USRE47589E1 - Phosphoramidate compounds and methods of use - Google Patents
Phosphoramidate compounds and methods of use Download PDFInfo
- Publication number
- USRE47589E1 USRE47589E1 US15/279,611 US200415279611A USRE47589E US RE47589 E1 USRE47589 E1 US RE47589E1 US 200415279611 A US200415279611 A US 200415279611A US RE47589 E USRE47589 E US RE47589E
- Authority
- US
- United States
- Prior art keywords
- nmr
- mhz
- mmol
- cdcl
- oph
- 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.)
- Active, expires
Links
- 0 *OC(=O)C(C)(C)N([H])P(=O)(O[Ar])OCC1CC(CN2C=C(C)C(C)CC2=O)C(C)([Y])C1O Chemical compound *OC(=O)C(C)(C)N([H])P(=O)(O[Ar])OCC1CC(CN2C=C(C)C(C)CC2=O)C(C)([Y])C1O 0.000 description 6
- VEJJASYKVYGJJT-UHFFFAOYSA-N CC(=O)C1(NP(=O)(Cl)OC2=CC=C(Cl)C=C2)CCCC1 Chemical compound CC(=O)C1(NP(=O)(Cl)OC2=CC=C(Cl)C=C2)CCCC1 VEJJASYKVYGJJT-UHFFFAOYSA-N 0.000 description 3
- MIRNCKKVFLWULN-UHFFFAOYSA-N CC(=O)C1(NP(=O)(Cl)OC2=CC=C(F)C=C2)CCCC1 Chemical compound CC(=O)C1(NP(=O)(Cl)OC2=CC=C(F)C=C2)CCCC1 MIRNCKKVFLWULN-UHFFFAOYSA-N 0.000 description 3
- ASZLYMZJYVAYAJ-UHFFFAOYSA-N CC(=O)C1(NP(=O)(Cl)OC2=CC=C([N+](=O)[O-])C=C2)CCCC1 Chemical compound CC(=O)C1(NP(=O)(Cl)OC2=CC=C([N+](=O)[O-])C=C2)CCCC1 ASZLYMZJYVAYAJ-UHFFFAOYSA-N 0.000 description 3
- RGJXNALGKLUTEG-UHFFFAOYSA-N CC(=O)C1(NP(=O)(Cl)OC2=CC=CC=C2)CCCC1 Chemical compound CC(=O)C1(NP(=O)(Cl)OC2=CC=CC=C2)CCCC1 RGJXNALGKLUTEG-UHFFFAOYSA-N 0.000 description 3
- JUKMWEYRFVWTJM-UHFFFAOYSA-N CC(C)(NP(=O)(Cl)OC1=CC=C(Cl)C=C1)C(=O)OCC1=CC=CC=C1 Chemical compound CC(C)(NP(=O)(Cl)OC1=CC=C(Cl)C=C1)C(=O)OCC1=CC=CC=C1 JUKMWEYRFVWTJM-UHFFFAOYSA-N 0.000 description 2
- PVRHMXVIVQAZFO-UHFFFAOYSA-N CC1=CN(CC2CC(CO)C(O)C2(C)[Y])C(=O)CC1C Chemical compound CC1=CN(CC2CC(CO)C(O)C2(C)[Y])C(=O)CC1C PVRHMXVIVQAZFO-UHFFFAOYSA-N 0.000 description 2
- LGOWQISYSCLEST-LQABBHMDSA-N CCOC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(F)C=C1 Chemical compound CCOC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(F)C=C1 LGOWQISYSCLEST-LQABBHMDSA-N 0.000 description 2
- RKTRMSPWWLPPAY-KDSGSHRDSA-N COC(=O)/C=C/C1=CN([C@H]2CC(O)[C@@H](CO)O2)C(=O)NC1=O Chemical compound COC(=O)/C=C/C1=CN([C@H]2CC(O)[C@@H](CO)O2)C(=O)NC1=O RKTRMSPWWLPPAY-KDSGSHRDSA-N 0.000 description 2
- MTURQALKJIEXHW-KUSNVBIKSA-N COC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(C(F)(F)F)C=C1 Chemical compound COC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(C(F)(F)F)C=C1 MTURQALKJIEXHW-KUSNVBIKSA-N 0.000 description 2
- KGLVSCYDEKUYIH-QNUGLTPUSA-N COC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(Cl)C=C1 Chemical compound COC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(Cl)C=C1 KGLVSCYDEKUYIH-QNUGLTPUSA-N 0.000 description 2
- SHILJTXZUDTONU-NQDUSRBKSA-N COC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C([N+](=O)[O-])C=C1 Chemical compound COC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C([N+](=O)[O-])C=C1 SHILJTXZUDTONU-NQDUSRBKSA-N 0.000 description 2
- AYEFPKPIWLVMED-UHFFFAOYSA-N O=C(OCC1=CC=CC=C1)C1(NP(=O)(Cl)OC2=CC=C(C(F)(F)F)C=C2)CCCC1 Chemical compound O=C(OCC1=CC=CC=C1)C1(NP(=O)(Cl)OC2=CC=C(C(F)(F)F)C=C2)CCCC1 AYEFPKPIWLVMED-UHFFFAOYSA-N 0.000 description 2
- MISIVVMTKGOXPM-UHFFFAOYSA-N CC(=O)C1(NP(=O)(Cl)OC2=CC=C(C)C=C2)CCCC1 Chemical compound CC(=O)C1(NP(=O)(Cl)OC2=CC=C(C)C=C2)CCCC1 MISIVVMTKGOXPM-UHFFFAOYSA-N 0.000 description 1
- CBWBWVNBGCRYQC-WFVOFKTRSA-N CC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(C)C=C1 Chemical compound CC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(C)C=C1 CBWBWVNBGCRYQC-WFVOFKTRSA-N 0.000 description 1
- VDIPZQGBTADMNI-ISJKBYAMSA-N CC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(F)C=C1 Chemical compound CC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(F)C=C1 VDIPZQGBTADMNI-ISJKBYAMSA-N 0.000 description 1
- ZOBYLGAAXJSAIR-GABSKQARSA-N CC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C(F)(F)C1O)OC1=CC=CC=C1 Chemical compound CC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C(F)(F)C1O)OC1=CC=CC=C1 ZOBYLGAAXJSAIR-GABSKQARSA-N 0.000 description 1
- HETKBSGIXYVXMS-YTJLLHSVSA-N CC(=O)[C@H](CC(C)C)NP(=O)(Cl)OC1=CC=CC=C1 Chemical compound CC(=O)[C@H](CC(C)C)NP(=O)(Cl)OC1=CC=CC=C1 HETKBSGIXYVXMS-YTJLLHSVSA-N 0.000 description 1
- DPEATBWCWKCPRX-UHFFFAOYSA-N CC(C)(N)C(=O)OCC1=CC=CC=C1.Cl Chemical compound CC(C)(N)C(=O)OCC1=CC=CC=C1.Cl DPEATBWCWKCPRX-UHFFFAOYSA-N 0.000 description 1
- VLSJKHUBIBOPFO-UHFFFAOYSA-N CC(C)(NP(=O)(Cl)OC1=CC=C(C(F)(F)F)C=C1)C(=O)OCC1=CC=CC=C1 Chemical compound CC(C)(NP(=O)(Cl)OC1=CC=C(C(F)(F)F)C=C1)C(=O)OCC1=CC=CC=C1 VLSJKHUBIBOPFO-UHFFFAOYSA-N 0.000 description 1
- MLQSDGLWBIQLQU-UHFFFAOYSA-N CC(C)(NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1)C(=O)OCC1=CC=CC=C1 Chemical compound CC(C)(NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1)C(=O)OCC1=CC=CC=C1 MLQSDGLWBIQLQU-UHFFFAOYSA-N 0.000 description 1
- XAQUBJXQYCBOKG-UHFFFAOYSA-N CC(C)(NP(=O)(Cl)OC1=CC=CC=C1)C(=O)OCC1=CC=CC=C1 Chemical compound CC(C)(NP(=O)(Cl)OC1=CC=CC=C1)C(=O)OCC1=CC=CC=C1 XAQUBJXQYCBOKG-UHFFFAOYSA-N 0.000 description 1
- HLTBXYQBXOJQOR-YFYDHDTPSA-N CC(C)(NP(=O)(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C(F)(F)C1O)OC1=CC=C(Cl)C=C1)C(=O)OCC1=CC=CC=C1 Chemical compound CC(C)(NP(=O)(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C(F)(F)C1O)OC1=CC=C(Cl)C=C1)C(=O)OCC1=CC=CC=C1 HLTBXYQBXOJQOR-YFYDHDTPSA-N 0.000 description 1
- OMLSJNBVPFLLOG-HSYKDVHTSA-N CC(C)C[C@H](NP(=O)(Cl)OC1=CC=C(Cl)C=C1)C(=O)OCC1=CC=CC=C1 Chemical compound CC(C)C[C@H](NP(=O)(Cl)OC1=CC=C(Cl)C=C1)C(=O)OCC1=CC=CC=C1 OMLSJNBVPFLLOG-HSYKDVHTSA-N 0.000 description 1
- MKBBATNZMHPSKV-STFFIMJZSA-N CC(C)C[C@H](NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1)C(=O)OCC1=CC=CC=C1 Chemical compound CC(C)C[C@H](NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1)C(=O)OCC1=CC=CC=C1 MKBBATNZMHPSKV-STFFIMJZSA-N 0.000 description 1
- XKRAUPDXFOEIQU-ZUGUBZTFSA-N CC(C)C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C(Cl)C=C1)C(=O)OCC1=CC=CC=C1 Chemical compound CC(C)C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C(Cl)C=C1)C(=O)OCC1=CC=CC=C1 XKRAUPDXFOEIQU-ZUGUBZTFSA-N 0.000 description 1
- VZCGTMWGIIUGFJ-ZNGSWZPGSA-N CC(C)C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1)C(=O)OCC1=CC=CC=C1 Chemical compound CC(C)C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1)C(=O)OCC1=CC=CC=C1 VZCGTMWGIIUGFJ-ZNGSWZPGSA-N 0.000 description 1
- XCYBGXDXWBDJKI-UHFFFAOYSA-N CC1(C(=O)OCC2=CC=CC=C2)CCCC1.Cl Chemical compound CC1(C(=O)OCC2=CC=CC=C2)CCCC1.Cl XCYBGXDXWBDJKI-UHFFFAOYSA-N 0.000 description 1
- LJTXUJRFMKKMTG-UHFFFAOYSA-N CC1=CN(C2C=CC(CO)O2)C(=O)NC1=O.[H]N(C(C)C(=O)OC)P(=O)(OCC1C=CC(N2C=C(C)C(=O)NC2=O)O1)OC1=CC=CC=C1 Chemical compound CC1=CN(C2C=CC(CO)O2)C(=O)NC1=O.[H]N(C(C)C(=O)OC)P(=O)(OCC1C=CC(N2C=C(C)C(=O)NC2=O)O1)OC1=CC=CC=C1 LJTXUJRFMKKMTG-UHFFFAOYSA-N 0.000 description 1
- DWLJKCGOCUODFL-UHFFFAOYSA-N CCOC(=O)C(C)(C)N.Cl Chemical compound CCOC(=O)C(C)(C)N.Cl DWLJKCGOCUODFL-UHFFFAOYSA-N 0.000 description 1
- SCKLNIGNMGIIIL-UHFFFAOYSA-N CCOC(=O)C(C)(C)NP(=O)(Cl)OC1=CC=C(Cl)C=C1 Chemical compound CCOC(=O)C(C)(C)NP(=O)(Cl)OC1=CC=C(Cl)C=C1 SCKLNIGNMGIIIL-UHFFFAOYSA-N 0.000 description 1
- SVHWDYQHIVXBKX-UHFFFAOYSA-N CCOC(=O)C(C)(C)NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1 Chemical compound CCOC(=O)C(C)(C)NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1 SVHWDYQHIVXBKX-UHFFFAOYSA-N 0.000 description 1
- LYTCPFOHUFMUAU-UHFFFAOYSA-N CCOC(=O)C(C)(C)NP(=O)(Cl)OC1=CC=CC=C1 Chemical compound CCOC(=O)C(C)(C)NP(=O)(Cl)OC1=CC=CC=C1 LYTCPFOHUFMUAU-UHFFFAOYSA-N 0.000 description 1
- HRENVGTVIBNRKD-UHFFFAOYSA-N CCOC(=O)C1(C)CCCC1.Cl Chemical compound CCOC(=O)C1(C)CCCC1.Cl HRENVGTVIBNRKD-UHFFFAOYSA-N 0.000 description 1
- BQPCTAHXVGQUHE-UHFFFAOYSA-N CCOC(=O)C1(NP(=O)(Cl)OC2=CC=C(C(F)(F)F)C=C2)CCCC1 Chemical compound CCOC(=O)C1(NP(=O)(Cl)OC2=CC=C(C(F)(F)F)C=C2)CCCC1 BQPCTAHXVGQUHE-UHFFFAOYSA-N 0.000 description 1
- QGAWJBPZMRRYOC-DWWPHITQSA-N CCOC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C(C(F)(F)F)C=C2)CCCC1 Chemical compound CCOC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C(C(F)(F)F)C=C2)CCCC1 QGAWJBPZMRRYOC-DWWPHITQSA-N 0.000 description 1
- CRQRGVSWCNENGN-FQTQYEEFSA-N CCOC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C(Cl)C=C2)CCCC1 Chemical compound CCOC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C(Cl)C=C2)CCCC1 CRQRGVSWCNENGN-FQTQYEEFSA-N 0.000 description 1
- WUXTZINZUWEXSK-FQTQYEEFSA-N CCOC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C(F)C=C2)CCCC1 Chemical compound CCOC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C(F)C=C2)CCCC1 WUXTZINZUWEXSK-FQTQYEEFSA-N 0.000 description 1
- ZEGCYDCBAMSYNC-AFDMZMCFSA-N CCOC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C([N+](=O)[O-])C=C2)CCCC1 Chemical compound CCOC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C([N+](=O)[O-])C=C2)CCCC1 ZEGCYDCBAMSYNC-AFDMZMCFSA-N 0.000 description 1
- XWMNMEYFUGRBSK-GDNJKBTMSA-N CCOC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=CC=C2)CCCC1 Chemical compound CCOC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=CC=C2)CCCC1 XWMNMEYFUGRBSK-GDNJKBTMSA-N 0.000 description 1
- LZEDNPJEEAPTOC-HKRMTGKASA-N CCOC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(C(F)(F)F)C=C1 Chemical compound CCOC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(C(F)(F)F)C=C1 LZEDNPJEEAPTOC-HKRMTGKASA-N 0.000 description 1
- PEYQUDAZUXFFHR-LQABBHMDSA-N CCOC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(Cl)C=C1 Chemical compound CCOC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(Cl)C=C1 PEYQUDAZUXFFHR-LQABBHMDSA-N 0.000 description 1
- ZQKOQWUGSWHMAG-CBPHCGDMSA-N CCOC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1 Chemical compound CCOC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1 ZQKOQWUGSWHMAG-CBPHCGDMSA-N 0.000 description 1
- NCRSWTKBLAQFFX-JUGYALQGSA-N CCOC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=CC=C1 Chemical compound CCOC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=CC=C1 NCRSWTKBLAQFFX-JUGYALQGSA-N 0.000 description 1
- NACGNBFQXVXZRN-DAPGBDOESA-N CCOC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C(F)C=C1 Chemical compound CCOC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C(F)C=C1 NACGNBFQXVXZRN-DAPGBDOESA-N 0.000 description 1
- POAQPPMCPWEDAN-NGJRCHQTSA-N CCOC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C([N+](=O)[O-])C=C1 Chemical compound CCOC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C([N+](=O)[O-])C=C1 POAQPPMCPWEDAN-NGJRCHQTSA-N 0.000 description 1
- ODNZZOVCMMUFBL-CVEOAZJVSA-N CCOC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1 Chemical compound CCOC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1 ODNZZOVCMMUFBL-CVEOAZJVSA-N 0.000 description 1
- HMZHEECHJWHZJX-UHFFFAOYSA-N COC(=O)C(C)(C)N.Cl Chemical compound COC(=O)C(C)(C)N.Cl HMZHEECHJWHZJX-UHFFFAOYSA-N 0.000 description 1
- STIIHYYDDNNJFG-UHFFFAOYSA-N COC(=O)C(C)(C)NP(=O)(Cl)OC1=CC=C(Cl)C=C1 Chemical compound COC(=O)C(C)(C)NP(=O)(Cl)OC1=CC=C(Cl)C=C1 STIIHYYDDNNJFG-UHFFFAOYSA-N 0.000 description 1
- COFSHNBOKZSLQO-UHFFFAOYSA-N COC(=O)C(C)(C)NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1 Chemical compound COC(=O)C(C)(C)NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1 COFSHNBOKZSLQO-UHFFFAOYSA-N 0.000 description 1
- LSXKEJBWQUEBHF-UHFFFAOYSA-N COC(=O)C(C)(C)NP(=O)(Cl)OC1=CC=CC=C1 Chemical compound COC(=O)C(C)(C)NP(=O)(Cl)OC1=CC=CC=C1 LSXKEJBWQUEBHF-UHFFFAOYSA-N 0.000 description 1
- SUCGJXDLZCDFRV-UHFFFAOYSA-N COC(=O)C1(C)CCCC1.Cl Chemical compound COC(=O)C1(C)CCCC1.Cl SUCGJXDLZCDFRV-UHFFFAOYSA-N 0.000 description 1
- UOIQZNGMQDBKDH-FPMXBPPISA-N COC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C(C(F)(F)F)C=C2)CCCC1 Chemical compound COC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C(C(F)(F)F)C=C2)CCCC1 UOIQZNGMQDBKDH-FPMXBPPISA-N 0.000 description 1
- QNRHEVHWSYXYDP-AIZIXLKWSA-N COC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C(Cl)C=C2)CCCC1 Chemical compound COC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C(Cl)C=C2)CCCC1 QNRHEVHWSYXYDP-AIZIXLKWSA-N 0.000 description 1
- GJMOEZGCFDTTNO-AIZIXLKWSA-N COC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C(F)C=C2)CCCC1 Chemical compound COC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C(F)C=C2)CCCC1 GJMOEZGCFDTTNO-AIZIXLKWSA-N 0.000 description 1
- QBRPTAVZVQSKPB-LYOCPBBWSA-N COC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C([N+](=O)[O-])C=C2)CCCC1 Chemical compound COC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=C([N+](=O)[O-])C=C2)CCCC1 QBRPTAVZVQSKPB-LYOCPBBWSA-N 0.000 description 1
- XTXDSMMINAANHW-MLBQJDMHSA-N COC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=CC=C2)CCCC1 Chemical compound COC(=O)C1(NP(=O)(OC[C@H]2O[C@@H](N3C=C(/C=C/Br)C(=O)NC3=O)CC2O)OC2=CC=CC=C2)CCCC1 XTXDSMMINAANHW-MLBQJDMHSA-N 0.000 description 1
- UGDDGQXFCWHDCA-QNUGLTPUSA-N COC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(F)C=C1 Chemical compound COC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C(F)C=C1 UGDDGQXFCWHDCA-QNUGLTPUSA-N 0.000 description 1
- FPXUSWBTIHITNX-DSMWMPORSA-N COC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1 Chemical compound COC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1 FPXUSWBTIHITNX-DSMWMPORSA-N 0.000 description 1
- GISNGKRLBICLGJ-CLBCNEFWSA-N COC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=CC=C1 Chemical compound COC(=O)[C@H](C)NP(=O)(Cl)OC1=CC=CC=C1 GISNGKRLBICLGJ-CLBCNEFWSA-N 0.000 description 1
- YMKTYINUSSCTLL-QKRSCJPFSA-N COC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C(F)C=C1 Chemical compound COC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C(F)C=C1 YMKTYINUSSCTLL-QKRSCJPFSA-N 0.000 description 1
- CFBLUORPOFELCE-WHOBBMBYSA-N COC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1 Chemical compound COC(=O)[C@H](C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1 CFBLUORPOFELCE-WHOBBMBYSA-N 0.000 description 1
- GCIDEHVBTYYVDU-SVZXGPMESA-N COC(=O)[C@H](CC(C)C)NP(=O)(Cl)OC1=CC=CC=C1 Chemical compound COC(=O)[C@H](CC(C)C)NP(=O)(Cl)OC1=CC=CC=C1 GCIDEHVBTYYVDU-SVZXGPMESA-N 0.000 description 1
- QBAPNPZKHYYQGD-BQQGHPGHSA-N COC(=O)[C@H](CC(C)C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1 Chemical compound COC(=O)[C@H](CC(C)C)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1 QBAPNPZKHYYQGD-BQQGHPGHSA-N 0.000 description 1
- HKAUOJUVHWWNSI-NGMICRHFSA-N COC(=O)[C@H](CC1=CC=CC=C1)NP(=O)(Cl)OC1=CC=CC=C1 Chemical compound COC(=O)[C@H](CC1=CC=CC=C1)NP(=O)(Cl)OC1=CC=CC=C1 HKAUOJUVHWWNSI-NGMICRHFSA-N 0.000 description 1
- JCMJRMZAYIDMMQ-IXHHAKCHSA-N COC(=O)[C@H](CC1=CC=CC=C1)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1 Chemical compound COC(=O)[C@H](CC1=CC=CC=C1)NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1 JCMJRMZAYIDMMQ-IXHHAKCHSA-N 0.000 description 1
- KQPDOKHKJAUNRW-JMSDCMLSSA-N C[C@H](NP(=O)(Cl)OC1=CC=C(Cl)C=C1)C(=O)OCC1=CC=CC=C1 Chemical compound C[C@H](NP(=O)(Cl)OC1=CC=C(Cl)C=C1)C(=O)OCC1=CC=CC=C1 KQPDOKHKJAUNRW-JMSDCMLSSA-N 0.000 description 1
- ORVBNDBBDNYCJC-ZPVYTRKOSA-N C[C@H](NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1)C(=O)OCC1=CC=CC=C1 Chemical compound C[C@H](NP(=O)(Cl)OC1=CC=C([N+](=O)[O-])C=C1)C(=O)OCC1=CC=CC=C1 ORVBNDBBDNYCJC-ZPVYTRKOSA-N 0.000 description 1
- AOZOBLLGZPZKKD-AVEISGIFSA-N C[C@H](NP(=O)(Cl)OC1=CC=CC=C1)C(=O)OCC1=CC=CC=C1 Chemical compound C[C@H](NP(=O)(Cl)OC1=CC=CC=C1)C(=O)OCC1=CC=CC=C1 AOZOBLLGZPZKKD-AVEISGIFSA-N 0.000 description 1
- JOJGBJOGNUOESV-FBAUCEMNSA-N C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C(C(F)(F)F)C=C1)C(=O)OCC1=CC=CC=C1 Chemical compound C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C(C(F)(F)F)C=C1)C(=O)OCC1=CC=CC=C1 JOJGBJOGNUOESV-FBAUCEMNSA-N 0.000 description 1
- UXOOYGYIOJRDLA-SCHRZIBNSA-N C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C(F)C=C1)C(=O)OCC1=CC=CC=C1 Chemical compound C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C(F)C=C1)C(=O)OCC1=CC=CC=C1 UXOOYGYIOJRDLA-SCHRZIBNSA-N 0.000 description 1
- VYEAMCNXRUDZDS-YCPMIWBNSA-N C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C([N+](=O)[O-])C=C1)C(=O)OCC1=CC=CC=C1 Chemical compound C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C([N+](=O)[O-])C=C1)C(=O)OCC1=CC=CC=C1 VYEAMCNXRUDZDS-YCPMIWBNSA-N 0.000 description 1
- FROKIRQRFMVARI-KVYPLTRQSA-N C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1)C(=O)OCC1=CC=CC=C1 Chemical compound C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1)C(=O)OCC1=CC=CC=C1 FROKIRQRFMVARI-KVYPLTRQSA-N 0.000 description 1
- YWGMHBBCJCBYHL-GLBWJQDGSA-N C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C(F)(F)C1O)OC1=CC=C(Cl)C=C1)C(=O)OCC1=CC=CC=C1 Chemical compound C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C(F)(F)C1O)OC1=CC=C(Cl)C=C1)C(=O)OCC1=CC=CC=C1 YWGMHBBCJCBYHL-GLBWJQDGSA-N 0.000 description 1
- NHTKGYOMICWFQZ-XXJIYXFHSA-N C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C(F)(F)C1O)OC1=CC=CC=C1)C(=O)OCC1=CC=CC=C1 Chemical compound C[C@H](NP(=O)(OC[C@H]1O[C@@H](N2C=CC(N)=NC2=O)C(F)(F)C1O)OC1=CC=CC=C1)C(=O)OCC1=CC=CC=C1 NHTKGYOMICWFQZ-XXJIYXFHSA-N 0.000 description 1
- JTVMGBUXANRVCM-UHFFFAOYSA-N NC1=NC(=O)N(C2OC(CO)C(O)C2(F)F)C=C1.NC1=NC(=O)N(C2OC(CO)C(O)C2O)C=C1.O=C1NC(=O)N(C2CC(O)C(CO)O2)C=C1F Chemical compound NC1=NC(=O)N(C2OC(CO)C(O)C2(F)F)C=C1.NC1=NC(=O)N(C2OC(CO)C(O)C2O)C=C1.O=C1NC(=O)N(C2CC(O)C(CO)O2)C=C1F JTVMGBUXANRVCM-UHFFFAOYSA-N 0.000 description 1
- YWQZUENVQOQEHJ-GIANCMQGSA-N O=C(O)/C=C/C1=CN([C@H]2CC(O)[C@@H](CO)O2)C(=O)NC1=O Chemical compound O=C(O)/C=C/C1=CN([C@H]2CC(O)[C@@H](CO)O2)C(=O)NC1=O YWQZUENVQOQEHJ-GIANCMQGSA-N 0.000 description 1
- QLZLNDWWOUGQFB-VBRCWRGFSA-N O=C1NC(=O)N(C2CC(O)C(CO)O2)C=C1/C=C/Br.[H]N(C(C)C(=O)OC)P(=O)(OCC1OC(N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1 Chemical compound O=C1NC(=O)N(C2CC(O)C(CO)O2)C=C1/C=C/Br.[H]N(C(C)C(=O)OC)P(=O)(OCC1OC(N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1 QLZLNDWWOUGQFB-VBRCWRGFSA-N 0.000 description 1
- ODZBBRURCPAEIQ-GIANCMQGSA-N O=C1NC(=O)N([C@H]2CC(O)[C@@H](CO)O2)C=C1/C=C/Br Chemical compound O=C1NC(=O)N([C@H]2CC(O)[C@@H](CO)O2)C=C1/C=C/Br ODZBBRURCPAEIQ-GIANCMQGSA-N 0.000 description 1
- GTGMSZZULQPDOX-JRSVPMRCSA-N O=C1NC(=O)N([C@H]2CC(O)[C@@H](COP(=O)(NC3(C(=O)OCC4=CC=CC=C4)CCCC3)OC3=CC=C(C(F)(F)F)C=C3)O2)C=C1/C=C/Br Chemical compound O=C1NC(=O)N([C@H]2CC(O)[C@@H](COP(=O)(NC3(C(=O)OCC4=CC=CC=C4)CCCC3)OC3=CC=C(C(F)(F)F)C=C3)O2)C=C1/C=C/Br GTGMSZZULQPDOX-JRSVPMRCSA-N 0.000 description 1
- NUPDOPONPXQMMR-YYZJXMOASA-N O=C1NC(=O)N([C@H]2CC(O)[C@@H](COP(=O)(NC3(C(=O)OCC4=CC=CC=C4)CCCC3)OC3=CC=C(Cl)C=C3)O2)C=C1/C=C/Br Chemical compound O=C1NC(=O)N([C@H]2CC(O)[C@@H](COP(=O)(NC3(C(=O)OCC4=CC=CC=C4)CCCC3)OC3=CC=C(Cl)C=C3)O2)C=C1/C=C/Br NUPDOPONPXQMMR-YYZJXMOASA-N 0.000 description 1
- LFYCAMXPZKMDHL-YYZJXMOASA-N O=C1NC(=O)N([C@H]2CC(O)[C@@H](COP(=O)(NC3(C(=O)OCC4=CC=CC=C4)CCCC3)OC3=CC=C(F)C=C3)O2)C=C1/C=C/Br Chemical compound O=C1NC(=O)N([C@H]2CC(O)[C@@H](COP(=O)(NC3(C(=O)OCC4=CC=CC=C4)CCCC3)OC3=CC=C(F)C=C3)O2)C=C1/C=C/Br LFYCAMXPZKMDHL-YYZJXMOASA-N 0.000 description 1
- GHVQCMJGWNFMFJ-AAUQGPSKSA-N O=C1NC(=O)N([C@H]2CC(O)[C@@H](COP(=O)(NC3(C(=O)OCC4=CC=CC=C4)CCCC3)OC3=CC=C([N+](=O)[O-])C=C3)O2)C=C1/C=C/Br Chemical compound O=C1NC(=O)N([C@H]2CC(O)[C@@H](COP(=O)(NC3(C(=O)OCC4=CC=CC=C4)CCCC3)OC3=CC=C([N+](=O)[O-])C=C3)O2)C=C1/C=C/Br GHVQCMJGWNFMFJ-AAUQGPSKSA-N 0.000 description 1
- HIGPOMMLRKLAGG-YAPSYNQCSA-N O=C1NC(=O)N([C@H]2CC(O)[C@@H](COP(=O)(NC3(C(=O)OCC4=CC=CC=C4)CCCC3)OC3=CC=CC=C3)O2)C=C1/C=C/Br Chemical compound O=C1NC(=O)N([C@H]2CC(O)[C@@H](COP(=O)(NC3(C(=O)OCC4=CC=CC=C4)CCCC3)OC3=CC=CC=C3)O2)C=C1/C=C/Br HIGPOMMLRKLAGG-YAPSYNQCSA-N 0.000 description 1
- YMMPRORUSDMQNW-UHFFFAOYSA-N O=P(Cl)(Cl)OC1=CC=C(C(F)(F)F)C=C1 Chemical compound O=P(Cl)(Cl)OC1=CC=C(C(F)(F)F)C=C1 YMMPRORUSDMQNW-UHFFFAOYSA-N 0.000 description 1
- CCZMQYGSXWZFKI-UHFFFAOYSA-N O=P(Cl)(Cl)OC1=CC=C(Cl)C=C1 Chemical compound O=P(Cl)(Cl)OC1=CC=C(Cl)C=C1 CCZMQYGSXWZFKI-UHFFFAOYSA-N 0.000 description 1
- DRKYVZZJAKOILZ-UHFFFAOYSA-N O=P(Cl)(Cl)OC1=CC=C(F)C=C1 Chemical compound O=P(Cl)(Cl)OC1=CC=C(F)C=C1 DRKYVZZJAKOILZ-UHFFFAOYSA-N 0.000 description 1
- JPHYUPLYSXATFC-SCBDZVAKSA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OC)OC1=CC=C(Cl)C=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OC)OC1=CC=C(Cl)C=C1 JPHYUPLYSXATFC-SCBDZVAKSA-N 0.000 description 1
- HLVCNSNLPILXPV-DFKSRVJQSA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OC)OC1=CC=C([N+](=O)[O-])C=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OC)OC1=CC=C([N+](=O)[O-])C=C1 HLVCNSNLPILXPV-DFKSRVJQSA-N 0.000 description 1
- KTGQXQNIRCSGGS-MOLDONJDSA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OC)OC1=CC=CC=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OC)OC1=CC=CC=C1 KTGQXQNIRCSGGS-MOLDONJDSA-N 0.000 description 1
- LKUDAMZMXZUZGJ-PBDHYSGWSA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC)OC1=CC=C(Cl)C=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC)OC1=CC=C(Cl)C=C1 LKUDAMZMXZUZGJ-PBDHYSGWSA-N 0.000 description 1
- KYNPPSYVZUTEBI-FTEXCKNYSA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC)OC1=CC=C([N+](=O)[O-])C=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC)OC1=CC=C([N+](=O)[O-])C=C1 KYNPPSYVZUTEBI-FTEXCKNYSA-N 0.000 description 1
- XBJWABUHAHFFCO-ABZAHZRMSA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC)OC1=CC=CC=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC)OC1=CC=CC=C1 XBJWABUHAHFFCO-ABZAHZRMSA-N 0.000 description 1
- PQAJFEDSQWYOFC-UTOIIQALSA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC1=CC=CC=C1)OC1=CC=C(C(F)(F)F)C=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC1=CC=CC=C1)OC1=CC=C(C(F)(F)F)C=C1 PQAJFEDSQWYOFC-UTOIIQALSA-N 0.000 description 1
- VNJWCYHAGVUTKT-QOIWLQHMSA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC1=CC=CC=C1)OC1=CC=C(Cl)C=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC1=CC=CC=C1)OC1=CC=C(Cl)C=C1 VNJWCYHAGVUTKT-QOIWLQHMSA-N 0.000 description 1
- YIEFVGRBMOKIDF-WJAARBLFSA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC1=CC=CC=C1)OC1=CC=C([N+](=O)[O-])C=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC1=CC=CC=C1)OC1=CC=C([N+](=O)[O-])C=C1 YIEFVGRBMOKIDF-WJAARBLFSA-N 0.000 description 1
- IZABVSHSZYBFQC-GDRBSSFNSA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC1=CC=CC=C1)OC1=CC=CC=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(NC(C)(C)C(=O)OCC1=CC=CC=C1)OC1=CC=CC=C1 IZABVSHSZYBFQC-GDRBSSFNSA-N 0.000 description 1
- VUNSOVSFXNGDLU-OYOPXIFASA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(N[C@@H](C)C(=O)OC)OC1=CC=C(C(F)(F)F)C=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(N[C@@H](C)C(=O)OC)OC1=CC=C(C(F)(F)F)C=C1 VUNSOVSFXNGDLU-OYOPXIFASA-N 0.000 description 1
- QVCAVLFJPMDUOB-QKRSCJPFSA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(N[C@@H](C)C(=O)OC)OC1=CC=C(Cl)C=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(N[C@@H](C)C(=O)OC)OC1=CC=C(Cl)C=C1 QVCAVLFJPMDUOB-QKRSCJPFSA-N 0.000 description 1
- QNCLQOFXGNBONY-VKVWKVJASA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(N[C@@H](C)C(=O)OCC)OC1=CC=C(C(F)(F)F)C=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(N[C@@H](C)C(=O)OCC)OC1=CC=C(C(F)(F)F)C=C1 QNCLQOFXGNBONY-VKVWKVJASA-N 0.000 description 1
- HUHZDLOLQTVWIQ-DAPGBDOESA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(N[C@@H](C)C(=O)OCC)OC1=CC=C(Cl)C=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(N[C@@H](C)C(=O)OCC)OC1=CC=C(Cl)C=C1 HUHZDLOLQTVWIQ-DAPGBDOESA-N 0.000 description 1
- BUIPWRHCOCAGKS-SCHRZIBNSA-N [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(N[C@@H](C)C(=O)OCC1=CC=CC=C1)OC1=CC=C(Cl)C=C1 Chemical compound [H]C1(O)C([H])([H])[C@]([H])(N2C=C(/C=C/Br)C(=O)NC2=O)O[C@]1([H])COP(=O)(N[C@@H](C)C(=O)OCC1=CC=CC=C1)OC1=CC=C(Cl)C=C1 BUIPWRHCOCAGKS-SCHRZIBNSA-N 0.000 description 1
- PYAASCFUWJDLQU-UHFFFAOYSA-N [H]N(C(C)(C)C(=O)OC)P(=O)(OCC1C=CC(N2C=C(C)C(=O)NC2=O)O1)OC1=CC=CC=C1.[H]N(C(C)C(=O)OC)P(=O)(OCC1C=CC(N2C=C(C)C(=O)NC2=O)O1)OC1=CC=C(C(F)(F)F)C=C1 Chemical compound [H]N(C(C)(C)C(=O)OC)P(=O)(OCC1C=CC(N2C=C(C)C(=O)NC2=O)O1)OC1=CC=CC=C1.[H]N(C(C)C(=O)OC)P(=O)(OCC1C=CC(N2C=C(C)C(=O)NC2=O)O1)OC1=CC=C(C(F)(F)F)C=C1 PYAASCFUWJDLQU-UHFFFAOYSA-N 0.000 description 1
- PQAJFEDSQWYOFC-OUKQBFOZSA-N [H]N(C(C)(C)C(=O)OCC1=CC=CC=C1)P(=O)(OCC1OC(N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C(C(F)(F)F)C=C1 Chemical compound [H]N(C(C)(C)C(=O)OCC1=CC=CC=C1)P(=O)(OCC1OC(N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=C(C(F)(F)F)C=C1 PQAJFEDSQWYOFC-OUKQBFOZSA-N 0.000 description 1
- FMTVDLRBWUHJSC-UHFFFAOYSA-N [H]N(C(C)C(=O)OC)P(=O)(OCC1C=CC(N2C=C(C)C(=O)NC2=O)O1)OC1=CC=CC=C1.[H]N(C(C)C(=O)OCC1=CC=CC=C1)P(=O)(OCC1C=CC(N2C=C(C)C(=O)NC2=O)O1)OC1=CC=CC=C1 Chemical compound [H]N(C(C)C(=O)OC)P(=O)(OCC1C=CC(N2C=C(C)C(=O)NC2=O)O1)OC1=CC=CC=C1.[H]N(C(C)C(=O)OCC1=CC=CC=C1)P(=O)(OCC1C=CC(N2C=C(C)C(=O)NC2=O)O1)OC1=CC=CC=C1 FMTVDLRBWUHJSC-UHFFFAOYSA-N 0.000 description 1
- FROKIRQRFMVARI-OUKQBFOZSA-N [H]N(C(C)C(=O)OCC1=CC=CC=C1)P(=O)(OCC1OC(N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1 Chemical compound [H]N(C(C)C(=O)OCC1=CC=CC=C1)P(=O)(OCC1OC(N2C=C(/C=C/Br)C(=O)NC2=O)CC1O)OC1=CC=CC=C1 FROKIRQRFMVARI-OUKQBFOZSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to nucleotide derivatives and their use in the treatment of cancer.
- Nucleoside analogues such as fluorodeoxyuridine (1), cytarabine (2) and gemcitabine (3) are well established as anticancer agents. They function as inhibitors of DNA synthesis after activation to their 5′-phosphate form.
- the phosphate prodrugs have biological properties and therapeutic activities that are similar to, or somewhat lower than, the parent nucleoside analogue.
- Lackey et al [Biochem Pharmacol., 2001, 61, 179-89] have reported the application of our phosphoramidate pro-drug method for antiviral nucleosides to the anti-herpetic agent bromovinyl-2′-deoxyuridine (BVDU) (6).
- BVDU bromovinyl-2′-deoxyuridine
- phenyl methoxyalaninyl phosphoramidate (7) has significant anti-cancer activity. This is in marked contrast to the parent (antiviral) nucleoside (6).
- a pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, ester or salt of such ester or any other compound which upon administration to a recipient is capable of providing (directly or indirectly) a compound of formula (I).
- R is 2-Bu (—CH 2 —CH(CH 3 ) 2 ) and one of R′ and R′′ is H and one of R′ and R′′ is methyl (—CH 3 ), when n is 1 and X and Y are both H, then Ar is not unsubstituted phenyl (—C 6 H 5 ).
- metabolite is meant a metabolite or residue of a
- n, Q, R, R′, R′′, X, Y, Z and Z′ have the meanings described above and below for formula I, and additionally R can be H, with the proviso that when n is 1, X and Y are both H, R is methyl (—CH 3 ), one of R′ and R′′ is H and one of R′ and R′′ is methyl (—CH 3 ), then Z is not —CH ⁇ CHBr.
- ROCOCR′R′′NH— corresponds neither to alanine (ie as above, R is not methyl (—CH 3 ), one of R′ and R′′ is not H and one of R′ and R′′ is not methyl (—CH 3 )) nor to tryptophan (ie ⁇ -amino- ⁇ -indolylpropionic acid).
- ROCOR′R′′NH is neither derived from nor corresponds to any naturally occurring amino acid.
- the moiety ROCOCR′R′′NH— does not correspond to alanine (ie R is not methyl (—CH 3 ), one of R′ and R′′ is is not H and one of R′ and R′′ is not methyl (—CH 3 )), does not preferably correspond to tryptophan, and even more preferably the said moiety does not correspond to any naturally occurring amino acid.
- ROCOCR′R′′NH— in compounds of formula II corresponds to a non-naturally occurring amino acid.
- an alkyl group means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical.
- the alkylene group is preferably C 3 to C 12 , more preferably C 5 to C 10 , more preferably C 5 to C 7 .
- the alkyl group is preferably C 1 to C 16 , more preferably C 1 to C 6 .
- an aryl group means an aromatic group containing 5 to 14 ring atoms, for example phenyl or naphthyl.
- the aromatic group may be a heteroaromatic group containing one, two, three or four, preferably one, heteroatoms selected, independently, from the group consisting of O, N and S.
- heteroaromatic groups include pyridyl, pyrrolyl, furanyl and thiophenyl.
- the aryl group comprises phenyl or substituted phenyl.
- alkyl and aryl groups may be substituted or unsubstituted. Where substituted, there will generally be one to three substituents present, preferably one substituent.
- Substituents may include halogen atoms, by which is meant F, Cl, Br and I atoms, and halomethyl groups such as CF 3 and CCl 3 ; oxygen containing groups such as oxo, hydroxy, carboxy, carboxyC 1-16 alkyl, alkoxy, alkoyl, alkoyloxy, aryloxy, aryloyl and aryloyloxy; nitrogen containing groups such as amino, C 1-6 alkylamino, diC 1-6 alkylamino, cyano, azide and nitro; sulphur containing groups such as thiol, C 1-6 alkylthiol, sulphonyl and sulphoxide; heterocyclic groups which may themselves be substituted; alkyl groups as defined above, which may themselves be substituted
- alkoxy and aryloxy groups means, respectively, alkyl-O— (for example where alkyl is C 1 to C 16 , preferably C 1 to C 6 ) and aryl-O— (for example where aryl is a 5 to 14 membered aromatic mono- or bifused ring moiety, optionally containing 1, 2, 3 or 4 heteroatoms selected, independently, from O, S and N, preferably aryl is phenyl).
- alkoyl and aryloyl groups means, respectively, alkyl-CO— (for example where alkyl is C 1 to C 16 , preferably C 1 to C 6 ) and aryl-CO— (for example where aryl is a 5 to 14 membered aromatic mono or bifused ring moiety, optionally containing 1, 2, 3 or 4 heteroatoms selected, independently, from O, S and N, preferably aryl is phenyl).
- alkoyloxy and aryloyloxy means, respectively, alkyl-CO—O (for example where alkyl is C 1 to C 16 , preferably C 1 to C 6 ) and aryl-CO—O (for example where aryl is a 5 to 14 membered mono- or bifused aromatic ring system, optionally containing 1, 2, 3 or 4 heteroatoms selected, independently, from O, S and N, preferably aryl is phenyl).
- heterocyclic groups means groups containing one or more, pyrrolyl, imidazolyl, pyraziolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronly, pyridyl, pyrazinyl, pyridazinyl, piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl, isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, is
- the group Ar comprises a substituted or unsubstituted aryl group, wherein the term “aryl group” and the possible substitution of said group is as defined herein.
- Ar is a substituted or unsubstituted phenyl group.
- Particularly preferred substituents are electron withdrawing groups such as halogen (preferably chlorine or fluorine), trihalomethyl (preferably trifluoromethyl), cyano and nitro groups.
- Ar can be phenyl, 3,5-dichloro-phenyl, p-trifluoromethyl-phenyl, p-cyano-phenyl, or p-nitro-phenyl.
- Ar is a heteroaromatic group, preferably it is optionally substituted pyridyl.
- R is a C 1-16 primary or secondary alkyl group, a C 5-7 carbocyclic aryl group or a C 1-6 alkylC 5-11 aryl group. More suitably, R is a C 1-10 alkyl group, a phenyl group or C 1-3 alkylC 5-7 aryl group. Preferably R is unsubstituted.
- R is methyl (—CH 3 ), ethyl (—C 2 H 5 ), n- or i-propyl (—C 3 H 7 ), n- or i-butyl (—C 4 H 9 ) or benzyl (—CH 2 C 6 H 5 ).
- R is benzyl.
- R is preferably benzyl when one of R′ and R′′ is H and one of R′ and R′′ is methyl (—CH 3 ), especially when Ar is unsubstituted phenyl, n is 0 and each of X and Y is F.
- R′ and R′′ are each independently selected from the group comprising H, C 1-6 primary, secondary or tertiary alkyl, C 1-3 alkylC 5-7 aryl, or, when together they form an alkylene chain, they provide, together the C atom to which they are attached, a C 3-8 carbocyclic aliphatic ring.
- R′ and R′′ are the same and are alkyl, more preferably they are both methyl, ethyl or n- or i-propyl.
- R′ and R′′ are, independently, H, methyl (—CH 3 ), secondary butyl (—CH 2 —CH—(CH 3 ) 2 ), benzyl (—CH 2 C 6 H 5 ), or, together with the C atom to which they are attached, provide a C 5-6 ring.
- Preferred compounds include those where R′ and R′′ are both methyl, one of R′ and R′′ is H and one of R′ and R′′ is methyl, and R′ and R′′, together with the C atom to which they are attached, provide a pentyl ring.
- the C atom to which they are attached is chiral.
- the present compounds can be L or D or a mixture of stereoiosomers. Preferably they are L.
- R′ and R′′ when one of R′ and R′′ is H and one of R′ and R′′ is Me or PhCH 2 , the moiety corresponds to alanine or phenylalanine, respectively.
- the stereochemistry at the asymmetric centre —CR′R′′ corresponds to an L-amino acid.
- the stereochemistry at the asymmetric centre —CR′R′′ can, however, correspond to a D-amino acid.
- mixtures of of compounds can be employed having asymmetric centres corresponding to L and D amino acids.
- naturally occurring amino acid we mean Alanine, Arginine, Asparagine, Aspartic Acid, Cysteine, Cystine, Glycine, Glutamic Acid, Glutamine, Histidine, Hydroxylysine, Hydroxyproline, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine and Valine.
- the present invention is not, however, limited to compounds having a moiety corresponding to a naturally occurring amino acid.
- the moiety ROCOCR′R′′NH— corresponds to or is derived from a non-naturally occurring amino acid.
- ROCOCR′R′′NH— preferably neither corresponds to nor is derived from alanine, more preferably neither corresponds to nor is derived from either of alanine or tryptophan, even more preferably neither corresponds to nor is derived from any naturally occurring amino acid.
- ROCOCR′R′′NH— preferably neither corresponds to nor is derived from alanine, more preferably neither corresponds to nor is derived from either of alanine or trytophan, even more preferably neither corresponds to nor is derived from any naturally occurring amino acid.
- Q is O.
- X and Y are, independently, selected from the group comprising F, H and OH.
- n 1, preferably each of X and Y is H.
- each of X and Y is F, or X is OH and Y is H, or X is H and Y is OH.
- n is 0 and X is OH and Y is H.
- Particularly preferred are compounds of formula I wherein n is 0, X is OH, Y is H, Q is O and Z is H, corresponding to phosphoramidated cytarabine.
- n is 0 and X is H and Y is OH.
- Particularly preferred are compounds of formula I wherein n is 0, X is H, Y is OH, Q is O and Z is H, corresponding to phosphoramidated cytidine.
- Ar is a 5 to 14 membered aromatic ring moiety.
- the one or two rings may include 1, 2, 3 or 4 heteroatoms, preferably 1, selected, independently, from O, S and N.
- Ar is a carbomonocyclic aromatic ring moiety. More preferably, Ar is a C 6 monocyclic aromatic ring moiety, ie is optionally substituted phenyl.
- One, two, three or four substituents which may be the same or different, may be present on Ar and are selected from the group comprising halogen, which may —F, —Cl, —Br or —I; —NO 2 ; —NH 2 ; optionally substituted —C 1-3 alkyl; optionally substituted —C 1-3 alkoxy, preferably methoxy (—OCH 3 ); optionally substituted —SC 1-3 alkyl; —CN; optionally substituted —COC 1-3 alkyl; and optionally substituted —CO 2 C 1-3 alkyl.
- halogen which may be —F, —Cl, —Br or —I
- —NO 2 ; —NH 2 ; optionally substituted —C 1-3 alkyl; optionally substituted —C 1-3 alkoxy, preferably methoxy (—OCH 3 ); optionally substituted —SC 1-3 alkyl; —CN; optionally substituted —COC
- the optional substitutents are one or more up to six, preferably three, members selected from the group comprising halogen which may be F, Cl, Br and I and NO 2 .
- Preferred substituents on Ar include F, Cl, CF 3 , and NO 2 .
- the substituents may be at any position on the ring moiety. Where the ring moiety is C 6 ie phenyl, a single substituent at the 2 (ortho) or 4 (para) position is preferred. Where Ar is phenyl, a single substituent at the 4 position is more preferred.
- Ar is an optionally substituted phenyl moiety. More preferably, Ar is selected form the group comprising: Ph—, pCF 3 C 6 H 4 —, pFC 6 H 4 —, pNO 2 C 6 H 4 —, pClC 6 H 4 — and oClC 6 H 4 —.
- Z is selected from the group comprising H, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 alkenyl, substituted C 1-6 alkenyl, C 1-6 alkynyl, substituted C 1-6 alkynyl and halogen, where halogen is F, Cl, Br or I.
- Substituents that may be present on the alkenyl or alkynyl moiety are selected from the group comprising F, Cl, Br, I, and —CO 2 Me. One, two or three substituents may be present.
- the alkenyl and alkynyl groups may contain one or more sites of unsaturation.
- Z is substituted alkenyl or alkynyl
- the substituent is preferably on the terminal C atom.
- Z is selected from the group comprising H, F, optionally substituted C 1-6 alkyl particularly Me (—CH 3 ), optionally substituted C 1-6 alkenyl and optionally substituted C 1-6 alkynyl, the optional substituents being as recited immediately above.
- Z′ is O
- Q is O
- X and Y are each H
- Z is a substituted C 2 alkenyl (i.e. ethenyl or vinyl) moiety (—CH ⁇ CH—); more preferably, Z is bromovinyl (—CH ⁇ CHBr) or methylpropenoate (—CH ⁇ CHCO 2 Me); and most preferably, Z is —CH ⁇ CHBr.
- n 1 and X and Y are both H, then Z is not F.
- X is not H and Y is not OH, more preferably X is OH and Y is H or X and Y are both F.
- a preferred compound embodying the present invention is the benzyl ester (8). It has surprisingly been found that the benzyl ester (8) is very significantly more potent against several cancer cell lines than the methyl ester (7):
- Compound (8) inhibits the growth of colon cancer cell line HT115 by 50% at 1.4 ⁇ M, whilst (7) requires a concentration of 244 ⁇ M; (8) is thus 174 times more potent. Compound (8) is also 8 times more potent than (7) versus prostate cancer cell line PC-3 (19 ⁇ M vs. 155 ⁇ M).
- compound (11) has simultaneous modification in these two regions, being the p-trifluoromethylphenyl benzyl [ ⁇ , ⁇ -dimethylglycinyl ]phosphoramidate.
- Compound 11 shows high potency against a range of cancer cell types and is significantly and surprisingly more potent than (7).
- breast cancer (11) is 60-fold more active (1.3 ⁇ M vs 79 ⁇ M)
- prostate cancer (11) is 254-fold more potent (0.61 ⁇ M vs. 155 ⁇ M).
- colon cancer (11) is 35-fold more potent (7 ⁇ M vs 244 ⁇ M).
- the degree of enhancement of the analogue (11) vs. (7) is surprising based on prior art.
- comparing (12) [dimethyl glycine modification] and (13) [p-CF 3 phenyl modification] to (9) shows no significant difference in potency.
- compounds embodying the present invention and having variations in one or more of the ester (R), amino acid (R′, R′′) and aryl (Ar) region of the phosphoramidate structure compared to phenyl methoxyalaninyl phosphoramidate can give surprising and substantial potency boosts of pro-tides derived from BVDU against a range of cancer cell types.
- a compound having formula I according to the present invention for use in a method of treatment, preferably in the prophylaxis or treatment of cancer.
- a method of phrophylaxis or treatment of cancer comprising administration to a patient in need of such treatment an effective dose of a compound having formula I according to the present invention.
- a pharmaceutical composition comprising a compound having formula I of the present invention in combination with a pharmaceutically acceptable excipient, carrier or diluent.
- a method of preparing a pharmaceutical composition comprising the step of combining a compound having formula I of the present invention with a pharmaceutically acceptable excipient, carrier or diluent.
- the present invention is particularly applicable for the treatment of a patient having breast cancer, colon cancer or prostate cancer.
- cancers include breast MDA MB231, colon HT115 and prostate PC-3.
- the compound having formula I or pharmaceutical composition according to the present invention can be administered to a patient, which may be human or animal, by any suitable means.
- the medicaments employed in the present invention can be administered by oral or parenteral routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.
- oral or parenteral routes including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.
- the compounds of the invention will generally be provided in the form of tablets or capsules, as a powder or granules, or as an aqueous solution or suspension.
- Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
- suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while cornstarch and alginic acid are suitable disintegrating agents.
- Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc.
- the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
- Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
- Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
- Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
- Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
- Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
- Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
- the compounds of the invention may also be presented as liposome formulations.
- a suitable dose will be in the range of 0.1 to 300 mg per kilogram body weight of the recipient per day.
- a preferred lower dose is 0.5 mg per kilogram body weight of recipient per day, a more preferred lower dose is 6 mg per kilogram body weight of recipient per day, an even more preferred lower dose is 10 mg per kilogram body weight per recipient per day.
- a suitable dose is preferably in the range of 6 to 150 mg per kilogram body weight per day, and most preferably in the range of 15 to 100 mg per kilogram body weight per day.
- the desired dose is preferably presented as two, three, four, five or six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1500 mg, preferably 20 to 1000 mg, and most preferably 50 to 700 mg of active ingredient per unit dosage form.
- TLC Thin layer chromatography
- Phosphorus oxychloride (1.0 mol eq.) and the appropriate substituted phenol (1.0 mol) were stirred with anhydrous diethylether (31 mol eq.). To this was added anhydrous triethylamine (1.0 mol eq) at ⁇ 80° C. and left to rise to room temperature over 16 hrs the triethylamine hydrochloride salt was filtered off, and the filtrate reduced to dryness to give the crude product as a clear liquid.
- the experimental procedures used human colon cancer cell line (HT115), human prostate cancer cell line (PC-3), human breast cancer cell line (MDA MB 231) and normal human umbilical vein endothelial cell (HUVEC). Compounds were diluted over a range of concentrations and added to cells over 1 to 3 days. The cytotoxity was determined using a MTT assay at the end of each experiment.
- ArO refers to Ar as defined above with respect to formula I;
- BVU stands for 2-bromovinyl uridine.
- GemCyt stands for Gemcitabine.
- Examples A, 1, 67 and G are comparative Examples.
- Example A is 5-(2-Bromovinyl)-2′-deoxyuridine.
- Example 1 is Example 1 above corresponding to compound (7) above.
- Example 67 is propenate-2′-deoxyuridine.
- Example G is gemcitabine.
- Examples 51, 52 and 53 are compounds embodying formula II above.
- Gemcitabine (Example G in the Table) and compound CPF31 (Example 31 in the Table: gemcitabine-[phenyl-(benzoxy-L-alaninyl)]-phosphate) were compared in a mouse model with xenografts of human cancer (colon HT115 and prostrate PC3).
- mice were dosed daily at a range of concentrations (0.01-10 ⁇ M) and tumour volume assessed versus control.
- FIG. 1 shows for the mouse xenograft the tumour volume for prostate data at day 13 using GemzarTM (gemcitabine available ex. Lilly);
- FIG. 2 shows for the mouse xenograft the tumour volume for prostate data at day 13 using CPF31;
- FIG. 3 shows the incident free survival functions v. day for each of CPF31 and gemcitabine.
- FIG. 4 shows for the mouse xenograft the tumour volume for colon data at day 24 using, respectively, Gemzar and compound CPF31.
- CPF31 can be seen to be significantly less toxic than gemcitabine.
- CPF31 was significantly effective at reducing prostate and colon tumour volume relative to control at daily dosing of 5 and 10 ⁇ M (3 and 6 ⁇ g/ml). Gemcitabine was not effective at the highest non-toxic concentration.
- Gemzar is seen from FIG. 1 to be toxic above 1 ⁇ M.
- CPF31 is seen from FIG. 2 to have substantially lower toxicity.
- FIG. 3 shows the Kaplan-Meier survival curve, incidence free survival: based on the loss according to weight loss.
- FIG. 4 shows the results of testing both in vivo at 5 ⁇ M. The greater activity of CPF31 in reducing tumour volume is shown in FIG. 4 .
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/279,611 USRE47589E1 (en) | 2003-07-21 | 2004-07-20 | Phosphoramidate compounds and methods of use |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0317009.9A GB0317009D0 (en) | 2003-07-21 | 2003-07-21 | Chemical compounds |
GB0317009.9 | 2003-07-21 | ||
US15/279,611 USRE47589E1 (en) | 2003-07-21 | 2004-07-20 | Phosphoramidate compounds and methods of use |
PCT/GB2004/003148 WO2005012327A2 (en) | 2003-07-21 | 2004-07-20 | Nucleotide phosphoramidates as anticancer agents |
US10/560,887 US7951787B2 (en) | 2003-07-21 | 2004-07-20 | Phosphoramidate compounds and methods of use |
Publications (1)
Publication Number | Publication Date |
---|---|
USRE47589E1 true USRE47589E1 (en) | 2019-09-03 |
Family
ID=27772362
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/279,611 Active 2026-07-25 USRE47589E1 (en) | 2003-07-21 | 2004-07-20 | Phosphoramidate compounds and methods of use |
US10/560,887 Ceased US7951787B2 (en) | 2003-07-21 | 2004-07-20 | Phosphoramidate compounds and methods of use |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US10/560,887 Ceased US7951787B2 (en) | 2003-07-21 | 2004-07-20 | Phosphoramidate compounds and methods of use |
Country Status (20)
Country | Link |
---|---|
US (2) | USRE47589E1 (xx) |
EP (5) | EP3040340B1 (xx) |
JP (1) | JP4923216B2 (xx) |
AU (1) | AU2004261455B2 (xx) |
CA (1) | CA2518115C (xx) |
CY (4) | CY1117960T1 (xx) |
DK (4) | DK3904365T3 (xx) |
ES (4) | ES2928202T3 (xx) |
FI (1) | FIC20230013I1 (xx) |
FR (1) | FR23C1014I2 (xx) |
GB (1) | GB0317009D0 (xx) |
HU (4) | HUE059970T2 (xx) |
MX (1) | MXPA05012606A (xx) |
NO (1) | NO333603B1 (xx) |
NZ (1) | NZ541974A (xx) |
PL (4) | PL3904365T3 (xx) |
PT (4) | PT1646639T (xx) |
SI (2) | SI3040340T1 (xx) |
TR (1) | TR201901246T4 (xx) |
WO (1) | WO2005012327A2 (xx) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20180346504A1 (en) * | 2017-05-01 | 2018-12-06 | Gilead Sciences, Inc. | Crystalline forms of (s)-2-ethylbutyl 2-(((s)-(((2r,3s,4r,5r)-5- (4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate |
US10988498B2 (en) | 2009-09-21 | 2021-04-27 | Gilead Sciences, Inc. | Processes and intermediates for the preparation of 1′-substituted carba-nucleoside analogs |
US11007208B2 (en) | 2015-09-16 | 2021-05-18 | Gilead Sciences, Inc. | Methods for treating arenaviridae and coronaviridae virus infections |
US11260070B2 (en) | 2017-03-14 | 2022-03-01 | Gilead Sciences, Inc. | Methods of treating feline coronavirus infections |
US11266666B2 (en) | 2014-10-29 | 2022-03-08 | Gilead Sciences, Inc. | Methods for treating Filoviridae virus infections |
US11266681B2 (en) | 2017-07-11 | 2022-03-08 | Gilead Sciences, Inc. | Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections |
US11377467B2 (en) | 2015-12-23 | 2022-07-05 | NuCana plc | Crystalline form of gemcitabine |
US11492353B2 (en) | 2010-07-22 | 2022-11-08 | Gilead Sciences, Inc. | Methods and compounds for treating Paramyxoviridae virus infections |
US11491169B2 (en) | 2020-05-29 | 2022-11-08 | Gilead Sciences, Inc. | Remdesivir treatment methods |
US11560400B2 (en) | 2017-12-05 | 2023-01-24 | NuCana plc | Salts of diphosphate phosphoramidate of nucleosides as anticancer compounds |
US11613553B2 (en) | 2020-03-12 | 2023-03-28 | Gilead Sciences, Inc. | Methods of preparing 1′-cyano nucleosides |
US11660307B2 (en) | 2020-01-27 | 2023-05-30 | Gilead Sciences, Inc. | Methods for treating SARS CoV-2 infections |
US11701372B2 (en) | 2020-04-06 | 2023-07-18 | Gilead Sciences, Inc. | Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs |
US11780844B2 (en) | 2022-03-02 | 2023-10-10 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
US11814406B2 (en) | 2020-08-27 | 2023-11-14 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
US11939347B2 (en) | 2020-06-24 | 2024-03-26 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and uses thereof |
Families Citing this family (120)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7462605B2 (en) | 1998-01-23 | 2008-12-09 | Celmed Oncology (Usa), Inc. | Phosphoramidate compounds and methods of use |
MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
EA200601591A1 (ru) | 2000-05-26 | 2007-02-27 | Айденикс (Кайман) Лимитед | Применение рибонуклеозидных соединений для лечения флавивирусных и пестивирусных инфекций |
HUE033832T2 (en) | 2002-11-15 | 2018-01-29 | Idenix Pharmaceuticals Llc | 2'-methyl nucleosides in combination with interferon and Flaviviridae mutation |
SI1633766T1 (sl) | 2003-05-30 | 2019-06-28 | Gilead Pharmasset Llc | Modificirani analogi fluoriranih nukleozidov |
CN101023094B (zh) * | 2004-07-21 | 2011-05-18 | 法莫赛特股份有限公司 | 烷基取代的2-脱氧-2-氟代-d-呋喃核糖基嘧啶和嘌呤及其衍生物的制备 |
NZ554442A (en) * | 2004-09-14 | 2011-05-27 | Pharmasset Inc | Preparation of 2'fluoro-2'-alkyl-substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives |
JP2008523082A (ja) | 2004-12-09 | 2008-07-03 | リージェンツ オブ ザ ユニバーシティ オブ ミネソタ | 抗菌活性および抗癌活性を有するヌクレオチド |
GB0505781D0 (en) * | 2005-03-21 | 2005-04-27 | Univ Cardiff | Chemical compounds |
DE102006037786A1 (de) * | 2006-08-11 | 2008-03-20 | Resprotect Gmbh | Nukleoside, diese enthaltendes Arzneimittel und deren Verwendung |
DK2099461T3 (da) * | 2006-11-13 | 2012-07-02 | Santaris Pharma As | LNA Nukleoside Phosphoramidates |
GB0623493D0 (en) | 2006-11-24 | 2007-01-03 | Univ Cardiff | Chemical compounds |
AU2014233579B2 (en) * | 2007-03-30 | 2016-06-23 | Gilead Pharmasset Llc | Nucleoside phosphoramidate prodrugs |
US7964580B2 (en) * | 2007-03-30 | 2011-06-21 | Pharmasset, Inc. | Nucleoside phosphoramidate prodrugs |
GB0709791D0 (en) * | 2007-05-22 | 2007-06-27 | Angeletti P Ist Richerche Bio | Antiviral agents |
FR2922551B1 (fr) * | 2007-10-17 | 2009-12-25 | Univ Claude Bernard Lyon | Prodrogues phosphoesters de la gemcitabine comme agents anticancereux |
US8173621B2 (en) | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
EA201100851A1 (ru) | 2008-12-23 | 2012-04-30 | Фармассет, Инк. | Аналоги нуклеозидов |
EP2671888A1 (en) | 2008-12-23 | 2013-12-11 | Gilead Pharmasset LLC | 3',5'-cyclic nucleoside phosphate analogues |
MX2011006891A (es) | 2008-12-23 | 2011-10-06 | Pharmasset Inc | Fosforamidatos de nucleosidos. |
US8618076B2 (en) | 2009-05-20 | 2013-12-31 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
TWI583692B (zh) | 2009-05-20 | 2017-05-21 | 基利法瑪席特有限責任公司 | 核苷磷醯胺 |
EP2552931B1 (en) | 2010-03-31 | 2014-07-23 | Gilead Pharmasset LLC | Stereoselective synthesis of phosphorus containing actives |
PL3290428T3 (pl) | 2010-03-31 | 2022-02-07 | Gilead Pharmasset Llc | Tabletka zawierająca krystaliczny (S)-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-diokso-3,4-dihydropirymidyn-1(2H)-ylo)-4-fluoro-3-hydroksy-4-metylotetrahydrofuran-2-ylo)metoksy)(fenoksy)fosforylo)amino)propanian izopropylu |
AP3584A (en) | 2010-09-22 | 2016-02-09 | Alios Biopharma Inc | Substituted nucleotide analogs |
GB201016855D0 (en) * | 2010-10-06 | 2010-11-17 | Nucana Biomed Ltd | Chemical compounds |
US8841275B2 (en) | 2010-11-30 | 2014-09-23 | Gilead Pharmasset Llc | 2′-spiro-nucleosides and derivatives thereof useful for treating hepatitis C virus and dengue virus infections |
US9156874B2 (en) | 2011-01-03 | 2015-10-13 | Nanjing Molecular Research, Inc. | Double-liver-targeting phosphoramidate and phosphonoamidate prodrugs |
US9095599B2 (en) | 2011-01-03 | 2015-08-04 | Nanjing Molecular Research, Inc. | O-(substituted benzyl) phosphoramidate compounds and therapeutic use |
RS54776B1 (sr) * | 2011-03-01 | 2016-10-31 | Nucana Biomed Ltd | Fosforoamidatni derivati 5-fluoro-2'-dezoksiuridina za upotrebu u tretmanu kancera |
WO2012154321A1 (en) | 2011-03-31 | 2012-11-15 | Idenix Pharmaceuticals, Inc. | Compounds and pharmaceutical compositions for the treatment of viral infections |
AR088441A1 (es) | 2011-09-12 | 2014-06-11 | Idenix Pharmaceuticals Inc | Compuestos de carboniloximetilfosforamidato sustituido y composiciones farmaceuticas para el tratamiento de infecciones virales |
BR112014006324B8 (pt) | 2011-09-16 | 2019-02-12 | Gilead Pharmassett Llc | composição e seu uso para o tratamento de hcv |
US8507460B2 (en) | 2011-10-14 | 2013-08-13 | Idenix Pharmaceuticals, Inc. | Substituted 3′,5′-cyclic phosphates of purine nucleotide compounds and pharmaceutical compositions for the treatment of viral infections |
CH707029B1 (de) | 2011-10-21 | 2015-03-13 | Abbvie Inc | Verfahren zur Behandlung von HCV, umfassend mindestens zwei direkt wirkende antivirale Wirkstoffe, Ribavirin, aber nicht Interferon. |
EP2583680A3 (en) | 2011-10-21 | 2013-06-12 | Abbvie Inc. | Mono (PSI-7977) or combination treatment of DAAs for use in treating HCV |
US8492386B2 (en) | 2011-10-21 | 2013-07-23 | Abbvie Inc. | Methods for treating HCV |
US8466159B2 (en) | 2011-10-21 | 2013-06-18 | Abbvie Inc. | Methods for treating HCV |
US8889159B2 (en) | 2011-11-29 | 2014-11-18 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis C virus |
DK2794629T3 (en) | 2011-12-20 | 2017-07-24 | Riboscience Llc | 2 ', 4'-DIFLUOR-2'-METHYL-SUBSTITUTED NUCLEOSIDE DERIVATIVES AS INHIBITORS OF HCV RNA REPLICATION |
PT2794628T (pt) | 2011-12-20 | 2017-07-05 | Riboscience Llc | Derivados nucleosídicos 4¿-azido-3¿-fluoro substituídos como inibidores de replicação de arn de vhc |
WO2013096680A1 (en) | 2011-12-22 | 2013-06-27 | Alios Biopharma, Inc. | Substituted phosphorothioate nucleotide analogs |
CN104321333A (zh) | 2012-03-21 | 2015-01-28 | 沃泰克斯药物股份有限公司 | 硫代氨基磷酸酯核苷酸前药的固体形式 |
NZ630805A (en) | 2012-03-22 | 2016-01-29 | Alios Biopharma Inc | Pharmaceutical combinations comprising a thionucleotide analog |
KR101770246B1 (ko) | 2012-03-28 | 2017-08-22 | 후지필름 가부시키가이샤 | 1-(2-디옥시-2-플루오로-4-티오-β-D-아라비노푸라노실)시토신의 염 |
EP2852605B1 (en) | 2012-05-22 | 2018-01-31 | Idenix Pharmaceuticals LLC | 3',5'-cyclic phosphate prodrugs for hcv infection |
WO2013177219A1 (en) | 2012-05-22 | 2013-11-28 | Idenix Pharmaceuticals, Inc. | D-amino acid compounds for liver disease |
EP2852604B1 (en) | 2012-05-22 | 2017-04-12 | Idenix Pharmaceuticals LLC | 3',5'-cyclic phosphoramidate prodrugs for hcv infection |
SG11201407336PA (en) | 2012-05-25 | 2015-03-30 | Janssen Sciences Ireland Uc | Uracyl spirooxetane nucleosides |
WO2013187978A1 (en) * | 2012-06-16 | 2013-12-19 | Nanjing Molecular Research, Inc. | Double-liver-targeting phosphoramidate and phosphonoamidate prodrugs |
AU2013303534B2 (en) | 2012-08-13 | 2016-06-30 | Fujifilm Corporation | Synthetic intermediate of 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)cytosine, synthetic intermediate of thionucleoside, and method for producing the same |
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 |
EP2900682A1 (en) | 2012-09-27 | 2015-08-05 | IDENIX Pharmaceuticals, Inc. | Esters and malonates of sate prodrugs |
TR201809048T4 (tr) | 2012-10-08 | 2018-07-23 | Centre Nat Rech Scient | Hcv enfeksiyonu için 2'-kloro nükleosit analogları. |
WO2014066239A1 (en) | 2012-10-22 | 2014-05-01 | Idenix Pharmaceuticals, Inc. | 2',4'-bridged nucleosides for hcv infection |
SG10201510324YA (en) | 2012-11-16 | 2016-01-28 | Univ Cardiff | Process for preparing nucleoside prodrugs |
EP2935304A1 (en) | 2012-12-19 | 2015-10-28 | IDENIX Pharmaceuticals, Inc. | 4'-fluoro nucleosides for the treatment of hcv |
MY172166A (en) | 2013-01-31 | 2019-11-15 | Gilead Pharmasset Llc | Combination formulation of two antiviral compounds |
US10034893B2 (en) | 2013-02-01 | 2018-07-31 | Enanta Pharmaceuticals, Inc. | 5, 6-D2 uridine nucleoside/tide derivatives |
WO2014137926A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | 3'-deoxy nucleosides for the treatment of hcv |
WO2014137930A1 (en) | 2013-03-04 | 2014-09-12 | Idenix Pharmaceuticals, Inc. | Thiophosphate nucleosides for the treatment of hcv |
EP2970357A1 (en) | 2013-03-13 | 2016-01-20 | IDENIX Pharmaceuticals, Inc. | Amino acid phosphoramidate pronucleotides of 2'-cyano, azido and amino nucleosides for the treatment of hcv |
WO2014165542A1 (en) | 2013-04-01 | 2014-10-09 | Idenix Pharmaceuticals, Inc. | 2',4'-fluoro nucleosides for the treatment of hcv |
AU2014250762A1 (en) | 2013-04-12 | 2015-10-29 | Achillion Pharmaceuticals, Inc. | Highly active nucleoside derivative for the treatment of HCV |
WO2014193663A1 (en) | 2013-05-16 | 2014-12-04 | Riboscience Llc | 4'-azido, 3'-deoxy-3'-fluoro substituted nucleoside derivatives |
CA2912682C (en) | 2013-05-16 | 2021-07-06 | Riboscience Llc | 4'-fluoro-2'-methyl substituted nucleoside derivatives |
US20180200280A1 (en) | 2013-05-16 | 2018-07-19 | Riboscience Llc | 4'-Fluoro-2'-Methyl Substituted Nucleoside Derivatives as Inhibitors of HCV RNA Replication |
US10005779B2 (en) | 2013-06-05 | 2018-06-26 | Idenix Pharmaceuticals Llc | 1′,4′-thio nucleosides for the treatment of HCV |
US20150037282A1 (en) | 2013-08-01 | 2015-02-05 | Idenix Pharmaceuticals, Inc. | D-amino acid phosphoramidate pronucleotides of halogeno pyrimidine compounds for liver disease |
PT3038601T (pt) | 2013-08-27 | 2020-06-30 | Gilead Pharmasset Llc | Formulação combinada de dois compostos antivirais |
EP3057976A1 (en) * | 2013-10-17 | 2016-08-24 | Medivir Ab | Hcv polymerase inhibitors |
RU2016125213A (ru) * | 2013-11-27 | 2017-12-29 | АЙДЕНИКС ФАРМАСЬЮТИКАЛЗ ЭлЭлСи | Нуклеотиды для лечения рака печени |
EP3109245B1 (en) | 2014-02-18 | 2018-01-03 | FUJIFILM Corporation | Method for producting thiolane skeleton-type glycoconjugate, and thiolane skeleton-type glycoconjugate |
JP6204223B2 (ja) | 2014-02-19 | 2017-09-27 | 富士フイルム株式会社 | チオピラノース化合物等の製造方法 |
CN103804446A (zh) * | 2014-02-27 | 2014-05-21 | 苏州东南药业股份有限公司 | 一种3,5-二苯甲酰基-2-去氧-2-氟-2甲基-D-核糖-γ-内酯的制备方法 |
WO2015161137A1 (en) | 2014-04-16 | 2015-10-22 | Idenix Pharmaceuticals, Inc. | 3'-substituted methyl or alkynyl nucleosides for the treatment of hcv |
NO3119794T3 (xx) * | 2014-06-25 | 2018-03-10 | ||
EP3757112B1 (en) * | 2014-06-25 | 2023-06-07 | Nucana PLC | Gemcitabine prodrugs |
WO2016012781A1 (en) * | 2014-07-22 | 2016-01-28 | Nucana Biomed Limited | Process for the preparation of gemcitabine-[phenyl(benzoxy-l-alaninyl)] phosphate |
EP3572410B1 (en) | 2014-08-25 | 2022-07-20 | Medivir Aktiebolag | Dioxolane analogues of uridine for the treatment of cancer |
WO2016033164A1 (en) | 2014-08-26 | 2016-03-03 | Enanta Pharmaceuticals, Inc. | Nucleoside and nucleotide derivatives |
GB201417644D0 (en) * | 2014-10-06 | 2014-11-19 | Nucana Biomed Ltd | Method of separating phosphate diastereoisomers |
CA2966033A1 (en) * | 2014-10-31 | 2016-05-06 | Cocrystal Pharma, Inc. | 2',2'-dihalo nucleoside analogs for treatment of the flaviviridae family of viruses and cancer |
TWI678373B (zh) * | 2014-10-31 | 2019-12-01 | 日商富士軟片股份有限公司 | 硫代核苷衍生物或其鹽及醫藥組合物 |
WO2016073756A1 (en) | 2014-11-06 | 2016-05-12 | Enanta Pharmaceuticals, Inc. | Deuterated nucleoside/tide derivatives |
EP3683225A1 (en) | 2014-11-28 | 2020-07-22 | Nucana PLC | New 2' and/or 5' amino-acid ester phosphoramidate 3'-deoxy adenosine derivatives as anti-cancer compounds |
US9732110B2 (en) | 2014-12-05 | 2017-08-15 | Enanta Pharmaceuticals, Inc. | Nucleoside and nucleotide derivatives |
BR112017012859A2 (pt) | 2014-12-15 | 2017-12-26 | Univ Emory | fosforamidatos para o tratamento do vírus da hepatite b |
WO2016134058A1 (en) | 2015-02-18 | 2016-08-25 | Abbvie Inc. | Combinations useful to treat hepatitis c virus |
GEP20217282B (en) | 2015-03-06 | 2021-08-10 | Atea Pharmaceuticals Inc | β-D-2'-DEOXY-2'α-FLUORO-2'-β-C-SUBSTITUTED-2-MODIFIED-N6-SUBSTITUTED PURINE NUCLEOTIDES FOR HCV TREATMENT |
EP3279207B1 (en) * | 2015-04-03 | 2024-01-24 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | Novel compound of 4'-thionucleoside, as well as preparation method therefor, pharmaceutical composition thereof and application thereof |
CN115837028A (zh) * | 2015-05-14 | 2023-03-24 | 努卡那有限公司 | 癌症治疗 |
TWI687431B (zh) * | 2015-06-22 | 2020-03-11 | 瑞典商米迪維艾克提伯拉公司 | 治療癌症之前藥 |
CA2997170A1 (en) | 2015-09-02 | 2017-03-09 | Abbvie Inc. | Anti-viral tetrahydrofurane derivatives |
CN106543252A (zh) * | 2015-09-16 | 2017-03-29 | 博瑞生物医药(苏州)股份有限公司 | 核苷氨基磷酸酯类前药的制备方法及其中间体 |
CN106478753A (zh) * | 2015-09-16 | 2017-03-08 | 博瑞生物医药(苏州)股份有限公司 | 一种nuc‑1031单一异构体的制备方法和用途 |
CN106543220A (zh) | 2015-09-16 | 2017-03-29 | 博瑞生物医药(苏州)股份有限公司 | 氨基磷酸酯化合物及其制备方法和晶体 |
JP7038653B2 (ja) * | 2015-10-05 | 2022-03-18 | ニューカナ パブリック リミテッド カンパニー | 併用療法 |
SG11201804774YA (en) | 2015-12-11 | 2018-07-30 | NuCana plc | Diastereoselective synthesis of phosphate derivatives and of the gemcitabine prodrug nuc-1031 |
CA3008749C (en) | 2015-12-23 | 2024-01-02 | NuCana plc | Treatment of ovarian cancer or biliary tract cancer with a combination of gemcitabine-(phenyl-benzoxy-l-alaninyl)]-phosphate and cisplatin |
US20190381084A1 (en) | 2015-12-23 | 2019-12-19 | Nucana Biomed Limited | Combination therapy |
EA201892448A1 (ru) | 2016-04-28 | 2019-06-28 | Эмори Юниверсити | Алкинсодержащие нуклеотидные и нуклеозидные терапевтические композиции и связанные с ними способы применения |
GB201609600D0 (en) * | 2016-06-01 | 2016-07-13 | Nucuna Biomed Ltd | Cancer treatments |
WO2017223421A1 (en) | 2016-06-24 | 2017-12-28 | Emory University | Phosphoramidates for the treatment of hepatitis b virus |
US10711029B2 (en) | 2016-07-14 | 2020-07-14 | Atea Pharmaceuticals, Inc. | Beta-d-2′-deoxy-2′-alpha-fluoro-2′-beta-c-substituted-4′fluoro-n6-substituted-6-amino-2-substituted purine nucleotides for the treatment of hepatitis c virus infection |
BR112019003946A2 (pt) | 2016-08-31 | 2019-05-21 | Fujifilm Corporation | agente antitumoral, reforçador do efeito antitumoral e kit antitumoral |
HRP20220278T1 (hr) | 2016-09-07 | 2022-05-13 | Atea Pharmaceuticals, Inc. | 2'-supstituirani-n6-supstituirani purinski nukleotidi za liječenje bolesti izazvanih rnk virusima |
GB201709471D0 (en) | 2017-06-14 | 2017-07-26 | Nucana Biomed Ltd | Diastereoselective synthesis of hosphate derivatives |
CN109134568B (zh) * | 2017-06-15 | 2022-11-22 | 北京美倍他药物研究有限公司 | 核苷磷酸酯/酰胺衍生物及其医药用途 |
EP3677267A4 (en) * | 2017-09-01 | 2021-06-02 | Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. | PHARMACEUTICAL COMPOSITION FOR TREATMENT OR PREVENTION OF TUMORS, METHOD AND USES THEREOF |
GB201715011D0 (en) | 2017-09-18 | 2017-11-01 | Nucana Biomed Ltd | Floxuridine synthesis |
CA3075645A1 (en) | 2017-09-21 | 2019-03-28 | Riboscience Llc | 4'-fluoro-2'-methyl substituted nucleoside derivatives as inhibitors of hcv rna replication |
TW201932119A (zh) | 2018-01-29 | 2019-08-16 | 日商富士軟片股份有限公司 | 膽道癌用抗腫瘤劑和膽道癌的處理方法 |
BR112020015745A2 (pt) | 2018-02-02 | 2020-12-08 | Maverix Oncology, Inc. | Conjugados de fármacos de moléculas pequenas de monofosfato de gemcitabina |
AU2019216514A1 (en) * | 2018-02-02 | 2020-09-24 | Maverix Oncology, Inc. | Novel small molecule drug conjugates of gemcitabine derivatives |
JP6810763B2 (ja) * | 2019-03-06 | 2021-01-06 | ニューカナ パブリック リミテッド カンパニー | がん治療 |
GB201904544D0 (en) | 2019-04-01 | 2019-05-15 | NuCana plc | Anticancer compounds |
WO2021173713A1 (en) | 2020-02-27 | 2021-09-02 | Atea Pharmaceuticals, Inc. | Highly active compounds against covid-19 |
US10874687B1 (en) | 2020-02-27 | 2020-12-29 | Atea Pharmaceuticals, Inc. | Highly active compounds against COVID-19 |
WO2022031150A1 (ko) * | 2020-08-07 | 2022-02-10 | 주식회사 피노바이오 | 데옥시사이티딘계 항암제 및 실릴 에테르 함유 링커를 포함하는 접합체 및 이의 용도 |
Citations (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2802005A (en) | 1957-08-06 | S-eluorourace | ||
US2945038A (en) | 1956-09-26 | 1960-07-12 | Hoffmann La Roche | 5-fluorocytosine and preparation thereof |
US3201387A (en) | 1963-09-18 | 1965-08-17 | Heidelberger Charles | 5-trifluoromethyluracil, derivatives thereof, and processes for preparing the same |
US4357324A (en) | 1981-02-24 | 1982-11-02 | The United States Of America As Represented By The Department Of Health And Human Services | Prodrug derivatives of 9β-D-arabinofuranosyl-2-fluoroadenine |
US5814639A (en) | 1990-02-01 | 1998-09-29 | Emory University | Method for the synthesis, compositions and use of 2'-deoxy-5-fluoro-3'-thiacytidine and related compounds |
US5914331A (en) | 1990-02-01 | 1999-06-22 | Emory University | Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane |
WO1999037753A1 (en) | 1998-01-23 | 1999-07-29 | Newbiotics, Inc. | Enzyme catalyzed therapeutic agents |
WO1999049873A1 (en) | 1998-03-27 | 1999-10-07 | Regents Of The University Of Minnesota | Nucleosides with antiviral and anticancer activity |
US6069252A (en) | 1990-02-01 | 2000-05-30 | Emory University | Method of resolution and antiviral activity of 1,3-oxathiolane nucleoside enantiomers |
US6180639B1 (en) | 1990-05-02 | 2001-01-30 | Biochem Pharma Inc. | 1,3-oxathiolane nucleoside analogues |
WO2001007454A1 (en) | 1999-07-22 | 2001-02-01 | Newbiotics, Inc. | Enzyme catalyzed therapeutic activation |
WO2003000713A1 (en) | 2001-06-21 | 2003-01-03 | Glaxo Group Limited | Nucleoside compounds in hcv |
US20030109697A1 (en) * | 1998-01-23 | 2003-06-12 | Shepard H. Michael | Novel phosphoramidate compounds and methods of use |
WO2003053989A1 (en) * | 2001-12-13 | 2003-07-03 | Mrc Technology Limited | Masked phosphate containing nucleoside derivatives and their use as antivirals |
WO2003068164A2 (en) | 2002-02-14 | 2003-08-21 | Pharmasset Ltd. | Dosing regimen for gemcitabine hcv therapy |
US6703396B1 (en) | 1990-02-01 | 2004-03-09 | Emory University | Method of resolution and antiviral activity of 1,3-oxathiolane nuclesoside enantiomers |
WO2004041203A2 (en) | 2002-11-04 | 2004-05-21 | Xenoport, Inc. | Gemcitabine prodrugs, pharmaceutical compositions and uses thereof |
US20040167096A1 (en) * | 2003-02-19 | 2004-08-26 | Yung-Chi Cheng | Anti-viral nucleoside analogs and methods for treating viral infections, especially HIV infections |
US20170226147A1 (en) * | 2014-10-06 | 2017-08-10 | Nucana Biomed Limited | Methods of separating gemcitabine-phosphate diastereoisomers |
US9834577B2 (en) | 2014-07-22 | 2017-12-05 | Laurus Labs Limited | Process for the preparation of gemcitabine-[phenyl(benzoxy-L-alaninyl)] phosphate |
US10005810B2 (en) | 2012-11-16 | 2018-06-26 | University College Cardiff Consultants Limited | Process for preparing nucleoside prodrugs |
US20180271889A1 (en) | 2015-10-05 | 2018-09-27 | NuCana plc | Combination therapy for cancer |
US20180289733A1 (en) | 2015-05-14 | 2018-10-11 | NuCana plc | Cancer treatments based on gemcitabine prodrugs |
US10117888B2 (en) | 2014-06-25 | 2018-11-06 | NuCana plc | Formulation comprising a gemcitabine-prodrug |
US20180362571A1 (en) | 2015-12-11 | 2018-12-20 | NuCana plc | Diastereoselective synthesis of phosphate derivatives |
US20180369266A1 (en) | 2015-12-23 | 2018-12-27 | NuCana plc | Formulations of phosphoramidate derivatives of nucleoside drugs |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2538397A1 (fr) | 1982-12-24 | 1984-06-29 | Charbonnages Ste Chimique | Procede continu de fabrication d'homopolymeres ou de copolymeres de l'ethylene |
GB9505025D0 (en) | 1995-03-13 | 1995-05-03 | Medical Res Council | Chemical compounds |
EP1251836A2 (en) | 1999-12-23 | 2002-10-30 | NewBiotics, Inc. | Use of bvdu for inhibiting the growth of hyperproliferative cells |
WO2002039952A2 (en) | 2000-11-16 | 2002-05-23 | Newbiotics, Inc. | Synergistic ecta compositions |
TW200500373A (en) | 2002-06-28 | 2005-01-01 | Idenix Cayman Ltd | 2'-c-methyl-3'-o-l-valine ester ribofuranosyl cytidine for treatment of flaviviridae infections |
SI1633766T1 (sl) | 2003-05-30 | 2019-06-28 | Gilead Pharmasset Llc | Modificirani analogi fluoriranih nukleozidov |
-
2003
- 2003-07-21 GB GBGB0317009.9A patent/GB0317009D0/en not_active Ceased
-
2004
- 2004-07-20 PL PL21180706.0T patent/PL3904365T3/pl unknown
- 2004-07-20 EP EP16155811.9A patent/EP3040340B1/en active Active
- 2004-07-20 PT PT47434832T patent/PT1646639T/pt unknown
- 2004-07-20 PL PL16155811T patent/PL3040340T3/pl unknown
- 2004-07-20 EP EP21180706.0A patent/EP3904365B1/en active Active
- 2004-07-20 AU AU2004261455A patent/AU2004261455B2/en not_active Ceased
- 2004-07-20 PT PT211807060T patent/PT3904365T/pt unknown
- 2004-07-20 TR TR2019/01246T patent/TR201901246T4/tr unknown
- 2004-07-20 EP EP04743483.2A patent/EP1646639B8/en active Active
- 2004-07-20 PT PT151547593T patent/PT2955190T/pt unknown
- 2004-07-20 PL PL15154759T patent/PL2955190T3/pl unknown
- 2004-07-20 JP JP2006520890A patent/JP4923216B2/ja active Active
- 2004-07-20 HU HUE21180706A patent/HUE059970T2/hu unknown
- 2004-07-20 MX MXPA05012606A patent/MXPA05012606A/es active IP Right Grant
- 2004-07-20 SI SI200432460T patent/SI3040340T1/sl unknown
- 2004-07-20 SI SI200432439T patent/SI2955190T1/en unknown
- 2004-07-20 EP EP18201295.5A patent/EP3486251A1/en not_active Withdrawn
- 2004-07-20 DK DK21180706.0T patent/DK3904365T3/da active
- 2004-07-20 DK DK16155811.9T patent/DK3040340T3/en active
- 2004-07-20 PL PL04743483.2T patent/PL1646639T3/pl unknown
- 2004-07-20 ES ES21180706T patent/ES2928202T3/es active Active
- 2004-07-20 ES ES04743483.2T patent/ES2589738T3/es active Active
- 2004-07-20 US US15/279,611 patent/USRE47589E1/en active Active
- 2004-07-20 DK DK15154759.3T patent/DK2955190T3/en active
- 2004-07-20 HU HUE16155811A patent/HUE042282T2/hu unknown
- 2004-07-20 ES ES16155811T patent/ES2708570T3/es active Active
- 2004-07-20 DK DK04743483.2T patent/DK1646639T3/en active
- 2004-07-20 WO PCT/GB2004/003148 patent/WO2005012327A2/en active Application Filing
- 2004-07-20 HU HUE04743483A patent/HUE030374T2/en unknown
- 2004-07-20 EP EP15154759.3A patent/EP2955190B1/en not_active Revoked
- 2004-07-20 US US10/560,887 patent/US7951787B2/en not_active Ceased
- 2004-07-20 CA CA2518115A patent/CA2518115C/en active Active
- 2004-07-20 ES ES15154759.3T patent/ES2667698T3/es active Active
- 2004-07-20 PT PT16155811T patent/PT3040340T/pt unknown
- 2004-07-20 NZ NZ541974A patent/NZ541974A/xx not_active IP Right Cessation
-
2005
- 2005-08-26 NO NO20053993A patent/NO333603B1/no not_active IP Right Cessation
-
2016
- 2016-09-05 CY CY20161100875T patent/CY1117960T1/el unknown
-
2018
- 2018-05-03 CY CY20181100460T patent/CY1120202T1/el unknown
-
2019
- 2019-01-30 CY CY20191100124T patent/CY1121218T1/el unknown
-
2022
- 2022-10-07 CY CY20221100667T patent/CY1125603T1/el unknown
-
2023
- 2023-02-28 HU HUS2300012C patent/HUS2300012I1/hu unknown
- 2023-02-28 FR FR23C1014C patent/FR23C1014I2/fr active Active
- 2023-03-01 FI FIC20230013C patent/FIC20230013I1/fi unknown
Patent Citations (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2802005A (en) | 1957-08-06 | S-eluorourace | ||
US2945038A (en) | 1956-09-26 | 1960-07-12 | Hoffmann La Roche | 5-fluorocytosine and preparation thereof |
US3201387A (en) | 1963-09-18 | 1965-08-17 | Heidelberger Charles | 5-trifluoromethyluracil, derivatives thereof, and processes for preparing the same |
US4357324A (en) | 1981-02-24 | 1982-11-02 | The United States Of America As Represented By The Department Of Health And Human Services | Prodrug derivatives of 9β-D-arabinofuranosyl-2-fluoroadenine |
US6069252A (en) | 1990-02-01 | 2000-05-30 | Emory University | Method of resolution and antiviral activity of 1,3-oxathiolane nucleoside enantiomers |
US5914331A (en) | 1990-02-01 | 1999-06-22 | Emory University | Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane |
US6703396B1 (en) | 1990-02-01 | 2004-03-09 | Emory University | Method of resolution and antiviral activity of 1,3-oxathiolane nuclesoside enantiomers |
US5814639A (en) | 1990-02-01 | 1998-09-29 | Emory University | Method for the synthesis, compositions and use of 2'-deoxy-5-fluoro-3'-thiacytidine and related compounds |
US6180639B1 (en) | 1990-05-02 | 2001-01-30 | Biochem Pharma Inc. | 1,3-oxathiolane nucleoside analogues |
WO1999037753A1 (en) | 1998-01-23 | 1999-07-29 | Newbiotics, Inc. | Enzyme catalyzed therapeutic agents |
JP2001220397A (ja) | 1998-01-23 | 2001-08-14 | Newbiotics Inc | 酵素に触媒される治療剤 |
JP2002500880A (ja) | 1998-01-23 | 2002-01-15 | ニューバイオティックス インコーポレイテッド | 酵素に触媒される治療剤 |
US6339151B1 (en) * | 1998-01-23 | 2002-01-15 | Newbiotics, Inc. | Enzyme catalyzed therapeutic agents |
US20030109697A1 (en) * | 1998-01-23 | 2003-06-12 | Shepard H. Michael | Novel phosphoramidate compounds and methods of use |
WO1999049873A1 (en) | 1998-03-27 | 1999-10-07 | Regents Of The University Of Minnesota | Nucleosides with antiviral and anticancer activity |
WO2001007454A1 (en) | 1999-07-22 | 2001-02-01 | Newbiotics, Inc. | Enzyme catalyzed therapeutic activation |
WO2003000713A1 (en) | 2001-06-21 | 2003-01-03 | Glaxo Group Limited | Nucleoside compounds in hcv |
WO2003053989A1 (en) * | 2001-12-13 | 2003-07-03 | Mrc Technology Limited | Masked phosphate containing nucleoside derivatives and their use as antivirals |
WO2003068164A2 (en) | 2002-02-14 | 2003-08-21 | Pharmasset Ltd. | Dosing regimen for gemcitabine hcv therapy |
WO2004041203A2 (en) | 2002-11-04 | 2004-05-21 | Xenoport, Inc. | Gemcitabine prodrugs, pharmaceutical compositions and uses thereof |
US20040167096A1 (en) * | 2003-02-19 | 2004-08-26 | Yung-Chi Cheng | Anti-viral nucleoside analogs and methods for treating viral infections, especially HIV infections |
US10005810B2 (en) | 2012-11-16 | 2018-06-26 | University College Cardiff Consultants Limited | Process for preparing nucleoside prodrugs |
US20180273575A1 (en) | 2012-11-16 | 2018-09-27 | NuCana plc | Process for preparing nucleoside prodrugs |
US10117888B2 (en) | 2014-06-25 | 2018-11-06 | NuCana plc | Formulation comprising a gemcitabine-prodrug |
US20190022118A1 (en) | 2014-06-25 | 2019-01-24 | NuCana plc | Formulation comprising a gemcitabine-prodrug |
US9834577B2 (en) | 2014-07-22 | 2017-12-05 | Laurus Labs Limited | Process for the preparation of gemcitabine-[phenyl(benzoxy-L-alaninyl)] phosphate |
US20170226147A1 (en) * | 2014-10-06 | 2017-08-10 | Nucana Biomed Limited | Methods of separating gemcitabine-phosphate diastereoisomers |
US20180289733A1 (en) | 2015-05-14 | 2018-10-11 | NuCana plc | Cancer treatments based on gemcitabine prodrugs |
US20180271889A1 (en) | 2015-10-05 | 2018-09-27 | NuCana plc | Combination therapy for cancer |
US20180362571A1 (en) | 2015-12-11 | 2018-12-20 | NuCana plc | Diastereoselective synthesis of phosphate derivatives |
US20180369266A1 (en) | 2015-12-23 | 2018-12-27 | NuCana plc | Formulations of phosphoramidate derivatives of nucleoside drugs |
Non-Patent Citations (33)
Title |
---|
Abraham et al., "Synthesis and Biological Activity of Aromatic Amino Acid Phosphoramidates of 5-Fluoro-2'-deoxyuridine and 1-beta-Arabinofuranosylcytosine: Evidence of Phosphoramidate Activity", J. Med. Chem. 39:4569-4575 (1996). |
Bundgard, H. in "Design of Prodrugs" (Bungaard, H., ed.) (1985) (Elsevier Science Publishers, Biomedical Division: Amsterdam) pp. 1-92. * |
David B. Lackey et al., "Enzyme-catalyzed therapeutic agent (ECTA) design: activation of the antitumor ECTA compound NB1011 by thymidylate synthase", Biochemical Pharmacology, 61 (2001), pp. 179-189. |
Edward J. McIntee, et al., "Amino Acid Phosphoramidate Nucleosides: Potential ADEPT/GDEPT Substrates", Bioorganic & Medicinal Chemistry Letters, 11 (2001), pp. 2803-2805. |
Galmarini, C. M., et al. Leukemia (2001). 15; pp. 875-890. * |
Gromova et al., "Optical Rotary Dispersion and Circular Dichroism of Mono- and Oligonucleotide-Amino Acids (Amidates)", Biochim Biophys Acta 240:1-11 (1971). |
Harris et al., "Synthesis and antiviral evaluation of phosphoramidate derivatives of (E)-5-(2-bromoviny1)-2'-deoxyuridine", Antiviral Chemistry and Chemotherapy, vol. 12 (2001), pp. 293-300. |
Juodka et al., "Oligonucleotides and nucleotide-peptide. XXXIV. Synthesis and some properties of complex nucleotidyl (oligonucleotidyl)-(P-N)-aminoacids (peptides) and their ethyl esters"; J Carbohydrates Nucleosides Nucleotides 6(4):333-357 (1979). |
Juodka et al., "Oligonucleotides and Nucleotide-Peptides. XXXV. Some Properties of Nucleotidyl-(5'→N)-Amino Acid Esters Differing in Amino Acid and Nucleotide Components)", J Carbohydrates Nucleosides Nucleotides 8 (1): 19-39 (1981). |
Juodka et al., "Oligonucleotides and nucleotide-peptides. XXXVII. On the Mechanism of Hydrolysis of Uridyly1-(5'→N)-amino acids. Intramolecular catalysis by the alpha-carboxyl group of amino acids"; J Carbohydrates Nucleosides Nucleotides 8(6):519-535 (1981). |
Juodka et al., "Oligonucleotides and Nucleotide-Peptides. XXXV. Some Properties of Nucleotidyl—(5'→N)-Amino Acid Esters Differing in Amino Acid and Nucleotide Components)", J Carbohydrates Nucleosides Nucleotides 8 (1): 19-39 (1981). |
Lehsten et al., "An improved procedure for the synthesis of nucleoside amidates"; Organic Process Research & Development 6:819-822 (2002). |
Liorancaite et al., "Synthesis and Some Properties of Oligonucleotidyl-(Pm->N)-Serines", Nucleic Acids Symposium Series 9:215-18 (1981). |
Lisa J. Whalen, et al., "Synthesis and Evaluation of Phosphoramidate Amino Acid-Based Inhibitors of Sialyltransferases", Bioorganic & Medicinal Chemistry Letters, 13 (2003), pp. 301-304. |
McGuigan et al. Antiviral Chem. Chemotherapy (2000) 11: 111-116. * |
McGuigan et al. Antiviral Chemistry & Chemotherapy 1993; 4:97-101. |
McGuigan et al. Antiviral Research 1991; 15:255-263. |
McGuigan et al., "Synthesis and Evaluation of some masked phosphate esters of the anti-herpesvirus drug 882C (Netivudine) as potential antiviral agents", Antiviral Chemistry & Chemotherapy 9:233-243 (1998). |
Negishi et al., "N4-Aminocytidine, a Nucleoside Analog that has an Exceptionally High Mutagenic Activity", Nucleic Acids Research 11(15):5223-5233 (1993). |
Parker et al. Mol. Pharmacol. 1999; 55:515-520. |
Patani et al. Chem. Rev. (1996) 96: 3147-3176. * |
Ramirez, M et al. Prostaglandins, Leukotrienes and Essential Fatty Acids 1991; 43: 49-54. |
Remy et al., "Studies on fluorinated pyrimidines. XIV. The synthesis of derivatives of 5-fluoro-2'-deoxyuridine-5'-phosphate and related compounds"; J Org Chem 27:2491-2500 (1962). |
Sa Harris, et al., "Synthesis and antiviral evaluation of phosphoramidate derivatives of (E)-5-(2-bromovinyl)-2′-deoxyuridine", Antiviral Chemistry and Chemotherapy, vol. 12 (2001), pp. 293-300. |
Search Report issued by the European Patent Office in corresponding Application No. EP 15154759.3, dated Jun. 20, 2017. |
Siddiqui et al., "Design and Synthesis of Liphophilic Phosphoramidate d4T-MP Prodrugs Expressing High Potency Against HIV in Cell Culture: Structure Determinants for in Vitro Activity and QSAR", J Med Chem 42 (1999), pp. 4122-4128. |
Slusarczyk, "Application of ProTide Technology to Gemcitabine: A Successful Approach to Overcome the Key Cancer Resistance Mechanisms Leads to a New Agent (NUC-1031) in Clinical Development," J Med Chem, 57:1531-1542 (2014). |
Stryer, L., "DNA and RNA: Molecules of Heredity", Biochemistry, Fourth Ed., Ch. 4. pp. 75, 76, 80-83 (1995). |
Stryer, L., "Flow of Genetic Information". Biochemistry, Fourth Ed., Ch. 5, pp. 95-97 (1995). |
Torres-Lopez, MI. Et al. Gut 1996; 38: 260-264. |
Wagner, et al. Bioorganic & Medicinal Chemistry Letters 1995; 5 (16):1819-1824. |
Wattig, B. et al. Acta Histochem Suppl. 1992; 42:333-339 (Abstract only). |
Zhou et al., "Simultaneous Formation of Peptides and Nucleotides from N-Phosphothreonine", Origins of Life and Evolution of the Biosphere 26:547-560 (1996). |
Cited By (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10988498B2 (en) | 2009-09-21 | 2021-04-27 | Gilead Sciences, Inc. | Processes and intermediates for the preparation of 1′-substituted carba-nucleoside analogs |
US11492353B2 (en) | 2010-07-22 | 2022-11-08 | Gilead Sciences, Inc. | Methods and compounds for treating Paramyxoviridae virus infections |
US11266666B2 (en) | 2014-10-29 | 2022-03-08 | Gilead Sciences, Inc. | Methods for treating Filoviridae virus infections |
US11344565B2 (en) | 2014-10-29 | 2022-05-31 | Gilead Sciences, Inc. | Methods for the preparation of ribosides |
US11382926B2 (en) | 2015-09-16 | 2022-07-12 | Gilead Sciences, Inc. | Methods for treating Arenaviridae and Coronaviridae virus infections |
US11007208B2 (en) | 2015-09-16 | 2021-05-18 | Gilead Sciences, Inc. | Methods for treating arenaviridae and coronaviridae virus infections |
US11377467B2 (en) | 2015-12-23 | 2022-07-05 | NuCana plc | Crystalline form of gemcitabine |
US11260070B2 (en) | 2017-03-14 | 2022-03-01 | Gilead Sciences, Inc. | Methods of treating feline coronavirus infections |
US11597742B2 (en) | 2017-05-01 | 2023-03-07 | Gilead Sciences, Inc. | Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate |
US10836787B2 (en) * | 2017-05-01 | 2020-11-17 | Gilead Sciences, Inc. | Crystalline forms of (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5- (4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphoryl)amino)propanoate |
US20180346504A1 (en) * | 2017-05-01 | 2018-12-06 | Gilead Sciences, Inc. | Crystalline forms of (s)-2-ethylbutyl 2-(((s)-(((2r,3s,4r,5r)-5- (4-aminopyrrolo[2,1-f] [1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (phenoxy) phosphoryl)amino)propanoate |
US11266681B2 (en) | 2017-07-11 | 2022-03-08 | Gilead Sciences, Inc. | Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections |
US11975017B2 (en) | 2017-07-11 | 2024-05-07 | Gilead Sciences, Inc. | Compositions comprising an RNA polymerase inhibitor and cyclodextrin for treating viral infections |
US11560400B2 (en) | 2017-12-05 | 2023-01-24 | NuCana plc | Salts of diphosphate phosphoramidate of nucleosides as anticancer compounds |
US11660307B2 (en) | 2020-01-27 | 2023-05-30 | Gilead Sciences, Inc. | Methods for treating SARS CoV-2 infections |
US11613553B2 (en) | 2020-03-12 | 2023-03-28 | Gilead Sciences, Inc. | Methods of preparing 1′-cyano nucleosides |
US11701372B2 (en) | 2020-04-06 | 2023-07-18 | Gilead Sciences, Inc. | Inhalation formulations of 1'-cyano substituted carba-nucleoside analogs |
US11903953B2 (en) | 2020-05-29 | 2024-02-20 | Gilead Sciences, Inc. | Remdesivir treatment methods |
US11975012B2 (en) | 2020-05-29 | 2024-05-07 | Gilead Sciences, Inc. | Remdesivir treatment methods |
US11491169B2 (en) | 2020-05-29 | 2022-11-08 | Gilead Sciences, Inc. | Remdesivir treatment methods |
US11939347B2 (en) | 2020-06-24 | 2024-03-26 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and uses thereof |
US11814406B2 (en) | 2020-08-27 | 2023-11-14 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
US11926645B2 (en) | 2020-08-27 | 2024-03-12 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
US11780844B2 (en) | 2022-03-02 | 2023-10-10 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
US11845755B2 (en) | 2022-03-02 | 2023-12-19 | Gilead Sciences, Inc. | Compounds and methods for treatment of viral infections |
US11851438B2 (en) | 2022-03-02 | 2023-12-26 | Gilead Sciences, Inc. | 1′-cyano nucleoside analogs and methods for treatment of viral infections |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
USRE47589E1 (en) | Phosphoramidate compounds and methods of use | |
AU2012223012C1 (en) | Phosphoramidate derivatives of 5 - fluoro - 2 ' - deoxyuridine for use in the treatment of cancer | |
US9321798B2 (en) | Phosphoramidite derivatives of gemcitabine for use in the treatment of cancer | |
AU610344B2 (en) | 2'-deoxy-5-fluorouridine derivatives | |
PT707591E (pt) | Esteres de acido metilfosfonico, processo para a sua preparacao e sua utilizacao | |
WO2007112348A2 (en) | Prodrug composition | |
KR20070103012A (ko) | 신규 피리미딘 뉴클레오시드화합물 또는 그의 염 | |
CZ295706B6 (cs) | Derivát 5´-deoxycytidinu, způsob jeho výroby a použití a farmaceutická kompozice a kit s jeho obsahem | |
US11414451B2 (en) | Floxuridine synthesis | |
JPWO2008010571A1 (ja) | 2’−シアノピリミジンヌクレオシド化合物 | |
GB2104060A (en) | Fluorinated hexene diamine derivatives | |
JPH08134093A (ja) | 制癌剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: NUCANA PLC, UNITED KINGDOM Free format text: CHANGE OF NAME;ASSIGNOR:NUCANA BIOMED LIMITED;REEL/FRAME:048621/0306 Effective date: 20170829 |
|
MAFP | Maintenance fee payment |
Free format text: PAYMENT OF MAINTENANCE FEE, 12TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1553); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Year of fee payment: 12 |