JP2002505333A5 - - Google Patents
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- JP2002505333A5 JP2002505333A5 JP2000534558A JP2000534558A JP2002505333A5 JP 2002505333 A5 JP2002505333 A5 JP 2002505333A5 JP 2000534558 A JP2000534558 A JP 2000534558A JP 2000534558 A JP2000534558 A JP 2000534558A JP 2002505333 A5 JP2002505333 A5 JP 2002505333A5
- Authority
- JP
- Japan
- Prior art keywords
- group
- aryl
- alkyl
- chr
- substituted
- 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.)
- Granted
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- 125000003118 aryl group Chemical group 0.000 description 341
- 125000000217 alkyl group Chemical group 0.000 description 285
- 239000000651 prodrug Substances 0.000 description 194
- 229940002612 prodrug Drugs 0.000 description 194
- 125000003710 aryl alkyl group Chemical group 0.000 description 190
- 125000002723 alicyclic group Chemical group 0.000 description 186
- 238000000034 method Methods 0.000 description 172
- 125000001072 heteroaryl group Chemical group 0.000 description 162
- 229910052698 phosphorus Inorganic materials 0.000 description 150
- 229910052760 oxygen Inorganic materials 0.000 description 149
- 239000001301 oxygen Substances 0.000 description 147
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 141
- 239000011574 phosphorus Substances 0.000 description 141
- 125000004429 atom Chemical group 0.000 description 124
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 116
- 125000004432 carbon atom Chemical group C* 0.000 description 102
- 125000004122 cyclic group Chemical group 0.000 description 102
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 97
- 125000003107 substituted aryl group Chemical group 0.000 description 90
- 125000005842 heteroatom Chemical group 0.000 description 80
- 150000001875 compounds Chemical class 0.000 description 79
- 229910052799 carbon Inorganic materials 0.000 description 77
- 125000004423 acyloxy group Chemical group 0.000 description 75
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 description 75
- 125000005200 aryloxy carbonyloxy group Chemical group 0.000 description 66
- -1 L-ddC Chemical compound 0.000 description 63
- 229940079593 drug Drugs 0.000 description 49
- 239000003814 drug Substances 0.000 description 49
- 150000001721 carbon Chemical group 0.000 description 47
- 150000003839 salts Chemical class 0.000 description 46
- 125000001424 substituent group Chemical group 0.000 description 46
- 125000005750 substituted cyclic group Chemical group 0.000 description 35
- 238000001727 in vivo Methods 0.000 description 32
- 229910052757 nitrogen Inorganic materials 0.000 description 31
- 125000004433 nitrogen atom Chemical group N* 0.000 description 31
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 30
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 30
- 125000000304 alkynyl group Chemical group 0.000 description 27
- 125000003342 alkenyl group Chemical group 0.000 description 26
- 229910052739 hydrogen Inorganic materials 0.000 description 24
- 241001465754 Metazoa Species 0.000 description 23
- 239000001257 hydrogen Substances 0.000 description 21
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 18
- 125000004414 alkyl thio group Chemical group 0.000 description 18
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 16
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 16
- 210000004185 liver Anatomy 0.000 description 16
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 16
- OIRDTQYFTABQOQ-UHTZMRCNSA-N Vidarabine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O OIRDTQYFTABQOQ-UHTZMRCNSA-N 0.000 description 15
- 229910052736 halogen Inorganic materials 0.000 description 15
- 150000002367 halogens Chemical class 0.000 description 15
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 14
- 125000003282 alkyl amino group Chemical group 0.000 description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 14
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 13
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 12
- 125000004093 cyano group Chemical group *C#N 0.000 description 12
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 12
- 208000006454 hepatitis Diseases 0.000 description 12
- 150000002391 heterocyclic compounds Chemical class 0.000 description 12
- 125000004430 oxygen atom Chemical group O* 0.000 description 12
- 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 description 11
- 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 11
- 150000002431 hydrogen Chemical class 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 10
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 10
- 125000006350 alkyl thio alkyl group Chemical group 0.000 description 10
- 125000005243 carbonyl alkyl group Chemical group 0.000 description 10
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 10
- 231100000283 hepatitis Toxicity 0.000 description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 10
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 10
- 101100002068 Bacillus subtilis (strain 168) araR gene Proteins 0.000 description 9
- 239000002246 antineoplastic agent Substances 0.000 description 9
- 239000003443 antiviral agent Substances 0.000 description 9
- 101150044616 araC gene Proteins 0.000 description 9
- 239000002532 enzyme inhibitor Substances 0.000 description 9
- 229940125532 enzyme inhibitor Drugs 0.000 description 9
- 125000004437 phosphorous atom Chemical group 0.000 description 9
- 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 9
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 8
- 125000002877 alkyl aryl group Chemical group 0.000 description 8
- 150000001409 amidines Chemical class 0.000 description 8
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 8
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- 125000000623 heterocyclic group Chemical group 0.000 description 8
- 150000003462 sulfoxides Chemical class 0.000 description 8
- HFEKDTCAMMOLQP-RRKCRQDMSA-N 5-fluorodeoxyuridine monophosphate Chemical compound O1[C@H](COP(O)(O)=O)[C@@H](O)C[C@@H]1N1C(=O)NC(=O)C(F)=C1 HFEKDTCAMMOLQP-RRKCRQDMSA-N 0.000 description 7
- BYEIJZFKOAXBBV-ATZCPNFKSA-N N-[(5S)-5-amino-5-carboxypentanoyl]-L-cysteinyl-D-valine Chemical compound CC(C)[C@H](C(O)=O)NC(=O)[C@H](CS)NC(=O)CCC[C@H](N)C(O)=O BYEIJZFKOAXBBV-ATZCPNFKSA-N 0.000 description 7
- 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 7
- 239000002253 acid Substances 0.000 description 7
- 229960000329 ribavirin Drugs 0.000 description 7
- 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 description 7
- XHXFQGAZAVKMFF-UHFFFAOYSA-N 2-(2,6-diaminopurin-9-yl)ethoxymethylphosphonic acid Chemical compound NC1=NC(N)=C2N=CN(CCOCP(O)(O)=O)C2=N1 XHXFQGAZAVKMFF-UHFFFAOYSA-N 0.000 description 6
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 6
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 6
- 0 C[C@](C=CC)C(C(N)=*)=C(CCC[C@](C(CC1C*OC)=CI)*1=C)N Chemical compound C[C@](C=CC)C(C(N)=*)=C(CCC[C@](C(CC1C*OC)=CI)*1=C)N 0.000 description 6
- RZMHECYBKLOMKN-UHFFFAOYSA-N OC(=O)CP(=O)=O Chemical compound OC(=O)CP(=O)=O RZMHECYBKLOMKN-UHFFFAOYSA-N 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- 208000036142 Viral infection Diseases 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 210000001853 liver microsome Anatomy 0.000 description 6
- 102000020233 phosphotransferase Human genes 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 231100000419 toxicity Toxicity 0.000 description 6
- 230000001988 toxicity Effects 0.000 description 6
- 239000001226 triphosphate Substances 0.000 description 6
- 235000011178 triphosphate Nutrition 0.000 description 6
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 6
- 230000009385 viral infection Effects 0.000 description 6
- IPVFGAYTKQKGBM-BYPJNBLXSA-N 1-[(2r,3s,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodopyrimidine-2,4-dione Chemical compound F[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 IPVFGAYTKQKGBM-BYPJNBLXSA-N 0.000 description 5
- GBBJCSTXCAQSSJ-JVZYCSMKSA-N 1-[(2r,3s,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1[C@@H](F)[C@H](O)[C@@H](CO)O1 GBBJCSTXCAQSSJ-JVZYCSMKSA-N 0.000 description 5
- QOVUZUCXPAZXDZ-RXMQYKEDSA-N 2-amino-9-[(3r)-3,4-dihydroxybutyl]-3h-purin-6-one Chemical compound O=C1NC(N)=NC2=C1N=CN2CC[C@@H](O)CO QOVUZUCXPAZXDZ-RXMQYKEDSA-N 0.000 description 5
- GIMSJJHKKXRFGV-BYPJNBLXSA-N 4-amino-1-[(2r,3s,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodopyrimidin-2-one Chemical compound C1=C(I)C(N)=NC(=O)N1[C@H]1[C@@H](F)[C@H](O)[C@@H](CO)O1 GIMSJJHKKXRFGV-BYPJNBLXSA-N 0.000 description 5
- HSBKFSPNDWWPSL-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@@H]1C=C[C@H](CO)O1 HSBKFSPNDWWPSL-VDTYLAMSSA-N 0.000 description 5
- QBEIABZPRBJOFU-VDTYLAMSSA-N 4-amino-5-fluoro-1-[(2s,5r)-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)CC1 QBEIABZPRBJOFU-VDTYLAMSSA-N 0.000 description 5
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 5
- SWFJAJRDLUUIOA-IBCQBUCCSA-N 5-ethyl-1-[(2r,3s,4r,5r)-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(CC)=CN1[C@H]1[C@@H](F)[C@H](O)[C@@H](CO)O1 SWFJAJRDLUUIOA-IBCQBUCCSA-N 0.000 description 5
- GSDZMZKDKWSUOV-OEJXEDHQSA-N 5-prop-1-ynyl-1-[(3S,4R,5R)-3,4,5-trihydroxyoxan-2-yl]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C#CC)=CN1C1[C@@H](O)[C@H](O)[C@H](O)CO1 GSDZMZKDKWSUOV-OEJXEDHQSA-N 0.000 description 5
- WOVKYSAHUYNSMH-UHFFFAOYSA-N BROMODEOXYURIDINE Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-UHFFFAOYSA-N 0.000 description 5
- YOOVTUPUBVHMPG-UHFFFAOYSA-N Coformycin Natural products OC1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 YOOVTUPUBVHMPG-UHFFFAOYSA-N 0.000 description 5
- VZKXOWRNJDEGLZ-WHFBIAKZSA-N Cys-Asp-Gly Chemical compound SC[C@H](N)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(O)=O VZKXOWRNJDEGLZ-WHFBIAKZSA-N 0.000 description 5
- RLAHNGKRJJEIJL-RFZPGFLSSA-N [(2r,4r)-4-(2,6-diaminopurin-9-yl)-1,3-dioxolan-2-yl]methanol Chemical compound C12=NC(N)=NC(N)=C2N=CN1[C@H]1CO[C@@H](CO)O1 RLAHNGKRJJEIJL-RFZPGFLSSA-N 0.000 description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- 229950004398 broxuridine Drugs 0.000 description 5
- YOOVTUPUBVHMPG-LODYRLCVSA-O coformycin(1+) Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C([NH+]=CNC[C@H]2O)=C2N=C1 YOOVTUPUBVHMPG-LODYRLCVSA-O 0.000 description 5
- 229940104302 cytosine Drugs 0.000 description 5
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 5
- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 5
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 5
- 229960002340 pentostatin Drugs 0.000 description 5
- HBUBKKRHXORPQB-FJFJXFQQSA-N (2R,3S,4S,5R)-2-(6-amino-2-fluoro-9-purinyl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O HBUBKKRHXORPQB-FJFJXFQQSA-N 0.000 description 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 description 4
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 description 4
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- UDMBCSSLTHHNCD-UHTZMRCNSA-N [(2r,3s,4s,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O UDMBCSSLTHHNCD-UHTZMRCNSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 150000001336 alkenes Chemical group 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 150000003973 alkyl amines Chemical class 0.000 description 4
- 125000004103 aminoalkyl group Chemical group 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 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 4
- 208000016097 disease of metabolism Diseases 0.000 description 4
- 239000002359 drug metabolite Substances 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 4
- 208000019423 liver disease Diseases 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 208000030159 metabolic disease Diseases 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 239000004059 squalene synthase inhibitor Substances 0.000 description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 125000006598 aminocarbonylamino group Chemical group 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
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- 239000003112 inhibitor Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 231100001274 therapeutic index Toxicity 0.000 description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 2
- 101710099475 3'-phosphoadenosine 5'-phosphate phosphatase Proteins 0.000 description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 description 2
- 102000014156 AMP-Activated Protein Kinases Human genes 0.000 description 2
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- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 206010008617 Cholecystitis chronic Diseases 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
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 206010016654 Fibrosis Diseases 0.000 description 2
- 101710196411 Fructose-1,6-bisphosphatase Proteins 0.000 description 2
- 101710186733 Fructose-1,6-bisphosphatase, chloroplastic Proteins 0.000 description 2
- 101710109119 Fructose-1,6-bisphosphatase, cytosolic Proteins 0.000 description 2
- 101710198902 Fructose-1,6-bisphosphate aldolase/phosphatase Proteins 0.000 description 2
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 2
- 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 2
- 101001028852 Homo sapiens Fructose-1,6-bisphosphatase 1 Proteins 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- MDBVZFGSKMWJFD-UHFFFAOYSA-N OP(O)=O.OP(O)(O)=O Chemical compound OP(O)=O.OP(O)(O)=O MDBVZFGSKMWJFD-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 208000030852 Parasitic disease Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- XVNPFKBFDDXQOD-UHFFFAOYSA-N [5-[6-chloro-1-(2-methylpropyl)benzimidazol-2-yl]furan-2-yl]phosphonic acid Chemical compound N=1C2=CC=C(Cl)C=C2N(CC(C)C)C=1C1=CC=C(P(O)(O)=O)O1 XVNPFKBFDDXQOD-UHFFFAOYSA-N 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 125000002015 acyclic group Chemical group 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
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| US60/077,164 | 1998-03-06 | ||
| US60/077,165 | 1998-03-06 | ||
| PCT/US1999/004908 WO1999045016A2 (en) | 1998-03-06 | 1999-03-05 | Novel prodrugs for phosphorus-containing compounds |
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| JP2002505333A5 true JP2002505333A5 (https=) | 2006-04-27 |
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| ES (1) | ES2401070T3 (https=) |
| WO (1) | WO1999045016A2 (https=) |
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| US6284748B1 (en) | 1997-03-07 | 2001-09-04 | Metabasis Therapeutics, Inc. | Purine inhibitors of fructose 1,6-bisphosphatase |
| KR100818845B1 (ko) | 1998-09-09 | 2008-04-01 | 메타베이시스 테라퓨틱스, 인크. | 신규한 프럭토스 1,6-비스포스파타제의 헤테로방향족 억제제 |
| US7205404B1 (en) | 1999-03-05 | 2007-04-17 | Metabasis Therapeutics, Inc. | Phosphorus-containing prodrugs |
| US6831069B2 (en) | 1999-08-27 | 2004-12-14 | Ribapharm Inc. | Pyrrolo[2,3-d]pyrimidine nucleoside analogs |
| AU7361400A (en) | 1999-09-08 | 2001-04-10 | Metabasis Therapeutics, Inc. | Prodrugs for liver specific drug delivery |
| AU784370B2 (en) * | 1999-12-22 | 2006-03-23 | Metabasis Therapeutics, Inc. | Novel bisamidate phosphonate prodrugs |
| US7638496B2 (en) | 2000-02-15 | 2009-12-29 | Valeant Pharmaceuticals North America | Nucleoside analogs with carboxamidine modified monocyclic base |
| JP2003525944A (ja) | 2000-03-08 | 2003-09-02 | メタバシス・セラピューティクス・インコーポレイテッド | 新規アリールフルクトース−１，６−ビスホスファターゼ阻害剤 |
| MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
| EP1736478B1 (en) | 2000-05-26 | 2015-07-22 | IDENIX Pharmaceuticals, Inc. | Methods and compositions for treating flaviviruses and pestiviruses |
| US7563774B2 (en) | 2000-06-29 | 2009-07-21 | Metabasis Therapeutics, Inc. | Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes |
| GB0115109D0 (en) | 2001-06-21 | 2001-08-15 | Aventis Pharma Ltd | Chemical compounds |
| EP1435974A4 (en) | 2001-09-28 | 2006-09-06 | Idenix Cayman Ltd | METHODS AND COMPOSITIONS FOR THE TREATMENT OF HEPATITIS C VIRUS USING 4 'MODIFIED NUCLEOSIDES |
| NZ537662A (en) | 2002-06-28 | 2007-10-26 | Idenix Cayman Ltd | 2'-C-methyl-3'-O-L-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
| TW200500375A (en) | 2002-06-28 | 2005-01-01 | Idenix Cayman Ltd | Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae |
| CN1678326A (zh) | 2002-06-28 | 2005-10-05 | 埃迪尼克斯(开曼)有限公司 | 用于治疗黄病毒感染的2'－c－甲基－3'－o－l－缬氨酸酯核糖呋喃基胞苷 |
| US7608600B2 (en) | 2002-06-28 | 2009-10-27 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
| BR0315795A (pt) | 2002-10-31 | 2005-09-13 | Metabasis Therapeutics Inc | Pró-medicamentos de monofosfato de citarabina |
| LT1576138T (lt) | 2002-11-15 | 2017-06-26 | Idenix Pharmaceuticals Llc | 2`-šakoti nukleozidai derinyje su interferonu ir flaviviridae mutacija |
| AU2003300901A1 (en) | 2002-12-12 | 2004-06-30 | Idenix (Cayman) Limited | Process for the production of 2'-branched nucleosides |
| US20050182252A1 (en) * | 2004-02-13 | 2005-08-18 | Reddy K. R. | Novel 2'-C-methyl nucleoside derivatives |
| EP1905778A3 (en) * | 2004-02-13 | 2012-05-09 | Metabasis Therapeutics, Inc. | Novel 2'-C-methyl nucleoside derivatives |
| CA2565966A1 (en) | 2004-06-08 | 2005-12-29 | Metabasis Therapeutics, Inc. | Lewis acid mediated synthesis of cyclic esters |
| US7524831B2 (en) | 2005-03-02 | 2009-04-28 | Schering Corporation | Treatments for Flaviviridae virus infection |
| MX2007014502A (es) | 2005-05-26 | 2008-02-07 | Metabasis Therapeutics Inc | Tiromimeticos para el tratamiento de enfermedades del higado graso. |
| CL2007002617A1 (es) | 2006-09-11 | 2008-05-16 | Sanofi Aventis | Compuestos derivados de pirrolo[2,3-b]pirazin-6-ilo; composicion farmaceutica que comprende a dichos compuestos; y su uso para tratar inflamacion de las articulaciones, artritis reumatoide, tumores, linfoma de las celulas del manto. |
| AR069740A1 (es) * | 2007-11-29 | 2010-02-17 | Metabasis Therapeutics Inc | Compuestos nucleosidos antivirales |
| WO2009129120A2 (en) | 2008-04-15 | 2009-10-22 | Rfs Pharma, Llc | Nucleoside derivatives for treatment of caliciviridae infections, including norovirus infections |
| US8394969B2 (en) | 2008-09-26 | 2013-03-12 | Merck Sharp & Dohme Corp. | Cyclic benzimidazole derivatives useful as anti-diabetic agents |
| EP2348857B1 (en) | 2008-10-22 | 2016-02-24 | Merck Sharp & Dohme Corp. | Novel cyclic benzimidazole derivatives useful anti-diabetic agents |
| US8329914B2 (en) | 2008-10-31 | 2012-12-11 | Merck Sharp & Dohme Corp | Cyclic benzimidazole derivatives useful as anti-diabetic agents |
| JP2013520502A (ja) | 2010-02-25 | 2013-06-06 | メルク・シャープ・エンド・ドーム・コーポレイション | 有用な抗糖尿病薬である新規な環状ベンズイミダゾール誘導体 |
| 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 |
| WO2014043380A1 (en) * | 2012-09-14 | 2014-03-20 | Ligand Pharmaceuticals Incorporated | Novel nucleotide prodrug compounds and use |
| AU2015217221A1 (en) | 2014-02-13 | 2016-08-11 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and their uses |
| CN106687118A (zh) * | 2014-07-02 | 2017-05-17 | 配体药物公司 | 前药化合物及其用途 |
| CN107540710B (zh) * | 2016-06-24 | 2020-10-16 | 浙江柏拉阿图医药科技有限公司 | 肝递送抗病毒前体药物核苷环磷酸酯化合物及应用 |
| JP2020500199A (ja) | 2016-11-21 | 2020-01-09 | バイキング・セラピューティクス・インコーポレイテッド | グリコーゲン蓄積症の治療方法 |
| AU2018280118B2 (en) | 2017-06-05 | 2021-07-15 | Viking Therapeutics, Inc. | Compositions for the treatment of fibrosis |
| CA3087932A1 (en) | 2018-01-09 | 2019-07-18 | Ligand Pharmaceuticals, Inc. | Acetal compounds and therapeutic uses thereof |
| ES3053674T3 (en) | 2018-03-22 | 2026-01-23 | Viking Therapeutics Inc | Crystalline forms and methods of producing crystalline forms of a compound |
| WO2020117962A1 (en) | 2018-12-05 | 2020-06-11 | Viking Therapeutics, Inc. | Compositions for the treatment of fibrosis and inflammation |
| CN111434671B (zh) * | 2019-01-11 | 2023-07-11 | 凯思凯迪（上海）医药科技有限公司 | 肝脏特异性ampk激动剂及其制法和应用 |
| JP7470456B2 (ja) | 2019-08-21 | 2024-04-18 | チャンチュン・チャンチェン・ファーマシューティカル・テクノロジー・カンパニー・リミテッド | アミン、アミド、フェノールの送達に用いられるプロドラッグプラットフォーム |
| JP2023500794A (ja) * | 2019-10-17 | 2023-01-11 | エーアイ‐バイオファーマ | 抗ウイルス薬および肝臓標的薬 |
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|---|---|---|---|---|
| NL222157A (https=) * | 1956-12-20 | |||
| US4579849A (en) * | 1984-04-06 | 1986-04-01 | Merck & Co., Inc. | N-alkylguanine acyclonucleosides as antiviral agents |
| NL8403224A (nl) * | 1984-10-24 | 1986-05-16 | Oce Andeno Bv | Dioxafosforinanen, de bereiding ervan en de toepassing voor het splitsen van optisch actieve verbindingen. |
| EP0338372A3 (en) * | 1988-04-22 | 1991-10-09 | American Cyanamid Company | Solubilized pro-drugs |
| CA1334752C (en) * | 1988-08-02 | 1995-03-14 | Ryozo Sakoda | Drug effect-enhancing agent for antitumor drug |
| 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 |
| DE69520360T2 (de) * | 1994-07-04 | 2001-08-09 | Takeda Chemical Industries, Ltd. | Phosphonsäure verbindungen imre herstellung und verwendung |
| ATE253920T1 (de) * | 1995-07-17 | 2003-11-15 | Cephalon Inc | Phosphor enthaltende hemmer von cystein- und serin-proteasen |
| US6284748B1 (en) * | 1997-03-07 | 2001-09-04 | Metabasis Therapeutics, Inc. | Purine inhibitors of fructose 1,6-bisphosphatase |
| DE69819311T2 (de) * | 1997-03-07 | 2004-07-29 | Metabasis Therapeutics Inc., San Diego | Neue benzimidazol inhibitoren der fructose-1,6-bisphosphatase |
-
1999
- 1999-03-05 CA CA2322487A patent/CA2322487C/en not_active Expired - Lifetime
- 1999-03-05 ES ES99912300T patent/ES2401070T3/es not_active Expired - Lifetime
- 1999-03-05 EP EP99912300A patent/EP1060182B1/en not_active Expired - Lifetime
- 1999-03-05 WO PCT/US1999/004908 patent/WO1999045016A2/en not_active Ceased
- 1999-03-05 AU AU30699/99A patent/AU767599B2/en not_active Expired
- 1999-03-05 JP JP2000534558A patent/JP4741725B2/ja not_active Expired - Lifetime
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