KR930021650A - 2-위치가 수정된 α-L-이두로닉-2-O-황산의 헤파린 또는 헤파란구조를 갖는 반-합성 글리코스아미노글리칸 - Google Patents
2-위치가 수정된 α-L-이두로닉-2-O-황산의 헤파린 또는 헤파란구조를 갖는 반-합성 글리코스아미노글리칸 Download PDFInfo
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- KR930021650A KR930021650A KR1019930006473A KR930006473A KR930021650A KR 930021650 A KR930021650 A KR 930021650A KR 1019930006473 A KR1019930006473 A KR 1019930006473A KR 930006473 A KR930006473 A KR 930006473A KR 930021650 A KR930021650 A KR 930021650A
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- 229920002683 Glycosaminoglycan Polymers 0.000 title claims abstract 14
- 229920002971 Heparan sulfate Chemical group 0.000 title claims abstract 4
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical group 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 claims abstract 4
- 229920000669 heparin Polymers 0.000 title claims abstract 4
- 229960002897 heparin Drugs 0.000 title claims abstract 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 title abstract 2
- 230000004048 modification Effects 0.000 title 1
- 238000012986 modification Methods 0.000 title 1
- 230000000269 nucleophilic effect Effects 0.000 claims abstract 2
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract 2
- 239000012434 nucleophilic reagent Substances 0.000 claims 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 8
- 239000000243 solution Substances 0.000 claims 7
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 6
- 239000002904 solvent Substances 0.000 claims 6
- 238000000034 method Methods 0.000 claims 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims 4
- -1 heterocyclic amine Chemical group 0.000 claims 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical group ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- 239000011541 reaction mixture Substances 0.000 claims 3
- 238000003756 stirring Methods 0.000 claims 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- 230000002378 acidificating effect Effects 0.000 claims 2
- 239000007864 aqueous solution Substances 0.000 claims 2
- 239000000539 dimer Substances 0.000 claims 2
- 125000003700 epoxy group Chemical group 0.000 claims 2
- 238000000605 extraction Methods 0.000 claims 2
- 238000001914 filtration Methods 0.000 claims 2
- YMAWOPBAYDPSLA-UHFFFAOYSA-N glycylglycine Chemical compound [NH3+]CC(=O)NCC([O-])=O YMAWOPBAYDPSLA-UHFFFAOYSA-N 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 239000011261 inert gas Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000002360 preparation method Methods 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 2
- 125000001424 substituent group Chemical group 0.000 claims 2
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- 239000011593 sulfur Substances 0.000 claims 2
- 239000008399 tap water Substances 0.000 claims 2
- 235000020679 tap water Nutrition 0.000 claims 2
- XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 claims 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 claims 2
- WFAUDCSNCWJJAA-RHYQMDGZSA-N (2s)-1-[(2s)-6-amino-2-[[(2s,3r)-2-amino-3-hydroxybutanoyl]amino]hexanoyl]pyrrolidine-2-carboxylic acid Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N1CCC[C@H]1C(O)=O WFAUDCSNCWJJAA-RHYQMDGZSA-N 0.000 claims 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- CHJFZKBUNXDBEL-UHFFFAOYSA-N 2-[(2-aminoacetyl)amino]ethanesulfonic acid Chemical compound NCC(=O)NCCS(O)(=O)=O CHJFZKBUNXDBEL-UHFFFAOYSA-N 0.000 claims 1
- AFLBTVGQCQLOFJ-UHFFFAOYSA-N 2-[[1-(2,6-diaminohexanoyl)pyrrolidine-2-carbonyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NCCCCC(N)C(=O)N1CCCC1C(=O)NC(CCCN=C(N)N)C(O)=O AFLBTVGQCQLOFJ-UHFFFAOYSA-N 0.000 claims 1
- PWKSKIMOESPYIA-UHFFFAOYSA-N 2-acetamido-3-sulfanylpropanoic acid Chemical compound CC(=O)NC(CS)C(O)=O PWKSKIMOESPYIA-UHFFFAOYSA-N 0.000 claims 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims 1
- VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical compound NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 claims 1
- LODHFNUFVRVKTH-ZHACJKMWSA-N 2-hydroxy-n'-[(e)-3-phenylprop-2-enoyl]benzohydrazide Chemical compound OC1=CC=CC=C1C(=O)NNC(=O)\C=C\C1=CC=CC=C1 LODHFNUFVRVKTH-ZHACJKMWSA-N 0.000 claims 1
- YJSMIMJDRSWLQQ-UHFFFAOYSA-N 4-(3-aminopropyl)-2-hydroxybenzoic acid Chemical compound NCCCC1=CC=C(C(O)=O)C(O)=C1 YJSMIMJDRSWLQQ-UHFFFAOYSA-N 0.000 claims 1
- 239000004475 Arginine Substances 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- JBCLFWXMTIKCCB-VIFPVBQESA-N Gly-Phe Chemical compound NCC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 JBCLFWXMTIKCCB-VIFPVBQESA-N 0.000 claims 1
- XBGGUPMXALFZOT-VIFPVBQESA-N Gly-Tyr Chemical compound NCC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-VIFPVBQESA-N 0.000 claims 1
- 239000004471 Glycine Substances 0.000 claims 1
- 108010008488 Glycylglycine Proteins 0.000 claims 1
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 claims 1
- 239000004158 L-cystine Substances 0.000 claims 1
- 235000019393 L-cystine Nutrition 0.000 claims 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims 1
- AIXUQKMMBQJZCU-IUCAKERBSA-N Lys-Pro Chemical compound NCCCC[C@H](N)C(=O)N1CCC[C@H]1C(O)=O AIXUQKMMBQJZCU-IUCAKERBSA-N 0.000 claims 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims 1
- 239000004472 Lysine Substances 0.000 claims 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims 1
- HMNSRTLZAJHSIK-YUMQZZPRSA-N Pro-Arg Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@@H]1CCCN1 HMNSRTLZAJHSIK-YUMQZZPRSA-N 0.000 claims 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- YKRQRPFODDJQTC-CSMHCCOUSA-N Thr-Lys Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN YKRQRPFODDJQTC-CSMHCCOUSA-N 0.000 claims 1
- WNEFDHCAKLWKAG-UHFFFAOYSA-N acetic acid;2-hydroxybenzoic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1O WNEFDHCAKLWKAG-UHFFFAOYSA-N 0.000 claims 1
- 150000001413 amino acids Chemical group 0.000 claims 1
- 229940124277 aminobutyric acid Drugs 0.000 claims 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims 1
- 229960001231 choline Drugs 0.000 claims 1
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims 1
- 229960003067 cystine Drugs 0.000 claims 1
- 238000000502 dialysis Methods 0.000 claims 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims 1
- 239000012153 distilled water Substances 0.000 claims 1
- WSYUEVRAMDSJKL-UHFFFAOYSA-N ethanolamine-o-sulfate Chemical compound NCCOS(O)(=O)=O WSYUEVRAMDSJKL-UHFFFAOYSA-N 0.000 claims 1
- 150000002169 ethanolamines Chemical class 0.000 claims 1
- YVKSGVDJQXLXDV-BYPYZUCNSA-N ethyl (2r)-2-amino-3-sulfanylpropanoate Chemical compound CCOC(=O)[C@@H](N)CS YVKSGVDJQXLXDV-BYPYZUCNSA-N 0.000 claims 1
- 238000004108 freeze drying Methods 0.000 claims 1
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical class NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims 1
- 150000002332 glycine derivatives Chemical class 0.000 claims 1
- XBGGUPMXALFZOT-UHFFFAOYSA-N glycyl-L-tyrosine hemihydrate Natural products NCC(=O)NC(C(O)=O)CC1=CC=C(O)C=C1 XBGGUPMXALFZOT-UHFFFAOYSA-N 0.000 claims 1
- 229940043257 glycylglycine Drugs 0.000 claims 1
- 108010081551 glycylphenylalanine Proteins 0.000 claims 1
- 108010087823 glycyltyrosine Proteins 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- TUJKJAMUKRIRHC-UHFFFAOYSA-N hydroxyl Chemical compound [OH] TUJKJAMUKRIRHC-UHFFFAOYSA-N 0.000 claims 1
- 108010044655 lysylproline Proteins 0.000 claims 1
- 229960003151 mercaptamine Drugs 0.000 claims 1
- 229930182817 methionine Natural products 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 230000007935 neutral effect Effects 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000002798 polar solvent Substances 0.000 claims 1
- 238000001556 precipitation Methods 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 108090000765 processed proteins & peptides Proteins 0.000 claims 1
- 108010004914 prolylarginine Proteins 0.000 claims 1
- 229960004889 salicylic acid Drugs 0.000 claims 1
- 150000003335 secondary amines Chemical class 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 229960003080 taurine Drugs 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical group SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 claims 1
- 108010071097 threonyl-lysyl-proline Proteins 0.000 claims 1
- 230000002785 anti-thrombosis Effects 0.000 abstract 2
- 208000032843 Hemorrhage Diseases 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 208000034158 bleeding Diseases 0.000 abstract 1
- 230000000740 bleeding effect Effects 0.000 abstract 1
- 230000014508 negative regulation of coagulation Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
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- 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
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- 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
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- 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
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- General Health & Medical Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
본 발명은 2-위치가 수정된 α-L-이두로닉-2-O-황산의 헤파린 또는 헤파란 구조를 갖는 신균한 반-합성 글리코스아미노글리칸의 합성에 관한 것이며 이 신규한 반-합성 글리코스 아미노글리칸은 설페이트기가 전부 또는 부분적으로 친핵성 래디칼로 치환된 것이다.
일반식(Ⅳ)를 갖는 이들 신규한 반-합성 글리코스아미노글리칸은 경구로 흡수될 수 있는 양호한 제약학적 특성을 가지며, 출혈의 위험성을 줄여주고 항-응고 활성을 감소시켜 주는 양호한 항-혈전(anti-thrombotic)활성을 갖는다.
Description
본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음
Claims (10)
- 다음의 일반식 Ⅳ의 헤파린 또는 헤파란 구조를 갖는 신규한 반-합성 글리코스아미노 글리칸.(위식에서 p+q=m이며, p는 0이외의 수이고, m 및 n은 1-100사의 값인 모든 수이며, R은 수소 또는 설페이트 (SO3 10)잔기이고, -Z(R2)R1은 친핵성 래디칼을 나타낸다).
- 제1항에 있어서, Z는 산소, 황 또는 질소를 나타내고, R1는 직쇄 또는 측쇄(C1-12)알킬 래디칼, 아민 래디칼, 방향족 래디칼, 디아조 래디칼 또는 히드록실 래디칼을 나타내며 치환되거나 또는 비치환되지 않았으며, R2는 생략 또는 수소, 직쇄 또는 측쇄(C1-6) 알킬 래디칼, 또는 R1과 함께 헤테로시클릭 고리를 형성하는 것을 특징으로 하는 신규한 반-합성 글리코스아미노글리칸.
- 제2항에 있어서, R1의 치환체는 할로겐화물, 아민 래디칼, 방향족 래디칼, 카복실 래디칼, 구아니딘 래디칼, 니트로 래디칼, 히드록실 래디칼, 술폰 래디칼, 설퍼 래디칼, 티올 래디칼, 또는 우레이드 래디칼로부터 선택되며, 치환되거나 치환되지 않을 수 있는 것을 특징으로 하는 신규한 반-합성 그릴코스 아미노글리칸.
- 제1 또는 2항중 어느 한항에 있어서, -Z(R2)R1래디칼은 1차 또는 2차 아민, 2차 헤테르 시클릭 아민, 아미노알코올, 아미노티올, 아미노산, 아미노에스테르, 펩티드, 알코올, 페놀, 머캅탄, 디틸올, 티오페놀, 히드록실아민, 히드라진, 히드라자이드 및 소디움 아자이드로부터 유도되는 것을 특징으로 하는 신규한 반-합성 글리코스아미노글리칸.
- 제4항에 있어서, -Z(R2)R1래디칼은 글리신, 글리실글리신, L-시스테인, 아세틸-L-시스테인, L-시스테인 에틸 에스테르, 2-아미노티오 페놀, 1,3-프로판디티올, 시스테아민, 소디움 아자이드, 2-아미노에틸비설페이트, 타우린, 티오글리콘산, α-알라닌 에틸에스테르, L-시스틴, 히드록실아민, 글리실타우린, 시스테닐타우린, 글리실시스테인, 글리실페닐아라닌, 글리실티로신, 2-아미노에탄올, 2-아미노 에탄올을 갖는 글리신 에스테르, 2-아미노에탄올을 갖는 글리신 아미드, 아르기닐리신, 아르기닌, 리신, 아세트산을 갖는 2-아미노에탄올 에스테르, 살리실 산, 메타오닌, 클리실프롤린,-아미노부티르산, 리실 프롤릴 아르기닌, 트레오닐 리실프롤린, 트레오닐리신, 프로릴 아르기닌, 리실프롤린, 콜린, 4-(3-아미노프로필)-2-히드록시벤조산 및 4-(2-아미노에틸)-2-히드록시벤조산으로부터 유도되는 것을 특징으로 하는 신규한 반-합성 글리코스아미노 글리칸.
- 다음 일반식 Ⅳ,의 헤파린 또는 헤파란 구조를 갖는 반-합성 글리코스아미노글리칸을 합성하는 방법으로서, 이 방법은 공고된 유럽 특허 제 EP 0347588호 명세서에 기술된 제조방법에 따라 얻어진 일반식 Ⅲ.의 2,3 에폭시글로닉 구조를 갖는 반-합성 글리코스아미노글리칸을, 0℃-70℃의 온도에서 2-120시간동안 교반하에 경우에 따라서는 불활성 기체의 분위기하에서, 친핵성 시약내에 존재하는 임의의 산(acid)기를 염화시키거나 또는 산성의 물질을 가질수도 있는 임의의 염으로부터 동일한 친핵성 시약을 방출시키기에 충분한 무기 또는 염기 및 용매의 존재하에, 래디칼이 일반식 Ⅱ에 포함되는 친핵성 시약과 반응시키는 공정과, 반응 용매가 물이 아닌 경우에는 상기 반응 혼합물을 물로 희석한 다음 염산 수용액을 첨가하여 수용액의 pH를 중성으로 만들고, 경우에 따라서는 과량의 친핵성시약을 제거하기 위해 물과 혼화되지 않는 용매로 추출하거나 또는 여과하며, 경우에 따라서는 이 수용액을 수돗물과 증류수에서 투석시킨 다음 이 수용액을 동결 건조시키거나 적당한 용매를 가하여 침전시킴에 의해서 생성물을 분리시키는 공정을 포함하는 것을 특징으로 하는 반-합성 글리코스아미노글리칸의 제조방법.
- 제6항에 있어서, 친핵성 시약의 량은 에폭시기를 포함하는 일반식Ⅲ의 반-합성 글리코스 아미노글리칸의 다이머(dimer)단위에 대하여 1-20몰당량인 것을 특징으로 하는 제조방법.
- 제6항에 있어서, 용매는 물, 및 디메틸아세트아미드, 디메틸포롬아미드, 아세토니트릴, 디옥산, 테트라히드로푸란, 또는 물과 이들의 혼합물로 부터 선택된 극성 용매로부터 선택될 수 있는 것을 특징으로 하는 제조방법.
- 제6항에 있어서, 사용된 염기는 수산화나트륨, 수산화 칼륨 또는 트리에틸아민으로부터 선택되는 것을 특징으로 하는 제조방법.
- 제6항에 있어서, 일반식 Ⅲ의 2,3에폭시글로닉 구조를 갖는 반-합성 글리코스아미노 글리칸을 물에 용해시키고 이 용액을, 불활성 기체의 분위기 하에서, 에폭시기를 포함하는 일반식Ⅲ의 글리코스아미노글리칸의 다이머 단위에 대하여 친핵성 시약 10-100몰 당량 및 이 친핵성 시약내에 존재하는 임의의 산 기를 염화시키거나, 산성의 물질을 갖는 가능한 염으로부터 친핵성 시약을 방출시키기에 충분한 량의 수산화 나트륨의 함유된 용액에 교반하면서 첨가한 다음, 이 반응 혼합물을 실온에서 24-96시간 동안 정치시켜준 후, 이 반응 혼합물의 pH가 중성이 아닐 경우에 염산 수용액을 사용하여 중화시켜주고, 경우에 따라서는 물에 혼화되지 않는 용매로 추출하거나 여과시켜서 과량의 친핵성 시약을 제거시켜주고 경우에 따라서는6-24시간 동안 수돗물 및 증류수를 사용하여 이 반응용액을 투석시켜 준 다음, 이 용액을 동격 건조 시키거나 또는 적당한 용매를 첨가함에 의하여 생성물을 분리해내는 것을 특징으로 하는 제조방법.※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| ITBO92A000141 | 1992-04-17 | ||
| ITBO920141A IT1260137B (it) | 1992-04-17 | 1992-04-17 | Glicosaminoglicani semisintetici a struttura eparinica od eparanica modificati nella posizione 2 dell'acido alfa-l-iduronico-2-0-solfato |
| ITB092A000141 | 1992-04-17 |
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| KR930021650A true KR930021650A (ko) | 1993-11-22 |
| KR0171624B1 KR0171624B1 (ko) | 1999-02-01 |
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| KR1019930006473A KR0171624B1 (ko) | 1992-04-17 | 1993-04-17 | 2-위치가 수정된 알파-엘-이두로닉-2-o-황산의 헤파린 또는 헤파란 구조를 갖는 반-합성 글리코스아미노글리칸 |
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| US (1) | US5430133A (ko) |
| EP (1) | EP0565863B1 (ko) |
| JP (1) | JP2702376B2 (ko) |
| KR (1) | KR0171624B1 (ko) |
| AT (1) | ATE154616T1 (ko) |
| AU (1) | AU658498B2 (ko) |
| CA (1) | CA2093147C (ko) |
| DE (1) | DE69311619T2 (ko) |
| DK (1) | DK0565863T3 (ko) |
| ES (1) | ES2103992T3 (ko) |
| FI (1) | FI106556B (ko) |
| GR (1) | GR3024419T3 (ko) |
| IL (1) | IL105112A (ko) |
| IT (1) | IT1260137B (ko) |
| NO (1) | NO305992B1 (ko) |
| NZ (1) | NZ247196A (ko) |
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| ZA (1) | ZA931798B (ko) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5696100A (en) * | 1992-12-22 | 1997-12-09 | Glycomed Incorporated | Method for controlling O-desulfation of heparin and compositions produced thereby |
| IT1264101B1 (it) * | 1993-03-29 | 1996-09-10 | Alfa Wassermann Spa | Processo per la sintesi di glicosaminoglicani semisintetici a struttura eparinica od eparanica modificati nella posizione 2 |
| IT1264102B1 (it) * | 1993-03-29 | 1996-09-10 | Alfa Wassermann Spa | Processo per la sintesi di glicosaminoglicani semisintetici contenenti acido alfa-l-galatturonico sostituito con radicali |
| US5583121A (en) * | 1994-01-12 | 1996-12-10 | Michigan State University | Non-anticoagulant chemically modified heparinoids for treating hypovolemic shock and related shock syndromes |
| US6127347A (en) * | 1994-01-12 | 2000-10-03 | Univ Michigan | Non-anticoagulant chemically modified heparinoids for treating hypovolemic shock and related shock syndromes |
| US6255295B1 (en) | 1996-12-23 | 2001-07-03 | Nutramax Laboratories, Inc. | Aminosugar, glycosaminoglycan or glycosaminoglycan-like compounds, and s-adenosylmethionine composition for the protection, treatment, repair, and reduction of inflammation of connective tissue |
| MXPA02000142A (es) * | 1999-06-30 | 2003-07-21 | Hamilton Civic Hospitals Res | Composiciones de heparina que inhiben los factores de coagulacion asociados con el coagulo. |
| US7259152B2 (en) | 2000-06-07 | 2007-08-21 | Alfa Wasserman, Inc. | Methods and compositions using sulodexide for the treatment of diabetic nephropathy |
| JP2004507562A (ja) * | 2000-09-08 | 2004-03-11 | ハミルトン シビック ホスピタルズ リサーチ ディベロップメント インコーポレイテッド | 抗血栓性組成物 |
| EP2402753A1 (en) * | 2002-03-11 | 2012-01-04 | Momenta Pharmaceuticals, Inc. | Analysis of sulfated polysaccharides |
| GB0216861D0 (en) * | 2002-07-19 | 2002-08-28 | Univ Birmingham | Saccharide libraries |
| US9139876B1 (en) | 2007-05-03 | 2015-09-22 | Momenta Pharmacueticals, Inc. | Method of analyzing a preparation of a low molecular weight heparin |
| WO2009014715A2 (en) * | 2007-07-23 | 2009-01-29 | The University Of North Carolina At Chapel Hill | Enzymatic synthesis of sulfated polysaccharides without iduronic acid residues |
| EP2526122B1 (en) * | 2010-01-19 | 2020-06-10 | Momenta Pharmaceuticals, Inc. | Evaluating heparin preparations |
| CN103209997B (zh) * | 2010-09-14 | 2016-03-16 | 国立大学法人宫崎大学 | 高纯度肝素及其制备方法 |
| US11203772B2 (en) | 2010-12-23 | 2021-12-21 | The University Of North Carolina At Chapel Hill | Chemoenzymatic synthesis of structurally homogeneous ultra-low molecular weight heparins |
| WO2012115952A1 (en) | 2011-02-21 | 2012-08-30 | Momenta Pharmaceuticals, Inc. | Evaluating heparin preparations |
| DE102011077393A1 (de) * | 2011-06-10 | 2012-12-13 | Johannes Reinmüller | Antiinfektives Mittel |
| CN105452479B (zh) | 2013-06-17 | 2021-05-18 | 北卡罗来纳大学查珀尔希尔分校 | 可逆肝素分子 |
| JP7330893B2 (ja) | 2017-03-10 | 2023-08-22 | ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル | 短時間作用型ヘパリンベースの抗凝集剤化合物及び方法 |
| US11993627B2 (en) | 2017-07-03 | 2024-05-28 | The University Of North Carolina At Chapel Hill | Enzymatic synthesis of homogeneous chondroitin sulfate oligosaccharides |
| WO2019090203A1 (en) | 2017-11-03 | 2019-05-09 | The University Of North Carolina At Chapel Hill | Sulfated oligosaccharides having anti-inflammatory activity |
| JP7538724B2 (ja) | 2018-06-20 | 2024-08-22 | ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル | 細胞保護の方法と組成物 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4987223A (en) * | 1981-12-23 | 1991-01-22 | Choay S.A. | Derivatives of the uronic acid |
| IT1234508B (it) * | 1988-06-10 | 1992-05-19 | Alfa Wassermann Spa | Derivati eparinici e procedimento per la loro preparazione |
| DE3821271A1 (de) * | 1988-06-23 | 1989-12-28 | Solco Basel Ag | Derivatisiertes heparin, verfahren zu dessen herstellung und arzneimittel, welches dieses enthaelt |
| IT1234826B (it) * | 1989-01-30 | 1992-05-29 | Alfa Wassermann Spa | Derivati eparinici e procedimento per la loro preparazione |
| ATE148713T1 (de) * | 1990-07-24 | 1997-02-15 | Seikagaku Kogyo Co Ltd | Glykosaminoglykan gemischt mit phospholipid oder lipid, seine herstellung und krebszellenmetastaseninhibitor |
| US5200523A (en) * | 1990-10-10 | 1993-04-06 | Monsanto Company | Synthesis of nojirimycin derivatives |
| IT1260136B (it) * | 1992-04-17 | 1996-03-28 | Alfa Wassermann Spa | Glicosaminoglicani semisintetici contenenti acido alfa-l-galatturonicosostituito con radicali nucleofili in posizione 3 |
-
1992
- 1992-04-17 IT ITBO920141A patent/IT1260137B/it active IP Right Grant
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1993
- 1993-03-10 AT AT93103848T patent/ATE154616T1/de not_active IP Right Cessation
- 1993-03-10 DE DE69311619T patent/DE69311619T2/de not_active Expired - Fee Related
- 1993-03-10 EP EP93103848A patent/EP0565863B1/en not_active Expired - Lifetime
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- 1993-03-19 TW TW082102014A patent/TW239148B/zh active
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Also Published As
| Publication number | Publication date |
|---|---|
| EP0565863B1 (en) | 1997-06-18 |
| ITBO920141A0 (it) | 1992-04-17 |
| DE69311619T2 (de) | 1997-12-11 |
| US5430133A (en) | 1995-07-04 |
| EP0565863A2 (en) | 1993-10-20 |
| ZA931798B (en) | 1993-11-22 |
| NO931184L (no) | 1993-10-18 |
| EP0565863A3 (en) | 1993-11-10 |
| IL105112A (en) | 1997-01-10 |
| TW239148B (ko) | 1995-01-21 |
| GR3024419T3 (en) | 1997-11-28 |
| KR0171624B1 (ko) | 1999-02-01 |
| CA2093147A1 (en) | 1993-10-18 |
| CA2093147C (en) | 1999-01-26 |
| AU3689593A (en) | 1993-10-21 |
| ITBO920141A1 (it) | 1993-10-17 |
| AU658498B2 (en) | 1995-04-13 |
| NO931184D0 (no) | 1993-03-30 |
| JP2702376B2 (ja) | 1998-01-21 |
| NO305992B1 (no) | 1999-08-30 |
| ATE154616T1 (de) | 1997-07-15 |
| IL105112A0 (en) | 1993-07-08 |
| DK0565863T3 (da) | 1997-12-15 |
| FI106556B (fi) | 2001-02-28 |
| NZ247196A (en) | 1995-02-24 |
| DE69311619D1 (de) | 1997-07-24 |
| JPH0616703A (ja) | 1994-01-25 |
| IT1260137B (it) | 1996-03-28 |
| ES2103992T3 (es) | 1997-10-01 |
| FI931741A0 (fi) | 1993-04-16 |
| FI931741A (fi) | 1993-10-18 |
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