AU2021205837A1 - Nanomaterials - Google Patents
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- AU2021205837A1 AU2021205837A1 AU2021205837A AU2021205837A AU2021205837A1 AU 2021205837 A1 AU2021205837 A1 AU 2021205837A1 AU 2021205837 A AU2021205837 A AU 2021205837A AU 2021205837 A AU2021205837 A AU 2021205837A AU 2021205837 A1 AU2021205837 A1 AU 2021205837A1
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- Australia
- Prior art keywords
- oxy
- compound
- bis
- dienoate
- propyl
- Prior art date
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- 239000002086 nanomaterial Substances 0.000 title description 2
- 238000000034 method Methods 0.000 claims abstract description 366
- 150000002632 lipids Chemical class 0.000 claims abstract description 123
- 239000000203 mixture Substances 0.000 claims abstract description 99
- 239000002105 nanoparticle Substances 0.000 claims abstract description 89
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 67
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 67
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 66
- -1 polyethylene Polymers 0.000 claims description 223
- 125000000217 alkyl group Chemical group 0.000 claims description 97
- 150000001875 compounds Chemical class 0.000 claims description 83
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 68
- 125000003118 aryl group Chemical group 0.000 claims description 50
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 46
- 125000001072 heteroaryl group Chemical group 0.000 claims description 44
- 125000000623 heterocyclic group Chemical group 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 40
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 39
- 125000004429 atom Chemical group 0.000 claims description 31
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 27
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 24
- 108020004459 Small interfering RNA Proteins 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 108091034117 Oligonucleotide Proteins 0.000 claims description 22
- 150000003904 phospholipids Chemical class 0.000 claims description 21
- 235000012000 cholesterol Nutrition 0.000 claims description 20
- 108020004999 messenger RNA Proteins 0.000 claims description 20
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- 239000011593 sulfur Chemical group 0.000 claims description 11
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 239000002679 microRNA Substances 0.000 claims description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 claims description 4
- 239000004698 Polyethylene Substances 0.000 claims description 4
- OLBVUFHMDRJKTK-UHFFFAOYSA-N [N].[O] Chemical compound [N].[O] OLBVUFHMDRJKTK-UHFFFAOYSA-N 0.000 claims description 4
- QRSFFHRCBYCWBS-UHFFFAOYSA-N [O].[O] Chemical compound [O].[O] QRSFFHRCBYCWBS-UHFFFAOYSA-N 0.000 claims description 4
- 239000000074 antisense oligonucleotide Substances 0.000 claims description 4
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- 108091070501 miRNA Proteins 0.000 claims description 4
- 230000003308 immunostimulating effect Effects 0.000 claims description 3
- 229920000573 polyethylene Polymers 0.000 claims description 3
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 238000012384 transportation and delivery Methods 0.000 abstract description 18
- 230000001225 therapeutic effect Effects 0.000 abstract description 13
- 230000008685 targeting Effects 0.000 abstract description 10
- 239000003446 ligand Substances 0.000 abstract description 8
- 239000000543 intermediate Substances 0.000 description 158
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 149
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 119
- AJAMRCUNWLZBDF-MURFETPASA-N propyl linoleate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OCCC AJAMRCUNWLZBDF-MURFETPASA-N 0.000 description 94
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 65
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 64
- 238000005160 1H NMR spectroscopy Methods 0.000 description 63
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 45
- 239000000243 solution Substances 0.000 description 45
- 239000001149 (9Z,12Z)-octadeca-9,12-dienoate Substances 0.000 description 38
- OYHQOLUKZRVURQ-HZJYTTRNSA-M 9-cis,12-cis-Octadecadienoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC([O-])=O OYHQOLUKZRVURQ-HZJYTTRNSA-M 0.000 description 36
- 238000005481 NMR spectroscopy Methods 0.000 description 34
- 102100031726 Endoplasmic reticulum junction formation protein lunapark Human genes 0.000 description 33
- 101000991410 Homo sapiens Nucleolar and spindle-associated protein 1 Proteins 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 29
- 239000002253 acid Substances 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 27
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 27
- 229920002477 rna polymer Polymers 0.000 description 27
- 125000003342 alkenyl group Chemical group 0.000 description 26
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 238000009472 formulation Methods 0.000 description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 23
- 102000053602 DNA Human genes 0.000 description 23
- 108020004414 DNA Proteins 0.000 description 23
- 125000000304 alkynyl group Chemical group 0.000 description 23
- 125000000392 cycloalkenyl group Chemical group 0.000 description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 22
- 239000004055 small Interfering RNA Substances 0.000 description 22
- WKCYFSZDBICRKL-UHFFFAOYSA-N 3-(diethylamino)propan-1-ol Chemical compound CCN(CC)CCCO WKCYFSZDBICRKL-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- 150000002431 hydrogen Chemical group 0.000 description 20
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 19
- 230000002829 reductive effect Effects 0.000 description 19
- UFFXQKBVALLYQW-UHFFFAOYSA-N (1-ethylpiperidin-3-yl)methanol Chemical compound CCN1CCCC(CO)C1 UFFXQKBVALLYQW-UHFFFAOYSA-N 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 16
- 108090000623 proteins and genes Proteins 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 16
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 15
- 239000013058 crude material Substances 0.000 description 15
- 108090000765 processed proteins & peptides Proteins 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- 239000012267 brine Substances 0.000 description 13
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 125000002947 alkylene group Chemical group 0.000 description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
- QPMJENKZJUFOON-PLNGDYQASA-N ethyl (z)-3-chloro-2-cyano-4,4,4-trifluorobut-2-enoate Chemical compound CCOC(=O)C(\C#N)=C(/Cl)C(F)(F)F QPMJENKZJUFOON-PLNGDYQASA-N 0.000 description 12
- 125000004122 cyclic group Chemical group 0.000 description 11
- 230000004048 modification Effects 0.000 description 11
- 238000012986 modification Methods 0.000 description 11
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 11
- 230000000069 prophylactic effect Effects 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
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- 238000002347 injection Methods 0.000 description 10
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- OYHQOLUKZRVURQ-UHFFFAOYSA-M octadeca-9,12-dienoate Chemical compound CCCCCC=CCC=CCCCCCCCC([O-])=O OYHQOLUKZRVURQ-UHFFFAOYSA-M 0.000 description 10
- NMRPBPVERJPACX-UHFFFAOYSA-N octan-3-ol Chemical compound CCCCCC(O)CC NMRPBPVERJPACX-UHFFFAOYSA-N 0.000 description 10
- 239000002953 phosphate buffered saline Substances 0.000 description 10
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 9
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 9
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Classifications
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- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
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- 2021-01-06 IL IL294318A patent/IL294318A/en unknown
- 2021-01-06 AU AU2021205837A patent/AU2021205837A1/en active Pending
- 2021-01-06 JP JP2022542118A patent/JP7791822B2/ja active Active
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2025
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- 2025-09-26 JP JP2025160231A patent/JP2026016394A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| IL294318A (en) | 2022-08-01 |
| KR20220123536A (ko) | 2022-09-07 |
| JP7791822B2 (ja) | 2025-12-24 |
| MX2022008455A (es) | 2022-08-22 |
| CN115175894A (zh) | 2022-10-11 |
| US20210230112A1 (en) | 2021-07-29 |
| US20260001838A1 (en) | 2026-01-01 |
| EP4103542A4 (en) | 2024-02-14 |
| EP4103542A1 (en) | 2022-12-21 |
| US12435035B2 (en) | 2025-10-07 |
| CN119684140A (zh) | 2025-03-25 |
| CA3163161A1 (en) | 2021-07-15 |
| JP2026016394A (ja) | 2026-02-03 |
| BR112022013599A2 (pt) | 2022-09-13 |
| WO2021141969A1 (en) | 2021-07-15 |
| JP2023510778A (ja) | 2023-03-15 |
| CN115175894B (zh) | 2024-09-06 |
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