JPH03218392A - Phosphate ester of oxetanocin, its use and its production - Google Patents
Phosphate ester of oxetanocin, its use and its productionInfo
- Publication number
- JPH03218392A JPH03218392A JP2092341A JP9234190A JPH03218392A JP H03218392 A JPH03218392 A JP H03218392A JP 2092341 A JP2092341 A JP 2092341A JP 9234190 A JP9234190 A JP 9234190A JP H03218392 A JPH03218392 A JP H03218392A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- residue
- group
- represented
- 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.)
- Pending
Links
- -1 Phosphate ester Chemical class 0.000 title claims abstract description 27
- 229910019142 PO4 Inorganic materials 0.000 title claims abstract description 8
- 239000010452 phosphate Substances 0.000 title claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- LMJVXGOFWKVXAW-UHFFFAOYSA-N Oxetanocin Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(CO)C1CO LMJVXGOFWKVXAW-UHFFFAOYSA-N 0.000 title abstract 3
- LMJVXGOFWKVXAW-OXOINMOOSA-N oxetanocin A Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@H]1CO LMJVXGOFWKVXAW-OXOINMOOSA-N 0.000 title abstract 3
- 125000006239 protecting group Chemical group 0.000 claims abstract description 21
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical group N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract 5
- 239000002253 acid Substances 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000003443 antiviral agent Substances 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 150000003014 phosphoric acid esters Chemical class 0.000 claims description 3
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical class OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims 7
- 239000001257 hydrogen Substances 0.000 claims 5
- 239000004480 active ingredient Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 84
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000000203 mixture Substances 0.000 description 23
- 230000002829 reductive effect Effects 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 241000700605 Viruses Species 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 13
- 238000003786 synthesis reaction Methods 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 238000010828 elution Methods 0.000 description 8
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 7
- 238000010531 catalytic reduction reaction Methods 0.000 description 7
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- 241000700721 Hepatitis B virus Species 0.000 description 6
- 102100034343 Integrase Human genes 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- AFQIYTIJXGTIEY-UHFFFAOYSA-N hydrogen carbonate;triethylazanium Chemical compound OC(O)=O.CCN(CC)CC AFQIYTIJXGTIEY-UHFFFAOYSA-N 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 5
- 239000007771 core particle Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical class [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 241000701022 Cytomegalovirus Species 0.000 description 4
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 4
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000001226 triphosphate Substances 0.000 description 4
- 235000011178 triphosphate Nutrition 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 208000007514 Herpes zoster Diseases 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 229920005654 Sephadex Polymers 0.000 description 3
- 239000012507 Sephadex™ Substances 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000001512 anti-cytomegaloviral effect Effects 0.000 description 3
- 230000036436 anti-hiv Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 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 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 3
- 235000011180 diphosphates Nutrition 0.000 description 3
- 241001493065 dsRNA viruses Species 0.000 description 3
- 239000011536 extraction buffer Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical group NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 229920000936 Agarose Polymers 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 206010061598 Immunodeficiency Diseases 0.000 description 2
- 208000029462 Immunodeficiency disease Diseases 0.000 description 2
- 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 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical group O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 230000007813 immunodeficiency Effects 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 2
- 229960000367 inositol Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 2
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 2
- 241001529453 unidentified herpesvirus Species 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- ZJNLYGOUHDJHMG-UHFFFAOYSA-N 1-n,4-n-bis(5-methylhexan-2-yl)benzene-1,4-diamine Chemical compound CC(C)CCC(C)NC1=CC=C(NC(C)CCC(C)C)C=C1 ZJNLYGOUHDJHMG-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- BCSLVBZWCFTDPK-UDJQAZALSA-N 2-amino-9-[(2r,3r,4s)-3,4-bis(hydroxymethyl)oxetan-2-yl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](CO)[C@H]1CO BCSLVBZWCFTDPK-UDJQAZALSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical group O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 1
- 241000712891 Arenavirus Species 0.000 description 1
- 101150023090 CAH gene Proteins 0.000 description 1
- 101150059114 CAPN8 gene Proteins 0.000 description 1
- 102100030004 Calpain-8 Human genes 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 229920000089 Cyclic olefin copolymer Polymers 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 108050009160 DNA polymerase 1 Proteins 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 241000711950 Filoviridae Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 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 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- 241000701076 Macacine alphaherpesvirus 1 Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000713112 Orthobunyavirus Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 101100459899 Oryza sativa subsp. japonica NCL2 gene Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 241000702263 Reovirus sp. Species 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 125000005103 alkyl silyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 230000003172 anti-dna Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 238000000211 autoradiogram Methods 0.000 description 1
- 238000000376 autoradiography Methods 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- HENZRBYHAMWFGX-UHFFFAOYSA-N carbonic acid;ethanamine Chemical compound CC[NH3+].OC([O-])=O HENZRBYHAMWFGX-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 125000002668 chloroacetyl group Chemical group ClCC(=O)* 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 150000003997 cyclic ketones Chemical class 0.000 description 1
- SUYVUBYJARFZHO-RRKCRQDMSA-N dATP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-RRKCRQDMSA-N 0.000 description 1
- SUYVUBYJARFZHO-UHFFFAOYSA-N dATP Natural products C1=NC=2C(N)=NC=NC=2N1C1CC(O)C(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-UHFFFAOYSA-N 0.000 description 1
- RGWHQCVHVJXOKC-SHYZEUOFSA-J dCTP(4-) Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)C1 RGWHQCVHVJXOKC-SHYZEUOFSA-J 0.000 description 1
- NHVNXKFIZYSCEB-XLPZGREQSA-N dTTP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C1 NHVNXKFIZYSCEB-XLPZGREQSA-N 0.000 description 1
- 238000002298 density-gradient ultracentrifugation Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 238000012869 ethanol precipitation Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000000434 field desorption mass spectrometry Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical group O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 1
- LFKYBJLFJOOKAE-UHFFFAOYSA-N imidazol-2-ylidenemethanone Chemical compound O=C=C1N=CC=N1 LFKYBJLFJOOKAE-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N monoethyl amine Natural products CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- WRMXOVHLRUVREB-UHFFFAOYSA-N phosphono phosphate;tributylazanium Chemical compound OP(O)(=O)OP([O-])([O-])=O.CCCC[NH+](CCCC)CCCC.CCCC[NH+](CCCC)CCCC WRMXOVHLRUVREB-UHFFFAOYSA-N 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 150000003212 purines Chemical group 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000005208 trialkylammonium 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
- 125000002264 triphosphate group Chemical class [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- 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 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 230000005727 virus proliferation Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明のオキセタノシン類のリン酸エステルはRNAウ
イルス(例えばHIV ( Humax Immuno
deficiency Virus) )のリバースト
ランスクリプターゼ( Rerierse ’I’ra
nscriptase, RTase )阻害活性や抗
RNAウイルス活性例えばHIV, nonA non
B肝炎ウィルス活性や抗I)NAウイルス活性例えば抗
B型肝炎ウイルス活性、抗サイトメガロウイルス活性、
抗水痘帯状庖疹ウィルスなどの抗ウイルス作用を示し、
HIVの治療薬、ウイルス性肝炎治療薬、抗サイトメガ
ロウイルス剤、抗水痘帯状庖疹ウイルス剤などの抗ウイ
ルス剤として有用)
である。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The oxetanosine phosphate ester of the present invention can be used to treat RNA viruses such as HIV (Humax Immuno
Reverse transcriptase (Reierse 'I'ra)
nscriptase, RTase) inhibitory activity and anti-RNA virus activity such as HIV, nonA non
Hepatitis B virus activity and anti-I) NA virus activity, such as anti-hepatitis B virus activity, anti-cytomegalovirus activity,
Shows antiviral effects such as anti-varicella zoster virus,
It is useful as an antiviral agent such as a treatment for HIV, a treatment for viral hepatitis, an anti-cytomegalovirus agent, and an anti-varicella zoster virus agent).
そこで発明者らは種々の研究の結果、一般式B
C式中R1はリン酸エステル残基、Bはプリン塩基残基
、XはH,OH又はCH20Hを示す。)で表わされる
オキセタノシン類のリン酸エステルが、HIVのリバー
ストランスクリプターゼ阻害活性、抗HIV活性やDN
AウイルスのDNAポリメレース阻害活性、抗DNAウ
イルス活性を有することを見い出し本発明を完成した。As a result of various studies, the inventors found that in the general formula B C, R1 represents a phosphate ester residue, B represents a purine base residue, and X represents H, OH or CH20H. ) The phosphate esters of oxetanosines expressed by
The present invention was completed based on the discovery that the present invention has A virus DNA polymerase inhibitory activity and anti-DNA virus activity.
本発明におけるリン酸エステル残基としてはあげられる
。Examples of phosphoric acid ester residues in the present invention include:
またプリン塩基の残基としては、下記式のプリン骨格の
9位においてオキセタン環に結合し5
ているプリン誘導体の残基で、例えばアデニン残基、グ
アニン残基、キサンチン残基、ヒボキサンチン残基、2
,6−ジアミノプリン残基などをあげることができる。In addition, purine base residues include residues of purine derivatives bonded to the oxetane ring at position 9 of the purine skeleton in the following formula, such as adenine residues, guanine residues, xanthine residues, hypoxanthine residues, 2
, 6-diaminopurine residue, etc.
本発明の一般式CI)の化合物の具体例を示すと第1表
の通りである。Specific examples of the compound of general formula CI) of the present invention are shown in Table 1.
なお表および以後の式中における略号は次の通りである
。The abbreviations in the table and the following formulas are as follows.
表 1 本発明における一般式(I)の化合物は次のよう にして得ることができる。table 1 The compound of general formula (I) in the present invention is as follows. You can get it.
R
〔式中XはH,
0−p:+又は
C H2
0−P3
(P3は
保護基)
Bはブリ
ン塩基の残基〕
で示されるオキセタノシン類に、
下記一般式
助−0−P=0
1
0
1’{c
(式中Ra,RbおよびRCは水素原子または低級アル
キル基を示す。)
で示される低級アルキルリン酸の存在下にオキシ塩化リ
ンを反応させ、Xが−0−P3又は−CH2一〇−P3
のときは次いで保護基を除去することにより、
R
(式中XはH, OH又はCH20H, Bはプリン塩
基残基を示す。)
で表わされるオキセタノシン類のモノリン酸エステルを
得ることができる。R [In the formula, Phosphorus oxychloride is reacted in the presence of a lower alkyl phosphoric acid represented by 1 0 1'{c (wherein Ra, Rb and RC represent a hydrogen atom or a lower alkyl group), and X is -0-P3 or -CH210-P3
In this case, by removing the protecting group, a monophosphoric acid ester of oxetanosine represented by R (wherein X is H, OH or CH20H, and B represents a purine base residue) can be obtained.
この反応は不活性な有機溶媒中で行うこともできるが、
通常反応の際に存在させるトリ低級アルキルリン酸を溶
媒とし、約−2 0 ’C〜約=9
50℃好ましくは約−10℃〜約20℃程度で行うこと
ができる。This reaction can also be carried out in an inert organic solvent, but
The reaction can be carried out using tri-lower alkyl phosphoric acid, which is usually present during the reaction, as a solvent at a temperature of about -20'C to about 950C, preferably about -10C to about 20C.
保護基の除去は常法によって行うことができる。このP
3は通常接触還元によって除去できる保護基が用いられ
るので、通常貴金属触媒を用いて接触還元によりこの保
護基を除去する。接触還元に用いる触媒は白金、Pd,
Pd−Cなどが使用される。接触還元は通常溶媒中で行
うのが好ましく、水、低級アルコール、低級アルキルケ
トン、低級脂肪酸などの極性溶媒が使用される。Removal of the protecting group can be carried out by conventional methods. This P
In No. 3, a protecting group that can be removed by catalytic reduction is usually used, and therefore this protecting group is usually removed by catalytic reduction using a noble metal catalyst. The catalyst used for catalytic reduction is platinum, Pd,
Pd-C or the like is used. Catalytic reduction is usually preferably carried out in a solvent, and polar solvents such as water, lower alcohols, lower alkyl ketones, and lower fatty acids are used.
反応温度は約00C〜溶媒の沸点(例えば約150℃)
程度で行えばよい。The reaction temperature is about 00C to the boiling point of the solvent (e.g. about 150C)
It should be done in moderation.
接触還元ではずすことのできる保護としては例えばペン
ジル基(非置換又は低級アルキル、低級アルコキシ、ハ
ロゲンなどで置換されていてもよい。)などが使用され
る。As the protection that can be removed by catalytic reduction, for example, a penzyl group (which may be unsubstituted or substituted with lower alkyl, lower alkoxy, halogen, etc.) is used.
また場合により、P3の保護基は低級アルキルカルボニ
ル、低級アルキルシリルなどの保護基でもよい。これら
の保護基の場合は常法により加水分解などにより保護基
をはずすことができる。Further, depending on the case, the protecting group for P3 may be a protecting group such as lower alkylcarbonyl or lower alkylsilyl. In the case of these protecting groups, the protecting groups can be removed by hydrolysis or the like in a conventional manner.
1〇一
次にオキセタノシン類のトリリン酸エステルの製造法に
ついて述べる。10 First, the method for producing triphosphate esters of oxetanosines will be described.
前記一般式(Ia)のオキセタノシン類のモノリン酸エ
ステルに、トリアルキルアミンの存在下にカルボニルジ
イミダゾールおよびトリアルキルアンモニウムピロフォ
スフェートを反応させることにより
B
(式中XおよびBは前記と同じ意味を示す。)で示され
るオキセタノシン類のトリリン酸エステルを得ることが
できる。By reacting the monophosphoric acid ester of oxetanosine of the general formula (Ia) with carbonyldiimidazole and trialkylammonium pyrophosphate in the presence of a trialkylamine, B (wherein X and B have the same meanings as above) is obtained. It is possible to obtain the triphosphate ester of oxetanosine represented by
この反応は通常低級アルコール、低級アルキルケトン、
還状ケトン、低級脂肪酸などの極性溶媒中で行われる。This reaction usually involves lower alcohols, lower alkyl ketones,
It is carried out in polar solvents such as cyclic ketones and lower fatty acids.
反応温度は通常約0℃から溶媒の沸点程度の温度(例え
ば150℃程度)で行われる。The reaction temperature is usually about 0°C to about the boiling point of the solvent (for example, about 150°C).
一般式(Ia)の化合物1モルに対して、トリ低級アル
キル(C1〜C5)アミン約1モル〜約10モル程度、
ジシクロヘキシルカルボジイミドなどのカルボニルイミ
ダゾール約2モル〜約10モルが使用される。About 1 mol to about 10 mol of tri-lower alkyl (C1-C5) amine per 1 mol of the compound of general formula (Ia),
About 2 moles to about 10 moles of carbonylimidazole, such as dicyclohexylcarbodiimide, are used.
目的化合物の分離は通常のクロマトグラフィーなどによ
って行うことができる。The target compound can be separated by conventional chromatography.
なお本発明で低級アルキル、低級アルコールなどにおけ
るアルキル基は炭素数1〜5程のものである。これらの
アルキルの例としてはメチル、エチル、プロビル、プチ
ル、ベンチルナトをあげることができる。これらは分枝
していてもよい。In the present invention, the alkyl group in lower alkyl, lower alcohol, etc. has about 1 to 5 carbon atoms. Examples of these alkyls include methyl, ethyl, proyl, butyl, ventilnato. These may be branched.
本発明化合物は酸又はアルカリと塩を形成する。塩を形
成するための酸としては、例えば薬理学上許容される酸
であればよく、例えば、塩酸、硫酸、リン酸などが好ま
しい。塩を形成するアルカリとしては水酸化アルカリな
どがあげられる。゛塩を形成するには常法により通常溶
媒中で一般式(I)の化合物に、酸又はアルカリを反応
させればよい。The compounds of the present invention form salts with acids or alkalis. The acid for forming the salt may be any pharmacologically acceptable acid, and preferably includes hydrochloric acid, sulfuric acid, phosphoric acid, and the like. Examples of alkalis that form salts include alkali hydroxides. ``Salts can be formed by reacting the compound of general formula (I) with an acid or an alkali in a normal solvent by a conventional method.
次に一般式(I)においてBがアデニン残基囚である場
合の代表的な化合物の製法につき原料の一般式(社)の
化合物の製法も含め簡単に説明する。Next, a method for producing a typical compound in the case where B is an adenine residue in the general formula (I) will be briefly explained, including a method for producing the compound of the general formula (Company) as a raw material.
なお下記式において、 (式中P2は保護基を示す。In addition, in the following formula, (In the formula, P2 represents a protecting group.
) で示される基を示す。) Indicates a group represented by
P2 P】 水酸基の保護 (Rと異なった手段ではずす保護基での保護)13 ■ 化合物歯I A 化合物N2 以下各工程を簡単に説明する。P2 P】 Protection of hydroxyl groups (Protection with a protecting group that is removed by a different method than R) 13 ■ Compound tooth I A Compound N2 Each step will be briefly explained below.
第1工程:N(6)一保護オキセタノシン■の2CH2
0Hの水酸基を何らかの保護基で選択的に保護する。1st step: 2CH2 of N(6) monoprotected oxetanosine■
The 0H hydroxyl group is selectively protected with some kind of protecting group.
化合物の及び■の保護基(式中R又はP2)としてはホ
ルミルまたは置換基を有してもよい低級アルキルカルボ
ニル(置換基としてはハロゲンi子、低級アルコキシ、
ベンゾイルなど)例えばアセチル、クロロアセチル、ト
リクロロアセチル、メトキシアセチル、ピバロイル、フ
ェノキシアセチル、トリチルオキシアセチルなど、また
はベンゾイルなどのアシル基、置換基を有14
しても良い低級アルキル基例えばt−ブチル基などの非
置換低級アルキル−トリチルまたはモノメトキシトリチ
ルまたはジメトキシトリチル、トリメトキシトリチルな
どの低級アルコキシトリチルなどの置換又は非置換トリ
チル基などの置換低級アルキル、さらには、各種置換基
を有するシリル基、例えばトリメチルシリル、tブチル
ジメチルシリルまたはt−プチルジフエニルシリル基な
どが挙げられる。The protecting group (R or P2 in the formula) of the compound and (2) is formyl or lower alkylcarbonyl which may have a substituent (substituents include halogen i, lower alkoxy,
benzoyl, etc.), for example, acetyl, chloroacetyl, trichloroacetyl, methoxyacetyl, pivaloyl, phenoxyacetyl, trityloxyacetyl, etc., or acyl groups such as benzoyl, lower alkyl groups which may have substituents, such as t-butyl group, etc. unsubstituted lower alkyl-trityl or substituted or unsubstituted trityl groups such as monomethoxytrityl or dimethoxytrityl, lower alkoxytrityl such as trimethoxytrityl, and also silyl groups with various substituents, such as trimethylsilyl. , t-butyldimethylsilyl or t-butyldiphenylsilyl group.
」二記の保護基を導入するには、公知の方法により行な
うことができるが、後に保護基を脱離する際に効率より
脱離できる様な保護基を選択するのが好ましい。化合物
■と化合物■はカラムクロマトグラフィーにより分離す
ることができる。Introducing the protecting group described in ``2'' can be carried out by a known method, but it is preferable to select a protecting group that can be removed later in terms of efficiency when removing the protecting group. Compound (1) and compound (2) can be separated by column chromatography.
第2工程:3’−CH20Hの水酸基の保護工程である
。P1がアシル基やシリル基のときは保護基として還元
などではずすことができるベンジル基、アリル基等が好
ましい。Second step: This is a step for protecting the hydroxyl group of 3'-CH20H. When P1 is an acyl group or a silyl group, a benzyl group, an allyl group, etc., which can be removed by reduction or the like as a protective group, are preferable.
第3丁程:保護基P1およびP2を除去する工程である
。P】が各種置換基を有するシリル基の場合には例えば
、テトラヒド口フラン中n−テトラプチルアンモニウム
フロリドを用いることができる。Third step: This is the step of removing protecting groups P1 and P2. When P] is a silyl group having various substituents, for example, n-tetraptylammonium fluoride in tetrahydrofuran can be used.
P2がアシル基の場合にはナトリウムメトキシドあるい
はアンモニア水などを用いることができる。When P2 is an acyl group, sodium methoxide or aqueous ammonia can be used.
第4工程:リン酸化工程であるリン酸化に用いられるリ
ン酸類としてはオキシ塩化リンが使用でき通常トリ低級
アルキルリン酸の存在下にて行われる。Fourth step: Phosphorylation step Phosphorous oxychloride can be used as the phosphoric acid used in the phosphorylation, and the step is usually carried out in the presence of tri-lower alkyl phosphoric acid.
第5工程: 2’−CH20Hの水酸基の保護基の除去
行程である。Fifth step: This is a step for removing the protecting group for the hydroxyl group of 2'-CH20H.
P3の保護基がベンジル基のような還元により除去でき
るものの場合には、通常パラジウムカーボンなどを使用
する接触還元が用られる。When the protecting group of P3 can be removed by reduction, such as a benzyl group, catalytic reduction using palladium on carbon or the like is usually used.
この工程により化合物Nnl(モノリン酸エステル)が
得られる。Compound Nnl (monophosphoric acid ester) is obtained through this step.
第6工程二トリリン酸エステル化の工程である。The sixth step is a step of ditriphosphate esterification.
トリリン酸エステル化はトリプチルアミンの存在下にカ
ルボニルジイミダゾールを反応させた後、トリブチルア
ンモニウムピロフオスフエートなどのトリ低級アルキル
アンモニウムビ口フォスフェートを反応させることによ
って得ることができる。Triphosphate esterification can be obtained by reacting carbonyldiimidazole in the presence of triptylamine and then reacting a tri-lower alkyl ammonium biphosphate such as tributylammonium pyrophosphate.
次に本発明化合物の生物汚性について説明する。Next, the biofouling properties of the compounds of the present invention will be explained.
本発明の化合物は浸れた抗ウイルス作用を有1,、抗ウ
イルス剤として使用される。The compounds of the present invention have strong antiviral activity 1, and are used as antiviral agents.
抗ウイルス活性が期待されるウイルスとしては次のよう
なものがあげられる。The following viruses are expected to have antiviral activity.
DNAウイルス
ボックスウイルス、ヘルペスウイルス、アデノウイルス
、パポバウイルス、ヘパドトウイルス、バルボウイルス
RNAウイルス
ラブドウイルス、フィロウイルス、パラミクソウイルス
、オルソミクソウイルス、アレナウィルス、レトロウイ
ルス、コロナウイル]7
ス、ブニャウイルス、トガウイルス、フラピウイルス、
カリンウイルス、ピコルナウイルス、レオウイルス
そして、各種のウイルス性疾患、例えばヘルペス、B型
肝炎、サイトメガロウイルスによる感染症、水痘帯状庖
疹、エイズなどの治療剤として期待される。DNA viruses, herpesviruses, adenoviruses, papovaviruses, hepadotoviruses, balboviruses, RNA viruses, rhabdoviruses, filoviruses, paramyxoviruses, orthomyxoviruses, arenaviruses, retroviruses, coronaviruses] 7, Bunyavirus, Toga virus, frapivirus,
It is expected to be used as a therapeutic agent for Karin virus, picorna virus, reo virus, and various viral diseases such as herpes, hepatitis B, infections caused by cytomegalovirus, varicella zoster, and AIDS.
一般式(I)においてBがアデニン残基又はヒボギサン
残基である化合物は特にH I V ( Hnman1
mmunodeficiency Virus )など
のRNAウイ/L/スやDNAウイルスである水痘−帯
状庖疹ウイルス( Varicella− Zoste
r Virus )などの抑制作用において優れている
。In general formula (I), the compound in which B is an adenine residue or a hibogysan residue is particularly suitable for HIV (Hnman1
RNA viruses such as immunodeficiency virus and varicella zoster virus, which is a DNA virus.
It is excellent in suppressing effects such as r Virus).
また一般式(1)において、Bがグアニン残基又は2−
アミノアデニン残基である化合物はB型肝炎ウイルス、
サイトメガロウイルス又はパルボウィルスなどのDNA
ウイルスの増殖抑制作用において優れている。Further, in general formula (1), B is a guanine residue or 2-
Compounds that are aminoadenine residues are hepatitis B virus,
DNA such as cytomegalovirus or parvovirus
Excellent in suppressing virus proliferation.
そして一般式(I)において、R1がモノリン酸エステ
ルである下記一般式
18
(式中XはH, OH又はCH20H, Bはプリン塩
基の残基を示す。)
で示されるオキセタノシン類のモノリン酸エステルはウ
イルス感染した温血動物(人を含む)次に、試験例およ
び実施例を示す。And in the general formula (I), a monophosphate ester of oxetanosine represented by the following general formula 18 (in the formula, X is H, OH or CH20H, and B represents a residue of a purine base) where R1 is a monophosphate ester Next, test examples and examples are shown.
試験例I
HIVの逆転写酵素( RTase )活性測定法1.
酵素標品
HI V ( Human Immunodefici
ency Virus )持続感染株であるMOLT−
4/HTLV−mB粒子をTritonX−100等で
破壊し、粗酵素(RTase)を調製した。Test Example I HIV reverse transcriptase (RTase) activity measurement method 1.
Enzyme preparation HIV (Human Immunodeficiency
MOLT-, a persistently infectious strain
4/HTLV-mB particles were disrupted with Triton X-100 or the like to prepare crude enzyme (RTase).
尚、POI3/ ( dT ) , Oligo (
dA )をテンプレイト・プライマーとして下記の反応
液を使用した。In addition, POI3/ (dT), Oligo (
The following reaction solution was used with dA) as a template primer.
2.
反応液組成
5mg/ml BovineSerumAlbumin
2,5 dI M Tris−HCt緩衝液
(I)H7.8) 2.OI Q QmMDith
iothreitol 2.OIM KC
t’ 2.251 0mM P
oly (dT) 1.0150μM
dATP 4.55 units
/ml Qligo ( d A ) 4.
01、2 5 mM Mn Ct22.51mCi/m
A’ ”H−dATP 2.25l’l
’ase 1 0.0蒸留水
27.0Total 6 0
.0
3.反応条件
37℃、1時間
以上の条件で得られた反応液の酸不溶性画分に取り込れ
た3H − AMP量を液体シンチレーションカウンタ
ーで測定した。2. Reaction liquid composition 5mg/ml BovineSerumAlbumin
2.5 dI M Tris-HCt buffer (I) H7.8) 2. OI Q QmMDith
iothreitol 2. OIM KC
t' 2.251 0mM P
oly (dT) 1.0150μM
dATP 4.55 units
/ml Qligo (dA) 4.
01, 2 5mM Mn Ct22.51mCi/m
A'"H-dATP 2.25l'l
'ase 1 0.0 distilled water
27.0Total 6 0
.. 0 3. The amount of 3H-AMP incorporated into the acid-insoluble fraction of the reaction solution obtained under the reaction conditions of 37° C. for 1 hour or more was measured using a liquid scintillation counter.
本化合物のRT阻害活性を表2に示した。Table 2 shows the RT inhibitory activity of this compound.
表2
本化合物のHIV
化合物lV&12(μM)
417
125
42.7
12,5
4.17
R Taseの阻害
RTase阻害■
98.8
93.0
69.4
33,9
1.0
00
実施例1
(化合物陥l及びI′I!12の合成)A
化合物■および■の合成
N(6)一ベンゾイル−9−(2−デオキシー2一ヒド
ロキシメチルーβ一D一エリスロオキセタノシル)アデ
ニン(化合物の) ( P2 =COC6H5 )12
3111gの無水ジメチルホルムアミド(1ml)溶液
中に、イミダゾール70n+gさラニtert − 7
”チルジメチルシリルクロリド60■の無水ジメチルホ
ルムアミド(2ml)溶液を加え、室温で21
2時間撹拌する。減圧下、溶媒を留去し、残渣に水(2
0ml)を加え、クロロホルムで抽出する。クロロホル
ム抽出液を飽和食塩水で洗浄し無水硫酸マグネシウムで
乾燥する。Table 2 HIV of the present compound Compound LV & 12 (μM) 417 125 42.7 12,5 4.17 Inhibition of R Tase Inhibition of RTase ■ 98.8 93.0 69.4 33,9 1.0 00 Example 1 (Compound Synthesis of compounds 1 and I'I!12) A Synthesis of compounds ■ and ■ ) (P2 = COC6H5)12
In a solution of 3111 g of anhydrous dimethylformamide (1 ml), 70 n+g of imidazole was added.
A solution of 60 μl of methyldimethylsilyl chloride in anhydrous dimethylformamide (2 ml) was added and stirred at room temperature for 212 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with water (2 ml).
0 ml) and extracted with chloroform. The chloroform extract is washed with saturated saline and dried over anhydrous magnesium sulfate.
硫酸マグネシウムを炉去し、減圧下溶媒を留去して淡黄
色シロップを得る。このものをシリカゲル20gのカラ
ムに付し、クロロホルムーメタノール(20:1)で溶
出する。シリカゲルTLC C展開溶媒;クロロホルム
ーメタノール(10:1))でl{f 0. 4 6付
近のフラクションを集め、減圧下溶媒を留去し、化合物
■( P21.
COCs H5, R ””+ 81 −) 4 9.
6■(30.6%)を得る。The magnesium sulfate was removed from the oven, and the solvent was distilled off under reduced pressure to obtain a pale yellow syrup. This was applied to a 20 g column of silica gel and eluted with chloroform-methanol (20:1). Silica gel TLC C developing solvent; chloroform-methanol (10:1)) l{f 0. Fractions around 4 6 were collected and the solvent was distilled off under reduced pressure to form compound (P21. COCs H5, R ””+ 81 −) 4 9.
6■ (30.6%).
又、RfO.60付近のフラクションを集め、減圧下溶
媒を留去し、化合物の( P2 −−COC6H6,
R化合物■: MSm/z : 470(M+H)
;NMR( 4 0 0MHZ, CDCt3. T
MS)ppm : 9−2 3 ( IH,s, N
H, 8.78 ( IH, s, 8−H),
8.68 ( IH,s, 2−H), 8.
0 3 ( 2H, d, J=7.5Hz,
ph ),8.50 〜8.63 ( 3H, m,
Ph ), 6.60 ( IH, d,−22
=
OSi +),
一
p
3.8 1 ( 1 1−I, dd,J
1 1. 7 Hz, 2. 8 Hz,( 3H,
s, 逮i+), 0.1 2 ( 3H, s, 一
&i+)l1
化合物■: MSm/z : 4 7 0 ( M+H
)+; NMR(400HHz,CDCta,TMS
)ppm:934.(IH, s,NH), 8.7
9 ( IH, s, 8−H), 8.34 (
IH, s,2−H), 8.3 5 ( 2H,
d, J−7.5Hz, Ph ),7.48 〜7
.63 ( 3H, m, Ph )t 6.50(
IH, d,J=5.7 Hz, 1’ 一H )
, 5、5 0 ( I H, broad s,一0
1{), 4.0 4 ( 2H, m, 3’−CH
20H ), 3.6 7〜3.8 7 ( 3
H, m, 2’−H, 2’−CH20
H ), 0.9 1( 9H, s, −S
i十), 0.1 0 ( 6H, s, −Si+)
11
化合物■の合成
水冷下、窒素気流中でソジウムハイドリド25■を無水
テトラヒドロフラン3 mlに懸濁しこれに化合物■1
00rr@の無水テトラヒドロフラン3ml溶液を加え
30分間撹拌後、ペンジルプロミド26紹を加え室温に
て2時間撹拌する。Also, RfO. Fractions around 60% were collected, the solvent was distilled off under reduced pressure, and the compound (P2--COC6H6,
R compound ■: MSm/z: 470 (M+H)
;NMR(400MHZ, CDCt3.T
MS) ppm: 9-2 3 (IH, s, N
H, 8.78 (IH, s, 8-H),
8.68 (IH, s, 2-H), 8.
0 3 (2H, d, J=7.5Hz,
ph), 8.50 to 8.63 (3H, m,
Ph), 6.60 (IH, d, -22
= OSi +), 1 p 3.8 1 ( 1 1-I, dd, J 1 1.7 Hz, 2.8 Hz, ( 3H,
s, i+), 0.1 2 (3H, s, 1&i+)l1 Compound ■: MSm/z: 4 7 0 (M+H
)+; NMR (400Hz, CDCta, TMS
) ppm: 934. (IH, s, NH), 8.7
9 (IH, s, 8-H), 8.34 (
IH, s, 2-H), 8.3 5 (2H,
d, J-7.5Hz, Ph), 7.48 ~7
.. 63 (3H, m, Ph)t 6.50(
IH, d, J=5.7 Hz, 1'-H)
, 5, 50 (IH, broads, 10
1{), 4.0 4 (2H, m, 3'-CH
20H), 3.6 7-3.8 7 (3
H, m, 2'-H, 2'-CH20
H), 0.9 1(9H, s, -S
i10), 0.10 (6H, s, -Si+)
11 Synthesis of Compound 1 Suspend 25 ml of sodium hydride in 3 ml of anhydrous tetrahydrofuran in a nitrogen stream under water cooling, and add compound 1 to this.
Add 3 ml of anhydrous tetrahydrofuran solution of 00rr@ and stir for 30 minutes, then add 26 penzylbromide and stir at room temperature for 2 hours.
反応液に飽和塩化アンモニウム水溶液を3 ml加えて
室温にて20分間撹拌した後、減圧下溶媒を留去する。After adding 3 ml of saturated ammonium chloride aqueous solution to the reaction mixture and stirring at room temperature for 20 minutes, the solvent was distilled off under reduced pressure.
残渣に水5 rnlを加えクロロホルム(1−Ornl
)で3回抽出し、有機層を飽和食塩水で洗浄した後無水
硫酸ナトリウムで乾燥する。Add 5 rnl of water to the residue and add chloroform (1-Ornl) to the residue.
) and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
硫酸ナトリウムを許去し、減圧下溶媒を留去しシロップ
を得る。このものをシリカゲルカラムクロマトクラフィ
ー〔20ml1クロロホルムメタノール(50:1)〕
により分離し化合物■『
( P2= COCaHs, P+ 一+St −t
P3−CH2 C6Hs )『
96.4■(収率85.6%)を得る。The sodium sulfate was removed and the solvent was distilled off under reduced pressure to obtain syrup. This was subjected to silica gel column chromatography [20ml 1 chloroform methanol (50:1)]
The compound ■'' (P2= COCaHs, P+ 1+St -t
P3-CH2C6Hs) 96.4 (yield: 85.6%) was obtained.
化合物■: NMR ( 6 0 MHz. CDCt
3, TMS ) ppm :9.29 ( IH,
br s, NH), 8.73 ( II−I, s
, 81{),8.62( LH,s,2−H),7.
70〜8.10( 2H, m), 7.1 7
〜7.6 0 ( 8H, rr+), 6.6
0( 11−I, d, J=6.2Hz,
1’−H ). 4.4. 0 〜4.8
7( 31{, m), 3.5 0 〜4.
1 0 ( 5H, m), 1.98( 9H,
s,), 1.2 0 ( 6H, s )化合
物■の合成
化合物■96.4111gのテトラヒド口フラン2ml
溶液にテトラブチルアンモニウムフロリトノ1. 0
5 Mテトラヒドロフラン溶液0. 3 mlを加え室
温で1時間撹拌する。反応液を減圧下溶媒を留去し、残
渣を得る。これにメタノールl,5ml,濃アンモニア
水1. 5 mlを加え60℃で2時間撹拌する。反応
液を減圧濃縮乾固し、残渣をメタノール3 mlに溶か
しシリカゲル800lTlgを加え減圧下溶媒を留去す
る。このものをクロロホルムーメタノール(20:1)
で平衡化したシリカゲルカラム50mlに積層しクロロ
ホルムーメタノール(20:1、10:1)で溶出し化
合物■( Pa= CH2 C6H5 ) 4 3■(
収率72.6%)を25
得る。Compound ■: NMR (60 MHz. CDCt
3, TMS) ppm: 9.29 (IH,
br s, NH), 8.73 (II-I, s
, 81{), 8.62 (LH, s, 2-H), 7.
70-8.10 (2H, m), 7.1 7
~7.6 0 (8H, rr+), 6.6
0(11-I, d, J=6.2Hz,
1'-H). 4.4. 0 to 4.8
7 (31{, m), 3.5 0 ~ 4.
10 (5H, m), 1.98 (9H,
s,), 1.20 (6H, s) Synthesis of compound ■ Compound ■ 96.4111 g of tetrahydrofuran 2 ml
1. Add tetrabutylammonium floritone to the solution. 0
5M tetrahydrofuran solution 0. Add 3 ml and stir at room temperature for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure to obtain a residue. Add 1 ml of methanol, 5 ml, and 1 ml of concentrated ammonia water. Add 5 ml and stir at 60°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in 3 ml of methanol, 800 lTlg of silica gel was added, and the solvent was distilled off under reduced pressure. Mix this with chloroform-methanol (20:1)
It was stacked on a 50 ml silica gel column equilibrated with
25 (yield 72.6%) is obtained.
化合物■: NMR( 6 0MI{z, CDaOD
, TMS )ppm: 8.65 ( IH, s,
8−H), 8.23 ( IH, s, 2H),
7.32(5H,s,ダ−CH2 −0−)t 6.
33( IHt d+ 6.0Hz* 1’−H)*
4.60 ( 2H, s,p−CH2 ),
3.6 6〜4.1 8 ( 5H, m )化合物
■の合成
一20℃冷却下、窒素気流中で化合物■322■のトリ
エチルリン酸6 ml懸濁液にオキシ塩化リンQ. 3
mlを加えた後、0℃で18時間撹拌する。反応液を
飽和重炭酸ナ} IJウム水溶液10mlに加えた後、
クロロホルム15mlで3回抽出する。この水層に水1
00+++A!を加え、これをDEAE − Seph
adex A − 2 5(炭酸型)60mlに通塔し
、水200mlで洗った後、0. 1 Mのトリエチル
アミン炭酸バッ7 y 3 0 0 ml ( p}
{ 7. 4 8 )続いて0. 3 Mのトリエチル
アミン炭酸バノファ−(pH7.38)500mlで溶
出し、シリカケルTLC [ブタノール:酢酸:水(
1 2 : 3 : 5 )]でRf0.37付近を集
め粗化合物■(P3−CH,+26
CaHs)を得た。Compound ■: NMR (60MI{z, CDaOD
, TMS) ppm: 8.65 (IH, s,
8-H), 8.23 (IH, s, 2H),
7.32 (5H, s, Da-CH2-0-)t 6.
33 (IHt d+ 6.0Hz* 1'-H)*
4.60 (2H, s, p-CH2),
3.6 6 to 4.1 8 (5H, m) Synthesis of Compound (1) - Phosphorus oxychloride Q. 3
ml and then stirred at 0° C. for 18 hours. After adding the reaction solution to 10 ml of saturated sodium bicarbonate aqueous solution,
Extract 3 times with 15 ml of chloroform. 1 water in this water layer
00+++A! and convert it into DEAE-Seph
After pouring into 60 ml of adex A-2 5 (carbonate type) and washing with 200 ml of water, 0. 1 M triethylamine carbonate bag 7 y 300 ml (p)
{7. 4 8) followed by 0. Elute with 500 ml of 3 M triethylamine carbonate (pH 7.38) and perform silica gel TLC [butanol:acetic acid:water (
1 2 : 3 : 5)] and collected the Rf around 0.37 to obtain a crude compound (P3-CH, +26 CaHs).
化合物■: NMR( 6 0 MHz, CDa O
D ) : 8.6 6(IH, s, 8−H),
8.20(IH, s, 2−H),7、30(5H,
s, Ph), 6.60(IH, d, J6.2
Hz, 1’−H ), 4.6 0 ( 2H, s
). 4.1 0 〜4、3 4 ( 2H, m
), 3.6 6 〜4、03(3H,m)化合物NC
LIの合成
粗化合物■416111gをエタノール20ml−水7
ml一酢酸3 mlの混液に溶解し10%パラジウム
カーボン4on’gを加え加熱還流下、接触還元を3時
間行った。反応液をろ過し触媒を除去後沖液を減圧濃縮
し無色の残渣を得た。このものを50%含水メタノール
に溶解し、同溶媒で平■
衡化したSephadex LH−2 0 ( 4 0
0 ml )カラムクロマトグラフィーにより分離す
る。シリカゲルTLC [ブタノールー酢酸一水(12
:3:5))にてRfO.13付近のフラクションを集
め減圧下溶媒を留去した。残渣を水5 ml.に溶解し
0.1規■
定塩酸にてI)H1.8に調製し、MCI GELCH
P20P(120++tl)カラムに通塔した。水洗後
、80%含水メタノールにて溶出し、減圧下、溶媒を留
去し、化合物Nlllの無色粉末138fflgを得た
。Compound ■: NMR (60 MHz, CDaO
D): 8.6 6 (IH, s, 8-H),
8.20 (IH, s, 2-H), 7, 30 (5H,
s, Ph), 6.60 (IH, d, J6.2
Hz, 1'-H), 4.60 (2H, s
). 4.1 0 ~ 4, 3 4 (2H, m
), 3.6 6 ~4, 03 (3H, m) Compound NC
Synthetic crude compound of LI ■416111g was mixed with 20ml of ethanol and 77ml of water
The mixture was dissolved in a mixture of 3 ml of monoacetic acid, 4 on'g of 10% palladium on carbon was added, and catalytic reduction was performed under heating under reflux for 3 hours. After filtering the reaction solution and removing the catalyst, the Oki solution was concentrated under reduced pressure to obtain a colorless residue. Sephadex LH-20 (40%) was dissolved in 50% aqueous methanol and equilibrated with the same solvent.
0 ml) separated by column chromatography. Silica gel TLC [butanol-acetic acid monohydrate (12
:3:5)) at RfO. Fractions around 13 were collected and the solvent was distilled off under reduced pressure. Dissolve the residue in 5 ml of water. MCI GELCH
It was passed through a P20P (120++ tl) column. After washing with water, it was eluted with 80% water-containing methanol, and the solvent was distilled off under reduced pressure to obtain 138 fflg of colorless powder of compound Nlll.
化合物lV!11 : FD−MS(m/z) : 3
3 2 (M+H) ,NMR(200MHz,D2
0)ppm: 8.73(IH,s,8H),8.1
2(IH,S,2−H),6.45(IH,d, J=
5.7HZ, 1’一H), 4.84 ( IH,
m),4.09 ( 2H, m), 3.7 4 〜
3.9 3 ( 3H, m)化合物N2の合成
化合物Nnlll1■の無水ジメチルホルムアミド3.
5 ml溶液にトリプチルアミン160d,カルボニ
ルジイミダゾール271.6■を加え、室温にて5時間
撹拌した後、メタノール107局を加え30分間撹拌し
た後、トリプチルアンモニウムピロフォスフェート60
31Q;のジメチルホルムアミド8ml溶液を加え室温
にて18時間撹拌した。生成した沈澱を泥過しジメチル
ホルムアミドにて洗浄後、F液と洗液を集め等量のメタ
ノールを加えた後、減圧濃縮乾固した。Compound lV! 11: FD-MS (m/z): 3
3 2 (M+H), NMR (200MHz, D2
0) ppm: 8.73 (IH, s, 8H), 8.1
2 (IH, S, 2-H), 6.45 (IH, d, J=
5.7HZ, 1'-H), 4.84 (IH,
m), 4.09 (2H, m), 3.7 4 ~
3.9 3 (3H, m) Synthesis of compound N2 Anhydrous dimethylformamide of compound Nnllll1■3.
Add triptylammonium 160d and carbonyldiimidazole 271.6cm to a 5ml solution, stir at room temperature for 5 hours, add 107ml of methanol and stir for 30 minutes, then add triptylammonium pyrophosphate 60ml.
8 ml of dimethylformamide solution of 31Q was added and stirred at room temperature for 18 hours. The generated precipitate was filtered and washed with dimethylformamide, then the F solution and the washing solution were collected, an equal amount of methanol was added thereto, and the mixture was concentrated to dryness under reduced pressure.
残渣を水に溶解しDEAE − Sephadex A
−2 5 (炭酸型)50mlに通塔し、トリエテルア
ミン炭酸バッファ一( pH 7. 5 )のリニアグ
ラジエント( 0.0 5→0.4M )各3 7 0
m.lで溶出した後さらに0. 4 Mの同バッファ
ーで溶出した。主生成物溶出画分を集め減圧濃縮乾固し
、メタノールを加え共沸させ脱塩を行った。残渣を水I
Qmlに溶解し水冷下01規定塩酸にてpH2.0に調
製した後、1規定水酸化ナトリウムにてpI{ 7.
0に調製した。そのものを活生炭末5 mlのカラムに
通塔し、2%食塩水、水で洗浄した後、エタノール−1
.5%アンモニア水(1:1)で溶出しシリカゲルTL
C [プタノールー酢酸一水(12:3:5)〕でRf
0.02付近のフラクションを集め減圧濃縮乾固し化合
物l′IIkL2ナトリウム塩を70I1g得た。The residue was dissolved in water and DEAE-Sephadex A
-25 (carbonate type) was passed through the column to 50ml, and a linear gradient (0.05→0.4M) of trietheramine carbonate buffer (pH 7.5) was applied to each 370ml.
m. After elution with 0.1 Elution was performed with 4 M of the same buffer. The main product elution fractions were collected and concentrated to dryness under reduced pressure, and methanol was added and azeotropically distilled for desalting. Water the residue
After dissolving in Qml and adjusting the pH to 2.0 with 01N hydrochloric acid under water cooling, the pH was adjusted to pI{7.0 with 1N sodium hydroxide.
It was adjusted to 0. The product was passed through a column containing 5 ml of activated carbon powder, washed with 2% saline and water, and then washed with ethanol-1.
.. Silica gel TL eluted with 5% ammonia water (1:1)
Rf with C [putanol-acetic acid monohydrate (12:3:5)]
Fractions around 0.02 were collected and concentrated to dryness under reduced pressure to obtain 70I1g of compound l'IIkL2 sodium salt.
化合物NCL 2 : FAB−MS(m/Z) :
4 9 2 (M+H) ,514(M+Na),53
6(M+2Na−H),558(M+3Na−2H),
NMR( 2 0 0 MHZ, D20 ) ppm
: 8.78(IH, S, 8H),8.08(I
H,S,2−H),6.44(IH,29
d, J=5.5Hz, 1’一H )s 4.8 3
( IH, m ),4.25 ( 2H,m),3
.80−4.00 ( 3H,m)実施例2,(化合物
陥3及び克5の合成)■
■
■
化合物聳5
30
化合物NcL3
(1) 化合物の、■の合成
窒素気流下化合物■(オキセタノシンーG(OXT−G
)50mgの無水ジメテルホルムアミド(1.5ml.
)溶液に4−ジメテルアミノビリジン(0521′[l
g)、トリエチルアミン(86.7μ1)、4.4−ジ
メトキシトリテルクロリド(139.3111g)を加
え遮光下、室温にて24時間撹拌する。減圧下、溶媒を
留去し、得られたシロソプをシリカゲルカラムクロマト
グラフィー(20ml,クロロホルムーメタノール50
:1)により分離する。Compound NCL2: FAB-MS (m/Z):
4 9 2 (M+H), 514 (M+Na), 53
6 (M+2Na-H), 558 (M+3Na-2H), NMR (200 MHZ, D20) ppm
: 8.78 (IH, S, 8H), 8.08 (I
H, S, 2-H), 6.44 (IH, 29 d, J=5.5Hz, 1'-H) s 4.8 3
(IH, m), 4.25 (2H, m), 3
.. 80-4.00 (3H, m) Example 2, (Synthesis of Compounds 3 and 5) ■ ■ ■ Compound 5 30 Compound NcL3 (1) Synthesis of Compound (1) Under a nitrogen atmosphere Compound ■ (Oxetanosine-G (OXT-G
) 50 mg of anhydrous dimethylformamide (1.5 ml.
) solution of 4-dimetelaminopyridine (0521'[l
g), triethylamine (86.7 μl), and 4,4-dimethoxytriterchloride (139.3111 g) were added, and the mixture was stirred at room temperature for 24 hours in the dark. The solvent was distilled off under reduced pressure, and the obtained silosop was subjected to silica gel column chromatography (20 ml, chloroform-methanol 50 ml).
: Separate by 1).
シリカゲルTLC [展開溶媒;クロロホルム−メタノ
ール(10:1)]でRf0.51付近のフラクション
を集め、減圧下、溶媒を留去し、化合物■の無色粉末2
7.1mg(16.6%)を得る。Silica gel TLC [Developing solvent: chloroform-methanol (10:1)] was used to collect fractions around Rf 0.51, and the solvent was distilled off under reduced pressure to form a colorless powder of compound 2.
Obtain 7.1 mg (16.6%).
又、Rf 0. 6 4付近のフラクションを集め、減
圧下、溶媒を留去し、化合物■42,0■(258%)
を得る。Also, Rf 0. 6 Fractions around 4 were collected, the solvent was distilled off under reduced pressure, and compound 42.0 (258%) was obtained.
get.
化合物■
MS(FAB) 873(M+H)+NMR(CDC
/L3,ppm) : 7.6 5 ( s, 1.
H )t 7.5〜6.6(m,27H),5.32
(d,IH),4.60(m, IH), 3.7 0
〜3.62(4.s,12H),3.4〜3.2 (m
, 4H), 3.0 1 (m, IH)化合物■
MS(FAB) 8 7 3 ( へ4+
H)+NMR(CD30D, pI)m) : 8.
2 1 ( s, IH), 7.4〜6.6(m,2
6H),5.49(d,IH),4..29(m,IH
),3、76(2s,6H),3.60(2s,6H)
,3.7 〜3.0(m,5H)(2) 化合物■の
合成
化合物■173g、触媒量のN,N−ジメテルアミノビ
リジン、トリエチルアミン331μ1及び無水酢酸19
6μ1を無水アセトニトリル3omlに加え、室温にて
40分撹拌した。反応終了後、溶媒を留去し、残直に水
50mlを加え、クロロホルム(50ml)で2回抽出
した。クロロホルムを留去後、得られたシロノプをカラ
ムクロマトクラフィー(300ml,クロロホルムメタ
ノール40:1)にて単離、精製を行い、化合物■1、
5 1. gを得た。Compound ■ MS (FAB) 873 (M+H) + NMR (CDC
/L3, ppm): 7.6 5 (s, 1.
H)t 7.5-6.6 (m, 27H), 5.32
(d, IH), 4.60 (m, IH), 3.7 0
~3.62 (4.s, 12H), 3.4~3.2 (m
, 4H), 3.0 1 (m, IH) compound ■ MS (FAB) 8 7 3 ( to 4+
H)+NMR (CD30D, pI)m): 8.
2 1 (s, IH), 7.4~6.6 (m, 2
6H), 5.49(d, IH), 4. .. 29 (m, IH
), 3, 76 (2s, 6H), 3.60 (2s, 6H)
, 3.7 ~ 3.0 (m, 5H) (2) Synthesis of compound (1) 173 g of compound (1), a catalytic amount of N,N-dimetelaminopyridine, 331 μ1 of triethylamine, and 19 acetic anhydride
6μ1 was added to 3oml of anhydrous acetonitrile, and the mixture was stirred at room temperature for 40 minutes. After the reaction was completed, the solvent was distilled off, 50 ml of water was added to the residue, and the mixture was extracted twice with chloroform (50 ml). After distilling off the chloroform, the obtained silonop was isolated and purified by column chromatography (300 ml, chloroform methanol 40:1) to obtain compound 1,
5 1. I got g.
TLC(シリカゲル):}{f 0.55(クロロホ
ルムーメタノール−10:1)
MS(FAB): 915(M+H)+NMR( CD
Ct3,ppm): 7. 6 7 ( s, I
H ), 7. 5〜6.6(m,27H),5.8
3(d,IH),4.53(m,IH),3.92(m
,2H),3.77〜3.70(4.s,12H),3
.35(m,2H),3.23(m,IH),2.0
6 ( s, 3H )
(3) 化合物■の合成
化合物■1.51gを80%含水酢酸5Qmlに溶解し
、室温にて5時間撹拌した。反応終了後反応液を濃縮乾
固し、残渣をメタノールから結晶化を行い化合物■を0
5g得た。TLC (silica gel):} {f 0.55 (chloroform-methanol-10:1) MS (FAB): 915 (M+H) + NMR (CD
Ct3, ppm): 7. 6 7 (s, I
H), 7. 5-6.6 (m, 27H), 5.8
3 (d, IH), 4.53 (m, IH), 3.92 (m
, 2H), 3.77-3.70 (4.s, 12H), 3
.. 35 (m, 2H), 3.23 (m, IH), 2.0
6 (s, 3H) (3) Synthesis of Compound (1) 1.51 g of Compound (2) was dissolved in 5Qml of 80% aqueous acetic acid and stirred at room temperature for 5 hours. After the reaction is completed, the reaction solution is concentrated to dryness, and the residue is crystallized from methanol to reduce compound (■) to 0.
I got 5g.
=33
TLC(シリカゲル):Rf O.38(n−ブタ/
−Jl/:酢酸:水−4:1:2)
MS(FAB): 310(M+H)+NMR(DMS
O−d6, I)pm) : 8.2 5 ( s,
I H ),6.5 5 ( bs, IH),
6。15(d,IH),5.28(m,IH),4.
48(m,IH),4.30(m,2H),3.9 〜
3.1(m,3H),2.03(s,3H)(4)fヒ
合物■の合成
20℃冷却下、窒素気流中で化合物■55■のトリエチ
ルリン酸1. 5 3 ml懸濁液にオキシ塩化リン7
6.8μlを加えた後、0゜Cで一夜撹拌した。反応液
を飽和炭酸水素ナ} IJウム水溶液5 mlに加えた
後、クロロホルム5 mlで2回抽出した。この水層に
水150+++lを加え、これをD EA E − S
ephadex A−2 5 (炭酸型)50m7に通
塔し、水50mlで洗浄後、0. 1 Mのトリエチル
アミン炭酸バソ77 17(1+l(pH7.48)
続いて0. 3 Mのトリエチルアミン炭酸バソファ−
1 7 0m.l. ( pH7.3 8 )で溶出し
、主生成物溶出画分を減圧濃縮乾固して、粗化合物■を
71.534
■得た。=33 TLC (silica gel): Rf O. 38 (n-pig/
-Jl/: acetic acid:water -4:1:2) MS (FAB): 310 (M+H) + NMR (DMS
O-d6, I) pm): 8.2 5 (s,
IH), 6.5 5 (bs, IH),
6.15 (d, IH), 5.28 (m, IH), 4.
48 (m, IH), 4.30 (m, 2H), 3.9 ~
3.1 (m, 3H), 2.03 (s, 3H) (4) f Synthesis of compound (2) Triethyl phosphate 1. 5 7 phosphorus oxychloride in 3 ml suspension
After adding 6.8 μl, the mixture was stirred at 0°C overnight. The reaction solution was added to 5 ml of a saturated aqueous solution of sodium bicarbonate, and then extracted twice with 5 ml of chloroform. Add 150 +++ l of water to this aqueous layer, and add this to DEA E-S.
Ephadex A-2 5 (carbonate type) was passed through a 50 m7 column, washed with 50 ml of water, and then 0. 1 M triethylamine carbonate batho 77 17 (1+l (pH 7.48)
Then 0. 3M triethylamine carbonate bathophore
170m. l. (pH 7.38), and the main product eluted fraction was concentrated to dryness under reduced pressure to obtain 71.534 ml of crude compound .
TLC(シリカゲル):Rf O.16(2−プロパ
ノール:濃アンモニア水:水=7:l2)
MS(FAB) : 3 9 0 (M+H)+, 4
1 2 (M+Na)+NMR(D20, I)T
)m) : 8.2 9 ( s, IH),
6.3 0 ( d,IH),4.82(m,IH),
4.34(m,2H),4.09(m,2H),3、9
4(m,IH),2.04(s,3H)
(5) 化合物Nl15の合成
化合物■71111gを水5 mlに溶解後、o℃にて
0.IN水酸化ナトリウム4.67mlを加えて、53
時間撹拌した。反応終了後、0.1規定塩酸にてpH
1. 5に調製し、さらに水50m/を加えた後、■
MCT GEL CHP−20P ( 8 0 ml
)カラムに通塔した。主生成物を水にて溶出し、減圧濃
縮乾固して、化合物1’4544.3■を得た。TLC (silica gel): Rf O. 16 (2-propanol: concentrated ammonia water: water = 7:l2) MS (FAB): 3 9 0 (M+H)+, 4
1 2 (M+Na)+NMR(D20, I)T
) m): 8.2 9 (s, IH),
6.3 0 (d, IH), 4.82 (m, IH),
4.34 (m, 2H), 4.09 (m, 2H), 3, 9
4(m, IH), 2.04(s, 3H) (5) Synthesis of Compound Nl15 Compound ① 71111 g was dissolved in 5 ml of water, and the mixture was heated to 0.0 ml at 0°C. Add 4.67 ml of IN sodium hydroxide to 53
Stir for hours. After the reaction is complete, adjust the pH with 0.1N hydrochloric acid.
1. 5, and after adding 50ml of water, ■ MCT GEL CHP-20P (80ml
) was passed through the column. The main product was eluted with water and concentrated to dryness under reduced pressure to obtain compound 1'4544.3.
TLC(シリカゲル):RfO、13(2−プロパノー
ル:濃アンモニア水:水=7:l2)
MS(FAB): 348(M+H)+NMR(D2
0,pprn) : 8.8 9 ( S,I H
)? 6.4 1( d, IH), 4.8
4 (m, IH), 4.1 0 (m,2H
),3.87(m,2H),3.70(m,IH)(6
) 化合物聳3の合成
化合物j4s50mg、t−プタノール1. 4 ml
,4−モルフオリン48.9μIを水1. 4 mlに
溶解し100°Cにて、ジシクロへキシルカルボジイミ
ド118.4mgのt−プタノール2 ml溶液を30
分間滴下した。反応終了後、t−プタノールを留去した
後、エーテル5 mlを加えて抽出した。TLC (silica gel): RfO, 13 (2-propanol: concentrated ammonia water: water = 7:l2) MS (FAB): 348 (M+H) + NMR (D2
0, pprn): 8.8 9 (S, I H
)? 6.4 1(d, IH), 4.8
4 (m, IH), 4.1 0 (m, 2H
), 3.87 (m, 2H), 3.70 (m, IH) (6
) Synthesis of Compound 3, Compound j4s 50mg, t-butanol 1. 4ml
, 48.9 μl of 4-morpholine was added to 1.0 μl of water. A solution of 118.4 mg of dicyclohexylcarbodiimide in 2 ml of t-butanol was dissolved in 2 ml of t-butanol at 100°C.
dripped for minutes. After the reaction was completed, t-butanol was distilled off, and then 5 ml of ether was added for extraction.
水層を減圧濃縮乾固後、得られた残渣に、トリフテルア
ンモニウムピロフオスフエート1 8 6.6■のジメ
テルスルフオキシド3 ml溶液を加え、37℃にて2
日間撹拌した。反応終了後、水200mlを加え、活性
炭末10mlOカラムに通塔し、2%食塩水、水で洗浄
後、70%含水メタノールで溶出した。溶出液を減圧乾
固後、水200mlに溶解し、DEA E−Sepha
dex A−2 5(炭酸型)50IILlに通塔した
。トリエチルアミン炭酸バッファ−(pH7.3)のリ
ニアグラジエント(0.1M−+0.4M)各500m
lで溶出した後、さらに、0. 4 M }リエチルア
ミン炭酸塩0.5M食塩混合水で溶出した。主生成物溶
出画分を1規定塩酸にてpH 2. 2に調製後、■規
定水酸化ナトリウムにてpH 7. 0に調製した。そ
のものを活性炭末3 mloカラムに通塔し、2%食塩
水、水にて洗浄後、70%含水メタノール1.5%アン
モニア水にて溶出した。溶出液を減圧濃縮乾固して、化
合物Nl13ナトリウム塩を17■得た。After concentrating the aqueous layer to dryness under reduced pressure, 3 ml of a solution of triphterammonium pyrophosphate 1 8 6.6 cm in dimethyl sulfoxide was added to the resulting residue, and the mixture was heated to 37°C for 2 hours.
The mixture was stirred for several days. After the reaction was completed, 200 ml of water was added, and the mixture was passed through a 10 ml O column of activated carbon powder, washed with 2% brine and water, and eluted with 70% aqueous methanol. After drying the eluate under reduced pressure, it was dissolved in 200 ml of water, and DEA E-Sepha
dex A-2 5 (carbonate type) was passed through the column to 50 IIL. Linear gradient of triethylamine carbonate buffer (pH 7.3) (0.1M-+0.4M) 500m each
After elution with 0. Elution was carried out with a water mixture of 4M}ethylamine carbonate and 0.5M sodium chloride. The main product elution fraction was adjusted to pH 2. with 1N hydrochloric acid. After adjusting the pH to 2, adjust the pH to 7. with normal sodium hydroxide. It was adjusted to 0. The product was passed through a 3 mlo activated carbon powder column, washed with 2% saline and water, and eluted with 70% aqueous methanol and 1.5% aqueous ammonia. The eluate was concentrated to dryness under reduced pressure to obtain 17 parts of the sodium salt of compound Nl13.
MS(FD): 508(M+H),576(M+3
Na)+”P−NMR(D20, pI)m) :−
3.2 8 ( d, I P ),−7.49(d,
IP),−18.50(t,IP)”H−NMR(D2
0, ppm) : 8.3 3 ( S, IH),
6.29(d,IH),4.82(m,IH),4.
27(m,2H), 3.8 7 (m, 3H)実施
例3.(化合物IIl&′l6の合成)37
20℃冷却下、窒素気流中で、化合物(2) 7. 7
■のトリエチルリン酸300d懸濁液に、オキシ塩化リ
ン15.1dを加えた後、0℃で、一夜撹拌する。反応
液を飽和炭酸水素ナトリウム水溶液3 mlで中和後、
クロロホルム5 mlで2回抽出する。この水層に水6
0mlを加え、これをDEA E−Sephadex
A−2 5 (炭酸型)12mlに通塔し、水洗浄後、
0.1M曵}リエチルアミン炭酸バッファ−75ml(
pH7.0)に続いて0. 4 Mのトリエチルアミン
炭酸バッファ−75ml(pH7,3)で溶出する。主
生成物溶出画分を集め、水冷下、1規定塩酸にてp}{
2. 0に調製後、1規定水酸化ナトリウムにてpi
{ 7. 0に調製した。そのものを活性炭末2 ml
oカラムに通塔し、2%食塩水、水で洗浄した後、80
%含水メタノールで溶出した。溶出液を濃縮乾固して化
合物(1)ナトリウム塩を3.0■得た。MS (FD): 508 (M+H), 576 (M+3
Na)+”P-NMR(D20, pI)m) :-
3.2 8 (d, I P ), -7.49 (d,
IP), -18.50 (t, IP)"H-NMR (D2
0, ppm): 8.3 3 (S, IH),
6.29 (d, IH), 4.82 (m, IH), 4.
27 (m, 2H), 3.8 7 (m, 3H) Example 3. (Synthesis of Compounds IIl&'l6) 37 Under cooling at 20°C in a nitrogen stream, compound (2) 7. 7
After adding 15.1 d of phosphorus oxychloride to the suspension of 300 d of triethyl phosphoric acid (2), the mixture was stirred at 0° C. overnight. After neutralizing the reaction solution with 3 ml of saturated aqueous sodium hydrogen carbonate solution,
Extract twice with 5 ml of chloroform. 6 water in this water layer
Add 0ml and add this to DEA E-Sephadex.
Pour into 12 ml of A-2 5 (carbonate type) and wash with water,
0.1M ethylamine carbonate buffer - 75ml (
pH 7.0) followed by 0. Elute with 75 ml of 4 M triethylamine carbonate buffer (pH 7.3). The main product elution fractions were collected and diluted with 1N hydrochloric acid under water cooling.
2. After adjusting to 0, pi with 1N sodium hydroxide.
{7. It was adjusted to 0. 2 ml of activated carbon powder
After passing through the o column and washing with 2% saline and water,
Elution was performed with % aqueous methanol. The eluate was concentrated to dryness to obtain 3.0 ml of compound (1) sodium salt.
UVmax (nm) 2 5 7 (0.01 N
HCI )MS(FAB)302(M+H),324(
M+Na)+NMR(D20, ppm) 8.9 2
( S, IH), 8.1 8 ( Sj38
IH),6.67(t,IH),5.02(m,IH)
,3.94 (m, 21−1), 3.4〜3.
1 (m, 2H).本化合物が抗ウィルス剤として
用いられる場合は、単独または賦形剤あるいは担体と混
合して注射剤、経口剤または坐剤などとして投与される
。賦形剤及び担体としては薬剤学的に許容されるものが
選ばれ、その種類及び組成は投与経路や投与方法によっ
て決まる。例えば液状担体として水、アルコールもしく
は大豆油、ピーナツ油、ゴム油、ミネラル油等の動植物
油、または合成油が用いられる。固体担体としてマルト
ース、シュクロースなどの糖類、アミノ酸類ヒドロキシ
プロビルセルロースなどセルロース誘導体、ステアリン
酸マグネシウムなどの有機酸塩などが使用される。注射
剤の場合一般に生埋食塩水、各種緩衝液、グルコース、
イノシトール、マンニトール等の糖類溶液、エテレング
リコール、ボリエチレングリコール等のグリコール類が
望ましい。また、イノシトール、マンニトール、クルコ
ース、マンノース、マルトース、シュクロース等の糖類
、フエニルアラニン等のアミノ酸類の賦形剤と共に凍結
乾燥製剤とし、それを投与時に注射用の適当な溶剤、例
えば滅菌水、生埋食塩水、ブドウ糖液、電解質溶液、ア
ミノ酸等の静脈投与用液体に溶解して投与することもで
きる。UVmax (nm) 2 5 7 (0.01 N
HCI) MS (FAB) 302 (M+H), 324 (
M+Na)+NMR(D20, ppm) 8.9 2
(S, IH), 8.1 8 (Sj38 IH), 6.67 (t, IH), 5.02 (m, IH)
, 3.94 (m, 21-1), 3.4-3.
1 (m, 2H). When the present compound is used as an antiviral agent, it is administered alone or mixed with an excipient or carrier as an injection, oral preparation, or suppository. Pharmaceutically acceptable excipients and carriers are selected, and their types and compositions are determined by the route and method of administration. For example, water, alcohol, animal or vegetable oils such as soybean oil, peanut oil, rubber oil, mineral oil, or synthetic oils are used as liquid carriers. As solid carriers, sugars such as maltose and sucrose, cellulose derivatives such as amino acids hydroxypropyl cellulose, organic acid salts such as magnesium stearate, etc. are used. Injectables generally contain saline, various buffer solutions, glucose,
Saccharide solutions such as inositol and mannitol, and glycols such as ethylene glycol and polyethylene glycol are preferable. In addition, it is made into a lyophilized preparation together with excipients such as sugars such as inositol, mannitol, glucose, mannose, maltose, and sucrose, and amino acids such as phenylalanine, and is then administered with a suitable solvent for injection, such as sterile water, It can also be administered by dissolving it in a fluid for intravenous administration such as saline solution, glucose solution, electrolyte solution, amino acid, or the like.
製剤中における本化合物の含量は製剤により種々異なる
が、通常01〜100重量%好ましくは1〜90重量%
である。例えば、注射液の場合には、通常01〜5重量
%の本化合物を含むようにすることがよい。経口投与す
る場合には、前記固体担体もしくは液状担体とともに錠
剤、カプセル剤、粉剤、顆粒剤、液剤、ドライシロップ
剤等の形態で用いられる。カプセル、錠剤、顆粒、粉剤
の場合は一般に本化合物の含量は約3〜100重量%好
ましくは5〜90重量%であり、残部は担体である。The content of this compound in the formulation varies depending on the formulation, but is usually 01 to 100% by weight, preferably 1 to 90% by weight.
It is. For example, in the case of an injection solution, it is usually preferable to contain the present compound in an amount of 01 to 5% by weight. When administered orally, it is used in the form of tablets, capsules, powders, granules, liquids, dry syrups, etc. together with the solid carrier or liquid carrier. In the case of capsules, tablets, granules and powders, the content of the compound is generally from about 3 to 100% by weight, preferably from 5 to 90% by weight, with the remainder being carrier.
投与量は、患者の年齢、体重、症状、治療目的等により
決定されるが、治療量は一般に非経口投与で1〜3 0
0 mg/kg・日、経口投与で5〜500■/ k
g・日である。The dose is determined depending on the patient's age, weight, symptoms, therapeutic purpose, etc., but the therapeutic dose is generally 1 to 30 mg for parenteral administration.
0 mg/kg/day, 5-500■/k by oral administration
It is g day.
本化合物は低毒性であり、またいずれの化合物も連続投
与による毒性の蓄積性が小さいことが特徴的である。本
化合物をマウス腹腔内にsooq/kgの投与量で1回
投与しても何ら毒性の徴候はみられなかった。The present compounds have low toxicity, and each compound is characterized by low toxicity accumulation upon continuous administration. No signs of toxicity were observed when this compound was intraperitoneally administered once to mice at a dose of sooq/kg.
次に本発明の製剤例を示す。Next, examples of formulations of the present invention will be shown.
製剤例1
化合物M1 30重量部(以下特に断らないかぎり重量
部を示す。)に対し精製水を加え全量を2000部とし
てこれを溶解後ミリポアフィルターGSタイプを用いて
除菌済遇する。この涙液2gを10mlのバイアル瓶に
とり凍結乾燥し、1バイアルに化合物1’thl3(l
lgを含む凍結乾燥注射剤を得た。Formulation Example 1 Purified water was added to 30 parts by weight of Compound M1 (hereinafter, parts by weight are shown unless otherwise specified) to make a total volume of 2000 parts, and the solution was sterilized using a Millipore filter GS type. 2 g of this tear fluid was placed in a 10 ml vial, freeze-dried, and 1 vial was filled with compound 1'thl3 (l
A lyophilized injection containing lg was obtained.
製剤例2,
顆粒剤
化合物N[L5を50部、乳糖600部、結晶セルロー
ス330部及びヒドロキシプロビルセルロース20部を
よく混和し、ロール型圧縮機41
(ローラーコンパクタ−9)を用いて圧縮し、破砕して
16メッシュと60メソシュの間に入るよう篩過し、顆
粒とした。Formulation Example 2, Granule Compound N [50 parts of L5, 600 parts of lactose, 330 parts of crystalline cellulose and 20 parts of hydroxypropyl cellulose were mixed well and compressed using a roll compactor 41 (roller compactor 9). The mixture was crushed and passed through a sieve between 16 mesh and 60 mesh to form granules.
製剤例3,
錠剤
化合物M5を30部、結晶乳糖120部、結晶セルロー
ス147部及びステアリン酸マグネシウム3部をV型混
合機で打錠し、1錠300■の錠剤を得た。Formulation Example 3 Tablets 30 parts of Compound M5, 120 parts of crystalline lactose, 147 parts of crystalline cellulose and 3 parts of magnesium stearate were compressed using a V-type mixer to obtain 300 square tablets.
次に本化合物の抗サイトメガ口ウイノレス作用及び抗H
IV作用、B型肝炎ウイルス(HBV)のDNAポリメ
ラーゼに対する阻害活性を試験例により具体例により具
体的に説明する。Next, we will discuss the anti-cytomegalytic action and anti-H
The IV action and inhibitory activity against DNA polymerase of hepatitis B virus (HBV) will be explained in detail using test examples.
試験例2
抗サイトメガロウイルス活性は人胎児線維芽細胞の単層
を有する35mmディシュ( dish ) にサイ
トメガロウイルス(A0169株)1 0 0P F
U ( Plaque Forming TJnit
)を感染させ、1時間吸着後、各濃度の本化合物を含む
培地〔0.5%アガロース( agarose )、2
%牛胎児血清( fetal42
calf serum) )で重層し、37℃、5%(
v/v )の炭酸ガスフ卵器中にて10日間培養した
後プラーク( Plaque )形成を測定し、50%
抑制値( EDso )を表1に示した。Test Example 2 Anti-cytomegalovirus activity was determined by injecting 100P of cytomegalovirus (strain A0169) into a 35 mm dish containing a monolayer of human fetal fibroblasts.
U (Plaque Forming TJnit
), and after adsorption for 1 hour, a medium containing each concentration of this compound [0.5% agarose, 2
% fetal bovine serum (fetal42 calf serum)) and incubated at 37°C with 5% (fetal 42% calf serum).
Plaque formation was measured after culturing for 10 days in a carbon dioxide incubator (v/v), and 50%
The inhibition values (EDso) are shown in Table 1.
試験例3
抗HI V ( Human Immunodefic
iency Virus )活惺24穴トレー[MT−
4細胞約10万個/ml入れ、さらに本発明化合物の一
定量を含む溶液100aを力[え、37℃、5%(v/
v) 炭酸ガスフ卵器中にて2時間培養した後、F■
■V103〜104感染単位を力[え、4日間培養後、
培養液の一部をスライドグラスに塗抹し、アセトン固定
をした後、蛍光抗体法にてウイルス抗原の発現をみた。Test Example 3 Anti-HIV (Human Immunodefic
ency Virus) Active 24-hole tray [MT-
Approximately 100,000 cells/ml of 4 cells were added thereto, and a solution 100a containing a certain amount of the compound of the present invention was added to the solution at 37°C and 5% (v/ml).
v) After culturing for 2 hours in a carbon dioxide gas incubator, F■
■ Collect V103-104 infectious units [after 4 days of culture,
A portion of the culture solution was smeared onto a slide glass, fixed with acetone, and then the expression of the viral antigen was observed using a fluorescent antibody method.
なお、蛍光抗体法の一次抗体にはエイズ患者の槓清、二
次抗体にはFITCをラベルした抗ヒトIgGを用いた
。In the fluorescent antibody method, serum serum from an AIDS patient was used as the primary antibody, and FITC-labeled anti-human IgG was used as the secondary antibody.
本発明化合物のHIVK対する活性
試験例4
化合物IlI&l13(OXT−Gトリリン酸エステル
〕のHBV内在性DNAポリメラーゼに対する阻害活性
測定法
1. HBVコア粒子の部分精製
}{B611細胞を抽出用緩衝液(利にてホモジナイズ
した後、遠心上清( 14.OOOrpm, O℃、3
0分)を304サンカロース含有抽出用緩衝液に重層し
、超遠心( 35000rpm、4℃、18R間) L
テWiコア粒子沈殿を得た。この粗コア粒子を抽出用
緩衝液に懸濁し、塩化セシウム密度勾配超遠心法にて精
製し、密度が1,30〜1. 35 g/mlの部分精
製コア粒子を得た。Activity test example 4 of compounds of the present invention against HIVK Method for measuring the inhibitory activity of compound IlI&l13 (OXT-G triphosphate ester) against HBV endogenous DNA polymerase 1. Partial purification of HBV core particles After homogenizing at
0 min) over 304 Suncarose-containing extraction buffer and ultracentrifuged (35000 rpm, 4°C, 18R) L
A TeWi core particle precipitate was obtained. The coarse core particles were suspended in an extraction buffer and purified by cesium chloride density gradient ultracentrifugation to a density of 1.30 to 1. Partially purified core particles of 35 g/ml were obtained.
米抽出用緩衝液: ( 0.1幅トリトンXIOO/0
.1壬2−メルカブトエタノー#/1mM PMSF)
を含む:10mM}リス・塩酸( pH 7. 4 )
、1mMEDTA,10mM塩化ナトリウム2. H
BV内在性ポリメラーゼ活性測定法部分精製コア粒子を
反応溶液(達)に加え、種々の濃度の化合物N5存在下
、37℃で2時間インキユベートした後、dCTPを最
終濃度1mMになるように加え、さらに1時間37℃で
インキユベートした。インキベート後、protein
ase K、SDS,EDTA,tRNAをそれぞれの
最終濃度が0.5mg/ml, 1%、1 0 mM,
2 0 0 μg/mlになるように加え、45℃で
2時間インキーベートした。その後、フェノール・クロ
ロフォルム抽出、エタノール沈澱法にてHBV−DNA
を精製し、1.5%アガロースで電気泳動し、オートラ
ジオグラフィーによってHBV 一DNA に取り込
まれた放射能量を測定した。オートラジオグラムをデン
シトメーターでスキャンニングして化合物30HBV−
DNAポリメラーゼ忙対する阻害活性を算出した。Rice extraction buffer: (0.1 width Triton XIOO/0
.. 1 2-Merkabutoethanol #/1mM PMSF)
Contains: 10mM} Liss hydrochloric acid (pH 7.4)
, 1mM EDTA, 10mM sodium chloride2. H
BV endogenous polymerase activity measurement method Partially purified core particles were added to the reaction solution(s) and incubated at 37°C for 2 hours in the presence of various concentrations of compound N5, then dCTP was added to a final concentration of 1 mM, and Incubate for 1 hour at 37°C. After incubation, protein
ase K, SDS, EDTA, and tRNA at final concentrations of 0.5 mg/ml, 1%, 10 mM,
It was added at a concentration of 200 μg/ml and incubated at 45° C. for 2 hours. After that, HBV-DNA was extracted by phenol/chloroform extraction and ethanol precipitation.
was purified, electrophoresed on 1.5% agarose, and the amount of radioactivity incorporated into HBV-DNA was measured by autoradiography. Scanning the autoradiogram with a densitometer revealed that compound 30HBV-
The inhibitory activity against DNA polymerase activity was calculated.
一45ー
米反応溶液:
50mM}リス・塩酸(pH7.4),30mM塩化マ
グネシウム、0,IM塩化アンモニウム0.2% 2−
メルカブトエタノール、05%トリトンXIOO、3
7 0 KBqα−32pdCTP各200μMdAT
P (IGTP dTTPを含む
結
果
化合物rb3(μM)
阻害率(%)
0
100
200
400
00
50.7
88,8
96.8
効果
以上から明らかなように、本化合物は、浸れた抗ウイル
ス作用を示す。特に化合物1’l!11及び聳6は優れ
た抗HIV作用を、化合物陥5はサイトメガロウイルス
、B型肝炎ウイルス及ヒヘルペスウイルスなどのDNA
ウイルスに優れた抗ウイルス作用を示す。145-Rice reaction solution: 50mM} Liss hydrochloric acid (pH 7.4), 30mM magnesium chloride, 0, IM ammonium chloride 0.2% 2-
Mercabutethanol, 05% Triton XIOO, 3
7 0 KBqα-32pdCTP each 200 μM dAT
Result compound rb3 (μM) containing P (IGTP dTTP) Inhibition rate (%) 0 100 200 400 00 50.7 88,8 96.8 Effect As is clear from the above, this compound exhibits strong antiviral activity. In particular, compounds 1'l!11 and 聳6 have excellent anti-HIV effects, and compound 5 has an excellent anti-HIV effect on the DNA of cytomegalovirus, hepatitis B virus, herpesvirus, etc.
Shows excellent antiviral activity against viruses.
また本化合物のトリリン酸エステル類はウ46
イルス増殖における酵素の阻害作用を示し、例えば化合
物克2はHIVのリバーストランスクリプターゼ阻害作
用を、化合物陥3は上記DNAウイルスのDNAポリメ
ラーゼを阻害する。Furthermore, the triphosphates of the present compound exhibit an inhibitory effect on enzymes in the proliferation of the virus. For example, Compound K2 inhibits the reverse transcriptase of HIV, and Compound K3 inhibits the DNA polymerase of the above-mentioned DNA virus.
Claims (4)
キシ基又はヒドロキシメチル基、Bはプリン塩基の残基
を示す。) で表わされるオキセタノシン類のリン酸エステル及びそ
の薬理学上許容される塩。(1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R_1 is a phosphate ester residue, X is hydrogen, a hydroxy group or a hydroxymethyl group, and B is a purine base residue. ) Phosphate esters of oxetanosines represented by: and pharmacologically acceptable salts thereof.
キシ基又はヒドロキシメチル基、Bはプリン塩基の残基
を示す。) で表わされるオキセタノシン類のリン酸エステル又はそ
の薬理学上許容される塩を有効成分とする抗ウィルス剤
。(2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R_1 is a phosphate ester residue, X is hydrogen, a hydroxy group or a hydroxymethyl group, and B is a purine base residue. ) An antiviral agent containing as an active ingredient a phosphate ester of oxetanosine or a pharmacologically acceptable salt thereof.
−P_3)(P_3は水酸基の保護基)、Bはプリン塩
基の残基を示す。〕 で示されるオキセタノシン類に、下記一般式▲数式、化
学式、表等があります▼ (式中Ra、RbおよびRcは水素原子または低級アル
キル基を示す。) で示される低級アルキルリン酸の存在下に、オキシ塩化
リンを反応させ、Xが−O−P_3のときは次いで保護
基を除去することを特徴とする ▲数式、化学式、表等があります▼( I a) (式中Xは水素、ヒドロキシ基又はヒドロ キシメチル基、Bは前記と同じ意味を示す。)で表わさ
れるオキセタノシン類のモノリン酸エステルの製造法(3) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula (X' is hydrogen, -O-P_3 or -CH_2O
-P_3) (P_3 is a hydroxyl protecting group), B represents a purine base residue. ] Oxetanosines represented by the following general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, Ra, Rb and Rc represent a hydrogen atom or a lower alkyl group.) In the presence of a lower alkyl phosphoric acid represented by There are ▲numerical formulas, chemical formulas, tables, etc.▼ (I a) (in the formula, X is hydrogen, A method for producing a monophosphoric acid ester of oxetanosine represented by a hydroxy group or a hydroxymethyl group (B has the same meaning as above)
、トリアルキルアミンの存在下にカルボニルジイミダゾ
ールおよびトリアルキルアンモニウムピロフォスフェー
トを反応させることを特徴とする ▲数式、化学式、表等があります▼( I b) (式中XおよびBは前記と同じ意味を示す。)で示され
るオキセタノシン類のトリリン酸エステルの製造法(4) Monophosphate ester of oxetanosine represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (Ia) (In the formula, X represents hydrogen or a hydroxymethyl group, and B represents the residue of a purine base.) There are ▲mathematical formulas, chemical formulas, tables, etc.▼ (I b) (in the formula, X and B are as above A method for producing triphosphate esters of oxetanosine represented by (same meaning)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2092341A JPH03218392A (en) | 1989-04-10 | 1990-04-09 | Phosphate ester of oxetanocin, its use and its production |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP8796189 | 1989-04-10 | ||
JP1-87961 | 1989-04-10 | ||
JP1-296232 | 1989-11-16 | ||
JP1-297443 | 1989-11-17 | ||
JP2092341A JPH03218392A (en) | 1989-04-10 | 1990-04-09 | Phosphate ester of oxetanocin, its use and its production |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH03218392A true JPH03218392A (en) | 1991-09-25 |
Family
ID=26429181
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2092341A Pending JPH03218392A (en) | 1989-04-10 | 1990-04-09 | Phosphate ester of oxetanocin, its use and its production |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH03218392A (en) |
-
1990
- 1990-04-09 JP JP2092341A patent/JPH03218392A/en active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4083691B2 (en) | Antiretroviral enantiomeric nucleotide analogs | |
EP0646125B1 (en) | 1,5-anhydrohexitol nucleoside analogues and pharmaceutical use thereof | |
US6573378B1 (en) | Antiviral guanine derivatives | |
AU614082B2 (en) | Nucleosides and nucleoside analogues, pharmaceutical composition and processes for the preparation of the compounds | |
EP0145739B1 (en) | Novel antiviral agents | |
CN103052646A (en) | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs | |
HU195657B (en) | Process for production of carbocyclic pirin nucleorids and medical compounds containing them | |
CA2093020A1 (en) | Nucleoside derivatives | |
JPH0822866B2 (en) | N-phosphonylmethoxyalkyl derivatives of purine and pyrimidine bases | |
EP0632048A1 (en) | Phosphonate-nucleotide ester derivatives | |
JPH0729979B2 (en) | Antiviral compound | |
JPH0725760B2 (en) | Antiviral compound | |
JPS63297381A (en) | 9-(2-(hydroxymethyl)cycloalkylmethyl)guanines | |
EP0138656B1 (en) | Cyclic pyrophosphates of purine and pyrimidine acyclonucleosides, their preparation and their application in anti-viral compositions | |
Uenishi et al. | Syntheses and antitumor activities of D-and L-2′-deoxy-4′-thio pyrimidine nucleosides | |
Yoo et al. | Synthesis of novel (2R, 4R)-and (2S, 4S)-iso dideoxynucleosides with exocyclic methylene as potential antiviral agents | |
EP0219838A2 (en) | Carbocyclic purine nucleosides, their production and use | |
JP3172801B2 (en) | Chiral 2- (phosphonomethoxy) propylguanine as antiviral agent | |
Bhushan et al. | Synthesis of conformationally restricted 2′, 3′-exo-Methylene carbocyclic nucleosides built on a bicyclo [3.1. 0] hexane template | |
JP2001504468A (en) | L-β-dioxolanuridine analogs and methods for treating and preventing viral infection | |
JPH03218392A (en) | Phosphate ester of oxetanocin, its use and its production | |
CS270235B2 (en) | Method of carbocyclic purine nicleotides preparation | |
US5179084A (en) | Antiviral phosphoric acid esters of oxetanocins | |
EP0416605B1 (en) | Novel oxetanocin derivatives and their salts as well as use thereof | |
EP0270885A1 (en) | Synthesis of purin-9-ylalkylenoxymethyl phosphonic acids |