TWI742015B - 用於醫療應用之化合物 - Google Patents
用於醫療應用之化合物 Download PDFInfo
- Publication number
- TWI742015B TWI742015B TW105137966A TW105137966A TWI742015B TW I742015 B TWI742015 B TW I742015B TW 105137966 A TW105137966 A TW 105137966A TW 105137966 A TW105137966 A TW 105137966A TW I742015 B TWI742015 B TW I742015B
- Authority
- TW
- Taiwan
- Prior art keywords
- compound
- ester
- pharmaceutically acceptable
- group
- virus
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 351
- 125000000129 anionic group Chemical group 0.000 claims abstract description 54
- 150000003839 salts Chemical class 0.000 claims abstract description 51
- 241000712461 unidentified influenza virus Species 0.000 claims abstract description 49
- 239000000203 mixture Substances 0.000 claims description 108
- 208000015181 infectious disease Diseases 0.000 claims description 68
- -1 cyclohexane-1,3,5-tricarboxylic acid ester Chemical class 0.000 claims description 62
- 238000011282 treatment Methods 0.000 claims description 52
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 claims description 52
- 229960001028 zanamivir Drugs 0.000 claims description 49
- 208000037797 influenza A Diseases 0.000 claims description 42
- 150000002148 esters Chemical class 0.000 claims description 34
- 108010006232 Neuraminidase Proteins 0.000 claims description 32
- 102000005348 Neuraminidase Human genes 0.000 claims description 32
- 238000009739 binding Methods 0.000 claims description 27
- 230000009385 viral infection Effects 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 125000005647 linker group Chemical group 0.000 claims description 17
- 229960003752 oseltamivir Drugs 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 16
- 239000012634 fragment Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000000427 antigen Substances 0.000 claims description 11
- 102000036639 antigens Human genes 0.000 claims description 11
- 108091007433 antigens Proteins 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- CYIDZMCFTVVTJO-UHFFFAOYSA-N pyromellityc acid Natural products OC(=O)C1=CC(C(O)=O)=C(C(O)=O)C=C1C(O)=O CYIDZMCFTVVTJO-UHFFFAOYSA-N 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 8
- 206010064097 avian influenza Diseases 0.000 claims description 7
- 238000001990 intravenous administration Methods 0.000 claims description 7
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 claims description 7
- 229960001084 peramivir Drugs 0.000 claims description 7
- KQTIIICEAUMSDG-UHFFFAOYSA-N tricarballylic acid Chemical class OC(=O)CC(C(O)=O)CC(O)=O KQTIIICEAUMSDG-UHFFFAOYSA-N 0.000 claims description 7
- 208000002979 Influenza in Birds Diseases 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 208000037798 influenza B Diseases 0.000 claims description 6
- 238000007918 intramuscular administration Methods 0.000 claims description 6
- 238000007912 intraperitoneal administration Methods 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 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 5
- 239000013543 active substance Substances 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 230000009885 systemic effect Effects 0.000 claims description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 claims description 3
- 102000008394 Immunoglobulin Fragments Human genes 0.000 claims description 3
- 206010057190 Respiratory tract infections Diseases 0.000 claims description 3
- 108010003723 Single-Domain Antibodies Proteins 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- QNRRHYPPQFELSF-CNYIRLTGSA-N Laninamivir Chemical compound OC[C@@H](O)[C@@H](OC)[C@@H]1OC(C(O)=O)=C[C@H](N=C(N)N)[C@H]1NC(C)=O QNRRHYPPQFELSF-CNYIRLTGSA-N 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- GGAUUQHSCNMCAU-UHFFFAOYSA-N butane-1,2,3,4-tetracarboxylic acid Chemical class OC(=O)CC(C(O)=O)C(C(O)=O)CC(O)=O GGAUUQHSCNMCAU-UHFFFAOYSA-N 0.000 claims description 2
- UVIRSBTTXOHPDA-UHFFFAOYSA-N cyclopropane-1,2,3-tricarboxylic acid Chemical class OC(=O)C1C(C(O)=O)C1C(O)=O UVIRSBTTXOHPDA-UHFFFAOYSA-N 0.000 claims description 2
- 229950004244 laninamivir Drugs 0.000 claims description 2
- GTZCVFVGUGFEME-UHFFFAOYSA-N aconitic acid Chemical class OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 claims 1
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 claims 1
- QMKYBPDZANOJGF-UHFFFAOYSA-N trimesic acid Natural products OC(=O)C1=CC(C(O)=O)=CC(C(O)=O)=C1 QMKYBPDZANOJGF-UHFFFAOYSA-N 0.000 claims 1
- 206010022000 influenza Diseases 0.000 abstract description 45
- 239000000651 prodrug Substances 0.000 abstract description 14
- 229940002612 prodrug Drugs 0.000 abstract description 14
- 239000012453 solvate Substances 0.000 abstract description 13
- 238000004873 anchoring Methods 0.000 abstract description 7
- 241000700605 Viruses Species 0.000 description 164
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 121
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 100
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 87
- 241000699670 Mus sp. Species 0.000 description 64
- 239000000243 solution Substances 0.000 description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 210000004027 cell Anatomy 0.000 description 54
- 239000002904 solvent Substances 0.000 description 54
- 230000002378 acidificating effect Effects 0.000 description 52
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 50
- 238000002360 preparation method Methods 0.000 description 48
- 238000004128 high performance liquid chromatography Methods 0.000 description 47
- 238000000034 method Methods 0.000 description 46
- 239000007787 solid Substances 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 38
- 241000699666 Mus <mouse, genus> Species 0.000 description 36
- XUJNEKJLAYXESH-UWTATZPHSA-N D-Cysteine Chemical compound SC[C@@H](N)C(O)=O XUJNEKJLAYXESH-UWTATZPHSA-N 0.000 description 33
- 238000004458 analytical method Methods 0.000 description 32
- 230000000694 effects Effects 0.000 description 31
- 238000009472 formulation Methods 0.000 description 30
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 29
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 28
- 230000015572 biosynthetic process Effects 0.000 description 28
- 238000003786 synthesis reaction Methods 0.000 description 28
- 239000000843 powder Substances 0.000 description 27
- 238000012360 testing method Methods 0.000 description 26
- 230000004083 survival effect Effects 0.000 description 25
- 239000004480 active ingredient Substances 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 23
- 239000011347 resin Substances 0.000 description 23
- 229920005989 resin Polymers 0.000 description 23
- 239000000725 suspension Substances 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 206010011732 Cyst Diseases 0.000 description 21
- 230000000840 anti-viral effect Effects 0.000 description 21
- 208000031513 cyst Diseases 0.000 description 21
- 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 21
- 238000001727 in vivo Methods 0.000 description 21
- 230000008569 process Effects 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 20
- 239000002953 phosphate buffered saline Substances 0.000 description 20
- 201000010099 disease Diseases 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 101710154606 Hemagglutinin Proteins 0.000 description 17
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 17
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 17
- 101710176177 Protein A56 Proteins 0.000 description 17
- 125000003118 aryl group Chemical group 0.000 description 17
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 17
- 239000002552 dosage form Substances 0.000 description 17
- 238000000338 in vitro Methods 0.000 description 17
- 108020004999 messenger RNA Proteins 0.000 description 17
- NENPYTRHICXVCS-YNEHKIRRSA-N oseltamivir acid Chemical compound CCC(CC)O[C@@H]1C=C(C(O)=O)C[C@H](N)[C@H]1NC(C)=O NENPYTRHICXVCS-YNEHKIRRSA-N 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 238000012216 screening Methods 0.000 description 16
- 239000000126 substance Substances 0.000 description 16
- 230000003612 virological effect Effects 0.000 description 16
- 239000000185 hemagglutinin Substances 0.000 description 15
- XVOYSCVBGLVSOL-UHFFFAOYSA-N L-cysteine sulfonic acid Natural products OC(=O)C(N)CS(O)(=O)=O XVOYSCVBGLVSOL-UHFFFAOYSA-N 0.000 description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 14
- 229910052786 argon Inorganic materials 0.000 description 14
- 239000007788 liquid Substances 0.000 description 14
- 239000002911 sialidase inhibitor Substances 0.000 description 14
- 239000003112 inhibitor Substances 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- 239000007921 spray Substances 0.000 description 13
- 239000000872 buffer Substances 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- 239000006260 foam Substances 0.000 description 12
- 125000000524 functional group Chemical group 0.000 description 12
- 210000004072 lung Anatomy 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 230000004580 weight loss Effects 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 11
- 239000002775 capsule Substances 0.000 description 11
- 230000034994 death Effects 0.000 description 11
- 150000002500 ions Chemical class 0.000 description 11
- 239000007937 lozenge Substances 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 241000712431 Influenza A virus Species 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 10
- 239000000902 placebo Substances 0.000 description 10
- 229940068196 placebo Drugs 0.000 description 10
- 230000009467 reduction Effects 0.000 description 10
- 241000282414 Homo sapiens Species 0.000 description 9
- 239000000443 aerosol Substances 0.000 description 9
- 239000003443 antiviral agent Substances 0.000 description 9
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 9
- 108090000765 processed proteins & peptides Proteins 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 8
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 230000002155 anti-virotic effect Effects 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 229940042406 direct acting antivirals neuraminidase inhibitors Drugs 0.000 description 8
- 102000004169 proteins and genes Human genes 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 241000252870 H3N2 subtype Species 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 7
- 108091000080 Phosphotransferase Proteins 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 102000004142 Trypsin Human genes 0.000 description 7
- 108090000631 Trypsin Proteins 0.000 description 7
- 235000011054 acetic acid Nutrition 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
- 235000001014 amino acid Nutrition 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 125000000623 heterocyclic group Chemical group 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 102000020233 phosphotransferase Human genes 0.000 description 7
- 239000002504 physiological saline solution Substances 0.000 description 7
- 239000002243 precursor Substances 0.000 description 7
- 238000002953 preparative HPLC Methods 0.000 description 7
- 102000004196 processed proteins & peptides Human genes 0.000 description 7
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 7
- 239000012588 trypsin Substances 0.000 description 7
- KLBPUVPNPAJWHZ-UUWRZZSWSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanylpropanoic acid Chemical compound C([C@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)SC(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 KLBPUVPNPAJWHZ-UUWRZZSWSA-N 0.000 description 6
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 241000937413 Axia Species 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- KXADPELPQCWDHL-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1.COC1=CC=CC=C1 KXADPELPQCWDHL-UHFFFAOYSA-N 0.000 description 6
- 229960005261 aspartic acid Drugs 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 230000003993 interaction Effects 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 210000001944 turbinate Anatomy 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- KAJBMCZQVSQJDE-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]butanedioic acid Chemical compound CC(C)(C)OC(=O)NC(C(O)=O)CC(O)=O KAJBMCZQVSQJDE-UHFFFAOYSA-N 0.000 description 5
- 241000272525 Anas platyrhynchos Species 0.000 description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 5
- 102000004310 Ion Channels Human genes 0.000 description 5
- 229940123424 Neuraminidase inhibitor Drugs 0.000 description 5
- 108010061100 Nucleoproteins Proteins 0.000 description 5
- 102000011931 Nucleoproteins Human genes 0.000 description 5
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 235000003704 aspartic acid Nutrition 0.000 description 5
- 239000011324 bead Substances 0.000 description 5
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 230000000241 respiratory effect Effects 0.000 description 5
- 210000002345 respiratory system Anatomy 0.000 description 5
- 239000000375 suspending agent Substances 0.000 description 5
- 239000002562 thickening agent Substances 0.000 description 5
- 239000003643 water by type Substances 0.000 description 5
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 4
- VLDPXPPHXDGHEW-UHFFFAOYSA-N 1-chloro-2-dichlorophosphoryloxybenzene Chemical compound ClC1=CC=CC=C1OP(Cl)(Cl)=O VLDPXPPHXDGHEW-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- 241000282339 Mustela Species 0.000 description 4
- 229920001213 Polysorbate 20 Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 108091034135 Vault RNA Proteins 0.000 description 4
- 108020000999 Viral RNA Proteins 0.000 description 4
- 208000036142 Viral infection Diseases 0.000 description 4
- 125000002877 alkyl aryl group Chemical group 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 150000001735 carboxylic acids Chemical class 0.000 description 4
- 230000034303 cell budding Effects 0.000 description 4
- 229960004106 citric acid Drugs 0.000 description 4
- 235000015165 citric acid Nutrition 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 210000000805 cytoplasm Anatomy 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 230000004927 fusion Effects 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 231100000518 lethal Toxicity 0.000 description 4
- 230000001665 lethal effect Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N methyl phenyl ether Natural products COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 230000010076 replication Effects 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 125000005629 sialic acid group Chemical group 0.000 description 4
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 4
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 3
- 0 *[C@]([C@@](CO)O)C([C@@]1*)OC(C(O)=O)=C[C@@]1NC(N)=N Chemical compound *[C@]([C@@](CO)O)C([C@@]1*)OC(C(O)=O)=C[C@@]1NC(N)=N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 0.000 description 3
- 102000004533 Endonucleases Human genes 0.000 description 3
- 108010042407 Endonucleases Proteins 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 125000004450 alkenylene group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 125000004419 alkynylene group Chemical group 0.000 description 3
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 3
- 229960003805 amantadine Drugs 0.000 description 3
- 150000001450 anions Chemical class 0.000 description 3
- 229940121357 antivirals Drugs 0.000 description 3
- 238000003491 array Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012737 fresh medium Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 230000009931 harmful effect Effects 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000002054 inoculum Substances 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 210000003928 nasal cavity Anatomy 0.000 description 3
- 210000002850 nasal mucosa Anatomy 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 210000004940 nucleus Anatomy 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 230000001932 seasonal effect Effects 0.000 description 3
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 3
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 3
- 230000029812 viral genome replication Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical compound NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 206010048610 Cardiotoxicity Diseases 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- 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 2
- 241000588724 Escherichia coli Species 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 2
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- 241000134304 Influenza A virus H3N2 Species 0.000 description 2
- 241000713196 Influenza B virus Species 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 240000007472 Leucaena leucocephala Species 0.000 description 2
- 239000000232 Lipid Bilayer Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 2
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- 101710144128 Non-structural protein 2 Proteins 0.000 description 2
- 101710199667 Nuclear export protein Proteins 0.000 description 2
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
- 108010088535 Pep-1 peptide Proteins 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000000540 analysis of variance Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000012911 assay medium Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000001588 bifunctional effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229960002685 biotin Drugs 0.000 description 2
- 235000020958 biotin Nutrition 0.000 description 2
- 239000011616 biotin Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 2
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 231100000259 cardiotoxicity Toxicity 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000002801 charged material Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 238000007796 conventional method Methods 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
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000010494 dissociation reaction Methods 0.000 description 2
- 230000005593 dissociations Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 2
- 210000001163 endosome Anatomy 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003797 essential amino acid Substances 0.000 description 2
- 235000020776 essential amino acid Nutrition 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000005828 hydrofluoroalkanes Chemical class 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000001537 neural effect Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 210000001331 nose Anatomy 0.000 description 2
- 230000030648 nucleus localization Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920000447 polyanionic polymer Polymers 0.000 description 2
- 230000002028 premature Effects 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000011669 selenium Chemical group 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 108010061514 sialic acid receptor Proteins 0.000 description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 229940054269 sodium pyruvate Drugs 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- GZUNGYDAMPRXSU-UHFFFAOYSA-N tert-butyl n-(9-aminononyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCCCCCCCN GZUNGYDAMPRXSU-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000027 toxicology Toxicity 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- 230000001131 transforming effect Effects 0.000 description 2
- 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 2
- 229960005486 vaccine Drugs 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- KSDTXRUIZMTBNV-MRXNPFEDSA-N (2r)-2-(9h-fluoren-9-ylmethoxycarbonylamino)butanedioic acid Chemical compound C1=CC=C2C(COC(=O)N[C@H](CC(=O)O)C(O)=O)C3=CC=CC=C3C2=C1 KSDTXRUIZMTBNV-MRXNPFEDSA-N 0.000 description 1
- ATVFTGTXIUDKIZ-RXMQYKEDSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-sulfanylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](CS)C(O)=O ATVFTGTXIUDKIZ-RXMQYKEDSA-N 0.000 description 1
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 1
- 125000006823 (C1-C6) acyl group Chemical group 0.000 description 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- 125000000196 1,4-pentadienyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])=C([H])[H] 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- JFLSOKIMYBSASW-UHFFFAOYSA-N 1-chloro-2-[chloro(diphenyl)methyl]benzene Chemical compound ClC1=CC=CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 JFLSOKIMYBSASW-UHFFFAOYSA-N 0.000 description 1
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 125000006023 1-pentenyl group Chemical group 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- GYDDACBLWFSXOM-UHFFFAOYSA-N 3,3,4-triphenylbutan-2-one Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)C)CC1=CC=CC=C1 GYDDACBLWFSXOM-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
- UVNNERNQDNNAMA-UHFFFAOYSA-N 5-[[(2,4,5-tricarboxybenzoyl)amino]carbamoyl]benzene-1,2,4-tricarboxylic acid Chemical compound N(NC(=O)C1=C(C=C(C(=C1)C(=O)O)C(=O)O)C(=O)O)C(=O)C1=C(C=C(C(=C1)C(=O)O)C(=O)O)C(=O)O UVNNERNQDNNAMA-UHFFFAOYSA-N 0.000 description 1
- CERZMXAJYMMUDR-QBTAGHCHSA-N 5-amino-3,5-dideoxy-D-glycero-D-galacto-non-2-ulopyranosonic acid Chemical compound N[C@@H]1[C@@H](O)CC(O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO CERZMXAJYMMUDR-QBTAGHCHSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 230000035502 ADME Effects 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 208000035742 Air-borne transmission Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 201000001178 Bacterial Pneumonia Diseases 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical group C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 1
- FISIUNILZONDDJ-UHFFFAOYSA-N C(=O)(OC(C)(C)C)C(CCCCN)(CCCCN)C(=O)OC(C)(C)C Chemical compound C(=O)(OC(C)(C)C)C(CCCCN)(CCCCN)C(=O)OC(C)(C)C FISIUNILZONDDJ-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 101710163595 Chaperone protein DnaK Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000011591 Cleavage And Polyadenylation Specificity Factor Human genes 0.000 description 1
- 108010076130 Cleavage And Polyadenylation Specificity Factor Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- IKYCZSUNGFRBJS-UHFFFAOYSA-N Euphorbia factor RL9 = U(1) = Resiniferatoxin Natural products COC1=CC(O)=CC(CC(=O)OCC=2CC3(O)C(=O)C(C)=CC3C34C(C)CC5(OC(O4)(CC=4C=CC=CC=4)OC5C3C=2)C(C)=C)=C1 IKYCZSUNGFRBJS-UHFFFAOYSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 101710178376 Heat shock 70 kDa protein Proteins 0.000 description 1
- 101710152018 Heat shock cognate 70 kDa protein Proteins 0.000 description 1
- 101710128560 Initiator protein NS1 Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 101150046652 M2 gene Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102220477256 Membrane-spanning 4-domains subfamily A member 10_S31N_mutation Human genes 0.000 description 1
- 102000006404 Mitochondrial Proteins Human genes 0.000 description 1
- 108010058682 Mitochondrial Proteins Proteins 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- SQVRNKJHWKZAKO-LUWBGTNYSA-N N-acetylneuraminic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)CC(O)(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-LUWBGTNYSA-N 0.000 description 1
- FDJKUWYYUZCUJX-AJKRCSPLSA-N N-glycoloyl-beta-neuraminic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@@H]1O[C@](O)(C(O)=O)C[C@H](O)[C@H]1NC(=O)CO FDJKUWYYUZCUJX-AJKRCSPLSA-N 0.000 description 1
- FDJKUWYYUZCUJX-UHFFFAOYSA-N N-glycolyl-beta-neuraminic acid Natural products OCC(O)C(O)C1OC(O)(C(O)=O)CC(O)C1NC(=O)CO FDJKUWYYUZCUJX-UHFFFAOYSA-N 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- MQUQNUAYKLCRME-INIZCTEOSA-N N-tosyl-L-phenylalanyl chloromethyl ketone Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](C(=O)CCl)CC1=CC=CC=C1 MQUQNUAYKLCRME-INIZCTEOSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 101710144127 Non-structural protein 1 Proteins 0.000 description 1
- 108090001074 Nucleocapsid Proteins Proteins 0.000 description 1
- JWIPGAFCGUDKEY-UHFFFAOYSA-L O[Cr](Cl)(=O)=O.C1=CC=NC=C1 Chemical compound O[Cr](Cl)(=O)=O.C1=CC=NC=C1 JWIPGAFCGUDKEY-UHFFFAOYSA-L 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000712464 Orthomyxoviridae Species 0.000 description 1
- 102100034574 P protein Human genes 0.000 description 1
- 101710181008 P protein Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 244000131316 Panax pseudoginseng Species 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 101710177166 Phosphoprotein Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000711902 Pneumovirus Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 230000006819 RNA synthesis Effects 0.000 description 1
- 208000035415 Reinfection Diseases 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical group [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 108010067390 Viral Proteins Proteins 0.000 description 1
- CHKFLBOLYREYDO-SHYZEUOFSA-N [[(2s,4r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-4-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)C[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 CHKFLBOLYREYDO-SHYZEUOFSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910001573 adamantine Inorganic materials 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 230000005557 airborne transmission Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- OBESRABRARNZJB-UHFFFAOYSA-N aminomethanesulfonic acid Chemical compound NCS(O)(=O)=O OBESRABRARNZJB-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 229940124411 anti-hiv antiviral agent Drugs 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000000890 antigenic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 235000021311 artificial sweeteners Nutrition 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000013096 assay test Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000000022 bacteriostatic agent Substances 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- QMKYBPDZANOJGF-UHFFFAOYSA-K benzene-1,3,5-tricarboxylate(3-) Chemical class [O-]C(=O)C1=CC(C([O-])=O)=CC(C([O-])=O)=C1 QMKYBPDZANOJGF-UHFFFAOYSA-K 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 239000012148 binding buffer Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229940126587 biotherapeutics Drugs 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 229960002504 capsaicin Drugs 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- FTHDNRBKSLBLDA-UHFFFAOYSA-N cyclohexane-1,3,5-tricarboxylic acid Chemical class OC(=O)C1CC(C(O)=O)CC(C(O)=O)C1 FTHDNRBKSLBLDA-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 230000017188 evasion or tolerance of host immune response Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 108700002148 exportin 1 Proteins 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 210000002288 golgi apparatus Anatomy 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 208000037801 influenza A (H1N1) Diseases 0.000 description 1
- 108700032552 influenza virus INS1 Proteins 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 150000002497 iodine compounds Chemical class 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000004779 membrane envelope Anatomy 0.000 description 1
- 230000034217 membrane fusion Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- NKVMCSDLYHGDMD-UHFFFAOYSA-N methanetetracarboxylic acid Chemical class OC(=O)C(C(O)=O)(C(O)=O)C(O)=O NKVMCSDLYHGDMD-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 230000000420 mucociliary effect Effects 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- AOTOAIFCUZOGTP-UHFFFAOYSA-N n-ethyl-2,3,4-trimethylpentan-3-amine Chemical compound CCNC(C)(C(C)C)C(C)C AOTOAIFCUZOGTP-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229940100656 nasal solution Drugs 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 235000021096 natural sweeteners Nutrition 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- CERZMXAJYMMUDR-UHFFFAOYSA-N neuraminic acid Natural products NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO CERZMXAJYMMUDR-UHFFFAOYSA-N 0.000 description 1
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 1
- SXJVFQLYZSNZBT-UHFFFAOYSA-N nonane-1,9-diamine Chemical compound NCCCCCCCCCN SXJVFQLYZSNZBT-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000030147 nuclear export Effects 0.000 description 1
- 230000008689 nuclear function Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000025308 nuclear transport Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000001543 one-way ANOVA Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- PGZUMBJQJWIWGJ-ONAKXNSWSA-N oseltamivir phosphate Chemical compound OP(O)(O)=O.CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 PGZUMBJQJWIWGJ-ONAKXNSWSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 229910052698 phosphorus Chemical group 0.000 description 1
- 239000011574 phosphorus Chemical group 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 108010077051 polycysteine Proteins 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical group C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- DSDNAKHZNJAGHN-UHFFFAOYSA-N resinferatoxin Natural products C1=C(O)C(OC)=CC(CC(=O)OCC=2CC3(O)C(=O)C(C)=CC3C34C(C)CC5(OC(O4)(CC=4C=CC=CC=4)OC5C3C=2)C(C)=C)=C1 DSDNAKHZNJAGHN-UHFFFAOYSA-N 0.000 description 1
- DSDNAKHZNJAGHN-MXTYGGKSSA-N resiniferatoxin Chemical compound C1=C(O)C(OC)=CC(CC(=O)OCC=2C[C@]3(O)C(=O)C(C)=C[C@H]3[C@@]34[C@H](C)C[C@@]5(O[C@@](O4)(CC=4C=CC=CC=4)O[C@@H]5[C@@H]3C=2)C(C)=C)=C1 DSDNAKHZNJAGHN-MXTYGGKSSA-N 0.000 description 1
- 229940073454 resiniferatoxin Drugs 0.000 description 1
- 230000005559 respiratory droplet transmission Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960000888 rimantadine Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- UZHDDUOPWFLWPC-UHFFFAOYSA-M sodium;aminomethanesulfonate Chemical compound [Na+].NCS([O-])(=O)=O UZHDDUOPWFLWPC-UHFFFAOYSA-M 0.000 description 1
- PANBYUAFMMOFOV-UHFFFAOYSA-N sodium;sulfuric acid Chemical compound [Na].OS(O)(=O)=O PANBYUAFMMOFOV-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000004354 sulfur functional group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 201000010740 swine influenza Diseases 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940061367 tamiflu Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- UTVFYAHWDOBYIZ-UHFFFAOYSA-N tert-butyl 2-aminoheptanoate hydrobromide Chemical compound Br.CCCCCC(N)C(=O)OC(C)(C)C UTVFYAHWDOBYIZ-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- RVZPDKXEHIRFPM-UHFFFAOYSA-N tert-butyl n-(6-aminohexyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCCCCN RVZPDKXEHIRFPM-UHFFFAOYSA-N 0.000 description 1
- BEHVGNKIRNVBPF-UHFFFAOYSA-N tert-butyl n-(8-aminooctyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCCCCCCN BEHVGNKIRNVBPF-UHFFFAOYSA-N 0.000 description 1
- QFNFDHNZVTWZED-UHFFFAOYSA-N tert-butyl n-[[(2-methylpropan-2-yl)oxycarbonylamino]-pyrazol-1-ylmethylidene]carbamate Chemical compound CC(C)(C)OC(=O)NC(=NC(=O)OC(C)(C)C)N1C=CC=N1 QFNFDHNZVTWZED-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 210000003956 transport vesicle Anatomy 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000007485 viral shedding Effects 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
-
- 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
- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K47/54—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 compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- 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
- A61K47/68—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6839—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting material from viruses
- A61K47/6841—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 antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting material from viruses the antibody targeting a RNA virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1018—Orthomyxoviridae, e.g. influenza virus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06104—Dipeptides with the first amino acid being acidic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0819—Tripeptides with the first amino acid being acidic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/10—Tetrapeptides
- C07K5/1021—Tetrapeptides with the first amino acid being acidic
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
- C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
- C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
- C07K2317/622—Single chain antibody (scFv)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pyrane Compounds (AREA)
- Materials For Medical Uses (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本發明提供用於治療及/或預防流感之化合物。該化合物包含第一結構域及第二結構域,其中該第一結構域包含結合至流感病毒之表面的至少一個錨定基團,且該第二結構域包含至少一個陰離子基團。該第一結構域與該第二結構域共價連接。本發明亦提供該等化合物之醫藥學上可接受之鹽、溶劑合物、前藥或立體異構體。
Description
本申請案係關於用於醫療用途,特定言之用於治療或預防病毒感染之化合物。本申請案亦係關於用於製備該等化合物之方法。
流感為一種每年5%至25%之美國人口感染之呼吸道感染,其中大約200,000人住院且25,000人死亡。流感感染仍舊不斷威脅人類健康且對健康服務造成負擔。近年來,來自禽類來源之高度致病性H5N1病毒及H7N9病毒之出現及其取得人類傳播性之潛能已增加與流感感染相關聯之風險。儘管疫苗仍然為預防之基石,但研發對抗任何新病毒株之頻繁突變的有效疫苗需要大量時間。諸如病毒神經胺糖酸酶抑制劑(NA抑制劑) (包括紮那米韋(Zanamivir) (瑞樂沙(Relenza))及奧司他韋(Oseltamivir) (克流感(Tamiflu)))及衍生自金剛烷之M2離子通道阻斷劑(包括金剛烷胺(amantidine)及金剛乙胺(rimantidine))之抗流感藥物為可用的且已市售超過20年,但其效力受到作用機制之限制。其效力可由於病毒突變及後續抗藥性之發展而進一步受損。 舉例而言,當前不建議使用M2離子通道阻斷劑,此係因為幾乎所有循環性季節A類病毒(包括H1Nipcim09)在M2基因中攜載S31N點突變,該突變賦予對金剛烷胺及金剛乙胺兩者之耐藥性。此情況已導致嚴重依賴於替代性NA抑制劑,諸如紮那米韋、奧司他韋及帕拉米韋(Peramivir)。 NA抑制劑在病毒生命週期方面影響A型流感病毒之裝配及出芽。對於待自細胞釋放之後代病毒粒子,神經胺糖酸酶(NA)必須自宿主醣蛋白裂解唾液酸基團,該唾液酸基團對於病毒擴散及再感染為至關重要的。因此,藉由特定抑制劑(NA抑制劑)阻斷神經胺糖酸酶之功能為治療流感之一種方式。然而,當此類抑制在病毒生命週期之後期(亦即,在病毒進入、複製、裝配及出芽至細胞表面上之後)發生時,已經對細胞造成許多損害。此外,僅細胞表面上之出芽病毒受到影響。不受抑制之病毒後代可感染新的細胞。此情況導致疾病嚴重程度之進展。為降低疾病之嚴重程度,用NA抑制劑藥物治療之最優治療窗為疾病進展之早期。然而,由於給定活性劑之治療功效通常由作用機制決定,因此NA抑制劑藥物被視為相對溫和的且具有有限之臨床益處。 需要用於治療流感之新方法。 A型流感之生命週期包含若干階段: (a) A型流感病毒具有脂質雙層包膜,該脂質雙層包膜內為八個RNA基因組片段,該等片段中之每一者與三聚病毒RNA聚合酶(PB1、PB2、PA)相關聯且包覆有多個核蛋白(NP)以形成vRNP。脂質包膜之外層帶有HA、NA及少數M2之多個複本,而M1分子保持vRNP附接至內層。 (b)病毒表面醣蛋白HA結合至宿主細胞表面唾液酸受體,且病毒在內吞囊泡中經輸送至細胞中。核內體中之低pH觸發HA蛋白質中之構形改變,該改變引起病毒與核內體膜之融合。低pH亦觸發質子經由M2離子通道流動至病毒中,從而將vRNP自M1基質蛋白質解離。當M1分子經解離時,釋放至細胞質中之vRNP藉由核蛋白上之核定位序列(NLS)之識別而經輸送至細胞核中。 (c)在細胞核中,病毒聚合酶引發的病毒mRNA與5'端加帽之RNA片段之合成自宿主前體mRNA裂解。PB2次單元結合宿主前體mRNA之5'端帽,且PA次單元中之核酸內切酶結構域自該帽向下游裂解前體mRNA 10至13核苷酸。病毒mRNA轉錄隨後自加帽RNA片段之經裂解3'端開始。此「帽攫取(cap snatching)」在新生前體mRNA上發生。 (d)病毒mRNA經輸送至細胞質以供轉譯成病毒蛋白質。表面蛋白質HA、M2及NA在內質網(ER)中經處理,在高基氏體(Golgi apparatus)中經糖基化且經輸送至細胞膜。 (e) A型流感病毒之NS1蛋白質在抑止宿主mRNA之產生中充當關鍵角色,其係藉由抑制宿主前體mRNA之3'端處理,從而阻斷宿主mRNA (包括干擾素β mRNA)之產生。不同於宿主前體mRNA,病毒mRNA不需要藉由宿主細胞機構進行之3'端處理。因此,病毒mRNA經輸送至細胞質,而宿主mRNA合成被顯著阻斷。 (f)病毒聚合酶不僅負責加帽RNA啟動之mRNA合成,且亦負責如下vRNA之無啟動複製: (-) vRNA → (+) cRNA → (-) vRNA. 核蛋白分子為此等兩個複製步驟所需要的且在RNA合成期間沈積於cRNA及vRNA上。所得vRNP隨後經輸送至細胞質,由結合至vRNP之M1-NS2複合物介導;NS2與自細胞核輸出vRNP之人類CRM1蛋白質相互作用。 (g) vRNP到達待併入至出芽之新病毒中的細胞膜。新病毒中之HA及NA蛋白質含有末端唾液酸,該等末端唾液酸將導致病毒叢集在一起且黏附至細胞表面。新形成之病毒之NA裂解此等唾液酸殘留物,從而自宿主細胞釋放病毒。 在流感病毒生命週期之階段(a)及(b)期間,病毒表面醣蛋白血球凝集素(HA)結合至宿主細胞上之唾液酸受體,接著受體介導之內吞作用將病毒內吞至細胞中。核內體中之低pH觸發HA蛋白質之構形改變,該改變引起病毒與核內體膜之融合。同時,低pH亦觸發質子經由M2離子通道流動至病毒中,從而將病毒遺傳物質釋放至細胞核以在細胞中開始病毒感染過程。 已認識到,將病毒曝露於細胞外環境中之低pH使病毒失活。低pH鼻內凝膠噴霧已顯示在活體外抑止流感病毒且保護雪貂免受流感感染。然而,在此類研究中,酸之有效濃度約為0.15M (大致pH 3.5)。此外,需要與病毒接觸以具有殺病毒作用。另外,噴霧僅在病毒感染之早期階段期間展現功效。儘管可藉由投與pH 3.5緩衝之鼻噴霧來達成接近3.5之pH值,但此經鼻遞送存在侷限性,此經鼻遞送由於黏液纖毛清除而在鼻中提供相對較短的產品滯留時間。經鼻投與之溶液在人體中之一般滯留時間約為12至15分鐘。 此外,在治療病毒感染之情況下,將需要將酸性緩衝劑深入遞送至呼吸道中。此類緩衝劑之酸性性質將可能在人體中引起刺激及不耐受性。因此,由於酸性鼻內噴霧基本上為受限的且非特異性的,因此酸性鼻內噴霧將不適合作為用於治療流感病毒感染之治療劑。 聚陰離子化合物作為抗HIV劑提供有吸引力的特徵。聚陰離子之抗病毒活性範圍擴展至多種包膜病毒,包括正黏液病毒及副黏液病毒(流感病毒)。此類聚陰離子已顯示在0.1至1 mg/mL之濃度下抑制細胞培養基中之病毒複製。有利地,此等化合物甚至在多達高10,000倍之濃度下不具有細胞毒性。然而,此等物質具有許多藥物動力學及毒理學缺陷,該等缺陷似乎損害該等物質之臨床效用,例如,該等物質在到達其作用位點之前可被各種血漿蛋白質保留在血流中。另外,一些硫酸化多醣因非所要抗凝血劑作用而臭名昭著。 需要有效對抗流感之新抗病毒劑。特定言之,需要展現以下中之一或多者之新抗病毒劑:i)對抗流感病毒之高效能,ii)快速作用以控制感染,iii)廣泛範圍抗病毒活性(包括A型流感、B型流感、禽流感),iv)對抗耐藥性病毒株之功效,v)低傾向之耐藥性,vi)延長之功效持續時間,vii)高選擇性,viii)改良之治療窗;ix)低毒性,x)較少副作用及/或xi)適用於治療性及預防性應用。
本發明提供用於治療及/或預防流感感染之化合物及方法。 本發明化合物,亦稱為「表面工程改造化合物」,被認為改變病毒表面,將表面轉換為微酸性/陰離子環境以選擇性地干擾病毒生命週期(包括上文概述之階段(a)及(b))。 此結果被認為係藉由本發明化合物達成,該等化合物將結合至流感病毒之基團與用以干擾血球凝集素至細胞之結合的酸性或陰離子基團合併。當本發明化合物用以防止細胞感染時,此提供優點且在細胞外發揮其作用。此避免對分子侵入細胞之需要,此情形可能引起較低毒性及/或較少副作用。 在一個態樣中,本發明提供一種包含第一結構域及第二結構域之化合物, 第一結構域包含結合至流感病毒之表面的至少一個錨定基團;且 第二結構域包含至少一個陰離子基團; 或其醫藥學上可接受之鹽、溶劑合物、前藥或立體異構體, 其中第一結構域與第二結構域共價連接。 在另一態樣中,提供第一結構域與第二結構域經由至少一個二價連接基團共價連接之化合物。 在另其他態樣中,本發明化合物可進一步包含多價主鏈基團。 在另一態樣中,提供式(I)化合物:式(I) 或其醫藥學上可接受之鹽、溶劑合物、前藥或立體異構體,其中: A在每次出現時為錨定基團; B為多價主鏈基團; C在每次出現時為陰離子基團; L1
及L2
在每次出現時為二價連接基團; n為1至4之整數;且 p為1至3之整數。 在其他態樣中,提供包含本發明化合物或其醫藥學上可接受之鹽、溶劑合物、前藥或立體異構體之醫藥組合物。在其他態樣中,提供本發明化合物或其醫藥學上可接受之鹽、溶劑合物、前藥或立體異構體之用途,其係用於製造用於治療或預防流感病毒感染之藥劑。 在其他態樣中,提供治療或預防流感病毒感染之方法,該等方法包含向有需要之個人投與治療有效量之本發明化合物或其醫藥學上可接受之鹽、溶劑合物、前藥或立體異構體。 在一些態樣中,流感病毒感染為A型流感、B型流感、禽流感或耐藥性流感病毒株。 除非另外定義,否則本文中所用之所有技術術語及科學術語具有與一般熟習此項技術者通常所理解相同之含義。 在本說明書中對任何先前技術之提及並非且不應視為承認或以任何形式暗示該先前技術形成普通常識之部分。 本文中引用之所有文獻各自以其全文引用之方式併入。
歸檔資料
本申請案與2015年11月20日申請之澳大利亞專利申請案第2015904895號相關聯且主張其優先權,該申請案之全部內容以引用之方式併入本文中。 如上文所論述,本發明化合物被認為改變病毒表面,將表面轉換為微酸性/陰離子環境以選擇性地干擾病毒生命週期中之各階段。 咸信本發明化合物之酸性/陰離子基團將病毒表面轉換為使病毒活性降低或失活之微酸性/陰離子環境。此外,咸信此等化合物在細胞外起作用且因此可能與副作用之發生減少、毒性降低及/或耐藥性傾向減少相關聯。更特定言之,咸信本發明化合物在細胞外、在病毒生命週期之多個目標點起作用,包括(但不限於): · 酸性/陰離子基團在病毒表面處產生低pH,該低pH觸發血球凝集素(HA)蛋白質之早期構形改變,該改變隨後可減少或阻滯病毒與細胞之融合。此過程特定於上文所提及之病毒生命週期階段(b)。 · 另外,咸信在病毒表面上創造低pH環境激發質子經由M2離子通道流動至病毒中,其可導致遺傳物質釋放在細胞外部。此過程特定於上文所提及之病毒生命週期階段(b)。 · 咸信本發明化合物之錨定基團可交聯NA/HA且聚集病毒粒子以降低病毒之遷移率及感染性。此過程特定於上文所提及之病毒生命週期階段(a)及(b)。 · 咸信錨定基團抑制神經胺糖酸酶(NA)之功能以減少或防止自細胞膜釋放新病毒。此過程特定於上文所提及之病毒生命週期階段(g)。 咸信擾亂病毒生命週期階段(a)及(b)可藉由降低病毒感染性(包括病毒侵入細胞、正常細胞核功能之病毒擾亂及/或病毒複製)來降低感染之潛在嚴重程度。因此,認為相比於當前可用的NA抑制劑藥物,投與本發明化合物可為患者提供對病毒感染之更有效治療及/或更快恢復。此外,咸信本發明化合物可預防性地用於預防流感感染。 因此,在一個態樣中,本發明提供一種包含第一結構域及第二結構域之化合物, 該第一結構域包含結合至流感病毒之表面的至少一個錨定基團;且 第二結構域包含至少一個陰離子基團; 或其醫藥學上可接受之鹽、溶劑合物、前藥或立體異構體, 其中該第一結構域與該第二結構域共價連接。 在一些態樣中,第一結構域及第二結構域可經由至少一個二價連接基團共價連接。在其他態樣中,本發明化合物可進一步包含多價主鏈基團。 在另一態樣中,本發明提供式(I)化合物:式(I) 或其醫藥學上可接受之鹽、溶劑合物、前藥、酯或立體異構體,其中: A在每次出現時為錨定基團; B為多價主鏈基團; C在每次出現時為陰離子基團; L1
及L2
在每次出現時為二價連接基團; n為1至4之整數;且 p為1至4之整數。 如本文所使用,「本發明化合物」或「式(I)化合物」意謂化合物或其醫藥學上可接受之鹽、溶劑合物、前藥、酯或立體異構體,或其生理學功能性衍生物。 如本文所用之術語「錨定基團」係指結合至流感病毒之表面的任何適合基團。在一些實施例中,錨定基團為結合至神經胺糖酸酶之基團,諸如神經胺糖酸酶抑制劑或其衍生物。適合的基團之實例包括(但不限於):唾液酸或其衍生物,包括神經胺糖酸之經N
取代之衍生物或經O
取代之衍生物,諸如紮那米韋或拉蘭那米韋(laninamivir)、奧司他韋、帕拉米韋、2,3-二氟唾液酸(DFSA)及其衍生物。在其他實施例中,錨定基團包含特異性地結合神經胺糖酸酶之抗體結合結構域。包含特異性地結合神經胺糖酸酶之抗體結合結構域的適合錨定基團之實例包括抗體(Ab)或抗體之抗原結合片段、單鏈抗體片段(scFV)或單結構域抗體(dAb)。 如本文所用之術語「主鏈基團」係指一或多個錨定基團及一或多個酸性或陰離子基團連接至之任何適合的多價基團。在一些態樣中,主鏈基團可為三價基團。在其他態樣中,主鏈基團可為四價基團。適合的主鏈基團之實例包括(但不限於):視情況經取代之丙烷-1,2,3-三羧酸酯、視情況經取代之環己烷-1,3,5-三羧酸酯及視情況經取代之苯-1,2,4,5-四羧酸酯。 術語「酸性或陰離子基團」及「酸性/陰離子基團」係指具有酸性及/或陰離子特性、作用以干擾血球凝集素至細胞之結合的任何適合的官能基。具體言之,術語「陰離子」描述官能基或材料之淨負電荷。應理解,給定的帶負電荷材料可具有與其相關聯之一或多個帶正電荷相對離子,或反之亦然。在溶液中,帶負電荷材料可與同其相關聯之一或多個帶正電荷相對離子解離。如本文所使用,術語「陰離子」用以描述彼材料或官能基之特性,而非具有將通常使得複合物呈中性之一或多個相對離子之整個複合物的特性。應理解,某些官能基在變化的pH值下帶負電荷、中性或帶正電荷。材料是否為陰離子將基於此等電荷之和進行判定。舉例而言,在本發明之範疇內,酸性或陰離子基團可包括以下官能基中之一或多者:羧酸、磺酸、磷酸及次膦酸及其同電子排列體或生物同電子排列體。適合的酸性或陰離子基團之實例包括:羧酸、胺基酸、二肽、三肽或多肽或其具有酸性及/或陰離子特性之衍生物,諸如天冬胺酸、氧化半胱胺酸、麩胺酸或衍生自天冬胺酸、氧化半胱胺酸及/或麩胺酸之肽。 術語「唾液酸」在此項技術中為眾所周知的且係指9-碳單醣,尤其係指衍生自神經胺糖酸之彼等者。適合的基團之實例包括(但不限於):衍生自N -
乙醯基神經胺糖酸(Neu5Ac)及N -
羥乙醯基神經胺糖酸(Neu5Gc)之N
取代物及/或O
取代物的視情況經取代之單醣。 術語「神經胺糖酸酶抑制劑」在此項技術中為眾所周知的且係指阻斷神經胺糖酸酶之一類化合物。在一些實施例中,錨定基團可為神經胺糖酸酶抑制劑或其衍生物。適合的神經胺糖酸酶抑制劑之實例包括(但不限於):唾液酸或唾液酸之衍生物,諸如2,3-二氟唾液酸。其他適合的神經胺糖酸酶抑制劑包括:紮那米韋 奧司他韋蘭那米韋 帕拉米韋 及其衍生物。 如本文關於抗體與第二化學物質之相互作用所使用之術語「特異性結合」或「特異性地結合」意謂該相互作用取決於化學物質上特定結構(例如,抗原決定子或抗原決定基)之存在;舉例而言,抗體識別且結合至特定蛋白質結構而非一般性地結合至蛋白質。 如本文使用之術語「抗體」廣義地係指由四條多肽鏈(兩條重(H)鏈及兩條輕(L)鏈)構成,保留免疫球蛋白(Ig)分子之主要抗原決定基結合特徵的任何Ig分子或其任何功能片段、突變體、變異體或衍生物。該等突變體、變異體或衍生物抗體形式在此項技術中已知。其非限制性實施例於下文加以論述。 在全長抗體中,各重鏈由重鏈可變區(本文中縮寫為HCVR或VH)及重鏈恆定區構成。重鏈恆定區由三個結構域CH1、CH2及CH3構成。各輕鏈由輕鏈可變區(本文中縮寫為LCVR或VL)及輕鏈恆定區構成。輕鏈恆定區由一個結構域CL構成。VH區及VL區可進一步再分成高變區,被稱為互補決定區(CDR),穿插有被稱為構架區(FR)之更保守區。各VH及VL由自胺基端至羧基端依以下順序排列之三個CDR及四個FR構成:FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。免疫球蛋白分子可具有任何類型(例如IgG、IgE、IgM、IgD、IgA及IgY)、類別(例如IgG1、IgG2、IgG3、IgG4、IgA1及IgA2)或子類別。 如本文所使用之術語抗體之「抗原結合結構域」或「抗原結合片段」係指保留特異性地結合至抗原(例如,IL-12)之能力的抗體或蛋白質之一或多個片段。經顯示,抗體之抗原結合功能可由全長抗體之片段來進行。此類抗體實施例亦可為雙特異性、雙重特異性或多特異性形式;特異性地結合至兩個或多於兩個不同抗原。涵蓋於術語抗體之「抗原結合部分」內之結合片段之實例包括:(i) Fab片段,由VL結構域、VH結構域、CL結構域及CHl結構域組成之單價片段;(ii) F(ab')2片段,包含藉由鉸鏈區處之二硫橋鍵連接之兩個Fab片段的二價片段;(iii) Fd片段,其由VH結構域及CHl結構域組成;(iv) Fv片段,其由抗體之單臂的VL結構域及VH結構域組成,(v) dAb片段(Ward等人,1989 Nature 341 544-6,Winter等人,PCT公開案WO 90/05144 Al,以引用之方式併入本文中),其包含單個可變結構域;及(vi)分離之互補決定區(CDR)。此外,儘管Fv片段之兩個結構域VL及VH藉由單獨基因寫碼,但其可使用重組方法藉由合成性連接基團接合,該合成性連接基團使得其能夠經形成為VL及VH區配對從而形成單價分子之單一蛋白質鏈(被稱為單鏈Fv (scFv));(例如參見Bird等人,1988 Science 242 423-6;Huston等人,1988 Proc Natl Acad Sci U S A 85 5879-83)。此類單鏈抗體亦意欲涵蓋於術語抗體之「抗原結合部分」內。亦涵蓋其他形式之單鏈抗體,諸如雙功能抗體。雙功能抗體為二價雙特異性抗體,其中VH結構域及VL結構域在單一多肽鏈上表現,但使用之連接基團過短以致不允許在同一條鏈上之兩個結構域之間進行配對,從而迫使該等結構域與另一條鏈之互補結構域配對且產生兩個抗原結合位點(例如參見Holliger, P.等人,1993,Proc. Natl. Acad. Sci. USA 90:6444-6448;Poljak, R. J.等人,1994,Structure 2:1121-1123)。此類抗體結合部分在此項技術中已知(Kontermann及Dubel編,Antibody Engineering 2001 Springer-Verlag. New York.第790頁,ISBN 3-540-41354-5)。 在一個實施例中,錨定基團在每次出現時為結合至流感病毒之表面的任何適合的錨定基團。在一些實施例中,錨定基團在每次出現時為結合至神經胺糖酸酶之基團,包括神經胺糖酸酶抑制劑或其衍生物。在某些實施例中,錨定基團為神經胺糖酸酶抑制劑或其衍生物,其係選自唾液酸(諸如,紮那米韋或蘭那米韋)、2,3-二氟唾液酸、奧司他韋、帕拉米韋及其衍生物。在其他實施例中,錨定基團在每次出現時包含特異性地結合神經胺糖酸酶之抗體結合結構域。在錨定基團為特異性地結合神經胺糖酸酶之抗體結合結構域的某些實施例中,錨定基團係選自由以下組成之群:抗體(Ab)、抗體之抗原結合片段、單鏈抗體片段(scFV)及單結構域抗體(dAb)。本發明化合物可總共包含1至6個錨定基團,較佳地2至4個錨定基團,更佳地2個錨定基團。 在另一實施例中,錨定基團為衍生自以下各基團之單價基團:式II之基團;( 式 II )
式III之基團;( 式 III )
式IV之基團;( 式 IV )
及式V之基團 ( 式 V )
其中E1
係選自由以下組成之群:-COOH、COOHR6
、-SO3
H、-PO3
H2
、-PO(OR6
)2
, G1
係選自-NH2
、-CH2
NH2
、-(CH2
)2
NH2
、, T1
係選自由以下組成之群:視情況經取代之C1
-C6
烷基、視情況經取代之C2
-C6
烯基或視情況經取代之C2
-C6
炔基, U1
係選自由以下組成之群:-CH2
R7
、-(CH2
)2
R7
、-CH2
CHR7
CH2
R7
, R7
係選自由以下組成之群:H、-OH、-OCH3
、-OAc、-NH2
或-SH, R8
及R8 '
各自獨立地選自由以下組成之群:氫、-N3
、-CN、-CH2
NH2
、胍基或-NR10
R11
; R9
係選自氫、視情況經取代之C1
-C6
烷基、視情況經取代之C2
-C6
烯基或視情況經取代之C2
-C6
炔基; R10
及R11
各自獨立地選自由以下組成之群:氫、視情況經取代之C1
-C6
烷基、視情況經取代之C1
-C6
醯基、-C(NH)NH2
、-CH2
COOH、CH2
CH2
OH或-CH2
CH(R12
)(R13
), R12
及R13
各自獨立地選自O及R14
N=,且 R14
係選自由以下組成之群:氫、-OH、-OCH3
、-NH2
及-N(CH3
)2
, R15
及R15 '
各自獨立地選自氫及CO2
R16
, R16
為H或視情況經取代之C1
-C6
烷基; R17
係選自NH2
及-NHC(═NH)NH2
; G2
為; R18
係選自由以下組成之群:氫、視情況經取代之C1
-C6
烷基、視情況經取代之C2
-C6
烯基及視情況經取代之C2
-C6
炔基。 在另其他實施例中,錨定基團在每次出現時係選自由式VI之基團及式VII之基團組成之群: ( 式 VI ) ( 式 VII )
其中R1
係選自由以下組成之群:-NR2
、胍基、-ONR2
,其中R為H或視情況經取代之C1
-C6
烷基, R2
係選自由以下組成之群:H、視情況經取代之C1
-C6
烷基及視情況經取代之芳基,且 R3
係選自由以下組成之群:H、視情況經取代之C1
-C6
烷基、視情況經取代之芳基及視情況經取代之C1
-C6
醯基。 在另一實施例中,錨定基團為式(VIa)之基團: 式 ( VIa )
。 在又一實施例中,錨定基團為式(VIIa)之基團: 式 ( VIIa )
。 在一實施例中,連接基團(諸如式I之L1
及/或L2
)在每次出現時為任何適合的二價連接基團。在一個實施例中,連接基團在每次出現時獨立地選自鍵、視情況經取代之C1
-C12
伸烷基、-C(O)-NR-、-O-C(O)O-NR-、-C=N-O-、-C=N-NR-、-SO2
-NR-、二硫鍵、-C(O)-NR-(CH2
)x
-NR-、-(CH2
)x
-NR-、-(CH2
)x
-(O-(CH2
)y
-)z
-、視情況經取代之-C=N-O-、視情況經取代之-C=N-NR-伸烷基、視情況經取代之伸烷基磺醯胺、視情況經取代之伸烷基二硫鍵,其中R獨立地為H或C1
-C6
烷基,且其中x、y及z各自為獨立地選自0、1、2、3及4之整數。 在錨定基團為式(VI)或式(VIa)之基團的一個實施例中,式(I)之連接基團L1
係選自-C(O)-NR-(CH2)x-NR-、-(CH2
)x
-NH-及-(CH2
)x
-(O-(CH2
)y
)z
,其中x、y及z各自為獨立地選自0、1、2、3及4之整數。在錨定基團為式(VII)或式(VIIa)之基團的另一實施例中,式(I)之連接基團L1
為-(CH2
)x
-NH-,其中x為選自0、1、2、3及4之整數。 在一個實施例中,式(I)之連接基團L2
為鍵。 在一實施例中,主鏈基團為任何適合的多價基團。在一個實施例中,主鏈基團為三價主鏈基團。在另一實施例中,主鏈基團為四價主鏈基團。在一個實施例中,主鏈基團係選自視情況經取代之三羧酸酯基團、視情況經取代之四羧酸酯基團或多價肽。在其他實施例中,主鏈基團係選自視情況經取代之丙烷-1,2,3-三羧酸酯、視情況經取代之丙-1-烯-1,2,3-三羧酸酯、視情況經取代之環丙烷-1,2,3-三羧酸酯、視情況經取代之環己烷-1,3,5-三羧酸酯、視情況經取代之苯-1,3,5-三羧酸酯、視情況經取代之甲烷四羧酸酯、視情況經取代之1,2,3,4-丁烷四羧酸酯、視情況經取代之伸乙基-1,1,2,2-四羧酸酯(諸如乙二胺四乙酸(EDTA))、視情況經取代之環己烷-1,2,4,5-四羧酸酯及視情況經取代之苯-1,2,4,5-四羧酸酯。在另其他實施例中,主鏈基團係選自視情況經取代之丙烷-1,2,3-三羧酸酯、視情況經取代之環己烷-1,3,5-三羧酸酯、視情況經取代之苯-1,2,4,5-四羧酸酯、視情況經取代之苯均四酸及由-C(O)-NH-NH-C(O)-鍵形成之視情況經取代之二苯均四酸(5,5'-(肼-1,2-二羰基)雙(苯-1,2,4-三羧酸))。在另其他實施例中,主鏈基團為多價肽。 在一實施例中,酸性或陰離子基團為具有酸性及/或陰離子特性、作用以干擾血球凝集素至細胞之結合的任何適合的官能基。在一些實施例中,酸性或陰離子基團為包含選自以下之一或多個官能基之任何適合的基團:羧酸、磺酸、磷酸及次膦酸及其同電子排列體或生物同電子排列體。在一些實施例中,酸性或陰離子基團為包含一或多個酸性官能基之任何適合的胺基酸、二肽、三肽、多肽或其衍生物。在一個實施例中,酸性或陰離子基團為天冬胺酸、氧化半胱胺酸、麩胺酸或衍生自天冬胺酸、氧化半胱胺酸及/或麩胺酸之肽。 在一實施例中,本發明化合物總共包含2至26個酸性/陰離子殘基,較佳地4至10個酸性/陰離子殘基。舉例而言,在酸性或陰離子基團包含二羧酸時,應瞭解,此部分包含兩個不同的酸性/陰離子殘基。借助於參考本發明化合物之代表性實例之實例,應注意,MD349總共包含九個酸性或陰離子殘基(五個羧酸殘基及四個磺酸殘基),MD348總共包含七個酸性或陰離子殘基(四個羧酸殘基及三個磺酸殘基),MD345總共包含八個酸性或陰離子殘基(一個羧酸殘基及七個磺酸殘基),MD352總共包含九個酸性或陰離子殘基(兩個羧酸殘基及七個磺酸殘基),MD356總共包含六個酸性或陰離子殘基(兩個羧酸殘基及四個磺酸殘基),MD357總共包含六個酸性或陰離子殘基(兩個羧酸殘基及四個磺酸殘基),MD358總共包含八個酸性或陰離子殘基(八個羧酸殘基),MD359總共包含八個酸性或陰離子殘基(兩個羧酸殘基及六個磺酸殘基),MD373總共包含八個酸性或陰離子殘基(八個羧酸殘基),且MD376總共包含十個酸性或陰離子殘基(十個羧酸殘基)。 在另一實施例中,酸性或陰離子基團為式VIII之基團: ( 式 VIII )
其中 R4
在每次出現時獨立地選自由以下組成之群:-COOH、-SO3
H、-NHCH2
SO3
H、-CONH-Cya、-CONH-Asp、-CONH-Asp(-NHCH2
SO3
H)w
及-CONH-Asp(-NHCH2
PO3
H)w
,其中w為整數1或2; R5
係選自由-OH及-NHCH2
SO3
H組成之群; u為0至3之整數; t為0至3之整數; r為0至6之整數; v為1至12之整數。 在一實施例中,n為1至4之整數。在另一實施例中,n為1至3之整數。在某些實施例中,n為1。在其他實施例中,n為2。在另其他實施例中,n為3。在又其他實施例中,n為4。 在一實施例中,p為1至4之整數。在另一實施例中,p為1至2之整數。在某些實施例中,p為1。在其他實施例中,p為2。在另其他實施例中,p為3。在又其他實施例中,p為4。
另外或替代地,在一些實施例中,式(I)化合物可在裝配之前、期間或之後經修改,以增強或修改對於流感病毒表面之生物活性及/或結合親和力。在一實施例中,在酸性或陰離子基團包含一或多個羧酸(包括胺基酸)時,羧酸可藉由硫酸化、磷酸化、官能基相互轉化及/或側鏈之連接進行修改。舉例而言,在酸性或陰離子基團包含羧酸時,羧酸可經修改為包括-C(=O)NH(CH2)nSO3H之醯胺或硫酸化醯胺。替代地或另外,在酸性或陰離子基團包含胺基酸或肽時,C端可經修改成包括替代性官能基,諸如將末端酸轉化為包括-C(=O)NH(CH2)nSO3H之醯胺或硫酸化醯胺。
對於本文揭示之式(I)化合物,涵蓋以下(i)至(vii)中之任一者或更多者之組合:(i)A為式(IIa);或A為式(IIIa);(ii)B為丙烷-1,2,3-三羧酸;或B為環己烷-1,3,5-三羧酸酯,或B為苯-1,2,4,5-四羧酸酯;(iii)L1為-C(O)-NH-;或L1為-C(O)-NH-(CH2)2-NH-;或L1為-C(O)-NH-(CH2)3-NH-;或L1為-C(O)-NH-(CH2)4-NH-;或L1為-C(O)-NH-(CH2)5-NH-;或L1為-C(O)-NH-(CH2)6-NH-;或L1為-C(O)-NH-(CH2)7-NH-;或L1為-C(O)-NH-(CH2)8-NH-;或
L1為-C(O)-NH-(CH2)9-NH-;或L1為-C(O)-NH-(CH2)10-NH-;或L1為-C(O)-NH-(CH2)12-NH-;或L1為-(CH2)6-NH-;或L1為-(CH2)8-NH-;或L1為-(CH2)9-NH-;或L1為-(CH2)10-NH-;或L1為-(CH2)12-NH-;(iv)L2為鍵;(v)C為L-天冬胺酸;或C為D-天冬胺酸;或C為L-氧化半胱胺酸;或C為D-氧化半胱胺酸;或C為-(L-Asp)2-OH;或C為-(D-Asp)2-OH;或C為-(L-Cya)2-OH;或C為-(D-Cya)2-OH;或C為-(L-Asp)3-OH;或C為-(D-Asp)3-OH;或C為-(L-Cya)3-OH;或C為-(D-Cya)3-OH;或C為-(L-Cya)7-OH;或C為-(D-Cya)7-OH;或 C為-(L-Asp-L-Cya)4
-OH;或 C為-(L-Asp-L-Cya)4
-OH;或 C為-[L-Asp(L-Cya)]3
-OH;或 C為-[D-Asp(D-Cya)]3
-OH;或 C為-[L-Asp(L-Cya)]4
-OH;或 C為-[(L-Asp)4
-(L-Cya)3
]-OH;或 C為-[(D-Asp)4
-(D-Cya)3
]-OH;或 C為-[L-Asp(L-Cya)]3
-OH;或 C為-[D-Asp(D-Cya)]3
-OH;或 C為-[L-Asp(L-Cya)]4
-OH;或 C為-[D-Asp(D-Cya)]4
-OH;或 C為L-Asp(NHCH2
SO3
H)2
;或 C為D-Asp(NHCH2
SO3
H)2
;或 C為-[L-Asp(NHCH2
SO3
)]3
-NHCH2
SO3
H;或 C為-[D-Asp(NHCH2
SO3
)]3
-NHCH2
SO3
H; (vi) n為2;或 n為3 (vii) p為1;或 p為2。 為方便參考,可縮寫本發明化合物之代表性實例。舉例而言,在代表性實例之上下文中,為方便參考,錨定基團(包括式(I)之A)及連接基團(包括式(I)之L1
)在每次出現時可經表示為單個基團,被稱作Zx
或Sy
。具體言之,在本發明化合物包含式Zx
之基團時,此類基團為唾液酸衍生物,其中官能基(胺基或胍基)取代唾液酸環之位置4處的羥基。此修改使得式Zx之基團能夠與流感病毒神經胺糖酸酶相互作用,但不與哺乳動物神經胺糖酸酶相互作用。此情形在將本發明化合物投與給包括人類之哺乳動物時提供安全態樣。式Sy之基團經由唾液酸之2-羥基連接。具體言之,硫基-糖苷連接基團用於與式Sy中之錨定基團(諸如,2-S-(CH2)mNHR)結合,該連接基團與等效醚連接基團(諸如,2-O-(CH2)mNHR)相比阻礙酶水解。為方便參考,Zx或Sy之結構概述如下:
表39:針對式(I)之代表性化合物之CPE分析中之抗流感病毒活性(EC50ng/ml/nM) 表 40 : 在不同病毒滴定度下針對式 ( I ) 之代表性化合物之 CPE 分析中之抗流感病毒活性 ( EC50 ng / ml / nM ) 實例 8 : 式 ( I ) 之代表性化合物之 ADME 毒理學
在hERG IC50
(hERG-CHO,自動化膜片鉗)分析中測試式(I)之兩種化合物MD185及MD317。MD 185之IC50
值不可計算。MD317之效量曲線展示在最高驗證測試濃度(亦即IC50
> 100 nM)下低於25%效力。 結果表明MD185及MD317在心臟毒性方面為安全的。實例 9 : 式 ( I ) 之代表性化合物之激酶組掃描分析
根據激酶分析之以下協定測試式(I)之兩種化合物MD185及MD317。 對於大多數分析,激酶標記之T7噬菌體病毒株同時生長於自BL21病毒株衍生之大腸桿菌宿主中之24孔方塊中。大腸桿菌生長至對數期並自冷凍儲備液用T7相感染(感染倍率 = 0.4)並藉由在32℃下振盪培育直至裂解(90至150分鐘)。將裂解物離心(6,000×g)並過濾(0.2 μm)以移除細胞殘渣。在HEK-293細胞中產生剩餘激酶且隨後標記有DNA以供qPCR檢測。在室溫下用生物素化小分子配位體處理經抗生蛋白鏈菌素塗佈之磁性珠粒持續30分鐘,產生用於激酶分析之親和樹脂。用過量生物素阻斷經配位之珠粒,且用阻斷緩衝液(SeaBlock (pierce),1% BSA、0.05% Tween20、1 mM DTT)洗滌以移除未結合之配位體及減少非特異性鍵結。結合反應藉由在1×結合緩衝液(20% SeaBlock、0.17×PBS、0.05% Tween20、6 mM DTT)中組合激酶、經配位之親和珠粒及測試化合物來組裝。將測試化合物製備為含40×原料之100%DMSO並直接稀釋至分析中。所有反應均在聚丙烯384孔培養盤中以0.04 ml之最終體積進行。將分析培養盤在室溫下在震盪下培育1小時,且用緩衝液(1×PBS、0.05% Tween 20)洗滌親和珠粒。接著將珠粒再懸浮於溶離緩衝液(1×PBS,0.05% Tween 20,0.5 μM未經生物素標記之親和配位體)中並藉由振盪在室溫下培育30分鐘。溶離液中之激酶濃度藉由qPCR來測量。 在100 nM下在化合物與激酶之間不存在顯著相互作用。結果概括於表41中。表 41 :選擇性評分表 本發明之代表性化合物之製備
為方便起見,許多化學部分使用熟知縮寫來表示,該等縮寫包括(但不限於):甲基(Me)、乙基(Et)、正丙基(nPr)、異丙基(iPr)、正丁基(nBu)、第三丁基(tBu)、正己基(nHex)、環己基(cHex)、苯基(Ph)、甲氧基(MeO)、乙氧基(EtO)、三甲基矽烷基(TMS)、第三丁氧基羰基(Boc)及乙醯基(Ac)。 為方便起見,許多化合物使用熟知縮寫來表示,該等縮寫包括(但不限於):甲醇(MeOH)、乙醇(EtOH)、乙醚(Et2O)、乙酸乙酯(EtOAc)、三乙胺(TEA)、二氯甲烷(dichloromethane) (二氯甲烷(methylene chloride)、DCM、CH2
Cl2
)、三氟乙酸(TFA)、三氟乙醇(TFE)、二甲基甲醯胺(DMF)、硫酸鈉(Na2
SO4
)、四氫呋喃(THF)、間氯過氧苯甲酸(m
CPBA)、六甲基二矽氮烷鈉鹽(NaHMDS)、O-(7-氮雜苯并三唑-1-基)-N,N,N',N'-四甲六氟磷酸酯(HATU)、O -
(苯并三唑-1-基)-N , N , N ', N '-
雙(四亞甲基)六氟磷酸酯(HBTU)、二甲亞碸(DMSO)、硫酸鎂(MgSO4
)、碳酸氫鈉(NaHCO3
)、第三丁醇(t
-BuOH)、1-乙基-3-(3-二甲胺基丙基)碳化二亞胺鹽酸鹽(EDCl.HCl)、氟化四正丁基銨(TBAF)、N,N-二異丙基乙胺(DIPEA)、第三丁基二甲基矽烷基(TBDMS)、1-羥基苯并三唑(HOBt)、反二氯雙(三苯膦)鈀(II) (PdCl2
(PPh3
)2
)、肆(三苯膦)鈀(0) (Pd(PPh3
)4
)、參(二苯苄基丙酮)二鈀(0) (Pd2
(dba)3
)、鏻四氟硼酸三-第三丁酯(t
-Bu3
PH.BF4
)、4,5-雙(二苯膦基)-9,9-二甲基二苯并哌喃(Xantphos)、三苯膦(PPh3
)、偶氮二甲酸二異丙酯(DIAD)、氯鉻酸吡啶(PCC)、甲硼烷二甲基硫醚(BMS)、異丙醇鈦(TiOiPr4
)、三乙醯氧基硼氫化鈉(NaBH(OAc)3
)、氰基硼氫化鈉(NaBH3
(CN))、硼氫化鈉(NaBH4
)、氯化銨(NH4
Cl)、氯仿(CHCl3
)、二氧化錳(MnO2
)、碳酸鉀(K2
CO3
)、1,2-二氯乙烷(DCE)、疊氮化鈉(NaN3
)、亞硝酸鈉(NaNO2
)、二碳酸二-第三丁酯(Boc2
O)及S-乙醯胺基甲基(Acm)。 式(I)化合物之一般合成概括於下方流程 1
中:流程 1 : 式 ( I ) 化合物之一般合成 實例 10 : N - Boc - 1 , 9 - 二胺基壬烷之製備
將1,9-二胺基壬烷(1 g,6.329毫莫耳)溶解於50 ml乙醇與50 ml水之混合物中,接著在R.T.下添加二碳酸二-第三丁酯(1.38 g,6.329毫莫耳)。在R.T.下攪拌全部混合物16小時,得到白色懸浮液。過濾出此懸浮液。在風乾之後固體為二-Boc-1,9-二胺基壬烷488 mg (1.36毫莫耳,21.53%產率)。用二氯甲烷(150 ml,100 ml)萃取濾過物。可將含有未反應之1,9-二胺基壬烷(289 mg,1.83毫莫耳)之水層再利用於下一批次之製備中。有機萃取物經合併且用50 ml水洗滌,接著與10 g無水Na2
SO4
一起在R.T.下攪拌隔夜。過濾有機懸浮液。將濾過物真空蒸發至乾燥,得到呈無色固體狀之N-Boc-1,9-二胺基壬烷809 mg (49.5%產率)。MS 295(M+1)。實例 11 : 錨定化合物 Zn ' 之製備
合成詳述於下方流程 2
中。以下化合物參考編號及合成步驟參照係關於流程 2
。 步驟A)在60℃至62℃下將唾液酸(1) (5 g,16.18毫莫耳)及Dowex 50×8 (H+
)樹脂(10 g)在無水甲醇(400 mL)中攪拌48小時。過濾出混合物。將濾過物真空蒸發至乾燥,得到呈白色固體狀之化合物(2) 4.5 g (13.25毫莫耳,82.5%產率)。MS 338(M+1)。 步驟B)將化合物(2) (4 g,11.87毫莫耳)與乙酸酐(40 mL,d 1.08,MW 102.29,423毫莫耳)及硫酸(2 mL)一起攪拌。接著在32℃至35℃下將混合物在油浴中攪拌72小時。在冰浴下將反應混合物逐滴添加至Na2
CO3
(51 g)於水(280 mL)及乙酸乙酯(14 mL)中之攪拌混合物中。然後,在冰浴中將混合物攪拌額外1.5小時,隨後用乙酸乙酯(400 mL,270 mL)萃取。乙酸乙酯萃取物經合併且用10% NaHCO3
溶液(270 mL×2)、飽和NaCl溶液(270 mL×2)洗滌,經無水Na2
SO4
乾燥隔夜。過濾,將濾過物真空蒸發至乾燥,得到化合物(3) 4.78 g (11.57毫莫耳,97.5%產率)。MS 414(M+1)。油狀殘餘物在儲存於裝有P2
O5
之乾燥器中3天之後變成灰白色固體。 步驟C)將化合物(3) (3.47 g,8.4毫莫耳)溶解於第三BuOH (25 mL)中。向此溶液中添加疊氮基三甲基矽烷(1.81 mL,13.63毫莫耳)。在80℃至82℃下在氬氣下將全部混合物攪拌24小時。反應混合物用乙酸乙酯(100 mL)稀釋,接著與含0.9 g NaNO2
之25 mL水一起攪拌,且在室溫下用5N HCl經1小時之時段調整至pH 2。將二相混合物分離,用乙酸乙酯(50 mL)萃取水層。有機萃取物經合併且用水(25 mL×2)、6% NaHCO3
溶液(25 mL)、水(25 mL×3)連續洗滌,接著經Na2
SO4
乾燥。將濾過物真空蒸發至乾燥,得到呈油狀物質之化合物(4) 3.17 g (6.95毫莫耳,82.7%產率)。MS 457(M+1),479(M+Na),925(2M+Na)。 步驟D)將化合物(4) (3.15 g,6.91毫莫耳)溶解於甲醇(100 mL)及甲苯(70 mL)中。將溶液放置於真空下以移除空氣(氧氣),接著用氬氣回填。向此混合物中添加Pd/C (10%) (616 mg),接著放置於真空下以排出氬氣,氬氣隨後經氫氣(H2
)替換。在室溫下進行氫化持續2小時且隨後過濾出觸媒。將濾過物真空蒸發至乾燥,得到呈灰白色固體狀之化合物(5) 2.82 g (6.55毫莫耳,94.7%產率)。MS 431 (M+1)。 步驟E)將化合物(5) (2.80 g,6.51毫莫耳)溶解於無水乙腈(15 mL)中。向此溶液中添加N,N'-二-Boc-1H-吡唑-1-甲脒[雙(Boc)PCH] (3.03 g,9.76毫莫耳)。在室溫下在氬氣下攪拌全部混合物40小時。將反應混合物真空蒸發至乾燥。將殘餘物溶解於乙酸乙酯(4 mL)中,接著用己烷(4 mL)稀釋,塗覆於急驟管柱層析上,用己烷(150 mL)洗滌,接著用溶劑(乙酸乙酯:己烷1:1) (150 mL)洗滌,最後用溶劑(乙酸乙酯:己烷1:1)溶離。真空蒸發所收集之部分,得到呈白色固體狀之產物化合物(6),3.23 g (4.8毫莫耳,73.7%產率)。MS 673(M+1)。 步驟F)將化合物(6) (2.8715 g,4.273毫莫耳)溶解於無水甲醇(22 mL)中。在氬氣下向此溶液中添加NaOCH3
(4.9134 mg,0.2136毫莫耳)。在R.T.下在氬氣下將全部混合物攪拌2.5小時,接著用Dowex50×8 (H+
)樹脂調整至pH 6.5,隨後將該樹脂過濾出。將濾過物真空蒸發至乾燥,得到呈白色固體狀之化合物(7) 2.2024 g (4.0337毫莫耳,94.4%產率)。MS 547(M+1)。 步驟G)將化合物(7) (2 g,3.66毫莫耳)溶解於無水乙腈中。向此溶液中添加1,1'-羰基二咪唑(714 mg,4.403毫莫耳)。在20℃至30℃下在氬氣下攪拌全部混合物18小時。將其真空蒸發至乾燥,接著對殘餘物進行急驟管柱層析,首先用己烷(150 mL)洗滌,接著用溶劑(乙酸乙酯:己烷2:1)展開。Rf
值為0.5之部分(乙酸乙酯:己烷2:1)經合併且真空蒸發至乾燥,得到呈白色固體狀之化合物(8) 1.35 g (2.36毫莫耳,64.5%產率)。MS 573(M+1)。 步驟H)將化合物(8) (1.3 g,2.27毫莫耳)溶解於無水吡啶(12.5 mL)中。向此溶液中添加氯甲酸對硝苯酯(503.3 mg,2.497毫莫耳)、4-二甲胺基-吡啶(808.5 mg,6.62毫莫耳)。在30℃下在氬氣下攪拌全部混合物7小時。向此反應混合物中添加N -
Boc-1,9-二胺基壬烷(690 mg,2.67毫莫耳)及4-二甲胺基吡啶(166 mg,1.36毫莫耳)於無水吡啶(4 mL)中之溶液。在30℃下在氬氣下攪拌反應混合物16小時,接著真空蒸發以移除吡啶。將殘餘物分配於乙酸乙酯(300 mL)與含有2.45 mL之5N HCl之水(50 mL)之間,用水(50 mL×2)、2% NaHCO3
溶液(50 mL×6)、水(50 mL×2)連續洗滌,經無水Na2
SO4
乾燥且過濾。將濾過物真空蒸發至乾燥,得到2.25 g油狀物質。對其進行急驟管柱層析(乙酸乙酯:己烷1.5:1作為溶離劑)。部分(Rf值為0.27 TLC,乙酸乙酯:己烷1.5:1作為展開溶劑)經合併且真空蒸發至乾燥,得到呈白色固體狀之化合物(9) 1.057 g (1.234毫莫耳,54.4%產率)。MS 857(M+1),879(M+Na)。1
H-NMR (DMSO-d6
) δ(ppm) 11.42 (1H, s, 胍NHBoc), 8.25 (1H, d, NH-4), 7.95 (1H, d, AcNH), 7.16 (1H, t, OCONH), 6.75 (1H, t, 壬基NHBoc), 5.80 (1H, s, H-3), 4.92 (2H, m,H-7, H-8), 4.75 (1H, m, H-4), 4.31-4.62 (4H, m, H-5, H-6, H-9, H-9'), 3.74 (3H, s, COOCH3
), 2.90 (4H, m, NHCH2
(CH2
)7
CH2
NH), 1.86 (3H, s, NHCOCH3
), 1.49 (9H, s, Boc), 1.38 (18H, s, Boc), 1.2-1.6 (14H, m, NHCH2
(CH2
)7
CH2
NH)。 步驟I)將化合物(9) (1 g,1.168毫莫耳)溶解於三氟乙酸(TFA) (36 ml)及甲基苯基醚(苯甲醚) (3.9 ml)於二氯甲烷(CH2
Cl2
) (36 ml)中之混合物中。在25℃下將全部混合物攪拌2小時及40分鐘,接著在35℃下將其真空蒸發持續2小時。在R.T.下在己烷(100 ml)中將殘餘物攪拌隔夜,傾析己烷且添加新鮮己烷(60 ml),且在R.T.下持續攪拌4小時。接著移除己烷。將殘餘物溶解於CH2
Cl2
(10 ml)中且在35℃至40℃下蒸發至乾燥。將殘餘物溶解於水(25 ml)中。將水溶液凍結乾燥,得到呈白色泡沫狀之TFA3
Zn ,
鹽之化合物(10) 1.026 g (1.143毫莫耳,97.8%產率)。MS 557 (M+1) [Zn ,
之MW = 556,TFA3
Zn ,
之MW = 898]。流程 2 : 錨定化合物 Zn ' 之製備 實例 12 : 錨定主鏈化合物 PYR ( Zn , ) 2 之製備
合成詳述於下方流程 3
中。以下化合物參考編號係關於流程 3
。 在室溫下向苯均四酸二酐(11) (27.25 mg,0.125毫莫耳)於無水DMF (2 ml)中之溶液中添加Zn ,
(10) (224.5 mg,0.25毫莫耳)及二異丙基乙胺(DIPEA) (130.64 μl,0.75毫莫耳)。使全部反應混合物在氬氣下在25℃下攪拌36小時,接著用醚:石油醚1:1 (100 ml)處理。將沈澱過濾,用醚洗滌且風乾,得到灰白色固體(197 mg),接著對該固體進行HPLC分離及純化。HPLC 分析 : pepl 梯度
管柱:Gemini C18管柱100A 5 μm 150×3.00 mm。波長:220/280 nm。流動速率:0.7 ml/min。溶劑A = 0.1%三氟乙酸。溶劑B = 100%乙腈。溫度:30℃。梯度:0-50% B,15分鐘。滯留時間:在14.35分鐘處PK1PYR(Zn ,
)2
(12),在14.53分鐘處PK2PYR(Zn ,
)2
(13)。HPLC 製備型 :
管柱:Water Xterra C18製備型MS管柱19×50 mm,5 μm。波長:220/280 nm。流動速率:8 ml/min。溶劑A = 0.1%三氟乙酸。溶劑B = 100%乙腈。溫度:30℃。梯度:10-100% B,80分鐘。PK1PYR(Zn ,
)2
及PK2PYR(Zn ,
)2
(13)之純部分經收集且分開凍結乾燥,分別得到PK1PYR(Zn ,
)2
(12) 49 mg及PK2PYR(Zn ,
)2
(13) 42 mg。 PK1PYR(Zn ,
)2
(12) MS指示ESI +ve 10V 1331.5離子。1
H-NMR (D2
O) δ (ppm):8.00 (2H, s, 芳族對位H x 2), 6.00 (2H, d, H-3 x 2), 5.20-5.50 (4H, m, H-7 x 2, H-8 x 2), 4.35-4.90 (8H, m, H-4 x 2, H-5 x 2, H-6 x 2, H-9 x 2), 4.15 (2H, dd, H-9' x 2), 3.80 (6H, s, COOCH3
x 2), 3.25-3.45 (4H, m, OCONHCH2
x 2), 2.90-3.20 (4H, m, NHCH2
x 2), 1.95 (6H, s, CH3
C0 x 2), 1.20-1.70 (28H, m, (CH2
)7
x 2)。 PK2PYR(Zn ,
)2
(13) MS指示ESI +ve 10V 1331.5離子。1
H-NMR (D2
O) δ (ppm) 8.35 (1H, s, 芳族H x 1), 7.50 (1H, s, 芳族H x 1), 6.00 (2H, d, H-3 x 2), 5.20-5.50 (4H, m, H-7 x 2, H-8 x 2), 4.35-4.90 (8H, m, H-4 x 2, H-5 x 2, H-6 x 2, H-9 x 2), 4.15 (2H, dd, H-9' x 2), 3.80 (6H, s, COOCH3
x 2),3.25-3.45 (4H, m, OCONHCH2
x 2), 2.90-3.20 (4H, m, NHCH2
x 2), 1.95 (6H, CH3
CO x 2), 1.20-1.70 (28H, m, (CH2
)7
x 2)。流程 3 :錨定主鏈化合物 PYR ( Zn , ) 2 之製備 實例 13 : 酸性 / 陰離子基團 D - Asp ( NHCH2
SO3
H ) 2 之製備
合成詳述於下方流程 4
中。以下化合物參考編號係關於流程 4
。 將Boc-D-天冬胺酸(14) (233 mg,1毫莫耳)及HBTU [O-(苯并三唑-1-基)-N , N , N ', N '-
雙(四亞甲基)六氟磷酸酯] (758 mg,2毫莫耳)溶解於DMF (10 ml)中。向此溶液中添加DIPEA (二異丙基乙胺) (349 μl,2毫莫耳)。在室溫下將溶液攪拌10分鐘,接著與胺基甲烷磺酸鈉(332 mg,2.5毫莫耳)於DMF (3 ml)中之溶液組合。在室溫下攪拌所得溶液隔夜。將反應混合物真空蒸發,得到淺橙色固體。將其溶解於水(20 ml)中,用乙酸乙酯(20 ml×3)洗滌,將水相真空蒸發以移除有機溶劑,接著凍結乾燥,得到呈白色固體狀之粗產物(15) 310 mg,對該固體進行HPLC分離及純化。HPLC 分析: pep1 梯度
管柱:Gemini C18管柱100A 5 μm 150×30 min。波長:220 nm。流動速率:0.7 ml/min。溶劑A = 0.1%三氟乙酸。溶劑B = 100%乙腈。溫度:30℃。梯度:0-50% B,15分鐘。滯留時間:化合物(15)在4.669分鐘處呈游離酸,MS ESI -ve 418(M-1),在1.658分鐘處溶劑峰,在2.722分鐘處胺基甲烷磺酸,在5.520分鐘處HBTU物質,在5.802分鐘處單Boc-D-Asp-NHCH2
SO3
H。HPLC 製備型
管柱:Germini AXIA C18管柱,5 μm 50×21.2 mm。波長:220 min。流動速率:8 ml/min;溶劑A = 0.1%三氟乙酸;溶劑B = 100%乙腈;溫度:30℃。梯度:0-100% B,100分鐘。 含有(15)之部分經收集且合併在一起,接著經凍結乾燥,得到呈游離酸之純產物(15)。MS ESI -ve 418(M-1)。將呈游離酸之化合物(15) (200 mg,0.477毫莫耳)溶解於含有苯甲醚(1 ml)之三氟乙酸(10 ml)中。在室溫下攪拌溶液一小時,接著真空蒸發至乾燥。在醚(20 ml×2)中濕磨殘餘物,過濾。將固體風乾,接著再溶解於水中,經凍結乾燥,得到呈白色固體狀之產物(16) 106 mg。MS ESI -ve 318(M-1)。將產物溶解於水(10 ml)中,接著用兩當量之氫氧化鈉中和,凍結乾燥,得到呈白色固體狀之二鈉鹽(16)。流程 4 : 酸性 / 陰離子基團 D - Asp ( NHCH2
SO3
H ) 2 之製備 實例 14 : 化合物 MD185 PK2PYR ( Zn ) 2 [( D - Asp )( NHCH2
SO3 ) 2 ] 2 之製備
合成詳述於下方流程 5
中。以下化合物參考編號係關於流程 5
。 向PK2PYR(Zn ,
)2
(13) (30 mg,22.56微莫耳)於無水DMF (5 ml)中之溶液中添加HATU [O-(7-氮雜苯并三唑-1-基)-N , N , N ', N '-
雙(四亞甲基)六氟磷酸酯] (17.14 mg,45.11微莫耳)及DIPEA (7.9 μl,45.31微莫耳)。將所得溶液在室溫下攪拌10分鐘,接著添加[D-Asp(NHCH2
SO3
Na)2
] (33 mg,91.16微莫耳)於DMF (5ml)中之二鈉鹽(16)。在室溫下攪拌反應混合物18小時,接著對其進行HPLC分離及純化。HPLC 分析: pep 1 梯度
管柱:Gemini C18管柱 100A 5 μm 150×3.00 mm;波長:220/280 nm;流動速率:0.7 ml/min;溶劑A = 0.1%三氟乙酸;溶劑B = 100%乙腈;溫度:30℃;梯度:0-50% B,15分鐘;滯留時間:在14.270分鐘處產物(17)呈游離酸。MS ESI +ve +30V 967.5,MS ESI --ve,-25v 965.4。其他峰如下:在11.7分鐘處起始物質PK2PYR(Zn ,
) (13),在13.6分鐘處PK2PYR(Zn ,
)2
-D-Asp(NHCH2
SO3
H)2
。HPLC 製備型
管柱:Water Xterra製備型MS C18管柱19×50 mm 5 μm;波長:220/280 nm;流動速率:8 ml/min;溶劑A = 0.1%三氟乙酸;溶劑B = 100%乙腈;溫度:30℃;梯度:0-100% B 100分鐘 產物以相對Gemini分析之逆向分佈溶離。溶離分佈在25-35%乙腈之間。將取樣之部分與具有大於90%純度之試管合併,且在Gemini AXIA管柱上分離其他物質。 將產物(17)凍結乾燥,得到白色蓬鬆粉末。MS ESI -ve -25v 965.4表明MW為1932。將化合物(17) PK2 PYR(Zn ,
)2
[D-Asp(NHCH2
SO3
H)2
]2
(8 mg,4.14微莫耳)溶解於50%甲醇水溶液(2 ml)中,接著添加三乙胺(40 μl,287.5微莫耳)。在室溫下攪拌所得溶液。藉由分析HPLC針對10.848分鐘處之峰監測反應。2小時之後,用乙酸(60 μl,1049微莫耳)酸化反應混合物且用水稀釋至10 ml。在Kinetex管柱上純化溶液。純部分經合併且凍結乾燥,得到呈白色粉末狀之產物(18) PK2 PYR(Zn
)2
[D-Asp(NHCH2
SO3
H)2
]2
6 mg。 HPLC滯留時間10.695 min。MS ESI -ve -30V 925.6。 為移除化合物中之TFA殘餘物,將純材料溶解於60 ml 4mM HCl中且凍結乾燥,接著溶解於60 ml 1mM HCl中且凍結乾燥,最後自60 ml水凍結乾燥。產率5.6 mg (18) MD185 MW1852。流程 5 : 化合物 MD185 PK2PYR ( Zn ) 2 [( D - Asp )( NHCH2
SO3 ) 2 ] 2 之製備 實例 15 : 錨定化合物 Z0 ' 之製備
合成詳述於下方流程 6
中。以下化合物參考編號及合成步驟參照係關於流程 6
。 根據實例11處描述之程序(H)及程序(I),使化合物(8)與氯甲酸對硝苯酯反應,接著與N-Boc-1,8-二胺基辛烷反應,在層析之後,得到呈白色固體狀之化合物(19)。MS 843(M+1)。用三氟乙酸(TFA)處理化合物(19),在處理後得到呈白色泡沫狀之TFA3
Z0 ,
鹽之化合物(20) Z0 ,
,MS 543 (M+1) [Z0 ,
之MW = 542,TFA3
Z0 ,
之MW = 884]。流程 6 : 錨定化合物 Z0 ' 之製備 實例 16 : 錨定主鏈化合物 PK1 TCA ( Z0 ' ) 2 及 PK2 TCA ( Z0 ' ) 2 之製備
合成詳述於下方流程 7
中。以下化合物參考編號係關於流程 7
。 向TCA (21) (3.085 mg,17.52微莫耳)於DMF (309 μl)中之溶液中添加HATU (13.32 mg,35.03微莫耳)及DIPEA (6.5 μl,37.32微莫耳)。在室溫下攪拌全部混合物10分鐘,接著逐滴添加Z0 '
(20) (30.97 mg,35.03微莫耳)及DIPEA (18.44 μl,105.9微莫耳)於DMF (600 μl)中之溶液。將反應混合物在室溫下攪拌隔夜。對所得混合物進行HPLC分離及純化。HPLC 分析 : pepl 梯度
管柱:Phenomenex C18 5 μl 110A 150×3 mm;波長:220/280 nm;流動速率:0.7 ml/min;溶劑A = 0.1%三氟乙酸;溶劑B = 100%乙腈;溫度:30℃;梯度:100-50% B 15分鐘;滯留時間:PK1 TCA(Z0 '
)2
(22) 11.100 min及PK2 TCA(Z0 '
)2
(23) 11.156 min。 在2.5 ppm下PK1 TCA(Z0 '
)2
(22)1
H-NMR (D2
O) δ ppm (AB對稱dd,4H,Ca
H2
=Cb
H2
)表明其對稱結構。MS 1225.4 (MW 1224)。 在2.35-2.75 ppm下PK2 TCA(Z0 '
)2
(23)1
H-NMR (D2
O) δ ppm (非對稱,dd,4H,(Ca
H2
≠ Cb
H2
))表明其非對稱結構。MS 1225.4 (MW 1224)。製備型 HPLC
用少量1M乙酸酸化溶液且在水中稀釋至25 ml。經由0.45 μm針筒過濾器過濾此溶液且在20%至80%緩衝劑A下泵取至Water Xterra製備型MS C18管柱19×50 mm上。流動速率8 ml/min,梯度0-100% B 100分鐘,波長210/280 nm。溶離曲線空隙DMF/DIPEA/HATU 在Phenomenex Gemini 5 μm C18 110A Axia 50×21.2 mm管柱上在0.1% TFA緩衝劑中進一步純化且分離PK1 TCA(Z0 '
)2
及PK2 TCA(Z0 '
)2
。 PK1/PK2比率為約1:2,兩者MS ESI +30V 1225.4。流程 7 : 錨定主鏈化合物 PK1 TCA ( Z0 ' ) 2 及 PK2 TCA ( Z0 ' ) 2 之製備 實例 17 : 酸性 / 陰離子基團 [ D - Cya - SO3
H ] 7 OH 之 製備
合成詳述於下方流程 8
中。以下化合物參考編號係關於流程 8
。 如流程8中所詳述,應用固相合成來製備[D-Cys-SH]7
-OH (33),接著氧化聚半胱胺酸(33)得到[D-CyaSO3
H]7
-OH (34)。 在50 ml Falcon試管中將Fmoc-D-Cys(Trt)-OH(24) (2.93 g,5毫莫耳)溶解於無水二氯甲烷(DCM) (35 ml)中,接著添加2-氯三苯甲基氯樹脂(25) (5 g),劇烈振盪,添加二異丙基乙胺(DIPEA) (3.5 ml,20毫莫耳)。在5 min之後,添加另一部分之DIPEA (1.3 ml,7.5毫莫耳)。將全部混合物振盪另外4小時。為封端任何剩餘的反應性2-氯三苯甲基氯,添加甲醇(4 ml)。將混合物振盪另外30分鐘。用DMF (20 ml ×3)、DCM (20 ml×3)、甲醇(20 ml×3)連續洗滌樹脂,接著真空乾燥隔夜。產率指示0.57 mM/g之負載量(26)。 為自樹脂移除Fmoc基團,在DCM (35 ml)中將樹脂(26)預膨脹,接著添加含50%哌啶之DMF (30 ml)。將全部混合物放置在旋轉器上30 min。用50%哌啶於DMF (30 ml)中之新鮮溶液重複過程持續60 min。接著用DMF (20 ml×2)、DCM (20 ml×2)、DMF (20 ml×3)連續洗滌樹脂。進行陽性寧海准(ninhydrin)測試。樹脂(27)準備好用於偶合。 向Fmoc-D-Cys(Trt)-OH (24) (1758 mg,3毫莫耳)於DMF (6 ml)中之溶液中添加HBTU [O-(苯并三唑-1-基)-N,N,N',N'-雙(四亞甲基)六氟磷酸酯] (1140 mg,3毫莫耳)及DIPEA (523 μl,3毫莫耳)。在室溫下攪拌混合物10分鐘,接著添加樹脂(27) (2.5 g,0.57 mM/g,1.5毫莫耳)。將反應混合物攪動24小時。寧海准測試陰性,用DMF (20 ml×3)洗滌樹脂,接著用含5%乙酸酐、1% DIPEA之DMF (20 ml)處理30分鐘。接著用DMF (20 ml×3)、DCM (20 ml×3)、甲醇(20 ml×3)洗滌樹脂(28)。在DCM中將樹脂(28)預膨脹,且添加含30%哌啶/N-甲基吡咯酮之DMF (20 ml)。將全部混合物放置在旋轉器上30 min,接著與30%哌啶及N-甲基吡咯酮之新鮮溶液一起放置另外60分鐘,在用DMF (20 ml×2)、DCM (20 ml×2)、DMF (20 ml×2)洗滌之後得到樹脂(29)。 使樹脂(29)與(24) (1758 mg,3毫莫耳)在DMF (6ml)中進一步偶合24小時,用HBTU (1140 mg,3毫莫耳)及DIPEA (523 μl,3毫莫耳)預活化10分鐘,在處理之後得到樹脂(30)。其中一半隨後遵循以下程序:由哌啶/甲基吡咯酮去保護,與(24)再偶合,用HBTU/DIPEA預活化,重複此程序4次,產生樹脂(31)。 用DCM (20 ml×5)洗滌樹脂(31),接著放入50 ml Falcon試管中,添加含40%乙酸之DCM (35 ml),在室溫下在旋轉器上振盪6小時。過濾樹脂懸浮液,將濾過物真空蒸發至淡黃色泡沫。用水(100 ml×3)洗滌殘餘物,在乾燥之後得到白色固體(32) [D-Cys(Trt)]7
-OH。 在TFA (20 ml)、三異丙基矽烷(1 ml)及水(0.5 ml)之溶液中攪拌(32)持續3小時。過濾所得懸浮液。將濾過物蒸發至油狀物質,用醚(20 ml×4)濕磨該物質,得到白色固體。將其在50%乙腈水溶液(100 ml)中攪拌。材料經超聲處理以形成白色懸浮液,將懸浮液凍結乾燥,得到(33) [D-Cys-SH]7
-OH (380 mg)之粗產物。HPLC 分析
管柱:Phenomenex Gemini 5 μm C18 110A 150×3.00 mm,溶劑A = 0.1%三氟乙酸,溶劑B = 100%乙腈,流動速率:0.7 ml/min,波長:210/280 nm,溫度:30℃,梯度:0-50% B 15分鐘,滯留時間:9.356分鐘。 MS Cone +25V主峰740 Cone -25V主峰738指示(33)之MW為739 [D-Cys-SH]7
-OH 將化合物(33) (10 mg,13.53微莫耳)添加至在冰鹽浴中預冷之過甲酸溶液(1 ml)中。將全部混合物在冰浴中攪拌1小時,接著用100 ml冷水稀釋,凍結乾燥,得到淡黃色形式(34)。在Phenomenex Kinetex 5 μm XB-C18 100A管柱上使用等度0.1% TFA作為溶離劑純化材料,得到呈無色粉末狀之化合物(34) [D-Cyst-SO3
H]7
-OH MW 1075,MS Cone +50V 1076(M+1)。 藉由將甲酸(8.74 ml)、水(0.96 ml)及30%過氧化氫(1 ml)混合來製備過甲酸,且使混合物在室溫下在靜止的燒瓶中靜置30分鐘。此過氧化物應在使用之前新製。流程 8 : 酸性 / 陰離子基團 [ D - 包囊 - SO3
H ] 7 OH 之製備 實例 18 : 化合物 MD345 PK2 TCA ( Z0 ) 2 -[ D - Cyst - SO3
H ] 7 - OH 之製備
合成詳述於下方流程 9
中。以下化合物參考編號係關於流程 9
。 向PK2 TCA(Z0 '
)2
(23) (4 mg,3.268微莫耳)於無水DMF (2 ml)中之溶液中添加含HATU (1.242 mg,3.268微莫耳)及2% DIPEA之DMF (30 μl,3.44微莫耳)。在室溫下攪拌混合物10分鐘,接著與(34) [D-Cyst-SO3
H]7
-OH (7.03 mg,6.54微莫耳)及DIPEA (9.11 μl,52.32微莫耳)於DMF (3 ml)中之溶液組合。在室溫下將全部反應混合物攪拌隔夜。用水/甲醇1/1將混合物稀釋至15 ml,接著對其進行HPLC分離及純化。HPLC 製備型 :
管柱:Phenomenex Kinetex 5 μm XB-C18 50×21.2 mm;波長:220/280 nm;流動速率:8 ml/min;溶劑A = 0.1%三氟乙酸(TFA);溶劑B = 100%乙腈;溫度:30℃;梯度:0-100% B,80分鐘。將含有(35)游離酸(B=H)之部分合併且凍結乾燥,得到呈白色粉末狀之化合物(35)游離酸(B=H) 4 mg。MS ESI +ve Cone 35V 1142.1 2 + 離子。 將化合物(35)游離酸(B=H) PK2 TCA(Z0 '
)2
-[D-Cyst-SO3
H]7
-OH (4 mg,1.754微莫耳)溶解於含有三乙胺(TEA) (20 μl,146微莫耳)之50%甲醇水溶液(800 μl)中。在室溫下攪拌混合物,藉由HPLC監測。在3小時之後將其處理。在Kinetex管柱上純化溶液。將11.254 min之滯留時間處之純部分合併且凍結乾燥,得到呈白色粉末狀之化合物(36) 2 mg。MS ESI +ve Cone 40V 1102.2 2 + 離子。 為移除化合物中之TFA殘餘物,將化合物(36)溶解於4 mM HCl (30 ml)中且凍結乾燥。接著將其溶解於1 mM HCl (30 ml)中且凍結乾燥。最後將其自水(30 ml)凍結乾燥,得到產物(36) 1.1 mg,MD345 PK2 TCA(Z0
)2
[D-Cyst-SO3
H]7
-OH MW2201 [MS 2202 (M+1)]。流程 9 : 化合物 MD345 、 PK2 TCA ( Z0 ) 2 -[ D - Cyst - SO3
H ] 7 - OH MW2201 之製備 實例 19 : 錨定化合物 Z ' 之製備
合成詳述於以下流程 10
中。以下化合物參考編號及合成步驟參照係關於流程 10
。 根據實例11中描述之程序(H)及程序(I),使化合物(8)與氯甲酸對-硝苯酯反應,接著與N-Boc-1,6-二胺基己烷反應,在層析之後,得到呈白色固體之化合物(37),MS 815(M+1)。用三氟乙酸(TFA)及苯甲醚處理化合物(37),在處理之後得到呈白色形式之TFA鹽之化合物(38)Z'。MS 515 (M+l)。 [ Z'之MW = 514,TFA3
Z' = 856]。流程 10 :錨定化合物 Z ' 之製備 實例 20 : 錨定主鏈化合物 CHTCA ( Z ' ) 2 之製備
合成詳述於下方流程 11
中。以下化合物參考編號係關於流程 11
。 向CHTCA (39) (4.4 mg,20微莫耳)於DMF (300 μl)中之溶液中添加HATU (15.2 mg,40微莫耳)及DIPEA (7.4 μl,42.4微莫耳)。在室溫下攪拌全部混合物10分鐘,接著逐滴添加Z' (38) (34.24 mg,40微莫耳)及DIPEA (21.06 μl,120.9微莫耳)於DMF (700 μl)中之溶液。將反應混合物在室溫下攪拌隔夜。用1M HAc (50 μl)及水(25 ml)稀釋所得混合物。經由0.45 μm針筒過濾器過濾此混合物。對濾過物進行HPLC分離及純化。 管柱:Water Xterra製備型MS C18管柱19×50 mm;波長:210/280 nm;流動速率:8 ml/min;溶劑A = 0.1% TFA;溶劑B = 100%乙腈;溫度:30℃;梯度:0-100% B 100分鐘;溶離曲線空隙DMF/DIPEA/HATU。 在Phenomenex Gemini 5 μm C18 110A AXIA 50×21.2 mm管柱上在0.1% TFA緩衝劑中進一步純化含有化合物(40)之部分。將該部分凍結乾燥,得到呈白色泡沫狀之化合物(40) CHTCA(Z')2
,15 mg。MS ESI +ve, +30v, 1209指示MW為1208。流程 11 : 錨定主鏈化合物 CHTCA ( Z ' ) 2 之製備 實例 20 : 錨定化合物 S6 之製備
合成詳述於下方流程 12
中。以下化合物參考編號及合成步驟參照係關於流程 12
。 步驟A)在室溫下在無水甲醇(100 ml)中攪拌化合物(1) 48小時,過濾出混合物。將濾過物真空蒸發至乾燥,得到呈白色固體狀之化合物(41),1.25 g (6.037毫莫耳,93%產率)。MS 324 (M+1)。 步驟B)在室溫下在乙醯氯(20 ml,281毫莫耳)中攪拌化合物(41) (1.95 g,6.037毫莫耳)持續3天,接著真空蒸發至乾燥,得到化合物(42) 3.06 g (6.01毫莫耳,99%產率)。MS 510.5 (M+1)。 步驟C)在二氯甲烷(DCM) (35ml)中攪拌殘餘物(42) (3.06 g,6.01毫莫耳),接著添加KSAc (3.57 g,31.26毫莫耳)。在氬氣下在室溫下攪拌反應混合物40小時,用二氯甲烷(50 ml)稀釋,接著分配於二氯甲烷與水(50 ml)之間。用5% NaCl溶液(22 ml×2)洗滌有機層,且經無水Na2
SO4
乾燥隔夜,過濾出。將濾過物蒸發至乾燥,得到呈灰白色泡沫狀之(43) 2.93 g (5.34毫莫耳,88.8%產率)。MS 550 (M+l)。 步驟D)在DMF (2 ml)中攪拌化合物(43) (200 mg,0.364毫莫耳)及Boc-胺基己烷溴化物(107.4 mg,0.385毫莫耳),向其中添加二乙胺(0.81 ml,7.83毫莫耳)。在氬氣下在25℃下將全部混合物攪拌2.5小時。將反應混合物分配於乙酸乙酯(EA) (80 ml)與飽和NaCl溶液之間。用飽和NaCl溶液(15 ml×3)、水(10 ml×3)洗滌有機層。將有機層經Na2
SO4
乾燥,過濾,將濾過物真空蒸發至乾燥。對殘餘物進行矽膠管柱層析(甲苯:丙酮= 2:1)。將含有化合物(44)之部分合併且真空蒸發至乾燥,得到呈白色泡沫狀之化合物(44) 98 mg (0.139毫莫耳,38%產率)。MS 706 (M+1)。 步驟E)將化合物(44) (95 mg,0.135毫莫耳)溶解於無水甲醇(1 ml)中。在氬氣下向此溶液中添加甲醇鈉(0.16 mg,6.94微莫耳),在室溫下攪拌反應混合物2.5小時,接著用Dowex50×8 (H+
)樹脂調整至pH 6.0至6.5,過濾出。在真空下將濾過物蒸發至乾燥,得到呈白色泡沫狀之化合物(45) 71 mg (0.132毫莫耳,97.9%產率)。MS 538(M+1)。 步驟F)在氬氣下在室溫下在0.2N NaOH (2 ml,0.4毫莫耳)中攪拌化合物(45) (60 mg,0.109毫莫耳) 2.5小時。用Dowex50×8 (H+
)樹脂將溶液調整至pH 3至4且過濾出。將濾過物凍結乾燥,得到呈白色泡沫狀之化合物(46) 56 mg (0.107毫莫耳,98%產率)。MS 524(M+1)。 步驟G)將化合物(46) (50 mg,0.0956毫莫耳)溶解於三氟乙酸(TFA) (2 ml,25.96毫莫耳)及甲基苯基醚(苯甲醚) (0.2 ml,1.84毫莫耳)於二氯甲烷(2 ml)中之混合物中。在25℃下將全部混合物攪拌2.5小時,接著在35℃下將其真空蒸發持續2小時。在室溫下在己烷(10 ml×2)中洗滌殘餘物隔夜,傾析己烷。在室溫下在醚(10 ml×2)中攪拌殘餘物,接著移除醚。將殘餘物溶解於水(1 ml)中,且凍結乾燥,得到呈白色泡沫狀之S6
•TFA鹽之化合物(47),51 mg (0.0949毫莫耳,99%產率)。MS 424(M+I) [S6
之MW = 423,S6
•TFA鹽之MW = 537]。流程 12 : 錨定化合物 S6 之製備 實例 21 : 化合物 MD012 CHTCA ( Z ) 2 ( S6 ) 之製備
合成詳述於下方流程 13
中。
以下化合物參考編號及合成步驟參照係關於流程 13
。 向CHTCA(Z')2
(40) (4 mg,3.3微莫耳)於DMF (100 μl)中之溶液添加HATU (1.254 mg,3.3微莫耳)及DIPEA (0.6 μl,3.44微莫耳)。在室溫下攪拌混合物10分鐘,接著添加S6
•TFA鹽(47) (1.8 mg,3.35微莫耳)及DIPEA (1.20 μl,6.89微莫耳)於DMF (100 μl)中之溶液。在室溫下將反應混合物攪拌隔夜。用1 M HAc (5 μl)及水(2 ml)稀釋所得混合物,接著經由0.45 μm針筒過濾器將其過濾。對濾過物進行HPLC分離及純化。 管柱:Phenomenex Gemini AXIA 5 μm,C18 110A 50×21.2 mm;波長:210/280 nm;流動速率:8 ml/min;溶劑A = 含0.1%三氟乙酸之超純水;溶劑B = 100%乙腈;梯度:0至100%B,100分鐘,線性;溫度:30℃。 採集含有化合物(48)之部分並凍結乾燥以得到呈白色泡沫狀之化合物(48)CHTCA (Z')2
(S6
)2.4 mg。MS ESI +30v 1615指示MW為1614。 在室溫下在含有三乙胺(6.6 μl)之50%甲醇水性溶液(90 μl)中攪拌化合物(48) (2.4 mg,1.486微莫耳)5小時,接著真空蒸發至乾燥。將殘餘物再溶解於水(100 μl)中,凍結乾燥以得到呈白色泡沫狀之產物(49)CHTCA (Z)2
(S6
),2 mg (1.303毫莫耳 87.7%產率)。MS ESI +30v 1535.7指示MW為1534.7。流程 13 : 化合物 MD012 、 CHTCA ( Z ) 2 ( S6 ) 之製備 實例22
:錨定主鏈化合物CHTCA ( Z0 ' ) 2
之製備
合成詳述於以下流程 14
中。以下化合物參考編號係關於流程 14
。 錨定化合物(20)Z0 '
之製備詳述於實例15處。根據詳述於實例20中之程序製備錨定主鏈化合物(50)CHTCA(Z0 '
)2
。獲得呈白色固體狀之錨定主鏈化合物(50)CHTCA(Z0 '
)2
。MS ESI +30v 1265指示MW為1264。流程 14 : 錨定主鏈化合物 CHTCA ( Z0 ' ) 2 之製備 實例 23 : 酸性 / 陰離子基團 D - Asp ( D - Cya )- D - Asp ( D - Cya )- D - Asp ( D - Cya )- OH 之製備
合成詳述於下方流程 15
中。以下化合物參考編號(A)至(I)及合成步驟參照係關於流程 15
。 將Boc-D-半胱胺酸(Acm)甲酯[Boc-D-Cys(Acm)-OMe] (1.532 g,5毫莫耳)溶解於含有苯甲醚(1 ml)之三氟乙酸(TFA) (10 ml)中,且在室溫下攪拌30分鐘。接著在真空下蒸發反應混合物以移除TFA以得到油狀物質,在醚(100 ml×2)中濕磨該物質,接著再溶解於20%乙腈水性溶液(100 ml)中,且凍結乾燥72小時,得到化合物TFA•D-Cys(Acm)-OMe,1.60 g。HPLC/MS指示MW為206.35 (呈游離鹼)。 在室溫下用含HBTU (MW 379.25) (1.517 g,4毫莫耳)及DIPEA (MW 129.25) (0.517 g,4毫莫耳)之DMF (20 ml)活化Fmoc-D-天冬胺酸-α-酸-β-O-第三丁酯[Fmoc-D-Asp-Obut] (1.646 g,4毫莫耳)持續10分鐘,接著與TFA•D-Cys(Acm)-OMe (1.47 g,4.2毫莫耳)及DIPEA (0.542 g,4.2毫莫耳)於DMF (10 ml)中之溶液合併。在室溫下將全部反應混合物攪拌16小時。藉由HPLC監測反應。在真空下蒸發混合物以移除DMF。接著向殘餘物中添加水(5×70 ml)以洗去殘餘DMF及D-Cys(Acm)OMe以得到灰白色固體,接著將該固體真空乾燥,得到呈白色固體狀之化合物(A) Fmoc-D-Asp[D-Cys(Acm)-OMe]-O-But。HPLC/MS指示MW為599.7。 在室溫下用含20%哌啶之乙腈(20 ml)處理化合物(A) (1.2 g,2毫莫耳)30分鐘,接著過濾。在真空下蒸發濾過物,得到化合物(B) D-Asp[D-Cys(Acm)-OMe]-OBut。HPLC/MS指示MW為377.4。 在室溫下用TFA (6 ml)處理化合物(A) (599.7 mg,1毫莫耳) 1小時。接著將其真空蒸發至乾燥。在醚(50 ml×3)中濕磨殘餘物,接著溶解於30%乙腈水溶液(100 ml)中,且凍結乾燥,得到呈白色固體狀之化合物(C) Fmoc-D-Asp[D-Cys(Acm)-OMe]-OH。HPLC/MS指示MW為542.7。 在室溫下用含HBTU (303.4 mg,0.8毫莫耳)及DIPEA (103.4 mg,0.8毫莫耳)之DMF (8 ml)活化化合物(C) Fmoc-D-Asp[D-Cys(Acm) -OMe]-OH (434 mg,0.8毫莫耳)10分鐘,接著向其中添加化合物(B) D-Asp[D-Cys(Acm)-OMe]-OBut (9332 mg,0.88毫莫耳)。在室溫下攪拌反應混合物16小時。在真空下蒸發DMF且藉由用水謹慎地洗滌白色固體物質來移除殘餘DMF。接著在真空下乾燥白色固體24小時,得到呈白色固體狀之化合物(D) Fmoc-D-Asp[D-Cys(Acm)-OMe]-D-Asp[D-Cys(Acm) -OMe]-OBut。HPLC/MS指示MW為902.19。在室溫下用TFA (16 ml)處理化合物(D) 1小時以移除第三丁酯。將TFA真空蒸發至乾燥。用水洗滌殘餘物以移除殘餘TFA,且將固體真空乾燥72小時,得到Fmoc-D-Asp[D-Cys(Acm)-OMe]-D-Asp[D-Cys(Acm)-OMe]-OH。HPLC/MS指示MW為846。 在室溫下用含HBTU (189.5 mg,0.5毫莫耳)及DIPEA (64.63 mg,0.5毫莫耳)之DMF (5 ml)活化Fmoc-D-Asp[D-Cys(Acm)-OMe]-OH-D- Asp[D-Cys(Acm)-OMe]-OH (423 mg,0.5毫莫耳) 10分鐘,接著向其中添加化合物(B) D-Asp[D-Cys(Acm)-OMe]-OBut (317 mg,0.84毫莫耳)。在室溫下攪拌全部混合物16小時。藉由HPLC檢查反應完成,且在真空下移除DMF。謹慎地用冷水洗滌所獲得之白色固體,接著在真空下乾燥48小時,得到化合物(E) Fmoc-D-Asp[D-Cys(Acm)-OMe]-D-Asp[D-Cys(Acm)-OMe]-D-Asp[D-Cys(Acm)-OMe]-OBut,MW 1206,藉由HPLC進一步純化該化合物。 此材料之分析HPLC指示純度為70%。將材料溶解於50%甲醇/水中且經由用於製備型HPLC之0.2 μm過濾器過濾。製備型 HPLC
管柱:Waters Xterra C18管柱 5 μm 19×50 mm,以40 mg之批次;波長:220/280 nm;流動速率:8 ml/min;溶劑A = 0.1%三氟乙酸;溶劑B = 100%乙腈;梯度:10-100% B,100分鐘;溫度:30℃。 接著在室溫下用TFA (10 ml)處理化合物(E) Fmoc-D-Asp[D-Cys(Acm)-OMe]-D-Asp[D-Cys(Acm)-OMe]-D-Asp[D-Cys(Acm)-OMe]-OBut 1小時且真空蒸發至乾燥。將殘餘物溶解於40%乙腈水溶液(100 ml)中,且凍結乾燥,得到呈白色固體狀之化合物(F) Fmoc-D-Asp[D-Cys(Acm)-OMe]-D-Asp[D-Cys(Acm)-OMe]-D-Asp[D-Cys(Acm)-OMe]-OH。HPLC/MS指示MW為1150.27。 在室溫下在攪拌下用含20%哌啶之乙腈(10 ml)處理化合物(F) Fmoc-D-Asp[D-Cys(Acm)-OMe]-D-Asp[D-Cys(Acm)-OMe]-D-Asp[D- Cys(Acm)-OMe]-OH (200 mg,0.1738毫莫耳) 30分鐘,且隨後過濾。將濾過物真空蒸發。在室溫下在含有三乙胺(500 μl)之50%水/甲醇(20 ml)中攪拌殘餘物6小時,藉由HPLC監測以指示反應完成。將此混合物真空蒸發至乾燥,得到化合物(G) D-Asp[D-Cys(Acm)-OH]-D-Asp[D-Cys(Acm) -OH]-D-Asp[D-Cys(Acm)-OH]-OH。HPLC/MS指示MW為885.9。 分析HPLC指示50%純度。 藉由製備型HPLC進一步純化化合物(G)。 管柱:Phenomenex Gemini Axia 110A 5 μm 50×21.2 mm C18 HPLC管柱;波長:210/280 nm;流動速率:8 ml/min;溶劑A = 0.1% TFA;溶劑B = 100%乙腈;梯度:0-100% B,100分鐘;溫度:30℃。 將樣本(100 mg)溶解於10%甲醇水溶液中,經超聲處理,且經由0.2 μm過濾器過濾。以梯度游程將20 mg/批次泵取至管柱中。使用Phenomenex Gemini C18 5 μm管柱藉由分析RF-HPLC監測部分。流動速率0.7 ml/min;波長210/280 nm;梯度0-50% B 15分鐘;溶劑A = 0.1% TFA;溶劑B = 100%乙腈。 將具有大於90%純度之校正MS之部分合併且凍結乾燥,得到經純化化合物(G)。 將化合物(G) D-Asp[D-Cys(Acm)-OH]-D-Asp-[D-Cys(Acm) -OH]-D-Asp[D-Cys(Acm)-OH]-OH (21.8 mg,0.0246毫莫耳)溶解於含有苯甲醚(200 μl)之TFA (10 ml)中,接著添加三氟甲烷磺酸銀(504 mg,1.96毫莫耳)。接著在室溫下攪拌反應混合物1小時。接著將其真空蒸發至乾燥。在醚(40 ml×2)中濕磨殘餘物,傾析出醚洗液。在25℃下在含有二硫蘇糖醇(403 mg,2.62毫莫耳)之1M乙酸(20 ml)中攪拌殘餘物3小時。在50 ml falcon試管中以4000 rpm將懸浮液離心10分鐘。謹慎地收集上清液,接著藉由HPLC純化且凍結乾燥,得到化合物(H) D-Asp(D-Cys-SH,-OH)-D-Asp(D-Cys-SH,-OH)-D-Asp(D-Cys-SH,-OH)-OH,HPLC/MS指示MW為672.3。 在室溫下將95%甲酸(7.36 ml)、30% H2
O2
(0.8 ml)及H2
O (0.368 ml)之混合物保持30分鐘,接著在-5℃冰浴下攪拌,向其中添加化合物(H) (8 mg,0.0119毫莫耳)且攪拌1小時,接著在真空下攪拌10分鐘。接著用水將剩餘的溶液稀釋至200 ml且凍結乾燥,得到呈白色固體狀之化合物(I) 9.5 mg,D-Asp[D-Cya-SO3
H,-OH]-D-Asp[D-Cya-SO3
H,-OH]-D-Asp[D-Cya-SO3
H, -OH]-OH,HPLC/MS指示MW為816.78。 藉由在以下條件下脫鹽來純化此化合物。 管柱:Phenomenex Gemini Axia 110A 5 μm 50×21.2 mm C18 HPLC管柱;波長:210/280 nm;流動速率:8 ml/min;溶劑A = 0.1% TFA;溶劑B = 100%乙腈;梯度:0-100% B,100分鐘;溫度:30℃。化合物(I)接近空隙溶離。 接著將此材料凍結乾燥,產生作為純化合物(I)之白色粉末。如下用三乙胺(TEA)中和化合物(I)以形成TEA鹽(51):* HBTU:O-1H-苯并三唑-1-基)-N,N,N',N'-四甲基-鈾六氟磷酸酯MW 379.24 TFA:三氟乙酸MW 114.02 DIPEA:二異丙基乙胺MW 129.25 TEA:三乙胺MW 101.19 Acm:作為硫基保護基之S-乙醯胺基甲基 OBut:第三丁酯流程 15 : 酸性 / 陰離子基團 D - Asp ( D - Cyst )- D - Asp ( D - Cyst )- D - Asp ( D - Cyst )- OH 之製備 實例 24 : 化合物 MD348 CHTCA ( Z0 ) 2 -[ D - Asp ( D - Cyst )- D - Asp ( D - Cyst )- D - Asp ( D - Cyst )]- OH 之製備
合成詳述於下方流程 16
中。以下化合物參考編號係關於流程 16
。 在室溫下在DMF (5 ml)中將來自實例22 (10.744 mg,8.5微莫耳)之化合物(50) CHTCA(Z0 '
)2
與HATU (3.23 mg,8.5微莫耳)及DIPEA (1.496 μl,8.56微莫耳)一起攪拌10分鐘,接著在DMF (5ml )中將其與來自含實例23 (13.2 mg,8.67微莫耳)之化合物(51) D-Asp(D-Cya-SO3
B,-OB)-D-Asp- (D-Cya-SO3
B,-OB)-D-Asp(D-Cya-SO3
B,-OB)-OB合併。在室溫下攪拌全部混合物16小時。藉由分析HPLC/MS在滯留時間峰1,12.903 min處監測所得混合物。44% MS ESI +ve,+20v 1032.3 2+離子,ESI-ve, ‑40v 1030.7 2+ion指示MW為2062,不含鹼之化合物(52),亦即CHTCA(Z0
)2
[D-Asp(D-Cya-SO3
H,-OH)-D-Asp(D-Cya-SO3
H,-OH)-D-Asp-(D-Cyst-SO3
H,-OH)]-OH。分析 HPLC :
管柱:Phenomenex Kinetex EVO 5 μm C18 100A 150×4.6 mm;波長:210/280 nm;流動速率:0.7 ml/min;溶劑A = 0.1% TFA;溶劑B = 100%乙腈;梯度:0-50% B,15分鐘,線性;溫度:30℃。 用檸檬酸酸化所得混合物,用水稀釋至20 ml,經由0.2 μm過濾器過濾,接著對其進行製備型HPLC來分離及純化。製備型 HPLC
管柱:Phenomenex Gemini AXIA 5 μm C18 110A 50×21.2 mm;波長:210/280 nm;流動速率:8 ml/min;溶劑A = 0.1 TFA;溶劑B = 100%乙腈;梯度:0-100% B,100分鐘,線性;溫度:30℃。 滯留時間為31.087 min之主峰為產物(52)。收集含有產物之部分且如下藉由進一步HPLC再純化。 管柱:Phenomenex Kinetex x B 5 μm C18 100A 50×21.2 mm;波長:210/280 nm;流動速率:8 ml/min;溶劑A = 0.1% TFA;溶劑B = 100%乙腈;梯度:5%至100% B,80 min,線性;溫度30℃。 將19.597 min之滯留時間處之經純化化合物(52)與21.714 min之滯留時間處之起始物質完全分離。 將化合物(52) (3.5 mg,1.697微莫耳)溶解於50%甲醇/含有三乙胺(TEA) (18 μl,129微莫耳)之水(5 ml)中。將其在室溫下攪拌3小時。HPLC指示反應未完成,因此,添加額外11 μl之TEA。將混合物攪拌另外60分鐘,接著HPLC指示反應完成。接著用1M乙酸將反應溶液中和至pH 6。接著用水將溶液稀釋至20 ml。對混合物進行HPLC。分析 HPLC
管柱:Phenomenex Kinetex Evo 5 μm C18 100A 150×3 mm;波長:210/280 nm 流動速率:0.7 ml/min;溶劑A = 20 mM NaHPO4
pH 7.0緩衝劑;溶劑B = 10 mM NaHPO4
pH 7.0緩衝劑+ 50%乙腈;梯度:0至100% B,30分鐘,線性;溫度:30℃。製備型 HPLC
管柱:Phenomenex Kinetex XB 5 μm C18 100A 50×21.2 mm;波長:210/280 nm;流動速率:8 ml/min;溶劑A = 0.1% TFA;溶劑B = 100%乙腈;梯度:0-100% B,80 min,線性;溫度:30℃。 在16.431 min之滯留時間處溶離產物(53)。 將純部分合併且凍結乾燥,接著使用HCl交換以移除殘餘TFA。冷凍乾燥得到呈白色固體狀之產物(53) CHTCA(Z0
)2
[D-Asp(D-Cya)-D- Asp(D-Cya)-D-Asp(D-Cya]-OH,純度>99%。MS ESI cone -20v, 990.5 2+離子指示MW為1982。流程 16 : 化合物 MD348 CHTCA ( Z0 ) 2 -[ D - Asp ( D - Cyst )- D - Asp ( D - Cyst ) - D - Asp ( D - Cyst )]- OH 之製備 參考文獻 1)
WHO: influenza (seasonal). 2009, accessed at:http://www.who.intimediacentre/factsheets/fs211/en.
2) Metersky ML, Masterton RG, Lode H, File TM Jr, Babinchak T: Epidemiology, microbiology, and treatment considerations for bacterial pneumonia complicating influenza.Int J infect Dis.,
2012 16:e 321-331. 3) Hale BG, Albrecht RA, Garcia-Sastre A: Innate immune evasion strategies of influenza viruses.Future Microbiol.
2010, 5:23-41. 4) Palese P, Shaw ML: orthomyxoviridae: the viruses and their replication,In Fields Virology
, 5 edition. Edited by: Knipe DM, Howley PM, Philadelphia, PA:Lippincott Williams 2007:1647- '689. 5) Salomon R.et al.
: The influenza virus enigma.Cell.
136 (3), 402-410 (2009). 6) Gao R. et al.: Human infection with a novel avian-origin influenza A (H7N9) virus. N. Engl. J. Med. 368 (2Q): 1888-1897 (2013). 7) Imal M. et al. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to reassortant H5 HA/H1N1 virus in ferrets.Nature,
486 (7403): 420-428 (2012). 8) Herfst S. et al.: Airborne transmission of influenza A/H5N1 virus between ferrets.Science,
336 (6088):1534-1541 (2012). 9) Russell C A, et al.: The potential for respiratory droplet-transmissible A/H5N1 influenza virus to evolve in a mammalian host.Science,
336 (6088): 1541-1547 (2012). 10) Hu Y, et al.: Association between adverse clinical outcome in human diseases caused by novel influenza A H7N9 virus and sustained viral shedding and emergences of antiviral resistance.Lancet,
381 (9885): 2273-2279 (2013). 11) Baz M, et al.: Emergence of Oseltainivir-resistant pandemic H1N1 virus during prophylaxis. N.Engl. J Med.,
361 (23): 2296-2297 (2009). 12) Hayden F, : Developing new antiviral agents for influenza treatment: what does the future hold?Clinical Infectious Diseases,
48:S3-13 (2009). 13) Das K, et al.: Structures of influenza A proteins and insights into antiviral drug targets.Nature Structural & Molecular Biology,
Vol.17, No.5, 530-538 (2010). 14) Hayden F. : Newer influenza antivirals, biotherapeutics and combinations. Influenza and OtherRespiratory Viruses
7 (Suppl. 1), 63-75 (2012). 15) Wathen M W, et al.: Antivirals in seasonal and pandemic influenza-future perspectives.Influenza and Other Respiratory Virus,
7 (Suppl. 1), 76-80 (2012). 16) Novel antiviral therapies for influenza and other respiratory viruses: Bench to Bedside. The 4th
ISIRV-AVG Conference, 2-4 June 2015, University of Texas at Austin USA. 17) Chen, W. et al. A novel influenza A virus mitochondrial protein that induces cell death. Nat. Med.
7, 1306-1312 (2001). 18) Rebel, J.J. & Wiley, D.C. Receptor binding and membrane fusion in virus entry; the influenza hemagglutinin.Annu. Rev. Biochem.
69, 531-569 (2000). 19) Wu. W.W.&
Pante, N. The directionality of the nuclear transport of the influenza A genome is driven by selective exposure of nuclear localization sequences on nucleoprotein.Virol. J.,
6, 68 (2009). 20) Ulmanen I., Broni, B.A. & Krug, R.M. The role of two of the influenza virus core P proteins in recognizing cap 1 structures (m7
GpppNm) on RNAs and in initiating viral RNA transcription.Proc. Natl. Acad. Sci. USA,
78, 7355-7359 (1981). 21) Plotch, S.J., Bouloy. M., Uhranen, I. & Krug, R.M. A unique cap(m7GpppXm)-dependent influenza virion endonuclease cleaves capped RNAs to generate the primers that initiate viral RNA transcription.Cell,
23, 847-858 (1981). 22) Hagen,M., Chung, T.D.Y., Butcher, A.&
Krystal, M. Recombinant influenza virus polymerase: requirement of both 5' and 3' viral ends for endonuclease activity.J. Virol.,
68, 1509-1515 (1994). 23) Shimizu, K., lguchi, A., Gornyou, R. & Ono, Y. Influenza virus inhibits cleavage of the HSP70 pre-mRNAs at the polyadenylation site.Virology,
254, 213-219 (1999). 24) Nemeroff, M.E., Barabino, S.M., Li, Y., Keller, W. & Krug, R.M. Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3'end formation of cellular premRNAs. Mol. Cell 1, 991-1000 (1998). 25) Newcomb, L.L.et al.
Interaction of the influenza a virus nucleocapsid protein with the viral RNA polymerase potentiates unprimed viral RNA replication.J. Virol.,
83, 29-36 (2009). 26) Neumann,G., Hughes, M.T. & Kawaoka, Y. Influenza A virus NS2 protein mediates vRNP nuclear export through NES-independent interaction with hCRM1.EMBO J.,
19, 6751-6758 (2000). 27) Nayak, D.P., Hui, E.K. & Barman, S. Assembly and budding of influenza virus.Virus Res,
106,147-165 (2004). 28) Rennie P., Bowell P. et al.
: Low pH intranasal sprays inactivate influenza virusesin
vitro
and protect ferrets against influenza infection.Respiratory Research,
8, 37 (2007). 29) Anderson I, Proctor DF: Measurement of nasal mucocillary clearance.Eur.J.
Respir. Dis
., 64, 37-40 (1983). 30) Lande E.A.et al.
: A comparative study of the effect of Citric acid, Capsaicin and, Resiniferatoxin on the cough challenge in Guinea-pig and man.Pulmonary Pharmacology,
6, 171-175 (1993). 31) Tanaka, M. et al. : Mechanisms of Capsaicin—and Citric-acid-induced cough reflexes in GuineaPig.J. Pharmacol. Sci.
, 99, 77-82 (2005). 32) Erik De Clercq, Toward improved anti-HIV chemotherapy, therapeutic strategies for intervention with HIV infections.Med. Chem..
vol. 38, No.14, P.2491 (1995). 33) Abed Y et al.: Generation and Characterization of recombinant influenza A (H1N1) virus harboring amantadine resistance mutation.Antimicrob. Agents Chemother.
49: 556-559 (2005). 34) Bright R. et al.: Adamantane resistance around influenza A viruses isolated early during the 2005-2006 influenza season in the United States.JAMA,
8: 891-894 (2006). 35) Bright R. et al.: Incidence of admantine resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet,
9492: 1175-1181 (2005). 36) Nelson M. et al.: The origin and global emergence of adamantine resistant A (H3N2) influenza virus.Virology
, 388: 270-278 (2009). 37) Von Itzsteinet al.
: Rational Design of Potent Sialidase-based Inhibitors of Influenza Virus Replication.Nature
, 363, 418-423 (1993). 38) Klumpp, K.: Recent Advances in the Discovery and Development of Anti-influenza Drugs.Expert Opin. Ther. Pat.,
14, 1153-1168 (2004). 39) Wang , G.: Recent Advances in the Discovery and Development of Anti-influenza Drugs.Expert Opin. Ther. Pat.,
12, 845-861 (2002). 40) Abdel-Magid, A. F. et al.: Synthesis of Influenza Neuraminidase Inhibitors.Curr. Opin. Drug Discuss. Dev.,
4, 776-791 (2001). 41) Wang, G. T. et al.: Design, Synthesis, and Structure Analysis of Influenza Neuraminidase Inhibitors Containing Pyrrolidine Cores.J. Med. Chem.,
44, 1192-1201 (2001) 42) Babu, Y.S. et al.: Discovery of a Novel, Highly Potent, Orally Active, and Selective Influenza Neuraminidase Inhibitor through Structure-based Drug Design. J. Med. Chem.,
43, 3482-3486 (2000). 43) Chand, P. et al.: Syntheses and Neuraminidase Inhibitory Activity of Multisubstituted Cyclopentane Amide Derivatives. J. Med. Chem
., 47, 1919-1929 (2004). 44) Honda, T. et al.: Synthesis and Anti-influenza Evaluation of Polyvalent Sialidase Inhibitors bearing 4-Guandino-Neu5Ac2en derivatives.Bioorg. Med. Chem. Lett.
12, 1929-1932 (2002). 45) Honda, T. et al.: Synthesis and Anti-influenza Virus Activity of 7-O-Alkylated derivatives Related to Zanamivir.Bioorg. Med. Chem. Lett.
12, 1925-1928 (2002). 46) Del Mar C. et al.: Neuraminidase inhibitors for influenza complications. Lancet 384, 1260 (2014). 47) Jefferson T. et al.: Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children.Cochrane Database Syst. Rev.,
4:CD008965 (2014). 48) Nguyen-Van-Tam J S. et al.: Antivirals for influenza where now for clinical practice and pandemic preparedness?Lancet,
384: 386-387 (2014). 49) Reece, P.A. et al.:PCT Int Appl.
W098/21243 (1998). CA1998, 12928172. 50) Watson, K.G.; et al.: Highly potent and long-acting trimeric and tetrameric inhibitors of influenza virus neuraminidase.Bioorg. Med. Chem.. Lett.,
14, 1589 (2004). 51) Demaine, D.A. et al.: Dimeric compounds and their use as anti-viral agents. W003/040138.Chem. Abstr.,
138:354175 (2003). 52) Macdonald , S.J.F. et al.: Potent and long-acting dimeric inhibitors of influenza virus neuraminidase are effective at a one-weekly dosing regimen.Antimicrob. Agents and Chemoth.,
48, 4542 (2004). 53) Macdonald, S.J.F.; et al.: Dimer zanamivir conjugates with various linking group are potent, long-lasting inhibitors of influenza neuraminidase including H5N1 Avian influenza.J. Med. Chem.,
48, 2964 (2005). 54) Fraser B.H. et al.: Synthesis of 1,4-triazole linked zanamivir dimers as highly potent inhibitors of influenza A and B.Med. Chem. Commun.,
4, 383 (2013). 55) Watanabe W. et al.J. of Virological Methods,
48, 257 (1994).
圖 1 :
在感染MDCK細胞之前用測試化合物預處理病毒(A/Sydney/250/99或A/Sydney/5/97)之不同條件之概述。圖 2 :
在感染MDCK細胞之前用測試化合物對病毒(A/Sydney/250/99)進行之預處理:A) MD348,B) MD345,及C)紮那米韋(對照)。圖 3 :
在感染MDCK細胞之前用測試化合物對病毒(A/Sydney/5/97)進行之預處理:A) MD348,B) MD345,及C)紮那米韋(對照)。圖 4 :
在感染MDCK細胞之前用MD345 (測試化合物)及紮那米韋(對照)在變化的時間段內及變化的條件下對病毒(A/Sydney/250/99)進行之預處理。圖 5 :
MD314-1與MD021-7對A/Sydney/5/97 (H3N2)之抗病毒活性之比較。圖 6
:MD314-1與MD021-7對A/Mississippi/03/01 (H1N1)野生型之抗病毒活性之比較。圖 7 :
MD021-7與MD051-3對A/Mississippi/03/01 (H1N1)野生型之抗病毒活性之比較。圖 8
:MD021-7與MD051-3對A/Mississippi/03/01 (H1N1) H274Y (耐奧司他韋)之抗病毒活性之比較。圖 9 :
MD314-1與MD021-7對A/Mississippi/03/01 (H1N1) H274Y (耐奧司他韋)之抗病毒活性之比較。圖 10 :
用於評定小鼠中之肺及鼻甲中之病毒清除率的治療、感染及器官採集之時序之概述。圖 11 :
用於評定關於MD021、紮那米韋及PBS之病毒清除率之小鼠中之比較性肺病毒滴定度。圖 12
:用於評定關於MD021、紮那米韋及PBS在感染後第1天、第3天、第5天及第7天之病毒清除率的小鼠中之比較性肺病毒滴定度。圖 13
:經表示為PBS對照組之平均值之百分比的比較性病毒滴定度。圖 14 :
用於評定關於MD021、紮那米韋及PBS之病毒清除率之小鼠中之比較性體重減輕。圖 15 :
A/California/7/09 (pan H1N1)在活體外之中和。
Claims (26)
- 一種具有式(I)之化合物或其醫藥學上可接受之鹽、酯或立體異構體,
- 如請求項1之化合物或其醫藥學上可接受之鹽、酯或立體異構體,其中該錨定基團係選自由以下組成之群:抗體(Ab)或抗體之抗原結合片段、單鏈抗體片段(scFV)及單結構域抗體(dAb)。
- 如請求項1之化合物或其醫藥學上可接受之鹽、酯或立體異構體,其中L1及L2在每次出現時獨立地選自由以下組成之群:鍵、視情況經取代之C1-C12伸烷基、-C(O)-NR-、-O-C(O)O-NR-、-C=N-O-、-C=N-NR-、-SO2-NR-、二硫鍵、-C(O)-NR-(CH2)X-NR-、-(CH2)X-NR-、-(CH2)X-(O-(CH2)y-)z-、視情況經取代之-C=N-O-、視情況經取代之-C=N-NR-伸烷基、視情況經取代之伸烷基磺醯胺、視情況經取代之伸烷基二硫鍵,其中R獨立地為H或C1-C6烷基,且其中x、y及z各自為獨立地選自0、1、2、3及4之整數。
- 如請求項1之化合物或其醫藥學上可接受之鹽、酯或立體異構體,其中B係選自由以下組成之群:視情況經取代之丙烷-1,2,3-三羧酸酯、視情況經取代之環己烷-1,3,5-三羧酸酯及視情況經取代之苯-1,2,4,5-四羧酸酯。
- 如請求項1、3及4中任一項之化合物或其醫藥學上可接受之鹽、酯或立體異構體,其中A為紮那米韋。
- 如請求項1至4中任一項之化合物或其醫藥學上可接受之鹽、酯或立體異構體,其中B為苯-1,2,4,5-四羧酸酯。
- 如請求項1至4中任一項之化合物或其醫藥學上可接受之鹽、酯或立體異構體,其中R4在每次出現時為-COOH,且R5為-OH。
- 如請求項1至4中任一項之化合物或其醫藥學上可接受之鹽、酯或立體異構體,其中L2在每次出現時為鍵。
- 如請求項12之化合物或其醫藥學上可接受之鹽、酯或立體異構體,其中該化合物為烷基酯。
- 一種醫藥組合物,其包含如請求項1至13中任一項之化合物或其醫藥學上可接受之鹽、酯或立體異構體。
- 如請求項14之醫藥組合物,其中該化合物或其醫藥學上可接受之鹽、酯或立體異構體為如請求項5之化合物或其醫藥學上可接受之鹽、酯或立體異構體。
- 如請求項14之醫藥組合物,其中該組合物用於吸入、經口投與、鼻內投與、腹膜內投與、靜脈內投與或肌肉內投與。
- 如請求項之14之醫藥組合物,其進一步包含額外活性劑。
- 一種如請求項1至13中任一項之化合物或其醫藥學上可接受之鹽、酯或立體異構體之用途,其係用於製造用於治療或預防流感病毒感染之藥劑。
- 如請求項18之用途,其中該流感病毒感染為A型流感、B型流感、禽流感,或耐藥性流感病毒株。
- 如請求項18或19之用途,其中該感染為呼吸道感染或全身性感染。
- 如請求項18之用途,其中該藥劑經調配以用於吸入、經口投與、鼻內投與、腹膜內投與、靜脈內投與或肌肉內投與。
- 如請求項1至5中任一項之化合物或其醫藥學上可接受之鹽、酯或立 體異構體,其係用於治療或預防流感病毒感染。
- 如請求項23之化合物或其醫藥學上可接受之鹽、酯或立體異構體,其中該流感病毒感染為A型流感、B型流感、禽流感,或耐藥性流感病毒株。
- 如請求項23之化合物或其醫藥學上可接受之鹽、酯或立體異構體,其中該感染為呼吸道感染或全身性感染。
- 如請求項23之化合物或其醫藥學上可接受之鹽、酯或立體異構體,其中該化合物或其醫藥學上可接受之鹽、酯或立體異構體係用於藉由吸入、經口投與、鼻內投與、腹膜內投與、靜脈內投與或肌肉內投與來進行投與。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2015904895 | 2015-11-20 | ||
AU2015904895A AU2015904895A0 (en) | 2015-11-20 | Compounds for medicinal applications |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201726641A TW201726641A (zh) | 2017-08-01 |
TWI742015B true TWI742015B (zh) | 2021-10-11 |
Family
ID=58717109
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW105137966A TWI742015B (zh) | 2015-11-20 | 2016-11-18 | 用於醫療應用之化合物 |
Country Status (19)
Country | Link |
---|---|
US (1) | US11007274B2 (zh) |
EP (1) | EP3377487B1 (zh) |
JP (1) | JP7034913B2 (zh) |
KR (1) | KR20180083402A (zh) |
CN (1) | CN108473483B (zh) |
AU (1) | AU2016356726C1 (zh) |
BR (1) | BR112018010027A2 (zh) |
CA (1) | CA3005774C (zh) |
EA (1) | EA033921B9 (zh) |
ES (1) | ES2911027T3 (zh) |
IL (1) | IL259425B (zh) |
MX (1) | MX2018005999A (zh) |
MY (1) | MY195168A (zh) |
PH (1) | PH12018501076A1 (zh) |
SG (1) | SG11201803962WA (zh) |
TW (1) | TWI742015B (zh) |
UA (1) | UA126654C2 (zh) |
WO (1) | WO2017083914A1 (zh) |
ZA (1) | ZA201803214B (zh) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000055149A1 (en) | 1999-03-12 | 2000-09-21 | Biota Scientific Management Pty. Ltd. | Dimeric compounds and as inhibitors of neuraminidase |
WO2002020514A1 (en) | 2000-09-08 | 2002-03-14 | Biota Scientific Management Pty Ltd | Multivalent neuraminidase inhibitor conjugates |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2052027T5 (es) | 1988-11-11 | 2005-04-16 | Medical Research Council | Clonacion de secuencias de dominio variable de inmunoglobulina. |
TR199901081T2 (xx) | 1996-11-14 | 1999-08-23 | Biota Scientific Management Pty.Ltd. | Y�ntem ve bu y�ntemde kullan�lan yeni bile�imler. |
AUPR879501A0 (en) | 2001-11-09 | 2001-12-06 | Biota Scientific Management Pty Ltd | Novel chemical compounds and their use |
DE102004002132A1 (de) * | 2004-01-15 | 2005-08-11 | Man Roland Druckmaschinen Ag | Einrichtung zur Erzeugung einer Beschichtung von Druckprodukten einer Druckmaschine |
JP5950390B2 (ja) * | 2012-03-26 | 2016-07-13 | 国立大学法人 琉球大学 | 新規ミモシン誘導体 |
US10130714B2 (en) * | 2012-04-14 | 2018-11-20 | Academia Sinica | Enhanced anti-influenza agents conjugated with anti-inflammatory activity |
GB201313201D0 (en) * | 2013-07-24 | 2013-09-04 | Univ East Anglia | Virus Detection |
CN105085455A (zh) * | 2014-05-13 | 2015-11-25 | 中国科学院广州生物医药与健康研究院 | 唾液酸类似物或其药学上可接受的盐及其应用 |
-
2016
- 2016-11-16 KR KR1020187017047A patent/KR20180083402A/ko not_active Application Discontinuation
- 2016-11-16 EA EA201891072A patent/EA033921B9/ru not_active IP Right Cessation
- 2016-11-16 UA UAA201806293A patent/UA126654C2/uk unknown
- 2016-11-16 MY MYPI2018701859A patent/MY195168A/en unknown
- 2016-11-16 WO PCT/AU2016/051100 patent/WO2017083914A1/en active Application Filing
- 2016-11-16 SG SG11201803962WA patent/SG11201803962WA/en unknown
- 2016-11-16 AU AU2016356726A patent/AU2016356726C1/en active Active
- 2016-11-16 ES ES16865298T patent/ES2911027T3/es active Active
- 2016-11-16 MX MX2018005999A patent/MX2018005999A/es unknown
- 2016-11-16 CN CN201680075964.XA patent/CN108473483B/zh active Active
- 2016-11-16 JP JP2018525746A patent/JP7034913B2/ja active Active
- 2016-11-16 CA CA3005774A patent/CA3005774C/en active Active
- 2016-11-16 EP EP16865298.0A patent/EP3377487B1/en active Active
- 2016-11-16 BR BR112018010027A patent/BR112018010027A2/pt active Search and Examination
- 2016-11-18 TW TW105137966A patent/TWI742015B/zh active
-
2018
- 2018-05-15 ZA ZA2018/03214A patent/ZA201803214B/en unknown
- 2018-05-16 IL IL259425A patent/IL259425B/en unknown
- 2018-05-18 US US15/984,029 patent/US11007274B2/en active Active
- 2018-05-18 PH PH12018501076A patent/PH12018501076A1/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000055149A1 (en) | 1999-03-12 | 2000-09-21 | Biota Scientific Management Pty. Ltd. | Dimeric compounds and as inhibitors of neuraminidase |
WO2002020514A1 (en) | 2000-09-08 | 2002-03-14 | Biota Scientific Management Pty Ltd | Multivalent neuraminidase inhibitor conjugates |
Non-Patent Citations (1)
Title |
---|
Zanini and Roy, "Synthesis of New R-Thiosialodendrimers and Their Binding Properties to the Sialic Acid Specific Lectin from Limax flaVus", Journal of American Chemical Society, 1997, 119(9), pp 2088-2095. |
Also Published As
Publication number | Publication date |
---|---|
PH12018501076A1 (en) | 2019-01-28 |
AU2016356726A1 (en) | 2018-06-07 |
US11007274B2 (en) | 2021-05-18 |
IL259425B (en) | 2021-10-31 |
JP2019502662A (ja) | 2019-01-31 |
EA033921B9 (ru) | 2020-01-22 |
CN108473483B (zh) | 2022-08-30 |
EP3377487A1 (en) | 2018-09-26 |
CA3005774A1 (en) | 2017-05-26 |
JP7034913B2 (ja) | 2022-03-14 |
SG11201803962WA (en) | 2018-06-28 |
TW201726641A (zh) | 2017-08-01 |
NZ742593A (en) | 2023-08-25 |
EP3377487A4 (en) | 2019-07-17 |
IL259425A (en) | 2018-07-31 |
CN108473483A (zh) | 2018-08-31 |
EA201891072A1 (ru) | 2018-11-30 |
AU2016356726B2 (en) | 2021-02-25 |
AU2016356726C1 (en) | 2021-12-09 |
EA033921B1 (ru) | 2019-12-10 |
WO2017083914A1 (en) | 2017-05-26 |
MY195168A (en) | 2023-01-11 |
CA3005774C (en) | 2024-01-09 |
ZA201803214B (en) | 2019-07-31 |
US20180264128A1 (en) | 2018-09-20 |
EP3377487B1 (en) | 2022-01-12 |
BR112018010027A2 (pt) | 2018-11-21 |
ES2911027T3 (es) | 2022-05-17 |
MX2018005999A (es) | 2018-11-22 |
KR20180083402A (ko) | 2018-07-20 |
UA126654C2 (uk) | 2023-01-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2644578T3 (es) | Derivados de betulina | |
KR20230057411A (ko) | 바이러스 감염 치료를 위한 화합물 및 방법 | |
JP7023466B2 (ja) | インフルエンザ受動免疫に有用な抗体ならびにその使用のための組成物、組合せおよび方法 | |
KR20150013527A (ko) | 항염증 활성과 접합된 증진된 항인플루엔자제 | |
NZ719729A (en) | Inhibitors of influenza viruses replication | |
JP7439367B2 (ja) | 最適化化合物 | |
JP2013503880A (ja) | オルトミクソウイルス感染の治療方法 | |
US20170189529A1 (en) | Antibodies useful in passive influenza immunization, and compositions, combinations and methods for use thereof | |
TWI742015B (zh) | 用於醫療應用之化合物 | |
NZ742593B2 (en) | Compounds for medicinal applications | |
JP2023531387A (ja) | 分岐脂質化合物 | |
CA3226951A1 (en) | Formulation | |
WO2024030938A1 (en) | Compositions, kits, and methods of immunizing against viral infections |