FI109699B - Process for the preparation of pharmacologically active liponucleotides of seconucleosides - Google Patents
Process for the preparation of pharmacologically active liponucleotides of seconucleosides Download PDFInfo
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- FI109699B FI109699B FI950533A FI950533A FI109699B FI 109699 B FI109699 B FI 109699B FI 950533 A FI950533 A FI 950533A FI 950533 A FI950533 A FI 950533A FI 109699 B FI109699 B FI 109699B
- Authority
- FI
- Finland
- Prior art keywords
- alkyl
- substituted
- mercapto
- group
- amino
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 14
- 238000002360 preparation method Methods 0.000 title claims description 9
- 239000002777 nucleoside Substances 0.000 claims abstract description 12
- -1 C - Chemical group 0.000 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 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
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000003545 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
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000003277 amino group Chemical class 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 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
- 150000002431 hydrogen Chemical class 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
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 239000011593 sulfur Substances 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
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 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
- 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
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 2
- 150000002367 halogens Chemical class 0.000 claims 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims 1
- 238000003776 cleavage reaction Methods 0.000 claims 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- 230000007017 scission Effects 0.000 claims 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims 1
- 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 1
- 229910019142 PO4 Inorganic materials 0.000 abstract description 3
- 239000003443 antiviral agent Substances 0.000 abstract description 3
- 150000002632 lipids Chemical class 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
- 150000003904 phospholipids 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
- 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 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- 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 11
- YZPZJYIBJTVVKO-UHFFFAOYSA-N 2-amino-9-(3-hydroxypropoxymethyl)-3h-purin-6-one Chemical compound O=C1NC(N)=NC2=C1N=CN2COCCCO YZPZJYIBJTVVKO-UHFFFAOYSA-N 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 238000011282 treatment Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 229960004150 aciclovir Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 125000003835 nucleoside group Chemical group 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- UYTPUPDQBNUYGX-UHFFFAOYSA-N Guanine Natural products O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000004480 active ingredient 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
- 229940079593 drug Drugs 0.000 description 3
- 229960002963 ganciclovir Drugs 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
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 description 3
- RMLUKZWYIKEASN-UHFFFAOYSA-M sodium;2-amino-9-(2-hydroxyethoxymethyl)purin-6-olate Chemical compound [Na+].O=C1[N-]C(N)=NC2=C1N=CN2COCCO RMLUKZWYIKEASN-UHFFFAOYSA-M 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
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- 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 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
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-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
- 102000011420 Phospholipase D Human genes 0.000 description 2
- 108090000553 Phospholipase D Proteins 0.000 description 2
- 235000018734 Sambucus australis Nutrition 0.000 description 2
- 244000180577 Sambucus australis Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000002585 base Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 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
- 150000004665 fatty acids Chemical group 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000005843 halogen group Chemical group 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
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 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
- 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
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000002265 prevention Effects 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
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-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
- YHGKEORTCHVBQH-UHFFFAOYSA-N 2,4,6-tri(propan-2-yl)benzenesulfonic acid Chemical compound CC(C)C1=CC(C(C)C)=C(S(O)(=O)=O)C(C(C)C)=C1 YHGKEORTCHVBQH-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
- UNJXYMOJQGIKHE-UHFFFAOYSA-N 3-(3-decylsulfonyldodecan-2-yloxy)propyl dihydrogen phosphate Chemical compound C(CCCCCCCCC)S(=O)(=O)C(C(C)OCCCOP(O)(O)=O)CCCCCCCCC UNJXYMOJQGIKHE-UHFFFAOYSA-N 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
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- LFKICVDRNDDVQA-UHFFFAOYSA-N C(CCCCCCCCC)SC(C(C)OCCCOP(O)(O)=O)CCCCCCCCC Chemical compound C(CCCCCCCCC)SC(C(C)OCCCOP(O)(O)=O)CCCCCCCCC LFKICVDRNDDVQA-UHFFFAOYSA-N 0.000 description 1
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- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 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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- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 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
- 102000004357 Transferases Human genes 0.000 description 1
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- 208000036142 Viral infection Diseases 0.000 description 1
- 208000010094 Visna Diseases 0.000 description 1
- 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 1
- WTHXTWHYLIZJBH-UHFFFAOYSA-N acetic acid;azane Chemical compound N.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O WTHXTWHYLIZJBH-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- IERHLVCPSMICTF-XVFCMESISA-N cytidine 5'-monophosphate Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(O)=O)O1 IERHLVCPSMICTF-XVFCMESISA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 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
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 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
- 229960000689 nevirapine Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 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
- 238000007911 parenteral administration Methods 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
- 229940067631 phospholipid Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 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
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000004434 sulfur atom Chemical group 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
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 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
- 239000003981 vehicle Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
109699109699
Menetelmä farmakologisesti aktiivisten seco-nukleosidien liponukleotidien valmistamiseksi - Förfarande för framställning av farmakologiskt aktiva lipo-nukleotider av seco-nukleosider 5 Esillä olevan keksinnön kohteena on menetelmä uusien seco-nukleosidien fosfolipi-dijohdannaisten valmistamiseksi, joissa lipidiosa, jossa on substituoitu C3-perusrakenne, on kytketty seco-nukleosidiin fosfaatin tai tiofosfaatin kautta. Näitä yhdisteitä voidaan käyttää virusten vastaisina lääkkeinä.The present invention relates to a process for the preparation of novel phospho-lipid moiety of the C-linked lipid moiety, which has a C-linked lipid moiety. seco nucleoside via phosphate or thiophosphate. These compounds can be used as antiviral drugs.
Näin ollen keksintö kohdistuu menetelmään farmakologisesti aktiivisten liponukle -10 otidien valmistamiseksi, kaava I: —X—R1 R4Accordingly, the present invention relates to a process for the preparation of pharmacologically active liponucle-10 otides of formula I: -X-R 1
-Y-R2 I-Y-R2 I
i / j ΐ I—o—P—o-1 N-^\N^\R5 /0\Ι OH \ ^ R3 (I)i / j ΐ I-o-P-o-1 N - ^ \ N ^ \ R5 / 0 \ Ι OH \ ^ R3 (I)
I t II t I
; ; * jossa R1 on suoraketjuinen tai haaroittunut, tyydyttynyt tai tyydyttämätön alkyyliketju, :jossa on 1-20 hiiliatomia ja joka mahdollisesti voi olla substituoitu yhden tai use-·...· ämmän kerran fenyyli-, halogeeni-, CrC6-alkoksi-, CrC6-alkyylimerkapto-, Ci-C0· : 15 alkoksikarbonyyli-, Q-Ce-alkyylisulfinyyli- tai Q-Cö-alkyylisulfonyyliryhmällä, • « · R on suoraketjuinen tai haaroittunut, tyydyttynyt tai tyydyttämätön alkyyliketju, jossa . on 1-20 hiiliatomia ja joka mahdollisesti voi olla substituoitu yhden tai useamman ker ran fenyyli-, halogeeni-, Ci-Cö-alkoksi-, Ci-C6-alkyylimerkapto-, Ci-C6-•; · * alkoksikarbonyyli-, Q -C6-alkyylisulfinyyli- tai Ci-Cö-alkyyhsulfonyyliryhmällä, 20 R on vety tai mahdollisesti hydroksilla substituoitu Ci-C6-alkyyliryhmä, R4 voi olla vety, hydroksi, amino tai yhden kerran tai kaksi kertaa Ci-C6-alkyylillä ....: substituoitu aminoryhmä, R5 voi olla vety, hydroksi, amino tai yhden kerran tai kaksi kertaa Ci-Cö-alkyylillä substituoitu aminoryhmä, 2 109699 X on valenssiviiva, happi, rikki, sulfmyyli tai sulfonyyli, Y:llä on sama merkitys kuin X:llä, jolloin kummatkin ryhmät X ja Y voivat olla samanlaisia tai erilaisia, Z voi olla happi tai rikki, 5 niiden tautomeerien ja niiden fysiologisesti siedettävien, ei-orgaanisten tai orgaanisten happojen tai emästen suolojen valmistamiseksi.; ; * wherein R 1 is a linear or branched, saturated or unsaturated alkyl chain: having 1-20 carbon atoms, which may be optionally substituted one or more times with phenyl, halo, C 1 -C 6 alkoxy, C 1 -C 6 alkylmercapto, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylsulfinyl or C 1 -C 6 alkylsulfonyl, • R is a linear or branched, saturated or unsaturated alkyl chain in which. has 1-20 carbon atoms and may be optionally substituted one or more times with phenyl, halo, C 1 -C 6 alkoxy, C 1 -C 6 alkyl mercapto, C 1 -C 6; · * Alkoxycarbonyl, C 1 -C 6 alkylsulfinyl or C 1 -C 6 alkylsulfonyl group, R 2 is hydrogen or a C 1 -C 6 alkyl group optionally substituted by hydroxy, R 4 may be hydrogen, hydroxy, amino or C 1 -C 6 once or twice alkyl ....: substituted amino group, R 5 may be hydrogen, hydroxy, amino or a once or twice C 1 -C 6 alkyl substituted amino group, 2 109699 X is a valence line, oxygen, sulfur, sulfmyl or sulfonyl, Y has the same as X, wherein both X and Y may be the same or different, Z may be oxygen or sulfur, for the preparation of their tautomers and their physiologically tolerable, inorganic or organic acid or base salts.
Kaavan I mukaiset yhdisteet voidaan keksinnön mukaisesti valmistaa oheisen patenttivaatimuksen 1 tunnusmerkkiosassa esitetyillä menetelmillä.The compounds of formula I according to the invention may be prepared by the methods set forth in the characterizing part of the appended claim 1.
Koska yleisen kaavan I mukaiset yhdisteet sisältävät asymmetrisiä hiiliatomeja, 10 keksinnön kohteena on myös näiden yhdisteiden kaikkien optisesti aktiivisten muotojen ja raseemisten seosten valmistus.Because the compounds of general formula I contain asymmetric carbon atoms, the invention also relates to the preparation of all optically active forms and racemic mixtures of these compounds.
J. Biol. Chem. 265:ssä, 6112 (1990) ja EP-0 350 287:ssä kuvataan liponukleotidien valmistaminen ja käyttö virusten vastaisina lääkkeinä. Tällöin tutkittiin ja syntetoi -tiin kuitenkin vain tunnettuja nukleosideja, kuten esimerkiksi AZT:tä (atsidotymi-15 diiniä) ja ddC:tä (didesoksisytidiiniä), kytkettyjä dimyristoyylifosfatidyyli- ja di-palmitoyylifosfatidyylitähteitä ja niiden rasvahapporakennetta. EP-0 350 287:ssä kuvataan glyseriinin vastaavia 1,2-diestereitä.J. Biol. Chem. 265, 6112 (1990) and EP-0 350 287 describe the preparation and use of liponucleotides as antiviral drugs. However, only known nucleosides such as AZT (azidothymic-15-dine) and ddC (didesoxycytidine), linked dimyristoyl phosphatidyl and di-palmitoyl phosphatidyl residues and their fatty acid structure were then studied and synthesized. EP-0 350 287 describes the corresponding 1,2-diesters of glycerin.
J. Med. Chem 33:ssa, 1380 (1990) kuvataan tioeetterilipidien nukleosidikonjugaat- : . ·. teja, joissa on sytidiinifosfaattia ja joilla on virusten vastainen vaikutus, sekä käyt- * · · 20 töäonkologiassa.J. Med. Chem 33, 1380 (1990) describes nucleoside conjugates of thioether lipids. ·. strains with cytidine phosphate and antiviral activity; and * · · 20 in oncology.
»« · i. : Chem. Pharm. Bull. 36:ssa (1988) kuvataan 5'-(3-SN-fosfatidyyli)nukleosideja, joil- • I » :, ·’ ·’ la on leukemian vastaista vaikutusta, sekä niiden entsymaattista synteesiä vastaavista nukleosideista ja fosfokoliineista fosfolipaasi D:n, jolla on transferaasiaktiivi-•; · · · suutta, läsnäollessa.»« · I .: Chem. Pharm. Bull. 36 (1988) describes 5 '- (3-SN-phosphatidyl) nucleosides having anti-leukemia activity, and their corresponding enzymatic synthesis of nucleosides and phosphocholines with phospholipase D having is transferase active; · · · Mouth, in the presence.
*;·' 25 Patenttihakemuksessa PCT/EP91/01541 kuvataan liponukleotideja, joissa on sokej : V: riosuus nukleosidissa sekä virusten vastainen vaikutus.Patent Application PCT / EP91 / 01541 describes liponucleotides having a nucleoside-blind and anti-viral activity.
* ** *
Acyklovir-fosfolipidikonjugaatti, joka koostuu L-alfa-dimyristoyylifosfatidyyli-haposta ja Acykloviristä, on kuvattu Acta Chem. Scnad. Ser. B 39:ssä, 47 (1985) : [vertaa myös Organophosphorus Chem. 18, 187 (1987)].Acyclovir phospholipid conjugate consisting of L-alpha-dimyristoyl phosphatidylic acid and Acyclovir is described in Acta Chem. Scnad. Ser. B 39, 47 (1985): [compare also Organophosphorus Chem. 18, 187 (1987)].
3 1096993, 109699
Esillä olevan keksinnön mukaisesti valmistetut eetteri/tioeetterilipidit (X, Y = O tai S) ovat uusia ja niissä on samaten arvokkaita farmakologisia ominaisuuksia. Ne sopivat erityisesti sellaisten infektioiden hoitoon ja ennaltaehkäisyyn, jotka aiheutuvat DNA-viruksista, kuten esim. Herpes simplex -viruksesta, sytomegaloviruksesta, pa-5 pillooma-viruksista, vesirokko-vyöruusu viruksesta tai Epstain Barr -viruksesta tai RNA-viruksista, kuten toogaviruksista, tai retroviruksista, kuten onko-viruksista HTLV-II ja II, sekä lentiviruksista Visna ja ihmisen immuunikatoviruksesta HIV-1 ja 2.The ether / thioether lipids (X, Y = O or S) prepared according to the present invention are novel and also have valuable pharmacological properties. They are particularly suitable for the treatment and prevention of infections caused by DNA viruses such as Herpes simplex virus, cytomegalovirus, p-5 pomaoma virus, chickenpox virus or Epstain Barr virus or RNA viruses such as toogaviruses, or retroviruses such as the onset viruses HTLV-II and II, and lentiviruses Visna and human immunodeficiency virus HIV-1 and 2.
Yleisen kaavan I mukaiset yhdisteet ovat erityisen sopivia ihmisen virusperäisen 10 herpes-infektion kliinisten ilmenemismuotojen hoitamiseen. Yleisen kaavan I mukaiset yhdisteet vaikuttavat virusten vastaisesti ilman, että ne ovat farmakologisesti relevantteina annoksina sytotoksisia.The compounds of general formula I are particularly suitable for the treatment of clinical manifestations of human viral herpes infection. The compounds of general formula I act against viruses without being cytotoxic at pharmacologically relevant doses.
Lisäksi yhdisteillä on erittäin hyvä oraalinen siedettävyys hyvässä biosaatavuudessa.In addition, the compounds have very good oral tolerability with good bioavailability.
15 Esillä olevan keksinnön mukaisesti valmistettuja yhdisteitä ja niiden farmaseuttisia valmisteita voidaan käyttää myös yhdessä muiden lääkeaineiden kanssa edellä mai nittujen infektioiden hoitoon ja ennaltaehkäisyyn. Esimerkit näistä muista lääkeaineista käsittävät aineet, jotka ovat käyttökelpoisia HIV-infektioiden tai tätä sairautta seuraavien sairausten hoitoon tai ennaltaehkäisyyn, kuten 3'-atsido-3'-desoksitymi- : 20 diini (AZT), 2',3'-didesoksinukleosidit, kuten 2',3'-didesoksysytidiini (ddC), • · · • 2',3'-didesoksiadenosiini ja 2',3'-didesoksi-inosiini (ddl) tai ei-nukleosidiset RT-·,· · inhibiittorit, kuten HEPT, nevirapiini tai L-697m661, ja vastaavat johdannaiset.The compounds of the present invention and their pharmaceutical preparations can also be used in combination with other drugs for the treatment and prevention of the aforementioned infections. Examples of these other drugs include agents useful in the treatment or prophylaxis of HIV infections or diseases following this disease, such as 3'-azido-3'-deoxythymin: AZT, 2 ', 3'-didesoxynucleosides, such as 2 ', 3'-didesoxycytidine (ddC), • · · • 2', 3'-didesoxyadenosine and 2 ', 3'-didesoxy-inosine (ddl) or non-nucleoside RT-, · · inhibitors such as HEPT, nevirapine or L-697m661, and related derivatives.
Esillä olevan keksinnön mukaisesti valmistetut yhdisteet ja muu lääkeaine voidaan • : *: antaa kulloinkin yksittäin, samanaikaisesti mahdollisesti tapauksessa yhtenä tai kah- » « · · . *: ’. 25 tena erillisenä formulointina tai eri aikoina.The compounds of the present invention and the other drug may be administered individually, concurrently, optionally in one or two instances. *: '. 25 separate formulation or at different times.
• · ·• · ·
Yleisen kaavan (I) mukaisten yhdisteiden mahdollisina suoloina tulevat kyseeseen ennen kaikkea fosfaattiryhmän alkali-, maa-alkali- ja ammoniumsuolat. Alka-lisuoloina ovat edullisia litium-, natrium- ja kaliumsuolat. Maa-alkalisuoloina tule-. v. vat kyseeseen erityisesti magnesium- ja kalsiumsuolat. Ammoniumsuoloina ymmär ,·’··, 30 retään keksinnön mukaisesti suolat, jotka sisältävät ammoniumionin, joka voi olla korkeintaan nelinkertaisesti substituoitu 1-4 hiiliatomilla ja/tai aralkyylitähteillä, edullisesti bentsyylitähteillä. Substituentit voivat olla tällöin samanlaisia tai erilai- » ': : siä.Possible salts of the compounds of the general formula (I) include, in particular, the alkali, alkaline earth and ammonium salts of the phosphate group. Preferred alkali salts are the lithium, sodium and potassium salts. The alkaline salts of fire. v. especially the magnesium and calcium salts. As ammonium salts, it is understood that according to the invention, salts containing an ammonium ion which may be up to four times substituted with 1-4 carbon atoms and / or aralkyl radicals, preferably benzyl radicals, are not excluded. The substituents may then be the same or different.
4 1096994, 109699
Yleisen kaavan I mukaiset yhdisteet voivat sisältää emäksisiä ryhmiä, erityisesti aminoryhmiä, jotka voidaan muuttaa sopivilla orgaanisilla tai ei-orgaanisilla hapoilla happoadditiosuoloiksi. Happoina tätä varten tulevat kyseeseen esimerkiksi suolahapot, bromivetyhappo, rikkihappo, fosforihappo, fumaarihappo, meripihkahappo, 5 viinihappo, sitruunahappo, maitohappo, maleiinihappo tai metaanisulfonihappo.The compounds of general formula I may contain basic groups, in particular amino groups, which can be converted into acid addition salts with suitable organic or inorganic acids. Suitable acids for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, tartaric acid, citric acid, lactic acid, maleic acid or methanesulfonic acid.
Yleisessä kaavassa I on edullisesti suoraketjuinen C9-C \4-alkyyliryhmä, joka voi olla substituoitu Ci-Cg-alkoksilla tai C j-Cg-alkyylimerkaptoryhmällä. R^ on erityisesti dekyyli-, undekyyli-, dodekyyli-, tridekyyli- tai tetradekyyliryhmä. R^:n Cj-Cg-alkoksisubtituentteina tulevat kyseeseen edullisesti metoksi-, etoksi-, butok-10 si- ja heksyylioksiryhmät. Jos R^ on substituoitu C j-C^-alkyylimerkaptotähteellä, ymmärretään sillä erityisesti metyylimerkapto-, etyylimerkapto-, propyylimerkap-to-, butyylimerkapto- ja heksyylimerkaptotähdettä.The general formula I preferably has a straight-chained C9-C4 alkyl group which may be substituted by C1-C8 alkoxy or a C1-C8 alkyl mercapto group. In particular, R 4 is a decyl, undecyl, dodecyl, tridecyl or tetradecyl group. Preferably, C 1-4 C 8 alkoxy substituents on R 1 are methoxy, ethoxy, butoxy-10 and hexyloxy groups. When R 4 is substituted with a C 1 -C 6 alkyl mercapto residue, it is particularly understood to be a methyl mercapto, ethyl mercapto, propyl mercapto, butyl mercapto and hexyl mercapto residue.
R2 on edullisesti suoraketjuinen C9-C 14-alkyyliryhmä, joka voi olla substituoitu vielä Cj-Cg-alkoksilla tai C \ -Cg-alkyylimerkaptoryhmällä. R2 on erityisesti dekyy-15 li-, undekyyli-, dodekyyli-, tridekyyli- tai tetradekyyliryhmä. R2:n C i-Cg-alkoksisubtituentteina tulevat kyseeseen edullisesti metoksi-, etoksi-, pro-poksi-, butoksi- ja heksyylioksiryhmät. Jos R2 on substituoitu C j-Cg-alkyylimer-kaptotähteellä, ymmärretään sillä erityisesti metyylimerkapto-, etyylimerkapto-, butyylimerkapto- ja heksyylimerkaptotähdettä.Preferably R 2 is a straight-chain C 9 -C 14 alkyl group which may be further substituted by C 1 -C 8 alkoxy or C 1 -C 8 alkyl mercapto group. In particular, R2 is a decyl, undecyl, dodecyl, tridecyl or tetradecyl group. Preferred C 1 -C 8 alkoxy substituents on R 2 are preferably methoxy, ethoxy, propoxy, butoxy and hexyloxy groups. When R 2 is substituted with a C 1 -C 8 alkylmercaptic residue, it is particularly understood to be a methylmercapto, ethylmercapto, butylmercapto and hexylmercaptic residue.
* » * : 20 R3:n määrittelysssä tarkoittaa alkyyliryhmä erityisesti suoraketjuista tai haaroitta· « · · • V nutta alkyyliryhmää, jossa on edullisesti korkeintaan neljä C-atomia, kuten metyy- : : *: liä, etyyliä, n-propyyliä, isopropyyliä tai n-butyyliä. Nämä alkyyliryhmät on substi- tuoitu edullisesti yhdellä tai kahdella hydroksiryhmällä, kuten hydroksimetyylillä, : 2-hydroksietyylillätai 3-hydroksipropyylillä.* »*: In the definition of R3," alkyl "means in particular a straight chain or branched alkyl group preferably having up to four C atoms, such as methyl: *, ethyl, n-propyl, isopropyl or n-butyl. These alkyl groups are preferably substituted with one or two hydroxy groups such as hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl.
• · · · ti» • · » *·’ ' 25 Ci-Cg-alkyyliryhmät ovat yleensä suoraketjuisia tai haaroittuneita alkyylitähteitä, joissa on edullisesti korkeintaa neljä hiiliatomia, kuten metyyli, etyyli, n-propyyli, ' isopropyyli, n-butyyli tai isobutyyli.C 1 -C 8 alkyl groups are generally straight-chain or branched alkyl radicals having preferably up to four carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl. .
• ·» • · . · / on edullisesti hydroksi- tai aminoryhmä.• · »• ·. Is preferably a hydroxy or amino group.
* » · • f : “ *: R^ on erityisesti vety tai hydroksi- tai aminoryhmä.* »· • f:“ *: R 4 is especially hydrogen or hydroxy or amino.
:: 30 X ja Y ovat edullisesti happi- tai rikkiatomi. Z on edullisesti happiatomi.X and Y are preferably an oxygen or sulfur atom. Preferably Z is an oxygen atom.
Erityisen edullisia kytkettyjä seco-nukleosideja yleisen kaavan I mukaisissa lipo·· nukleotideissa ovat Ganciclovir ja Acyklovir.Particularly preferred coupled seco nucleosides in lipo ··· nucleotides of general formula I are Ganciclovir and Acyklovir.
5 1096995, 109699
Yleisen kaavan I mukaiset yhdisteet voidaan valmistaa 1. saattamalla yhdiste, jolla on kaava II: -X-R1 -Y-R2Compounds of general formula I may be prepared by: 1. Compound II: -X-R 1 -Y-R 2
ZZ
IIII
-O-P-OH-O-P-OH
I OH (II) jossa Rl;n, R^.n, X:n, Y:n ja Z:n merkitykset ovat edellä mainitut, ja yhdiste, jolla 5 on kaava III: R4 0H—I ΐ''^ιΤ'ν • R (III) * · · • 1 · . · · ·. jossa R^ :n, R^:n ja R^.n merkitykset ovat edellä annetut, reagoimaan kondensointi- : ", aineen, kuten DCC:n (disykloheksyylikarbodi-imidi), kanssa pyridiinissä taiI OH (II) wherein R 1, R 4, X, Y and Z have the meanings given above, and a compound of Formula III: R 4 OH-I ΐ '' ^ ιΤ ' ν • R (III) * · · • 1 ·. · · ·. wherein R 4, R 4 and R 4 have the meanings given above, to react with a condensing agent such as DCC (dicyclohexylcarbodiimide) in pyridine or
• t I• t I
‘il. ‘ 2,4,6-tri-isopropyylibentseenisulfonihappokloridin ja tertiaarisen typpiemäksen, ku- • 10 ten pyridiinin tai lutidiinin läsnä ollessa inertissä liuottimessa, kuten tolueenissa tai suoraan pyridiinissä ja tapahtuneen hydrolyysin jälkeen happisuojaryhmät lohkais-‘ ' taan mahdollisesti vastaavasti nukleosidikemiassa tavanomaisilla menetelmillä, tai » 6 109699 2. saattamalla yhdiste, jolla on kaava IV: -X-R1 -Y-R2 CH3 z +Il. In the presence of '2,4,6-triisopropylbenzenesulfonic acid chloride and a tertiary nitrogen base such as pyridine or lutidine in an inert solvent such as toluene or directly in pyridine and after hydrolysis, the oxygen protecting groups may be cleaved or 6 109699 2. by reacting a compound of formula IV: -X-R 1 -Y-R 2 CH 3 z +
Il y-N+-CH3 -o—P—o-' ch3 o- (IV) jossa R1 :n, R^-.n, X:n, Y:n ja Z:n merkitykset ovat edellä mainitut, reagoimaan kaavan III mukaisen yhdisteen kanssa, jossa R^:n, R^:n ja R^:n merkitykset ovat edellä 5 annetut, fosfolipaasi D:n läsnä ollessa inertissä liuottimessa, kuten kloroformissa, sopivan puskurin läsnä ollessa ja tapahtuneen reaktion jälkeen happisuojaryhmät mahdollisesti lohkaistaan vastaavasti nukleosidikemiassa tavanomaisilla menetelmillä.Il-N + -CH 3 -o-P-o- 'ch 30 -O- (IV) wherein R 1, R 1 -, N, X, Y and Z have the meanings given above for the reaction of formula III wherein R 1, R 4 and R 6 have the meanings given above, in the presence of phospholipase D in an inert solvent such as chloroform, in the presence of a suitable buffer, and after the reaction, the oxygen protecting groups are optionally cleaved accordingly in nucleoside chemistry. by conventional methods.
Kaavan II ja IV mukaisten yhdisteiden valmistaminen on kuvattu DE-39 29 10 217.7:ssä tai WO 91/05558:ssa.Preparation of compounds of formula II and IV is described in DE-39 29 10 217.7 or WO 91/05558.
Yleisen kaavan III mukaisten yhdisteiden valmistaminen on kuvattu Progress inThe preparation of compounds of general formula III is described in Progress
Vt Medicinal Chemistryssä, Voi. 23, 187 (1986) ja siinä viitatussa kiijallisuudessa.See Medicinal Chemistry, Vol. 23, 187 (1986) and in the quoted reference therein.
* · ; ',· Acyclovir ja Ganciclovir ovat kaupallisesti saatavissa.* ·; ', · Acyclovir and Ganciclovir are commercially available.
* * ** * *
Virusinfektoiden hoitoon tarkoitetut kaavan I mukaisia yhdisteitä sisältävät lääkkeet 15 voidaan antaa nestemäisessä tai kiinteässä muodossa enteraalisesti tai pa- · ;· renteraalisesti. Tällöin tulevat kyseeseen tavalliset antomuodot, kuten esimerkiksi ** * tabletit, kapselit, rakeet, siirapit, liuokset tai suspensiot. Injektointiväliaineena käy tetään edullisesti vettä, joka sisältää injektioliuoksissa tavanomaisia lisäaineita, ku- » ‘: ten stabilointiaineita, liuoksen välitysainetta ja puskuria. Tällaisia lisäaineita ovat ‘ ( ; 20 esim. tartraatti- ja sitraattipuskuri, etanoli, kompleksinmuodostaja, kuten etyleenidi-,v, amiinitetraetikkahappo ja sen ei-toksiset suolat, suurmolekyyliset polymeerit, kuten i * * ,. 1 nestemäinen polyetyleenioksidi viskositeetin säätöön. Injektointiliuoksiin tarkoitet- • « tujen nestemäisten kantoaineiden tulee olla steriilejä ja ne täytetään edullisesti am- »* · pulleihin. Kiinteitä kantoaineita ovat esimerkiksi tärkkelys, laktoosi, manniitti, ': ‘' i 25 suurmolekyyliset rasvahapot, kuten steariinihappo, gelatiini, agar-agar, kalsiumfos-faatti, magnesiumstearaatti, eläin- ja kasvirasvat, kiinteät suurmolekyyliset poly- 7 109699 meerit, kuten polyetyleeniglykoli jne. Oraaliseen antamiseen sopivat valmisteet voivat sisältää haluttaessa maku- tai makeutusaineita.Medicaments containing compounds of formula I for the treatment of viral infections may be administered in liquid or solid form by enteral or parenteral administration. Suitable forms of administration are, for example, ** tablets, capsules, granules, syrups, solutions or suspensions. Preferably, the injection medium is water, which contains conventional additives in injection solutions, such as stabilizers, solution vehicle and buffer. Such additives include (e.g., tartrate and citrate buffer, ethanol, a complexing agent such as ethylene di, v, amine tetraacetic acid and its non-toxic salts, high molecular weight polymers such as i * *, 1 liquid polyethylene oxide for controlling viscosity. Liquid carriers should be sterile and preferably filled in ampoules. Solid carriers include, for example, starch, lactose, mannitol, high molecular weight fatty acids such as stearic acid, gelatin, agar, calcium phosphate. , magnesium stearate, animal and vegetable fats, high molecular weight solid polymers such as polyethylene glycol, etc. Formulations suitable for oral administration may, if desired, contain flavoring or sweetening agents.
Annostus voi riippua erilaisista tekijöistä, kuten antotapa, laji, ikä tai yksilöllinen tila. Keksinnön mukaisesti valmistettuja yhdisteitä voidaan antaa tavallisesti määrinä 5 0,1-100 mg, edullisesti 0,2-80 mg päivässä ja ruumiin painokiloa kohti. On edullista jakaa päiväannos 2-5 antoon, jolloin jokaisessa annossa annetaan 1-2 tablettia, joiden vaikuttavan aineen pitoisuus on 0,5-500 mg. Tabletit voivat olla myös viivästettyjä, jolloin antamismäärä päivässä laskee l-3:een. Viivästettyjen tablettien vaikuttavan aineen pitoisuus voi olla 2-1000 mg. Vaikuttava aine voidaan antaa myös 10 jatkuvalla infuusiolla, jolloin normaalisti riittävät määrät 5-1000 mg päivässä.The dosage may depend on various factors such as the route of administration, the species, the age or the individual condition. The compounds of the invention may generally be administered in amounts of 0.1 to 100 mg, preferably 0.2 to 80 mg per day and per kg body weight. It is preferable to divide the daily dose into 2 to 5 administrations, with 1 to 2 tablets having an active ingredient concentration of 0.5 to 500 mg per dose. The tablets may also be delayed so that the daily dose is reduced to 1-3. Delayed tablets may have an active ingredient concentration of 2 to 1000 mg. The active ingredient can also be administered by 10 continuous infusions, normally in the range of 5 to 1000 mg per day.
Esillä olevan keksinnön hengessä tulevat kyseeseen esimerkeissä mainittujen yhdisteiden lisäksi seuraavat kaavan I mukaiset yhdisteet: 1. 2'-[9-(etoksimetyyli)guaniini]fosforihappo-(3 -dodekyyli-merkapto-2-dekyyli-oksi)-1-propyyliesteri 15 2. 2'-(9-{[(l-hydroksimetyyli)etoksi]metyyli}guaniini)fosforihappo-(3-dodekyyli- sulfinyyli-2-dekyylioksi)-l-propyyliesteri 3. 2-(9- {[(1 -hydroksimetyyli)etoksi]metyyli}guaniini)fosforihappo-(3 -dodekyyli- •. ·. sulfonyyli-2-dekyylioksi)- 1-propyyliesteri • · · : 4. 2'-(9-{[(l-hydroksimetyyli)etoksi]metyyli}guaniini)fosforihappo-(3-dodeky- : 20 ylimerkapto-2-dekyylioksi)-1-propyyliesteri ."5. 2'-[9-(etoksimetyyli)guaniini]fosforihappo-(3-undekyylimerkapto-2-dekyyli- • » · *". 1 oksi)-1 -propyyliesteri I < · 6. 2'-[9-(etoksimetyyli)guaniini]fosforihappo-(3-dodekyylioksi-2-dekyylioksi)-*: · · · 1 -propyyliesteri 25 7. 2'-(9-{[(l-hydroksimetyyli)etoksi]metyyli}guaniini)fosforihappo-(3-dodekyyli·· : V: merkapto-2-nonyylioksi)-1 -propyyliesteri ‘ ” 8. 2'-(9-{[(l-hydroksimetyyli)etoksi]metyyli}guaniini)fosforihappo-(3-dodekyyli- :: merkapto-2-dekyylioksi)-1 -propyyliesteri 9. 2-(9- {[(1 -hydroksimetyyli)etoksi]metyyli} guaniini)fosforihappo-(3 -undekyyli- 3 0 merkapto-2-dekyylioksi)-1 -propyyliesteri S 109699 10. 2'-[9-(etoksimetyyli)guaniini]fosforihappo-(3-tridekyylimerkapto-2-dekyyli-oksi)-1 -propyyliesteri 11. 2'-(9- {[(1 -hydroksimetyyli)etoksi]metyyli}guaniini)fosforihappo-(3 -tridekyy-limerkapto-2-dekyylioksi)-1 -propyyliesteri 5 12. 2'-[9-(etoksimetyyli)guaniini]fosforihappo-(3-dodekyylimerkapto-2-dode- kyylioksi)- 1-propyyliesteri 13. 2'-[9-(etoksimetyyli)guaniini]fosforihappo-(3 -dodekyylimerkapto-2-unde-kyylioksi)-1 -propyyliesteri 14. 2'-(9-{[(l-hydroksimetyyli)etoksi]metyyli}guaniini)fosforihappo(2,3-bis(do-10 dekyylimerkapto)-1-propyyliesteri 15. 2'-(9- {[(l-hydroksimetyyli)etoksi]metyyli} guaniim)fosforihappo-(3 -dekyyli-merkapto-2-dodekyylioksi)-1 -propyyliesteri 16. 2'-[9-(etoksimetyyli)guaniini]fosforihappo-(3 -undekyylimerkapto-2-dode-kyylioksi)- 1-propyyliesteri 15 17. 2'-[9-(etoksimetyyli)guaniini]fosforihappo-(3-dekyylisulfonyyli-2-dode- kyylioksi)- 1-propyyliesteri • · : . 18. 2,-[9-(etoksimetyyli)guaniini]fosforihappo-(3-dekyylioksi-2-dekyyli- J ,1. oksi)-1-propyyliesteri • · · I • · « :; 19. 2'-[9-(etoksimetyyli)guaniini]fosforihappo-(3-dodekyylmierkapto-2-dode- ·,· j 20 kyylioksi)-1-propyyliesteri 20. 2-(9- {[(1 -hydroksimetyyli)etoksi]metyyli} guaniini)fosforihappo-(3 -tetrade- . kyylimerkapto-2-dekyylioksi)-1 -propyyliesteri •' ’ ]: 21. 2'-[9-(etoksimetyyli)guaniini]fosforihappo-(3 -pentadekyylimerkapto-2- dekyylioksi)-1 -propyyliesteri * · · 25 22. 2'-(9-{[(l-hydroksimetyyli)etoksi]metyyli}guanimi)fosforihappo-(3-tridekyy- .···. limerkapto-2-dekyylioksi)- 1-propyyliesteri 1 : 23. 2'-[9-(etoksimetyyli)guaniini]fosforihappo-(3-dodekyyliinerkapto-2-oktyyli- oksi)- 1-propyyliesteri 9 109699In the spirit of the present invention, in addition to the compounds mentioned in the examples, the following compounds of formula I are useful: 1. 2 '- [9- (ethoxymethyl) guanine] phosphoric acid (3-dodecyl-mercapto-2-decyloxy) -1-propyl ester. 2 '- (9 - {[(1-hydroxymethyl) ethoxy] methyl} guanine) phosphoric acid (3-dodecylsulfinyl-2-decyloxy) -1-propyl ester 3. 2- (9 - {[(1-Hydroxymethyl) ) ethoxy] methyl} guanine) phosphoric acid (3-dodecyl-4 · sulfonyl-2-decyloxy) -1-propyl ester · · ·: 4. 2 '- (9 - {[(1-hydroxymethyl) ethoxy] methyl) } guanine) phosphoric acid (3-dodecyl: 20-mercapto-2-decyloxy) -1-propyl ester. "5,2 '- [9- (ethoxymethyl) guanine] phosphoric acid (3-undecylmercapto-2-decyl)» · * ". 1 oxy) -1-propyl ester I <· 6. 2 '- [9- (ethoxymethyl) guanine] phosphoric acid (3-dodecyloxy-2-decyloxy) *: · · · 1-propyl ester 25 7. 2 '- (9 - {[(1-hydroxymethyl) ethoxy] methyl} guanine) phosphoric acid (3-dodecyl ···: V: mercapto-2-nonyloxy) -1-prop opyl ester '' 8. 2 '- (9 - {[(1-hydroxymethyl) ethoxy] methyl} guanine) phosphoric acid (3-dodecyl :: mercapto-2-decyloxy) -1-propyl ester 9. 2- (9- {[(1-Hydroxymethyl) ethoxy] methyl} guanine) phosphoric acid (3-undecyl-30-mercapto-2-decyloxy) -1-propyl ester S 109699 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 5 12. 2 '- [9- (ethoxymethyl) guanine] phosphoric acid (3-dodecylmercapto-2-dodecyloxy) -1-propyl ester 13. 2' - [9- (ethoxymethyl) guanine] phosphoric acid (3 -dodecylmercapto-2-unde-oxyloxy) -1-propyl ester 14. 2 '- (9 - {[(1-hydroxymethyl) ethoxy] methyl} guanine) phosphoric acid (2,3-bis (do-10 decylmercapto) -1- propyl ester 15. 2 '- (9 - {[(1-hydroxymethyl) ethoxy] methyl} guanine) phosphoric acid (3-decyl mercapto-2-dodecyloxy) -1-propyl ester 16. 2' - [9- (ethoxymethyl) guanii ni] Phosphoric acid (3-undecylmercapto-2-dodecyloxy) -1-propyl ester 15 17. 2 '- [9- (Ethoxymethyl) guanine] Phosphoric acid (3-decylsulfonyl-2-dodecyloxy) -1-propyl ester • ·:. 18. 2- [9- (Ethoxymethyl) guanine] phosphoric acid (3-decyloxy-2-decyl-1,1-oxy) -1-propyl ester · · · · · · · · ·: 19. 2 '- [9- (Ethoxymethyl) guanine] phosphoric acid (3-dodecylmercapto-2-dodecyl) oxy] -1-propyl ester 20. 2- (9 - {[(1-Hydroxymethyl) ethoxy) ] methyl} guanine) phosphoric acid (3-tetrade-methylmercapto-2-decyloxy) -1-propyl ester • '']: 21. 2 '- [9- (ethoxymethyl) guanine] phosphoric acid (3-pentadecylmercapto-2- decyloxy) -1-propyl ester * · 25 22. 2 '- (9 - {[(1-hydroxymethyl) ethoxy] methyl} guanimide) phosphoric acid (3-tridecyl- ···. limercapto-2-decyloxy) - 1-Propyl Ester 1: 23. 2 '- [9- (Ethoxymethyl) guanine] Phosphoric Acid (3-dodecylinercapto-2-octyloxy) -1-Propyl Ester 9 109699
Esimerkki 1Example 1
Fosforihappo-(3-dodekwlimerkapto-2-dekwlioksiVl-propwliesteriThe phosphoric acid (3-dodecylmercapto-2-dekwlioksiVl-propwliesteri
Suspensioon, jossa on 4,26 g P4O10 60 ml:ssa abs. pyridiiniä, lisättiin huoneenlämpötilassa 13 ml heksametyylisiloksaania ja kuumennettiin 1 h 100 C:een. Sitten sitä 5 jäähdytettiin hieman, lisättiin 25 g 3-dodekyylimerkapto-2-dekyylioksi-l-propanolia ja sitä kuumennettiin edelleen 2,5 h 100 C:een.To a suspension of 4.26 g P4O10 in 60 mL abs. pyridine, 13 ml of hexamethylsiloxane was added at room temperature and heated to 100 ° C for 1 h. It was then cooled slightly, 25 g of 3-dodecylmercapto-2-decyloxy-1-propanol was added and it was further heated to 100 ° C for 2.5 h.
Täydellisesti huoneenlämpötilaan jäähtymisen ja heikosti haihtuvien aineosien tyh jössä poistamisen jälkeen voitiin fosfaatti uuttaa eetterillä jäännöksen vesisuspensiosta. Eetterifaasin haihdutusjäännös puhdistettiin pylväskromatografialla piidioksi-10 digeelillä 60 vast. RP 18. Saanto 18,7 g (63 %), Rf = 0,66 (CH2Cl2/Me0H/H20 6,5/2,5/0,4) DC-levyillä Merck 5715, piidioksidigeeli 60.After cooling to room temperature completely and removing the volatile constituents in vacuo, the phosphate was extracted with ether from an aqueous suspension of the residue. The ethereal phase evaporation residue was purified by column chromatography on silica gel 10 60. RP 18. Yield 18.7 g (63%), R f = 0.66 (CH 2 Cl 2 / MeOH / H 2 O 6.5 / 2.5 / 0.4) on DC plates Merck 5715, silica gel 60.
Esimerkki 2 2’-( 9-ΙΓΓ 1-hvdroksimetwliletoksilmetwlil guaniinilfosfori-happo-(3-dodekwlimerkapto-2-dekwlioksiVl-propwliesteri 15 1,45 g:aan (3 mmoolia) fosforihappo-(3-dodekyylimerkapto-2-dekyylioksi)- 1-propyyliesteriin ja 770 mgiaan (3 mmoolia) Gancicloviriä lisättiin kahdesti 20 ml . . abs. pyridiiniä ja haihdutetttiin. Jäännös otettiin 20 ml:aan abs. pyridiiniä, lisättiin ; typen alaisena 2,7 g (8,5 mmoolia) 2,4,6-tri-isopropyylibentseenisulfoni- '· ·* happokloridia ja sekoitettiin 24 h 40 C:ssa. Sitten lisättiin 10 ml vettä, seosta sekoi - :.: : 20 tettiin edelleen 2 h huoneenlämpötilassa ja liuotin poistettiin kiertohaihduttimessa.Example 2 2 '- (9-1-Hydroxymethyl-ethylethyl) guanyl-phosphoric acid (3-dodecylmercapto-2-decoxy) -1-propyl ester 15 1.45 g (3 mmol) of phosphoric acid (3-dodecylmercapto-1-decyloxy) propyl ester and 770 mg (3 mmol) of Ganciclovir were added twice with 20 ml of abs. pyridine and evaporated. The residue was taken up in 20 ml of abs. pyridine, added; under nitrogen, 2.7 g (8.5 mmol) of 2.4, 6-Triisopropylbenzenesulfonic acid chloride was stirred for 24 h at 40. Then 10 mL of water was added, the mixture stirred for a further 2 h at room temperature and the solvent was removed in a rotary evaporator.
: Öljyinen jäännös vapautettiin pyridiinitähteistä haihduttamalla tolueenin avulla ja puhdistettiin pylväskromatografialla RP 18:11a lineaarisella gradientilla metano-'·’ li/vesi 7/3-9,5/0,5 eluenttina. Saanto 0,75 g (34 % teoreett.), öljy. Rf = 0,73 (H20/MeOH 0,5/9,5 RP 8:11a, Rf = 0,30 (CH2Cl2/Me0H/H20 6,5/2,5/0,4) DC-* ‘ 25 levyillä Merck 5715, piidioksidigeeli 60 F.: The oily residue was freed from the pyridine residues by evaporation with toluene and purified by column chromatography on RP 18 with a linear gradient of methanol / water 7 / 3-9.5 / 0.5 as eluent. Yield 0.75 g (34% of theory), oil. R f = 0.73 (H 2 O / MeOH 0.5 / 9.5 with RP 8, R f = 0.30 (CH 2 Cl 2 / MeOH / H 2 O 6.5 / 2.5 / 0.4) on DC 25 Merck 5715, 60 F silica gel.
Esimerkki 3 2l-r9-(etoksimetwlilguaniini1fosforihappo-(3-dodekwlimerkapto-2-dekwlioksiV .···. l-propwliesteri ‘ ‘ Tämä yhdiste valmistettiin analogisesti esimerkin 1 kanssa Acycloviristä 47 % 30 saantona. Öljy. Rf = 0,77 (H20/MeOH 0,5/9,5 RP 8:11a, Rf = 0,35 (CH2Cl2/Me0H/H20 6,5/2,5/0,4) DC-levyillä Merck 5715, piidioksidigeeli 60 F.Example 3 2-1-9- (Ethoxymethylglylguanine) -phosphoric acid (3-dodecylmercapto-2-decoxy) -1'-1'-propyl ester This compound was prepared analogously to Example 1 from Acyclovir in 47% yield. Oil. Rf = 0.77 (H2 O / MeOH 0.5 / 9.5 with RP 8, Rf = 0.35 (CH 2 Cl 2 / MeOH / H 2 O 6.5 / 2.5 / 0.4) on DC plates Merck 5715, silica gel 60F.
Claims (8)
Applications Claiming Priority (4)
| 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 |
| DE4226279 | 1992-08-08 | ||
| EP9302101 | 1993-08-06 | ||
| PCT/EP1993/002101 WO1994003465A1 (en) | 1992-08-08 | 1993-08-06 | Liponucleotides of seco-nucleosides, their preparation and their use as anti-viral drugs |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| FI950533A0 FI950533A0 (en) | 1995-02-07 |
| FI950533A FI950533A (en) | 1995-02-07 |
| FI109699B true FI109699B (en) | 2002-09-30 |
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ID=6465143
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FI950533A FI109699B (en) | 1992-08-08 | 1995-02-07 | Process for the preparation of pharmacologically active liponucleotides of seconucleosides |
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 |
|---|---|---|---|---|
| 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 |
| US6599887B2 (en) | 1988-07-07 | 2003-07-29 | Chimerix, Inc. | Methods of treating viral infections using antiviral liponucleotides |
| 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
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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 ZA ZA935718A patent/ZA935718B/en unknown
- 1993-08-06 JP JP50502594A patent/JP3479299B2/en not_active Expired - Fee Related
- 1993-08-06 WO PCT/EP1993/002101 patent/WO1994003465A1/en active IP Right Grant
- 1993-08-06 CA CA002141030A patent/CA2141030A1/en not_active Abandoned
- 1993-08-06 HU HU9500374A patent/HUT72605A/en unknown
- 1993-08-06 EP EP93917764A patent/EP0654036B1/en not_active Expired - Lifetime
- 1993-08-06 DE DE59306286T patent/DE59306286D1/en not_active Expired - Fee Related
- 1993-08-06 DK DK93917764.8T patent/DK0654036T3/en active
- 1993-08-06 AU AU47082/93A patent/AU672994B2/en not_active Ceased
- 1993-08-06 NZ NZ254813A patent/NZ254813A/en unknown
- 1993-08-06 KR KR1019950700463A patent/KR100243440B1/en not_active IP Right Cessation
- 1993-08-06 ES ES93917764T patent/ES2104163T3/en not_active Expired - Lifetime
- 1993-08-06 AT AT93917764T patent/ATE152114T1/en not_active IP Right Cessation
- 1993-08-07 CN CN93107987A patent/CN1040984C/en not_active Expired - Fee Related
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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
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1997
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Also Published As
| Publication number | Publication date |
|---|---|
| GR3023960T3 (en) | 1997-09-30 |
| AU672994B2 (en) | 1996-10-24 |
| WO1994003465A1 (en) | 1994-02-17 |
| JPH08500345A (en) | 1996-01-16 |
| CA2141030A1 (en) | 1994-02-09 |
| ATE152114T1 (en) | 1997-05-15 |
| TW306924B (en) | 1997-06-01 |
| DE4226279A1 (en) | 1994-02-10 |
| NZ254813A (en) | 1996-05-28 |
| HU9500374D0 (en) | 1995-03-28 |
| HUT72605A (en) | 1996-05-28 |
| EP0654036A1 (en) | 1995-05-24 |
| FI950533A0 (en) | 1995-02-07 |
| JP3479299B2 (en) | 2003-12-15 |
| NO304986B1 (en) | 1999-03-15 |
| DK0654036T3 (en) | 1997-11-03 |
| IL106588A0 (en) | 1993-12-08 |
| DE59306286D1 (en) | 1997-05-28 |
| ES2104163T3 (en) | 1997-10-01 |
| CN1085908A (en) | 1994-04-27 |
| CN1040984C (en) | 1998-12-02 |
| KR950702998A (en) | 1995-08-23 |
| NO950445L (en) | 1995-02-07 |
| IL106588A (en) | 1998-01-04 |
| EP0654036B1 (en) | 1997-04-23 |
| NO950445D0 (en) | 1995-02-07 |
| AU4708293A (en) | 1994-03-03 |
| FI950533A (en) | 1995-02-07 |
| MX9304676A (en) | 1994-03-31 |
| ZA935718B (en) | 1995-02-06 |
| KR100243440B1 (en) | 2000-03-02 |
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Legal Events
| Date | Code | Title | Description |
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| HC | Name/ company changed in application |
Owner name: ROCHE DIAGNOSTICS GMBH |
|
| MA | Patent expired |