Po may be identical or different from one another, the interglycosidic bonds may be of the α or β type.
Ces monosaccharides sont avantageusement choisis parmi les hexoses D ou L alose, altrose, glucose, mannose, galose, idose, galactose, talose (dans ce cas h = 2) ou parmi les pentoses D ou L ribose, arabinose, xylose, lyxose (dans ce cas h = 2).These monosaccharides are advantageously chosen from hexoses D or L shad, altrose, glucose, mannose, galose, idose, galactose, talose (in this case h = 2) or from the pentoses D or L ribose, arabinose, xylose, lyxose (in this case h = 2).
D'autres monosaccharides tels que par exemple les sucres désoxy peuvent également être utilisés (h = 1 et/ou -CH2R1 = CH3).Other monosaccharides such as for example deoxy sugars can also be used (h = 1 and / or -CH 2 R 1 = CH 3 ).
La partie polysaccharidique Po peut être constituée de O à 25 unités monosaccharidiques alkylées et di- ou trisulfatées.The polysaccharide portion Po may consist of from 0 to 25 monosaccharide units alkylated and di- or trisulfated.
La partie polysaccharidique Po peut être également constituée de O à 25 unités monosaccharidiques alkylées et mono- ou disulfatées. La partie polysaccharidique Po peut être constituée de O à 25 unités monosaccharidiques alkylées non chargées et/ou partiellement chargées et/ou totalement chargées.The polysaccharide part Po may also consist of from 0 to 25 monosaccharide mono- saccharide units and mono- or disulfated. The polysaccharide portion Po may consist of from 0 to 25 unloaded and / or partially charged and / or fully charged alkylated monosaccharide units.
Les unités chargées ou non chargées peuvent être dispersées tout au long de la chaîne ou elles peuvent au contraire être groupées en domaines saccharidiques chargés ou non chargés.The charged or uncharged units may be dispersed throughout the chain or they may instead be grouped into charged or uncharged saccharide domains.
Les liaisons entre les unités peuvent être 1 ,2 ; 1 ,3 ; 1 ,4 ; 1 ,5 ; 1 ,6 ; et du type α ou β.The links between the units can be 1, 2; 1, 3; 1, 4; 1, 5; 1, 6; and of the α or β type.
Dans la présente description, il a été choisi de représenter les conformations 1C4 pour l'acide-L-iduronique, 4C1 pour l'acide D-glucuronique, mais il est notoire que, d'une
façon générale, la conformation en solution des unités monosaccharides est fluctuante. Ainsi, l'acide L-iduronique peut être de conformation 1C4 2S0 ou 4C1.In the present description, it has been chosen to represent the conformations 1 C 4 for the acid-L-iduronic acid, 4 C 1 for the D-glucuronic acid, but it is well known that In general, the conformation in solution of the monosaccharide units is fluctuating. Thus, L-iduronic acid may be 1 C 4 2 S 0 or 4 C 1 conformation.
Selon un de ses aspects, l'invention concerne les polysaccharides de formule (1.1) :According to one of its aspects, the invention relates to the polysaccharides of formula (1.1):
(1.1) dans lesquels : - la formule :(1.1) in which: - the formula:
désigne une famille particulière de polysaccharides Po, liés par leur carbone anomère à Pe tel que défini pour (I), - la formule :denotes a particular family of polysaccharides Po, linked by their anomeric carbon to Pe as defined for (I), - the formula:
est telle que définie pour (I),is as defined for (I),
- les groupes R1 sont tels que définis pour (I) et, pour un même monosaccharide, peuvent être identiques ou différents, - le monosaccharide contenu dans [ ]m est répété m fois, le monosaccharide contenu dans [ ]t est répété t fois, le monosaccharide contenu dans [ ]p est répété p fois,
- m est un entier variant de 1 à 5, t est un entier variant de 0 à 24 et p est un entier variant de 0 à 24 étant entendu que 1 < m + 1 + p < 25, ainsi que leurs sels pharmaceutiquement acceptables.the groups R 1 are as defined for (I) and, for the same monosaccharide, may be identical or different, the monosaccharide contained in [] m is repeated m times, the monosaccharide contained in [] t is repeated t times , the monosaccharide contained in [] p is repeated p times, m is an integer varying from 1 to 5, t is an integer varying from 0 to 24 and p is an integer varying from 0 to 24, provided that 1 <m + 1 + p <25, as well as their pharmaceutically acceptable salts.
Parmi ces polysaccharides de formule (1.1), les polysaccharides dans lesquels un seul des substituants R1, R2, R3 ou R4 représente un groupe -NH-CO-(CH2)S-NH2, ainsi que leurs sels pharmaceutiquement acceptables, constituent un sous-groupe de l'invention.Among these polysaccharides of formula (1.1), polysaccharides in which only one of the substituents R 1 , R 2 , R 3 or R 4 represents a group -NH-CO- (CH 2 ) S -NH 2 , as well as their pharmaceutically acceptable salts acceptable, constitute a subgroup of the invention.
Selon un aspect particulier, l'invention concerne les hexadécasaccharides de formule (1.2) :According to a particular aspect, the invention relates to hexadecasaccharides of formula (1.2):
(1.2)(1.2)
dans laquelle : - T représente un groupe -NH-CO-(CH2)5-NH2, - Pe représente un pentasaccharide de structure :in which: - T represents a group -NH-CO- (CH 2 ) 5 -NH 2 , - Pe represents a pentasaccharide of structure:
dans lequel :in which :
- R1 représente un groupe (C1-C6JaIcOXy ou un groupe -OSO3 ",- R 1 represents a group (C 1 -C 6 JaClOXy or a group -OSO 3 " ,
- R2 représente un groupe (C1-C6JaIcOXy ou un groupe -OSO3 ",- R 2 represents a group (C 1 -C 6 JaClOXy or a group -OSO 3 " ,
- R3 représente un groupe (CrC6)alcoxy,- R 3 represents a group (C r C 6 ) alkoxy,
- R4 représente un groupe (CrC6)alcoxy ou un groupe -OSO3 ", ou bien R4 constitue un pont -0-CH2-, le groupe -CH2- étant lié à l'atome de carbone porteur de la fonction carboxylique sur le même cycle,- R 4 represents a group (CrC 6 ) alkoxy or a group -OSO 3 " , or R 4 constitutes a bridge -O-CH 2 -, the group -CH 2 - being bonded to the carbon atom carrying the carboxylic function on the same cycle,
- W représente un atome d'oxygène ou un groupe méthylène,
ainsi que leurs sels pharmaceutiquement acceptables.W represents an oxygen atom or a methylene group, as well as their pharmaceutically acceptable salts.
Selon un autre de ses aspects, l'invention concerne les pentasaccharides de formule (1.3) :According to another of its aspects, the invention relates to the pentasaccharides of formula (1.3):
dans lesquels R1, R2, R3, R4 et W sont tels que définis pour (I), ainsi que leurs sels pharmaceutiquement acceptables.in which R 1 , R 2 , R 3 , R 4 and W are as defined for (I), as well as their pharmaceutically acceptable salts.
Parmi ces pentasaccharides de formule (1.3), les pentasaccharides dans lesquels un seul des substituants R1, R2, R3 ou R4 représente un groupe -NH-CO-(CH2)5-NH2, ainsi que leurs sels pharmaceutiquement acceptables, constituent un sous-groupe de l'invention.Among these pentasaccharides of formula (1.3), pentasaccharides in which only one of the substituents R 1 , R 2 , R 3 or R 4 represents a group -NH-CO- (CH 2 ) 5 -NH 2 , as well as their pharmaceutically acceptable salts acceptable, constitute a subgroup of the invention.
Parmi ces pentasaccharides de formule (1.3), l'invention a également pour objet les pentasaccharides de formule (1.4) :Among these pentasaccharides of formula (1.3), the subject of the invention is also the pentasaccharides of formula (1.4):
dans laquelle :in which :
- T représente un groupe -NH-CO-(CH2)5-NH2,T represents a group -NH-CO- (CH 2 ) 5 -NH 2 ,
- R1 représente un groupe (C1-C6JaIcOXy ou un groupe -OSO3 ",- R 1 represents a group (C 1 -C 6 JaClOXy or a group -OSO 3 " ,
- R2 représente un groupe (C1-C6JaIcOXy ou un groupe -OSO3 ', - R3 représente un groupe (C1-C6)BlCOXy,
- R4 représente un groupe (C1-C6JaIcOXy ou un groupe -OSO3 ', ou bien R4 constitue un pont -0-CH2-, le groupe -CH2- étant lié à l'atome de carbone porteur de la fonction carboxylique sur le même cycle,- R 2 represents a group (C 1 -C 6 JaClOXy) or a group -OSO 3 ' , - R 3 represents a group (C 1 -C 6 ) BlCOXy, - R 4 represents a group (C 1 -C 6 JaClOXy) or a group -OSO 3 ' , or R 4 constitutes a bridge -O-CH 2 -, the group -CH 2 - being bonded to the carrier carbon atom of the carboxylic function on the same cycle,
- W représente un atome d'oxygène ou un groupe méthylène, ainsi que leurs sels pharmaceutiquement acceptables.- W represents an oxygen atom or a methylene group, and their pharmaceutically acceptable salts.
Selon un autre de ses aspects, l'invention concerne le polysaccharide suivant : Méthyl (2-[N-(6-aminohexanoyl)]-2-désoxy-3,4-di-0-méthyl-6-0-sulfonato-α-D- glucopyranosyl)-(1 -→4)-(acide 2,3-di-O-méthyl-β-D-glucopyranosyluronique)-(1 →4)- (2,3,6-tri-O-sulfonato-α-D-glucopyranosyl)-(1 →4)-(acide 2,3-di-O-méthyl-α-L- idopyranosyluronique)-(1 ->4)-2,3,6-tri-O-sulfonato-α-D-glucopyranoside, sel de sodium.According to another of its aspects, the invention relates to the following polysaccharide: Methyl (2- [N- (6-aminohexanoyl)] - 2-deoxy-3,4-di-O-methyl-6-O-sulfonato-α -D-glucopyranosyl) - (1 - → 4) - (2,3-di-O-methyl-β-D-glucopyranosyluronic acid) - (1 → 4) - (2,3,6-tri-O-sulfonato) -α-D-glucopyranosyl) - (1 → 4) - (2,3-di-O-methyl-α-L-idopyranosyluronic acid) - (1 → 4) -2,3,6-tri-O- sulfonato-α-D-glucopyranoside, sodium salt.
s'agit du pentasaccharide de formule suivante (composé 1):is the pentasaccharide of the following formula (compound 1):
L'invention englobe les polysaccharides sous leur forme acide ou sous la forme de l'un quelconque de leurs sels pharmaceutiquement acceptables. Dans la forme acide, les fonctions -COO' et -SO3 " sont respectivement sous forme -COOH et -SO3H.The invention includes polysaccharides in their acid form or in the form of any of their pharmaceutically acceptable salts. In the acid form, the -COO ' and -SO 3 "functions are respectively in the form of -COOH and -SO 3 H.
On entend par sel pharmaceutiquement acceptable des polysaccharides de l'invention, un polysaccharide dans lequel une ou plusieurs des fonctions -COO" ou/et -SO3 " sont liées de façon ionique à un cation pharmaceutiquement acceptable. Les sels préférés selon l'invention sont ceux dont le cation est choisi parmi les cations des métaux alcalins et plus préférablement encore ceux dont le cation est Na+ ou K+.
Les composés de la formule (I) ci-dessus comprennent également ceux dans lesquels un ou plusieurs atomes d'hydrogène ou de carbone ont été remplacés par leur isotope radioactif par exemple le tritium ou le carbone-14. De tels composés marqués sont utiles dans les travaux de recherche, de métabolisme ou de pharmacocinétique, dans les essais biochimiques en tant que ligands.By pharmaceutically acceptable salt is meant polysaccharides of the invention, a polysaccharide 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 and more preferably still those whose cation is Na + or K + . The compounds of formula (I) above 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. Such labeled compounds are useful in research, metabolism or pharmacokinetics, in biochemical assays as ligands.
Dans son principe le procédé de préparation des composés selon l'invention utilise des synthons de base di- ou oligosaccharidiques préparés comme précédemment rapporté dans la littérature. On se référera notamment aux brevets ou demandes de brevet EP 0 300 099, EP 0 529 715, EP 0 621 282 et EP 0 649 854 ainsi qu'aux documents C. van Boeckel, M. Petitou, Angew. Chem. Int. Ed. Engi, 1993, 32, 1671-1690. Ces synthons sont ensuite couplés les uns aux autres de façon à fournir un équivalent entièrement protégé d'un polysaccharide selon l'invention. Cet équivalent protégé est ensuite transformé en un composé selon l'invention. L'un des synthons de base évoqués ci-dessus contient une fonction protégée particulière permettant l'introduction ultérieure du groupe -CO-(CH2)S-NH2 (de façon à former la chaîne -NH-CO-(CH2)5-NH2 sur le polysaccharide), par exemple une fonction aminé latente sous forme de groupe azido ou protégée sous forme de N-phtalimido.In principle, 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 and to the documents C. van Boeckel, M. Petitou, Angew. Chem. Int. Ed Engi, 1993, 32, 1671-1690. These synthons are then coupled to each other so as to provide a fully protected equivalent of a polysaccharide according to the invention. This protected equivalent is then converted into a compound according to the invention. One of the basic synthons mentioned above contains a particular protected function allowing the subsequent introduction of the group -CO- (CH 2 ) S -NH 2 (so as to form the chain -NH-CO- (CH 2 ) 5 -NH 2 on the polysaccharide), for example a latent amine function in the form of an azido group or protected in the form of N-phthalimido.
Dans les réactions de couplage évoquées ci-dessus, un di- ou oligosaccharide "donneur", activé sur son carbone anomère, réagit avec un di- ou oligosaccharide "accepteur", possédant un hydroxyle libre.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.
La présente invention concerne un procédé pour la préparation des composés de formule (I) caractérisé en ce que : dans une première étape, un équivalent complètement protégé du polysaccharide (I) désiré, contenant un précurseur protégé du domaine Pe prolongé à son extrémité non réductrice par un précurseur protégé du polysaccharide sulfaté Po est synthétisé, l'un de ces précurseurs contenant notamment une fonction aminé convenablement protégée pour l'introduction ultérieure du groupe -CO-(CH2)5-NH2 , lui-même convenablement protégé; dans une seconde étape, les groupes chargés négativement sont introduits et/ou démasqués ; dans une troisième étape, on déprotège la fonction aminé sur le polysaccharide puis on introduit le groupe -CO-(CH2)5-NH2 protégé ; dans une quatrième étape le groupe NH2 terminal est démasqué.
La synthèse de Pe est réalisée selon les méthodes décrites en particulier dans les demandes de brevet publiées sous les numéros WO 98/03554 et WO 99/36443, ainsi que dans la littérature sur les polysaccharides.The present invention relates to a process for the preparation of compounds of formula (I) characterized in that: in a first step, a completely protected equivalent of the desired polysaccharide (I), containing a protected precursor of the domain Pe extended at its non-reducing end by a protected precursor of the sulphated polysaccharide Po is synthesized, one of these precursors containing in particular a suitably protected amino function for the subsequent introduction of the -CO- (CH 2 ) 5 -NH 2 group , itself suitably protected; in a second step, the negatively charged groups are introduced and / or unmasked; in a third step, the amine function is deprotected on the polysaccharide and then the -CO- (CH 2 ) 5 -NH 2 protected group is introduced; in a fourth step, the NH 2 terminal group is unmasked. The synthesis of Pe is carried out according to the methods described in particular in the patent applications published under the numbers WO 98/03554 and WO 99/36443, as well as in the literature on polysaccharides.
La synthèse de la partie polysaccharidique précurseur de Po est réalisée selon des réactions bien connues de l'homme de l'art, en utilisant les méthodes de la synthèse d'oligosaccharides (GJ. Boons, Tetrahedron, 1996, 52, 1095-1121 , WO 98/03554 et WO 99/36443). Typiquement, un oligosaccharide donneur de liaison glycosidique est couplé avec un oligosaccharide accepteur de liaison glycosidique pour conduire à un autre oligosaccharide dont la taille est égale à la somme des tailles des deux espèces réactives. Cette séquence est répétée jusqu'à l'obtention du composé de formule (I) désiré. La nature et le profil de la charge du composé final désiré déterminent la nature des entités chimiques utilisées dans les différentes étapes de la synthèse, selon les règles bien connues de l'homme de l'art. On pourra se référer par exemple à C. van Boeckel, M. Petitou, Angew. Chem. Int. Ed. Engl., 1993, 32, 1671-1690 ou encore à H. Paulsen, "Advances in sélective Chemical synthèses of complex oligosaccharides" Angew. Chem. Int. Ed. Engl., 21 , 155-173 (1982).The synthesis of the polysaccharide precursor part of Po is carried out according to reactions well known to those skilled in the art, using the methods of oligosaccharide synthesis (GJ Boons, Tetrahedron, 1996, 52, 1095-1121, WO 98/03554 and WO 99/36443). Typically, a glycosidic link donor oligosaccharide is coupled with a glycosidic link acceptor oligosaccharide to yield another oligosaccharide the size of which is equal to the sum of the sizes of the two reactive species. This sequence is repeated until the desired compound of formula (I) is obtained. 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. We can refer for example to C. van Boeckel, Mr. Petitou, Angew. Chem. Int. Ed. Engl., 1993, 32, 1671-1690 or to H. Paulsen, "Advances in selective chemical syntheses of complex oligosaccharides" Angew. Chem. Int. Ed. Engl., 21, 155-173 (1982).
Les composés de l'invention sont obtenus à partir de leurs précurseurs polysaccharidiques complètement protégés en utilisant l'enchaînement suivant de réactions :The compounds of the invention are obtained from their completely protected polysaccharide precursors using the following sequence of reactions:
- les fonctions alcool devant être transformées en un groupe 0-sulfo et les acides carboxyliques sont déprotégés par l'élimination des groupes protecteurs utilisés durant l'élaboration du squelette,the alcohol functions to be converted into an O-sulpho group and the carboxylic acids are deprotected by the elimination of the protective groups used during the development of the skeleton,
- les groupes sulfo sont ensuite introduits, - la fonction aminé du polysaccharide permettant d'introduire le groupe -CO-(CH2)5- NH2 est déprotégée,the sulpho groups are then introduced, the amine function of the polysaccharide making it possible to introduce the -CO- (CH 2 ) 5 -NH 2 group is deprotected,
- le groupe -CO-(CH2)5-NH2 convenablement protégé est introduit par une réaction classique de couplage amino/acide, puisthe suitably protected -CO- (CH 2 ) 5 -NH 2 group is introduced by a conventional amino / acid coupling reaction, and then
- le groupe -NH2 terminal est démasqué.- the group -NH 2 terminal is unmasked.
Les composés de l'invention peuvent naturellement être préparés en utilisant différentes stratégies connues par l'homme de l'art de la synthèse des oligosaccharides.The compounds of the invention can naturally be prepared using various strategies known to those skilled in the art of oligosaccharide synthesis.
Le procédé décrit ci-dessus est le procédé préféré de l'invention. Toutefois, les composés de formule (I) peuvent être préparés par d'autres méthodes bien connues
de la chimie des sucres décrites par exemple dans Monosaccharides, Their chemistry and their rôles in natural products, P. M. Collins et RJ. Ferrier, J. Wiley & Sons, 1995 et dans GJ. Boons, Tetrahedron, 1996, 52, 1095-1121.The process described above is the preferred method of the invention. However, the compounds of formula (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 in GJ. Boons, Tetrahedron, 1996, 52, 1095-1121.
Les pentasaccharides Pe peuvent donc être obtenus à partir de synthons disaccharidiques de la façon décrite dans la publication de C. van Boeckel, M. Petitou, Angew. Chem. Int. Ed. Engl., 1993, 32, 1671-1690.The pentasaccharides Pe can thus be obtained from disaccharide synthons in the manner described in the publication by C. van Boeckel, M. Petitou, Angew. Chem. Int. Ed. Engl., 1993, 32, 1671-1690.
D'une façon générale, les groupes protecteurs utilisés dans le procédé de préparation des composés (I) sont ceux couramment utilisés dans la chimie des sucres, tels que décrits par exemple dans Protective Groups in Organic Synthesis, TW Greene, John Wiley & sons, New- York, 1981. Les groupes protecteurs peuvent par exemple être choisis parmi les groupes acétyles, halogénométhyles, benzoyles, lévulinyles, benzyles, benzyles substitués, trityles éventuellement substitués, tétrahydropyranyles, allyles, pentenyles, tert-butyldiméthylsilyles (tBDMS) ou triméthylsilyléthyles. Les groupes activateurs sont ceux classiquement utilisés en chimie des sucres selon par exemple GJ. Boons, Tetrahedron, 1996, 52, 1095-1121. Ces groupes activateurs sont choisis par exemple parmi les imidates, les thioglycosides, les penténylglycosides, les xanthates, les phosphites ou les halogénures.In general, the protecting groups used in the process for the preparation of compounds (I) are those commonly used in the chemistry of sugars, as described, for example, in Protective Groups in Organic Synthesis, TW Greene, John Wiley & Son, New York, 1981. The protecting groups may for example be selected from acetyl, halomethyl, benzoyl, levulinyl, benzyl, substituted benzyl, optionally substituted trityl, tetrahydropyranyl, allyl, pentenyl, tert-butyldimethylsilyl (tBDMS) or trimethylsilylethyl groups. Activator groups are those conventionally used in sugar chemistry according to GJ for example. Boons, Tetrahedron, 1996, 52, 1095-1121. These activating groups are chosen for example from imidates, thioglycosides, pentenylglycosides, xanthates, phosphites or halides.
Notamment, l'introduction du groupe -CO-(CH2)S-NH2 sur la fonction aminé libre du polysaccharide, selon le procédé décrit ci-dessus, peut être réalisée à l'aide d'un réactif de type Act-CO-(CH2)5-NH-Pg, dans lequel "Act" représente un groupe activateur d'une fonction acide (tel qu'un imide, par exemple un dérivé de succinimide, ou encore un anhydride mixte, ou bien tout autre agent activateur connu en chimie peptidique pour les réactions de couplage amino/acide) et "Pg" représente un groupe protecteur de fonction aminé (tel qu'un groupe benzyloxycarbonyle).In particular, the introduction of the -CO- (CH 2 ) S -NH 2 group onto the free amine function of the polysaccharide, according to the process described above, can be carried out using an Act-CO type reagent. - (CH 2 ) 5 -NH-Pg, wherein "Act" represents an activating group of an acid function (such as an imide, for example a succinimide derivative, or a mixed anhydride, or any other agent known activator in peptide chemistry for amino / acid coupling reactions) and "Pg" represents an amine protecting group (such as a benzyloxycarbonyl group).
Le procédé décrit ci-dessus permet d'obtenir les composés de l'invention sous forme de sels. Pour obtenir les acides correspondants, les composés de l'invention sous forme de sels sont mis en contact avec une résine échangeuse de cations sous forme acide. Les composés de l'invention sous forme d'acides peuvent être ensuite neutralisés par une base pour obtenir le sel souhaité. Pour la préparation des sels des composés de formule (I), on peut utiliser toute base minérale ou organique, donnant avec les composés de formule (I), des sels pharmaceutiquement acceptables. On utilise de manière préférentielle comme base l'hydroxyde de sodium, de potassium, de
calcium ou de magnésium. Les sels de sodium et de calcium des composés de formule (I) sont les sels préférés.The process described above makes it possible to obtain the compounds of the invention in the form of salts. To obtain the corresponding acids, the compounds of the invention in the form of salts are 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. For the preparation of the salts of the compounds of formula (I), any inorganic or organic base can be used, giving with the compounds of formula (I), pharmaceutically acceptable salts. Sodium, potassium, potassium hydroxide is preferably used as the base. calcium or magnesium. The sodium and calcium salts of the compounds of formula (I) are the preferred salts.
L'invention sera mieux comprise à l'aide de l'exemple détaillé qui suit, relatif à la préparation d'un composé selon l'invention de type pentasaccharide, répondant à la formule (1.4). Cet exemple n'est pas limitatif et ne fait qu'illustrer la présente invention.The invention will be better understood with the aid of the following detailed example relating to the preparation of a compound according to the invention of pentasaccharide type, corresponding to formula (1.4). This example is not limiting and only illustrates the present invention.
Exemple de préparation du composé 1 :Preparation Example of Compound 1
Méthyl (2-[N-(6-aminohexanoyl)]-2-désoxy-3,4-di-O-méthyl-6-O-sulfonato-u-D- glucopyranosyl)-(1 →4)-(acide 2, 3-di-O-méthyl-β-D-glucopyranosyluronique)- (1-rf)-(2,3,6-tri-O-sulfonato-a-D-glucopyranosyl)-(1→4)-(acide 2,3-di-O-méthyl-a- L-idopyranosyluronique)-(1→4)-2,3,6-tri-Osulfonato-a-D-glucopyranoside, sel de sodiumMethyl (2- [N- (6-aminohexanoyl)] - 2-deoxy-3,4-di-O-methyl-6-O-sulfonato-D-glucopyranosyl) - (1 → 4) - (2,3-acid) -di-O-methyl-β-D-glucopyranosyluronic acid) - (1-rf) - (2,3,6-tri-O-sulfonato-α-D-glucopyranosyl) - (1 → 4) - di-O-methyl-α-L-idopyranosyluronic acid) - (1 → 4) -2,3,6-tri-Osulfonato-α-D-glucopyranoside, sodium salt
Composé 1Compound 1
1) Préparation du 6-(benzyloxycarbonylamino)hexanoate de succinimidyle1) Preparation of succinimidyl 6- (benzyloxycarbonylamino) hexanoate
A une solution d'acide 6-(benzyloxycarbonylamino) hexanoïque (1.00 g, 3.77 mmol) dans du diméthylformamide (20 mL), on ajoute du triéthylamine (0.63 mL, 4.52 mmol) et on laisse agiter le mélange à température ambiante et sous argon pendant 30 minutes. On refroidit la solution à O0C et on ajoute goutte à goutte du chloroformiate d'éthyle (0.43 mL, 4.52 mmol). Après deux heures à température ambiante, on ajoute du N-hydroxysuccinimide (0.52 g, 4.52 mmol) et on laisse agiter le mélange pendant la nuit à température ambiante. On évapore à sec avant de reprendre le résidu dans de l'eau à laquelle on ajoute de l'acétate d'éthyle. Les phases sont séparées et la phase aqueuse est extraite par de l'acétate d'éthyle. Les phases organiques sont réunies, séchées sur sulfate de sodium, filtrées et évaporée à sec avant purification sur une colonne de gel de silice avec un mélange d'acétate d'éthyle / pentane (75/25 v/v)
comme éluant. Les fractions une fois évaporées donnent 1.13 g de 6- (benzyloxycarbonylamino)hexanoate de succinimidyle sous forme d'huile. CCM : Rf = 0.22 sur plaque de gel de silice avec un mélange n-heptane/acétate d'éthyle (30/70 v/v) comme éluant.To a solution of 6- (benzyloxycarbonylamino) hexanoic acid (1.00 g, 3.77 mmol) in dimethylformamide (20 mL) is added triethylamine (0.63 mL, 4.52 mmol) and the mixture is stirred at room temperature and under argon. during 30 minutes. The solution is cooled to 0 ° C. and ethyl chloroformate (0.43 ml, 4.52 mmol) is added dropwise. After two hours at room temperature, N-hydroxysuccinimide (0.52 g, 4.52 mmol) is added and the mixture is stirred overnight at room temperature. It is evaporated to dryness and the residue is taken up in water to which ethyl acetate is added. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulphate, filtered and evaporated to dryness before purification on a column of silica gel with a mixture of ethyl acetate / pentane (75/25 v / v) as an eluent. The fractions, once evaporated, give 1.13 g of succinimidyl 6- (benzyloxycarbonylamino) hexanoate in the form of an oil. TLC: R f = 0.22 on silica gel plate with n-heptane / ethyl acetate (30/70 v / v) as eluent.
2) Préparation du composé l'2) Preparation of the compound
Le greffage de la chaîne aminée est réalisée sur le pentasaccharide 44, ou méthyl (2- amino-2-désoxy-3,4-di-0-méthyl-6-0-sulfonato-α-D-glucopyranosyl)-(1→4)-(acide 2,3- di-0-méthyl-β-D-glucopyranosyluronique)-(1->4)-(2,3,6-tri-0-sulfonato-α-D-gluco- pyranosyl)-(1 →4)-(acide 2,3-di-O-méthyl-α-L-idopyranosyl-uronique)-(1 →4)- 2,3,6-tri- O-sulfo-nato-α-D-glucopyranoside, sel de sodium, dont la préparation est décrite dans la demande de brevet WO 02/24754:The grafting of the amino chain is carried out on pentasaccharide 44, or methyl (2-amino-2-deoxy-3,4-di-O-methyl-6-O-sulfonato-α-D-glucopyranosyl) - (1 → 4) - (2,3-di-O-methyl-β-D-glucopyranosyluronic acid) - (1-> 4) - (2,3,6-tri-O-sulfonato-α-D-glucopyranosyl) - (1 → 4) - (2,3-di-O-methyl-α-L-idopyranosyl-uronic acid) - (1 → 4) - 2,3,6-tri-O-sulfonemono-α- D-glucopyranoside, sodium salt, the preparation of which is described in patent application WO 02/24754:
4444
A une solution de 6-(benzyloxycarbonylamino)hexanoate de succinimidyle (783 mg, 2,16 mmol) dans du N,N-diméthylformamide (10 mL), on ajoute le pentasaccharide 44 (505 mg, 0.29 mmol). Après 24 heures d'agitation en atmosphère inerte et à température ambiante, on évapore le solvant sous pression réduite et on dissout le résidu dans de l'eau (40 mL) avant de laver la solution par du chloroforme (2 x 30 mL). La phase chloroformique est lavée à l'eau (10 mL) et les phases aqueuses sont réunies, puis évaporées à sec sous pression réduite. Le résidu solide est trituré par du 2-propanol (10 mL) et la suspension centrifugée pendant 5 minutes à 2500 tpm. La phase alcoolique est soutirée et remplacée par du 2-propanol (10 mL) et la centrifugation est répétée. Après avoir soutiré le solvant, le produit brut est séché sous vide.To a solution of succinimidyl 6- (benzyloxycarbonylamino) hexanoate (783 mg, 2.16 mmol) in N, N-dimethylformamide (10 mL) was added pentasaccharide 44 (505 mg, 0.29 mmol). After 24 hours of stirring in an inert atmosphere and at room temperature, the solvent is evaporated under reduced pressure and the residue is dissolved in water (40 ml) before washing the solution with chloroform (2 × 30 ml). The chloroform phase is washed with water (10 mL) and the aqueous phases are combined and then evaporated to dryness under reduced pressure. The solid residue is triturated with 2-propanol (10 mL) and the suspension centrifuged for 5 minutes at 2500 rpm. The alcohol phase is withdrawn and replaced by 2-propanol (10 mL) and the centrifugation is repeated. After withdrawing the solvent, the crude product is dried under vacuum.
On obtient ainsi 399 mg du composé l', ou méthyl (2-[N-(6-benzyloxycarbonyl- aminohexanoyl)]-2-désoxy-3,4-di-0-méthyl-6-0-sulfonato-α-D-glucopyranosyl)-(1→4)- (acide 2l3-di-0-méthyl-β-D-glucopyranosyluronique)-(1→4)-(2,3,6-tri-0-sulfonato-α-D- glucopyranosyl)-(1 -»4)-(acide 2,3-di-0-méthyl-α-L-idopyranosyluronique)-(1 -→4)-2,3,6-
tri-O-sulfonato-α-D-glucopyranoside, dans lequel Pg représente un groupe benzyloxycarbonyle :399 mg of compound 1 'or methyl (2- [N- (6-benzyloxycarbonylaminohexanoyl)] - 2-deoxy-3,4-di-O-methyl-6-O-sulfonato-α-D are thus obtained. -glucopyranosyl) - (1 → 4) - (2- l 3-di-0-methyl-β-D-glucopyranosyluronic) - (1 → 4) - (2,3,6-tri-0-sulfonato-α- D-glucopyranosyl) - (1-4) - (2,3-di-O-methyl-α-L-idopyranosyluronic acid) - (1 → 4) -2,3,6- tri-O-sulfonato-α-D-glucopyranoside, wherein Pg is a benzyloxycarbonyl group:
Composé 11 Compound 1 1
RMN du proton à 200 MHz dans l'eau deuteriée : La structure du produit attendu est confirmée, du fait que le spectre obtenu est identique à celui effectué sur un produit synthétisé conformément à l'exemple 5 de la demande de brevet WO 02/24754, sans les signaux dus aux atomes de la partie biotine mais avec des signaux de 7.4 à 7.5 ppm dus au groupement benzyloxy.Proton NMR at 200 MHz in deuterated water: The structure of the expected product is confirmed, since the spectrum obtained is identical to that produced on a product synthesized according to Example 5 of patent application WO 02/24754. , without the signals due to the atoms of the biotin part but with signals from 7.4 to 7.5 ppm due to the benzyloxy group.
3) Préparation du composé 13) Preparation of compound 1
Le produit l' obtenu à l'issue de l'étape précédente (399 mg) est dissous dans de l'eau deuteriée (10 mL). On traite la solution par du palladium sur charbon à 10% (25 mg) et on laisse agiter la solution 20 heures en présence d'hydrogène à pression atmosphérique. On dilue le mélange avec de l'eau (15 mL), on filtre le catalyseur et on lave la solution avec du chloroforme (2 x 15 mL) avant d'évaporer à sec sous pression réduite. Un aliquote (98 mg sur 320 mg) de ce produit est purifié sur une colonne de gel Sephadex G-25 (2.5 x 50 cm) avec de l'eau comme éluant pour donner 25 mg du composé 1.The product obtained after the previous step (399 mg) is dissolved in deuterated water (10 mL). The solution is treated with 10% palladium on carbon (25 mg) and the solution is stirred for 20 hours in the presence of hydrogen at atmospheric pressure. The mixture is diluted with water (15 mL), the catalyst is filtered and the solution is washed with chloroform (2 x 15 mL) and evaporated to dryness under reduced pressure. An aliquot (98 mg on 320 mg) of this product is purified on a column of Sephadex G-25 gel (2.5 x 50 cm) with water as eluent to give 25 mg of compound 1.
HPLC : Tr = 15.4 min sur colonne X-Terra RP-18 15O x 4.6 mm, particules de 5μ de chez Waters SA. Détection avec lampe UV à 211 nm. Eluant 1 : eau contenant 0.02M d'acétate d'ammonium et 0.05M de di-n-butylamine, ajusté à pH7 avec de l'acide acétique. Eluant 2 : mélange acétonitrile/eau (90/10 v/v) contenant 0.05M de di-n- butylamine et 0.08M d'acide acétique. Les proportions des éluants sont programmées de sorte que la composition en éluant 2 est de 10% à 0 min. ; de 20% à 25 min. ; de 50% à 40 min. ; de 50% à 43 min. et de 5% à 50 minutes.
RMN du proton à 600 MHz dans l'eau deuteriée : La structure du produit attendu est confirmée, du fait que le spectre obtenu est identique à celui effectué sur un produit synthétisé conformément à l'exemple 5 de la demande de brevet WO 02/24754, sans les signaux dus aux atomes de la partie biotine.HPLC: Tr = 15.4 min on X-Terra RP-18 column 15O x 4.6 mm, 5μ particles from Waters SA. Detection with UV lamp at 211 nm. Eluent 1: water containing 0.02M ammonium acetate and 0.05M di-n-butylamine, adjusted to pH7 with acetic acid. Eluent 2: acetonitrile / water mixture (90/10 v / v) containing 0.05M di-n-butylamine and 0.08M acetic acid. The proportions of the eluents are programmed so that the eluent 2 composition is 10% to 0 min. ; from 20% to 25 min. ; from 50% to 40 min. ; from 50% to 43 min. and from 5% to 50 minutes. Proton NMR at 600 MHz in deuterated water: The structure of the expected product is confirmed, since the spectrum obtained is identical to that produced on a product synthesized according to Example 5 of patent application WO 02/24754. , without the signals due to the atoms of the biotin part.
Pharmacologie :Pharmacology:
Les composés selon l'invention ont fait l'objet d'études biochimiques et pharmacologiques.The compounds according to the invention have been the subject of biochemical and pharmacological studies.
L'activité pharmacologique de ces produits a notamment été étudiée dans un modèle in vitro d'inhibition du facteur Xa de la coagulation, en présence d'antithrombine (activité anti-facteur Xa dépendante de la présence d'antithrombine), tel que décrit par J.-M. Herbert et al., Blood, 1998, 91, 4197-4205 . Dans ce modèle, on confirme les propriétés antithrombotiques des composés selon l'invention. En particulier pour le composé 1 selon l'invention : CI50 = 1.69.10"2 μg/ml (CI50 : dose permettant une inhibition de 50%).The pharmacological activity of these products has in particular been studied in an in vitro model of inhibition of coagulation factor Xa, in the presence of antithrombin (anti-factor Xa activity dependent on the presence of antithrombin), as described by J.-M. Herbert et al., Blood, 1998, 91, 4197-4205. In this model, the antithrombotic properties of the compounds according to the invention are confirmed. In particular for compound 1 according to the invention: IC 50 = 1.69 × 10 -2 μg / ml (IC 50: dose allowing a 50% inhibition).
Grâce à leur activité biochimique et pharmaceutique, les oligosaccharides de la présente invention constituent des médicaments très intéressants. Leur toxicité est parfaitement compatible avec cette utilisation. Ils sont également très stables et sont donc particulièrement appropriés pour constituer le principe actif de spécialités pharmaceutiques.Thanks to their biochemical and pharmaceutical activity, the oligosaccharides of the present invention constitute very interesting drugs. Their toxicity is perfectly compatible with this use. They are also very stable and are therefore particularly suitable for constituting the active principle of pharmaceutical specialties.
Ils peuvent être utilisés dans diverses pathologies consécutives à une modification de l'homéostasie du système de la coagulation apparaissant en particulier lors des troubles du système cardio-vasculaire et cérébro-vasculaire comme les troubles thromboemboliques associés à l'arthérosclérose et au diabète tels que l'angine instable, l'attaque cérébrale, la resténose après angioplastie, l'endartérectomie, la pose de prothèses endovasculaires ; ou les troubles thromboemboliques associés à la rethrombose après thrombolyse, à l'infarctus, à la démence d'origine ischémique, aux maladies artérielles périphériques, à l'hémodialyse, aux fibrillations auriculaires ou encore lors de l'utilisation de prothèses vasculaires de pontages aorto-coronariens. Ces produits peuvent par ailleurs être utilisés pour le traitement ou la prévention de
pathologies thromboemboliques d'origine veineuse, telles que les embolies pulmonaires et la thrombose veineuse profonde. Ils peuvent être utilisés ou pour prévenir ou pour traiter les complications thrombotiques observés par exemple à la suite d'opérations chirurgicales, de développements tumoraux ou de dérèglements de la coagulation, induits par des activateurs bactériens, viraux, ou enzymatiques. Dans le cas de leur utilisation lors de la pose de prothèses, les composés de la présente invention peuvent recouvrir des prothèses et les rendre ainsi hémocompatibles. En particulier, ils peuvent être fixés à des prothèses intravasculaires (stents). Dans ce cas, ils peuvent éventuellement être modifiés chimiquement par introduction à l'extrémité non réductrice ou réductrice d'un bras approprié, comme décrit selon EP 649854. Les composés de la présente invention peuvent également être utilisés comme adjuvants lors d'endartérectomie réalisée avec des ballonnets poreux.They can be used in various pathologies resulting from a change in the homeostasis of the coagulation system appearing in particular during disorders of the cardiovascular and cerebrovascular system such as thromboembolic disorders associated with atherosclerosis and diabetes such as unstable angina, cerebral attack, restenosis after angioplasty, endarterectomy, placement of endovascular prostheses; or thromboembolic disorders associated with rethrombosis after thrombolysis, infarction, dementia of ischemic origin, peripheral arterial diseases, hemodialysis, atrial fibrillation, or the use of aortic bypass graft vascular prostheses. -coronariens. These products can also be used for the treatment or prevention of venous thromboembolic pathologies, such as pulmonary embolism and deep vein thrombosis. They can be used or to prevent or treat thrombotic complications observed for example as a result of surgical operations, tumor development or disruption of coagulation, induced by bacterial, viral or enzymatic activators. In the case of their use during prosthesis placement, the compounds of the present invention can cover prostheses and thus make them hemocompatible. In particular, they can be attached to intravascular prostheses (stents). In this case, they may optionally be chemically modified by introduction to the non-reducing or reducing end of a suitable arm, as described in EP 649854. The compounds of the present invention may also be used as adjuvants during endarterectomy performed with porous balloons.
Les composés selon l'invention peuvent être utilisés pour la préparation de médicaments destinés à traiter ou prévenir les maladies ci-dessus.The compounds of the invention may be used for the preparation of medicaments for treating or preventing the above diseases.
Selon un autre de ses aspects, la présente invention a donc pour objet une composition pharmaceutique contenant, en tant que principe actif, un polysaccharide de synthèse selon l'invention ou un de ses sels pharmaceutiquement acceptables, éventuellement en association avec un ou plusieurs excipients inertes et appropriés. Lesdits excipients sont choisis selon la forme pharmaceutique et le mode d'administration souhaités : orale, sublinguale, sous-cutanée, intramusculaire, intraveineuse, transdermique, transmuqueux, locale ou rectale. Le principe actif peut être également présenté sous forme de complexe avec une cyclodextrine, par exemple α, β ou γ cyclodextrine, 2-hydroxypropyl-β-cyclodextrine ou méthyl-β-cyclodextrine.According to another of its aspects, the subject of the present invention is therefore a pharmaceutical composition containing, as active ingredient, a synthetic polysaccharide according to the invention or a pharmaceutically acceptable salt thereof, optionally in combination with one or more inert excipients. and appropriate. Said excipients are chosen according to the desired pharmaceutical form and mode of administration: oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, transmucosal, local or rectal. The active ingredient may also be presented in the form of a complex with a cyclodextrin, for example α, β or γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.
Le principe actif peut également être libéré par un ballonnet le contenant ou par un extenseur endovasculaire introduit dans les vaisseaux sanguins. L'efficacité pharmacologique du principe actif n'est ainsi pas affectée.The active ingredient can also be released by a balloon containing it or by an endovascular stent introduced into the blood vessels. The pharmacological effectiveness of the active ingredient is thus not affected.
Dans chaque unité de dosage, le principe actif est présent dans les quantités adaptées afin d'obtenir l'effet prophylactique ou thérapeutique désiré. Chaque unité de dosage peut contenir de 0,1 à 100 mg de principe actif, de préférence 0,5 à 50 mg, de façon encore préférée de 2.5 à 3.0 mg.
Les composés selon l'invention peuvent également être utilisés en association avec un ou plusieurs autres principes actifs utiles pour la thérapeutique souhaitée tels que par exemple des antithrombotiques, des anticoagulants, des antiagrégants plaquettaires tels que par exemple le dipyridamole, l'aspirine, la ticlopidine, le clopidogrel ou des antagonistes du complexe de la glycoprotéine Ilb/IIIa.
In each dosage unit, the active ingredient is present in the appropriate amounts in order to obtain the desired prophylactic or therapeutic effect. Each dosage unit may contain from 0.1 to 100 mg of active ingredient, preferably 0.5 to 50 mg, more preferably 2.5 to 3.0 mg. The compounds according to the invention may also be used in combination with one or more other active ingredients that are useful for the desired therapy, such as, for example, antithrombotics, anticoagulants, antiplatelet agents such as, for example, dipyridamole, aspirin or ticlopidine. , clopidogrel or antagonists of the glycoprotein Ilb / IIIa complex.
Claims
1. Polysaccharides synthétiques à activité antithrombotique répondant à la formule1. Synthetic polysaccharides with antithrombotic activity corresponding to the formula
dans laquelle :in which :
- le trait ondulé désigne une liaison située soit au-dessous soit au-dessus du plan du cycle pyranosique,the wavy line designates a link situated either below or above the plane of the pyranosic cycle,
- la formule :- the formula :
désigne un polysaccharide contenant n unités monosaccharidiques identiques ou différentes, lié par son carbone anomère à Pe, - la formule :denotes a polysaccharide containing n identical or different monosaccharide units, linked by its anomeric carbon to Pe, - the formula:
est une représentation schématique d'une unité monosaccharidique à structure pyranosique choisie parmi les hexoses, les pentoses et les sucres desoxy correspondants, cette unité étant liée par son carbone anomère à une autre unité monosaccharidique, et les groupes hydroxy de cette unité étant substitués par des groupes Ri identiques ou différents, Ri étant tel que défini ci-dessous, - Pe représente un pentasaccharide de structure : is a schematic representation of a monosaccharide unit with a pyranosic structure chosen from hexoses, pentoses and corresponding desoxy sugars, this unit being linked by its anomeric carbon to another monosaccharide unit, and the hydroxyl groups of this unit being substituted by identical or different R 1 groups, Ri being as defined below, - Pe represents a pentasaccharide of structure:
- h est égal à 1 ou 2,h is 1 or 2,
- n est un entier et peut prendre toute valeur de O à 25, - R1 représente un groupe -NH-CO-(CH2)S-NH2, un groupe (CrC6)alcoxy ou un groupe -OSO3 ",n is an integer and can take any value from 0 to 25, R 1 represents a group -NH-CO- (CH 2 ) S -NH 2 , a group (C r C 6 ) alkoxy or a group -OSO 3 " ,
- R2 représente un groupe -NH-CO-(CH2)5-NH2, un groupe (CrC6)alcoxy ou un groupe -OSO3 ",R 2 represents a group -NH-CO- (CH 2 ) 5 -NH 2 , a group (C r C 6 ) alkoxy or a group -OSO 3 " ,
- R3 représente un groupe -NH-CO-(CH2)S-NH2 ou un groupe (C1-C6JaIcOXy, - R4 représente un groupe -NH-CO-(CH2)5-NH2, un groupe (CrC6)alcoxy ou un groupe -OSO3 " ou bien R4 constitue un pont -0-CH2-, le groupe -CH2- étant lié à l'atome de carbone porteur de la fonction carboxylique sur le même cycle ; étant entendu que l'un au moins des substituants R1, R2, R3 ou R4 représente un groupe -NH-CO-(CH2)5-NH2, - W représente un atome d'oxygène ou un groupe méthylène,- R 3 represents a group -NH-CO- (CH 2 ) S -NH 2 or a group (C 1 -C 6 JaClOXy, - R 4 represents a group -NH-CO- (CH 2 ) 5 -NH 2 , a group (C r C 6 ) alkoxy or a group -OSO 3 " or R 4 constitutes a bridge -O-CH 2 -, the group -CH 2 - being bonded to the carbon atom carrying the carboxylic function on the same ring, it being understood that at least one of the substituents R 1 , R 2 , R 3 or R 4 represents a group -NH-CO- (CH 2 ) 5 -NH 2 , -W represents an oxygen atom or a methylene group,
ainsi que leurs sels pharmaceutiquement acceptables.as well as their pharmaceutically acceptable salts.
2. Polysaccharides selon la revendication 1 , caractérisés en ce qu'ils répondent à la formule (1.1) :2. Polysaccharides according to claim 1, characterized in that they correspond to formula (1.1):
(1.1 ) dans laquelle : - la formule : (1.1) in which: - the formula:
désigne une famille particulière de polysaccharides Po, liés par leur carbone anomère à Pe tel que défini pour (I) selon la revendication 1 , - la formule :denotes a particular family of polysaccharides Po, linked by their anomeric carbon to Pe as defined for (I) according to claim 1, - the formula:
est telle que définie pour (I) selon la revendication 1 ,is as defined for (I) according to claim 1,
- les groupes R1 sont tels que définis pour (I) selon la revendication 1 et, pour un même monosaccharide, peuvent être identiques ou différents,the groups R 1 are as defined for (I) according to claim 1 and, for the same monosaccharide, may be identical or different,
- le monosaccharide contenu dans [ ]m est répété m fois, le monosaccharide contenu dans [ ]t est répété t fois, le monosaccharide contenu dans [ ]p est répété p fois,- the monosaccharide contained in [] m is repeated m times, the monosaccharide contained in [] t is repeated t times, the monosaccharide contained in [] p is repeated p times,
- m est un entier variant de 1 à 5, t est un entier variant de O à 24 et p est un entier variant de O à 24 étant entendu que 1 < m + 1 + p < 25, ainsi que leurs sels pharmaceutiquement acceptables.m is an integer varying from 1 to 5, t is an integer varying from 0 to 24 and p is an integer varying from 0 to 24, provided that 1 <m + 1 + p <25, as well as their pharmaceutically acceptable salts.
3. Polysaccharides selon la revendication 2, caractérisés en ce que un seul des substituants R1, R2, R3 ou R4 représente un groupe -NH-CO-(CH2)S-NH2, ainsi que leurs sels pharmaceutiquement acceptables.3. Polysaccharides according to claim 2, characterized in that only one of the substituents R 1 , R 2 , R 3 or R 4 represents a group -NH-CO- (CH 2 ) S -NH 2 , as well as their pharmaceutically acceptable salts. .
4. Polysaccharides selon l'une quelconque des revendications 1 à 3, caractérisés en ce qu'ils consistent en des hexadécasaccharides de formule (1.2) : 4. Polysaccharides according to any one of claims 1 to 3, characterized in that they consist of hexadecasaccharides of formula (1.2):
(1.2)(1.2)
dans laquelle :in which :
- T représente un groupe -NH-CO-(CH2)S-NH2, - Pe représente un pentasaccharide de structure :T represents a group -NH-CO- (CH 2 ) S -NH 2 , - Pe represents a pentasaccharide of structure:
dans lequel : - R1 représente un groupe (C1-C6JaIcOXy ou un groupe -OSO3 ",in which: R 1 represents a group (C 1 -C 6 JaClOXy) or a group -OSO 3 " ,
- R2 représente un groupe (CrC6)alcoxy ou un groupe -OSO3 ",R 2 represents a group (C r C 6 ) alkoxy or a group -OSO 3 " ,
- R3 représente un groupe (CrC6)alcoxy,- R 3 represents a group (CrC 6 ) alkoxy,
- R4 représente un groupe (C1-C6JaICOXy ou un groupe -OSO3 ', ou bien R4 constitue un pont -0-CH2-, le groupe -CH2 étant lié à l'atome de carbone porteur de la fonction carboxylique sur le même cycle,- R 4 represents a group (C 1 -C 6) JaICOXy or a group -OSO 3 ' , or R 4 constitutes a bridge -O-CH 2 -, the group -CH 2 being bonded to the carbon atom carrying the carboxylic function on the same cycle,
- W représente un atome d'oxygène ou un groupe méthylène,W represents an oxygen atom or a methylene group,
ainsi que leurs sels pharmaceutiquement acceptables.as well as their pharmaceutically acceptable salts.
5. Polysaccharides selon la revendication 1 , caractérisés en ce qu'ils consistent en des pentasaccharides de formule (1.3) :5. Polysaccharides according to claim 1, characterized in that they consist of pentasaccharides of formula (1.3):
dans lesquels R1, R2, R3, R4 et W sont tels que définis pour (I) selon la revendication 1 , ainsi que leurs sels pharmaceutiquement acceptables. in which R 1 , R 2 , R 3 , R 4 and W are as defined for (I) according to claim 1, as well as their pharmaceutically acceptable salts.
6. Pentasaccharides selon la revendication 5, caractérisés en ce que un seul des substituants R1, R2, R3 ou R4 représente un groupe -NH-CO-(CH2)5-NH2, ainsi que leurs sels pharmaceutiquement acceptables.6. Pentasaccharides according to claim 5, characterized in that only one of the substituents R 1 , R 2 , R 3 or R 4 represents a group -NH-CO- (CH 2 ) 5 -NH 2 , as well as their pharmaceutically acceptable salts. .
7. Pentasaccharides selon la revendication 5 ou 6, caractérisés en ce qu'ils répondent à la formule (1.4) :7. Pentasaccharides according to claim 5 or 6, characterized in that they correspond to formula (1.4):
dans laquelle :in which :
- T représente un groupe -NH-CO-(CH2)5-NH2, - R1 représente un groupe (C1-C6JaIcOXy ou un groupe -OSO3 ",T represents a group -NH-CO- (CH 2 ) 5 -NH 2 , - R 1 represents a group (C 1 -C 6 JaClOXy) or a group -OSO 3 " ,
- R2 représente un groupe (C1-C6JaIcOXy ou un groupe -OSO3 ',- R 2 represents a group (C 1 -C 6 JaClOXy or a group -OSO 3 ' ,
- R3 représente un groupe (C1-C6JaIcOXy,- R 3 represents a group (C 1 -C 6 JaClOXy,
- R4 représente un groupe (C1-C6JaIcOXy ou un groupe -OSO3 ', ou bien R4 constitue un pont -0-CH2-, le groupe -CH2- étant lié à l'atome de carbone porteur de la fonction carboxylique sur le même cycle,- R 4 represents a group (C 1 -C 6 JaClOXy) or a group -OSO 3 ' , or R 4 constitutes a bridge -O-CH 2 -, the group -CH 2 - being bonded to the carrier carbon atom of the carboxylic function on the same cycle,
- W représente un atome d'oxygène ou un groupe méthylène,W represents an oxygen atom or a methylene group,
ainsi que leurs sels pharmaceutiquement acceptables.as well as their pharmaceutically acceptable salts.
8. Polysaccharide selon l'une quelconque des revendications 1 , 5, 6 ou 7, caractérisé en ce qu'il s'agit du méthyl (2-[N-(6-aminohexanoyl)]-2-désoxy-3,4-di-O-méthyl-6-O- sulfonato-α-D-glucopyranosyl)-(1→4)-(acide 2,3-di-O-méthyl-β-D- glucopyranosyluronique)-(1→4)-(2,3,6-tri-O-sulfonato-α-D-glucopyranosyl)-(1→4)- (acide 2,3-di-0-méthyl-α-L-idopyranosyluronique)-(1→4)-2,3,6-tri-0-sulfonato-α-D- glucopyranoside, sel de sodium. 8. Polysaccharide according to any one of claims 1, 5, 6 or 7, characterized in that it is methyl (2- [N- (6-aminohexanoyl)] -2-deoxy-3,4- di-O-methyl-6-O-sulfonato-α-D-glucopyranosyl) - (1 → 4) - (2,3-di-O-methyl-β-D-glucopyranosyluronic acid) - (1 → 4) - (2,3,6-tri-O-sulfonato-α-D-glucopyranosyl) - (1 → 4) - (2,3-di-O-methyl-α-L-idopyranosyluronic acid) - (1 → 4) -2,3,6-tri-O-sulfonato-α-D-glucopyranoside, sodium salt.
9. Médicaments, caractérisés en ce qu'ils comprennent un polysaccharide selon l'une quelconque des revendications 1 à 8.Medicaments, characterized in that they comprise a polysaccharide according to any one of claims 1 to 8.
10. Compositions pharmaceutiques contenant, en tant que principe actif, un polysaccharide selon l'une quelconque des revendications 1 à 8, ainsi qu'un ou plusieurs excipients inertes et appropriés.10. Pharmaceutical compositions containing, as active ingredient, a polysaccharide according to any one of claims 1 to 8, and one or more inert and suitable excipients.
11. Utilisation d'un polysaccharide selon l'une quelconque des revendications 1 à 8 pour la préparation d'un médicament destiné au traitement et à la prévention des pathologies consécutives à une modification de l'homéostasie du système de la coagulation apparaissant lors des troubles du système cardio-vasculaire et cérébro- vasculaire comme les troubles thromboemboliques associés à l'arthérosclérose et au diabète tels que l'angine instable, l'attaque cérébrale, la resténose après angioplastie, l'endartérectomie, la pose de prothèses endovasculaires, ou les troubles thromboemboliques associés à la rethrombose après thrombolyse, à l'infarctus, à la démence d'origine ischémique, aux maladies artérielles périphériques, à l'hémodialyse, aux fibrillations auriculaires, lors de l'utilisation de prothèses vasculaires de pontages aorto-coronariens, dans le traitement ou la prévention de pathologies thromboemboliques d'origine veineuse telles les embolies pulmonaires et la thrombose veineuse profonde, pour prévenir ou pour traiter les complications thrombotiques observés à la suite d'opérations chirurgicales, de développements tumoraux ou de dérèglements de la coagulation, induits par des activateurs bactériens, viraux, ou enzymatiques.11. Use of a polysaccharide according to any one of claims 1 to 8 for the preparation of a medicament for the treatment and prevention of pathologies resulting from a change in the homeostasis of the coagulation system appearing during the disorders. the cardiovascular and cerebrovascular system such as thromboembolic disorders associated with atherosclerosis and diabetes such as unstable angina, cerebral attack, restenosis after angioplasty, endarterectomy, endovascular prosthesis, or thromboembolic disorders associated with rethrombosis after thrombolysis, infarction, dementia of ischemic origin, peripheral arterial diseases, hemodialysis, atrial fibrillation, when using vascular prostheses of coronary artery bypass grafts, in the treatment or prevention of thromboembolic pathologies of venous origin such as embolisms p ulmonary and deep venous thrombosis, to prevent or treat thrombotic complications observed following surgical operations, tumor development or disruption of coagulation, induced by bacterial, viral or enzymatic activators.
12. Utilisation d'un polysaccharide selon l'une quelconque des revendications 1 à 8 pour recouvrir des prothèses.12. Use of a polysaccharide according to any one of claims 1 to 8 for covering prostheses.
13. Utilisation d'un polysaccharide selon l'une quelconque des revendications 1 à 8 comme adjuvant lors d'une endartérectomie réalisée avec des ballonnets poreux. 13. Use of a polysaccharide according to any one of claims 1 to 8 as an adjunct in an endarterectomy performed with porous balloons.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0804704A FR2935386B1 (en) | 2008-08-26 | 2008-08-26 | NOVEL POLYSACCHARIDES WITH ANTITHROMBOTIC ACTIVITY COMPRISING A COVALENT LIAISON WITH AN AMINO CHAIN |
| PCT/FR2009/001023 WO2010023374A1 (en) | 2008-08-26 | 2009-08-24 | Polysaccharides with antithrombotic activity, including a covalent bond and an amino chain |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP2328935A1 true EP2328935A1 (en) | 2011-06-08 |
Family
ID=40521663
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP09737025A Withdrawn EP2328935A1 (en) | 2008-08-26 | 2009-08-24 | Polysaccharides with antithrombotic activity, including a covalent bond and an amino chain |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US8492352B2 (en) |
| EP (1) | EP2328935A1 (en) |
| JP (1) | JP2012500884A (en) |
| FR (1) | FR2935386B1 (en) |
| WO (1) | WO2010023374A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2013537181A (en) | 2010-09-10 | 2013-09-30 | サノフイ | Biotinylated polysaccharides with antithrombotic activity and improved metabolic stability |
| JP6225321B1 (en) | 2016-08-31 | 2017-11-08 | 王子ホールディングス株式会社 | Method for producing polysulfate pentosan |
| CN111148749A (en) | 2016-08-31 | 2020-05-12 | 王子控股株式会社 | Production method of acidic xylo-oligosaccharide and acidic xylo-oligosaccharide |
| JP6281659B1 (en) | 2017-02-28 | 2018-02-21 | 王子ホールディングス株式会社 | Polysulfate pentosan, pharmaceutical composition and anticoagulant |
| EP3632451A4 (en) | 2017-05-31 | 2021-03-10 | Oji Holdings Corporation | Moisturizing topical preparation |
| WO2019054344A1 (en) | 2017-09-12 | 2019-03-21 | 王子ホールディングス株式会社 | Pentosan polysulfate and method for producing pentosan polysulfate |
| CN111511773B (en) | 2017-12-20 | 2023-01-13 | 王子控股株式会社 | Pentosan polysulfate and medicament containing same |
| CN112717207A (en) * | 2020-12-15 | 2021-04-30 | 山东大学 | Long-acting antibacterial multifunctional coating based on bionic dopamine and preparation method and application thereof |
| CN113616861A (en) * | 2021-08-03 | 2021-11-09 | 广州维力医疗器械股份有限公司 | Layer-by-layer self-assembly composite anticoagulant coating, preparation method thereof and medical instrument |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2751334B1 (en) * | 1996-07-19 | 1998-10-16 | Sanofi Sa | SYNTHETIC POLYSACCHARIDES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2773804B1 (en) * | 1998-01-19 | 2000-02-18 | Sanofi Sa | SYNTHESIS POLYSACCHARIDES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| FR2814463B1 (en) * | 2000-09-22 | 2002-11-15 | Sanofi Synthelabo | NOVEL POLYSACCHARIDES WITH ANTITHROMBOTIC ACTIVITY COMPRISING AT LEAST ONE COVALENT BINDING WITH BIOTIN OR A BIOTINE DERIVATIVE |
-
2008
- 2008-08-26 FR FR0804704A patent/FR2935386B1/en not_active Expired - Fee Related
-
2009
- 2009-08-24 US US13/060,810 patent/US8492352B2/en not_active Expired - Fee Related
- 2009-08-24 WO PCT/FR2009/001023 patent/WO2010023374A1/en active Application Filing
- 2009-08-24 JP JP2011524423A patent/JP2012500884A/en active Pending
- 2009-08-24 EP EP09737025A patent/EP2328935A1/en not_active Withdrawn
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| Title |
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| See references of WO2010023374A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| US8492352B2 (en) | 2013-07-23 |
| WO2010023374A1 (en) | 2010-03-04 |
| FR2935386B1 (en) | 2010-09-10 |
| FR2935386A1 (en) | 2010-03-05 |
| JP2012500884A (en) | 2012-01-12 |
| US20110306567A1 (en) | 2011-12-15 |
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