CA2952488C - Polyalkylene glycol with moiety for conjugating biologically active compounds - Google Patents
Polyalkylene glycol with moiety for conjugating biologically active compounds Download PDFInfo
- Publication number
- CA2952488C CA2952488C CA2952488A CA2952488A CA2952488C CA 2952488 C CA2952488 C CA 2952488C CA 2952488 A CA2952488 A CA 2952488A CA 2952488 A CA2952488 A CA 2952488A CA 2952488 C CA2952488 C CA 2952488C
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- group
- biologically
- formula
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 384
- 229920001515 polyalkylene glycol Polymers 0.000 title abstract description 68
- 230000001268 conjugating effect Effects 0.000 title description 5
- 239000000203 mixture Substances 0.000 claims abstract description 83
- -1 cyano, nitro, azido, sulfhydryl Chemical group 0.000 claims description 358
- 229920006395 saturated elastomer Polymers 0.000 claims description 224
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 204
- 125000003118 aryl group Chemical group 0.000 claims description 162
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 161
- 239000002243 precursor Substances 0.000 claims description 150
- 125000001072 heteroaryl group Chemical group 0.000 claims description 136
- 150000002148 esters Chemical class 0.000 claims description 123
- 125000000217 alkyl group Chemical group 0.000 claims description 117
- 229910052736 halogen Inorganic materials 0.000 claims description 115
- 150000002367 halogens Chemical class 0.000 claims description 115
- 229910052739 hydrogen Inorganic materials 0.000 claims description 115
- 239000001257 hydrogen Substances 0.000 claims description 115
- 150000001412 amines Chemical class 0.000 claims description 113
- 125000000623 heterocyclic group Chemical group 0.000 claims description 88
- 238000006243 chemical reaction Methods 0.000 claims description 85
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 81
- 125000003545 alkoxy group Chemical group 0.000 claims description 79
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 79
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 77
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 75
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 74
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 73
- 150000007970 thio esters Chemical class 0.000 claims description 73
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 claims description 72
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 claims description 72
- 125000002252 acyl group Chemical group 0.000 claims description 71
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 71
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 71
- 150000007942 carboxylates Chemical class 0.000 claims description 70
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 70
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 70
- 150000002431 hydrogen Chemical group 0.000 claims description 69
- 150000002466 imines Chemical class 0.000 claims description 69
- 125000003368 amide group Chemical group 0.000 claims description 68
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 68
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 68
- 150000001409 amidines Chemical class 0.000 claims description 65
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 62
- AWIJRPNMLHPLNC-UHFFFAOYSA-N methanethioic s-acid Chemical compound SC=O AWIJRPNMLHPLNC-UHFFFAOYSA-N 0.000 claims description 59
- 125000004414 alkyl thio group Chemical group 0.000 claims description 57
- 125000005647 linker group Chemical group 0.000 claims description 51
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 43
- 238000011282 treatment Methods 0.000 claims description 42
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 239000000243 solution Substances 0.000 claims description 22
- 239000007972 injectable composition Substances 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 238000006467 substitution reaction Methods 0.000 claims description 7
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 229920000136 polysorbate Polymers 0.000 claims description 4
- 239000004475 Arginine Substances 0.000 claims description 3
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 3
- 229950008882 polysorbate Drugs 0.000 claims description 3
- 238000010254 subcutaneous injection Methods 0.000 claims description 3
- 239000000730 antalgic agent Substances 0.000 claims description 2
- 239000002221 antipyretic Substances 0.000 claims description 2
- 229940125716 antipyretic agent Drugs 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000007929 subcutaneous injection Substances 0.000 claims description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 4
- 159000000021 acetate salts Chemical class 0.000 claims 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 2
- 230000000202 analgesic effect Effects 0.000 claims 1
- 230000021615 conjugation Effects 0.000 abstract description 27
- 238000000034 method Methods 0.000 abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 8
- 231100000419 toxicity Toxicity 0.000 abstract description 5
- 230000001988 toxicity Effects 0.000 abstract description 5
- 230000004071 biological effect Effects 0.000 abstract description 4
- 230000009467 reduction Effects 0.000 abstract description 2
- 125000001424 substituent group Chemical group 0.000 description 103
- 150000001299 aldehydes Chemical class 0.000 description 98
- 229920001223 polyethylene glycol Polymers 0.000 description 87
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 84
- 102000014150 Interferons Human genes 0.000 description 82
- 108010050904 Interferons Proteins 0.000 description 82
- 229940079322 interferon Drugs 0.000 description 72
- 229920000642 polymer Polymers 0.000 description 59
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical group O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 description 58
- 108090000765 processed proteins & peptides Proteins 0.000 description 58
- 125000003342 alkenyl group Chemical group 0.000 description 48
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 44
- 125000002619 bicyclic group Chemical group 0.000 description 42
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 41
- 108090000467 Interferon-beta Proteins 0.000 description 41
- 150000001241 acetals Chemical class 0.000 description 41
- AFOSIXZFDONLBT-UHFFFAOYSA-N divinyl sulfone Chemical compound C=CS(=O)(=O)C=C AFOSIXZFDONLBT-UHFFFAOYSA-N 0.000 description 40
- 238000001990 intravenous administration Methods 0.000 description 40
- 239000012948 isocyanate Substances 0.000 description 40
- 150000003457 sulfones Chemical class 0.000 description 40
- 229910052717 sulfur Inorganic materials 0.000 description 40
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 39
- KGIGUEBEKRSTEW-UHFFFAOYSA-N 2-vinylpyridine Chemical compound C=CC1=CC=CC=N1 KGIGUEBEKRSTEW-UHFFFAOYSA-N 0.000 description 39
- CYWHLOXWVAWMFO-UHFFFAOYSA-N 3-sulfanyl-1h-pyridine-2-thione Chemical compound SC1=CC=CN=C1S CYWHLOXWVAWMFO-UHFFFAOYSA-N 0.000 description 39
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 39
- 150000002118 epoxides Chemical class 0.000 description 39
- 150000002513 isocyanates Chemical class 0.000 description 39
- 150000002540 isothiocyanates Chemical class 0.000 description 39
- 150000003573 thiols Chemical class 0.000 description 39
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 38
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 38
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 38
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 37
- PGLTVOMIXTUURA-UHFFFAOYSA-N iodoacetamide Chemical compound NC(=O)CI PGLTVOMIXTUURA-UHFFFAOYSA-N 0.000 description 37
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 32
- 230000000840 anti-viral effect Effects 0.000 description 32
- 102000003996 Interferon-beta Human genes 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000000562 conjugate Substances 0.000 description 27
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 27
- 239000002202 Polyethylene glycol Substances 0.000 description 26
- 208000036142 Viral infection Diseases 0.000 description 26
- 239000003814 drug Substances 0.000 description 26
- 230000009385 viral infection Effects 0.000 description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 23
- 108090000623 proteins and genes Proteins 0.000 description 23
- 125000000524 functional group Chemical group 0.000 description 22
- 229940015043 glyoxal Drugs 0.000 description 21
- 229960001388 interferon-beta Drugs 0.000 description 21
- 125000003277 amino group Chemical group 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 20
- 229940079593 drug Drugs 0.000 description 20
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 19
- 230000000694 effects Effects 0.000 description 19
- 235000018102 proteins Nutrition 0.000 description 19
- 102000004169 proteins and genes Human genes 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 125000004093 cyano group Chemical group *C#N 0.000 description 18
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 18
- 239000003443 antiviral agent Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- 241000282414 Homo sapiens Species 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 241000711549 Hepacivirus C Species 0.000 description 15
- 208000005176 Hepatitis C Diseases 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 229940047124 interferons Drugs 0.000 description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 15
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- 239000013543 active substance Substances 0.000 description 14
- 150000003384 small molecules Chemical class 0.000 description 14
- 108010005716 Interferon beta-1a Proteins 0.000 description 13
- 125000004122 cyclic group Chemical group 0.000 description 13
- 230000004044 response Effects 0.000 description 13
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 13
- 101150041968 CDC13 gene Proteins 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 12
- 229960004461 interferon beta-1a Drugs 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 12
- 239000001301 oxygen Substances 0.000 description 12
- 239000002096 quantum dot Substances 0.000 description 12
- 230000002285 radioactive effect Effects 0.000 description 12
- 229960000329 ribavirin Drugs 0.000 description 12
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- IPRPPFIAVHPVJH-UHFFFAOYSA-N (4-hydroxyphenyl)acetaldehyde Chemical compound OC1=CC=C(CC=O)C=C1 IPRPPFIAVHPVJH-UHFFFAOYSA-N 0.000 description 11
- 125000003275 alpha amino acid group Chemical group 0.000 description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 11
- 125000000753 cycloalkyl group Chemical group 0.000 description 11
- 208000010710 hepatitis C virus infection Diseases 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 11
- 229960002555 zidovudine Drugs 0.000 description 11
- IWUCXVSUMQZMFG-RGDLXGNYSA-N 1-[(2s,3s,4r,5s)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2,4-triazole-3-carboxamide Chemical compound N1=C(C(=O)N)N=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 IWUCXVSUMQZMFG-RGDLXGNYSA-N 0.000 description 10
- 208000006154 Chronic hepatitis C Diseases 0.000 description 10
- 102100026720 Interferon beta Human genes 0.000 description 10
- 108091034117 Oligonucleotide Proteins 0.000 description 10
- 229960004150 aciclovir Drugs 0.000 description 10
- LLYJISDUHFXOHK-GOCONZMPSA-N ferroptocide Chemical compound C[C@@H]1CC[C@@]23C[C@@H](C(=O)[C@]2([C@@]1([C@@H](C[C@H]([C@@H]3C)C4=CCN5C(=O)N(C(=O)N5C4)C6=CC=CC=C6)OC(=O)CCl)C)O)O LLYJISDUHFXOHK-GOCONZMPSA-N 0.000 description 10
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 10
- 229960002963 ganciclovir Drugs 0.000 description 10
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- 239000007832 Na2SO4 Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 241000700605 Viruses Species 0.000 description 9
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 102000004196 processed proteins & peptides Human genes 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 9
- 230000003213 activating effect Effects 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 150000002334 glycols Chemical class 0.000 description 8
- 230000013595 glycosylation Effects 0.000 description 8
- 238000006206 glycosylation reaction Methods 0.000 description 8
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 8
- 108020004707 nucleic acids Proteins 0.000 description 8
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- 238000002560 therapeutic procedure Methods 0.000 description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 description 8
- 238000010626 work up procedure Methods 0.000 description 8
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- 108010082126 Alanine transaminase Proteins 0.000 description 7
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- 125000006239 protecting group Chemical group 0.000 description 7
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- 235000000346 sugar Nutrition 0.000 description 7
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 6
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- 241001465754 Metazoa Species 0.000 description 6
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 125000000304 alkynyl group Chemical group 0.000 description 5
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