JP4740321B2 - フィブリノーゲンのためのアフィニティー吸着剤 - Google Patents
フィブリノーゲンのためのアフィニティー吸着剤 Download PDFInfo
- Publication number
- JP4740321B2 JP4740321B2 JP2008510635A JP2008510635A JP4740321B2 JP 4740321 B2 JP4740321 B2 JP 4740321B2 JP 2008510635 A JP2008510635 A JP 2008510635A JP 2008510635 A JP2008510635 A JP 2008510635A JP 4740321 B2 JP4740321 B2 JP 4740321B2
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- Prior art keywords
- gel
- formula
- water
- fibrinogen
- washed
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 108010049003 Fibrinogen Proteins 0.000 title claims description 30
- 102000008946 Fibrinogen Human genes 0.000 title claims description 30
- 229940012952 fibrinogen Drugs 0.000 title claims description 30
- 239000003463 adsorbent Substances 0.000 title claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 108090000623 proteins and genes Proteins 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- -1 β -phenylethyl Chemical group 0.000 claims description 6
- 102000004169 proteins and genes Human genes 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 125000006850 spacer group Chemical group 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- 125000006414 CCl Chemical group ClC* 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 239000011159 matrix material Substances 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 238000012512 characterization method Methods 0.000 claims 1
- 238000011002 quantification Methods 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 138
- 239000000499 gel Substances 0.000 description 84
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 63
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- 238000001223 reverse osmosis Methods 0.000 description 57
- 238000004458 analytical method Methods 0.000 description 40
- 239000000203 mixture Substances 0.000 description 32
- 239000002002 slurry Substances 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 239000003446 ligand Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- NHJVRSWLHSJWIN-UHFFFAOYSA-N 2,4,6-trinitrobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O NHJVRSWLHSJWIN-UHFFFAOYSA-N 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 239000011543 agarose gel Substances 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 125000003700 epoxy group Chemical group 0.000 description 5
- 230000005484 gravity Effects 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- ORLGPUVJERIKLW-UHFFFAOYSA-N 5-chlorotriazine Chemical class ClC1=CN=NN=C1 ORLGPUVJERIKLW-UHFFFAOYSA-N 0.000 description 4
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 4
- 108010073385 Fibrin Proteins 0.000 description 4
- 102000009123 Fibrin Human genes 0.000 description 4
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 4
- 229910021538 borax Inorganic materials 0.000 description 4
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 description 4
- 238000010828 elution Methods 0.000 description 4
- 229950003499 fibrin Drugs 0.000 description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 description 4
- 235000011009 potassium phosphates Nutrition 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 235000010339 sodium tetraborate Nutrition 0.000 description 4
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 229920000936 Agarose Polymers 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 3
- 108090000190 Thrombin Proteins 0.000 description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001212 derivatisation Methods 0.000 description 3
- 125000005647 linker group Chemical group 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229960004072 thrombin Drugs 0.000 description 3
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 2
- WITMXBRCQWOZPX-UHFFFAOYSA-N 1-phenylpyrazole Chemical compound C1=CC=NN1C1=CC=CC=C1 WITMXBRCQWOZPX-UHFFFAOYSA-N 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- IHDBZCJYSHDCKF-UHFFFAOYSA-N 4,6-dichlorotriazine Chemical class ClC1=CC(Cl)=NN=N1 IHDBZCJYSHDCKF-UHFFFAOYSA-N 0.000 description 2
- PTAYFGHRDOMJGC-UHFFFAOYSA-N 4-aminobutyl(diaminomethylidene)azanium;hydrogen sulfate Chemical compound OS(O)(=O)=O.NCCCCN=C(N)N PTAYFGHRDOMJGC-UHFFFAOYSA-N 0.000 description 2
- PHNDZBFLOPIMSM-UHFFFAOYSA-N 4-morpholin-4-ylaniline Chemical compound C1=CC(N)=CC=C1N1CCOCC1 PHNDZBFLOPIMSM-UHFFFAOYSA-N 0.000 description 2
- QYPPJABKJHAVHS-UHFFFAOYSA-N Agmatine Natural products NCCCCNC(N)=N QYPPJABKJHAVHS-UHFFFAOYSA-N 0.000 description 2
- 0 C*1C(*N*)NC(*)=*C1**(C)(C)C Chemical compound C*1C(*N*)NC(*)=*C1**(C)(C)C 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- ULEBESPCVWBNIF-BYPYZUCNSA-N L-arginine amide Chemical compound NC(=O)[C@@H](N)CCCNC(N)=N ULEBESPCVWBNIF-BYPYZUCNSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical group C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- QYPPJABKJHAVHS-UHFFFAOYSA-P agmatinium(2+) Chemical compound NC(=[NH2+])NCCCC[NH3+] QYPPJABKJHAVHS-UHFFFAOYSA-P 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000000740 bleeding effect Effects 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000535 fibrinogen concentrate Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 208000002004 Afibrinogenemia Diseases 0.000 description 1
- 208000032170 Congenital Abnormalities Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010016075 Factor I deficiency Diseases 0.000 description 1
- 108010000196 Factor XIIIa Proteins 0.000 description 1
- 108010080379 Fibrin Tissue Adhesive Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010051125 Hypofibrinogenaemia Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 229960002086 dextran Drugs 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229940106780 human fibrinogen Drugs 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000004880 lymph fluid Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000005429 oxyalkyl group Chemical group 0.000 description 1
- GHEHNICLPWTXJC-UHFFFAOYSA-N p-Aminobenzamidine dihydrochloride Chemical compound [Cl-].[Cl-].NC(=[NH2+])C1=CC=C([NH3+])C=C1 GHEHNICLPWTXJC-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000009894 physiological stress Effects 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000004252 protein component Nutrition 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001810 trypsinlike Effects 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
- C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
- C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
- C07D251/40—Nitrogen atoms
- C07D251/48—Two nitrogen atoms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
- B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/281—Sorbents specially adapted for preparative, analytical or investigative chromatography
- B01J20/286—Phases chemically bonded to a substrate, e.g. to silica or to polymers
- B01J20/289—Phases chemically bonded to a substrate, e.g. to silica or to polymers bonded via a spacer
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
- B01J20/3206—Organic carriers, supports or substrates
- B01J20/3208—Polymeric carriers, supports or substrates
- B01J20/3212—Polymeric carriers, supports or substrates consisting of a polymer obtained by reactions otherwise than involving only carbon to carbon unsaturated bonds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3214—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the method for obtaining this coating or impregnating
- B01J20/3217—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond
- B01J20/3219—Resulting in a chemical bond between the coating or impregnating layer and the carrier, support or substrate, e.g. a covalent bond involving a particular spacer or linking group, e.g. for attaching an active group
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
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Description
本発明は、化合物、及びアフィニティーリガンドとしてのそれらの使用に関する。
フィブリノーゲンは、その各々半分が、Aα,Bβ、及びγといわれるジスルフィド結合ポリペプチド鎖から成る2量体タンパク質である。肝臓においては、Aα−及びBβ−鎖の遺伝子は、それぞれ、610と461個のアミノ酸残基の単一産物をコードする。これに反し、γ鎖遺伝子の転写物の他のスプライシングは、僅かに異なる長さ(411と427残基)のγ鎖バリアントを生成し、その内の短い方は、最終産物の約90%を構成する。フィブリノーゲンの優勢な形態は、約340kDaの分子質量をもって循環中に分泌される。肝臓からのその分泌の後、当該タンパク質は血漿中に存在するだけではなく、リンパ液及び間質液中にも存在する。健康な個体においては、血漿中のフィブリノーゲンの濃度は4〜10μMの間にある。重要なことには、この濃度は、生理学的ストレス時の間には、400%程にも上昇しうる。
1のXはNであり、そして他のXはN,C−Cl又はC−CNであり;
YはO,S又はNR2であり;
ZはO,S又はNR3であり;
R2とR3は各々、H、アルキル、ヒドロキシアルキル、ベンジル又はB−フェニルエチルであり;
Qはベンゼン、ナフタレン、ベンズチアゾール、ベンズオキサゾール、1−フェニルピラゾール、インダゾール又はベンズイミダゾールであり;
R4、R5とR6は各々、H,OH、アルキル、アルコキシ、アミノ、NH2、アシルオキシ、アシルアミノ、CO2H、スルホン酸、カルバモイル、スルファモイル、アルキルスルフォニル又はハロゲンであり;
nは0〜6であり;
pは0〜20であり;そして
Aは、スペーサーによりトリアジン環に場合により連結された支持マトリックスである}で表されるトリアジン・ベースの化合物を開示している。
驚ろくべきことに、その内の多くが新規であるところの特定の化合物が、フィブリノーゲンのアフィニティー・ベースの単離に有用であることが発見された。これらの化合物は以下の式(II):
R7は中性pHにおいて正電荷をもつ基であり;
Wは任意的リンカーであり;
VはQのために先に記載したものと同じであるが、節構造であってもよく;そして
R8とR9はR4,R5とR6のために定義したものと同じであるが、さらに環状構造を含むか、又はR8とR9は連結して当該環構造を形成する。}を有する。
WO97/10887,WO00/67900、及びWO03/097112は、リガンドのコンビナトリアル・ライブラリーが固体支持体上でどのようにして構築されうるかを開示する。本発明に共通する態様及び手順の例を含むそれらの開示は、本明細書中に援用する。供給原料としてのプールされたヒト血漿を用いたこれらのコンビナトリアル・ライブラリーのセットのスクリーニングの間、ヒト・フィブリノーゲンに選択的に結合し、かつ、これを溶離させうる多数のリガンドが固定された。
ここで、
TはO,S又は−NR7−であり;
mは0又は1であり;
V1は2〜20Cの場合により置換された炭化水素基であり;そして
V2はO,S,−COO−,−CONH−,−NHCO−,−PO3H−,−NH−アリーレン−SO2−CH2−CH2−又は−NR8−であり;そしてR7とR8は各々独立にH又はC1-6アルキルである。
以下の実施例は本発明を説明する。
塩化シアヌール酸(16.1g)をテトラヒドロフラン(130mL)に溶解し、そして氷/塩浴内で0℃に冷却した。THF(400mL)中4−(4−モルフォリノ)アニリン(29.61g)を、温度が0℃を上廻らない速度で、塩化シアヌール酸の溶液に添加した。添加完了後、混合物をさらに30分間0℃で撹拌し、そしてその後、溶液を、氷(700g)と水(1.5L)の混合物に添加した。得られた固体を、癒別し、水(1L)で洗浄し、その後、真空オーブン内45℃で一定重量(28.54g)まで乾燥させた。
6%架橋purabeadアガロースゲル(Reverse Osmosis(RO)水中に沈殿した1000g)を、RO水(667mL)、10M水酸化ナトリウム(NaOH)(90mL)、及びエピクロロヒドリン(127mL)でスラリー化した。このスラリーを2時間にわたり撹拌した。サンプルを分析のために採取した後、スラリーを濾過し、その後RO水(12×1L)で洗浄した。エポキシ基についての分析は、ゲルが沈殿ゲル1g当り19.2μmolエポキシ基で誘導体化されたことを示した。
6%架橋purabeadアガロースゲル(RO水中に沈殿した650g)を、RO水(438mL)、10M水酸化ナトリウム(NaOH)(59mL)、及びエピクロロヒドリン(83mL)でスラリー化した。このスラリーを2時間にわたり撹拌した。サンプルを分析のために採取した後、スラリーを濾過し、その後RO水(12×1L)で洗浄した。エポキシ基についての分析は、ゲルが、沈殿ゲル1g当り16.5μmolエポキシ基で誘導体化されたことを示した。
6%架橋purabeadアガロースゲル(RO水中に沈殿した650g)を、RO水(438mL)、10M水酸化ナトリウム(NaOH)(59mL)、及びエピクロロヒドリン(83mL)でスラリー化した。このスラリーを2時間にわたり撹拌した。サンプルを分析のために採取した後、スラリーを濾過し、その後RO水(12×1L)で洗浄した。エポキシ基についての分析は、ゲルが、沈殿ゲル1g当り16.5μmolエポキシ基で誘導体化されたことを示した。
6%架橋Purabead アガロース・ゲル(RO水中沈殿650g)をRO水(438mL)、10M水酸化ナトリウム(NaOH)(59mL)、及びエピクロロヒドリン(83mL)でスラリー化した。このスラリーを2時間にわたり撹拌した。サンプルを分析のために採取した後、スラリーを濾過し、その後RO水(12×1L)で洗浄した。エポキシ基の分析は、ゲルが、沈殿ゲル1g当り16.5μmolのエポキシ基で誘導体化されたことを示した。
6%架橋Purabead アガロース・ゲル(RO水中沈殿650g)をRO水(438mL)、10M水酸化ナトリウム(NaOH)(59mL)、及びエピクロロヒドリン(83mL)でスラリー化した。このスラリーを2時間にわたり撹拌した。サンプルを分析のために採取した後、スラリーを濾過し、その後RO水(12×1L)で洗浄した。エポキシ基の分析は、ゲルが、沈殿ゲル1g当り16.5μmolのエポキシ基で誘導体化されたことを示した。
クロマトグラフィー実験を、Biologic LP クロマトグラフィーシステムを用いて1cm直径10mLカラム容量オムニフィット・カラムを用いて吸着剤III,IV,V,VI、及びVIIの各々を用いて実施した。このカラムを、100cm/時間で13mMクエン酸ナトリウム、140mM塩化ナトリウムpH7.0の5カラム容量で平衡化した。次いで、ヒト血漿(0.45μm濾過、100mL)を50cm/時間でロードした。ロード後洗浄を、13mMクエン酸ナトリウム、140mM塩化ナトリウムpH7.0で行ってベースライン吸光にした。次いで、カラムを0.3Mグリシン.0.5M塩化ナトリウム、及び1%w/vコール酸ナトリウムpH9.0で溶出させ、そして2M塩酸グアニジンpH7.0で殺菌した。溶出フラクションを直ちに0.4MHClで中和し、その後分析した。ロード、非結合、及び溶出フラクションを、比濁計により分析して、結合及び溶出能力を測定した。SDS PAGEを実施して純度を測定した。
Claims (7)
- フィブリノーゲン又はフィブリノーゲン・アナログであるタンパク質の分離、除去、単離、精製、特徴付け、同定又は定量のためのアフィニティー吸着剤の使用であって、当該アフィニティー吸着剤は、以下の式(II):
YはO,S又はNR2であり;
ZはO,S又はNR3であり;
R2とR3は各々、H、アルキル、ヒドロキシアルキル、ベンジル又はβ−フェニルエチルであり;
nは0〜6であり;
Aは、スペーサーによりトリアジンに連結されていてもよい支持マトリックスであり;
R7は中性pHにおいて正電荷をもつ基であり;
Wは任意的リンカーであり;
Vは、芳香族基であり、R 8 は、H,OH、アルキル、アルコキシ、アミノ、アシルオキシ、アシルアミノ、CO2H、スルホン酸、カルバモイル、スルファモイル、アルキルスルフォニル又はハロゲンであり、かつ、R 9 はモルフォリノ基であるか、あるいはVR 8 R 9 が、モルフォリノ基である。}で表される化合物である前記使用。 - 前記フィブリノーゲンが、血漿のサンプル中に存在する、請求項1〜6のいずれか1項に記載の使用。
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CN101171077A (zh) | 2008-04-30 |
NO20075783L (no) | 2007-12-07 |
CA2607863A1 (en) | 2006-11-16 |
BRPI0611233A2 (pt) | 2010-08-24 |
JP2008541083A (ja) | 2008-11-20 |
CA2607863C (en) | 2014-10-07 |
AU2006245482A8 (en) | 2006-11-16 |
US20090326201A1 (en) | 2009-12-31 |
US20130317217A1 (en) | 2013-11-28 |
EP1885487B1 (en) | 2016-03-23 |
US9221768B2 (en) | 2015-12-29 |
MX2007013948A (es) | 2008-02-05 |
AU2006245482B2 (en) | 2010-01-28 |
US8551994B2 (en) | 2013-10-08 |
GB0509442D0 (en) | 2005-06-15 |
EP1885487A1 (en) | 2008-02-13 |
DK1885487T3 (en) | 2016-06-06 |
NZ563164A (en) | 2011-01-28 |
CN101171077B (zh) | 2010-12-08 |
ES2573467T3 (es) | 2016-06-08 |
AU2006245482A1 (en) | 2006-11-16 |
PT1885487E (pt) | 2016-06-02 |
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