WO1995022330A1 - Antiviral agents - Google Patents
Antiviral agents Download PDFInfo
- Publication number
- WO1995022330A1 WO1995022330A1 PCT/AU1995/000076 AU9500076W WO9522330A1 WO 1995022330 A1 WO1995022330 A1 WO 1995022330A1 AU 9500076 W AU9500076 W AU 9500076W WO 9522330 A1 WO9522330 A1 WO 9522330A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- optionally substituted
- hydroxy
- compound
- formula
- bis
- Prior art date
Links
- 239000003443 antiviral agent Substances 0.000 title description 5
- 239000000203 mixture Substances 0.000 claims abstract description 155
- 150000001875 compounds Chemical class 0.000 claims abstract description 129
- -1 hydroxylamino Chemical group 0.000 claims abstract description 110
- 238000000034 method Methods 0.000 claims abstract description 110
- 239000001257 hydrogen Substances 0.000 claims abstract description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 52
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 37
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 36
- 125000002252 acyl group Chemical group 0.000 claims abstract description 26
- 125000000547 substituted alkyl group Chemical group 0.000 claims abstract description 23
- 238000011282 treatment Methods 0.000 claims abstract description 22
- 208000015181 infectious disease Diseases 0.000 claims abstract description 21
- 241000700739 Hepadnaviridae Species 0.000 claims abstract description 19
- 238000011321 prophylaxis Methods 0.000 claims abstract description 19
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 18
- 150000002367 halogens Chemical group 0.000 claims abstract description 18
- 125000004104 aryloxy group Chemical group 0.000 claims abstract description 16
- 125000005415 substituted alkoxy group Chemical group 0.000 claims abstract description 16
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 13
- 150000002148 esters Chemical class 0.000 claims abstract description 13
- UGUUDTWORXNLAK-UHFFFAOYSA-N azidoalcohol Chemical group ON=[N+]=[N-] UGUUDTWORXNLAK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229940002612 prodrug Drugs 0.000 claims abstract description 11
- 239000000651 prodrug Substances 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 230000008569 process Effects 0.000 claims abstract description 9
- 235000011178 triphosphate Nutrition 0.000 claims abstract description 9
- 239000001226 triphosphate Substances 0.000 claims abstract description 9
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims abstract description 7
- 125000002092 orthoester group Chemical group 0.000 claims abstract description 6
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims abstract description 3
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims abstract 9
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 79
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 12
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 10
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 8
- 239000002671 adjuvant Substances 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 208000002672 hepatitis B Diseases 0.000 claims description 6
- 125000004036 acetal group Chemical group 0.000 claims description 5
- 159000000021 acetate salts Chemical class 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 125000004442 acylamino group Chemical group 0.000 claims description 4
- 150000001768 cations Chemical class 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- PDPNIOJPDRVCEN-HOTGVXAUSA-N [2-(acetyloxymethyl)-2-[[(2s)-2-amino-3-methylbutanoyl]oxymethyl]-4-(2-amino-6-oxo-3h-purin-9-yl)butyl] (2s)-2-amino-3-methylbutanoate Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(COC(=O)[C@@H](N)C(C)C)(COC(C)=O)COC(=O)[C@@H](N)C(C)C)C=N2 PDPNIOJPDRVCEN-HOTGVXAUSA-N 0.000 claims description 3
- WATBEZKBLSLFIG-AWEZNQCLSA-N [4-(2-amino-6-oxo-3h-purin-9-yl)-2,2-bis(hydroxymethyl)butyl] (2s)-2-amino-3-phenylpropanoate Chemical compound C([C@H](N)C(=O)OCC(CO)(CO)CCN1C2=C(C(N=C(N)N2)=O)N=C1)C1=CC=CC=C1 WATBEZKBLSLFIG-AWEZNQCLSA-N 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000005587 carbonate group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 3
- 239000010452 phosphate Substances 0.000 claims description 3
- 125000003107 substituted aryl group Chemical group 0.000 claims description 3
- HSAQOLBAZHHUMI-UHFFFAOYSA-N [2,2-bis(acetyloxymethyl)-4-(2-amino-6-oxo-3h-purin-9-yl)butyl] acetate Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(COC(=O)C)(COC(C)=O)COC(C)=O)C=N2 HSAQOLBAZHHUMI-UHFFFAOYSA-N 0.000 claims description 2
- RJSZDGIZYYQUHI-UHFFFAOYSA-N [2,2-bis(acetyloxymethyl)-4-(2-aminopurin-9-yl)butyl] acetate Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)(COC(C)=O)COC(C)=O)C=NC2=C1 RJSZDGIZYYQUHI-UHFFFAOYSA-N 0.000 claims description 2
- SVCZUWPTEDLYND-UHFFFAOYSA-N [4-(2-amino-6-oxo-3h-purin-9-yl)-2,2-bis(hydroxymethyl)butyl] cyclohexanecarboxylate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1CCC(CO)(CO)COC(=O)C1CCCCC1 SVCZUWPTEDLYND-UHFFFAOYSA-N 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- YCPTZDCUNVVRMG-UHFFFAOYSA-N [4-(2-acetamido-6-oxo-3h-purin-9-yl)-2,2-bis(acetyloxymethyl)butyl] acetate Chemical compound N1C(NC(=O)C)=NC(=O)C2=C1N(CCC(COC(C)=O)(COC(C)=O)COC(C)=O)C=N2 YCPTZDCUNVVRMG-UHFFFAOYSA-N 0.000 claims 1
- WZBDAMVEIHJZIF-UHFFFAOYSA-N [4-(2-amino-6-oxo-3h-purin-9-yl)-1-hydroxy-2-(2-methylpropanoyloxy)butan-2-yl] 2-methylpropanoate Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)(OC(=O)C(C)C)OC(=O)C(C)C)C=N2 WZBDAMVEIHJZIF-UHFFFAOYSA-N 0.000 claims 1
- BYWOXSJYGJWBBY-UHFFFAOYSA-N [4-(2-amino-6-oxo-3h-purin-9-yl)-2,2-bis(hydroxymethyl)butyl] heptanoate Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)(CO)COC(=O)CCCCCC)C=N2 BYWOXSJYGJWBBY-UHFFFAOYSA-N 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 abstract description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 153
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 111
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 98
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 94
- 239000002904 solvent Substances 0.000 description 93
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 88
- 239000000047 product Substances 0.000 description 69
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 63
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 53
- 239000003921 oil Substances 0.000 description 51
- 235000019198 oils Nutrition 0.000 description 50
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 230000002829 reductive effect Effects 0.000 description 37
- 239000012043 crude product Substances 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 239000000284 extract Substances 0.000 description 32
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 239000007787 solid Substances 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- 239000004480 active ingredient Substances 0.000 description 22
- 239000012298 atmosphere Substances 0.000 description 22
- OXJQDINZDGLQNI-UHFFFAOYSA-N 2-amino-9-[4-hydroxy-3,3-bis(hydroxymethyl)butyl]-3h-purin-6-one Chemical compound O=C1NC(N)=NC2=C1N=CN2CCC(CO)(CO)CO OXJQDINZDGLQNI-UHFFFAOYSA-N 0.000 description 20
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- 241000725618 Duck hepatitis B virus Species 0.000 description 18
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
- 239000000725 suspension Substances 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 17
- 239000000377 silicon dioxide Substances 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 15
- 239000011780 sodium chloride Substances 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 238000009472 formulation Methods 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 238000002390 rotary evaporation Methods 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- 108020004414 DNA Proteins 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 241000700605 Viruses Species 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000010992 reflux Methods 0.000 description 11
- 235000017557 sodium bicarbonate Nutrition 0.000 description 11
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
- 229940024606 amino acid Drugs 0.000 description 10
- 235000001014 amino acid Nutrition 0.000 description 10
- 150000001413 amino acids Chemical class 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 210000003494 hepatocyte Anatomy 0.000 description 10
- 238000009396 hybridization Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- FUYUQWGBKUIXNZ-UHFFFAOYSA-N [2,2-bis(acetyloxymethyl)-4-(2-amino-6-chloropurin-9-yl)butyl] acetate Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)(COC(C)=O)COC(C)=O)C=NC2=C1Cl FUYUQWGBKUIXNZ-UHFFFAOYSA-N 0.000 description 9
- 229910052786 argon Inorganic materials 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 description 8
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 8
- 239000004615 ingredient Substances 0.000 description 8
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 8
- BWGQZNLJZYFKHO-UHFFFAOYSA-N [2-(acetyloxymethyl)-4-(2-amino-6-chloropurin-9-yl)-2-fluorobutyl] acetate Chemical compound N1=C(N)N=C2N(CCC(F)(COC(=O)C)COC(C)=O)C=NC2=C1Cl BWGQZNLJZYFKHO-UHFFFAOYSA-N 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZLEXXNDMXYVOLV-UHFFFAOYSA-N [2-(acetyloxymethyl)-4-(2-amino-6-chloropurin-9-yl)-2-methylbutyl] acetate Chemical compound N1=C(N)N=C2N(CCC(C)(COC(=O)C)COC(C)=O)C=NC2=C1Cl ZLEXXNDMXYVOLV-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 6
- 239000012300 argon atmosphere Substances 0.000 description 6
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 239000012528 membrane Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 235000011181 potassium carbonates Nutrition 0.000 description 6
- 235000015096 spirit Nutrition 0.000 description 6
- 125000003396 thiol group Chemical class [H]S* 0.000 description 6
- 0 *c1c2nc[n](CCC(CO)(CO)CO)c2nc(N)n1 Chemical compound *c1c2nc[n](CCC(CO)(CO)CO)c2nc(N)n1 0.000 description 5
- 241000272525 Anas platyrhynchos Species 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- FFBDKROYDQHPHC-UHFFFAOYSA-N diethyl 2-(2-phenylmethoxyethyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)CCOCC1=CC=CC=C1 FFBDKROYDQHPHC-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 4
- JXRHQJOIEDOIQS-UHFFFAOYSA-N [2-(acetyloxymethyl)-4-(2-amino-6-chloropurin-9-yl)-2-hydroxybutyl] acetate Chemical compound N1=C(N)N=C2N(CCC(O)(COC(=O)C)COC(C)=O)C=NC2=C1Cl JXRHQJOIEDOIQS-UHFFFAOYSA-N 0.000 description 4
- MNCCLYXABMFQIC-UHFFFAOYSA-N [2-(acetyloxymethyl)-4-(2-aminopurin-9-yl)-2-fluorobutyl] acetate Chemical compound N1=C(N)N=C2N(CCC(F)(COC(=O)C)COC(C)=O)C=NC2=C1 MNCCLYXABMFQIC-UHFFFAOYSA-N 0.000 description 4
- VWQMZNXDLVUTDQ-UHFFFAOYSA-N [3,3-bis(acetyloxymethyl)-5-(2-amino-6-chloropurin-9-yl)pentyl] acetate Chemical compound N1=C(N)N=C2N(CCC(CCOC(=O)C)(COC(C)=O)COC(C)=O)C=NC2=C1Cl VWQMZNXDLVUTDQ-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 125000004423 acyloxy group Chemical group 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000013270 controlled release Methods 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 208000006454 hepatitis Diseases 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 229940069328 povidone Drugs 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000011550 stock solution Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- SZQMTCSQWUYUML-UHFFFAOYSA-N 2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound CCC(C(O)=O)NC(=O)OCC1=CC=CC=C1 SZQMTCSQWUYUML-UHFFFAOYSA-N 0.000 description 3
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 241000272517 Anseriformes Species 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- UHBNYTCUCRQVQH-UHFFFAOYSA-N [2-(acetyloxymethyl)-2-(2-hydroxyethyl)-4-phenylmethoxybutyl] acetate Chemical compound CC(=O)OCC(CCO)(COC(C)=O)CCOCC1=CC=CC=C1 UHBNYTCUCRQVQH-UHFFFAOYSA-N 0.000 description 3
- AJYIXFGPVLQCJG-UHFFFAOYSA-N [2-(acetyloxymethyl)-4-(2-amino-6-chloropurin-9-yl)-2-(propan-2-yloxymethyl)butyl] acetate Chemical compound N1=C(N)N=C2N(CCC(COC(C)C)(COC(C)=O)COC(C)=O)C=NC2=C1Cl AJYIXFGPVLQCJG-UHFFFAOYSA-N 0.000 description 3
- XBNDERJDTIHDRH-UHFFFAOYSA-N [4-(2-amino-6-chloropurin-9-yl)-2,2-bis(propan-2-yloxymethyl)butyl] acetate Chemical compound N1=C(N)N=C2N(CCC(COC(C)C)(COC(C)C)COC(C)=O)C=NC2=C1Cl XBNDERJDTIHDRH-UHFFFAOYSA-N 0.000 description 3
- JUEIBPDSMZSHQE-NSOVKSMOSA-N [4-(2-amino-6-oxo-3h-purin-9-yl)-2-(hydroxymethyl)-2-[[(2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]oxymethyl]butyl] (2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoate Chemical compound N([C@@H](C(C)C)C(=O)OCC(CO)(CCN1C2=C(C(N=C(N)N2)=O)N=C1)COC(=O)[C@@H](NC(=O)OCC=1C=CC=CC=1)C(C)C)C(=O)OCC1=CC=CC=C1 JUEIBPDSMZSHQE-NSOVKSMOSA-N 0.000 description 3
- 125000002015 acyclic group Chemical group 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 239000012267 brine Substances 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
- 239000001273 butane Substances 0.000 description 3
- 239000007963 capsule composition Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- IFIXMMDUBBVKJI-UHFFFAOYSA-N diethyl 2-(hydroxymethyl)-2-(2-phenylmethoxyethyl)propanedioate Chemical compound CCOC(=O)C(CO)(C(=O)OCC)CCOCC1=CC=CC=C1 IFIXMMDUBBVKJI-UHFFFAOYSA-N 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 231100000283 hepatitis Toxicity 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- KNZUVXAPGCTDGP-UHFFFAOYSA-N methyl 2,2-bis(acetyloxymethyl)-4-(2-amino-6-chloropurin-9-yl)butanoate Chemical compound N1=C(N)N=C2N(CCC(C(=O)OC)(COC(C)=O)COC(C)=O)C=NC2=C1Cl KNZUVXAPGCTDGP-UHFFFAOYSA-N 0.000 description 3
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 3
- 239000006072 paste Substances 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- OGLQEYICTWWJQB-UHFFFAOYSA-N 12-methoxydodecanoic acid Chemical compound COCCCCCCCCCCCC(O)=O OGLQEYICTWWJQB-UHFFFAOYSA-N 0.000 description 2
- UUROXABLNXIEFB-UHFFFAOYSA-N 2,2-bis(acetyloxymethyl)-4-phenylmethoxybutanoic acid Chemical compound CC(=O)OCC(C(O)=O)(COC(C)=O)CCOCC1=CC=CC=C1 UUROXABLNXIEFB-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- GEITZXNBUMXITR-UHFFFAOYSA-N 2-amino-9-[4,5-dihydroxy-3-(hydroxymethyl)pentyl]-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)C(O)CO)C=N2 GEITZXNBUMXITR-UHFFFAOYSA-N 0.000 description 2
- VSKGYRJYDWRUFB-UHFFFAOYSA-N 2-amino-9-[5-hydroxy-3,3-bis(hydroxymethyl)pentyl]-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)(CO)CCO)C=N2 VSKGYRJYDWRUFB-UHFFFAOYSA-N 0.000 description 2
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- WJRFMEFSYATRFI-UHFFFAOYSA-N 2-methylidene-4-phenylmethoxybutan-1-ol Chemical compound OCC(=C)CCOCC1=CC=CC=C1 WJRFMEFSYATRFI-UHFFFAOYSA-N 0.000 description 2
- CUZKCNWZBXLAJX-UHFFFAOYSA-N 2-phenylmethoxyethanol Chemical compound OCCOCC1=CC=CC=C1 CUZKCNWZBXLAJX-UHFFFAOYSA-N 0.000 description 2
- WRCFQQXCKZAOPC-UHFFFAOYSA-N 2-phenylmethoxyethyl methanesulfonate Chemical compound CS(=O)(=O)OCCOCC1=CC=CC=C1 WRCFQQXCKZAOPC-UHFFFAOYSA-N 0.000 description 2
- MQXNIGXLKYBWCN-UHFFFAOYSA-N 3-[2-(2-aminopurin-9-yl)ethyl]butane-1,2,4-triol Chemical compound NC1=NC=C2N=CN(CCC(CO)C(O)CO)C2=N1 MQXNIGXLKYBWCN-UHFFFAOYSA-N 0.000 description 2
- HJLMXFLQDJKQNH-UHFFFAOYSA-N 4-phenylmethoxy-2,2-bis(propan-2-yloxymethyl)butan-1-ol Chemical compound CC(C)OCC(CO)(COC(C)C)CCOCC1=CC=CC=C1 HJLMXFLQDJKQNH-UHFFFAOYSA-N 0.000 description 2
- TYROJDFHUXSBHC-UHFFFAOYSA-N 4-phenylmethoxybutan-1-ol Chemical compound OCCCCOCC1=CC=CC=C1 TYROJDFHUXSBHC-UHFFFAOYSA-N 0.000 description 2
- QTISZPXYPZNBQB-UHFFFAOYSA-N 4-phenylmethoxybutanal Chemical compound O=CCCCOCC1=CC=CC=C1 QTISZPXYPZNBQB-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 239000003298 DNA probe Substances 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 241000700721 Hepatitis B virus Species 0.000 description 2
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000007984 Tris EDTA buffer Substances 0.000 description 2
- 108020005202 Viral DNA Proteins 0.000 description 2
- YNJKLAOQSYKFQB-UHFFFAOYSA-N [2-(acetyloxymethyl)-2-(hydroxymethyl)-4-phenylmethoxybutyl] acetate Chemical compound CC(=O)OCC(CO)(COC(C)=O)CCOCC1=CC=CC=C1 YNJKLAOQSYKFQB-UHFFFAOYSA-N 0.000 description 2
- JZAZICNLAQCRKM-UHFFFAOYSA-N [2-(acetyloxymethyl)-2-fluoro-4-hydroxybutyl] acetate Chemical compound CC(=O)OCC(F)(CCO)COC(C)=O JZAZICNLAQCRKM-UHFFFAOYSA-N 0.000 description 2
- CEVGCAVBSHASRN-UHFFFAOYSA-N [2-(acetyloxymethyl)-4-(2-amino-6-oxo-3h-purin-9-yl)-2-(hydroxymethyl)butyl] acetate Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)(COC(=O)C)COC(C)=O)C=N2 CEVGCAVBSHASRN-UHFFFAOYSA-N 0.000 description 2
- YYBHRBMGAJEZBK-KBPBESRZSA-N [2-[[(2s)-2-amino-3-methylbutanoyl]oxymethyl]-4-(2-amino-6-oxo-3h-purin-9-yl)-2-(hydroxymethyl)butyl] (2s)-2-amino-3-methylbutanoate Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)(COC(=O)[C@@H](N)C(C)C)COC(=O)[C@@H](N)C(C)C)C=N2 YYBHRBMGAJEZBK-KBPBESRZSA-N 0.000 description 2
- CGOJKOLRBQGGQT-UHFFFAOYSA-N [3,3-bis(acetyloxymethyl)-5-(2-aminopurin-9-yl)pentyl] acetate Chemical compound N1=C(N)N=C2N(CCC(CCOC(=O)C)(COC(C)=O)COC(C)=O)C=NC2=C1 CGOJKOLRBQGGQT-UHFFFAOYSA-N 0.000 description 2
- MZBMXIFVHLFVMQ-UHFFFAOYSA-N [3,3-bis(acetyloxymethyl)-5-methylsulfonyloxypentyl] acetate Chemical compound CC(=O)OCCC(COC(C)=O)(COC(C)=O)CCOS(C)(=O)=O MZBMXIFVHLFVMQ-UHFFFAOYSA-N 0.000 description 2
- OTPALXIAAWKCPX-UHFFFAOYSA-N [4-(2-amino-6-oxo-1H-purin-9-yl)-2,2-bis(hydroxymethyl)butyl] 2-amino-2-methylpropanoate Chemical compound OCC(CCN1C=2N=C(NC(C=2N=C1)=O)N)(COC(C(C)(C)N)=O)CO OTPALXIAAWKCPX-UHFFFAOYSA-N 0.000 description 2
- PIXOMNGRDFUBMX-JTQLQIEISA-N [4-(2-amino-6-oxo-3h-purin-9-yl)-2,2-bis(hydroxymethyl)butyl] (2s)-2-amino-3-methylbutanoate Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)(CO)COC(=O)[C@@H](N)C(C)C)C=N2 PIXOMNGRDFUBMX-JTQLQIEISA-N 0.000 description 2
- MRYBNIOJIDMHTM-UHFFFAOYSA-N [4-hydroxy-2,2-bis(propan-2-yloxymethyl)butyl] acetate Chemical compound CC(C)OCC(CCO)(COC(C)C)COC(C)=O MRYBNIOJIDMHTM-UHFFFAOYSA-N 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 238000000376 autoradiography Methods 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 150000005676 cyclic carbonates Chemical group 0.000 description 2
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 2
- DIRYRDXNJAXFRU-UHFFFAOYSA-N diethyl 2-(oxan-2-yloxymethyl)-2-(2-phenylmethoxyethyl)propanedioate Chemical compound C1CCCOC1OCC(C(=O)OCC)(C(=O)OCC)CCOCC1=CC=CC=C1 DIRYRDXNJAXFRU-UHFFFAOYSA-N 0.000 description 2
- RKEYPXSBOPJUKA-UHFFFAOYSA-N diethyl 2-fluoro-2-(2-phenylmethoxyethyl)propanedioate Chemical compound C(C1=CC=CC=C1)OCCC(C(=O)OCC)(C(=O)OCC)F RKEYPXSBOPJUKA-UHFFFAOYSA-N 0.000 description 2
- BVXGYVYUBNBSFN-UHFFFAOYSA-N diethyl 2-methyl-2-(2-phenylmethoxyethyl)propanedioate Chemical compound CCOC(=O)C(C)(C(=O)OCC)CCOCC1=CC=CC=C1 BVXGYVYUBNBSFN-UHFFFAOYSA-N 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 229960001031 glucose Drugs 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- VDAVNLWQISLHBQ-UHFFFAOYSA-N methyl 2,2-bis(acetyloxymethyl)-4-hydroxybutanoate Chemical compound CC(=O)OCC(CCO)(C(=O)OC)COC(C)=O VDAVNLWQISLHBQ-UHFFFAOYSA-N 0.000 description 2
- GLKOSOSVKUYRKP-UHFFFAOYSA-N methyl 2,2-bis(acetyloxymethyl)-4-phenylmethoxybutanoate Chemical compound CC(=O)OCC(COC(C)=O)(C(=O)OC)CCOCC1=CC=CC=C1 GLKOSOSVKUYRKP-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- TYRGLVWXHJRKMT-QMMMGPOBSA-N n-benzyloxycarbonyl-l-serine-betalactone Chemical compound OC(=O)[C@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-QMMMGPOBSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 229960005190 phenylalanine Drugs 0.000 description 2
- 239000013612 plasmid Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- 229940083542 sodium Drugs 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 229940080313 sodium starch Drugs 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound 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](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- HDPNBNXLBDFELL-UHFFFAOYSA-N 1,1,1-trimethoxyethane Chemical compound COC(C)(OC)OC HDPNBNXLBDFELL-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- YJTKZCDBKVTVBY-UHFFFAOYSA-N 1,3-Diphenylbenzene Chemical group C1=CC=CC=C1C1=CC=CC(C=2C=CC=CC=2)=C1 YJTKZCDBKVTVBY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- XYHKNCXZYYTLRG-UHFFFAOYSA-N 1h-imidazole-2-carbaldehyde Chemical compound O=CC1=NC=CN1 XYHKNCXZYYTLRG-UHFFFAOYSA-N 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- FFFPDNWQYLSALR-UHFFFAOYSA-N 2-(hydroxymethyl)-2-(2-phenylmethoxyethyl)propane-1,3-diol Chemical compound OCC(CO)(CO)CCOCC1=CC=CC=C1 FFFPDNWQYLSALR-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- FUNHGMQBKQUYCG-UHFFFAOYSA-N 2-[2-(2,6-diaminopurin-9-yl)ethyl]-2-(hydroxymethyl)propane-1,3-diol Chemical compound NC1=NC(N)=C2N=CN(CCC(CO)(CO)CO)C2=N1 FUNHGMQBKQUYCG-UHFFFAOYSA-N 0.000 description 1
- FGTCQIHUXAHVHV-UHFFFAOYSA-N 2-[2-(2-amino-6-methoxypurin-9-yl)ethyl]-2-(hydroxymethyl)propane-1,3-diol Chemical compound COC1=NC(N)=NC2=C1N=CN2CCC(CO)(CO)CO FGTCQIHUXAHVHV-UHFFFAOYSA-N 0.000 description 1
- HVJFHRCICWDIFD-UHFFFAOYSA-N 2-[2-(2-aminopurin-9-yl)ethyl]-2-(hydroxymethyl)butane-1,4-diol Chemical compound NC1=NC=C2N=CN(CCC(CO)(CO)CCO)C2=N1 HVJFHRCICWDIFD-UHFFFAOYSA-N 0.000 description 1
- KGDPUXHQTXXLIK-UHFFFAOYSA-N 2-[2-(2-aminopurin-9-yl)ethyl]-2-(hydroxymethyl)propane-1,3-diol Chemical compound NC1=NC=C2N=CN(CCC(CO)(CO)CO)C2=N1 KGDPUXHQTXXLIK-UHFFFAOYSA-N 0.000 description 1
- BGKUGEAYIYNOLI-UHFFFAOYSA-N 2-[2-(2-aminopurin-9-yl)ethyl]-3-(12-methoxydodecoxy)butane-1,4-diol Chemical compound N1=C(N)N=C2N(CCC(CO)C(CO)OCCCCCCCCCCCCOC)C=NC2=C1 BGKUGEAYIYNOLI-UHFFFAOYSA-N 0.000 description 1
- LRUZPFORKCSOHD-UHFFFAOYSA-N 2-amino-9-[3,3-bis(hydroxymethyl)-4-propan-2-yloxybutyl]-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)(CO)COC(C)C)C=N2 LRUZPFORKCSOHD-UHFFFAOYSA-N 0.000 description 1
- YNZCNDPEYZKCGG-UHFFFAOYSA-N 2-amino-9-[3-(hydroxymethyl)-4-propan-2-yloxy-3-(propan-2-yloxymethyl)butyl]-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)(COC(C)C)COC(C)C)C=N2 YNZCNDPEYZKCGG-UHFFFAOYSA-N 0.000 description 1
- NRICTVVCNDISCT-UHFFFAOYSA-N 2-amino-9-[4-hydroxy-3,3-bis(hydroxymethyl)butyl]-3h-purin-6-one;sodium Chemical compound [Na].N1C(N)=NC(=O)C2=C1N(CCC(CO)(CO)CO)C=N2 NRICTVVCNDISCT-UHFFFAOYSA-N 0.000 description 1
- JZCPXUMEPASCBJ-UHFFFAOYSA-N 2-amino-9-[4-hydroxy-5-(12-methoxydodecoxy)-3-(12-methoxydodecoxymethyl)pentyl]-3h-purin-6-one Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(C(O)COCCCCCCCCCCCCOC)COCCCCCCCCCCCCOC)C=N2 JZCPXUMEPASCBJ-UHFFFAOYSA-N 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000004336 3,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M 3-Methylbutanoic acid Natural products CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- NXTDJHZGHOFSQG-UHFFFAOYSA-N 3-phenoxybenzoic acid Chemical compound OC(=O)C1=CC=CC(OC=2C=CC=CC=2)=C1 NXTDJHZGHOFSQG-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- AFLWPAGYTPJSEY-CODXZCKSSA-N 4-[2-[(8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-oxoethoxy]-4-oxobutanoic acid;hydrate Chemical compound O.O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COC(=O)CCC(O)=O)[C@@H]4[C@@H]3CCC2=C1 AFLWPAGYTPJSEY-CODXZCKSSA-N 0.000 description 1
- FLJFMDYYNMNASJ-UHFFFAOYSA-N 6-methyl-5,6-dihydrothieno[2,3-b]thiopyran-4-one Chemical compound S1C(C)CC(=O)C2=C1SC=C2 FLJFMDYYNMNASJ-UHFFFAOYSA-N 0.000 description 1
- UYEDARPHKIPRAS-UHFFFAOYSA-N 7-(2-hydroxy-3-propan-2-yloxypropyl)-3-methyl-8-(3-methylbutylamino)purine-2,6-dione Chemical compound CN1C(=O)NC(=O)C2=C1N=C(NCCC(C)C)N2CC(O)COC(C)C UYEDARPHKIPRAS-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000167854 Bourreria succulenta Species 0.000 description 1
- GOFYFINOPYGDSL-UHFFFAOYSA-N CC(C)C(C(OCC(CC[n]1c2nc(N)nc(O)c2nc1)(COC(C(C(C)C)NC(OCc1ccccc1)=O)=O)COC(C(C(C)C)NC(OCc1ccccc1)=O)=O)=O)NC(OCc1ccccc1)=O Chemical compound CC(C)C(C(OCC(CC[n]1c2nc(N)nc(O)c2nc1)(COC(C(C(C)C)NC(OCc1ccccc1)=O)=O)COC(C(C(C)C)NC(OCc1ccccc1)=O)=O)=O)NC(OCc1ccccc1)=O GOFYFINOPYGDSL-UHFFFAOYSA-N 0.000 description 1
- PDPNIOJPDRVCEN-UHFFFAOYSA-N CC(C)C(C(OCC(CC[n]1c2nc(N)nc(O)c2nc1)(COC(C)=O)COC(C(C(C)C)N)=O)=O)N Chemical compound CC(C)C(C(OCC(CC[n]1c2nc(N)nc(O)c2nc1)(COC(C)=O)COC(C(C(C)C)N)=O)=O)N PDPNIOJPDRVCEN-UHFFFAOYSA-N 0.000 description 1
- ZMNXZKJJKXBFJX-UHFFFAOYSA-N CC(C)OCC(CCN1c2nc(N)nc(O)c2NC1)(CO)COC(C)C Chemical compound CC(C)OCC(CCN1c2nc(N)nc(O)c2NC1)(CO)COC(C)C ZMNXZKJJKXBFJX-UHFFFAOYSA-N 0.000 description 1
- CHIYBIWUYJCNFE-UHFFFAOYSA-N CC(C)OCC(CCN1c2nc(N)ncc2N(C)C1)(COC(C)=O)COC(C)=O Chemical compound CC(C)OCC(CCN1c2nc(N)ncc2N(C)C1)(COC(C)=O)COC(C)=O CHIYBIWUYJCNFE-UHFFFAOYSA-N 0.000 description 1
- RRURQKPRHHWBTG-UHFFFAOYSA-N CC(CCOCc1ccccc1)(CO)CO Chemical compound CC(CCOCc1ccccc1)(CO)CO RRURQKPRHHWBTG-UHFFFAOYSA-N 0.000 description 1
- OPSSDDUVGYNREK-UHFFFAOYSA-N CC(CC[n]1c2nc(N)nc(O)c2nc1)(CO)CO Chemical compound CC(CC[n]1c2nc(N)nc(O)c2nc1)(CO)CO OPSSDDUVGYNREK-UHFFFAOYSA-N 0.000 description 1
- XZZAKNFXMQNSIT-UHFFFAOYSA-N CC(NC(Cc1cnc[nH]1)C(OCC(CC[n]1c2nc(N)nc(O)c2nc1)(CO)CO)=O)=O Chemical compound CC(NC(Cc1cnc[nH]1)C(OCC(CC[n]1c2nc(N)nc(O)c2nc1)(CO)CO)=O)=O XZZAKNFXMQNSIT-UHFFFAOYSA-N 0.000 description 1
- SNYGBZNSZMLLSD-UHFFFAOYSA-N CC(OCC(CCN1c2nc(N)nc(Cl)c2N(C)C1)(COC)COC(C)=O)=O Chemical compound CC(OCC(CCN1c2nc(N)nc(Cl)c2N(C)C1)(COC)COC(C)=O)=O SNYGBZNSZMLLSD-UHFFFAOYSA-N 0.000 description 1
- TWPZGVWNQVJUJJ-UHFFFAOYSA-O CC1C=CC(COCC[OH2+])=CC1 Chemical compound CC1C=CC(COCC[OH2+])=CC1 TWPZGVWNQVJUJJ-UHFFFAOYSA-O 0.000 description 1
- KWMAOQPURWDYJK-UHFFFAOYSA-N CCONC1=NC(C)(N)Nc2c1nc[n]2CCC(COC(C)=O)(COC(C)=O)COC(C)=O Chemical compound CCONC1=NC(C)(N)Nc2c1nc[n]2CCC(COC(C)=O)(COC(C)=O)COC(C)=O KWMAOQPURWDYJK-UHFFFAOYSA-N 0.000 description 1
- 208000000419 Chronic Hepatitis B Diseases 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 108020003215 DNA Probes Proteins 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- GJAARPKBDFKHFS-UHFFFAOYSA-N Gerin Natural products COC(=O)C(=C)C1CC2C(=C)C(=O)C=CC2(C)CC1OC(=O)C GJAARPKBDFKHFS-UHFFFAOYSA-N 0.000 description 1
- 108010068370 Glutens Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 244000148687 Glycosmis pentaphylla Species 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 1
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical group C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000712431 Influenza A virus Species 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical class 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920003094 Methocel™ K4M Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- USPFMEKVPDBMCG-LBPRGKRZSA-N N-benzyloxycarbonyl-L-leucine Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 USPFMEKVPDBMCG-LBPRGKRZSA-N 0.000 description 1
- RSTADUDGIYJUGM-UHFFFAOYSA-N Nc1nc(Cl)c2NCN(CCC(CO)(CO)CO)c2n1 Chemical compound Nc1nc(Cl)c2NCN(CCC(CO)(CO)CO)c2n1 RSTADUDGIYJUGM-UHFFFAOYSA-N 0.000 description 1
- LFWZFFYHYLJMMD-UHFFFAOYSA-N Nc1nc(O)c2NCN(CCC(CO)(CO)CO)c2n1 Chemical compound Nc1nc(O)c2NCN(CCC(CO)(CO)CO)c2n1 LFWZFFYHYLJMMD-UHFFFAOYSA-N 0.000 description 1
- ZDXKPDZFPHUOSP-UHFFFAOYSA-N Nc1nc(O)c2nc[n](CCC(CO)(CO)COC(c3cc(Oc4ccccc4)ccc3)=O)c2n1 Chemical compound Nc1nc(O)c2nc[n](CCC(CO)(CO)COC(c3cc(Oc4ccccc4)ccc3)=O)c2n1 ZDXKPDZFPHUOSP-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 208000002606 Paramyxoviridae Infections Diseases 0.000 description 1
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- 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 1
- 208000037581 Persistent Infection Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 235000011034 Rubus glaucus Nutrition 0.000 description 1
- 244000235659 Rubus idaeus Species 0.000 description 1
- 235000009122 Rubus idaeus Nutrition 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- 241000283925 Spermophilus Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 241001492404 Woodchuck hepatitis virus Species 0.000 description 1
- 229920002494 Zein Polymers 0.000 description 1
- NXGHDLZNMORVMN-AWEZNQCLSA-N [2,2-bis(acetyloxymethyl)-4-(2-amino-6-oxo-3h-purin-9-yl)butyl] (2s)-2-amino-3-methylbutanoate Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(COC(=O)[C@@H](N)C(C)C)(COC(C)=O)COC(C)=O)C=N2 NXGHDLZNMORVMN-AWEZNQCLSA-N 0.000 description 1
- DRNYRMDYFCHCBJ-NRFANRHFSA-N [2,2-bis(acetyloxymethyl)-4-(2-amino-6-oxo-3h-purin-9-yl)butyl] (2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoate Chemical compound N([C@@H](C(C)C)C(=O)OCC(CCN1C2=C(C(N=C(N)N2)=O)N=C1)(COC(C)=O)COC(C)=O)C(=O)OCC1=CC=CC=C1 DRNYRMDYFCHCBJ-NRFANRHFSA-N 0.000 description 1
- ADELKZZQNGFJJL-UHFFFAOYSA-N [2-(2-aminobutanoyloxymethyl)-4-(2-amino-6-oxo-3h-purin-9-yl)-2-(hydroxymethyl)butyl] 2-aminobutanoate Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)(COC(=O)C(N)CC)COC(=O)C(N)CC)C=N2 ADELKZZQNGFJJL-UHFFFAOYSA-N 0.000 description 1
- LPQDQKZJZOAAMX-KYJUHHDHSA-N [2-(acetyloxymethyl)-4-(2-amino-6-oxo-1H-purin-9-yl)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]oxymethyl]butyl] (2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoate Chemical compound C(C)(=O)OCC(CCN1C=2N=C(NC(C=2N=C1)=O)N)(COC([C@@H](NC(=O)OCC1=CC=CC=C1)C(C)C)=O)COC([C@@H](NC(=O)OCC1=CC=CC=C1)C(C)C)=O LPQDQKZJZOAAMX-KYJUHHDHSA-N 0.000 description 1
- SRTBUUUNUOBQHR-UHFFFAOYSA-N [2-(acetyloxymethyl)-4-hydroxy-2-(propan-2-yloxymethyl)butyl] acetate Chemical compound CC(C)OCC(CCO)(COC(C)=O)COC(C)=O SRTBUUUNUOBQHR-UHFFFAOYSA-N 0.000 description 1
- HZACVVZHEVDWFU-UHFFFAOYSA-N [2-(acetyloxymethyl)-4-hydroxy-2-methylbutyl] acetate Chemical compound CC(=O)OCC(C)(CCO)COC(C)=O HZACVVZHEVDWFU-UHFFFAOYSA-N 0.000 description 1
- YBBZGTYGQYNVOP-GGHNLIEISA-N [2-[[(2S)-2-amino-3-methylbutanoyl]oxymethyl]-4-(2-amino-6-oxo-1H-purin-9-yl)-2-methylbutyl] (2S)-2-amino-4-[(2S)-2-amino-3-methylbutanoyl]oxy-3-methylbutanoate Chemical compound N[C@@H](C(C)C)C(=O)OCC([C@H](N)C(=O)OCC(CCN1C=2N=C(NC(C=2N=C1)=O)N)(C)COC([C@@H](N)C(C)C)=O)C YBBZGTYGQYNVOP-GGHNLIEISA-N 0.000 description 1
- GTFWTZSFLHUTTO-UHFFFAOYSA-N [3,4-diacetyloxy-2-[2-(2-amino-6-chloropurin-9-yl)ethyl]butyl] acetate Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)C(COC(C)=O)OC(C)=O)C=NC2=C1Cl GTFWTZSFLHUTTO-UHFFFAOYSA-N 0.000 description 1
- RQUJXQPHFXFCRQ-KRWDZBQOSA-N [4-(2-amino-6-oxo-3h-purin-9-yl)-2,2-bis(hydroxymethyl)butyl] (2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoate Chemical compound N([C@@H](C(C)C)C(=O)OCC(CO)(CO)CCN1C2=C(C(N=C(N)N2)=O)N=C1)C(=O)OCC1=CC=CC=C1 RQUJXQPHFXFCRQ-KRWDZBQOSA-N 0.000 description 1
- CAYBBOMFLGXZHT-NRFANRHFSA-N [4-(2-amino-6-oxo-3h-purin-9-yl)-2,2-bis(hydroxymethyl)butyl] (2s)-3-phenyl-2-(phenylmethoxycarbonylamino)propanoate Chemical compound C([C@@H](C(=O)OCC(CO)(CO)CCN1C=NC=2C(=O)N=C(NC=21)N)NC(=O)OCC=1C=CC=CC=1)C1=CC=CC=C1 CAYBBOMFLGXZHT-NRFANRHFSA-N 0.000 description 1
- DFVOJGZXUUSSLO-UHFFFAOYSA-N [4-(2-amino-6-oxo-3h-purin-9-yl)-2,2-bis(hydroxymethyl)butyl] acetate Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)(CO)COC(=O)C)C=N2 DFVOJGZXUUSSLO-UHFFFAOYSA-N 0.000 description 1
- NAPJFTLCAMDOKR-UHFFFAOYSA-N [4-(2-amino-6-oxo-3h-purin-9-yl)-2-(hydroxymethyl)-2-[2-(phenylmethoxycarbonylamino)butanoyloxymethyl]butyl] 2-(phenylmethoxycarbonylamino)butanoate Chemical compound C1=NC(C(N=C(N)N2)=O)=C2N1CCC(CO)(COC(=O)C(CC)NC(=O)OCC=1C=CC=CC=1)COC(=O)C(CC)NC(=O)OCC1=CC=CC=C1 NAPJFTLCAMDOKR-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 125000005035 acylthio group Chemical group 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229940023476 agar Drugs 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 229960003767 alanine Drugs 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000006323 alkenyl amino group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005138 alkoxysulfonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 125000006319 alkynyl amino group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910000091 aluminium hydride Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000001124 arachidoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical group 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000005251 aryl acyl group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000005116 aryl carbamoyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 125000003289 ascorbyl group Chemical group [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- 229940092782 bentonite Drugs 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- SIWSSFYFGKVQPT-UHFFFAOYSA-N benzyl 2-(2-amino-2-methylpropanoyl)oxy-5-(2-amino-6-oxo-3h-purin-9-yl)-3,3-bis(hydroxymethyl)pentanoate Chemical compound C1=NC(C(N=C(N)N2)=O)=C2N1CCC(CO)(CO)C(OC(=O)C(C)(N)C)C(=O)OCC1=CC=CC=C1 SIWSSFYFGKVQPT-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N beta-methyl-butyric acid Natural products CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- CDQSJQSWAWPGKG-UHFFFAOYSA-N butane-1,1-diol Chemical compound CCCC(O)O CDQSJQSWAWPGKG-UHFFFAOYSA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000019693 cherries Nutrition 0.000 description 1
- 208000016350 chronic hepatitis B virus infection Diseases 0.000 description 1
- 125000002676 chrysenyl group Chemical group C1(=CC=CC=2C3=CC=C4C=CC=CC4=C3C=CC12)* 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229960002424 collagenase Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 125000006254 cycloalkyl carbonyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006639 cyclohexyl carbonyl group Chemical group 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000006638 cyclopentyl carbonyl group Chemical group 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- RGWHQCVHVJXOKC-SHYZEUOFSA-J dCTP(4-) Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)C1 RGWHQCVHVJXOKC-SHYZEUOFSA-J 0.000 description 1
- 125000003074 decanoyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000004986 diarylamino group Chemical group 0.000 description 1
- ZTCWPSJUPIWQJC-UHFFFAOYSA-N diethyl 2,2-bis(2-phenylmethoxyethyl)propanedioate Chemical compound C=1C=CC=CC=1COCCC(C(=O)OCC)(C(=O)OCC)CCOCC1=CC=CC=C1 ZTCWPSJUPIWQJC-UHFFFAOYSA-N 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 235000010300 dimethyl dicarbonate Nutrition 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000531 effect on virus Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 1
- 229960002963 ganciclovir Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 235000021312 gluten Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000005291 haloalkenyloxy group Chemical group 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000000232 haloalkynyl group Chemical group 0.000 description 1
- 125000003106 haloaryl group Chemical group 0.000 description 1
- 125000004996 haloaryloxy group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940094991 herring sperm dna Drugs 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229950006240 hydrocortisone succinate Drugs 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- RCBVKBFIWMOMHF-UHFFFAOYSA-L hydroxy-(hydroxy(dioxo)chromio)oxy-dioxochromium;pyridine Chemical compound C1=CC=NC=C1.C1=CC=NC=C1.O[Cr](=O)(=O)O[Cr](O)(=O)=O RCBVKBFIWMOMHF-UHFFFAOYSA-L 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960001078 lithium Drugs 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229940091250 magnesium supplement Drugs 0.000 description 1
- 125000000628 margaroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000001525 mentha piperita l. herb oil Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- VXZUDZJEQVPSHE-UHFFFAOYSA-N methoxy formate Chemical compound COOC=O VXZUDZJEQVPSHE-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- ZIDLYFMBCRMBLQ-UHFFFAOYSA-N methyl 2,2-bis(acetyloxymethyl)-4-(2-aminopurin-9-yl)butanoate Chemical compound N1=C(N)N=C2N(CCC(C(=O)OC)(COC(C)=O)COC(C)=O)C=NC2=C1 ZIDLYFMBCRMBLQ-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 125000001419 myristoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 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 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000005146 naphthylsulfonyl group Chemical group C1(=CC=CC2=CC=CC=C12)S(=O)(=O)* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- 125000004999 nitroaryl group Chemical group 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 125000001402 nonanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- AQFWNELGMODZGC-UHFFFAOYSA-N o-ethylhydroxylamine Chemical compound CCON AQFWNELGMODZGC-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid group Chemical group C(CCCCCCC\C=C/CCCCCCCC)(=O)O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002905 orthoesters Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N pentanoic acid group Chemical class C(CCCC)(=O)O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 235000019477 peppermint oil Nutrition 0.000 description 1
- 125000001792 phenanthrenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C=CC12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- ZAEQTGTVGUJEFV-UHFFFAOYSA-N phenylmethanesulfonate;pyridin-1-ium Chemical compound C1=CC=[NH+]C=C1.[O-]S(=O)(=O)CC1=CC=CC=C1 ZAEQTGTVGUJEFV-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000001725 pyrenyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000003211 trypan blue cell staining Methods 0.000 description 1
- 125000000297 undecanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
- 229940093612 zein Drugs 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- 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
-
- 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
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/6574—Esters of oxyacids of phosphorus
- C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
Definitions
- the present invention relates to purine acyclonucleosides, processes for f their preparation and their use as agents in the treatment or prophylaxis of
- HB V human hepatitis B virus
- R4, R5 and R are the same or different and selected from optionally substituted alkyl, optionally substituted aralkyl, halogen, hydroxy, azide, optionally substituted alkoxy, optionally substituted aryloxy, mercapto, optionally substituted alkylthio, optionally substituted amino, optionally substituted acyl, optionally substituted ester, cyano, carboxy and mono-, di- or tri- phosphate; two of R4, R5 and R are joined together to form a cyclic group; or R4, R5 and Rg are joined together to form a cyclic ortho ester group,
- an “effective amount” of the compound of Formula (1) is an amount sufficient to inhibit or reduce viral replication, generally by greater than 50% (as measured by viral DNA levels or reverse transcriptase activity).
- salts of the compound of Formula (1) are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.
- pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicyclic
- alkyl used either alone or in compound words such as “optionally substituted alkyl”, “optionally substituted alkylthio” and “aralkyl” denotes straight chain, branched or cyclic alkyl, preferably C1.30 alkyl or cycloalkyl.
- phenylacetyl phenylpropanoyl, phenylbutanoyl, phenylisobutyl, phenylpentanoyl and phenylhexanoyl
- naphthylalkanoyl e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl
- aralkenoyl such as phenylalkenoyl (e.g.
- benzyloxycarbonyl aryloxycarbonyl such as phenoxycarbonyl and naphthyloxycarbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and naphthylsulfonyl; heterocycUccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl,
- aralkyl used either alone or in compound words such as “optionally substituted aralkyl” denotes arylalkyl groups wherein the terms “aryl” and “alkyl” are as defined above, such as, for example, benzyl.
- optionally substituted means that a group may or may not be further substituted with one or more groups, preferably 1 to 5 groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, carboxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, azido, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, preferably 1 to 5
- R j is hydroxy
- R2 is amino
- R2 is amino
- Rg is other than fluoro, hydroxy or methoxy
- R2 is amino
- Rj is benzyloxy
- R2 is amino
- R j is hydroxy; R2 is amino; and
- R4' and R5' are hydrogen, then Rg is other than fluoro, hydroxy, methoxy, methyl or hydroxymethyl;
- R2 is amino
- Rj is chloro
- R2 is amino
- Preferred Regroups are hydrogen, halogen, hydroxy, optionally substituted
- R 2 groups are -NR Rg, wherein R is hydrogen, optionally
- Rg is hydrogen or alkyl
- R4', R5', Rg' and/or R7 groups are those selected from hydrogen, aminoacyl, R9- C (O)- and R9-C (S)- ,wherein Rg is hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or -NRJ Q R, . ,
- Rj2 and R13 are the same or different and are selected from hydrogen
- alkyl optionally substituted aryl, optionally substituted aralkyl and pharmaceutically acceptable cations, preferably hydrogen and pharmaceutically acceptable cations.
- R 14 and R j5 are the same or different and are selected from hydrogen or C. , alkyl.
- R or R ⁇ -' and/or R fi or Rg' together form the group:
- R, . is as defined above.
- a preferred group of compounds of Formula (la) are those wherein
- R* is hydrogen, halogen, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, amino,
- R2 is amino or acylamino
- R ⁇ R ⁇ -' and/or R are the same or different and selected from hydrogen, halogen,
- R ⁇ R ⁇ -' and/or R,' are joined together to form a cyclic acetal group or a cyclic
- R j and R2 are as defined above with a compound of Formula (4):
- R a and R j may be the same or different and are selected from R4' and R5'as defined above, hydrogen and benzoyl;
- R c is the same as Rg as defined above, hydroxy, hydroxyalkyl or protected derivatives thereof;
- R is preferably chlorine or benzyloxy, more preferably chlorine and R 2 is preferably amino or aminoacyl, more preferably amino.
- protected hydroxy may be acyloxy or alkoxy; protected hydroxyalkyl may be acyloxyalkyl or alkoxyalkyl; and protected amino may be acylamino.
- Compounds of Formula (6) can be readily converted into compounds of Formula (1) or (la) using methods known in the art.
- Compounds of Formula (1) or (la) can be converted into other compounds of Formula (1) or (la) using similar known methods.
- Such known methods may include the removal of protecting groups, hydrogenation, aminolysis, hydrolysis, alkylation, acylation and phosphorylation.
- compounds of Formula (1) or (la) that have acyclic hydroxyl groups may be readily converted into the compounds of Formula (1) or (la) with either acyl or phosphate groups or a mixture of these groups on the acyclic chain.
- Such intermediates may be prepared in accordance with known methods and when no longer required the protecting groups removed using known methods. Examples of suitable protecting groups are trimethylsilyl and monomethoxytrityl groups.
- acylation reaction of compounds of Formula (1) or (la) with acyclic hydroxyl groups may be carried out using an acylating agent containing a group
- the acylation reactions may produce a single compound of Formula (1) or (la) incorporating one or more acyl groups or may produce a mixture of compounds of Formula (1) or (la) incorporating acyl groups.
- the outcome depends on a number of factors, such as the relative amounts and chemical nature of the reactants, the physical conditions of the reaction, and the solvent system. Any mixture produced in this way may be separated using standard techniques, preferably chromatography.
- Protected intermediates of the compounds of Formula (1) or (la) may also be used to prepare compounds of Formula (1) or (la) incorporating phosphate . esters.
- the present invention also extends to a pharmaceutical or veterinary composition for the treatment and/or prophylaxis of a Hepadnaviridae associated infection which comprises a compound of Formula (1) or (la) as defined above in association with a pharmaceutically or veterinarily acceptable carrier, diluent, adjuvant and/or excipient.
- the compounds of the invention may be advantageously used in combination therapy with other antiviral agents such as Ganciclovir, Famcyclovir, Pencyclovir, Lamivudine and interferon.
- antiviral agents such as Ganciclovir, Famcyclovir, Pencyclovir, Lamivudine and interferon.
- a preferred method in accordance with the present invention utilises the compound of Formula (1) or (la), analogue or derivative in conjunction with another antiviral agent.
- the compound of Formula (1) or (la), also referred to herein as the "active ingredient” may be administered for therapy by any suitable route, including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal).
- administration will be by the oral route, however it will be appreciated that the preferred route will vary with the condition and age of the subject and the chosen active ingredient.
- compositions of the present invention comprise at least one compound of Formula (1) or (la), together with one or more pharmaceutically acceptable carriers, diluents, adjuvants and/or excipients and optionally other antiviral or therapeutic agents.
- Each carrier, diluent, adjuvant and/or excipient must be pharmaceutically "acceptable” in the sense of being compatible with the other ingredients of the composition and not injurious to the subject.
- Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
- the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
- Such methods include the step of bringing into association the active ingredient with the carrier diluent, adjuvant and/or excipient which constitutes one or more accessory ingredients.
- the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, diluents, adjuvants and/or excipients or finely divided solid carriers or both, and then if necessary shaping the product.
- compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
- a binder e.g inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
- compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
- compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
- compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
- Preferred unit dosage compositions are those containing a daily dose or unit, daily sub-dose such as one or more unit dosage forms per day or an appropriate fraction thereof, of an active ingredient.
- the compound of Formula (1) or (la) may also be presented for use in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art.
- veterinary compositions include those adapted for:
- oral administration external application, for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
- drenches e.g. aqueous or non-aqueous solutions or suspensions
- tablets or boluses e.g. aqueous or non-aqueous solutions or suspensions
- pastes for application to the tongue for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
- parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced into the udder via the teat;
- topical application e.g. as a cream, ointment or spray applied to the skin;
- compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents.
- Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin.
- Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar.
- Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring.
- Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten.
- Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite.
- Suitable lubricants include magnesium stearate, steric acid, sodium oleate, sodium chloride or talc.
- Suitable time delay agents include glyceryl monostearate or glyce
- the multiplicity patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad).
- High resolution mass measurements were recorded on a JEOL DX303 mass spectrometer.
- Merck silica gel 230-400 mesh ASTM was employed in column chromatography. Unless otherwise stated, all organic extracts were dried over magnesium sulfate, filtered and solvents removed on a rotary evaporator. Unless otherwise specified, unreferenced reagents were obtained commercially and used as supplied.
- Butanediol (901.5 g, 10 mol) and potassium hydroxide (85%, 264 g, 4 mol) were stirred, at room temperature, with a mechanical stirrer overnight. The mixture was then heated to 130° and vacuum applied to remove water. 49 g of water was condensed. The mixture was then cooled to 90° and benzyl chloride (506.4 g, 465 ml, 4 mol) added dropwise over 2 hrs. The mixture was stirred at 90° for 1 hr then heated to 130° and stirred for 1 hr. The mixture was allowed to cool to room temperature overnight.
- n.m.r. (CDCI3) ⁇ 1.83, m; 2.68, s, br; 3.36, s; 3.54, s; 3.70, m; 4.53, s;
- iH n.m.r. (CDCI3) ⁇ 1.19, t; 1.53, m, br; 2.39, t; 3.43-3.90, m; 3.58, t; 4.06-4.20, m; 4.43, s; 4.79-4.96, m; 7.30, s.
- reaction mixture was allowed to warm to room temperature, transfered to a separating funnel and washed successively with 30 ml portions of 2M HCl (x 2), sat. aqueous sodium hydrogen carbonate and 5% aqueous sodium chloride. The organic phase was dried and the solvent removed to give an oil.
- Example 9 Yield 1.31 g (53%). m.p. 100°. *H n.m.r. (DMSO-dg) ⁇ 1.05, d; 1.92, t; 2.01, s; 3.33, s; 3.46, m; 3.99, s; 4.16, t; 6.86, s, br; 8.16, s. 1 C n.m.r. (CDCI3) ⁇
- the suspension was filtered and die filtrate preadsorbed onto silica and chromatographed, eluting witii 5:95 methanokethyl acetate.
- the product was eluted and the solvent removed to give a white solid.
- a third product from Example 26 was eluted and die solvent removed to give a white soUd that was precipitated from methanol. Yield 0.19 g. Second crop. Yield
- Example 32 Concentration of die eluate containing band B from Step A, Example 32 gave 9- [4- hydroxy-3,3-bis(N-benzyloxycarbonyl-L-valyloxymethyl)but-l-yl]guanine (1.78 g, 34%) as a near colourless foam. Yield 1.78 g (34%). A H n.m.r.
- Example 37 The second product from Step A, Example 37 was eluted and the solvent removed to give a white soUd. Yield 0.043 g (1.1%). mp 183.0-184.0°. l U-n.m.r., (DMSO- d6) ⁇ 0.90, t, J 8.3 Hz, 3H; 1.73, m, 4H; 4.03, m, 5H; 4.67, t, 2H; 5.00, d, 2H; 6.43, s, br, 2H; 7.33, s, 5H; 7.67, s, IH; 7.73, d, J 8.3 Hz, IH; 10.53, s, br, IH.
- DMSO- d6 ⁇ 0.90, t, J 8.3 Hz, 3H; 1.73, m, 4H; 4.03, m, 5H; 4.67, t, 2H; 5.00, d, 2H; 6.43, s, br, 2H; 7.33, s
- a H n.m.r. (CDCI3) ⁇ 1.67, t, 76.7 Hz, 2H; 1.78, t, 76.4 Hz, 2H; 2.04, s, 6H; 3.56, t, 7 6.4 Hz, 2H; 3.73, t, 76.7 Hz, 2H; 4.00, s, 4H, 4.49, s, 2H; 7.27-7.38, m, 5H.
- n.m.r. (DMSO-dg) ⁇ 2.16, dt, 7, 18 Hz, 2H; 2.51, s; 3.53, dd, 6, 18 Hz, 4H; 4.21, t, 7 Hz, 2H; 5.00, t, 6 Hz, 2H; 6.51, s, 2H, br; 8.08, s, IH; 8.56, s, IH. 13c n.m.r. (D2O) ⁇ 34.2, 34.7, 43.7, 100.2, 103.6, 127.5, 142.1, 154.8, 158.2, 160.8.
- a second product from Example 72 was eluted and d e solvent removed to give a solid. m.p. 132-134°. iH n.m.r. (DMSO-dg) ⁇ 1.89, m, 2H; 2.02, s, 6H; 3.99, s, 4H; 4.17, m, 2H; 4.95, s, IH, br; 6.47, s, 2H, br; 8.10, s, IH; 8.57, s, IH.
- DMSO-dg ⁇ 1.89, m, 2H; 2.02, s, 6H; 3.99, s, 4H; 4.17, m, 2H; 4.95, s, IH, br; 6.47, s, 2H, br; 8.10, s, IH; 8.57, s, IH.
- the second band collected from Example 75 was concentrated under reduced pressure to give the product.
- iH n.m.r. (DMSO-d6) ⁇ 1.42, s, 18H; 1.83, m, 2H; 3.96, s, 4H; 4.04, m, 2H; 5.0, m, IH; 6.4, br s, 2H; 7.69, s, IH; 10.5 br s, IH.
- the second band collected from Example 78 was concentrated under reduced pressure to give the product.
- iH n.m.r. (DMSO-d6) ⁇ 1.92, m, 2H; 2.03, s, 3H; 3.72, s, 6H; 4.04, br, 4H; 4.14, s, 4H; 6.4, br s, 2H; 7.72, s, IH; 10.6, br s, IH.
- Example 81 The crude product from Example 81 was treated as per Example 13 to give crude product. A portion of the crude product was purified by reverse phase HPLC, eluting with a non-linear gradient of 10/90 CH3CN/H2O to 30/70 CH3CN/H2O. The first band was collected and concentrated under reduced pressure to give the product.
- iH n.m.r. (DMSO-dg) ⁇ 1.98, m, 2H; 2.02, s, 3H; 3.72, s, 6H; 4.04, s, 2H; 4.14, s, 4H; 4.16, m, 2H; 6.46, br s, 2H; 8.09, s, IH; 8.57, s, IH.
- Example 86 Prepared from Example 86 as per method described for Example 13.
- the product was crystalUsed from methanol as a white crystalUne soUd.
- iH n.m.r. DMSO-dg
- DMSO-dg DMSO-dg
- Example 92 A second product from Example 92 was eluted, and the solvent removed to give a solid.
- iH n.m.r. (DMSO-d6) ⁇ 1.12-1.90, m, 24H; 2.30, m, 2H; 3.41, d, 2H; 3.95, s, 4H; 4.05, m, 2H; 4.90, t, IH; 6.40, s, 2H; 7.70, s, IH; 10.58, s, IH.
- a second product from Example 94 was eluted, and the solvent removed to give a soUd. iH n.m.r. (DMSO-d6) ⁇ 0.85, t, 6H; 1.22, s, 12H; 1.50, m, 4H; 1.82, m, 2H; 2.29, t, 4H; 3.40, d, 2H; 3.97, s, 4H; 4.05, m, 2H; 4.93, t, IH; 6.47, s, 2H; 7.69, s, IH; 10.61, s, IH.
- DMSO-d6 ⁇ 0.85, t, 6H; 1.22, s, 12H; 1.50, m, 4H; 1.82, m, 2H; 2.29, t, 4H; 3.40, d, 2H; 3.97, s, 4H; 4.05, m, 2H; 4.93, t, IH; 6.47, s, 2H; 7.69,
- a third product from Example 94 was eluted, and the solvent removed to give a soUd. iH n.m.r. (DMSO-d6) ⁇ 0.87, t, 9H; 1.22, s, 18H; 1.51, m, 6H; 1.92, m, 2H; 2.31, t, 6H; 4.02, s, 6H; 4.05, m, 2H; 6.41, s, 2H; 7.70, s, IH; 10.59, s, IH.
- the crude product was preadsorbed onto siUca and chromatographed, eluting with 10:90:0.2 methanol:dichloro-methane:acetic acid.
- the product was eluted and die solvent removed to give a white solid.
- the soUd was recrystalUzed from methanol /acetone.Yield 0.543 g (27%).m.p. 259-261°. iH n.m.r.
- Example 1 Step I Isolated from Example 1 Step I as a minor by-product.
- iH n.m.r. (DMSO-d6) ⁇ 1.85-2.0, m, 2H; 2.05, s, 6H; 3.25, s, 3H; 3.35, s, 2H; 4.05, s, 4H; 4.1-4.25, m, 2H; 6.9, s, 2H; 8.2, s, IH.
- Hepatocytes were purified from the cell mass using Percoll density gradients (Pharmacia, Sweden) following a modification of the manufacturer's specifications.
- the gradient medium stock solution (SIP; stock isotonic Percoll) consisted of nine parts Percoll mixed witii one part 1.5 M NaCl solution. Percoll of the required density of 1.05 g/ml was then generated by diluting six parts SIP with four parts MEM at a final pH of 7.4. Five ml of hepatocyte ceU suspension was layered onto 30 ml of this solution and centrifuged at 20,000 rpm for 20 min at 20°C in a JA-20 fixed angle rotor (Beckman, USA).
- the bands of cells corresponding to die density of hepatocytes (1.07 - 1.09 g/cm 3 ) were collected and washed in L 15 medium (CSL, AustraUa) supplemented with 5% fetal bovine serum (FBS) and counted in a haemocytometer. Cell viability was established using trypan blue dye exclusion.
- Hepatocytes were diluted and subsequently seeded with L 15 complete (L 15) which consisted of L 15 media supplemented with 15 mM Tris, insuUn, glucose, hydrocortisone hemisuccinate, penicillin and streptomycin according to Tuttleman et al, supra and 5% FBS was also included. Hepatocytes were seeded at approximately 2.0 x 10 6 cells per well into 6 well multiplates (Greiner, West Germany) or at approximately 0.5 x 10 6 cells per well into 24 well plates (Costar, Cambridge Mass.).
- Total intracellular viral DNA was extracted from cell lysates by a modification of the method of Tuttleman et al, supra. Cells were lysed in a solution containing 0.5% sodium dodecyl sulphate (SDS), 20 mM Tris-HCl (pH 7.4), 10 mM EDTA, 5 mM EGTA, and 150 mM NaCl. DNA was extracted from all samples by digestion with 200 ug per ml of proteinase K (International Biosciences Incorporated, USA) at 37°C for 1 hour, and deproteinised by extraction with an equal volume of phenoUchloroform (1:1), followed by chloroform.
- SDS sodium dodecyl sulphate
- a full length clone of the Australian strain of DHBV was propagated in E. coli and the plasmid extracted using standard techniques (J. Sambrook, E. F. Fritsch and T. Maniatis "Molecular Cloning: A Laboratory Manual” Second Edition Cold Spring Harbour Laboratory Press 1989).
- the cloned DHBV DNA sequences were excised from the plasmid by EcoRI digestion and were separated by preparative gel electrophoresis using a Prep-A-Gene DNA purification kit (Bio- Rad, Hercules Calif.) according to the manufacturer's recommendations.
- a 648 bp DNA fragment was also prepared by further digesting the EcoRI DHBV and purifying the smaller fragment as described above.
- DHBV DNA was radiolabelled with [ ⁇ - 32 P] dCTP using a NEN Random Primer Plus Extension kit (NEN Research Products, DuPont, Wilmington, USA) to a specific activity of 0.5-1.0 x l0 9 c ⁇ m/mg.
- DHBV DNA in cell culture was detected by slot-blot hybridization.
- Extracted DNA dissolved in TE buffer was diluted in 6x saUne sodium citrate (SSC) lxSSC is 0.15M NaCl + 0.15M sodium citrate, pH7.0), denatured by rapid boiUng and quenching then serially diluted in 6xSSC.
- SSC 6x saUne sodium citrate
- lxSSC 0.15M NaCl + 0.15M sodium citrate, pH7.0
- DNA was baked onto membranes at 80°C for 2 hours before pre-hybridisation in a buffer consisting of 50% deionised formamide, 6xSSC, 5mM NaH 2 P0 4 (pH 6.5), 2 x Denhardt solution and 100 mg/ml of herring sperm DNA (Boeringer Manheim, Germany). After pre-hybridisation at 42°C for at least 3 hours in a hybridization oven (Hybaid, England) heat-denatured radio-labelled DHBV DNA probe was added to a concentration of at least 2xl0 6 cpm and hybridisation allowed to proceed overnight at 42°C.
- a hybridization oven Hybaid, England
- membranes were washed twice in 2 x SSC-0.1% SDS at 24°C and twice in 0.1 x SSC/0.1% SDS for 30 min at 50°C to remove unbound probe.
- Radiolabelled DHBV probe bound to die air-dried filters was detected with the aid of intensifying screens by autoradiography at -70°C onto
- test compounds were prepared in sterile deionised distilled water.
- stock solutions were prepared in ceU culture grade dimethylsulphoxide (DMSO).
- DMSO ceU culture grade dimethylsulphoxide
- dilutions of test compound stock solutions were prepared in deionised distilled water or DMSO at lOOx the final test concentration. These dilutions were then added to complete cell culture medium at the rate of 10ml per ml (a dilution of 1 in 100), so that the final concentration of distilled water or DMSO added in every case was constant at 1%, a concentration at which neither DMSO nor distiUed water had any effect on virus replication.
- DHBV DNA standards were used to estabUsh both the detection Umit, and prove that the relationship between the 32 P count and die amount of bound DHBV was linear over the range of interest.
- the extent of viral repUcation (measured as cpm bound 32 P bound DHBV probe detected) in the presence of test compounds is expressed as a percentage of viral repUcation in the control cultures.
- the effective concentration for 50% inhibition of repUcation is shown in Table 1.
- formulation A may be prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
- the following formulation B may be prepared by direct compression of the admixed ingredients.
- This formulation may be prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and compression.
- a capsule formulation may be prepared by admixing the ingredients of Formulation B in Example 4 above and filUng into a two-part hard gelatin capsule.
- Formulation B (infra) may be prepared in a similar manner.
- the following controlled release capsule formulation may be prepared by extruding ingredients a, b and c using an extruder, followed by spheronisation of the extrudate and drying. The dried pellets may then be coated witii release-controlUng membrane (d) and filled into a two-piece, hard gelatin capsule.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for the treatment and/or prophylaxis of a Hepadnaviridae associated infection which comprises administration of an effective amount of a compound of Formula (1), wherein R1 is hydrogen, halogen, hydroxy, azide, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, mercapto, optionally substituted alkylthio, optionally substituted amino, optionally substituted hydrazino or optionally substituted hydroxylamino; R2 is hydrogen, halogen, hydroxy, azide, optionally substituted alkoxy, optionally substituted aryloxy, mercapto, optionally substituted alkylthio or optionally substituted amino; R3 and R3' are the same or different and selected from hydrogen, optionally substituted alkyl, halogen, hydroxy, azide, optionally substituted alkoxy, optionally substituted aryloxy, mercapto, optionally substituted thio and optionally substituted amino; or R3 and R3' together form =O, =S, =NOH or =NOR, wherein R is optionally substituted alkyl; and R4, R5 and R6 are the same or different and selected from optionally substituted alkyl, optionally substituted aralkyl, halogen, hydroxy, azide, optionally substituted alkoxy, optionally substituted aryloxy, mercapto, optionally substituted alkylthio, optionally substituted amino, optionally substituted acyl, optionally substituted ester, cyano, carboxy and mono-, di- or tri- phosphate; two of R4, R5 and R6 are joined together to form a cyclic group; or R4, R5 and R6 are joined together to form a cyclic ortho ester group, salts thereof, pharmaceutically acceptable derivatives thereof, pro-drugs thereof, tautomers thereof and/or isomers thereof to a subject requiring said treatment and/or prophylaxis. The invention also relates to novel compounds of Formula (1), processes for their preparation and pharmaceutical or veterinary compositions containing them.
Description
ANTIVIRAL AGENTS
The present invention relates to purine acyclonucleosides, processes for f their preparation and their use as agents in the treatment or prophylaxis of
Hepadnaviridae associated infections, in particular hepatitis B.
Infection with human hepatitis B virus (hereinafter referred to as "HB V") is a major public health problem because of the ability of the virus to cause acute and chronic infections. Chronic hepatitis B virus infection causes serious liver disease in humans and frequently results in cirrhosis and hepatocellular carcinoma. Currently there is no effective therapy for the successful management of chronic HBV infections. The >250 million chronic HBV carriers throughout the world are unable to benefit from the commercial vaccine now available.
HBV is a member of the Hepadnaviridae family, of which several animal viruses have been identified. These include woodchuck hepatitis virus, ground squirrel, and duck hepatitis virus (hereinafter referred to as "DHBV") (W.S. Mason, G. Seal, and J Summers J Virology 36, 829-836(1980). These viruses share common biological features with HBV including the virion ultrastructure, genomic structure, and a unique mechanism of replication (I.D. Gust, C. J. Burrell, A. G. Coulepsis, W. S. Robinson and A. Zuckerman, Intervirology 25, 14-29 (1986)) and consequently may be used for assaying in vitro the activity of potential anti-HBV agents.
Hannah and Tolman in EP 0 381 531 disclose purine and pyrimidine acyclonucleosides and nucleotides stated to be particularly effective against the herpes group of viruses with special utility against cytomegalovirus(CMV) and varicella-zoster virus (VZV) and against retroviruses such as HTLV HI. EP 0 381 531 provides no evidence for the antiviral activity of the disclosed compounds even against the above viruses. However, Hannah et al in J Heterocyclic Chem., 26, 1261 (1989) give the activity of N-7 and N-9 substituted guanines against the Herpes simplex viruses HSV-1 and HSV-2. These results show that the N-7 substituted guanines disclosed are not active against these viruses. While the N-9 substituted guanines disclosed are mostly weakly active, m the 3' methoxybutyl N-9 substituted guanine is not active.
Bailey and Harnden in J. Chem. Soc. Perkin Trans. I (1988) 2767 independently reported the synthesis and activity of the N-9 substituted guanine compounds confirming that the 3' fluoro compound had good activity against HSV 1 and HSV 2 and that 3' methyl-, hydroxy-, and hydroxymethyl- substituted compounds had slight activity against HSV 1 and HSV 2. They reported that these compounds were not active against Influenza A virus, or para-influenza type 1 (Sendai ) virus.
This reported antiviral activity data show that the activity of a chemical compound does not translate from one virus to another even in a related virus group.
It has now been found that compounds of Formula (1) below are inhibitors of replication of duck and human hepatitis B virus and may be useful control agents for hepatitis B infections when used alone or with another antiviral agent.
According to one aspect of the present invention there is provided a method for the treatment and/or prophylaxis of a Hepadnaviridae associated infection which comprises administration of an effective amount of a compound of Formula (1):
(1) wherein Rj is hydrogen, halogen, hydroxy, azide, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, mercapto, optionally substituted alkylthio, optionally substituted amino, optionally substituted hydrazino or optionally substituted hydroxylamino;
R2 is hydrogen, halogen, hydroxy, azide, optionally substituted alkoxy, optionally substituted aryloxy, mercapto, optionally substituted alkylthio or optionally substituted amino;
R3 and R3' are the same or different and selected from hydrogen, optionally substituted alkyl, halogen, hydroxy, azide, optionally substituted alkoxy, optionally substituted aryloxy, mercapto, optionally substituted thio and optionally substituted amino; or R3 and R3' together form =0, =S, =NOH or =NOR, wherein R is optionally substituted alkyl; and
R4, R5 and R are the same or different and selected from optionally substituted alkyl, optionally substituted aralkyl, halogen, hydroxy, azide, optionally substituted alkoxy, optionally substituted aryloxy, mercapto, optionally substituted alkylthio, optionally substituted amino, optionally substituted acyl, optionally substituted ester, cyano, carboxy and mono-, di- or tri- phosphate; two of R4, R5 and R are joined together to form a cyclic group; or R4, R5 and Rg are joined together to form a cyclic ortho ester group,
salts thereof, pharmaceutically acceptable derivatives thereof, pro-drugs thereof, tautomers thereof and/or isomers thereof to a subject requiring said treatment and/or prophylaxis
Throughout this specification unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
The term "Hepadnaviridae associated infection" is used herein in its broadest sense. A particular example of such an infection is human hepatitis B.
The subject may be a human or an animal such as a domestic or wild animal, particularly an animal of economic importance.
An "effective amount" of the compound of Formula (1) is an amount sufficient to inhibit or reduce viral replication, generally by greater than 50% (as measured by viral DNA levels or reverse transcriptase activity).
The salts of the compound of Formula (1) are preferably pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicyclic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.
By "pharmaceutically acceptable derivative" is meant any pharmaceutically acceptable salt, hydrate or any other compound which, upon administration to the subject, is capable of providing (directly or indirectly) a compound of Formula (I) or an antivirally active metabolite or residue thereof.
The term "pro-drug" is used herein in its broadest sense to include those compounds which are converted in vivo to compounds of Formula (1). For example, a compound of Formula (1) wherein R. and/or R~ are acyloxy substituted alkyl groups may be converted in vivo to a compound of Formula (1) wherein R. and/or R5 as appropriate is a hydroxy substituted alkyl group.
The term "tautomer" is used herein in its broadest sense to include compounds of Formula (1) which are capable of existing in a state of equilibrium between two isomeric forms. Such compounds may differ in the bond connecting
two atoms or groups and the position of these atoms or groups in the compound, for example, -OH and -SH substituents on the compound of Formula (1) may be replaced by =0 and =S substituents, respectively.
The term "isomer" is used herein in its broadest sense and includes structural, geometric and stereo isomers. As the compound of Formula (1) has a chiral centre, it is capable of existing in enantiomeric forms. The present invention includes enantiomers in isolated form and mixtures thereof. When R^, R5 and R6 are different then the present invention includes all enantiomers and diasteriomers of the compound of Formula (1) that may result from this situation in isolated form and mixtures thereof.
The term "halogen" denotes fluorine, chlorine, bromine or iodine, preferably chlorine or fluorine.
The term "alkyl" used either alone or in compound words such as "optionally substituted alkyl", "optionally substituted alkylthio" and "aralkyl" denotes straight chain, branched or cyclic alkyl, preferably C1.30 alkyl or cycloalkyl. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, sec-amyl, 1,2-dimethylpropyl, 1,1- dimethylpropyl, hexyl, 4-methylpentyl, 1-methylpentyl, 2-methylpentyl, 3- methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2- dimethylbutyl, 1,3-dimethylbutyl, 1,2,2,-trimethylpropyl, 1,1,2-trimethylpropyl, heptyl, 5-methylhexyl, 1-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4- dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3,- trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, 6-methylheptyl, 1- methylheptyl, 1,1,3,3-tetramethylbutyl, nonyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-methyloctyl, 1-, 2-, 3-, 4- or 5-ethylheptyl, 1-, 2- or 3-propylhexyl, decyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- and 8-methylnonyl, 1-, 2-, 3-, 4-, 5- or 6-ethyloctyl, 1-, 2-, 3- or 4-propylheptyl, undecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8- or 9-methyldecyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-
ethylnonyl, 1-, 2-, 3-, 4- or 5-propyloctyl, 1-, 2- or 3-butylheptyl, 1-pentylhexyl, dodecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10-methylundecyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or
8-ethyldecyl, 1-, 2-, 3-, 4-, 5- or 6-propylnonyl, 1-, 2-, 3- or 4-butyloctyl, 1-2- pentylheptyl and the like. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and d e like.
The term "alkoxy" used either alone or in compound words such as "optionally substituted alkoxy" denotes straight chain or branched alkoxy, preferably Cj_3o alkoxy. Examples of alkoxy include methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy isomers.
The term "acyl" used either alone or in compound words such as "optionally substituted acyl" denotes carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl or a heterocyclic ring which is referred to as heterocyclic acyl, preferably
acyl. Examples of acyl include carbamoyl; straight chain or branched alkanoyl such as formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl and heptyloxycarbonyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; alkylsulfonyl such as methylsulfonyl and ethylsulfonyl; alkoxysulfonyl such as methoxysulfonyl and ethoxysulfonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl,
naphthylpropanoyl and naphthylbutanoyl); aralkenoyl such as phenylalkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacrylyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aralkoxycarbonyl such as phenylalkoxycarbonyl (e.g. benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl and naphthyloxycarbonyl; aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylcarbamoyl such as phenylcarbamoyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and naphthylsulfonyl; heterocycUccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocycUchexenoyl; and heterocyclicglyoxyloyl such as thiazolylglyoxyloyl and thienylglyoxyloyl.
The term "aryl" used either alone or in compound words such as "optionally substituted aryloxy" denotes single, polynuclear, conjugated and fused residues of aromatic hydrocarbons or aromatic heterocyclic ring systems. Examples of aryl include phenyl, biphenyl, terphenyl, quaterphenyl, phenoxyphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, indenyl, azulenyl, chrysenyl, pyridyl, 4-phenylpyridyl, 3-phenylpyridyl, thienyl, furyl, pyrryl, pyrrolyl, furanyl, imadazolyl, pyrrolydinyl, pyridinyl, piperidinyl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benzoxazolyl, benzothiazolyl and the like. Preferably, the aromatic heterocylic ring system
contains 1 to 4 heteratoms independently selected from N, O and S and containing up to 9 carbon atoms in the ring.
The term "ester" used either alone or in compound words such as "optionally substituted ester" denotes acyloxy, acylalkoxy or acyloxyaryl groups wherein the terms "acyl", "alkoxy" and "aryl" are as defined above.
The term "aralkyl" used either alone or in compound words such as "optionally substituted aralkyl" denotes arylalkyl groups wherein the terms "aryl" and "alkyl" are as defined above, such as, for example, benzyl.
The term "cyclic group" denotes the aryl groups defined above and non- aromatic ring systems which may also contain the additional heteroatom P. Examples of suitable cyclic groups include optionally substituted cyclic acetals, carbonates, alkyls, phosphates, or orthoesters.
In this specification "optionally substituted" means that a group may or may not be further substituted with one or more groups, preferably 1 to 5 groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, carboxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, azido, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, aldehydo, alkylsulphonyloxy, arylsulphonyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy, mercapto, alkylthio, arylthio, acylthio and phosphorus-containing groups.
Preferably R., R- and/or Rfi in the compound of Formula (1) are optionally substituted alkyl, for example, alkyl substituted with hydroxy or optionally substituted alkoxy.
A preferred sub-class of compounds of Formula (1) have the Formula (la):
(la) wherein Rj, R2 and Rg are as defined above; and
R4'and R5' are the same or different and selected from hydrogen, optionally substituted alkyl, optionally substituted aralkyl, optionally substituted aminoacyl, optionally substituted acyl, optionally substituted ester and mono-, di- or tri- phosphate, provided that when one of R4', Rζ' or R5 is or contains mono-, di- or tri- phosphate then the remaining groups are other than phosphate; two of R4', R5' and
R are joined together to form a cyclic acetal group, a cyclic carbonate group or a cyclic phosphate group; or R4', R5' and Rg are joined together to form a cyclic ortho ester group.
Thus, in an alternative aspect, the present invention provides a method for the treatment and/or prophylaxis of a Hepadnaviridae associated infection which comprises adminstration of an effective amount of a compound of Formula (la) defined above.
The present invention also provides use of a compound of Formula (1) or
(la) as defined above in the manufacture of a medicament for the treatment and/or prophylaxis of Hepadnaviridae associated infection.
The present invention further provides a compound of Formula (1) or (la) as defined above for use in the treatment and/or prophylaxis of a Hepadnaviridae associated infection.
Most of the compounds of Formula (1) are novel per se. Thus in another aspect of the present invention there is provided a compound of the Formula (1) as defined above with the provisos that:
(a) when
Rj is benzyloxy;
R2 is amino; and
R4 and R5 together form 2,2-dimethyl-l,3-dioxane, then β is other than fluoro, methoxy or hydroxy;
(b) when
Rj is hydroxy;
R2 is amino; and
R4 and R5 are hydroxymethyl, then R-g is other than fluoro, hydroxy, methoxy, methyl or hydroxymethyl;
(c) when
Rj is hydroxy;
R2 is amino; and
then Rg is other than fluoro, hydroxy or methoxy; or
(d) when
Rj is chloro;
R2 is amino; and
R4 and R5 together form 2,2-dimethyl-l,3-dioxane, then Rg is other than methyl or hydroxymethyl.
The present invention also provides a compound of Formula (la) as defined above with the provisos that: (a) when
Rj is benzyloxy;
R2 is amino; and
R4' and R5' together form
:CR14 R15
wherein R14 and Rj5 are methyl, then Rg is other than fluoro, methoxy or hydroxy;
(b) when
Rj is hydroxy;
R2 is amino; and
R4' and R5' are hydrogen, then Rg is other than fluoro, hydroxy, methoxy, methyl or hydroxymethyl;
(c) when
Rj is hydroxy;
R2 is amino; and
R4' and R5' together form
wherein R is as defined above, then Rg is other than fluoro, hydroxy or methoxy; or
(d) when
Rj is chloro;
R2 is amino; and
R4' and R5' together form
CR1 R15
wherein Rj4 and R15 are methyl,
then Rg is other than methyl or hydroxymethyl.
Preferred Regroups are hydrogen, halogen, hydroxy, optionally substituted
alkoxy, optionally substituted hydroxylamino or optionally substituted hydrazino.
Preferred R2 groups are -NR Rg, wherein R is hydrogen, optionally
substituted alkyl or optionally substituted acyl and Rg is hydrogen or alkyl.
Preferred R^ groups are -alkylORg', fluorine, -ORg' or methyl, wherein Rg'
is hydrogen, optionally substituted alkyl, optionally substituted aminoacyl, optionally substituted acyl or mono-, di- or tri-phosphate.
Preferred R4', R5', Rg' and/or R7 groups are those selected from hydrogen, aminoacyl, R9- C (O)- and R9-C (S)- ,wherein Rg is hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl or -NRJQR, . ,
wherein RJQ and Rj j are the same or different and are selected from hydrogen and alkyl or together with the nitrogen to which they are attached form a 3-7 membered heterocyclic ring.
RΛ R-\ Rg' and/or R7 may also represent other suitable acyl groups such
as those derived from amino acids. These amino acyl derivatives may be derived for example from naturally occuring amino acids, preferably neutral amino acids, that is, amino acids with one amino group and one carboxyl group. Examples of suitable amino acids include phenylalanine and aliphatic acids containing up to 6 carbon atoms such as glycine, alanine, valine and isoleucine. The amino acids may be D-, L-and DL amino acids, with the natural L-amino acids being most preferred.
Suitable examples of phosphate groups for R, or RΛ or R<- or R<-' and/or
R6 or Rg' form the group:
R1 2 O
R13 O P o
o
wherein Rj2 and R13 are the same or different and are selected from hydrogen,
alkyl, optionally substituted aryl, optionally substituted aralkyl and pharmaceutically acceptable cations, preferably hydrogen and pharmaceutically acceptable cations.
Suitable examples of a cyclic acetal group, a cyclic carbonate group or a
cyclic phosphate group formed when two of RΛ R^' and R^ or Rg' together form the groups:
wherein R, « s as defined above; R14 and Rj5 are the same or different and are selected from hydrogen or C. , alkyl.
A suitable example of cyclic ortho ester groups formed when R. or RΛ or
R or R<-' and/or Rfi or Rg' together form the group:
^ CR14
wherein R, . is as defined above.
A preferred group of compounds of Formula (la) are those wherein
R*. is hydrogen, halogen, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, amino,
benzyloxy, hydroxy lamino or hydrazino, preferably R, is hydrogen, hydroxy or
Cj g alkoxy;
R2 is amino or acylamino;
Rg is CH2-OR6' or C2H4-OR6';
RΛ R<-' and/or R are the same or different and selected from hydrogen, halogen,
optionally substituted alkyl, optionally substituted aralkyl, optionally substituted ester, optionally substituted aminoacyl and optionally substituted acyl; or two of
R Λ R<-' and/or R,' are joined together to form a cyclic acetal group or a cyclic
carbonate group.
Many of these preferred compounds act as prodrugs of the compound of Formula (2). That is they are converted in vivo to the compound of Formula (2):
Accordingly in a preferred aspect of the present invention the compound of Formula (1) is a compound of Formula (2) or pharmaceutically acceptable salts
thereof, esters, ethers, acyl or aminoacyl derivatives thereof and/or pro-drugs thereof.
Some of the compounds of Formulae (1) and (la) may be prepared by known methods such as those disclosed by Hannah and Tolman in EP 0381531 and Heterocyclic Chem., 26, 1261 (1989) or by Bailey and Harnden in J Chem. Soc. Perkin Trans. I, (1988) 2767.
In a further aspect of the present invention, there is provided a process for the preparation of the novel compounds of Formula (la) which comprises the steps of: (a) reacting a compound of Formula (3):
(3) wherein
Rj and R2 are as defined above with a compound of Formula (4):
(4)
wherein
Ra and Rj, may be the same or different and are selected from R4' and R5'as defined above, hydrogen and benzoyl;
Rc is the same as Rg as defined above, hydroxy, hydroxyalkyl or protected derivatives thereof; and
Z is a leaving group, to form a compound of Formula (6):
Rj , R2, Ra, Rb and Rc are as defined above; and
(b) if necessary, converting the compound of Formula (6) to a compound of Formula (la).
It will be appreciated that the process of the invention may also be used to prepare the known compounds of Formulae (1) and (la).
In the compound of Formula (3), R, is preferably chlorine or benzyloxy, more preferably chlorine and R2 is preferably amino or aminoacyl, more preferably amino.
In the compound of Formula (4), protected hydroxy may be acyloxy or alkoxy; protected hydroxyalkyl may be acyloxyalkyl or alkoxyalkyl; and protected amino may be acylamino.
Suitable examples of the leaving group Z are methane sulfonate or bromine.
The compound of Formula (4) may be prepared from a compound of Formula (5):
(5) wherein R , R, and R are as defined above, either by activation of the hydroxyl
group to form the leaving group Z or by replacement of the hydroxyl group to give a leaving group Z. An example of the former process is treatment of the compound of Formula (5) with methane sulfonyl chloride under conventional conditions to form the compound of Formula (4) wherein Z is a methane sulfonyl group. An example of the latter process is the treatment of the compound of Formula (5) with carbon tetrabromide and triphenylphosphine in an organic, aprotic solvent, such as, dimethylformamide to prepare the compound of Formula (4) wherein Z is bromine.
Compounds of Formula (5) may be prepared by the methods disclosed by Hannah and Tolman in EP 0381531 and J Heterocyclic Chem., 26, 1261 (1989) and by Bailey and Harnden in J Chem. Soc. Perkin Trans. I, (1988) 2767 or modifications of these methods.
The product of the reaction between the compound of Formula (3) and the compound of Formula (4) is a compound of Formula (6):
(6)
wherein R , R, and R are as defined above. The compound of Formula (6) may
also, depending on the nature of the groups R , R, and R , be a compound of
Formula (la).
Compounds of Formula (6) can be readily converted into compounds of Formula (1) or (la) using methods known in the art. Compounds of Formula (1) or (la) can be converted into other compounds of Formula (1) or (la) using similar known methods. Such known methods may include the removal of protecting groups, hydrogenation, aminolysis, hydrolysis, alkylation, acylation and phosphorylation.
In accordance with conventional processes known in the art, compounds of Formula (1) or (la) that have acyclic hydroxyl groups may be readily converted into the compounds of Formula (1) or (la) with either acyl or phosphate groups or a mixture of these groups on the acyclic chain. In some instances it may be useful
to utilise protected intermediates of the compounds of Formula (1) or (la) in order to prepare the desired final product of Formula (la). Such intermediates may be prepared in accordance with known methods and when no longer required the protecting groups removed using known methods. Examples of suitable protecting groups are trimethylsilyl and monomethoxytrityl groups.
The acylation reaction of compounds of Formula (1) or (la) with acyclic hydroxyl groups may be carried out using an acylating agent containing a group
aminoacyl or R9- C (0)-, wherein Rg is as defined above.
Examples of other acylating agents suitable for use in the process are carboxylic acids, acid halides and acid anhydrides. The reaction may be carried out in a conventional manner, for example in a solvent such as pyridine or dimethylformamide, optionally in the presence of a coupling agent such as N,N'- dicyclohexylcarbodiimide and optionally in the presence of a catalytic base such as 4-dimethylaminopyridine. The product of the reaction may be isolated in a conventional manner.
In the case of amino acids or their functional equivalents, for example acid halides, it may be advantageous, in order to avoid side reactions, to use amino protected derivatives of the amino acid or amino acid equivalent, for example benzyloxycarbonyl derivatives. Such derivatives are commercially available. The protecting groups may be removed utilising standard procedures.
The acylation reactions may produce a single compound of Formula (1) or (la) incorporating one or more acyl groups or may produce a mixture of compounds of Formula (1) or (la) incorporating acyl groups. The outcome depends on a number of factors, such as the relative amounts and chemical nature of the reactants, the physical conditions of the reaction, and the solvent system.
Any mixture produced in this way may be separated using standard techniques, preferably chromatography.
It will be appreciated that it is possible to produce compounds of Formula (1) or (la) which may have a mixture of different acyl and/or alkyl groups.
Protected intermediates of the compounds of Formula (1) or (la) may also be used to prepare compounds of Formula (1) or (la) incorporating phosphate . esters.
Compounds of Formula (1) incorporating cyclic monophosphates may be produced according to the known methods discussed above.
The present invention also extends to a pharmaceutical or veterinary composition for the treatment and/or prophylaxis of a Hepadnaviridae associated infection which comprises a compound of Formula (1) or (la) as defined above in association with a pharmaceutically or veterinarily acceptable carrier, diluent, adjuvant and/or excipient.
The compounds of the invention may be advantageously used in combination therapy with other antiviral agents such as Ganciclovir, Famcyclovir, Pencyclovir, Lamivudine and interferon. Hence a preferred method in accordance with the present invention utilises the compound of Formula (1) or (la), analogue or derivative in conjunction with another antiviral agent.
The compound of Formula (1) or (la), also referred to herein as the "active ingredient", may be administered for therapy by any suitable route, including oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). Preferably, administration will be by the oral route, however it will be appreciated that the
preferred route will vary with the condition and age of the subject and the chosen active ingredient.
The compositions of the present invention comprise at least one compound of Formula (1) or (la), together with one or more pharmaceutically acceptable carriers, diluents, adjuvants and/or excipients and optionally other antiviral or therapeutic agents. Each carrier, diluent, adjuvant and/or excipient must be pharmaceutically "acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the subject. Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier diluent, adjuvant and/or excipient which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, diluents, adjuvants and/or excipients or finely divided solid carriers or both, and then if necessary shaping the product.
Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing
in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions
which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage compositions are those containing a daily dose or unit, daily sub-dose such as one or more unit dosage forms per day or an appropriate fraction thereof, of an active ingredient.
The compound of Formula (1) or (la) may also be presented for use in the form of veterinary compositions, which may be prepared, for example, by methods that are conventional in the art. Examples of such veterinary compositions include those adapted for:
(a) oral administration, external application, for example drenches (e.g. aqueous or non-aqueous solutions or suspensions); tablets or boluses; powders, granules or pellets for admixture with feed stuffs; pastes for application to the tongue;
(b) parenteral administration for example by subcutaneous, intramuscular or intravenous injection, e.g. as a sterile solution or suspension; or (when appropriate) by intramammary injection where a suspension or solution is introduced into the udder via the teat;
(c) topical application, e.g. as a cream, ointment or spray applied to the skin; or
(d) intravaginally, e.g. as a pessary, cream or foam.
It should be understood that in addition to the active ingredients particularly mentioned above, the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents.
Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrating agents include corn starch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, steric acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.
The invention will now be described with reference to the following non- limiting Examples. These Examples are not intended to limit the scope of the invention in any way. The term "active ingredient" as used in Examples 111 to 113 refers to the compound of Formula (1) or (la) or a pharmaceutically acceptable derivative thereof. All temperatures are in degrees Celsius (°C) unless otherwise stated.
GENERAL
All melting points were determined on a Mettler FP51, an Electrothermal 9300 or a Reichert apparatus, and are uncorrected. Microanalyses were performed by the National Analytical Laboratories Pty. Ltd.. H n.m.r. specta were recorded on a Varian Gemini (200 MHz, Fourier mode), a Bniker (200 MHz, Fourier mode) or a Bruker (250 MHz, Fourier mode) n.m.r. spectrometer and 13c n.m.r. spectra were performed on the same instruments at 50 MHz. or 62.5 MHz. All chemical shifts are expressed in parts per million (ppm) downfϊeld from TMS (δ scale). The multiplicity patterns are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) and br (broad). High resolution mass measurements were recorded on a JEOL DX303 mass spectrometer. Merck silica gel (230-400 mesh ASTM) was employed in column chromatography. Unless otherwise stated, all organic extracts were dried over magnesium sulfate, filtered and solvents removed on a rotary evaporator. Unless otherwise specified, unreferenced reagents were obtained commercially and used as supplied.
EXAMPLE 1
9-[4-Acetoxy-3,3-bis(acetoxymethyl)-but-l-yl]-2-amino-6-chloropurine
Step A
2-Benzyloxyethanol
To potassium hydroxide (1900 g, 35 mol) was added 1,2-ethanediol (4800 ml, 87 mol). The mixture was heated to 90°. Benzyl chloride (4000 ml, 35 mol) was added dropwise over 3 hrs, maintaining the temperature at 90°. The mixture was then heated to 130° and held for 2 hrs. The mixture was then allowed to cool to room temperature. The product was separated into two batches and each half extracted with ethyl acetate (6 x 1000 ml) from water (8000 ml). The combined organic extract was backwashed with water, dried and the solvent removed. The crude product was distilled to give an oil. Yield 3800 g (72%). b.p. 123-127 8 mm Hg (Lit. 265 760 mm Hg). IH n.m.r. (CDCI3) δ 2.25, q; 3.60, m; 3.75, m;
4.56, s; 7.35, s.
Step B
2-Benzyloxyethyl methanesulfonate
To 2-benzyloxyethanol (30 g, 20 ml, 0.2 mol), triethylamine (1.4 eq., 39 ml) and dichloromethane (375 ml), immersed in an ice/water bath under an atmosphere of argon, was added dropwise a solution of methane sulfonyl chloride (1.1 eq., 17.1 ml, 0.22 mol) in dichloromethane (114 ml) over 100 min. The reaction mixture was allowed to stir at approximately 4° for an additional 1 hr. The mixture was then transfered to a separating funnel and washed successively with 400 ml portions of 2M HC1 (x 2), sat. aqueous sodium hydrogen carbonate, and 5% aqueous sodium chloride. The organic phase was dried and the solvent removed to
give an oil. Crude yield 46.3 g (quant.). H n.m.r. (CDCI3) δ 3.05, s; 3.75, m;
4.41, m; 4.60, s; 7.35, s.
Step C
Diethyl (2-benzyloxyethyl)malonate
To a stirred suspension of NaH (83% in oil, 3.66 g, 0.13 mol) in THF (32 ml) immersed in an ice/water bath was added dropwise, over 90 min, diethyl malonate (33.76 g, 32.15 ml, 0.211 mol). To the resulting enolate solution was added dropwise 2-benzyloxyethyl methanesulfonate (25 g, 0.109 mol) and the mixture stirred at reflux for 11 hrs. The reaction was allowed to cool to room temperature, then transfered to a conical flask containing 2M HC1 (200 ml) and diethyl ether (300 ml) and stirred for 30 min. The phases were separated and the aqueous phase further extracted with ether (2 x 100 ml). The combined organic extracts were dried and the solvent removed to give an oil. The crude product was distilled.
Yield 25.83 g (81%). b.p. 150-15570.4 mm Hg. IH n.m.r. (CDCI3) δ 1.25, t; 2.23, q; 3.55, t; 4.60, t; 4.15, q; 4.50, s; 7.30, s.
Step D
Diethyl hydroxymethyl(2-benzyloxyethyl)malonate
A mixture of diethyl (2-benzyloxyethyl)malonate (2 eq., 20.0 g, 67.9 mmol), formalin (37% w/v, 2.6 ml, 34.7 mmol), ethanol (4.0 ml) and potassium hydrogen carbonate (7.5 g, 74.9 mmol) in a 100 ml flask, under an atmosphere of argon, was stirred at room temperature for 3 days. The mixture was transfered to a separating funnel and 5% aqueous sodium chloride (130 ml) added, the product was extracted with diethyl ether (3 x 100 ml). The combined organic extracts were dried and the solvent removed. The crude product was preadsorbed onto silica and flash chromatographed, eluting with 1:9 ethanol:petroleum spirits (60-80°). Fractions containing the second peak were combined and the solvent removed to give an oil.
Yield 8.78 g (79.7%). IH n.m.r. (CDCI3) δ 1.24, t; 1.60, s; 2.33, t; 3.05, t; 3.61, t;
4.02, d; 4.18, q; 4.48, s; 7.70, s.
Step E
2-(2-Benzyloxyethyl)-2-hydroxymethylpropane-l,3-diol
To solid sodium borohydride (95%, 2.45 g, 61.5 mmol) in a 100 ml flask, under an atmosphere of argon, immersed in an ice/water bath with a reflux condenser, was added dropwise over 20 min a solution of diethyl hydroxymethyl(2- benzyloxyethyl)malonate (1.0 g, 3.08 mmol) in methanol (15 ml). The mixture was then gently heated to reflux and stirred overnight. The methanol was found to have completely evaporated, thus additional methanol was added and the mixture allowed to reflux for a further 17 hrs. The mixture was then cooled to room temperature and water (12 ml) was carefully added to the mixture and stirred for 30 min. The methanol was removed. The residue was then placed in a separating funnel and washed with chloroform (4 x 20 ml). The combined organic extracts were dried and the solvent removed, to give the diol, yield 0.09 g (14%). The aqueous phase was freeze dried and the residue refluxed in ethanol (100 ml) for 2 hrs. The hot ethanolic solution was then placed on a short silica column, conditioned with ethanol, and eluted with additional ethanol. The solvent was removed to give an oil. Crude yield 0.34 g (42%). IH n.m.r. (CDCI3) δ 1.68, t;
2.92, m; 3.63, s; 4.53, s; 7.33, s.
Step F
l-Acetoxy-2,2-bis(acetoxymethyl)-4-benzyloxybutane
2-(2-Benzyloxyethyl)-2-hydroxymethylpropane-l,3-diol (25.2 g, 0.1 mol), acetic anhydride (100 ml) and 4-dimethylaminopyridine (200 mg), with a drying tube attached, were stirred at room temperature overnight. The acetic anhydride was removed under reduced pressure. The residue was added to water and repeatedly extracted with dichloromethane. The combined organic extracts were dried and the solvent removed to give an oil. Yield 36.3 g (94%). JH n.m.r. (CDCI3) δ 1.75, t;
2.05, s; 3.57, t; 4.05, s; 4.48, s; 7.35, s.
Step G
l-Acetoxy-2,2-bis(acetoxymethyl)-4-hydroxybutane
A mixture of l-acetoxy-2,2-bis(acetoxymethyl)-4-benzyloxybutane (3.86 g, 11.5 mmol), 10% palladium on carbon (0.1 g), ethanol (35 ml) and glacial acetic acid (1 ml), in a 100 ml flask under an atmosphere of hydrogen, was stirred at room temperature for 24 hrs. The mixture was filtered through a bed of celite®, washed with ethanol, the solvent removed, and the residue extracted from water (30 ml) with dichloromethane (30 ml). The organic phase was dried and the solvent removed to give an oil. Yield 3.42 g (quant.). IH n.m.r. (CDCI3) δ 1.73, t; 2.07, s;
3.77, t; 4.09, s.
Step H
l-Acetoxy-2,2-bis(acetoxymethyl)-4-methanesulfoxybutane
To l-acetoxy-2,2-bis(acetoxymethyl)-4-hydroxybutane (3.4 g, 12.3 mmol), triethylamine (1.1 eq., 2.4 ml) and dichloromethane (30 ml), in an ice/water bath, under an argon atmosphere, was added dropwise over 1 hr, a solution of methane sulfonyl chloride (1.2 eq., 1.15 ml) in dichloromethane (15 ml). The reaction mixture was then stirred at approximately 4° for 110 min. The reaction mixture was allowed to warm to room temperature. The mixture was placed in a separating funnel and washed successively with 50 ml portions of 2M HCl (x 2), sat. aqueous sodium hydrogen carbonate and 5% aqueous sodium chloride. The organic phase
was dried and the solvent removed to give an oil. Crude yield 4.29 g (98%). H n.m.r. (CDCI3) δ 1.95, t; 2.08, s; 3.02, s; 4.07, s; 4.36, t.
Step I
9-[4-Acetoxy-3,3-bis(acetoxymethyl)but-l-yl]-2-amino-6-chloropurine
A mixture of 2-amino-6-chloropurine (97%, 1.1 eq., 2.25 g, 12.9 mmol), l-acetoxy-2,2-bis(acetoxymethyl)-4-methanesulfoxybutane (4.29 g, 12.1 mmol), potassium carbonate (4.1 g, 29.7 mmol) and dry dimethylformamide (30 ml) under an argon atmosphere was stirred at 35° for 22 hrs. The dimethylformamide was removed under reduced pressure. To the residue was added water (75 ml) and dichloromethane (75 ml), transfered to a separating funnel and the phases separated. The aqueous phase was further extracted with dichloromethane (2 x 75 ml). The combined organic extracts were dried and the solvent removed. The crude product was preadsorbed onto silica and flash chromatographed eluting with 1:99 methanol:ethyl acetate. Some fractions contained product that crystallized overnight and were filtered and kept separate, yield 2.01 g (39%). Additional fractions containing product and the mother liquor from the crystallized fractions were combined, the solvent removed and crystallized from ethyl acetate/methanol.
Yield 0.54 g (49% total), m.p. 172°. IH n.m.r. (DMSO-dg) δ 1.98, t; 2.02, s; 4.04, s; 4.17, t; 6.88, s, br; 8.19, s. 1 C n.m.r. (CDCI3) δ 22.8, 33.4, 41.0, 42.4, 65.8,
143.8, 153.5, 155.7, 161.0, 172.6.
Alternative synthesis of 2-(2-Benzyloxyethyl)-2-hydroxymethylpropane-l,3-diol
Step J
4-(Benzyloxy)butan-l-ol
Butanediol (901.5 g, 10 mol) and potassium hydroxide (85%, 264 g, 4 mol) were stirred, at room temperature, with a mechanical stirrer overnight. The mixture was then heated to 130° and vacuum applied to remove water. 49 g of water was condensed. The mixture was then cooled to 90° and benzyl chloride (506.4 g, 465 ml, 4 mol) added dropwise over 2 hrs. The mixture was stirred at 90° for 1 hr then heated to 130° and stirred for 1 hr. The mixture was allowed to cool to room temperature overnight. The mixture was dissolved in water (2000 ml) and dichloromethane (2000 ml), separated and the aqueous phase further extracted with dichloromethane (2 x 500 ml). The combined organic extract was backwashed with water, dried and the solvent removed. The crude product was distilled to give an oil. Yield 515.3 g (71.5%). b.p. 105-10670.2-0.3 mm Hg. 1H n.m.r. (CDCI3) δ 1.69, tt; 2.39, s; 3.52, t; 3.63, t; 4.52, s; 7.33, s.
Step K
4-(Benzyloxy)butanal
To an open vessel, immersed in an ice/water bath, containing 4-(benzyloxy)butan- l-ol (100 g, 0.55 mol), 2,2,6,6-tetramethyl-l-ρiρeridiinyloxy, free radical (0.75 g, 4.8 mmol) dissolved in dichloromethane (500 ml), potassium bromide (5.0 g, 42 mmol) dissolved in sat. aqueous sodium hydrogen carbonate (250 ml) and tetrabutylammonium chloride (5.0 g, 18.0 mmol) was added dropwise, over 45 min, a solution of sodium hydrogen carbonate (46.5 g, 0.55 mol) and sodium chloride (17.5 g, 0.3 mol) in sodium hypochlorite (0.5M, 1120 ml, 0.56 mol). The mixture was stirred, at approximately 4°, for a further 45 min. The two phases were separated and the aqueous phase extracted with dichloromethane (x 3). The combined organic extracts were washed with sat. aqueous sodium hydrogen carbonate and brine, dried and the solvent removed. The crude product was purified by distillation to give an oil. b.p. Yield 89.0 g (90%). b.p. 57-7070.01 mm
Hg. !H n.m.r. (CDCI3) δ 1.95, tt; 2.55, t; 3.53, t; 4.50, s; 7.32, s; 9.80, s.
Step L
2-(2-Benzyloxyethyl)-2-hydroxymethylpropane-l,3-diol
To a mixture of paraformaldehyde (5.0 eq., 4.19 g, 0.14 mol) and tetrahydrofuran (115 ml), immersed in an ice/water bath, was added a cold (<10°) aqueous solution of sodium hydroxide (2 eq., 1M, 56.2 ml, 0.56 mol). The temperature was allowed to stabilise at approximately 4°. To the mixture was then added dropwise, over 15 min, a solution of 4-(benzyloxy)butanal (5.0 g, 0.028 mol) in tetrahydrofuran (115 ml). The mixture was stirred at 4° for a further 30 min and then at room temperature for 2 hrs. The tetrahydrofuran was removed by rotary evaporation. Water was added to the residue and the product extracted repeatedly with dichloromethane. The organic extract was washed with brine, dried and the solvent removed to give an oil. Yield 4.5 g. The aqueous phase was adjusted to pH 8 and extracted with dichloromethane (x 4) to give 0.5 g product. The aqueous phase was then adjusted to pH 0 and extracted with dichloromethane (x 4) to give 0.5 g of product. Total yield 5.5 g (82%). IH n.m.r. (CDCI3) δ 1.57, t; 3.33, s; 3.50, s;
4.43, s; 7.26, s.
EXAMPLE 2
9-[4-Hydroxy-3,3-bis(hydroxymethyl)but-l-yl]guanine
9-[4-Acetoxy-3,3-bis(acetoxymethyl)but-l-yl]-2-amino-6-chloropurine (2.4 g, 5.6 mmol), and 2M HCl (50 ml) were stirred at reflux for 2 hr. The mixture was cooled in an ice/water bath and 5% NaOH added dropwise until a precipitate formed. The solid was filtered and crystallized from water as the monohydrate. Yield 0.98 g. A second crop gave an additional 0.29 g (75% total), m.p. 294-297°. (@47min dec.) (Lit. 295-299° dec). [Found: 284.1357 Calc. for Ci 1H17N5O4 requires 284.1359]. *H n.m.r. (DMSO-dg ) δ 1.69, m; 4.04, m; 4.41, t; 6.42, s;
7.66, s; 10.52, s. 13C n.m.r. (D2O) δ 33.5, 45.7, 47.7, 66.3, 111.8, 141.5, 154.1, 159.6.
EXAMPLE 3
9-[4-Hydroxy-3,3-bis(hydroxymethyl)but-l-yl]guanine sodium salt
To a stirring suspension of 9-[4-hydroxy-3,3-bis(hydroxymethyl)-but-l-yl]guanine (0.5 g, 1.8 mmol) in water immersed in an ice/water bath was added slowly 0.1N NaOH (17.6 ml, 1.8 mmol). The mixture was allowed to warm to room temperature, filtered, washed with cold water and freeze dried overnight. Yield 0.54 g (99.3%). m.p. 257° dec. (Found: C, 38.45; H, 5.68; N, 19.03. Calc. for cllH16N5°4Na requires C, 38.43; H, 5.57; N, 19.05). IH n.m.r. (DMSO-dg) ) δ
1.64, m; 3.61, s, br; 3.96, m; 4.82, s, br; 7.36, s. 13C n.m.r. (D2O) ) δ 33.9, 43.1, 47.8, 66.4, 121.9, 142.5, 155.5, 165.3, 172.5.
EXAMPLE 4
9-(4-Acetoxy-3-acetoxymethyl-3-hydroxybut-l-yl)-2-amino-6-chloropurine
Step A
2-(2-Benzyloxyethyl)-2-propen-l-ol
A solution of diethyl 2-(benzyloxyethyl)malonate (10.0 g, 34 mmol), sodium hydride (80% in oil, 1.25 g, 41.7 mmol) and 1,2-dimethoxyethane (80 ml), in a 1000 ml flask with a condenser and thermometer, under an atmosphere of argon, was refluxed for 2 hrs. The mixture was cooled to room temperature and immersed in an ice/water bath. Lithium aluminium hydride (powder, 4.0 g, 105.4 mmol) was added portion-wise over 10 min. The mixture was heated to 55° and stirred for 2.5 hrs. The mixture was allowed to cool to room temperature and a solution of ethyl formate (25 ml, 0.31 mol) in diethyl ether (375 ml) was added and stirred for 15 min. A solution of aqueous sodium hydroxide (2M, 15 ml) was added and the mixture allowed to stir overnight at room temperature. The mixture was filtered and the product extracted with 1,2-dichloroethane. The organic extract was dried and the solvent removed. The crude product was distilled to give an oil. Yield 2.1
g (32%). b.p. 130-15071 mm Hg. *H n.m.r. (CDCI3) δ 2.43, t; 3.62, t; 4.53, s;
4.93, s; 5.07, s; 7.34, s.
Step B
4-Benzyloxy-2-hydroxymethylbutane-l,2-diol
A mixture of AD-mix (36.4 g), t-butyl alcohol (130 ml) and water (130 ml), in a 1000 ml flask, was stirred, at room temperature, until two clear phases were observed. The mixture was then immersed in an ice/water bath and 2-(2- benzyloxyethyl)-2-propen-l-ol (5.0 g, 26 mmol) was added. The mixture was stirred, at approximately 4°, for 3 hrs. Sodium sulfite (39 g, 0.31 mol) was added and the mixture allowed to warm to room temperature. Dichloromethane (300 ml) was added and the mixture stirred for 30 min. The phases were separated and the aqueous phase extracted with dichloromethane (2 x 300 ml). The combined organic extracts were dried and the solvent removed to give an oil. Yield 6.0 g
(quant.). n.m.r. (CDCI3) δ 1.83, m; 2.68, s, br; 3.36, s; 3.54, s; 3.70, m; 4.53, s;
7.33, s.
Step C
l-Acetoxy-2-acetoxoxymethyl-4-benzyloxybutan-2-ol
A mixture of 4-benzyloxy-2-hydroxymethylbutane-l,2-diol (5.9 g, 26 mmol), acetic anhydride (50 ml) and dimethylaminopyridine (0.5 g, 4.1 mmol), in a 150 ml flask, were stirred, at room temperature, overmght. The acetic anhydride was removed under reduced pressure. To the residue was added water (100 ml) and diethyl ether (100 ml). The phases were separated and the aqueous phase further extracted with diethyl ether (2 x 100 ml). The combined organic extracts were dried and the solvent removed. The crude product was flash chromatographed eluting with ethyl acetate. Product containing fractions were combined and the solvent removed to give an oil. Yield 7.4 g (91%). !H n.m.r. (CDCI3) δ 1.90, t;
2.80, s; 3.74, t; 4.08, s; 4.10, s; 4.52, s; 7.33, s.
Step D
l-Acetoxy-2-acetoxoxymethyl-4-benzyloxybutan-2-ol (5.0 g, 16.1 mmol), 10% palladium on carbon (0.2 g), ethanol (50 ml) and glacial acetic acid (1 drop), in a 100 ml flask, under an atmosphere of hydrogen,, was stirred, at room temperature, for 3 days. The mixture was filtered through a bed of celite® then filter paper and the solvent removed to give an oil. Yield 3.26 g (92%). *H n.m.r. (CDCI3) δ 1.84, t; 2.09, s; 3.92, t; 4.12, s.
Step E
l-Acetoxy-2-acetoxoxymethyl-3-methanesulfoxybutan-2-oI
To 4-acetoxy-3-acetoxoxymethyl-butane-l,3-diol (3.20 g, 14.5 mmol), triethylamine (1.1 eq., 2.84 ml, 20.3 mmol) and dichloromethane (20 ml), immersed in an ice/water bath, under an atmosphere of nitrogen, was added dropwise, over 1 hr, a solution of methane sulfonyl chloride (1.1 eq., 1.35 ml, 16 mmol) in dichloromethane (15 ml). The mixture was stirred, at approximately 4°, for 90 min. The mixture was allowed to warm to room temperature, transfered to a separating funnel and washed successively with 50 ml portions of 2M HCl ( x 2),
sat. aqueous sodium hydrogen carbonate, and 5% sodium chloride. The organic extract was dried and the solvent removed to give an oil. Yield 3.28 (75%). H n.m.r. (CDCI3) δ 2.41, t; 2.22, s; 3.20, s; 4.10, d; 4.45, t.
Step F
9-(4-Acetoxy-3-acetoxymethyl-3-hydroxybut-l-yl)-2-amino-6-chloropurine
A mixture of 2-amino-6-chloropurine (99%, 1.1 eq., 0.66 g, 3.8 mmol), 1-acetoxy- 2-acetoxoxymethyl-3-methanesulfoxybutan-2-ol (1.19 g, 3.5 mmol), potassium carbonate (1.2 g, 8.7 mmol) and dry dimethylformamide (15 ml), with a drying tube attached, was stirred, at room temperature, for 60 hrs. The dimethylformamide was removed under reduced pressure. To the residue was added water (25 ml), transfered to a separating funnel and extracted with dichloromethane (4 x 25 ml). The combined organic extracts were dried and the solvent removed. The crude product was preadsorbed onto silica and flash chromatographed eluting with 1:9 methanokdichloromethane. The major fraction was collected and the solvent removed (5072 x 10~2 mm Hg). The product was crystallized from methanol/dichloromethane as fine white crystals, yield 72 mg. A
second crop gave a further 107 mg (12.5% total). !H n.m.r. (DMSO-dg) δ 2.00, s;
3.94, m; 4.18, t; 5.32, s; 6.90, s, br; 8.14, s.
EXAMPLE 5
2-Amino-9-[3,3-bis(acetoxymethyl)but-l-yl]-6-chloropurine
Step A
Diethylmethyl(2-benzyloxyethyl)malonate
To sodium hydride (dry, 1.80 g, 75 mmol), under an atmosphere of nitrogen, was added a solution of diethyl (2-benzyloxyethyl)malonate (20.0 g, 68 mmol) in dioxane (400 ml). The mixture was heated at reflux for 3 hrs. The mixture was allowed to cool and methyl iodide (1.5 eq., 1.90 ml, 30.7 mmol) added and allowed to stir at room temperature for 1 hr and then gently heated and refluxed overnight. The solvent was removed. 0.4M HCl (186 ml) was added to the residue and the product extracted with diethyl ether (4 x 150 ml). The combined organic extracts were dried and the solvent removed. The crude product was distilled to
give an oil. Yield 18.6 g (89%). b.p. 12571.5 x 10"2 mm Hg. iH n.m.r. (CDCI3) δ
1.15, t; 1.38, s; 2.18, t; 3.48, t; 4.05, q; 4.39, s; 7.25, s.
Step B
2-Methyl-2-(2-benzyloxyethyl)propane-l,3-diol
A solution of diethyl methyl(2-benzyloxyethyl)malonate (18.0 g, 58.4 mmol) in methanol (270 ml) was added dropwise over 1.5 hrs to solid sodium borohydride (45.0 g, 1.19 mol), in a flask with a reflux condenser, mechanical stirrer, immersed in an ice/water bath and under an argon atmosphere. After addition was complete additional methanol (270 ml) was added and the reaction mixture refluxed for 20 hrs. The mixture was allowed to cool to room temperature and water (225 ml) carefully added and stirred for 1 hr. The methanol was removed and the water residue extracted with chloroform (3 x 220 ml). The combined organic extracts were backwashed with water (2 x 270 ml), dried and the solvent removed. The crude product was preadsorbed onto silica and flash chromatographed eluting with 6:4 ethyl acetate:petroleum spirits. The fractions containing the product were
combined and evaporated to give an oil. Yield 7.35 g (56%). XH n.m.r. (CDCI3) δ
0.79, s; 1.76, t; 3.50, s; 3.63, t; 4.53, s; 7.34, s.
Step C
l-Acetoxy-2-acetoxyoxymethyl-4-benzyloxy-2-methylbutane
2-Methyl-2-(2-benzyloxyethyl)propane-l,3-diol (7.35 g, 32.8 mmol), acetic anhydride (76 nil) and 4-dimethylaminopyridine (152 mg, 18.6 mmol), in a stoppered flask, were stirred together at room temperature over the weekend. The excess acetic anhydride was removed, water (80 ml) and diethyl ether (50 ml) were added to the residue and stirred for 30 min. The phases were separated and the aqueous phase further extracted with diethyl ether (3 x 70 ml). The combined organic extracts were dried and the solvent removed. The crude product was distilled to give an oil. Yield 9.03 g (89%). b.p. 15071.5 x 10"2 mm Hg. AH n.m.r. (CDCI3) δ 0.98, s; 1.71, t; 2.04, s; 3.55, t; 3.95, s; 4.49, s; 7.32, s.
Step D
4-Acetoxy-3-acetoxymethyl-3-methyIbutan-l-ol
l-Acetoxy-2-acetoxymethyl-4-benzyloxy-2-methylbutane (9.0 g, 29.2 mmol), 10% palladium on carbon (1.13 g), ethanol (95 ml) and glacial acetic acid (1 drop), under an atmosphere of hydrogen, were stirred vigorously at room temperature for 17 hrs. The mixture was filtered through a bed of celite®, washed with ethanol and the solvent removed to give an oil. Yield 6.29 g (quant.). *H n.m.r. (CDCI3) δ 0.98, s; 1.61, t; 2.05, s; 3.71, t; 3.94, s.
Step E
l-Acetoxy-2-acetoxymethyl-4-methanesulfoxy-2-methylbutane
To 4-acetoxy-3-acetoxymethyl-3-methylbutan-l-ol (6.29 g, 28.8 mmol), triethylamine (1.5 eq., 6.12 ml, 43.9 mmol) and dichloromethane (85 ml), immersed in an ice/water bath and under an atmosphere of nitrogen, was added
dropwise, over 30 min, a solution of methane sulfonyl chloride (1.2 eq., 2.72 ml,
35.1 mmol) in dichloromethane (30 ml). The mixture was stirred for a further 2 hrs, transfered to a separating funnel and washed successively with 60 ml portions of 2M HCl (x 3), sat. aqueous sodium hydrogen carbonate and 5% aqueous sodium chloride. The organic extract was dried and the solvent removed. The crude product was placed under vacuum (90° at 3.7 x 10_5 mm Hg) to remove low boiling impurities to give an oil. Yield 7.4 g (87%). *H n.m.r. (CDCI3) δ 1.02, s; 1.85, t; 2.07, s; 3.02, s; 3.95, s; 4.32, t.
Step F
2-Amino-9-[3,3-bis(acetoxymethyl)but-l-yl]-6-chloropurine
A mixture of 2-amino-6-chloropurine (1.01 eq., 4.25 g, 25.1 mmol), l-acetoxy-2- acetoxymethyl-4-methanesulfoxy-2-methylbutane (7.4 g, 25.0 mmol), potassium carbonate (7.8 g, 56.4 mmol) and dry dimethylformamide (105 ml) under an argon atmosphere was stirred at room temperature for 40 hrs. The temperature was increased to 35° and stirred for a further 7 hrs. Additional 2-amino-6-chloropurine (0.5 g) was added to the mixture and stirred at 35° over the weekend. The dimethylformamide was removed under reduced pressure. Water (200 ml) was
added to the residue and the product extracted with dichloromethane (5 x 100 ml). The combined organic extracts were washed with water (200 ml), dried and the solvent removed by rotary evaporation. The crude product was preadsorbed onto silica and flash chromatographed eluting with ethyl acetate. Fractions containing product were combined and the solvent removed to give a solid. Yield 6.4 g
(69%). m.p. 86°. iH n.m.r. (CDC13) δ 1.00, s; 1.82, m; 2.02, s; 3.95, s; 4.09, m;
5.06, s, br; 7.71, s.
EXAMPLE 6
9-[3,3-Bis(hydroxy--nethyl)but-l-yI]guanine
2-Amino-9-[3,3-bis(acetoxymethyl)but-l-yl]-6-chloropurine (6.40 g, 17.2 mmol) in 2M HCl (145 ml) was refluxed for 3 hrs. The mixture was allowed to cool to room temperature and was then immersed in an ice/water bath. Aqueous sodium hydroxide (19.2 g in 40 ml) was added and the mixture stirred, at room temperature, for 2 hrs. HCl was added until a precipitate formed (pH 5). The solid was filtered, washed with water and recrystallized from water. Yield 4.18 g (90%). m.p. 278° (Lit. 284-287°) JH n.m.r. (DMSO-dg) δ 0.82, s; 1.67, m; 3.25, d; 3.98, m; 4.50, t; 6.43, s, br; 7.70, s; 10.53, s, br.
EXAMPLE 7
9-(4-Acetoxy-3-acetoxymethyl-3-fluorobut-l-yl)-2-amino-6-chloropurine
Step A
Diethyl (2-Benzyloxyethyl)fluoromalonate
To a stirred suspension of sodium hydride (95%, 9.4 g, 0.37 mol) in tetra¬ hydrofuran (dry, 1000 ml), immersed in an ice/ethanol bath, under an atmosphere of argon, was added dropwise, over 2.5 hr, a solution of diethyl (2- benzyloxyethyl)malonate (100 g, 0.34 mol) in tetrahydrofuran (400 ml). The solution was allowed at warm to room temperature and stirred overnight. The mixture was immersed in an ice/ethanol bath and dimethylformamide (70 ml) added then l-chloromethyl-4-fluoro-l,4-diazobicyclo[2.2.2]octane bis tetrafluoroborate (120.3 g, 0.34 mol) added in portions over 30 min and stirred at room temperature for 2 hrs. The mixture was added to diethyl ether (2000 ml) and washed successively with 1000 ml portions of 2M H2SO4 , water and sat. aqueous
sodium hydrogen carbonate (500 ml). The organic extract was dried, filtered and the solvent removed to give an oil. Yield 102.4 g (96%). Rp 0.56 (1:9
Ethanol:Petroleum spirits (60-80°)). *H n.m.r. (CDCI3) δ 1.25, t; 2.52, dt; 3.66, t; 4.20, q; 4.45, s; 7.31, s. 13c n.m.r. (CDCI3) δ 14.1, 34.4, 34.8, 62.7, 64.1, 90.9, 94.8, 127.9, 128.0, 128.5, 138.1, 166.2, 166.7.
Step B
2-(2-Benzyloxyethyl)-2-fluoropropane-l,3-diol
To sodium borohydride (95%, 33.75 g, 847 mmol) in a 1000 ml flask, fitted with a thermometer, condenser, dropping funnel, mechanical stirrer and under an atmosphere of argon, was added dropwise, over 2.75 hrs, a solution of diethyl (2- benzyloxyethyl)fluoromalonate (13.5 g, 43.2 mmol) in methanol (200 ml). The mixture was then gently heated to reflux and stirred for 2.5 hrs. Heating was removed and the mixture stirred at room temperature overnight. Water (150 ml) was added carefully and stirred at room temperature until all excess sodium boro¬ hydride was destroyed and all salts dissolved. The methanol was removed and the product was extracted with chloroform (4 x 100 ml). The combined organic extracts were backwashed with water (70 ml), dried and the solvent removed to
give an oil. Yield 7.04 g (71%). Rp 0.33 (4:6 Ethyl acetate:Hexane). H n.m.r.
(CDCI3) δ 2.07, dt; 2.64, t; 3.66, t; 3.71, dd; 3.75, dd; 4.54, s; 7.35, s.
Step C
l-Acetoxy-2-acetoxymethyl-4-benzyloxy-2-fluorobutane
2-(2-Benzyloxyethyl)-2-fluoropropane-l,3-diol (11.96 g, 52.4 mmol), acetic anhydride (150 ml) and 4-dimethylaminopyridine (250 mg, 2.0 mmol), in a 1000 ml flask with a drying tube, were stirred at 40° for 2 hrs. The acetic anhydride was removed. Water (100 ml) and dichloromethane (150 ml) were added to the residue and stirred virorously for 5 min. The phases were separated and the aqueous phase further extracted with dichloromethane (2 x 100 ml). The combined organic extracts were dried and the solvent removed to give an oil. Yield 18.4 g (quant.) approximately 14% w/w acetic anhydride impurity. XH n.m.r. (CDCI3) δ 2.08, dt;
2.08, s; 2.09, s; 3.62, t; 4.27, dd; 4.29, dd; 4.50, s; 7.33, s.
Step D
4-Acetoxy-3-acetoxymethyl-3-fluorobutan-l-ol
A mixture of l-acetoxy-2-acetoxymethyl-4-benzyloxy-2-fluorobutane (86%, 18.4 g, 52.4 mmol), 10% palladium on carbon (700 mg), ethanol (120 ml) and glacial acetic acid (1 ml), in a 250 ml flask under an atmosphere of hydrogen, was stirred at room temperature for 3.5 hrs. The mixture was filtered through filter paper, then through a bed of celite® and the solvent and acetic acid removed overnight to give an oil. Yield 10.4 g (89%). *H n.m.r. (CDCI3) δ 2.03, dt; 2.10, s; 2.11, s; 3.85, t; 4.28, dd; 4.30, dd.
Step E
l-Acetoxy-2-acetoxymethyl-2-fluoro-4-methanesulfoxybutane
To a stirring mixture 4-acetoxy-3-acetoxymethyl-3-fluorobutan-l-ol (10.4 g, 46.8 mmol), triethylamine (1.4 eq., 9.13 ml, 65.5 mmol) and dichloromethane (100 ml) in a 500 ml flask, immersed in an ice/water bath under an atmosphere of argon, was added dropwise, over 2 hrs, a solution of methane sulfonyl chloride (1.2 eq.,
4.35 ml, 56.2 mmol) in dichloromethane (50 ml). The mixture was stirred, at approximately 4°, for a further 100 min. The mixture was then transfered to a separating funnel and washed successively with 150 ml portions of 2M HCl (x 2), sat. aqueous sodium hydrogen carbonate and 5% sodium chloride. The organic extract was dried, filtered and the solvent removed to give an oil. Yield 13.85 g (98.6%). *H n.m.r. (CDCI3) δ 2.12, s; 2.24, dt; 3.04, s; 4.26, dd; 4.42, t.
Step F
9-(4-Acetoxy-3-acetoxymethyl-3---luorobut-l-yl)-2-amino-6-chloropurine
A mixture of 2-amino-6-chloropurine (1.1 eq., 4.11 g, 24.2 mmol), l-acetoxy-2- acetoxymethyl-2-fluoro-4-methanesulfoxybutane (6.62 g, 22.0 mmol), potassium carbonate (7.4 g, 53.5 mmol) and dimethylformamide (dry, 50 ml), in a flask with a drying tube attached, was stirred, at room temperature, for 18 hrs. The dimethylformamide was removed under reduced pressure. The residue was dissolved in water (150 ml) and dichloromethane added (100 ml). The phases were separated and the aqueous phase further extracted with dichloromethane (2 x 100 ml). The combined organic extract was dried and the solvent removed. The crude product was preadsorbed onto silica and flash chromatographed eluting with 1:99
methanokethyl acetate. Fractions containing pure product were combined and evaporated to give a solid. Yield 2.54 g. Additional less pure fractions were combined, evaporated and crystallized from methanol/ethyl acetate. Total yield
3.94 g (48%). m.p. 128-129°. [Found: 374.1030 Calc. for Ci4HιgClFN5C>4 requires 374.1031]. !H n.m.r. (CDCI3) δ 2.01, s; 2.30, dt; 4.28, d; 5.15, s, br; 7.78, s. 13c n.m.r. (CDCI3) δ 22.7, 34.3, 34.7, 40.3, 65.6, 66.1, 144.0, 151.3, 155.5, 160.9, 172.2.
EXAMPLE 8
9-(4-Acetoxy-3-acetoxymethyl-3-methoxycarbonylbut-l-yl)-2-amino-6- chloropurine
Step A
Diethyl tetrahydropyranyloxymethyl(2-benzyloxyethyl)malonate
To a solution of diethyl hydroxymethyl(2-benzyloxyethyl)malonate (56.17 g, 173 mmol) and dihydropyran (23.8 ml, 260 mmol), under an atmosphere of argon, was
added a solution of pyridiniump-toluenesulfonate (4.36 g, 17 mmol) in dichloromethane (600 ml). The mixture was stirred at room temperature for 4 hrs. Diethyl ether (400 ml) was added and the mixture tranfered to a separating funnel and washed with brine (700 ml). The organic extract was dried and the solvent removed to give an oil. Yield 66.5 g (94%). iH n.m.r. (CDCI3) δ 1.19, t; 1.53, m, br; 2.39, t; 3.43-3.90, m; 3.58, t; 4.06-4.20, m; 4.43, s; 4.79-4.96, m; 7.30, s.
Step B
2-Tetrahydropyranyloxymethyl-2-(2-benzyloxyethyl)propane-l,3-diol
To lithium aluminium hydride (30.73 g, 0.81 mol) was added diethyl ether (dry, 600 ml). The mixture was stirred, at room temperature, for 10 min. Diethyl tetrahydropyranyloxymethyl(2-benzyloxyethyl)malonate (66.5 g, 0.162 mol) in diethyl ether (dry, 200 ml) was added dropwise, over 2 hrs. The mixture was gently heated and refluxed for 2 hrs. Sat. aqueous sodium sulfate (90 ml) was added dropwise to die reaction mixture. The mixture was filtered and the phases separated. The organic phase was dried and the solvent removed to give an oil.
Yield 53.6 g (quant.). !H n.m.r. (CDCI3) δ 1.52, br; 1.70, t; 2.75, s, br; 3.36-3.72, m; 3.56, s; 4.51, s; 4.68-4.95, m; 7.32, s.
Step C l-Acetoxy-2-acetoxymethyI-4-benzyloxy-2-tetrahydropyranyloxymethyl butane
A mixture of 2-tetrahydropyranyloxymethyl-2-(2-benzyloxyethyl)propane-l,3-diol (17.3 g, 53.3 mmol), acetic anhydride (35 ml) and dimethylaminopyridine (100 mg, 0.8 mmol) was stirred, at room temperature, for 66 hrs. The acetic anhydride was removed by rotary evaporation. To the residue was added water and dichloromethane. The phases were separated and the aqueous phase further extracted with dichloromethane. The combined organic extract was dried and the solvent removed to give an oil. Yield 21.4 g (98%). !H n.m.r. (CDCI3) δ 1.58, br;
1.82, t; 2.04, s; 3.22-3.76, m; 3.57, t; 4.08, s; 4.48, s; 4.81-4.97, m; 7.32, s.
Step D
2,2-Bis(acetoxymethyl)-4-benzyloxybutan-l-ol
A solution of l-acetoxy-2-acetoxymethyl-4-benzyloxy-2- tetrahydropyranyloxymethylbutane (21.0 g, 51.4 mmol), pyridinium - toluenesulfonate (0.1 eq., 1.3 g, 5.14 mmol) in ethanol (410 ml) was stirred at 55° for 3 hrs. The solvent was removed by rotary evaporation. The crude product was preadsorbed onto silica and flash chromatographed eluting initially with 1:4 ethyl acetate:petroleum spirits, changing to 2:3 ethyl acetate:petroleum spirits when the impurities had eluted. Fractions containing the product were combined and die solvent removed to give an oil. Yield 9.05 g (54%). Rp 0.31 (1:4 etiiyl acetate:petroleum spirits) H n.m.r. (CDCI3) δ 1.77, t; 2.05, s; 3.05, s; 3.61, t; 4.04, s; 4.53, s; 7.33, s.
Step E
2,2-Bis(acetoxymethyl)-4-benzyloxybutanoic acid
A mixture of 2,2-bis(acetoxymethyl)-4-benzyloxybutan-l-ol (4.0 g, 12.3 mmol), pyridinium dichromate (3.5 eq., 16.0 g, 56.8 mmol) and dry dimethylformamide (64 ml), in a 250 ml flask, under an atmosphere of argon, was stirred, at room temperature, for 43.5 hrs. The mixture was added to water (100 ml) and the product extracted with dietiiyl ether (4 x 100 ml). The combined organic extract was backwashed with 5% aqueous sodium chloride, dried and the solvent removed to give an oil. Yield 3.47 g (83%). *H n.m.r. (CDCI3) δ 2.04, s; 3.58, t; 4.33, s;
4.46, s; 7.29, s; 8.63, s.
Step F
To 2,2-bis(acetoxymethyl)-4-benzyloxybutanoic acid (3.47 g, 10.3 mmol) in methanol (22 ml) and benzene (69 ml) in a 250 ml flask, at room temperature, was added (trimethylsilyl)diazomethane (2M in hexane, 1.3 eq., 6.7 ml, 13.4 mmol). Rapid evolution of nitrogen gas was observed. The mixture was stirred, at room temperature, for 1 hr. The solvent and by-products were removed. The crude product was distilled to give an oil. Yield 2.43 g (67%). b.p. 170-19071.5 x 10"4 mm Hg *H n.m.r. (CDCI3) δ 1.96, t; 2.03, s; 3.51, t; 3.59, s; 4.30, s; 4.43, s; 7.31, s.
Step G
Methyl 2,2-bis(acetoxymethyl)-4-hydroxybutanoate
A mixture of methyl 2,2-bis(acetoxymethyl)-4-benzyloxybutanoate (2.4 g, 6.8 mmol), 10% palladium on carbon (100 mg), ethanol (20 ml) and glacial acetic acid
(2 drops), under an atmosphere of hydrogen, was stirred, at room temperature, for 19 hrs. The mixture was filtered through a bed of celite®, washed with hot ethanol, and the solvent removed. Yield 1.75 g (98%). !H n.m.r. (CDCI3) δ 1.91, t; 2.05, s; 2.35, t; 3.72, t; 3.73, s; 4.31, s.
Step H
Methyl 2,2-bis(acetoxymethyl)-4-methanesulfoxybutanoate
To methyl 2,2-bis(acetoxymethyl)-4-hydroxybutanoate (1.75 g, 6.7 mmol), triethylamine (1.1 eq., 1.3 ml, 7.4 mmol) and dichloromethane (18 ml), in an ice/water bath, under an argon atmosphere, was added dropwise over 1 hr, a solution of methane sulfonyl chloride (1.2 eq., 0.62 ml, 8.0 mmol) in dichloromethane (9.5 ml). The reaction mixture was then stirred, at approximately 4°, for 2 hrs. The reaction mixture was allowed to warm to room temperature, transfered to a separating funnel and washed successively with 30 ml portions of 2M HCl (x 2), sat. aqueous sodium hydrogen carbonate and 5% aqueous sodium chloride. The organic phase was dried and the solvent removed to give an oil.
Yield 2.09 g (92%). iH n.m.r. (CDCI3) δ 2.07, s; 3.00, s; 3.76, s; 4.30, s.
Step I
9-(4-Acetoxy-3-acetoxymethyl-3-methoxycarbonylbut-l-yl)-2-amino-6- chloropurine
A mixture of 2-amino-6-chloropurine (97%, 1.1 eq., 1.14 g, 6.7 mmol) methyl 2,2- bis(acetoxymethyl)-4-methanesulfoxybutanoate (2.08 g, 6.1 mmol), potassium carbonate (2.7 g, 19.5 mmol) and dry dimethylformamide (17 ml) under an argon atmosphere was stirred at room temperature for 137 hrs. The dimetitiy lformamide was removed under reduced pressure. To die residue was added water (75 ml), transfered to a separating funnel and extracted with dichloromethane (2 x 75 ml). The combined organic extracts were dried and die solvent removed. The crude product was preadsorbed onto silica and flash chromatographed eluting with 1:99 methanol:ethyl acetate. Fractions containing product were combined and die solvent removed to give a solid. Yield 1.41 g (56%). Rp 0.64 (1:99
MethanokEtiiyl acetate) AH n.m.r. (DMSO-dg) δ 2.02, s; 2.22, t; 3.54, s; 4.15, t; 4.23, s; 6.93, s, br; 8.15, s.
EXAMPLE 9
9-[4-Acetoxy-3,3-bis(isopropoxymethyl)but-l-yl]-2-amino-6-chloropurine
Step A
4-Benzyloxy-2,2-bis(isopropoxymethyl)butan-l-ol
A mixture of 2-(2-benzyloxyethyl)-2-hydroxymethylproρane-l,3-diol (10.0 g, 42 mmol), potassium hydroxide (dry powder, 11.6 g, 208 mmol), 2-bromopropane (4 eq., 20.4 g, 15.6 ml, 166 mmol) and tetrabutylammonium bromide (0.1 eq., 1.35 g, 4.2 mmol), in a 150 ml oven dried flask with a mechanical stirrer and a drying tube, was stirred at 35° for 6 hrs. Additional sodium hydroxide (1 eq., 1.66 g, 42 mmol) and 2-bromopropane (10.2 g, 7.8 ml, 83 mmol) were added. The mixture was stirred for 18 hrs, still at 35°, whereupon additional sodium hydroxide (1 eq., 1.66 g, 42 mmol) and 2-bromopropane (10.2 g, 7.8 ml, 83 mmol) were added and stirred for 26 hrs. The mixture was allowed to cool to room temperature. Water (200 ml) and dichlorometiiane (200 ml) were added and d e solution transfered to
2000 ml beaker. The mixture was neutralised by the dropwise addition of 2M HCl.
The phases were separated and die aqueous phase further extracted with dichloromemane (2 x 100 ml). The combined organic extracts were dried and the solvent removed. The crude product was chromatographed on silica eluting with
1:4 diediyl etheπhexane. Fractions containing the product were combined and die solvent removed to give an oil. Yield 2.02 g (15%). *H n.m-r. (CDCI3) δ 1.11, d;
1.67, t; 3.40, s; 3.42-3.63, m; 3.60, d; 4.50, s; 7.33, s.
Step B
l-Acetoxy-4-benzyloxy-2,2-bis(isopropoxymethyl)butane
4-Benzyloxy-2,2-bis(isopropoxymethyl)butan-l-ol (1.87 g, 6.6 mmol), acetic anhydride (35 ml) and 4-dimethylaminopyridine (100 mg, 0.8 mmol), with a drying tube attached, were stirred at room temperature for 27 hrs. The acetic anhydride was removed by rotary evaporation. The residue was added to water and extracted with dichloromethane (x 3). The combined organic extracts were dried
and die solvent removed to give an oil. Yield 2.30 g (95%). H n.m.r. (CDCI3) δ 1.08, d; 1.75, t; 2.02, s; 3.29, s; 3.44, sept; 3.59, t; 4.05, s; 4.49, s; 7.33, s.
Step C
4-Acetoxy-3,3-bis(isopropoxymethyl)butan-l-ol
A mixture of l-acetoxy-4-benzyloxy-2,2-bis(isopropoxymethyl)butane (2.31 g, 6.3 mmol), palladium on carbon (10%, 0.1 g), etiianol (25 ml) and glacial acetic acid (2 drops), under an atmosphere of hydrogen, was stirred at room temperature for 5 hrs. The mixture was filtered through a bed of celite® and die solvent removed to give an oil. Yield 1.72 g (99%). *H n.m.r. (CDCI3) δ 1.14, d; 1.68, t; 2.05, s; 3.35, s; 3.53, sept; 3.66, t; 4.05, s.
Step D
l-Acetoxy-2 -bis(isopropoxymethyl)-4-methanesulfoxybutane
To 4-acetoxy-3,3-bis(isopropoxymethyl)butan-l-ol (1.70 g, 6.2 mmol), triethylamine (1.4 eq., 1.2 ml, 8.6 mmol) and dichloromethane (15 ml), in an ice/water bath, under a nitrogen atmosphere, was added dropwise over 45 min, a solution of methane sulfonyl chloride (1.2 eq., 0.57 ml, 0.85 g, 7.4 mmol) in dichloromethane (8 ml). The reaction mixture was then stirred, at approximately 4°, for 2 hrs. The reaction mixture was allowed to warm to room temperature. The mixture was placed in a separating funnel and washed successively witii 25 ml portions of 2M HCl (x 2), sat. aqueous sodium hydrogen carbonate and 5% aqueous sodium chloride. The organic phase was dried and die solvent removed to give an oil. Yield 2.14 g (98%). *H n.m.r. (CDCI3) δ 1.02, d; 1.88, t; 2.07, s; 3.00, s; 3.31, s; 3.48, sept; 4.04, s; 4.41, t.
Step E
9-[4-Acetoxy-3,3-bis(isopropoxymethyl)but-l-yl]-2-amino-6-chloropurine
A mixture of 2-amino-6-chloropurine (97%, 1.1 eq., 1.13 g, 6.64 mmol), l-acetoxy-2,2-bis(isopropoxymethyl)-4-methanesulfoxybutane (2.14 g, 6.04 mmol), potassium carbonate (2.7 g, 19.5 mmol) and dry dimethylformamide (17 ml), with a drying tube attached, was stirred, at room temperature, for 1 ldays. The dimethylformamide was removed under reduced pressure. To die residue was added water and extracted with dichloromethane (x 3). The combined organic extracts were dried and die solvent removed. The crude product was preadsorbed onto silica and flash chromatographed eluting with dietiiyl ether. Fractions containing product were combined and the solvent removed to give a sohd. Yield 1.11 g (43%). m.p. 116°. Rp 0.83 (Diethyl ether). [Found: 428.2093 Calc. for
C19H30CIN5O4 requires 428.2064]. iH n.m.r. (DMSO-dg) δ 1.42, d; 1.87, t;
2.01, s; 3.30, s; 3.46, sept; 3.95, s; 4.16, t; 6.86, s, br; 8.15, s. 13C n.m.r. (CDCI3) δ 22.9, 23.0, 34.1, 41.8, 43.7, 67.4, 70.8, 127.2, 144.4, 153.0, 155.7, 160.9, 172.9.
EXAMPLE 10
9-[4-Hydroxy-3,3-bis(isopropoxymethyl)but-l-yl]guanine
9-[4-Acetoxy-3,3-bis(isopropoxymethyl)but-l-yl]-2-amino-6-chloropurine (170 mg, 5.6 mmol), and 2M HCl (5 ml) were stirred at reflux for 1 hr. The mixture was cooled in an ice/water bath and 5% NaOH added dropwise until precipitate formed. The solid was filtered, washed witii ice cold water an dried under reduced pressure at 60° for 2 days. Yield 90 mg (62%). [Found: 368.2317 Calc. for
C17H29N5O4 requires 368.229]. n.m.r. (DMSO-dg) δ 1.73, d; 2.02, m; 3.25, s; 3.35, s; 3.45, sept; 4.03, m; 4.48, t; 6.37, s, br; 7.63, s; 10.52, s. 13c n.m.r. (D20) δ 25.3, 34.0, 45.7, 46.8, 66.9, 72.9, 77.9, 111.7, 141.4, 154.1, 159.2, 159.5.
EXAMPLE 11
9-(4-Acetoxy-3-acetoxymethyl-3-isopropoxymethylbut-l-yl)-2-amino-6- chloropurine
Step A
2-(2-Benzyloxyethyl)-2-isopropoxymethylpropane-l,3-diol
A second product from Step A in Example 9 was eluted and d e solvent removed to give the diol as an oil, 1.87 g (16%). *H n.m.r. (CDCI3) δ 1.13, d; 1.74, t; 3.41, s; 3.55, s; 3.61, t; 4.54, s; 7.33, s.
Step B
l-Acetoxy-2-acetoxymethyl-4-benzyloxy-2-isopropoxymethylbutane
Prepared from 2-(2-benzyloxyethyl)-2-isopropoxymethylpropane-l,3-diol using the method of Step B, Example 9. Yield 2.30 g (95%). XH n.m.r. (CDCI3) δ 1.07, d; 1.78, t; 2.03, s; 3.31, s; 3.43, sept; 3.56, t; 4.06, s; 4.48, s; 7.33, s.
Step C
4-Acetoxy-3-acetoxymethyl-3-isopropoxymethylbutan-l-ol
Prepared from l-acetoxy-2-acetoxymethyl-4-benzyloxy-2- isopropoxymethylbutane using the method of Step C, Example 9. Yield 1.61 g
(93%). iH n.m.r. (CDCI3) δ 1.16, d; 1.69, t; 2.05, s; 3.41, s; 3.57, m; 3.70, 14.04, s.
Step D
l-Acetoxy-2-acetoxymethyl-2-isopropoxymethyl-4-methanesulfoxybutane
Prepared from 4-acetoxy-3-acetoxymemyl-3-isopropoxymethylbutan-l-ol using die method of Step D, Example 9. Yield 2.15 g (quant.). JH n.m.r. (CDCI3) δ 1.12, d; 1.92, t; 2.07, s; 3.01, s; 3.34, s; 3.49, m; 4.05, s; 4.38, s.
Step E
9-(4-Acetoxy-3-acetoxymethyl-3-isopropoxymethylbut-l-yl)-2-amino-6- chloropurine
Prepared from l-acetoxy-2-acetoxymethyl-2-isopropoxymethyl-4- methanesulfoxybutane and 2-amino-6-chloropurine using the method of Step E,
Example 9. Yield 1.31 g (53%). m.p. 100°. *H n.m.r. (DMSO-dg) δ 1.05, d; 1.92, t; 2.01, s; 3.33, s; 3.46, m; 3.99, s; 4.16, t; 6.86, s, br; 8.16, s. 1 C n.m.r. (CDCI3) δ
22.9, 23.9, 33.8, 41.4, 43.0, 66.6, 70.3, 74.4, 127.2, 144.1, 153.2, 155.6, 160.9, 172.7.
EXAMPLE 12
9-(4-Hydroxy-3-hydroxymethyl-3-isopropoxymethylbut-l-yl)guanine
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-isopropoxymethylbut- 1 -yl)-2- amino-6-chloropurine using the method of Example 10. Yield 259 mg (76%). m.p.
261°. iH n.m.r. (DMSO-dg) δ 1.07, d; 1.70, m; 3.26, s; 3.46, m; 4.03, m; 4.43, t;
6.40, s, br; 7.63, s; 10.56, s, br. 13c n.m.r. (D2O) δ 25.3, 33.7, 45.7, 47.2, 669.6, 72.9, 77.9, 111.8, 141.4, 154.1, 159.3, 159.5.
EXAMPLE 13
9-[4-Acetoxy-3,3-bis(acetoxymethyl)but-l-yl]-2-a--mnopurine
A mixture of 9-[4-acetoxy-3,3-bis(acetoxymethyl)but-l-yl]-2-amino-6- chloropurine (5.98 g, 26.2 mmol), 10% palladium on carbon (0.5 g), triethylamine (1.1 eq., 2.35 ml, 27.5 mmol) and etiianol (120 ml), all in a 250 ml flask, under an atmosphere of hydrogen, was stirred vigorously at room temperature for 18 hours. The hydrogen was removed and the mixture filtered through a bed of celite® and die solvent removed by rotary evaporation. The crude product was dissolved in dichloromemane, washed twice with water, dried over magnesium sulfate, filtered and the solvent removed by rotary evaporation. The product was crystallized from methanol as a white crystalline solid. Yield 4.32 g (78.6%). m.p. 152-153°. (@l°C/min). (Found: C, 51.83; H, 5.92; N, 18.09;. Calc. for C17H23N5θ requires C, 51.90; H, 5.89; N, 17.80;). [Found: 255.3654 Calc. for CχoHgN3 requires 253.2854]. 'H n.m.r. (DMSO-dg) δ 2.05, s; 4.05, s; 4.17, m; 6.45, s, br;
8.12, s; 8.58, s. 13c n.m.r. (CDCI3) δ 20.8, 31.3, 38.3, 40.3, 63.8, 128.2, 142.0, 149.6, 153.0, 159.7, 170.5.
EXAMPLE 14
2-Amino-9-[4-hydroxy-3,3-bis(hydroxymethyl)but-l-yl]-6-methoxypurine
A mixture of 9-[4-acetoxy-3,3-bis(acetoxymethyl)but-l-yl]-2-amino-6- chloropurine (200 mg, 0.47 mmol), sodium hydroxide (4.26 g, 0.11 mol), methanol (15 ml) and water (1.6 ml) was stirred, at room temperature, for 30 min. The mixture was diluted witii water (8 ml), transfered to a beaker and neutralised by die addition of aqueous HCl. The solvents were removed by rotary evaporation and the residue refluxed in ethanol for 20 min. The ethanolic solution was applied to a short silica column and eluted witii hot etiianol. The eluent was collected and d e solvent removed by rotary evaporation. The crude product was crystallized from water. Yield 66 mg (48%). *H n.m.r. (DMSO-dg) δ 1.72, m; 4.11, m; 4.43, t;
6.39, s, br; 7.84, s.
EXAMPLE 15
2,6-Diamino-9-(4-hydroxy-3,3-bis(hydroxymethyl)but-l-yl)-purine
A mixture 9-[4-acetoxy-3,3-bis(acetoxymethyl)but-l-yl]-2-amino-6-chloropurine (100 mg, 0.2 mmol) and ammonia saturated methanol (20 ml), in a glass-lined stainless steel bomb, was stirred, at 100°, for 21 hrs. The mixture was allowed to cool to room temperature and die solvent removed by rotary evaporation. The solid residue was suspended in metiianol and filtered. The methanol was removed by rotary evaporation and die product crystalUzed from water. Yield 13 mg (20%). H n.m.r. (DMSO-dg) δ 1.71, m; 4.06, m; 4.45, t; 5.75, s, br; 6.64, s, br; 7.69, s.
EXAMPLE 16
2-Amino-6-hydroxyamino-9-[4-hydroxy-3,3-bis(hydroxyπιethyl)but-l- yl]purine
A mixture of 9-[4-acetoxy-3,3-bis(acetoxymethyl)but-l-yl]-2-amino-6- chloropurine (100 mg, 0.2 mmol), monohydroxylamine hydrochloride (0.49 g, 7.1 mmol), potassium hydroxide (dry powder, 0.46 g, 8.2 mmol) and etiianol (stored over 4A sieves, 8.2 ml), in oven dried glassware, was refluxed for 18 hrs. The mixture was allowed to cool to room temperature. The residue was dissolved in methanol/water and dietiiyl ether added until a precipitate formed. The solid was filtered and dried under reduced pressure at 60° for 1 hr. Yield 33 mg (47%).
[Found: 299.1465 Calc. for C11H19O4N4: 299.1468]. JH n.m.r. (DMSO-dg) δ
1.71, m; 4.07, m; 4.44, s, br; 6.83, s, br; 7.84, s.
EXAMPLE 17
2-An-dno-6-hydrazino-9-[4-hydroxy-3,3-bis(hydroxymethyl)but-l-yl]purine
A mixture of 9-[4-acetoxy-3,3-bis(acetoxymethyl)but-l-yl]-2-amino-6- chloropurine(1.0 g, 2.3 mmol), hydrazine hydrate (55%, 2.65 ml, 1.5 g, 46.7 mmol) and etiianol (100 ml) was stirred, at reflux, for 19 hrs. The mixture was allowed to cool to room temperature then allowed to stand at 4° for 1 hr. The solid precipitate was filtered and die product crystallized from water. Yield 290 mg
(43%). AH n.m.r. (DMSO-dg) δ 1.71, m; 4.06, m; 4.42, s, br; 4.44, t; 5.89, s, br;
7.69, s; 8.39, s, br.
EXAMPLE 18
9-[4-Acetoxy-3,3-bis(acetoxymethyl)but-l-yl]guanine
9-[4-Hydroxy-3,3-bis(hydroxymethyl)but-l-yl]guanine (1.0 g, 3.53 mmol), 4- dimemylaminopyridine (100 mg) and acetic anhydride (30 ml) were stirred at room temperature for 65 hrs. The acetic anhydride was removed in vacuo at 60°C. The crude residue was preadsorbed onto silica and flash chromatographed eluting witii 1:9 methanokdichloromethane. Fractions containing the pure compound were combined arid evaporated to give a sohd. Yield 0.29 g. Additional less pure fractions were combined evaporated and recrystallized from dichloromethane/metiianol. Total yield 0.99 g (69%). m.p. 242-245°. *H n.m.r. (DMSO-dg) δ 1.84-1.97, m; 2.02, s; 3.90-4.14, m; 4.02, s; 6.38, s; 7.71, s; 10.58, s, br.
EXAMPLE 19
9-[4-Hydroxy-3,3-bis(acetoxymethyl)but-l-yl]guanine
9-[4-Hydroxy-3,3-bis(hydroxymethyl)butyl-l-yl]guanine (5.0 g, 17.7 mmol), 4- dimemylaminopyridine (250 mg), acetic anhydride (2.34 ml, 24.8 mmol) in dimethylformamide (300 ml) were stirred at room temperature for 20 hrs. The dimethylformamide was removed in vacuo at 60°C. The crude residue was preadsorbed onto silica and flash chromatographed eluting with 1:9 methanol:di'chloromethane. Fractions containing the pure 9-[4-hydroxy-3,3- bis(acetoxymethyl)but-l-yl]guanine were combined and evaporated to give a solid.
Yield 1.25 g (19%). m.p. 229.5-232.5°C. !H n.m.r. (DMSO-dg) δ 1.75-1.88, m;
2.01, s; 3.34, s; 3.39, d, 75 Hz; 3.88-4.10, m; 3.96, s; 4.89, t; 6.38, s; 7.69, s; 10.53, s.
EXAMPLE 20
9-[4-Acetoxy-3,3-bis(hydroxymethyl)but-l-yl]guanine
A second product from Example 19 was eluted and die solvent removed to give a solid. Yield 0.96 g (17%) m.p. 224-225°. !H n.m.r. (DMSO-dg) δ 1.66-1.80, m; 2.00, s; 3.35, s; 3.91, s; 3.95-4.09, m; 4.65, br s; 6.46, s; 7.66, s; 10.70, s.
EXAMPLE 21
A mixture of 1,1-carbonyldiimidazole (1.55 eq., 0.89 g, 5.5 mmol), 3- phenoxybenzoic acid (1.5 eq., 1.13 g, 5.3 mmol) and dry dimethylformamide (50 ml) was stirred at room temperature, under an atmosphere of nitrogen, for 75 minutes. 9-[4-Hydroxy-3,3-bis(hydroxymemyl)but-l-yl]guanine (1.0 g, 3.5 mmol) was added in one portion to die mixture and stirred for a further 24 hours. The DMF was removed under reduced pressure. The crude product was suspended in 1:2 methano edianol at 50°. The suspension was filtered and die filtrate preadsorbed onto silica and chromatographed, eluting witii 5:95 methanokethyl acetate. The product was eluted and the solvent removed to give a white solid.
Crude yield 1.21 g (39%). n.m.r. (DMSO-dg) δ 2.18, m, 2H; 4.16, m, 2H; 4.46, s, 6H; 6.28, s, 2H, br; 7.02-7.71, complex, 27H; 7.47, s, IH; 10.50, s, IH.
EXAMPLE 22
A second product from Example 21 was eluted and die solvent removed to give a solid. Yield 0.39 g (16%). m.p. 187-188°. (Found: C, 65.25; H, 4.56; N, 10.09.
Calc. for C37H33N5O5 requires C, 65.77; H, 4.92; N, 10.36) iH n.m.r. (DMSO-
dg) δ 2.02, m, 2H; 4.13, m, 2H; 4.31, s, 4H; 6.35, s, 2H, br; 7.04-7.73, complex, 18H; 7.67, s, IH; 10.55, s, IH.
EXAMPLE 23
A third product from Example 21 was eluted and the solvent removed to give a solid. Yield 0.17 g (10%). !H n.m.r. (DMSO-dg) δ 1.84, m, 2H; 3.44, d, 75 Hz
4H; 4.07, m, 2H; 4.19, s, 2H; 4.74, t, 75 Hz, 2H; 6.42, s, 2H, br; 7.08-7.76, complex, 9H; 7.67, s, IH; 10.57, s, IH.
EXAMPLE 24
2-Amino-9-[3,3-bis(acetoxymethyl)but-l-yl]-6-chloropurine (0.14 g, 0.42 mmol) and a solution of metiianol saturated with ammonia at 4° (5.0 ml) were stirred at room temperature for 1 hr.The solvent was removed by rotary evaporation. HPLC analysis indicated that the reaction had not gone to completion. The crude product was purified by preparative reverse-phase HPLC, eluting witii a non-linear gradient of 25/75 CH3CN/H2O to 45/55 CH3CN/H2O. The product was eluted and die solvent removed to give a white solid. Yield 0.05 g (44%). m.p. 154-156°. iH n.m.r. (DMSO-dg) δ 0.83, s, 3H; 1.73, m, 2H; 3.27, d, 75.5 Hz, 4H; 4.09, m, 2H; 4.53, t, 75.5 Hz, 2H; 6.49, s, 2H, br; 8.08, s, IH; 8.56, s, IH.
EXAMPLE 25
A second product from Example 24 was eluted and the solvent removed to give a white solid. Yield 0.03 g (26%). m.p. 125-129°. AH n.m.r. (DMSO-dg) δ 0.90, s,
3H; 1.78, m, 2H; 2.01, s, 3H; 3.28, s, 2H; 3.86, s, 2H; 4.10, m, 2H; 4.78, s, IH, br; 6.48, s, 2H, br; 8.09, s, IH; 8.56, s, IH.
EXAMPLE 26
Prepared from 9-[4-Acetoxy-3,3-bis(acetoxymethyl)but-l-yl]-2-amino-6- chloropurine using the method of Example 24. H n.m.r. (DMSO-dg) δ 1.89, m,
2H; 2.02, s, 6H; 3.42, s, 2H; 3.98, s, 4H; 4.18, m, 2H; 4.93, s, IH; 6.89, s, 2H , br; 8.17, s, IH.
EXAMPLE 27
A second product from Example 26 was eluted and the solvent removed to give a solid that was crystalUsed from methanol. Yield 0.71 g (18%). m.p. 159-160°. *H n.m.r. (DMSO-dg) δ 1.81, m, 2H; 2.01, s, 3H; 3.94, s, 2H; 4.27, m, 2H; 4.67, t, 2H; 6.91, s, 2H, br; 8.15, s, IH.
EXAMPLE 28
A third product from Example 26 was eluted and die solvent removed to give a white soUd that was precipitated from methanol. Yield 0.19 g. Second crop. Yield
0.47 g (19%). m.p. 207-214°. iH n.m.r. (DMSO-dg) δ 1.75, m, 2H; 3.36, d, 75
Hz, 6H; 4.16, m, 2H; 4.43, t, 75 Hz, 3H; 6.90, s, 2H, br; 8.13, s, IH.
EXAMPLE 29
Prepared from 2-amino-9- [4-hydroxy-3 ,3-bis(hydroxymethyl)but- 1 -yl]purine using the method of Example 21. n.m.r. (DMSO-dg) δ 1.93, m; 3.50, s; 4.20, m; 4.77, s; 6.43, s, br; 7.05-8.01, complex; 8.08, s; 8.54, s.
EXAMPLE 30
Prepared from 9-(4-acetoxy-3-acetoxymeti yl-3-isopropoxymethylbut- 1 -yl)-2- amino-6-chloropurine using the method of Example 13. m.p. 166-167°. XH n.m.r. (DMSO-dg) δ 1.07, d; 1.93, m; 2.03, s; 3.48, m; 4.01, s; 4.17, m; 6.45, s, br; 8.10, s; 8.58, s.
EXAMPLE 31
Prepared from 9-[4-hydroxy-3,3-bis(isopropoxymetiιyl)but-l-yl]guanine using the method of Example 18. m.p. 245-248°. AH n.m.r. (DMSO-dg) δ 1.08, d, 76 Hz, 12H; 1.81, m, 2H; 2.02, s, 3H; 3.29, s, 4H; 3.47, dt, 76 Hz, 2H; 3.95, s, 2H; 4.04, m, 2H; 6.36, s, 2H, br; 7.67, s, IH; 10.56, s, IH. 13c n.m.r. (DMSO-dg) δ 22.4, 23.7, 33.3, 43.1, 66.3, 69.8, 73.2, 118.4, 138.9, 152.8, 155.1, 158.6, 172.1.
EXAMPLE 32
9-[4-L-Valyloxy-3,3-bis(L-valyloxymethyI)but-l-yl]guanine
Step A
9-[4-(iV-Benzyloxycarbonyl-L-valyloxy)-3,3-bis(iV-benzyloxycarbonyl-L- valyloxymethyl)but-l-yl]guanine
A suspension of 9-(4-hydroxy-3,3-bis(hydroxymethyl)but-l-yl)guanine (2.00 g, 7.06 mmol) in dry dimemylformamide (60 ml) was warmed to 60° and stirred until the solid dissolved. N-Benzyloxycarbonyl-L-vaUne (7.20 g, 28.7 mmol), 4- dimethylaminopyridine (0.36 g, 2.9 mmol) and dicyclohexylcarbodiimide (7.14 g, 34.6 mmol) were then added and die resulting solution stirred at 22° for 3 days tiien the white soUd filtered off and washed with dimethylformamide. The filtrate was concentrated under reduced pressure, and die residual oil subjected to flash chromatography (Merck Kieselgel 60). Elution with a gradient from 5 to 15% methanol in dichloromediane gave 3 bands A, B and C, witii RF values of 0.75, 0.52 and 0.20 respectively.
Concentration of the eluate containing band A gave 9-(4-N-benzyloxycarbonyl-L- valyloxy-3,3-bis(N-benzyloxycarbonyl-L-valyloxymethyl)but-l-yl)guanine as a
near colourless foam. Yield 0.82 g (12%). !H n.m.r. (DMSO-dg) δ 0.87, d, 77 Hz,
18H; 1.82-2.19, m, 5H; 3.98, t, 76 Hz, 2H; 4.15, br s, 2H; 4.93, d, 7 12 Hz, 3H; 5.05, d, 7 12 Hz, 3H; 6.35, br s, 2H; 7.14, s, 15H; 7.67, s, IH; 7.79, d, 77 Hz, 3H.
Step B
9-[4-L-Valyloxy-3,3-bis(L-valyloxymethyl)but-l-yl]guanine
A suspension of 9-[4-N-(benzyloxycarbonyl-L-valyloxy)-3,3-bis(N- benzyloxycarbonyl-L-valyloxymethyl)but-l-yl]guanine (0.50 g, 0.51 mmol), ethanol (20 ml), 10% palladium on carbon (0.40 g) and glacial acetic acid (2 drops) was stirred vigorously at room temperature under latin of hydrogen overnight then filtered d rough a pad of activated charcoal on celite. The pad was washed with ethanol, and d e combined filtrates diluted with toluene and concentrated under reduced pressure at 22° to give 9-(4'-valyloxy-3',3'- bis(valyloxymethyl)but-l-yl)guanine as a thermally unstable brown film. Yield
0.22 g (74%). iH n.m.r. (DMSO-dg) δ 0.80, d, 76.8 Hz, 9H; 0.85, d, 76.8 Hz, 9H;
1.64-2.00, m, 5H; 3.15, d, 75.3 Hz, 3H; 3.91-4.16, m, 8H; 6.59, br s, 2H; 7.67, s,
IH.
EXAMPLE 33
9-[4-Hydroxy-3,3-bis(L-valyloxymethyl)but-l-yl]guanine
Step A
9-[4-Hydroxy-3,3-bis(iV-benzyloxycarbonyl-L-valyloxymethyl)but-l- yl]guanine
Concentration of die eluate containing band B from Step A, Example 32 gave 9- [4- hydroxy-3,3-bis(N-benzyloxycarbonyl-L-valyloxymethyl)but-l-yl]guanine (1.78 g, 34%) as a near colourless foam. Yield 1.78 g (34%). AH n.m.r. (DMSO-d6) δ 0.87, br d, 76.6 Hz, 12H; 1.70-1.92, m, 2H; 1.92-2.14, m, 2H; 3.40, s, 2H (after D2θ exchange); 3.91-4.11, m, 8H; 4.88-5.10, m, 5H; 6.38, br s, 2H; 7.33, s, 10H; 7.66, s, IH; 7.73, d, 78.1 Hz, 2H; 10.54, s, IH.
Step B
9-[4-Hydroxy-3,3-bis(L-valyloxymethyl)but-l-yl]guanine
Prepared from 9-[4-hydroxy-3,3-bis(N-benzyloxycarbonyl-L-valyloxymethyl)but- l-yl]guanine using the method of Step B, Example 32. Yield
0.22 g, (68%). iH n.m.r. (DMSO-d6) δ 0.83, d, 77 Hz, 6H; 0.87, d, 77 Hz, 6H; 1.68-1.95, m, 4H; 3.12, d, J 8 Hz, 2H; 3.93-4.14, m, 6H; 6.55, br s, IH; 6.57, br s, IH; 7.67, 7.69, 2 peaks, IH.
EXAMPLE 34
9-[4-Hydroxy-3-(hydroxymethyl)-3-(L-valyloxymethyl)but-l-yl]guanine
Step A
9-[4-Hydroxy-3-(hydroxymethyl)-3-(N-benzyIoxycarbonyl-L- valyloxymethyl)but-l-yl]guanine
Concentration of the eluate containing band C from Step A, Example 32 gave 9-[4- hydroxy-3-(hydroxymethyl)-3-(N-benzyloxycarbonyl-L-valyloxymethyl)but-l- yl)guanine as a colourless soUd. m.p 166-170°. Yieldl.15 g (32%). *H n.m.r. (DMSO-d6) δ 0.88, d, 77 Hz, 3H; 0.89 d, 77 Hz, 3H; 1.73-1.91, m, 2H; 2.00-2.25, m, IH; 3.36, s, 4H (after D2O exchange); 3.94-4.17, m, 5H; 4.65, br t, 75 Hz, 2H;
4.97, d, J 12 Hz, IH; 5.05, d, J 12 Hz, IH; 6.40, br s, 2H; 7.34, s, 5H; 7.66, s, IH; 7.70, d, J 8 Hz, IH; 10.53, s, IH.
Step B
9-[4-Hydroxy-3-(hydroxymethyl)-3-(L-valyloxymethyl)but-l-yl]guanine
Prepared from 9-[4-hydroxy-3-(hydroxymethyl)-3-(N-benzyloxycarbonyl-L- valyloxymethyl)but-l-yl]guanine using the method of Step B, Example 32. Yield
0.09 g (58%). iH n.m.r. (DMSO-d6) δ 0.82, d, 76.8 Hz; 0.87, d, 76.8 Hz; 1.61- 1.98, m, 3H; 3.16, d, 74.2 Hz; 3.38, s, 4H (after D2θ exchange); 3.97, s, 2H; 3.89- 4.11, m, 2H; 6.59, br s, 7.66, s, IH; 10.74, br s, IH.
EXAMPLE 35
9-[4-Acetoxy-3,3-bis(L-valyloxymethyl)but-l-yl]guanine
9-[4-Acetoxy-3,3-bis(iV-benzyloxycarbonyl-L-valyloxymethyl)but-l-yl]guanine
Prepared from 9-[4-hydroxy-3,3-bis(N-benzyloxycarbonyl-L-valyloxymethyl)but- l-yl]guanine using the method of Step F, Example 1. Yield 0.40 g (62%). *H n.m.r. (DMSO-d6) δ 0.91, d, 77 Hz, 12H; 0.83-2.15, m, 7H; 3.89-4.22, m, 8H; 4.97, d, 7 12 Hz, 2H; 5.07, d, 712 Hz, 2H; 6.38, br s, 2H; 7.37, s, 10H; 7.70, s, IH; 7.80, d, 78 Hz, 2H.
9-[4-Acetoxy-3,3-bis(L-valyloxymethyl)but-l-yl]guanine
Prepared from 9-[4-acetoxy-3,3-bis(N-benzyloxycarbonyl-L-valyloxymethyl)but- l-yl]guanine in methanol using the method of Step B, Example 32. Yield 0.14 g,
(74%). !H n.m.r. (DMSO-d6) δ 0.75-0.98, m, 12H; 1.73-2.05, m, 4H; 2.02, s, 3H; 3.05-3.24, m, 2H; 3.90-4.18, m, 8H; 6.49-6.65, m, 2H; 7.68, 7.71, 2 peaks, IH.
EXAMPLE 36
9-[4-Acetoxy-3-acetoxymethyl-3-L-valyloxymethylbutyl]guanine
OAc
Step A
9-[4-Acetoxy-3-(acetoxymethyl)-3-(iV-benzyloxycarbonyl-L" valyloxymethyl)but-l-yϊ]guanine
Prepared from 9-[4-hydroxy-3-(hydroxymethyl)-3-(N-benzyloxycarbonyl-L- valyloxymethyl)but-lyl]guanine using the method of Step F, Example 1. Yield 0.26 g, (59%). !H n.m.r. (DMSO-dg) δ 0.87, d, 76.7 Hz; 1.81-2.22, m, 3H; 2.02, s, 6H; 3.88-4.18, m, 9H; 4.96, d, 7 12.5 Hz, IH; 5.04, d, 7 12.5 Hz, IH; 6.36, br s, 2H; 7.34, s, 5H; 7.70, s, IH; 7.77, d, 78 Hz, IH; 10.55, s, IH.
Step B
9-[4-Acetoxy-3-(acetoxymethyl)-3-(L-valyloxymethyl)but-l-yl]guanine
OAc
Prepared from 9-[4-acetoxy-3-(acetoxymethyl)-3-(N-benzyloxycarbonyl-L- valyloxymethyl)but-l-yl]guanine in methanol using the procedure of Step B, Example 32. m.p. 172-176° dec. Yield 0.16 g, (95%). iH n.m.r. (DMSO-d6) δ 0.82, d, 76.8 Hz, 3H; 0.87, d, 76.8 Hz, 3H; 1.77-2.05, m, 3H; 2.01, s, 6H; 3.16, d, J 5.4 Hz, IH; 3.95-4.17, m, 8H; 6.53, br s, 2H; 7.72, s, IH.
EXAMPLE 37
9-[4-Hydroxy-3,3-bis(D,L-2-a--ninobutyroxymethyl)but-l-yl]guanine
Step A
9-[4-Hydroxy-3,3-bis( V-benzyloxycarbonyl-D,L-2-aminobutyroxymethyl)but- l-yl]guanine
A suspension of 9-[4-hydroxy-3,3-bis(hydroxymethyl)but-l-yl]guanine (2.11 g, 7.45 mmol) in dry dimemylformamide (150 ml) was heated to 60° with stirring. D, L-N-benzyloxycarbonyl-2-aminobutyric acid (3.36 g, 0.015 mmol), 4- dimemylaminopyridine (0.185 g, 1.51 mmol) and dicyclohexylcarbodiimide (3.77 g, 0.018 mmol) were then added to the suspension while still at 60°. The resulting mixture was allowed to cool to room temperature and stirred for 6 days. Additional D, L-N-benzyloxycarbonyl-2-aminobutyric acid (1.66 g, 7.45 mmol) and dicyclohexylcarbodiimide (1.54 g, 7.45 mmol) were, added to the reaction mixture and stirring continued for 3 days at room temperature. Additional D, L-N- benzyloxycarbonyl-2-aminobutyric acid (1.66 g, 7.45 mmol) and dicyclohexylcarbodiimide (1.54 g, 7.45 mmol) were added to the reaction mixture and stirring continued for a further 11 days at room temperature. The white solid which formed was filtered off, washed witii dimemylformamide and the filtrate concentrated under reduced pressure. The filtrate was preadsorbed onto siUca and flash chromatographed eluting with 10:90 methanol-ethyl acetate to give two products. Yield 0.932 g (17%). m.p.97-99°. iH n.m.r., (DMSO-d6) δ 0.93, t, J 8.3 Hz, 3H; 1.73, m, 2H; 3.43, m; 4.07, m, 4H; 5.03, m, 3H; 6.5, s, br, 2H; 7.37, s, 5H; 7.67, s, IH; 7.77, J 8.3 Hz, d, IH; 10.6, s, br, IH. 13c n.m.r., (DMSO-dg ) 10.4, 24.0, 31.0, 41.5, 61.0, 55.4, 64.5, 65.5, 117.8, 127.8, 128.3, 136.7, 136.8, 150.1, 151.7, 153.4, 156.2, 156.7, 172.0
Step B
9-[4-Hydroxy-3,3-bis(D,L-2aminobutyroxymethyl)but-l-yl]guanine
Prepared from 9-[4-hydroxy-3,3-bis(N-benzyloxycarbonyl-D,L-2- aminobutyroxymethyl)but-l-yl]guanine by the memod of Step B, Example 32. AH n.m.r., (DMSO-dg) δ 0.87, t, 6H, 5.5 Hz; 1.50, m, 4H; 1.73, m, 2H; 3.17-3.50, complex, 2H; 3.40, s, IH; 3.80-4.17, m, 6H; 6.50, s, br, 2H; 7.67, 7.70, 2 peaks, IH.
EXAMPLE 38
9-[4-Hydroxy-3-hydroxymethyI-3-(Λ^-benzyloxycarbonyl-2-amino- butyroxymethylbut-l-yI]guanine
The second product from Step A, Example 37 was eluted and the solvent removed to give a white soUd. Yield 0.043 g (1.1%). mp 183.0-184.0°. lU-n.m.r., (DMSO- d6) δ 0.90, t, J 8.3 Hz, 3H; 1.73, m, 4H; 4.03, m, 5H; 4.67, t, 2H; 5.00, d, 2H; 6.43, s, br, 2H; 7.33, s, 5H; 7.67, s, IH; 7.73, d, J 8.3 Hz, IH; 10.53, s, br, IH. ^C n.m.r, (DMSO-d6 ) 12.3, 25.9, 33.0, 44.4, 57.3, 63.3, 67.4, 129.6, 130.14, 138.6, 138.8, 152.2, 155.2, 158.1, 158.6, 174.1.
EXAMPLE 39
9-[4-Hydroxy-3-(hydroxymethyl)-3-(2-amino-2,2-dimethylacetoxymethyl)but- l-yl]guanine
Step A
9-[4-Hydroxy-3-(hydroxymethyl)-3-( -benzyloxycarbonyl-2-amino-2,2- dimethylacetoxymethyl)but-l-yl]guanine
Prepared from 9-[4-hydroxy-3,3-bis(hydroxymethyl)but-l-yl]guanine and N- benzyloxycarbonyl-2-amino-2,2-dimedιylacetic acid using the method of Step A,
Example 32. *H n.m.r. (DMSO-d6) δ 1.37, s, 6H; 1.67-1.84, m, 2H; 3.91-4.10, m,
4H; 4.61, br t, J Hz, 2H; 4.91, s, 2H; 6.41, br s, 2H; 7.25-7.44, m, 5H; 7.66, s, IH; 7.80, br s, IH.
Step B
9-[4-Hydroxy-3-(hydroxymethyl)-3-(iV-benzyloxycarbonyl-2-amino-2,2- dimethylacetoxymethyl)but-l-yl]guanine
Prepared from 9-[4-hydroxy-3-(hydroxymethyl)-3-(N-benzyloxycarbonyl-2- amino-2,2-dimed ylacetoxymethyl)but-l-yl]guanine using the method of Step B, Example 32. 1H n.m.r. (DMSO-d6) δ 1.20, s, 3H; 1.22, s, 3H; 1.59-1.90, m, 2H; 3.37, br s, 4H(after D2θ exchange); 3.94, s, 2H; 3.89-4.12, m, 2H, 6.54, br s, 2H; 7.65, 7.66, 2 peaks, IH; 10.16, br s, IH.
EXAMPLE 40
9-(4-Hydroxy-3,3-bis(iV-benzyIoxycarbonyl-L-alanyloxyπιethyl)but-l- yl)guanine
Prepared from 9-[4-hydroxy-3,3-bis(hydroxymethyl)but-l-yl]guanine and N- benzyloxycarbonyl-L-alanine using the method of Step A, Example 37. XH n.m.r., (DMSO-dg) δ 1.30, d, J 5.6 Hz, 6H; 1.80, m, 2H; 3.90-4.30, m, 8H; 4.87-5.13, m, 4H; 6.43, s, br, 2H; 7.33, s, 10H; 7.67, s, IH; 7.83 d, 2H, J 5.6 Hz; 10.57, s, br, IH.
EXAMPLE 41
9-[4-Hydroxy-3-(hydroxymethyl)-3-(L-alanyloxymethyl)but-l-yl)guanine, acetate salt
Step A
9-[4-Hydroxy-3-(hydroxymethyl)-3-(N-benzyloxycarbonyl-L- alanyloxymethyl)but-l-yl)guanine
Prepared from 9-[4-hydroxy-3,3-bis(hydroxymethyl)but-l-yl]guanine and N- benzyloxycarbonyl-L-alanine using the method of Step A, Example 37. ^H n.m.r., (DMSO-d6) δ 1.33, d, J 5.6 Hz, 2H; 1.77, m, 2H; 4.10, m, 5H; 4.70, t, 2H; 5.00, d, 2H; 6.43, s, br, 2H; 7.37, s, 5H; 7.67, s, IH; 7.77, J 5.6 Hz, d, IH; 10.57, s, br, IH.
!3c n.m.r., (DMSO-dg ) 16.9, 31.1, 42.6, 49.4, 61.5, 65.0, 65.5, 116.5, 127.8, 128.3, 136.8, 137.0, 150.9, 153.3, 155.8, 156.8, 172.7
Step B
9-[4-Hydroxy-3-(hydroxymethyl)-3-(L-alanyloxymethyl)but-l-yl)guanine, acetate salt
Prepared from 9-[4-hydroxy-3-(hydroxymethyl)-3-(N-benzyloxycarbonyl-L- alanyloxymethyl)but-l-yl)guanine in methanol with one equivalent of acetic acid using the metiiod of Step B, Example 32. AH n.m.r., (DMSO-d6) δ 1.10, m, 3H; 1.70, m, 2H; 2.90, s, 3H; 3.33, complex, 5H; 4.03, m, 4H; 6.47, s, br, 2H; 7.67, s, IH.
EXAMPLE 42
Prepared using the method of Example 32, Step A, with N-benzyloxy carbonyl L- leucine. Yield 600 mg (16%). !H n.m.r. (DMSO-d6) δ 0.88, t, 6H; 1.41-1.79, m,
4H; 3.38, s, 4H; 4.05, m, 4H; 4.39 and 4.68(ratio 1:4), 2t, 2H; 5.01, s, 2H; 6.41, s, 2H; 7.34, s, 5H; 7.68, s, IH; 7.75, d, IH; 10.55, s, IH.
EXAMPLE 43
A second product from Example 42 was eluted, and the solvent removed to give a solid. Yield 1.13 g (21%). lU n.m-r. (DMSO-d6) δ 0.85, t, 12H; 1.41- 1.89, m, 8H; 3.19, d, IH; 3.41, s, br, 2H; 4.18, s, br, 8H; 5.01, m, 4H; 6.42, s, 2H; 7.31, s, 10H; 7.69, s, IH; 7.80, d, 2H; 10.61, s, IH.
EXAMPLE 44
9-(4-Hydroxy-3,3-bis(Λ^-benzyloxycarbonyl-L-prolyloxymethyI)but-l- yl)guanine
Prepared from 9-(4-hydroxy-3,3-bis(hydroxymethyl)but-l-yl)guanine and N- benzyloxycarbonyl-L proUne using the method of Step A, Example 32. AH n.m.r. (DMSO-dg) δ 1.63-2.06, m, 8H; 2.08-2.40, m, 2H; 3.25-3.52, m, 2H (after D2O exchange); 3.85-4.16, m, 9H; 4.24-4.44, m, 3H; 4.90-5.15, m, 5H; 6.38, br s, 2H; 7.16-7.42, m, 10H; 7.58, 7.63, 7.64, 7.68, 4 peaks, IH.
EXAMPLE 45
9-[4-Hydroxy-3-(hydroxymethyl)-3-(iV-benzyloxycarbonyl-L- prolyloxymethyl)but-l-yI]guanine
Prepared from 9-(4-hydroxy-3,3-bis(hydroxymetiιyl)but-l-yl)guanine and N- benzyloxycarbonyl-L-proUne using the method of Step A, Example 32. AH n.m.r. (DMSO-d6) δ 1.65-2.07, m, 5H; 2.10-2.38, m, IH; 3.31-3.46, m, 5H (after D2O exchange); 3.90-4.15, m, 5H; 4.27-4.45, m, IH; 4.69, t, 76 Hz, 2H; 4.93-5.15, m, 2H; 6.42, br s, 2H; 7.22-7.44, m, 5H; 7.64, 7.68, 2 peaks, IH; 10.54, br s, IH.
EXAMPLE 46
9-[4-Hydroxy-3-(hydroxymethyl)-3-(L-phenylalanyloxymethyl)but-l- yl]guanine, acetate salt
Step A
9-[4-Hydroxy-3-(hydroxymethyl)-3-(iV-benzyloxycarbonyl-L- phenylalanyloxymethyl)but-l-yl]guanine
Prepared from 9-[4-hydroxy-3,3-bis(hydroxymethyl)but-l-yl]guanine and L- phenylalanine using the method of Step A, Example 37. m.p. 103-105°. !H n.m.r., (DMSO-d6) δ 1.73, m, 2H; 3.00, m, 2H; 4.07, m, 4H; 4.37, m, IH; 4.70, t, 2H; 4.97, s, 2H; 6.50, s, br, 2H; 7.27, m, 5H; 7.70, s, IH; 7.87, d, IH; 10.63, s, br, IH.
Step B
9-[4-Hydroxy-3-(hydroxymethyl)-3-(L-phenylalanyloxymethyl)but-l- yl]guanine, acetate salt
Prepared from 9-[4-hydroxy-3-(hydroxymethyl)-3-(N-benzyloxycarbonyl-L- phenylalanyloxymethyl)but-l-yl]guanine in methanol with one equivalent of acetic acid using the method of Step B, Example 32. AH n.m.r., (DMSO-d6) δ 1.67, m, 2H; 1.83, s, 3H; 2.80, m, 2H; 3.20-3.80, complex, 5H; 3.90, m, 4H; 6.50, s, br, 2H; 7.20, m, 5H; 7.67, s, IH.
EXAMPLE 47
Prepared from the crude product from step A of Example 46 using the method of Step F, Example 1. m.p. 147-148°. AH n.m.r., (DMSO-d6) δ 1.87, m, 2H; 2.03, s, 6H; 3.00, m, 2H; 3.90-4.20, complex, 8H; 4.33, m, IH; 4.97, s, 2H; 6.43, s, br, 2H; 7.30, m, 10H; 7.73, s, IH; 7.93,75.5 Hz, d, IH.
EXAMPLE 48
9-(5-Acetoxy-3,3-bis(acetoxymethyl)pentyl)-2-amino-6-chloropurine
l,5-Bis(benzyloxy)-3,3-bis(hydroxymethyl)pentane
Anhydrous etiier (100 ml) was carefully added to stirred litiiium aluminium hydride (3.54 g, 93 mmol) maintained under nitrogen. A solution of 1,5- bis(benzyloxy)-3,3-bis(ethoxycarbonyl)pentane (10.0 g, 23.3 mmol) in anhydrous ether (100 ml) was then added portionwise at such a rate that the mixture gently refluxed. The resulting suspension was heated to reflux for 5.5 hr then cooled and stirred at room temperature overnight. Ethyl acetate was then carefully added to destroy die remaining hydride, followed by ethanol then water until the soUd turned from grey to white. The soUd was tiien filtered off and washed witii hot THF (ca 200 ml). The combined filtrates were partially concentrated under reduced pressure, diluted with water and extracted with ether (3 x 200 ml). The combined organic phases were dried, filtered and concentrated under reduced pressure to give l,5-bis(benzyloxy)-3,3-bis(hydroxymethyl)pentane as an oil.
Yield 8.0 g (96% pure, 96%). iH n.m.r. (CDCI3): d 1.57, t, 76 Hz, 4H; 3.31, br s, 4H; 3.48, t, 76 Hz, 4H; 3.65, br s, 2H; 4.39, s, 4H; 7.05-7.31, m, 10H.
Step B
3,3-Bis(acetoxymethyl)-l,5-bis(benzyloxy)pentane
Prepared from l,5-bis(benzyloxy)-3,3-bis(hydroxymethyl)pentane using the method of Step F, Example 1. Yield 8.51 g (89%). b.p. 200-220° (oven temρerature)/cα 2-4 x 10"4 mm. *H n.m.r. (CDCI3) δ 1.68, t, 76 Hz, 4H; 1.95, s, 6H; 3.48, t, 76 Hz, 4H; 3.93, s, 4H; 4.39, s, 4H; 7.12-7.33, m, 10H.
Step C
5-Benzyloxy-3,3-bis(acetoxymethyl)-l-hydroxypentane
A suspension of 3,3-bis(acetoxymethyl)-l,5-bis(benzyloxy)pentane (5.00 g, 11.7 mmol), 10% paUadium on activated carbon (0.30 g) and ethanol (45 ml) was stirred vigorously under latin of hydrogen until 270 ml of hydrogen had been absorbed. It was then filtered tiiough ceUte, which was washed with additional
ethanol. The combined filtrates were concentrated under reduced pressure to a pale yellow oil (3.95 g). Radial chromatography (4 mm plate, Merck Kieselgel 60PF254) of the crude oil (dichloromethane elution followed by ether elution) gave two chromophoric bands A and B with RF values of 0.63 and 0.33 (dichloromethane) respectively. Concentration of the eluate corresponding to band A gave 3,3-bis(acetoxymethyl)-l,5-bis(benzyloxy)pentane (0.55 g, 11% recovery) as a colourless oil with properties in accord with those described above. Concentration of the eluate corresponding to band B gave 5-benzyloxy-3,3- bis(acetoxymethyl)-l-hydroxypentane as a colourless oil. Yield 2.94 g (74%). AH n.m.r. (CDCI3) δ 1.67, t, 76.7 Hz, 2H; 1.78, t, 76.4 Hz, 2H; 2.04, s, 6H; 3.56, t, 7 6.4 Hz, 2H; 3.73, t, 76.7 Hz, 2H; 4.00, s, 4H, 4.49, s, 2H; 7.27-7.38, m, 5H.
Step D
l-Acetoxy-5-benzyloxy-3,3-bis(acetoxymethyl)pentane
Prepared from 5-benzyloxy-3,3-bis(acetoxymethyl)-l-hydroxypentane using the method of Step F, Example 1. Yield 3.35 g (99%). !H n.m.r. (CDCI3) δ 1.64-1.84, m, 4H; 2.03, s, 3H; 2.05, s, 6H; 3.55, t, 77 Hz, 2H; 4.00, s, 4H; 4.17, t, 77 Hz, 2H; 4.47, s, 2H; 7.19-7.41, m, 5H.
Step E
l-Hydroxy-5-acetoxy-3,3-bis(acetoxymethyl)pentane
Prepared from l-acetoxy-5-benzyloxy-3,3-bis(acetoxymethyl)pentane using the method of Step G, Example 1. Yield 2.5 g (quant.). H n.m.r. (CDCI3) δ 1.65, dt, 7 3.3, 7.1 Hz, 2H; 1.73 dt, 71.7, 6.9 Hz, 2H; 1.99, s, 3H; 2.02, s, 6H; 3.70, t, 76.9 Hz, 2H; 3.96, s, 4H; 4.04-4.18, m, 2H.
Step F
5-Acetoxy-3,3-bis(acetoxymethyl)-l-methanesulphonyloxypentane
Prepared from l-hydroxy-5-acetoxy-3,3-bis(acetoxymethyl)pentane using the method of Step H, Example 1. Yield 3.2 g (98%). *H n.m.r. (CDCI3) δ 1.60-1.79, m, 2H; 1.85, t, 77.1 Hz, 2H; 1.98, s, 3H; 2.01, s, 6H; 2.98, s, 3H; 3.96, s, 4H; 4.02- 4.18, m, 2H; 4.30, t, 77.1 Hz, 2H.
Step G
9-(5-Acetoxy-3,3-bis(acetoxymethyl)pent-l-yl)-2-amino-6-chIoropurine
Prepared from 5-acetoxy-3 ,3-bis(acetoxymethyl)- 1 -methanesulphonyloxypentane using the method of Step I, Example 1. Yield 1.58 g (40%). m.p 154-155°.^ n.m.r. ( DMSO-d6) δ 1.81, t, 77 Hz, 2H; 1.99, br t, 2H; 2.04, s, 3H; 2.06, s, 6H;
4.02, s, 4H; 4.10-4.29, m, 4H; 6.88, br s, 2H; 8.24, s, 1 C n.m.r. (CDCI3) δ 22.8, 23.0, 31.7, 33.6, 40.8, 41.1, 62.3, 67.7, 127.0, 143.9, 153.2, 155.6, 161.3, 172.6, 173.2.
EXAMPLE 49
9-{2-[(3-hydroxymethyl)oxolan-3-yl]eth-l-yl}guanine
Prepared from 9-(5'-acetoxy-3,,3'-bis(acetoxymethyl)pentyl)-2-amino-6- chloropurine using the method of Example 2. Yield 0.47 g (93%). m.p. 266-271°. AH n.m.r. (DMSO-d6) δ 1.49-1.75, m, 2H; 1.79-1.96, m, 2H; 3.29, d, 78 Hz, IH (after D2O exchange); 3.33, s, 2H; 3.56, d, 78 Hz, IH (after D2O exchange); 3.69, t, 77 Hz, 2H; 3.99, br t, 78 Hz, 2H; 4.89, br t, 75 Hz, IH; 6.42, br s, 2H; 7.72, s, IH; 10.53, br s, IH.
EXAMPLE 50
9-(5-Acetoxy-3,3-bis(acetoxymethyl)pent-l-yl)-2-aminopurine
Prepared from 9-(5'-acetoxy-3',3'-bis(acetoxymethyl)pentyl)-2-amino-6- chloropurine using the method of Example 13. Yield (quant.), m.p. 137-138°. AH n.m.r. (DMSO-d6) δ 1.78, t, 76.8 Hz, 2H; 1.83-2.04, m, 2H; 1.99, s, 3H; 2.01, s, 6H; 3.97, s, 4H; 4.05-4.24, m, 4H; 6.44, br s, 2H; 8.11, s, IH; 8.57, s, IH.
EXAMPLE 51
9-(5-Hydroxy-3,3-bis(hydroxymethyl)pent-l-yl)-2-aminopurine
Prepared from 9-(5'-acetoxy-3',3'-bis(acetoxymethyl)pentyl)-2-aminopurine using the method of Example 24. Yield (quant.). !H n.m.r. (DMSO-d6) δ 1.49, t, 76.9 Hz, 2H; 1.66-1.76, m, 2H; 3.17, d, 75.1 Hz, 2H; 3.30, d, 75 Hz, 2H; 3.55, q, 74.8 Hz, 2H; 4.01-4.16, m, 2H; 4.49-4.62, m, 2H; 6.47, br s, 2H; 8.05, s, IH; 8.55, s, IH.
EXAMPLE 52
9-(5-Hydroxy-3,3-bis(hydroxymethyl)pent-l-yl)guanine
A mixture of 9-(5'-acetoxy-3',3'-bis(acetoxymethyl)pentyl)-2-amino-6- chloropurine (0.19 g, 0.43 mmol) and 50% aqueous formic acid (3 ml) was stirred and heated at 100° for 100 min then concentrated under reduced pressure. A chilled (0-5°) saturated solution of ammonia in methanol (20 ml) was then added to the residual oil and the mixture stirred at room temperature overnight. After concentration under reduced pressure, a further aUquot of ammonia saturated methanol (20 ml) was added and die solution stirred overnight then concentrated under reduced pressure. Recrystallisation (water) o the crude solid gave 9-(5'- hydroxy-3',3'-bis(hydroxymethyl)pentyl)guanine as cream needles. Yield 114 mg
(89%). m.p. 232-234° dec. tø n.m.r. ( DMSO-d6) δ 1.46, t, 76.9 Hz, 2H; 1.59- 1.73, m, 2H; 3.28, s, 4H; 3.49, t, 77.0 Hz, 2H; 3.89-4.04, m, 2H; 4.56, br s, 3H; 6.49, br s, 2H; 7.64, s, IH; 10.21-11.15, br s, IH.
EXAMPLE 53
A slurry of 9-[4-hydroxy-3,3-bis(hydroxymethyl)-but-l-yl]guanine (1 g) in 10 ml DMF, protected from moisture with Ar, was treated with 1 ml methyl orthoacetate followed by 0.35 ml trifluoroacetic acid. A clear solution was obtained which, after several minutes, deposited a white powder. The mixture was stirred at room temp, for 1 hr and then 3 ml triethylamine were added and the soUd collected and washed witii dietiiyl ether. It was then warmed to 100 ° in 10 ml DMF, cooled to
ambient temperature, collected and washed with dichloromethane before drying in vacuo at 70 ° for several hr. Yield 0.77 g. !H n.m.r. (DMSO-dg) δ 1.28, s, 3H;
1.68, t, 2H; 6.44, s, 2H; 3.89, t, overlapping with 3.85, s, 8H; 7.71, s, IH; 10.56, s, IH.
EXAMPLE 54
To a suspension of 9-[4-hydroxy-3,3-bis(hydroxymethyl)-but-l-yl]guanine (1 g) and 0.1 g LiBr in 40 ml CH2CI2 was added 0.45 ml CF3CO2H followed by 2.5 ml 2,2-dimethoxypropane. After stirring for 1.5-2 days at room temp., the mixture was extracted with 100-150 ml 10% NaHCθ3 solution and die soUd collected and washed well with water. After drying at 80 ° under vacuum, the product (0.61 g) was obtained as a sUghtly greyish to white powder. XH n.m.r. (DMSO-dg) δ 1.29, d, 6H; 1.71, t, 2H; 3.46, s, 2H; 3.56, s, 4H; 3.99, t, 2H; 4.76 s, IH,; 6.42, s, 2H; 7.70, s, IH; 10.54, s, IH.
EXAMPLE 55
A solution of 9-[4-hydroxy-3,3-bis(hydroxymethyl)-but-l-yl]guanine (1 g) in 40 ml DMF at 145 °, protected from moisture with Ar, was treated dropwise with a solution of 0.58 g 1,1-carbonyldiimidazole in 25 ml DMF over 15-20 mins. After 2 hr the reaction (clear, pale yellow solution) was removed from the oil bath and the solvent stripped off to near dryness at 75 °. The product was stirred with several aliquots (50-75 ml) of CH2CI2, collected on a frit and washed several more times before air drying. Buff-yellow colour, yield 1.29 g. The washings contained ca. 0.25 g imidazole. iH n.m.r. (DMSO-dg) δ 1.74, m, 2H; 3.33, s, 4H; 4.00, m, 4H;
4.35 to 5.1(ca. 2H, three br. peaks, H/D exchange, OH); 6.43, s, 2H; 5.76, s, IH, imidazole; 7.01, s, IH, imidazole; 7.71, 7.68, 7.64, 2H, imidazole; 10.54, s, IH.
EXAMPLE 56
9-[4-Acetoxy-3,4-bis(acetoxymethyI)but-l-yl]-2-amino-6-methylaminopurine
9-[4-Acetoxy-3,4-bis(acetoxymethyl)but-l-yl]-2-amino-6-chloropurine (2.0 g, 4.7 mmol) and 33% methylamine in ethanol (560 ml, 4.7 mmol) in dichloromethane
(13 ml) and ethanol (7 ml) was stirred in a stoppered flask for 18 hrs. A further portion of 33% methylamine (1.12 ml, 9.4 mmol) was added and the reaction allowed to stir for a further 5 hrs. The solvent was removed in vacuo and the crude product preadsorbed onto siUca and flash chromatographed eluting with 1:19 methanokdichloromethane. Fractions 7-14 were combined and recrystalUzed from dichloromethane and methanol to give white crystals. Yield 0.70 g (36%). m.p.
154-156°. H n.m.r. (DMSO-d6) δ 1.85-2.00, m, 2H; 2.02, s, 9H; 2.80-2.95, br s,
3H; 3.95-4.13, m, 2H; 4.03, s, 6H; 5.76, s, 2H; 7.13, br s, IH; 7.71, s, IH.
EXAMPLE 57
9-[4-(12-Methoxydodecanoxy)-3,4-bis(hydroxymethyl)but-l-yl]-2- aminopurine
12-Methoxydodecanoic acid (1.72 g, 7.5 mmol) and l, -carbonyldiimidazole (1.34 g, 8.3 mmol) were stirred together in dry dimethylformamide (50 ml) for 1.5 hrs under a nitrogen atmosphere. To this solution was added 9-[4-hydroxy-3,4- bis(hydroxymethyl)but-l-yl]-2-aminopurine (2.0 g, 7.5 mmol) δissolved in dimethylformamide (80 ml) and 4-dimethylaminopyridine (0.22 g). The reaction
mixture was stirred for 16 hrs, when hplc analysis indicated 50% completion. The solvent was removed in vacuo and the crude material was preadsorbed onto siUca and flash chromatographed eluting with 3:17 methanol:dichloromethane. Fraction 5 (1.18 g)was found to contain the desired product. This was further purified by hplc eluting with 2:3 acetonitrile:water to give the product as white crystals, m.p.
91-92°.lH n.m.r. (DMSO-d6)) δ 1.20,br s, 14H; 1.37-1.57, m, 4H; 1.73-1.86, m, 2H; 2.27, t, 77.2 Hz, 2H; 3.21, s, 3H; 3.28, t, 76.4 Hz, 2H; 3.36, s (after D2O exchange), 4H; 3.94, s, 2H; 4.08-4.22, m, 2H; 4.63-4.73, m, 2H; 6.46, s, 2H; 8.05, s, IH; 8.55, s, IH.
EXAMPLE 58
9-[4-Hydroxy-3,4-bis(12-methoxydodecanoxymethyl)but-l-yl]guanine
12-Methoxydodecanoic acid (1.63 g, 7.1 mmol) and l,r-carbonyldiimidazole (1.27 g, 7.8 mmol) were stirred together in dry dimethylformamide (70 ml) for 1.5 hrs under a nitrogen atmosphere. To this solution was added 9-[4-hydroxy-3,4- bis(hydroxymethyl)but-l-yl]guanine (1.0 g, 3.53 mmol) and 4- dimethylaminopyridine (0.20 g). The reaction mixture was stirred for 2 days. The solvent was removed in vacuo and the crude material was preadsorbed onto siUca
and flash chromatographed eluting with 1:19 methanol:dichloromethane, 1:9 methanokdichloromethane and 3:17 methanol:dichloromethane. Fractions 17-21 were combined to give the product as white crystals, m.p. 174-176°. H n.m.r. (DMSO-d6) δ 1.21, s, 28H; 1.13-1.58, m, 8H; 1.74-1.89, m, 2H; 2.27, t, 77.2 Hz, 4H; 3.20, s, 6H; 3.27, t, 76.4 Hz, 4H; 3.36-3.44, m, 2H; 3.83-4.17, m, 2H; 3.95, s, 4H; 4.80-4.95, m, IH; 6.39, s, 2H; 7.67, s, IH; 10.55, br s, IH.
EXAMPLE 59
Prepared from 9-[4-hydroxy-3,4-bis(hydroxymethyl)but- 1 -yl]-2-aminopurine using the method of Example 57. !H n.m.r. (DMSO-d6)) δ 1.67-1.84, m, 2H; 3.33, s (after D2O exchange), 4H; 3.69, s, 2H; 3.98, s, 2H; 4.04-4.18, m, 2H; 4.61-4.75, m, 2H; 6.48, s, 2H; 7.01-7.06, m, IH; 7.29-7.34, m, IH; 7.41-7.47, m, IH; 8.00, s, IH; 8.56, s, IH.
EXAMPLE 60
9-[4-Hydroxy-3,4-bis(hydroxymethyl)butyl]guanine (1.0 g, 3.53 mmol) and 1,1'- carbonyldiimidazole (0.69 g, 4.24 mmol) were stirred together in dry dimethylformamide (60 ml) for 1.0 hr under a nitrogen atmosphere. To this solution was added methylamine (8.03M in ethanol, 0.53 ml, 4.24 mmol) and the reaction was stirred for 4 days. The solvent was removed in vacuo and the crude material was purified by hplc eluting with 1:19 acetonitrile: water to give the product as white crystals, m.p. 213-215°. *H n.m.r. (DMSO-d6) δ 1.65-1.82, m, 2H; 2.56, d, 74.6 Hz, 3H; 3.33, s (after D2O exchange), 4H; 3.90, s, 2H; 3.95- 4.17, m, 2H; 6.47, s, 2H; 6.90-7.06, m, IH; 7.64, s, IH.
EXAMPLE 61
H2N
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-fluorobut- l-yl)-2-amino-6- chloropurine using the method of Example 2. [Found: 272.1162 Calc. for
C10H15FN5O3 requires 272.1159]. !H n.m.r. (DMSO-dg) δ 2.09, dt, 76, 18 Hz, 2H; 3.51, dd, 75, 18 Hz, 4H; 4.08, t, 76 Hz, 2H; 4.98, t, 75 Hz, 2H; 6.46, s, IH, br; 7.69, s, IH; 10.55, s, IH, br.
EXAMPLE 62
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-fluorobut- 1 -yl)-2-amino-6- chloropurine using the method of Example 17. m.p. 200-206°. AH n.m.r. (DMSO- dg) δ 2.09, dt, 76, 18 Hz, 2H; 3.51, dd, 75, 18 Hz, 4H; 4.12, t, 76 Hz, 2H; 4.41, s,
2H, br; 5.01, t, 76 Hz, 2H; 5.93, s, 2H, br; 7.72, s, IH; 8.38, s, IH.
EXAMPLE 63
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-fluorobut- 1 -yl)-2-aminopurine using the method of Example 24. iH n.m.r. (DMSO-dg) δ 2.16, dt, 7, 18 Hz, 2H; 2.51, s; 3.53, dd, 6, 18 Hz, 4H; 4.21, t, 7 Hz, 2H; 5.00, t, 6 Hz, 2H; 6.51, s, 2H, br; 8.08, s, IH; 8.56, s, IH. 13c n.m.r. (D2O) δ 34.2, 34.7, 43.7, 100.2, 103.6, 127.5, 142.1, 154.8, 158.2, 160.8.
EXAMPLE 64
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-fluorobut- 1 -yl)-2-amino-6- chloropurine using the method of Example 13. XH n.m.r. (DMSO-dg) δ 2.05, s, 6H; 2.34, m, 2H; 4.52, d, 720 Hz; 6.53, s, 2H, br; 8.13, s, IH; 8.58, s, IH.
EXAMPLE 65
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-fluorobut- l-yl)-2-amino-6- chloropurine using the method of Example 14. AH n.m.r. (DMSO-dg) δ 2.14, s, 6H; 2.34, m, 2H; 4.52, d, 720 Hz; 6.53, s, 2H, br; 8.13, s, IH; 8.58, s, IH.
EXAMPLE 66
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-fluorobut- 1 -yl)-2-amino-6- chloropurine using the method of Example 15. AH n.m.r. (DMSO-dg) δ 2.10, m,
2H; 4.10, m, 2H; 4.15, s, 4H; 5.15, m, 2H; 5.78, s, 2H, br; 6.64, s, 2H, br; 7.79, s, IH.
EXAMPLE 67
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-fluorobut- 1 -yl)-2-amino-6- chloropurine using the method of Example 16. ^H n.m.r. (DMSO-dg) δ 2.17, dt, 8,
18 Hz, 2H; 3.53, dd, 6, 18 Hz, 4H; 4.22, t, 8 Hz, 2H; 5.02, t, 6 Hz, 2H; 6.94, s, 2H, br; 8.17, s, IH.
EXAMPLE 68
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-fluorobut- 1 -yl)-2-aminopurine using the method of Example 24. *H n.m.r. (DMSO-dg) δ 2.00, s 3H; 2.20, m; 3.61, dd, 6, 15 Hz, 2H, 4.16, d, 15 Hz, 2H; 4.22, m, 2H; 5.61, s, 2H, br; 7.78, s,
IH; 8.51, s, IH. 13c n.m.r. (DMSO-d6) δ 20.2, 31.5, d, 21 Hz, 37.1, 61.8, d, 28 Hz, 64.0, d, 25 Hz, 95.0, d, 176 Hz, 127.2, 141.8, 148.6, 152.5, 159.6, 169.7.
EXAMPLE 69
Prepared from 2-amino-9-[3,3-bis(acetoxymethyl)but-l-yl]-6-chloropurine using the method of Example 14. m.p. 212° dec. iH n.m.r. (DMSO-dg) δ 0.80, s, 3H; 1.67, m, 2H; 1.70, s,
EXAMPLE 70
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-hydroxybut- 1 -yl)-2-amino-6- chloropurine using the method of Example 14. m.p. 188° dec. iH n.m.r. (DMSO-
dg) δ 1.85, m, 2H; 3.51, s, 4H; 3.97, s, 3H; 4.13, m, 2H; 6.41, s, 2H, br; 7.84, s, IH.
EXAMPLE 71
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-methoxycarbonylbut- 1 -yl)-2- amino-6-chloropurine using the method of Example 13. m.p. 132-133°. iH n.m.r. (DMSO-dg) δ 2.02, s, 6H; 2.21, m, 2H; 3.53, s, 3H; 4.16, m, 2H; 4.24, s, 4H; 6.51, s, 2H, br; 8.07,- s, IH; 8.58, s, IH. 13c n.m.r. (D2O) δ 24.6, 33.3, 44.6, 56.2, 55.7, 66.0, 127.4, 142.1, 154.8, 158.1, 160.9, 179.8, 180.8.
EXAMPLE 72
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-fluorobut- 1 -yl)-2-aminopurine using the method of Example 24. iH n.m.r. (DMSO-dg) δ 1.81, m, 2H; 2.01, s, 3H; 3.95, s 2H; 4.16, m, 2H; 4.69, m, 2H; 6.48, s, 2H, br; 8.07, s, IH; 8.57, s, IH.
EXAMPLE 73
A second product from Example 72 was eluted and d e solvent removed to give a solid. m.p. 132-134°. iH n.m.r. (DMSO-dg) δ 1.89, m, 2H; 2.02, s, 6H; 3.99, s, 4H; 4.17, m, 2H; 4.95, s, IH, br; 6.47, s, 2H, br; 8.10, s, IH; 8.57, s, IH.
EXAMPLE 74
HoN
Prepared from 9-[4-acetoxy-3,3-bis(acetoxymethyl)but-l-yl]-2-aminopurine using the method of Example 24. m.p. 190-191°. (Found: C, 48.94; H, 6.59; N, 25.82;. Calc. for Cl 1H17N5O3 requires C, 49.43; H, 6.41; N, 26.20;). iH n.m.r. (DMSO- dg) δ 1.76, m, 2H; 3.38, d, 75 Hz, 6H; 4.18, m, 2H; 4.44, t, 75 Hz, 3H; 6.50, s, 2H, br; 8.06, s, IH; 8.57, s, IH. 13c n.m.r. (DMSO-d6) δ 32.6, 45.4, 63.9,
128.7, 144.2, 150.6, 154.7, 162.2.
EXAMPLE 75
9-[4-Hydroxy-3,3-bis(hydroxymethyl)but-l-yl]guanine (1.07 g, 3.8 mmol), 4-dimemylaminopyridine (100 mg, 0.8 mmol) and dimethylformamide (60 ml), were stirred at 0°. Di-t-butyl dicarbonate (3.74 g, 17.1 mmol) was added portionwise to the mixture and stirred at room temperature overnight. The dimethylformamide was removed under reduced pressure. HPLC analysis indicated a mixture of products. A portion of the crude product was purified by reverse phase HPLC, eluting with a non-Unear gradient of 10/90 CH3CN/H2O to 30/70 CH3CN/H2O. The first band was collected and concentrated under reduced pressure to give the product. iH n.m.r. (DMSO-d6) δ 1.42, s, 9H; 1.83, m, 2H; 3.96, s, 2H; 4.04, m, 2H; 5.0, m, 2H; 6.4, br s, 2H; 7.69, s, IH; 10.5 br s, IH.
EXAMPLE 76
The second band collected from Example 75 was concentrated under reduced pressure to give the product. iH n.m.r. (DMSO-d6) δ 1.42, s, 18H; 1.83, m, 2H; 3.96, s, 4H; 4.04, m, 2H; 5.0, m, IH; 6.4, br s, 2H; 7.69, s, IH; 10.5 br s, IH.
EXAMPLE 77
The third band collected from Example 75 was concentrated under reduced pressure to give the product. JH n.m.r. (DMSO-d6) δ 1.42, s, 27H; 1.83, m, 2H; 4.02, s, 6H; 4.04, m, 2H; 6.4, br s, 2H; 7.69, s, IH; 10.5 br s, IH.
EXAMPLE 78
9-[4-Hydroxy-3,3-bis(hydroxymethyl)but-l-yl]guanine (1.00 g, 3.5 mmol), 4-dimethylaminopyridine (100 mg, 0.8 mmol) and dimethylformamide (60 ml), were stirred at 0°. Dimethyl pyrocarbonate (2.27 ml, 21.2 mmol) was added dropwise to the mixture and stirred at room temperature overnight. The dimethylformamide was removed under reduced pressure. The crude product was dissolved in acetic anhydride (20 ml) and stirred at room temperature overnight. The acetic anhydride was removed under reduced pressure. HPLC analysis indicated a mixture of products. A portion of the crude product was purified by reverse phase HPLC, eluting with 20/80 CH3CN/H2O. The first band was collected and concentrated under reduced pressure to give die product. iH n.m.r. (DMSO-dg) δ 1.92, m, 2H; 2.03, s, 6H; 3.72, s, 3H; 4.04, br, 6H; 4.14, s, 2H; 6.4, br s, 2H; 7.72, s, IH; 10.6, br s, IH.
EXAMPLE 79
The second band collected from Example 78 was concentrated under reduced pressure to give the product. iH n.m.r. (DMSO-d6) δ 1.92, m, 2H; 2.03, s, 3H; 3.72, s, 6H; 4.04, br, 4H; 4.14, s, 4H; 6.4, br s, 2H; 7.72, s, IH; 10.6, br s, IH.
EXAMPLE 80
The third band collected from Example 75 was concentrated under reduced pressure to give the product. H n.m.r. (DMSO-d6) δ 1.92, m, 2H; 3.72, s, 9H; 4.04, m, 2H; 4.14, s, 6H; 6.4, br s, 2H; 7.72, s, IH; 10.6, br s, IH.
EXAMPLE 81
To a stirred solution of methyl chloroformate (2.2 ml, 28.5 mmol) in pyridine (10 ml) at 0° was added dropwise 2-(2-benzyloxyethyl)-2-hydroxymethylpropane- 1,3-diol (1.05 g, 4.4 mmol) dissolved in pyridine (2 ml). The mixture was stirred under nitrogen overnight. The mixture was poured onto ice water (100 ml) and extracted with chloroform (3x100 ml). The organics were separated and concentrated under reduced pressure to give a yellow oil. The oil was dissolved in acetic anhydride (10 ml) with 4-dimethylaminopyridine (50 mg, 0.4 mmol) and stirred overnight. The mixture was poured onto water (100 ml) and extracted witii chloroform (3 x 100 ml). The organics were separated and concentrated under reduced pressure to give a yellow oil. Distillation (200°C, lxl0"5 bar) gave a mixture of 2,2-bis(methoxycarbonyloxymethyl)- 4-benzy loxybutan- 1 -ol and 2,2-bis(methoxy carbony loxymethy l)-4-benzyloxybut- 1-yl methoxy methanoate. The distilate was treated as per Example 1 steps G, H and I to give crude product. A portion of the crude product was purified by reverse phase HPLC, eluting with a non-Unear gradient of 10/90 CH3CN/H2O to 30/70 CH3CN/H2O. The first band was coUected and concentrated under reduced
pressure to give the product. iH n.m.r. (DMSO-dg) δ 1.98, m, 2H; 2.02, s, 3H; 3.72, s, 6H; 4.04, s, 2H; 4.14, s, 4H; 4.16, m, 2H; 6.89, br s, 2H; 8.17, s, IH.
EXAMPLE 82
The second band collected from Example 81 was concentrated under reduced pressure to give the product. iH n.m.r. (DMSO-d6) δ 1.98, m, 2H; 3.72, s, 9H; 4.14, s, 6H; 4.16, m, 2H; 6.89, br s, 2H; 8.17, s, IH.
EXAMPLE 83
The crude product from Example 81 was treated as per Example 13 to give crude product. A portion of the crude product was purified by reverse phase HPLC, eluting with a non-linear gradient of 10/90 CH3CN/H2O to 30/70 CH3CN/H2O. The first band was collected and concentrated under reduced pressure to give the product. iH n.m.r. (DMSO-dg) δ 1.98, m, 2H; 2.02, s, 3H; 3.72, s, 6H; 4.04, s, 2H; 4.14, s, 4H; 4.16, m, 2H; 6.46, br s, 2H; 8.09, s, IH; 8.57, s, IH.
EXAMPLE 84
The second band collected from Example 83 was concentrated under reduced pressure to give the product. iH n.m.r. (DMSO-dg) δ 1.98, m, 2H; 3.72, s, 9H; 4.14, s, 6H; 4.16, m, 2H; 6.46, br s, 2H; 8.09, s, IH, 8.57, s, IH.
EXAMPLE 85
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-hydroxybut- 1 -yl)-2-amino-6- chloropurine using the method of Example 13. iH n.m.r. (DMSO-dg) δ 2.03, s, 6H and NCH2CH22H overlapping; 3.97, dd, 11Hz, 4H; 4.21, m, 2H; 5.34, s, IH; 6.50, s, 2H, br; 8.09, s, IH; 8.57, s, IH.
EXAMPLE 86
Isolated as a bi-product from Reaction 1 step I. CrystalUsed from methanol as a white crystalUne sold. JH n.m.r. (DMSO-dg) δ 1.92, m, 2H; 2.03, s, 6H; 2.07, s, 3H, 3.62, s, 2H; 4.00, s, 4H; 4.16, m, 2H; 5.22, s, 2H; 6.89, s, br, 2H; 8.17, s, IH.
EXAMPLE 87
Prepared from Example 86 as per method described for Example 13. The product was crystalUsed from methanol as a white crystalUne soUd. iH n.m.r. (DMSO-dg) δ 1.93, m, 2H; 2.03, s, 6H; 2.07, s, 3H; 3.63, s, 2H; 4.01, s, 4H; 4.16, m, 2H; 5.23, s, 2H; 6.47, s, br, 2H; 8.09, s, IH; 8.58, s, IH.
EXAMPLE 88
Prepared from 9-(4-acetoxy-3-acetoxymethyl-3-methoxycarbonylbut- 1 -yl)-2-
aminopurine using the method of Example 24. m.p. 121-123°. iH n.m.r. (DMSO- dg) δ 2.02, t, 77 Hz, 2H; 3.40, s, 2H; 3.61, t, 5 Hz, 4H; 4.11, t, 77 Hz, 2H; 4.85, t,
5 Hz, 2H; 6.49, s, 2H, br; 8.01, s, IH; 8.56, s, IH.
EXAMPLE 89
Prepared from 2-amino-9-[3,3-bis(acetoxymethyl)but-l-yl]-6-chloropurine using the method of Example 13. m.p. 125-9° dec. JH n.m.r. (DMSO-dg) δ 1.00, s, 3H;
1.85, m, 2H; 2.01, s, 6H; 3.90, s, 4H; 4.11, m, 2H; 6.46, s, 2H, br; 8.09, s, IH; 8.55, s, IH.
EXAMPLE 90
Prepared using the method of Example 14, with ethanol. Yield 400 mg ( 55%). iH n.m.r. ( DMSO-d6) δ 1.35, t, 3H; 1.72, m, 2H; 3.35, s, 6H; 4.12, m, 2H; 4.45, s, 3H; 4.47, q, 2H; 6.38, s, 2H; 7.85, s, IH.
EXAMPLE 91
Prepared using die metiiod of Example 14, with benzyl alcohol. Yield 640 mg (73%). iH n.m.r. (DMSO-dg) δ 1.72, m, 2H; 3.38, s, 6H; 4.12, m, 2H; 4.45, s, 3H; 5.50, s, 2H; 6.45, s, 2H; 7.30-7.55, m, 5H; 7.88, s, IH.
EXAMPLE 92
Prepared using the method of Example 32, Step A, with cyclohexane carboxylic acid. Yield 150 mg ( 11%). iH n.m.r. (DMSO-dg) δ 1.15-1.88, m, 12H; 2.20 to 2.35, m, IH; 3.35, s, 4H; 3.91, s, 2H; 4.05, m, 2H; 4.63, s, 2H; 6,40, s, 2H; 7.67, s, IH.
EXAMPLE 93
A second product from Example 92 was eluted, and the solvent removed to give a solid. iH n.m.r. (DMSO-d6) δ 1.12-1.90, m, 24H; 2.30, m, 2H; 3.41, d, 2H; 3.95, s, 4H; 4.05, m, 2H; 4.90, t, IH; 6.40, s, 2H; 7.70, s, IH; 10.58, s, IH.
EXAMPLE 94
Prepared using the method of Example 32, Step A, with heptanoic acid. iH n.m.r. (DMSO-dg) δ 0.87, t, 3H; 1.22, m, 6H; 1.51, m, 2H; 1.77, m, 2H; 2.30, t, 2H; 3.38, d, 4H; 3.95, s, 2H; 4.05, m, 2H; 4.41 and 4.65 (ratio 1:4), 2t, 2H; 6.43, s, 2H; 7.68, s, IH; 10.57, s, IH.
EXAMPLE 95
H2N
A second product from Example 94 was eluted, and the solvent removed to give a soUd. iH n.m.r. (DMSO-d6) δ 0.85, t, 6H; 1.22, s, 12H; 1.50, m, 4H; 1.82, m, 2H; 2.29, t, 4H; 3.40, d, 2H; 3.97, s, 4H; 4.05, m, 2H; 4.93, t, IH; 6.47, s, 2H; 7.69, s, IH; 10.61, s, IH.
EXAMPLE 96
A third product from Example 94 was eluted, and the solvent removed to give a soUd. iH n.m.r. (DMSO-d6) δ 0.87, t, 9H; 1.22, s, 18H; 1.51, m, 6H; 1.92, m, 2H; 2.31, t, 6H; 4.02, s, 6H; 4.05, m, 2H; 6.41, s, 2H; 7.70, s, IH; 10.59, s, IH.
EXAMPLE 97
Prepared using the method of Example 19, with isobutyric anhydride. Yield 780 mg (31%). iH n.m-r. (DMSO-d6) δ 1.10, d, 6H; 1.77, m, 2H; 2.52, m, IH; 3.40, d, 4H; 3.92, s, 2H; 4.07, m, 2H; 4.42 and 4.67(ratio 1:3), 2t, 2H; 6.41, s, 2H; 7.69, s, IH; 10.58, s, IH.
EXAMPLE 98
A second product from Example 97 was eluted and die solvent removed to give a soUd. Yield 710 mg (24%). iH n.m.r. (DMSO-d6) δ 1.11, d, 12H; 1.87, m, 2H;
2.55, m, 2H; 3.42, s, 2H; 3.95, s, 4H; 4.05, m, 2H; 4.92, s, br, IH; 6.40, s, 2H; 7.71, s, IH; 10.61, s, IH.
EXAMPLE 99
Prepared using the method of Example 32, Step A, with isovaleric acid. Yield 805 mg (31%). iH n.m.r. (DMSO-d6) δ 0.91, d, 6H; 1.78, m, 2H; 2.00, m, IH; 2.20, d,
2H; 3.39, d, 4H; 3.95, s, 2H; 4.05, m, 2H; 4.67, t, 2H; 6.42, s, 2H; 7.69, s, IH; 10.57, s, IH.
EXAMPLE 100
A second product from Example 99 was eluted, and the solvent removed to give a soUd. Yield 513 mg (16%). iH n.m.r. (DMSO-dg) δ 0.91, d, 12H; 1.87, m, 2H;
1.97, m, 2H; 2.20, d, 4H; 3.42, s, 2H; 3.98, s, 4H; 4.06, m, 2H; 4.91, s, br, IH;
6.45, s, 2H; 7.70, s, IH; 10.63, s, IH.
EXAMPLE 101
A third product from Example 99 was eluted, and the solvent removed to give a solid. Yield 427 mg (11%). iH n.m.r. (DMSO-dg) δ 0.91, d, 18H; 1.71, m, 2H;
1.96, m, 3H; 2.21, d, 6H; 4.02, s, 6H; 4.05, m, 2H; 6.39, s, 2H; 7.71, s, IH; 10.59, s, IH.
EXAMPLE 102
Prepared using the method of Example 18. Yield 360 mg (73%). iH n.m-r. (DMSO-dg) δ 0.89, d, 6H; 1.91, m, 3H; 2.03, s, 6H; 2.20, d, 2H; 4.01, s, 6H; 4.05, m, 2H; 6.41, s, 2H; 7.72, s, IH; 10.61, s, IH.
EXAMPLE 103
9-[4-Acetoxy-3,3-bis(acetoxymethyl)but-l-yl]-2-amino-6-chloropurine (2.02 g, 4.72 mmol) was dissolved in a 7:3 solution of ethanokdichloromethane (60 ml). 40% Ethoxylamine in water (2.85 mis, 4 eq. 18.8 mmol) was added and the reaction mixture was heated to 45° for four days in a glass pressure sealed reaction
vessel. Solvent was removed by rotary evaporation. The crude product was preadsorbed onto silica and flash chromatographed, eluting with 10% metiianol in dichloromethane. Fractions containing product were combined and the solvent removed by rotary evaporation. Yield 600 mg (28%). H n.m.r. (DMSO-d6) δ 1.25, t, 3H; 1.88, m, 2H; 2.03, s, 9H; 3.99, m, 4H; 4.02, s, 6H; 5.97 and 6.49(ratio 1:7), 2s, 2H; 7.51 and 7.80(ratio 1:7), 2s, IH; 9.64 and 10.22(ratio 1 :7), 2s, IH.
EXAMPLE 104
9-[4-Hydroxy-3,3-bis(hydroxymethyl)but-l-yl]guanine (1.0 g, 3.53 mmol), 4- dimethylaminopyridine (0.1 g) and acetic anhydride (60 ml) were stirred at 45° for 23 hours.The acetic anhydride was removed in vacuo at 60°.The crude residue was preadsorbed onto siUca and flash chromatographed eluting with methanol. Fractions containing the pure compound were combined and evaporated to give a soUd. The soUd was recrystalUzed from methanol.Yield 0.475 g (30%). m.p. 202-
205°. iH n.m.r. (DMSO-d6) δ 1.90-2.0, m, 2H; 2.05, s, 9H; 2.2, s, 3H; 4.05, s, 6H; 4.25-4.10, m, 2H; 8.05, s, IH; 11.7, s, lH,br; 12.0, s, IH, br.
EXAMPLE 105
A mixture of l,l-carbonyldimidazole(3.3 eq, 1.89 g, 11.6 mmol), 2-furoic acid(3.0 eq, 1.19 g, 10.6 mmol) and dry dimemylformamide (60 ml) were stirred at room temperature, under an atmosphere of nitrogen for 90 minutes. 9-[4-Hydroxy-3,3- bis(hydroxymethyl)but-l-yl]guanine (1.0 g, 3.53 mmol), was added in one portion to die mixture and stirred for a further 24 hours. The solvent was removed under reduced pressure. The crude product was preadsorbed onto siUca and chromatographed, eluting with 10:90:0.2 methanol:dichloro-methane:acetic acid. The product was eluted and die solvent removed to give a white solid. The soUd was recrystalUzed from methanol /acetone.Yield 0.543 g (27%).m.p. 259-261°. iH n.m.r. (DMSO-d6) δ 2.2, m, 2H; 4.2, m, 2H; 4.4, s, 6H; 6.3, s, 2H; 6.65, s, 3H; 7.35, s, 3H; 7.7, s, IH; 7.95, s, 3H; 10.55, s, IH.
EXAMPLE 106
9-[4-Acetoxy-3,3-bis(acetoxymethyl)but-l-yl]guanine(0.5 g, 1.22 mmol),4- dimethylaminopyridine(0.5 g), n-caprylic anhydride(3 ml, 9.2 mmol) and dry dimethylformamide(l ml) were combined under nitrogen and stirred overnight at 70°C. The solvents were removed under reduced pressure at 95°C. The crude residue was preabsorbed onto silica and flash chromatographed eluting with 2:98:0.2 methanol:chloroform:acetic acid. Fractions containing the pure compound were combined, evaporated and recrystalUzed from ethyl acetate/petroleum spirit to give a white soUd. Yield 0.470 g (73%).m.p.l02-105°. iH n.m.r. (DMSO-dg) δ 0.8-0.9, m, 3H; 1.25, s, 10H, br; 1.45-1.65, m, 2H; 2.0, s, 11H; 3.35, s, IH; 4.0, s, 6H; 4.15, m, 2H; 8.05, s, IH.
EXAMPLE 107
Isolated from Example 1 Step I as a minor by-product. iH n.m.r. (DMSO-d6) δ 1.85-2.0, m, 2H; 2.05, s, 6H; 3.25, s, 3H; 3.35, s, 2H; 4.05, s, 4H; 4.1-4.25, m, 2H; 6.9, s, 2H; 8.2, s, IH.
EXAMPLE 108
A mixture of 9-[4-acetoxy-3-acetoxymethyl-3-methoxymethylbut-l-yl)-2-amino- 6-chloropurine (0.280 g, 0.62 mmol), 10% palladium on carbon (0.1 g), triethylamine (l.leq, 0.078 g, 0.6 ml) and ethanol (20 ml) were placed in a 100 ml flask,under an atmosphere of hydrogen. The mixture was stirred vigorously at room temperature for 2.5 hours. The mixture was filtered through glass fibre
paper. The solution was evaporated and recrystalUzed from methanol to produce a white solid. Yield 0.08 g ( 31.6%). m.p. 136-138°.lH n.m.r. (DMSO-dg) δ 2.0- 1.85, m, 2H; 2.05, s, 6H; 3.25, s, 3H; 3.35, s, 2H; 4.0, s, 4H; 4.05-4.25, m, 2H; 6.5, s, 2H; 8.1, s, IH; 8.6, s, IH.
EXAMPLE 109
Prepared from 9-[4-hydroxy-3,3-bis(hydroxymethyl)but-l-yl]guanine using the method of Step A, Example 37. H n.m.r., (DMSO-d6) δ 1.73, m, 2H; 1.83, s, 3H; 2.93, m, 2H; 3.87-4.17, complex, 4H; 4.57 m, IH; 4.87, s, br, 2H; 6.50 s, br, 2H; 6.87, s, br, IH; 7.53, s, IH; 7.67, s, IH; 8.20, d, IH, J 5.3 Hz; 10.60, s, br, IH.
EXAMPLE 110 ANTI-HEPATITIS TESTING
1. Duck
(a) Experimental Animals, Virus and Cell Culture
One day old Pekin-Aylesbury cross-bred ducks congenitally infected witii an AustraUan strain of DHB V (CJ.Freiman and Y.E. Cossart, AustraUan Journal of Experimental Biology and Medical Science 64477-484 (1986)) were obtained
from a commercial supplier. Ten to fourteen day old ducks were used to obtain primary duck hepatocyte(PDH) cultures. Sera from these animals were tested for DHBV DNA by the dot blot hybridization method (W.S. Mason, M.S. Halpern, J.M. England, G. Seal, J. Egan, L. Coates, C. Aldrich, and J. Summers, Virology 131 373-384 (1983)) and duckUngs with an intermediate virus litre [5-10xl08 viral genome equivalents per ml] were selected for the preparation of congenitally infected primary duck hepatocyte (PDH) cultures. The genome of this strain of DHBV has been molecularly cloned. Hepatocytes were obtained by a modification of the method described by J.S. Tuttleman, J.C. Pugh, and J.Summers Journal of Virology 5B17-25 (1986). Ducks were anaesthetized witii ketamine (Parke-Davis, USA) at 30 mg per kg, the liver was surgically removed and perfused with 200 ml of pre-warmed (37°C) Hanks balanced salt solution (calcium and magnesium free) containing 0.5 mM EGTA followed by 200 ml of pre- warmed serum-free Eagle's Essential Medium (MEM) supplemented with 100 mg collagenase type 1 (Boehringer Mannheim, West Germany) and 2.5 mM CzCl. (Ajax Chemicals, AustraUa). A single cell suspension was prepared in MEM by gently extruding the perfused liver through a fine wire-gauze mesh. Hepatocytes were purified from the cell mass using Percoll density gradients (Pharmacia, Sweden) following a modification of the manufacturer's specifications. The gradient medium stock solution (SIP; stock isotonic Percoll) consisted of nine parts Percoll mixed witii one part 1.5 M NaCl solution. Percoll of the required density of 1.05 g/ml was then generated by diluting six parts SIP with four parts MEM at a final pH of 7.4. Five ml of hepatocyte ceU suspension was layered onto 30 ml of this solution and centrifuged at 20,000 rpm for 20 min at 20°C in a JA-20 fixed angle rotor (Beckman, USA). The bands of cells corresponding to die density of hepatocytes (1.07 - 1.09 g/cm3) were collected and washed in L 15 medium (CSL, AustraUa) supplemented with 5% fetal bovine serum (FBS) and
counted in a haemocytometer. Cell viability was established using trypan blue dye exclusion.
Hepatocytes were diluted and subsequently seeded with L 15 complete (L 15) which consisted of L 15 media supplemented with 15 mM Tris, insuUn, glucose, hydrocortisone hemisuccinate, penicillin and streptomycin according to Tuttleman et al, supra and 5% FBS was also included. Hepatocytes were seeded at approximately 2.0 x 106 cells per well into 6 well multiplates (Greiner, West Germany) or at approximately 0.5 x 106 cells per well into 24 well plates (Costar, Cambridge Mass.). Hepatocytes were allowed to attach overnight before the first medium change (on day 1 post plating) and were maintained with L 15 complete media, at 37°C in a 5% C02 humidified incubator, for a total of 10 days The culture medium in both control and treated cultures (see below) was changed every second day. (b) Preparation of DHBV from Cell Cultures
Total intracellular viral DNA was extracted from cell lysates by a modification of the method of Tuttleman et al, supra. Cells were lysed in a solution containing 0.5% sodium dodecyl sulphate (SDS), 20 mM Tris-HCl (pH 7.4), 10 mM EDTA, 5 mM EGTA, and 150 mM NaCl. DNA was extracted from all samples by digestion with 200 ug per ml of proteinase K (International Biosciences Incorporated, USA) at 37°C for 1 hour, and deproteinised by extraction with an equal volume of phenoUchloroform (1:1), followed by chloroform. The aqueous phase was collected and adjusted to 0.2 M NaCl and the nucleic acids precipitated with 2 volumes of absolute ethanol at -20°C overnight. The pellets were washed in 70% ethanol and then air dried and finally redispersed in TE buffer (10 mM Tris-HCl (pH 8), 1 mM EDTA).
(c) Preparation of radiolabelled DHBV DNA probes
A full length clone of the Australian strain of DHBV was propagated in E. coli and the plasmid extracted using standard techniques (J. Sambrook, E. F. Fritsch and T. Maniatis "Molecular Cloning: A Laboratory Manual" Second Edition Cold Spring Harbour Laboratory Press 1989). The cloned DHBV DNA sequences were excised from the plasmid by EcoRI digestion and were separated by preparative gel electrophoresis using a Prep-A-Gene DNA purification kit (Bio- Rad, Hercules Calif.) according to the manufacturer's recommendations. A 648 bp DNA fragment was also prepared by further digesting the EcoRI DHBV and purifying the smaller fragment as described above. Excised, purified DHBV DNA was radiolabelled with [α-32P] dCTP using a NEN Random Primer Plus Extension kit (NEN Research Products, DuPont, Wilmington, USA) to a specific activity of 0.5-1.0 x l09 cρm/mg.
(d) Analysis of DHBV DNA from Hepatocyte Cultures
DHBV DNA in cell culture was detected by slot-blot hybridization. Extracted DNA dissolved in TE buffer was diluted in 6x saUne sodium citrate (SSC) lxSSC is 0.15M NaCl + 0.15M sodium citrate, pH7.0), denatured by rapid boiUng and quenching then serially diluted in 6xSSC. A commercial slot-blot apparatus was used to apply the DNA samples to nitrocellulose hybridisation membranes (Hybond C extra, Amersham International, England). DNA was baked onto membranes at 80°C for 2 hours before pre-hybridisation in a buffer consisting of 50% deionised formamide, 6xSSC, 5mM NaH2P04 (pH 6.5), 2 x Denhardt solution and 100 mg/ml of herring sperm DNA (Boeringer Manheim, Germany). After pre-hybridisation at 42°C for at least 3 hours in a hybridization oven (Hybaid, England) heat-denatured radio-labelled DHBV DNA probe was added to a concentration of at least 2xl06cpm and hybridisation allowed to proceed overnight at 42°C. After hybridisation, membranes were washed twice in 2 x SSC-0.1% SDS at 24°C and twice in 0.1 x SSC/0.1% SDS for 30 min at 50°C to
remove unbound probe. Radiolabelled DHBV probe bound to die air-dried filters was detected with the aid of intensifying screens by autoradiography at -70°C onto
X-OMAT RP film, (Eastman Kodak Co., USA).
(e) Preparation of test compounds
Where possible, stock solutions of test compounds were prepared in sterile deionised distilled water. For compounds witii poor aqueous solubility stock solutions were prepared in ceU culture grade dimethylsulphoxide (DMSO). Immediately before each test, dilutions of test compound stock solutions were prepared in deionised distilled water or DMSO at lOOx the final test concentration. These dilutions were then added to complete cell culture medium at the rate of 10ml per ml (a dilution of 1 in 100), so that the final concentration of distilled water or DMSO added in every case was constant at 1%, a concentration at which neither DMSO nor distiUed water had any effect on virus replication. For tests of antiviral activity, media containing a range of dilutions of test compound were tested against appropriate controls. Negative controls were drug-free media containing only 1% distilled water or DMSO ; positive controls were compounds previously tested and found to have reproducible anti-DHBV activity in this test system.
(f) Assay of viral repUcation
Following incubation total cellular DNA was extracted as described above (b), and the amount of DHBV DNA detected by slot-blot hybridization and autoradiography as in (d) above.
Areas of hybridization membranes corresponding to each sample were located by aUgnment with the autoradiographs, cut out and counted for 32P in a gamma radiation counter.
DHBV DNA standards were used to estabUsh both the detection Umit, and prove that the relationship between the 32P count and die amount of bound DHBV was linear over the range of interest.
The extent of viral repUcation (measured as cpm bound 32P bound DHBV probe detected) in the presence of test compounds is expressed as a percentage of viral repUcation in the control cultures. The effective concentration for 50% inhibition of repUcation is shown in Table 1.
TABLE 1 : DUCK HEPATITIS B ACTIVITY
Compoundof EC50 (μM) ExampleNo.
1 70
2 2
3 9
5 700
6 10
7 5
12 5
13 5
14 30
15 100
16 6
17 90
18 10
24 5
27 <5
28 6
32 <50
33 <100
50 3
51 25
53 <50
54 <50
61 7
63 200
64 8
65 10
66 20
67 70
68 10
69 20
70 600
72 3
73 10
74 3
Human
Tests of antiviral activity in human cells infected witii Hepatitis B were performed according to the method of Korba and Gerin reported in Antiviral Research, 19, 55-70 (1992) and the results are shown in Table 2. .
TABLE 2 : HUMAN HEPATITIS B ACTIVITY
Compound of EC50 (μM) EC90 (μM) Example No
2 1.0 5.8
6 1.5 11
62 0.6 4.7
74 0.16 1.1
EXAMPLE : 111 Tablet Formulations
The following formulation A may be prepared by wet granulation of the ingredients with a solution of povidone, followed by addition of magnesium stearate and compression.
Formulation A mg/tablet
(a) Active ingredient 250 250
(b) Lactose B.P. 210 26
(c) Povidone B.P. 15 9
(d) Sodium starch glycollate 20 12
(e) Magnesium stearate _5 _3
500 300
The following formulation B, may be prepared by direct compression of the admixed ingredients.
Formulation B mg/capsule or tablet Active ingredient 250 Pregelatinised starch NF15 150
400
Formulation C (Controlled release formulation)
This formulation may be prepared by wet granulation of the ingredients (below) with a solution of povidone followed by the addition of magnesium stearate and compression.
mg/tablet
(a) Active ingredient 500
(b) Hydroxypropylmethylcellulose 112
(methocel K4M Premium)
(c) Lactose B.P. •53
(d) Povidone B.P.C. 28
(e) Magnesium stearate _7
700
EXAMPLE : 112 Capsule Formulations
Formulation A
A capsule formulation may be prepared by admixing the ingredients of Formulation B in Example 4 above and filUng into a two-part hard gelatin capsule. Formulation B (infra) may be prepared in a similar manner.
Formulation B mg/capsule
(a) Active ingredient 250
(b) Lactose B.P. 143
(c) Sodium starch glycoUate 25
(d) Magnesium stearate _2 420
Formulation C (Controlled release capsule)
The following controlled release capsule formulation may be prepared by extruding ingredients a, b and c using an extruder,
followed by spheronisation of the extrudate and drying. The dried pellets may then be coated witii release-controlUng membrane (d) and filled into a two-piece, hard gelatin capsule.
mg/capsule
(a) Active ingredient 250
(b) MicrocrystalUne cellulose 125
(c) Lactose B.P. 125
(d) Ethyl cellulose 13
513
EXAMPLE : 113 Injectable Formulation
Formulation:
Active ingredient 0.200 g
Hydrochloric acid solution, 0.1M qs to pH 5.0-7.0
Sodium hydroxide solution, 0.1M qs to pH 5.0-7.0
Sterile water qs to 10 ml
The active ingredient may be dissolved in most of the water at 35-40C. and the pH adjusted to between 5.0 and 7.0 with the hydrochloric acid or the sodium hydroxide as appropriate. The batch may then be made up to volume with the water and filtered through a sterile micropore filter into a sterile 10 ml amber glass vial (type 1) and sealed with sterile closures and overseals.
EXAMPLE 114
The tendency for many of the compounds of Formula (1) or (la) to act as pro-drugs of other compounds of Formula (1) or (la) is demonstrated in the
following example where various compounds of Formula (la) where Rfi is the
group -CH^OR are orally absorbed and converted to the compound of Formula
(2), 9-[4-hydroxy-3,3-bis(hydroxymethyl)but-l-yl]guanine, in rats. This example
is merely demonstrative of the ability of some compounds of Formula (la) to act as pro-drugs and is not intended in any way to limit the scope of the invention or
the scope of the nature of the groups R, , R2, Rg, R4' or R5' that may be present in
pro-drugs. Those skilled in the art will appreciate that other compounds of
Formula (la) where one or more of R« , R2, Rg, R/ or R ' are different from the
exact examples shown may also act as pro-drugs of other compounds of Formula (la).
PROCEDURE
Compounds of Formula (la) were administered (50 mg/kg) by oral gavage (50 mg/ml of water) to groups of three Sprague-Dawley rats. The rats were housed separately in metabolic cages and urine was collected from each animal at 6 and 24 hours after treatment. The volume of urine was measured and recorded and aliquots taken. The aliquots were clarified by centrifugation and die supernatant transferred to a fresh tube and stored at -20°C until analysed.
Samples for analysis were allowed to warm to ~4°C, 100 μl was withdrawn and diluted to 10 ml with aqueous 40 mM ammonium acetate solution, pH 6.5. The diluted samples were filtered tiirough 0.2 μm membrane filters and analysed by high performance liquid chromatography.
In Table 3 below, the total number of moles of 9-[4-hydroxy-3,3- bis(hydroxymethyl)but-l-yl] guanine recovered in the urine is expressed as a percentage of the number of moles of compound administered.
TABLE 3 : RAT METABOLIC STUDIES
Total proportion (%) of 9-[4-hydroxy-3,3- bis(hydroxymethyl)but- 1 -yl]guanine
Example No recovered at stated times after administration
(averaged results )
6 hours 24 hours
2 1.2 1.2
12 1.8 9.4
13 9.6 9.6
18 2.9 12.5
29 7.2 8.9
32 4.6 18.4
35 4.3 10.4
45 0.0 3.4
46 2.1 8.0
55 2.0 5.2
92 0.7 5.0
94 2.0 -
98 0.9 5.9
104 0.9 -
Claims
1. A method for the treatment and/or prophylaxis of a Hepadnaviridae associated infection which comprises administration of an effective amount of a compound of Formula (1):
(1) wherein Rj is hydrogen, halogen, hydroxy, azide, optionaUy substituted alkyl, optionally substituted alkoxy, optionaUy substimted aryloxy, mercapto, optionally substituted alkylthio, optionaUy substimted amino, optionaUy substituted hydrazino or optionally substituted hydroxylamino; R2 is hydrogen, halogen, hydroxy, azide, optionaUy substimted alkoxy, optionally substimted aryloxy, mercapto, optionaUy substituted alkylthio or optionally substituted amino;
R3 and R3' are me same or different and selected from hydrogen, optionally substituted alkyl, halogen, hydroxy, azide, optionally substituted alkoxy, optionaUy substimted aryloxy, mercapto, optionally substituted thio and optionaUy substituted amino; or R3 and R3' together form =0, =S, =NOH or =NOR, wherein R is optionaUy substituted alkyl; and
R4, R5 and Rg are the same or different and selected from optionally substituted alkyl, optionaUy substimted aralkyl, halogen, hydroxy, azide, optionally substituted alkoxy, optionaUy substituted aryloxy, mercapto, optionally substimted alkylthio, optionaUy substituted amino, optionally substituted acyl, optionally substituted ester, cyano, carboxy and mono-, di- or tri- phosphate; two of R4, R5 and Rg are joined together to form a cycUc group; or R4, R5 and Rg are joined togetiier to form a cycUc ortho ester group, salts thereof, pharmaceuticaUy acceptable derivatives thereof, pro-drugs thereof, tautomers thereof and/or isomers thereof to a subject requiring said treatment and/or prophylaxis.
2. A method according to Claim 1, wherein R4, R5 and/or Rg are optionally substituted alkyl or optionally substituted alkoxy.
3. A method according to Claim 1 or Claim 2, wherein R4, R5 and/or Rg are alkyl substituted with hydroxy.
4. A method according to any one of the preceding claims wherein the compound of Formula (1) has the Formula (la):
(la) wherein Rj, R2 and Rg are as defined in Claim 1; and R4'and R5'are d e same or different and selected from hydrogen, optionally substimted alkyl, optionally substimted aralkyl, optionally substimted aminoacyl, optionally substituted acyl, optionaUy substituted ester and mono-, di- or tri- phosphate, provided tiiat when one of R4', R5' or Rg is or contains mono-, di- or tri- phosphate then the remaining groups are other than phosphate; two of R4', R5' and
Rg are joined togetiier to form a cycUc acetal group, a cycUc carbonate group or a cycUc phosphate group; or R4', R5' and Rg are joined togetiier to form a cycUc ortho ester group.
5. A method according to any one of the preceding claims, wherein Rj is hydrogen, halogen, hydroxy, optionally substimted alkoxy, optionally substimted hydroxylamino or optionally substimted hydrazino.
6. A method according to any one of the preceding claims, wherein R2 is -NR Rg, wherein R7 is hydrogen, optionally substimted alkyl, optionaUy substituted aminoacyl or optionaUy substituted acyl and Rg is hydrogen or alkyl.
7. A method according to any one of the preceding claims, wherein Rg is -alkylORg', fluorine, -ORg' or methyl and Rg' is hydrogen, optionally substimted alkyl, optionally substituted acyl or mono-, di- or tri-phosphate.
8. A method according to Claim 6 or Claim 7 wherein R4', R5', Rg'
and/or R7 groups are those selected from hydrogen, aminoacyl, R9-C (O)- and R9- C (S)-, wherein Rg is hydrogen, optionally substituted alkyl, optionally
substituted alkoxy, optionaUy substituted aryl, optionaUy substituted aralkyl,
optionally substituted heterocyclyl or -NR, QR. , , wherein Rχo and Rj j are the same
or different and are selected from hydrogen and alkyl or together with the nitrogen to which they are attached form a 3-7 membered heterocycUc ring.
9. A method according to any one of the preceding claims, wherein one of R4 or R4', R5 or R5' and/or Rgor Rg' form
R1 2 O
R1 3 O p o
wherein R 2 and Rχ3 are the same or different and selected from hydrogen, alkyl, aryl, aralkyl and a pharmaceutically acceptable cation.
10. A method according to any one of die preceding claims wherein two of R4 or R4', R5 or R5' and/or Rg or Rg' are joined together to form
CRuR -s • :C=0 or ^P(0)OR 12
wherein Rχ2 is as defined above in Claim 9 and Rχ and R 5 are the same or different and are selected from hydrogen and Cχ.g alkyl.
11. A method according to any one of Claims 4 to 8, wherein R4', R5' and Rg or Rg' are joined together to form
Rχ4 is as defined in Claim 10.
12. A method according to Claim 4, wherein Rj is hydrogen, halogen, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, amino, benzyloxy, hydroxylamino or
hydrazino; R2 is amino or acylamino; Rg is CH2-ORg'or G2H4OR ; R4', R5' and
Rg' are the same or different and are selected from hydrogen, optionally substimted alkyl, optionally substimted aralkyl, optionally substimted ester, optionaUy substimted aminoacyl and optionaUy substimted acyl; or two of R4', R5' and Rg' are joined together to form a cycUc acetal group or a cycUc carbonate group.
13. A method according to Claim 12 wherein Rj is hydrogen, hydroxy or alkoxy.
14. A method according to any one of Claims 1 to 8, 12 or 13 wherein the compound of Formula (1) or (la) has the Formula (2):
15. A method according to any one of Claims 1 to 13 wherein d e compound of Formula (1) or (la) is:
9-(4-hydroxy-3-hydroxymemyl-3-isopropoxymethylbut- 1 - yl)guanine;
9-[4-acetoxy-3,3-bis(acetoxymethyl)but-l-yl]-2-aminopurine;
9-[4-acetoxy-3,3-bis(acetoxymethyl)but-l-yl]guanine;
2-amino-9-[4-(4' -phenoxy)phenylcarbonyl-3,3-bis(hydroxymethyl)but- 1 - yl]purine;
9-[4-L-valyloxy-3,3-bis(L-valyloxymethyl)but-l-yl]guanine;
9-[4-acetoxy-3,3-bis(L-valyloxymethyl)but-l-yl]guanine;
9-[4-hydroxy-3-(hydroxymethyl)-3-(N-benzyloxycarbonyl-L- proly loxy methy l)but- 1 -y 1] guanine;
9-[4-hydroxy-3-(hydroxymethyl)-3-(L-phenylalanyloxymethyl)but- 1 - yl]guanine, acetate salt;
9-[4-(iιnidazol-l-yl)-3,3-bis(hydroxymethyl)but-l-yl]guanine;
9-[4-cyclohexylcarbonyloxy-3,3-bis(hydroxymethyl)but-l-yl]guanine;
9-[4-hexylcarbonyloxy-3,3-bis(hydroxymethyl)but-l-yl]guanine; 9-[3,3-bis(isopropylcarbonyloxy)-4-hydroxybut-l-yl]guanine; or
9-[4-acetoxy-3,3-bis(acetoxymethyl)but-l-yl]-2-acetylamino-6- hydroxypurine.
16. A method according to any one of die preceding claims, wherein the Hepadnaviridae associated infection is Hepatitis B.
17. A method according to any one of die preceding claims, wherein the compound of Formula (1), (la) or (2) is administered in the form of two or more sub-doses per day.
18. A method according to Claim 15, wherein die sub-doses are administered in unit dosage forms.
19. Use of a compound of Formula (1), (la) or (2) as defined in any one of Claims 1 to 15 in the manufacture of a medicament for the treatment and/or prophylaxis of a Hepadnaviridae associated infection.
20. A compound of Formula (1), (la) or (2) as defined in any one of Claims 1 to 15 for use in the treatment and/or prophylaxis of a Hepadnaviridae associated infection.
21. A pharmaceutical or veterinary composition for the treatment and/or prophylaxis of a Hepadnaviridae associated infection which comprises a compound of Formula (1), (la) or (2) as defined in any one of Claims 1 to 15 in association witii a pharmaceuticaUy or veterinarily acceptable carrier, diluent, adjuvant and/or excipient.
22. A compound of Formula (1) as defined in any one of Claims 1 to 4, with the provisos that:
(a) when
Rj is benzyloxy;
R2 is amino; and and R4 and R5 together form 2,2-dimethyl-l,3-dioxane, then Rg is other than fluoro, methoxy or hydroxy;
(b) when
Rj is hydroxy;
R2 is amino; and
R4 and R5 are hydroxymethyl, then Rg is otiier than fluoro, hydroxy, methoxy, methyl or hydroxymethyl;
(c) when
Rj is hydroxy;
R2 is amino; and
R4 and R5 together form
(d) when
Rj is chloro;
R2 is amino; and
R4 and R5 togetiier form 2,2-dimethyl-l,3-dioxane, tiien Rg is otiier than methyl or hydroxymethyl.
23. A compound of Formula (la) as defined in any one of Claims 4 to 13 with the provisos that: (a) when
Rj is benzyloxy;
R2 is amino; and
R4' and R5' together form
•CRi R15
wherein Rχ2 and Rχ3 are methyl, then Rg is otiier tiian fluoro, methoxy or hydroxy;
(b) when
Rj is hydroxy;
R2 is amino; and
R4' andR5' are hydrogen, then Rg is other than fluoro, hydroxy, methoxy, methyl or hydroxymethyl;
(c) when
Rj is hydroxy;
R2 is amino; and
R4' and R5' together form
Rj is chloro;
R2 is amino; and
R4' and R5' togetiier form
R-i 4 R15
wherein R 2 and Rχ3 are methyl, then Rg is other than methyl or hydroxymethyl.
24. A compound of Formula (2) as defined in Claim 14 with the provisos as defined in Claim 23.
25. A compound as defined in Claim 15.
26. A process for the preparation of the compound of Formula (la) as defined in Claim 23 or Formula (2) as defined in Claim 24 which comprises the steps of:
(a) reacting a compound of Formula (3):
(3) wherein Rj and R2 are as defined in Claim 23 with a compound of Formula (4):
(4) wherein Ra and R^ may be the same or different and are selected from R4' and Rζ'as defined in Claim 23, hydrogen and benzoyl;
Rc is the same as Rg as defined in Claim 23, hydroxy, hydroxyaUcyl or protected derivatives thereof; and
Z is a leaving group, to form a compound of Formula (6):
wherein
Rj, R2, Ra, R , and R are as defined above; and
(b) if necessary, converting the compound of Formula (6) to a compound of Formula (la) or (2).
27. A method for the treatment and/or prophylaxis of a Hepadnaviridae associated infection which comprises administration of an effective amount of a compound as defined in any one of Claims 22 to 25 to a subject requiring said treatment and/or prophylaxis.
28. A method according to Claim 27, wherein the Hepadnaviridae associated infection is Hepatitis B.
29. A method according to Claim 27 or Claim 28 wherein the compound is administered in the form of two or more sub-doses per day.
30. A method according to Claim 29, wherein the sub-doses are administered in unit dosage forms.
31. Use of a compound as defined in any one of Claims 22 to 25 in the manufacture of a medicament for the treatment and/or prophylaxis of a Hepadnaviridae associated infection.
32. A compound as defined in any one of Claims 22 to 25 for use in the treatment and/or prophylaxis of a Hepadnaviridae associated infection.
33. A pharmaceutical or veterinary composition for the treatment and/or prophylaxis of a Hepadnaviridae associated infection which comprises a compound as defined in any one of Claims 22 to 25 in association with a pharmaceutically or veterinarily acceptable carrier, diluent, adjuvant and/or excipient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU18010/95A AU1801095A (en) | 1994-02-17 | 1995-02-17 | Antiviral agents |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AUPM3934A AUPM393494A0 (en) | 1994-02-17 | 1994-02-17 | Antiviral agents |
AUPN0320A AUPN032094A0 (en) | 1994-12-23 | 1994-12-23 | Antiviral agents |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995022330A1 true WO1995022330A1 (en) | 1995-08-24 |
Family
ID=25644625
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/AU1995/000076 WO1995022330A1 (en) | 1994-02-17 | 1995-02-17 | Antiviral agents |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO1995022330A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997030052A1 (en) * | 1996-02-16 | 1997-08-21 | Medivir Ab | Synthesis of acyclic nucleosides |
US5736549A (en) * | 1994-10-05 | 1998-04-07 | Chiroscience Limited | Hypoxanthine and guanine compounds |
WO1998034917A2 (en) * | 1997-02-10 | 1998-08-13 | Medivir Ab | Synthesis of acyclic nucleoside derivatives |
US6184376B1 (en) | 1997-02-10 | 2001-02-06 | Mediver Ab | Synthesis of acyclic nucleoside derivatives |
US6703394B2 (en) | 1996-02-16 | 2004-03-09 | Medivir Ab | Acyclic nucleoside derivatives |
WO2006030906A1 (en) * | 2004-09-16 | 2006-03-23 | Gifu University | Nucleoside analogues or salts thereof |
US7157448B2 (en) | 2001-01-19 | 2007-01-02 | Lg Life Sciences Ltd. | Acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same |
CN107312168A (en) * | 2017-06-15 | 2017-11-03 | 温州大学 | The monomer initiator and its synthetic method of hydroxyl synthesis are protected with 3,4 dihydro 2H pyrans |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0203736A1 (en) * | 1985-05-02 | 1986-12-03 | The Wellcome Foundation Limited | Antiviral compounds |
DE3529497A1 (en) * | 1985-08-17 | 1987-02-26 | Boehringer Mannheim Gmbh | N (ARROW HIGH) 6 (ARROW HIGH) -DISUBSTITUTED PURINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
EP0388049A2 (en) * | 1989-03-03 | 1990-09-19 | Beecham Group Plc | Derivatives of penciclovir for the treatment of hepatitis-B infections |
WO1993017020A2 (en) * | 1992-02-25 | 1993-09-02 | The Wellcome Foundation Limited | Therapeutic nucleosides |
WO1993017651A2 (en) * | 1992-03-04 | 1993-09-16 | Max-Delbrück-Centrum für Molekulare Medizin | Antiviral nucleoside analogues, their production and use |
-
1995
- 1995-02-17 WO PCT/AU1995/000076 patent/WO1995022330A1/en active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0203736A1 (en) * | 1985-05-02 | 1986-12-03 | The Wellcome Foundation Limited | Antiviral compounds |
DE3529497A1 (en) * | 1985-08-17 | 1987-02-26 | Boehringer Mannheim Gmbh | N (ARROW HIGH) 6 (ARROW HIGH) -DISUBSTITUTED PURINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
EP0388049A2 (en) * | 1989-03-03 | 1990-09-19 | Beecham Group Plc | Derivatives of penciclovir for the treatment of hepatitis-B infections |
WO1993017020A2 (en) * | 1992-02-25 | 1993-09-02 | The Wellcome Foundation Limited | Therapeutic nucleosides |
WO1993017651A2 (en) * | 1992-03-04 | 1993-09-16 | Max-Delbrück-Centrum für Molekulare Medizin | Antiviral nucleoside analogues, their production and use |
Cited By (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5736549A (en) * | 1994-10-05 | 1998-04-07 | Chiroscience Limited | Hypoxanthine and guanine compounds |
US6703394B2 (en) | 1996-02-16 | 2004-03-09 | Medivir Ab | Acyclic nucleoside derivatives |
WO1997030051A1 (en) * | 1996-02-16 | 1997-08-21 | Medivir Ab | Acyclic nucleoside derivatives |
US8124609B2 (en) | 1996-02-16 | 2012-02-28 | Medivir Ab | Acyclic nucleoside derivatives |
US7432274B2 (en) | 1996-02-16 | 2008-10-07 | Medivir Ab | Acyclic nucleoside derivatives |
US5869493A (en) * | 1996-02-16 | 1999-02-09 | Medivir Ab | Acyclic nucleoside derivatives |
WO1997030052A1 (en) * | 1996-02-16 | 1997-08-21 | Medivir Ab | Synthesis of acyclic nucleosides |
CN1067073C (en) * | 1996-02-16 | 2001-06-13 | 美迪维尔公司 | Acyclic nucleoside derivatives |
US6255312B1 (en) | 1996-02-16 | 2001-07-03 | Medivir Ab | Acyclic nucleoside derivatives |
US6576763B1 (en) | 1996-02-16 | 2003-06-10 | Medivir Ab | Acyclic nucleoside derivatives |
US7189849B2 (en) | 1997-02-10 | 2007-03-13 | Medivir Ab | Synthesis of acyclic nucleoside derivatives |
US6878844B2 (en) | 1997-02-10 | 2005-04-12 | Medivir Ab | Synthesis of acyclic nucleoside derivatives |
US6184376B1 (en) | 1997-02-10 | 2001-02-06 | Mediver Ab | Synthesis of acyclic nucleoside derivatives |
WO1998034917A3 (en) * | 1997-02-10 | 1999-01-14 | Abbott Lab | Synthesis of acyclic nucleoside derivatives |
WO1998034917A2 (en) * | 1997-02-10 | 1998-08-13 | Medivir Ab | Synthesis of acyclic nucleoside derivatives |
US6613936B1 (en) | 1998-02-06 | 2003-09-02 | Medivir Ab | Synthesis of acyclic nucleoside derivatives |
US7157448B2 (en) | 2001-01-19 | 2007-01-02 | Lg Life Sciences Ltd. | Acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same |
US7605147B2 (en) | 2001-01-19 | 2009-10-20 | Lg Life Sciences Ltd. | Acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same |
US7723319B2 (en) | 2001-01-19 | 2010-05-25 | Lg Life Sciences Ltd. | Acyclic nucleoside phosphonate derivatives, salts thereof and process for the preparation of the same |
WO2006030906A1 (en) * | 2004-09-16 | 2006-03-23 | Gifu University | Nucleoside analogues or salts thereof |
JP4887500B2 (en) * | 2004-09-16 | 2012-02-29 | 国立大学法人岐阜大学 | Nucleoside analogue or salt thereof |
CN107312168A (en) * | 2017-06-15 | 2017-11-03 | 温州大学 | The monomer initiator and its synthetic method of hydroxyl synthesis are protected with 3,4 dihydro 2H pyrans |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US6573378B1 (en) | Antiviral guanine derivatives | |
EP0343133B1 (en) | Derivatives of purine, process for their preparation and a pharmaceutical preparation | |
JPH0586792B2 (en) | ||
IL90752A (en) | 4-(2-amino-6-substituted-9H-purin-9-YL)-2-cyclopentene-1-methanol derivatives, their preparation and pharmaceutical compositions containing them | |
US5532225A (en) | Acyclic purine phosphonate nucleotide analogs as antiviral agents, and related synthetic methods | |
WO2017219915A1 (en) | Phosphonate prodrug for adenine derivative, and medical applications thereof | |
JPS63297381A (en) | 9-(2-(hydroxymethyl)cycloalkylmethyl)guanines | |
JP2923933B2 (en) | Novel cyclopropane derivative, process for producing the same, and antiviral composition containing the same | |
WO1995022330A1 (en) | Antiviral agents | |
HU202550B (en) | Process for producing 2-substituted adenosyl derivatives and pharmaceutical compositions comprising such compounds | |
JPH07503453A (en) | Antiviral acyclic phosphonomethoxyalkyl-substituted alkenyl and alkynyl purine and pyrimidine derivatives | |
US7557118B2 (en) | Preparation of fused polycyclic alkaloids by ring closure of azomethine ylides, novel compounds thereof and their use as chemotherapeutic agents | |
US2881164A (en) | Ribofuranosyl derivatives of 6-aralkylamino and 6-heterocyclicalkylaminopurines | |
US5565461A (en) | Derivatives of purine, process for their preparation and a pharmaceutical preparation | |
WO1999012927A1 (en) | Purine acyclonucleosides as antiviral agents | |
EP0366385B1 (en) | Guanine derivatives having antiviral activity and their pharmaceutically acceptable salts | |
TW201829420A (en) | New solid forms of [(1s)-1-[(2s,4r,5r)-5-(5-amino-2-oxo-thiazolo[4,5-d]pyrimidin-3-yl)-4-hydroxy-tetrahydrofuran-2-yl]propyl] acetate | |
US11149013B2 (en) | Crystal form of urate transporter 1 inhibitor and preparation method and use thereof | |
PT87605B (en) | PROCESS FOR THE PREPARATION OF THE ISOMER S OF A PURINE DERIVATIVE | |
JPH07126282A (en) | New thionucleoside derivative | |
IE44708B1 (en) | Esters of hydroxyalkoxylkyl purines, their preparation, and pharmaceutical compositions containing them | |
AU740264C (en) | Antiviral agents | |
WO2001094348A1 (en) | Antiviral agents | |
AU626300C (en) | Derivatives of purine, process for their preparation and a pharmaceutical preparation | |
JPH08503927A (en) | Antiretroviral enantiomeric nucleotide analogue |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU JP KE KG KP KR KZ LK LR LT LU LV MD MG MN MW MX NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA UG US UZ VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): KE MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: CA |