WO2015193504A1 - Separation material comprising phosphoryl choline derivatives - Google Patents
Separation material comprising phosphoryl choline derivatives Download PDFInfo
- Publication number
- WO2015193504A1 WO2015193504A1 PCT/EP2015/063887 EP2015063887W WO2015193504A1 WO 2015193504 A1 WO2015193504 A1 WO 2015193504A1 EP 2015063887 W EP2015063887 W EP 2015063887W WO 2015193504 A1 WO2015193504 A1 WO 2015193504A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ethyl
- hydrogen phosphate
- dimethyl
- ammonio
- ethyl hydrogen
- Prior art date
Links
- 239000000463 material Substances 0.000 title claims abstract description 70
- 238000000926 separation method Methods 0.000 title claims abstract description 68
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical class C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 title abstract 2
- 239000007787 solid Substances 0.000 claims abstract description 38
- 239000013060 biological fluid Substances 0.000 claims abstract description 21
- 238000011282 treatment Methods 0.000 claims abstract description 16
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims abstract description 15
- 208000026278 immune system disease Diseases 0.000 claims abstract description 14
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 13
- 238000011321 prophylaxis Methods 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 59
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
- -1 tautomers Chemical class 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 32
- 229920002684 Sepharose Polymers 0.000 claims description 28
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 26
- 229920000110 poly(aryl ether sulfone) Polymers 0.000 claims description 19
- 229920002492 poly(sulfone) Polymers 0.000 claims description 19
- ZJXZSIYSNXKHEA-UHFFFAOYSA-M ethyl hydrogen phosphate(1-) Chemical compound CCOP(O)([O-])=O ZJXZSIYSNXKHEA-UHFFFAOYSA-M 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 12
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 229920012266 Poly(ether sulfone) PES Polymers 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- WXIUWUUGQUPYKK-UHFFFAOYSA-N 2-[3-aminopropyl(dimethyl)azaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](C)(C)CCCN)(O)[O-] WXIUWUUGQUPYKK-UHFFFAOYSA-N 0.000 claims description 7
- 208000007536 Thrombosis Diseases 0.000 claims description 6
- 206010052779 Transplant rejections Diseases 0.000 claims description 6
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 6
- 210000002381 plasma Anatomy 0.000 claims description 6
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 201000006370 kidney failure Diseases 0.000 claims description 5
- DBQYNNZGDPPTIS-UHFFFAOYSA-N 2-[2-[2-(6-aminohexanoylamino)ethoxy]ethyl-dimethylazaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](C)(C)CCOCCNC(CCCCCN)=O)(O)[O-] DBQYNNZGDPPTIS-UHFFFAOYSA-N 0.000 claims description 4
- UNBLOZOVCOMPPN-UHFFFAOYSA-N 2-[3-(6-aminohexanoylamino)propyl-dimethylazaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](C)(C)CCCNC(CCCCCN)=O)(O)[O-] UNBLOZOVCOMPPN-UHFFFAOYSA-N 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- 229920000936 Agarose Polymers 0.000 claims description 4
- 208000023275 Autoimmune disease Diseases 0.000 claims description 4
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- MCMNRKCIXSYSNV-UHFFFAOYSA-N Zirconium dioxide Chemical compound O=[Zr]=O MCMNRKCIXSYSNV-UHFFFAOYSA-N 0.000 claims description 4
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 4
- 210000004369 blood Anatomy 0.000 claims description 4
- 239000008280 blood Substances 0.000 claims description 4
- 239000011521 glass Substances 0.000 claims description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- 229920002454 poly(glycidyl methacrylate) polymer Polymers 0.000 claims description 4
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims description 4
- 229920002239 polyacrylonitrile Polymers 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 239000004926 polymethyl methacrylate Substances 0.000 claims description 4
- 239000004810 polytetrafluoroethylene Substances 0.000 claims description 4
- 229920001343 polytetrafluoroethylene Polymers 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 239000000377 silicon dioxide Substances 0.000 claims description 4
- JWUPVQRTYHOWHH-UHFFFAOYSA-N 2-[2-(2-aminoethoxy)ethyl-dimethylazaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](C)(C)CCOCCN)(O)[O-] JWUPVQRTYHOWHH-UHFFFAOYSA-N 0.000 claims description 3
- 208000006011 Stroke Diseases 0.000 claims description 3
- 210000003567 ascitic fluid Anatomy 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 239000012530 fluid Substances 0.000 claims description 3
- 230000001926 lymphatic effect Effects 0.000 claims description 3
- VYORAZLRZMJXQP-UHFFFAOYSA-N 2-[1-[2-(2-aminoethoxy)ethyl]piperidin-1-ium-1-yl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+]1(CCCCC1)CCOCCN)(O)[O-] VYORAZLRZMJXQP-UHFFFAOYSA-N 0.000 claims description 2
- UYBQTINIKUFADU-UHFFFAOYSA-N 2-[1-[2-[2-(6-aminohexanoylamino)ethoxy]ethyl]piperidin-1-ium-1-yl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+]1(CCCCC1)CCOCCNC(CCCCCN)=O)(O)[O-] UYBQTINIKUFADU-UHFFFAOYSA-N 0.000 claims description 2
- DXALSJMHVOPXHZ-UHFFFAOYSA-N 2-[2-(2-aminoethoxy)ethyl-diethylazaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](CC)(CC)CCOCCN)(O)[O-] DXALSJMHVOPXHZ-UHFFFAOYSA-N 0.000 claims description 2
- DRQJXYMPGRKJHT-UHFFFAOYSA-N 2-[2-(6-aminohexanoylamino)ethyl-dimethylazaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](C)(C)CCNC(CCCCCN)=O)(O)[O-] DRQJXYMPGRKJHT-UHFFFAOYSA-N 0.000 claims description 2
- WLCGKYXUZLHKBH-UHFFFAOYSA-N 2-[3-(6-aminohexanoylamino)propyl-diethylazaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](CC)(CC)CCCNC(CCCCCN)=O)(O)[O-] WLCGKYXUZLHKBH-UHFFFAOYSA-N 0.000 claims description 2
- STQOJPQQCKMJKO-UHFFFAOYSA-N 2-[4-[2-(2-aminoethoxy)ethyl]morpholin-4-ium-4-yl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+]1(CCOCC1)CCOCCN)(O)[O-] STQOJPQQCKMJKO-UHFFFAOYSA-N 0.000 claims description 2
- NKKFHIMNHHMQDD-UHFFFAOYSA-N 2-[4-azidobutyl(dimethyl)azaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](C)(C)CCCCN=[N+]=[N-])(O)[O-] NKKFHIMNHHMQDD-UHFFFAOYSA-N 0.000 claims description 2
- FIVHWOKSYQVWCT-UHFFFAOYSA-N 2-[dimethyl(4-sulfanylbutyl)azaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](CCCCS)(C)C)(O)[O-] FIVHWOKSYQVWCT-UHFFFAOYSA-N 0.000 claims description 2
- RWYMGKOKYAOHAL-UHFFFAOYSA-N 2-[dimethyl(pent-4-ynyl)azaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](CCCC#C)(C)C)(O)[O-] RWYMGKOKYAOHAL-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 206010002383 Angina Pectoris Diseases 0.000 claims description 2
- 208000032467 Aplastic anaemia Diseases 0.000 claims description 2
- 200000000007 Arterial disease Diseases 0.000 claims description 2
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 2
- 201000001320 Atherosclerosis Diseases 0.000 claims description 2
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 2
- 229920002101 Chitin Polymers 0.000 claims description 2
- 208000011231 Crohn disease Diseases 0.000 claims description 2
- 208000024869 Goodpasture syndrome Diseases 0.000 claims description 2
- 201000005569 Gout Diseases 0.000 claims description 2
- 206010020772 Hypertension Diseases 0.000 claims description 2
- 206010061216 Infarction Diseases 0.000 claims description 2
- 239000000020 Nitrocellulose Substances 0.000 claims description 2
- 208000031481 Pathologic Constriction Diseases 0.000 claims description 2
- 239000004793 Polystyrene Substances 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 2
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 2
- 208000007718 Stable Angina Diseases 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 208000007814 Unstable Angina Diseases 0.000 claims description 2
- 239000004676 acrylonitrile butadiene styrene Substances 0.000 claims description 2
- 229940072056 alginate Drugs 0.000 claims description 2
- 235000010443 alginic acid Nutrition 0.000 claims description 2
- 229920000615 alginic acid Polymers 0.000 claims description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 2
- 230000003143 atherosclerotic effect Effects 0.000 claims description 2
- 230000017531 blood circulation Effects 0.000 claims description 2
- 239000000679 carrageenan Substances 0.000 claims description 2
- 235000010418 carrageenan Nutrition 0.000 claims description 2
- 229920001525 carrageenan Polymers 0.000 claims description 2
- 229940113118 carrageenan Drugs 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 208000020832 chronic kidney disease Diseases 0.000 claims description 2
- 206010009887 colitis Diseases 0.000 claims description 2
- 230000006378 damage Effects 0.000 claims description 2
- 201000010099 disease Diseases 0.000 claims description 2
- 208000028208 end stage renal disease Diseases 0.000 claims description 2
- 201000000523 end stage renal failure Diseases 0.000 claims description 2
- 230000003511 endothelial effect Effects 0.000 claims description 2
- 230000009843 endothelial lesion Effects 0.000 claims description 2
- 238000002657 hormone replacement therapy Methods 0.000 claims description 2
- 150000004677 hydrates Chemical class 0.000 claims description 2
- 230000007574 infarction Effects 0.000 claims description 2
- 230000000302 ischemic effect Effects 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 206010028417 myasthenia gravis Diseases 0.000 claims description 2
- 229920001220 nitrocellulos Polymers 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- 230000001575 pathological effect Effects 0.000 claims description 2
- 229920002401 polyacrylamide Polymers 0.000 claims description 2
- 229920000058 polyacrylate Polymers 0.000 claims description 2
- 239000004814 polyurethane Substances 0.000 claims description 2
- 208000037803 restenosis Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 230000036262 stenosis Effects 0.000 claims description 2
- 208000037804 stenosis Diseases 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 238000002054 transplantation Methods 0.000 claims description 2
- 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 claims description 2
- KQTRJDOIGDJSSN-UHFFFAOYSA-N 2-[1-[2-[2-[6-(6-aminohexanoylamino)hexanoylamino]ethoxy]ethyl]pyrrolidin-1-ium-1-yl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+]1(CCCC1)CCOCCNC(CCCCCNC(CCCCCN)=O)=O)(O)[O-] KQTRJDOIGDJSSN-UHFFFAOYSA-N 0.000 claims 1
- LQXFRYIEJXNLGM-UHFFFAOYSA-N 2-[2-[2-[3-(6-aminohexanoylamino)propanoylamino]ethoxy]ethyl-dimethylazaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](C)(C)CCOCCNC(CCNC(CCCCCN)=O)=O)(O)[O-] LQXFRYIEJXNLGM-UHFFFAOYSA-N 0.000 claims 1
- GPHOLXLVVIKKLX-UHFFFAOYSA-N 2-[3-azidopropyl(dimethyl)azaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](C)(C)CCCN=[N+]=[N-])(O)[O-] GPHOLXLVVIKKLX-UHFFFAOYSA-N 0.000 claims 1
- QBDHITUOHOMXLZ-UHFFFAOYSA-N 2-[4-[2-[2-[3-(6-aminohexanoylamino)propanoylamino]ethoxy]ethyl]morpholin-4-ium-4-yl]ethyl hydrogen phosphate Chemical compound NCCCCCC(=O)NCCC(=O)NCCOCC[N+]1(CCOCC1)CCOP(=O)(O)[O-] QBDHITUOHOMXLZ-UHFFFAOYSA-N 0.000 claims 1
- RRDSJRVRFCKSSC-UHFFFAOYSA-N 2-[dimethyl-[2-[2-(prop-2-ynoxycarbonylamino)ethoxy]ethyl]azaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](CCOCCNC(=O)OCC#C)(C)C)(O)[O-] RRDSJRVRFCKSSC-UHFFFAOYSA-N 0.000 claims 1
- OCURJAQMUCKHBW-UHFFFAOYSA-N 2-[dimethyl-[3-[6-(prop-2-ynoxycarbonylamino)hexanoylamino]propyl]azaniumyl]ethyl hydrogen phosphate Chemical compound P(=O)(OCC[N+](CCCNC(CCCCCNC(=O)OCC#C)=O)(C)C)(O)[O-] OCURJAQMUCKHBW-UHFFFAOYSA-N 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 108010074051 C-Reactive Protein Proteins 0.000 abstract description 30
- 102100032752 C-reactive protein Human genes 0.000 abstract description 30
- 229950004354 phosphorylcholine Drugs 0.000 abstract description 18
- 102000004169 proteins and genes Human genes 0.000 abstract description 4
- 108090000623 proteins and genes Proteins 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 71
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 25
- 238000003786 synthesis reaction Methods 0.000 description 23
- 238000000034 method Methods 0.000 description 17
- PYJNAPOPMIJKJZ-UHFFFAOYSA-N phosphorylcholine chloride Chemical class [Cl-].C[N+](C)(C)CCOP(O)(O)=O PYJNAPOPMIJKJZ-UHFFFAOYSA-N 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 239000004593 Epoxy Substances 0.000 description 16
- 238000010511 deprotection reaction Methods 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 125000006239 protecting group Chemical group 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000006366 phosphorylation reaction Methods 0.000 description 12
- 230000026731 phosphorylation Effects 0.000 description 11
- 125000003277 amino group Chemical group 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 150000001414 amino alcohols Chemical class 0.000 description 9
- 239000013058 crude material Substances 0.000 description 9
- 239000012634 fragment Substances 0.000 description 9
- 238000005956 quaternization reaction Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 0 CC(C(C1CCCC1)C1C*CC1)C1(C)CCCC1 Chemical compound CC(C(C1CCCC1)C1C*CC1)C1(C)CCCC1 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 125000000524 functional group Chemical group 0.000 description 7
- 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 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000003776 cleavage reaction Methods 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 150000004985 diamines Chemical class 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 230000007017 scission Effects 0.000 description 6
- GIAFURWZWWWBQT-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanol Chemical compound NCCOCCO GIAFURWZWWWBQT-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 5
- 239000010949 copper Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000011877 solvent mixture Substances 0.000 description 5
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- ABJJOEMFVQYFLC-UHFFFAOYSA-N 2-hydroxyethyl-dimethyl-[3-(phenylmethoxycarbonylamino)propyl]azanium bromide Chemical compound [Br-].C(C1=CC=CC=C1)OC(=O)NCCC[N+](C)(C)CCO ABJJOEMFVQYFLC-UHFFFAOYSA-N 0.000 description 4
- PEFFHHWMJTUOGQ-UHFFFAOYSA-N 2-hydroxyethyl-dimethyl-[3-[6-(phenylmethoxycarbonylamino)hexanoylamino]propyl]azanium bromide Chemical compound [Br-].C(C1=CC=CC=C1)OC(=O)NCCCCCC(=O)NCCC[N+](C)(C)CCO PEFFHHWMJTUOGQ-UHFFFAOYSA-N 0.000 description 4
- RXQDBVWDABAAHL-UHFFFAOYSA-N 6-(phenylmethoxycarbonylamino)hexanoic acid Chemical compound OC(=O)CCCCCNC(=O)OCC1=CC=CC=C1 RXQDBVWDABAAHL-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- OKAYDGYLIXSZCR-UHFFFAOYSA-N benzyl N-[6-[3-(dimethylamino)propylamino]-6-oxohexyl]carbamate Chemical compound CN(CCCNC(CCCCCNC(OCC1=CC=CC=C1)=O)=O)C OKAYDGYLIXSZCR-UHFFFAOYSA-N 0.000 description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- DFATVAIOSVCLRN-UHFFFAOYSA-N 2-[2-(1,3-dioxoisoindol-2-yl)ethoxy]ethyl methanesulfonate Chemical compound C1=CC=C2C(=O)N(CCOCCOS(=O)(=O)C)C(=O)C2=C1 DFATVAIOSVCLRN-UHFFFAOYSA-N 0.000 description 3
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical class [H]C([*])([H])C([H])([H])O[H] 0.000 description 3
- PYSGFFTXMUWEOT-UHFFFAOYSA-N 3-(dimethylamino)propan-1-ol Chemical compound CN(C)CCCO PYSGFFTXMUWEOT-UHFFFAOYSA-N 0.000 description 3
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical class [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 3
- QJDSLDWVMCWWCO-UHFFFAOYSA-N 6-(1,3-dioxoisoindol-2-yl)hexanoic acid Chemical compound C1=CC=C2C(=O)N(CCCCCC(=O)O)C(=O)C2=C1 QJDSLDWVMCWWCO-UHFFFAOYSA-N 0.000 description 3
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 229960002684 aminocaproic acid Drugs 0.000 description 3
- 238000010461 azide-alkyne cycloaddition reaction Methods 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 3
- ISVXWCNOKYBQII-UHFFFAOYSA-N benzyl n-[3-(dimethylamino)propyl]carbamate Chemical compound CN(C)CCCNC(=O)OCC1=CC=CC=C1 ISVXWCNOKYBQII-UHFFFAOYSA-N 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 239000012148 binding buffer Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 229910052802 copper Inorganic materials 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000002118 epoxides Chemical class 0.000 description 3
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 3
- 229960002449 glycine Drugs 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- CXWGKAYMVASWDQ-UHFFFAOYSA-N 1,2-dithiane Chemical compound C1CCSSC1 CXWGKAYMVASWDQ-UHFFFAOYSA-N 0.000 description 2
- WKGZJBVXZWCZQC-UHFFFAOYSA-N 1-(1-benzyltriazol-4-yl)-n,n-bis[(1-benzyltriazol-4-yl)methyl]methanamine Chemical compound C=1N(CC=2C=CC=CC=2)N=NC=1CN(CC=1N=NN(CC=2C=CC=CC=2)C=1)CC(N=N1)=CN1CC1=CC=CC=C1 WKGZJBVXZWCZQC-UHFFFAOYSA-N 0.000 description 2
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 2
- SQFCBBLSKSECMB-UHFFFAOYSA-N 2-(3-aminopropoxy)ethanol Chemical compound NCCCOCCO SQFCBBLSKSECMB-UHFFFAOYSA-N 0.000 description 2
- ZIPJJLQSZYZOBO-UHFFFAOYSA-M 2-[2-(1,3-dioxoisoindol-2-yl)ethoxy]ethyl-(2-hydroxyethyl)-dimethylazanium methanesulfonate Chemical compound CS([O-])(=O)=O.C[N+](C)(CCO)CCOCCN1C(=O)c2ccccc2C1=O ZIPJJLQSZYZOBO-UHFFFAOYSA-M 0.000 description 2
- ZBYXIJWAXDFBEB-UHFFFAOYSA-M 2-[2-(1,3-dioxoisoindol-2-yl)ethoxy]ethyl-(3-hydroxypropyl)-dimethylazanium methanesulfonate Chemical compound CS([O-])(=O)=O.C[N+](C)(CCCO)CCOCCN1C(=O)c2ccccc2C1=O ZBYXIJWAXDFBEB-UHFFFAOYSA-M 0.000 description 2
- ASDQMECUMYIVBG-UHFFFAOYSA-N 2-[2-(2-aminoethoxy)ethoxy]ethanol Chemical compound NCCOCCOCCO ASDQMECUMYIVBG-UHFFFAOYSA-N 0.000 description 2
- JBKIFGNPYPHRJA-UHFFFAOYSA-N 2-[2-(2-hydroxyethoxy)ethyl]isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCOCCO)C(=O)C2=C1 JBKIFGNPYPHRJA-UHFFFAOYSA-N 0.000 description 2
- SHKUUQIDMUMQQK-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)butoxymethyl]oxirane Chemical compound C1OC1COCCCCOCC1CO1 SHKUUQIDMUMQQK-UHFFFAOYSA-N 0.000 description 2
- KYGLIWLEJXTQJE-UHFFFAOYSA-N 2-hydroxyethyl-dimethyl-[2-[2-[6-(phenylmethoxycarbonylamino)hexanoylamino]ethoxy]ethyl]azanium methanesulfonate Chemical compound CS([O-])(=O)=O.C[N+](C)(CCO)CCOCCNC(=O)CCCCCNC(=O)OCc1ccccc1 KYGLIWLEJXTQJE-UHFFFAOYSA-N 0.000 description 2
- ZHEZZDWAXWFREJ-UHFFFAOYSA-N 3-(3-aminopropoxy)propan-1-ol Chemical compound NCCCOCCCO ZHEZZDWAXWFREJ-UHFFFAOYSA-N 0.000 description 2
- ZGTGJVOYANFAHN-UHFFFAOYSA-N 3-[2-(2-aminoethoxy)ethyl-dimethylazaniumyl]propyl hydrogen phosphate Chemical compound P(=O)(OCCC[N+](C)(C)CCOCCN)(O)[O-] ZGTGJVOYANFAHN-UHFFFAOYSA-N 0.000 description 2
- PJLOHVAAPSXEQI-UHFFFAOYSA-N 4-(3-aminopropoxy)butan-1-ol Chemical compound NCCCOCCCCO PJLOHVAAPSXEQI-UHFFFAOYSA-N 0.000 description 2
- BLFRQYKZFKYQLO-UHFFFAOYSA-N 4-aminobutan-1-ol Chemical compound NCCCCO BLFRQYKZFKYQLO-UHFFFAOYSA-N 0.000 description 2
- LQGKDMHENBFVRC-UHFFFAOYSA-N 5-aminopentan-1-ol Chemical compound NCCCCCO LQGKDMHENBFVRC-UHFFFAOYSA-N 0.000 description 2
- JJMDCOVWQOJGCB-UHFFFAOYSA-N 5-aminopentanoic acid Chemical compound [NH3+]CCCCC([O-])=O JJMDCOVWQOJGCB-UHFFFAOYSA-N 0.000 description 2
- SUTWPJHCRAITLU-UHFFFAOYSA-N 6-aminohexan-1-ol Chemical compound NCCCCCCO SUTWPJHCRAITLU-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 101000942118 Homo sapiens C-reactive protein Proteins 0.000 description 2
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 2
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 2
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 2
- 108010045517 Serum Amyloid P-Component Proteins 0.000 description 2
- 102100036202 Serum amyloid P-component Human genes 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000024932 T cell mediated immunity Effects 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 150000001336 alkenes Chemical group 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WMLMAYDNEVGAJL-UHFFFAOYSA-N benzyl N-[6-[2-(2-hydroxyethoxy)ethylamino]-6-oxohexyl]carbamate Chemical compound OCCOCCNC(CCCCCNC(OCC1=CC=CC=C1)=O)=O WMLMAYDNEVGAJL-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 150000003842 bromide salts Chemical class 0.000 description 2
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229960002887 deanol Drugs 0.000 description 2
- 238000010908 decantation Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 2
- 239000012972 dimethylethanolamine Substances 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- LOZWAPSEEHRYPG-UHFFFAOYSA-N dithiane Natural products C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 2
- 239000012149 elution buffer Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- SBUYBNIDQXQZSZ-UHFFFAOYSA-N p-aminophenylphosphocholine Chemical compound C[N+](C)(C)CCOP([O-])(=O)OC1=CC=C(N)C=C1 SBUYBNIDQXQZSZ-UHFFFAOYSA-N 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 230000010412 perfusion Effects 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000005086 pumping Methods 0.000 description 2
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 2
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 238000003419 tautomerization reaction Methods 0.000 description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 150000003852 triazoles Chemical group 0.000 description 2
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- 150000000177 1,2,3-triazoles Chemical class 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- SPXOTSHWBDUUMT-UHFFFAOYSA-N 138-42-1 Chemical compound OS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-N 0.000 description 1
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- CGJFKQFYZOARRV-UHFFFAOYSA-N 2-(2-azidoethoxy)ethanol Chemical compound OCCOCCN=[N+]=[N-] CGJFKQFYZOARRV-UHFFFAOYSA-N 0.000 description 1
- CZENOVOYTXTOKE-UHFFFAOYSA-N 2-(2-azidoethylsulfonyl)ethanol Chemical compound OCCS(=O)(=O)CCN=[N+]=[N-] CZENOVOYTXTOKE-UHFFFAOYSA-N 0.000 description 1
- HUSDTFBXUYBZJD-UHFFFAOYSA-N 2-(2-prop-2-ynoxyethoxy)ethanol Chemical compound OCCOCCOCC#C HUSDTFBXUYBZJD-UHFFFAOYSA-N 0.000 description 1
- PQRFOXXNMIPQFX-UHFFFAOYSA-N 2-(3-aminopropoxy)acetic acid Chemical compound NCCCOCC(O)=O PQRFOXXNMIPQFX-UHFFFAOYSA-N 0.000 description 1
- CQJAWZCYNRBZDL-UHFFFAOYSA-N 2-(methylazaniumyl)butanoate Chemical compound CCC(NC)C(O)=O CQJAWZCYNRBZDL-UHFFFAOYSA-N 0.000 description 1
- FPDYKABXINADKS-UHFFFAOYSA-N 2-(methylazaniumyl)hexanoate Chemical compound CCCCC(NC)C(O)=O FPDYKABXINADKS-UHFFFAOYSA-N 0.000 description 1
- KKFDCBRMNNSAAW-UHFFFAOYSA-N 2-(morpholin-4-yl)ethanol Chemical compound OCCN1CCOCC1 KKFDCBRMNNSAAW-UHFFFAOYSA-N 0.000 description 1
- RUVRGYVESPRHSZ-UHFFFAOYSA-N 2-[2-(2-azaniumylethoxy)ethoxy]acetate Chemical compound NCCOCCOCC(O)=O RUVRGYVESPRHSZ-UHFFFAOYSA-N 0.000 description 1
- PMNIHDBMMDOUPD-UHFFFAOYSA-N 2-[2-(2-azidoethoxy)ethoxy]ethanol Chemical compound OCCOCCOCCN=[N+]=[N-] PMNIHDBMMDOUPD-UHFFFAOYSA-N 0.000 description 1
- CXJWUJYYDLYCCQ-UHFFFAOYSA-N 2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethanol Chemical compound OCCOCCOCCOCC#C CXJWUJYYDLYCCQ-UHFFFAOYSA-N 0.000 description 1
- WLTXANJUTDPXHU-UHFFFAOYSA-N 2-[2-(methylamino)ethoxy]acetic acid Chemical compound CNCCOCC(O)=O WLTXANJUTDPXHU-UHFFFAOYSA-N 0.000 description 1
- IPKWSCDDLHLVMC-UHFFFAOYSA-N 2-[2-(methylamino)ethoxy]ethanol Chemical compound CNCCOCCO IPKWSCDDLHLVMC-UHFFFAOYSA-N 0.000 description 1
- DGRJZSGHEKZYHP-UHFFFAOYSA-N 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetic acid Chemical compound NCCOCCOCCOCC(O)=O DGRJZSGHEKZYHP-UHFFFAOYSA-N 0.000 description 1
- MBQYGQMGPFNSAP-UHFFFAOYSA-N 2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethanol Chemical compound OCCOCCOCCOCCN=[N+]=[N-] MBQYGQMGPFNSAP-UHFFFAOYSA-N 0.000 description 1
- WUIZFHDAQGKOIW-UHFFFAOYSA-N 2-[2-[2-(methylamino)ethoxy]ethoxy]acetic acid Chemical compound CNCCOCCOCC(O)=O WUIZFHDAQGKOIW-UHFFFAOYSA-N 0.000 description 1
- OJIGMRILIXVTEA-UHFFFAOYSA-N 2-[2-[2-(methylamino)ethoxy]ethoxy]ethanol Chemical compound CNCCOCCOCCO OJIGMRILIXVTEA-UHFFFAOYSA-N 0.000 description 1
- TZUHQVYGEUFELU-UHFFFAOYSA-N 2-[2-[6-(phenylmethoxycarbonylamino)hexanoylamino]ethoxy]ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCOCCNC(CCCCCNC(=O)OCC1=CC=CC=C1)=O TZUHQVYGEUFELU-UHFFFAOYSA-N 0.000 description 1
- CLHVJJSWWMLHSQ-UHFFFAOYSA-N 2-[3-(methylamino)propoxy]acetic acid Chemical compound CNCCCOCC(=O)O CLHVJJSWWMLHSQ-UHFFFAOYSA-N 0.000 description 1
- XNOQLOBLSIFFSE-UHFFFAOYSA-N 2-[3-(methylamino)propoxy]ethanol Chemical compound CNCCCOCCO XNOQLOBLSIFFSE-UHFFFAOYSA-N 0.000 description 1
- BSULWPSUVMOMAN-UHFFFAOYSA-N 2-azidoethanol Chemical compound OCCN=[N+]=[N-] BSULWPSUVMOMAN-UHFFFAOYSA-N 0.000 description 1
- IZDJJYRXECMSLX-UHFFFAOYSA-N 2-chloro-5-methylpyridine-3-carbaldehyde Chemical compound CC1=CN=C(Cl)C(C=O)=C1 IZDJJYRXECMSLX-UHFFFAOYSA-N 0.000 description 1
- QSECPQCFCWVBKM-UHFFFAOYSA-N 2-iodoethanol Chemical compound OCCI QSECPQCFCWVBKM-UHFFFAOYSA-N 0.000 description 1
- GHGCQQRMJCSIBQ-UHFFFAOYSA-N 2-prop-2-ynoxyethanol Chemical compound OCCOCC#C GHGCQQRMJCSIBQ-UHFFFAOYSA-N 0.000 description 1
- LUDUIFJPKHXOLJ-UHFFFAOYSA-N 3-(3-aminopropoxy)propanoic acid Chemical compound NCCCOCCC(O)=O LUDUIFJPKHXOLJ-UHFFFAOYSA-N 0.000 description 1
- KRGXWTOLFOPIKV-UHFFFAOYSA-N 3-(methylamino)propan-1-ol Chemical compound CNCCCO KRGXWTOLFOPIKV-UHFFFAOYSA-N 0.000 description 1
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical group OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 1
- WXWSYEQAJAILKG-UHFFFAOYSA-N 3-[3-(methylamino)propoxy]propan-1-ol Chemical compound CNCCCOCCCO WXWSYEQAJAILKG-UHFFFAOYSA-N 0.000 description 1
- RNAUKNGAFSXZSF-UHFFFAOYSA-N 3-[3-(methylamino)propoxy]propanoic acid Chemical compound CNCCCOCCC(=O)O RNAUKNGAFSXZSF-UHFFFAOYSA-N 0.000 description 1
- WHVSIWLMCCGHFW-UHFFFAOYSA-N 3-azidopropan-1-ol Chemical compound OCCCN=[N+]=[N-] WHVSIWLMCCGHFW-UHFFFAOYSA-N 0.000 description 1
- YIPVUXAMZQBALD-UHFFFAOYSA-N 3-azidopropanoic acid Chemical compound OC(=O)CCN=[N+]=[N-] YIPVUXAMZQBALD-UHFFFAOYSA-N 0.000 description 1
- CQVWOJSAGPFDQL-UHFFFAOYSA-N 3-iodopropan-1-ol Chemical compound OCCCI CQVWOJSAGPFDQL-UHFFFAOYSA-N 0.000 description 1
- DKIDEFUBRARXTE-UHFFFAOYSA-N 3-mercaptopropanoic acid Chemical compound OC(=O)CCS DKIDEFUBRARXTE-UHFFFAOYSA-N 0.000 description 1
- KVNQQGIGXFPPCN-UHFFFAOYSA-N 4-(3-aminopropoxy)butanoic acid Chemical compound NCCCOCCCC(O)=O KVNQQGIGXFPPCN-UHFFFAOYSA-N 0.000 description 1
- DBKSSENEKWOVKL-UHFFFAOYSA-N 4-(methylamino)butan-1-ol Chemical compound CNCCCCO DBKSSENEKWOVKL-UHFFFAOYSA-N 0.000 description 1
- ZJLANBMBXAOBIQ-UHFFFAOYSA-N 4-[3-(methylamino)propoxy]butan-1-ol Chemical compound CNCCCOCCCCO ZJLANBMBXAOBIQ-UHFFFAOYSA-N 0.000 description 1
- ZWDYAWYFIOHXJG-UHFFFAOYSA-N 4-[3-(methylamino)propoxy]butanoic acid Chemical compound CNCCCOCCCC(=O)O ZWDYAWYFIOHXJG-UHFFFAOYSA-N 0.000 description 1
- USAVSXJFTZUOGV-UHFFFAOYSA-N 4-azidobutan-1-ol Chemical compound OCCCCN=[N+]=[N-] USAVSXJFTZUOGV-UHFFFAOYSA-N 0.000 description 1
- WAGMYTXJRVPMGW-UHFFFAOYSA-N 4-azidobutanoic acid Chemical compound OC(=O)CCCN=[N+]=[N-] WAGMYTXJRVPMGW-UHFFFAOYSA-N 0.000 description 1
- DTRIDVOOPAQEEL-UHFFFAOYSA-M 4-sulfanylbutanoate Chemical compound [O-]C(=O)CCCS DTRIDVOOPAQEEL-UHFFFAOYSA-M 0.000 description 1
- UABIDSXFBNNUFT-UHFFFAOYSA-N 5-(methylamino)hexan-1-ol Chemical compound C(CO)CCC(C)NC UABIDSXFBNNUFT-UHFFFAOYSA-N 0.000 description 1
- CMVZMERLBCRJAH-UHFFFAOYSA-N 5-(methylamino)pentanoic acid Chemical compound CNCCCCC(O)=O CMVZMERLBCRJAH-UHFFFAOYSA-N 0.000 description 1
- SBZDIRMBQJDCLB-UHFFFAOYSA-N 5-azidopentanoic acid Chemical compound OC(=O)CCCCN=[N+]=[N-] SBZDIRMBQJDCLB-UHFFFAOYSA-N 0.000 description 1
- RURWAYHDLRPVAE-UHFFFAOYSA-N 6-(methylamino)hexan-1-ol Chemical compound CNCCCCCCO RURWAYHDLRPVAE-UHFFFAOYSA-N 0.000 description 1
- JCORXJUUSVCJEP-UHFFFAOYSA-N 6-azidohexanoic acid Chemical compound OC(=O)CCCCCN=[N+]=[N-] JCORXJUUSVCJEP-UHFFFAOYSA-N 0.000 description 1
- PCHBEKKEZRNRFU-UHFFFAOYSA-N 7-(methylamino)heptan-1-ol Chemical compound CNCCCCCCCO PCHBEKKEZRNRFU-UHFFFAOYSA-N 0.000 description 1
- KBMWCYLQINPRTE-UHFFFAOYSA-N 7-(methylamino)heptanoic acid Chemical compound CNCCCCCCC(O)=O KBMWCYLQINPRTE-UHFFFAOYSA-N 0.000 description 1
- XDOLZJYETYVRKV-UHFFFAOYSA-N 7-Aminoheptanoic acid Chemical compound NCCCCCCC(O)=O XDOLZJYETYVRKV-UHFFFAOYSA-N 0.000 description 1
- BSFODEXXVBBYOC-UHFFFAOYSA-N 8-[4-(dimethylamino)butan-2-ylamino]quinolin-6-ol Chemical compound C1=CN=C2C(NC(CCN(C)C)C)=CC(O)=CC2=C1 BSFODEXXVBBYOC-UHFFFAOYSA-N 0.000 description 1
- 108010062271 Acute-Phase Proteins Proteins 0.000 description 1
- 102000011767 Acute-Phase Proteins Human genes 0.000 description 1
- 241001116389 Aloe Species 0.000 description 1
- GNRLUBOJIGSVNT-UHFFFAOYSA-N Aminoethoxyacetic acid Chemical compound NCCOCC(O)=O GNRLUBOJIGSVNT-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- AABBTBMHRIPJSD-UHFFFAOYSA-O CCCC[N+](C)(C)CCOP(O)(O)=O Chemical compound CCCC[N+](C)(C)CCOP(O)(O)=O AABBTBMHRIPJSD-UHFFFAOYSA-O 0.000 description 1
- LQMPKAWSFVXAHI-UHFFFAOYSA-O C[N+](C)(CCOCCNC(OCC=C)=O)CCOP(C)(O)=O Chemical compound C[N+](C)(CCOCCNC(OCC=C)=O)CCOP(C)(O)=O LQMPKAWSFVXAHI-UHFFFAOYSA-O 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 101000922020 Homo sapiens Cysteine and glycine-rich protein 1 Proteins 0.000 description 1
- 101001082142 Homo sapiens Pentraxin-related protein PTX3 Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 102000004889 Interleukin-6 Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- VDIPNVCWMXZNFY-UHFFFAOYSA-N N-methyl-beta-alanine Chemical compound CNCCC(O)=O VDIPNVCWMXZNFY-UHFFFAOYSA-N 0.000 description 1
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 1
- 101150038768 NPG1 gene Proteins 0.000 description 1
- BFHAYPLBUQVNNJ-UHFFFAOYSA-N Pectenotoxin 3 Natural products OC1C(C)CCOC1(O)C1OC2C=CC(C)=CC(C)CC(C)(O3)CCC3C(O3)(O4)CCC3(C=O)CC4C(O3)C(=O)CC3(C)C(O)C(O3)CCC3(O3)CCCC3C(C)C(=O)OC2C1 BFHAYPLBUQVNNJ-UHFFFAOYSA-N 0.000 description 1
- 102100027351 Pentraxin-related protein PTX3 Human genes 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 239000004695 Polyether sulfone Substances 0.000 description 1
- 239000005700 Putrescine Substances 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 108700012920 TNF Proteins 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- JNRFANKHQTXHCH-UHFFFAOYSA-N acetonitrile 2-(dimethylamino)ethanol Chemical compound CC#N.CN(C)CCO JNRFANKHQTXHCH-UHFFFAOYSA-N 0.000 description 1
- WHQRAOBYNSVATO-UHFFFAOYSA-N acetonitrile 3-(dimethylamino)propan-1-ol Chemical compound CC#N.CN(C)CCCO WHQRAOBYNSVATO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000001261 affinity purification Methods 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000002355 alkine group Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 235000011399 aloe vera Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003373 anti-fouling effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 125000000656 azaniumyl group Chemical group [H][N+]([H])([H])[*] 0.000 description 1
- 238000010462 azide-alkyne Huisgen cycloaddition reaction Methods 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- MJSHDCCLFGOEIK-UHFFFAOYSA-N benzyl (2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)OCC1=CC=CC=C1 MJSHDCCLFGOEIK-UHFFFAOYSA-N 0.000 description 1
- NFPGZLVPTVWFSY-UHFFFAOYSA-N benzyl n-[2-(2-hydroxyethoxy)ethyl]carbamate Chemical compound OCCOCCNC(=O)OCC1=CC=CC=C1 NFPGZLVPTVWFSY-UHFFFAOYSA-N 0.000 description 1
- 102000023732 binding proteins Human genes 0.000 description 1
- 108091008324 binding proteins Proteins 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- OTJZCIYGRUNXTP-KTXUZGJCSA-N but-3-yn-1-ol Chemical compound OC[11CH2]C#C OTJZCIYGRUNXTP-KTXUZGJCSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000007213 cerebrovascular event Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000004154 complement system Effects 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- FERLMVOJTRSOAQ-UHFFFAOYSA-N cyclohex-3-yne-1,2-diamine Chemical compound NC1CCC#CC1N FERLMVOJTRSOAQ-UHFFFAOYSA-N 0.000 description 1
- VKIRRGRTJUUZHS-UHFFFAOYSA-N cyclohexane-1,4-diamine Chemical compound NC1CCC(N)CC1 VKIRRGRTJUUZHS-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 229940042400 direct acting antivirals phosphonic acid derivative Drugs 0.000 description 1
- SPBWMYPZWNFWES-UHFFFAOYSA-N disodium;azanylidyneoxidanium;iron(2+);pentacyanide;dihydrate Chemical compound O.O.[Na+].[Na+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].[O+]#N SPBWMYPZWNFWES-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical group C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- YEUAOTZWAWUYBH-UHFFFAOYSA-N hexanethioic s-acid Chemical compound CCCCCC(S)=O YEUAOTZWAWUYBH-UHFFFAOYSA-N 0.000 description 1
- 102000051143 human CRP Human genes 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940100601 interleukin-6 Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000005649 metathesis reaction Methods 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- QHJABUZHRJTCAR-UHFFFAOYSA-N n'-methylpropane-1,3-diamine Chemical compound CNCCCN QHJABUZHRJTCAR-UHFFFAOYSA-N 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- CRWVOXFUXPYTRK-UHFFFAOYSA-N pent-4-yn-1-ol Chemical compound OCCCC#C CRWVOXFUXPYTRK-UHFFFAOYSA-N 0.000 description 1
- MLBYLEUJXUBIJJ-UHFFFAOYSA-N pent-4-ynoic acid Chemical compound OC(=O)CCC#C MLBYLEUJXUBIJJ-UHFFFAOYSA-N 0.000 description 1
- OTIJNTWWDCIUNM-UHFFFAOYSA-N pentanethioic s-acid Chemical compound CCCCC(S)=O OTIJNTWWDCIUNM-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000004713 phosphodiesters Chemical class 0.000 description 1
- 150000003007 phosphonic acid derivatives Chemical class 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- ZWLUXSQADUDCSB-UHFFFAOYSA-N phthalaldehyde Chemical compound O=CC1=CC=CC=C1C=O ZWLUXSQADUDCSB-UHFFFAOYSA-N 0.000 description 1
- 229920006393 polyether sulfone Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 125000003186 propargylic group Chemical group 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229940083618 sodium nitroprusside Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
- B01D15/38—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving specific interaction not covered by one or more of groups B01D15/265 - B01D15/36
- B01D15/3804—Affinity chromatography
- B01D15/3809—Affinity chromatography of the antigen-antibody type, e.g. protein A, G, L chromatography
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/34—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration
- A61M1/3472—Filtering material out of the blood by passing it through a membrane, i.e. hemofiltration or diafiltration with treatment of the filtrate
- A61M1/3486—Biological, chemical treatment, e.g. chemical precipitation; treatment by absorbents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3621—Extra-corporeal blood circuits
- A61M1/3627—Degassing devices; Buffer reservoirs; Drip chambers; Blood filters
- A61M1/3633—Blood component filters, e.g. leukocyte filters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
- B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
- B01J20/24—Naturally occurring macromolecular compounds, e.g. humic acids or their derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/59—Hydrogenated pyridine rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/6533—Six-membered rings
-
- 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
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0036—Galactans; Derivatives thereof
- C08B37/0039—Agar; Agarose, i.e. D-galactose, 3,6-anhydro-D-galactose, methylated, sulfated, e.g. from the red algae Gelidium and Gracilaria; Agaropectin; Derivatives thereof, e.g. Sepharose, i.e. crosslinked agarose
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/11—Compounds covalently bound to a solid support
Definitions
- the present invention provides phosphoryl choline derivatives of general formula (I), which are suitable to be immobilized on a solid support to provide a separation material of general formula (II), which bind with both high affinity and high specificity to a protein, more specifically to C-reactive protein and anti-phosphoryl choline antibodies.
- Said separation materials are particularly useful in the extracorporeal removal of C-reactive protein and anti-phosphoryl choline antibodies from a biological fluid of a patient for prophylaxis and/or treatment of immune dysfunctions and cardiovascular diseases.
- a column that comprises the separation material of general formula (II), as well as a device containing the column.
- C-reactive protein is an acute phase reactant produced by the liver in response to cytokine release during inflammation. It has long been used in clinical practice to follow systemic inflammation, especially bacterial infection. More recently, epidemiological evidence has shown that basal levels of CRP, in the absence of apparent inflammatory disease may be informative in predicting future myocardial or cerebrovascular events (Ridker et al. Circulation, 2001 103, 1813). Also of interest is the fact that CRP is a potential inflammatory marker believed to be of value in the prediction of coronary events (Danesh et al. N. Engl. J. Med. 2004 350, 1387) and that CRP is a causative factor of the destructive processes observed during the weeks after myocardial infarction (Slagman et al., Blood Purif. 2011 , 31, 9).
- PC phosphoryl choline
- WO 90/12632 describes a method for removing CRP and anti-phosphoryl choline antibodies from biological fluids to improve the cellular immune responses thereof, and a method for removing CRP and anti-phosphoryl choline antibodies from the circulation of patients with cancer by conducting extracorporeal perfusion of a patient's blood plasma through a phosphoryl choline-matrix adsorption device so as to improve the patient's cellular immune responses against the cancer.
- WO 2007/076844 describes a method for treating the risk of accumulating CRP by performing an extracorporeal perfusion of blood plasma of patients presenting a risk of cardiovascular diseases or immune dysfunctions such as autoimmune diseases by means of a column, which contains absorbent matrix material including PC derivatives to eliminate CRP from a patient's biological liquids so as to prevent and/or treat autoimmune diseases, cardiovascular diseases such as myocardial infarction, stroke, diabetes, rheumatism, and renal insufficiency.
- a column which contains absorbent matrix material including PC derivatives to eliminate CRP from a patient's biological liquids so as to prevent and/or treat autoimmune diseases, cardiovascular diseases such as myocardial infarction, stroke, diabetes, rheumatism, and renal insufficiency.
- PC-BSA bovine serum albumin
- WO 2013/176084 A1 discloses also a silylalkyi phosphoramidate compound of general formula (1 ) for coating a medical device in order to suppress the adhesion of biological material, such as platelets.
- WO 2012/160187 A1 provides ammonium-containing phosphonic acid derivatives for use in the treatment of an inflammatory, autoimmune and/or allergic disorder. It is postulated that the disclosed compounds exert their pharmacological activity through inhibition of the phosphoinositide 3-kinase (PI3K)/Akt kinase pathway.
- PI3K phosphoinositide 3-kinase
- up to present the immobilization of PC on solid support was achieved only via formation of a phosphodiester bond.
- the immobilization of PC derivatives via phosphodiester bond formation has some advantages, but also severe drawbacks.
- the main drawback of this approach is that formation of phosphodiester bond changes the overall charge (net charge) of the molecule of PC and thereby, alters the orientation of so modified PC in a binding pocket.
- a phosphodiester bond can be easily cleaved by non-specific phosphodiesterases present in the biological fluids leading to instability issues of the matrices, which were substituted
- b is selected from 2 and 3;
- R 1 and R 2 are independently of each other selected from: -CH 3 , -C2H 5 , -C3H7, -C 4 H 9 , -C5H11 and -C6H 13, or R 1 and R 2 can form together with the nitrogen atom to which the are connected a heteroc cle selected from:
- R 3 is selected from: -H, -CH 3 , -C 2 H 5 and -C 3 H 7 ;
- -L- is selected from: -L a - -L a -L e - -L a -L b -L e - and -L a -L b -L d -L c -L e -, wherein
- -L a - is selected from: - CH -CH -
- -L - and -L c - are independently of each other selected from: -O-, -NH-C(O)-, -C(O)-NH- -O-C(O)-NH- and -SO2-;
- -L d - is selected from: - CH -CH -
- n, p1 and p2 are independently of each other selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10;
- tautomer refers to an organic compound that is interconvertible by a chemical reaction called tautomerization. Tautomerization is catalyzed by bases, acids or other suitable compounds.
- Preferred compounds of the current invention are compounds of general formula (I):
- b is selected from 2 and 3;
- R 1 and R 2 are independently of each other selected from: -CH 3 and -C2H 5 , R 1 and R 2 can form together with the nitrogen atom to which they are connected, heterocycle selected from:
- R 3 is selected from: -H, -CH 3 , -C 2 H 5 and -C 3 H 7 ;
- -L- is selected from: -L a - -L a -L e - -L a -L b -L e - and -L a -L b -L d -L c -L e -, wherein
- -L a - represents: -(CH 2 ) m - or -(CH 2 -CH 2 -0) m -CH 2 -;
- -L b - and -L c - are independently of each other selected from: -O-, -NH-C(O)-, -C(O)-NH- -O-C(O)-NH- and -SO 2 -;
- -L d - represents: -(CH 2 ) n - or -(CH 2 -CH 2 -O) n -CH 2 -;
- -L e - is selected from: -(CH 2 ) p i- and -(CH 2 ) p i-O-(CH 2 ) p2 -;
- n, p1 and p2 are independently of each other selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10.
- a preferred embodiment according to the present invention is directed to compounds of general formula (I), wherein X is selected from: -SH, -NHR 3 , and -CHO, and more preferably is selected from: -SH and -NHR 3 .
- Preferred compounds of the current invention are compounds of the following general formula (III), (IV), (V) and (VI):
- -L a - represents: -(CH 2 ) m - or -(CH 2 -CH 2 -0) m -CH 2 -;
- -L b - and -L c - are independently of each other selected from: -O-, -NH-C(O)-, -C(O)-NH- -O-C(O)-NH- and -SO 2 -;
- -L d - represents: -(CH 2 ) n - or -(CH 2 -CH 2 -O) n -CH 2 -;
- -L e - is selected from: -(CH 2 ) p i- and -(CH 2 ) p i-O-(CH 2 ) p2 - m, n, p1 and p2 are independently of each other selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10;
- Especially preferred compounds are compounds of general formulae (I), (III), (IV), (V) and (VI), wherein
- R 1 and R 2 are independently of each other selected from: -CH 3 and -C 2 H 5 ;
- X is selected from: -SH and -NHR 3 ;
- R 3 is selected from: -H, -CH 3 , -C 2 H 5 and -C 3 H 7 ;
- a even more preferred embodiment is directed to compounds of general formula (I)
- b is selected from 2 and 3;
- R 1 and R 2 are independently of each other selected from: -CH 3 , -C 2 H 5 , -C 3 H 7 , -C 4 H 9 , -C5H 11 , -C6Hi 3 , or R 1 and R 2 can form together with the nitrogen atom to which they are connected a heterocycle selected from:
- R 3 is selected from: -H, -CH 3 , -C 2 H 5 , -C 3 H 7 ;
- -L- is selected from: -(CH 2 ) m - -(CH 2 ) m -O-C(O)-NH— (CH 2 ) P i- -(CH 2 ) m -O-(CH 2 ) p1 -, -(CH 2 ) m -C(O)-NH-(CH 2 ) p1 -, -(CH 2 ) m -NH-C(O)-(CH 2 ) p1 -, -(CH 2 ) m -C(O)-NH-(CH2)n-O-(CH2)pi-,
- n, p1 and p2 are independently of each other selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10.
- the compounds of general formula (I) are selected from:
- inventive compounds of the present invention were designed so that they can be immobilized on solid supports to provide separation materials that present increased stability, increased affinity and increased selectivity for CRP in comparison to the separation materials disclosed by the prior art. This was achieved by replacing one of the alkyl substituent of the tri-alkyl ammonium group of the phosphoryl choline with the moiety -L-X.
- the moiety -L-X enables the immobilization of the compounds of general formula (I) to a solid support without modifying the overall charge of the phosphoryl choline molecule and by avoiding the presence of the unstable phosphodiester bond in the construct.
- the present invention further provides a separation material of general formula (II):
- b is selected from 2 and 3;
- R 1 and R 2 are independently of each other selected from: -CH 3 , -C2H 5 , -C3H7, -C 4 H 9 , -C5H11 and -C6H13, or R 1 and R 2 can form together with the nitrogen atom to which they are connected a heterocycle selected from:
- Y is selected from: -CH(OH)-CH 2 -N(R 4 )- -CH(OH)-CH 2 -S- -CH 2 -NH- -NH-CH2- -CH2-CH2-S-, -S-CH2-CH2-,
- R 4 is selected from: -H, -CH 3 , -C 2 H 5 , -C 3 H 7 and -C(O)-CH 3 ;
- -L- is selected from: -L a - -L a -L e - -L a -L b -L e - and -L a -L b -L d -L c -L e -, wherein
- -L - and -L c - are independently of each other selected from: -O-, -NH-C(O)-, -C(O)-NH- -O-C(O)-NH- and -SO 2 -;
- -L d - is selected from: - C - Ch -Ch -O -Ch -
- -L e - is selected from: -(CH 2 ) P i- -(CH 2 ) p i-O-(CH 2 ) p2 -,
- -L * - is selected from: -L *a - -L *a -L *e - and -L *a -L *b -L *e -, wherein
- -L *a - is selected from: -(CH 2 ) 0 - -(CH2-CH 2 -O)o-C 2 H 4 -, -(CH 2 -CH 2 -O)o-CH 2 - and -CH 2 -CH(OH)-CH 2 -;
- -L *e - is selected from: -(CH 2 ) q - -C 2 H 4 -(O-CH 2 -CH 2 ) q -, and -CH 2 -(O-CH 2 -CH 2 ) q -;
- -L *b - is selected from: -SO 2 -, -S-, -O-, -NH-C(O), -C(O)-NH- and -S-S-; and
- n, p1 , p2, o, r, q are independently of each other selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10;
- A is a solid support selected from the group consisting of: polyvinylpyrrolidone (PVP), polysulfone (PS), polyethersulfone (PES), polyarylethersulfone (PAES), polyacrylate, poly(methyl methacrylate) (PMMA), poly(glycidyl methacrylate) (PGMA), poly(hydroxy metacrylate), polystyrene (PS), polytetrafluoroethylene (PTFE), polyacrylamide, polyacrolein, acrylonitrile butadiene styrene (ABS), polyacrylonitrile (PAN), polyurethane (PU), eupergit®, polyethylene glycol (PEG), hyperfluorocarbon, agarose, alginate, carrageenan, chitin, starch, cellulose, nitrocellulose, sepharose®, glass, silica, kieselguhr, zirconia, alumina, iron oxide and mixture and/or derivatives of said solid supports;
- the solid support A refers to an inert solid support that in anticipation of the covalent immobilization of the inventive compounds of general formula (I), (III), (IV), (V) and (VI) is functionalized with the moiety -L * -FG, wherein FG is a reactive functional group that is suitable to react with the functional group X.
- the functionalization of the solid support is achieved through methods well known to the person skilled in the art (Chin. J. Chem.
- the solid support can be subjected to cross-linking or other treatments to increase physical or chemical stability, and can be formed into various shapes, including but not limited to fibers, sheets, rods, beads, and membranes.
- the solid support A is selected from polysulfone (PS), polyethersulfone (PES), polyarylethersulfone (PAES), mixtures and/or derivatives thereof.
- PS, PES and PAES based solid supports can be modified so that to present on their surface the moiety -L * -FG, wherein FG is a reactive functional group that is 5 suitable to react with the functional group X (Chin. J. Chem. 2012, 30, 2473; Polym. Int. 2013, 62, 991 ). Such modification results in the increase of the antifouling property, biocompatibility and other specific functions.
- Preferred separation materials of the current invention are separation materials of general formula (II): and protonated and deprotonated forms thereof
- b is selected from 2 and 3;
- R 1 and R 2 are independently of each other selected from: -CH 3 , -C2H 5 , or R 1 and R 2 can form together with the nitrogen atom to which they are connected a heterocycle selected from: wherein one or several hydrogen atom(s) can be replaced with (a) fluorine atom(s);
- Y is selected from: -CH(OH)-CH 2 -N(R 4 )-, -CH(OH)-CH 2 -S- -CH2-NH-, -NH-CH2-, -CH2-CH2-S-, -S-CH2-CH2-,
- R 4 is selected from: -H, -CH 3 , -C 2 H 5 , -C 3 H 7 , -C(O)-CH 3 ;
- -L- is selected from: -L a - -L a -L e - -L a -L b -L e - and -L a -L b -L d -L c -L e -, wherein
- -L a - represents: -(CH 2 ) m - or -(CH 2 -CH 2 -0) m -CH 2 -;
- -L b - and -L c - are independently of each other selected from: -O-, -NH-C(O)-, -C(O)-NH-, -O-C(O)-NH- and -SO 2 -;
- -L d - is selected from: -(CH 2 ) n - and -(CH 2 -CH 2 -O) n -CH 2 -,
- -L e - is selected from: -(CH 2 ) p i- and -(CH 2 ) p i-O-(CH 2 ) p2 -;
- -L * - is selected from: -L *a - -L *a -L *e - and -L *a -L *b -L *e -, wherein
- -L *a - is selected from: -(CH 2 ) 0 - -(CH 2 -CH 2 -O) 0 -C 2 H 4 -,
- -L *e - is selected from: -(CH 2 ) q - -C 2 H 4 -(O-CH 2 -CH 2 ) q -, and -CH 2 -(O-CH 2 -CH 2 ) q -;
- -L *b - is selected from: -O-iCH ⁇ r -O- -S-iCH ⁇ r -S-, -SO 2 -, -S-, -O-, -NH-C(O)-, -C(O)-NH- and -S-S-;
- n, p1 , p2, o, r, q are independently of each other selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10;
- A has the meaning defined above, and more preferably A is selected from polysulfone (PS), polyethersulfone (PES), polyarylethersulfone (PAES), mixtures and/or derivatives thereof.
- PS polysulfone
- PES polyethersulfone
- PAES polyarylethersulfone
- a preferred embodiment according to the present invention is directed to separation materials of general formula (II), wherein Y is selected from:
- Preferred compounds of the current invention are compounds of the following general formula (VII), (VIII), (IX) and (X)
- -L a - is selected from: -(CH 2 ) m - and -(CH 2 -CH 2 -0) m -CH 2 -;
- -L b - and -L c - are independently of each other selected from: -O-, -NH-C(O)-, -C(O)-NH- -O-C(O)-NH- and -SO 2 -;
- -L d - is selected from: -(CH 2 ) n - and -(CH 2 -CH 2 -O) n -CH 2 -;
- -L e - is selected from: -(CH 2 ) p i- and -(CH 2 ) p i-O-(CH 2 ) p2 -;
- separation materials are separation materials of general formula (II), (VII), (VIII), (IX) and (X), wherein
- -L * - is selected from: -L *a - -
- -L *a - is selected from: -(CH 2 ) 0 - and -CH 2 -CH(OH)-CH 2 -;
- -L *b - is selected from: -O-(CH 2 )r-O- -S-(CH 2 )r-S- -S- and -O-; and o, q and r are independently of each other selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10.
- L * preferably represents -L *a -L *b -L *e - and A is preferably selected from: polysulfone (PS), polyethersulfone (PES), polyarylethersulfone (PAES), mixtures and/or derivatives thereof.
- PS polysulfone
- PES polyethersulfone
- PAES polyarylethersulfone
- Another preferred embodiment of the present invention is directed to separation materials of general formulae (II), (VII), (VIII), (IX) and (X), wherein
- R 1 and R 2 are independently of each other selected from: -CH 3 and -C 2 H 5 ;
- Y is selected from: -CH(OH)-CH 2 -N(R 4 )-, -CH(OH)-CH 2 -S-
- R 4 is selected from: -H, -CH 3 , -C 2 H 5 , -C 3 H 7 and -C(O)-CH 3;
- a even more preferred embodiment is directed to a separation material of general formula (II)
- R 1 and R 2 are independently of each other selected from: -CH 3 , -C2H 5 , -C3H7, -C 4 H 9 , -C5H11 and -C6H 13, or R 1 and R 2 can form together with the nitrogen atom to which they are connected a heterocycle selected from:
- Y is selected from: -CH(OH)-CH 2 -N(R 4 )-, -CH(OH)-CH 2 -S-
- R 4 is selected from: -H, -CH 3 , -C 2 H 5 , -C 3 H 7 and -C(O)-CH 3 ;
- -L- is selected from: -(CH 2 ) m - -(CH 2 ) m -O-C(O)-NH-(CH 2 )pi-,
- n, p1 and p2 are independently of each other selected from 1 , 2, 3, 4, 5, 6, 7, 8,
- a and L * have the meanings defined above, and more preferably A is selected from: polysulfone (PS), polyethersulfone (PES), polyarylethersulfone
- b is selected from 2 and 3;
- R 1 and R 2 are independently of each other selected from: -CH 3 , -C2H 5 , -C3H 7 , -C 4 H 9 , -C5H11 and -C6H 13, or R 1 and R 2 can form together with the nitrogen tom to which the are connected a heteroc cle selected from:
- Y is selected from: -CH(OH)-CH 2 -N(R 4 )-, -CH(OH)-CH 2 -S- -S-CH2-CH2- and -CH2-CH2-S-;
- R 4 is selected from: -H, -CH 3 , -C 2 H 5 , -C 3 H 7 and -C(O)-CH 3 ;
- -L- is selected from: -(CH 2 ) m - -(CH 2 ) m -O-C(O)-NH-(CH 2 )pi-,
- n, p1 and p2 are independently of each other selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10;
- -L * - is selected from: -(CH 2 ) 0 - -(CH2-CH 2 -O)o-C 2 H 4 -,
- o, r and q are independently of each other selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10; and A has the meaning defined above and more preferably is selected from: polysulfone (PS), polyethersulfone (PES), polyarylethersulfone (PAES), mixtures and/or derivatives thereof.
- PS polysulfone
- PES polyethersulfone
- PAES polyarylethersulfone
- Another preferred embodiment relates to separation materials of general formula (II)
- b is selected from 2 and 3;
- R 1 and R 2 are independently of each other selected from: -CH 3 , -C2H 5 , -C3H 7 , -C 4 H 9 , -C5H11 and -C6H 13, or R 1 and R 2 can form together with the nitrogen atom to which they are connected a heterocycle selected from:
- Y is selected from:
- -L- is selected from: -(CH 2 ) m - -(CH 2 ) m -O-C(O)-NH— (CH 2 ) P i- -(CH 2 ) m -O-(CH 2 ) P i-, -(CH 2 ) m -C(O)-NH-(CH 2 ) p1 -, -(CH 2 ) m -NH-C(O)-(CH 2 ) p1 - -(CH 2 ) m -C(O)-NH-(CH 2 ) n -O-(CH 2 ) p1 -,
- n, p1 and p2 are independently of each other selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10;
- -L*- is selected from: -(CH 2 ) 0 - -(CH 2 -CH 2 -O) 0 -C 2 H 4 -,
- o, r, and q are independently of each other selected from 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10; and A has the meaning defined above and more preferably is selected from polysulfone (PS), polyethersulfone (PES), polyarylethersulfone (PAES), mixtures and/or derivatives thereof.
- PS polysulfone
- PES polyethersulfone
- PAES polyarylethersulfone
- inventive compounds and separation materials are useful for removal of CRP and anti-phosphoryl choline antibodies from biological fluids.
- An embodiment of the present invention is directed to a method of extracorporeal removal of CRP from a biological fluid of a patient for prophylaxis and/or treatment of immune dysfunctions and cardiovascular diseases comprising the steps:
- the separation material of general formula (II), (VII), (VIII), (IX) and (X) is loaded into a column, said column being useful for extracorporeal removal of CRP from a biological fluid of a patient for prophylaxis and/or treatment of immune dysfunctions and cardiovascular diseases.
- biological fluid encompasses blood, blood plasma, peritoneal fluid and lymphatic fluid.
- the dimensions of the column are not critical, and they have to be chosen so that they are adapted to the flow rate of the biological fluid removed from the patient, which is highly associated to the body weight of the patient.
- the column comprising the separation material of the present invention must be sterilized, for example with a sterilant gas such as ethylene oxide, and either used immediately or sealed and stored for later use. Prior to use, the column must be washed with normal saline followed by a wash with normal saline containing any other suitable preparatory ingredients.
- the column may be of a conventional cartridge design, fluidized bed, expandable bed or a monolith. The preparation of such columns is well known to the skilled person. For example, the preparation of a column of a conventional cartridge design can be performed as described in the patent application EP 0237659 A1 .
- Regeneration of the column is also possible.
- a 0.9% saline solution could, for instance, be used for flushing the column.
- the pH value is lowered by the use of a glycine/HCI buffer (pH 2.8) in order to break the connection between the CRP and the separation material, followed by a washing step with PBS (Phosphate Buffered Saline) at a pH value of 7.4 and a final washing step with 0.9% saline solution.
- PBS Phosphate Buffered Saline
- the column comprising the separation material of the present invention contains additional separation materials suitable for removal of other substances of interest from a biological fluid of a patient.
- the other substances are preferable proteins.
- examples for other substances are interleukin-6, interleukin-1 , TNFa, serum amyloid P-component (SAP), PTX3, fibrinogen, antibodies (such as IgG, IgE), anti-phospholipid antibodies and components of the complement system such as C1 q, C3a or C5a.
- the column of the present invention can be incorporated into a device to provide a device suitable for extracorporeal removal of CRP from a biological fluid of a patient for prophylaxis and/or treatment of immune dysfunctions and cardiovascular diseases.
- the device according to the present invention comprises:
- the column comprising the separation material of general formula (II), (VII), (VIII), (IX) or (X)
- the device comprising the column, which comprises the separation material of general formula (II), (VII), (VIII), (IX) or (X) are particularly useful in the extracorporeal removal of CRP from a biological fluid of a patient for prophylaxis and/or treatment of immune dysfunctions and cardiovascular diseases.
- the biological fluid is selected from: blood, blood plasma, peritoneal fluid and lymphatic fluid.
- cardiovascular diseases includes, but it is not limited to infarction, stroke, diabetes, end-stage renal disease, renal insufficiency, renal insufficiency due to hypertension, endothelial lesions, endothelial destruction, arteriosclerosis, thrombosis, atherosclerosis, stenosis, restenosis, atherosclerotic or thrombotic diseases, blood flow insufficiency, ischemic events, pulmonary embolism, stable and unstable angina pectoris, coronary arterial diseases, myocardial infarction, as well as pathologic results of arteriosclerotic or thrombotic diseases.
- immune dysfunctions includes, but it is not limited to immune diseases, autoimmune diseases, rejection reactions in transplantations, allo-transplant rejection, xeno-transplant rejection, graft-versus-host rejection, host-versus-graft rejection, diabetes mellitus, rheumatism, rheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis, multiple sclerosis, myasthenia gravis, psoriasis vulgaris, Graves ' disease, Goodpasture syndrome, idiopathic thrombocytopenia purpura (ITP), aplastic anemia, inflammatory bowel disease (IBD), Crohn's disease (also known as Crohn syndrome), colitis ulcerosa, dilatative cardiomyopathy (DCM), autoimmune thyroiditis, Hashimoto's thyroiditis, hormone replacement therapy (HRT), osteoarthritis and gout.
- ITP idiopathic thrombocytopenia purpura
- IBD inflammatory bowel disease
- Scheme 1 Synthesis of compounds of general formula 5 and 6: a. protection amino group; b. conversion hydroxyl group to a leaving group LG; c. quaternization; d. phosphorylation; e. deprotection.
- the synthesis involves protection of the terminal amino group of the amino alcohol 1 with a protecting group PG 1 , followed by the conversion of the terminal hydroxyl group to a leaving group LG to provide intermediate 3.
- Suitable amino protecting group PG 1 are well known to the skilled person and include carbamates, phthaloyi group and substituted phthaloyi groups.
- carbamates include, but are not restricted to: benzyloxycarbonyl (Cbz or Z), 4-nitro-benzyloxycarbonyl, 4- chloro-benzyloxycarbonyl, 4-methoxy-benzyloxycarbonyl, 4-methyl- benzyloxycarbonyl, 4-azido-benzyloxycarbonyl, 9-fluorenylmethoxy carbonyl (Fmoc), allyloxy carbonyl (Aloe), propargyloxy carbonyl, terf-i utyloxy carbonyl (Boc).
- Phtaloyl and substituted phtaloyl protecting groups are particularly useful for protection of primary amines (R 3 represents H).
- Example of substituted phtaloyl groups include, but are not restricted to 4-nitro-phtaloyl, 3-nitro-phtaloyl and tetrachlorophtaloyl.
- protecting group PG 1 is selected from allyloxy carbonyl, propargyloxy carbonyl, benzyloxycarbonyl and phtaloyl.
- Leaving group LG installed at step b can be selected from the group comprising chloride, bromide, iodide, tosylate, benzensulfonate, p-nitro-benzenesulfonate, mesylate or triflate group.
- the leaving group LG is an ester of a sulfonic acid (i.e.
- LG is a mesylate group.
- the conversion of the alcohol functionality to a group LG can be accomplished for example by treatment of alcohol 2 with MsCI or TsCI in presence of triethylamine, using dicholoromethane as solvent at 0 °C.
- Intermediate 3 is further reacted with an amino alcohol of general formula NHR 1 R 2 -(CH 2 )b-OH, such as dimethylethanolamine, dimethylpropanolamine, ⁇ /,/V-diethylethanolamine, N-(2- hydroxyethyl)morpholine, or A/-(2-hydroxyethyl)piperidine to provide amino alcohol 4 via a quaternization reaction.
- a variety of commercially available amino alcohols of general formula NHR 3 -L 1 -OH (1 ) can function as a starting material for the synthetic pathway described in Scheme 1.
- Such commercially available amino alcohols include, but are not restricted to 2-aminoethanol, 3-amino propan-1 -ol, 4-amino butan-1 -ol, 5-amino pentan-1 -ol, 6-amino hexan-1 -ol, 2-(2-aminoethoxy)ethanol, 2-[2-(2-aminoethoxy)ethoxy]ethanol, 2-(3-aminopropoxy)ethanol.
- propargylic alcohol 3-azido propan-1 -ol, 2-azidoethanol, 4- azidobutan-1 -ol, 2-(2-azidoethoxy)ethanol, 2-[2-(2-azidoethoxy)ethoxy]ethanol, 2- [2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethanol, 2-(2-azidoethylsulfonyl)ethanol, but-3- yn-1 -ol, pent-4-yn-1 -ol, 2-prop-2-ynoxyethanol, 2-(2-prop-2-ynoxyethoxy)ethanol, 2-[2-(2-prop-2-ynoxyethoxy)ethoxy]ethanol can be used as starting materials.
- the synthesis commences with the protection of the amino group on amino acid 9 with a protecting group PG 1 , wherein PG 1 has the meaning defined at the paragraph A.1 to give carboxylic acid 12.
- Coupling of the carboxylic acid 12 with the amino alcohol 10 furnishes primary alcohol 13 on which the hydroxyl group is further converted to leaving group LG, wherein leaving group LG has the defined at the paragraph A.1 to provide intermediate 14.
- Treatment of intermediate 14 with amino alcohol 10 of general formula NHR 1 R 2 -(CH 2 )b-OH e.g.
- Scheme 2 Synthesis of compounds of general formula 7, 8, 18 and 19: a. protection amino group; b. 10, coupling; c. conversion hydroxyl group to a leaving group LG; d. quaternization; e. phosphorylation; f. deprotection; g. 11 , coupling; h. quaternization.
- carboxylic alcohol 12 can be coupled with diamine 11 to provide amide 16 that is subsequently subjected to quaternization reaction by treatment with a 2-hydroxyethyl or 3-hydroxypropyl derivative.
- Suitable 2-hydroxyethyl and 3-hydroxy propyl derivatives include 2-bromo- and 2-iodo-ethanol and 3-bromo and 3-iodo propanol.
- the quaternization reaction is preferably performed in acetonitrile, at room temperature.
- phosphorylation reaction, followed by deprotection reaction applied to alcohol 18 furnishes target compound 19.
- Amino acids 9 of general formula NHR 3 -L 2 -CO 2 H include, but are not restricted to 7-aminoheptanoic acid, 6-aminohexanoic acid, 5-aminopentanoic acid, 4- aminobutanoic acid, 3-aminopropanoic acid, 2-amino acetic acid, 2-[2-(2- aminoethoxy)ethoxy]acetic acid, 2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]acetic acid, 2-(2-aminoethoxy)acetic acid, 2-(3-aminopropoxy)acetic acid, 3-(3- aminopropoxy)propanoic acid, 4-(3-aminopropoxy)butanoic acid, 2- (methylamino)acetic acid, 3-(methylamino)propanoic acid, 4-
- Amino alcohols 10 of general formula NHR 1 R 2 -(CH 2 )b-OH suitable to be used in the synthetic scheme displayed by Scheme 2 include, but are not limited to: 2-aminoethanol, 3-amino propan-1 -ol, 4-amino butan-1 -ol, 5-amino pentan-1 -ol, 6-amino hexan-1 -ol, 2-(2-aminoethoxy)ethanol, 2-[2-(2- aminoethoxy)ethoxy]ethanol, 2-(3-aminopropoxy)ethanol. 3-(3- aminopropoxy)propan-1 -ol, 4-(3-aminopropoxy)butan-1 -ol.
- Example of diamines 11 of general formula H 2 N-L e -NR 1 R 2 that are commercially available include, but are not limited to ethylenediamine; 1 ,3 diaminopropane; /V-methylethylenediamine; 1 ,4-diaminobutane; 3-(methylamino)-propylamine; ⁇ /, ⁇ /'-dimethylethylenediamine; /V-ethylethylenediamine; 3-(dimethylamino)-1 - propylamine; /V-isopropyl-ethylenediamine; /V-propylethylenediamine; hexamethylenediamine; 1 ,2- diaminocyclohexyne; 1 ,4-diaminocyclohexane; and /V-hexylethylenediamine.
- Example of suitable carboxylic acids to be used as starting material for obtaining analogues 7a-7e include, but are not restricted to: 6-thiohexanoic acid, 6-azidohexanoic acid, 5-thiopentanoic acid, 5-azidopentanoic acid, 4-thiobutanoic acid, 4-azidobutanoic acid, 3-thiopropanoic acid,
- diamines of general formula R 3 HN-L 4 -NR 1 R 2 (20) can be successfully used for accessing compounds of general formula I, wherein X represents -NHR 3 , R 3 is selected from: -H, -CH 3 , -C 2 H 5 , -C 3 H 7 and -L- represents -L a - (see Scheme 3).
- Diamines 20 can be commercially available (e.g. A/,/V-dimethyl-1 ,3-propanediamine) or can be easily obtained for example starting from the corresponding halogeno derivatives via a two steps synthetic including conversion of the halogeno derivatives to the azido derivatives and reduction of the azido derivatives to the corresponding primary amines.
- the compounds of general formula 24 can be accessed in four steps including protection of the primary of secondary amine with protecting group PG 1 wherein PG 1 has the meaning defined at paragraph A.1 , quaternization of the tertiary amine by treatment with an appropriate 2-hydroxyethyl or 3-hydroxypropyl derivative, followed by phosphorylation and deprotection of the primary or secondary amine.
- Scheme 3 Synthesis of compounds of general formula 24: a. protection amino group; b. quaternization; c. phosphorylation; d. deprotection.
- the separation material of general formula (II) can be prepared by coupling the compounds of general formula (I) with a solid support A functionalized with a moiety -L*-FG, wherein FG is a functional group that is suitable to react with the functional group X.
- Scheme 4 summarizes different coupling methodologies that can be employed to access the separation materials of general formula (II).
- the compounds of general formula (I), wherein X is selected from -SH, -OH, and -NHR 3 are coupled to a solid support A via epoxide ring opening (see Scheme 5 a, b).
- a notable variant of the Huisgen 1 ,3-dipolar cycloaddition is the copper(l) catalyzed variant, in which organic azides and terminal alkynes are united to afford 1 ,4-regioisomers of 1 ,2,3- triazoles as sole products.
- This reaction is termed the copper(l)-catalyzed Azide- Alkyne Cycloaddition (CuAAC).
- CuAAC Copper(l)-catalyzed Azide- Alkyne Cycloaddition
- the reaction can be performed using commercial sources of copper(l) such as cuprous bromide or iodide. However, the reaction works much better using a mixture of copper (II) (e.g. copper(ll) sulfate) and a reducing agent (e.g. sodium ascorbate) to produce in situ Cu(l).
- the reaction can be run in a variety of solvents and mixtures of water and a variety of (partially) miscible organic solvents including alcohols, DMSO, DMF, f-BuOH, dioxane, acetone and mixtures thereof.
- the reaction can be catalyzed by ruthenium.
- the ruthenium-catalyzed 1 ,3-dipolar azide-alkyne cycloaddition (RuAAC) gives 1 ,5-triazoles.
- azide-alkyne cycloaddition separation materials of general formula (II), wherein Y is selected from:
- Separation materials of general formula (II), wherein Y is selected from -CH 2 -NH- and -NH-CH 2 - can be prepared by reductive amination using for example NaBH as reductant, starting from compounds of general formula (I), wherein X is -NH 2 or -CH(O) and solid supports functionalized A with a moiety -L * -FG, wherein functional group FG represents -CH(O) and -NH 2 , respectively (see Scheme 4 f, g).
- the resulting solution was cooled to 0 °C on ice/salt bath and a mixture of N,N-dimethyl-1 ,3-propanediamine (25.55 g, 0.25 mol) and triethylamine (55.65 g, 0.55 mol ) was added dropwise with stirring and cooling during 2 h.
- the reaction mixture was stirred for 6 h and the progress of the reaction was monitored by TLC and LC-MS.
- the precipitate was filtered, washed with a small volume of dichloromethane.
- Example 5 Synthesis of 3-[6-(benzyloxycarbonylamino)hexanoylamino]propyl-(2- hydroxyethyl)-dimethyl-ammonium bromide 5*).
- the target compound was obtained after pumping out the trace solvent in vacuum as viscous oil (5*, 66.3 g, 87.2% as bromide salt).
- the product was homogeneous by LC/MS and TLC, and was used in the phosphorylation step with no further purification. MS m/z 394.1 M + (394.27 calculated).
- 2-(2-aminoethoxy)ethanol 25.23 g, 0.240 mol was dissolved in 530 mL of 10% triethylamine in MeOH (48 ml, 0.345 mol of triethylamine, 480 ml of methanol) and cooled to 0 °C.
- Benzyl chloroformate technical grade, 95%, 34.4 ml, 0.229 mol was added all at once, and the reaction was allowed to warm to room temperature.
- Example 8 Synthesis of 2-[2-[6-(benzyloxycarbonylamino) hexanoylamino]ethoxy] ethyl methanesulfonate (8*).
- a 1 L three-neck round bottom flask equipped with a mechanical stirrer, a nitrogen inlet-outlet, and a Dean-Stark trap topped by a reflux condenser was charged a solution of phthalic anhydride (88.87 g, 0.6 mol) and 2-(2-aminoethoxy)ethanol (63.08 g, 0.6 mol) in toluene (540 ml).
- the reaction mixture was refluxed until 1 equiv of water was collected in the Dean-Stark trap (approximately 24 h).
- Example 12 Synthesis of 2-[2-(1 ,3-dioxoisoindolin-2-yl)ethoxy]ethyl methanesulfonate (12*).
- This example illustrates a method for preparation of methanesulfonate ester of N- protected 2-(2-aminoethoxy)ethanol.
- Example 14 Synthesis of 2-[2-(1,3-dioxoisoindolin-2-yl)ethoxy]ethyl-(3- hydroxypropyl)-dimethyl-ammonium methanesulfonic acid salt (14*).
- Example 15 Epoxy-activation of Sepharose 6B.
- Sepharose 6B (GE Healthcare Life Sciences) was washed on a glass filter-funnel with 3 x 1000 ml portions of water and suction-dried. Then one hundred gram of suction-dried Sepharose 6B was mixed with 100 ml of 1 ,4-butanediol diglycidyl ether (CAS N° 2425-79-8) and 100 ml of 0.6 M sodium hydroxide solution containing 2 mg of sodium borohydride per milliliter. The suspension was mixed by rotation for 8 h at room temperature and the reaction was stopped by washing of the gel on a glass filter-funnel with 10 x 400 ml portions of hot (40 - 60 °C) water. The oxirane content of the gel was 67 ⁇ /g of suction-dried gel.
- Example 16 Assay for determining the number of epoxy-groups.
- the epoxy-activated Sepharose 6B is reacted with mercaptoacetic acid and the number of acidic groups introduced is determined by titration according to a method described in Scoble, JA and Scopes, RK Journal of Chromatography A, 1996, 752, 67.
- Example 15 Ten grams of suction-dried epoxy-activated Sepharose 6B (example 15) was added into a 50 ml 1 M solution of sodium azide in water. The mixture was incubated on a laboratory rotating mixer 24 h at room temperature. The gel was washed with 4 x 100 ml of water and kept in 20% (v/v) ethanol until further use.
- xample 18 Assay for determining the number of azido-groups.
- Azido groups of azido Sepharose 6B were quantitatively reduced to amino groups by reaction with DTT (Handlon, AL and Oppenheimer, NJ, Pharmaceutical Research 1988, 5, 297.) and the resulting amino groups were quantified with TNBS according to published procedure (Antoni, G et al. Analytical Biochemistry 1983, 129, 60). The method is based on the reaction of the matrix with excess 2,4,6-trinitrobenzenesulfonic acid (TNBS) and subsequent quantitative determination of unreacted TNBS by reaction with glycine.
- Example 19 Determination of free primary amino groups by spectrophotometric method.
- the amount of primary amino groups was directly quantitated using a standard curve generated after reaction of L-glutamic acid with o-phthaldehyde and N-acetyl-L-cysteine at room temperature and pH 9.5 (Medina Hernandez, MJ et al. Microchemical Journal 1990, 42, 288). N-acetyl-L-cysteine derivatives are highly stable and not requiring a strict control of the time of reaction unlike to 2-metcaptoethanol. The relationship between UV absorbance at 335 nm and concentration of amino-groups was found to be linear.
- Example 20 Determination of free secondary amino groups by spectrophotometric method.
- Example 21 Immobilization of 2-[3-aminopropyl(dimethyl)ammonio]ethyl hydrogen phosphate on epoxy-activated of Sepharose 6B (Separation material 1).
- Example 15 Twenty grams of suction-dried epoxy-activated Sepharose 6B (example 15) were added into a solution of 2-[3-aminopropyl(dimethyl)ammonio]ethyl hydrogen phosphate (40 ml). pH of the resulting suspension was adjusted to 1 1 .0 with 1 M sodium hydroxide solution. The mixture was incubated on a laboratory rotating mixer 24 h at room temperature. The gel was washed with 4 x 100 ml of autoclaved water and kept in 20% (v/v) ethanol until further use.
- Example 22 Immobilization of 2-[3-(6-aminohexanoylamino)propyl-dimethyl- ammonio]ethyl hydrogen phosphate on epoxy-activated of Sepharose 6B (Separation material 2).
- Example 15 Twenty grams of suction-dried epoxy-activated Sepharose 6B (example 15) were added into a solution of 2-[3-(6-aminohexanoylamino)propyl-dimethyl-ammonio]ethyl hydrogen phosphate (40 ml). pH of the resulting suspension was adjusted to 1 1 .0 with 1 M sodium hydroxide solution. The mixture was incubated on a laboratory rotating mixer 24 h at room temperature. The gel was washed with 4 x 100 ml of autoclaved water and kept in 20% (v/v) ethanol until further use.
- Example 23 Immobilization of 2-[2-[2-(6-aminohexanoylamino)ethoxy]ethyl- dimethyl-ammonio]ethyl hydrogen phosphate on epoxy-activated of Sepharose 6B (Separation material 3).
- Example 15 Twenty grams of suction-dried epoxy-activated Sepharose 6B (example 15) were added into a solution of 2-[2-[2-(6-aminohexanoylamino)ethoxy]ethyl-dimethyl-ammonio]ethyl hydrogen phosphate (40 ml). The pH of the resulting suspension was adjusted to 1 1 .0 with 1 M sodium hydroxide solution. The mixture was incubated on a laboratory rotating mixer 24 h at room temperature. The gel was washed with 4 x 100 ml of autoclaved water and kept in 20% (v/v) ethanol until further use.
- Example 24 Immobilization of 2-[2-(2-aminoethoxy)ethyl-dimethyl-ammonio]ethyl hydrogen phosphate on epoxy-activated of Sepharose 6B (Separation material 4).
- Example 15 Twenty grams of suction-dried epoxy-activated Sepharose 6B (example 15) was added into a solution of 2-[2-(2-aminoethoxy)ethyl-dimethyl-ammonio]ethyl hydrogen phosphate (40 ml). pH of the resulting suspension was adjusted to 1 1 .0 with 1 M sodium hydroxide solution. The mixture was incubated on a laboratory rotating mixer 24 h at room temperature. The gel was washed with 4 x 100 ml of autoclaved water and kept in 20% (v/v) ethanol until further use.
- Example 25 Immobilization of 3-[2-(2-aminoethoxy)ethyl-dimethyl- ammonio]propyl hydrogen phosphate on epoxy-activated of Sepharose 6B (Separation material 5).
- Example 15 Twenty grams of suction-dried epoxy-activated Sepharose 6B (example 15) was added into a solution of 3-[2-(2-aminoethoxy)ethyl-dimethyl-ammonio]propyl hydrogen phosphate (40 ml). pH of the resulting suspension was adjusted to 1 1 .0 with 1 M sodium hydroxide solution. The mixture was incubated on a laboratory rotating mixer 24 h at room temperature. The gel was washed with 4 x 100 ml of autoclaved water and kept in 20% (v/v) ethanol until further use.
- Example 26 Comparative example
- Example 15 Twenty grams of suction-dried epoxy-activated Sepharose 6B (example 15) was added into a solution of (4-aminophenyl) 2-(trimethylammonio)ethyl phosphate (4.41 g in 40 ml of water). pH of the resulting suspension was adjusted to 1 1 .5 with 1 M sodium hydroxide solution. The mixture was incubated on a laboratory rotating mixer 24 h at room temperature. The gel was washed with 4 x 100 ml of autoclaved water and kept in 20% (v/v) ethanol until further use.
- Binding and washing buffer 100 mM Tris, pH 8,0, 200 mM sodium chloride, 2 mM calcium chloride.
- Elution buffer 100 mM Tris, pH 8,0, 200 mM sodium chloride, 2 mM EDTA.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Biomedical Technology (AREA)
- Analytical Chemistry (AREA)
- Cardiology (AREA)
- Rheumatology (AREA)
- Endocrinology (AREA)
- Physical Education & Sports Medicine (AREA)
- Vascular Medicine (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Neurology (AREA)
- Mechanical Engineering (AREA)
- Materials Engineering (AREA)
- Polymers & Plastics (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Neurosurgery (AREA)
- Emergency Medicine (AREA)
- Reproductive Health (AREA)
Abstract
Description
Claims
Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP15729863.9A EP3041852B1 (en) | 2014-06-19 | 2015-06-19 | Separation material comprising phosphoryl choline derivatives |
PL15729863T PL3041852T3 (en) | 2014-06-19 | 2015-06-19 | Separation material comprising phosphoryl choline derivatives |
CN201580032919.1A CN106459108B (en) | 2014-06-19 | 2015-06-19 | Separation material comprising Phosphorylcholine derivative |
RU2017101500A RU2666357C2 (en) | 2014-06-19 | 2015-06-19 | Separation material comprising phosphoryl choline derivatives |
KR1020177000206A KR101971958B1 (en) | 2014-06-19 | 2015-06-19 | Separation material comprising phosphoryl choline derivatives |
CA2952713A CA2952713C (en) | 2014-06-19 | 2015-06-19 | Separation material comprising phosphoryl choline derivatives |
US15/319,782 US10065133B2 (en) | 2014-06-19 | 2015-06-19 | Separation material comprising phosphoryl choline derivatives |
ES15729863.9T ES2636484T3 (en) | 2014-06-19 | 2015-06-19 | Separation material comprising phosphoryl choline derivatives |
JP2017518600A JP6416392B2 (en) | 2014-06-19 | 2015-06-19 | Separating substances containing phosphorylcholine derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP14173195.0 | 2014-06-19 | ||
EP14173195.0A EP2957563A1 (en) | 2014-06-19 | 2014-06-19 | Separation material comprising phosphoryl choline derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2015193504A1 true WO2015193504A1 (en) | 2015-12-23 |
Family
ID=50976502
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2015/063887 WO2015193504A1 (en) | 2014-06-19 | 2015-06-19 | Separation material comprising phosphoryl choline derivatives |
Country Status (10)
Country | Link |
---|---|
US (1) | US10065133B2 (en) |
EP (2) | EP2957563A1 (en) |
JP (1) | JP6416392B2 (en) |
KR (1) | KR101971958B1 (en) |
CN (1) | CN106459108B (en) |
CA (1) | CA2952713C (en) |
ES (1) | ES2636484T3 (en) |
PL (1) | PL3041852T3 (en) |
RU (1) | RU2666357C2 (en) |
WO (1) | WO2015193504A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109865505A (en) * | 2017-12-05 | 2019-06-11 | 中国科学院大连化学物理研究所 | A kind of biomass derived carbon application type chromatographic stationary phases and its preparation and application |
JP7425609B2 (en) * | 2020-01-17 | 2024-01-31 | 第一工業製薬株式会社 | Polyurethane or polyurethaneurea, antithrombotic coating agent, antithrombotic medical device, and manufacturing method |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990012632A1 (en) * | 1989-04-19 | 1990-11-01 | The United States Of America, Represented By The Secretary, United States Department Of Commerce | Process for removing c-reactive protein and anti-phosphorylcholine antibodies from biological fluids |
WO2007076844A1 (en) * | 2005-12-22 | 2007-07-12 | Beta V3 Gmbh | Use of a matrix for removing c-reactive protein from biological liquids |
WO2012160187A1 (en) * | 2011-05-26 | 2012-11-29 | Jado Technologies Gmbh | Amino- or ammonium-containing sulfonic acid, phosphonic acid and carboxylic acid derivatives and their medical use |
WO2013176084A1 (en) * | 2012-05-22 | 2013-11-28 | 日産化学工業株式会社 | Silane coupling agent containing silylalkyl phosphoramidate compound |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4181634A (en) * | 1977-06-17 | 1980-01-01 | Johnson & Johnson | Mild cleansing compositions comprising an alkyleneoxylated bisquaternary ammonium compound and an anionic or amphoteric detergent such as a phosphobetaine |
US4681870A (en) | 1985-01-11 | 1987-07-21 | Imre Corporation | Protein A-silica immunoadsorbent and process for its production |
JPH085904B2 (en) * | 1986-05-02 | 1996-01-24 | オリエンタル酵母工業株式会社 | Method for producing new phosphorylcholine derivative |
KR20010085485A (en) * | 2000-02-29 | 2001-09-07 | 추후제출 | Method for measuring C-creative protein and regent thereof |
GB0211136D0 (en) * | 2002-05-15 | 2002-06-26 | Univ London | Treatment and prevention of tissue damage |
CN101415727A (en) * | 2006-04-07 | 2009-04-22 | 莫德普罗股份公司 | Binder for C-reactive protein |
RU2325171C1 (en) * | 2007-01-09 | 2008-05-27 | Михаил Борисович Раев | Method of trophoblastic beta-1-glycoprotein release and purification |
JP5353020B2 (en) * | 2007-07-26 | 2013-11-27 | 株式会社リコー | Image forming apparatus |
CN101134764A (en) * | 2007-10-18 | 2008-03-05 | 重庆医科大学 | Method for synthesizing target compound-ligustrazine derivant preventing cerebrovascular disease |
CN102912640B (en) * | 2012-10-25 | 2014-06-25 | 上虞市皇马化学有限公司 | Crude-oil polyester industrial yarn finish and preparation method thereof |
-
2014
- 2014-06-19 EP EP14173195.0A patent/EP2957563A1/en not_active Withdrawn
-
2015
- 2015-06-19 WO PCT/EP2015/063887 patent/WO2015193504A1/en active Application Filing
- 2015-06-19 JP JP2017518600A patent/JP6416392B2/en active Active
- 2015-06-19 US US15/319,782 patent/US10065133B2/en active Active
- 2015-06-19 CA CA2952713A patent/CA2952713C/en active Active
- 2015-06-19 ES ES15729863.9T patent/ES2636484T3/en active Active
- 2015-06-19 RU RU2017101500A patent/RU2666357C2/en active
- 2015-06-19 PL PL15729863T patent/PL3041852T3/en unknown
- 2015-06-19 CN CN201580032919.1A patent/CN106459108B/en active Active
- 2015-06-19 EP EP15729863.9A patent/EP3041852B1/en active Active
- 2015-06-19 KR KR1020177000206A patent/KR101971958B1/en active IP Right Grant
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990012632A1 (en) * | 1989-04-19 | 1990-11-01 | The United States Of America, Represented By The Secretary, United States Department Of Commerce | Process for removing c-reactive protein and anti-phosphorylcholine antibodies from biological fluids |
WO2007076844A1 (en) * | 2005-12-22 | 2007-07-12 | Beta V3 Gmbh | Use of a matrix for removing c-reactive protein from biological liquids |
WO2012160187A1 (en) * | 2011-05-26 | 2012-11-29 | Jado Technologies Gmbh | Amino- or ammonium-containing sulfonic acid, phosphonic acid and carboxylic acid derivatives and their medical use |
WO2013176084A1 (en) * | 2012-05-22 | 2013-11-28 | 日産化学工業株式会社 | Silane coupling agent containing silylalkyl phosphoramidate compound |
Non-Patent Citations (3)
Title |
---|
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 1980, "Betaine derivatives", XP002732939, retrieved from STN Database accession no. 1980:200147 * |
DATABASE CA [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 2013, JIN, YIFENG ET AL: "Oiling agent for industrial polyester filament and its manufacture", XP002732938, retrieved from STN Database accession no. 2013:209183 * |
MARTIN L M: "Facile Reduction in the Synthesis of Phosphorylcholine Affinity Columns", TETRAHEDRON LETTERS, PERGAMON, GB, vol. 37, no. 44, 28 October 1996 (1996-10-28), pages 7921 - 7924, XP004031006, ISSN: 0040-4039, DOI: 10.1016/0040-4039(96)01797-2 * |
Also Published As
Publication number | Publication date |
---|---|
RU2017101500A3 (en) | 2018-07-19 |
KR101971958B1 (en) | 2019-04-24 |
EP3041852A1 (en) | 2016-07-13 |
CN106459108A (en) | 2017-02-22 |
CA2952713A1 (en) | 2015-12-23 |
RU2017101500A (en) | 2018-07-19 |
JP2017526732A (en) | 2017-09-14 |
CA2952713C (en) | 2020-08-11 |
RU2666357C2 (en) | 2018-09-07 |
KR20170020842A (en) | 2017-02-24 |
CN106459108B (en) | 2019-10-15 |
EP3041852B1 (en) | 2017-05-31 |
PL3041852T3 (en) | 2017-10-31 |
US10065133B2 (en) | 2018-09-04 |
US20170120163A1 (en) | 2017-05-04 |
JP6416392B2 (en) | 2018-10-31 |
EP2957563A1 (en) | 2015-12-23 |
ES2636484T3 (en) | 2017-10-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Kiuchi et al. | Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1, 3-diols and 2-aminoethanols | |
JP4869247B2 (en) | Mixed anion exchange separation material | |
JP5404655B2 (en) | New chiral selector and stationary phase for separation of enantiomeric mixtures | |
JP2022106974A (en) | Carbamoyloxymethyl triazole cyclohexyl acids as lpa antagonists | |
CN103562200A (en) | Novel imidazole derivatives useful for the treatment of arthritis | |
JP2008509897A (en) | Enantioselective production method | |
KR20140106750A (en) | Benzyl sulfonamide derivatives useful as mogat-2 inhibitors | |
US7666906B2 (en) | β-Benzyloxyaspartate derivatives with amino group on benzene ring | |
EP3041852B1 (en) | Separation material comprising phosphoryl choline derivatives | |
UA119805C2 (en) | Hydroxyalkyl-piperazine derivatives as cxcr3 receptor modulators | |
JP5647231B2 (en) | Process for the preparation of amphiphilic nitrogen-containing imidazolinium derivative compounds | |
WO2004025297A1 (en) | Method of inhibiting nonspecific interaction between molecules on solid phase support | |
KR19990075668A (en) | Chiral stationary phase and LC-filled chiral column for LC for optical division of racemic compounds having a primary amino group | |
JP2001500484A (en) | Method for producing pharmaceutical compounds | |
JP2006522332A (en) | Production method of affinity ligand | |
JP3595025B2 (en) | Vitamin D3 derivative and method for producing the same | |
JP2006182696A (en) | beta-BENZYLOXYASPARTIC ACID DERIVATIVE BEARING TWO SUBSTITUENTS ON BENZENE RING | |
US20060199950A1 (en) | Preparation of a metal chelating separation medium | |
JP2006516928A (en) | Compositions and methods for separating amines and amino acids from their enantiomers | |
JPS63264536A (en) | Separation agent | |
Kaushik | Synthesis of cyclen based receptors and their use in separations biotechnology. | |
JPH0429958A (en) | Production of optically active alpha-aromatic group-substituted propionic acid derivative | |
JPS5963565A (en) | Chromatograph filler and analyzing method of mixture of enantiomer using chromatograph filler | |
KR20030001171A (en) | Chiral stationary phase and chiral LC column for optical resolution of racemic compounds | |
JP2013540728A (en) | Synthesis of tripod catechol derivatives with adamantyl basic structure for surface functionalization |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 15729863 Country of ref document: EP Kind code of ref document: A1 |
|
REEP | Request for entry into the european phase |
Ref document number: 2015729863 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2015729863 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2952713 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15319782 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: 2017518600 Country of ref document: JP Kind code of ref document: A |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 20177000206 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2017101500 Country of ref document: RU Kind code of ref document: A |