CN1085673C - 膦酸酯－核苷酸化合物 - Google Patents
膦酸酯－核苷酸化合物 Download PDFInfo
- Publication number
- CN1085673C CN1085673C CN97198592A CN97198592A CN1085673C CN 1085673 C CN1085673 C CN 1085673C CN 97198592 A CN97198592 A CN 97198592A CN 97198592 A CN97198592 A CN 97198592A CN 1085673 C CN1085673 C CN 1085673C
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- CN
- China
- Prior art keywords
- compound
- general formula
- ethyl
- hex
- alkyl
- 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
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- -1 Phosphonate nucleotide compounds Chemical class 0.000 title abstract description 60
- 125000005843 halogen group Chemical group 0.000 claims abstract description 28
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000012453 solvate Substances 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 130
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 41
- 239000002773 nucleotide Substances 0.000 claims description 7
- 230000000840 anti-viral effect Effects 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 9
- 241000700721 Hepatitis B virus Species 0.000 abstract description 5
- 241000725303 Human immunodeficiency virus Species 0.000 abstract description 4
- 229910052757 nitrogen Chemical group 0.000 abstract description 3
- 241000700584 Simplexvirus Species 0.000 abstract description 2
- 239000003443 antiviral agent Substances 0.000 abstract description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 106
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 101
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 46
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 44
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 43
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 41
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 41
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 34
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 25
- 238000000034 method Methods 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 23
- 238000002360 preparation method Methods 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 17
- 229910052760 oxygen Inorganic materials 0.000 description 15
- 239000001301 oxygen Substances 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 229910052708 sodium Inorganic materials 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 239000011593 sulfur Substances 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 5
- 229910000105 potassium hydride Inorganic materials 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- SUVIGLJNEAMWEG-UHFFFAOYSA-N propane-1-thiol Chemical compound CCCS SUVIGLJNEAMWEG-UHFFFAOYSA-N 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229960001866 silicon dioxide Drugs 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- PMBXCGGQNSVESQ-UHFFFAOYSA-N 1-Hexanethiol Chemical compound CCCCCCS PMBXCGGQNSVESQ-UHFFFAOYSA-N 0.000 description 2
- BDFAOUQQXJIZDG-UHFFFAOYSA-N 2-methylpropane-1-thiol Chemical compound CC(C)CS BDFAOUQQXJIZDG-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 238000002105 Southern blotting Methods 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000002155 anti-virotic effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 229960004217 benzyl alcohol Drugs 0.000 description 2
- WQAQPCDUOCURKW-UHFFFAOYSA-N butanethiol Chemical compound CCCCS WQAQPCDUOCURKW-UHFFFAOYSA-N 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- YNLAOSYQHBDIKW-UHFFFAOYSA-M diethylaluminium chloride Chemical compound CC[Al](Cl)CC YNLAOSYQHBDIKW-UHFFFAOYSA-M 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 210000000936 intestine Anatomy 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000005905 mesyloxy group Chemical group 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- LXXSWZYRKAQQDI-UHFFFAOYSA-N n-ethyl-n-silylethanamine Chemical compound CCN([SiH3])CC LXXSWZYRKAQQDI-UHFFFAOYSA-N 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DEUJSGDXBNTQMY-UHFFFAOYSA-N 1,2,2-trifluoroethanol Chemical compound OC(F)C(F)F DEUJSGDXBNTQMY-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- LUTWEKBTDWRTSE-UHFFFAOYSA-N 1-chloro-2-(chloromethoxy)ethane Chemical compound ClCCOCCl LUTWEKBTDWRTSE-UHFFFAOYSA-N 0.000 description 1
- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 1
- 125000004776 1-fluoroethyl group Chemical group [H]C([H])([H])C([H])(F)* 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- NQEPEERUUJEBHK-UHFFFAOYSA-N 2-butylsulfanyl-7h-purine Chemical compound CCCCSC1=NC=C2NC=NC2=N1 NQEPEERUUJEBHK-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- BNKDQKJMJDGFGA-UHFFFAOYSA-N 2-ethyl-7h-purin-6-amine Chemical compound CCC1=NC(N)=C2NC=NC2=N1 BNKDQKJMJDGFGA-UHFFFAOYSA-N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- ZKBQDFAWXLTYKS-UHFFFAOYSA-N 6-Chloro-1H-purine Chemical compound ClC1=NC=NC2=C1NC=N2 ZKBQDFAWXLTYKS-UHFFFAOYSA-N 0.000 description 1
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 description 1
- GQGAOOHHHZLIMM-UHFFFAOYSA-N 7h-purine;dihydrochloride Chemical compound Cl.Cl.C1=NC=C2NC=NC2=N1 GQGAOOHHHZLIMM-UHFFFAOYSA-N 0.000 description 1
- BWXRJDSRXYQKQX-UHFFFAOYSA-N 8-ethyl-7h-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC(CC)=NC2=N1 BWXRJDSRXYQKQX-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Virology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Biotechnology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
由下式表示的膦酸酯-核苷酸化合物，其盐、其水合物及其溶剂合物，以及含有这些化合物的药品，式中R1为C1-C6烷基；R2为氢原子，由1个或1个以上卤原子取代的C1-C4烷基；R3为氢原子，由1个或1个以上卤原子取代的C1-C4烷基；R4为氢原子，由1个或1个以上卤原子取代的C1-C4烷基；X为碳或氮原子。这些化合物可用于对人免疫缺陷病毒、单纯疱疹病毒、乙型肝炎病毒等抗病毒药物，以及抗肿瘤药物。
Description
技术领域
本发明涉及新型膦酸酯-核苷酸化合物，尤其涉及具有抗病毒活性的、用作医药的膦酸酯-核苷酸化合物、其盐类、水合物或其溶剂合物。
背景技术
感染性病毒疾病在医学上被认为是重要问题，为了治疗这类疾病，要开发具有抗病毒活性但对正常细胞系的生长无抑制作用的药物。例如，膦酸酯-核苷酸类是现今进行活跃研究的选择性抗病毒药物。具体的有，9-(2-膦酰甲氧基)乙基腺嘌呤(PMEA)、9-(2-膦酰甲氧基)乙基-2，6-二氨基嘌呤(PMDAP)等报导对单纯型疱疹1型和2型(HSV-1和HSV-2)、人免疫缺陷病毒(HIV)、人乙型肝炎病毒(HBV)是有效的(横田等：Antimicrob. AgentsChemother.，35，394(1991)；Votruba et al.，Mol.Pharmacol.，32，524(1987))。
然而，这些已知的膦酸酯-核苷酸可显示出以机体骨髓细胞生长受到抑制为代表的毒性和诱变作用，因而有安全性问题(AntiviralResearch，16，77(1991))，而且这类化合物口服不能吸收(De Clercqet al.，Antimicrob.Agents Chemother.，33，185(1989))，为发挥药效而达到必要的血药浓度，只限于静脉和肌肉注射等非经口给药。非经口给药对于非住院患者的治疗是困难的，这对于需长期治疗的艾滋病或乙型肝炎病毒疾病不是个好方法。
另一方面，本发明者在以前发现膦酸酯-核苷酸特定的酯显示有很高的口服吸收性能(EP 632048号)，但尚未实用化。
发明的公开
本发明所提供的新型化合物显示出高的抗病毒活性，且与以前提出的化合物相比，对机体有良好的安全性，同时，具有很高的口服吸收性。
本发明内容是关于下面通式(I)所示的膦酸酯核苷酸化合物、其盐、水合物以及溶剂合物，和含这种化合物的药物组合物及抗病毒药。通式I中，R1为C1-C6烷基或C7-C10芳烷基；R2和R3各自独立代表氢原子(但R2及R3不能同时是氢)，C1-C22烷基，酰氧甲基，酰硫乙基，或由一个或一个以上的卤原子取代的乙基；R4为氢原子，C1-C4烷基，C1-C4羟烷基，或一个或一个以上的卤原子取代的C1-C4烷基；X为碳或氮原子。
本发明的最佳方案
于上面通式(I)所示的膦酸酯核苷酸衍生物中，R1代表的C1-C6烷基中，例如有甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
R1代表的C7-C10芳烷基中，例如有苄基、苯乙基、苯丙基、苯丁基等。
本发明中R1优选的基团为C1-C6烷基或苄基，更优选的化合物R1为C1-C6烷基。
R2和R3代表的C1-C22烷基，例如有甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、十六烷基、十七烷基、十八烷基、十九烷基、二十烷基、二十一烷基、二十二烷基，等等。
R2和R3为酰氧甲基时，例如有乙酰氧甲基、丙酰氧甲基、丁酰氧甲基、异丁酰氧甲基、戊酰氧甲基、异戊酰氧甲基、新戊酰氧甲基等。
R2和R3为酰硫乙基时，例如有乙酰硫乙基、丙酰硫乙基、丁酰硫乙基、异丁酰硫乙基、戊酰硫乙基、异戊酰硫乙基、新戊酰硫乙基等。
R2和R3为1个或1个以上的卤原子取代的乙基时，卤素可为氟、氯、溴、碘原子。1个或1个以上的卤原子取代的乙基有：1-氟乙基、2-氟乙基、1-氯乙基、2-氯乙基、2-溴乙基、2，2-二氟乙基、2，2-二氯乙基、2，2-二溴乙基、2，2，2-三氟乙基、2，2，2-三氯乙基、2，2，2-三溴乙基等，优选的取代位置是在乙基的2-位，优选的卤原子为氟原子。
R2和R3优选为至少一个是由一个或一个以上的卤原子取代的乙基，尤其优选为2，2，2-三氟乙基。
R4为C1-C4烷基中，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等。
R4为C1-C4羟烷基中，例如为羟甲基、1-羟乙基、2-羟乙基、1-羟丙基、2-羟丙基、3-羟丙基、1-羟丁基、2-羟丁基、3-羟丁基、4-羟丁基等。
R4为由一个或一个以上卤原子取代的C1-C4烷基中，例如卤原子为氟、氯等原子，C1-C4烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基等。由一个或一个以上卤原子取代的C1-C4烷基有氟甲基、二氟甲基、三氟甲基、氟乙基、氯乙基、氟丙基、氯丙基、氟丁基、氯丁基等。
本发明中优选R4为氢原子的化合物。
本发明中优选X为碳原子的化合物。
上述通式(I)所示的本发明膦酸酯核苷酸化合物可以形成药用盐。例如当有酸性基团存在时，这种盐的具体实例有锂盐、钠盐、钾盐、镁盐、钙盐等金属盐，铵盐、甲胺盐、二甲胺盐、三甲胺盐、二环己胺盐等胺盐；当有碱性基团存在时，可形成盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等无机酸盐，或形成例如甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、乙酸盐、丙酸盐、酒石酸盐、富马酸盐、马来酸盐、苹果酸盐、草酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、杏仁酸盐、桂皮酸盐、乳酸盐等有机酸盐。
上述通式(I)表示的本发明的膦酸酯核苷酸化合物或其盐，可以以水合物或溶剂合物形式存在，本发明也包括了这些水合物和溶剂合物。形成溶剂合物的溶剂例如有甲醇，乙醇，异丙醇，丙酮，乙酸乙酯，二氯甲烷等。
本发明化合物的具体实例列于表1中。表中Me代表甲基，Et为乙基，n-Pr为正丙基，i-Pr为异丙基，n-Bu为正丁基，i-Bu为异丁基，s-Bu为仲丁基，t-Bu为叔丁基，n-Pen为正戊基，n-Hex为正己基，等等。
化合物2-氨基-9-[2-(膦酰甲氧基)乙基]-6-烷硫基嘌呤，其为膦酸根部分可离解的本发明化合物的类似物，已由美国健康与人类服务部申请为专利(US-7683432)。但该专利中未记载抗病毒作用的具体数据，而且也没有该化合物的合成实施例及物理常数。如同后面试验例2所述，本发明化合物与上述的化合物比较，具有优异的经口吸收性和在肝脏中特异地聚集的特点。
表-1
| 化合物No | R1 | R2 | R3 | R4 | X |
| 1234567891011121314151617181920 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | HHHHHHHHHHHHHHHHHHHH | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 2122232425262728293031323334353637383940 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | MeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMe | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | HHHHHHHHHHHHHHHHHHHH | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 4142434445464748495051525354555657585960 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | EtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEt | HHHHHHHHHHHHHHHHHHHH | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 6162636465666768697071727374757677787980 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | n-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Pr | HHHHHHHHHHHHHHHHHHHH | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 81828384858687888990919293949596979899100 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | n-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bu | HHHHHHHHHHHHHHHHHHHH | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 101102103104105106107108109110111112113114115116117118119120 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | MeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMe | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 121122123124125126127128129130131132133134135136137138139140 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | MeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMe | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | MeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMe | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 141142143144145146147148149150151152153154155156157158159160 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | EtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEt | MeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMe | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R1 | X |
| 161162163164165166167168169170171172173174175176177178179180 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | n-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Pr | MeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMe | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 181182183184185186187188189190191192193194195196197198199200 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | n-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bu | MeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMe | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 201202203204205206207208209210211212213214215216217218219220 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | -CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 221222223224225226227228229230231232233234235236237238239240 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | MeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMe | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | -CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 241242243244245246247248249250251252253254255256257258259260 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | EtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEt | -CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 261262263264265266267268269270271272273274275276277278279280 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | n-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Pr | -CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 281282283284285286287288289290291292293294295296297298299300 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | n-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bu | -CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F-CH2F | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 301302303304305306307308309310311312313314315316317318319320 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | -CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 321322323324325326327328329330331332333334335336337338339340 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | MeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMeMe | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | -CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 341342343344345346347348349350351352353354355356357358359360 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | EtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEtEt | -CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 361362363364365366367368369370371372373374375376377378379380 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | n-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Prn-Pr | -CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH | CCCCCCCCCCNNNNNNNNNN |
表-1(续)
| 化合物No | R1 | R2 | R3 | R4 | X |
| 381382383384385386387388389390391392393394395396397398399400 | MeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-HexMeEtn-Pri-Prn-Bui-Bus-But-Bun-Penn-Hex | -CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3-CH2CF3 | n-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bun-Bu | -CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH-CH2OH | CCCCCCCCCCNNNNNNNNNN |
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本发明化合物的制法中，通式(I)化合物的R2和R3为C1-C22烷基或由1个或1个以上卤原子取代的乙基，且R2＝R3的化合物，例如可由下记的路线(1)或(2)加以合成。反应路线(1)
(式中R1，R4及X的定义同前所述，R5为C1-C22烷基或是由1个或1个以上的卤素取代的乙基，W为卤原子、对甲苯磺酰氧基、甲磺酰氧基或三氟甲磺酰氧基等离去基团)。
首先，上述通式(II)的化合物与通式(III)化合物于10～250℃、优选为130～180℃温度下，反应0.1～20小时，优选反应3～6小时。
反应得到的通式(IV)化合物必要时可用通常的分离纯化手段例如蒸馏，吸附或分配色谱等分离纯化之。通式(IV)化合物按照上述分离纯化后或不必纯化直接进行下步反应。
继之，通式(IV)化合物与通式(V)化合物，在碱的存在下，例如碳酸钠，碳酸钾，碳酸铯，氢化钠，氢化钾，三乙胺，二氮杂双环十一碳烯等，于适当的溶剂如乙腈，四氢呋喃，二甲基亚砜，二甲基甲酰胺，甲基吡咯烷酮中，于10～200℃，优选为50～150℃温度下反应0.1～100小时，优选为5～20小时，得到通式(I′)化合物。通式(I′)化合物为通式(I)中R2与R3为C1-C22烷基或是由一个或一个以上卤原子取代的乙基，且R2＝R3的化合物。
这里，作为反应路线(1)的原料的上述通式(II)、(III)和(IV)化合物的来源并没有限定，它们可以作为试剂买到，也可用已知方法加以合成。上述通式(V)化合物可由下述的通式(VI)化合物与通式(VIII)化合物或其盐在乙腈、二甲基亚砜等适当溶剂中于50～100℃温度范围内加热生成。
上述的通式(I′)化合物也可由下述方法制备。反应路线(2)式中R1，R4，R5，X和W的定义同前所述。
由反应路线(1)得到的通式(IV)化合物与通式(VI)化合物在乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等适当的溶剂中，在碱的存在下，例如碳酸钠、碳酸钾、碳酸铯、氢化钠、氢化钾、三乙胺、二氮杂双环十一碳烯等，于10～200℃，优选为50～150℃温度下，加热0.1～100小时，优选为5～20小时，得到上述的通式(VII)化合物。然后将通式(VII)化合物与通式(VIII)表示的硫醇或其盐(例如钠盐、钾盐、锂盐、三乙胺盐等)，置于适当的溶剂中例如乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等，如果必要，在适当的三级胺存在下，于10～200℃，优选为70～120℃ 反应0.1～100小时，优选为5～12小时，得到上述的通式(I′)化合物。
这里，作为反应路线(2)的原料的上述通式(VI)的化合物，其来源并没有限定，它们可以作为试剂买到，或者用已知的方法加以合成。
上述通式(I′)化合物也可用下述方法制备。反应路线(3)
式中R1、R4、R5、X及W的定义同前，Y为氯、溴、碘等卤原子，或甲磺酰氧基或对甲苯磺酰氧基。
反应路线(1)得到的上述通式(IV)化合物和通式(IX)化合物在适当的溶剂如乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等中，在碱的存在下，例如碳酸钠、碳酸钾、碳酸铯、氢化钠、氢化钾、三乙胺、二氮杂双环十一碳烯等，于10～200℃，优选为50～150℃、反应时间0.1～100小时，优选为5～20小时，得到上述通式(X)化合物。然后，上述通式(X)化合物与上述通式(XI)所示的卤代烷、甲磺酰烷酯或对甲苯磺酸烷酯，于碱的存在下如碳酸钠、碳酸钾、碳酸铯、氢化钠、氢化钾、三乙胺、二氮杂双环十一碳烯等，于适当的溶剂如乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等中，于10～200℃，优选为50～150℃，反应0.1～100小时，优选为1～20小时，得到上述通式(I′)化合物。
此外，上述通式(X)化合物也可由下述方法制备。
式中R4、R5及X的定义同前。
反应路线(2)得到的通式(VII)化合物在硫脲等的存在下，于适当的溶剂如乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮、乙醇、甲醇、2，2，2-三氟乙醇等中，于10～200℃，优选为50～150℃，反应0.1～100小时，优选为0.25～4小时，得到上述通式(X)化合物。
这里，作为反应路线(3)的原料的通式(IX)化合物的来源无特殊限定，可作为试剂买到，或用已知方法加以合成。
将通式(I′)化合物进一步反应，可得到具有R5为通式(I′)以外取代基的通式(I)化合物。
通式(I)化合物中R3为氢、C1-C22烷基、酰硫乙基、或由一个或一个以上的卤原子取代的乙基，R2为C1-C4烷基，或由一个或一个以上卤原子取代的乙基的化合物是这样制备的：将上述通式(I′)化合物与下述通式(XII)表示的化合物：
R6OH (XII)(R6为氢原子、C1-C4烷基、酰硫乙基或由一个或一个以上的卤原子取代的乙基)，在无溶剂或有适当的溶剂如含氯的溶剂二氯甲烷、吡啶、乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等溶剂中，如果必要，在对甲苯磺酸、甲磺酸、盐酸、磷酸等酸的存在下，于10～100℃，优选为20～30℃范围内反应0.1～100小时，优选为5～12小时。
式中R1，R4，R5，R6和X的定义同前。
通式(I)中R2和R3各自独立为C1-C22烷基、酰硫乙基或由1个或1个以上卤原子取代的乙基的化合物由下述方法制备：
式中R1，R4和X的定义同前，R7或R8各自独立为氢原子，C1-C22烷基，酰硫乙基或由1个或1个以上卤原子取代的乙基。
首先，将(I′)水解得到的通式(I)化合物与三甲硅烷基二乙胺溶解于适当溶剂中，例如二氯甲烷，二氯乙烷，氯仿等含氯溶剂中，于室温下反应1小时左右。此时所用的三甲硅烷基二乙胺用量与通式(I)化合物的摩尔比为2(或更多)∶1。
然后将反应液浓缩至干，将残留物溶于适当溶剂，例如二氯甲烷等含氯溶剂，加入相当于通式(I)化合物2倍摩尔量或更多的草酰氯，在催化量的二甲基甲酰胺存在和冰冷下反应1小时，再于室温下反应1小时。
这样得到的通式(XIII)化合物蒸去溶剂后，不必精制，于适当溶剂例如二氯甲烷等含氯溶剂、吡啶、乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等中，与通式(XIV)化合物和/或通式(XV)化合物于10～100℃，优选为20～30℃，温度范围内反应0.1～100小时优选为5～12小时，得到通式(XVI)化合物，它是通式(I)化合物中R2和R3各自独立为氢、C1-C22烷基、酰硫乙基或由一个或一个以上卤原子取代的乙基所代表的化合物。
此外，作为上述反应原料的通式(I)化合物虽可由通式(I′)化合物经水解得到，但更可高效率地由通式(IV)中R5为C1-C4烷基的化合物得到通式(I′)化合物，然后，与三乙基碘硅烷或三甲基溴硅烷等反应而得到。
通式(I)化合物的R2和R3均为酰氧甲基的化合物，或者一个是酰氧甲基，另一个是氢原子的化合物其制法是：将上述通式(I)化合物与通式(XVII)表示的酰氧甲基卤，
R9Y (XVII)(R9为酰氧甲基，Y为氯、溴、碘等卤原子)，于适当溶剂如乙腈、四氢呋喃、二甲基亚砜、二甲基甲酰胺、甲基吡咯烷酮等中，在碱的存在下，例如碳酸钠、碳酸钾、碳酸铯、氢化钠、氢化钾、三乙胺、吡啶、二氮杂双环十一碳烯、N，N′-二氯己基-4-吗啉羧基脒等，于0～200℃，优选为10～100℃，反应1～300小时，优选为10～200小时。
R2和R3均为酰氧甲基时，通式(I)化合物对通式(XVII)化合物的摩尔比为2∶1，或者若一个基团是酰氧甲基时，可用等摩尔量。
此外，当R2和R3之一是酰氧甲基，另一个是C1-C22烷基、酰硫乙基或由1个或一个以上卤原子取代的乙基时，其制法是首先制备化合物(I″)，其中R2和R3之一是C1-C22烷基，酰硫乙基，或由一个或一个以上的卤原子取代的乙基，另一个是氢原子(但R6为氢原子)，然后按照上述的方法使所得化合物与通式(XVII)化合物反应。
得到的通式(I)化合物，必要时用通常核苷酸分离纯化的手段，例如重结晶、吸附、离子交换或分配色谱等选择适宜方法自反应液中分离纯化之。
如同下面试验例所述，本发明化合物可以作为抗病毒药物，并且也有其它离解性膦酸酯核苷酸类似物所呈现的抗肿瘤活性。作为靶点的病毒类型无特殊的限定，被处理病毒的具体实例包括人免疫缺陷病毒，流感病毒，丙肝病毒等和RNA病毒如单纯疱疹病毒I，II型，巨细胞病毒，水痘带状疱疹病毒，乙肝病毒等，优选是对乙肝病毒。
本发明化合物作为医药品可以单独应用，或与药用载体组成药物组合物而应用。其组成取决于化合物的溶解度、化学性质、给药途径、剂量方式等。例如口服剂型有颗粒剂、微粉剂、散剂、片剂、浓糖浆剂、软胶囊剂、糖锭剂、糖浆剂、乳剂、软明胶胶囊剂、凝胶剂、糊剂、悬浊剂、脂质体等；作为注射剂可以静脉注射，肌肉注射或皮下注射，也可用粉针剂，用时配制成注射液。
药用载体用于经口、经肠、非经肠或局部用药时，可用有机或无机固体或液体载体。制备固体剂型所用的固体载体例如有乳糖、蔗糖、淀粉、滑石粉、纤维素、糊精、高岭土、碳酸钙、琼脂、果胶、硬脂酸、硬脂酸镁、卵磷脂、氯化钠等。口服用液体剂型所用的液体载体例如有甘油、花生油、聚乙烯吡咯烷酮、橄榄油、乙醇、苯甲醇、丙二醇、生理盐水、水等。在制备制剂时除上述载体外，还可加入辅料，例如湿润剂、悬浮剂、增甜剂、香料、色素或防腐剂。而液体剂型置于胶囊内时，胶囊要用可吸附物质如用明胶制成。
非经口给药的注射剂所用的溶剂或悬浮剂可用例如水、丙二醇、聚乙二醇、苯甲醇、油酸乙酯、卵磷脂等。
本发明化合物特别是前述的通式(I′)表示的酯类衍生物，如下述的试验例所述具有很高的口服吸收性，这正符合以口服剂型给药的要求。上述各种制剂可按常规方法制备。
临床用量，成人口服本发明化合物一般是每日1～500mg/kg，优选为5～50mg/kg，根据年龄、病情、症状，是否同时用其它药而适当增减。每日服用1次或分成2次或多次，或者间隔用药。
注射用药，成人每日量为0.1～50mg/kg，优选为0.1～5mg/kg。
实施例
下面对本发明以实施例形式加以具体地说明，但并不限制本发明范围。实施例1 制备2-氨基-9-[ 2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-乙基硫代嘌呤(表1，化合物No.2)
2-氯乙基氯甲醚87g(670mmol)和亚磷酸三(2，2，2-三氟乙酯)200g(610mmol)于160℃加热反应7小时，定量地生成2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基氯化物。
2-[双-(2，2，2-三氟乙基)膦酰甲氧基]乙基氯化物206g溶解于甲乙酮2000ml中，加入碘化钠270g，加热回流8小时，反应毕，冷却至室温，浓缩至干，剩余物溶解于氯仿/己烷中，硅胶柱吸附，用氟仿/己烷洗脱，得到定量的2-[双-(2，2，2-三氟乙基)膦酰甲氧基]乙基碘化物。
2-氨基-6-氯嘌呤15.0g(88mmol)悬浮于二甲基甲酰胺360ml，与1，8-二氮杂双环[5.4.0]十一碳-7-烯13.9ml(93mmol)于80℃反应1小时，然后加入上述的2-[双-(2，2，2-三氟乙基)膦酰甲氧基]乙基碘化物23.8ml于反应液中，于100℃反应5小时。反应毕，冷却至室温，浓缩至干，剩余物溶解于氯仿，硅胶柱吸附，用5％甲醇-氯仿洗脱，得到2-氨基-9-[2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-氯嘌呤23.3g(56％)。
于含2-氨基-9-[2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-氯嘌呤47.1g的二甲基甲酰胺溶液400ml中，加入乙硫醇钠8.0g，于80℃搅拌30分钟。反应混合物冷却至室温，浓缩至干。剩余物溶解于氯仿中，硅胶柱吸附，用0.4％～1.2％甲醇-氯仿洗脱，得到2-氨基-9-[ 2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-乙硫基嘌呤14.3g(30％)。
UV：λmax＝248，322(0.01N-HCl/CH3OH)
λmax＝245，309(0.01N-NaOH/CH3OH)
1H-NMR(CDCl3，δ)：1.41(t，J＝7.3Hz，3H)，3.30(q，J＝7.4Hz，2H)，3.88-3.98(m，4H)，4.20-4.48(m，6H)，4.88(bs，2H)，7.68(s，1H)实施例2 制备2-氨基-9-[2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-甲硫嘌呤(表1，化合物No.1)
按照实施例1同样的方法，只是用甲硫醇钠代替乙硫醇钠，得到本标题化合物。
UV：λmax＝248，322(0.01N-HCl/CH3OH)
λmax＝245，309(0.01N-NaOH/CH3OH)
1H-NMR(CDCl3，δ)：2.64(s，3H)，3.88-4.00(m，4H)，4.27(t，J＝5.0Hz，2H)，4.37(septet，J＝8.3Hz，4H)，4.89(s，2H)，7.69(s，1H)实施例3 制备9-[ 2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-苄硫基鸟嘌呤(表1，化合物No.481)
按照实施例1同样的方法，只是用苄硫醇和三乙胺代替乙硫醇钠，得到本标题化合物。
UV：λmax＝248，322(0.01N-HCl/CH3OH)
λmax＝245，309(0.01N-NaOH/CH3OH)
1H-NMR(CDCl3，δ)：3.86-3.96(m，4H)，4.20-4.48(m，6H)，4.57(s，2H)，4.91(bs，2H)，7.20-7.50(m，5H)，7.68(s，1H)实施例4 制备2-氨基-9-[2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-正丁硫基嘌呤(表1，化合物No.5)
按照实施例1同样的方法，只是用正丁硫醇和三乙胺代替乙硫醇钠，得到本标题化合物。
UV：λmax＝248，322(0.01N-HCl/CH3OH)
λmax＝245，309(0.01N-NaOH/CH3OH)
1H-NMR(CDCl3，δ)：0.95(t，J＝7.3Hz，3H)，1.40-1.60(m，2H)，1.68-1.84(m，2H)，3.30(t，J＝7.1Hz，2H)，3.84-4.05(m，4H)，4.18-4.50(m，6H)，4.88(s，2H)，7.68(s，1H)实施例5 制备2-氨基-9-[2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-异丁硫基嘌呤(表1，化合物No.6)
按照实施例1同样的方法，只是用异丁硫醇和三乙胺代替乙硫醇钠，得到本标题化合物。
UV：λmax＝248，322(0.01N-HCl/CH3OH)
λmax＝245，309(0.01N-NaOH/CH3OH)
1H-NMR(CDCl3，δ)：1.06(d，J＝6.7Hz，6H)，2.00(apparent septet，J＝6.7Hz，1H)，3.22(d，J＝6.8Hz，2H)，3.84-4.03(m，4H)，4.20-4.47(m，6H)，4.86(s，2H)，7.68(s，1H)实施例6 制备2-氨基-9-[2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-正己硫基嘌呤(表1，化合物No.10)
按照实施例1同样的方法只是用正己硫醇和三乙胺代替乙硫醇钠，得到本标题化合物。
UV：λmax＝248，322(0.01N-HCl/CH3OH)
λmax＝245，309(0.01N-NaOH/CH3OH)
1H-NMR(CDCl3，δ)：0.89(t，J＝6.9Hz，3H)，1.22-1.58(m，6H)，1.67-1.82(m，2H)，3.29(t，J＝7.2Hz，2H)，3.86-4.00(m，4H)，4.20-4.48(m，6H)，4.86(bs，2H)，7.68(s，1H)实施例7 制备2-氨基-9-[2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-正丙硫基嘌呤(表1，化合物No.3)
按照实施例1同样的方法，只是将正丙硫醇和三乙胺代替乙硫醇钠，得到本标题化合物。
UV：λmax＝248，322(0.01N-HCl/CH3OH)
λmax＝245，309(0.01N-NaOH/CH3OH)
1H-NMR(CDC13，δ)：1.06(t，J＝7.2Hz，3H)，1.78(q，J＝7.2Hz，2H)，3.28(t，J＝7.0Hz，2H)，3.84-3.98(m，4H)，4.23-4.45(m，6H)，4.87(bs，2H)，7.68(s，1H)实施例8 制备2-氨基-9-[2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-异丙硫基嘌呤(表1，化合物No.4)
按照实施例1同样的方法，只是用并丙硫醇和三乙胺代替乙硫醇钠，得到本标题化合物。
UV：λmax＝248，322(0.01N-HCl/CH3OH)
λmax＝245，309(0.01N-NaOH/CH3OH)
1H-NMR(CDCl3，δ)：1.45(d，J＝6.9Hz，6H)，3.86-3.98(m，4H)，4.20-4.46(m，7H)，4.86(bs，2H)，7.67(s，1H)实施例9 制备2-氨基-9-[ 2-[钠(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-乙硫基嘌呤
将2-氨基-9-[2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-乙硫基嘌呤334mg溶解于THF 2.6ml，向其中加1N氢氧化钠水溶液0.71ml，于室温下搅拌3小时，冻干，得本标题化合物257mg(89％)。
UV：λmax＝248，322(0.01N-HCl/CH3OH)
λmax＝245，309(0.01N-NaOH/CH3OH)
1H-NMR(D2O，δ)：1.38(t，J＝7.4Hz，3H)，3.26(q，J＝7.4Hz，2H)，3.69(q，J＝8.8Hz，2H)，3.85-4.07(m，4H)，4.31(t，J＝5.0Hz，2H)，7.99(s，1H)实施例10 制备2-氨基-9-[2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-乙硫基嘌呤二盐酸盐(表1，化合物No.2)
向2-氨基-9-[2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-6-乙硫基嘌呤763mg与8ml乙酸乙酯的溶液中，滴加入饱和HCl/乙酸乙酯溶液2ml，室温搅拌30分钟。减压浓缩，析出的结晶用乙酸乙酯洗涤，干燥后得本标题化合物747mg(99％)。
UV：λmax＝248，322(0.01N-HCl/CH3OH)
λmax＝245，309(0.01N-NaOH/CH3OH)
1H-NMR(DMSO-d6，δ)：1.32(t，J＝7.3Hz，3H)，3.30(q，J＝7.3Hz，2H)，3.80-3.94(m，2H)，4.13(d，J＝7.9Hz，2H)，4.22-4.30(m，2H)，4.53-4.77(m，4H)，8.21(s，1H)实施例11 制备2-氨基-9-[2-(二乙基膦酰甲氧基)乙基]-6-乙硫基嘌呤
按照实施例1同样的方法，只是用亚磷酸三乙酯代替磷酸2，2，2-三氟乙酯，得到本标题化合物。
1H-NMR(CDCl3，δ)：1.30(t，J＝7.0Hz，3H)，1.42(t，J＝7.4Hz，3H)，3.31(q，J＝7.5Hz，2H)，3.77(d，J＝8.3Hz，2H)，3.89(t，J＝5.0Hz，2H)，4.09(quintet，J＝7.4Hz，4H)，4.26(t，J＝5.0Hz，2H)，4.87(bs，2H)，7.75(s，1H)试验例1 对乙肝病毒(HBV)增殖的抑制作用
按照皆知的方法(K.Ueda等，Virology，169：213-216(1989))，测定化合物对HBV增殖的抑制作用。
含HB 611细胞(产生HBV的重组人肝癌细胞)2×104个，于含10％胎牛血清，链霉素(100μg/ml)，青霉素(100IU/ml)及Geneticin(商品名，Life Technologits公司制抗生素)(0.2mg/ml)的DulbeccoME培养基中于37℃湿孵。在第2日和第5日将培养基交换后，在培养了第8日、第11日和14日换成含有受试化合物的最终浓度为0.005～100μM的培养基后，培养17日后，回收细胞的DNA。测定细胞内HBV-DNA量(用Southern Blot法)，计算抑制50％细胞内HBV-DNA合成的化合物浓度。也计算引起50％HB611细胞死亡所需的每种化合物的浓度。作为对照物，用公认的化合物PMEA及PMEA的二新戊酰氧甲酯(参考例1)及公布于EP632048中的公认的化合物9-[2-[双(2，2，2-三氟乙基)膦酰甲氧基]乙基]-2-氨基-6-对甲苯硫基嘌呤(参考例2)作同样的试验，结果列于表2。表2中化合物编号No.与表1的编号相同。
表2
化合物 HBV-DNA 50％ 对HB 611细胞50％
No. 合成抑制浓度(μM) 细胞毒性浓度(μM)
2 0.06 ＞1000
3 0.02 ＞1000
4 0.07 ＞1000
PMEA 0.3 334参考例-1 1.08 17.7参考例-2 0.06 108试验例2 小鼠口服受试化合物后由肝匀浆制备的低分子量部分对HBV增殖的抑制作用
每组三只小鼠一次经口给受试物0.2g/kg，给药后自门静脉作肝灌注1小时，然后做肝切除。加入等重于切除肝的生理盐水，并匀浆，然后，用超滤膜制备均浆的低于5000分子量的低分子量部分样品。
HB 611细胞2×104个，在含10％胎牛血清、链霉素(100μg/ml)，青霉素(100 IU/ml)及Geneticin(0.2mg/ml)的Dulbecco ME培养基中于37℃湿孵。培养的第2日及第5日交换培养基后，于第8日、11日及14日后换成含有1％上述低分子量部分样品的培养基，培养17日后回收细胞中的DNA。用Southern Blot法测定细胞内HBV-DNA含量，计算出细胞内HBV-DNA合成的抑制作用。作为对照，同时测定公开于US-7683432中的有代表性的化合物2-氨基-9-(2-膦酰甲氧乙基)-6-正丙硫基嘌呤(参考例-3)的作用。
表3化合物No. HBV-DNA合成抑制率(％)
3 49参考例-3 17
工业利用性
本发明的膦酸酯-核苷酸衍生物具有优良的抗病毒活性，和显示高口服吸收性，此外，还有在肝脏细胞中良好的分布，预期会成为有用的药物。
Claims (5)
1.通式(I)表示的膦酸酯-核苷酸化合物、其盐、其水合物及其溶剂合物，
式中，R1为C1-C6烷基或C7-C10芳烷基；R2及R3各自独立为氢原子，但R2和R3不能同时是氢，C1-C22烷基，或由1个或1个以上的卤原子取代的乙基；R4为氢原子，C1-C4烷基，C1-C4羟烷基，或由1个或1个以上卤原子取代的C1-C4烷基；X为碳原子。
2.权利要求1的化合物，其特征是，R1为C1-C6烷基，R2和R3各自独立为由1个或1个以上的卤原子取代的乙基。
3.权利要求1的化合物，其特征是，R1是C1-C6烷基，R2和R3各自独立为2，2，2-三氟乙基。
4.含有权利要求1-3中任一化合物及药用载体的药物组合物。
5.含有权利要求1-3中任一化合物的抗病毒药物。
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| WO2003050129A1 (en) * | 2001-12-07 | 2003-06-19 | Eli Lilly And Company | Use of phosphonate nucleotide analogue for treating hepatitis b virus infections |
| MXPA04010527A (es) | 2002-04-26 | 2004-12-13 | Gilead Sciences Inc | Acumulacion celular de analogos de fosfonato de los compuestos inhibidores de la proteasa del virus de inmunodeficiencia humana (vih). |
| ES2357770T3 (es) * | 2003-04-25 | 2011-04-29 | Gilead Sciences, Inc. | Análogos de fosfonatos antivirales. |
| US7432261B2 (en) | 2003-04-25 | 2008-10-07 | Gilead Sciences, Inc. | Anti-inflammatory phosphonate compounds |
| US7407965B2 (en) | 2003-04-25 | 2008-08-05 | Gilead Sciences, Inc. | Phosphonate analogs for treating metabolic diseases |
| US7452901B2 (en) | 2003-04-25 | 2008-11-18 | Gilead Sciences, Inc. | Anti-cancer phosphonate analogs |
| WO2004096285A2 (en) | 2003-04-25 | 2004-11-11 | Gilead Sciences, Inc. | Anti-infective phosphonate conjugates |
| US7417055B2 (en) | 2003-04-25 | 2008-08-26 | Gilead Sciences, Inc. | Kinase inhibitory phosphonate analogs |
| US7470724B2 (en) | 2003-04-25 | 2008-12-30 | Gilead Sciences, Inc. | Phosphonate compounds having immuno-modulatory activity |
| US7427636B2 (en) | 2003-04-25 | 2008-09-23 | Gilead Sciences, Inc. | Inosine monophosphate dehydrogenase inhibitory phosphonate compounds |
| WO2005002626A2 (en) | 2003-04-25 | 2005-01-13 | Gilead Sciences, Inc. | Therapeutic phosphonate compounds |
| EP1628685B1 (en) | 2003-04-25 | 2010-12-08 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
| US7427624B2 (en) | 2003-10-24 | 2008-09-23 | Gilead Sciences, Inc. | Purine nucleoside phosphorylase inhibitory phosphonate compounds |
| US7432273B2 (en) | 2003-10-24 | 2008-10-07 | Gilead Sciences, Inc. | Phosphonate analogs of antimetabolites |
| CA2543144A1 (en) | 2003-10-24 | 2005-05-12 | Gilead Sciences, Inc. | Methods and compositions for identifying therapeutic compounds |
| US20080287471A1 (en) | 2003-12-22 | 2008-11-20 | Maria Fardis | 4'-Substituted Carbovir And Abacavir-Derivatives As Well As Related Compounds With Hiv And Hcv Antiviral Activity |
| PL216369B1 (pl) | 2004-07-27 | 2014-03-31 | Gilead Sciences | Pochodne fosfonianowe, kompozycje farmaceutyczne zawierające te pochodne oraz zastosowanie tych pochodnych do wytwarzania leku do hamowania wirusa HIV |
| WO2007014491A1 (fr) * | 2005-08-03 | 2007-02-08 | Beijing Fu Kang Ren Bio-Pharm Tech.Co.Ltd. | Phosphonates de nucléotides acycliques et leur utilisation dans des agents antiviraux |
| EP2244631A4 (en) | 2008-01-15 | 2014-01-22 | Nicholas L Taro | METHOD AND APPARATUS FOR DETERMINING DETERIORATION OF RESPIRATORY FUNCTION |
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| US6194398B1 (en) | 2001-02-27 |
| DE69716924D1 (de) | 2002-12-12 |
| EP0919562A4 (en) | 1999-10-13 |
| DE69716924T2 (de) | 2003-03-20 |
| CN1232466A (zh) | 1999-10-20 |
| WO1998006726A1 (fr) | 1998-02-19 |
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| EP0919562A1 (en) | 1999-06-02 |
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