KR101486449B1 - 다작용성 형태의 폴리옥시졸린 공중합체 및 이를 포함하는 약물 조성물 - Google Patents
다작용성 형태의 폴리옥시졸린 공중합체 및 이를 포함하는 약물 조성물 Download PDFInfo
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- KR101486449B1 KR101486449B1 KR1020107017208A KR20107017208A KR101486449B1 KR 101486449 B1 KR101486449 B1 KR 101486449B1 KR 1020107017208 A KR1020107017208 A KR 1020107017208A KR 20107017208 A KR20107017208 A KR 20107017208A KR 101486449 B1 KR101486449 B1 KR 101486449B1
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- polyoxazoline
- unsubstituted
- rti
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- 229920000765 poly(2-oxazolines) Polymers 0.000 title claims description 114
- 239000000203 mixture Substances 0.000 title abstract description 54
- 239000003814 drug Substances 0.000 title abstract description 8
- 229940079593 drug Drugs 0.000 title description 2
- 125000000524 functional group Chemical group 0.000 claims abstract description 132
- -1 2-substituted 2-oxazolines Chemical class 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 27
- 229920005604 random copolymer Polymers 0.000 claims abstract description 14
- 229920001400 block copolymer Polymers 0.000 claims abstract description 11
- 230000008685 targeting Effects 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 150000001412 amines Chemical class 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000003342 alkenyl group Chemical group 0.000 claims description 18
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 18
- 125000002947 alkylene group Chemical group 0.000 claims description 17
- 150000001735 carboxylic acids Chemical class 0.000 claims description 17
- 125000005647 linker group Chemical group 0.000 claims description 17
- 150000002148 esters Chemical class 0.000 claims description 16
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 14
- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- 150000001299 aldehydes Chemical class 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 150000001298 alcohols Chemical class 0.000 claims description 10
- 150000001345 alkine derivatives Chemical class 0.000 claims description 10
- 150000002576 ketones Chemical class 0.000 claims description 10
- 230000001225 therapeutic effect Effects 0.000 claims description 10
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims description 9
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 9
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 claims description 8
- 230000000977 initiatory effect Effects 0.000 claims description 7
- 150000001540 azides Chemical class 0.000 claims description 6
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical class C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical class ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 230000000269 nucleophilic effect Effects 0.000 claims description 4
- 150000003457 sulfones Chemical class 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 150000003923 2,5-pyrrolediones Chemical class 0.000 claims 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical class O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims 2
- 150000002019 disulfides Chemical class 0.000 claims 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical class OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 1
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 229920005862 polyol Polymers 0.000 claims 1
- 150000003077 polyols Chemical class 0.000 claims 1
- 229920000642 polymer Polymers 0.000 abstract description 49
- 229920001577 copolymer Polymers 0.000 abstract description 6
- 229940124597 therapeutic agent Drugs 0.000 abstract description 4
- 229940039227 diagnostic agent Drugs 0.000 abstract description 3
- 239000000032 diagnostic agent Substances 0.000 abstract description 3
- 230000001268 conjugating effect Effects 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 60
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 33
- 125000000623 heterocyclic group Chemical group 0.000 description 28
- 238000006116 polymerization reaction Methods 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 150000001875 compounds Chemical class 0.000 description 24
- 239000000843 powder Substances 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 125000004434 sulfur atom Chemical group 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 239000000178 monomer Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 125000004430 oxygen atom Chemical group O* 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 description 11
- NYEZZYQZRQDLEH-UHFFFAOYSA-N 2-ethyl-4,5-dihydro-1,3-oxazole Chemical compound CCC1=NCCO1 NYEZZYQZRQDLEH-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 230000007062 hydrolysis Effects 0.000 description 10
- 238000006460 hydrolysis reaction Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000000816 matrix-assisted laser desorption--ionisation Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 239000003999 initiator Substances 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 229920002271 DEAE-Sepharose Polymers 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 150000001768 cations Chemical class 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000004255 ion exchange chromatography Methods 0.000 description 7
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 7
- 229960004768 irinotecan Drugs 0.000 description 7
- 125000005936 piperidyl group Chemical group 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical group C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 229920002684 Sepharose Polymers 0.000 description 6
- 125000005677 ethinylene group Chemical class [*:2]C#C[*:1] 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 125000003107 substituted aryl group Chemical group 0.000 description 6
- MNUUNDKDTPELEI-UHFFFAOYSA-N 2-pent-4-ynyl-4,5-dihydro-1,3-oxazole Chemical compound C#CCCCC1=NCCO1 MNUUNDKDTPELEI-UHFFFAOYSA-N 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 5
- 239000002480 mineral oil Substances 0.000 description 5
- 235000010446 mineral oil Nutrition 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000007334 copolymerization reaction Methods 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000005342 ion exchange Methods 0.000 description 4
- 125000005439 maleimidyl group Chemical class C1(C=CC(N1*)=O)=O 0.000 description 4
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000003396 thiol group Chemical group [H]S* 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 150000001241 acetals Chemical class 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 229920001429 chelating resin Polymers 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- LDTLDBDUBGAEDT-UHFFFAOYSA-N methyl 3-sulfanylpropanoate Chemical compound COC(=O)CCS LDTLDBDUBGAEDT-UHFFFAOYSA-N 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 125000005981 pentynyl group Chemical group 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 230000004962 physiological condition Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 150000003852 triazoles Chemical class 0.000 description 3
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 2
- GUXJXWKCUUWCLX-UHFFFAOYSA-N 2-methyl-2-oxazoline Chemical group CC1=NCCO1 GUXJXWKCUUWCLX-UHFFFAOYSA-N 0.000 description 2
- 125000003504 2-oxazolinyl group Chemical group O1C(=NCC1)* 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical compound NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108091034117 Oligonucleotide Proteins 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 150000003973 alkyl amines Chemical group 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 description 2
- 150000004982 aromatic amines Chemical group 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- PYMCWVIXPLQKHO-UHFFFAOYSA-N azido hexanoate Chemical compound CCCCCC(=O)ON=[N+]=[N-] PYMCWVIXPLQKHO-UHFFFAOYSA-N 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 2
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000005266 diarylamine group Chemical group 0.000 description 2
- 239000012039 electrophile Substances 0.000 description 2
- DZIYAIZKJOHVQC-KLXURFKVSA-N ethyl (2s)-2,6-diaminohexanoate;dihydrochloride Chemical compound Cl.Cl.CCOC(=O)[C@@H](N)CCCCN DZIYAIZKJOHVQC-KLXURFKVSA-N 0.000 description 2
- 229960002442 glucosamine Drugs 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 150000003949 imides Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
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- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
- C08G73/02—Polyamines
- C08G73/0233—Polyamines derived from (poly)oxazolines, (poly)oxazines or having pendant acyl groups
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
- C08G73/06—Polycondensates having nitrogen-containing heterocyclic rings in the main chain of the macromolecule
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
- C08G73/02—Polyamines
- C08G73/028—Polyamidoamines
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
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- Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Animal Behavior & Ethology (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Physics & Mathematics (AREA)
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- Cell Biology (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)
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| PCT/US2009/030762 WO2009089542A2 (en) | 2008-01-11 | 2009-01-12 | Multifunctional forms of polyoxazoline copolymers and drug compositions comprising the same |
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| US8101706B2 (en) | 2008-01-11 | 2012-01-24 | Serina Therapeutics, Inc. | Multifunctional forms of polyoxazoline copolymers and drug compositions comprising the same |
| US8110651B2 (en) * | 2008-01-11 | 2012-02-07 | Serina Therapeutics, Inc. | Multifunctional forms of polyoxazoline copolymers and drug compositions comprising the same |
| EP2310440A4 (en) * | 2008-07-10 | 2013-06-05 | Serina Therapeutics Inc | POLYOXAZOLINES WITH INTERNAL END GROUPS, POLYOXAZOLINES MANUFACTURED FROM PROTECTED INITIAL GROUPS AND CORRESPONDING COMPOUNDS |
| BR112013017140B1 (pt) | 2011-01-04 | 2019-12-17 | Bender Analytical Holding Bv | polímeros reticulados e implantes provenientes de polioxazolina eletrofilicamente ativada |
| CN102731791B (zh) * | 2011-04-13 | 2016-04-13 | 北京大学 | 温度敏感型嵌段共聚物及其水凝胶和其用途 |
| US20140271527A1 (en) * | 2011-11-01 | 2014-09-18 | Serina Therapeutics, Inc. | Subcutaneous delivery of polymer conjugates of therapeutic agents |
| US8383093B1 (en) * | 2011-11-01 | 2013-02-26 | Serina Therapeutics, Inc. | Subcutaneous delivery of poly(oxazoline) conjugates |
| BR112014016338B1 (pt) * | 2012-01-02 | 2021-01-26 | Universiteit Gent | polímeros de polioxazolina e processos para a sua preparação, conjugados destes polímeros e usos médicos dos mesmos |
| US9416228B2 (en) | 2012-03-16 | 2016-08-16 | Bender Analytical Holding B.V. | Cross-linked polymers and medical products derived from nucleophilically activated polyoxazoline |
| US10035822B2 (en) | 2012-11-15 | 2018-07-31 | Apellis Pharmaceuticals, Inc. | Cell-reactive, long-acting, or targeted compstatin analogs and related compositions and methods |
| US10071168B2 (en) | 2014-07-31 | 2018-09-11 | Serina Therapeutics, Inc. | Polyoxazoline antibody drug conjugates |
| EP3197940B1 (en) | 2014-09-26 | 2023-02-15 | Alcon Inc. | Polymerizable polysiloxanes with hydrophilic substituents |
| JP6683398B2 (ja) | 2014-10-06 | 2020-04-22 | ガット テクノロジーズ ビー．ブイ．Ｇａｔｔ Ｔｅｃｈｎｏｌｏｇｉｅｓ Ｂ．Ｖ． | 組織接着性多孔質止血製品 |
| KR20180090785A (ko) | 2015-10-07 | 2018-08-13 | 아펠리스 파마슈티컬스 인코포레이티드 | 투여 요법 |
| CN105418911A (zh) * | 2015-12-29 | 2016-03-23 | 南京工业大学 | 一种聚(2-r-2-噁唑啉)嵌段聚(肌氨酸)双亲性嵌段共聚物的制备方法 |
| BR112019020955A2 (pt) | 2017-04-07 | 2020-05-05 | Apellis Pharmaceuticals, Inc. | regimes de dosagem e composições e métodos relacionados |
| DE102018000650A1 (de) * | 2018-01-27 | 2019-08-01 | Friedrich-Schiller-Universität Jena | Verfahren zur Bestimmung von Verunreinigungen in Polyalkylenethern oder Polyalkylenaminen und dessen Verwendung |
| CN120154736A (zh) * | 2018-07-27 | 2025-06-17 | 塞瑞纳治疗阿拉巴马公司 | 儿茶酚化合物和水溶性聚合物的可裂解缀合物以及使用它们的治疗方法 |
| US12485181B2 (en) * | 2019-06-28 | 2025-12-02 | Serina Therapeutics (Al), Inc. | Polyoxazoline-drug conjugates with novel pharmacokinetic properties |
| CN113354811B (zh) * | 2020-02-19 | 2024-05-07 | 华东理工大学 | 一种侧链含有氨基和/或羟基的噁唑啉聚合物，其制备方法及应用 |
| CN112661961B (zh) * | 2020-12-28 | 2022-05-06 | 中国科学院长春应用化学研究所 | 两亲性聚噁唑啉共聚物、其制备方法及应用 |
| WO2022173667A1 (en) | 2021-02-09 | 2022-08-18 | Serina Therapeutics, Inc. | Polyoxazoline-lipid conjugates and lipid nanoparticles and pharmaceutical compositions including same |
| IL309502A (en) | 2021-09-03 | 2024-02-01 | CureVac SE | Lipid nanoparticles for nucleic acid delivery involving phosphatidylserine |
| EP4763287A2 (en) | 2021-09-03 | 2026-06-24 | CureVac SE | Novel lipid nanoparticles for delivery of nucleic acids |
| KR20230044782A (ko) | 2021-09-27 | 2023-04-04 | 삼성전자주식회사 | 패치 안테나를 포함하는 안테나 구조 및 이를 포함하는 전자 장치 |
| EP4422698A1 (en) | 2021-10-29 | 2024-09-04 | CureVac SE | Improved circular rna for expressing therapeutic proteins |
| EP4469091A1 (en) | 2022-01-28 | 2024-12-04 | CureVac SE | Nucleic acid encoded transcription factor inhibitors |
| KR20250153298A (ko) | 2023-03-08 | 2025-10-24 | 큐어백 에스이 | 핵산 전달을 위한 신규의 지질 나노입자 제형 |
| WO2024230934A1 (en) | 2023-05-11 | 2024-11-14 | CureVac SE | Therapeutic nucleic acid for the treatment of ophthalmic diseases |
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| US8110651B2 (en) * | 2008-01-11 | 2012-02-07 | Serina Therapeutics, Inc. | Multifunctional forms of polyoxazoline copolymers and drug compositions comprising the same |
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- 2009-01-12 DK DK16154587.6T patent/DK3042922T3/en active
- 2009-01-12 WO PCT/US2009/030762 patent/WO2009089542A2/en not_active Ceased
- 2009-01-12 EP EP13181892.4A patent/EP2669313B1/en active Active
- 2009-01-12 KR KR1020107017208A patent/KR101486449B1/ko active Active
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- 2009-01-12 EP EP16154587.6A patent/EP3042922B1/en active Active
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2012
- 2012-02-06 US US13/367,128 patent/US9169354B2/en active Active
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| US4709039A (en) | 1986-03-21 | 1987-11-24 | The Dow Chemical Company | Vinyloxazoline monomer and preparation thereof |
| US20060051315A1 (en) | 2002-02-01 | 2006-03-09 | Scaria Puthupparampil V | Polymers for delivering peptides and small molecules in vivo |
| JP2003268391A (ja) | 2002-03-13 | 2003-09-25 | Infineum Internatl Ltd | 粒状物トラップを備えるディーゼルエンジン用燃料添加剤組成物 |
| JP2005082810A (ja) | 2003-09-05 | 2005-03-31 | Infineum Internatl Ltd | 安定化ディーゼル燃料添加剤組成物 |
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| US20110009594A1 (en) | 2011-01-13 |
| EP3042922B1 (en) | 2017-07-19 |
| WO2009089542A2 (en) | 2009-07-16 |
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| US9169354B2 (en) | 2015-10-27 |
| KR20110007084A (ko) | 2011-01-21 |
| JP5514736B2 (ja) | 2014-06-04 |
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| CN101959934A (zh) | 2011-01-26 |
| JP2011510120A (ja) | 2011-03-31 |
| US20120136123A1 (en) | 2012-05-31 |
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| WO2009089542A3 (en) | 2009-10-01 |
| EP2669313A1 (en) | 2013-12-04 |
| EP3042922A1 (en) | 2016-07-13 |
| CN101959934B (zh) | 2012-12-12 |
| EP2669313B1 (en) | 2016-03-23 |
| EP2235090A4 (en) | 2011-10-05 |
| EP2235090B1 (en) | 2013-09-04 |
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