CN100999503B - Hexanary carbocycle azole like nucleoside analogue, its synthesizing process and use in anti virus and tumor thereof - Google Patents
Hexanary carbocycle azole like nucleoside analogue, its synthesizing process and use in anti virus and tumor thereof Download PDFInfo
- Publication number
- CN100999503B CN100999503B CN2006101709913A CN200610170991A CN100999503B CN 100999503 B CN100999503 B CN 100999503B CN 2006101709913 A CN2006101709913 A CN 2006101709913A CN 200610170991 A CN200610170991 A CN 200610170991A CN 100999503 B CN100999503 B CN 100999503B
- Authority
- CN
- China
- Prior art keywords
- acid
- inositol
- methyl
- azole
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229940127073 nucleoside analogue Drugs 0.000 title claims abstract description 40
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 title claims description 94
- 238000000034 method Methods 0.000 title claims description 15
- -1 nucleoside analogue Chemical compound 0.000 title claims description 13
- 230000000259 anti-tumor effect Effects 0.000 title claims description 12
- 230000002194 synthesizing effect Effects 0.000 title claims description 3
- 206010028980 Neoplasm Diseases 0.000 title description 2
- 230000002155 anti-virotic effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 17
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 5
- 239000003443 antiviral agent Substances 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 50
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 47
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 31
- 239000007787 solid Substances 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 20
- 239000001530 fumaric acid Substances 0.000 claims description 20
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 20
- 239000007788 liquid Substances 0.000 claims description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 238000010189 synthetic method Methods 0.000 claims description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 16
- 239000013078 crystal Substances 0.000 claims description 16
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 14
- 150000002460 imidazoles Chemical class 0.000 claims description 14
- 239000000047 product Substances 0.000 claims description 13
- 239000002777 nucleoside Substances 0.000 claims description 12
- 239000012964 benzotriazole Substances 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 238000001291 vacuum drying Methods 0.000 claims description 10
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 238000001953 recrystallisation Methods 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 8
- 125000003368 amide group Chemical group 0.000 claims description 8
- QFXZANXYUCUTQH-UHFFFAOYSA-N ethynol Chemical group OC#C QFXZANXYUCUTQH-UHFFFAOYSA-N 0.000 claims description 8
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 8
- 150000002473 indoazoles Chemical class 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 claims description 7
- JCZAVVUIFWZMQI-UHFFFAOYSA-N 1h-thieno[2,3-d]imidazole Chemical compound N1C=NC2=C1C=CS2 JCZAVVUIFWZMQI-UHFFFAOYSA-N 0.000 claims description 7
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 7
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 150000002475 indoles Chemical class 0.000 claims description 7
- 239000012442 inert solvent Substances 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 150000003217 pyrazoles Chemical class 0.000 claims description 7
- 150000003233 pyrroles Chemical class 0.000 claims description 7
- MHOZZUICEDXVGD-UHFFFAOYSA-N pyrrolo[2,3-d]imidazole Chemical class C1=NC2=CC=NC2=N1 MHOZZUICEDXVGD-UHFFFAOYSA-N 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 150000003852 triazoles Chemical class 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 5
- 229960004756 ethanol Drugs 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 5
- DSCFFEYYQKSRSV-UHFFFAOYSA-N 1L-O1-methyl-muco-inositol Natural products COC1C(O)C(O)C(O)C(O)C1O DSCFFEYYQKSRSV-UHFFFAOYSA-N 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims description 4
- 238000005352 clarification Methods 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 239000004310 lactic acid Substances 0.000 claims description 4
- 235000014655 lactic acid Nutrition 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 3
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- DCTOHCCUXLBQMS-UHFFFAOYSA-N 1-undecene Chemical compound CCCCCCCCCC=C DCTOHCCUXLBQMS-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 229920000742 Cotton Polymers 0.000 claims description 2
- VJXUJFAZXQOXMJ-UHFFFAOYSA-N D-1-O-Methyl-muco-inositol Natural products CC12C(OC)(C)OC(C)(C)C2CC(=O)C(C23OC2C(=O)O2)(C)C1CCC3(C)C2C=1C=COC=1 VJXUJFAZXQOXMJ-UHFFFAOYSA-N 0.000 claims description 2
- DSCFFEYYQKSRSV-KLJZZCKASA-N D-pinitol Chemical compound CO[C@@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@H]1O DSCFFEYYQKSRSV-KLJZZCKASA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- CUBCNYWQJHBXIY-UHFFFAOYSA-N benzoic acid;2-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1O CUBCNYWQJHBXIY-UHFFFAOYSA-N 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 claims description 2
- 229940005991 chloric acid Drugs 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- 239000005457 ice water Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- 238000005303 weighing Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 2
- MMQFYDQGJNKDBV-UHFFFAOYSA-N 1h-imidazole;1h-indole Chemical class C1=CNC=N1.C1=CC=C2NC=CC2=C1 MMQFYDQGJNKDBV-UHFFFAOYSA-N 0.000 claims 1
- 238000007865 diluting Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 24
- 230000005764 inhibitory process Effects 0.000 abstract description 17
- 206010005003 Bladder cancer Diseases 0.000 abstract description 11
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 11
- 201000005202 lung cancer Diseases 0.000 abstract description 10
- 208000020816 lung neoplasm Diseases 0.000 abstract description 10
- 241000725303 Human immunodeficiency virus Species 0.000 abstract description 7
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 abstract description 6
- 201000005112 urinary bladder cancer Diseases 0.000 abstract description 6
- 230000029812 viral genome replication Effects 0.000 abstract description 2
- 229940034982 antineoplastic agent Drugs 0.000 abstract 1
- 150000003851 azoles Chemical class 0.000 abstract 1
- 125000002837 carbocyclic group Chemical group 0.000 abstract 1
- 230000010076 replication Effects 0.000 abstract 1
- 241001529453 unidentified herpesvirus Species 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 17
- 229940079593 drug Drugs 0.000 description 10
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 10
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 8
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 8
- 229960002555 zidovudine Drugs 0.000 description 8
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 7
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 208000031886 HIV Infections Diseases 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 230000000452 restraining effect Effects 0.000 description 6
- 208000010201 Exanthema Diseases 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 201000001531 bladder carcinoma Diseases 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 201000005884 exanthem Diseases 0.000 description 5
- 150000003833 nucleoside derivatives Chemical class 0.000 description 5
- 206010037844 rash Diseases 0.000 description 5
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000004593 Epoxy Substances 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 235000014347 soups Nutrition 0.000 description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 3
- 235000014676 Phragmites communis Nutrition 0.000 description 3
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- DSCFFEYYQKSRSV-FIZWYUIZSA-N (-)-Quebrachitol Chemical compound CO[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@H]1O DSCFFEYYQKSRSV-FIZWYUIZSA-N 0.000 description 2
- CSCPPACGZOOCGX-MICDWDOJSA-N 1-deuteriopropan-2-one Chemical compound [2H]CC(C)=O CSCPPACGZOOCGX-MICDWDOJSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 230000036436 anti-hiv Effects 0.000 description 2
- 230000003622 anti-hsv Effects 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000006143 cell culture medium Substances 0.000 description 2
- 238000004043 dyeing Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 1
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 description 1
- HBOMLICNUCNMMY-UHFFFAOYSA-N 1-[4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1C1OC(CO)C(N=[N+]=[N-])C1 HBOMLICNUCNMMY-UHFFFAOYSA-N 0.000 description 1
- CDAISMWEOUEBRE-LKPKBOIGSA-N 1D-chiro-inositol Chemical compound O[C@H]1[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O CDAISMWEOUEBRE-LKPKBOIGSA-N 0.000 description 1
- HIHOEGPXVVKJPP-JTQLQIEISA-N 5-fluoro-2-[[(1s)-1-(5-fluoropyridin-2-yl)ethyl]amino]-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile Chemical compound N([C@@H](C)C=1N=CC(F)=CC=1)C(C(=CC=1F)C#N)=NC=1NC=1C=C(C)NN=1 HIHOEGPXVVKJPP-JTQLQIEISA-N 0.000 description 1
- 102100023701 C-C motif chemokine 18 Human genes 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 101000978371 Homo sapiens C-C motif chemokine 18 Proteins 0.000 description 1
- OBZJZDHRXBKKTJ-UHFFFAOYSA-N Sangivamycin Natural products C12=NC=NC(N)=C2C(C(=O)N)=CN1C1OC(CO)C(O)C1O OBZJZDHRXBKKTJ-UHFFFAOYSA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 241000726445 Viroids Species 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960000329 ribavirin Drugs 0.000 description 1
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 description 1
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 1
- OBZJZDHRXBKKTJ-JTFADIMSSA-N sangivamycin Chemical compound C12=NC=NC(N)=C2C(C(=O)N)=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OBZJZDHRXBKKTJ-JTFADIMSSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a group six dim carbocyclic ring azoles nucleoside analogues and their acceptable pharmaceutical compounds and their preparation methods and the application as antiviral and antineoplastic agents.The described compounds have varying degrees of inhibition effects on the human immunodeficiency virus replication and the replication of herpes virus; have varying degrees of inhibition on human lung cancer cell lines and human bladder cancer cell lines.
Description
Technical field:
The present invention relates to one group of six-membered carbon ring azole like nucleoside analogue thing and described six-membered carbon ring azole like nucleoside analogue thing and sour mixture (1: 1); The invention still further relates to the synthetic method of described compound and mixture and in antiviral and application anti-tumor aspect.
Background technology:
In recent years, nucleoside medicine has been subjected to extensive concern as the main curative of virus type disease.Be used for the treatment of human immunodeficiency virus (human immunodificiency virus, HIV) and hsv (herpes simplex virus, HSV) nucleoside medicine that catches generally all is HIV viral reverse transcriptase inhibitor and HSV vDNA (deoxyribonucleic acid, DNA) inhibitor of polysaccharase.Nucleoside medicine be still at present anti-HIV and anti-HSV the most effectively medicine [(a) Tang Yanbo, Li Zhuorong. Chinese biochemical drug magazine Chinese Journal of BiochemicalPharmaceutics, 2004,25 (1): 44-47; (b) plum becomes, Chen Shuhua, Jiang Ning, Lv Ding .2002,14 (1): 15-20; (c) De Clercq E.Frontiers in Medicinal Chemistry-Online, 2004,37 (1): 543-579.].
Research like thing rarely has report, but does not see that about the synthetic and antiviral activity of inositol class nucleoside analog bibliographical information is arranged.
Summary of the invention:
The purpose of this invention is to provide one group of new six-membered carbon ring azole like nucleoside analogue thing and described six-membered carbon ring azole like nucleoside analogue thing and sour mixture (1: 1).
Another object of the present invention provides the synthetic method of above-claimed cpd and mixture.
The further purpose of the present invention provides above-claimed cpd and mixture in antiviral and application anti-tumor aspect.
The present invention is to be lead compound with Ribavirin, five yuan of sugar rings are replaced with six-membered carbon ring, and with a collection of azole base generation coupling reaction, ribavirin analogue, benzimidazole nucleoside analogue, benzotriazole nucleoside analog and benzopyrazoles (indazole) nucleoside analog of the novel quebrachitol of a class synthesized in design, and the mixture of described compound and acid (1: 1), and studied their antiviral and anti-tumor activity.
Six-membered carbon ring azole like nucleoside analogue thing of the present invention, its structure are suc as formula (I) with (II):
Wherein:
B is one of triazole, benzoglyoxaline, benzotriazole, benzopyrazoles (indazole), imidazoles, pyrazoles, pyrroles, indoles, carbazole, pyrrolo-imidazoles, Thienoimidazole, thiazole and imidazoles.
Wherein:
Can be selected from following substituent group and replace by one or more on the described ring-type azole base group: (1) hydroxyl; (2) halogen atom; (3) itrile group; (4) nitro; (5) amino; (6) C
1-C
5Alkyl, C
2-C
5Thiazolinyl or C
2-C
5Alkynyl, wherein each group all can be replaced by at least one or a plurality of halogen atom; (7) C
1-C
5Alkoxyl group, C
2-C
5Alkenyloxy or C
2-C
5Chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (8) C
1-C
5Alkylthio, C
2-C
5Alkenyl thio or C
2-C
5Sulfur-based chain acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (9) amido; (10) nitrogen base repeatedly; (11) C
1-C
5Ester group.
Substituting group on the described ring-type azole base group is more preferably in following groups: (1) chlorine atom or fluorine atom; (2) nitro; (3) C
1-C
2Alkyl, C
2Thiazolinyl or C
2Alkynyl, wherein each group all can be replaced by at least one or a plurality of chlorine or fluorine atom; (4) C
1-C
2Alkoxyl group, C
2Alkenyloxy or C
2Chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of chlorine or fluorine atom; (5) C
1Alkylthio, C
2Alkenyl thio or C
2Sulfur-based chain acetylene, wherein each group all can be replaced by at least one or a plurality of chlorine or fluorine atom; (6) amido; (7) nitrogen base repeatedly; (8) C
1-C
2Ester group.
The synthetic method of above-mentioned six-membered carbon ring azole like nucleoside analogue thing is characterized in that, described target compound is synthetic through the reaction of five steps:
The first step: 1,2:5,6-two-O-isopropylidene-3-O-methyl D-inositol synthetic
Take by weighing pinitol and join acetone and 2, in the mixed solvent of 2-Propanal dimethyl acetal, add the tosic acid and the dewatering agent anhydrous magnesium sulfate of catalytic amount again, 10～80 ℃ were stirred 5～24 hours down, in reaction mixture, add sodium bicarbonate, after the stirring, filter, filter residue merges with ethyl acetate washing 2～5 times and filtrate, use equal proportion normal hexane and ether mixed solvent recrystallization behind the concentrating under reduced pressure, get the cotton-shaped crystallization 1 of white cotton, 2:5,6-two-O-isopropylidene-3-O-methyl D-inositol;
Second step: 1,2:5,6-two-O-isopropylidene-3-O-methyl-4-O-methylsulfonyl-D-inositol synthetic
The methylsulfonyl chloride adding is slowly added in the organic basic solvent, stirring is fully dissolved solid, ice-water bath is cooled to-10～0 ℃, reaction afterwards maintains under-10～10 ℃ and adds 1 in batches, 2:5,6-two-O-isopropylidene-3-O-methyl D-inositol, stir after 1～24 hour, pour in the hydrochloric acid ice aqueous solution of 0.5～5 volumetric molar concentration, suction filtration, white filter cake also dewaters to neutral with absolute ethanol washing, the dehydrated alcohol recrystallization, get white particle crystal 1,2:5,6-two-O-isopropylidene-3-O-methyl-4-O-methylsulfonyl-D-inositol;
This step is applicable to that all are above-mentioned 1,2:5,6-two-O-isopropylidene-3-O-methyl-4-O-methylsulfonyl-D-inositol synthetic.
The 3rd step: 3-O-methyl-4-O-methylsulfonyl-D-inositol synthetic
With 1,2:5,6-two-O-isopropylidene-3-O-methyl-4-O-methylsulfonyl-D-inositol joins in the acid solvent, stirring reaction is after 4～24 hours under 40～90 ℃ of conditions, removal of solvent under reduced pressure gets white particle crystal 3-O-methyl-4-O-methylsulfonyl-D-inositol with equal proportion ethanol and acetone mixed solvent recrystallization;
This step is applicable to the synthetic of all above-mentioned 3-O-methyl-4-O-methylsulfonyl-D-inositols.
The 4th step: 3-O-methyl-4,5-epoxy-D-inositol synthetic
3-O-methyl-4-O-methylsulfonyl-D-inositol adds in the absolute alcohol solvent, add anhydrous basic catalyst again, stirring reaction is 2～12 hours under the mixed liquid chamber temperature, TLC detects the raw material completely dissolve, it is 8 ± 0.2 that reaction solution is neutralized to pH with rare hydrochloric acid methanol liquid, remove by filter inorganic salt, filtrate rotation evaporate to dryness gets white solid 3-O-methyl-4,5-epoxy-D-inositol;
This step is applicable to all above-mentioned 3-O-methyl-4,5-epoxy-D-inositol synthetic.
The 5th step: 3-O-methyl D-inositol-5-azole like nucleoside analogue thing and 3-O-methyl D-inositol-4-azole like nucleoside analogue thing synthetic
3-O-methyl-4,5-epoxy-D-inositol and the adding of exsiccant azole base are equipped with in the there-necked flask of anhydrous inert solvent, in 70～150 ℃ of whipping process of suspension liquid, with 1,8-diazabicylo hendecene (1,8-diazabicyclo[5.4.0] undec-7-ene, DBU) with after the anhydrous inert solvent dilution, slowly add with the normal pressure dropping funnel, reaction solution becomes the clarification back and continued stirring reaction 12～72 hours under this temperature, the oil pump underpressure distillation removes and desolvates the orange-yellow residue rapid column chromatography of gained (MeOH/CHCl
3=1: 8), promptly make add the corresponding 3-O-methyl D-inositol of azole base-5-azole like nucleoside analogue thing and 3-O-methyl D-inositol-4-azole like nucleoside analogue thing white powder solid.
This step is applicable to the synthetic of all above-mentioned 3-O-methyl D-inositol-5-azole like nucleoside analogue things and 3-O-methyl D-inositol-4-azole like nucleoside analogue thing.
Wherein, the organic basic solvent in the reaction of second step is pyridine or triethylamine; Acid solvent in the three-step reaction is that volume percent is the aqueous solution of 5%～95% hydrochloric acid, acetate or trifluoroacetic acid; Absolute alcohol solvent in the four-step reaction is anhydrous methanol or dehydrated alcohol; Anhydrous basic catalyst is Anhydrous potassium carbonate or sodium methylate; Azole base in the reaction of the 5th step is one of triazole, benzoglyoxaline, benzotriazole, benzopyrazoles (indazole), imidazoles, pyrazoles, pyrroles, indoles, carbazole, pyrrolo-imidazoles, Thienoimidazole, thiazole and imidazoles.Can be selected from following substituent group and replace by one or more on the wherein above-mentioned ring-type azole base group: (1) hydroxyl; (2) halogen atom; (3) itrile group; (4) nitro; (5) amino; (6) C
1-C
5Alkyl, C
2-C
5Thiazolinyl or C
2-C
5Alkynyl, wherein each group all can be replaced by at least one or a plurality of halogen atom; (7) C
1-C
5Alkoxyl group, C
2-C
5Alkenyloxy or C
2-C
5Chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (8) C
1-C
5Alkylthio, C
2-C
5Alkenyl thio or C
2-C
5Sulfur-based chain acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (9) amido; (10) nitrogen base repeatedly; (11) C
1-C
5Ester group; Anhydrous inert solvent is N, dinethylformamide or dimethyl sulfoxide (DMSO).
In the synthetic method of above-mentioned six-membered carbon ring nucleoside analog, the organic basic solvent in the reaction of second step is preferably pyridine; It is 20%～95% the acetate or the aqueous solution of trifluoroacetic acid that acid solvent in the three-step reaction is preferably volume percent; Absolute alcohol solvent in the four-step reaction is preferably anhydrous methanol; Anhydrous basic catalyst is preferably Anhydrous potassium carbonate; One of the preferred triazole of azole base, benzoglyoxaline, benzotriazole, benzopyrazoles (indazole), imidazoles, pyrazoles, pyrroles, indoles, carbazole, pyrrolo-imidazoles, Thienoimidazole, thiazole and imidazoles in the reaction of the 5th step.Can be selected from following substituent group and replace by one or more on the wherein above-mentioned ring-type azole base group: (1) hydroxyl; (2) halogen atom; (3) itrile group;
(4) nitro; (5) amino; (6) C
1-C
5Alkyl, C
2-C
5Thiazolinyl or C
2-C
5Alkynyl, wherein each group all can be replaced by at least one or a plurality of halogen atom; (7) C
1-C
5Alkoxyl group, C
2-C
5Alkenyloxy or C
2-C
5Chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (8) C
1-C
5Alkylthio, C
2-C
5Alkenyl thio or C
2-C
5Sulfur-based chain acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (9) amido; (10) nitrogen base repeatedly; (11) C
1-C
5Ester group; Anhydrous inert solvent is preferably dimethyl sulfoxide (DMSO).
In the synthetic method of above-mentioned six-membered carbon ring nucleoside analog, the building-up reactions formula that relates to is as follows:
The present invention also provides the mixture of the pharmaceutically acceptable of one group of above-mentioned six-membered carbon ring azole like nucleoside analogue thing with acid, and its structure is as (III) with (IV):
Wherein:
B is one of triazole, benzoglyoxaline, benzotriazole, benzopyrazoles (indazole), imidazoles, pyrazoles, pyrroles, indoles, carbazole, pyrrolo-imidazoles, Thienoimidazole, thiazole and imidazoles.Can be selected from following substituent group and replace by one or more on the wherein above-mentioned ring-type azole base group: (1) hydroxyl; (2) halogen atom; (3) itrile group; (4) nitro; (5) amino; (6) C
1-C
5Alkyl, C
2-C
5Thiazolinyl or C
2-C
5Alkynyl, wherein each group all can be replaced by at least one or a plurality of halogen atom; (7) C
1-C
5Alkoxyl group, C
2-C
5Alkenyloxy or C
2-C
5Chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (8) C
1-C
5Alkylthio, C
2-C
5Alkenyl thio or C
2-C
5Sulfur-based chain acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (9) amido; (10) nitrogen base repeatedly; (11) C
1-C
5Ester group.Acid is selected from: one of hydrochloric acid, Hydrogen bromide, sulfuric acid, mistake chloric acid, fumaric acid, toxilic acid, phosphoric acid, oxyacetic acid, lactic acid, Whitfield's ointment, succsinic acid, tosic acid, tartrate, acetate, citric acid, methylsulfonic acid, formic acid, phenylformic acid, propanedioic acid and Phenylsulfonic acid.
The synthetic method of above-mentioned mixture, realized by following steps:
Six-membered carbon ring azole like nucleoside analogue thing is in polar solvent, being stirred to solid with equimolar acid under 20 ℃～60 ℃ dissolves fully, crystal is separated out in the room temperature cooling then, filter solid, and use ether washed product, vacuum-drying to obtain ribavirin analogue, benzimidazole nucleoside analogue, benzotriazole nucleoside analog and benzopyrazoles (indazole) nucleoside analog of quebrachitol and the mixture of acid.
Wherein, the polar solvent described in the above-mentioned steps is preferably one of ethanol, Virahol, propyl carbinol, DMF, DMSO; Described acid is preferably one of hydrochloric acid, fumaric acid, lactic acid.
Above-mentioned steps is applicable to pharmaceutically acceptable mixture synthetic of all above-mentioned six-membered carbon ring azole like nucleoside analogue things.
In the synthetic method of the pharmaceutically acceptable mixture of above-mentioned six-membered carbon ring azole like nucleoside analogue thing, the reaction formula that relates to is as follows:
Wherein B and formula (I) and (II) identical are one of triazole, benzoglyoxaline, benzotriazole, benzopyrazoles (indazole), imidazoles, pyrazoles, pyrroles, indoles, carbazole, pyrrolo-imidazoles, Thienoimidazole, thiazole and imidazoles.Can be selected from following substituent group and replace by one or more on the wherein above-mentioned ring-type azole base group: (1) hydroxyl; (2) halogen atom; (3) itrile group; (4) nitro; (5) amino; (6) C1-C5 alkyl, C2-C5 thiazolinyl or C2-C5 alkynyl, wherein each group all can be replaced by at least one or a plurality of halogen atom; (7) C1-C5 alkoxyl group, C2-C5 alkenyloxy or C2-C5 chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (8) C1-C5 alkylthio, C2-C5 alkenyl thio or C2-C5 sulfur-based chain acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (9) amido; (10) nitrogen base repeatedly; (11) C1-C5 ester group.
The present invention also provides the application of described six-membered carbon ring azole like nucleoside analogue thing as antiviral and antitumor drug the time.
The application of pharmacy acceptable salt as antiviral and antitumor drug time of described six-membered carbon ring azole like nucleoside analogue thing also is provided simultaneously.
The present invention also provides and has been used for antiviral and antitumor medicine composition, wherein contains six-membered carbon ring azole like nucleoside analogue thing of the present invention and pharmaceutically acceptable one or more carriers for the treatment of significant quantity; Pharmacy acceptable salt and pharmaceutically acceptable one or more carriers of perhaps wherein containing the six-membered carbon ring azole like nucleoside analogue thing of the present invention for the treatment of significant quantity.
Below with the pharmacy acceptable salt of six-membered carbon ring azole like nucleoside analogue thing of the present invention or described six-membered carbon ring azole like nucleoside analogue thing antiviral and antitumor, especially to human immunodeficiency virus (HIV) and born of the same parents' rash viroid (HSV) activity, and the human transitional cell bladder carcinoma cell line (T of Human Lung Cancer cell (PG)
24) etc. the experiment of aspect further set forth its application.
Utilize cell culture method, measure The compounds of this invention in external influence to virus replications such as HIV-1, HIV-2, HSV-1, HSV-2.In the antiviral activity research, with 50 μ l MT-4 and CCL18 cell respectively with 2 * 10
5/ ml concentration is inoculated in the 96 porocyte culture plates, adds 50 μ l 10 respectively
-2HIV-1 (HIV-2) zoo virus strain IIIB nutrient solution and HSV-1 (HSV-2) virus-culturing fluid, add simultaneously 10,3.33,1.11 with the 0.37 μ g/ml positive control drug zidovudine (Zidovudine of totally 4 different concns medicines or different weaker concns, AZT) soup 100 μ l are at 37 ℃, 5%CO
2With cultivate under the saturated humidity, the observation of cell pathology was inhaled in the 7th day and to be abandoned supernatant 100 μ l, every hole adds 10 μ l 5mg/ml MTT dyeing, 37 ℃, 5%CO
2Continue in the saturated humidity incubator to cultivate 4 hours, every hole adds 100 μ l 50%DMF-17%Triton X-100 destainers, and 37 ℃ are spent the night, and measuring wavelength on enzyme connection instrument is the OD of 570nm
570nmValue adopts Reed﹠amp; The Muench method calculates medicine medium effective concentration (EC in cell cultures
50) and viral inhibiting rate.
Adopt mtt assay, measure The compounds of this invention external to Human Lung Cancer cell strain (PG) and human bladder cancer cell line (T
24) restraining effect.In the anti-tumor activity research, Human Lung Cancer cell strain (PG) and human bladder cancer cell line (T
24) be target cell, cell culture medium is 1640 substratum that contain 10%BCS, the logarithmic phase cell with trysinization after, regulating cell density is 3～5 * 10
3Individual/hole, be seeded in 96 well culture plates, every hole 100 μ l, putting into temperature is 37 ℃, CO
2Content is to cultivate 24 hours in 0.5% the incubator.The sample of the different concns for preparing is added 50 μ l/ holes in 96 well culture plates, (put into temperature is 37 ℃ to the positive control drug zidovudine of different weaker concns, CO for Zidovudine, AZT) the positive contrast of soup
2Content is to continue in 0.5% the incubator to cultivate 48 hours.Take out 96 well culture plates, every hole adds the MTT of the 5mg/mL of 20 μ l, continues to cultivate 4 hours.Take out culture plate, pour out substratum, every hole adds 150 μ l DMSO, and 37 ℃ vibrated 6 minutes, and the 490nm place measures the optical density value in each hole.Calculate inhibiting rate: (OD
Negative control-OD
Sample)/OD
Negative control* 100%.
Compound of the present invention and pharmaceutical composition can be used for preparing antiviral and medicine tumour.
The various formulations of pharmaceutical composition of the present invention can for example make activeconstituents mix with one or more carriers according to the conventional production method preparation of pharmaceutical field, are made into required formulation then.
Pharmaceutical composition of the present invention preferably contains the activeconstituents that weight ratio is 0.1%-99.5%, most preferably contains the activeconstituents that weight ratio is 0.5%-95%.
According to aforementioned said synthetic route and method, can stablize, repeatable synthesizing obtain compound of the present invention; Adopt the synthetic compound of the present invention of the inventive method, with low cost, easy and simple to handle; Repeatedly the extracorporeal antivirus effect activity test proves, The compounds of this invention is antiviral and anti-tumor activity test result circulation ratio is good.
Embodiment:
The anti-HIV of The compounds of this invention and anti-HSV activity test result show: all test compounds all have restraining effect to HIV-1, HIV-2, HSV-1, HSV-2; Antitumor activity in vitro is the result show: all test compounds are to Human Lung Cancer cell strain (PG) and human bladder cancer cell line (T
24) restraining effect all arranged
Following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.The structure warp of all compounds
1H-NMR,
13C-NMR determines.
Embodiment 1: 3-O-methyl D-inositol-5-deoxidation-5-(1 '-(1 ', 2 ', 4 '-triazole)) and 3-O-methyl D-inositol-4-deoxidation-4-'s (1 '-(1 ', 2 ', 4 '-triazole)) (compound number is respectively 1a and 1b) is synthetic
(1) 1,2:5,6-two-O-isopropylidene-3-O-methyl D-inositol synthetic
In the 500mL three-necked bottle, add 25mLDMF, 50mL 2, behind 2-Propanal dimethyl acetal and the 150mL acetone, add 3-O-methyl D-inositol 10.0g (51.5mmol), tosic acid 380mg (2.0mmol) and anhydrous magnesium sulfate 9.0g, suspension liquid at room temperature stirred 16 hours, add sodium bicarbonate 1.0g, stir after-filtration half an hour, filter residue merges with ethyl acetate washing 3 times and filtrate, use equal proportion normal hexane and ether mixed solvent recrystallization behind the concentrating under reduced pressure, get white solid product 1,2:5,6-two-O-isopropylidene-3-O-methyl D-inositol 12.6g (46.0mmol, 89%), thick product can be directly used in the next step.Fusing point: 95-96 ℃,
(c=0.021g/mL, CHCl
3).IR(KBr)：3431，2996，2981，1370，1210，1092，1066cm
-1.
1H-NMR(300MHz，acetone-d
6)δ，ppm：4.19-4.17(m，4H，CH×4)，3.55(dd，1H，J＝11.2，6.8Hz，CH)，3.52(s，3H，OCH
3)，3.16(dd，1H，J＝11.1，6.3Hz，CH)，2.99(bs，1H，OH)，1.45(s，3H，CH
3)，1.41(s，3H，CH
3)，1.31(s，3H，CH
3)，1.23(s，3H，CH
3).
13C-NMR(75MHz，acetone-d
6)δ，ppm：109.9(C(CH
3)
2)，109.8(C(CH
3)
2)，82.7(CH)，80.2(CH)，79.9(CH)，78.2(CH)，77.9(CH)，72.2(CH)，59.4(OCH
3)，28.0(CH
3)，27.9(CH
3)，25.4(CH
3)，25.3(CH
3)。
(2) 1,2:5,6-two-O-isopropylidene-3-O-methyl-4-O-methylsulfonyl-D-inositol synthetic
3.56g (13mmol) ketal compound is joined in the there-necked flask that fills the 15mL dry pyridine; ice bath is cooled to 0-5 ℃; slowly in reaction flask, drip 1.1ml (142mmol) methylsulfonyl chloride; after dropwising; keep uniform temp reaction 24 hours; reaction solution is poured in the hydrochloric acid ice aqueous solution of 3 volumetric molar concentrations while stirring, has a large amount of white precipitates to separate out suction filtration; the white filter cake also dewaters to neutral with absolute ethanol washing; the dehydrated alcohol recrystallization gets white particle crystal 1,2:5; 6-two-O-isopropylidene-3-O-methyl-4-O-methylsulfonyl-thick the product of D-inositol 4.53g; productive rate is 99%, and thick product can be directly used in the next step, fusing point: 120-122 ℃.IR(KBr)：2998，2989，2941，1384，1373，1350，1224，1172，1185，1071cm
-1.
1H?NMR(600MHz，CDCl
3)δ，ppm：4.51(dd，1H，J＝8.4，11.16Hz，CH)，4.44(dd，1H，J＝3.06，6.06Hz，CH)，4.41(q，1H，CH)，4.30(dd，1H，J＝6.42，8.04Hz，CH)，4.24(t，1H，J＝6.86Hz)，3.60(s，3H，OCH
3)，3.26(dd，1H，J＝7.56，11.16)，3.14(s，3H，OMs)，1.53(s，3H，CH
3)，1.52(s，3H，CH
3)，1.37(s，3H，CH
3)，1.36(s，3H，CH
3).
13C?NMR(150MHz，CDCl
3)δ，ppm：110.29(C(CH
3)
2)，109.77(C(CH
3)
2)，82.66(CH)，80.07(CH)，79.15(CH)，76.73(CH)，75.82(CH)，75.43(CH)，60.53(OCH
3)，39.49(OMs)，28.17(CH
3)，27.83(CH
3)，25.85(CH
3)，25.80(CH
3)。
(3) 3-O-methyl-4-O-methylsulfonyl-D-inositol is synthetic
The ketal list methanesulfonates 7.2g (20.46mmol) of protection adding is equipped with in the reaction flask of 60mL 80%AcOH solution fully; 80 ℃ of stirring reactions 10 hours; after the removal of solvent under reduced pressure; get white particle crystal 3-O-methyl-4-O-methylsulfonyl-D-inositol 4.49g (16.51mmol) with equal proportion ethanol and acetone mixed solvent recrystallization; productive rate is 80.68%, fusing point: 144-146 ℃.
1H?NMR(600MHz，DMSO-d
6)δ，ppm：3.15(s，3H，MsO)，3.24(t，J＝9.5Hz，1H，CH)，3.44(s，3H，MeO)，3.60(m，1H，CH)，3.64(dd，J＝3.7，7.1Hz，1H，CH)，3.67-3.72(m，2H，2×CH)，4.43(t，J＝9.53Hz，1H，CH)，4.88(d，J＝6.72Hz，1H，OH)，5.03(d，J＝0.82Hz，1H，OH)，5.04(dd，J＝2.1Hz，1H，OH)，5.14(d，J＝3.93Hz，1H，OH).
13C?NMR(150MHz，DMSO-d
6)δ，ppm：39.14(MsO)，59.83(MeO)，68.63，70.40，72.03，72.37，81.27，85.41。
(4) 3-O-methyl-4,5-epoxy-D-inositol synthetic
The single methanesulfonates 1.088g (4mmol) that sloughs ketal protected group adds in the 30mL anhydrous methanol, adds the 0.72g anhydrous K again
2CO
3Stirring reaction is 8 hours under the mixed liquid chamber temperature, TLC detects the raw material completely dissolve, it is about 8 that reaction solution is neutralized to pH with rare hydrochloric acid methanol liquid, remove by filter inorganic salt, filtrate rotation evaporate to dryness gets white solid 3-O-methyl-4,5-epoxy-D-inositol 0.514g, productive rate is 73%, fusing point: 192-194 ℃.
1H?NMR(600MHz，D
2O)δ，ppm：3.44(s，3H，CH
3O)，3.50(t，J＝3.54Hz，1H)，3.58(dd，J＝1.78，5.86Hz，1H)，3.62(t，J＝3.22Hz，1H)，3.72-3.75(m，2H)，4.04(dd，J＝3.16，5.84Hz，1H)。
13C?NMR(150MHz，D
2O)δ，ppm：53.61(epoxy)，56.02(epoxy)，56.85(CH
3O)，67.86，69.28，71.04，77.41。
(5) 3-O-methyl D-inositol-5-deoxidation-5-(1 '-(1 ', 2 ', 4 '-triazole)) (1a) and (1b) synthetic of 3-O-methyl D-inositol-4-deoxidation-4-(1 '-(1 ', 2 ', 4 '-triazole))
Epoxy compounds 352mg (2mmol) and exsiccant 1 ', 2 ', 4 '-triazole 207mg (3mmol) adding is equipped with in the there-necked flask of the anhydrous DMSO of 4ml, in 100 ℃ of whipping process of suspension liquid, with DBU 0.5ml (3.3mmol) with the anhydrous DMSO of 2ml dilution after, slowly add with the normal pressure dropping funnel, reaction solution becomes the clarification back and continued stirring reaction 36 hours under this temperature, DMSO is removed in the oil pump underpressure distillation, the orange-yellow residue rapid column chromatography of gained (MeOH/CHCl
3=1: 8), get white powder solid 1a 103mg and 1b 255mg productive rate respectively and be respectively 21% and 52%.
3-O-methyl D-inositol-5-deoxidation-5-(1 '-(1 ', 2 ', 4 '-triazole)) is (1a): fusing point: 235-236 ℃.
1H?NMR(600MHz，D
2O)δ，ppm：3.41(s，3H，CH
3O)，3.66(t，J＝3.59Hz，1H，H-3’)，3.73(dd，J＝3.26，9.83Hz，1H，H-1’)，4.01(t，J＝9.92Hz，1H，H-4’)，4.23(t，J＝3.60Hz，1H，H-6’)，4.25(m，1H，H-5’)，4.31(dd，J＝3.22，10.77Hz，1H，H-2’)，8.04(s，1H，H-3)，8.38(s，1H，H-5).
13C?NMR(150MHz，D
2O)δ，ppm：61.22(CH
3O)，67.31(C-5’)，70.19(C-2’)，70.39(C-6’)，72.23(C-4’)，73.35(C-1’)，83.63(C-3’)，148.43(C-5)，154.51(C-3).ESI-MS：(MH
+)246.5.
3-O-methyl D-inositol-4-deoxidation-4-(1 '-(1 ', 2 ', 4 '-triazole)) is (1b): fusing point: 273-275 ℃.
1H?NMR(600MHz，D
2O)δ，ppm：3.44(s，3H，CH
3O)，3.58(t，J＝3.69Hz，1H，H-3’)，3.80(dd，J＝3.44，9.76Hz，1H，H-2’)，4.12(t，J＝9.88Hz，1H，H-5’)，4.26(t，J＝3.84Hz，1H，H-1’)，4.25(m，1H，H-6’)，4.24(dd，J＝3.16，10.84Hz，1H，H-4’)，8.12(s，1H，H-3)，8.41(s，1H，H-5).
13C?NMR(150MHz，D
2O)δ，ppm：60.84(CH
3O)，67.56(C-4’)，71.79(C-2’)，71.92(C-6’)，72.34(C-5’)，73.35(C-1’)，84.01(C-3’)，147.68(C-5)，153.28(C-3).ESI-MS：(MH
+)246.6.
Embodiment 2: 3-O-methyl D-inositol-5-deoxidation-5-(1 '-(5 '-nitro indazole)) and 3-O-methyl D-inositol-4-deoxidation-4-'s (1 '-(5 '-nitro indazole)) (compound number is respectively 2a and 2b) is synthetic
(1) 1,2:5,6-two-O-isopropylidene-3-O-methyl D-inositol synthetic
Synthetic as embodiment 1 (1) method and condition.
(2) 1,2:5,6-two-O-isopropylidene-3-O-methyl-4-O-methylsulfonyl-D-inositol synthetic
Synthetic as embodiment 1 (2) method and condition.
(3) 3-O-methyl-4-O-methylsulfonyl-D-inositol is synthetic
Synthetic as embodiment 1 (3) method and condition.
(4) 3-O-methyl-4,5-epoxy-D-inositol synthetic
Synthetic as embodiment 1 (4) method and condition.
(5) 3-O-methyl D-inositol-5-deoxidation-5-(1 '-(5 '-nitro indazole)) and 3-O-methyl D-inositol-4-deoxidation-4-'s (1 '-(5 '-nitro indazole)) (compound number is respectively 2a and 2b) is synthetic
Epoxy compounds 352mg (2mmol) and exsiccant 5 '-nitro indazole 489mg (3mmol) adding is equipped with in the there-necked flask of the anhydrous DMSO of 4ml, in 100 ℃ of whipping process of suspension liquid, after the anhydrous DMSO dilution of DBU 0.5ml (3.3mmol) usefulness 2ml, slowly add with the normal pressure dropping funnel, reaction solution becomes the clarification back and continued stirring reaction 36 hours under this temperature, DMSO is removed in the oil pump underpressure distillation, and the orange-yellow residue rapid column chromatography of gained gets white powder solid 2a217mg and 2b 380mg productive rate respectively and is respectively 32% and 56%.
3-O-methyl D-inositol-5-deoxidation-5-(1 '-(5 '-nitro indazole)) is (2a):
1H NMR (600MHz, D
2O) δ, ppm:3.57 (s, 3H, CH
3O), 3.83 (m, 1H, H-3 '), 3.96 (dd, J=3.25,9.82Hz, 1H, H-6 '), 4.29 (m, 1H, H-2 '), 4.40 (t, J=3.62Hz, 1H, H-4 '), 4.57 (m, 1H, H-5 '), 4.60 (m, 1H, H-1 '), 7.71 (d, J=9.38Hz, 1H, H-1), 8.31 (dd, J=2.15,9.37Hz, 1H, H-6), 8.47 (s, 1H, H-7), 8.84 (d, J=1.94Hz, 1H, H-4) ..
13C NMR (150MHz, D
2O) δ, ppm:61.31 (CH
3O), 70.63 (C-4 '), 71.01 (C-1 '), 71.50 (C-5 '), 73.28 (C-2 '), 73.77 (C-6 '), 83.96 (C-3 '), 112.72 (C-1), 122.11 (C-4), 122.61 (C-3), 124.84 (C-6), 140.49 (C-7), 144.91 (C-5), 147.02 (C-2).ESI-MS：(MH
+)340.5。
3-O-methyl D-inositol-4-deoxidation-4-(1 '-(5 '-nitro indazole)) is (2b):
1H NMR (600MHz, D
2O) δ, ppm:3.55 (s, 3H, CH
3O), 3.82 (m, 1H, H-3 '), 3.91 (dd, J=3.22,9.75Hz, 1H, H-1 '), 4.32 (m, 1H, H-6 '), 4.38 (t, J=3.59Hz, 1H, H-5 '), 4.54 (m, 1H, H-4 '), 4.62 (m, 1H, H-2 '), 7.76 (d, J=9.52Hz, 1H, H-1), 8.14 (dd, J=2.22,9.51Hz, 1H, H-6), 8.66 (s, 1H, H-7), 8.86 (d, J=1.75Hz, 1H, H-4).
13C NMR (150MHz, D
2O) δ, ppm:61.44 (CH
3O), 70.63 (C-4 '), 71.09 (C-2 '), 71.50 (C-5 '), 73.08 (C-6 '), 73.65 (C-1 '), 83.96 (C-3 '), 119.98 (C-1), 123.61 (C-4), 123.78 (C-3), 124.82 (C-6), 134.40 (C-7), 145.31 (C-5), 152.80 (C-2).ESI-MS：(MH
+)340.5。
Can synthesize with above-mentioned same similarly method and to obtain 3-O-methyl D-inositol-5-deoxidation-5-(1 '-benzotriazole) and 3-O-methyl D-inositol-4-deoxidation-4-(1 '-benzotriazole) (compound number is respectively 3a and 3b), 3-O-methyl D-inositol-5-deoxidation-5-(1 '-(6 '-nitro indazole)) and 3-O-methyl D-inositol-4-deoxidation-4-(1 '-(6 '-nitro indazole)) (compound number is respectively 4a and 4b), 3-O-methyl D-inositol-5-deoxidation-5-(1 '-imidazoles) and 3-O-methyl D-inositol-4-deoxidation-4-(1 '-imidazoles) (compound number is respectively 5a and 5b), 3-O-methyl D-inositol-5-deoxidation-5-(1 '-pyrazoles) and 3-O-methyl D-inositol-4-deoxidation-4-(1 '-pyrazoles) (compound number is respectively 6a and 6b) etc.
Embodiment 3: 3-O-methyl D-inositol-5-deoxidation-5-(1 '-(1 ', 2 ', 4 '-triazole)) fumaric acid mixture (1c) synthetic
3-O-methyl D-inositol-5-deoxidation-5-(1 '-(1 ', 2 ', 4 '-triazole)) synthetic method of fumaric acid mixture (1c) is as follows: 3-O-methyl D-inositol-5-deoxidation-5-(1 '-(1 ', 2 ', 4 '-triazole)) 245mg (1mmol) is mixed with fumaric acid 124mg (1mmol) and 2ml Virahol, the mixed liquid of gained is stirred to solid and dissolves fully under 50 ℃, crystal is separated out in the room temperature cooling then, filter solid, and use the ether washed product, vacuum-drying gets 269mg, and productive rate is 73%
1Remove among the H NMR (DMSO) outside 3-O-methyl D-inositol-5-deoxidation-5-(1 '-(1 ', 2 ', 4 '-triazole)) signal, (s 2H) locates to demonstrate the signal of the two key hydrogen of fumaric acid at δ (ppm) 6.185.
Embodiment 4: 3-O-methyl D-inositol-4-deoxidation-4-(1 '-(1 ', 2 ', 4 '-triazole)) fumaric acid mixture (1d) synthetic
3-O-methyl D-inositol-4-deoxidation-4-(1 '-(1 ', 2 ', 4 '-triazole)) synthetic method of fumaric acid mixture (1d) is as follows: 3-O-methyl D-inositol-4-deoxidation-4-(1 '-(1 ', 2 ', 4 '-triazole)) 245mg (1mmol) is mixed with fumaric acid 124mg (1mmol) and 2ml Virahol, the mixed liquid of gained is stirred to solid and dissolves fully under 50 ℃, crystal is separated out in the room temperature cooling then, filter solid, and use the ether washed product, vacuum-drying gets 255mg, and productive rate is 69%
1Remove among the H NMR (DMSO) outside 3-O-methyl D-inositol-4-deoxidation-4-(1 '-(1 ', 2 ', 4 '-triazole)) signal, (s 2H) locates to demonstrate the signal of the two key hydrogen of fumaric acid at δ (ppm) 6.367.
Embodiment 5: 3-O-methyl D-inositol-5-deoxidation-5-(9 '-(5 '-nitro indazole)) fumaric acid mixture (2c) synthetic
The synthetic method of 3-O-methyl D-inositol-5-deoxidation-5-(9 '-(5 '-nitro indazole)) fumaric acid mixture (2c) is as follows: 3-O-methyl D-inositol-5-deoxidation-5-(9 '-(5 '-nitro indazole)) 339mg (1mmol) is mixed with fumaric acid 124mg (1mmol) and 2ml Virahol, the mixed liquid of gained is stirred to solid and dissolves fully under 50 ℃, crystal is separated out in the room temperature cooling then, filter solid, and use the ether washed product, vacuum-drying gets 357mg, and productive rate is 77%
1Except that 3-O-methyl D-inositol-5-deoxidation-5-(9 '-(5 '-nitro indazole)) signal, (s 2H) locates to demonstrate the signal of the two key hydrogen of fumaric acid at δ (ppm) 6.264 among the H NMR (DMSO).
Embodiment 6: 3-O-methyl D-inositol-4-deoxidation-4-(9 '-(5 '-nitro indazole)) fumaric acid mixture (2d) synthetic
The synthetic method of 3-O-methyl D-inositol-4-deoxidation-4-(9 '-(5 '-nitro indazole)) fumaric acid mixture (2d) is as follows: 3-O-methyl D-inositol-4-deoxidation-4-(9 '-(5 '-nitro indazole)) 339mg (1mmol) is mixed with fumaric acid 124mg (1mmol) and 2ml Virahol, the mixed liquid of gained is stirred to solid and dissolves fully under 50 ℃, crystal is separated out in the room temperature cooling then, filter solid, and use the ether washed product, vacuum-drying gets 329mg, and productive rate is 71%
1Except that 3-O-methyl D-inositol-4-deoxidation-4-(9 '-(5 '-nitro indazole)) signal, (s 2H) locates to demonstrate the signal of the two key hydrogen of fumaric acid at δ (ppm) 6.508 among the H NMR (DMSO).
Embodiment 7: 3-O-methyl D-inositol-5-deoxidation-5-(1 '-(1 ', 2 ', 4 '-triazole))) hydrochloric acid mixture (1e) is synthetic
3-O-methyl D-inositol-5-deoxidation-5-(1 '-(1 ', 2 ', 4 '-triazole)) synthetic method of hydrochloric acid mixture (1e) is as follows: 3-O-methyl D-inositol-5-deoxidation-5-(1 '-(1 ', 2 ', 4 '-triazole)) 245mg (1mmol) is mixed with hydrochloric acid 83 μ l (1mmol) and 2ml Virahol, the mixed liquid of gained is stirred to solid and dissolves fully under 50 ℃, crystal is separated out in the room temperature cooling then, filter solid, and use the ether washed product, vacuum-drying gets 220mg, and productive rate is 78%
1Signal is identical for signal and 3-O-methyl D-inositol-5-deoxidation-5-(1 '-(1 ', 2 ', 4 '-triazole)) among the H NMR (DMSO), but ESI-MS is (MH
+) 282.5, (MNa
+) 304.5, just in time have more the molecular weight of hydrochloric acid.
Embodiment 8: 3-O-methyl D-inositol-4-deoxidation-4-(1 '-(1 ', 2 ', 4 '-triazole)) hydrochloric acid mixture (1f) synthetic
3-O-methyl D-inositol-4-deoxidation-4-(1 '-(1 ', 2 ', 4 '-triazole)) synthetic method of hydrochloric acid mixture (1f) is as follows: 3-O-methyl D-inositol-4-deoxidation-4-(1 '-(1 ', 2 ', 4 '-triazole)) 245mg (1mmol) is mixed with hydrochloric acid 83 μ l (1mmol) and 2ml Virahol, the mixed liquid of gained is stirred to solid and dissolves fully under 50 ℃, crystal is separated out in the room temperature cooling then, filter solid, and use the ether washed product, vacuum-drying gets 214mg, and productive rate is 76%
1Signal is identical for signal and 3-O-methyl D-inositol-4-deoxidation-4-(1 '-(1 ', 2 ', 4 '-triazole)) among the H NMR (DMSO), but ESI-MS is (MH
+) 282.5, (MNa
+) 304.5, just in time have more the molecular weight of hydrochloric acid.
Embodiment 9: 3-O-methyl D-inositol-5-deoxidation-5-(9 '-(5 '-nitro indazole)) hydrochloric acid mixture (2e) synthetic
The synthetic method of 3-O-methyl D-inositol-5-deoxidation-5-(9 '-(5 '-nitro indazole)) hydrochloric acid mixture (2e) is as follows: 3-O-methyl D-inositol-5-deoxidation-5-(9 '-(5 '-nitro indazole)) 339mg (1mmol) is mixed with hydrochloric acid 83 μ l (1mmol) and 2ml Virahol, the mixed liquid of gained is stirred to solid and dissolves fully under 50 ℃, crystal is separated out in the room temperature cooling then, filter solid, and use the ether washed product, vacuum-drying gets 304mg, and productive rate is 81%
1Signal is identical with 3-O-methyl D-inositol-5-deoxidation-5-(9 '-(5 '-nitro indazole)) among the H NMR (DMSO), but ESI-MS is ESI-MS:(MH
+) 376.5, (MNa
+) 398.5, just in time have more the molecular weight of hydrochloric acid.
Embodiment 10: 3-O-methyl D-inositol-4-deoxidation-4-(9 '-(5 '-nitro indazole)) hydrochloric acid mixture (2f) synthetic
The synthetic method of 3-O-methyl D-inositol-4-deoxidation-4-(9 '-(5 '-nitro indazole)) hydrochloric acid mixture (2f) is as follows: 3-O-methyl D-inositol-4-deoxidation-4-(9 '-(5 '-nitro indazole)) 339mg (1mmol) is mixed with hydrochloric acid 83 μ l (1mmol) and 2ml Virahol, the mixed liquid of gained is stirred to solid and dissolves fully under 50 ℃, crystal is separated out in the room temperature cooling then, filter solid, and use the ether washed product, vacuum-drying gets 282mg, and productive rate is 75%
1Signal is identical with 3-O-methyl D-inositol-4-deoxidation-4-(9 '-(5 '-nitro indazole)) among the H NMR (DMSO), but ESI-MS is ESI-MS:(MH
+) 376.5, (MNa
+) 398.5, just in time have more the molecular weight of hydrochloric acid.
Embodiment 11: to the inhibition determination of activity of human immunodeficiency virus HIV-1
With MT-4 cell 2 * 10
5/ ml 50 μ l are inoculated in the 96 porocyte culture plates, add 50 μ l 10
-2HIV-1 zoo virus strain IIIB nutrient solution, add simultaneously 10,3.33,1.11 with 0.37 μ g/ml the positive control drug AZT (zidovudine) and the NVP soup 100 μ l of totally 4 different concns medicines or different weaker concns, at 37 ℃, 5%CO
2With cultivate under the saturated humidity, the observation of cell pathology was inhaled in the 7th day and to be abandoned supernatant 100 μ l, every hole adds 10 μ l 5mg/ml MTT dyeing, 37 ℃, 5%CO
2Continue in the saturated humidity incubator to cultivate 4 hours, every hole adds 100 μ l 50%DMF-17%Triton X-100 destainers, and 37 ℃ are spent the night, and measuring wavelength on enzyme connection instrument is the OD of 570nm
570nmValue adopts Reed﹠amp; The Muench method calculates medicine medium effective concentration (EC in cell cultures
50) and in cell cultures the viral inhibiting rate under the 10 μ g/ml drug levels.
Embodiment 12: to the inhibition determination of activity of human immunodeficiency virus HIV-2
Measure the inhibition activity of described compound with embodiment 11 similar approach to human immunodeficiency virus HIV-2.
Embodiment 13: to the inhibition determination of activity of born of the same parents' exanthema virus HSV-1
Measure the inhibition activity of described compound with embodiment 11 similar approach to human born of the same parents' exanthema virus HSV-1.
Implement 14: to the inhibition determination of activity of born of the same parents' exanthema virus HSV-2
Measure the inhibition activity of described compound with embodiment 11 similar approach to human born of the same parents' exanthema virus HSV-2.
The activity data that described each compound suppresses HIV-1, HIV-2, HSV-1 and HSV-2 is as shown in table 1:
Table 1: six-membered carbon ring azole like nucleoside analogue thing suppresses the activity data of HIV-1, HIV-2, HSV-1 and HSV-2
The result shows: all test compounds of the present invention all have the activity of inhibition to HIV-1, HIV-2, HSV-1 and HSV-2, wherein the inhibition HIV-1 activity of 1a has surpassed positive control drug AZT, the inhibition HSV-1 activity of 2b has surpassed positive control drug AZT, and 2a, 2c, 1e, 2e etc. have presented stronger inhibition HIV virus activity in addition; And 1a, 1b, 1c, 1d, 2d, 1e, 2f etc. have presented stronger inhibition HSV virus activity.
Embodiment 15: to the inhibition determination of activity of Human Lung Cancer cell strain (PG)
Adopting mtt assay, be target cell with Human Lung Cancer cell strain (PG), and cell culture medium is 1640 substratum that contain 10%BCS, the logarithmic phase cell with trysinization after, the adjusting cell density is 3～5 * 10
3Individual/hole, be seeded in 96 well culture plates, every hole 100 μ l, putting into temperature is 37 ℃, CO
2Content is to cultivate 24 hours in 0.5% the incubator.The sample of the different concns for preparing is added 50 μ l/ holes in 96 well culture plates, the positive contrast of positive control drug Sangivamycin soup of different weaker concns, putting into temperature is 37 ℃, CO
2Content is to continue in 0.5% the incubator to cultivate 48 hours.Take out 96 well culture plates, every hole adds the MTT of the 5mg/mL of 20 μ l, continues to cultivate 4 hours.Take out culture plate, pour out substratum, every hole adds 150 μ l DMSO, and 37 ℃ vibrated 6 minutes, and the 490nm place measures the optical density value in each hole.Calculate inhibiting rate: (OD
Negative control-OD
Sample)/OD
Negative control* 100%, and adopt Reed﹠amp; The Muench method calculates medicine medium effective concentration (EC in cell cultures
50).
Embodiment 16: to human bladder cancer cell line (T
24) the inhibition determination of activity
Measure described compound to human bladder cancer cell line (T with embodiment 15 similar approach
24) the inhibition activity.
Described each compound suppresses Human Lung Cancer cell (PG) and human transitional cell bladder carcinoma cell line (T
24) activity data as shown in table 2:
Table 2: six-membered carbon ring azole like nucleoside analogue thing suppresses lung carcinoma cell (PG) and transitional cell bladder carcinoma cell line (T
24) activity data
The result shows: all test compounds of the present invention are to Human Lung Cancer cell (PG) and human transitional cell bladder carcinoma cell line (T
24) restraining effect is in various degree all arranged, wherein compound 1a has strong restraining effect, EC to Human Lung Cancer cell (PG)
50Be 11.3 μ M, and compound 1d is to human transitional cell bladder carcinoma cell line (T
24) strong restraining effect, EC arranged
50Be 15.5 μ M.
Claims (10)
1. six-membered carbon ring azole like nucleoside analogue thing, its structure is suc as formula (I) with (II):
Wherein: B is one of triazole, benzoglyoxaline, benzotriazole, benzopyrazoles, imidazoles, pyrazoles, pyrroles, indoles, carbazole, pyrrolo-imidazoles, Thienoimidazole, thiazole and imidazoles; Can be selected from following substituent group and replace by one or more on the above-mentioned ring-type azole base group: (1) hydroxyl; (2) halogen atom; (3) itrile group; (4) nitro; (5) amino; (6) C
1-C
5Alkyl, C
2-C
5Thiazolinyl or C
2-C
5Alkynyl, wherein each group all can be replaced by at least one or a plurality of halogen atom; (7) C
1-C
5Alkoxyl group, C
2-C
5Alkenyloxy or C
2-C
5Chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (8) C
1-C
5Alkylthio, C
2-C
5Alkenyl thio or C
2-C
5Sulfur-based chain acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (9) amido; (10) nitrogen base repeatedly; (11) C
1-C
5Ester group.
2. the synthetic method of six-membered carbon ring azole like nucleoside analogue thing according to claim 1 is characterized in that, described compound is synthetic through the reaction of five steps:
The first step: 1,2:5,6-two-O-isopropylidene-3-O-methyl D-inositol synthetic
Take by weighing pinitol and join acetone and 2, in the mixed solvent of 2-Propanal dimethyl acetal, the tosic acid and the dewatering agent anhydrous magnesium sulfate that add catalytic amount again, 10～80 ℃ were stirred 5～24 hours down, in reaction mixture, add sodium bicarbonate, after the stirring, filter, filter residue merges with ethyl acetate washing 2～5 times and filtrate, with equal proportion normal hexane and ether mixed solvent recrystallization, get the cotton-shaped crystallization 1 of white cotton, 2:5 behind the concentrating under reduced pressure, 6-two-O-isopropylidene-3-O-methyl D-inositol, its structure is suc as formula shown in (i):
Second step: 1,2:5,6-two-O-isopropylidene-3-O-methyl-4-O-methylsulfonyl-D-inositol synthetic
The methylsulfonyl chloride adding is slowly added in the organic basic solvent; stirring is fully dissolved solid; ice-water bath is cooled to-10～0 ℃; reaction afterwards maintains under-10～10 ℃ and adds 1 in batches; 2:5; 6-two-O-isopropylidene-3-O-methyl D-inositol; stir after 1～24 hour, pour in the hydrochloric acid ice aqueous solution of 0.5～5 volumetric molar concentration suction filtration into; the white filter cake also dewaters to neutral with absolute ethanol washing; the dehydrated alcohol recrystallization gets white particle crystal 1,2:5; 6-two-O-isopropylidene-3-O-methyl-4-O-methylsulfonyl-D-inositol, its structure is suc as formula shown in (ii):
The 3rd step: 3-O-methyl-4-O-methylsulfonyl-D-inositol synthetic
With 1; 2:5; 6-two-O-isopropylidene-3-O-methyl-4-O-methylsulfonyl-D-inositol joins in the acid solvent; stirring reaction is after 4～24 hours under 40～90 ℃ of conditions; removal of solvent under reduced pressure; get white particle crystal 3-O-methyl-4-O-methylsulfonyl-D-inositol with equal proportion ethanol and acetone mixed solvent recrystallization, its structure is suc as formula shown in (iii):
The 4th step: 3-O-methyl-4,5-epoxy-D-inositol synthetic
3-O-methyl-4-O-methylsulfonyl-D-inositol adds in the absolute alcohol solvent; add anhydrous basic catalyst again; stirring reaction is 2～12 hours under the mixed liquid chamber temperature; TLC detects the raw material completely dissolve; it is 8 ± 0.2 that reaction solution is neutralized to pH with rare hydrochloric acid methanol liquid, removes by filter inorganic salt, and filtrate rotation evaporate to dryness gets white solid 3-O-methyl-4; 5-epoxy-D-inositol, its structure is suc as formula shown in (iv):
The 5th step: six-membered carbon ring azole like nucleoside analogue thing formula (I) and synthesizing (II)
3-O-methyl-4,5-epoxy-D-inositol and the adding of exsiccant azole base are equipped with in the there-necked flask of anhydrous inert solvent, in 70～150 ℃ of whipping process of suspension liquid, with 1,8-diazabicylo hendecene slowly adds with the normal pressure dropping funnel after diluting with anhydrous inert solvent, and reaction solution becomes the clarification back and continued stirring reaction 12～72 hours under this temperature, the oil pump underpressure distillation is desolvated, and the orange-yellow residue of gained is with MeOH/CHCl
3=1: 8 condition rapid column chromatographies, promptly make add the corresponding 3-O-methyl D-inositol-5-azole nucleosides shown in claim 1 Chinese style (I) of azole base and 3-O-methyl D-inositol-4-azole nucleosides white powder solid shown in claim 1 Chinese style (II).
3. as the synthetic method of six-membered carbon ring azole like nucleoside analogue thing as described in the claim 2, it is characterized in that the organic basic solvent in the reaction of second step is pyridine or triethylamine; Acid solvent in the three-step reaction is that volume percent is the aqueous solution of 5%～95% hydrochloric acid, acetate or trifluoroacetic acid; Absolute alcohol solvent in the four-step reaction is anhydrous methanol or dehydrated alcohol; Anhydrous basic catalyst is Anhydrous potassium carbonate or sodium methylate; Azole base in the reaction of the 5th step is one of triazole, benzoglyoxaline, benzotriazole, benzo pyrrole imidazoles, imidazoles, pyrazoles, pyrroles, indoles, carbazole, pyrrolo-imidazoles, Thienoimidazole, thiazole and imidazoles; Can be selected from following substituent group and replace by one or more on the wherein above-mentioned ring-type azole base group: (1) hydroxyl; (2) halogen atom; (3) itrile group; (4) nitro; (5) amino; (6) C
1-C
5Alkyl, C
2-C
5Thiazolinyl or C
2-C
5Alkynyl, wherein each group all can be replaced by at least one or a plurality of halogen atom; (7) C
1-C
5Alkoxyl group, C
2-C
5Alkenyloxy or C
2-C
5Chain oxy-acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (8) C
1-C
5Alkylthio, C
2-C
5Alkenyl thio or C
2-C
5Sulfur-based chain acetylene, wherein each group all can be replaced by at least one or a plurality of halogen atom; (9) amido; (10) nitrogen base repeatedly; (11) C
1-C
5Ester group; Anhydrous inert solvent is N, dinethylformamide or dimethyl sulfoxide (DMSO).
4. the application of six-membered carbon ring azole like nucleoside analogue thing in preparing antiviral and antitumor drug according to claim 1.
According to claim 1 six-membered carbon ring azole like nucleoside analogue thing pharmaceutically acceptable with acid mixture, its structure is as (III) with (IV):
Wherein:
Identical in B and the claim 1; Acid is selected from: one of hydrochloric acid, Hydrogen bromide, sulfuric acid, mistake chloric acid, fumaric acid, toxilic acid, phosphoric acid, oxyacetic acid, lactic acid, Whitfield's ointment, succsinic acid, tosic acid, tartrate, acetate, citric acid, methylsulfonic acid, formic acid, phenylformic acid, propanedioic acid and Phenylsulfonic acid.
6. as the preparation method of mixture as described in the claim 5, it is characterized in that realizing by following steps:
Six-membered carbon ring azole like nucleoside analogue thing is in polar solvent according to claim 1, being stirred to solid with equimolar acid under 20 ℃～60 ℃ dissolves fully, crystal is separated out in the room temperature cooling then, filter solid, and use ether washed product, vacuum-drying to obtain six-membered carbon ring azole like nucleoside analogue thing and sour mixture.
7. as the preparation method of mixture as described in the claim 6, it is characterized in that the polar solvent described in the step is one of ethanol, Virahol, propyl carbinol, DMF, DMSO; Described acid is one of hydrochloric acid, fumaric acid, lactic acid.
8. as the application in the antiviral and antitumor drug of the mixture of the pharmaceutically acceptable of six-membered carbon ring azole like nucleoside analogue thing as described in the claim 5 and acid in preparation.
9. be used for antiviral and antitumor medicine composition, wherein contain the claim 1 for the treatment of significant quantity described six-membered carbon ring azole like nucleoside analogue thing and pharmaceutically acceptable carrier.
10. be used for antiviral and antitumor medicine composition, wherein contain the pharmaceutically acceptable of the described six-membered carbon ring azole like nucleoside analogue of the claim 5 for the treatment of significant quantity thing and sour mixture and pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006101709913A CN100999503B (en) | 2006-12-26 | 2006-12-26 | Hexanary carbocycle azole like nucleoside analogue, its synthesizing process and use in anti virus and tumor thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006101709913A CN100999503B (en) | 2006-12-26 | 2006-12-26 | Hexanary carbocycle azole like nucleoside analogue, its synthesizing process and use in anti virus and tumor thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN100999503A CN100999503A (en) | 2007-07-18 |
| CN100999503B true CN100999503B (en) | 2011-03-16 |
Family
ID=38258339
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006101709913A Expired - Fee Related CN100999503B (en) | 2006-12-26 | 2006-12-26 | Hexanary carbocycle azole like nucleoside analogue, its synthesizing process and use in anti virus and tumor thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100999503B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1803819A (en) * | 2006-01-13 | 2006-07-19 | 山东大学 | A group of six-carbocycle nucleoside analogue, its synthesis method and antiviral application |
-
2006
- 2006-12-26 CN CN2006101709913A patent/CN100999503B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1803819A (en) * | 2006-01-13 | 2006-07-19 | 山东大学 | A group of six-carbocycle nucleoside analogue, its synthesis method and antiviral application |
Non-Patent Citations (2)
| Title |
|---|
| 李子成等.核苷类抗病毒药物的研究进展.化学研究与应用14 1.2002,14(1),15-20. |
| 李子成等.核苷类抗病毒药物的研究进展.化学研究与应用14 1.2002,14(1),15-20. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100999503A (en) | 2007-07-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2804375A1 (en) | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs | |
| EA028709B1 (en) | N-[(2'R)-2'-DEOXY-2'-FLUORO-2'-METHYL-p-PHENYL-5'-URIDYL]-L-ALANINE 1-METHYLETHYL ESTER AND PROCESS FOR PRODUCTION THEREOF | |
| CN103896954A (en) | Pyrazol norcantharidin derivative as well as preparation method and application thereof | |
| CN106795150A (en) | 1,3,4 thiadiazole compounds and its purposes in treating cancer | |
| CN104530021A (en) | Compounds and preparation method thereof, application of compounds in preparing antineoplastic drugs and antineoplastic drugs prepared from compounds | |
| KR100588803B1 (en) | Indirubin derivatives having anticancer property against human cancer cell line | |
| EA000033B1 (en) | Bis(2-haloethyl) aminophenyl substituted distamycin derivatives as antitumor and antiviral agents | |
| CN101215305B (en) | Glucosyl thiourea heterocyclic compound and its synthetic method and application in antineoplastic | |
| CN100999503B (en) | Hexanary carbocycle azole like nucleoside analogue, its synthesizing process and use in anti virus and tumor thereof | |
| CN100412083C (en) | A group of six-carbocycle nucleoside analogue, its synthesis method and antiviral application | |
| CN110183503B (en) | Sulfonyl azaspirodecadienone compounds and application thereof | |
| CN108997176B (en) | 4-chloro-N-substituted phenyl-3-sulfonyl aminobenzamide compound, and preparation and anti-tumor application thereof | |
| Hayes et al. | Preparation and characterisation of solid state forms of paracetamol-O-glucuronide | |
| EP1622913A1 (en) | Heterocyclic compounds for use in the treatment of viral infections | |
| Almerico et al. | Glycosidopyrroles. part 4. 1-β-D-ribofuranosyl-pyrroles and indoles as potential antiviral agents | |
| CN116096372A (en) | EGFR inhibitor, preparation method and pharmaceutical application thereof | |
| CN102260273B (en) | Deoxypodophyllo and 5-fluorouracil spliced compounds and preparation and application thereof | |
| Liu et al. | Synthesis and in vitro antitumour activity of 4 (R)-methyl-3-O-phosphonomethyl-α-l-threose nucleosides | |
| CN101307078B (en) | Galactosyl thiourea heterocyclic compounds, synthetic method thereof and antineoplastic applications | |
| CN105481830A (en) | Antitumor compound and preparation method thereof | |
| KR20080086481A (en) | Dioxolane derivates for the treatment of cancer | |
| Kumar | 5-Bromo (or chloro)-6-azido-5, 6-dihydro-2′-deoxyuridine and-thymidine derivatives with potent antiviral activity | |
| CN109206473B (en) | C12 and C13 substituted oleanolic acid derivatives, and preparation and application thereof | |
| CN115304605B (en) | Oxetane derivatives with antitumor activity, and preparation method and application thereof | |
| CN108863860A (en) | A kind of application of N- substituted-phenyl -3- sulphonamidobenzamide class compound and its preparation and anti-breast cancer activity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110316 Termination date: 20111226 |