JP7173613B2 - 多標的ヌクレオシド誘導体 - Google Patents
多標的ヌクレオシド誘導体 Download PDFInfo
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- JP7173613B2 JP7173613B2 JP2020508974A JP2020508974A JP7173613B2 JP 7173613 B2 JP7173613 B2 JP 7173613B2 JP 2020508974 A JP2020508974 A JP 2020508974A JP 2020508974 A JP2020508974 A JP 2020508974A JP 7173613 B2 JP7173613 B2 JP 7173613B2
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- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
-
- 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
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
-
- 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
-
- 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
Description
(i)酵素チミジル酸シンターゼ(すべてのフルオロピリミジン)
(ii)FUとウラシルの誤取り込みによる核酸DNA(フロクスウリジンとカペシタビン)。
(iii)FUの誤取り込みによる核酸RNA(テガフール、ドキシフルリジンおよびカペシタビン、フロクスウリジンによるよりも程度は小さい)。
この実施例は、3',5'-Di-O-ベンゾイル-2'-デオキシ-2',2',5-トリフルオロシチジン(4)の合成の説明を提供する。
この実施例は、2'-デオキシ-2',2',5-トリフルオロシチジン(5)の合成の説明を提供する。
この実施例は、2'-デオキシ-2',2',5-トリフルオロシチジン塩酸塩(5.HCl)の合成の説明を提供する。
この実施例は、N4-ペンチルオキシカルボニル-2'-デオキシ-2',2',5-トリフルオロシチジン(6a)((ペンチル(1-((2R,4R,5R)-3,3-ジフルオロ-4-ヒドロキシ-5-(ヒドロキシメチル)テトラヒドロフラン-2-イル)-5-フルオロ-2-オキソ-1,2-ジヒドロピリミジン-4-イル)カルバメート))の合成の説明を提供する。
この実施例は、構造‐活性関係の説明を提供する。
部分2:5-フルオロシトシンベースのN4位上のプロドラッグ修飾置換基であり、これは、肝臓カルボキシルエステラーゼCES1およびCES2による代謝活性化のために式Iの化合物を主に肝臓に導き、それによって、フルオロピリミジンの特徴的な毒性副作用である胃腸毒性から保護する;
部分3:2'-デオキシリボース糖の2'-位のジェミナルジフルオロ置換基は、リボヌクレオチドレダクターゼおよびDNAポリメラーゼαの阻害に必須である;
部分4:2',2'-ジフルオロ-2'-デオキシリボース糖の5'-OH基上のプロドラッグ修飾置換基であり、式Iの化合物の完全な5'-一リン酸生成を細胞内に送達することを可能にすることができる;Pが三リン酸である場合、対応する代謝産物はDNAポリメラーゼの基質として働くことができ、DNA中への誤取り込みを引き起こすことができる;
部分5:溶解性および透過性を調節する加水分解性3'-OH保護基であり、酵素触媒加水分解によって除去される。
この実施例は、F3dUMP代謝産物によるチミジル酸シンターゼ(TS)の不活性化の分子メカニズムの説明を提供する。
この実施例は、F3dCDP代謝産物によるリボヌクレオチドレダクターゼ(RR)の不活性化の分子メカニズムについての説明を提供する。
この実施例は、DNAに組み込まれたF3dCMP代謝産物によるDNA(シトシン-5)-メチルトランスフェラーゼ(MTase)の不活性化の分子メカニズムの説明を提供する。
この実施例は、N4-アルキルカルバメートプロドラッグ部分の代謝活性化のメカニズムの説明を提供する。
本実施例は、2',2'-ジフルオロ-2'-デオキシリボース部分の5'-位置におけるアミノ酸エステルホスホロジアミデートプロドラッグ(プロドラッグヌクレオチド)部分の代謝活性化のメカニズムの説明を提供する。
Claims (12)
- 前記R"が、一リン酸エステル、二リン酸エステル、または三リン酸エステルであることを特徴とする請求項1に記載の化合物。
- 請求項1の化合物と、薬学的に許容されるキャリアを含むことを特徴とする組成物。
- 前記の個体が、ヒトまたは非ヒト哺乳動物であることを特徴とする請求項6に記載の医薬組成物。
- 前記の癌が、腎臓腺癌、急性骨髄性白血病、結腸癌、非小細胞肺癌、転移性悪性黒色腫、乳腺癌、膵臓腺癌、及び卵巣癌からなるグループより選ばれたものであることを特徴とする請求項6に記載の医薬組成物。
- 癌細胞におけるDNA合成が阻害されることを特徴とする請求項6に記載の医薬組成物。
- リボヌクレオチドレダクターゼ、DNAポリメラーゼα、チミジル酸シンターゼ、DNA(シトシン-5)-メチルトランスフェラーゼ、またはそれらの組み合わせが阻害されることを特徴とする請求項6に記載の医薬組成物。
- 前記組成物が、DNAへの類似体誤取り込みを引き起こし、DNAの構造および機能の変化を生じさせ、癌細胞の死をもたらすことを特徴とする請求項6に記載の医薬組成物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762490212P | 2017-04-26 | 2017-04-26 | |
US62/490,212 | 2017-04-26 | ||
PCT/US2018/029631 WO2018200859A1 (en) | 2017-04-26 | 2018-04-26 | Multitargeted nucleoside derivatives |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2020518657A JP2020518657A (ja) | 2020-06-25 |
JP2020518657A5 JP2020518657A5 (ja) | 2021-06-10 |
JP7173613B2 true JP7173613B2 (ja) | 2022-11-16 |
Family
ID=63918748
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020508974A Active JP7173613B2 (ja) | 2017-04-26 | 2018-04-26 | 多標的ヌクレオシド誘導体 |
Country Status (7)
Country | Link |
---|---|
US (1) | US10751358B2 (ja) |
EP (1) | EP3618837A4 (ja) |
JP (1) | JP7173613B2 (ja) |
CN (1) | CN110831605A (ja) |
BR (1) | BR112019022470A2 (ja) |
CA (1) | CA3061621A1 (ja) |
WO (1) | WO2018200859A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023089617A1 (en) * | 2021-11-21 | 2023-05-25 | Biosight Ltd. | Cytarabine-amino acid based prodrug for the treatment of cancer |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006111058A1 (en) | 2005-04-18 | 2006-10-26 | Chengdu Zhengkai Biotech Co. Ltd. | N4- (substituted oxycarbonyl)-2’,2’-difluoro-2’-deoxycytidines and uses thereof |
JP2011503084A (ja) | 2007-11-07 | 2011-01-27 | シェーリング コーポレイション | 新規の細胞周期チェックポイント調節剤およびこれらの調節剤とチェックポイント阻害剤との併用 |
WO2016078397A1 (zh) | 2014-11-17 | 2016-05-26 | 常州方圆制药有限公司 | 新型胞苷衍生物及其应用 |
Family Cites Families (12)
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 |
CA1327358C (en) | 1987-11-17 | 1994-03-01 | Morio Fujiu | Fluoro cytidine derivatives |
CA2004695C (en) | 1988-12-12 | 1999-08-10 | Rosanne Bonjouklian | Phospholipid nucleosides |
UA41261C2 (uk) | 1992-06-22 | 2001-09-17 | Елі Ліллі Енд Компані | Спосіб одержання збагачених бета-аномером нуклеозидів |
EP1311524A2 (en) * | 2000-08-09 | 2003-05-21 | Kolon Industries, Inc. | 5'-deoxy-n-(substituted oxycarbonyl)-5-fluorocytosine and derivatives thereof, method of preparing same, and anticancer composition comprising same as active ingredients |
WO2003068162A2 (en) * | 2002-02-14 | 2003-08-21 | Pharmasset Ltd. | Modified fluorinated nucleoside analogues |
GB0421294D0 (en) * | 2004-09-24 | 2004-10-27 | Angiogene Pharm Ltd | Bioreductively-activated prodrugs |
DE602005019626D1 (de) | 2005-03-04 | 2010-04-08 | Fresenius Kabi Oncology Ltd | Zwischenprodukt und verfahren zur herstellung von an beta-anomeren angereicherten 2'-desoxy,2',2'-difluor-d-ribufuranosylnukleosiden |
RU2630577C2 (ru) * | 2008-12-04 | 2017-09-11 | Чунси ЮЙ | Композиции интенсивного проникновения и их применение |
AU2013345007B2 (en) | 2012-11-13 | 2018-08-30 | BoYen Therapeutics, Inc. | Gemcitabine prodrugs and uses thereof |
WO2016078160A1 (zh) * | 2014-11-17 | 2016-05-26 | 常州方圆制药有限公司 | 胞苷衍生物及其应用 |
CN107709344B (zh) * | 2015-05-01 | 2022-07-15 | 共晶制药股份有限公司 | 用于治疗黄病毒科病毒和癌症的核苷类似物 |
-
2018
- 2018-04-26 WO PCT/US2018/029631 patent/WO2018200859A1/en unknown
- 2018-04-26 CN CN201880042937.1A patent/CN110831605A/zh active Pending
- 2018-04-26 BR BR112019022470-0A patent/BR112019022470A2/pt unknown
- 2018-04-26 JP JP2020508974A patent/JP7173613B2/ja active Active
- 2018-04-26 CA CA3061621A patent/CA3061621A1/en active Pending
- 2018-04-26 EP EP18791858.6A patent/EP3618837A4/en not_active Withdrawn
-
2019
- 2019-10-25 US US16/664,522 patent/US10751358B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006111058A1 (en) | 2005-04-18 | 2006-10-26 | Chengdu Zhengkai Biotech Co. Ltd. | N4- (substituted oxycarbonyl)-2’,2’-difluoro-2’-deoxycytidines and uses thereof |
JP2011503084A (ja) | 2007-11-07 | 2011-01-27 | シェーリング コーポレイション | 新規の細胞周期チェックポイント調節剤およびこれらの調節剤とチェックポイント阻害剤との併用 |
WO2016078397A1 (zh) | 2014-11-17 | 2016-05-26 | 常州方圆制药有限公司 | 新型胞苷衍生物及其应用 |
Non-Patent Citations (1)
Title |
---|
J. Med. Chem.,1997年,Vol.40,p.3635-3644 |
Also Published As
Publication number | Publication date |
---|---|
EP3618837A4 (en) | 2020-11-04 |
CA3061621A1 (en) | 2018-11-01 |
JP2020518657A (ja) | 2020-06-25 |
US20200054661A1 (en) | 2020-02-20 |
US10751358B2 (en) | 2020-08-25 |
EP3618837A1 (en) | 2020-03-11 |
CN110831605A (zh) | 2020-02-21 |
BR112019022470A2 (pt) | 2020-05-12 |
WO2018200859A1 (en) | 2018-11-01 |
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