JP4476802B2 - ロックト核酸誘導体の製造 - Google Patents
ロックト核酸誘導体の製造 Download PDFInfo
- Publication number
- JP4476802B2 JP4476802B2 JP2004503481A JP2004503481A JP4476802B2 JP 4476802 B2 JP4476802 B2 JP 4476802B2 JP 2004503481 A JP2004503481 A JP 2004503481A JP 2004503481 A JP2004503481 A JP 2004503481A JP 4476802 B2 JP4476802 B2 JP 4476802B2
- Authority
- JP
- Japan
- Prior art keywords
- lna
- alkyl
- formula
- halogen
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 238000004519 manufacturing process Methods 0.000 title claims description 34
- 108020004707 nucleic acids Proteins 0.000 title abstract description 4
- 150000007523 nucleic acids Chemical class 0.000 title abstract description 4
- 102000039446 nucleic acids Human genes 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- -1 methylene LNA Chemical compound 0.000 claims abstract description 59
- 239000012038 nucleophile Substances 0.000 claims abstract description 31
- 125000001424 substituent group Chemical group 0.000 claims description 90
- 229910052736 halogen Inorganic materials 0.000 claims description 79
- 239000011734 sodium Substances 0.000 claims description 59
- 150000002367 halogens Chemical class 0.000 claims description 53
- 238000000034 method Methods 0.000 claims description 50
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 claims description 35
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 32
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 30
- 125000005843 halogen group Chemical group 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000005947 C1-C6 alkylsulfonyloxy group Chemical group 0.000 claims description 17
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical group O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 16
- 229940113082 thymine Drugs 0.000 claims description 15
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 14
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical group NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 14
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical group O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 229930024421 Adenine Natural products 0.000 claims description 13
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 13
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 13
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical group O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 150000002118 epoxides Chemical class 0.000 claims description 12
- 125000002346 iodo group Chemical group I* 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 11
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical group NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 claims description 10
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical group [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003880 polar aprotic solvent Substances 0.000 claims description 10
- 108091034117 Oligonucleotide Proteins 0.000 claims description 9
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 8
- 125000002524 organometallic group Chemical group 0.000 claims description 8
- 229940035893 uracil Drugs 0.000 claims description 8
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 7
- FGZFFVCJLAVVJY-ZIFCJYIRSA-N [(3s,4r,5r)-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-4-methylsulfonyloxy-2-(methylsulfonyloxymethyl)-3-phenylmethoxyoxolan-2-yl]methyl methanesulfonate Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](OS(C)(=O)=O)[C@H](OCC=2C=CC=CC=2)C(COS(C)(=O)=O)(COS(C)(=O)=O)O1 FGZFFVCJLAVVJY-ZIFCJYIRSA-N 0.000 claims description 7
- 229960000643 adenine Drugs 0.000 claims description 7
- 229940104302 cytosine Drugs 0.000 claims description 7
- 125000003107 substituted aryl group Chemical group 0.000 claims description 7
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical group ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical group NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 claims description 6
- 229960004413 flucytosine Drugs 0.000 claims description 6
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 claims description 6
- 229940075420 xanthine Drugs 0.000 claims description 6
- HWPZZUQOWRWFDB-UHFFFAOYSA-N 1-methylcytosine Chemical group CN1C=CC(N)=NC1=O HWPZZUQOWRWFDB-UHFFFAOYSA-N 0.000 claims description 5
- JYWKEVKEKOTYEX-UHFFFAOYSA-N 2,6-dibromo-4-chloroiminocyclohexa-2,5-dien-1-one Chemical compound ClN=C1C=C(Br)C(=O)C(Br)=C1 JYWKEVKEKOTYEX-UHFFFAOYSA-N 0.000 claims description 5
- ZLAQATDNGLKIEV-UHFFFAOYSA-N 5-methyl-2-sulfanylidene-1h-pyrimidin-4-one Chemical group CC1=CNC(=S)NC1=O ZLAQATDNGLKIEV-UHFFFAOYSA-N 0.000 claims description 5
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 claims description 5
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical group NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- 239000000178 monomer Substances 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 3
- LMRDBJZQDUVCQH-UHFFFAOYSA-N 2-(1,3-dioxoisoindol-2-yl)acetaldehyde Chemical compound C1=CC=C2C(=O)N(CC=O)C(=O)C2=C1 LMRDBJZQDUVCQH-UHFFFAOYSA-N 0.000 claims description 2
- QWZDKYIWDGZVDK-JFGNBEQYSA-N [(3s,4r,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-4-methylsulfonyloxy-2-(methylsulfonyloxymethyl)oxolan-2-yl]methyl methanesulfonate Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](OS(C)(=O)=O)[C@H](N=[N+]=[N-])C(COS(C)(=O)=O)(COS(C)(=O)=O)O1 QWZDKYIWDGZVDK-JFGNBEQYSA-N 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- RCYFOPUXRMOLQM-UHFFFAOYSA-N pyrene-1-carbaldehyde Chemical compound C1=C2C(C=O)=CC=C(C=C3)C2=C2C3=CC=CC2=C1 RCYFOPUXRMOLQM-UHFFFAOYSA-N 0.000 claims description 2
- FNRNHFMKSCPBDA-UHFFFAOYSA-N pyrene-1-carbonyl chloride Chemical compound C1=C2C(C(=O)Cl)=CC=C(C=C3)C2=C2C3=CC=CC2=C1 FNRNHFMKSCPBDA-UHFFFAOYSA-N 0.000 claims description 2
- 150000003934 aromatic aldehydes Chemical class 0.000 claims 2
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical compound CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 claims 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims 1
- HUMNYLRZRPPJDN-KWCOIAHCSA-N benzaldehyde Chemical group O=[11CH]C1=CC=CC=C1 HUMNYLRZRPPJDN-KWCOIAHCSA-N 0.000 claims 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 76
- 239000000543 intermediate Substances 0.000 abstract description 36
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 196
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 158
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 144
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 120
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 103
- 235000019439 ethyl acetate Nutrition 0.000 description 98
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 68
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- 239000002777 nucleoside Substances 0.000 description 61
- 229920006395 saturated elastomer Polymers 0.000 description 58
- 238000005481 NMR spectroscopy Methods 0.000 description 57
- 150000003833 nucleoside derivatives Chemical class 0.000 description 55
- 239000012044 organic layer Substances 0.000 description 52
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 48
- 239000012267 brine Substances 0.000 description 47
- 239000000243 solution Substances 0.000 description 37
- 239000011541 reaction mixture Substances 0.000 description 36
- 239000008346 aqueous phase Substances 0.000 description 33
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 33
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
- 239000000203 mixture Substances 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- 239000006260 foam Substances 0.000 description 26
- 239000012071 phase Substances 0.000 description 26
- 239000007787 solid Substances 0.000 description 22
- 238000000921 elemental analysis Methods 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 16
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 125000003294 thymin-1-yl group Chemical group [H]N1C(=O)N(*)C([H])=C(C1=O)C([H])([H])[H] 0.000 description 12
- 239000003480 eluent Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- JBWYRBLDOOOJEU-UHFFFAOYSA-N 1-[chloro-(4-methoxyphenyl)-phenylmethyl]-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1C(Cl)(C=1C=CC(OC)=CC=1)C1=CC=CC=C1 JBWYRBLDOOOJEU-UHFFFAOYSA-N 0.000 description 9
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- ODEPBWGSLLPTNG-XYJFISCASA-N [(2r,3s,4s)-2-(5-methyl-2,4-dioxopyrimidin-1-yl)-5,5-bis(methylsulfonyloxymethyl)-4-phenylmethoxyoxolan-3-yl] trifluoromethanesulfonate Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@@H](OS(=O)(=O)C(F)(F)F)[C@H](OCC=2C=CC=CC=2)C(COS(C)(=O)=O)(COS(C)(=O)=O)O1 ODEPBWGSLLPTNG-XYJFISCASA-N 0.000 description 8
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- XGDRLCRGKUCBQL-UHFFFAOYSA-N 1h-imidazole-4,5-dicarbonitrile Chemical compound N#CC=1N=CNC=1C#N XGDRLCRGKUCBQL-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 5
- HWQFBVJAFAMNJX-YQQAZPJKSA-N [(3s,4s,5r)-4-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2,2-bis(methylsulfonyloxymethyl)oxolan-3-yl] benzoate Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@@H](O)[C@H](OC(=O)C=2C=CC=CC=2)C(COS(C)(=O)=O)(COS(C)(=O)=O)O1 HWQFBVJAFAMNJX-YQQAZPJKSA-N 0.000 description 5
- KGOUDEBGIAOXFH-XYJFISCASA-N [(3s,4s,5r)-4-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)-2-(methylsulfonyloxymethyl)-3-phenylmethoxyoxolan-2-yl]methyl methanesulfonate Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@@H](O)[C@H](OCC=2C=CC=CC=2)C(COS(C)(=O)=O)(COS(C)(=O)=O)O1 KGOUDEBGIAOXFH-XYJFISCASA-N 0.000 description 5
- 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 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 229940125782 compound 2 Drugs 0.000 description 5
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 5
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- RKVHNYJPIXOHRW-UHFFFAOYSA-N 3-bis[di(propan-2-yl)amino]phosphanyloxypropanenitrile Chemical compound CC(C)N(C(C)C)P(N(C(C)C)C(C)C)OCCC#N RKVHNYJPIXOHRW-UHFFFAOYSA-N 0.000 description 4
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- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- DUYAAUVXQSMXQP-UHFFFAOYSA-M thioacetate Chemical compound CC([S-])=O DUYAAUVXQSMXQP-UHFFFAOYSA-M 0.000 description 1
- 125000006168 tricyclic group Chemical group 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
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- Chemical & Material Sciences (AREA)
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- Engineering & Computer Science (AREA)
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- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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| DKPA200200712 | 2002-05-08 | ||
| DKPA200201214 | 2002-08-16 | ||
| PCT/DK2003/000305 WO2003095467A1 (en) | 2002-05-08 | 2003-05-08 | Synthesis of locked nucleic acid derivatives |
Publications (3)
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| JP2005532319A JP2005532319A (ja) | 2005-10-27 |
| JP2005532319A5 JP2005532319A5 (enExample) | 2006-04-27 |
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| DE (1) | DE60315444T2 (enExample) |
| DK (1) | DK1501848T3 (enExample) |
| ES (1) | ES2290448T3 (enExample) |
| WO (1) | WO2003095467A1 (enExample) |
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| USRE44779E1 (en) | 1997-03-07 | 2014-02-25 | Santaris Pharma A/S | Bicyclonucleoside and oligonucleotide analogues |
| HUE037352T2 (hu) | 2002-04-05 | 2018-08-28 | Roche Innovation Ct Copenhagen As | A HIF-1alfa expresszálódását módosító oligomer vegyületek |
| CA2506576C (en) | 2002-11-18 | 2018-03-06 | Santaris Pharma A/S | Antisense gapmer oligonucleotides |
| US7713738B2 (en) | 2003-02-10 | 2010-05-11 | Enzon Pharmaceuticals, Inc. | Oligomeric compounds for the modulation of survivin expression |
| EP1606406B2 (en) | 2003-03-21 | 2013-11-27 | Santaris Pharma A/S | SHORT INTERFERING RNA (siRNA) ANALOGUES |
| EP1706489B9 (en) | 2003-12-23 | 2011-01-05 | Santaris Pharma A/S | Oligomeric compounds for the modulation of bcl-2 |
| US9447138B2 (en) | 2004-11-09 | 2016-09-20 | Roche Innovation Center Copenhagen A/S | Potent LNA oligonucleotides for the inhibition of HIF-1a expression |
| NZ555644A (en) | 2004-11-09 | 2009-04-30 | Santaris Pharma As | Potent LNA oligonucleotides for the inhibition of HIF-1A expression |
| US20060154888A1 (en) | 2004-11-09 | 2006-07-13 | Santaris Pharma A/S | LNA oligonucleotides and the treatment of cancer |
| US8071306B2 (en) | 2005-01-25 | 2011-12-06 | Merck Sharp & Dohme Corp. | Methods for quantitating small RNA molecules |
| DK2002004T3 (en) | 2006-03-23 | 2015-11-30 | Roche Innovation Ct Copenhagen As | LITTLE INTERNAL SEGMENTED INTERFERENCE RNA |
| PL2666859T3 (pl) | 2006-04-03 | 2019-09-30 | Roche Innovation Center Copenhagen A/S | Kompozycja farmaceutyczna zawierająca antysensowne oligonukleotydy anty-miRNA |
| CA3024953A1 (en) | 2006-04-03 | 2007-10-11 | Roche Innovation Center Copenhagen A/S | Pharmaceutical composition comprising anti-mirna antisense oligonucleotides |
| WO2008006369A1 (en) * | 2006-07-14 | 2008-01-17 | Santaris Pharma A/S | Adenosine receptor antagonists |
| DK2149605T3 (da) | 2007-03-22 | 2013-09-30 | Santaris Pharma As | Korte RNA antagonist forbindelser til modulering af det ønskede mRNA |
| WO2008113830A1 (en) | 2007-03-22 | 2008-09-25 | Santaris Pharma A/S | Rna antagonist compounds for the inhibition of apo-b100 expression |
| EP2173373B1 (en) | 2007-06-06 | 2020-04-15 | Sarepta Therapeutics, Inc. | Soluble her2 and her3 splice variant proteins, splice-switching oligonucleotides, and their use in the treatment of disease |
| WO2009027978A1 (en) | 2007-08-30 | 2009-03-05 | Hadasit Medical Research Services & Development Ltd. | NUCLEIC ACID SEQUENCES COMPRISING NF-ϰB BINDING SITE WITHIN O(6)-METHYLGUANINE-DNA-METHYLTRANSFERASE (MGMT) PROMOTER REGION AND USES THEREOF FOR THE TREATMENT OF CANCER AND IMMUNE-RELATED DISORDERS |
| DK2195428T3 (en) | 2007-09-19 | 2014-03-03 | Applied Biosystems Llc | SIRNA SEQUENCE-INDEPENDENT MODIFICATION FORMS TO REDUCE TARGET-FAILING PHENOTYPIC EFFECTS OF RNAI, AND STABILIZED FORMS THEREOF |
| KR101889518B1 (ko) | 2007-10-04 | 2018-08-17 | 로슈 이노베이션 센터 코펜하겐 에이/에스 | 마이크로ＭＩＲｓ |
| WO2009109665A1 (en) | 2008-03-07 | 2009-09-11 | Santaris Pharma A/S | Pharmaceutical compositions for treatment of microrna related diseases |
| EP2315832B1 (en) | 2008-08-01 | 2015-04-08 | Roche Innovation Center Copenhagen A/S | Micro-rna mediated modulation of colony stimulating factors |
| JP5773535B2 (ja) | 2009-04-24 | 2015-09-02 | ロシュ・イノベーション・センター・コペンハーゲン・アクティーゼルスカブＲｏｃｈｅ Ｉｎｎｏｖａｔｉｏｎ Ｃｅｎｔｅｒ Ｃｏｐｅｎｈａｇｅｎ Ａ／Ｓ | インターフェロンに非応答性のｈｃｖ患者の治療のための医薬組成物 |
| US8563528B2 (en) | 2009-07-21 | 2013-10-22 | Santaris Pharma A/S | Antisense oligomers targeting PCSK9 |
| WO2011105902A2 (en) | 2010-02-23 | 2011-09-01 | Academisch Ziekenhuis Bij De Universiteit Van Amsterdam | Antagonists of complement component 8-beta (c8-beta) and uses thereof |
| WO2011105901A2 (en) | 2010-02-23 | 2011-09-01 | Academisch Ziekenhuis Bij De Universiteit Van Amsterdam | Antagonists of complement component 9 (c9) and uses thereof |
| WO2011105900A2 (en) | 2010-02-23 | 2011-09-01 | Academisch Ziekenhuis Bij De Universiteit Van Amsterdam | Antagonists of complement component 8-alpha (c8-alpha) and uses thereof |
| WO2011108930A1 (en) | 2010-03-04 | 2011-09-09 | Interna Technologies Bv | A MiRNA MOLECULE DEFINED BY ITS SOURCE AND ITS DIAGNOSTIC AND THERAPEUTIC USES IN DISEASES OR CONDITIONS ASSOCIATED WITH EMT |
| EP2591106A1 (en) | 2010-07-06 | 2013-05-15 | InteRNA Technologies B.V. | Mirna and its diagnostic and therapeutic uses in diseases or conditions associated with melanoma, or in diseases or conditions associated with activated braf pathway |
| GB201012418D0 (en) | 2010-07-23 | 2010-09-08 | Santaris Pharma As | Process |
| EP2474617A1 (en) | 2011-01-11 | 2012-07-11 | InteRNA Technologies BV | Mir for treating neo-angiogenesis |
| JP6262131B2 (ja) * | 2011-07-21 | 2018-01-17 | ローディア オペレーションズ | グアーヒドロキシプロピルトリメチルアンモニウムクロリドおよびヘアトリートメント組成物でのその使用 |
| WO2013095132A1 (en) | 2011-12-22 | 2013-06-27 | Interna Technologies B.V. | Mirna for treating head and neck cancer |
| EP2794627B1 (en) | 2011-12-22 | 2018-09-26 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| US9441007B2 (en) | 2012-03-21 | 2016-09-13 | Alios Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
| WO2014072357A1 (en) | 2012-11-06 | 2014-05-15 | Interna Technologies B.V. | Combination for use in treating diseases or conditions associated with melanoma, or treating diseases or conditions associated with activated b-raf pathway |
| EP2943570B1 (en) | 2013-01-14 | 2018-01-03 | Pierfrancesco Tassone | Inhibitors of mirnas 221 and 222 for anti-tumor activity in multiple myeloma |
| US9428537B2 (en) | 2013-03-15 | 2016-08-30 | The Board Of Trustees Of The Leland Stanford Junior University | tRNA derived small RNAs (tsRNAs) involved in cell viability |
| SG10201908122XA (en) | 2013-06-27 | 2019-10-30 | Roche Innovation Ct Copenhagen As | Antisense oligomers and conjugates targeting pcsk9 |
| GB201410693D0 (en) | 2014-06-16 | 2014-07-30 | Univ Southampton | Splicing modulation |
| EP3201339A4 (en) | 2014-10-03 | 2018-09-19 | Cold Spring Harbor Laboratory | Targeted augmentation of nuclear gene output |
| US10731154B2 (en) | 2015-02-15 | 2020-08-04 | Arcturus Therapeutics, Inc. | Acyl-amino-LNA and/or hydrocarbyl-amino-LNA oligonucleotides |
| TW201718618A (zh) | 2015-09-18 | 2017-06-01 | 田邊三菱製藥股份有限公司 | 架橋型核酸ＧｕＮＡ，其製造方法，及中間體化合物 |
| KR102422625B1 (ko) | 2015-10-09 | 2022-07-20 | 유니버시티 오브 사우스앰톤 | 유전자 발현의 조절 및 탈조절된 단백질 발현의 스크리닝 |
| US11096956B2 (en) | 2015-12-14 | 2021-08-24 | Stoke Therapeutics, Inc. | Antisense oligomers and uses thereof |
| KR102604132B1 (ko) | 2015-12-14 | 2023-11-17 | 콜드스프링하버러보러토리 | 상염색체 우성 정신 지체 5 및 드라베 증후군의 치료를 위한 안티센스 올리고머 |
| SG11201809002RA (en) | 2016-04-29 | 2018-11-29 | Univ Nanyang Tech | G-quadruplex-containing antisense oligonucleotides |
| EP3494219A1 (en) | 2016-08-03 | 2019-06-12 | Aalborg Universitet | ANTISENSE OLIGONUCLEOTIDES (ASOs) DESIGNED TO INHIBIT IMMUNE CHECKPOINT PROTEINS |
| SG11202001590RA (en) | 2017-08-25 | 2020-03-30 | Stoke Therapeutics Inc | Antisense oligomers for treatment of conditions and diseases |
| CN111566212A (zh) | 2017-11-03 | 2020-08-21 | 因特尔纳技术有限公司 | miRNA分子，等同物，安塔够妙或其来源用于治疗和/或诊断与神经元缺陷相关的病症和/或疾病或用于神经元生成和/或再生 |
| JP2021513508A (ja) | 2018-02-12 | 2021-05-27 | インテアールエヌエー テクノロジーズ ビー．ヴイ．ＩｎｔｅＲＮＡ Ｔｅｃｈｎｏｌｏｇｉｅｓ Ｂ．Ｖ． | 抗がんマイクロｒｎａ及びその脂質製剤 |
| EP3788169A4 (en) | 2018-05-04 | 2022-08-10 | Stoke Therapeutics, Inc. | Methods and compositions for treatment of cholesteryl ester storage disease |
| IT201900017234A1 (it) | 2019-09-25 | 2021-03-25 | Int Centre For Genetic Engineering And Biotechnology | Anti-miRNA per il trattamento del leiomioma |
| MX2022014151A (es) | 2020-05-11 | 2022-11-30 | Stoke Therapeutics Inc | Oligomeros antisentido de opa1 para tratamiento de afecciones y enfermedades. |
| JP2024506371A (ja) | 2021-02-12 | 2024-02-13 | メランド ファーマシューティカルズ，インコーポレイテッド | 低酸素症及び虚血関連障害を処置する薬剤、組成物及び方法 |
| EP4313074A1 (en) | 2021-03-26 | 2024-02-07 | Neumirna Therapeutics ApS | Microrna-27b inhibitors |
| EP4313073A1 (en) | 2021-03-26 | 2024-02-07 | Neumirna Therapeutics ApS | Microrna-134 inhibitors |
| AU2022287241A1 (en) | 2021-06-04 | 2023-12-14 | Neumirna Therapeutics Aps | Antisense oligonucleotides targeting adenosine kinase |
| JP2024531363A (ja) | 2021-08-17 | 2024-08-29 | コリア アドバンスト インスティテュート オブ サイエンス アンド テクノロジー | Ｃａｖ３．１遺伝子を標的とするアンチセンスオリゴヌクレオチド及びその使用 |
| JP2024531342A (ja) | 2021-08-19 | 2024-08-29 | ニューミルナ セラピューティクス エーピーエス | アデノシンキナーゼを標的とするアンチセンスオリゴヌクレオチド |
| EP4332239A1 (en) | 2022-08-30 | 2024-03-06 | Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" - IRST S.r.l. | Mir-based assay for gastro-entero-pancreatic neuroendocrine tumor diagnosis and prognosis |
| EP4450626A1 (en) | 2023-04-21 | 2024-10-23 | IFOM - Istituto Fondazione di Oncologia Molecolare ETS | Fnip2 inhibitors for treating ataxia telangiectasia |
| KR20250050953A (ko) * | 2023-07-21 | 2025-04-15 | 레드필드 파마슈티컬 인크. | 탄소 고리형 뉴클레오시드, 올리고뉴클레오티드 및 이의 제조 방법과 의약 용도 |
| EP4512899A1 (en) | 2023-08-23 | 2025-02-26 | Lipigon Pharmaceuticals AB | Angptl4 aso compositions for treatment of atherosclerosis in humans |
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| CN102180924A (zh) * | 1999-05-04 | 2011-09-14 | 桑塔里斯制药公司 | L-核糖-lna类似物 |
| JP4413493B2 (ja) * | 2000-10-04 | 2010-02-10 | サンタリス ファーマ アー／エス | プリンｌｎａ類似体の改善された合成方法 |
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2003
- 2003-05-08 DK DK03718663T patent/DK1501848T3/da active
- 2003-05-08 DE DE60315444T patent/DE60315444T2/de not_active Expired - Lifetime
- 2003-05-08 AT AT03718663T patent/ATE369375T1/de not_active IP Right Cessation
- 2003-05-08 AU AU2003222743A patent/AU2003222743B2/en not_active Expired
- 2003-05-08 ES ES03718663T patent/ES2290448T3/es not_active Expired - Lifetime
- 2003-05-08 WO PCT/DK2003/000305 patent/WO2003095467A1/en not_active Ceased
- 2003-05-08 JP JP2004503481A patent/JP4476802B2/ja not_active Expired - Lifetime
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Also Published As
| Publication number | Publication date |
|---|---|
| ATE369375T1 (de) | 2007-08-15 |
| ES2290448T3 (es) | 2008-02-16 |
| JP2005532319A (ja) | 2005-10-27 |
| EP1501848B1 (en) | 2007-08-08 |
| DE60315444T2 (de) | 2008-04-30 |
| AU2003222743B2 (en) | 2008-12-11 |
| WO2003095467A1 (en) | 2003-11-20 |
| AU2003222743A1 (en) | 2003-11-11 |
| DE60315444D1 (en) | 2007-09-20 |
| CA2484526A1 (en) | 2003-11-20 |
| DK1501848T3 (da) | 2007-10-22 |
| EP1501848A1 (en) | 2005-02-02 |
| CA2484526C (en) | 2009-10-13 |
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