EP0500776A1 - Poly(alkyl and alkenyl phosphate)s and their thiophosphate and selenophosphate derivatives as antiviral agents - Google Patents
Poly(alkyl and alkenyl phosphate)s and their thiophosphate and selenophosphate derivatives as antiviral agentsInfo
- Publication number
- EP0500776A1 EP0500776A1 EP91900534A EP91900534A EP0500776A1 EP 0500776 A1 EP0500776 A1 EP 0500776A1 EP 91900534 A EP91900534 A EP 91900534A EP 91900534 A EP91900534 A EP 91900534A EP 0500776 A1 EP0500776 A1 EP 0500776A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- alkenyl
- poly
- group
- derivative
- 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.)
- Withdrawn
Links
- 125000000217 alkyl group Chemical group 0.000 title claims abstract description 21
- -1 alkenyl phosphate Chemical compound 0.000 title claims description 15
- 229910019142 PO4 Inorganic materials 0.000 title claims description 11
- 239000010452 phosphate Substances 0.000 title claims description 10
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 title description 5
- 239000003443 antiviral agent Substances 0.000 title description 4
- JRPHGDYSKGJTKZ-UHFFFAOYSA-N selenophosphoric acid Chemical class OP(O)([SeH])=O JRPHGDYSKGJTKZ-UHFFFAOYSA-N 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 19
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 9
- 208000036142 Viral infection Diseases 0.000 claims abstract description 6
- 230000009385 viral infection Effects 0.000 claims abstract description 6
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 11
- 239000002777 nucleoside Substances 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 239000011593 sulfur Substances 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
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 claims description 3
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 claims description 3
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 230000000840 anti-viral effect Effects 0.000 claims description 3
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 claims description 3
- 229910052711 selenium Inorganic materials 0.000 claims description 3
- 239000011669 selenium Substances 0.000 claims description 3
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 claims description 2
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 claims description 2
- 229940104230 thymidine Drugs 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 7
- 229910052799 carbon Inorganic materials 0.000 claims 7
- 230000037396 body weight Effects 0.000 claims 2
- 125000005842 heteroatom Chemical group 0.000 claims 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 2
- 239000000203 mixture Substances 0.000 abstract description 10
- 229920000388 Polyphosphate Polymers 0.000 abstract description 2
- 208000015181 infectious disease Diseases 0.000 abstract description 2
- 239000000178 monomer Substances 0.000 abstract description 2
- 229920000642 polymer Polymers 0.000 abstract description 2
- 239000001205 polyphosphate Substances 0.000 abstract description 2
- 235000011176 polyphosphates Nutrition 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 17
- 230000000120 cytopathologic effect Effects 0.000 description 14
- 230000005764 inhibitory process Effects 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000003556 assay Methods 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000036436 anti-hiv Effects 0.000 description 6
- 235000021317 phosphate Nutrition 0.000 description 6
- 239000007790 solid phase Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000000074 antisense oligonucleotide Substances 0.000 description 3
- 238000012230 antisense oligonucleotides Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 2
- VKIGAWAEXPTIOL-UHFFFAOYSA-N 2-hydroxyhexanenitrile Chemical compound CCCCC(O)C#N VKIGAWAEXPTIOL-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 229910017974 NH40H Inorganic materials 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000005289 controlled pore glass Substances 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000003835 nucleoside group Chemical group 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 108091033319 polynucleotide Proteins 0.000 description 2
- 239000002157 polynucleotide Substances 0.000 description 2
- 102000040430 polynucleotide Human genes 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000013014 purified material Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000010532 solid phase synthesis reaction Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JBWYRBLDOOOJEU-UHFFFAOYSA-N 1-[chloro-(4-methoxyphenyl)-phenylmethyl]-4-methoxybenzene Chemical compound C1=CC(OC)=CC=C1C(Cl)(C=1C=CC(OC)=CC=1)C1=CC=CC=C1 JBWYRBLDOOOJEU-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- 108020000948 Antisense Oligonucleotides Proteins 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 1
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 101001034830 Mus musculus Interferon-induced transmembrane protein 5 Proteins 0.000 description 1
- GMMNLIRRNYKBOP-UHFFFAOYSA-N N-[dihydroxy-bis(1H-imidazole-2-carbonyl)-lambda5-phosphanyl]-1H-imidazole-2-carboxamide Chemical compound C1=CN=C(N1)C(=O)NP(C(=O)C2=NC=CN2)(C(=O)C3=NC=CN3)(O)O GMMNLIRRNYKBOP-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 241001074085 Scophthalmus aquosus Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000007248 cellular mechanism Effects 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000007515 enzymatic degradation Effects 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 229940029575 guanosine Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012457 nonaqueous media Substances 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
- 244000045947 parasite Species 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- WCNLCIJMFAJCPX-UHFFFAOYSA-N pethidine hydrochloride Chemical compound Cl.C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 WCNLCIJMFAJCPX-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- CGPPXVAUDMUIPK-UHFFFAOYSA-N phosphoric acid trihydroxy(sulfanylidene)-lambda5-phosphane Chemical compound OP(O)(O)=O.OP(O)(O)=S CGPPXVAUDMUIPK-UHFFFAOYSA-N 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
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- 238000011321 prophylaxis Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IGFXRKMLLMBKSA-UHFFFAOYSA-N purine Chemical compound N1=C[N]C2=NC=NC2=C1 IGFXRKMLLMBKSA-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012260 resinous material Substances 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000005987 sulfurization reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- LZTRCELOJRDYMQ-UHFFFAOYSA-N triphenylmethanol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(O)C1=CC=CC=C1 LZTRCELOJRDYMQ-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000003211 trypan blue cell staining Methods 0.000 description 1
- 230000009447 viral pathogenesis Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
-
- 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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/141—Esters of phosphorous acids
- C07F9/1411—Esters of phosphorous acids with hydroxyalkyl compounds with further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H21/04—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with deoxyribosyl as saccharide radical
Definitions
- the invention concerns the use of certain 0 phosphate- and thiophosphate-based oligomers to treat viral infections.
- anti-sense oligonucleotides as antiviral agents, especially in the case of the human inmmunodeficiency virus (HIV), e.g. Matsukura et al, Proc. Natl. Acad. Sci., Vol. 84, pgs. 7706-7710 (1987).
- An anti-sense oligonucleotide is a synthetic oligonucleotide of varying length, usually in the range of about 12 to 30 nucleotides, or nucleotide analogs, whose sequence is complementary to a predetermined segment of the RNA, either freshly transcribed or the messenger (mRNA), critical to some viral function. It is believed that when an anti-sense oligonucleotide hybridizes to its target RNA, it either blocks translation or processing of the RNA or makes it susceptible to enzymatic degradation.
- the invention relates to a method of treating viral diseases by administering with a pharmaceutical carrier an effective amount of a poly(alkyl or alkenyl phosphate) or a thiophosphate derivative thereof defined by the following formula:
- X and Y are separately selected from the group consisting of selenium, oxygen and sulfur; more preferably, X and Y are separately selected from the group consisting of oxygen and sulfur; and most preferably, at least one of X and Y are sulfur; n is in the range of about 16 to 60 inclusive; and more preferably, n is in the range of about 20 to 30;
- R is alkyl or alkenyl having from 1 to 8 carbon atoms, alkyloxy or alkylthio having from 1 to 8 carbon atoms and having from 0 to 2 heteroatom ⁇ ; more preferably R is alkyl or alkenyl having from 3 to 6 carbon atoms, or alkoxy having from 3 to 6 carbon atoms and one oxygen atom; most preferably, R is alkyl having from 3 to 6 carbon atoms or a cyclic alkoxy having from 4 to 5 carbon atoms and one oxygen; and
- Q and Q' are separately hydrogen, R-OH, or a nucleoside selected from the group consisting of adeno ⁇ ine, cytidine, guanosine, and thymidine.
- Figures 1A and B illustrate data on the anti-HIV effect of two 28-mer compounds of the invention in a cytopathic effect inhibition assay.
- Figure 1C illustrates data on the anti-HIV effect of the control compound, 28-mer polydeoxycytidine, in a cytopathic effect inhibition assay.
- Figures 2 and 3 illustrate data on the anti-HIV effect of a 14-mer and a 28-mer of the invention, respectively, in a cytopathic effect inhibition assay.
- Compounds of the invention can be synthesized by several different routes. Preferably, they are synthesized by solid phase procedures using hydrogen phosphonate, phosphoramidite, or thiophosphoramidite precursors. Preferably, phosphates and monothiophosphates of the invention are synthesized by hydrogen phosphonate chemistry and polyphosphorodithioates of the invention are synthesized by thiophosphoramidite chemistry. Polyphosphates and polyphosphoromonothioates of the invention may be synthesized by the following steps using the hydrogen phosphonate approach. Precusor 1_ defined by the following formula:
- R is reacted with a tris-phosphoramidite, or alternative synthon according to reported procedures, e.g. Garreg et al, Chem. Scripta, Vol. 25, pg. 280 (1985), or Marugg et al, Tetrahedron Lett., Vol. 27, pg. 227 (1986), to obtain the corresponding alkane hydrogen phosphonate 2 ⁇ defined by the formula:
- (R 1 )(R ) (R'")C is an acid labile protection group as commonly used to protect 5 1 hydroxyl ⁇ in solid phase synthesis of polynucleotides.
- (R , )(R")(R"')C is trityl, or a derivative thereof.
- the unspecified cation associated with 2 is usually triethylammonium.
- _2 is employed as a reagent in n cycles of automated solid phase synthesis using conventional procedures, e.g. Andrus et al, U.S. patent 4,816,571, to obtain a hydrogen phosphonate-linked oligomer .3 attached to a solid phase support:
- W 0- D-G, where G i ⁇ a standard support material, e.g. controlled pore glas ⁇ or polystyrene, and D i ⁇ a linking group, usually cleavable under basic conditions. ,3 is preferably synthe ⁇ ized in the form in which the nucleoside is between the growing chain and • the solid phase support.
- nucleosides Commercially available solid phase support ⁇ that have been derivatized with protected nucleosides are a convenient starting material.
- the presence of the nucleoside also provides a convenient method of identifying and quantifying the final product by means employing the spectrophotometric propertie ⁇ of the nucleoside.
- the final step of the chain elongation can be to add either a terminal nucleoside or terminal monomer .1, to achieve the following intermediate A i
- j4 can be sulfurized by standard techniques, e.g.Matsukura et al. Gene, Vol. 72, pg. 343 (1988). After cleavage from the solid phase support and deprotection of the bases the following material j> is obtained:
- dithiophosphates of the invention may be synthesized using thiophosphoramidite chemi ⁇ try.
- R and (R 1 ) (R ) (R" ' )C are as defined above, Ar is halo-substituted phenyl (such as, 2,4- dichlorophenyl) , and R2 is dimethyl or pyrrolidinyl.
- j6 is employed as a reagent in n cyc les of automated so lid phase synthesis , as taught by Bril l et al (cited above) , to obtain dithiophosphates 7_:
- 8 jB_ i ⁇ readily purified and isolated as described above for 5.
- the purified material JB is treated with aqueous acetic acid to remove the (R')(R )(R'")C moiety, which is separated from 8 ⁇ by extraction with ethyl acetate, ether, or the like, to give the final product.
- the size of the poly(alkyl or alkenyl phosphate)s and/or their thio analogs ranges between about 20 and 30 monomeric units. Compounds larger than 30-mers may be readily employed for their biological effect, but longer polymers are increa ⁇ ingly difficult to ⁇ ynthe ⁇ ize and purify.
- ATH8 cells an immortalized T4+ T cell line, are used a ⁇ target cell ⁇ becau ⁇ e of their sensitivity to the cytopathic effect of HIV, Mitsuya et al, Proc. Natl. Acad. Sci., Vol. 83, pg ⁇ . 1911-1915 (1986).
- ATH8 cells are available under catalog number 307 from the AIDS Research and Reference Reagent Program Repository establi ⁇ hed by the National In ⁇ titute of Allergy and Infectiou ⁇ Disease and operated by ERC BioServices Corporation (Rockville, MD). 2xl0 5 ATH8 cell ⁇ incubated with HTLV-III B for 30 minute ⁇ (about 500 viru ⁇ particle ⁇ per cell).
- the HTLV-III B viru ⁇ i ⁇ al ⁇ o available from the AIDS
- Re ⁇ earch and Reference Reagents Program Repository (under catalog number 398). This dose is about 100- 1000 times higher than the minimum cytopathic dose in the assay.
- Complete medium (2 ml of RPMI 1640) supplemented with L-glutamine (4 mM), 2-mercaptoethanol (50 nM), penicillin (50 units/ml), and streptomycin (50 ug/ l) and containing 15% fetal calf serum and interleukin-2 is u ⁇ ed with addition of the indicated concentrations of the compounds of the invention added. The number of viable cells is counted in a hemocytometer using the trypan blue dye-exclusion method on day 7 following exposure to the virus.
- a mock sample without virus can be used at each concentration tested to evaluate toxicity.
- the highly active phosphorothioate oligodeoxycytidine 28-mer (S- dC2 R in figure 1C) can be used as a po ⁇ itive control for antiviral activity with the particular batches of ATH8 cells and HTLV-III B viru ⁇ particle ⁇ u ⁇ ed for the pre ⁇ ently de ⁇ cribed de novo infection assay.
- compositions contain a therapeutic amount of at least one of the poly(alkyl or alkenyl phosphate)s of the invention and/or at least one of their thiophosphate analog ⁇ in a pharmaceutically effective carrier.
- the poly(alkyl or alkenyl pho ⁇ phate)s and their thio analogs may be administered either as a ⁇ ingle chainlength (i.e. one value of n), or a ⁇ a defined mixture containing polymer ⁇ of more than one chainlength, e.g. a composition can contain a mixture of the compound of
- Formula I wherein X, Y, R, B, and Q are the ⁇ ame for each component of the mixture, but wherein n may have more than one value or be di ⁇ tributed around some average value.
- a pharmaceutical carrier can be any compatible, non-toxic ⁇ ub ⁇ tance suitable for delivering the compositions of the invention to a patient.
- Sterile water, alcohol, fat ⁇ , waxes, neutral lipids, cationic lipid ⁇ , and inert ⁇ olid ⁇ may be included in a carrier.
- Pharaceutically acceptible adjuvants e.g. buffering agents, dispersing agents, and the like, may also be incorporated into the pharmaceutical composition.
- compositions useful for parenteral admini ⁇ tration of drug ⁇ are well known, e.g. Remington's Pharmaceutical Science, 15th ED. (Mack Publishing Company, Easton, PA, 1980).
- compositions of the invention may be administered by way of an implantable or injectable drug delivery system, e.g. ⁇ rquhart et al, Ann. Rev. Pharmacol. Toxicol., Vol.24, pgs.199-236 (1984); Lewis, ed. Controlled Release of Pesticides and Pharmaceuticals
- compositions of the invention are administered parenterally, and more preferably, intravenously.
- pharmaceutical carriers include saline solution ⁇ , dextrose solution ⁇ , combinations of the two, nonaqueous solutions such as ethyl oleate, and the like.
- an administration regimen for a co po ⁇ ition of the invention depends on several factors, including the rate of degradation of the particular compounds in serum, the acce ⁇ ibility of the target tissues and cells, pharmacokinetics, toxicity, and the like.
- an admini ⁇ tration regimen maximize ⁇ the amount of compound delivered to a patient con ⁇ i ⁇ tent with an acceptable level of side effects. Accordingly, the amount of compound delivered may depend on the particular compound and the severity of the viral infection being treated.
- a daily do ⁇ e of the compound ⁇ of the invention i ⁇ in the range of about 1-2 ug/kg to about 10-20 mg/kg.
- the trityl alcohol precursor la (388 mg, 1 mmol) i ⁇ converted into corresponding hydrogen pho ⁇ phonate Ila with tris(imidazoyl)phosphoramidite according to known procedures, e.g. Garreg et al (cited above).
- Synthesi ⁇ of oligophosphorothioate Ilia is performed using triethylammoniu 1-0-4,4'- dimethoxytrityl-butane-3-0-hydrogen phosphonate Ila on a Cyclone 6000-Biosearch DNA synthesizer, or like instrument.
- B of Ilia is as defined above.
- the starting solid phase support IVa is controlled pore glass (CPG) with 1 umol nucleoside loaded at 40 umol/g. Pivaloyl chloride is used as the H-pho ⁇ phonate activator.
- the resultant 5'-0-4,4'- dimethoxytrityl (5'-DMT) derivative of Ilia is purified by HPLC on a uBondapak C 18 column (Waters), elution time 17 minutes, gradient 5-40% (or more) CH3CN versus 0.1 M triethylammonium acetate, pH 7.4, for about 20 minute ⁇ , followed by i ⁇ ocratic flow, all at about 1.5 ml/min.
- the 5'DMT IVa i ⁇ collected, concentrated in vacuo and then detritylated with 80% acetic acid in water prior to HPLC collection of final product Ilia, elution time about 15 minutes using the same column and flow rate but with a gradient of 5-30% (or more) CH3CN versu ⁇ 0.1 M triethylammonium acetate, pH 7.4, at 1.25 ml/min.
- - ⁇ P-NMR of Ilia about 55 ppm.
- the final material as a triethylammonium salt i ⁇ obtained by evaporation in vacuo.
- Example 4 The Anti-HIV Effect of CV 26 C A compound of the following formula, designated cv 26 c w s s Y nt hesized using the methods described above:
- CE2gC wa ⁇ u ⁇ ed in the cytopathic effect inhibition assay described above in the concentrations indicated in Figure IB. Control ⁇ were employed as described. A clear do ⁇ e-re ⁇ pon ⁇ e relation ⁇ hip i ⁇ ⁇ hown between inhibition of cytopathic effect and concentration of CE25C at 2.5 uM.
- Example 6 Lack of cytopathic inhibition of a_ 14-mer compound A 14-mer analog of the compound of Example 4, de ⁇ ignated CV- ⁇ C, was synthe ⁇ ized u ⁇ ing the method ⁇ described above. As shown in Figure 2, no discernable cytopathic inhibition was observed over the indicated range of concentrations.
- Example 7 Cytopathic inhibition of a_ 28-mer compound A 28-mer analog of the compound of Example 4, designated V ⁇ gC wa ⁇ re-tested in parallel with cV- j ⁇ C using the methods described above. As shown in Figure 3, a clear inhibition of the cytopathic effect ⁇ of HIV i ⁇ ⁇ een.
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Abstract
Procédés et compositions employant des polyphosphates d'alkyle et d'alcényle et/ou leurs dérivés de thiophosphate afin de traiter des infections virales. On utilise, de préférence, les polymères de l'invention d'une longueur de 20 à 30 monomères, seuls ou combinés afin de traiter des infections dues au VIH.Methods and compositions employing alkyl and alkenyl polyphosphates and / or their thiophosphate derivatives to treat viral infections. Preferably, the polymers of the invention of 20 to 30 monomers in length are used, alone or in combination, to treat infections due to HIV.
Description
Claims
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US438355 | 1982-11-01 | ||
US43835589A | 1989-11-17 | 1989-11-17 |
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EP19910900534 Withdrawn EP0500776A4 (en) | 1989-11-17 | 1990-11-13 | Poly(alkyl and alkenyl phosphate)s and their thiophosphate and selenophosphate derivatives as antiviral agents |
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US6057093A (en) | 1992-09-28 | 2000-05-02 | Chiron Corporation | Methods and compositions for controlling translation of HCV proteins |
US5604097A (en) | 1994-10-13 | 1997-02-18 | Spectragen, Inc. | Methods for sorting polynucleotides using oligonucleotide tags |
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EP0288163A2 (en) * | 1987-03-25 | 1988-10-26 | THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce | Oligodeoxynucleotides as inhibitors of the replication of retroviruses and the expression of oncogenes |
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US4826823A (en) * | 1985-02-05 | 1989-05-02 | Warner-Lambert Company | Methods of using 2-chloro-2'-deoxyadenosine-5'-phosphate and its salts |
-
1990
- 1990-11-13 JP JP50105890A patent/JPH05501709A/en active Pending
- 1990-11-13 WO PCT/US1990/006630 patent/WO1991007092A1/en not_active Application Discontinuation
- 1990-11-13 EP EP19910900534 patent/EP0500776A4/en not_active Withdrawn
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EP0288163A2 (en) * | 1987-03-25 | 1988-10-26 | THE UNITED STATES OF AMERICA as represented by the Secretary United States Department of Commerce | Oligodeoxynucleotides as inhibitors of the replication of retroviruses and the expression of oncogenes |
Non-Patent Citations (4)
Title |
---|
JOURNAL OF CELLULAR BIOCHEMISTRY vol. SUPPL, no. 14D, March 1990, page 100 W. EGAN ET AL. 'SYNTHESIS AND EVALUATION OF ABASIC OLIGODESOXYRIBONUCLEOTIDE PHOSPHOROTHIOATES AS ANTI-HIV-1 AGENTS' * |
NUCLEIC ACIDS RESEARCH vol. 17, no. 20, 1989, pages 8207 - 8219 K. MORI ET AL. 'PHOSPHOROSELENOATE OLIGODEOXYNUCLEOTIDES: SYNTHESIS, PHYSICO-CHEMICAL CHARACTERIZATION, ANTI-SENSE INHIBITORY PROPERTIES AND ANTI-HIV ACTIVITY' * |
NUCLEIC ACIDS RESEARCH vol. 18, no. 10, 25 May 1990, pages 2855 - 2859 R.P. LYER ET AL. 'ABASIC OLIGODEOXYRIBONUCLEOTIDE PHOSPHOROTHIOATES: SYNTHESIS AND EVALUATION AS ANTI-HIV-1 AGENTS' * |
See also references of WO9107092A1 * |
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WO1991007092A1 (en) | 1991-05-30 |
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