HRP20211812T1 - Dijastereoselektivna sinteza derivata fosfata i prolijeka gemcitabina nuc-1031 - Google Patents
Dijastereoselektivna sinteza derivata fosfata i prolijeka gemcitabina nuc-1031 Download PDFInfo
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- HRP20211812T1 HRP20211812T1 HRP20211812TT HRP20211812T HRP20211812T1 HR P20211812 T1 HRP20211812 T1 HR P20211812T1 HR P20211812T T HRP20211812T T HR P20211812TT HR P20211812 T HRP20211812 T HR P20211812T HR P20211812 T1 HRP20211812 T1 HR P20211812T1
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- 230000015572 biosynthetic process Effects 0.000 title claims 2
- NHTKGYOMICWFQZ-KKQYNPQSSA-N benzyl (2s)-2-[[[(2r,3r,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-4,4-difluoro-3-hydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate Chemical compound N1([C@@H]2O[C@@H]([C@H](C2(F)F)O)COP(=O)(N[C@@H](C)C(=O)OCC=2C=CC=CC=2)OC=2C=CC=CC=2)C=CC(N)=NC1=O NHTKGYOMICWFQZ-KKQYNPQSSA-N 0.000 title 1
- 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 title 1
- 229960005277 gemcitabine Drugs 0.000 title 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 title 1
- 229940002612 prodrug Drugs 0.000 title 1
- 239000000651 prodrug Substances 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims 15
- 239000000203 mixture Substances 0.000 claims 11
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims 10
- 239000002585 base Substances 0.000 claims 7
- 150000001412 amines Chemical class 0.000 claims 5
- 150000001875 compounds Chemical class 0.000 claims 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 3
- -1 cyclic amine Chemical class 0.000 claims 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 3
- 150000007529 inorganic bases Chemical class 0.000 claims 3
- 125000006239 protecting group Chemical group 0.000 claims 3
- 239000002904 solvent Substances 0.000 claims 3
- 239000004215 Carbon black (E152) Substances 0.000 claims 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 229910019142 PO4 Inorganic materials 0.000 claims 2
- 229910052783 alkali metal Inorganic materials 0.000 claims 2
- 229930195733 hydrocarbon Natural products 0.000 claims 2
- 150000002430 hydrocarbons Chemical class 0.000 claims 2
- 238000002156 mixing Methods 0.000 claims 2
- 150000007530 organic bases Chemical class 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims 2
- 239000010452 phosphate Substances 0.000 claims 2
- 239000007818 Grignard reagent Substances 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims 1
- 150000008041 alkali metal carbonates Chemical class 0.000 claims 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 150000001340 alkali metals Chemical class 0.000 claims 1
- 125000006575 electron-withdrawing group Chemical group 0.000 claims 1
- 150000004795 grignard reagents Chemical class 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 claims 1
- 239000003495 polar organic solvent Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
- 150000003222 pyridines Chemical class 0.000 claims 1
- 239000000725 suspension Substances 0.000 claims 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000005270 trialkylamine group Chemical class 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/02—Phosphorylation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/222—Amides of phosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/22—Amides of acids of phosphorus
- C07F9/24—Esteramides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Claims (17)
1. Postupak za dijastereoizomerno obogaćivanje spoja formule II;
[image]
naznačen time što R1 predstavlja grupu koja povlači elektrone i a je cijeli broj od 1 do 5,
pri čemu postupak sadrži:
a) suspendiranje ili rastvaranje R-dijastereoizomera spoja formule II; ili mješavine (R)- i (S)-dijastereoizomera spoja formule II u otapalu (S2);
b) tretiranje otopine ili suspenzije sa organskom bazom amina ili neorganskom bazom (B2) da bi se dobio (S)-dijastereoizomer u značajno dijastereomerno čistom obliku; i
c) izoliranje (S)-dijastereoizomera formule II.
2. Postupak prema zahtjevu 1, naznačen time što postupak dalje sadrži
formiranje spoja formule II kao mješavine (R)- i (S)-dijastereoizomera; i
pri čemu korak a) sadrži suspendiranje ili rastvaranje mješavine (R)- i (S)-dijastereoizomera spoja formule II u otapalu (S2).
3. Postupak prema zahtjevu 1 ili zahtjevu 2, naznačen time što B2 je organska baza amina.
4. Postupak prema zahtjevu 3, naznačen time što organska baza amina je organska primarna, sekundarna, tercijarna ili ciklična baza amina; poželjno pri čemu, organska baza amina je trietilamin.
5. Postupak prema zahtjevu 3, naznačen time što organska baza amina je N-alkilimidazol, imidazol, izborno supstituirani piridin ili trialkilamin.
6. Postupak prema zahtjevu 1 ili zahtjevu 2, naznačen time što B2 je neorganska baza; poželjno pri čemu, neorganska baza je hidroksid alkalnog metala, karbonat alkalnog metala, alkoksid alkalnog metala ili ariloksid alkalnog metala.
7. Postupak prema bilo kojem od zahtjeva 1 do 6, naznačen time što S2 je ugljikovodik ili mješavina koja sadrži ugljikovodik.
8. Postupak prema zahtjevu 7, naznačen time što S2 je heksan ili heptan; ili pri čemu, S2 je mješavina heksana ili heptana i polarnog organskog otapala, pri čemu mješavina sadrži preko 50 zapreminskih % heksana ili heptana; poželjno pri čemu S2 je mješavina heptana ili heksana i etil acetata, pri čemu mješavina sadrži preko 50 zapreminskih % heptana ili heksana.
9. Postupak prema bilo kojem od zahtjeva 1 do 8, naznačen time što korak b) sadrži miješanje mješavine spoja formule II i baze B2 tokom 6 h ili duže; i/ili, što korak b) sadrži miješanje mješavine spoja formule II i baze B2 na temperaturi od 0 do 50°C.
10. Postupak prema bilo kojem od zahtjeva 1 do 9, naznačen time što spoj formule II je spoj izabran od:
[image]
[image]
[image]
[image]
[image]
*predstavlja kiralni centar
11. Postupak prema bilo kojem od zahtjeva 1 do 9, naznačen time što spoj formule II je:
[image]
12. Postupak prema bilo kojem od zahtjeva 1 do 9, naznačen time što spoj formule II je:
[image]
13. Postupak prema bilo kojem zahtjevu 1 do 12, naznačen time što postupak je postupak za pripremu (S)-dijastereoizomera gemcitabin-[fenil (benzoksi-L-alaninil)] fosfata (formula I) u značajno dijastereoizomerno čistom obliku:
[image]
pri čemu postupak dalje sadrži korak d) i izborno korak e):
d) reagiranje spoja (S)-dijastereoizomera formule II dobivenog u koraku c) sa spojem formule III u prisustvu baze (B1) da bi se dobio spoj formule IV u značajno dijastereomerno čistom obliku; pri čemu P1, P2 i P3 neovisno predstavljaju vodik ili zaštitnu grupu; i gdje je spoj formule II u značajno dijastereomerno čistom obliku:
[image]
; i
e) gdje bilo koji ili više od P1, P2 i P3 su zaštitne grupe, izborno uklanjajući zaštitne grupe P1, P2 i P3 iz spoja formule IV da bi se dobio (S)-gemcitabin-[fenil (benzoksi-L-alaninil)] fosfat u značajno dijastereomerno čistom obliku.
14. Postupak prema zahtjevu 13, naznačen time što P1 je -C(O)OC1-C6-alkil ili izborno supstituirani -C(O)OCH2-aril; poželjno pri čemu P1 je -C(O)OtBu; a poželjno i dalje gdje se korak e) postiže reakcijom proizvoda iz koraka d) sa mješavinom C1-C4-alkohola i vode.
15. Postupak prema bilo kojem od zahtjeva 13 do 14, naznačen time što P2 je H; i/ili pri čemu P3 je H.
16. Postupak prema bilo kojem od zahtjeva 13 do 15, naznačen time što B1 je Grignardov reagens; poželjno pri čemu B1 je tBuMgCl.
17. Postupak prema bilo kojem od zahtjeva 13 do 16, naznačen time što se korak d) izvodi u etarskom otapalu; poželjno pri čemu se korak d) izvodi u THF.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN6635CH2015 | 2015-12-11 | ||
| GBGB1602185.9A GB201602185D0 (en) | 2016-02-08 | 2016-02-08 | Diastereoselective synthesis of phosphate derivatives |
| PCT/GB2016/053875 WO2017098252A1 (en) | 2015-12-11 | 2016-12-09 | Diastereoselective synthesis of phosphate derivatives and of the gemcitabine prodrug nuc-1031 |
| EP16812797.5A EP3386998B1 (en) | 2015-12-11 | 2016-12-09 | Diastereoselective synthesis of phosphate derivatives and of the gemcitabine prodrug nuc-1031 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20211812T1 true HRP20211812T1 (hr) | 2022-03-04 |
Family
ID=57570086
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20211812TT HRP20211812T1 (hr) | 2015-12-11 | 2016-12-09 | Dijastereoselektivna sinteza derivata fosfata i prolijeka gemcitabina nuc-1031 |
Country Status (28)
| Country | Link |
|---|---|
| US (2) | US10774104B2 (hr) |
| EP (2) | EP3386998B1 (hr) |
| JP (1) | JP6889180B2 (hr) |
| KR (1) | KR20180101370A (hr) |
| CN (2) | CN108779136B (hr) |
| AU (1) | AU2016367237B2 (hr) |
| BR (1) | BR112018011695A2 (hr) |
| CA (1) | CA3007347C (hr) |
| CL (1) | CL2018001541A1 (hr) |
| CY (1) | CY1124809T1 (hr) |
| EA (1) | EA038658B1 (hr) |
| ES (1) | ES2898890T3 (hr) |
| HR (1) | HRP20211812T1 (hr) |
| HU (1) | HUE059026T2 (hr) |
| IL (1) | IL259887B (hr) |
| LT (1) | LT3386998T (hr) |
| MA (1) | MA43405B1 (hr) |
| MD (1) | MD3386998T2 (hr) |
| MX (1) | MX2018007083A (hr) |
| MY (1) | MY196772A (hr) |
| PH (1) | PH12018501224A1 (hr) |
| PL (1) | PL3386998T3 (hr) |
| PT (1) | PT3386998T (hr) |
| RS (1) | RS62593B1 (hr) |
| SA (1) | SA518391776B1 (hr) |
| SG (1) | SG11201804774YA (hr) |
| SI (1) | SI3386998T1 (hr) |
| WO (1) | WO2017098252A1 (hr) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0317009D0 (en) | 2003-07-21 | 2003-08-27 | Univ Cardiff | Chemical compounds |
| MY176133A (en) | 2012-11-16 | 2020-07-24 | Nucana Biomed Ltd | Process for preparing nucleoside prodrugs |
| EP3160978B1 (en) | 2014-06-25 | 2020-07-29 | NuCana plc | Gemcitabine prodrugs |
| MX2016015629A (es) | 2014-06-25 | 2017-08-02 | Nucana Biomed Ltd | Formulacion que comprende un profarmaco de gemcitabina. |
| GB201417644D0 (en) | 2014-10-06 | 2014-11-19 | Nucana Biomed Ltd | Method of separating phosphate diastereoisomers |
| EA037248B1 (ru) | 2015-10-05 | 2021-02-26 | НУКАНА ПиЭлСи | Применение гемцитабин[фенил-бензокси-l-аланинил]фосфата в комбинации с карбоплатином |
| EP3386998B1 (en) | 2015-12-11 | 2021-11-10 | NuCana plc | Diastereoselective synthesis of phosphate derivatives and of the gemcitabine prodrug nuc-1031 |
| GB201522771D0 (en) | 2015-12-23 | 2016-02-03 | Nucana Biomed Ltd | Crystalline form of a phosphate derivative |
| GB201709471D0 (en) * | 2017-06-14 | 2017-07-26 | Nucana Biomed Ltd | Diastereoselective synthesis of hosphate derivatives |
| CN114644651A (zh) * | 2022-04-13 | 2022-06-21 | 中国人民解放军军事科学院军事医学研究院 | 芳氧基磷酰化氨基酸酯化合物的制备方法 |
Family Cites Families (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4526988A (en) | 1983-03-10 | 1985-07-02 | Eli Lilly And Company | Difluoro antivirals and intermediate therefor |
| GB0317009D0 (en) | 2003-07-21 | 2003-08-27 | Univ Cardiff | Chemical compounds |
| US8618076B2 (en) * | 2009-05-20 | 2013-12-31 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
| TWI576352B (zh) * | 2009-05-20 | 2017-04-01 | 基利法瑪席特有限責任公司 | 核苷磷醯胺 |
| AU2011235112B2 (en) * | 2010-03-31 | 2015-07-09 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
| JP5937073B2 (ja) | 2010-07-19 | 2016-06-22 | ギリード・サイエンシズ・インコーポレーテッド | ジアステレオマーとして純粋なホスホルアミデートプロドラッグの調製方法 |
| AU2011336632B2 (en) | 2010-11-30 | 2015-09-03 | Gilead Pharmasset Llc | Compounds |
| US20130143835A1 (en) * | 2011-12-05 | 2013-06-06 | Medivir Ab | HCV Polymerase Inhibitors |
| CN104640444B (zh) | 2012-06-16 | 2016-12-14 | 河南美泰宝生物制药有限公司 | 双肝脏靶向氨基磷酸酯和氨基膦酸酯前药 |
| MY176133A (en) | 2012-11-16 | 2020-07-24 | Nucana Biomed Ltd | Process for preparing nucleoside prodrugs |
| EP3160978B1 (en) | 2014-06-25 | 2020-07-29 | NuCana plc | Gemcitabine prodrugs |
| MX2016015629A (es) | 2014-06-25 | 2017-08-02 | Nucana Biomed Ltd | Formulacion que comprende un profarmaco de gemcitabina. |
| JP6646663B2 (ja) | 2014-07-22 | 2020-02-14 | ニューカナ バイオメッド リミテッドＮｕｃａｎａ Ｂｉｏｍｅｄ Ｌｉｍｉｔｅｄ | ゲムシタビン−［フェニル（ベンゾキシ−ｌ−アラニニル）］ホスフェートの製造方法リン酸誘導体を製造する方法 |
| CN107074826B (zh) | 2014-08-25 | 2020-05-22 | 美迪维尔公司 | 用于治疗癌症的尿苷的二氧戊环类似物 |
| GB201417644D0 (en) | 2014-10-06 | 2014-11-19 | Nucana Biomed Ltd | Method of separating phosphate diastereoisomers |
| MX2020009154A (es) | 2015-05-14 | 2022-03-08 | NuCana plc | Nuc-1031 (gemcitabina-[fenil-benzoxi-l-alaninil])-fosfato) para usarse en el tratamiento neoadyuvante y adyuvante en pacientes con cáncer. |
| CN106539810B (zh) | 2015-09-16 | 2021-03-09 | 济南高合医疗科技有限公司 | 一种富集了nuc-1031单一异构体的组合物及其制备方法和用途 |
| 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 |
| 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 |
| EA037248B1 (ru) | 2015-10-05 | 2021-02-26 | НУКАНА ПиЭлСи | Применение гемцитабин[фенил-бензокси-l-аланинил]фосфата в комбинации с карбоплатином |
| EP3386998B1 (en) | 2015-12-11 | 2021-11-10 | NuCana plc | Diastereoselective synthesis of phosphate derivatives and of the gemcitabine prodrug nuc-1031 |
| WO2017109444A1 (en) | 2015-12-23 | 2017-06-29 | Nucana Biomed Limited | Combination therapy |
| SG11201805184TA (en) | 2015-12-23 | 2018-07-30 | NuCana plc | Combination therapy |
| GB201522771D0 (en) | 2015-12-23 | 2016-02-03 | Nucana Biomed Ltd | Crystalline form of a phosphate derivative |
| GB201709471D0 (en) | 2017-06-14 | 2017-07-26 | Nucana Biomed Ltd | Diastereoselective synthesis of hosphate derivatives |
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