JP5901610B2 - 5位修飾ピリミジンとその使用 - Google Patents
5位修飾ピリミジンとその使用 Download PDFInfo
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- JP5901610B2 JP5901610B2 JP2013505056A JP2013505056A JP5901610B2 JP 5901610 B2 JP5901610 B2 JP 5901610B2 JP 2013505056 A JP2013505056 A JP 2013505056A JP 2013505056 A JP2013505056 A JP 2013505056A JP 5901610 B2 JP5901610 B2 JP 5901610B2
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- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 239000001177 diphosphate Substances 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- NAGJZTKCGNOGPW-UHFFFAOYSA-N dithiophosphoric acid Chemical class OP(O)(S)=S NAGJZTKCGNOGPW-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000021550 forms of sugar Nutrition 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229910001412 inorganic anion Inorganic materials 0.000 description 1
- 229910001411 inorganic cation Inorganic materials 0.000 description 1
- 239000000138 intercalating agent Substances 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 229940033355 lauric acid Drugs 0.000 description 1
- 230000029226 lipidation Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 230000014759 maintenance of location Effects 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
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- YACKEPLHDIMKIO-UHFFFAOYSA-N methylphosphonic acid Chemical class CP(O)(O)=O YACKEPLHDIMKIO-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- GTWJETSWSUWSEJ-UHFFFAOYSA-N n-benzylaniline Chemical compound C=1C=CC=CC=1CNC1=CC=CC=C1 GTWJETSWSUWSEJ-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 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
- 244000052769 pathogen Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical group [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001737 promoting effect Effects 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
- 125000006239 protecting group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 125000001453 quaternary ammonium 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
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 230000007019 strand scission Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- 235000015523 tannic acid Nutrition 0.000 description 1
- 229940033123 tannic acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 description 1
- 125000002264 triphosphate group Chemical class [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- 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
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/115—Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith ; Nucleic acids binding to non-nucleic acids, e.g. aptamers
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- 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
- C07H19/06—Pyrimidine radicals
- C07H19/067—Pyrimidine radicals with ribosyl as the saccharide radical
-
- 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
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
-
- 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
- C07H19/167—Purine radicals with ribosyl as the saccharide radical
-
- 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
- C07H19/173—Purine radicals with 2-deoxyribosyl as the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/16—Aptamers
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/30—Chemical structure
- C12N2310/33—Chemical structure of the base
- C12N2310/335—Modified T or U
Description
技術分野
[0002] 本開示は、核酸化学の分野に、具体的には、5位修飾ウリジン、並びにそのホスホロアミダイト及び三リン酸誘導体に関する。本開示はまた、それらを作製して使用する方法に関する。本開示には、この修飾されたヌクレオシドの、オリゴヌクレオチド又はアプタマーの一部としての使用が含まれる。
Rは、−(CH2)n−RX1からなる群より選択され;
RX1は:
RX4は、分岐鎖又は直鎖の低級アルキル(C1−C20);ハロゲン(F、Cl、Br、I);ニトリル(CN);ボロン酸(BO2H2);カルボン酸(COOH);カルボン酸エステル(COORX2);一級アミド(CONH2);二級アミド(CONHRX2);三級アミド(CONRX2RX3);スルホンアミド(SO2NH2);N−アルキルスルホンアミド(SONHRX2)からなる群より選択され;
ここでRX2、RX3は、分岐鎖又は直鎖の低級アルキル(C1−C20);フェニル(C6H5);RX4置換フェニル環(RX4C6H4)(ここでRX4は、上記に定義される);カルボン酸(COOH);カルボン酸エステル(COORX5)(ここでRX5は、分岐鎖又は直鎖の低級アルキル(C1−C20)である);及びシクロアルキル(ここでRX2=RX3=(CH2)nである)からなる群より独立して選択される}からなる群より選択され;
ここで、n=0〜10であり;
式中、
Xは、限定されないが、−H、−OH、−OMe、−O−アリル、−F、−OEt、−OPr、−OCH2CH2OCH3、及び−アジドが含まれる群より選択され;
式中、
R’は、限定されないが、−Ac;−Bz、及び−SiMe 2 tBuが含まれる群より選択され;
式中、
R”は、限定されないが、H、DMT、及び三リン酸(−P(O)(OH)−O−P(O)(OH)−O−P(O)(OH)2)又はその塩が含まれる群より選択され;そしてここで、
[0015] 本開示の化合物は、そのような化合物を製造する標準的な合成法又は酵素法を使用して、オリゴヌクレオチド又はアプタマーへ取り込むことができる。
[0017] 1つの態様では、C−5修飾アミノカルボニルピリミジンを製造するための方法が提供され、前記方法は、5位がトリフルオロエトキシカルボニルで修飾されたピリミジンを塩基の存在下にアミンと反応させる工程;及び、前記C−5修飾アミノカルボニルピリミジンを単離する工程を含んでなる。
a)以下の式:
RとXは、上記に定義される通りである]を有するC−5修飾アミノカルボニルピリミジンを塩基の存在下に無水酢酸と反応させることに続く、5’−DMT基の酸での切断で、以下の構造:
b)工程a)の3'−アセテートに対してルートヴィヒ−エックシュタイン(Ludwig-Eckstein)反応に続いてアニオン交換クロマトグラフィーを実施する工程;及び
c)以下の構造:
[0026] 「それぞれの」という用語は、本明細書において複数の項目に言及するために使用されるとき、その項目の少なくとも2つに言及すると企図される。その複数性を形成する必ずしもすべての項目が関連する追加の限定条件を満たすことが求められるわけではない。
[0029] 1つの態様において、本開示は、以下の式化合物を提供する:
Rは、−(CH2)n−RX1からなる群より選択され;
RX1は:
RX4は、限定されないが、分岐鎖又は直鎖の低級アルキル(C1−C20);ハロゲン(F、Cl、Br、I);ニトリル(CN);ボロン酸(BO2H2);カルボン酸(COOH);カルボン酸エステル(COORX2);一級アミド(CONH2);二級アミド(CONHRX2);三級アミド(CONRX2RX3);スルホンアミド(SO2NH2);及びN−アルキルスルホンアミド(SONHRX2)が含まれる群より選択され;
ここでRX2、RX3は、限定されないが、分岐鎖又は直鎖の低級アルキル(C1−C20);フェニル(C6H5);RX4置換フェニル環(RX4C6H4)(ここでRX4は、上記に定義される);カルボン酸(COOH);カルボン酸エステル(COORX5)(ここでRX5は、分岐鎖又は直鎖の低級アルキル(C1−C20)である);及びシクロアルキル(ここでRX2=RX3=(CH2)nである)が含まれる群より独立して選択される}からなる群より選択され;
ここで、n=0〜10であり;
式中、
Xは、限定されないが、−H、−OH、−OMe、−O−アリル、−F、−OEt、−OPr、−OCH2CH2OCH3、及び−アジドが含まれる群より選択され;
式中、
R’は、限定されないが、−H、−Ac;−Bz、−C(O)CH2OCH3、及び−SiMe 2 tBuが含まれる群より選択され;
式中、
R”は、限定されないが、−H、4,4−ジメトキシトリチル(DMT)、及び三リン酸(−P(O)(OH)−O−P(O)(OH)−O−P(O)(OH)2)又はその塩が含まれる群より選択され;そしてここで、
[0031] なお他の態様において、本開示は、以下の式の化合物又はその塩を提供する:
[0032] 本明細書に使用されるように、「C−5修飾カルボキシアミドウリジン」又は「C−5修飾アミノカルボニルウリジン」という用語は、限定されないが、上記に例示した(R)部分が含まれる、ウリジンのC−5位でのカルボキシアミド(−C(O)NH−)修飾があるウリジンを意味する。C−5修飾カルボキシアミドウリジンの例には、米国特許第5,719,273号及び5,945,527号、並びに、「ヌクレアーゼ抵抗性のオリゴヌクレオチド(Nuclease Resistant Oligonucleotides)」と題した米国仮特許出願シリアル番号61/422,957(’957出願)(2010年12月14日出願)に記載されるものが含まれる。代表的なC−5修飾ピリミジンには、5−(N−ベンジルカルボキシアミド)−2’−デオキシウリジン(BndU)、5−(N−ベンジルカルボキシアミド)−2’−O−メチルウリジン、5−(N−ベンジルカルボキシアミド)−2’−フルオロウリジン、5−(N−イソブチルカルボキシアミド)−2’−デオキシウリジン(iBudU)、5−(N−イソブチルカルボキシアミド)−2’−O−メチルウリジン、5−(N−イソブチルカルボキシアミド)−2’−フルオロウリジン、5−(N−トリプタミノカルボキシアミド)−2’−デオキシウリジン(TrpdU)、5−(N−トリプタミノカルボキシアミド)−2’−O−メチルウリジン、5−(N−トリプタミノカルボキシアミド)−2’−フルオロウリジン、5−(N−[1−(3−トリメチルアンモニウム)プロピル]カルボキシアミド)−2’−デオキシウリジンクロリド、5−(N−ナフチルメチルカルボキシアミド)−2’−デオキシウリジン(NapdU)、5−(N−ナフチルメチルカルボキシアミド)−2’−O−メチルウリジン、5−(N−ナフチルメチルカルボキシアミド)−2’−フルオロウリジン、又は5−(N−[1−(2,3−ジヒドロキシプロピル)]カルボキシアミド)−2’−デオキシウリジン)が含まれる。
[0035] 化合物の対応する塩、例えば、医薬的に許容される塩を製造、精製、及び/又は処理することが簡便であるか又は望ましい場合がある。医薬的に許容される塩の例については、Berge et al.「Pharmaceutically Acceptable Salts(医薬的に許容される塩)」 (1977) J. Pharm. Sci. 66: 1-19 に考察されている。
オリゴヌクレオチドの製造
[0040] 1つの側面において、本開示は、本明細書に記載の修飾ヌクレオシドを、単独で、又は他の修飾ヌクレオシド及び/又は天然に存在するヌクレオシドと組み合わせて使用して、修飾オリゴヌクレオチドを製造する方法を提供する。オリゴデオキシヌクレオシドの自動合成は、多くの研究室で定型的な作業である(例えば、その内容が参照により本明細書に組み込まれる、Matteucci, M. D. and Caruthers, M. H., (1990) J. Am. Chem. Soc., 103: 3185-3191 を参照のこと)。オリゴリボヌクレオシドの合成についてもよく知られている(例えば、参照により本明細書に組み込まれる、Scaringe, S. A., et al., Nucleic Acids Res. 18: 5433-5441 (1990) を参照のこと)。上記で注目されるように、ホスホロアミダイトは、修飾ヌクレオシドをオリゴヌクレオチドへ化学合成によって取り込むのに有用であって、三リン酸塩は、修飾ヌクレオシドをオリゴヌクレオチドへ酵素合成によって取り込むのに有用である(例えば、Vaught, J. V., et al. (2010) J. Am. Chem. Soc., 132, 4141-4151; Gait, M. J. 「オリゴヌクレオチド合成:実践アプローチ(Oligonucleotide Synthesis a practical approach)」(1984)IRLプレス(イギリス、オックスフォード); Herdewijn, P. 「オリゴヌクレオチド合成(Oligonucleotide Synthesis)」(2005)(ヒュマナ・プレス、ニュージャージー州トトワ)を参照のこと。これらのいずれもその全体が参照により本明細書に組み込まれる)。
[0050] 「SELEX」及び「SELEX法」という用語は、本明細書において可換的に使用されて、(1)標的分子と望ましいやり方で相互作用する(例えば、高いアフィニティーでタンパク質へ結合する)核酸の選択と、(2)そのような選択された核酸の増幅の組合せを一般に意味する。SELEX法を使用して、特定の標的分子又はバイオマーカーへの高いアフィニティーがあるアプタマーを同定することができる。
[0055] 本開示に提供する化合物の化学合成の方法について本明細書に記載する。これらの、及び/又は他のよく知られた方法を既知のやり方で修飾及び/又は適用して、本開示で提供する追加の化合物の合成を促進してよい。
Xは、限定されないが、−H、−OH、−OMe、−O−アリル、−F、−OEt、−OPr、−OCH2CH2OCH3、及び−アジドが含まれる群より選択され;そしてここで、
Rは、−(CH2)n−RX1からなる群より選択され;
RX1は:
RX4は、分岐鎖又は直鎖の低級アルキル(C1−C20);ハロゲン(F、Cl、Br、I);ニトリル(CN);ボロン酸(BO2H2);カルボン酸(COOH);カルボン酸エステル(COORX2);一級アミド(CONH2);二級アミド(CONHRX2);三級アミド(CONRX2RX3);スルホンアミド(SO2NH2);N−アルキルスルホンアミド(SONHRX2)からなる群より選択され;
ここで、RX2、RX3は、分岐鎖又は直鎖の低級アルキル(C1−C20);フェニル(C6H5);RX4置換フェニル環(RX4C6H4)(ここでRX4は、上記に定義される);カルボン酸(COOH);カルボン酸エステル(COORX5)(ここでRX5は、分岐鎖又は直鎖の低級アルキル(C1−C20)である);及びシクロアルキル(ここでRX2=RX3=(CH2)nである)からなる群より独立して選択され;
ここで、n=0〜10である。
[0059] いくつかの態様において、この塩基は、トリエチルアミン、ジイソプロピルアミン、等からなる群より選択される三級アミンである。
a)式:
RはとXは、上記に定義される通りである]を有するC−5修飾アミノカルボニルピリミジンを、塩基の存在下に無水酢酸と反応させることに続き、5’−DMT基の酸での切断で、以下の構造:
b)工程a)の3'−アセテートに対してルートヴィヒ−エックシュタイン反応を、続いてアニオン交換クロマトグラフィーを実施する工程;及び
c)以下の構造:
[0062] 使用する塩基は、限定されないが、三級アミンが含まれる群より選択される。いくつかの態様において、塩基は、ピリジンである。工程a)において使用する酸は、限定されないが、ジクロロ酢酸、トリクロロ酢酸、及び1,1,1,3,3,3−ヘキサフルオロ−2−プロパノールが含まれる群より選択される。
[0067] 5’−O−ジメトキシトリチル−5−(4−フルオロベンジルアミノカルボニル)−2’−デオキシウリジン(3a)。出発材料の5’−O−ジメトキシトリチル−5−トリフルオロエトキシカルボニル−2’−デオキシウリジン(1)は、Matsuda et al (Nomura, Y.; Ueno, Y.; Matsuda, A. Nucleic Acid Research 1997, 25: 2784-2791; Ito, T., Ueno, Y.; Matsuda, A. Nucleic Acid Research 2003, 31: 2514-2523)の手順によって製造した。(1)(9.85g,15ミリモル)、4−フルオロベンジルアミン(2a)(2.25g,18ミリモル、1.3当量)、トリエチルアミン(4.2mL,30ミリモル)、及び無水アセトニトリル(30mL)の溶液を不活性雰囲気下に60〜70℃で2〜24時間加熱した。薄層クロマトグラフィー(シリカゲル60,5%メタノール/ジクロロメタン)又はHPLCによって、(1)のアミド(3a)への定量的な変換を確認した。この反応混合物を真空で濃縮して、1%トリエチルアミン/99%酢酸エチル中0〜3%メタノールの溶出液を使用するシリカゲルフラッシュクロマトグラフィー(Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43: 2923)によって残渣を精製した。純粋な生成物を含有する画分を合わせて、蒸発させた。無水アセトニトリルとの同時蒸発によって微量の残留溶媒を除去して、高真空下での乾燥を続けて、(3a)(6.57g,収率64%)を白色の固形物として得た。1H-NMR (300 MHz, CD3CN) δ 2.20-2.40 (2H, m), 3.28 (2H, d, J = 4.3 Hz), 3.76 (6H, s), 4.01 (1H, dd, J = 3.8, 4.2 Hz), 4.26-4.30 (1H, m), 4.48 (2H, bd, J = 6.1 Hz), 6.11 (1H, t, J = 6.5 Hz), 6.85-7.46 (13H, m), 7.03-7.36 (4H, m), 8.58 (1H, s), 9.01 (1H, t, J = 6.1 Hz)。MS (m/z) C38H36FN3O8, の計算値:681.25;実測値:680.4 [M-H]-。
[0072] 5’−O−ジメトキシトリチル−5−(4−フルオロベンジルアミノカルボニル)−3’−O−[(2−シアノエチル)(N,N−ジイソプロピルアミノ)ホスフィニル]−2’−デオキシウリジン(4a)。DMT−保護化ヌクレオシド(3a)(4.00g,5.9ミリモル)の無水ジクロロメタン(40mL)溶液を乾燥アルゴンの雰囲気下にほぼ−10℃へ冷やした。ジイソプロピルエチルアミン(3.1mL,17.6ミリモル、3当量)を加え、2−シアノエチルジイソプロピルクロロホスホロアミダイト(1.7mL,7.7ミリモル、1.3当量)の滴下を続けた。この溶液を1時間撹拌して、薄層クロマトグラフィー(シリカゲル60,酢酸エチル/ヘキサン)によって完全な反応を確認した。この反応混合物を氷冷2%重炭酸ナトリウム溶液(200mL)と酢酸エチル(200mL)の間で分配した。有機層を塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過して、濃縮した。この残渣を、1%トリエチルアミン/99%酢酸エチルの移動相を使用するシリカゲルフラッシュクロマトグラフィーによって精製した。純粋な生成物を含有する画分を合わせて、真空(<30℃)で蒸発させた。微量の残留クロマトグラフィー溶媒を無水アセトニトリルとの同時蒸発によって除去し、高真空で乾燥させて、(4a)(4.10g,収率80%)を白色の固体フォームとして得た。1H-NMR (CD3CN, 2つの異性体) δ 1.02-1.16 (12H, m), 2.27-2.57 (2H, m), 2.51/2.62 (2H, 2t, J = 6.0/6.0 Hz), 3.25-3.37 (2H, m), 3.50-3.79 (4H, m 重複), 3.738 (3H, s), 3.742 (3H, s), 4.13/4.16 (1H, 2q, J = 3.5/3.7 Hz), 4.37-4.43 (1H, m), 4.44-4.47 (2H, m), 6.09/6.10 (1H, 2t, J = 6.4/7.1 Hz), 6.83-7.44 (13H, m), 7.01-7.30 (4H, m), 8.58/8.60 (1H, 2s), 8.98 (1H, b, J~5.5 Hz), 9.24 (1H, bs)。31P-NMR (CD3CN) δ 148.01 (s), 148.06 (s)。19F-NMR (CD3CN) δ -117.65 (m)。MS (m/z) C47H53FN5O9P の計算値:881.36;実測値:880.3 [M-H]-。
[0077] 5−(4−フルオロベンジルアミノカルボニル)−3’−O−アセチル−2’−デオキシウリジン(5a)
[0087] 3’−O−アセチル−ヌクレオシド(5a〜d)はまた、出発材料の3’−O−アセチル−5’−O−ジメトキシトリチル−5−ヨード−2’−デオキシウリジン(7)(Vaught, J. D., Bock, C., Carter, J., Fitzwater, T., Otis, M., Schneider, D., Rolando, J., Waugh, S., Wilcox, S. K., Eaton, B. E. J. Am. Chem. Soc. 2010, 132, 4141-4151)より、代替経路(スキーム2)によって合成した。簡潔には、スキーム2に言及すると、このヨウ化物のパラジウム(II)−触媒化トリフルオロエトキシカルボニル化によって、活性化エステル中間体(8)を得た。アミン(2a〜d)(1.3当量)、トリエチルアミン(3当量)、アセトニトリルと(8)の縮合(60〜70℃,2〜24時間)に続く、5’−O−DMT−保護基の切断(3%トリクロロ酢酸/ジクロロメタン又は1,1,1,3,3,3−ヘキサフルオロ−2−プロパノール、室温)によって、中間体(3a〜d)(スキーム1)より製造される生成物に一致した(5a〜d)を得た。
[0089] 5−(4−フルオロベンジルアミノカルボニル)−2’−デオキシウリジン−5’−O−三リン酸塩(トリス−トリエチルアンモニウム塩)(6a)。この三リン酸塩(6a)は、3’−O−アセチル−ヌクレオシド(5a)より、ルートヴィヒ及びエックシュタインの手法(Ludwig, J. and Eckstein, F. J. Org. Chem. 1989, 54: 631)によって500マイクロモルスケール(5x)で合成した。この粗製の三リン酸塩生成物は、アンモニア分解と蒸発の後で、一般手順(下記)に記載のように、アニオン交換クロマトグラフィーによって精製した。
Claims (9)
- 以下の構造:
[式中、
Rは、−(CH2)n−RX1からなる群より選択され;
RX1は:
からなる群より選択され、式中、*は、RX1基の(CH2)nへの付加点を示し、RX4は、Fであり;
n=0〜10であり;
Xは、−H、−OH、−OMe、−O−アリル、−F、−OEt、−OPr、−OCH2CH2OCH3、及び−アジドからなる群より選択され;
R’は、Ac;−P(N(iPr)2(O(CH2)2)CN;Bz、及びSiMe2tBuからなる群より選択され;そして、
R”は、H、DMT、及び三リン酸(−P(O)(OH)−O−P(O)(OH)−O−P(O)(OH)2)又はその塩からなる群より選択される]を有する化合物
より選択される化合物又はその塩。 - 以下の構造:
を有する、請求項1に記載の化合物又はその塩。 - 以下の構造:
を有する化合物又はその塩。 - 以下の構造:
[式中、
Rは、−(CH2)n−RX1からなる群より選択され;
RX1は:
からなる群より選択され、式中、*は、RX1基の(CH2)n連結基への付加点を示し、RX4は、Fであり;
n=0〜10であり;
Xは、−H、−OH、−OMe、−O−アリル、−F、−OEt、−OPr、−OCH2CH2OCH3、及び−アジドからなる群より選択される]を有する少なくとも1つの修飾ヌクレオチドを含んでなるオリゴヌクレオチド。 - 以下の構造:
[式中、
Xは、−H、−OH、−OMe、−O−アリル、−F、−OEt、−OPr、−OCH2CH2OCH3、及び−アジドからなる群より選択される]より独立して選択される少なくとも1つの修飾ヌクレオチドを含んでなる、請求項4に記載のオリゴヌクレオチド。 - オリゴヌクレオチドがリボ核酸又はデオキシリボ核酸より選択され、前記オリゴヌクレオチドが、リボース位置、デオキシリボース位置、リン酸位置、及び塩基位置より独立して選択される1以上の位置での化学置換を含んでなる少なくとも1つの化学修飾をさらに含んでいてもよく、前記化学修飾が、2’位の糖修飾、2’−アミノ(2’−NH2)、2’−フルオロ(2’−F)、2’−O−メチル(2’−OMe)、2’−O−エチル(2’−OEt)、2’−O−プロピル(2’−OPr)、2’−O−CH2CH2OCH3、5位のピリミジン修飾、骨格修飾、メチル化、3’キャップ、及び5’キャップからなる群より独立して選択されてもよい、請求項4または5に記載のオリゴヌクレオチド。
- 以下の構造:
[式中、
Rは、−(CH2)n−RX1からなる群より選択され;
RX1は、
からなる群より選択され、式中、*は、RX1の(CH2)n連結基への付加点を示し、RX4は、Fであり;
n=0〜10であり;
Xは、−H、−OH、−OMe、−O−アリル、−F、−OEt、−OPr、−OCH2CH2OCH3、及び−アジドからなる群より選択される]
を有する少なくとも1つの修飾ヌクレオチドを含んでなるアプタマー。 - 以下の構造:
より独立して選択される少なくとも1つの修飾ヌクレオチドを含んでなる、請求項7のアプタマー。 - アプタマーがリボ核酸又はデオキシリボ核酸より選択され、前記アプタマーがリボース位置、デオキシリボース位置、リン酸位置、及び塩基位置より独立して選択される1以上の位置での化学置換を含んでなる少なくとも1つの化学修飾をさらに含んでいてもよく、前記化学修飾が、2’位の糖修飾、2’−アミノ(2’−NH2)、2’−フルオロ(2’−F)、2’−O−メチル(2’−OMe)、2’−O−エチル(2’−OEt)、2’−O−プロピル(2’−OPr)、2’−O−CH2CH2OCH3、5位のピリミジン修飾、骨格修飾、メチル化、3’キャップ、及び5’キャップからなる群より独立して選択されてもよい、請求項7または8に記載のアプタマー。
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