CA2742842A1

CA2742842A1 - Releasable conjugates for nucleic acids delivery systems

Releasable conjugates for nucleic acids delivery systems Download PDF

Info

Publication number: CA2742842A1
Authority: CA; Canada
Prior art keywords: ch2ch2o; group; compound; ch2s; ch2ch2nh
Prior art date: 2008-11-17
Legal status : Abandoned

Application number

CA2742842A

Other languages

English (en)

French (fr)

Inventor

Hong Zhao

Jing Xia

Prasanna Reddy

Current Assignee

Belrose Pharma Inc

Original Assignee

Enzon Pharmaceuticals Inc

Priority date

2008-11-17

Filing date

2009-11-17

Publication date

2010-05-20

2009-11-17 Application filed by Enzon Pharmaceuticals Inc filed Critical Enzon Pharmaceuticals Inc

2010-05-20 Publication of CA2742842A1 publication Critical patent/CA2742842A1/en

Status Abandoned legal-status Critical Current

Links

150000007523 nucleic acids Chemical class 0.000 title claims abstract description 64
102000039446 nucleic acids Human genes 0.000 title claims abstract description 59
108020004707 nucleic acids Proteins 0.000 title claims abstract description 59
230000008685 targeting Effects 0.000 claims abstract description 86
238000000034 method Methods 0.000 claims abstract description 63
108090000623 proteins and genes Proteins 0.000 claims abstract description 46
230000014509 gene expression Effects 0.000 claims abstract description 26
108010077850 Nuclear Localization Signals Proteins 0.000 claims abstract description 24
150000001875 compounds Chemical class 0.000 claims description 244
108091034117 Oligonucleotide Proteins 0.000 claims description 111
239000013543 active substance Substances 0.000 claims description 80
210000004027 cell Anatomy 0.000 claims description 74
-1 azido, carboxy Chemical group 0.000 claims description 68
229910052739 hydrogen Inorganic materials 0.000 claims description 66
239000001257 hydrogen Substances 0.000 claims description 65
125000000217 alkyl group Chemical group 0.000 claims description 63
229920000642 polymer Polymers 0.000 claims description 54
108090000765 processed proteins & peptides Proteins 0.000 claims description 53
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 52
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235000014304 histidine Nutrition 0.000 claims description 31
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125000003107 substituted aryl group Chemical group 0.000 claims description 17
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125000000547 substituted alkyl group Chemical group 0.000 claims description 16
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125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 14
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235000019152 folic acid Nutrition 0.000 claims description 12
239000011724 folic acid Substances 0.000 claims description 12
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
239000002246 antineoplastic agent Substances 0.000 claims description 10
235000019256 formaldehyde Nutrition 0.000 claims description 10
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
125000003710 aryl alkyl group Chemical group 0.000 claims description 9
125000004404 heteroalkyl group Chemical group 0.000 claims description 9
230000037361 pathway Effects 0.000 claims description 9
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
125000006850 spacer group Chemical group 0.000 claims description 9
125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 8
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 8
230000002401 inhibitory effect Effects 0.000 claims description 8
229910052717 sulfur Inorganic materials 0.000 claims description 8
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
150000001412 amines Chemical class 0.000 claims description 7
201000010099 disease Diseases 0.000 claims description 7
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
239000011593 sulfur Substances 0.000 claims description 7
GUCPYIYFQVTFSI-UHFFFAOYSA-N 4-methoxybenzamide Chemical compound COC1=CC=C(C(N)=O)C=C1 GUCPYIYFQVTFSI-UHFFFAOYSA-N 0.000 claims description 6
102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 claims description 6
IYMAXBFPHPZYIK-BQBZGAKWSA-N Arg-Gly-Asp Chemical class NC(N)=NCCC[C@H](N)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(O)=O IYMAXBFPHPZYIK-BQBZGAKWSA-N 0.000 claims description 6
230000002222 downregulating effect Effects 0.000 claims description 6
229940014144 folate Drugs 0.000 claims description 6
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
229910052760 oxygen Inorganic materials 0.000 claims description 6
101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 claims description 5
108020004459 Small interfering RNA Proteins 0.000 claims description 5
125000004405 heteroalkoxy group Chemical group 0.000 claims description 5
125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims description 5
108010025628 Apolipoproteins E Proteins 0.000 claims description 4
102000013918 Apolipoproteins E Human genes 0.000 claims description 4
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102000015735 Beta-catenin Human genes 0.000 claims description 4
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108700020796 Oncogene Proteins 0.000 claims description 4
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239000000074 antisense oligonucleotide Substances 0.000 claims description 4
238000012230 antisense oligonucleotides Methods 0.000 claims description 4
108010072041 arginyl-glycyl-aspartic acid Proteins 0.000 claims description 4
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NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 claims description 4
RAVVEEJGALCVIN-AGVBWZICSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-2-[[(2s)-2-[[(2s)-6-amino-2-[[(2s)-6-amino-2-[[(2s)-2-[[2-[[(2s)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-(diamino Chemical compound NC(N)=NCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCN=C(N)N)NC(=O)CNC(=O)[C@@H](N)CC1=CC=C(O)C=C1 RAVVEEJGALCVIN-AGVBWZICSA-N 0.000 claims description 3
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