JP2006507308A5 - - Google Patents
Download PDFInfo
- Publication number
- JP2006507308A5 JP2006507308A5 JP2004550339A JP2004550339A JP2006507308A5 JP 2006507308 A5 JP2006507308 A5 JP 2006507308A5 JP 2004550339 A JP2004550339 A JP 2004550339A JP 2004550339 A JP2004550339 A JP 2004550339A JP 2006507308 A5 JP2006507308 A5 JP 2006507308A5
- Authority
- JP
- Japan
- Prior art keywords
- pharmaceutical composition
- agent
- pharmaceutically acceptable
- animal
- cancer
- 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
Links
- 239000003795 chemical substances by application Substances 0.000 claims 18
- 239000008194 pharmaceutical composition Substances 0.000 claims 17
- 150000001875 compounds Chemical class 0.000 claims 13
- -1 prikamycin Chemical compound 0.000 claims 12
- 229960000390 fludarabine Drugs 0.000 claims 9
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims 9
- 206010028980 Neoplasm Diseases 0.000 claims 8
- 201000010099 disease Diseases 0.000 claims 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 8
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims 8
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims 8
- 230000000174 oncolytic effect Effects 0.000 claims 8
- 201000011510 cancer Diseases 0.000 claims 7
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims 6
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 claims 6
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims 6
- 229960005420 etoposide Drugs 0.000 claims 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims 6
- 150000003839 salts Chemical class 0.000 claims 6
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims 4
- 229960000684 cytarabine Drugs 0.000 claims 4
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 claims 3
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims 3
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 claims 3
- FUXVKZWTXQUGMW-FQEVSTJZSA-N 9-Aminocamptothecin Chemical compound C1=CC(N)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 FUXVKZWTXQUGMW-FQEVSTJZSA-N 0.000 claims 3
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims 3
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims 3
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 claims 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims 3
- 108010092160 Dactinomycin Proteins 0.000 claims 3
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 claims 3
- 229930189413 Esperamicin Natural products 0.000 claims 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims 3
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 claims 3
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 claims 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims 3
- 229930192392 Mitomycin Natural products 0.000 claims 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims 3
- 229930012538 Paclitaxel Natural products 0.000 claims 3
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 claims 3
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims 3
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims 3
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 claims 3
- 229940124675 anti-cancer drug Drugs 0.000 claims 3
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 claims 3
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims 3
- 229960002092 busulfan Drugs 0.000 claims 3
- 229930195731 calicheamicin Natural products 0.000 claims 3
- HXCHCVDVKSCDHU-LULTVBGHSA-N calicheamicin Chemical compound C1[C@H](OC)[C@@H](NCC)CO[C@H]1O[C@H]1[C@H](O[C@@H]2C\3=C(NC(=O)OC)C(=O)C[C@](C/3=C/CSSSC)(O)C#C\C=C/C#C2)O[C@H](C)[C@@H](NO[C@@H]2O[C@H](C)[C@@H](SC(=O)C=3C(=C(OC)C(O[C@H]4[C@@H]([C@H](OC)[C@@H](O)[C@H](C)O4)O)=C(I)C=3C)OC)[C@@H](O)C2)[C@@H]1O HXCHCVDVKSCDHU-LULTVBGHSA-N 0.000 claims 3
- 229960004562 carboplatin Drugs 0.000 claims 3
- 229960005243 carmustine Drugs 0.000 claims 3
- 229960004630 chlorambucil Drugs 0.000 claims 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims 3
- 229960004316 cisplatin Drugs 0.000 claims 3
- 229960002436 cladribine Drugs 0.000 claims 3
- LRCTTYSATZVTRI-UHFFFAOYSA-L cyclohexane-1,2-diamine;platinum(4+);tetradecanoate Chemical compound [Pt+4].NC1CCCCC1N.CCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCC([O-])=O LRCTTYSATZVTRI-UHFFFAOYSA-L 0.000 claims 3
- 229960004397 cyclophosphamide Drugs 0.000 claims 3
- 229960000640 dactinomycin Drugs 0.000 claims 3
- 229960000975 daunorubicin Drugs 0.000 claims 3
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims 3
- 229960003668 docetaxel Drugs 0.000 claims 3
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 claims 3
- 229950005454 doxifluridine Drugs 0.000 claims 3
- 229960004679 doxorubicin Drugs 0.000 claims 3
- 229960001904 epirubicin Drugs 0.000 claims 3
- LJQQFQHBKUKHIS-WJHRIEJJSA-N esperamicin Chemical compound O1CC(NC(C)C)C(OC)CC1OC1C(O)C(NOC2OC(C)C(SC)C(O)C2)C(C)OC1OC1C(\C2=C/CSSSC)=C(NC(=O)OC)C(=O)C(OC3OC(C)C(O)C(OC(=O)C=4C(=CC(OC)=C(OC)C=4)NC(=O)C(=C)OC)C3)C2(O)C#C\C=C/C#C1 LJQQFQHBKUKHIS-WJHRIEJJSA-N 0.000 claims 3
- 229960002949 fluorouracil Drugs 0.000 claims 3
- 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 claims 3
- 229960005277 gemcitabine Drugs 0.000 claims 3
- 229960000908 idarubicin Drugs 0.000 claims 3
- 229960001101 ifosfamide Drugs 0.000 claims 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims 3
- 229960004768 irinotecan Drugs 0.000 claims 3
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 claims 3
- 210000004185 liver Anatomy 0.000 claims 3
- 229960001924 melphalan Drugs 0.000 claims 3
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims 3
- 229960001428 mercaptopurine Drugs 0.000 claims 3
- 229960000485 methotrexate Drugs 0.000 claims 3
- 229950004962 miriplatin Drugs 0.000 claims 3
- 229960004857 mitomycin Drugs 0.000 claims 3
- 229950007221 nedaplatin Drugs 0.000 claims 3
- 229960001592 paclitaxel Drugs 0.000 claims 3
- 229960001221 pirarubicin Drugs 0.000 claims 3
- 238000001356 surgical procedure Methods 0.000 claims 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims 3
- 229960004964 temozolomide Drugs 0.000 claims 3
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims 3
- 229960001278 teniposide Drugs 0.000 claims 3
- 229960001196 thiotepa Drugs 0.000 claims 3
- 229960003087 tioguanine Drugs 0.000 claims 3
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 claims 3
- 229960000303 topotecan Drugs 0.000 claims 3
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims 3
- 229960000653 valrubicin Drugs 0.000 claims 3
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 claims 3
- 206010009944 Colon cancer Diseases 0.000 claims 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 2
- 208000015634 Rectal Neoplasms Diseases 0.000 claims 2
- 210000001072 colon Anatomy 0.000 claims 2
- 201000010989 colorectal carcinoma Diseases 0.000 claims 2
- 229940079593 drug Drugs 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 201000007270 liver cancer Diseases 0.000 claims 2
- 208000014018 liver neoplasm Diseases 0.000 claims 2
- 206010038038 rectal cancer Diseases 0.000 claims 2
- 201000001275 rectum cancer Diseases 0.000 claims 2
- 231100001274 therapeutic index Toxicity 0.000 claims 2
- 230000009385 viral infection Effects 0.000 claims 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 230000001461 cytolytic effect Effects 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 claims 1
- 239000000651 prodrug Substances 0.000 claims 1
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US42325902P | 2002-10-31 | 2002-10-31 | |
| US42321102P | 2002-10-31 | 2002-10-31 | |
| US60/423,211 | 2002-10-31 | ||
| US60/423,259 | 2002-10-31 | ||
| PCT/US2003/034690 WO2004041837A1 (en) | 2002-10-31 | 2003-10-31 | Novel cytarabine monophosphate prodrugs |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2006507308A JP2006507308A (ja) | 2006-03-02 |
| JP2006507308A5 true JP2006507308A5 (enExample) | 2006-12-28 |
| JP4689274B2 JP4689274B2 (ja) | 2011-05-25 |
Family
ID=32314479
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2004550339A Expired - Fee Related JP4689274B2 (ja) | 2002-10-31 | 2003-10-31 | 新規なシタラビン・モノホスフェートプロドラッグ |
| JP2004550353A Expired - Fee Related JP5046219B2 (ja) | 2002-10-31 | 2003-10-31 | １，３−プロパン−１−アリールジオールの新規環状リン酸ジエステルおよびそのプロドラッグへの使用 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2004550353A Expired - Fee Related JP5046219B2 (ja) | 2002-10-31 | 2003-10-31 | １，３−プロパン−１−アリールジオールの新規環状リン酸ジエステルおよびそのプロドラッグへの使用 |
Country Status (13)
| Country | Link |
|---|---|
| US (4) | US7148349B2 (enExample) |
| EP (2) | EP1556398B1 (enExample) |
| JP (2) | JP4689274B2 (enExample) |
| KR (2) | KR101026294B1 (enExample) |
| AT (1) | ATE442375T1 (enExample) |
| AU (2) | AU2003287389B2 (enExample) |
| BR (2) | BR0315795A (enExample) |
| CA (2) | CA2503729C (enExample) |
| DE (1) | DE60329211D1 (enExample) |
| IL (2) | IL167990A (enExample) |
| MX (2) | MXPA05004504A (enExample) |
| PL (2) | PL376474A1 (enExample) |
| WO (2) | WO2004041834A2 (enExample) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6312662B1 (en) | 1998-03-06 | 2001-11-06 | Metabasis Therapeutics, Inc. | Prodrugs phosphorus-containing compounds |
| IL164809A0 (en) * | 2002-05-13 | 2005-12-18 | Metabasis Therapeutics Inc | Novel phosphonic acid basdrugs of pmea and its analogues |
| JP4332496B2 (ja) | 2002-05-13 | 2009-09-16 | メタバシス・セラピューティクス・インコーポレイテッド | Ｐｍｅａおよびｐｍｐａ環生成合成 |
| DE60329211D1 (de) * | 2002-10-31 | 2009-10-22 | Metabasis Therapeutics Inc | Cytarabin-monophosphate prodrugs |
| US20050182252A1 (en) * | 2004-02-13 | 2005-08-18 | Reddy K. R. | Novel 2'-C-methyl nucleoside derivatives |
| RU2006138907A (ru) | 2004-06-08 | 2008-07-20 | Метабазис Терапеутикс | Синтез сложных циклических эфиров с применением кислоты льюиса |
| AU2006279720A1 (en) * | 2005-08-12 | 2007-02-22 | Merck & Co., Inc. | Novel 2'-C-methyl and 4'-C-methyl nucleoside derivatives |
| US20070241502A1 (en) * | 2006-04-14 | 2007-10-18 | Campbell Darrell C | Poker game and apparatus for play thereof |
| US7584968B2 (en) * | 2006-04-14 | 2009-09-08 | Seven Generations, Inc. | Poker game and apparatus for play thereof |
| US8063025B2 (en) * | 2007-11-29 | 2011-11-22 | Metabasis Therapeutics, Inc. | Nucleoside prodrugs and uses thereof |
| BRPI0821106A2 (pt) * | 2007-11-29 | 2015-06-16 | Ligand Pharm Inc | Pró-fármacos de nucleosídeo e usos dos mesmos |
| CA2722858C (en) * | 2008-04-30 | 2017-08-29 | Siemens Medical Solutions Usa, Inc. | Substrate based pet imaging agents |
| CN101787064B (zh) * | 2009-01-23 | 2013-03-13 | 高峰 | 阿糖胞苷衍生物及其在抗癌抗肿瘤中的用途 |
| JP5631414B2 (ja) * | 2010-01-15 | 2014-11-26 | ビーエーエスエフ ソシエタス・ヨーロピアＢａｓｆ Ｓｅ | ホスホ置換アルコキシアミン化合物 |
| WO2011113174A1 (zh) * | 2010-03-15 | 2011-09-22 | Gao Feng | 阿糖胞苷衍生物及其在抗癌抗肿瘤中的用途 |
| JP6401255B2 (ja) * | 2013-06-24 | 2018-10-10 | 株式会社 キャンバス | ペプチド及びペプチド模倣物の併用並びに癌患者亜集団の処置 |
| GB201317166D0 (en) * | 2013-09-27 | 2013-11-06 | Astex Therapeutics Ltd | Pharmaceutical compounds |
| WO2015123352A1 (en) | 2014-02-13 | 2015-08-20 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and their uses |
| US9994600B2 (en) | 2014-07-02 | 2018-06-12 | Ligand Pharmaceuticals, Inc. | Prodrug compounds and uses therof |
| BR112018002399A2 (pt) | 2015-08-06 | 2018-09-25 | Chimerix, Inc. | nucleosídeos de pirrolopirimidina e análogos dos mesmos, úteis como agentes antivirais |
| US12064445B2 (en) | 2015-12-03 | 2024-08-20 | Biosight Ltd. | Cytarabine conjugates for cancer therapy |
| CA3007065C (en) * | 2015-12-03 | 2023-02-14 | Biosight Ltd. | Salts of conjugates for cancer therapy |
| AU2016362830B2 (en) | 2015-12-03 | 2022-07-14 | Biosight Ltd. | Cytarabine conjugates for cancer therapy |
| US12071450B2 (en) | 2015-12-03 | 2024-08-27 | Biosight Ltd. | Salts of conjugates for cancer therapy |
| US11224578B2 (en) * | 2016-09-20 | 2022-01-18 | Shimadzu Corporation | Medicinal agent-containing molecular assembly which uses amphiphilic block polymer |
| EP3684771B1 (en) | 2017-09-21 | 2024-11-27 | Chimerix, Inc. | Morphic forms of 4-amino-7-(3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2-methyl-7h-pyrrolo(2,3-d)pyrimidine-5-carboxamide and uses thereof |
| CN109956985A (zh) * | 2017-12-22 | 2019-07-02 | 浙江柏拉阿图医药科技有限公司 | 肝递送阿糖胞苷前体药物核苷环磷酸酯化合物及应用 |
| AU2019207625A1 (en) | 2018-01-09 | 2020-07-30 | Ligand Pharmaceuticals, Inc. | Acetal compounds and therapeutic uses thereof |
Family Cites Families (82)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR75178E (enExample) * | 1956-12-20 | 1961-09-08 | ||
| US3116282A (en) | 1960-04-27 | 1963-12-31 | Upjohn Co | Pyrimidine nucleosides and process |
| US3328388A (en) | 1964-09-02 | 1967-06-27 | Merck & Co Inc | Arabinofuranosyl pyrimidines and methods of preparing same |
| US4440740A (en) * | 1982-04-26 | 1984-04-03 | Merck & Co., Inc. | α-Keto aldehydes as enhancing agents of gastro-intestinal drug absorption |
| US4579849A (en) | 1984-04-06 | 1986-04-01 | Merck & Co., Inc. | N-alkylguanine acyclonucleosides as antiviral agents |
| FR2562543B1 (fr) | 1984-04-10 | 1987-09-25 | Elf Aquitaine | Nouveaux phosphonites cycliques, leur preparation et applications |
| US4749694A (en) | 1984-04-26 | 1988-06-07 | Merck & Co., Inc. | Novel lysine esters used as absorption |
| US4537772A (en) * | 1984-05-02 | 1985-08-27 | Merck & Co., Inc. | Enhancing absorption of drugs from gastrointestinal tract using acylcarnitines |
| 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. |
| US4973579A (en) * | 1985-06-28 | 1990-11-27 | Merck & Co., Inc. | Enhancment of absorption of drugs from gastrointestinal tract using choline ester salts |
| US4729989A (en) * | 1985-06-28 | 1988-03-08 | Merck & Co., Inc. | Enhancement of absorption of drugs from gastrointestinal tract using choline ester salts |
| US4822773A (en) * | 1985-06-28 | 1989-04-18 | Merck & Co., Inc. | Enhancement of absorption of drugs from gastrointestinal tract using choline ester salts |
| US4731360A (en) * | 1985-08-16 | 1988-03-15 | Merck & Co., Inc. | Acylcarnitines as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal compartments |
| US4963525A (en) * | 1985-08-16 | 1990-10-16 | Merck & Co., Inc. | Acylcarnitines as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal compartments |
| US4963556A (en) | 1985-08-16 | 1990-10-16 | Merck & Co., Inc. | Choline esters as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal cavities |
| US4692441A (en) * | 1985-08-16 | 1987-09-08 | Merck & Co., Inc. | Chorine esters as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal cavities |
| US4847298A (en) | 1985-08-16 | 1989-07-11 | Merck & Co., Inc. | Acylcarnitines as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal compartments |
| US5159067A (en) | 1987-01-28 | 1992-10-27 | University Of Georgia Research Foundation Inc. | 5'-Diphosphohexose nucleoside pharmaceutical compositions |
| US5077280A (en) * | 1988-04-12 | 1991-12-31 | Brown University Research Foundation | Treatment of viral infections |
| 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 |
| US5658889A (en) | 1989-01-24 | 1997-08-19 | Gensia Pharmaceuticals, Inc. | Method and compounds for aica riboside delivery and for lowering blood glucose |
| US5118672A (en) * | 1989-07-10 | 1992-06-02 | University Of Georgia Research Foundation | 5'-diphosphohexose nucleoside pharmaceutical compositions |
| DE69115694T2 (de) | 1990-06-13 | 1996-10-17 | Arnold Newton Mass. Glazier | Phosphorylierte prodrugs |
| DE10399025I2 (de) | 1990-09-14 | 2007-11-08 | Acad Of Science Czech Republic | Wirkstoffvorläufer von Phosphonaten |
| WO1993016388A1 (en) | 1992-02-13 | 1993-08-19 | The Uab Research Foundation | Method of detecting and monitoring levels of 3'-amino-3'-deoxythymidine in body fluids and antibodies for same |
| GB2266527A (en) | 1992-03-17 | 1993-11-03 | Merck & Co Inc | Substituted azetidinones useful in the treatment of leukemia |
| GB2266525A (en) | 1992-03-17 | 1993-11-03 | Merck & Co Inc | Substituted cephalosporin sulfone compositions useful in the treatment of leukemia |
| JP4117901B2 (ja) | 1993-05-21 | 2008-07-16 | アメリカ合衆国 | デオキシヌクレオチド合成の阻害剤を使用することによって逆転写酵素依存ウイルスの複製を阻害する新規な方法 |
| EP0632048B1 (en) | 1993-06-29 | 2001-03-21 | Mitsubishi Chemical Corporation | Phosphonate-nucleotide ester derivatives |
| US5567689A (en) * | 1993-08-13 | 1996-10-22 | The Uab Research Foundation | Methods for increasing uridine levels with L-nucleosides |
| FR2709754B1 (fr) | 1993-09-10 | 1995-12-01 | Centre Nat Rech Scient | Composés 2' ou 3'-déoxy- et 2', 3'-didéoxy-beta-L-pentofuranonucléosides, procédé de préparation et application thérapeutique, notamment anti-virale. |
| US20020120130A1 (en) | 1993-09-10 | 2002-08-29 | Gilles Gosselin | 2' or 3' -deoxy and 2', 3' -dideoxy-beta-L-pentofuranonucleo-side compounds, method of preparation and application in therapy, especially as anti- viral agents |
| CA2171550C (en) | 1993-09-10 | 2008-08-26 | Raymond F. Schinazi | Nucleosides with anti-hepatitis b virus activity |
| CA2171743C (en) | 1993-09-17 | 2007-11-20 | Norbert W. Bischofberger | Nucleotide analogs |
| US5437772A (en) | 1993-11-01 | 1995-08-01 | The Electrosynthesis Co., Inc. | Portable lead detector |
| US5599686A (en) | 1994-06-28 | 1997-02-04 | Merck & Co., Inc. | Peptides |
| US5866679A (en) | 1994-06-28 | 1999-02-02 | Merck & Co., Inc. | Peptides |
| US6143864A (en) * | 1994-06-28 | 2000-11-07 | Merck & Co., Inc. | Peptides |
| DE69520360T2 (de) | 1994-07-04 | 2001-08-09 | Takeda Chemical Industries, Ltd. | Phosphonsäure verbindungen imre herstellung und verwendung |
| US5665713A (en) | 1995-04-12 | 1997-09-09 | Procter & Gamble Company | Pharmaceutical composition for inhibiting the growth of viruses and cancers |
| ATE346651T1 (de) * | 1995-06-07 | 2006-12-15 | Univ Emory | Nucleoside mit anti-hepatitis b virus wirksamkeit |
| ES2210377T3 (es) | 1995-07-17 | 2004-07-01 | Cephalon, Inc. | Inhibidores de cisteina y serina proteasa que contienen fosforo. |
| US5750493A (en) * | 1995-08-30 | 1998-05-12 | Raymond F. Schinazi | Method to improve the biological and antiviral activity of protease inhibitors |
| RU2111970C1 (ru) | 1996-06-25 | 1998-05-27 | Иван Игоревич Федоров | 3'-оксимино-2',3'-дидезоксинуклеозиды |
| US6177404B1 (en) * | 1996-10-15 | 2001-01-23 | Merck & Co., Inc. | Conjugates useful in the treatment of benign prostatic hyperplasia |
| US5948750A (en) * | 1996-10-30 | 1999-09-07 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
| WO1998039344A1 (en) * | 1997-03-07 | 1998-09-11 | Metabasis Therapeutics, Inc. | Novel purine inhibitors of fructose-1,6-bisphosphatase |
| ATE253073T1 (de) | 1997-03-07 | 2003-11-15 | Metabasis Therapeutics Inc | Neue benzimidazol inhibitoren der fructose-1,6- bisphosphatase |
| WO1998039342A1 (en) * | 1997-03-07 | 1998-09-11 | Metabasis Therapeutics, Inc. | Novel indole and azaindole inhibitors of fructose-1,6-bisphosphatase |
| US6130504A (en) | 1997-07-11 | 2000-10-10 | Sharp Kabushiki Kaisha | Plasma addressing display device and method for producing the same |
| US6391305B1 (en) * | 1997-09-10 | 2002-05-21 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
| US20020115596A1 (en) * | 1997-10-27 | 2002-08-22 | Merk & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
| US6312662B1 (en) * | 1998-03-06 | 2001-11-06 | Metabasis Therapeutics, Inc. | Prodrugs phosphorus-containing compounds |
| ES2401070T3 (es) * | 1998-03-06 | 2013-04-16 | Metabasis Therapeutics, Inc. | Nuevos profármacos para compuestos que contienen fósforo |
| AU4716299A (en) | 1998-06-24 | 2000-01-10 | Emory University | Use of 3'-azido-2',3'-dideoxyuridine in combination with further anti-hiv drugs for the manufacture of a medicament for the treatment of hiv |
| IT1305313B1 (it) | 1998-07-17 | 2001-05-04 | Colla Paolo | 3,4 - diidro- 6- benzil-4-oxopirimidine sostituite e relativo processodi produzione e impiego nella terapia delle infezioni da hiv-1. |
| WO2000009531A2 (en) * | 1998-08-10 | 2000-02-24 | Novirio Pharmaceuticals Limited | β-L-2'-DEOXY-NUCLEOSIDES FOR THE TREATMENT OF HEPATITIS B |
| US6444652B1 (en) * | 1998-08-10 | 2002-09-03 | Novirio Pharmaceuticals Limited | β-L-2'-deoxy-nucleosides for the treatment of hepatitis B |
| EP1112275B9 (en) | 1998-09-09 | 2004-03-10 | Metabasis Therapeutics, Inc. | Novel heteroaromatic inhibitors of fructose 1,6-bisphosphatase |
| CA2348470C (en) * | 1998-11-05 | 2007-06-05 | Centre National De La Recherche Scientifique | Nucleosides with anti-hepatitis b virus activity |
| US6407077B1 (en) | 1998-11-05 | 2002-06-18 | Emory University | β-L nucleosides for the treatment of HIV infection |
| IL145052A0 (en) | 1999-03-05 | 2002-06-30 | Metabasis Therapeutics Inc | Novel phosphorus-containing prodrugs |
| AU7361400A (en) * | 1999-09-08 | 2001-04-10 | Metabasis Therapeutics, Inc. | Prodrugs for liver specific drug delivery |
| WO2001054688A1 (en) | 2000-01-28 | 2001-08-02 | Merck & Co., Inc. | Treatment or prevention of prostate cancer with a cox-2 selective inhibiting drug |
| CA2400197A1 (en) * | 2000-02-17 | 2001-08-23 | Merck & Co., Inc. | Treatment or prevention of prostate cancer with a cox-2 selective inhibiting drug |
| MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
| CN100490818C (zh) * | 2000-05-26 | 2009-05-27 | 诺瓦蒂斯有限公司 | β-L-2′-脱氧核苷在制备用于治疗丁型肝炎病毒感染的药物中的用途 |
| CZ301182B6 (cs) * | 2000-05-26 | 2009-12-02 | Idenix (Cayman) Limited | Použití nukleosidových derivátu pro výrobu farmaceutických prostredku pro lécení infekcí vyvolaných flaviviry a pestiviry |
| US6875751B2 (en) | 2000-06-15 | 2005-04-05 | Idenix Pharmaceuticals, Inc. | 3′-prodrugs of 2′-deoxy-β-L-nucleosides |
| CA2428753C (en) * | 2000-11-17 | 2013-05-21 | Idenix (Cayman) Limited | Methods for inhibiting the transmission of hiv using topically applied substituted 6-benzyl-4-oxopyrimidines |
| HUP0400726A3 (en) * | 2001-01-22 | 2007-05-29 | Merck & Co Inc | Nucleoside derivatives as inhibitors of rna-dependent rna viral polymerase |
| DE60234760D1 (de) | 2001-04-11 | 2010-01-28 | Idenix Cayman Ltd | Phenylindole zur behandlung von hiv |
| US20030232760A1 (en) | 2001-09-21 | 2003-12-18 | Merck & Co., Inc. | Conjugates useful in the treatment of prostate cancer |
| WO2003026589A2 (en) | 2001-09-28 | 2003-04-03 | Idenix (Cayman) Limited | Methods and compositions for treating hepatitis c virus using 4'-modified nucleosides |
| US20040006002A1 (en) | 2001-09-28 | 2004-01-08 | Jean-Pierre Sommadossi | Methods and compositions for treating flaviviruses and pestiviruses using 4'-modified nucleoside |
| JP4332496B2 (ja) | 2002-05-13 | 2009-09-16 | メタバシス・セラピューティクス・インコーポレイテッド | Ｐｍｅａおよびｐｍｐａ環生成合成 |
| IL164809A0 (en) * | 2002-05-13 | 2005-12-18 | Metabasis Therapeutics Inc | Novel phosphonic acid basdrugs of pmea and its analogues |
| TW200500375A (en) | 2002-06-28 | 2005-01-01 | Idenix Cayman Ltd | Modified 2' and 3'-nucleoside prodrugs for treating flaviviridae |
| WO2004002422A2 (en) | 2002-06-28 | 2004-01-08 | Idenix (Cayman) Limited | 2’-c-methyl-3’-o-l-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
| KR20050055630A (ko) | 2002-06-28 | 2005-06-13 | 이데닉스 (케이만) 리미티드 | 플라비비리다에 감염 치료를 위한 1'-, 2'- 및 3'-변형된뉴클레오시드 유도체 |
| DE60329211D1 (de) * | 2002-10-31 | 2009-10-22 | Metabasis Therapeutics Inc | Cytarabin-monophosphate prodrugs |
-
2003
- 2003-10-31 DE DE60329211T patent/DE60329211D1/de not_active Expired - Lifetime
- 2003-10-31 WO PCT/US2003/034709 patent/WO2004041834A2/en not_active Ceased
- 2003-10-31 US US10/698,924 patent/US7148349B2/en not_active Expired - Lifetime
- 2003-10-31 BR BR0315795-4A patent/BR0315795A/pt not_active IP Right Cessation
- 2003-10-31 EP EP03778030A patent/EP1556398B1/en not_active Expired - Lifetime
- 2003-10-31 BR BR0315806-3A patent/BR0315806A/pt not_active IP Right Cessation
- 2003-10-31 AT AT03778030T patent/ATE442375T1/de not_active IP Right Cessation
- 2003-10-31 JP JP2004550339A patent/JP4689274B2/ja not_active Expired - Fee Related
- 2003-10-31 PL PL03376474A patent/PL376474A1/xx not_active Application Discontinuation
- 2003-10-31 MX MXPA05004504A patent/MXPA05004504A/es active IP Right Grant
- 2003-10-31 EP EP03781623.8A patent/EP1556393B1/en not_active Expired - Lifetime
- 2003-10-31 JP JP2004550353A patent/JP5046219B2/ja not_active Expired - Fee Related
- 2003-10-31 WO PCT/US2003/034690 patent/WO2004041837A1/en not_active Ceased
- 2003-10-31 AU AU2003287389A patent/AU2003287389B2/en not_active Expired
- 2003-10-31 CA CA2503729A patent/CA2503729C/en not_active Expired - Lifetime
- 2003-10-31 CA CA2503730A patent/CA2503730C/en not_active Expired - Lifetime
- 2003-10-31 KR KR1020057007605A patent/KR101026294B1/ko not_active Expired - Fee Related
- 2003-10-31 MX MXPA05004503A patent/MXPA05004503A/es active IP Right Grant
- 2003-10-31 AU AU2003286816A patent/AU2003286816B2/en not_active Ceased
- 2003-10-31 US US10/698,928 patent/US7151092B2/en not_active Expired - Lifetime
- 2003-10-31 PL PL376327A patent/PL212929B1/pl unknown
- 2003-10-31 KR KR1020057007626A patent/KR101115210B1/ko not_active Expired - Fee Related
-
2005
- 2005-04-12 IL IL167990A patent/IL167990A/en unknown
- 2005-04-12 IL IL167984A patent/IL167984A/en active IP Right Grant
-
2006
- 2006-09-28 US US11/528,283 patent/US7498320B2/en not_active Expired - Lifetime
- 2006-10-18 US US11/582,383 patent/US7553826B2/en not_active Expired - Lifetime
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2006507308A5 (enExample) | ||
| CA2503730A1 (en) | Cytarabine monophosphate prodrugs | |
| ES2576289T3 (es) | Nanopartículas de paclitaxel y albúmina en combinación con bevacizumab contra el cáncer | |
| JP2022121594A5 (enExample) | ||
| JP2010533206A5 (enExample) | ||
| JP2010514787A5 (enExample) | ||
| RU2008138560A (ru) | Улучшенные способы лечения опухолей | |
| JP2008514577A5 (enExample) | ||
| WO2023035223A1 (zh) | 药物组合物及其用途 | |
| Binello et al. | Osteonecrosis and the jaws and bevacizumab therapy: A case report | |
| JPWO2016024595A1 (ja) | エピルビシン複合化ブロック共重合体と、抗癌剤とを含むミセル、及び当該ミセルを含む癌又は耐性癌、転移癌の治療に適用可能な医薬組成物 | |
| KR101572529B1 (ko) | 암 치료를 위한 육산화사비소의 병용요법 | |
| TW202435896A (zh) | 包含阿茲夫定和化療試劑的抗腫瘤藥物組合物 | |
| Hunt | Precision targeting of intraperitoneal tumors with peptideguided nanocarriers | |
| HUP0301247A2 (hu) | Antitumor terápia disztamicin származékokkal | |
| AU2002221622A1 (en) | Antitumor therapy comprising distamycin derivatives | |
| US12377089B2 (en) | Quinoline derivative used for soft tissue sarcoma combination therapy | |
| JP2025163103A (ja) | 放射線および／または抗がん治療補助療法としてアデノシン二リン酸リボースの活用 | |
| TWI332834B (enExample) | ||
| US8124593B2 (en) | Methods of treatment using sapacitabine | |
| CN101155600B (zh) | 放射线治疗增强剂 | |
| Choi et al. | Phase I trial of neoadjuvant concurrent chemoradiotherapy with S-1 and weekly irinotecan in locally advanced rectal cancer | |
| KR102896612B1 (ko) | 방사선 및/또는 항암 치료 보조 요법으로 아데노신 디포스페이트 리보오스의 활용 | |
| JP7698252B2 (ja) | 治療薬の核酸媒介性送達 | |
| Shimada | Clinical trials for advanced gastrointestinal cancers in Japan |