IL106588A - Phospholipids of seco- nucleosides, processes for the preparation thereof and pharmaceutical compositions with antiviral action containing them - Google Patents
Phospholipids of seco- nucleosides, processes for the preparation thereof and pharmaceutical compositions with antiviral action containing themInfo
- Publication number
- IL106588A IL106588A IL106588A IL10658893A IL106588A IL 106588 A IL106588 A IL 106588A IL 106588 A IL106588 A IL 106588A IL 10658893 A IL10658893 A IL 10658893A IL 106588 A IL106588 A IL 106588A
- Authority
- IL
- Israel
- Prior art keywords
- general formula
- liponucleotides
- radical
- substituted
- amino group
- Prior art date
Links
- 239000002777 nucleoside Substances 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
- 150000003904 phospholipids Chemical class 0.000 title abstract description 3
- 230000000840 anti-viral effect Effects 0.000 title description 5
- -1 sulphinyl Chemical group 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 26
- 125000003277 amino group Chemical group 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 239000001301 oxygen Substances 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 3
- 102000011420 Phospholipase D Human genes 0.000 claims description 3
- 108090000553 Phospholipase D Proteins 0.000 claims description 3
- 239000000872 buffer Substances 0.000 claims description 3
- 239000012876 carrier material Substances 0.000 claims description 3
- 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 claims description 3
- 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 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000002889 tridecyl 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])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 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 claims description 3
- 208000036142 Viral infection Diseases 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 230000003612 virological effect Effects 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 2
- 125000001931 aliphatic group Chemical group 0.000 claims 2
- 229910052739 hydrogen Inorganic materials 0.000 claims 2
- 239000001257 hydrogen Substances 0.000 claims 2
- 206010038997 Retroviral infections Diseases 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229910019142 PO4 Inorganic materials 0.000 abstract description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract description 3
- 239000010452 phosphate Substances 0.000 abstract description 3
- 150000002632 lipids Chemical class 0.000 abstract description 2
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical group OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 abstract 1
- 239000003443 antiviral agent Substances 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 23
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 150000003254 radicals Chemical class 0.000 description 5
- 229960004150 aciclovir Drugs 0.000 description 4
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000011149 active material Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 3
- 229960002963 ganciclovir Drugs 0.000 description 3
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 125000003835 nucleoside group Chemical group 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 229960002555 zidovudine Drugs 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- FZWGECJQACGGTI-UHFFFAOYSA-N 2-amino-7-methyl-1,7-dihydro-6H-purin-6-one Chemical compound NC1=NC(O)=C2N(C)C=NC2=N1 FZWGECJQACGGTI-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 229920006158 high molecular weight polymer Polymers 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- HDMHBHNRWDNNCD-UHFFFAOYSA-N 1-[(2-hydroxyethoxy)methyl]-6-(phenylsulfanyl)thymine Chemical compound OCCOCN1C(=O)NC(=O)C(C)=C1SC1=CC=CC=C1 HDMHBHNRWDNNCD-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- WVXRAFOPTSTNLL-NKWVEPMBSA-N 2',3'-dideoxyadenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1CC[C@@H](CO)O1 WVXRAFOPTSTNLL-NKWVEPMBSA-N 0.000 description 1
- JAPYIBBSTJFDAK-UHFFFAOYSA-N 2,4,6-tri(propan-2-yl)benzenesulfonyl chloride Chemical compound CC(C)C1=CC(C(C)C)=C(S(Cl)(=O)=O)C(C(C)C)=C1 JAPYIBBSTJFDAK-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- RLAROAJHRJLSSF-UHFFFAOYSA-N 2-decoxy-3-dodecylsulfanylpropan-1-ol Chemical compound CCCCCCCCCCCCSCC(CO)OCCCCCCCCCC RLAROAJHRJLSSF-UHFFFAOYSA-N 0.000 description 1
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- QVMPJWUVHUUAAF-UHFFFAOYSA-N 3-(3-dodecylsulfanyldecan-2-yloxy)propyl dihydrogen phosphate Chemical compound CCCCCCCCCCCCSC(CCCCCCC)C(C)OCCCOP(O)(O)=O QVMPJWUVHUUAAF-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-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
- QJFAVWACSYMXQL-UHFFFAOYSA-N C(CCCCCCCCCCCC)SC(C(C)OCCCOP(O)(O)=O)CCCCCCC Chemical compound C(CCCCCCCCCCCC)SC(C(C)OCCCOP(O)(O)=O)CCCCCCC QJFAVWACSYMXQL-UHFFFAOYSA-N 0.000 description 1
- ZWIADYZPOWUWEW-XVFCMESISA-N CDP Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(O)=O)O1 ZWIADYZPOWUWEW-XVFCMESISA-N 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 1
- 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 1
- 239000001828 Gelatine Substances 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 206010019973 Herpes virus infection Diseases 0.000 description 1
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 1
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- 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
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
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- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
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- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
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- OWZREIFADZCYQD-NSHGMRRFSA-N deltamethrin Chemical compound CC1(C)[C@@H](C=C(Br)Br)[C@H]1C(=O)O[C@H](C#N)C1=CC=CC(OC=2C=CC=CC=2)=C1 OWZREIFADZCYQD-NSHGMRRFSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
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- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 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
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 125000002525 phosphocholine group Chemical class OP(=O)(OCC[N+](C)(C)C)O* 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 125000005624 silicic acid group Chemical class 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Communicable Diseases (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention concerns phospholipid derivatives of seco-nucleosides, in which a lipid with a substituted three-carbon-atom basic structure is linked to a seco-nucleoside via a phosphate or thiophosphate group. The invention also concerns the use of such derivatives as anti-viral drugs.
Description
/29/219 106588/2 Jimpii νί.)-πι oiiiun G^TIJI , νηχ^ρη-ιρν o>t>a io 7io PHOSPHOLIProS OF SECO-NUCLEOSIDES, PROCESSES FOR THE PREPARATION THEREOF PHARMACEUTICAL COMPOSITIONS WITH ANTIVIRAL ACTION CONTAINING THEM The present invention is concerned with nev; phospholipid derivatives of seco-nucleosides which connect a lipid part, which is a substituted C,-basic structure, via "a phosphate or thiophosphate with a sec o-nucleoside and is also concerned with orocesses for the preparation thereof and with pharmaceutical compositions containing them with anti-viral properties.
Tnus, according to the present invention, there are provided compounds of the general formula :- saturated or unsaturated aliphatic radical containing up to 20 carbon atoms which can optionally be substituted one or more times by phenyl, halo, ^i"^6~ C^-Cg-alkylsulphinyl or C-^-Cg-alkylsulphonyl, H is a straight-chained or branched, saturated or unsaturated aliphatic radical containing up to 20 carbon atoms which can optionally be substituted one or more times by phenyl, halo, C^-Cg-alkox , C^-Gg-alkyl- mercapto, or G^-Gg-alkylsulphonyl , R^ is a hydrogen atom or a C-^-Gg-alkyl radical optionally substituted by hydroxyl, R is a hydrogen atom, a hydroxyl or amino group or 5 an amino group substituted once or twice by C-^-Gg- alkyl, is a hydrogen atom, a hydroxyl or amino group or an amino group substituted once or twice by G^-Gg-alkyl, X' is a valency bond, an oxygen or sulphur atom or a sulphinyl or sulphonyl group, Y has the 10 same meaning as X, whereby X and Y can be the same or different and Z is an oxygen or sulphur atom, the tautomers thereof and the physiologically acceptable salts thereof with inorganic and organc acids and bases. 15 Since the compounds of general formula I contain asymmet;ric carbon atoms, all optically-active forms ana" racemic mixtures are also the sub ect of the present invention,, In J. Biol. Chem., 26 , 5112/1990 and in EP- 20 0 350 287 s described the preparation and use of liponmcleotides as anti-viral medicaments. However, there was here only investigated and synthesised the dimyristoylphosphatidyl and dipalmitoylphosphatidyl radicals coupled with their fatty acid ester structure 25 to known nucleosides, for example AZT (azidothymidine) and ddG (didesoxycytidine) . ΞΡ-0 350 287 describes the corresponding diesters of glycerol.
In J. Med. Chem., 5£, 1380/1990 are described nucleoside conjugates of thioether lipids with cytidine diphosphate which display an anti-tumour action and which find use in oncology.
In Chem. Pharm. Bull., J6, 209/1988 are described 5 ' - ( 3-SN-phosphatidyl) -nucleosides with antileukemic activity, as well as the enzymatic synthesis thereof from the corresponding nucleosides and phosphocholines in the presence of phospho-lipase D with transferase activity.
In International Patent Application PCT/W091/01541 . are described liponucleotides with a cyclic sugar moiety in the nucleoside with anti-viral action. The acyclovir-phospholipid conjugate from L- -dimyristoylphosphatidyl acid and acyclovir is described in Acta Chem. Scand., Ser. B, j>9, 47/1985 (cf. also Organophosphorus Chem., 18, 187/1987).
The ether/thioether lipids (X, T = oxygen or sulphur) of the present invention are new and also display valuable pharmacological properties. In particular, they can be used for the therapy and prophylaxis of infections which are Caused by MA viruses, for example herpes simplex virus, cytomegalovirus, papillomaviruses, varicella zoster virus or EpStein-Barr virus, or by HNS viruses, for example togaviruses , or by retroviruses, for example oncoviruses HTLV I and II, as well as by the lenti-viruses visna and human immune deficiency virus HIV 1 and 2.
The compounds of general formula I appear to be especially suitable for the treatment of the clinical manifestations of viral herpes infections in humans. The compounds of general formula I act anti-virally without being cytotoxic in the pharmacologically relevant doses.
The compounds of general formula I are also characterised by a very good oral compatibility with good bioavailability.
The compounds according to the present invention and pharmaceutical compositions containing them can also be used in combination with other medicaments for the treatment and prophylaxis of the above-mentioned infections. Examples of these agents containing further medicaments which can be used for the treatment and prophylaxis of HIV infections and of illnesses accompanying this disease include, for example, 3' -azido-3' -desoxythymidine (AZT) , 2',3'-didesoxy nucleosides, such as 2' ,3* -didesoxy;r~ cytidine (ddC), 2' ,3' -didesoxyadenosine and 2',3'-didesoxyinosine (ddl), and non-nucleosidic RT inhibitors, for example HEPT, nevirapin and L-697,661 and corresponding derivatives. The compounds of the present invention and the other medicaments can, in each case, be used individually, simultaneously possibly in a single or two separate formulations or at different times.
As possible salts of the compounds of general formula I, there are especially preferred the alkali metal, alkaline earth metal and ammonium saits of the phosphate group. Preferred alkali metal salts are the lithium, sodium and potassium salts and preferred alkaline earth metal salts are especially the magnesium and calcium salts. By ammonium salts, according to the present invention there are to be understood salts which contain the ammonium ion which can be substit-uted up to four times by alkyl radicals containing up carbon atoms and/or aralkyl radicals, the benzyl radicals being preferred. The substituents can hereby be the same or different.
The compounds of general formula I can contain basic groups and especially amino groups which can be converted with appropriate organic or inorganic acids into acid-addition salts. As acids, there can be used, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid and methanesulphonic acid.
In general formula I, R^ is preferably a straight-chained radical which can also be substituted by a C^-Cg-alkoxy or a C^-Cg-alkyl-mercapto radical. In particular, R^* can be a decyl, undecyl, dodecyl, tridecyl or tetradecyl radical.
As C^-Gg-alkoxy substituents of R1, the methoxy, ethoxy, butox and hexyloxy radicals are preferred.
If R is substituted by a C-^-Cg-alkylmercapto radical, then this is preferably a methylmercapto, ethylmercapto, propylmercapto, butylmercapto or hexylmercapto radical, R is preferably a straight-chained radical which can also be substituted by a C^-G^-alkoxy radical or by a radical.
As C-j.-Cg-alkoxy substituents of R , the methoxy, ethoxy, propoxy, butoxy and hexyloxy radicals are 2 preferred. If R is substituted by a C^-Cg-alkyl-mercapto radical, then this is preferably a methylmercapto, ethylmercapto, butylmercapto or hexylmercapto radical.
In the definition of R^, the alkyl radical is preferably a straight-chained or branched alkyl radical, especially with up to 4 carbon atoms, for example a methyl, ethyl, n-propyl, isopropyl or n-butyl radical. These alkyl radicals are preferably substituted by one or two hydroxyl groups, for example hydroxymethyl, 2-hydroxyethyl or 3-hyduoxy-propyl.
In general, C^-C^-a ky! radicals mean straight-chained or branched alkyl radicals contining up to 4 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
R^ is preferably a hydroxyl or amino group, ^ is especially a hydrogen atom or a hydroxyl or amino group, X and Y are preferably oxygen or sulphur atoms and Z is preferably an oxygen a,tom.
Especially preferred coupled seco-nucleosides in the liponucleotides of general formula I are ganciclovir and acyclovir.
The compounds of general formula I according t the present invention can be prepared, for example as follows: 1, reaction of a compound of the general formula:- OH 1 2 in which R , R , , Y and Z have the above-given meanings, with a compound of the general formula :- in which R , R and Br have the above-given meanings, with a condensation agent, such as dicyclohexyl-carbodiimide (DCC), n pyridine or in the presence of 2,4 ,6~triisopropylbenzenesulphonic acid chloride and of a tert.-nitrogen base, for example pyridine or lutidine, in an inert solvent, for example toluene, or directly in pyridine and, after hydrolysis has taken place, the oxygen protective groups are split off by processes conventional in nucleoside chemistry, or 2. reaction of a compound of the general formula:- in which R , R , X, Y and Z have the above-given meanings, with a compound of general formula III, in which R?, R^ and R^ have the above-given meanings, in the presence of phospholipase D in an inert solvent, for example chloroform, in the presence of an appropriate buffer and, after reaction has taken place, the oxygen protective groups are split off by processes conventional in nucleoside chemistry.
The preparation of compounds of general formulae II and IV is described in DE 39 29217.7 and in WO 91/05558. The preparation of compounds of general formula III is described in Progress in Medicinal Chemistry, 2J5, 187/1986 and in the literature cited therein. Acyclovir and ganciclovir are commercially available.
The pharmaceutical compositions containing compounds of general formula I for the treatment of viral infections can be administered enterally or parenterally in liquid or solid form. For this purpose, there can be used the conveiitipnal forms of administration, for example tablets, capsules, dragees, syrups, solutions and suspensions. As injection medium, it is preferred to use water which contains the additives usual in the case of injection solutions, for example stablising agents, solubilising agents and buffers. Such additivesinclude , for example, tartrate and citrate buffers, etbanol, complex formers, such as ethylenediamine-tetraacetic acid and the nontoxic salts thereof, high molecular weight polymers, such as liquid polyethylene oxide, for viscosity regulation. Liquid carrier materials for injection solutions must be sterile and are preferably filled into ampoules. Solid carrier materials include, for example, starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids, such as stearic acid, gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers, such as polyethylene glycol and the like.
Compositions suitable for oral a dministration can, if desired, contain flavouring or sweetening agents.
The dosaging can depend upon various factors, such as mode of administration, species, age or individual state of health. The compounds according to the present invention are usually administered in amounts of from 0.1 to 100 mg and preferably of from 0.2 to 80 mg per day and per kg of body weight. It is preferred to divide up the daily dosage into 2 to 5 administrations, whereby, in the case of each administration, there are given 1 or 2 tablets with an active material content of 0.5 to 500 mg. The tablets can also be retarded, whereby the number of admin strations per day can be reduced to 1 to 3· The active material content of the* retarded tablets can be 2 to 1000 mg. The active material can also be given by continuous infusion, whereby amounts of from to 1000 mg per day normally suffice.
In the meaning of the present invention, apart from the compounds mentioned in the following Examples and those obtained by combination of all of the meanings of the substituents mentioned in the claims, the following compounds of general formula I are also preferred: 1. 2· -^-(ethoxymethyl) -guanine7-phosphoric a cid (3- dodecylmercapto-2-decyloxy)-l-propyl ester guanine) -phosphoric acid (3-dodecylsulphinyl-2- decyloxy)-l-propyl ester 3. 2' -(9- { ^Cl-hyd£oxymethyl)-ethoxy-methyl} - guanine) -phosphoric acid (3-dodecylsulphonyl-2- decyloxy) -1-propyl ester decyloxy) -1-propyl ester . 2' -^9-(ethoxymethyl)-guanine7-phosphoric acid (3-undecylmercapto-2-decyloxy) -1-propyl ester . 2' -^9-(ethoxymethyl) -guanine7-phosphoric acid (3-dodecyloxy-2-decyloxy) -1-propyl ester . 2'-(9- Cl-hydroxymethyl)-ethox27-methyl - guanine)- phosphoric acid (3-dodecylmercapto-2-nonyloxy)-l- propyl ester . 2'-(9- -i /Cl-hydroxymethyl)_ethox2;7-methyl^-guanine,) - phosphoric acid (3-dodecylmercapto-2-decylmercapto)- 1-propyl ester · 2'-(9- {. Cl-hydroxymethyl)-ethox;jr7-niethyl ^ -guanine) phosphoric acid (3- ndecylmercapto-2-decyloxy)-l- propyl e ster 0. 2' -^9-(ethoxymethyl)-guanine/-phosphoric acid (3-tridecylmercapto-2-decyloxy) -1-propyl ester . 2' -(9- ^ l- dro ymeth l)-etho 27-niethylJ -guanine) phosphoric acid (3-tridecylmercapto-2-decyloxy)-l- propyl ester . 2' -^9-(ethox,7meth.yl)-guanine7-phosphoric acid (3-dodecylmercapto-2-dodecyloxy) -1-propyl e ster 3. 2' -guanine7-phosphoric acid (3-dodecylmercapto-2-undecyloxy) -1-propyl e ster . 2' -(9- {/Cl-hydroxyraethyl)-ethox£7-methyl - guanine) -phosphoric acid (2,3-bis-(dodecyl- mercapto) -1-propyl ester 15. 2' -(9- { Cl-hydroxymethyl)-ethox^-niethylj - guanine) -phosphoric acid (3-decylmercapto-2- dodecyloxy) -1-propyl ester 16. 2' -/9-(ethoxymethyl) -guanine7-phosphoric acid (3-undecyloxy-2-dodecyloxy) -1-propyl ester 17o 2' -^9-(ethoxymethyl) -guanine7-phosphoric acid (3-decylsulphonyl-2-dodecyloxy) -1-propyl e ster 18. 21 -/9-(ethoxymethyl)-guanine7-phosphoric acid (3-decyloxy-2-decylox ) -1-propyl ester 19. 2' -^9-(ethoxymethyl) -guanine7-phosphoric acid (3-dodecylmercapto-2-dodecyloxy) -1-propyl ester 20. 2' -(9- { /Cl-hydroxymethyl)-ethoxy_7-methylV- guanine)-phosphoric acid (3-tetradecylmercapto- 2-decyloxy) -1-propyl ester 21. 2' -/9-(ethoxymethyl) -guanine7-phosphoric acid (3-pentadecylmercapto-2-decyloxy) -1-propyl ester 22» 2' -(9- &-hydroxymethyl)-ethoxy_7-methylj -guanine)- phosphoric acid (3-tridecylmercapto-2-decyloxy) -1- propyl ester 23. 2* -^9-(ethoxymethyl)-guanine7-phosphoric acid (3-dodecylmercapto-2-octyloxy) -1-propyl e ster.
The following Examples are given for the purpose of illustrating the present invention: Example 1. • - ■ ■ ■.· ■ 1 ' Phosphoric acid C3-dodecylmercapto-2-decyloxy)-l- propyl ester.
A suspension of 4.26 g phosphorus pentoxide in 60 ml anhydrous pyridine was mixed at ambient - -temperature with 13 ml hexamethyldisiloxane and heated for 1 hour to 100°C. The reaction mixture was then ί I . slightly cooled, mixed with 25 g 3-dodecylmercapto-2-decyloxy-l-propanol and heated to 100°C for a further 2.5 hours. After completely cooling to ambient temperature and removal of the readily volatile components in a vacuum, the phosphate could be extracted with diethyl ether from the aqueous suspension of the residue. The evaporation residue of the ethereal phase was purified by column chromatography on silica gel 60 or RP 18. Yield 18.7 g (63 of theory); Rf = 0.66 (dichloromethane/methanol/water 6.5 : 2.5 : 0,4 v/v/v) on TLC plates Merck 5715 , silica gel 60.
Example 2» 2' -C9-f/"*(l-Hydroxymethyl)-ethoxy7-methyl^ -guanine)-phosphoric acid (3-dodecylmercapto-2-decyloxy)-l-propyl ester. 1. 5 g (3 mmol) phosphoric acid (3-dodecyl-mercapto-2-decyloxy) -1-propyl ester and 770 mg (3 mmol) ganciclovir were mixed twice with, in each case, 20 ml. anhydrous pyridine and evaporated. The residue was taken up in 20 ml anhydrous pyridine, mixed under an atmosphere of nitrogen with 2.7 g (8.5 mmol) 2 ,4 ,6-triisopropylbenzenesulphonic acid chloride and stirred for 24 hours at 40°C. 10 ml of water were then added thereto, the reaction mixture stirred for a further 2 hours at ambient temperature and the solvent removed on a rotary evaporator.
The oily residue was freed from pyridine residues by evaporating with toluene and purified by column chromatography on RP 18 with a linear gradient of methanol/water 7/3 to 9.5/0.5 as eluent. Yield 0.75 g (34# of theory); oil. Rf = 0^73 (water/ methanol 0.5 :9.5 v/v) on RP 18; Rf = 0.30 (dichloromethane/methanol/water 6.5: 2.5: 0.4 v/v/v) on TLC plates Merck 5715 silica gel 50.
Example . 2 ' -/9-(E hoxyPeth.7l)-guanine7-Phosphoric acid (3-dodecylmercapto-2-deoyloxy) -1-propyl ester.
T is compound was prepared analogously to Example 1 from acyclovir in a yield of 7 of theory; oil; Rf = 0.77 ( ater/methanol 0.5:9 ,5 v/v) on RP 8'; Rf = 0.35 (dichloromethane/methanol/water 6.5:2.5: 0.4 v/v/v) on TLC plates Merck 5715 , silica gel 60.
Claims (14)
1. 06588/2 -16- Patent Claims 1· Liponucleotides of the general formula: - wherein R is a straight-chained or branched, saturated or unsaturated aliphatic chain containing up to 20 carbon atoms which can optionally be substit- uted one alkoxy, , 2 C^-Cg-alkylsulphiny or C^-Cg-alkylsulphonyl, R is a straight-chained or branched , saturated or unsaturated aliphatic chain containing up to 20 carbon atoms which can optionally be substituted one or more times by phenyl, halo* Cj-Cg-alkoxycarbonyl, C^-Cg-alkylsulphinyl or C^-Cg- alkylsulphonyl, R^ is a hydrogen atom or a C^-Cg- alkyl radical optionally substituted by hydroxyl, ^ is a hydrogen a torn, a hydroxyl or amino group or an amino group substituted once or twice by C^-Cg- alkyl radicals, ^ is a hydrogen atom, a hydroxyl or amino group or an amino group substituted once or twice by C-^-Gg-alkyl radicals, X is a valency bond or an oxygen or sulphur atom or a sulphinyl or 106588/2 -17-sulphonyl group, Y. has the same meaning as X, whereby X and Y can be the same or different and Z is an oxygen or sulphur atom, the tautomers thereof and the physiologically acceptable salts thereof with inorganic and organic acids and bases and all optically-active forms and racemic mixtures thereof.
2. Liponucleotides according to claim 1, wherein R is a straight-chained C^-C-^-alk l radical which can be substituted by a C^-C^-alkoxy or C-^-Cg-alkyl-mercapto radical.
3. Liponucleotides according to claim 2, wherein R^" is a decyl, undecyl, dodecyl, tridecyl or tetradecyl radical which can be substituted by a methoxy, ethoxy, butoxy, hexyloxy, methylmercapto , ethylmercapto , propylmercapto , butylmercapto or hexylmercapto radical.
4. Liponucleotides according to any o£ the preceding claims, wherein R is a straight-chained C^-C^-alkyl radical which can be substituted by a C-^-Cg-alkoxy or
5. Liponucleotides accord ng to c a m 4, w erein is a decyl, undecyl, dodecyl, tridecyl or tetradecyl radical which can be substituted by a methoxy, ethoxy, propoxy, butoxy, hexyloxy, methylmercapto, ethyl-mercapto, butylmercapto or hexylmercapto radical.
6. Liponucleotides according to any of the preceding claims , wherein ^ is a hydrogen atom or a hydrox -C,-Cc-alkyl radical.
7. Liponucleotides according to any of the preceding claims, wherein R is a hydroxy1 or amino group.
8. Liponucleotides according to any of claims 1 to 7, wherein is hydrogen or an amino group.
9. · Liponucleotides according to claim 1 which are hereinbefore specifically mentipnedo
10. , Process for the preparation of liponucleotides of general formula I according to an of claims 1 to 9, wherein a) a compound of the general formula:- 1 OH in which R 1 , R2, X, Y and Z have the above-given meanings, is reacted with a compound of the general formula:- in which , ^ and R have the above-given meanings, with a condensation agent in an inert solvent and, after hydrolysis has taken place, oxygen protective groups possibly present are split off by processes conventional in nucleoside chemistry, b) a compound of the general formula:- in which R 1 R2, X, Y and Z have t he above-given meanings, is reacted with a compound of general formula III, in which ^, ^ and ^ have the above-given meanings, in the presence of phospholipase D in an inert solvent in the presence of an appropriate buffer and, after the reaction has taken place, oxygen protective groups possibly present are split off by processes conventional in nucleoside chemistry and subsequently the compound obtained of general formula I is, if desired, converted into a physiologically compatible salt.
11. Process for the preparation of lipbmicl otides of general formula X according to claim 1, substantially as hereinbefore described and exemplified.
12. Liponucleotides of general formula I according to claim 1, whenever prepared by the process according to claim 10 or 11.
13. Pharmaceutical compositions containing at least one liponucleotide of general formula I according to any of claims 1 to 9 and 12, as well as further 106588/2 conventional pharmaceutical adjuvant and carrier materials.
14. Use of liponudeotides of general formula I according to any of claims 1 to 9 and 12 n the preparation of a pharmaceutical composition or the treatment of viral and retroviral infections, substantially as described in the specification.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4226279A DE4226279A1 (en) | 1992-08-08 | 1992-08-08 | Lipo nucleotides of seco-nucleosides, their production and their use as antiviral drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL106588A0 IL106588A0 (en) | 1993-12-08 |
| IL106588A true IL106588A (en) | 1998-01-04 |
Family
ID=6465143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL106588A IL106588A (en) | 1992-08-08 | 1993-08-04 | Phospholipids of seco- nucleosides, processes for the preparation thereof and pharmaceutical compositions with antiviral action containing them |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP0654036B1 (en) |
| JP (1) | JP3479299B2 (en) |
| KR (1) | KR100243440B1 (en) |
| CN (1) | CN1040984C (en) |
| AT (1) | ATE152114T1 (en) |
| AU (1) | AU672994B2 (en) |
| CA (1) | CA2141030A1 (en) |
| DE (2) | DE4226279A1 (en) |
| DK (1) | DK0654036T3 (en) |
| ES (1) | ES2104163T3 (en) |
| FI (1) | FI109699B (en) |
| GR (1) | GR3023960T3 (en) |
| HU (1) | HUT72605A (en) |
| IL (1) | IL106588A (en) |
| MX (1) | MX9304676A (en) |
| NO (1) | NO304986B1 (en) |
| NZ (1) | NZ254813A (en) |
| TW (1) | TW306924B (en) |
| WO (1) | WO1994003465A1 (en) |
| ZA (1) | ZA935718B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6599887B2 (en) | 1988-07-07 | 2003-07-29 | Chimerix, Inc. | Methods of treating viral infections using antiviral liponucleotides |
| US6252060B1 (en) | 1988-07-07 | 2001-06-26 | Nexstar Pharmaceuticals, Inc. | Antiviral liponucleosides: treatment of hepatitis B |
| US5817638A (en) * | 1988-07-07 | 1998-10-06 | Nexstar Pharmaceuticals, Inc. | Antiviral liponucleosides: treatment of hepatitis B |
| DE4402492A1 (en) * | 1994-01-28 | 1995-08-03 | Boehringer Mannheim Gmbh | Process for the production of asymmetrical phosphoric acid diesters |
| US7517858B1 (en) * | 1995-06-07 | 2009-04-14 | The Regents Of The University Of California | Prodrugs of pharmaceuticals with improved bioavailability |
| KR100389558B1 (en) * | 2000-10-11 | 2003-06-27 | 주식회사 한스환경엔지니어링 | Surface Treating Fabric For FRP |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5223263A (en) * | 1988-07-07 | 1993-06-29 | Vical, Inc. | Liponucleotide-containing liposomes |
| DE4026265A1 (en) * | 1990-08-20 | 1992-02-27 | Boehringer Mannheim Gmbh | NEW PHOSPHOLIPID DERIVATIVES OF NUCLEOSIDES, THEIR PRODUCTION AND THEIR USE AS ANTIVIRAL MEDICINAL PRODUCTS |
-
1992
- 1992-08-08 DE DE4226279A patent/DE4226279A1/en not_active Withdrawn
-
1993
- 1993-07-07 TW TW082105422A patent/TW306924B/zh active
- 1993-08-03 MX MX9304676A patent/MX9304676A/en not_active IP Right Cessation
- 1993-08-04 IL IL106588A patent/IL106588A/en not_active IP Right Cessation
- 1993-08-06 JP JP50502594A patent/JP3479299B2/en not_active Expired - Fee Related
- 1993-08-06 AU AU47082/93A patent/AU672994B2/en not_active Ceased
- 1993-08-06 NZ NZ254813A patent/NZ254813A/en unknown
- 1993-08-06 WO PCT/EP1993/002101 patent/WO1994003465A1/en active IP Right Grant
- 1993-08-06 EP EP93917764A patent/EP0654036B1/en not_active Expired - Lifetime
- 1993-08-06 CA CA002141030A patent/CA2141030A1/en not_active Abandoned
- 1993-08-06 AT AT93917764T patent/ATE152114T1/en not_active IP Right Cessation
- 1993-08-06 ES ES93917764T patent/ES2104163T3/en not_active Expired - Lifetime
- 1993-08-06 HU HU9500374A patent/HUT72605A/en unknown
- 1993-08-06 DK DK93917764.8T patent/DK0654036T3/en active
- 1993-08-06 KR KR1019950700463A patent/KR100243440B1/en not_active IP Right Cessation
- 1993-08-06 DE DE59306286T patent/DE59306286D1/en not_active Expired - Fee Related
- 1993-08-06 ZA ZA935718A patent/ZA935718B/en unknown
- 1993-08-07 CN CN93107987A patent/CN1040984C/en not_active Expired - Fee Related
-
1995
- 1995-02-07 FI FI950533A patent/FI109699B/en not_active IP Right Cessation
- 1995-02-07 NO NO950445A patent/NO304986B1/en not_active IP Right Cessation
-
1997
- 1997-06-30 GR GR970401610T patent/GR3023960T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK0654036T3 (en) | 1997-11-03 |
| EP0654036B1 (en) | 1997-04-23 |
| KR100243440B1 (en) | 2000-03-02 |
| MX9304676A (en) | 1994-03-31 |
| EP0654036A1 (en) | 1995-05-24 |
| FI109699B (en) | 2002-09-30 |
| NZ254813A (en) | 1996-05-28 |
| JPH08500345A (en) | 1996-01-16 |
| ES2104163T3 (en) | 1997-10-01 |
| WO1994003465A1 (en) | 1994-02-17 |
| TW306924B (en) | 1997-06-01 |
| DE4226279A1 (en) | 1994-02-10 |
| CA2141030A1 (en) | 1994-02-09 |
| GR3023960T3 (en) | 1997-09-30 |
| NO950445L (en) | 1995-02-07 |
| DE59306286D1 (en) | 1997-05-28 |
| CN1085908A (en) | 1994-04-27 |
| CN1040984C (en) | 1998-12-02 |
| HU9500374D0 (en) | 1995-03-28 |
| AU4708293A (en) | 1994-03-03 |
| ATE152114T1 (en) | 1997-05-15 |
| AU672994B2 (en) | 1996-10-24 |
| IL106588A0 (en) | 1993-12-08 |
| NO304986B1 (en) | 1999-03-15 |
| FI950533A0 (en) | 1995-02-07 |
| JP3479299B2 (en) | 2003-12-15 |
| NO950445D0 (en) | 1995-02-07 |
| FI950533A (en) | 1995-02-07 |
| ZA935718B (en) | 1995-02-06 |
| KR950702998A (en) | 1995-08-23 |
| HUT72605A (en) | 1996-05-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FF | Patent granted | ||
| KB | Patent renewed | ||
| KB | Patent renewed | ||
| HP | Change in proprietorship | ||
| KB | Patent renewed | ||
| MM9K | Patent not in force due to non-payment of renewal fees |