CA2421040C - Methods for synthesizing nucleosides, nucleoside derivatives and non-nucleoside derivatives - Google Patents
Methods for synthesizing nucleosides, nucleoside derivatives and non-nucleoside derivatives Download PDFInfo
- Publication number
- CA2421040C CA2421040C CA002421040A CA2421040A CA2421040C CA 2421040 C CA2421040 C CA 2421040C CA 002421040 A CA002421040 A CA 002421040A CA 2421040 A CA2421040 A CA 2421040A CA 2421040 C CA2421040 C CA 2421040C
- Authority
- CA
- Canada
- Prior art keywords
- moiety
- nucleoside
- tert
- deoxy
- product
- 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 - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 202
- 230000002194 synthesizing effect Effects 0.000 title claims description 45
- 239000002777 nucleoside Substances 0.000 title abstract description 382
- 150000003833 nucleoside derivatives Chemical class 0.000 title abstract description 44
- 125000003835 nucleoside group Chemical group 0.000 title abstract description 26
- -1 nucleoside phosphoramidites Chemical class 0.000 claims abstract description 137
- 150000001875 compounds Chemical class 0.000 claims description 117
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 96
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 54
- 239000003153 chemical reaction reagent Substances 0.000 claims description 49
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 48
- 239000002253 acid Substances 0.000 claims description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 125000005353 silylalkyl group Chemical group 0.000 claims description 23
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical group [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims description 22
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 18
- 238000010511 deprotection reaction Methods 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 230000027629 depyrimidination Effects 0.000 claims description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 11
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 11
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 8
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- 238000005828 desilylation reaction Methods 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 5
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 4
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 3
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 3
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 3
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 claims description 3
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 3
- NRTYMEPCRDJMPZ-UHFFFAOYSA-N pyridine;2,2,2-trifluoroacetic acid Chemical compound C1=CC=NC=C1.OC(=O)C(F)(F)F NRTYMEPCRDJMPZ-UHFFFAOYSA-N 0.000 claims description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 3
- 150000003461 sulfonyl halides Chemical class 0.000 claims description 3
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 claims description 3
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- USJRLGNYCQWLPF-UHFFFAOYSA-N chlorophosphane Chemical compound ClP USJRLGNYCQWLPF-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- NTJPIRDYMVYFNP-UHFFFAOYSA-M trimethylsilylmethanesulfonate Chemical group C[Si](C)(C)CS([O-])(=O)=O NTJPIRDYMVYFNP-UHFFFAOYSA-M 0.000 claims description 2
- 125000002264 triphosphate group Chemical group [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 claims description 2
- QARBMVPHQWIHKH-KHWXYDKHSA-N methanesulfonyl chloride Chemical group C[35S](Cl)(=O)=O QARBMVPHQWIHKH-KHWXYDKHSA-N 0.000 claims 1
- SXADIBFZNXBEGI-UHFFFAOYSA-N phosphoramidous acid Chemical group NP(O)O SXADIBFZNXBEGI-UHFFFAOYSA-N 0.000 claims 1
- 125000000542 sulfonic acid group Chemical group 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 91
- 239000000047 product Substances 0.000 description 188
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 129
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 111
- 230000015572 biosynthetic process Effects 0.000 description 105
- OIRDTQYFTABQOQ-KQYNXXCUSA-N Adenosine Natural products C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 93
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 80
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical group C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 70
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 70
- 229960005305 adenosine Drugs 0.000 description 70
- 150000007523 nucleic acids Chemical class 0.000 description 67
- 108020004707 nucleic acids Proteins 0.000 description 65
- 102000039446 nucleic acids Human genes 0.000 description 65
- 238000002955 isolation Methods 0.000 description 58
- 239000000243 solution Substances 0.000 description 58
- 238000006243 chemical reaction Methods 0.000 description 53
- 125000000217 alkyl group Chemical group 0.000 description 44
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 43
- 150000008300 phosphoramidites Chemical class 0.000 description 43
- 239000000203 mixture Substances 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 37
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Natural products C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 36
- 239000012038 nucleophile Substances 0.000 description 35
- 239000011541 reaction mixture Substances 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 34
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 34
- 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 34
- 125000003118 aryl group Chemical group 0.000 description 33
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 32
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 31
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 31
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 30
- 125000002252 acyl group Chemical group 0.000 description 30
- 125000006239 protecting group Chemical group 0.000 description 30
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 28
- UYTPUPDQBNUYGX-UHFFFAOYSA-N Guanine Natural products O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 25
- 238000002515 oligonucleotide synthesis Methods 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 24
- 230000002255 enzymatic effect Effects 0.000 description 23
- 229940029575 guanosine Drugs 0.000 description 23
- 239000000725 suspension Substances 0.000 description 23
- QWTBDIBOOIAZEF-UHFFFAOYSA-N 3-[chloro-[di(propan-2-yl)amino]phosphanyl]oxypropanenitrile Chemical group CC(C)N(C(C)C)P(Cl)OCCC#N QWTBDIBOOIAZEF-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 21
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 21
- DSWNRHCOGVRDOE-UHFFFAOYSA-N n,n-dimethylmethanimidamide Chemical compound CN(C)C=N DSWNRHCOGVRDOE-UHFFFAOYSA-N 0.000 description 21
- 238000002360 preparation method Methods 0.000 description 21
- 229940045145 uridine Drugs 0.000 description 21
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 20
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 20
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 20
- HUHKPYLEVGCJTG-UHFFFAOYSA-N [ditert-butyl(trifluoromethylsulfonyloxy)silyl] trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)O[Si](C(C)(C)C)(OS(=O)(=O)C(F)(F)F)C(C)(C)C HUHKPYLEVGCJTG-UHFFFAOYSA-N 0.000 description 19
- 125000003545 alkoxy group Chemical group 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 18
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 17
- 238000006073 displacement reaction Methods 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 16
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Natural products NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- VSCBATMPTLKTOV-UHFFFAOYSA-N 2-tert-butylimino-n,n-diethyl-1,3-dimethyl-1,3,2$l^{5}-diazaphosphinan-2-amine Chemical compound CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C VSCBATMPTLKTOV-UHFFFAOYSA-N 0.000 description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 229940104302 cytosine Drugs 0.000 description 15
- 239000006260 foam Substances 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 235000019341 magnesium sulphate Nutrition 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 15
- 230000000692 anti-sense effect Effects 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 14
- 125000004122 cyclic group Chemical group 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 14
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 150000001412 amines Chemical class 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- 239000002773 nucleotide Substances 0.000 description 13
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 13
- 238000006884 silylation reaction Methods 0.000 description 13
- OVYNGSFVYRPRCG-UHFFFAOYSA-N 2'-O-Methylguanosine Natural products COC1C(O)C(CO)OC1N1C(NC(N)=NC2=O)=C2N=C1 OVYNGSFVYRPRCG-UHFFFAOYSA-N 0.000 description 12
- 108091034117 Oligonucleotide Proteins 0.000 description 12
- 230000029936 alkylation Effects 0.000 description 12
- 238000005804 alkylation reaction Methods 0.000 description 12
- 150000008064 anhydrides Chemical class 0.000 description 12
- 229960003786 inosine Drugs 0.000 description 12
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 12
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 11
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 229910052736 halogen Inorganic materials 0.000 description 11
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 11
- 230000004048 modification Effects 0.000 description 11
- 238000012986 modification Methods 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- 125000003729 nucleotide group Chemical group 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 108020004414 DNA Proteins 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 10
- 125000006350 alkyl thio alkyl group Chemical group 0.000 description 10
- DDYAZDRFUVZBMM-UHFFFAOYSA-N chloro-[chloro-di(propan-2-yl)silyl]oxy-di(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)O[Si](Cl)(C(C)C)C(C)C DDYAZDRFUVZBMM-UHFFFAOYSA-N 0.000 description 10
- 150000002367 halogens Chemical group 0.000 description 10
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 238000011160 research Methods 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 229930024421 Adenine Natural products 0.000 description 9
- 229930010555 Inosine Natural products 0.000 description 9
- 229960000643 adenine Drugs 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 125000000753 cycloalkyl group Chemical group 0.000 description 9
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical group O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 9
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 9
- 125000001072 heteroaryl group Chemical group 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 9
- XZQPQOSSEMTXOW-UVLLPENVSA-N n-[9-[(2r,3r,4r,5r)-3-[tert-butyl(dimethyl)silyl]oxy-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-6-yl]benzamide Chemical compound CC(C)(C)[Si](C)(C)O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(NC(=O)C=3C=CC=CC=3)=C2N=C1 XZQPQOSSEMTXOW-UVLLPENVSA-N 0.000 description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 9
- 231100000252 nontoxic Toxicity 0.000 description 9
- 230000003000 nontoxic effect Effects 0.000 description 9
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- OECPUBRNDKXFDX-UHFFFAOYSA-N 2,2-dimethyl-1-phenylpropan-1-one Chemical group CC(C)(C)C(=O)C1=CC=CC=C1 OECPUBRNDKXFDX-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 238000013459 approach Methods 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 235000000346 sugar Nutrition 0.000 description 8
- IVRREEZTGNMKRH-NGGVXWQZSA-N (2R,3R,4S,5R)-5-(1-hydroxy-2,2-dimethylpropyl)-2-(6-imino-8-silylidenepurin-9-yl)-4-[(2-methylpropan-2-yl)oxy]oxolan-3-ol Chemical compound C(C)(C)(C)C([C@@H]1[C@H]([C@H]([C@@H](O1)N1C(N=C2C(=N)N=CN=C12)=[SiH2])O)OC(C)(C)C)O IVRREEZTGNMKRH-NGGVXWQZSA-N 0.000 description 7
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 7
- 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 7
- 125000003710 aryl alkyl group Chemical group 0.000 description 7
- 125000004966 cyanoalkyl group Chemical group 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 125000001183 hydrocarbyl group Chemical group 0.000 description 7
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- NSMOSDAEGJTOIQ-CRCLSJGQSA-N (2r,3s)-2-(hydroxymethyl)oxolan-3-ol Chemical class OC[C@H]1OCC[C@@H]1O NSMOSDAEGJTOIQ-CRCLSJGQSA-N 0.000 description 6
- GLIIBPHTYXSBPC-LBZRBCMTSA-N 1-[(2R,3R,4R,5R)-4-[tert-butyl(dimethyl)silyl]oxy-5-(6-imino-8-silylidenepurin-9-yl)-3-[(2-methylpropan-2-yl)oxy]oxolan-2-yl]-2,2-dimethylpropan-1-ol Chemical compound C(C)(C)(C)C([C@@H]1[C@H]([C@H]([C@@H](O1)N1C(N=C2C(=N)N=CN=C12)=[SiH2])O[Si](C)(C)C(C)(C)C)OC(C)(C)C)O GLIIBPHTYXSBPC-LBZRBCMTSA-N 0.000 description 6
- LOSXTWDYAWERDB-UHFFFAOYSA-N 1-[chloro(diphenyl)methyl]-2,3-dimethoxybenzene Chemical compound COC1=CC=CC(C(Cl)(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1OC LOSXTWDYAWERDB-UHFFFAOYSA-N 0.000 description 6
- FPUGCISOLXNPPC-IOSLPCCCSA-N 2'-methoxyadenosine Natural products CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(N)=C2N=C1 FPUGCISOLXNPPC-IOSLPCCCSA-N 0.000 description 6
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 6
- 150000001263 acyl chlorides Chemical class 0.000 description 6
- 238000005576 amination reaction Methods 0.000 description 6
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000003776 cleavage reaction Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 6
- 229940093499 ethyl acetate Drugs 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 238000005731 phosphitylation reaction Methods 0.000 description 6
- 108091092562 ribozyme Proteins 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 230000007017 scission Effects 0.000 description 6
- 229910001961 silver nitrate Inorganic materials 0.000 description 6
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 229910052722 tritium Inorganic materials 0.000 description 6
- 102000053642 Catalytic RNA Human genes 0.000 description 5
- 108090000994 Catalytic RNA Proteins 0.000 description 5
- 108091027757 Deoxyribozyme Proteins 0.000 description 5
- 108091028664 Ribonucleotide Proteins 0.000 description 5
- 229910018557 Si O Inorganic materials 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000002480 mineral oil Substances 0.000 description 5
- 235000010446 mineral oil Nutrition 0.000 description 5
- ZQRBSCXRHDJZBS-UHFFFAOYSA-N n,n-dibutylbutan-1-amine;hydrofluoride Chemical compound F.CCCCN(CCCC)CCCC ZQRBSCXRHDJZBS-UHFFFAOYSA-N 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000002336 ribonucleotide Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Inorganic materials [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- AYQZFVZTNUOLCQ-OJAKKHQRSA-N 1-[(2r,3r,4r,5r)-3-[tert-butyl(dimethyl)silyl]oxy-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound CC(C)(C)[Si](C)(C)O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 AYQZFVZTNUOLCQ-OJAKKHQRSA-N 0.000 description 4
- LLIPTMWIZVIUSX-XVFCMESISA-N 1-[(2r,3r,4s,5r)-3-amino-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 LLIPTMWIZVIUSX-XVFCMESISA-N 0.000 description 4
- FPUGCISOLXNPPC-UHFFFAOYSA-N 2'-O-Methyladenosine Natural products COC1C(O)C(CO)OC1N1C2=NC=NC(N)=C2N=C1 FPUGCISOLXNPPC-UHFFFAOYSA-N 0.000 description 4
- BONIIQYTWOPUQI-UHFFFAOYSA-N 4-nitroisoindole-1,3-dione Chemical compound [O-][N+](=O)C1=CC=CC2=C1C(=O)NC2=O BONIIQYTWOPUQI-UHFFFAOYSA-N 0.000 description 4
- QJPBDGMPYPSJSF-UHFFFAOYSA-N 5,6-dichloroisoindole-1,3-dione Chemical compound C1=C(Cl)C(Cl)=CC2=C1C(=O)NC2=O QJPBDGMPYPSJSF-UHFFFAOYSA-N 0.000 description 4
- ANYWGXDASKQYAD-UHFFFAOYSA-N 5-nitroisoindole-1,3-dione Chemical compound [O-][N+](=O)C1=CC=C2C(=O)NC(=O)C2=C1 ANYWGXDASKQYAD-UHFFFAOYSA-N 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 230000006820 DNA synthesis Effects 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- 230000006819 RNA synthesis Effects 0.000 description 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical class O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 4
- 230000010933 acylation Effects 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 150000003973 alkyl amines Chemical class 0.000 description 4
- 125000003282 alkyl amino group Chemical group 0.000 description 4
- 125000002877 alkyl aryl group Chemical group 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 230000002152 alkylating effect Effects 0.000 description 4
- 150000001408 amides Chemical group 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical class Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 238000011067 equilibration Methods 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 230000014509 gene expression Effects 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000011987 methylation Effects 0.000 description 4
- 238000007069 methylation reaction Methods 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 125000002652 ribonucleotide group Chemical group 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- BABPEPRNSRIYFA-UHFFFAOYSA-N silyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)O[SiH3] BABPEPRNSRIYFA-UHFFFAOYSA-N 0.000 description 4
- 125000003107 substituted aryl group Chemical group 0.000 description 4
- 229910052717 sulfur Inorganic materials 0.000 description 4
- 239000011593 sulfur Substances 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 239000001226 triphosphate Substances 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- GMOAOEGBMSRFFQ-UHFFFAOYSA-N 3-nitrobenzene-1,2-dicarboxamide Chemical compound NC(=O)C1=CC=CC([N+]([O-])=O)=C1C(N)=O GMOAOEGBMSRFFQ-UHFFFAOYSA-N 0.000 description 3
- FECRKKQKJNKYNF-XVFCMESISA-N 4-amino-1-[(2r,3r,4s,5r)-3-amino-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C=C1 FECRKKQKJNKYNF-XVFCMESISA-N 0.000 description 3
- XWCDSCYRIROFIO-UHFFFAOYSA-N 4-nitrobenzene-1,2-dicarboxamide Chemical compound NC(=O)C1=CC=C([N+]([O-])=O)C=C1C(N)=O XWCDSCYRIROFIO-UHFFFAOYSA-N 0.000 description 3
- IVRMZWNICZWHMI-UHFFFAOYSA-N Azide Chemical compound [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 3
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 3
- 101150041968 CDC13 gene Proteins 0.000 description 3
- 102000053602 DNA Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 101710163270 Nuclease Proteins 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 241000251131 Sphyrna Species 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- MUJAPBLBQIDQSQ-CCUFREDKSA-N [(2r,3s,4r,5r)-5-(2-amino-6-oxo-3h-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxyphosphonamidous acid Chemical class O[C@@H]1[C@H](O)[C@@H](COP(O)N)O[C@H]1N1C(N=C(N)NC2=O)=C2N=C1 MUJAPBLBQIDQSQ-CCUFREDKSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- OJJGXBWOPWYGBJ-UYXJWNHNSA-N butanedioic acid (2R,3S)-2-(hydroxymethyl)oxolan-3-ol Chemical class OC[C@H]1OCC[C@@H]1O.OC(=O)CCC(O)=O OJJGXBWOPWYGBJ-UYXJWNHNSA-N 0.000 description 3
- 125000001589 carboacyl group Chemical group 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000003651 drinking water Substances 0.000 description 3
- 235000020188 drinking water Nutrition 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 239000002342 ribonucleoside Substances 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 235000010288 sodium nitrite Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 235000011178 triphosphate Nutrition 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- CRWLATSHAHNVOV-XDTPYFJJSA-N (2r,3s,4r)-2-(hydroxymethyl)-5-(7h-purin-2-yl)oxolane-3,4-diol Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)OC1C1=NC=C(NC=N2)C2=N1 CRWLATSHAHNVOV-XDTPYFJJSA-N 0.000 description 2
- CQKMBZHLOYVGHW-QYYRPYCUSA-N (2r,3s,4r,5r)-4-amino-5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-ol Chemical compound N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CQKMBZHLOYVGHW-QYYRPYCUSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- KGGIGLBWCMVACN-XOADWRRZSA-N 1-[(2R,3R,4R,5R)-5-(6-imino-8-silylidenepurin-9-yl)-4-methoxy-3-[(2-methylpropan-2-yl)oxy]oxolan-2-yl]-2,2-dimethylpropan-1-ol Chemical compound C(C)(C)(C)C([C@@H]1[C@H]([C@H]([C@@H](O1)N1C(N=C2C(=N)N=CN=C12)=[SiH2])OC)OC(C)(C)C)O KGGIGLBWCMVACN-XOADWRRZSA-N 0.000 description 2
- ATQYQEZERUBCBG-OZVIIMIRSA-N 1-[(2s,4s,5r)-2-dimethylsilyl-4-hydroxy-5-[(2-methylpropan-2-yl)oxymethyl]oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound C1=C(C)C(=O)NC(=O)N1[C@@]1([SiH](C)C)C[C@H](O)[C@@H](COC(C)(C)C)O1 ATQYQEZERUBCBG-OZVIIMIRSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- OVYNGSFVYRPRCG-KQYNXXCUSA-N 2'-O-methylguanosine Chemical compound CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=C(N)NC2=O)=C2N=C1 OVYNGSFVYRPRCG-KQYNXXCUSA-N 0.000 description 2
- ZDTFMPXQUSBYRL-UUOKFMHZSA-N 2-Aminoadenosine Chemical compound C12=NC(N)=NC(N)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O ZDTFMPXQUSBYRL-UUOKFMHZSA-N 0.000 description 2
- ROPTVRLUGSPXNH-DXTOWSMRSA-N 2-amino-9-[(2r,3r,4s,5r)-3-amino-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(NC(N)=NC2=O)=C2N=C1 ROPTVRLUGSPXNH-DXTOWSMRSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- RYSMHWILUNYBFW-GRIPGOBMSA-N 3'-amino-3'-deoxy-N(6),N(6)-dimethyladenosine Chemical compound C1=NC=2C(N(C)C)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](N)[C@H]1O RYSMHWILUNYBFW-GRIPGOBMSA-N 0.000 description 2
- 244000215068 Acacia senegal Species 0.000 description 2
- 235000006491 Acacia senegal Nutrition 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 108020004491 Antisense DNA Proteins 0.000 description 2
- 108091023037 Aptamer Proteins 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 241001432959 Chernes Species 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- SHFHQTFHYZIVRW-UYXJWNHNSA-N NP(O)O.OC[C@H]1OCC[C@@H]1O Chemical class NP(O)O.OC[C@H]1OCC[C@@H]1O SHFHQTFHYZIVRW-UYXJWNHNSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- 108020004682 Single-Stranded DNA Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- OWNKJJAVEHMKCW-XVFCMESISA-N [(2r,3s,4r,5r)-4-amino-5-(2,4-dioxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methyl dihydrogen phosphate Chemical compound N[C@@H]1[C@H](O)[C@@H](COP(O)(O)=O)O[C@H]1N1C(=O)NC(=O)C=C1 OWNKJJAVEHMKCW-XVFCMESISA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000006978 adaptation Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- PYMYPHUHKUWMLA-LMVFSUKVSA-N aldehydo-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000003816 antisense DNA Substances 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 150000005829 chemical entities Chemical class 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000010549 co-Evaporation Methods 0.000 description 2
- 239000002178 crystalline material Substances 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- IKGLACJFEHSFNN-UHFFFAOYSA-N hydron;triethylazanium;trifluoride Chemical compound F.F.F.CCN(CC)CC IKGLACJFEHSFNN-UHFFFAOYSA-N 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 125000005647 linker group Chemical group 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 2
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical group CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- PHFHSPQCDRKMQJ-XWXWGSFUSA-N n-[9-[(2r,3r,4r,5r)-4-hydroxy-5-(hydroxymethyl)-3-methoxyoxolan-2-yl]purin-6-yl]benzamide Chemical compound CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(NC(=O)C=3C=CC=CC=3)=C2N=C1 PHFHSPQCDRKMQJ-XWXWGSFUSA-N 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- QMMOXUPEWRXHJS-UHFFFAOYSA-N pentene-2 Natural products CCC=CC QMMOXUPEWRXHJS-UHFFFAOYSA-N 0.000 description 2
- 150000002972 pentoses Chemical class 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000005543 phthalimide group Chemical class 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 239000002718 pyrimidine nucleoside Substances 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- DWRXFEITVBNRMK-JXOAFFINSA-N ribothymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 DWRXFEITVBNRMK-JXOAFFINSA-N 0.000 description 2
- 238000002390 rotary evaporation Methods 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 229940104230 thymidine Drugs 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 150000008648 triflates Chemical class 0.000 description 2
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- OIRDTQYFTABQOQ-DEGSGYPDSA-N (2S,3S,4R,5S)-2-(6-aminopurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound [C@H]1([C@@H](O)[C@@H](O)[C@@H](O1)CO)N1C2=NC=NC(=C2N=C1)N OIRDTQYFTABQOQ-DEGSGYPDSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- CYEZJYAMLNTSKN-VOTSOKGWSA-N (e)-2-methylhept-3-ene Chemical compound CCC\C=C\C(C)C CYEZJYAMLNTSKN-VOTSOKGWSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 description 1
- LKUDPHPHKOZXCD-UHFFFAOYSA-N 1,3,5-trimethoxybenzene Chemical compound COC1=CC(OC)=CC(OC)=C1 LKUDPHPHKOZXCD-UHFFFAOYSA-N 0.000 description 1
- SGKGZYGMLGVQHP-ZOQUXTDFSA-N 1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-methylpyrimidine-2,4-dione Chemical compound CC1=CC(=O)NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 SGKGZYGMLGVQHP-ZOQUXTDFSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 1
- 102100027962 2-5A-dependent ribonuclease Human genes 0.000 description 1
- 108010000834 2-5A-dependent ribonuclease Proteins 0.000 description 1
- QMQXVNHINOVNSD-UHFFFAOYSA-N 2-[chloro(diphenyl)methyl]-5,5-dimethoxycyclohexa-1,3-diene Chemical compound C1=CC(OC)(OC)CC=C1C(Cl)(C=1C=CC=CC=1)C1=CC=CC=C1 QMQXVNHINOVNSD-UHFFFAOYSA-N 0.000 description 1
- FINYOTLDIHYWPR-UHFFFAOYSA-N 2-cyanoethoxy-n,n-di(propan-2-yl)phosphonamidous acid Chemical compound CC(C)N(C(C)C)P(O)OCCC#N FINYOTLDIHYWPR-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- DQQNMIPXXNPGCV-UHFFFAOYSA-N 3-hexyne Chemical compound CCC#CCC DQQNMIPXXNPGCV-UHFFFAOYSA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- LPUUYZVKCMCHLO-UHFFFAOYSA-N 4,5,6,7-tetrachloroisoindole-1,3-dione Chemical compound ClC1=C(Cl)C(Cl)=C2C(=O)NC(=O)C2=C1Cl LPUUYZVKCMCHLO-UHFFFAOYSA-N 0.000 description 1
- WNLMYNASWOULQY-UHFFFAOYSA-N 4-tert-butylbenzoyl chloride Chemical compound CC(C)(C)C1=CC=C(C(Cl)=O)C=C1 WNLMYNASWOULQY-UHFFFAOYSA-N 0.000 description 1
- HTMGQIXFZMZZKD-UHFFFAOYSA-N 5,6,7,8-tetrahydroisoquinoline Chemical compound N1=CC=C2CCCCC2=C1 HTMGQIXFZMZZKD-UHFFFAOYSA-N 0.000 description 1
- ZAYHVCMSTBRABG-UHFFFAOYSA-N 5-Methylcytidine Natural products O=C1N=C(N)C(C)=CN1C1C(O)C(O)C(CO)O1 ZAYHVCMSTBRABG-UHFFFAOYSA-N 0.000 description 1
- AGFIRQJZCNVMCW-UAKXSSHOSA-N 5-bromouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 AGFIRQJZCNVMCW-UAKXSSHOSA-N 0.000 description 1
- ZAYHVCMSTBRABG-JXOAFFINSA-N 5-methylcytidine Chemical compound O=C1N=C(N)C(C)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 ZAYHVCMSTBRABG-JXOAFFINSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- UGQMRVRMYYASKQ-DEGSGYPDSA-N 9-[(2s,3s,4r,5s)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-DEGSGYPDSA-N 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- AQNYJJIRTGOIQA-UHFFFAOYSA-N C(C)(C)NN(P(=O)(Cl)[ClH]CCC#N)NC(C)C Chemical compound C(C)(C)NN(P(=O)(Cl)[ClH]CCC#N)NC(C)C AQNYJJIRTGOIQA-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 1
- 102100031780 Endonuclease Human genes 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 102100030011 Endoribonuclease Human genes 0.000 description 1
- 108010093099 Endoribonucleases Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical group NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 108010070875 Human Immunodeficiency Virus tat Gene Products Proteins 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 101710203526 Integrase Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- NIDVTARKFBZMOT-PEBGCTIMSA-N N(4)-acetylcytidine Chemical compound O=C1N=C(NC(=O)C)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NIDVTARKFBZMOT-PEBGCTIMSA-N 0.000 description 1
- LVDRREOUMKACNJ-BKMJKUGQSA-N N-[(2R,3S)-2-(4-chlorophenyl)-1-(1,4-dimethyl-2-oxoquinolin-7-yl)-6-oxopiperidin-3-yl]-2-methylpropane-1-sulfonamide Chemical compound CC(C)CS(=O)(=O)N[C@H]1CCC(=O)N([C@@H]1c1ccc(Cl)cc1)c1ccc2c(C)cc(=O)n(C)c2c1 LVDRREOUMKACNJ-BKMJKUGQSA-N 0.000 description 1
- XGYUOGLHVKHRRK-SCFUHWHPSA-N O[C@@H]1[C@H](OP(O)(CCC#N)N(C(C)C)C(C)C)[C@@H](CO)O[C@H]1N1C(N=C(N)NC2=O)=C2N=C1 Chemical compound O[C@@H]1[C@H](OP(O)(CCC#N)N(C(C)C)C(C)C)[C@@H](CO)O[C@H]1N1C(N=C(N)NC2=O)=C2N=C1 XGYUOGLHVKHRRK-SCFUHWHPSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- LZMFLNUNIIJLJN-VTBLMVRQSA-N [(2R,3R,4R,5R)-5-(6-aminopurin-9-yl)-3-hydroxy-4-silyloxyoxolan-2-yl]methoxyphosphonamidous acid Chemical compound [SiH3]O[C@@H]1[C@H](O)[C@@H](COP(O)N)O[C@H]1N1C2=NC=NC(N)=C2N=C1 LZMFLNUNIIJLJN-VTBLMVRQSA-N 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000004036 acetal group Chemical group 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical group C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- PYMYPHUHKUWMLA-MROZADKFSA-N aldehydo-L-ribose Chemical compound OC[C@H](O)[C@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-MROZADKFSA-N 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- OIRDTQYFTABQOQ-UHFFFAOYSA-N ara-adenosine Natural products Nc1ncnc2n(cnc12)C1OC(CO)C(O)C1O OIRDTQYFTABQOQ-UHFFFAOYSA-N 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000004640 cellular pathway Effects 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cis-cyclohexene Natural products C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000013604 expression vector Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000005021 gait Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical class CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- HXJZHJLLMIGFCM-UHFFFAOYSA-N hydroxy-imino-di(propan-2-yloxy)-$l^{5}-phosphane Chemical compound CC(C)OP(N)(=O)OC(C)C HXJZHJLLMIGFCM-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical compound [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- MRWXACSTFXYYMV-FDDDBJFASA-N nebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC=C2N=C1 MRWXACSTFXYYMV-FDDDBJFASA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 125000005492 nosylate group Chemical group 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 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
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-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
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 125000006245 phosphate protecting group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- MWWATHDPGQKSAR-UHFFFAOYSA-N propyne Chemical compound CC#C MWWATHDPGQKSAR-UHFFFAOYSA-N 0.000 description 1
- 239000002212 purine nucleoside Substances 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011935 selective methylation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical group [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 125000002730 succinyl group Chemical group C(CCC(=O)*)(=O)* 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 1
- DVFXLNFDWATPMW-IWOKLKJTSA-N tert-butyldiphenylsilyl Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO[Si](C=2C=CC=CC=2)(C=2C=CC=CC=2)C(C)(C)C)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)OP(O)(=O)OC[C@@H]2[C@H](CC(O2)N2C3=NC=NC(N)=C3N=C2)OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(NC(N)=N3)=O)N=C2)O)C1 DVFXLNFDWATPMW-IWOKLKJTSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 239000005450 thionucleoside Substances 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000006098 transglycosylation Effects 0.000 description 1
- 238000005918 transglycosylation reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical compound [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
- 239000013598 vector Substances 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
- C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
- C07H11/04—Phosphates; Phosphites; Polyphosphates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide 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
-
- 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
- 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
-
- 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
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US23005700P | 2000-09-01 | 2000-09-01 | |
| US60/230,057 | 2000-09-01 | ||
| US28657101P | 2001-04-25 | 2001-04-25 | |
| US60/286,571 | 2001-04-25 | ||
| PCT/US2001/027116 WO2002018405A2 (en) | 2000-09-01 | 2001-08-31 | Methods for synthesizing nucleosides, nucleoside derivatives and non-nucleoside derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2421040A1 CA2421040A1 (en) | 2002-03-07 |
| CA2421040C true CA2421040C (en) | 2010-01-12 |
Family
ID=26923871
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002421040A Expired - Fee Related CA2421040C (en) | 2000-09-01 | 2001-08-31 | Methods for synthesizing nucleosides, nucleoside derivatives and non-nucleoside derivatives |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US6686463B2 (https=) |
| EP (1) | EP1313752B1 (https=) |
| JP (1) | JP2004522695A (https=) |
| AT (1) | ATE506372T1 (https=) |
| AU (2) | AU8695901A (https=) |
| CA (1) | CA2421040C (https=) |
| DE (1) | DE60144479D1 (https=) |
| WO (1) | WO2002018405A2 (https=) |
Families Citing this family (55)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
| KR20080021797A (ko) | 2000-05-26 | 2008-03-07 | 이데닉스(케이만)리미티드 | 플라비바이러스 및 페스티바이러스의 치료방법 및 조성물 |
| US7608600B2 (en) | 2002-06-28 | 2009-10-27 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
| US20050136437A1 (en) * | 2003-08-25 | 2005-06-23 | Nastech Pharmaceutical Company Inc. | Nanoparticles for delivery of nucleic acids and stable double-stranded RNA |
| US20060019914A1 (en) * | 2004-02-11 | 2006-01-26 | University Of Tennessee Research Foundation | Inhibition of tumor growth and invasion by anti-matrix metalloproteinase DNAzymes |
| WO2005097817A2 (en) * | 2004-04-05 | 2005-10-20 | Alnylam Pharmaceuticals, Inc. | Process and reagents for oligonucleotide synthesis and purification |
| AU2005325262B2 (en) | 2004-04-27 | 2011-08-11 | Alnylam Pharmaceuticals, Inc. | Single-stranded and double-stranded oligonucleotides comprising a 2-arylpropyl moiety |
| US7674778B2 (en) * | 2004-04-30 | 2010-03-09 | Alnylam Pharmaceuticals | Oligonucleotides comprising a conjugate group linked through a C5-modified pyrimidine |
| CA2572151A1 (en) | 2004-06-30 | 2006-08-24 | Alnylam Pharmaceuticals, Inc. | Oligonucleotides comprising a non-phosphate backbone linkage |
| AU2005328382C1 (en) | 2004-07-21 | 2013-01-24 | Alnylam Pharmaceuticals, Inc. | Oligonucleotides comprising a modified or non-natural nucleobase |
| CA2574603C (en) | 2004-08-04 | 2014-11-04 | Alnylam Pharmaceuticals, Inc. | Oligonucleotides comprising a ligand tethered to a modified or non-natural nucleobase |
| US8658608B2 (en) * | 2005-11-23 | 2014-02-25 | Yale University | Modified triple-helix forming oligonucleotides for targeted mutagenesis |
| US8420613B2 (en) | 2006-11-15 | 2013-04-16 | The J. David Gladstone Institutes | Methods and compositions for reducing amyloid beta levels |
| JP2010515464A (ja) * | 2007-01-11 | 2010-05-13 | イエール・ユニバーシテイ | Ｈｉｖ細胞表面受容体の標的化不活性化のための組成物および方法 |
| CA2680600A1 (en) | 2007-03-12 | 2008-09-18 | Antigen Express, Inc. | Li-rnai involved li suppression in cancer immunotherapy |
| EP2341924A4 (en) | 2008-10-02 | 2013-01-23 | David Gladstone Inst | METHOD FOR THE TREATMENT OF HEPATITIS C VIRUS INFECTIONS |
| US20120149888A1 (en) * | 2009-02-22 | 2012-06-14 | Srivastava Suresh C | Synthesis of ara-2'-o-methyl-nucleosides, corresponding phosphoramidites and oligonucleotides incorporating novel modifications for biological application in therapeuctics, diagnostics, g- tetrad forming oligonucleotides and aptamers |
| EP2408917A2 (en) | 2009-03-19 | 2012-01-25 | Merck Sharp&Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF BTB AND CNC HOMOLOGY 1, BASIC LEUCINE ZIPPER TRANSCRIPTION FACTOR 1 (BACH 1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) SEQUENCE LISTING |
| EP2408915A2 (en) | 2009-03-19 | 2012-01-25 | Merck Sharp&Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF GATA BINDING PROTEIN 3 (GATA3) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
| WO2010107952A2 (en) | 2009-03-19 | 2010-09-23 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF CONNECTIVE TISSUE GROWTH FACTOR (CTGF) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
| EP2408458A1 (en) | 2009-03-19 | 2012-01-25 | Merck Sharp&Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 6 (STAT6) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
| JP2012521764A (ja) | 2009-03-27 | 2012-09-20 | メルク・シャープ・エンド・ドーム・コーポレイション | 低分子干渉核酸（ｓｉＮＡ）を用いた胸腺間質性リンパ球新生因子（ＴＳＬＰ）遺伝子発現のＲＮＡ干渉媒介性阻害 |
| US20120004281A1 (en) | 2009-03-27 | 2012-01-05 | Merck Sharp & Dohme Corp | RNA Interference Mediated Inhibition of the Nerve Growth Factor Beta Chain (NGFB) Gene Expression Using Short Interfering Nucleic Acid (siNA) |
| JP2012521760A (ja) | 2009-03-27 | 2012-09-20 | メルク・シャープ・エンド・ドーム・コーポレイション | 低分子干渉核酸（ｓｉＮＡ）を用いたアポトーシスシグナル調節キナーゼ１（ＡＳＫ１）遺伝子発現のＲＮＡ干渉媒介性阻害 |
| WO2010111471A2 (en) | 2009-03-27 | 2010-09-30 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 1 (STAT1) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
| AU2010229847A1 (en) | 2009-03-27 | 2011-10-13 | Merck Sharp & Dohme Corp. | RNA interference mediated inhibition of the intercellular adhesion molecule 1 (ICAM-1)gene expression using short interfering nucleic acid (siNA) |
| WO2011115817A1 (en) * | 2010-03-16 | 2011-09-22 | Isis Pharmaceuticals, Inc. | Methods of preparing 2'-o-substituted purine nucleosides |
| MX2012011222A (es) | 2010-04-01 | 2013-01-18 | Centre Nat Rech Scient | Compuestos y composiciones farmaceuticas para el tratamiento de infecciones virales. |
| CA2805265A1 (en) | 2010-08-02 | 2012-02-09 | Merck Sharp & Dohme Corp. | Rna interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (ctnnb1) gene expression using short interfering nucleic acid (sina) |
| WO2012024170A2 (en) | 2010-08-17 | 2012-02-23 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF HEPATITIS B VIRUS (HBV) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
| WO2012027467A1 (en) | 2010-08-26 | 2012-03-01 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF PROLYL HYDROXYLASE DOMAIN 2 (PHD2) GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACID (siNA) |
| WO2012058210A1 (en) | 2010-10-29 | 2012-05-03 | Merck Sharp & Dohme Corp. | RNA INTERFERENCE MEDIATED INHIBITION OF GENE EXPRESSION USING SHORT INTERFERING NUCLEIC ACIDS (siNA) |
| EP2691409B1 (en) | 2011-03-31 | 2018-02-21 | Idenix Pharmaceuticals LLC. | Compounds and pharmaceutical compositions for the treatment of viral infections |
| EP2755985B1 (en) | 2011-09-12 | 2017-11-01 | Idenix Pharmaceuticals LLC | Compounds and pharmaceutical compositions for the treatment of viral infections |
| WO2013165816A2 (en) | 2012-05-02 | 2013-11-07 | Merck Sharp & Dohme Corp. | SHORT INTERFERING NUCLEIC ACID (siNA) COMPOSITIONS |
| US9512162B2 (en) | 2012-07-31 | 2016-12-06 | Ased, Llc | Synthesis of deuterated ribo nucleosides, N-protected phosphoramidites and oligonucleotides |
| US9045521B2 (en) | 2012-07-31 | 2015-06-02 | Ased, Llc | Synthesis of deuterated ribo nucleosides N-protected phosphoramidites, and oligonucleotides |
| CA2916533C (en) | 2013-06-25 | 2022-12-20 | University Of Canberra | Methods and compositions for modulating cancer stem cells |
| EP3046560B1 (en) | 2013-09-18 | 2021-01-06 | EpiAxis Therapeutics Pty Ltd | Stem cell modulation ii |
| CA2958704A1 (en) | 2014-08-25 | 2016-03-03 | University Of Canberra | Compositions for modulating cancer stem cells and uses therefor |
| CN107683336A (zh) | 2015-05-06 | 2018-02-09 | 贝尼泰克生物制药有限公司 | 用于治疗乙型肝炎病毒(hbv)感染的试剂及其用途 |
| CA3026154A1 (en) | 2015-06-03 | 2016-12-08 | The University Of Queensland | Mobilizing agents and uses therefor |
| EP3331536A4 (en) | 2015-08-03 | 2019-03-27 | The Regents of The University of California | COMPOSITIONS AND METHODS OF MODULATING THE ABHD2 ACTIVITY |
| US11136597B2 (en) | 2016-02-16 | 2021-10-05 | Yale University | Compositions for enhancing targeted gene editing and methods of use thereof |
| CA3020754C (en) | 2016-04-14 | 2023-07-25 | Benitec Biopharma Limited | Reagents for treatment of oculopharyngeal muscular dystrophy (opmd) and use thereof |
| EP3516062A1 (en) | 2016-09-21 | 2019-07-31 | Alnylam Pharmaceuticals, Inc. | Myostatin irna compositions and methods of use thereof |
| WO2018187493A1 (en) | 2017-04-04 | 2018-10-11 | Yale University | Compositions and methods for in utero delivery |
| US11660311B2 (en) | 2017-10-10 | 2023-05-30 | Bristol-Myers Squibb Company | Cyclic dinucleotides as anticancer agents |
| WO2019090390A1 (en) | 2017-11-08 | 2019-05-16 | University Of Canberra | Immunogenic compositions and uses therefor |
| EP3762395A1 (en) | 2018-03-07 | 2021-01-13 | Sanofi | Nucleotide precursors, nucleotide analogs and oligomeric compounds containing the same |
| JP7667775B2 (ja) | 2019-09-05 | 2025-04-23 | サノフイ | ヌクレオチド類似体を含有するオリゴヌクレオチド |
| IL293327B2 (en) * | 2019-11-27 | 2026-04-01 | Alnylam Pharmaceuticals Inc | Synthesis of 3'-RNA oligonucleotides |
| EP4232455A2 (en) | 2020-10-20 | 2023-08-30 | Sanofi | Novel ligands for asialoglycoprotein receptor |
| CN119019444B (zh) * | 2023-05-24 | 2025-09-30 | 成都先导药物开发股份有限公司 | 一种反向脱氧核糖亚磷酰胺单体的合成方法及其中间体化合物 |
| CN117417401A (zh) * | 2023-10-19 | 2024-01-19 | 康羽生命科学技术(苏州)有限公司 | 一种2-tbs尿苷单体合成方法 |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4987071A (en) | 1986-12-03 | 1991-01-22 | University Patents, Inc. | RNA ribozyme polymerases, dephosphorylases, restriction endoribonucleases and methods |
| US6469158B1 (en) | 1992-05-14 | 2002-10-22 | Ribozyme Pharmaceuticals, Incorporated | Synthesis, deprotection, analysis and purification of RNA and ribozymes |
| JPH0667492A (ja) | 1992-08-24 | 1994-03-11 | N T T Advance Tekunoroji Kk | 像形成方法 |
| WO1995006731A2 (en) | 1993-09-02 | 1995-03-09 | Ribozyme Pharmaceuticals, Inc. | Non-nucleotide containing enzymatic nucleic acid |
| DE69637256T2 (de) | 1996-01-16 | 2008-06-19 | Sirna Therapeutics, Inc., Boulder | Synthese von Methoxynukleoside und enzymatische Nukleisäure Moleküle |
| US5998203A (en) | 1996-04-16 | 1999-12-07 | Ribozyme Pharmaceuticals, Inc. | Enzymatic nucleic acids containing 5'-and/or 3'-cap structures |
| US5962675A (en) | 1996-02-13 | 1999-10-05 | Ribozyme Pharmaceuticals, Inc. | Chemical syntheses of 2'-O-methoxy purine nucleosides |
| US5849902A (en) | 1996-09-26 | 1998-12-15 | Oligos Etc. Inc. | Three component chimeric antisense oligonucleotides |
| ATE342911T1 (de) | 1996-12-24 | 2006-11-15 | Sirna Therapeutics Inc | Synthese von nukleosiden und polynukleotiden |
| JP3032815B2 (ja) | 1997-02-18 | 2000-04-17 | 工業技術院長 | ２’−ｏ−シリル環状ケイ素化ヌクレオシド誘導体、その製造方法及びこれを用いた２’−ｏ−シリルヌクレオシドの製造方法 |
| US6300483B1 (en) | 1997-06-19 | 2001-10-09 | Ribozyme Pharmaceuticals, Inc. | Compositions inducing cleavage of RNA motifs |
| CA2295207A1 (en) | 1997-06-19 | 1998-12-23 | Innovir Laboratories, Inc. | Hammerhead ribozymes with extended cleavage rule |
| CA2304813A1 (en) | 1997-09-22 | 1999-04-08 | Fritz Eckstein | Nucleic acid catalysts with endonuclease activity |
| EP1073732A2 (en) | 1998-04-29 | 2001-02-07 | Ribozyme Pharmaceuticals, Inc. | Nucleoside triphosphates and their incorporation into ribozymes |
-
2001
- 2001-08-31 DE DE60144479T patent/DE60144479D1/de not_active Expired - Lifetime
- 2001-08-31 WO PCT/US2001/027116 patent/WO2002018405A2/en not_active Ceased
- 2001-08-31 AU AU8695901A patent/AU8695901A/xx active Pending
- 2001-08-31 CA CA002421040A patent/CA2421040C/en not_active Expired - Fee Related
- 2001-08-31 EP EP01966449A patent/EP1313752B1/en not_active Expired - Lifetime
- 2001-08-31 US US09/944,554 patent/US6686463B2/en not_active Expired - Lifetime
- 2001-08-31 AU AU2001286959A patent/AU2001286959B2/en not_active Ceased
- 2001-08-31 JP JP2002523919A patent/JP2004522695A/ja active Pending
- 2001-08-31 AT AT01966449T patent/ATE506372T1/de not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AU8695901A (en) | 2002-03-13 |
| US6686463B2 (en) | 2004-02-03 |
| US20020120129A1 (en) | 2002-08-29 |
| DE60144479D1 (https=) | 2011-06-01 |
| JP2004522695A (ja) | 2004-07-29 |
| WO2002018405A2 (en) | 2002-03-07 |
| AU2001286959B2 (en) | 2007-09-06 |
| ATE506372T1 (de) | 2011-05-15 |
| EP1313752B1 (en) | 2011-04-20 |
| EP1313752A2 (en) | 2003-05-28 |
| WO2002018405A3 (en) | 2003-01-03 |
| CA2421040A1 (en) | 2002-03-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2421040C (en) | Methods for synthesizing nucleosides, nucleoside derivatives and non-nucleoside derivatives | |
| AU2001286959A1 (en) | Methods for synthesizing nucleosides, nucleoside derivatives and non-nucleoside derivatives | |
| US20020150936A1 (en) | Methods for synthesizing nucleosides, nucleoside derivatives and non-nucleoside derivatives | |
| Mansuri et al. | Preparation of 1-(2, 3-dideoxy-. beta.-D-glycero-pent-2-enofuranosyl) thymine (d4T) and 2', 3'-dideoxyadenosine (ddA): general methods for the synthesis of 2', 3'-olefinic and 2', 3'-dideoxy nucleoside analogs active against HIV | |
| JP5677716B2 (ja) | オリゴヌクレオチド類似体を含むキット及び方法並びにオリゴヌクレオチド類似体の使用 | |
| JP4151751B2 (ja) | 新規ビシクロヌクレオシド類縁体 | |
| ES2516815T3 (es) | Análogos de ácidos nucleicos bicíclicos modificados en la posición 6 | |
| US6090932A (en) | Method of preparation of known and novel 2'-modified nucleosides by intramolecular nucleophilic displacement | |
| DE69115702T2 (de) | Verbindungen und verfahren zur unterdrückung der genexpression | |
| JP3535519B2 (ja) | Ｎ−２置換プリン類 | |
| JPH08225589A (ja) | 修飾オリゴヌクレオチド、それらの製造、およびそれらの使用 | |
| EP2006293B1 (en) | 2'-hydroxyl-modified ribonucleoside derivative | |
| US5552539A (en) | Process for the synthesis of ribonucleic acid (RNA) using a novel deprotection reagent | |
| Hunziker et al. | Nucleic acid analogues: synthesis and properties | |
| US5674856A (en) | Modified oligodeoxyribonucleoditides | |
| Meher et al. | Nucleobase Protection of Deoxyribo‐and Ribonucleosides | |
| RU2131436C1 (ru) | Резистентные к нуклеазе олигонуклеозиды, способ их получения и резистентный к нуклеазе нуклеозидный димер | |
| EP0799834A1 (en) | Modified nucleotides | |
| US6509459B1 (en) | Base protecting groups and rapid process for oligonucleotide synthesis | |
| WO1995031470A2 (en) | Antisense inhibitors of gene expression | |
| JP4255227B2 (ja) | Ｎ３’−ｐ５’結合を有する２’，４’−ｂｎａオリゴヌクレオチド | |
| US20210238213A1 (en) | SOLID-PHASE SYNTHESIS OF OLIGONUCLEOTIDES CONTAINING N6-(2-DEOXY-ALPHA,BETA-DERYTHROPENTOFURANOSYL)-2,6-DIAMINO-4-HYDROXY-5-FORMAMIDOPYRIMIDINE (Fapy.dG) | |
| CA2078256A1 (en) | Synthesis of sulfide-linked di-or oligonucleotide analogs and incorporation into antisense dna or rna | |
| JPH0551599B2 (https=) | ||
| WO1998033806A1 (en) | Base protecting groups and process for oligonucleotide synthesis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20150831 |