CA2806561C - Synthetic heparin pentasaccharides - Google Patents
Synthetic heparin pentasaccharides Download PDFInfo
- Publication number
- CA2806561C CA2806561C CA2806561A CA2806561A CA2806561C CA 2806561 C CA2806561 C CA 2806561C CA 2806561 A CA2806561 A CA 2806561A CA 2806561 A CA2806561 A CA 2806561A CA 2806561 C CA2806561 C CA 2806561C
- Authority
- CA
- Canada
- Prior art keywords
- group
- substituted
- benzyl
- protecting group
- arylacyl
- 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.)
- Expired - Fee Related
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 title description 27
- 229960002897 heparin Drugs 0.000 title description 22
- 229920000669 heparin Polymers 0.000 title description 22
- 150000002016 disaccharides Chemical class 0.000 claims abstract description 29
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 208
- -1 trichloroacetimidoyl Chemical group 0.000 claims description 190
- 125000006239 protecting group Chemical group 0.000 claims description 163
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 132
- 125000005251 aryl acyl group Chemical group 0.000 claims description 131
- 230000015572 biosynthetic process Effects 0.000 claims description 119
- 125000005258 alkyl aryl acyl group Chemical group 0.000 claims description 96
- 238000003786 synthesis reaction Methods 0.000 claims description 96
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 84
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 65
- 125000005587 carbonate group Chemical group 0.000 claims description 61
- 125000004122 cyclic group Chemical group 0.000 claims description 57
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 56
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 39
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 34
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 21
- 125000003342 alkenyl group Chemical group 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 150000001412 amines Chemical class 0.000 claims description 20
- 125000004001 thioalkyl group Chemical group 0.000 claims description 19
- 125000005000 thioaryl group Chemical group 0.000 claims description 19
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 18
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 13
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 11
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 10
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 9
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 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 claims description 6
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 2
- 229910052708 sodium Inorganic materials 0.000 claims 2
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 61
- 150000004043 trisaccharides Chemical class 0.000 abstract description 24
- 229920001499 Heparinoid Polymers 0.000 abstract description 22
- 239000002554 heparinoid Substances 0.000 abstract description 22
- 229940025770 heparinoids Drugs 0.000 abstract description 21
- 150000004044 tetrasaccharides Chemical class 0.000 abstract description 12
- 150000002772 monosaccharides Chemical class 0.000 abstract description 10
- 238000010561 standard procedure Methods 0.000 description 271
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 156
- 239000000243 solution Substances 0.000 description 111
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 109
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 90
- 125000003118 aryl group Chemical group 0.000 description 86
- 150000001875 compounds Chemical class 0.000 description 61
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 58
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 58
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- 239000000203 mixture Substances 0.000 description 52
- 238000006243 chemical reaction Methods 0.000 description 49
- 238000010898 silica gel chromatography Methods 0.000 description 47
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 45
- 239000000047 product Substances 0.000 description 44
- 239000011541 reaction mixture Substances 0.000 description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 38
- 238000000746 purification Methods 0.000 description 38
- 238000003756 stirring Methods 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 33
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 32
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 30
- 229910019142 PO4 Inorganic materials 0.000 description 30
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 30
- 229940093499 ethyl acetate Drugs 0.000 description 30
- 235000019439 ethyl acetate Nutrition 0.000 description 30
- 239000010452 phosphate Substances 0.000 description 30
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 28
- 229910052739 hydrogen Inorganic materials 0.000 description 28
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
- 238000002425 crystallisation Methods 0.000 description 26
- 230000008025 crystallization Effects 0.000 description 26
- 239000007858 starting material Substances 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- 238000000034 method Methods 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 239000007832 Na2SO4 Substances 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 23
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 23
- 229910052938 sodium sulfate Inorganic materials 0.000 description 23
- 235000011152 sodium sulphate Nutrition 0.000 description 23
- 239000012044 organic layer Substances 0.000 description 22
- 235000017557 sodium bicarbonate Nutrition 0.000 description 21
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 21
- 238000003776 cleavage reaction Methods 0.000 description 18
- 230000007017 scission Effects 0.000 description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 15
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 14
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 14
- 235000019341 magnesium sulphate Nutrition 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 11
- 229930182475 S-glycoside Natural products 0.000 description 11
- 238000010511 deprotection reaction Methods 0.000 description 11
- 230000013595 glycosylation Effects 0.000 description 11
- 238000006206 glycosylation reaction Methods 0.000 description 11
- 125000000547 substituted alkyl group Chemical group 0.000 description 11
- 150000003569 thioglycosides Chemical class 0.000 description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- 235000000346 sugar Nutrition 0.000 description 10
- 229940086542 triethylamine Drugs 0.000 description 10
- 102000004411 Antithrombin III Human genes 0.000 description 9
- 108090000935 Antithrombin III Proteins 0.000 description 9
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 9
- 229960005348 antithrombin iii Drugs 0.000 description 9
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 230000003197 catalytic effect Effects 0.000 description 8
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 8
- 230000021615 conjugation Effects 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- UPQQXPKAYZYUKO-UHFFFAOYSA-N 2,2,2-trichloroacetamide Chemical class OC(=N)C(Cl)(Cl)Cl UPQQXPKAYZYUKO-UHFFFAOYSA-N 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 125000003545 alkoxy group Chemical group 0.000 description 7
- 125000004104 aryloxy group Chemical group 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 229930182470 glycoside Natural products 0.000 description 7
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 239000006188 syrup Substances 0.000 description 6
- 235000020357 syrup Nutrition 0.000 description 6
- SDTORDSXCYSNTD-UHFFFAOYSA-N 1-methoxy-4-[(4-methoxyphenyl)methoxymethyl]benzene Chemical compound C1=CC(OC)=CC=C1COCC1=CC=C(OC)C=C1 SDTORDSXCYSNTD-UHFFFAOYSA-N 0.000 description 5
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 description 5
- 101100456566 Caenorhabditis elegans dpy-22 gene Proteins 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 238000006640 acetylation reaction Methods 0.000 description 5
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 5
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 5
- 238000006664 bond formation reaction Methods 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 5
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 5
- 101100310641 Caenorhabditis elegans sop-2 gene Proteins 0.000 description 4
- 239000002841 Lewis acid Substances 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- UDCDOJQOXWCCSD-UHFFFAOYSA-N N,N-dimethyl-N'-p-tolylsulfamide Chemical compound CN(C)S(=O)(=O)NC1=CC=C(C)C=C1 UDCDOJQOXWCCSD-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 208000007536 Thrombosis Diseases 0.000 description 4
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 description 4
- 206010047249 Venous thrombosis Diseases 0.000 description 4
- 150000001241 acetals Chemical class 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 125000003302 alkenyloxy group Chemical group 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 238000006480 benzoylation reaction Methods 0.000 description 4
- 238000005574 benzylation reaction Methods 0.000 description 4
- 229920001429 chelating resin Polymers 0.000 description 4
- 229960004132 diethyl ether Drugs 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 229940052303 ethers for general anesthesia Drugs 0.000 description 4
- 239000000937 glycosyl acceptor Substances 0.000 description 4
- 150000002373 hemiacetals Chemical class 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 229910052742 iron Inorganic materials 0.000 description 4
- 150000007517 lewis acids Chemical class 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- 206010051055 Deep vein thrombosis Diseases 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 239000000370 acceptor Substances 0.000 description 3
- 230000021736 acetylation Effects 0.000 description 3
- 229940127219 anticoagulant drug Drugs 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- FFHWGQQFANVOHV-UHFFFAOYSA-N dimethyldioxirane Chemical compound CC1(C)OO1 FFHWGQQFANVOHV-UHFFFAOYSA-N 0.000 description 3
- 239000000386 donor Substances 0.000 description 3
- 229960002442 glucosamine Drugs 0.000 description 3
- 150000002338 glycosides Chemical class 0.000 description 3
- 239000000348 glycosyl donor Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229940127215 low-molecular weight heparin Drugs 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
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Classifications
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- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
- C07H15/10—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical containing unsaturated carbon-to-carbon bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/02—Acyclic radicals
- C07H7/033—Uronic acids
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- Chemical & Material Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
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- Biotechnology (AREA)
- Genetics & Genomics (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| AUPR7587 | 2001-09-07 | ||
| AUPR758701 | 2001-09-07 | ||
| CA2459562A CA2459562C (en) | 2001-09-07 | 2002-09-06 | Synthetic heparin pentasaccharides |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CA2459562A Division CA2459562C (en) | 2001-09-07 | 2002-09-06 | Synthetic heparin pentasaccharides |
Publications (2)
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| CA2806561A1 CA2806561A1 (en) | 2003-03-20 |
| CA2806561C true CA2806561C (en) | 2015-12-22 |
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| CA2459562A Expired - Fee Related CA2459562C (en) | 2001-09-07 | 2002-09-06 | Synthetic heparin pentasaccharides |
| CA2806561A Expired - Fee Related CA2806561C (en) | 2001-09-07 | 2002-09-06 | Synthetic heparin pentasaccharides |
| CA2806723A Expired - Fee Related CA2806723C (en) | 2001-09-07 | 2002-09-06 | Synthetic heparin pentasaccharides |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
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| CA2806604A Expired - Fee Related CA2806604C (en) | 2001-09-07 | 2002-09-06 | Synthetic heparin pentasaccharides |
| CA2459562A Expired - Fee Related CA2459562C (en) | 2001-09-07 | 2002-09-06 | Synthetic heparin pentasaccharides |
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| Application Number | Title | Priority Date | Filing Date |
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| CA2806723A Expired - Fee Related CA2806723C (en) | 2001-09-07 | 2002-09-06 | Synthetic heparin pentasaccharides |
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| AU (1) | AU2002331426B2 (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2806604C (en) | 2001-09-07 | 2014-04-08 | Alchemia Limited | Synthetic heparin pentasaccharides |
| AU2002950657A0 (en) * | 2002-08-08 | 2002-09-12 | Alchemia Limited | Derivatives of monosaccharides for drug discovery |
| JP2006143694A (ja) * | 2004-11-16 | 2006-06-08 | Tokyo Kasei Kogyo Kk | 新規ｐ−メトキシフェニル糖誘導体 |
| ES2336297B1 (es) | 2008-10-08 | 2011-01-24 | Laboratorios Farmaceuticos Rovi, S.A. | Procedimiento de sintesis de pentasacaridos desprotegidos a partir deun pentasacarido precursos protegido. |
| EP2414371A4 (en) * | 2009-03-30 | 2014-06-25 | Univ Georgia | HEPARANSULFATSYNTHESE |
| CA2777099C (en) * | 2009-07-31 | 2018-03-27 | Reliable Biopharmaceutical Corporation | Process for preparing fondaparinux sodium and intermediates useful in the synthesis thereof |
| US8420790B2 (en) | 2009-10-30 | 2013-04-16 | Reliable Biopharmaceutical Corporation | Efficient and scalable process for the manufacture of Fondaparinux sodium |
| WO2011073408A2 (en) * | 2009-12-18 | 2011-06-23 | Endotis Pharma | Pharmaceutical oral dosage form containing a synthetic oligosaccharide |
| WO2012121617A1 (en) * | 2011-03-10 | 2012-09-13 | Industrial Research Limited | Oligosaccharide compounds |
| US20130005954A1 (en) * | 2011-06-28 | 2013-01-03 | Apicore, Llc | Process for preparing heparinoids and intermediates useful in the synthesis thereof |
| CN103360439B (zh) * | 2012-04-02 | 2017-12-15 | 浙江海正药业股份有限公司 | 制备肝素五糖的新中间体及其制备方法 |
| JP6138241B2 (ja) * | 2012-05-25 | 2017-05-31 | ツェジャン ハイサン ファーマシューティカル カンパニー リミテッド | 完全に保護されたヘパリン五糖類およびその中間体を調製するための方法 |
| CN102690302B (zh) * | 2012-05-30 | 2015-07-01 | 济南圣泉唐和唐生物科技有限公司 | 1,2-O-异亚丙基-3-O-苄基-α-D-呋喃葡萄糖苷的制备方法 |
| CN102718808A (zh) * | 2012-06-04 | 2012-10-10 | 浙江星月药物科技股份有限公司 | 一类多糖衍生物及其中间体的制备方法 |
| WO2013184564A1 (en) * | 2012-06-05 | 2013-12-12 | Academia Sinica | Methods and intermediates for the preparation of fondaparinux |
| CN102775450B (zh) * | 2012-07-03 | 2015-04-08 | 华东师范大学 | 一种1,6-脱水-2-叠氮-2-脱氧-β-D-吡喃葡萄糖的制备方法 |
| CN102898487B (zh) * | 2012-11-13 | 2016-03-09 | 麦科罗夫（南通）生物制药有限公司 | 一种磺达肝葵钠二糖中间体片段ba及其合成方法 |
| CN102942601B (zh) * | 2012-11-30 | 2015-09-30 | 江苏华泰晨光药业有限公司 | 一种磺达肝癸钠的中间体的制备方法 |
| WO2014205115A2 (en) | 2013-06-19 | 2014-12-24 | The Regents Of The University Of California | Regioselective silyl exchange of per-silylated oligosaccharides |
| JP6321798B2 (ja) * | 2013-07-25 | 2018-05-09 | サイノファーム タイワン，リミティド | フォンダパリヌクスナトリウムを製造するための方法 |
| CN105431444A (zh) * | 2013-07-25 | 2016-03-23 | 台湾神隆股份有限公司 | 磺达肝素钠的生产工艺 |
| US10072039B2 (en) * | 2013-07-25 | 2018-09-11 | Scinopharm Taiwan, Ltd. | Process for the production of Fondaparinux sodium |
| US9346844B2 (en) | 2013-07-25 | 2016-05-24 | Scinopharm Taiwan, Ltd. | Process for the production of fondaparinux sodium |
| CN103601765B (zh) * | 2013-09-02 | 2017-01-04 | 上海艾康睿医药科技有限公司 | 磺达肝癸钠及其中间体、以及制备方法 |
| WO2015070571A1 (zh) | 2013-11-14 | 2015-05-21 | 浙江海正药业股份有限公司 | 一种二糖中间体及其合成方法 |
| CN104098618A (zh) * | 2014-07-25 | 2014-10-15 | 河北常山生化药业股份有限公司 | 磺达肝癸钠中间体及其中间体和磺达肝癸钠的制备方法 |
| WO2016040779A1 (en) * | 2014-09-12 | 2016-03-17 | The Board Of Trustees Of The University Of Illinois | Urea derivatives of polyene macrolide antibiotics |
| US9909534B2 (en) | 2014-09-22 | 2018-03-06 | Ini Power Systems, Inc. | Carbureted engine having an adjustable fuel to air ratio |
| CN105985388A (zh) * | 2015-02-04 | 2016-10-05 | 苏州朗科生物技术有限公司 | 磺达肝癸钠杂质化合物及其制备方法和应用 |
| CN105985387A (zh) * | 2015-02-04 | 2016-10-05 | 苏州朗科生物技术有限公司 | 一种磺达肝癸钠杂质化合物及其制备方法和用途 |
| CN104910217B (zh) * | 2015-06-19 | 2018-04-17 | 天津红日药业股份有限公司 | 用于磺达肝癸钠质量控制的参比化合物 |
| CN104876979B (zh) * | 2015-06-19 | 2018-10-09 | 天津红日药业股份有限公司 | 一种具有抗Xa因子活性的磺酸化五糖化合物 |
| US10023603B2 (en) | 2015-07-16 | 2018-07-17 | Formosa Laboratories, Inc. | Preparation of monosaccharides, disaccharides, trisaccharides, and pentasaccharides of heparinoids |
| CN106518935B (zh) * | 2016-10-26 | 2019-05-21 | 陕西国防工业职业技术学院 | 一种3,6-二去氧-3-氨基-l-艾杜糖及其衍生物的合成方法 |
| CN107501359B (zh) * | 2017-08-24 | 2020-07-31 | 深圳市海滨制药有限公司 | 一种磺达肝癸钠杂质化合物及其制备方法与应用 |
| US11306157B2 (en) | 2018-12-21 | 2022-04-19 | California Institute Of Technology | Expedient synthesis of core disaccharide building blocks from natural polysaccharides for heparan sulfate oligosaccharide assembly |
| CN109734757B (zh) * | 2019-03-11 | 2020-09-11 | 淮北师范大学 | 一种磺达肝癸钠注射液有关物质b的制备方法 |
| WO2021043631A1 (en) | 2019-09-02 | 2021-03-11 | Hepoligo Solutions Aps | Intermediates useful for preparing iduronic acid containing di- and polysaccharides |
| WO2021083735A1 (en) | 2019-10-29 | 2021-05-06 | Hepoligo Solutions Aps | Process for the production of 1,6-anhydro sugars |
| CN110746471B (zh) * | 2019-11-04 | 2021-06-25 | 江苏美迪克化学品有限公司 | 一种磺达肝癸钠双糖中间体的制备方法 |
| WO2022107013A1 (en) * | 2020-11-19 | 2022-05-27 | Indian Institute Of Science Education And Research | Silver assisted gold catalysis for the preparation of fondaparinux pentasaccharide and intermediates |
| CN112552359B (zh) * | 2020-12-21 | 2022-11-25 | 北京大学 | 一种磺达肝葵钠五糖中间体自动化制备方法 |
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| US187381A (en) * | 1877-02-13 | Improvement in air and steasvj blowers for furnaces | ||
| US13862A (en) * | 1855-12-04 | Cutting pile fabrics | ||
| US684691A (en) | 1901-03-23 | 1901-10-15 | Donald E Webster | Micrometer-gage. |
| IL61201A (en) | 1979-10-05 | 1984-09-30 | Choay Sa | Oligosaccharides having no more than 8 saccharide moieties,their obtention from heparin and pharmaceutical compositions containing them |
| CA1171375A (en) | 1980-09-15 | 1984-07-24 | Ulf P.F. Lindahl | Oligosaccharides having selective anticoagulation activity |
| FR2531436A1 (fr) * | 1982-08-06 | 1984-02-10 | Choay Sa | Pentasaccharides substitues possedant des proprietes biologiques, leur preparation et leurs applications en tant que medicaments |
| FR2504535B1 (fr) * | 1981-04-28 | 1987-08-14 | Choay Sa | Disaccharides derives d'un acide uronique et d'une glucosamine et compositions pharmaceutiques les contenant pour le controle de la coagulation sanguine |
| US4818816A (en) * | 1981-04-28 | 1989-04-04 | Choay, S.A. | Process for the organic synthesis of oligosaccharides and derivatives thereof |
| FR2519987A1 (fr) * | 1982-01-15 | 1983-07-22 | Choay Sa | Trisaccharides a structures d-glucosamine, acide d-glucuronique, d-glucosamine et leur preparation |
| FR2518550A1 (fr) * | 1981-12-23 | 1983-06-24 | Choay Sa | Procede de preparation de monosaccharides a structure acide l-iduronique |
| CA1247608A (fr) * | 1981-12-23 | 1988-12-28 | Jean Choay | Derives a structure acide uronique, leur preparation et leurs applications biologiques |
| FR2564468B1 (fr) * | 1984-05-16 | 1994-12-23 | Choay Sa | Nouveaux oligosaccharides, leur preparation par voie de synthese et leurs applications biologiques |
| AU563351C (en) * | 1982-01-15 | 2003-06-19 | Glaxo Group Limited | Synthesis of oligosaccharides |
| US4801583A (en) * | 1982-01-15 | 1989-01-31 | Choay S.A. | Oligosaccharides and their biological applications |
| JPS63218691A (ja) * | 1987-03-09 | 1988-09-12 | Rikagaku Kenkyusho | 新規な５糖類化合物及びその製造法並びに抗凝血及び抗血栓剤 |
| EP0333243A3 (en) * | 1988-03-10 | 1989-09-27 | Akzo N.V. | Sulphated k5 antigen and sulphated k5 antigen fragments |
| JPH03237101A (ja) * | 1989-12-18 | 1991-10-23 | Rikagaku Kenkyusho | グリコシルフォスファチジルイノシトールアンカー合成中間体及びグリコシルフォスファチジルイノシトールアンカー類縁体の合成中間体 |
| JPH0616692A (ja) * | 1992-07-03 | 1994-01-25 | Nisshin Oil Mills Ltd:The | 新規糖誘導体 |
| CA2100821C (en) * | 1993-07-19 | 2001-01-16 | Stephen Hanessian | Stereocontrolled glycosidation |
| JP3837876B2 (ja) * | 1996-11-05 | 2006-10-25 | 和光純薬工業株式会社 | アジドハロゲノベンジル誘導体及び水酸基の保護方法 |
| JP3005669B2 (ja) | 1996-12-19 | 2000-01-31 | 工業技術院長 | 不斉な含フッ素一級アミンの製造法 |
| US6538117B1 (en) * | 1999-08-10 | 2003-03-25 | The Scripps Research Institute | Programmable one-pot oligosaccharide synthesis |
| TWI289566B (en) * | 1999-12-07 | 2007-11-11 | N.V.Organon | Antithrombotic compound |
| WO2002058633A2 (en) * | 2001-01-23 | 2002-08-01 | Massachusetts Institute Of Technology | Solid- and solution -phase synthesis of heparin and other glycosaminoglycans |
| CA2806604C (en) | 2001-09-07 | 2014-04-08 | Alchemia Limited | Synthetic heparin pentasaccharides |
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2002
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- 2002-09-06 CN CN028218558A patent/CN1558911B/zh not_active Expired - Fee Related
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- 2002-09-06 PT PT2766941T patent/PT1440077E/pt unknown
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2014
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| US9243018B2 (en) | 2016-01-26 |
| AU2002331426A1 (en) | 2003-03-24 |
| CA2806723C (en) | 2015-12-29 |
| US8404833B2 (en) | 2013-03-26 |
| AU2002331426B2 (en) | 2008-01-10 |
| ES2423888T3 (es) | 2013-09-25 |
| US20150005485A1 (en) | 2015-01-01 |
| EP2557086A3 (en) | 2014-11-05 |
| US20090187013A1 (en) | 2009-07-23 |
| CA2459562C (en) | 2013-05-07 |
| US20050080042A1 (en) | 2005-04-14 |
| PT1440077E (pt) | 2013-06-04 |
| CA2806723A1 (en) | 2003-03-20 |
| CN1558911A (zh) | 2004-12-29 |
| US8686131B2 (en) | 2014-04-01 |
| US8114970B2 (en) | 2012-02-14 |
| CN1558911B (zh) | 2010-05-12 |
| CA2806604C (en) | 2014-04-08 |
| EP1440077A1 (en) | 2004-07-28 |
| WO2003022860A1 (en) | 2003-03-20 |
| EP2557086A2 (en) | 2013-02-13 |
| CA2459562A1 (en) | 2003-03-20 |
| US20120208993A1 (en) | 2012-08-16 |
| CA2806604A1 (en) | 2003-03-20 |
| JP2005505565A (ja) | 2005-02-24 |
| JP4688414B2 (ja) | 2011-05-25 |
| EP1440077B1 (en) | 2013-05-01 |
| US20120220759A1 (en) | 2012-08-30 |
| DK1440077T3 (da) | 2013-07-08 |
| US7541445B2 (en) | 2009-06-02 |
| EP1440077A4 (en) | 2010-06-02 |
| CA2806561A1 (en) | 2003-03-20 |
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