NZ547204A - Methods and compositions for treating flaviviruses and pestiviruses - Google Patents
Methods and compositions for treating flaviviruses and pestivirusesInfo
- Publication number
- NZ547204A NZ547204A NZ547204A NZ54720401A NZ547204A NZ 547204 A NZ547204 A NZ 547204A NZ 547204 A NZ547204 A NZ 547204A NZ 54720401 A NZ54720401 A NZ 54720401A NZ 547204 A NZ547204 A NZ 547204A
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- compound
- pharmaceutically acceptable
- acyl
- base
- Prior art date
Links
- 241000710778 Pestivirus Species 0.000 title claims abstract description 38
- 241000710831 Flavivirus Species 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title description 55
- 239000000203 mixture Substances 0.000 title description 25
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 511
- 150000001875 compounds Chemical class 0.000 claims abstract description 219
- 125000002252 acyl group Chemical group 0.000 claims abstract description 209
- 229910019142 PO4 Inorganic materials 0.000 claims abstract description 190
- 239000010452 phosphate Substances 0.000 claims abstract description 189
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims abstract description 185
- 239000001177 diphosphate Substances 0.000 claims abstract description 176
- 235000011180 diphosphates Nutrition 0.000 claims abstract description 176
- 239000001226 triphosphate Substances 0.000 claims abstract description 160
- 235000011178 triphosphate Nutrition 0.000 claims abstract description 160
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims abstract description 144
- 150000004712 monophosphates Chemical class 0.000 claims abstract description 125
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims abstract description 124
- 150000003839 salts Chemical class 0.000 claims abstract description 120
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims abstract description 91
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 88
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims abstract description 73
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 67
- IGFXRKMLLMBKSA-UHFFFAOYSA-N purine Chemical compound N1=C[N]C2=NC=NC2=C1 IGFXRKMLLMBKSA-UHFFFAOYSA-N 0.000 claims abstract description 65
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 62
- 238000001727 in vivo Methods 0.000 claims abstract description 57
- 150000001720 carbohydrates Chemical class 0.000 claims abstract description 56
- 150000001413 amino acids Chemical class 0.000 claims abstract description 55
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 44
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 41
- 238000011282 treatment Methods 0.000 claims abstract description 27
- 150000002148 esters Chemical class 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 157
- 239000001257 hydrogen Substances 0.000 claims description 145
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 64
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 54
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000003443 antiviral agent Substances 0.000 claims description 10
- 230000003441 anti-flavivirus Effects 0.000 claims description 9
- 241000710780 Bovine viral diarrhea virus 1 Species 0.000 claims description 8
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims description 8
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims description 8
- 229960000329 ribavirin Drugs 0.000 claims description 8
- 241000282414 Homo sapiens Species 0.000 claims description 7
- 150000003548 thiazolidines Chemical class 0.000 claims description 7
- 102000014150 Interferons Human genes 0.000 claims description 5
- 108010050904 Interferons Proteins 0.000 claims description 5
- 229940079322 interferon Drugs 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 4
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims description 4
- 241000710772 Yellow fever virus Species 0.000 claims description 2
- 238000007920 subcutaneous administration Methods 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims description 2
- 229940051021 yellow-fever virus Drugs 0.000 claims description 2
- KDOPAZIWBAHVJB-UHFFFAOYSA-N 5h-pyrrolo[3,2-d]pyrimidine Chemical compound C1=NC=C2NC=CC2=N1 KDOPAZIWBAHVJB-UHFFFAOYSA-N 0.000 claims 1
- 241000725619 Dengue virus Species 0.000 claims 1
- 229940121759 Helicase inhibitor Drugs 0.000 claims 1
- 229940123066 Polymerase inhibitor Drugs 0.000 claims 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims 1
- 241000710886 West Nile virus Species 0.000 claims 1
- OGEBRHQLRGFBNV-RZDIXWSQSA-N chembl2036808 Chemical compound C12=NC(NCCCC)=NC=C2C(C=2C=CC(F)=CC=2)=NN1C[C@H]1CC[C@H](N)CC1 OGEBRHQLRGFBNV-RZDIXWSQSA-N 0.000 claims 1
- 238000001990 intravenous administration Methods 0.000 claims 1
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical compound BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 claims 1
- -1 cinnamoyl moiety Chemical group 0.000 description 242
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical group NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 194
- 239000002585 base Substances 0.000 description 192
- 235000021317 phosphate Nutrition 0.000 description 187
- 229940002612 prodrug Drugs 0.000 description 153
- 239000000651 prodrug Substances 0.000 description 153
- 229940104302 cytosine Drugs 0.000 description 112
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 106
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 106
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 86
- 239000002777 nucleoside Substances 0.000 description 78
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 77
- 125000003118 aryl group Chemical group 0.000 description 61
- 150000002431 hydrogen Chemical group 0.000 description 61
- 229960000643 adenine Drugs 0.000 description 60
- 229920002554 vinyl polymer Polymers 0.000 description 60
- 150000002632 lipids Chemical class 0.000 description 57
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 56
- 125000001424 substituent group Chemical group 0.000 description 56
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 54
- 235000014633 carbohydrates Nutrition 0.000 description 54
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 54
- 229940024606 amino acid Drugs 0.000 description 53
- 235000012000 cholesterol Nutrition 0.000 description 53
- 229910003204 NH2 Inorganic materials 0.000 description 52
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 description 52
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 51
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 50
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 50
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 50
- 229910052794 bromium Inorganic materials 0.000 description 50
- 239000000460 chlorine Substances 0.000 description 50
- 229910052801 chlorine Inorganic materials 0.000 description 50
- 150000003904 phospholipids Chemical class 0.000 description 49
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 45
- 229930024421 Adenine Natural products 0.000 description 43
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 40
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 37
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical group CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 36
- 125000003835 nucleoside group Chemical group 0.000 description 34
- 235000000346 sugar Nutrition 0.000 description 34
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical group O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 31
- 238000003786 synthesis reaction Methods 0.000 description 31
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical group O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 30
- 150000003833 nucleoside derivatives Chemical class 0.000 description 30
- DEMJYWYZJFNNNB-UHFFFAOYSA-N OP(O)(O)=O.OP(O)(O)=O.OP(O)(O)=O Chemical compound OP(O)(O)=O.OP(O)(O)=O.OP(O)(O)=O DEMJYWYZJFNNNB-UHFFFAOYSA-N 0.000 description 28
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 28
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 26
- 230000009467 reduction Effects 0.000 description 26
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 25
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 24
- 239000003112 inhibitor Substances 0.000 description 24
- 229910052740 iodine Inorganic materials 0.000 description 24
- 239000011630 iodine Substances 0.000 description 24
- 125000006239 protecting group Chemical group 0.000 description 24
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 21
- 125000004093 cyano group Chemical group *C#N 0.000 description 21
- 239000002342 ribonucleoside Substances 0.000 description 21
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Natural products 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 20
- 230000000694 effects Effects 0.000 description 19
- 230000000840 anti-viral effect Effects 0.000 description 18
- 125000003729 nucleotide group Chemical group 0.000 description 18
- 229940113082 thymine Drugs 0.000 description 18
- QVLTXCYWHPZMCA-UHFFFAOYSA-N po4-po4 Chemical compound OP(O)(O)=O.OP(O)(O)=O QVLTXCYWHPZMCA-UHFFFAOYSA-N 0.000 description 17
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 16
- 229940035893 uracil Drugs 0.000 description 15
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 14
- 229960002949 fluorouracil Drugs 0.000 description 14
- CPRRHERYRRXBRZ-SRVKXCTJSA-N methyl n-[(2s)-1-[[(2s)-1-hydroxy-3-[(3s)-2-oxopyrrolidin-3-yl]propan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]carbamate Chemical compound COC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CO)C[C@@H]1CCNC1=O CPRRHERYRRXBRZ-SRVKXCTJSA-N 0.000 description 14
- 239000002773 nucleotide Substances 0.000 description 14
- WYVPBFVWZCTMPP-UHFFFAOYSA-N OP(O)(=O)OP(=O)(O)OP(=O)(O)O.OP(O)(=O)OP(=O)(O)OP(=O)(O)O.OP(O)(=O)OP(=O)(O)OP(=O)(O)O Chemical compound OP(O)(=O)OP(=O)(O)OP(=O)(O)O.OP(O)(=O)OP(=O)(O)OP(=O)(O)O.OP(O)(=O)OP(=O)(O)OP(=O)(O)O WYVPBFVWZCTMPP-UHFFFAOYSA-N 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 12
- 208000005176 Hepatitis C Diseases 0.000 description 12
- CSSIWXFUZVBFND-UHFFFAOYSA-N OP(O)(=O)OP(=O)(O)O.OP(O)(=O)OP(=O)(O)O.OP(O)(=O)OP(=O)(O)O Chemical compound OP(O)(=O)OP(=O)(O)O.OP(O)(=O)OP(=O)(O)O.OP(O)(=O)OP(=O)(O)O CSSIWXFUZVBFND-UHFFFAOYSA-N 0.000 description 12
- 241000700605 Viruses Species 0.000 description 12
- 238000010511 deprotection reaction Methods 0.000 description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
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- RDMGMZAMWLSHNS-UHFFFAOYSA-N 3,7-dihydropurin-6-one;phosphoric acid Chemical compound OP(O)(O)=O.O=C1NC=NC2=C1NC=N2 RDMGMZAMWLSHNS-UHFFFAOYSA-N 0.000 description 8
- ZKLKXUYJIUGECX-UHFFFAOYSA-N 5-methyl-1h-pyrimidine-2,4-dione;phosphoric acid Chemical compound OP(O)(O)=O.CC1=CNC(=O)NC1=O ZKLKXUYJIUGECX-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 208000004571 Pestivirus Infections Diseases 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
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- 210000004027 cell Anatomy 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 8
- 238000010168 coupling process Methods 0.000 description 8
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 8
- 239000007800 oxidant agent Substances 0.000 description 8
- KPYHRMNYOUGKKI-UHFFFAOYSA-N phosphoric acid;1h-pyrimidine-2,4-dione Chemical compound OP(O)(O)=O.O=C1C=CNC(=O)N1 KPYHRMNYOUGKKI-UHFFFAOYSA-N 0.000 description 8
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 8
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- YONPFOKPAKAQLX-UHFFFAOYSA-N 5-fluoro-1h-pyrimidine-2,4-dione;phosphoric acid Chemical compound OP(O)(O)=O.FC1=CNC(=O)NC1=O YONPFOKPAKAQLX-UHFFFAOYSA-N 0.000 description 7
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- ZHTWWICNKGBOAV-UHFFFAOYSA-N 2,8-difluoro-7H-purin-6-amine phosphoric acid Chemical compound OP(O)(O)=O.Nc1nc(F)nc2nc(F)[nH]c12 ZHTWWICNKGBOAV-UHFFFAOYSA-N 0.000 description 4
- ZKKBWNOSVZIFNJ-UHFFFAOYSA-N 2-amino-3,7-dihydropurin-6-one;diphosphono hydrogen phosphate Chemical compound O=C1NC(N)=NC2=C1NC=N2.OP(O)(=O)OP(O)(=O)OP(O)(O)=O ZKKBWNOSVZIFNJ-UHFFFAOYSA-N 0.000 description 4
- JWDLEVZYUTZUBA-UHFFFAOYSA-N 2-amino-3,7-dihydropurin-6-one;phosphono dihydrogen phosphate Chemical compound OP(O)(=O)OP(O)(O)=O.O=C1NC(N)=NC2=C1NC=N2 JWDLEVZYUTZUBA-UHFFFAOYSA-N 0.000 description 4
- BALXSYQWXWVVJJ-UHFFFAOYSA-N 2-amino-3,7-dihydropurin-6-one;phosphoric acid Chemical compound OP(O)(O)=O.O=C1NC(N)=NC2=C1NC=N2 BALXSYQWXWVVJJ-UHFFFAOYSA-N 0.000 description 4
- CDKQXPWHBOXGGT-UHFFFAOYSA-N 2-amino-8-fluoro-1,7-dihydropurin-6-one phosphono dihydrogen phosphate Chemical compound OP(O)(=O)OP(O)(O)=O.Nc1nc2nc(F)[nH]c2c(=O)[nH]1 CDKQXPWHBOXGGT-UHFFFAOYSA-N 0.000 description 4
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| US20767400P | 2000-05-26 | 2000-05-26 | |
| US28327601P | 2001-04-11 | 2001-04-11 |
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| NZ547204A NZ547204A (en) | 2000-05-26 | 2001-05-23 | Methods and compositions for treating flaviviruses and pestiviruses |
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