JPH04321687A - 6'-o-alkylneplanocin a, its production and use - Google Patents
6'-o-alkylneplanocin a, its production and useInfo
- Publication number
- JPH04321687A JPH04321687A JP3112271A JP11227191A JPH04321687A JP H04321687 A JPH04321687 A JP H04321687A JP 3112271 A JP3112271 A JP 3112271A JP 11227191 A JP11227191 A JP 11227191A JP H04321687 A JPH04321687 A JP H04321687A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- compound
- alkylneplanocin
- chemical
- 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.)
- Withdrawn
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 239000003443 antiviral agent Substances 0.000 claims abstract description 8
- 125000003277 amino group Chemical group 0.000 claims abstract description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 10
- ZOGIBYIZRGKFQR-VDAHYXPESA-N 9-[(1r,4r,5s)-4,5-dihydroxy-3-(hydroxymethyl)cyclopent-2-en-1-yl]-3h-purin-6-one Chemical compound O[C@@H]1[C@H](O)C(CO)=C[C@H]1N1C(NC=NC2=O)=C2N=C1 ZOGIBYIZRGKFQR-VDAHYXPESA-N 0.000 claims description 7
- ZOGIBYIZRGKFQR-UHFFFAOYSA-N Neplanocin D Natural products OC1C(O)C(CO)=CC1N1C(NC=NC2=O)=C2N=C1 ZOGIBYIZRGKFQR-UHFFFAOYSA-N 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000005804 alkylation reaction Methods 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 230000029936 alkylation Effects 0.000 claims 1
- 230000002140 halogenating effect Effects 0.000 claims 1
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 4
- 230000003013 cytotoxicity Effects 0.000 abstract description 4
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 229910052801 chlorine Inorganic materials 0.000 abstract 1
- 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 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 31
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 11
- XUGWUUDOWNZAGW-UHFFFAOYSA-N neplanocin A Natural products C1=NC=2C(N)=NC=NC=2N1C1C=C(CO)C(O)C1O XUGWUUDOWNZAGW-UHFFFAOYSA-N 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- XUGWUUDOWNZAGW-VDAHYXPESA-N (1s,2r,5r)-5-(6-aminopurin-9-yl)-3-(hydroxymethyl)cyclopent-3-ene-1,2-diol Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1C=C(CO)[C@@H](O)[C@H]1O XUGWUUDOWNZAGW-VDAHYXPESA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 7
- 102000055025 Adenosine deaminases Human genes 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- -1 isopropylidene, benzylidene Chemical group 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N Vilsmeier-Haack reagent Natural products CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 229940105329 carboxymethylcellulose Drugs 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000012320 chlorinating reagent Substances 0.000 description 2
- 230000000120 cytopathologic effect Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012156 elution solvent Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001341 hydroxy propyl starch Substances 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- HLVFKOKELQSXIQ-UHFFFAOYSA-N 1-bromo-2-methylpropane Chemical compound CC(C)CBr HLVFKOKELQSXIQ-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 1
- ANGGPYSFTXVERY-UHFFFAOYSA-N 2-iodo-2-methylpropane Chemical group CC(C)(C)I ANGGPYSFTXVERY-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 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
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 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 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-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
- 229920000084 Gum arabic Polymers 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 229930182507 Neplanocin Natural products 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 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 1
- 241000712908 Tacaribe mammarenavirus Species 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical compound [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004660 morphological change Effects 0.000 description 1
- FDRVTDDJHPPAGK-UHFFFAOYSA-N n,n-dimethylformamide;thionyl dichloride Chemical compound ClS(Cl)=O.CN(C)C=O FDRVTDDJHPPAGK-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 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
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002798 polar solvent Substances 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
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- RKSOPLXZQNSWAS-UHFFFAOYSA-N tert-butyl bromide Chemical compound CC(C)(C)Br RKSOPLXZQNSWAS-UHFFFAOYSA-N 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
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 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
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【発明の詳細な説明】[Detailed description of the invention]
【０００１】0001
【産業上の利用分野】本発明は、新規なネプラノシンＡ
の誘導体に関し、更に詳細には、医薬、特に抗ウイルス
剤として有用なネプラノシンＡの誘導体、その製法およ
びその用途に関する。[Industrial Application Field] The present invention provides novel neplanocin A
The present invention relates to derivatives of neplanocin A, and more particularly, to derivatives of neplanocin A useful as medicines, particularly antiviral agents, methods for producing the same, and uses thereof.
【０００２】0002
【従来の技術およびその課題】ネプラノシンＡは、微生
物である、アンプラリエーラ・スピーシーズ（Ａｍｐｕ
ｌｌａｒｉｅｌｌａ ｓｐ．）Ａ１１０７９の産生する
、次の式（ＶＩＩＩ）、[Prior Art and its Problems] Neplanocin A is produced from the microorganism Ampulariella sp.
llariella sp. ) A11079 produces the following formula (VIII),
【化１３】
で表される制癌作用および植物病原菌糸状菌成育阻害作
用を有する抗生物質であるが（特開昭 ５４−１５４７
９２号）、近年、このものは更に抗ウイルス作用をも有
することが見出され（ ＡＮＴＩＭＩＣＲＯＢＩＡＬ
ＡＧＥＮＴＳ ＡＮＤ ＣＨＥＭＯＴＨＥＲＡＰＹ，
Ｊｕｌｙ１９８５， Ｐ．８４−８９）、抗ウイルス剤
としての利用も検討されている。It is an antibiotic that has an anticancer effect and an inhibitory effect on the growth of plant-pathogenic mycelium expressed by the formula (Japanese Patent Application Laid-open No. 54-1547
92), and in recent years it has been discovered that this substance also has antiviral effects (ANTIMICROBIAL).
AGENT AND CHEMOTHERAPY,
July1985, P. 84-89), and its use as an antiviral agent is also being considered.
【０００３】しかしながら、ネプラノシンＡは、生体内
に広く存在するアデノシンデアミナーゼの作用を受けや
すく、すみやかに不活性化されるという欠点があり、医
薬として利用する上での問題となっていた。また、ネプ
ラノシンＡの細胞毒性の高さも医薬として使用する場合
無視しえない問題であった。[0003] However, neplanocin A has the disadvantage that it is susceptible to the action of adenosine deaminase, which is widely present in living organisms, and is quickly inactivated, which has been a problem in its use as a medicine. Furthermore, the high cytotoxicity of neplanocin A was also a problem that could not be ignored when used as a medicine.
【０００４】0004
【課題を解決するための手段】本発明者らは、ネプラノ
シンＡの有する前記課題を解決し、優れた抗ウイルス剤
を得べく鋭意研究を行なった結果、ネプラノシンＡの６
位水酸基をアルキルで修飾することにより、その抗ウイ
ルス作用を低下させずに、アデノシンデアミナーゼに対
する抵抗性を向上させることができることおよび６位水
酸基がアルキル修飾されたネプラノシンＡは細胞毒性も
低いことを見出し本発明を完成した。[Means for Solving the Problems] The present inventors have conducted intensive research to solve the above-mentioned problems of neplanocin A and obtain an excellent antiviral agent.
It was discovered that resistance to adenosine deaminase can be improved by modifying the hydroxyl group at the 6-position with an alkyl group without reducing its antiviral effect, and that neplanocin A in which the hydroxyl group at the 6-position is modified with an alkyl group has low cytotoxicity. The invention has been completed.
【０００５】すなわち本発明の第一の目的は、次の式（
Ｉ）That is, the first object of the present invention is to solve the following equation (
I)
【化１４】
（式中、Ｒは低級アルキル基を示す）で表わされる６’
−Ｏ−アルキルネプラノシンＡおよびその塩を提供する
ものである。また、本発明の他の目的は、６’−Ｏ−ア
ルキルネプラノシンＡの製造法を提供するものである。
更に、本発明の他の目的は、６’−Ｏ−アルキルネプラ
ノシンＡを有効成分として含有する抗ウイルス剤を提供
するものである。6' represented by [Formula 14] (wherein R represents a lower alkyl group)
-O-alkylneplanocin A and salts thereof are provided. Another object of the present invention is to provide a method for producing 6'-O-alkylneplanocin A. Furthermore, another object of the present invention is to provide an antiviral agent containing 6'-O-alkylneplanocin A as an active ingredient.
【０００６】本発明の６’−Ｏ−アルキルネプラノシン
Ａ（Ｉ）における低級アルキル基としては、炭素数１〜
４程度の直鎖または分岐鎖のアルキル基が挙げられ、具
体的にはメチル基、エチル基、ｎ−プロピル基、ｉ−プ
ロピル基、ｎ−ブチル基、ｉ−ブチル基、ｔｅｒｔ−ブ
チル基等が挙げられる。The lower alkyl group in 6'-O-alkylneplanocin A (I) of the present invention has 1 to 1 carbon atoms.
Examples include straight chain or branched alkyl groups of about 4, specifically methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, tert-butyl group, etc. can be mentioned.
【０００７】本発明の６’−Ｏ−アルキルネプラノシン
Ａ（Ｉ）は、例えば次の式に従い、ネプラノシンＤ（Ｉ
Ｉ）の２’、３’および６’位の水酸基を保護して保護
ネプラノシンＤ（ＩＩＩ）とした後、これにクロル化剤
を作用させてクロル体（ＩＶ）とし、再度当該クロル体
（ＩＶ）の２’および３’位を保護して化合物（Ｖ）と
した後、その６’位をアルキル化剤でアルキル化して化
合物（ＶＩ）を得、更にその６位クロル基をアミノ基に
変換し、水酸基保護基を除去することにより製造される
。The 6'-O-alkyl neplanocin A (I) of the present invention can be prepared, for example, from neplanocin D (I) according to the following formula.
After protecting the hydroxyl groups at the 2', 3' and 6' positions of I) to obtain protected neplanocin D (III), this was treated with a chlorinating agent to form the chloride (IV), and then the chloride (IV) was obtained again. ) is protected at the 2' and 3' positions to give compound (V), and then the 6' position is alkylated with an alkylating agent to obtain compound (VI), and the 6-position chloro group is further converted to an amino group. It is produced by removing the hydroxyl protecting group.
【化１５】
（式中、Ｒ１およびＲ２は各々単独でまたは一緒になっ
て水酸基の保護基を、Ｒは前記した意味を有する）[Image Omitted] (In the formula, R1 and R2 each represent a hydroxyl-protecting group alone or together, and R has the meaning described above.)
【０
００８】上記方法における、ネプラノシンＤ（ＩＩ）の
水酸基の保護は特に限定されるものではなく、通常、糖
、核酸化学で用いる方法によって行なうことができる。
より具体的には、ネプラノシンＤ（ＩＩ）の水酸基は、
例えば、アセチル基等で保護することが好ましく、大過
剰の有機塩基、例えば、ピリジン、トリエチルアミン、
ジメチルアミノピリジン中、３〜１０当量の無水酢酸を
、０℃〜室温で、１〜３時間作用させることにより行な
われる。0
[008] In the above method, the protection of the hydroxyl group of neplanocin D (II) is not particularly limited, and can be carried out by a method generally used in sugar and nucleic acid chemistry. More specifically, the hydroxyl group of neplanocin D (II) is
For example, it is preferable to protect with an acetyl group, etc., and use a large excess of an organic base, such as pyridine, triethylamine,
This is carried out by reacting 3 to 10 equivalents of acetic anhydride in dimethylaminopyridine at 0° C. to room temperature for 1 to 3 hours.
【０００９】保護ネプラノシンＤ（ＩＩＩ）のクロル化
は、例えば、クロロホルム、エーテル、炭化水素等の不
活性溶媒中、塩化チオニル−ジメチルホルムアミド（Ｄ
ＭＦ）（Ｖｉｌｓｍｅｉｅｒ−Ｈａａｃｋ試薬）、オキ
シ塩化リン等のクロル化剤を、還流条件下、２〜５時間
作用させ、次いで、メタノール等の溶媒中、０℃〜室温
で、３〜１０時間アンモニアを作用させることにより行
なわれる。Chlorination of protected neplanocin D (III) can be carried out, for example, by chlorination of thionyl chloride-dimethylformamide (D
MF) (Vilsmeier-Haack reagent), a chlorinating agent such as phosphorus oxychloride is allowed to react for 2 to 5 hours under reflux conditions, and then ammonia is reacted for 3 to 10 hours at 0°C to room temperature in a solvent such as methanol. It is done by making it act.
【００１０】上記のクロル化反応で得られたクロル体（
ＩＶ）は、再度その２’および３’位が保護されて化合
物（Ｖ）に導かれ、つづいて更にアルキル化により化合
物（ＶＩ）とされる。[0010] The chloride obtained by the above chlorination reaction (
IV) is again protected at its 2' and 3' positions to give compound (V), and then further alkylated to give compound (VI).
【００１１】このクロル体（ＩＶ）の水酸基の保護は特
に限定されるものではないが、２’および３’位の水酸
基を同時に保護可能なイソプロピリデン等、ベンジリデ
ン、エトキシメチレン基などの保護基を用いることが好
ましい。具体的には、０．５〜５当量程度のｐ−トルエ
ンスルホン酸、硫酸、トリフルオロ酢酸等の強酸の存在
下、アセトン、２，２−ジメトキシプロパン等を用いて
保護反応が行なわれる。Protection of the hydroxyl group of this chloride (IV) is not particularly limited, but protective groups such as isopropylidene, benzylidene, and ethoxymethylene groups that can simultaneously protect the 2' and 3' hydroxyl groups are used. It is preferable to use Specifically, the protection reaction is carried out using acetone, 2,2-dimethoxypropane, etc. in the presence of about 0.5 to 5 equivalents of a strong acid such as p-toluenesulfonic acid, sulfuric acid, or trifluoroacetic acid.
【００１２】また、化合物（Ｖ）のアルキル化反応は、
ＤＭＦ、ＤＭＳＯ、ＤＭＡ等の極性溶媒中、ヨウ化メチ
ル、ヨウ化エチル、ヨウ化ｎ−プロピル、ヨウ化ｉ−プ
ロピル、ヨウ化ｎ−ブチル、ヨウ化ｉ−ブチル、ヨウ化
ｔｅｒｔ−ブチル基、臭化メチル、臭化エチル、臭化ｎ
−プロピル、臭化ｉ−プロピル、臭化ｎ−ブチル、臭化
ｉ−ブチル、臭化ｔｅｒｔ−ブチル基等のアルキル化剤
を作用させることにより行なわれる。Furthermore, the alkylation reaction of compound (V) is as follows:
In a polar solvent such as DMF, DMSO, DMA, methyl iodide, ethyl iodide, n-propyl iodide, i-propyl iodide, n-butyl iodide, i-butyl iodide, tert-butyl iodide group, Methyl bromide, ethyl bromide, n bromide
This is carried out by using an alkylating agent such as -propyl, i-propyl bromide, n-butyl bromide, i-butyl bromide, or tert-butyl bromide.
【００１３】更に、アルキル化されたクロル体（ＶＩ）
の６位クロルは、メタノールやエタノール等の溶媒中、
大過剰のアンモニアを作用させることによりアミノ基へ
と変換することができ、残存する水酸基保護基を、通常
の糖、核酸化学で用いる方法、例えば９０％蟻酸水、酢
酸水、塩酸水と接触させる方法によって除去することに
より６’−Ｏ−アルキルネプラノシンＡ（Ｉ）を得るこ
とができる。Furthermore, alkylated chloride (VI)
The 6-position chloro in a solvent such as methanol or ethanol,
It can be converted to an amino group by the action of a large excess of ammonia, and the remaining hydroxyl protecting group is brought into contact with conventional methods used in sugar and nucleic acid chemistry, such as 90% formic acid, acetic acid, and hydrochloric acid. 6'-O-alkylneplanocin A(I) can be obtained by removal according to the method.
【００１４】以上のようにして得られた６’−Ｏ−アル
キルネプラノシンＡ（Ｉ）を反応液から取り出すには、
公知の分離、精製手段を利用することができる。 例え
ば、反応に用いた溶媒を留去し、その残査をメタノール
等の溶媒に溶解し、これをシリカゲル等の吸着剤に吸着
させた後、クロロホルム−メタノール系等の溶出溶媒で
溶出させるカラムクロマトグラフィーにより分離、精製
することができる。[0014] To remove the 6'-O-alkylneplanocin A (I) obtained as described above from the reaction solution,
Known separation and purification means can be used. For example, column chromatography involves distilling off the solvent used in the reaction, dissolving the residue in a solvent such as methanol, adsorbing it onto an adsorbent such as silica gel, and then eluting with an elution solvent such as chloroform-methanol. It can be separated and purified by graphics.
【００１５】更に必要に応じ、６’−Ｏ−アルキルネプ
ラノシンＡ（Ｉ）を公知の方法でその医薬上許容される
非毒性塩とすることもできる。このような塩の例として
は、塩酸、硫酸、リン酸などの無機酸の塩、酢酸、プロ
ピオン酸、酒石酸、クエン酸、グリコール酸、グルコン
酸、コハク酸、リンゴ酸、グルタミン酸、アスパラギン
酸、メタンスルホン酸などの有機酸の塩等が挙げられる
。Further, if necessary, 6'-O-alkylneplanocin A (I) can be converted into a pharmaceutically acceptable non-toxic salt by a known method. Examples of such salts include salts of inorganic acids such as hydrochloric, sulfuric, and phosphoric acids, acetic, propionic, tartaric, citric, glycolic, gluconic, succinic, malic, glutamic, aspartic, and methane. Examples include salts of organic acids such as sulfonic acids.
【００１６】本発明化合物（Ｉ）またはその塩を抗ウイ
ルス剤として用いるには、有効量の化合物（Ｉ）または
その塩をそのままで、もしくは公知の担体とともに製剤
化して投与すればよい。In order to use the compound (I) of the present invention or a salt thereof as an antiviral agent, an effective amount of the compound (I) or a salt thereof may be administered as it is or in the form of a formulation with a known carrier.
【００１７】投与方法としては、経口、直腸内、非経口
（例えば静脈内、筋肉内、皮下、腹腔内）または点眼等
の投与方法を利用することができ、上記製剤化もこれら
投与方法に応じて行なうことができる。例えば、剤型と
しては、錠剤、丸薬、散剤、顆粒剤、カプセル剤、注射
剤、坐剤、点眼剤等が挙げられるが、その製造のために
は、これら製剤に応じた各種担体、例えば、錠剤、顆粒
剤、カプセル剤などの経口剤は、澱粉、乳糖、白糖、マ
ンニット、カルボキシメチルセルロース、コーンスター
チ、無機塩類などの賦形剤、澱粉、デキストリン、アラ
ビアゴム、ゼラチン、ヒドロキシプロピルスターチ、メ
チルセルロース、カルボキシメチルセルロースナトリウ
ム、ヒドロキシプロピルセルロース、結晶セルロース、
エチルセルロース、ポリビニルピロリドン、マクロゴー
ルなどの結合剤、澱粉、ヒドロキシプロピルスターチ、
カルボキシメチルセルロース、カルボキシメチルセルロ
ースナトリウム、ヒドロキシプロピルセルロースなどの
崩壊剤、ラウリル硫酸ナトリウム、大豆レシチン、ショ
糖脂肪酸エステル、ポリソルベート８０などの界面活性
剤、タルク、ロウ、水素添加植物油、ショ糖脂肪酸エス
テル、ステアリン酸マグネシウム、ステアリン酸カルシ
ウムなどの滑沢剤、流動性促進剤、矯味剤、着色剤、香
料などを使用することができる。[0017] As for the administration method, oral, rectal, parenteral (for example, intravenous, intramuscular, subcutaneous, intraperitoneal) or ophthalmic administration methods can be used, and the formulation described above also depends on these administration methods. can be done. For example, dosage forms include tablets, pills, powders, granules, capsules, injections, suppositories, eye drops, etc. In order to manufacture them, various carriers depending on these formulations, such as Oral preparations such as tablets, granules, and capsules contain excipients such as starch, lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch, and inorganic salts, starch, dextrin, gum arabic, gelatin, hydroxypropyl starch, methyl cellulose, Carboxymethyl cellulose sodium, hydroxypropyl cellulose, crystalline cellulose,
Ethyl cellulose, polyvinylpyrrolidone, binders such as macrogol, starch, hydroxypropyl starch,
Disintegrants such as carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, surfactants such as sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80, talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, stearic acid Lubricants such as magnesium and calcium stearate, fluidity promoters, flavoring agents, colorants, fragrances, and the like can be used.
【００１８】また、本発明化合物（Ｉ）またはその塩は
、懸濁液、エマルジョン剤、シロップ剤、エリキシル剤
としても使用することができる。非経口剤は希釈剤とし
て一般に注射用蒸留水、生理食塩水、ブドウ糖水溶液、
注射用植物油、プロピレングリコール、ポリエチレング
リコールなどを用いることができる。さらに必要に応じ
、殺菌剤、防腐剤、安定剤を加えてもよい。また、この
非経口剤は安定性の点から、バイアルなどに充填後凍結
乾燥し、使用直前に希釈剤で再調整することもできる。
さらに必要に応じ、適宣等張化剤、安定剤、防腐剤、無
痛化剤などを加えてもよい。The compound (I) of the present invention or a salt thereof can also be used as a suspension, emulsion, syrup, or elixir. Diluents for parenteral preparations generally include distilled water for injection, physiological saline, aqueous glucose solution,
Injectable vegetable oil, propylene glycol, polyethylene glycol, etc. can be used. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation can be lyophilized after being filled into a vial or the like, and readjusted with a diluent immediately before use. Further, appropriate tonicity agents, stabilizers, preservatives, soothing agents, etc. may be added as necessary.
【００１９】本発明化合物（Ｉ）またはその塩の投与量
は、投与経路、被投与者の年齢、体重、症状等によって
異なるが、一般には、大人一人当り化合物（Ｉ）として
１日５ｍｇ〜１ｇ程度、好ましくは ２５〜 ３００ｍ
ｇ程度とし、これを１〜３回に分けて投与すればよい。The dosage of the compound (I) of the present invention or a salt thereof varies depending on the route of administration, the age, body weight, symptoms, etc. of the recipient, but is generally 5 mg to 1 g of the compound (I) per adult per day. approximately, preferably 25-300m
The dosage may be approximately 1.5 g, and the dose may be divided into 1 to 3 doses and administered.
【００２０】次に、叙上の如くして得られた６’−Ｏ−
アルキルネプラノシンＡ（Ｉ）について、その薬理作用
を検討した結果を示す。Next, 6'-O- obtained as described above
The results of examining the pharmacological effects of alkylneplanocin A (I) are shown.
【００２１】（１）抗ウイルス作用および細胞毒性ウイ
ルスとしてＴａｃａｒｉｂｅウイルスを、細胞としてＶ
ｅｒｏ細胞を用い、本発明化合物の細胞変性抑制効果お
よびウイルス非感染細胞に対する影響を調べた。 すな
わち、細胞にウイルスを感染させた直後に、種々の濃度
の被験化合物を加え、３日経過後に細胞変性およびウイ
ルス非感染細胞の形態の変化を調べた。 ウイルスが
引き起こす細胞変性効果を５０％抑制する化合物濃度を
ＭＩＣ、ウイルス非感染細胞に形態的変化を引き起こす
最小濃度をＭＴＣとし、これから化学療法係数を求めた
。 この結果を第１表に示す。(1) Tacaribe virus as an antiviral and cytotoxic virus, V as a cell
Using ero cells, the cytopathic inhibitory effects of the compounds of the present invention and their effects on virus-uninfected cells were investigated. That is, immediately after infecting cells with a virus, various concentrations of test compounds were added, and after 3 days, cell degeneration and changes in the morphology of non-virus-infected cells were examined. The concentration of the compound that suppressed the cytopathic effect caused by the virus by 50% was defined as MIC, and the minimum concentration that caused morphological changes in virus-uninfected cells was defined as MTC, and the chemotherapeutic coefficient was determined from this. The results are shown in Table 1.
【００２２】
第 １ 表───────────
─────────────────────────
被 験 化 合 物 ＭＩＣ
ＭＴＢ 化学療
法係数
（μｇ／ｍｌ） （μｇ／ｍｌ） （ＭＴ
Ｃ／ＭＩＣ）───────────────────
───────────────── ６’−Ｏ−メ
チル
ネプラノシンＡ ０．４
４００ １０
００ ネプラノシンＡ ０．０４
１０
２５０─────────────────────
───────────────[0022]
Table 1────────────
──────────────────────────
Test compound MIC
MTB chemotherapy coefficient
(μg/ml) (μg/ml) (MT
C/MIC)────────────────────
────────────────── 6'-O-Methyl Neplanocin A 0.4
400 10
00 Neplanocin A 0.04
10
250──────────────────────
────────────────
【００２３】（２）アデノシンデアミナーゼ耐性各被験
化合物を０．５ｍＭの濃度となるよう０．０５Ｍトリス
−塩酸緩衝液（ｐＨ７．２）に溶解して被験液とした。
一方、アデノシンデアミナーゼ（ＣａｌｆＩｎｔｅｓ
ｔｉｎｅ， ４００Ｕ／ｍｌグリセリン， ベーリンガ
ー１０２０９１）を０．０５Ｍトリス−塩酸緩衝液（ｐ
Ｈ７．２）で１０倍に希釈してアデノシンデアミナーゼ
（ＡＤ）溶液とした。上記の被験液０．５ｍｌにＡＤ溶
液１０μｌを加えて混合した。 これを２５℃水溶中に
放置し、０、３０分後に各々４μｌを分取した後、次の
条件による高速液体クロマトグラフィー（ＨＰＬＣ）に
より残存被験物量を測定した。 この結果を第２表に示
す。
（ＨＰＬＣ条件）
カ ラ ム ； Ｓｕｐｅｒｓｐｈｅｒ ＲＰ−１８−
４溶出溶媒 ； １５％メタノール
溶出速度 ； １．０ｍｌ／分
温 度 ； ５０℃(2) Adenosine deaminase resistance Each test compound was dissolved in 0.05M Tris-HCl buffer (pH 7.2) to a concentration of 0.5mM to prepare a test solution. On the other hand, adenosine deaminase (CalfIntes)
tine, 400 U/ml glycerin, Boehringer 102091) in 0.05 M Tris-HCl buffer (p
H7.2) to prepare an adenosine deaminase (AD) solution. 10 μl of AD solution was added to 0.5 ml of the above test solution and mixed. This was left in an aqueous solution at 25° C., and after 0 and 30 minutes, 4 μl each was collected, and the amount of the remaining test substance was measured by high performance liquid chromatography (HPLC) under the following conditions. The results are shown in Table 2. (HPLC conditions) Column; Superspher RP-18-
4 Elution solvent: 15% methanol Elution rate: 1.0ml/min Temperature: 50℃
【００２４】（ 結 果 ）(Result)
【００２５】[0025]
【発明の効果】上記の薬理作用試験の結果から明らかな
ように、本発明の６’−Ｏ−アルキルネプラノシンＡ（
Ｉ）は優れた抗ウイルス作用を示し、しかも、ネプラノ
シンに比べ、その細胞毒性は低いものである。 また、
この化合物をマウスに２００ｍｇ／ｋｇ経口投与しても
死亡例がないことから明らかなように安全性も高いもの
であり抗ウイルス剤として有利に利用することができる
ものである。Effects of the Invention As is clear from the results of the above pharmacological test, the 6'-O-alkylneplanocin A of the present invention (
I) exhibits excellent antiviral activity and, moreover, has lower cytotoxicity than neplanocin. Also,
Even when this compound was orally administered to mice at a dose of 200 mg/kg, there were no deaths, as is clear from this fact that it is highly safe and can be advantageously used as an antiviral agent.
【００２６】[0026]
【実施例】次に実施例を挙げ、本発明を更に詳しく説明
する。 なお、以下の実施例において、シリカゲルフラ
ッシュカラムには、メルク Ａｒｔ．９３８５シリカゲ
ルを使用した。EXAMPLES Next, the present invention will be explained in more detail with reference to Examples. In the following examples, the silica gel flash column was manufactured by Merck Art. 9385 silica gel was used.
【００２７】実 施 例 １
２’，３’，６’−トリ−Ｏ−アセチルネプラノシンＤ
（化合物３）の合成：ネプラノシンＤ ２．６４ｇ（１
０ｍｍｏｌ）を５０ｍｌのピリジンに溶かし、無水酢酸
４．３ｍｌ（４．５ｍｍｏｌ）を加え、室温で３時間撹
拌した。１０ｍｌのメタノールを加えた後、反応液を減
圧下乾固した。 残渣をクロロホルムと水で分液し、有
機層をワットマン １ｐｓ濾紙を通した後、減圧下乾固
した。残渣をシリカゲルフラッシュカラム（ＣＨＣｌ３
／ＭｅＯＨ，３０：１）で精製した後、エタノールより
結晶化して、２’，３’，６’−トリ−Ｏ−アセチルネ
プラノシンＤを２．５２ｇ（収率６５％）得た。
融 点 ：２１３−２１５℃．
Ｍ Ｓ（ＦＡＢ），ｍ／ｅ： ３９１（ＭＨ＋）．Example 1 2',3',6'-tri-O-acetylneplanocin D
Synthesis of (compound 3): Neplanocin D 2.64g (1
0 mmol) was dissolved in 50 ml of pyridine, 4.3 ml (4.5 mmol) of acetic anhydride was added, and the mixture was stirred at room temperature for 3 hours. After adding 10 ml of methanol, the reaction solution was dried under reduced pressure. The residue was separated between chloroform and water, and the organic layer was passed through Whatman 1ps filter paper, and then dried under reduced pressure. The residue was purified by silica gel flash column (CHCl3
/MeOH, 30:1) and then crystallized from ethanol to obtain 2.52 g of 2',3',6'-tri-O-acetylneplanocin D (yield 65%). Melting point: 213-215℃. MS (FAB), m/e: 391 (MH+).
【
００２８】実 施 例 ２
６−デアミノ−６−クロロネプラノシンＡ（９−［（１
Ｒ，２Ｓ，３Ｒ）−２，３−ジヒドロキシ−４−ヒドロ
キシメチル−４−シクロペンテン−１−イル］−６−ク
ロロプリン；化合物４）の合成：２’，３’，６’−ト
リ−Ｏ−アセチルネプラノシンＤ ２．３４ｇ（６ｍｍ
ｏｌ）を乾燥クロロホルム１２０ｍｌに溶かし、ＤＭＦ
２．４ｍｌ及びチオニルクロライド ４．８ｍｌを加え
、４時間還流した。 放冷後、氷水５００ｍｌに注ぎ、
水層に１Ｎ ＮａＨＣＯ３を加えて中和し、分液した後
、クロロホルム層を水洗し、ワットマン １ｐｄ濾紙を
通し、減圧下溶媒を留去した。 残渣をメタノール １
００ｍｌに溶かし、氷冷下、アンモニアガスを飽和させ
た後、室温で３時間撹拌した。 残渣をエタノールより
結晶化させ、１．４９ｇ（収率８６．６％）の６−デア
ミノ−６−クロロネプラノシンＡを得た。
融 点 ： １９４−１９６℃．
ＭＳ（ＦＡＢ），ｍ／ｅ： ２８３，ｄ２８５（ＭＨ＋
）．[
Example 2 6-deamino-6-chloroneplanocin A (9-[(1
Synthesis of compound 4): 2',3',6'-tri-O -Acetylneplanocin D 2.34g (6mm
ol) in 120 ml of dry chloroform and diluted with DMF.
2.4 ml and 4.8 ml of thionyl chloride were added, and the mixture was refluxed for 4 hours. After cooling, pour into 500ml of ice water.
After neutralizing the aqueous layer by adding 1N NaHCO3 and separating the layers, the chloroform layer was washed with water, passed through Whatman 1PD filter paper, and the solvent was distilled off under reduced pressure. Dilute the residue with methanol 1
After saturated with ammonia gas under ice cooling, the mixture was stirred at room temperature for 3 hours. The residue was crystallized from ethanol to obtain 1.49 g (yield: 86.6%) of 6-deamino-6-chloroneplanocin A. Melting point: 194-196℃. MS (FAB), m/e: 283, d285 (MH+
).
【００２９】実 施 例 ３
６−デアミノ−６−クロロ−２’，３’−Ｏ−イソプロ
ピリデンネプラノシンＡ（９−［（１Ｒ，２Ｓ，３Ｒ）
−２，３−イソプロピリデンジオキシ−４−ヒドロキシ
メチル−４−シクロペンテン−１−イル］−６−クロロ
プリン；化合物５）の合成：６−デアミノ−６−クロロ
ネプラノシンＡ ８４８ｍｇ（３ｍｍｏｌ）とＴｓＯＨ
．Ｈ２Ｏ ２８５ｍｇ（０．５ｅｇ）を１００ｍｌのア
セトン中で１時間還流した。 ０．８Ｎ ＮａＨＣＯ３
を加えて中和後、放冷し、析出した不溶塩を濾去し、濾
液を減圧下乾固した。 残渣を酢酸エチルに溶かし、飽
和食塩水と分液の後、ワットマン １ｐｓ濾紙を通して
、減圧下溶媒を留去した。 残渣を水より結晶化させ、
６−デアミノ−６−クロロ−２’，３’−Ｏ−イソプロ
ピリデンネプラノシンＡ １．０５ｇ（収率８４．５％
）を得た。
融 点 ： １４０−１４２℃．
ＭＳ（ＦＡＢ），ｍ／ｅ： ３２３，３２５（ＭＨ＋）
．Example 3 6-deamino-6-chloro-2',3'-O-isopropylideneneplanocin A (9-[(1R,2S,3R)
-2,3-isopropylidenedioxy-4-hydroxymethyl-4-cyclopenten-1-yl]-6-chloropurine; Synthesis of compound 5): 6-deamino-6-chloroneplanocin A 848 mg (3 mmol) and TsOH
．． 285 mg (0.5 eg) of H2O was refluxed in 100 ml of acetone for 1 hour. 0.8N NaHCO3
After neutralization, the mixture was allowed to cool, the precipitated insoluble salts were filtered off, and the filtrate was dried under reduced pressure. The residue was dissolved in ethyl acetate, separated from saturated brine, passed through Whatman 1ps filter paper, and the solvent was distilled off under reduced pressure. Crystallize the residue from water,
6-deamino-6-chloro-2',3'-O-isopropylideneneplanocin A 1.05g (yield 84.5%
) was obtained. Melting point: 140-142℃. MS (FAB), m/e: 323,325 (MH+)
．．
【００３０】実 施 例 ４
６−デアミノ−６−クロロ−２’，３’−Ｏ−イソプロ
ピリデン−６’−Ｏ−メチルネプラノシンＡ（９−［（
１Ｒ，２Ｓ，３Ｒ）−２，３−イソプロピリデンジオキ
シ−４−メトキシメチル−４−シクロペンテン−１−イ
ル］−６−クロロプリン；化合物６）の合成：６−デア
ミノ−６−クロロ−２’，３’−Ｏ−イソプロピリデン
ネプラノシンＡ３２３ｍｇ（１ｍｍｏｌ）をＤＭＦ１０
ｍｌに溶かし、５５％水素化ナトリウム５７ｍｇ（１．
３ｅｑ）を加え、室温下、３分間撹拌した後、ヨウ化
６２３μｌ（１０ｅｑ）を加え、室温下、３０分間撹拌
した。 溶媒を減圧下留去し、残渣をクロロホルムと０
．５Ｎ−ＨＣｌで分液し、クロロホルム層を飽和食塩水
で洗浄した後、ワットマン１ｐｓ濾紙を通して、溶媒を
減圧下留去した。 残渣を少量のクロロホルムに溶かし
、シリカゲルフラッシュカラム（φ２×１５ｃｍ、ＣＨ
Ｃｌ３→ＣＨＣｌ３：ＭｅＯＨ＝５０：１）で精製して
、１５７ｍｇの６−デアミノ−６−クロロ−２’，３’
−Ｏ−イソプロピリデン−６’−Ｏ−メチルネプラノシ
ンＡ をあめ状物質として得た。 収率４６．７％。
ＵＶλＭｅＯＨ ｍａｘ ： ２６４ｎｍ．ＭＳ（ＦＡ
Ｂ）．ｍ／ｅ： ３３７，３３９（ＭＨ＋）．Example 4 6-deamino-6-chloro-2',3'-O-isopropylidene-6'-O-methylneplanocin A (9-[(
Synthesis of compound 6): 6-deamino-6-chloro-2 ',3'-O-isopropylidene neplanocin A 323 mg (1 mmol) was added in DMF10
ml, 57 mg of 55% sodium hydride (1.
After adding 3 eq) and stirring for 3 minutes at room temperature, iodination
623 μl (10 eq) was added and stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was dissolved in chloroform and 0.
．． After separating the layers with 5N-HCl and washing the chloroform layer with saturated brine, the mixture was passed through a Whatman 1ps filter, and the solvent was distilled off under reduced pressure. Dissolve the residue in a small amount of chloroform and apply it to a silica gel flash column (φ2 x 15 cm, CH
Cl3→CHCl3:MeOH=50:1) to give 157 mg of 6-deamino-6-chloro-2',3'
-O-isopropylidene-6'-O-methylneplanocin A was obtained as a candy-like substance. Yield 46.7%. UVλMeOH max: 264nm. MS(F.A.
B). m/e: 337,339 (MH+).
【００３
１】実 施 例 ５
６’−Ｏ−メチルネプラノシンＡ（化合物１）の合成：
６−デアミノ−６−クロロ−２’，３’−Ｏ−イソプロ
ピリデン−６’−Ｏ−メチルネプラノシンＡ化合物６
１４５ｍｇ（０．４３ｍｏｌ）を２０ｍｌのメタノール
に溶かし、−２０℃にて、ＮＨ３ガスを飽和させ、封管
中、１００℃で、１８時間撹拌した。 冷却後、溶媒を
留去し、残渣にクロロホルム２０ｍｌを加え、不溶物を
減圧下濾取した。 濾液を減圧乾固し、残渣に９０％ギ
酸 ３ｍｌを加え、室温で３時間撹拌した。 残渣を少
量のメタノールに溶かし、シリカゲル（和光Ｃ−２００
）３ｇを加えて減圧乾固し、シリカゲルフラッシュカラ
ム（φ１．５×１２ｃｍ， ＣＨＣｌ３→ＣＨＣｌ３：
ＭｅｏＨ＝２０：１→１５：１→１０：１）により精製
した。 さらにエタノールより結晶化させ、６８ｍｇの
６’−Ｏ−メチルネプラノシンＡを得た。 収率５６％
。003
1] Example 5 Synthesis of 6'-O-methylneplanocin A (compound 1):
6-deamino-6-chloro-2',3'-O-isopropylidene-6'-O-methylneplanocin A compound 6
145 mg (0.43 mol) was dissolved in 20 ml of methanol, saturated with NH3 gas at -20°C, and stirred in a sealed tube at 100°C for 18 hours. After cooling, the solvent was distilled off, 20 ml of chloroform was added to the residue, and insoluble matter was filtered off under reduced pressure. The filtrate was dried under reduced pressure, 3 ml of 90% formic acid was added to the residue, and the mixture was stirred at room temperature for 3 hours. Dissolve the residue in a small amount of methanol and add silica gel (Wako C-200
) was added to dryness under reduced pressure, and a silica gel flash column (φ1.5 x 12 cm, CHCl3→CHCl3:
MeoH=20:1→15:1→10:1). Further, 68 mg of 6'-O-methylneplanocin A was obtained by crystallization from ethanol. Yield 56%
.
【００３２】ＵＶλＭｅＯＨｍａｘ： ２６０ｎｍ．Ｍ
Ｓ（ＦＡＢ），ｍ／ｅ： ２７８（ＭＨ＋）．１Ｈ−Ｎ
ＭＲ（ＣＤ３ＯＤ，９０ＭＨｚ），δ：８．１８（ｓ，
１Ｈ，Ｈ−２），８．０９（ｓ，１Ｈ，Ｈ−８），５．
３１（ｄｄ，１Ｈ，Ｈ−５’），５．５７−５．４３（
ｍ，１Ｈ，Ｈ−１’），４．６２（ｄｄ，１Ｈ，Ｈ−３
’），４．４０（ｄｄ，１Ｈ），４．１６（ｄ，２Ｈ，
Ｈ−６’），３．４２（ｓ，３Ｈ，ＣＨ３Ｏ）．
元素分析（Ｃ１２Ｈ１５Ｎ５Ｏ３として）：計算値；
Ｃ，５１．９８ Ｈ，５．４５ Ｎ，２５．２６．実
測値； Ｃ，５２．１１ Ｈ，５．５０ Ｎ，２５．
４８．融 点 ： ２０１℃
以 上UVλMeOHmax: 260nm. M
S (FAB), m/e: 278 (MH+). 1H-N
MR (CD3OD, 90MHz), δ: 8.18 (s,
1H, H-2), 8.09 (s, 1H, H-8), 5.
31 (dd, 1H, H-5'), 5.57-5.43 (
m, 1H, H-1'), 4.62 (dd, 1H, H-3
'), 4.40 (dd, 1H), 4.16 (d, 2H,
H-6'), 3.42 (s, 3H, CH3O). Elemental analysis (as C12H15N5O3): Calculated value;
C, 51.98 H, 5.45 N, 25.26. Actual value: C, 52.11 H, 5.50 N, 25.
48. Melting point: 201℃ or higher
Claims (6)
−Ｏ−アルキルネプラノシンＡまたはその塩。Claim 1: 6' represented by general formula (I) [Formula 1] (wherein R represents a lower alkyl group)
-O-alkylneplanocin A or a salt thereof.
基を示す）で表わされる化合物のクロルのアミノ基への
変換反応および脱保護反応をおこなうことを特徴とする
次の式（Ｉ） 【化３】 （式中、Ｒは前記した意味を有する）で表わされる６’
−Ｏ−アルキルネプラノシンＡまたはその塩の製造法。[Claim 2] Conversion reaction of chloro to amino group and deprotection of a compound represented by general formula (VI) [Chemical formula 2] (wherein R represents a lower alkyl group and R2 represents a hydroxyl group-protecting group) 6' represented by the following formula (I) [Chemical formula 3] (wherein R has the above-mentioned meaning), which undergoes a reaction.
- A method for producing O-alkylneplanocin A or a salt thereof.
合物をアルキル化して一般式（ＶＩ） 【化５】 （式中、Ｒは低級アルキル基を示し、Ｒ２は前記した意
味を有する）で表わされる化合物を得、次いで当該化合
物のクロルをアミノ基に変換し、脱保護をおこなうこと
を特徴とする一般式（Ｉ） 【化６】 （式中、Ｒは前記した意味を有する）で表される６’−
Ｏ−アルキルネプラノシンＡまたはその塩の製造法。Claim 3: A compound represented by the general formula (V) [Chemical 4] (wherein, R2 represents a hydroxyl group protecting group) is alkylated to form the general formula (VI) [Chemical 5] (wherein, R is (representing a lower alkyl group, R2 has the meaning described above) is obtained, and then the chloro of the compound is converted to an amino group, and deprotection is performed. ] (wherein R has the meaning described above) 6'-
A method for producing O-alkylneplanocin A or a salt thereof.
ゲン化剤を作用せしめて式（ＩＶ） 【化８】 で表わされる化合物とし、その２’および３’位水酸基
を保護した後アルキル化して式（ＶＩ）（式中、Ｒは低
級アルキル基を、Ｒ２は水酸基保護基を示す）【化９】 で表される化合物とした後、クロルをアミノ基に変換し
脱保護することを特徴とする式（Ｉ） 【化１０】 （式中、Ｒは低級アルキル基を示す）で表される６’−
Ｏ−アルキルネプラノシンＡまたはその塩の製造法。[Claim 4] After protecting the hydroxyl group of neplanocin D represented by general formula (II) [Chemical 7], a halogenating agent is applied to form a compound represented by formula (IV) [Chemical 8], which 2 After protecting the hydroxyl groups at the ' and 3' positions, alkylation is performed to obtain a compound represented by the formula (VI) (wherein, R represents a lower alkyl group and R2 represents a hydroxyl group-protecting group) [Chemical formula 9]. Formula (I) characterized by converting into an amino group and deprotecting the 6'-
A method for producing O-alkylneplanocin A or a salt thereof.
−Ｏ−アルキルネプラノシンＡまたはその塩を有効成分
とする抗ウイルス剤。5. 6' represented by the general formula (I): (wherein R represents a lower alkyl group)
-An antiviral agent containing O-alkylneplanocin A or a salt thereof as an active ingredient.
”は水素原子またはアルキル基を示す）で表わされる化
合物。[Claim 6] General formula (VII) [Image Omitted] (wherein, R' represents a hydrogen atom or a hydroxyl group-protecting group, and R
” indicates a hydrogen atom or an alkyl group).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3112271A JPH04321687A (en) | 1991-04-18 | 1991-04-18 | 6'-o-alkylneplanocin a, its production and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3112271A JPH04321687A (en) | 1991-04-18 | 1991-04-18 | 6'-o-alkylneplanocin a, its production and use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH04321687A true JPH04321687A (en) | 1992-11-11 |
Family
ID=14582529
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP3112271A Withdrawn JPH04321687A (en) | 1991-04-18 | 1991-04-18 | 6'-o-alkylneplanocin a, its production and use |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH04321687A (en) |
-
1991
- 1991-04-18 JP JP3112271A patent/JPH04321687A/en not_active Withdrawn
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0269574B1 (en) | Novel adenosine derivatives and pharmaceutical compositions containing them as an active ingredient | |
| DE60026861T2 (en) | PURINE DERIVATIVES | |
| JP4100955B2 (en) | Process for the preparation of 4 "-substituted-9-deoxo-9A-aza-9A-homoerythromycin A derivatives | |
| US6083953A (en) | 2- (2-amino-1,6-dihydro-6-oxo-purin-9-yl) methoxy-1,3- propanediol derivative | |
| JP3090305B2 (en) | 2- (2-amino-1,6-dihydro-6-oxo-purin-9-yl) methoxy-1,3-propanediol derivative | |
| JPH04327587A (en) | 6'-c-alkyl-3-deazaneplanocin a derivative, its production and use | |
| JPH0637394B2 (en) | Tumor therapeutic agent | |
| CA2880040A1 (en) | N-alkyl 2-(disubstituted)alkynyladenosine-5-uronamides as a2a agonists | |
| AU637831B2 (en) | Therapeutic necleosides | |
| FR2531962A1 (en) | NOVEL DERIVATIVES OF DESOXYURIDINE, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS | |
| ITRM930147A1 (en) | PROCEDURE FOR THE PREPARATION OF SALTS OF CLAVULANIC ACID. | |
| JP5680535B2 (en) | New flavanone derivatives | |
| JPH0240369A (en) | Novel neplanosin derivatives | |
| JP2001515900A (en) | Antiviral drugs | |
| WO2021023693A1 (en) | Process for the preparation of a nitric oxide donating prostaglandin analogue | |
| JPH02108695A (en) | Nucleotide for treatment | |
| JPH04321687A (en) | 6'-o-alkylneplanocin a, its production and use | |
| JPH0560478B2 (en) | ||
| EP4288413A1 (en) | Process for the preparation of a nitric oxide donating prostaglandin analogue | |
| JPH03240793A (en) | Purification of anfotelycine b and composition | |
| US6599886B2 (en) | Macrolide intermediates in the preparation of clarithromycin | |
| JPS6225149B2 (en) | ||
| EP1590353B1 (en) | A process for the preparation of cefpodoxime proxetil | |
| WO1992019638A1 (en) | 1-β-D-ARABINOFURANOSYL-(E)-5-(2-HALOGENOVINYL)-URACIL DERIVATIVE | |
| JPH08510228A (en) | Preparation of fluoro-nucleosides and intermediates for use therein |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A300 | Application deemed to be withdrawn because no request for examination was validly filed |
Free format text: JAPANESE INTERMEDIATE CODE: A300 Effective date: 19980711 |