CA2742776A1 - Releasable cationic lipids for nucleic acids delivery systems - Google Patents

Info

Publication number

CA2742776A1

CA2742776A1 CA2742776A CA2742776A CA2742776A1 CA 2742776 A1 CA2742776 A1 CA 2742776A1 CA 2742776 A CA2742776 A CA 2742776A CA 2742776 A CA2742776 A CA 2742776A CA 2742776 A1 CA2742776 A1 CA 2742776A1

Authority

CA

Canada

Prior art keywords

substituted

ch2ch2o

compound

ch2ch2

2nhc

Prior art date

2008-11-17

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Abandoned

Links

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 150000007523 nucleic acids Chemical class 0.000 title claims abstract description 109
• 102000039446 nucleic acids Human genes 0.000 title claims abstract description 104
• 108020004707 nucleic acids Proteins 0.000 title claims abstract description 104
• 125000002091 cationic group Chemical group 0.000 title abstract description 43
• 239000002105 nanoparticle Substances 0.000 claims abstract description 267
• 239000000203 mixture Substances 0.000 claims abstract description 152
• 238000000034 method Methods 0.000 claims abstract description 77
• 108090000623 proteins and genes Proteins 0.000 claims abstract description 44
• 230000014509 gene expression Effects 0.000 claims abstract description 27
• 239000002253 acid Substances 0.000 claims abstract description 9
• 150000001875 compounds Chemical class 0.000 claims description 113
• 150000002632 lipids Chemical class 0.000 claims description 109
• 108091034117 Oligonucleotide Proteins 0.000 claims description 108
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical group 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 101
• 125000000217 alkyl group Chemical group 0.000 claims description 86
• 210000004027 cell Anatomy 0.000 claims description 68
• -1 azido, carboxy Chemical class 0.000 claims description 66
• 229910052739 hydrogen Inorganic materials 0.000 claims description 61
• 239000001257 hydrogen Substances 0.000 claims description 59
• 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 claims description 58
• 206010028980 Neoplasm Diseases 0.000 claims description 48
• 235000012000 cholesterol Nutrition 0.000 claims description 47
• 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 40
• 125000003118 aryl group Chemical group 0.000 claims description 40
• 150000001412 amines Chemical class 0.000 claims description 37
• 125000005647 linker group Chemical group 0.000 claims description 37
• 201000011510 cancer Diseases 0.000 claims description 36
• 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 36
• 230000000692 anti-sense effect Effects 0.000 claims description 35
• 125000001072 heteroaryl group Chemical group 0.000 claims description 32
• 239000002773 nucleotide Substances 0.000 claims description 32
• 230000001588 bifunctional effect Effects 0.000 claims description 31
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 30
• 229940106189 ceramide Drugs 0.000 claims description 29
• 230000000799 fusogenic effect Effects 0.000 claims description 27
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 26
• 125000003107 substituted aryl group Chemical group 0.000 claims description 25
• 125000003729 nucleotide group Chemical group 0.000 claims description 24
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 20
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 19
• 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 description 18
• 241000124008 Mammalia Species 0.000 claims description 18
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
• 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 16
• 125000004423 acyloxy group Chemical group 0.000 claims description 15
• 125000006850 spacer group Chemical group 0.000 claims description 15
• JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 14
• 229910052757 nitrogen Inorganic materials 0.000 claims description 14
• 229910052760 oxygen Inorganic materials 0.000 claims description 14
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 13
• 201000010099 disease Diseases 0.000 claims description 12
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
• 125000005017 substituted alkenyl group Chemical group 0.000 claims description 12
• 125000004426 substituted alkynyl group Chemical group 0.000 claims description 12
• 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 11
• 239000002246 antineoplastic agent Substances 0.000 claims description 11
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 10
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 10
• 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 10
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 10
• 125000004093 cyano group Chemical class *C#N 0.000 claims description 10
• WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 10
• 125000004405 heteroalkoxy group Chemical group 0.000 claims description 9
• 229910052717 sulfur Inorganic materials 0.000 claims description 9
• 230000002401 inhibitory effect Effects 0.000 claims description 8
• RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 claims description 8
• YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 claims description 7
• CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 claims description 7
• 108020004459 Small interfering RNA Proteins 0.000 claims description 7
• 125000004414 alkyl thio group Chemical group 0.000 claims description 7
• 229910052799 carbon Inorganic materials 0.000 claims description 7
• ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 claims description 7
• VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 claims description 7
• 239000004055 small Interfering RNA Substances 0.000 claims description 7
• 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 claims description 6
• 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 claims description 6
• 239000000074 antisense oligonucleotide Substances 0.000 claims description 6
• 238000012230 antisense oligonucleotides Methods 0.000 claims description 6
• 230000002222 downregulating effect Effects 0.000 claims description 6
• 230000037361 pathway Effects 0.000 claims description 6
• 229910052698 phosphorus Inorganic materials 0.000 claims description 6
• 108060000903 Beta-catenin Proteins 0.000 claims description 5
• 102000015735 Beta-catenin Human genes 0.000 claims description 5
• 108700020796 Oncogene Proteins 0.000 claims description 5
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
• 125000004104 aryloxy group Chemical group 0.000 claims description 5
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 5
• 108700011259 MicroRNAs Proteins 0.000 claims description 4
• 102000043276 Oncogene Human genes 0.000 claims description 4
• 150000002466 imines Chemical class 0.000 claims description 4
• 239000002679 microRNA Substances 0.000 claims description 4
• 108091023037 Aptamer Proteins 0.000 claims description 3
• 102000053642 Catalytic RNA Human genes 0.000 claims description 3
• 108090000994 Catalytic RNA Proteins 0.000 claims description 3
• 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 claims description 3
• 108700005077 Viral Genes Proteins 0.000 claims description 3
• 230000004663 cell proliferation Effects 0.000 claims description 3
• 230000012010 growth Effects 0.000 claims description 3
• 210000005260 human cell Anatomy 0.000 claims description 3
• 239000012678 infectious agent Substances 0.000 claims description 3
• 230000004647 pro-inflammatory pathway Effects 0.000 claims description 3
• 230000009443 proangiogenesis Effects 0.000 claims description 3
• 108091092562 ribozyme Proteins 0.000 claims description 3
• 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 claims description 2
• 108091030071 RNAI Proteins 0.000 claims description 2
• 229960001231 choline Drugs 0.000 claims description 2
• 230000009368 gene silencing by RNA Effects 0.000 claims description 2
• KITHNHJPIHPBQH-UHFFFAOYSA-N nitro(nitrosilyloxy)silane Chemical class [N+](=O)([O-])[SiH2]O[SiH2][N+](=O)[O-] KITHNHJPIHPBQH-UHFFFAOYSA-N 0.000 claims description 2
• 230000035755 proliferation Effects 0.000 claims description 2
• 125000000472 sulfonyl group Chemical class *S(*)(=O)=O 0.000 claims description 2
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 14
• 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 8
• 125000001589 carboacyl group Chemical group 0.000 claims 4
• 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
• 108091093037 Peptide nucleic acid Proteins 0.000 claims 1
• 108091028664 Ribonucleotide Proteins 0.000 claims 1
• DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims 1
• 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 1
• 125000001475 halogen functional group Chemical class 0.000 claims 1
• 150000004713 phosphodiesters Chemical class 0.000 claims 1
• 239000002336 ribonucleotide Substances 0.000 claims 1
• 125000002652 ribonucleotide group Chemical group 0.000 claims 1
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
• 229920001223 polyethylene glycol Polymers 0.000 description 71
• 239000002202 Polyethylene glycol Substances 0.000 description 61
• 239000000243 solution Substances 0.000 description 39
• 238000002360 preparation method Methods 0.000 description 38
• MWRBNPKJOOWZPW-CLFAGFIQSA-N dioleoyl phosphatidylethanolamine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COP(O)(=O)OCCN)OC(=O)CCCCCCC\C=C/CCCCCCCC MWRBNPKJOOWZPW-CLFAGFIQSA-N 0.000 description 34
• 150000002431 hydrogen Chemical class 0.000 description 32
• 238000011282 treatment Methods 0.000 description 30
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 26
• 238000006243 chemical reaction Methods 0.000 description 25
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 25
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 22
• 230000001225 therapeutic effect Effects 0.000 description 22
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 21
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• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
• 230000008685 targeting Effects 0.000 description 18
• RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical group OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 17
• 125000000753 cycloalkyl group Chemical group 0.000 description 17
• 238000000338 in vitro Methods 0.000 description 17
• 210000001519 tissue Anatomy 0.000 description 17
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• 125000003545 alkoxy group Chemical group 0.000 description 16
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 16
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• 238000001727 in vivo Methods 0.000 description 15
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
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• 230000004048 modification Effects 0.000 description 13
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• 150000003839 salts Chemical class 0.000 description 13
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
• 125000003277 amino group Chemical group 0.000 description 12
• 125000000592 heterocycloalkyl group Chemical group 0.000 description 12
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• 239000000725 suspension Substances 0.000 description 11
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
• 238000009472 formulation Methods 0.000 description 10
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
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• 239000000463 material Substances 0.000 description 9
• KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 8
• SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 description 8
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
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• 239000011541 reaction mixture Substances 0.000 description 8
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• 102100021663 Baculoviral IAP repeat-containing protein 5 Human genes 0.000 description 6
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• 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
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• OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 6
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