CA2141030A1 - Liponucleotides of seco-nucleosides, their production as well as their use as antiviral pharmaceutical agents - Google Patents
Liponucleotides of seco-nucleosides, their production as well as their use as antiviral pharmaceutical agentsInfo
- Publication number
- CA2141030A1 CA2141030A1 CA002141030A CA2141030A CA2141030A1 CA 2141030 A1 CA2141030 A1 CA 2141030A1 CA 002141030 A CA002141030 A CA 002141030A CA 2141030 A CA2141030 A CA 2141030A CA 2141030 A1 CA2141030 A1 CA 2141030A1
- Authority
- CA
- Canada
- Prior art keywords
- liponucleotides
- denotes
- substituted
- group
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000002777 nucleoside Substances 0.000 title claims abstract description 16
- 239000008177 pharmaceutical agent Substances 0.000 title claims description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 230000000840 anti-viral effect Effects 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 25
- -1 hydroxy, amino Chemical group 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000004414 alkyl thio group Chemical group 0.000 claims description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Chemical group CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- 238000007796 conventional method Methods 0.000 claims description 4
- 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 4
- 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 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000012442 inert solvent Substances 0.000 claims description 4
- 125000001421 myristyl 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])C([H])([H])[H] 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- 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 4
- 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 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 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
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 208000036142 Viral infection Diseases 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 230000003612 virological effect Effects 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 2
- 206010038997 Retroviral infections Diseases 0.000 claims 1
- 239000000126 substance 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 group 0.000 abstract description 2
- 150000003904 phospholipids Chemical class 0.000 abstract description 2
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 abstract description 2
- 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 14
- AVEGLFHOBOAVIJ-UHFFFAOYSA-N 2-amino-9-(ethoxymethyl)-3h-purin-6-one Chemical compound N1=C(N)NC(=O)C2=C1N(COCC)C=N2 AVEGLFHOBOAVIJ-UHFFFAOYSA-N 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003826 tablet Substances 0.000 description 5
- 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 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 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
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- 239000013543 active substance 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
- 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
- 239000000203 mixture Substances 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229960002555 zidovudine Drugs 0.000 description 3
- 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 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 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
- 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 239000002585 base Chemical class 0.000 description 2
- 239000012876 carrier material 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
- 230000008020 evaporation Effects 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 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
- 229920000642 polymer Polymers 0.000 description 2
- 239000002904 solvent 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
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- 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
- 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
- LDXJRKWFNNFDSA-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound C1CN(CC2=NNN=C21)CC(=O)N3CCN(CC3)C4=CN=C(N=C4)NCC5=CC(=CC=C5)OC(F)(F)F LDXJRKWFNNFDSA-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
- YLZOPXRUQYQQID-UHFFFAOYSA-N 3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-1-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]propan-1-one Chemical compound N1N=NC=2CN(CCC=21)CCC(=O)N1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F YLZOPXRUQYQQID-UHFFFAOYSA-N 0.000 description 1
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- 239000007979 citrate buffer Substances 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- POCFBDFTJMJWLG-UHFFFAOYSA-N dihydrosinapic acid methyl ester Natural products COC(=O)CCC1=CC(OC)=C(O)C(OC)=C1 POCFBDFTJMJWLG-UHFFFAOYSA-N 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- IVSXFFJGASXYCL-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=NC=N[C]21 IVSXFFJGASXYCL-UHFFFAOYSA-N 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
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 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
- 229940098779 methanesulfonic acid Drugs 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
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 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
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000003381 stabilizer Substances 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
- 229910052717 sulfur Inorganic materials 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
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 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
- 230000020192 tolerance induction in gut-associated lymphoid tissue Effects 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
- 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 present invention concerns new phospholipid derivatives of seco-nucleosides that link a lipid moiety, which represents a substituted C3 backbone, to a seco-nucleoside via a phosphate or thiophosphate.
Description
Boehringer Mannheim GmbH
Liponucleotides of seco-nucleosides, their ~roduction as well as their use as antiviral ~harmaceutical a~ents The present invention concerns new phospholipid derivatives of seco-nucleosides that link a lipid moiety which represents a substituted C3 backbone with a seco-nucleoside via a phosphate or thiophosphate as well as their use as antiviral pharmaceutical agents.
The invention concerns compounds of formula I, - X Rl ~4 _ O _ I O _ I ~ N ~ RS
OH ~ O ~
\R3 in which R1 denotes a straight-chained or branched, saturated or unsaturated aliphatic residue with 1-20 carbon atoms which can be substituted, if desired, once or several times by phenyl, halogen, Cl-C6 alkoxy, Cl-C6 alkyl-mercapto, C1-C6 alkoxycarbonyl, C1-C6 alkylsulfinyl or Cl-C6 alkylsulfonyl groups, ._ R2 denotes a straight-chained or branched, saturated or unsaturated aliphatic residue with 1-20 carbon atoms which can be substituted, if desired, once or several times by phenyl, halogen, Cl-C6 alkoxy, Cl-C6 alkyl-mercapto, Cl-C6 alkoxycarbonyl, Cl-C6 alkylsulfinyl or Cl-C6 alkylsulfonyl groups, R3 denotes hydrogen or a Cl-C6 alkyl group which is substituted, if desired, by hydroxy R4 can be hydrogen, hydroxy, amino or an amino group substituted once or twice by Cl-C6 alkyl, R5 can be hydrogen, hydroxy, amino or an amino group substituted once or twice by Cl-C6 alkyl, X represents a valency dash, oxygen, sulphur, sulfinyl or sulfonyl, Y can have the same meaning as X and the two groups X
and Y can be the same or different, Z can be oxygen or sulphur, their tautomers and their physiologically tolerated salts of inorganic and organic acids and bases.
Since the compounds of the general formula I contain asymmetric carbon atoms, all optically active forms and racemic mixtures of these compounds are also the subject matter of the present invention.
21410~0 The production and use of liponucleotides as antiviral pharmaceutical agents are described in J. Biol. Chem.
265, 6112 (1990) and EP 0 350 287. In this case only dimyristoylphosphatidyl and dipalmitoylphosphatidyl residues with their fatty acid ester structure coupled to known nucleosides such as e.g. AZT (azidothymidine) and ddC (dideoxycytidine) were examined and synthesized.
EP 0 350 287 describes the respective 1,2-diesters of glycerol.
In J. Med. Chem. 33, 1380 (1990) nucleoside conjugates of thioether lipids with cytidine diphosphate are described which exhibit an antitumour action and which can be used in oncology.
5'-(3-SN-phosphatidyl)nucleosides having an antileukaemic activity are described in Chem. Pharm.
Bull. 36, 209 (1988), as well as their enzymatic synthesis from the appropriate nucleosides and phosphocholines in the presence of phospholipase D
having transferase activity.
Liponucleotides with a cyclic sugar moiety in the nucleoside which have an antiviral action are described in the patent application PCT/EP91/01541.
The Acyclovir-phospholipid conjugate from L-a-dimyristoylphosphatidyl acid and Acyclovir is described in Acta Chem. Scand., Ser. B. 39, 47 (1985) [cf. also Organophosphorus Chem. 18, 187 (1987)].
The ether-/thioether lipids (X, Y = O or S) of the present invention are novel and also exhibit valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections which are caused by DNA viruses such as e.g. the herpes-simplex virus, the cytomegaly virus, papilloma viruses, the varicella-zoster virus or Epstein-Barr virus or RNA
viruses such as toga viruses or retroviruses such as the oncoviruses HTLV-I and II as well as the lentiviruses Visna and human immunodeficiency virus HIV-1 and 2.
The compounds of formula I appear to be particularly suitable for treating clinical manifestations of viral herpes infection in humans. The compounds of the general formula I act antivirally without being cytotoxic in pharmacologically relevant doses.
The compounds are additionally distinguished by a very good oral tolerance with good bioavailability.
The compounds of the present invention and their pharmaceutical preparations can also be used in combination with other pharmaceutical agents for the treatment and prophylaxis of the above-mentioned infections. Examples of these agents containing further pharmaceutical agents which can be used for the treatment and prophylaxis of HIV infections or diseases which accompany this illness are 3'-azido-3'-deoxy-thymidine (AZT), 2',3'-dideoxynucleosides such as e.g.
Liponucleotides of seco-nucleosides, their ~roduction as well as their use as antiviral ~harmaceutical a~ents The present invention concerns new phospholipid derivatives of seco-nucleosides that link a lipid moiety which represents a substituted C3 backbone with a seco-nucleoside via a phosphate or thiophosphate as well as their use as antiviral pharmaceutical agents.
The invention concerns compounds of formula I, - X Rl ~4 _ O _ I O _ I ~ N ~ RS
OH ~ O ~
\R3 in which R1 denotes a straight-chained or branched, saturated or unsaturated aliphatic residue with 1-20 carbon atoms which can be substituted, if desired, once or several times by phenyl, halogen, Cl-C6 alkoxy, Cl-C6 alkyl-mercapto, C1-C6 alkoxycarbonyl, C1-C6 alkylsulfinyl or Cl-C6 alkylsulfonyl groups, ._ R2 denotes a straight-chained or branched, saturated or unsaturated aliphatic residue with 1-20 carbon atoms which can be substituted, if desired, once or several times by phenyl, halogen, Cl-C6 alkoxy, Cl-C6 alkyl-mercapto, Cl-C6 alkoxycarbonyl, Cl-C6 alkylsulfinyl or Cl-C6 alkylsulfonyl groups, R3 denotes hydrogen or a Cl-C6 alkyl group which is substituted, if desired, by hydroxy R4 can be hydrogen, hydroxy, amino or an amino group substituted once or twice by Cl-C6 alkyl, R5 can be hydrogen, hydroxy, amino or an amino group substituted once or twice by Cl-C6 alkyl, X represents a valency dash, oxygen, sulphur, sulfinyl or sulfonyl, Y can have the same meaning as X and the two groups X
and Y can be the same or different, Z can be oxygen or sulphur, their tautomers and their physiologically tolerated salts of inorganic and organic acids and bases.
Since the compounds of the general formula I contain asymmetric carbon atoms, all optically active forms and racemic mixtures of these compounds are also the subject matter of the present invention.
21410~0 The production and use of liponucleotides as antiviral pharmaceutical agents are described in J. Biol. Chem.
265, 6112 (1990) and EP 0 350 287. In this case only dimyristoylphosphatidyl and dipalmitoylphosphatidyl residues with their fatty acid ester structure coupled to known nucleosides such as e.g. AZT (azidothymidine) and ddC (dideoxycytidine) were examined and synthesized.
EP 0 350 287 describes the respective 1,2-diesters of glycerol.
In J. Med. Chem. 33, 1380 (1990) nucleoside conjugates of thioether lipids with cytidine diphosphate are described which exhibit an antitumour action and which can be used in oncology.
5'-(3-SN-phosphatidyl)nucleosides having an antileukaemic activity are described in Chem. Pharm.
Bull. 36, 209 (1988), as well as their enzymatic synthesis from the appropriate nucleosides and phosphocholines in the presence of phospholipase D
having transferase activity.
Liponucleotides with a cyclic sugar moiety in the nucleoside which have an antiviral action are described in the patent application PCT/EP91/01541.
The Acyclovir-phospholipid conjugate from L-a-dimyristoylphosphatidyl acid and Acyclovir is described in Acta Chem. Scand., Ser. B. 39, 47 (1985) [cf. also Organophosphorus Chem. 18, 187 (1987)].
The ether-/thioether lipids (X, Y = O or S) of the present invention are novel and also exhibit valuable pharmacological properties. They are particularly suitable for the therapy and prophylaxis of infections which are caused by DNA viruses such as e.g. the herpes-simplex virus, the cytomegaly virus, papilloma viruses, the varicella-zoster virus or Epstein-Barr virus or RNA
viruses such as toga viruses or retroviruses such as the oncoviruses HTLV-I and II as well as the lentiviruses Visna and human immunodeficiency virus HIV-1 and 2.
The compounds of formula I appear to be particularly suitable for treating clinical manifestations of viral herpes infection in humans. The compounds of the general formula I act antivirally without being cytotoxic in pharmacologically relevant doses.
The compounds are additionally distinguished by a very good oral tolerance with good bioavailability.
The compounds of the present invention and their pharmaceutical preparations can also be used in combination with other pharmaceutical agents for the treatment and prophylaxis of the above-mentioned infections. Examples of these agents containing further pharmaceutical agents which can be used for the treatment and prophylaxis of HIV infections or diseases which accompany this illness are 3'-azido-3'-deoxy-thymidine (AZT), 2',3'-dideoxynucleosides such as e.g.
2'-3-dideoxycytidine (ddC), 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine (ddI) or non-nucleosidic RT
inhibitors such as HEPT, Nevirapin or L-697, 661 and corresponding derivatives. The compounds of the present invention and the other pharmaceutical agent can each be administered individually, simultaneously and optionally in a single or two separate formulations or at different times.
Alkali, alkaline-earth and ammonium salts of the phosphate group come into consideration as possible salts of compounds of the general formula I. Lithium, sodium and potassium salts are preferred as alkali salts. In particular magnesium and calcium salts come into consideration as the alkaline-earth salts.
According to the invention ammonium salts are understood as salts which contain the ammonium ion which can be substituted up to four times by alkyl residues with 1-4 carbon atoms and/or aralkyl residues, preferably benzyl residues. The substituents can in this case be the same or different.
The compounds of the general formula I can contain basic groups, in particular amino groups, which can be converted into acid addition salts using suitable organic and inorganic acids. Hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid come for example into consideration as the acid.
In the general formula I R1 preferably denotes a straight-chained Cg-Cl4 alkyl group which can additionally be substituted by a C1-C6 alkoxy or a Cl-C6 alkylmercapto group. R1 in particular represents a decyl, undecyl, dodecyl, tridecyl or tetradecyl group.
Methoxy, ethoxy, butoxy and hexyloxy groups preferably come into consideration as the C1-C6 alkoxy substituents of R1. If Rl is substituted by a Cl-C6 alkylmercapto residue, this is to be understood in particular as a methylmercapto, ethylmercapto, propylmercapto, butyl-mercapto and hexylmercapto residue.
R2 preferably denotes a straight-chained Cg-Cl4 alkyl group which can in addition be substituted by a C1-C6 alkoxy group or a C1-C6 alkylmercapto group. R2 in particular represents a decyl, undecyl, dodecyl, tridecyl or tetradecyl group. The methoxy, ethoxy, propoxy, butoxy and hexyloxy group preferably come into consideration as the C1-C6 alkoxy substituents of R2. If R2 is substituted by a C1-C6 alkylmercapto residue, then this is understood in particular to be a methylmercapto, ethylmercapto, butylmercapto and hexylmercapto residue.
In the definition of R3 the alkyl group denotes in particular a straight-chained or branched alkyl group preferably having up to four C atoms such as e.g.
methyl, ethyl, n-propyl, isopropyl or n-butyl. These alkyl groups are preferably substituted by one or two hydroxy groups such as e.g. hydroxymethyl, 2-hydroxy-ethyl or 3-hydroxypropyl.
Cl-C6 alkyl groups in general denote straight-chained or branched alkyl residues preferably having up to four C
atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
R4 preferably denotes a hydroxy or amino group.
R5 in particular denotes hydrogen or a hydroxy or amino group.
X and Y preferably represent an oxygen or sulphur atom.
Z is preferably an oxygen atom.
Especially preferred coupled seco-nucleosides in the -claimed liponucleotides of the general formula I are Ganciclovir or Acyclovir.
The compounds of formula I can be prepared by reacting 1. a compound of formula II, Y- R
z (II) Il O P - OH
OH
in which Rl, R2, X, Y and Z have the stated meAn;ngs, with a compound of the general formula III, . .
</ ~ (III) HO ~ N ~ R5 ~O~
in which R3, R4 and R5 have the above-mentioned meAn;ng using a condensing agent such as DCC
(dicyclohexylcarbodiimde) in pyridine or in the presence of 2,4,6-triisopropylbenzenesulfonic acid chloride and a tert. nitrogen base e.g. pyridine or lutidine in an inert solvent such as e.g. toluene or directly in pyridine and, after hydrolysis is 21~1030 completed, the oxygen protecting groups are cleaved if desired according to conventional methods in nucleoside chemistry or 2. a compound of formula IV
(IV) I / N~ CH~
O- O
CH~
in which R1, R2, X, Y and Z have the above-mentioned meaning is reacted with a compound of formula III in which R3, R4 and R5 have the stated meanings in the presence of phospholipase D in an inert solvent such as e.g. chloroform in the presence of a buffer and, after the reaction is completed, the oxygen protecting group is cleaved if desired according to conventional methods in nucleoside chemistry.
The production of compounds of formula II and IV is described in DE 39 29 217.7 and W0 91/05558.
The production of compounds of the general formula III
is described in Progress in Medicinal Chemistry, vol.
23, 187 (1986) and in the literature cited there.
g Acyclovir and Ganciclovir are commercially available.
The pharmaceutical agents containing compounds of formula I for the treatment of viral infections can be administered enterally or parenterally in a liquid or solid form. The usual methods of administration come into consideration in this case such as for example tablets, capsules, coated tablets, syrups, solutions or suspensions. Water is preferably used as the injection medium which contains the usual additives for injection solutions such as stabilizers, solubilizers and buffers.
Such additives are e.g. tartrate and citrate buffer, ethanol, complexing agents such as ethylenediamine-tetraacetic acid and their non-toxic salts, high molecular polymers such as liquid polyethylene oxide to regulate viscosity. Liquid carrier materials for injection solutions have to be sterile and are preferably dispensed into ampoules. Solid carrier materials are for example starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acid, higher molecular fatty acids such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and plant fats, solid high molecular polymers such as polyethylene glycols etc.. Suitable preparations for oral applications can if desired contain flavourings or sweeteners.
The dosage can depend on various factors such as mode of administration, species, age or individual condition.
The compounds according to the invention are usually administered in amounts of 0.1 - 100 mg, preferably 0.2 - 80 mg per day and per kg body weight. It is preferable to divide the daily dose into 2-5 administrations, 1-2 tablets being administered at each application with a content of active substance of 0.5 - 500 mg. The tablets 21 ~1030 can also be retarded by which means the number of applications per day can be reduced to 1-3. The content of active substance of the retarded tablets can be 2 -1000 mg. The active substance can also be administered by continuous infusion in which case amounts of 5 -1000 mg per day are normally sufficient.
The following compounds of formula I come into consideration within the sense of the present invention in addition to the compounds mentioned in the examples and combinations of all the meanings mentioned in the claims for the substituents:
1. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-dodecylmercapto-2-decyloxy)-1-propyl ester 2. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-dodecylsulfonyl-2-decyloxy)-1-propyl ester 3. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-dodecylsulfonyl-2-decyloxy)-1-propyl ester 4. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-dodecylmercapto-2-decyloxy)-1-propyl ester S. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-undecylmercapto-2-decyloxy)-1-propyl ester 6. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-dodecyloxy-2-decyloxy)-1-propyl ester 214103~
7. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-dodecylmercapto-2-nonyloxy)-1-propyl ester 8. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-dodecylmercapto-2-decyl-mercapto)-l-propyl ester 9. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-undecylmercapto-2-decyloxy)-1-propyl ester 10. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-tridecylmercapto-2-decyloxy)-1-propyl ester 11. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-tridecylmercapto-2-decyloxy)-1-propyl ester 12. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-dodecylmercapto-2-dodecyloxy)-1-propyl ester 13. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-dodecylmercapto-2-undecyloxy)-1-propyl ester 14. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(2,3-bis(dodecylmercapto)-1-propyl ester 15. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-dodecylmercapto-2-dodecyloxy)-1-propyl ester 16. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-undecyloxy-2-dodecyloxy)-1-propyl ester 17. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-decylsulfonyl-2-dodecyloxy)-1-propyl ester 18. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-decyloxy-2-decyloxy)-l-propyl ester 19. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-dodecylmercapto-2-dodecyloxy)-1-propyl ester 20. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-tetradecylmercapto-2-decyloxy)-l-propyl ester 21. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-pentadecylmercapto-2-decyloxy)-1-propyl ester 22. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-tridecylmercapto-2-decyloxy)-1-propyl ester 23. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-dodecylmercapto-2-octyloxy)-1-propyl ester 21410~0 Example Phosphoric acid-(3-dodecYlmercapto-2-decyloxy)-1-propyl ester A suspension of 4.26 g P4Olo in 60 ml absolute pyridine was admixed at room temperature with 13 ml hexamethyldisiloxane and heated to 100C for 1 hour. It was then slightly cooled, admixed with 25 g 3-dodecylmercapto-2-decyloxy-1-propanol and heated for a further 2.5 hours to 100C.
After completely cooling to room temperature and removing the highly volatile components in a vacuum, the phosphate could be extracted with ether from the aqueous suspension of the residue. The evaporation residue of the ether phase was purified by column chromatography on silica gel 60 or RP 18. Yield 18.7 g (63 %), Rf = 0.66 (CH2C12/MeOH/H20 6.5/2.5/0.4) on TLC plates, Merck 5715, silica gel 60.
Example 2 2'-(9-~ r tl-hydroxymethyl)ethoxYlmethyl~guanine)Phos-phoric acid-(3-dodecylmercapto-2-decyloxy)-1-~ropyl ester 1.45 g (3 mmol) phosphoric acid-(3-dodecylmercapto-2-decyloxy)-l-propyl ester and 770 mg (3 mmol) Ganciclovir were twice admixed with 20 ml absolute pyridine each time and evaporated. The residue was taken up in 20 ml absolute pyridine, 2.7 g (8.5 mmol) 2,4,6-triisopropyl-benzenesulfonic acid chloride was added under nitrogen and it was stirred for 24 hours at 40C. Then 10 ml water was added, the mixture was stirred for a further 2 hours at room temperature and the solvent was removed in a rotary evaporator.
The oily residue was freed from residual pyridine by evaporation with toluene and purified by means of column chromatography on RP 18 with a linear gradient of methanol/water 7/3 to 9.S/0.5 as the eluant. Yield 0.75 g (34 ~ of theory), oil. Rf = 0.73 (H20/MeOH
0.5/9.5) on RP 8, Rf = O . 30 (CH2C12/MeOH/H20 6.5/2.5/0.4) on TLC plates, Merck 5715, silica gel 60 F.
Example 3 2'- r 9-(ethoxYmethYl)quanine~phosPhoric acid-(3-dodecyl-mercapto-2-decyloxy)-1-proPYl ester This compound was produced analogously to example 1 from Acyclovir in a 47 % yield, oil, Rf = 0.77 (H20/MeOH
0.5/9.5) on RP 8, Rf = O . 35 (CH2C12/MeOH/H20 6.5/2.5/0.4) on TLC plates, Merck 5715, silica gel 60.
inhibitors such as HEPT, Nevirapin or L-697, 661 and corresponding derivatives. The compounds of the present invention and the other pharmaceutical agent can each be administered individually, simultaneously and optionally in a single or two separate formulations or at different times.
Alkali, alkaline-earth and ammonium salts of the phosphate group come into consideration as possible salts of compounds of the general formula I. Lithium, sodium and potassium salts are preferred as alkali salts. In particular magnesium and calcium salts come into consideration as the alkaline-earth salts.
According to the invention ammonium salts are understood as salts which contain the ammonium ion which can be substituted up to four times by alkyl residues with 1-4 carbon atoms and/or aralkyl residues, preferably benzyl residues. The substituents can in this case be the same or different.
The compounds of the general formula I can contain basic groups, in particular amino groups, which can be converted into acid addition salts using suitable organic and inorganic acids. Hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid come for example into consideration as the acid.
In the general formula I R1 preferably denotes a straight-chained Cg-Cl4 alkyl group which can additionally be substituted by a C1-C6 alkoxy or a Cl-C6 alkylmercapto group. R1 in particular represents a decyl, undecyl, dodecyl, tridecyl or tetradecyl group.
Methoxy, ethoxy, butoxy and hexyloxy groups preferably come into consideration as the C1-C6 alkoxy substituents of R1. If Rl is substituted by a Cl-C6 alkylmercapto residue, this is to be understood in particular as a methylmercapto, ethylmercapto, propylmercapto, butyl-mercapto and hexylmercapto residue.
R2 preferably denotes a straight-chained Cg-Cl4 alkyl group which can in addition be substituted by a C1-C6 alkoxy group or a C1-C6 alkylmercapto group. R2 in particular represents a decyl, undecyl, dodecyl, tridecyl or tetradecyl group. The methoxy, ethoxy, propoxy, butoxy and hexyloxy group preferably come into consideration as the C1-C6 alkoxy substituents of R2. If R2 is substituted by a C1-C6 alkylmercapto residue, then this is understood in particular to be a methylmercapto, ethylmercapto, butylmercapto and hexylmercapto residue.
In the definition of R3 the alkyl group denotes in particular a straight-chained or branched alkyl group preferably having up to four C atoms such as e.g.
methyl, ethyl, n-propyl, isopropyl or n-butyl. These alkyl groups are preferably substituted by one or two hydroxy groups such as e.g. hydroxymethyl, 2-hydroxy-ethyl or 3-hydroxypropyl.
Cl-C6 alkyl groups in general denote straight-chained or branched alkyl residues preferably having up to four C
atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
R4 preferably denotes a hydroxy or amino group.
R5 in particular denotes hydrogen or a hydroxy or amino group.
X and Y preferably represent an oxygen or sulphur atom.
Z is preferably an oxygen atom.
Especially preferred coupled seco-nucleosides in the -claimed liponucleotides of the general formula I are Ganciclovir or Acyclovir.
The compounds of formula I can be prepared by reacting 1. a compound of formula II, Y- R
z (II) Il O P - OH
OH
in which Rl, R2, X, Y and Z have the stated meAn;ngs, with a compound of the general formula III, . .
</ ~ (III) HO ~ N ~ R5 ~O~
in which R3, R4 and R5 have the above-mentioned meAn;ng using a condensing agent such as DCC
(dicyclohexylcarbodiimde) in pyridine or in the presence of 2,4,6-triisopropylbenzenesulfonic acid chloride and a tert. nitrogen base e.g. pyridine or lutidine in an inert solvent such as e.g. toluene or directly in pyridine and, after hydrolysis is 21~1030 completed, the oxygen protecting groups are cleaved if desired according to conventional methods in nucleoside chemistry or 2. a compound of formula IV
(IV) I / N~ CH~
O- O
CH~
in which R1, R2, X, Y and Z have the above-mentioned meaning is reacted with a compound of formula III in which R3, R4 and R5 have the stated meanings in the presence of phospholipase D in an inert solvent such as e.g. chloroform in the presence of a buffer and, after the reaction is completed, the oxygen protecting group is cleaved if desired according to conventional methods in nucleoside chemistry.
The production of compounds of formula II and IV is described in DE 39 29 217.7 and W0 91/05558.
The production of compounds of the general formula III
is described in Progress in Medicinal Chemistry, vol.
23, 187 (1986) and in the literature cited there.
g Acyclovir and Ganciclovir are commercially available.
The pharmaceutical agents containing compounds of formula I for the treatment of viral infections can be administered enterally or parenterally in a liquid or solid form. The usual methods of administration come into consideration in this case such as for example tablets, capsules, coated tablets, syrups, solutions or suspensions. Water is preferably used as the injection medium which contains the usual additives for injection solutions such as stabilizers, solubilizers and buffers.
Such additives are e.g. tartrate and citrate buffer, ethanol, complexing agents such as ethylenediamine-tetraacetic acid and their non-toxic salts, high molecular polymers such as liquid polyethylene oxide to regulate viscosity. Liquid carrier materials for injection solutions have to be sterile and are preferably dispensed into ampoules. Solid carrier materials are for example starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acid, higher molecular fatty acids such as stearic acid, gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and plant fats, solid high molecular polymers such as polyethylene glycols etc.. Suitable preparations for oral applications can if desired contain flavourings or sweeteners.
The dosage can depend on various factors such as mode of administration, species, age or individual condition.
The compounds according to the invention are usually administered in amounts of 0.1 - 100 mg, preferably 0.2 - 80 mg per day and per kg body weight. It is preferable to divide the daily dose into 2-5 administrations, 1-2 tablets being administered at each application with a content of active substance of 0.5 - 500 mg. The tablets 21 ~1030 can also be retarded by which means the number of applications per day can be reduced to 1-3. The content of active substance of the retarded tablets can be 2 -1000 mg. The active substance can also be administered by continuous infusion in which case amounts of 5 -1000 mg per day are normally sufficient.
The following compounds of formula I come into consideration within the sense of the present invention in addition to the compounds mentioned in the examples and combinations of all the meanings mentioned in the claims for the substituents:
1. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-dodecylmercapto-2-decyloxy)-1-propyl ester 2. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-dodecylsulfonyl-2-decyloxy)-1-propyl ester 3. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-dodecylsulfonyl-2-decyloxy)-1-propyl ester 4. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-dodecylmercapto-2-decyloxy)-1-propyl ester S. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-undecylmercapto-2-decyloxy)-1-propyl ester 6. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-dodecyloxy-2-decyloxy)-1-propyl ester 214103~
7. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-dodecylmercapto-2-nonyloxy)-1-propyl ester 8. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-dodecylmercapto-2-decyl-mercapto)-l-propyl ester 9. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-undecylmercapto-2-decyloxy)-1-propyl ester 10. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-tridecylmercapto-2-decyloxy)-1-propyl ester 11. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-tridecylmercapto-2-decyloxy)-1-propyl ester 12. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-dodecylmercapto-2-dodecyloxy)-1-propyl ester 13. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-dodecylmercapto-2-undecyloxy)-1-propyl ester 14. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(2,3-bis(dodecylmercapto)-1-propyl ester 15. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-dodecylmercapto-2-dodecyloxy)-1-propyl ester 16. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-undecyloxy-2-dodecyloxy)-1-propyl ester 17. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-decylsulfonyl-2-dodecyloxy)-1-propyl ester 18. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-decyloxy-2-decyloxy)-l-propyl ester 19. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-dodecylmercapto-2-dodecyloxy)-1-propyl ester 20. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-tetradecylmercapto-2-decyloxy)-l-propyl ester 21. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-pentadecylmercapto-2-decyloxy)-1-propyl ester 22. 2'-(9-{[(1-hydroxymethyl)ethoxy]methyl}guanine)-phosphoric acid-(3-tridecylmercapto-2-decyloxy)-1-propyl ester 23. 2'-[9-(ethoxymethyl)guanine]phosphoric acid-(3-dodecylmercapto-2-octyloxy)-1-propyl ester 21410~0 Example Phosphoric acid-(3-dodecYlmercapto-2-decyloxy)-1-propyl ester A suspension of 4.26 g P4Olo in 60 ml absolute pyridine was admixed at room temperature with 13 ml hexamethyldisiloxane and heated to 100C for 1 hour. It was then slightly cooled, admixed with 25 g 3-dodecylmercapto-2-decyloxy-1-propanol and heated for a further 2.5 hours to 100C.
After completely cooling to room temperature and removing the highly volatile components in a vacuum, the phosphate could be extracted with ether from the aqueous suspension of the residue. The evaporation residue of the ether phase was purified by column chromatography on silica gel 60 or RP 18. Yield 18.7 g (63 %), Rf = 0.66 (CH2C12/MeOH/H20 6.5/2.5/0.4) on TLC plates, Merck 5715, silica gel 60.
Example 2 2'-(9-~ r tl-hydroxymethyl)ethoxYlmethyl~guanine)Phos-phoric acid-(3-dodecylmercapto-2-decyloxy)-1-~ropyl ester 1.45 g (3 mmol) phosphoric acid-(3-dodecylmercapto-2-decyloxy)-l-propyl ester and 770 mg (3 mmol) Ganciclovir were twice admixed with 20 ml absolute pyridine each time and evaporated. The residue was taken up in 20 ml absolute pyridine, 2.7 g (8.5 mmol) 2,4,6-triisopropyl-benzenesulfonic acid chloride was added under nitrogen and it was stirred for 24 hours at 40C. Then 10 ml water was added, the mixture was stirred for a further 2 hours at room temperature and the solvent was removed in a rotary evaporator.
The oily residue was freed from residual pyridine by evaporation with toluene and purified by means of column chromatography on RP 18 with a linear gradient of methanol/water 7/3 to 9.S/0.5 as the eluant. Yield 0.75 g (34 ~ of theory), oil. Rf = 0.73 (H20/MeOH
0.5/9.5) on RP 8, Rf = O . 30 (CH2C12/MeOH/H20 6.5/2.5/0.4) on TLC plates, Merck 5715, silica gel 60 F.
Example 3 2'- r 9-(ethoxYmethYl)quanine~phosPhoric acid-(3-dodecyl-mercapto-2-decyloxy)-1-proPYl ester This compound was produced analogously to example 1 from Acyclovir in a 47 % yield, oil, Rf = 0.77 (H20/MeOH
0.5/9.5) on RP 8, Rf = O . 35 (CH2C12/MeOH/H20 6.5/2.5/0.4) on TLC plates, Merck 5715, silica gel 60.
Claims (11)
1. Liponucleotides of formula I
(I) in which R1 denotes a straight-chained or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms which can be substituted if desired once or several times by phenyl, halogen, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkoxycarbonyl, C1-C6 alkylsulfinyl or C1-C6 alkylsulfonyl groups, R2 denotes a straight-chained or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms which can be substituted if desired once or several times by phenyl, halogen, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkoxycarbonyl, C1-C6 alkylsulfinyl or C1-C6 alkylsulfonyl groups, R3 denotes hydrogen or a C1-C6 alkyl group which is substituted if desired by hydroxy, R4 can be hydrogen, hydroxy, amino or an amino group substituted once or twice by C1-C6 alkyl, R5 can be hydrogen, hydroxy, amino or an amino group substituted once or twice by C1-C6 alkyl, X represents a valency dash, oxygen, sulphur, sulfinyl or sulfonyl, Y has the same meaning as X and the two groups X
and Y can be the same or different, Z can be oxygen or sulphur, their tautomers and their physiologically tolerated salts of inorganic and organic acids and bases.
(I) in which R1 denotes a straight-chained or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms which can be substituted if desired once or several times by phenyl, halogen, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkoxycarbonyl, C1-C6 alkylsulfinyl or C1-C6 alkylsulfonyl groups, R2 denotes a straight-chained or branched, saturated or unsaturated alkyl chain with 1-20 carbon atoms which can be substituted if desired once or several times by phenyl, halogen, C1-C6 alkoxy, C1-C6 alkylmercapto, C1-C6 alkoxycarbonyl, C1-C6 alkylsulfinyl or C1-C6 alkylsulfonyl groups, R3 denotes hydrogen or a C1-C6 alkyl group which is substituted if desired by hydroxy, R4 can be hydrogen, hydroxy, amino or an amino group substituted once or twice by C1-C6 alkyl, R5 can be hydrogen, hydroxy, amino or an amino group substituted once or twice by C1-C6 alkyl, X represents a valency dash, oxygen, sulphur, sulfinyl or sulfonyl, Y has the same meaning as X and the two groups X
and Y can be the same or different, Z can be oxygen or sulphur, their tautomers and their physiologically tolerated salts of inorganic and organic acids and bases.
2. Liponucleotides as claimed in claim 1, wherein R1 denotes a straight-chained C9-C14 alkyl group which can be substituted by a C1-C6 alkoxy or a C1-C6 alkylmercapto group.
3. Liponucleotides as claimed in claim 2, wherein Rl denotes a decyl, undecyl, dodecyl, tridecyl or tetradecyl group which can be substituted by a methoxy, ethoxy, butoxy, hexyloxy, methylmercapto, ethylmercapto, propylmercapto, butylmercapto or hexylmercapto group.
4. Liponucleotides as claimed in one of the claims 1-3, wherein R2 denotes a straight-chained C9-C14 alkyl group which can be substituted by a C1-C6 alkoxy or C1-C6 alkylmercapto group.
5. Liponucleotides as claimed in claim 4, wherein R2 denotes a decyl, undecyl, dodecyl, tridecyl or tetradecyl group which can be substituted by a methoxy, ethoxy, propoxy, butoxy, hexyloxy, methylmercapto, ethylmercapto, butylmercapto or hexylmercapto group.
6. Liponucleotides as claimed in one of the claims 1-5, wherein R3 denotes hydrogen or hydroxy C1-C6 alkyl.
7. Liponucleotides as claimed in one of the claims 1-6, wherein R4 denotes hydroxy or amino.
8. Liponucleotides as claimed in one of the claims 1-7, wherein R5 denotes hydrogen or amino.
9. Process for the production of liponucleotides of formula I as claimed in one of the claims 1-8, wherein a) a compound of formula II, in which R1, R2, X, Y and Z have the stated, meanings is reacted in an inert solvent with a compound of the general formula III, ( III) in which R3, R4 and R5 have the above-mentioned meaning, using a condensing agent and after completion of hydrolysis the oxygen protecting groups which may be present are cleaved off if desired according to conventional methods in nucleoside chemistry or 2. a compound of formula IV
(IV) in which R1, R2, X, Y and Z have the above-mentioned meanings is reacted with a compound of formula III, in which R3, R4 and R5 have the stated meanings, in the presence of phospholipase D in an inert solvent in the presence of a suitable buffer and after the reaction is completed the oxygen protecting group which may be present is cleaved off if desired according to conventional methods in nucleoside chemistry, and subsequently compounds of formula I are converted into their physiologically tolerated salts if desired.
(IV) in which R1, R2, X, Y and Z have the above-mentioned meanings is reacted with a compound of formula III, in which R3, R4 and R5 have the stated meanings, in the presence of phospholipase D in an inert solvent in the presence of a suitable buffer and after the reaction is completed the oxygen protecting group which may be present is cleaved off if desired according to conventional methods in nucleoside chemistry, and subsequently compounds of formula I are converted into their physiologically tolerated salts if desired.
10. Pharmaceutical agent containing at least one liponucleotide of formula I as claimed in one of the claims 1-8 as well as further conventional pharmaceutical auxiliary or carrier substances.
11. Use of liponucleotides of formula I as claimed in one of the claims 1-8 for the production of pharmaceutical agents for the treatment of viral or retroviral infections.
Applications Claiming Priority (2)
| 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 |
| DEP4226279.8 | 1992-08-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2141030A1 true CA2141030A1 (en) | 1994-02-09 |
Family
ID=6465143
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002141030A Abandoned CA2141030A1 (en) | 1992-08-08 | 1993-08-06 | Liponucleotides of seco-nucleosides, their production as well as their use as antiviral pharmaceutical agents |
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|---|---|
| EP (1) | EP0654036B1 (en) |
| JP (1) | JP3479299B2 (en) |
| KR (1) | KR100243440B1 (en) |
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| AT (1) | ATE152114T1 (en) |
| AU (1) | AU672994B2 (en) |
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| TW (1) | TW306924B (en) |
| WO (1) | WO1994003465A1 (en) |
| ZA (1) | ZA935718B (en) |
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|---|---|---|---|---|
| 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 |
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| 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 |
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1992
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1993
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| EP0654036B1 (en) | 1997-04-23 |
| KR100243440B1 (en) | 2000-03-02 |
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| 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 |
| GR3023960T3 (en) | 1997-09-30 |
| NO950445L (en) | 1995-02-07 |
| IL106588A (en) | 1998-01-04 |
| 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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