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- Withdrawn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
Description
Claims
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) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2012042123A1 (en) | 2010-09-10 | 2012-04-05 | Sanofi | Biotinylated polysaccharides having an antithrombotic activity and improved metabolic stability |
MX2020002288A (en) | 2016-08-31 | 2020-07-14 | Oji Holdings Corp | Production method for acidic xylooligosaccharide, and acidic xylooligosaccharide. |
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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 |
US11344570B2 (en) | 2017-12-20 | 2022-05-31 | Oji Holdings Corporation | Pentosan polysulfate and medicine containing pentosan polysulfate |
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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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 |
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US20110306567A1 (en) | 2011-12-15 |
JP2012500884A (en) | 2012-01-12 |
FR2935386B1 (en) | 2010-09-10 |
FR2935386A1 (en) | 2010-03-05 |
US8492352B2 (en) | 2013-07-23 |
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