CA2889717A1 - Pyrimidine nucleotides and their monophosphate prodrugs for treatment of viral infections and cancer - Google Patents
Pyrimidine nucleotides and their monophosphate prodrugs for treatment of viral infections and cancer Download PDFInfo
- Publication number
- CA2889717A1 CA2889717A1 CA2889717A CA2889717A CA2889717A1 CA 2889717 A1 CA2889717 A1 CA 2889717A1 CA 2889717 A CA2889717 A CA 2889717A CA 2889717 A CA2889717 A CA 2889717A CA 2889717 A1 CA2889717 A1 CA 2889717A1
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- Prior art keywords
- alkyl
- cycloalkyl
- substituted
- compound
- aryl
- 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 116
- 239000000651 prodrug Substances 0.000 title claims abstract description 116
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 39
- 201000011510 cancer Diseases 0.000 title claims abstract description 31
- 238000011282 treatment Methods 0.000 title claims description 34
- 150000004712 monophosphates Chemical class 0.000 title abstract description 67
- 208000036142 Viral infection Diseases 0.000 title abstract description 8
- 230000009385 viral infection Effects 0.000 title abstract description 7
- 239000002719 pyrimidine nucleotide Substances 0.000 title 1
- 150000003230 pyrimidines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 265
- 238000000034 method Methods 0.000 claims abstract description 79
- 241000713772 Human immunodeficiency virus 1 Species 0.000 claims abstract description 55
- 239000000203 mixture Substances 0.000 claims abstract description 55
- 241001263478 Norovirus Species 0.000 claims abstract description 49
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- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 241000700588 Human alphaherpesvirus 1 Species 0.000 claims abstract description 23
- 241000725619 Dengue virus Species 0.000 claims abstract description 21
- 241000701074 Human alphaherpesvirus 2 Species 0.000 claims abstract description 21
- 208000003152 Yellow Fever Diseases 0.000 claims abstract description 19
- 241000713340 Human immunodeficiency virus 2 Species 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 232
- -1 C1-C6alkoxy Chemical group 0.000 claims description 160
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 113
- 125000003118 aryl group Chemical group 0.000 claims description 111
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 101
- 125000001072 heteroaryl group Chemical group 0.000 claims description 99
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 91
- 239000003814 drug Substances 0.000 claims description 85
- 125000001424 substituent group Chemical group 0.000 claims description 81
- 241000700605 Viruses Species 0.000 claims description 78
- 125000001153 fluoro group Chemical group F* 0.000 claims description 73
- 235000000346 sugar Nutrition 0.000 claims description 71
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 62
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 60
- 239000003795 chemical substances by application Substances 0.000 claims description 60
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 53
- 125000003545 alkoxy group Chemical group 0.000 claims description 47
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 45
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 claims description 41
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 41
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 38
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 37
- 125000003107 substituted aryl group Chemical group 0.000 claims description 37
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 35
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 34
- 229910052731 fluorine Inorganic materials 0.000 claims description 30
- 229910052801 chlorine Inorganic materials 0.000 claims description 29
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 229910052717 sulfur Inorganic materials 0.000 claims description 27
- 229910052794 bromium Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 229910052740 iodine Inorganic materials 0.000 claims description 25
- 150000002191 fatty alcohols Chemical group 0.000 claims description 23
- 230000035772 mutation Effects 0.000 claims description 22
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- 125000002252 acyl group Chemical group 0.000 claims description 21
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 21
- 125000005842 heteroatom Chemical group 0.000 claims description 20
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- 239000001226 triphosphate Substances 0.000 claims description 20
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- 208000001490 Dengue Diseases 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 235000011178 triphosphate Nutrition 0.000 claims description 18
- 235000011180 diphosphates Nutrition 0.000 claims description 17
- 125000004076 pyridyl group Chemical group 0.000 claims description 17
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 16
- 239000003937 drug carrier Substances 0.000 claims description 16
- 125000000548 ribosyl group Chemical group C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 15
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- 238000002360 preparation method Methods 0.000 claims description 14
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 13
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- XXJGBENTLXFVFI-UHFFFAOYSA-N 1-amino-methylene Chemical compound N[CH2] XXJGBENTLXFVFI-UHFFFAOYSA-N 0.000 claims description 10
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 10
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 claims description 10
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- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 150000002632 lipids Chemical class 0.000 claims description 10
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 229910052711 selenium Inorganic materials 0.000 claims description 9
- 125000004055 thiomethyl group Chemical group [H]SC([H])([H])* 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 8
- 229910052700 potassium Inorganic materials 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 7
- JLXCKKKWUBELSL-UHFFFAOYSA-N diphosphono hydrogen phosphate;pyrimidine Chemical class C1=CN=CN=C1.OP(O)(=O)OP(O)(=O)OP(O)(O)=O JLXCKKKWUBELSL-UHFFFAOYSA-N 0.000 claims description 7
- 150000002148 esters Chemical class 0.000 claims description 7
- 229910052744 lithium Inorganic materials 0.000 claims description 7
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical group C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 6
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004442 acylamino group Chemical group 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- OOFGXDQWDNJDIS-UHFFFAOYSA-N oxathiolane Chemical compound C1COSC1 OOFGXDQWDNJDIS-UHFFFAOYSA-N 0.000 claims description 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 235000012000 cholesterol Nutrition 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 150000003904 phospholipids Chemical class 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000006649 (C2-C20) alkynyl group Chemical group 0.000 claims description 3
- 150000008575 L-amino acids Chemical class 0.000 claims description 3
- 229910003870 O—Li Inorganic materials 0.000 claims description 3
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- 239000000194 fatty acid Substances 0.000 claims description 3
- 150000004665 fatty acids Chemical group 0.000 claims description 3
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 14
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- 125000006823 (C1-C6) acyl group Chemical group 0.000 claims 1
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- Bioinformatics & Cheminformatics (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
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| US201261719696P | 2012-10-29 | 2012-10-29 | |
| US61/719,696 | 2012-10-29 | ||
| US201361763534P | 2013-02-12 | 2013-02-12 | |
| US61/763,534 | 2013-02-12 | ||
| PCT/US2013/067309 WO2014070771A1 (en) | 2012-10-29 | 2013-10-29 | Pyrimidine nucleotides and their monophosphate prodrugs for treatment of viral infections and cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2889717A1 true CA2889717A1 (en) | 2014-05-08 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2889717A Abandoned CA2889717A1 (en) | 2012-10-29 | 2013-10-29 | Pyrimidine nucleotides and their monophosphate prodrugs for treatment of viral infections and cancer |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US9809616B2 (enExample) |
| EP (1) | EP2912050A4 (enExample) |
| JP (1) | JP2015535261A (enExample) |
| KR (1) | KR20150090894A (enExample) |
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| BR (1) | BR112015009636A8 (enExample) |
| CA (1) | CA2889717A1 (enExample) |
| HK (1) | HK1214270A1 (enExample) |
| MX (1) | MX2015005500A (enExample) |
| RU (1) | RU2015119999A (enExample) |
| WO (1) | WO2014070771A1 (enExample) |
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| DK2620428T3 (da) | 2010-09-24 | 2019-07-01 | Wave Life Sciences Ltd | Asymmetrisk hjælpegruppe |
| CN107365339A (zh) | 2011-07-19 | 2017-11-21 | 波涛生命科学有限公司 | 合成官能化核酸的方法 |
| KR102072041B1 (ko) | 2011-12-22 | 2020-01-31 | 앨리오스 바이오파마 인크. | 치환된 뉴클레오사이드, 뉴클레오타이드 및 그의 유사체 |
| USRE48171E1 (en) | 2012-03-21 | 2020-08-25 | Janssen Biopharma, Inc. | Substituted nucleosides, nucleotides and analogs thereof |
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| WO2014010250A1 (en) | 2012-07-13 | 2014-01-16 | Chiralgen, Ltd. | Asymmetric auxiliary group |
| 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 |
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| CN110075291B (zh) * | 2019-02-01 | 2023-01-06 | 广州中医药大学(广州中医药研究院) | 一种单磷酸类酯A缀合Tn抗肿瘤疫苗及其应用 |
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| CN113278041B (zh) * | 2021-07-16 | 2021-10-19 | 南京颐媛生物医学研究院有限公司 | 一种核苷磷酸酯及其合成方法与抗肝炎病毒的制药应用 |
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| CN115819483B (zh) * | 2021-09-17 | 2026-04-28 | 南京知和医药科技有限公司 | 用于治疗癌症的核苷类衍生物及其用途 |
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| WO2024123206A1 (ru) * | 2022-12-08 | 2024-06-13 | федеральное государственное бюджетное учреждение "Национальный исследовательский центр эпидемиологии и микробиологии имени почетного академика Н.Ф. Гамалеи" Министерства здравоохранения Российской Федерации | Способ получения 5',-о-(3-фенилпропионил)-n4-гидроксицитидина |
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-
2013
- 2013-10-29 US US14/066,461 patent/US9809616B2/en active Active
- 2013-10-29 EP EP13851564.8A patent/EP2912050A4/en not_active Withdrawn
- 2013-10-29 BR BR112015009636A patent/BR112015009636A8/pt not_active Application Discontinuation
- 2013-10-29 RU RU2015119999A patent/RU2015119999A/ru not_active Application Discontinuation
- 2013-10-29 MX MX2015005500A patent/MX2015005500A/es unknown
- 2013-10-29 WO PCT/US2013/067309 patent/WO2014070771A1/en not_active Ceased
- 2013-10-29 KR KR1020157014128A patent/KR20150090894A/ko not_active Ceased
- 2013-10-29 JP JP2015539919A patent/JP2015535261A/ja active Pending
- 2013-10-29 CN CN201380068925.3A patent/CN104884462A/zh active Pending
- 2013-10-29 HK HK16102408.4A patent/HK1214270A1/zh unknown
- 2013-10-29 CA CA2889717A patent/CA2889717A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| US20140235566A1 (en) | 2014-08-21 |
| EP2912050A1 (en) | 2015-09-02 |
| MX2015005500A (es) | 2016-02-09 |
| KR20150090894A (ko) | 2015-08-06 |
| WO2014070771A1 (en) | 2014-05-08 |
| RU2015119999A (ru) | 2016-12-20 |
| EP2912050A4 (en) | 2016-09-28 |
| JP2015535261A (ja) | 2015-12-10 |
| HK1214270A1 (zh) | 2016-07-22 |
| US9809616B2 (en) | 2017-11-07 |
| BR112015009636A8 (pt) | 2018-04-17 |
| CN104884462A (zh) | 2015-09-02 |
| BR112015009636A2 (pt) | 2017-12-12 |
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