CA2575520A1 - Prodrugs activated by rna-dependent dna-polymerases - Google Patents
Prodrugs activated by rna-dependent dna-polymerases Download PDFInfo
- Publication number
- CA2575520A1 CA2575520A1 CA002575520A CA2575520A CA2575520A1 CA 2575520 A1 CA2575520 A1 CA 2575520A1 CA 002575520 A CA002575520 A CA 002575520A CA 2575520 A CA2575520 A CA 2575520A CA 2575520 A1 CA2575520 A1 CA 2575520A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- deoxy
- cytotoxic
- treatment
- blood
- 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.)
- Abandoned
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- 229940002612 prodrug Drugs 0.000 title claims abstract description 29
- 239000000651 prodrug Substances 0.000 title claims abstract description 29
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 title claims abstract description 22
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 25
- 238000002360 preparation method Methods 0.000 claims abstract description 24
- 108010017842 Telomerase Proteins 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 239000008280 blood Substances 0.000 claims abstract description 11
- 210000004369 blood Anatomy 0.000 claims abstract description 11
- 206010038997 Retroviral infections Diseases 0.000 claims abstract description 9
- 239000003914 blood derivative Substances 0.000 claims abstract description 9
- 241001430294 unidentified retrovirus Species 0.000 claims abstract description 9
- 102100034343 Integrase Human genes 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
- 230000002489 hematologic effect Effects 0.000 claims abstract description 8
- 208000006994 Precancerous Conditions Diseases 0.000 claims abstract description 6
- 208000015181 infectious disease Diseases 0.000 claims abstract description 6
- 230000001177 retroviral effect Effects 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 73
- 230000001472 cytotoxic effect Effects 0.000 claims description 36
- 231100000433 cytotoxic Toxicity 0.000 claims description 35
- -1 citarabine Chemical compound 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 14
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 238000001727 in vivo Methods 0.000 claims description 8
- 239000002243 precursor Substances 0.000 claims description 8
- 229940104302 cytosine Drugs 0.000 claims description 7
- 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 description 6
- XQSPYNMVSIKCOC-NTSWFWBYSA-N Emtricitabine Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1O[C@@H](CO)SC1 XQSPYNMVSIKCOC-NTSWFWBYSA-N 0.000 claims description 6
- 230000000340 anti-metabolite Effects 0.000 claims description 6
- 229940100197 antimetabolite Drugs 0.000 claims description 6
- 239000002256 antimetabolite Substances 0.000 claims description 6
- 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 description 6
- 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 description 6
- 229960005277 gemcitabine Drugs 0.000 claims description 6
- 229910019142 PO4 Inorganic materials 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 5
- 239000010452 phosphate Substances 0.000 claims description 5
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- 229960002555 zidovudine Drugs 0.000 claims description 5
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 claims description 4
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 claims description 4
- 229960004150 aciclovir Drugs 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000002777 nucleoside Substances 0.000 claims description 4
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims description 4
- XSSYCIGJYCVRRK-RQJHMYQMSA-N (-)-carbovir Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1C[C@H](CO)C=C1 XSSYCIGJYCVRRK-RQJHMYQMSA-N 0.000 claims description 3
- QOXJRLADYHZRGC-SHYZEUOFSA-N 1-[(2r,3r,5s)-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione Chemical compound O1[C@H](CO)C[C@@H](O)[C@@H]1N1C(=O)NC(=O)C=C1 QOXJRLADYHZRGC-SHYZEUOFSA-N 0.000 claims description 3
- PFCLMNDDPTZJHQ-XLPZGREQSA-N 2-amino-7-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1h-pyrrolo[2,3-d]pyrimidin-4-one Chemical compound C1=CC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PFCLMNDDPTZJHQ-XLPZGREQSA-N 0.000 claims description 3
- OCLZPNCLRLDXJC-NTSWFWBYSA-N 2-amino-9-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1CC[C@@H](CO)O1 OCLZPNCLRLDXJC-NTSWFWBYSA-N 0.000 claims description 3
- CBOKZNLSFMZJJA-PEBGCTIMSA-N 3-Deazauridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)C=C(O)C=C1 CBOKZNLSFMZJJA-PEBGCTIMSA-N 0.000 claims description 3
- AOVVOPPTVPIDKZ-UHFFFAOYSA-N 4-amino-1-(1,3-dihydroxypropan-2-yloxymethyl)pyrimidin-2-one Chemical compound NC=1C=CN(COC(CO)CO)C(=O)N=1 AOVVOPPTVPIDKZ-UHFFFAOYSA-N 0.000 claims description 3
- AIXRWWZYXZZWTM-ZETCQYMHSA-N 4-amino-1-[(1s)-3-hydroxy-1-methoxypropyl]pyrimidin-2-one Chemical compound OCC[C@H](OC)N1C=CC(N)=NC1=O AIXRWWZYXZZWTM-ZETCQYMHSA-N 0.000 claims description 3
- HSBKFSPNDWWPSL-CAHLUQPWSA-N 4-amino-5-fluoro-1-[(2r,5s)-5-(hydroxymethyl)-2,5-dihydrofuran-2-yl]pyrimidin-2-one Chemical compound C1=C(F)C(N)=NC(=O)N1[C@H]1C=C[C@@H](CO)O1 HSBKFSPNDWWPSL-CAHLUQPWSA-N 0.000 claims description 3
- CKZJTNZSBMVFSU-UBKIQSJTSA-N 4-amino-5-hydroxy-1-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound C1=C(O)C(N)=NC(=O)N1[C@@H]1O[C@H](CO)[C@@H](O)C1 CKZJTNZSBMVFSU-UBKIQSJTSA-N 0.000 claims description 3
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 claims description 3
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 claims description 3
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 3
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 claims description 3
- CKZJTNZSBMVFSU-UHFFFAOYSA-N 5-hydroxydeoxycytidine Natural products C1=C(O)C(N)=NC(=O)N1C1OC(CO)C(O)C1 CKZJTNZSBMVFSU-UHFFFAOYSA-N 0.000 claims description 3
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 claims description 3
- OGHAROSJZRTIOK-KQYNXXCUSA-O 7-methylguanosine Chemical compound C1=2N=C(N)NC(=O)C=2[N+](C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OGHAROSJZRTIOK-KQYNXXCUSA-O 0.000 claims description 3
- 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 description 3
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims description 3
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 claims description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 3
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 claims description 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 description 3
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 claims description 3
- 229960001997 adefovir Drugs 0.000 claims description 3
- WOZSCQDILHKSGG-UHFFFAOYSA-N adefovir depivoxil Chemical compound N1=CN=C2N(CCOCP(=O)(OCOC(=O)C(C)(C)C)OCOC(=O)C(C)(C)C)C=NC2=C1N WOZSCQDILHKSGG-UHFFFAOYSA-N 0.000 claims description 3
- 229960002756 azacitidine Drugs 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229960002436 cladribine Drugs 0.000 claims description 3
- 229960000684 cytarabine Drugs 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 229960000366 emtricitabine Drugs 0.000 claims description 3
- 229950011487 enocitabine Drugs 0.000 claims description 3
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 claims description 3
- 229960000390 fludarabine Drugs 0.000 claims description 3
- 229960005304 fludarabine phosphate Drugs 0.000 claims description 3
- 229960002949 fluorouracil Drugs 0.000 claims description 3
- 229960002963 ganciclovir Drugs 0.000 claims description 3
- 229960004716 idoxuridine Drugs 0.000 claims description 3
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 claims description 3
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- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 claims description 3
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- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 3
- 229960001179 penciclovir Drugs 0.000 claims description 3
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims description 3
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- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 claims description 3
- GFFXZLZWLOBBLO-ASKVSEFXSA-N tezacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(=C/F)/[C@H](O)[C@@H](CO)O1 GFFXZLZWLOBBLO-ASKVSEFXSA-N 0.000 claims description 3
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- 229950003873 triciribine Drugs 0.000 claims description 3
- HOGVTUZUJGHKPL-HTVVRFAVSA-N triciribine Chemical compound C=12C3=NC=NC=1N(C)N=C(N)C2=CN3[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O HOGVTUZUJGHKPL-HTVVRFAVSA-N 0.000 claims description 3
- YKBGVTZYEHREMT-KVQBGUIXSA-N 2'-deoxyguanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 YKBGVTZYEHREMT-KVQBGUIXSA-N 0.000 claims description 2
- DYPDKNUWDNOWPU-JWIUVKOKSA-N 4-amino-1-[(2r,3s,4s,5r)-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidin-2-one Chemical compound C[C@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=C(N)C=C1 DYPDKNUWDNOWPU-JWIUVKOKSA-N 0.000 claims description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 2
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- JFIWEPHGRUDAJN-DYUFWOLASA-N 4-amino-1-[(2r,3r,4s,5r)-4-ethynyl-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@](O)(C#C)[C@@H](CO)O1 JFIWEPHGRUDAJN-DYUFWOLASA-N 0.000 claims 1
- QGYIFQKZZSSUCR-OBXARNEKSA-N [[(2s,4r,5r)-5-(2-amino-6-oxo-3h-purin-9-yl)-4-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C[C@H]1O QGYIFQKZZSSUCR-OBXARNEKSA-N 0.000 claims 1
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- RAJMXAZJKUGYGW-POYBYMJQSA-N 2',3'-dideoxycytidine-5'-monophosphate Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP(O)(O)=O)CC1 RAJMXAZJKUGYGW-POYBYMJQSA-N 0.000 description 2
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- FVSQWXITYSICAK-POYBYMJQSA-N [(2s,5r)-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl phosphono hydrogen phosphate Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)CC1 FVSQWXITYSICAK-POYBYMJQSA-N 0.000 description 2
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- 238000006243 chemical reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
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- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 229920005989 resin Polymers 0.000 description 2
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- HLUIWGCMLRIUNQ-UHFFFAOYSA-N tributylazanium;phosphate Chemical compound [O-]P([O-])([O-])=O.CCCC[NH+](CCCC)CCCC.CCCC[NH+](CCCC)CCCC.CCCC[NH+](CCCC)CCCC HLUIWGCMLRIUNQ-UHFFFAOYSA-N 0.000 description 2
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- UJQBOUAGWGVOTI-XSSZXYGBSA-N 1-[(2r,4s,5r)-4-azido-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@](O)(N=[N+]=[N-])C1 UJQBOUAGWGVOTI-XSSZXYGBSA-N 0.000 description 1
- NIJSNUNKSPLDTO-DJLDLDEBSA-N 2'-deoxytubercidin Chemical compound C1=CC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 NIJSNUNKSPLDTO-DJLDLDEBSA-N 0.000 description 1
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 description 1
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- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- 101000655352 Homo sapiens Telomerase reverse transcriptase Proteins 0.000 description 1
- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010081734 Ribonucleoproteins Proteins 0.000 description 1
- 102000004389 Ribonucleoproteins Human genes 0.000 description 1
- LBEVDDGVSNMSON-ZQFJPEKXSA-N [(2r,3s,5r)-3-azido-3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl phosphate;triethylazanium Chemical compound CC[NH+](CC)CC.CC[NH+](CC)CC.O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP([O-])([O-])=O)[C@](O)(N=[N+]=[N-])C1 LBEVDDGVSNMSON-ZQFJPEKXSA-N 0.000 description 1
- OIFWQOKDSPDILA-XLPZGREQSA-N [(2s,3s,5r)-3-azido-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl dihydrogen phosphate Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](N=[N+]=[N-])C1 OIFWQOKDSPDILA-XLPZGREQSA-N 0.000 description 1
- GAYOHXAVXAOIDX-WQPQHRBMSA-N [[(2S,5R)-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-oxidophosphoryl] phosphate triethylazanium Chemical compound CC[NH+](CC)CC.CC[NH+](CC)CC.CC[NH+](CC)CC.O=C1N=C(N)C=CN1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])([O-])=O)CC1 GAYOHXAVXAOIDX-WQPQHRBMSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 208000037844 advanced solid tumor Diseases 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
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- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003903 antiretrovirus agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 125000006487 butyl benzyl group Chemical group 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
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- SUYVUBYJARFZHO-RRKCRQDMSA-N dATP Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 SUYVUBYJARFZHO-RRKCRQDMSA-N 0.000 description 1
- HAAZLUGHYHWQIW-KVQBGUIXSA-N dGTP Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O1 HAAZLUGHYHWQIW-KVQBGUIXSA-N 0.000 description 1
- NHVNXKFIZYSCEB-XLPZGREQSA-N dTTP Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)C1 NHVNXKFIZYSCEB-XLPZGREQSA-N 0.000 description 1
- KHWCHTKSEGGWEX-UHFFFAOYSA-N deoxyadenylic acid Natural products C1=NC=2C(N)=NC=NC=2N1C1CC(O)C(COP(O)(O)=O)O1 KHWCHTKSEGGWEX-UHFFFAOYSA-N 0.000 description 1
- 238000011038 discontinuous diafiltration by volume reduction Methods 0.000 description 1
- AGSQMPPRYZYDFV-ZJWYQBPBSA-L disodium;[(2r,3s,5r)-3-hydroxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methyl phosphate Chemical compound [Na+].[Na+].O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](COP([O-])([O-])=O)[C@@H](O)C1 AGSQMPPRYZYDFV-ZJWYQBPBSA-L 0.000 description 1
- CTPAMSRBXKGZCJ-FVALZTRZSA-L disodium;[(2r,3s,5r)-5-(2-amino-6-oxo-3h-purin-9-yl)-3-hydroxyoxolan-2-yl]methyl phosphate Chemical compound [Na+].[Na+].C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](COP([O-])([O-])=O)O1 CTPAMSRBXKGZCJ-FVALZTRZSA-L 0.000 description 1
- SNYHHRDGEJPLGT-OJSHLMAWSA-L disodium;[(2r,3s,5r)-5-(6-aminopurin-9-yl)-3-hydroxyoxolan-2-yl]methyl phosphate Chemical compound [Na+].[Na+].C1=NC=2C(N)=NC=NC=2N1[C@H]1C[C@H](O)[C@@H](COP([O-])([O-])=O)O1 SNYHHRDGEJPLGT-OJSHLMAWSA-L 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000009088 enzymatic function Effects 0.000 description 1
- 230000007247 enzymatic mechanism Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- NCGWKCHAJOUDHQ-UHFFFAOYSA-N n,n-diethylethanamine;formic acid Chemical compound OC=O.OC=O.CCN(CC)CC NCGWKCHAJOUDHQ-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000010309 neoplastic transformation Effects 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
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- 125000003729 nucleotide group Chemical group 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical group C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- 239000010414 supernatant solution Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
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- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
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- 125000003944 tolyl group Chemical group 0.000 description 1
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- 229960000523 zalcitabine Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7115—Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Enzymes And Modification Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000173A ITFI20040173A1 (it) | 2004-08-03 | 2004-08-03 | Profarmaci attivati da dna polimerasi dipendenti da rna |
| ITFI2004A000173 | 2004-08-03 | ||
| PCT/EP2005/053765 WO2006013203A2 (en) | 2004-08-03 | 2005-08-02 | Prodrugs activated by rna-dependent dna-polymerases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2575520A1 true CA2575520A1 (en) | 2006-02-09 |
Family
ID=35589591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002575520A Abandoned CA2575520A1 (en) | 2004-08-03 | 2005-08-02 | Prodrugs activated by rna-dependent dna-polymerases |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US8110676B2 (enExample) |
| EP (1) | EP1778254A2 (enExample) |
| JP (1) | JP2008509110A (enExample) |
| CN (1) | CN101031308A (enExample) |
| AU (1) | AU2005268775A1 (enExample) |
| CA (1) | CA2575520A1 (enExample) |
| IT (1) | ITFI20040173A1 (enExample) |
| WO (1) | WO2006013203A2 (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB0625283D0 (en) | 2006-12-19 | 2007-01-24 | Cyclacel Ltd | Combination |
| WO2009114325A2 (en) * | 2008-03-03 | 2009-09-17 | Tosk, Incorporated | Methotrexate adjuvants to reduce toxicity and methods for using the same |
| CA2857490C (en) | 2011-12-22 | 2020-03-31 | Geron Corporation | Guanine analogs as telomerase substrates and telomere length affectors |
| CN107312039B (zh) | 2012-08-30 | 2019-06-25 | 江苏豪森药业集团有限公司 | 一种替诺福韦前药的制备方法 |
| WO2017180309A1 (en) * | 2016-04-12 | 2017-10-19 | The Board Of Trustees Of The Leland Stanford Junior University | Direct activity assays and compositions for nucleotide pool sanitizing enzymes |
| EP4377326A1 (en) * | 2021-07-30 | 2024-06-05 | CureVac SE | Cap analogs having an acyclic linker to the guanine derivative nucleobase |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR880000094B1 (ko) * | 1984-12-07 | 1988-02-23 | 보령제약 주식회사 | 뉴클레오시드 유도체의 제조방법 |
| JPH0920792A (ja) * | 1995-07-11 | 1997-01-21 | Soyaku Gijutsu Kenkyusho:Kk | ヌクレオチドダイマー |
| RU2004128943A (ru) * | 2002-02-28 | 2005-04-20 | Байота, Инк. (Us) | Средства, имитирующие нуклеотиды, и их пролекарственные формы |
| AU2004206820B2 (en) | 2003-01-16 | 2010-06-10 | Idera Pharmaceuticals, Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by utilizing modified immunostimulatory dinucleotides |
-
2004
- 2004-08-03 IT IT000173A patent/ITFI20040173A1/it unknown
-
2005
- 2005-08-02 WO PCT/EP2005/053765 patent/WO2006013203A2/en not_active Ceased
- 2005-08-02 EP EP05779043A patent/EP1778254A2/en not_active Withdrawn
- 2005-08-02 CN CNA2005800260597A patent/CN101031308A/zh active Pending
- 2005-08-02 JP JP2007524340A patent/JP2008509110A/ja active Pending
- 2005-08-02 CA CA002575520A patent/CA2575520A1/en not_active Abandoned
- 2005-08-02 AU AU2005268775A patent/AU2005268775A1/en not_active Abandoned
- 2005-08-02 US US11/659,269 patent/US8110676B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| WO2006013203A2 (en) | 2006-02-09 |
| EP1778254A2 (en) | 2007-05-02 |
| WO2006013203A3 (en) | 2006-07-27 |
| US20080300215A1 (en) | 2008-12-04 |
| ITFI20040173A1 (it) | 2004-11-03 |
| JP2008509110A (ja) | 2008-03-27 |
| CN101031308A (zh) | 2007-09-05 |
| AU2005268775A1 (en) | 2006-02-09 |
| US8110676B2 (en) | 2012-02-07 |
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