JP2006527702A5 - - Google Patents
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- JP2006527702A5 JP2006527702A5 JP2006515644A JP2006515644A JP2006527702A5 JP 2006527702 A5 JP2006527702 A5 JP 2006527702A5 JP 2006515644 A JP2006515644 A JP 2006515644A JP 2006515644 A JP2006515644 A JP 2006515644A JP 2006527702 A5 JP2006527702 A5 JP 2006527702A5
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- JP
- Japan
- Prior art keywords
- compound
- formula
- independently
- hydroxy
- alkyl
- 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.)
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- 150000001875 compounds Chemical class 0.000 claims description 152
- -1 —N (R 5 ) 2 Chemical group 0.000 claims description 100
- 229910052799 carbon Inorganic materials 0.000 claims description 73
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 64
- 229910052739 hydrogen Inorganic materials 0.000 claims description 49
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 48
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 43
- 150000002148 esters Chemical class 0.000 claims description 42
- 150000001408 amides Chemical class 0.000 claims description 41
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 40
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 37
- 125000004970 halomethyl group Chemical group 0.000 claims description 27
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 24
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 125000006239 protecting group Chemical group 0.000 claims description 22
- 101100516572 Caenorhabditis elegans nhr-8 gene Proteins 0.000 claims description 20
- 125000001072 heteroaryl group Chemical group 0.000 claims description 19
- 239000002585 base Substances 0.000 claims description 18
- 150000001721 carbon Chemical group 0.000 claims description 18
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 18
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 16
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 241000700605 Viruses Species 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 11
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 11
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 10
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 10
- 125000005843 halogen group Chemical group 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000011593 sulfur Chemical group 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 7
- 239000000010 aprotic solvent Substances 0.000 claims description 7
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 6
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 claims description 6
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 6
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 5
- 150000001540 azides Chemical class 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 208000036142 Viral infection Diseases 0.000 claims description 4
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 241001430294 unidentified retrovirus Species 0.000 claims description 4
- 230000009385 viral infection Effects 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims 2
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 239000004480 active ingredient Substances 0.000 description 22
- 241000725303 Human immunodeficiency virus Species 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 21
- 238000009472 formulation Methods 0.000 description 19
- JSPYZDUIKDWUQG-UHFFFAOYSA-N 2-(2,6-diamino-5-methylpyrimidin-4-yl)oxyethoxymethylphosphonic acid Chemical compound CC1=C(N)N=C(N)N=C1OCCOCP(O)(O)=O JSPYZDUIKDWUQG-UHFFFAOYSA-N 0.000 description 18
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 description 18
- 229910052698 phosphorus Inorganic materials 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 16
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 230000000840 anti-viral effect Effects 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 125000000623 heterocyclic group Chemical group 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 9
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical group OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 208000015181 infectious disease Diseases 0.000 description 9
- 150000003863 ammonium salts Chemical class 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 239000000839 emulsion Substances 0.000 description 8
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000011159 matrix material Substances 0.000 description 7
- 238000002953 preparative HPLC Methods 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical group N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 208000031886 HIV Infections Diseases 0.000 description 5
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Chemical group 0.000 description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 description 5
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000000798 anti-retroviral effect Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 230000035772 mutation Effects 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical group [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- UQQHOWKTDKKTHO-ICQCTTRCSA-N (2r,3s,4s,5r)-2-(hydroxymethyl)-5-(6-methoxypurin-9-yl)oxolane-3,4-diol Chemical compound C1=NC=2C(OC)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O UQQHOWKTDKKTHO-ICQCTTRCSA-N 0.000 description 3
- 0 **COC(*)C*c1nc(N)nc(Cl)c1* Chemical compound **COC(*)C*c1nc(N)nc(Cl)c1* 0.000 description 3
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 3
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- 102100034343 Integrase Human genes 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 229940122313 Nucleoside reverse transcriptase inhibitor Drugs 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 3
- 230000036436 anti-hiv Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000003925 fat Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 125000003729 nucleotide group Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 150000003230 pyrimidines Chemical class 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 230000005740 tumor formation Effects 0.000 description 3
- 241001529453 unidentified herpesvirus Species 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- XSSYCIGJYCVRRK-RQJHMYQMSA-N (-)-carbovir Chemical class C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1C[C@H](CO)C=C1 XSSYCIGJYCVRRK-RQJHMYQMSA-N 0.000 description 2
- RHLWQEFHFQTKNT-UHFFFAOYSA-N (2z)-1-cyclooctyl-2-diazocyclooctane Chemical compound [N-]=[N+]=C1CCCCCCC1C1CCCCCCC1 RHLWQEFHFQTKNT-UHFFFAOYSA-N 0.000 description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- LNLWTBZUOHKMNI-UHFFFAOYSA-N 2,4-diamino-6-(2-hydroxyethoxy)pyrimidine-5-carbonitrile Chemical compound NC1=NC(N)=C(C#N)C(OCCO)=N1 LNLWTBZUOHKMNI-UHFFFAOYSA-N 0.000 description 2
- SVAXESXADJHWBR-UHFFFAOYSA-N 2,4-diamino-6-[2-[di(propan-2-yloxy)phosphorylmethoxy]ethoxy]pyrimidine-5-carbonitrile Chemical compound CC(C)OP(=O)(OC(C)C)COCCOC1=NC(N)=NC(N)=C1C#N SVAXESXADJHWBR-UHFFFAOYSA-N 0.000 description 2
- QBUGISJBWNVBKD-UHFFFAOYSA-N 2-(2,6-diamino-5-chloropyrimidin-4-yl)oxyethoxymethylphosphonic acid Chemical compound NC1=NC(N)=C(Cl)C(OCCOCP(O)(O)=O)=N1 QBUGISJBWNVBKD-UHFFFAOYSA-N 0.000 description 2
- MAGFWTQIBVYZHP-UHFFFAOYSA-N 2-(2,6-diamino-5-cyanopyrimidin-4-yl)oxyethoxymethylphosphonic acid Chemical compound NC1=NC(N)=C(C#N)C(OCCOCP(O)(O)=O)=N1 MAGFWTQIBVYZHP-UHFFFAOYSA-N 0.000 description 2
- NVNLWRXWFIBJKB-UHFFFAOYSA-N 2-[2,4-diamino-6-[2-(phosphonomethoxy)ethoxy]pyrimidin-5-yl]acetic acid Chemical compound NC1=NC(N)=C(CC(O)=O)C(OCCOCP(O)(O)=O)=N1 NVNLWRXWFIBJKB-UHFFFAOYSA-N 0.000 description 2
- GQKNZBNHBMKKBS-UHFFFAOYSA-N 2-[2,6-diamino-5-(2-ethoxy-2-oxoethyl)pyrimidin-4-yl]oxyethoxymethylphosphonic acid Chemical compound CCOC(=O)CC1=C(N)N=C(N)N=C1OCCOCP(O)(O)=O GQKNZBNHBMKKBS-UHFFFAOYSA-N 0.000 description 2
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- 102000002723 Atrial Natriuretic Factor Human genes 0.000 description 2
- 101800001288 Atrial natriuretic factor Proteins 0.000 description 2
- 101800001890 Atrial natriuretic peptide Proteins 0.000 description 2
- ODZBBRURCPAEIQ-DJLDLDEBSA-N Brivudine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C=CBr)=C1 ODZBBRURCPAEIQ-DJLDLDEBSA-N 0.000 description 2
- VWFCHDSQECPREK-LURJTMIESA-N Cidofovir Chemical compound NC=1C=CN(C[C@@H](CO)OCP(O)(O)=O)C(=O)N=1 VWFCHDSQECPREK-LURJTMIESA-N 0.000 description 2
- 241000450599 DNA viruses Species 0.000 description 2
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000709661 Enterovirus Species 0.000 description 2
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 238000011785 NMRI mouse Methods 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 241000725643 Respiratory syncytial virus Species 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 241000700618 Vaccinia virus Species 0.000 description 2
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 2
- 229960004748 abacavir Drugs 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP1906971A2 (en) * | 2005-07-27 | 2008-04-09 | Gilead Sciences, Inc. | Antiviral compounds |
| FR2908133B1 (fr) * | 2006-11-08 | 2012-12-14 | Centre Nat Rech Scient | Nouveaux analogues de nucleotides comme molecules precurseurs d'antiviraux |
| WO2011027222A2 (en) | 2009-09-02 | 2011-03-10 | Novartis Ag | Immunogenic compositions including tlr activity modulators |
| EP2558466A4 (en) | 2010-04-14 | 2013-11-13 | Univ California | PHOSPHONATES WITH REDUCED TOXICITY FOR THE TREATMENT OF VIRUS INFECTIONS |
| WO2012031045A2 (en) * | 2010-08-31 | 2012-03-08 | Chimerix, Inc. | Phosphonate ester derivatives and methods of synthesis thereof |
| AU2011295853A1 (en) * | 2010-09-01 | 2013-04-04 | Irm Llc | Adsorption of immunopotentiators to insoluble metal salts |
| WO2012079035A1 (en) | 2010-12-10 | 2012-06-14 | Sigmapharm Laboratories, Llc | Highly stable compositions of orally active nucleotide analogues or orally active nucleotide analogue prodrugs |
| WO2012117377A1 (en) | 2011-03-02 | 2012-09-07 | Novartis Ag | Combination vaccines with lower doses of antigen and/or adjuvant |
| EP3578563B1 (en) | 2011-12-22 | 2021-04-14 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
| MX372965B (es) | 2012-03-08 | 2020-04-01 | Glaxosmithkline Biologicals Sa | Formulaciones adyuvadas de vacunas de difteria, tetanos y tos ferina (dtp) de refuerzo. |
| CN103665043B (zh) * | 2012-08-30 | 2017-11-10 | 江苏豪森药业集团有限公司 | 一种替诺福韦前药及其在医药上的应用 |
| CN102796138B (zh) * | 2012-09-07 | 2014-10-22 | 山东大学 | (2-(3-甲硫基-1,2,4-噻二嗪)乙氧基)甲基膦酸酯类衍生物及其制备与应用 |
| SG10201800188SA (en) | 2013-03-15 | 2018-02-27 | Univ California | Acyclic nucleoside phosphonate diesters |
| CN111808136B (zh) | 2014-09-15 | 2024-06-11 | 加利福尼亚大学董事会 | 核苷酸类似物 |
| EP3350191B9 (en) | 2015-09-15 | 2021-12-22 | The Regents of the University of California | Nucleotide analogs |
| KR20250052378A (ko) | 2022-07-21 | 2025-04-18 | 안티바 바이오사이언시즈, 인크. | Hpv 감염 및 hpv-유도 신생물의 치료를 위한 조성물 및 투여 형태 |
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| CS233665B1 (en) * | 1983-01-06 | 1985-03-14 | Antonin Holy | Processing of isomere o-phosphonylmethylderivative of anantiomere racemic vicinal diene |
| US4740365A (en) * | 1984-04-09 | 1988-04-26 | Toyo Boseki Kabushiki Kaisha | Sustained-release preparation applicable to mucous membrane in oral cavity |
| CS263951B1 (en) | 1985-04-25 | 1989-05-12 | Antonin Holy | 9-(phosponylmethoxyalkyl)adenines and method of their preparation |
| CS263952B1 (en) | 1985-04-25 | 1989-05-12 | Holy Antonin | Remedy with antiviral effect |
| US4725233A (en) * | 1985-10-30 | 1988-02-16 | Jens Planert | Device for removing crowns, bridges, and similar structures from the stumps of teeth |
| US5141752A (en) | 1986-05-09 | 1992-08-25 | Alza Corporation | Delayed drug delivery device |
| CS264222B1 (en) * | 1986-07-18 | 1989-06-13 | Holy Antonin | N-phosphonylmethoxyalkylderivatives of bases of pytimidine and purine and method of use them |
| NZ222553A (en) | 1986-11-18 | 1991-07-26 | Bristol Myers Co | Phosphonomethoxyalkylene purine and pyrimidine derivatives and pharmaceutical compositions |
| CA2001715C (en) | 1988-11-14 | 1999-12-28 | Muzammil M. Mansuri | Carbocyclic nucleosides and nucleotides |
| US5098443A (en) * | 1989-03-23 | 1992-03-24 | University Of Miami | Method of implanting intraocular and intraorbital implantable devices for the controlled release of pharmacological agents |
| CA2297294C (en) | 1989-05-15 | 2005-11-08 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Phosphonomethoxymethylpurine/pyrimidine derivatives |
| MY104575A (en) | 1989-12-22 | 1994-04-30 | The Wellcome Foundation Ltd | Therapeutic nucleosides. |
| US5302585A (en) * | 1990-04-20 | 1994-04-12 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Use of chiral 2-(phosphonomethoxy)propyl guanines as antiviral agents |
| CZ285420B6 (cs) | 1990-04-24 | 1999-08-11 | Ústav Organické Chemie A Biochemie Avčr | N-(3-Fluor-2-fosfonylmethoxypropyl)deriváty purinových a pyrimidinových heterocyklických bazí, způsoby jejich přípravy a použití |
| JPH05509307A (ja) * | 1990-07-19 | 1993-12-22 | ビーチャム・グループ・パブリック・リミテッド・カンパニー | プリンの抗ウイルス性ホスホノ―アルケン誘導体 |
| EP0468119A1 (en) | 1990-07-24 | 1992-01-29 | Merrell Dow Pharmaceuticals Inc. | Novel carbocyclic analogs of certain nucleosides |
| EP0481214B1 (en) | 1990-09-14 | 1998-06-24 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
| US5208221A (en) * | 1990-11-29 | 1993-05-04 | Bristol-Myers Squibb Company | Antiviral (phosphonomethoxy) methoxy purine/pyrimidine derivatives |
| US5378475A (en) | 1991-02-21 | 1995-01-03 | University Of Kentucky Research Foundation | Sustained release drug delivery devices |
| CZ284678B6 (cs) * | 1991-05-20 | 1999-01-13 | Ústav Organické Chemie A Biochemie Avčr | Di(2-propyl)estery 1-fluor-2-fosfonomethoxy-3-p -toluensulfonyloxypropanů, způsob jejich přípravy a použití |
| HU225970B1 (en) | 1991-10-11 | 2008-01-28 | Acad Of Science Czech Republic | Antiviral acyclic phosphonomethoxyalkyl-substituted alkenyl purine and pyrimidine derivatives, and pharmaceutical preparations containing them |
| US6057305A (en) | 1992-08-05 | 2000-05-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Antiretroviral enantiomeric nucleotide analogs |
| EP0618214A1 (en) | 1993-04-01 | 1994-10-05 | Merrell Dow Pharmaceuticals Inc. | Unsaturated phosphonate derivatives of purines and pyrimidines |
| EP0719273B1 (en) | 1993-09-17 | 2010-11-03 | Gilead Sciences, Inc. | Nucleotide analogs |
| CN100409844C (zh) | 1995-02-27 | 2008-08-13 | 吉里德科学公司 | 神经氨酸苷酶抑制剂 |
| US5977061A (en) | 1995-04-21 | 1999-11-02 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | N6 - substituted nucleotide analagues and their use |
| CA2261619C (en) | 1996-07-26 | 2006-05-23 | Gilead Sciences, Inc. | Nucleotide analogs |
| EP1406911B1 (en) * | 2001-06-29 | 2016-01-06 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | 6-[2-(phosphonomethoxy)alkoxy] pyrimidine derivatives having antiviral activity |
-
2004
- 2004-06-16 NZ NZ543864A patent/NZ543864A/en not_active IP Right Cessation
- 2004-06-16 AT AT04738454T patent/ATE496056T1/de not_active IP Right Cessation
- 2004-06-16 KR KR1020057024279A patent/KR101102815B1/ko not_active Expired - Lifetime
- 2004-06-16 EA EA200600046A patent/EA011948B1/ru not_active IP Right Cessation
- 2004-06-16 AU AU2004247305A patent/AU2004247305B2/en not_active Expired
- 2004-06-16 EP EP04738454A patent/EP1644389B1/en not_active Expired - Lifetime
- 2004-06-16 CA CA2527805A patent/CA2527805C/en not_active Expired - Lifetime
- 2004-06-16 SI SI200431649T patent/SI1644389T1/sl unknown
- 2004-06-16 CN CN2004800168859A patent/CN1805966B/zh not_active Expired - Lifetime
- 2004-06-16 WO PCT/CZ2004/000034 patent/WO2004111064A1/en not_active Ceased
- 2004-06-16 DE DE602004031115T patent/DE602004031115D1/de not_active Expired - Lifetime
- 2004-06-16 US US10/869,005 patent/US7115592B2/en not_active Expired - Lifetime
- 2004-06-16 JP JP2006515644A patent/JP5280631B2/ja not_active Expired - Lifetime
- 2004-06-16 DK DK04738454.0T patent/DK1644389T3/da active
-
2005
- 2005-11-17 IL IL172015A patent/IL172015A/en active IP Right Grant
-
2006
- 2006-06-23 US US11/473,924 patent/US20060241081A1/en not_active Abandoned
-
2012
- 2012-05-21 JP JP2012115602A patent/JP2012153731A/ja active Pending
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