WO2016155593A1 - 4'-硫代核苷的新型化合物及其制备方法、药物组合物和应用 - Google Patents

4'-硫代核苷的新型化合物及其制备方法、药物组合物和应用 Download PDF

Info

Publication number
WO2016155593A1
WO2016155593A1 PCT/CN2016/077519 CN2016077519W WO2016155593A1 WO 2016155593 A1 WO2016155593 A1 WO 2016155593A1 CN 2016077519 W CN2016077519 W CN 2016077519W WO 2016155593 A1 WO2016155593 A1 WO 2016155593A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
optionally substituted
hydrogen
alkyl
Prior art date
Application number
PCT/CN2016/077519
Other languages
English (en)
French (fr)
Chinese (zh)
Inventor
叶红
刘钢
郁楠
曾宏
赵明亮
卿燕
邓华
李雯佳
李栋宏
苏东海
钟维
李少华
巫循伟
王利春
王晶翼
Original Assignee
四川科伦药物研究院有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 四川科伦药物研究院有限公司 filed Critical 四川科伦药物研究院有限公司
Priority to EA201791535A priority Critical patent/EA034375B1/ru
Priority to CN201680001812.5A priority patent/CN106661077B/zh
Priority to CA2975990A priority patent/CA2975990A1/en
Priority to AU2016240117A priority patent/AU2016240117C1/en
Priority to EP16771348.6A priority patent/EP3279207B1/en
Priority to JP2017541855A priority patent/JP6769000B2/ja
Priority to US15/558,620 priority patent/US10662214B2/en
Publication of WO2016155593A1 publication Critical patent/WO2016155593A1/zh
Priority to HK17105803.7A priority patent/HK1232229A1/zh
Priority to HK18103052.9A priority patent/HK1243424A1/zh
Priority to US16/851,217 priority patent/US20200262860A1/en

Links

Images

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
    • A61K31/7042—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
    • A61K31/70—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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • 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
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • 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
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the present invention relates to novel compounds of 4'-thionucleosides, processes for their preparation, pharmaceutical compositions comprising the same, and uses thereof.
  • the present invention relates to a phosphoramide derivative of a 4'-thionucleoside, a process for the preparation thereof, a pharmaceutical composition comprising the same, and a medicament for preventing or treating a cell proliferation abnormality (for example, a tumor or a cancer and a related disorder) ) or a method of viral infectious disease.
  • Natural nucleosides are glycosides produced by ribose or deoxyribose and a base such as adenine, thymine, guanine, cytosine or uracil, which are important components of DNA and RNA.
  • Synthetic nucleoside analogues are an important class of cancer chemotherapy drugs known as antimetabolites. It mainly functions by inhibiting the enzyme system of tumor cells, thereby inhibiting the synthesis of DNA and RNA. According to WHO statistics, cancer has become one of the most deadly diseases in the world. In addition, cancer cells are generally resistant to drugs, and new anticancer drugs are urgently needed for human health. Therefore, it is an arduous task for the pharmaceutical R&D community to research and develop safe and reliable anticancer drugs from different angles. Treatment with organ-specific nucleoside prodrugs is one of the most promising new treatments.
  • Nucleoside drugs such as gemcitabine, azacytidine, decitabine, cytarabine, fludarabine, cladribine, 6-azide uridine, thiazolidine and clofibrate have been widely used. For the treatment of various cancers. At present, there are many nucleoside drugs in the clinical research stage.
  • Gemcitabine is a pyrimidine nucleoside analogue developed by Eli Lilly and Company. It is an important nucleoside antitumor drug for advanced pancreatic cancer, advanced non-small cell lung cancer, localized or metastatic bladder cancer, and metastatic breast cancer. First-line treatment. Its anti-tumor spectrum is wide, and it has curative effect on many other solid tumors. It is generally desirable to combine gemcitabine with paclitaxel, cisplatin and/or carboplatin. Gemcitabine has poor cell permeability, low bioavailability, and short half-life in cells (between 32 and 94 min), so it must be maintained in large doses (recommended dose of 1000 mg/m 2 ) for continuous intravenous administration.
  • Gemcitabine Blood concentration and toxicity to cancer cells.
  • Gemcitabine is used in large doses, and this dose-limiting toxicity affects clinical efficacy and leads to a range of side effects and safety issues such as leukopenia, transaminase abnormalities, proteinuria and nausea and vomiting.
  • side effects and safety issues such as leukopenia, transaminase abnormalities, proteinuria and nausea and vomiting.
  • gemcitabine also has a lack of tissue specificity, systemic toxic side effects; rapid metabolism in the body, short plasma half-life; tumors are prone to drug resistance; oral effects are poor, generally require intravenous administration, large doses, side effects; Poor drug effect, need to be combined with other anti-cancer drugs and other shortcomings.
  • the oral bioavailability of gemcitabine is poor and generally requires intravenous administration.
  • the poor oral bioavailability is caused by first pass metabolism (see Shipley LA. et al., "Metabolism and disposition of gemcitabine, and oncolytic Deoxycytidine analog, in mice, rats, and dogs", Drug Metabolism & Disposition. 20 (6): 849-55, 1992).
  • gemcitabine when gemcitabine is administered orally, it causes unfavorable limited-dose intestinal damage characterized by when gemcitabine is administered in a single oral dose of 167 mg/kg, 333 mg/kg or 500 mg/kg.
  • gemcitabine is a hydrophilic compound that does not penetrate the cell membrane into the cell by passive diffusion. It requires specific transport proteins to be transported into the tumor cells. Alterations in nucleoside transport activity have been identified as an important cause of gemcitabine resistance.
  • Human equilibrative nucleoside transporters 1, hENT1 are important transporters found to transport gemcitabine into tumor cells. The decrease in sensitivity of intracellular drug accumulation is likely to lead to a decrease in the sensitivity of gemcitabine.
  • Scientists from Clavis Pharma, Norway synthesized the 5'-transoleate derivative CP-4126 of gemcitabine, which is significantly more lipophilic than gemcitabine. The study found that CP-4126 can be ingested into tumor cells independent of hENT1 transporter, so it is expected that tumor patients with low expression of hENT1 also show better anti-tumor effects.
  • the 4'-thionucleoside refers to a nucleoside analog in which an oxygen atom in the furanose ring is replaced by a sulfur atom.
  • the synthetic route is long and difficult, which greatly restricts the study of such compounds.
  • US6147058 discloses a 4'-thionucleoside compound which exhibits an inhibitory effect in a colon cancer model in nude mice. Such compounds are more potent than gemcitabine in tumor growth inhibition (Cancer Let. 1999, 144, 177-182; Int. J. Cancer, 2005, 114, 1002-1009).
  • US 5,128,458 discloses 2', 3'-two off Oxygen-4'-thioribonucleoside, which has a good effect in the treatment of viral infectious diseases such as HIV, hepatitis B or hepatitis C and cell proliferative disorders.
  • 4'-thionucleoside drugs have a good effect on tumor growth inhibition, they also have similar defects as gemcitabine, such as low oral bioavailability, rapid metabolism, many adverse reactions, and resistance to drug resistance. Sex and other issues.
  • the drug resistance of 4'-thionucleoside drugs is the main reason for the short survival of patients and the unsatisfactory effect of cancer treatment.
  • the main reasons for drug resistance include: 1) the lack of corresponding transfer factors on the surface of tumor cells, 4'-thionucleoside drugs can not effectively cross the cell membrane; 2) the efficiency of the drug into triphosphate active substances is not High; 3) The drug is metabolized to an inactive substance by the action of an enzyme.
  • 4'-thionucleoside drugs are rapidly metabolized into inactive substances in the liver and inactivated; so far, no 4'-thionucleoside drugs have been used to treat cancers such as liver cancer.
  • nucleoside drug After the nucleoside drug enters the body, it is phosphorylated into the active metabolite monophosphate under the catalysis of the corresponding kinase, and then the triphosphate is formed. Monophosphorylation of nucleoside drugs is often the rate-limiting step in drug metabolism.
  • a kinase that catalyzes the production of nucleoside monophosphates in humans thymidine kinase (TK), deoxycytidine kinase (dCK), deoxyguanosine kinase (dGK), and adenine nucleoside kinase (AK), etc.
  • nucleosides The affinity for nucleosides is limited, and the enzyme activity is easily inhibited by nucleotide monophosphate (NA-MP), thus resulting in limited in vivo activation of nucleoside drugs, which affects the activity of the drug.
  • NA-MP nucleotide monophosphate
  • the researchers attempted to phosphorylate nucleoside drugs, for example, to prepare phosphates or phosphoramides (ChemMedChem. 2009, 4, 1779-1791).
  • X is hydrogen, C 1-6 alkyl, halogen, N 3 , OH, CN or SH;
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic ring And optionally substituted heteroaryl, wherein both R 2 and R 6 may be joined to form a 3-8 membered carbocyclic ring, and said carbocyclic ring may contain 0-3 heteroatoms selected from N, O and S and It may be a saturated ring, an unsaturated ring or an aromatic ring;
  • R 3 is selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group;
  • R 4 is selected from the group consisting of hydrogen and optionally substituted C 1-10 acyl
  • Q is a pyrimidine base or a purine base having the following structure:
  • R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-10 alkyl, and optionally substituted cycloalkyl;
  • Z is hydrogen, optionally substituted C 1-10 alkyl or halogen
  • the above “optionally substituted” means unsubstituted or independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, Hydroxyalkyl, alkoxyalkyl, amido, sulfonylamino, cyano, nitro, nitroso, azide, aldehyde, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl , aryloxy, heteroaryl, heteroaryloxy, acyl, carboxy, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl and carboxylate;
  • the substituents may be bonded to each other to form a 3-8 membered saturated ring, an unsaturated ring or an aromatic ring containing 0-3 hetero atoms selected from N, O and S;
  • a pharmaceutical composition or pharmaceutical preparation comprising the above 4'-thio-2'-fluoro-nucleoside phosphorus as shown in formula (I)
  • the pharmaceutical composition or pharmaceutical preparation may be in a form suitable for administration to a mammal, including a solid preparation, a semisolid preparation, a liquid preparation, a gaseous preparation, and the like.
  • the mammalian cell proliferation abnormality disease is, for example, a mammalian cancer and/or a tumor and a related condition thereof.
  • the medicament optionally further comprises other anti-tumor agents.
  • a method of preventing or treating a cell proliferation abnormal disease and/or a viral infectious disease in a mammal comprising administering to the mammal an effective amount of the above formula (I) a 4'-thio-2'-fluoro-nucleoside phosphoramidite compound or a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer thereof, any crystal form or racemization thereof , their metabolite form or a mixture thereof.
  • the mammalian cell proliferation abnormality disease is, for example, a mammalian cancer and/or a tumor and a related condition thereof.
  • the mammalian cell proliferation abnormality disease is, for example, a mammalian cancer and/or a tumor and a related condition thereof.
  • each group is as defined above, wherein the first step reaction is preferably carried out in the presence of POCl 3 .
  • Figure 1 shows the effectiveness of the compound of Example 8 (C8) against four different tumor cells at various concentrations.
  • One embodiment of the invention provides a compound of formula (I),
  • X is hydrogen, C 1-6 alkyl, halogen, N 3 , OH, CN or SH;
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic ring And optionally substituted heteroaryl, wherein both R 2 and R 6 may be joined to form a 3-8 membered carbocyclic ring, and said carbocyclic ring may contain 0-3 heteroatoms selected from N, O and S and It may be a saturated ring, an unsaturated ring or an aromatic ring;
  • R 3 is selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group;
  • R 4 is selected from the group consisting of hydrogen and optionally substituted C 1-10 acyl
  • Q is a pyrimidine base or a purine base having the following structure:
  • R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-10 alkyl, and optionally substituted cycloalkyl;
  • Z is hydrogen, optionally substituted C 1-10 alkyl or halogen
  • the above “optionally substituted” means unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkane Alkyl, alkoxyalkyl, amido, sulfonylamino, cyano, nitro, nitroso, azide, aldehyde, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, aromatic An oxy group, a heteroaryl group, a heteroaryloxy group, an acyl group, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, and a carboxylate group; the substituents may be bonded to each other to constitute 0-3 selected from a 3-8 membered saturated ring, an unsaturated ring or an
  • Another embodiment of the invention provides a compound of formula (I) above, wherein
  • Q is a pyrimidine base having the following structure:
  • Z is hydrogen, methyl or halogen
  • a further embodiment of the invention provides a compound of formula (I) above, wherein
  • Q is a pyrimidine base represented by the following formula:
  • Z is hydrogen, methyl or halogen
  • a further embodiment of the invention provides a compound of formula (I) above, wherein
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; wherein R 2 and R 6 The two may be linked to form a 3-8 membered carbocyclic ring, and the carbocyclic ring may contain 0-3 heteroatoms selected from N, O and S and may be a saturated ring, an unsaturated ring or an aromatic ring;
  • a further embodiment of the invention provides a compound of formula (I) above, wherein Q is selected from
  • a further embodiment of the invention provides a compound of formula (I) above, wherein X is hydrogen or halogen, said halogen being fluorine, chlorine, bromine or iodine.
  • a further embodiment of the invention provides a compound of formula (I) above, wherein Y is oxygen.
  • a further embodiment of the invention provides a compound of formula (I) above, wherein R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, and optionally substituted aryl a group (preferably optionally substituted C 6-14 aryl), said "optionally substituted” means unsubstituted or substituted by one or more selected from the group consisting of halogen, C 1-6 alkyl and C 6-14 aryl Substituent substitution. Most preferably, R 1 , R 2 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl and 4-fluorobenzyl.
  • a further embodiment of the present invention provides a compound of the above formula (I) wherein R 3 is selected from optionally substituted aryl, preferably optionally substituted C 6-14 aryl group, more preferably optionally substituted phenyl,
  • the "optionally substituted” means unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 alkoxy, which may be linked to each other to constitute 0. -3 (for example 1, 2 or 3) 3-8-membered saturated, unsaturated or aromatic rings of O.
  • R 3 most preferably has the structure shown below:
  • a further embodiment of the present invention provides a compound of the above formula (I), wherein is independently selected from hydrogen and optionally substituted C when R 5 each occurrence, C1-10 alkyl (e.g. heptyl-4-yl).
  • a further embodiment of the invention provides a compound of formula (I) above, wherein Z is hydrogen, methyl, fluoro or chloro.
  • the present invention encompasses the compounds of the above formula (I) obtained by any combination of the groups defined in the above respective embodiments, without being bound by the respective individual embodiments.
  • a further embodiment of the invention provides a compound of formula (I) above, wherein Q is
  • X is hydrogen, C 1-6 alkyl, halogen, N 3 , OH, CN or SH;
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic ring And optionally substituted heteroaryl, wherein both R 2 and R 6 may be joined to form a 3-8 membered carbocyclic ring, and said carbocyclic ring may contain 0-3 heteroatoms selected from N, O and S and It may be a saturated ring, an unsaturated ring or an aromatic ring;
  • R 3 is selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group;
  • R 4 is selected from the group consisting of hydrogen and optionally substituted C 1-10 acyl
  • R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-10 alkyl, and optionally substituted cycloalkyl;
  • Z is hydrogen, methyl or halogen
  • the above “optionally substituted” means unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkane Alkyl, alkoxyalkyl, amido, sulfonylamino, cyano, nitro, nitroso, azide, aldehyde, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, aromatic An oxy group, a heteroaryl group, a heteroaryloxy group, an acyl group, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, and a carboxylate group; the substituents may be each independently or may be bonded to each other to form a 0- 3 3-8-membered saturated, unsaturated or aromatic rings
  • a further embodiment of this aspect provides a compound of formula (I) above, wherein Q is cytosine, the structural formula of which is as follows:
  • X is hydrogen, C 1-6 alkyl, halogen, N 3 , OH, CN or SH;
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; wherein R 2 and R 6 The two may be linked to form a 3-8 membered carbocyclic ring, and the carbocyclic ring may contain 0-3 heteroatoms selected from N, O and S and may be a saturated ring, an unsaturated ring or an aromatic ring;
  • R 3 is selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group;
  • R 4 is selected from the group consisting of hydrogen and optionally substituted C 1-10 acyl
  • R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-10 alkyl, and optionally substituted cycloalkyl;
  • Z is hydrogen, optionally substituted C 1-10 alkyl or halogen
  • the above “optionally substituted” means unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxy Alkyl, alkoxyalkyl, amido, sulfonylamino, cyano, nitro, nitroso, azide, aldehyde, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl An aryloxy group, a heteroaryl group, a heteroaryloxy group, an acyl group, a carboxyl group, an alkylcarbonyl group, an arylcarbonyl group, a heteroarylcarbonyl group, and a carboxylate group; the substituents may be bonded to each other to form 0-3 a 3-8 membered saturated ring, an unsaturated ring or an aromatic ring of
  • a further embodiment of the invention provides a compound of formula (I) above:
  • X is hydrogen, C 1-6 alkyl, halogen, N 3 , OH, CN or SH;
  • Y is oxygen or sulfur
  • R 1 , R 2 , R 6 and R 7 are each independently selected from hydrogen, optionally substituted C 1-10 alkyl, optionally substituted cycloalkyl, and optionally substituted aryl; wherein R 2 and R 6 The two may be linked to form a 3-8 membered carbocyclic ring, and the carbocyclic ring may contain 0-3 heteroatoms selected from N, O and S and may be a saturated ring, an unsaturated ring or an aromatic ring;
  • R 3 is selected from the group consisting of an optionally substituted aryl group and an optionally substituted heteroaryl group;
  • R 4 is selected from the group consisting of hydrogen and optionally substituted C 1-10 acyl
  • Q is a ⁇ base with the following structure:
  • R 5 is independently selected from the group consisting of hydrogen, optionally substituted C 1-10 alkyl, and optionally substituted cycloalkyl;
  • Z is hydrogen, methyl or halogen
  • the above “optionally substituted” means unsubstituted or substituted by one or more substituents selected from the group consisting of: Halogen, alkyl, amino, alkylamino, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, amido, sulfonylamino, cyano, nitro, nitroso , azido, aldehyde, alkynyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxy, heteroaryl, heteroaryloxy, acyl, carboxy, alkylcarbonyl, arylcarbonyl a heteroarylcarbonyl group and a carboxylate group; the substituents may be each independently or may be bonded to each other to form a 3-8 membered saturated ring or an unsaturated ring containing 0-3 hetero atoms selected from N, O and S or Aromatic ring;
  • a further embodiment of the present invention provides a compound of the above formula (I) which is a 4'-thio-2,2-difluoro-nucleoside phosphoramidite compound (i.e., X in the formula (I) is F), And Q is a pyrimidine group in the defined group, and the remaining substituents are as defined above.
  • a further embodiment of the present invention provides a compound of the above formula (I) which is a 4'-thio-2,2-difluoro-nucleoside phosphoramidite compound (i.e., X in the formula (I) is F), And Q is a cytosine group in the defined group, and the remaining substituents are as defined above.
  • the compound of the present invention has superior pharmacological effects (including antitumor/cancer and antiviral infectious diseases), and at the same time increases its fat solubility, improves bioavailability, reduces irritation and improves absorption, and solves existing drugs.
  • the problem of metabolic speed significantly reduces toxicity and improves safety; and the effectiveness of drug administration through different routes of administration has been achieved.
  • the compound of the formula (I) according to the invention refers to a compound encompassed by the formula (I), a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer thereof, any crystal form or racemate thereof, Or their metabolite form, or a mixture thereof.
  • a further embodiment of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the formula (I) or a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer thereof, or any crystal thereof Forms or racemates, their metabolite forms or mixtures thereof as active ingredient, together with pharmaceutically acceptable carriers, adjuvants, excipients or equivalent pharmaceutically acceptable vehicles.
  • the pharmaceutical composition may contain a compound of the formula (I) in a unit dosage range of from 0.1 to 1000 mg, preferably from 1 to 800 mg, more preferably from 10 to 600 mg, particularly preferably from 50 to 450 mg, most preferably from 100 to 300 mg.
  • the pharmaceutical composition may be, for example, in the form of a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation or the like.
  • the solid preparation is a tablet, a capsule, a powder, a granule or a suppository, etc., and a liquid preparation such as a solution, a suspension or an injection.
  • the composition may also be in the form of a liposome, microsphere or the like.
  • the pharmaceutical composition is in the form of a preparation suitable for oral administration.
  • the pharmaceutical composition may be in the form of a single or multiple dosage units each containing a suitable amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, hydrate thereof, Solvates, isomers, any crystal form or racemate thereof, their metabolite form, or mixtures thereof.
  • a further embodiment of the present invention provides the compound of the formula (I) or a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer thereof, any crystal form or racemate thereof, or a metabolite thereof Use of the form or a mixture thereof as an active ingredient in the preparation of a medicament for preventing or treating a cell proliferative disorder or a viral infectious disease in a mammal.
  • the medicament may contain a compound of the formula (I) in a unit dosage range of from 0.1 to 1000 mg, preferably from 1 to 800 mg, more preferably from 10 to 600 mg, particularly preferably from 50 to 450 mg, most preferably from 100 to 300 mg.
  • a further embodiment of the invention provides a method of treating or preventing a cell proliferative disorder or a viral infectious disease in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable compound thereof Accepted salts, esters, hydrates, solvates, isomers, any crystal form or racemate thereof, their metabolite form, or mixtures thereof.
  • a further embodiment of the present invention provides the compound of the formula (I) or a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer thereof, any crystal form or racemate thereof, or a metabolite thereof A form or a mixture thereof for use in the treatment or prevention of a cell proliferative disorder or a viral infectious disease in a mammal.
  • the cell proliferative disorder or viral infectious disease is, for example, a cancer and/or a tumor and a related disorder thereof.
  • the tumor and/or cancer includes esophagus, stomach, intestine, rectum, mouth, pharynx, larynx, lung, colon, breast, uterus, endometrium, ovary, prostate, testis, bladder, kidney, liver, pancreas, bone Tumors and/or cancers and related conditions occurring in areas such as connective tissue, skin, eyes, brain, and central nervous system, as well as thyroid cancer, leukemia, Hodgkin's disease, lymphoma, and myeloma.
  • the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt, ester, hydrate, solvate, isomer thereof, any crystal form or racemate thereof, a metabolite form thereof or a mixture thereof may be
  • Other anti-tumor agents are used in combination to prevent or treat mammalian cell proliferative disorders such as tumors or cancer and related disorders.
  • the other anti-tumor agent refers to a substance having activity against tumors/cancers and related disorders including, but not limited to, erlotinib or cisplatin.
  • a compound of the formula (I) according to the invention can be combined with other antiviral agents to prevent or treat viral infectious diseases.
  • Such other antiviral agents include, but are not limited to, lamivudine, entecavir, nevirapine or stavudine.
  • the “combination” includes the simultaneous, sequential, and alternate use of two or more drugs, particularly including the preparation of two or more drugs in one or more dosage units for obtaining a suitable combination.
  • a pharmaceutical product, and the pharmaceutical product is administered to a mammal in need of a combination.
  • a further embodiment of the invention provides a process for the preparation of a compound of formula (I) above, which comprises the steps of:
  • each group is as defined above, wherein the first step reaction is preferably carried out in the presence of POCl 3 .
  • the "compound of the present invention” as used herein generally refers to the range of the compound defined by the above formula (I), or a pharmaceutically acceptable salt, ester, solvate, hydrate, isomer thereof, or any crystal thereof. Type or racemate, or their metabolite form, or a mixture thereof.
  • metabolite form refers to a compound that is produced in vivo after administration to an individual in need thereof.
  • salts refer to those salts which retain the biological effectiveness and properties of the parent compound, which can be prepared by protonating a proton accepting moiety and/or deprotonating a proton donating moiety. . It should be noted that proton accepting partial protonation leads to the formation of cationic species. A substance in which the cationic charge is balanced by the presence of a physiological anion, and deprotonation of the proton supply portion results in the formation of an anionic species, wherein the anionic charge is balanced by the presence of physiological cations.
  • Pharmaceutically acceptable salts of the compounds of the invention include the acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts, including inorganic acids and organic acids.
  • a suitable inorganic acid is, for example, a mineral acid as defined in the chemical field, such as hydrochloric acid, sulfuric acid or phosphoric acid.
  • Suitable organic acids include organic sulfonic acids, organic carboxylic acids or amino acids, and the like, suitable organic sulfonic acids such as C 6-16 aryl sulfonic acid, C 6-16 heteroaryl sulfonic acid and C 1-16 alkyl sulfonic acid, Suitable organic carboxylic acids are, for example, mono- or polycarboxylic acids, including C 1-16 alkyl carboxylic acids, C 6-16 aryl carboxylic acids and C 4-16 heteroaryl carboxylic acids.
  • the organic carboxylic acid may also be, for example, an amino acid, and there are many suitable amino acids, particularly natural amino acids found as protein components.
  • the salt formed from the above acid include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, hydrogensulfate/sulfate, Borate, camphor sulfonate, citrate, cyclamate, ethanedisulfonate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, Portuguese Uronic acid salt, hexafluorophosphate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, cis.
  • Oleate malonate, methanesulfonate, methyl sulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate , palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannic acid, tartaric acid Salt, tosylate, trifluoroacetate and xinofoate.
  • Suitable base addition salts are formed from bases which form non-toxic salts, including inorganic bases and organic bases. Specific examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinates, lysine salts, magnesium salts, meglumine salts, ethanolamine salts , potassium salt, sodium salt, tromethamine salt and zinc salt.
  • isomer refers to different compounds having the same molecular formula, including stereoisomers.
  • stereoisomer refers to a heterogeneous manner that differs only in the manner in which the atoms are spatially aligned. body.
  • ⁇ - refers to a specific stereochemical configuration of a substituent on an asymmetric carbon atom in the chemical structure shown.
  • the compounds of the invention have one or more chiral centers and various stereoisomeric configurations can exist. Due to the presence of these chiral centers, the compounds of the invention may exist as racemates, mixtures of enantiomers and individual enantiomers as well as mixtures of diastereomers and diastereomers. All such racemates, enantiomers and diastereomers are within the scope of "compounds of the invention”. "R” and "S” are commonly used in organic chemistry to represent the specific configuration of a chiral center.
  • the compounds of the invention may exist in the form of hydrates or solvates wherein the compounds of the invention comprise a polar solvent which is a structural element of the crystal lattice of the compound, especially such as water, methanol or ethanol.
  • a polar solvent which is a structural element of the crystal lattice of the compound, especially such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • the invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • substituents or “optionally” means that it may or may not be present under the circumstances or conditions, the term includes instances where the substituent is present or absent; the “optional” also includes the presence of one Or an example of a plurality of such substituent substitutions.
  • substituted means that one or more (eg, one, two, three or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not exceeded. The normal valence of the current case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • the term "optionally substituted” includes the case where one or more substituents are substituted, and when “optionally substituted” means that a plurality of substituents are present, the substituent The two may be appropriately connected to each other to constitute a saturated ring, an unsaturated ring or an aromatic ring containing 0 to 3 hetero atoms selected from the group consisting of oxygen (O), nitrogen (N) and sulfur (S), the saturated ring, The saturated or aromatic ring may also form a ring together with the substituted group.
  • the term “optionally substituted aryl” includes benzodihydrothiophenyl and a group having the following structure:
  • alkyl denotes an unbranched or branched chain or cyclic saturated monovalent hydrocarbon residue, preferably having from 1 to 14 carbon atoms (C 1-14 alkyl), more preferably 1 To 10 carbon atoms (C 1-10 alkyl group), more preferably 1 to 6 carbon atoms (C 1-6 alkyl group), particularly preferably 1 to 4 carbon atoms (C 1-4 alkyl group).
  • alkyl groups include, but are not limited to, lower alkyl groups including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl or pentyl, isopentyl, neopentyl, hexyl Heptyl (eg, hept-4-yl) and octyl.
  • cycloalkyl refers to a saturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring. When it consists of two or more rings, the rings may be joined together in a fused manner.
  • the cycloalkyl group can have 3 to 10 atoms (C 3-10 cycloalkyl group) in the ring, preferably 3 to 8 ring atoms (C 3-8 cycloalkyl group), more preferably 3 to 6 ring atoms ( C 3-6 cycloalkyl), particularly preferably contains 3-4 ring atoms (C 3-4 cycloalkyl).
  • Cycloalkyl groups include, but are not limited to, monocyclic rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused or bridged a system (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl or bicyclo [5.2.0] decyl, decalinyl, etc.), optionally Substituted by one or more (such as 1 to 3) suitable substituents.
  • monocyclic rings such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused
  • alkenyl denotes a hydrocarbon residue having 2 to 10 carbon atoms and having one or two olefinic double bonds, preferably having 2 to 8 carbon atoms (C 2-8 alkenyl), more It preferably contains 2 to 6 carbon atoms (C 2-6 alkenyl), particularly preferably 2 to 4 carbon atoms (C 2-4 alkenyl), unless otherwise specified.
  • alkenyl group include a vinyl group, a 1-propenyl group, a 2-propenyl group or a 2-butenyl group, and the like.
  • alkynyl denotes an unbranched or branched hydrocarbon chain radical having from 2 to 10 carbon atoms (C 2-10 alkynyl) and having one or two triple bonds, preferably containing 2 to 8 carbon atoms (C 2-8 alkynyl), more preferably 2 to 6 carbon atoms (C 2-6 alkynyl), particularly preferably 2 to 4 carbon atoms (C 2-6 alkynyl), Except as specified.
  • alkynyl groups are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl or 3-butynyl and the like.
  • amino denotes -NH 2
  • alkylamino represents -NR'R
  • R' and R" are the same or different and are H or an alkyl or cycloalkyl group as defined above.
  • alkoxy denotes -O-alkyl, wherein alkyl is as defined above (eg, C 1-14 alkyl, C 1-10 alkyl, C 1-6 alkyl or C 1-4 alkane).
  • Base for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and their Structure, etc.
  • halogen or "halo" as used herein denotes fluoro, chloro, bromo or iodo.
  • haloalkyl denotes an alkyl group as defined above wherein 1, 2, 3 or more hydrogen atoms are replaced by a halogen.
  • Examples are 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, 1-iodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl Base, 1-chloroethyl, 1-bromoethyl Base, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3-bromopropyl or 2,2 , 2-trifluoroethyl, and the like.
  • haloalkoxy denotes an alkoxy group as defined above wherein 1, 2, 3 or more hydrogen atoms are replaced by halogen.
  • alkyl denotes a radical of the formula -R-OH wherein R is alkylene.
  • alkylene denotes 1 to 10 carbon atoms (C 1-10 alkylene group), more preferably 1 to 6 carbon atoms (C 1-6 alkylene group), particularly preferably 1 a divalent saturated linear hydrocarbon group of 4 carbon atoms (C 1-4 alkylene) or 3 to 10 carbon atoms (C 3-10 alkylene), more preferably 3 to 8 carbon atoms (C 3-8 alkylene), particularly preferably a branched saturated divalent hydrocarbon group having 3 to 5 carbon atoms (C 3-5 alkylene), unless otherwise indicated.
  • alkylene groups include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, butylene, 2-ethylbutylene, and the like.
  • aryl refers to a group having at least one aromatic ring, that is, having a conjugated ⁇ -electron system, including monocyclic aryl groups, bicyclic aryl groups, and the like. It contains 6 to 14 carbon atoms (C 6-14 aryl) such as phenyl, naphthyl and the like.
  • the optionally substituted aryl group includes an aryl group substituted with a plurality of substituents, and the substituents may be appropriately bonded to each other to form a saturated ring containing 0 to 3 hetero atoms selected from oxygen, nitrogen and sulfur, an unsaturated ring and / or aromatic ring.
  • the aryl group preferably includes the following groups:
  • aralkyl denotes a radical R'R"-, wherein R' is aryl as defined herein, R" is alkylene as defined herein, it is understood that the aralkyl moiety The point of attachment will be on the alkylene group.
  • the aryl group can have from 6 to 14 carbon atoms and the alkyl group can have from 1 to 6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, 4-fluorobenzyl, phenylethyl, phenylpropyl, and phenylbutyl.
  • aryloxy as used herein denotes -O-R, and R is aryl as defined above.
  • heterocyclyl refers to 3- to 3 (eg, one, two, three or four) heteroatoms selected from N, O, S and P and the remaining atoms are carbon atoms.
  • a 16-membered saturated or unsaturated ring group is
  • the 3-10 membered heterocyclic group is a group having 3 to 10 carbon atoms and a hetero atom in the ring, such as, but not limited to, an oxiranyl group, an aziridine group, an azetidinyl group ( Azetidinyl), oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyridyl Oryl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • an oxiranyl group an aziridine group
  • an azetidinyl group Azetidinyl
  • oxetanyl tetrahydrofuranyl
  • dioxolinyl pyrrolidinyl
  • heteroaryl refers to a cyclic aromatic group having from 1 to 3 heteroatoms selected from N, O and S as ring atoms and the remaining ring atoms being carbon, wherein said ring is 4- A 16-membered monocyclic or fused ring, preferably a 5-12 membered monocyclic or fused ring, a 5-8 membered monocyclic or fused ring.
  • heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrrole Base, pyrazolyl, N-alkylpyrrolyl, Pyrimidinyl, pyrazinyl, imidazolyl, pyridazinyl, pyridazinyl, pyridazine-1-(2H)-1-yl, pyrido[3,2-d]pyridazin-5(6H)-8- Bases, triazine groups and the like and their benzo derivatives.
  • heteroaryloxy denotes a radical of the formula heteroaryl-O-, wherein said heteroaryl is as defined above.
  • sulfonamido refers to a radical of the formula -SO 2 NR'R", wherein R' and R" are the same or different and are each independently hydrogen or alkyl or cycloalkyl as defined above.
  • carboxy refers to a group of the formula -COOH, and the term “carboxylate group” as used herein denotes -COOR, wherein each R independently represents an alkyl group as defined above.
  • each group or atom or ion group includes a group or atom or ion group of its isotopic substitution, for example, the "hydrogen” includes H, 2 H ( ⁇ ), 3 H( ⁇ );
  • the C 1-14 alkyl group includes the case where one or more carbon atoms or all are 12 C, 13 C, 14 C, and other examples include N, P, O isotopes.
  • pharmaceutically acceptable carrier refers to a non-active ingredient in a pharmaceutical or pharmaceutical formulation that does not cause significant irritation to the organism and does not interfere with the biological activity of the administered compound, including The diluent, adjuvant, excipient or equivalent pharmaceutically acceptable medium to which the therapeutic agent is administered together.
  • excipient refers to a substance used in the preparation of a pharmaceutical composition that is generally safe, non-toxic and neither biologically undesirable nor otherwise undesirable, and includes suitable for veterinary applications as well as humans. Various excipients for medicinal use.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, carbonic acid Magnesium, etc. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).
  • formulation or "dosage form” as used herein shall include solid preparations, semisolid preparations, liquid preparations and gaseous preparations of the compounds of the present invention.
  • the preparation or dosage form includes, but is not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous mixtures Suspension, injectable solution, expectorant, syrup.
  • Those skilled in the art will appreciate that the compounds of the present invention can be formulated into different formulations depending on the desired dosage and pharmacokinetic parameters.
  • the unit dosage of the compound of the present invention is in the range of from 0.1 to 1000 mg, preferably in the range of from 1 to 800 mg, more preferably in the range of from 10 to 600 mg, particularly preferably in the range of from 50 to 450 mg, most preferably in unit dose.
  • the range is 100-300 mg.
  • Formulations or dosage forms of the invention may comprise a single or multiple unit doses of a compound of the invention as described above.
  • the compounds of the invention are administered orally.
  • routes of administration may be used, or preferably, such as intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by buccal, nasal, transmucosal, topical, ophthalmic formulations.
  • the form is administered by inhalation or the like.
  • Transdermal administration may be highly desirable for patients who are increasingly or unacceptable to oral medications.
  • the compounds of the invention may also be administered by the transdermal, intramuscular, intranasal or intrarectal route.
  • the route of administration can be altered in any manner, depending on the physical characteristics of the drug, the convenience of the patient and caregiver, and other relevant circumstances (Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990)).
  • the invention also provides the use of a compound of the invention for simultaneous, separate and sequential administration with other therapeutic agents, such as other anti-cancer/neoplastic agents or other antiviral agents.
  • the compound of the present invention or a product containing the same is administered in an amount ranging from 0.1 to 1000 mg/kg body weight per day, and a preferred dosage range is from 1 to 800 mg/kg body weight per day, preferably The dosage range is 10-600 mg/kg body weight/day, a particularly preferred dosage range is 100-400 mg/kg body weight/day, and the most preferred dosage range is 120-250 mg/kg body weight/day.
  • the precise dose required to treat the patient is determined by the physician based on the stage and severity of the disease and the specific needs and responses of the individual individual.
  • treating means reversing, alleviating, inhibiting a condition or condition to which such a term applies or a condition or condition of such a condition or condition.
  • “Mammal” as used herein includes human or non-human animals.
  • Exemplary human subjects include a human individual (referred to as a patient) or a normal individual having a disease or condition, such as a disease or condition described herein.
  • Non-human animals in the present invention include non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • Phosphorus oxychloride (1.53 g, 10 mmol) was dissolved in dichloromethane (10 mL), cooled to -60 ° C, and phenol (940 mg, 10 mmol) and triethylamine (1.01 g, 10 mmol) in dichloromethane (10 mL). After stirring at room temperature overnight, it was cooled to 0 ° C, and then ethylamine (ethyl acetate). After cooling to -60 ° C, a solution of triethylamine (2.02 g, 20 mmol) in dichloromethane (5 mL) was evaporated.
  • Compound C2 was prepared in the same manner as in Example 1 using phosphorus oxychloride, phenol, L-alanine benzyl ester hydrochloride, pentafluorophenol and Compound A as starting materials.
  • Compound C3 was prepared in the same manner as in Example 1 using phosphorus oxychloride, phenol, L-alanine phenyl ester hydrochloride, pentafluorophenol and Compound A as starting materials.
  • Phosphorus oxychloride (1.53 g, 10 mmol) was dissolved in dichloromethane (10 mL), cooled to -60 ° C, and 4-fluorophenol (1.12 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) were slowly added dropwise.
  • Dichloromethane solution (10 mL). After stirring at room temperature overnight, it was cooled to 0 ° C, and then EtOAc (EtOAc) After cooling to -60 ° C, a solution of triethylamine (2.02 g, 20 mmol) in dichloromethane (5 mL) was evaporated.
  • Compound C5 was prepared in the same manner as in Example 1 using phosphorus oxychloride, 4-chlorophenol, L-alanine isopropyl ester hydrochloride, pentafluorophenol and Compound A as starting materials.
  • Compound C6 was prepared in the same manner as in Example 1 using phosphorus oxychloride, 4-bromophenol, L-alanine isopropyl ester hydrochloride, pentafluorophenol and Compound A as starting materials.
  • Phosphorus oxychloride (1.53 g, 10 mmol) was dissolved in dichloromethane (10 mL), cooled to -60 ° C, phenol (1.12 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) Solution (10 mL). After stirring at room temperature overnight, it was cooled to 0 ° C and then added 2-methyl-alanine isopropyl ester hydrochloride (1.82 g, 10 mmol). After cooling to -60 ° C, a solution of triethylamine (2.02 g, 20 mmol) in dichloromethane (5 mL) was evaporated.
  • Phosphorus oxychloride (1.53 g, 10 mmol) was dissolved in dichloromethane (10 mL), cooled to -60 ° C, and succinol (1.38 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) of dichloride were slowly added dropwise.
  • Methane solution (10 mL). After stirring at room temperature overnight, it was cooled to 0 ° C, and then EtOAc (EtOAc) After cooling to -60 ° C, a solution of triethylamine (2.02 g, 20 mmol) in dichloromethane (5 mL) was evaporated.
  • the diastereomer mixture obtained in the previous step was separated by preparative HPLC, and the separation conditions were as follows: octadecyl-bonded silica gel as a filler (20 ⁇ 250 mm, 5 ⁇ m), column temperature 40° C., flow rate 10.0 mL/ Min, detection wavelength 220nm, mobile phase A is water (neutral), mobile phase B is methanol, linear gradient elution.
  • the first main peak was collected and lyophilized to obtain (S)-isopropyl 2-(((R))-(4-(R)-(5R)-(4-) (2H)-yl)-4-fluoro-3-hydroxy-tetrahydrothiophen-2-yl)methoxy)(benzo[d][1,3]dioxolan-5-yloxy)phosphorus Acyl)amino)propionate (C13) 17 mg; the second main peak was collected and lyophilized to give (S)-isopropyl 2-(((S)-(((2R,3S,4S,5R)-5-) (4-Amino-2-oxopyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-tetrahydrothiophen-2-yl)methoxy)(benzo[d][1,3] Dioxypenta-5-yloxy)phosphoryl)amino)propionate (C14) 30 mg.
  • Compound C15 was prepared in a similar manner to that of Example 1 using phosphorus oxychloride, phenol, L-alanine-4-fluorobenzyl ester hydrochloride, pentafluorophenol and Compound A as starting materials.
  • the compound was prepared by the similar method of Example 1 using phosphorus oxychloride, 6-hydroxy-2,3-dihydrobenzofuran, L-alanine isopropyl ester hydrochloride, pentafluorophenol and compound A as raw materials. C18.
  • Compound C19 was prepared in a similar manner to that of Example 1 using phosphorus oxychloride, 6-hydroxybenzofuran, L-alanine isopropyl ester hydrochloride, pentafluorophenol and Compound A as starting materials.
  • This experimental example was used to evaluate the effectiveness of the compounds of the present invention against proliferation inhibition of human gastric cancer NCI-N87, colorectal cancer HCT-116, colorectal cancer HCT-15, and pancreatic cancer BxPC-3 cell lines.
  • the tumor cell lines used in this experiment were: gastric cancer cell NCI-N87 (from Guangzhou Jini Biotechnology Co., Ltd.), colorectal cancer cell HCT-116 (from Chengdu An evaluation center), colorectal cancer cell HCT-15 And pancreatic cancer cells BxPC-3 (both from the US ATCC).
  • the above cell lines were cultured in vitro in a single layer, and the culture conditions were as follows: 10% heat-inactivated fetal bovine serum (Fetal Bovine Serum) was added to the corresponding medium (RPMI-1640, IMDM and L-15 cell culture medium, manufacturer: Gibco) of each cell. , manufacturer: Sigma), cultured in an incubator containing 5% CO 2 at 37 °C. Digestion treatment was carried out with trypsin-EDTA.
  • a blank group, a vehicle group (containing 1 DMSO), and 8 test compound concentrations of 5 nM, 10 nM, 50 nM, 100 nM, 500 nM, 1000 nM, 5000 nM, and 10000 nM were set for each tumor cell, and 3 replicate wells were used for each concentration.
  • the experiment was carried out by the CCK-8 method: 100 ⁇ l/well of the tumor cells to be tested at a concentration of 5 to 10 ⁇ 10 4 /ml in a 96-well plate, and the cells were incubated at 37 ° C under 5% CO 2 after inoculation. After 24 hours of culture, the culture solution was discarded, and 200 ⁇ l of an incubation solution of different drug concentrations was added to each well, and the cells were further incubated for 72 hours. After the incubation was completed, 20 ⁇ l/well of CCK-8 solution was added to the well to be tested, and incubation was continued for 4 hours in the incubator. The OD value of the dual wavelength was measured using a multifunctional automatic microplate reader at a detection wavelength of 450 nm and a reference wavelength of 650 nm.
  • inhibition rate [(OD solvent - OD blank) - (OD drug group - OD blank)] / (OD solvent - OD blank) * 100%
  • the IC 50 was calculated by fitting the concentration-inhibition rate curve according to the inhibition rate using GraphPad prism 5.0 software.
  • Figure 1 shows that the compound of Example 8 (C8) has potent effects on gastric cancer cells NCI-N87, colorectal cancer cells HCT-116, colorectal cancer cells HCT-15, and pancreatic cancer cells BxPC-3 at the above 8 concentrations. Inhibition.
  • the IC 50 of each of the example compounds of the present invention for each cancer cell is shown in Table 1-1 to Table 1-4.
  • IC 50 values of gastric cancer cell NCI-N87 is 0.1 ⁇ 1 ⁇ M
  • IC 50 value range of colorectal cancer cells HCT-116 is a 0.1 ⁇ 1 ⁇ M
  • on colorectal cancer cells HCT The IC 50 value of -15 ranges from 0.5 to 10 ⁇ M
  • the IC 50 value for pancreatic cancer cell BxPC-3 ranges from 0.1 to 5 ⁇ M. Therefore, the compound of the present invention has an inhibitory activity against tumor cells.
  • the compound (C8) of Example 8 of the present invention has an effective anti-tumor effect in vitro, and is excellent for gastric cancer cells NCI-N87, colorectal cancer cells HCT-116, colorectal cancer cells HCT-15, and pancreatic cancer cells BxPC-3. Inhibition.
  • the compounds of Examples 2, 14 and 15 of the present invention have excellent effective inhibitory effects on gastric cancer cells NCI-N87, colorectal cancer cells HCT-15 and pancreatic cancer cells BxPC-3, respectively.
  • the compounds of Examples 16, 17 and 19 of the present invention have excellent and effective inhibitory effects on gastric cancer cells NCI-N87 and pancreatic cancer cells BxPC-3, and the compound of Example 13 has an effective inhibitory effect on gastric cancer cell NCI-N87.
  • the compound of Example 18 of the present invention has an effective inhibitory effect on pancreatic cancer cell BxPC-3.
  • This experimental example was used to evaluate the inhibitory effect of the compounds of the present invention on the proliferation of human tumor cell subcutaneous xenografts by different routes of administration.
  • this experimental example examines changes in tumor volume and animal body weight of human colorectal cancer cell line HCT-116 and gastric cancer cell line NCI-N87 subcutaneously transplanted mice after administration of compound C8 by different administration routes.
  • This test samples each of the colorectal cancer HCT-116 and gastric cancer cells The efficacy and toxicity of NCI-N87 tumor-bearing mice.
  • Both gastric cancer cell NCI-N87 and colorectal cancer cell HCT-116 were cultured in vitro.
  • the culture conditions were 10% heat-inactivated fetal bovine serum in RPMI 1640 medium at 37 ° C with 5% CO 2 air. Culture in an incubator. Digestion treatment was carried out with trypsin-EDTA.
  • Tumor cells were inoculated separately into BALB/c nude mice (SPF grade, female, 16-18 g/only, about 6-8 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.).
  • Each nude mice were inoculated subcutaneously in the right axilla to about 2.5 ⁇ 10 6 th HCT-116 tumor cells, or from about 3 ⁇ 10 6 th NCI-N87 tumor cells (suspended in 0.1ml PBS). After inoculation the tumor grew to a range of about 100-200mm 3, excluding tumors too small volume (less than 100mm 3) or too large (greater than 200mm 3) in nude mice, the remaining nude mice were randomized.
  • the sulfobutylether- ⁇ -cyclodextrin was prepared, and a 10% solution was prepared with physiological saline, and sterilized by filtration through a 0.22 ⁇ m sterile filter.
  • Tumor-bearing mice with a tumor volume of about 100-200 mm 3 were selected and randomly divided into 5 groups, 8 rats/group, and the administration volume was 10 ml/kg, administered twice a week (intravenous (iv) or oral administration). Medicine (po)) for a total of 3 weeks. Tumor volume and animal body weight were measured twice a week after administration, and animal death was observed every day.
  • Tumor volume The tumor diameter is measured.
  • TGI tumor growth inhibition rate
  • TGI (%) [1 - (V T end - V T start ) / (V C end - V C start )] * 100%
  • V T is the mean tumor volume at the end of the treatment group
  • V T at the beginning mean volume of tumor at the beginning of administration in the treatment group
  • V C end tumor volume mean at the end of the vehicle control experiment
  • V C start mean tumor volume at the start of drug control group administration
  • the C8 sample group significantly inhibited tumor growth, and the administration by different routes showed safety and tolerance.
  • TGI and tumor regression in each group were as shown in Table 2 below.
  • Table 2 TGI and tumor regression in gastric cancer cell NCI-N87 model
  • PR indicates partial regression of the tumor, indicating a decrease in tumor volume compared to the start of administration.
  • I.v. means intravenous administration
  • the compound C8 treatment group can significantly inhibit tumor growth and has excellent safety and tolerability.
  • TGI and tumor regression of each group were as shown in Table 4 below.
  • Table 4 TGI and tumor regression in colorectal cancer cell model HCT-116
  • the tumor volume in the gemcitabine injection group was not reduced compared with the vehicle control group; in the compound C8 treatment group (including intravenous administration and oral administration), each group was In one animal, the tumor completely subsided, and in 7 animals, the tumor partially subsided, thereby demonstrating that Compound C8 has a particularly excellent antitumor effect in vivo.
  • compound C8 has good polarity and fat solubility, improving metabolic properties and bioavailability.
  • pancreatic cancer BxPC-3 cells were performed using a method similar to that of 1-2 in Experimental Example 2.
  • the sulfobutylether- ⁇ -cyclodextrin was prepared, and a 10% solution was prepared with physiological saline, and sterilized by filtration through a 0.22 ⁇ m sterile filter. An appropriate amount of the test compound was weighed, DMSO was added, and 10% sulfobutylether- ⁇ -cyclodextrin was added as needed to make the final concentration of DMSO 2.5%. Gemcitabine injection (positive control) was diluted to the desired concentration with physiological saline. 10% sulfobutylether- ⁇ -cyclodextrin containing 2.5% DMSO was prepared as a vehicle control.
  • Tumor-bearing mice with a tumor volume of 100-200 mm 3 were randomly divided into 14 groups, 7 rats/group, and the administration volume was 20 ml/kg, which was administered every 3 days (intravenous administration (iv)) once. A total of 4 doses were administered. Tumor volume and animal body weight were measured twice a week after administration, and animal death was observed every day.
  • the compound C8 of the present invention can effectively inhibit the growth of subcutaneous xenografts of human pancreatic cancer BxPC-3 nude mice at different doses, and the compound C8 is superior to gemcitabine injection.
  • Pancreatic cancer BxPC-3 cells in vitro monolayer culture, inoculation and animal grouping, and sample preparation were performed using a method similar to that of 1-3 in Experimental Example 2.
  • Tumor-bearing mice with a tumor volume of 80-250 mm 3 were selected and randomly divided into 6 groups, 8 rats/group, and the administration volume was 10 ml/kg. Tumor volume and animal body weight were measured twice a week after administration, and animal death was observed every day.
  • the drug was administered twice a week for a total of 3 weeks.
  • the experimental results are shown in Table 7-1.
  • the drug was administered once a week (intravenous (i.v.) or orally (p.o.)) for a total of 3 weeks, and the results of the experiment are shown in Table 7-2.
  • the compound C8 of the present invention can effectively inhibit the growth of subcutaneous xenografts of human pancreatic cancer BxPC-3 nude mice at different doses, and the compound C8 is superior to gemcitabine injection and the compound C8 expression. Excellent oral efficacy. Since oral administration is a route of administration more acceptable to patients, the compound C8 of the present invention improves patient tolerance.
  • the sample preparation was the same as in Experimental Example 2.
  • Tumor-bearing mice with a tumor volume of 100-200 mm 3 were randomly divided into 7 groups, 7 rats/group, and the administration volume was 20 ml/kg, once every 3 days (intravenous (iv) or oral administration). Dosing (po)), a total of 6 doses. Tumor volume and animal body weight were measured twice a week after administration, and animal death was observed every day.
  • the compound C8 of the present invention can effectively inhibit the growth of subcutaneous xenografts of human pancreatic cancer Capan-1 nude mice at different doses, and the compound C8 is superior to gemcitabine injection, and the compound C8 is orally administered. Both drug and intravenous administration have the efficacy of gemcitabine administered in excess of its three-fold dose.
  • Tumor-bearing mice with a tumor volume of 100-200 mm 3 were randomly divided into 4 groups, 6 rats/group, and the administration volume was 10 ml/kg, once every 3 days (intravenous (iv) or oral administration). Dosing (po)), a total of 6 doses. Tumor volume and animal body weight were measured twice a week after administration, and animal death was observed every day.
  • the compound C8 of the present invention can effectively inhibit the growth of subcutaneous xenografts of human pancreatic cancer PANC-1 nude mice at different doses, and its pharmacological effect is significantly better than that of gemcitabine injection.
  • mice Normal Kunming mice (SPF grade, Experimental Animal Center of Sichuan Academy of Traditional Chinese Medicine) were randomly divided into male and female body weights.
  • the test compound and the vehicle control were prepared in reference to Experimental Example 2, and the administration volume was 10 ml/kg, and the administration was intragastric administration once a day for 7 days.
  • the toxicity of Compound A at about 77 ⁇ mol/kg resulted in partial death of the animal, while the compound C8 showed a death caused by Compound A at a dose of about 77 ⁇ mol/kg at very high doses ( ⁇ 115 ⁇ mol/kg).
  • the compound C8 survived at about 77 ⁇ mol/kg, indicating that the compound had little toxic effect in oral administration in mice and the mouse could be recovered, thereby confirming that the compound C8 had attenuated toxic effects in oral administration to mice. .
  • mice that were quarantined were randomly divided into 4 groups, 3 rats/sex/group.
  • the test compound and the vehicle control were prepared in reference to Experimental Example 2, and the administration volume was 10 ml/kg.
  • the doses are shown in Table 11. Animals were observed daily for death, appearance, behavior, mental state, secretions, excretions, etc., and were observed continuously for 7 days and dissected on the 8th day.
  • the animals showed symptoms such as archback and weight loss, while the compound C8 treatment group in the third group showed no abnormalities.
  • the body weight gradually decreased until the 8th day.
  • the body weight of female and male mice decreased by 20.2% and 18.1%, respectively.
  • the body weight of the compound C8 treatment group gradually increased.
  • the weight of female and male mice increased by 13.1% and 26.7%, respectively.
  • the white blood cells of the male and female animals in the compound C8 treatment group decreased by 45% and 49%, respectively, and the platelets decreased by 43% and 39%, respectively; while the white blood cells of the male and female animals in the compound A treatment group decreased by 83, respectively.
  • % and 87% platelets decreased by 71% and 77%, respectively.
  • the compound of the example was determined as described above, and it was found that the compound prepared in the present invention has a very good antitumor effect in vivo, whether it is intravenous or oral administration, so that the tumor disappears or partially regresses. More unexpectedly, the efficacy of the compounds of the present invention obtained by two different routes of administration was superior to that of gemcitabine injection (the number of tumors in the gemcitabine injection group was not subsided or the number of regressions was small), completely overcoming the oral organism of gemcitabine. The use of poor defects.
  • the 4'-thio-2'-fluoronucleoside compound of the present invention has a very excellent pharmacological effect, and has increased fat solubility and improved bioavailability as compared with the parent compound (Compound A). It reduces irritation and improves absorption, and solves the problem of metabolic rate. The most critical breakthrough is to significantly reduce toxicity and improve safety; and it is effective to administer in different routes of administration (intravenous or oral).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/CN2016/077519 2015-04-03 2016-03-28 4'-硫代核苷的新型化合物及其制备方法、药物组合物和应用 WO2016155593A1 (zh)

Priority Applications (10)

Application Number Priority Date Filing Date Title
EA201791535A EA034375B1 (ru) 2015-04-03 2016-03-28 Новое соединение 4'-тионуклеозида, а также способ его получения, его фармацевтическая композиция и применение
CN201680001812.5A CN106661077B (zh) 2015-04-03 2016-03-28 4’-硫代核苷的新型化合物及其制备方法、药物组合物和应用
CA2975990A CA2975990A1 (en) 2015-04-03 2016-03-28 Novel compound of 4'-thionucleoside, as well as preparation method therefor, pharmaceutical composition thereof and application thereof
AU2016240117A AU2016240117C1 (en) 2015-04-03 2016-03-28 Novel compound of 4'-thionucleoside, as well as preparation method therefor, pharmaceutical composition thereof and application thereof
EP16771348.6A EP3279207B1 (en) 2015-04-03 2016-03-28 Novel compound of 4'-thionucleoside, as well as preparation method therefor, pharmaceutical composition thereof and application thereof
JP2017541855A JP6769000B2 (ja) 2015-04-03 2016-03-28 ４’−チオヌクレオシドの新規な化合物、並びにその調製方法、その医薬組成物及びその用途
US15/558,620 US10662214B2 (en) 2015-04-03 2016-03-28 Compound of 4′-thionucleoside, as well as preparation method therefor, pharmaceutical composition thereof and application thereof
HK17105803.7A HK1232229A1 (zh) 2015-04-03 2017-06-12 '- '-硫代核苷的新型化合物及其製備方法、藥物組合物和應用
HK18103052.9A HK1243424A1 (zh) 2015-04-03 2018-03-02 4'-硫代核苷的新型化合物及其製備方法、藥物組合物和應用
US16/851,217 US20200262860A1 (en) 2015-04-03 2020-04-17 Novel compound of 4'-thionucleoside, as well as preparation method therefor, pharmaceutical composition thereof and application thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510157772 2015-04-03
CN201510157772.0 2015-04-03

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US15/558,620 A-371-Of-International US10662214B2 (en) 2015-04-03 2016-03-28 Compound of 4′-thionucleoside, as well as preparation method therefor, pharmaceutical composition thereof and application thereof
US16/851,217 Continuation US20200262860A1 (en) 2015-04-03 2020-04-17 Novel compound of 4'-thionucleoside, as well as preparation method therefor, pharmaceutical composition thereof and application thereof

Publications (1)

Publication Number Publication Date
WO2016155593A1 true WO2016155593A1 (zh) 2016-10-06

Family

ID=57004251

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/077519 WO2016155593A1 (zh) 2015-04-03 2016-03-28 4'-硫代核苷的新型化合物及其制备方法、药物组合物和应用

Country Status (9)

Country Link
US (2) US10662214B2 (US07794700-20100914-C00152.png)
EP (1) EP3279207B1 (US07794700-20100914-C00152.png)
JP (1) JP6769000B2 (US07794700-20100914-C00152.png)
CN (2) CN106661077B (US07794700-20100914-C00152.png)
AU (1) AU2016240117C1 (US07794700-20100914-C00152.png)
CA (1) CA2975990A1 (US07794700-20100914-C00152.png)
EA (1) EA034375B1 (US07794700-20100914-C00152.png)
HK (2) HK1232229A1 (US07794700-20100914-C00152.png)
WO (1) WO2016155593A1 (US07794700-20100914-C00152.png)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107148423A (zh) * 2014-10-31 2017-09-08 富士胶片株式会社 硫代核苷衍生物或其盐及医药组合物
US9896471B2 (en) 2012-03-28 2018-02-20 Fujifilm Corporation Salt of 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine
WO2018113592A1 (zh) * 2016-12-22 2018-06-28 四川科伦博泰生物医药股份有限公司 4'-硫代-2'-氟代核苷磷酰胺化合物的固体形式及其制备方法和用途
WO2019001292A1 (zh) * 2017-06-29 2019-01-03 四川科伦博泰生物医药股份有限公司 4'-硫代核苷的新型化合物的制备方法和此制备方法中的中间体
WO2019042226A1 (zh) 2017-09-01 2019-03-07 四川科伦博泰生物医药股份有限公司 用于肿瘤治疗或预防的药物组合物、方法及其用途
WO2019146130A1 (ja) * 2018-01-29 2019-08-01 富士フイルム株式会社 胆道がん用抗腫瘍剤および胆道がんの処置方法
US10570112B2 (en) 2012-08-13 2020-02-25 Fujifilm Corporation Synthetic intermediate of 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine, synthetic intermediate of thionucleoside, and method for producing the same
WO2020108343A1 (zh) * 2018-11-28 2020-06-04 四川科伦博泰生物医药股份有限公司 以4'-硫代核苷类化合物为活性成分的口服药物组合物、其制备方法及其用途
JP2021522197A (ja) * 2018-04-19 2021-08-30 サウザーン リサーチ インスチチュート 癌の治療のための４’−チオ−ヌクレオチドおよび−ヌクレオシドプロドラッグ
US11369625B2 (en) 2016-08-31 2022-06-28 Fujifilm Corporation Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106661077B (zh) * 2015-04-03 2019-02-12 四川科伦博泰生物医药股份有限公司 4’-硫代核苷的新型化合物及其制备方法、药物组合物和应用
WO2021020879A1 (en) * 2019-07-30 2021-02-04 Pinotbio, Inc. Dinucleotide compounds for treating cancers and medical uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6147058A (en) * 1996-04-09 2000-11-14 Yamasa Corporation 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)cytosine
WO2014197578A1 (en) * 2013-06-05 2014-12-11 Idenix Pharmaceuticals, Inc. 1',4'-thio nucleosides for the treatment of hcv

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5128458A (en) 1990-04-20 1992-07-07 Southern Research Institute 2',3'-dideoxy-4'-thioribonucleosides as antiviral agents
JPH1087687A (ja) * 1996-04-09 1998-04-07 Yamasa Shoyu Co Ltd ５−置換−１−（２−デオキシ−２−フルオロ−４−チオ−β−Ｄ−アラビノフラノシル）ウラシル
GB0317009D0 (en) * 2003-07-21 2003-08-27 Univ Cardiff Chemical compounds
WO2005027962A1 (en) 2003-09-18 2005-03-31 Isis Pharmaceuticals, Inc. 4’-thionucleosides and oligomeric compounds
WO2007056596A2 (en) 2005-11-09 2007-05-18 Wayne State University Phosphoramidate derivatives of fau
GB201016855D0 (en) * 2010-10-06 2010-11-17 Nucana Biomed Ltd Chemical compounds
WO2013013009A2 (en) * 2011-07-19 2013-01-24 Nanjing Molecular Research, Inc. 2',3'-DIDEOXY-2'-α-FLUORO-2'-β-C-METHYLNUCLEOSIDES AND PRODRUGS THEREOF
WO2014124430A1 (en) * 2013-02-11 2014-08-14 Emory University Nucleotide and nucleoside therapeutic compositions and uses related thereto
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
CN106661077B (zh) * 2015-04-03 2019-02-12 四川科伦博泰生物医药股份有限公司 4’-硫代核苷的新型化合物及其制备方法、药物组合物和应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6147058A (en) * 1996-04-09 2000-11-14 Yamasa Corporation 1-(2-deoxy-2-fluoro-4-thio-beta-D-arabinofuranosyl)cytosine
WO2014197578A1 (en) * 2013-06-05 2014-12-11 Idenix Pharmaceuticals, Inc. 1',4'-thio nucleosides for the treatment of hcv

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3279207A4 *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9896471B2 (en) 2012-03-28 2018-02-20 Fujifilm Corporation Salt of 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine
US10570112B2 (en) 2012-08-13 2020-02-25 Fujifilm Corporation Synthetic intermediate of 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl)cytosine, synthetic intermediate of thionucleoside, and method for producing the same
CN107148423A (zh) * 2014-10-31 2017-09-08 富士胶片株式会社 硫代核苷衍生物或其盐及医药组合物
US10059734B2 (en) 2014-10-31 2018-08-28 Fujifilm Corporation Thionucleoside derivative or salt thereof, and pharmaceutical composition
EP3214090A4 (en) * 2014-10-31 2017-09-13 Fujifilm Corporation Thionucleoside derivative or salt thereof, and pharmaceutical composition
US10385089B2 (en) 2014-10-31 2019-08-20 Fujifilm Corporation Thionucleoside derivative or salt thereof, and pharmaceutical composition
US11369625B2 (en) 2016-08-31 2022-06-28 Fujifilm Corporation Anti-tumor agent, anti-tumor effect enhancer, and anti-tumor kit
AU2017383598B2 (en) * 2016-12-22 2021-06-03 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Solid form of 4'-thio-2'-fluoronucleoside phosphamide compound and preparation method therefor and use thereof
CN109952307A (zh) * 2016-12-22 2019-06-28 四川科伦博泰生物医药股份有限公司 4’-硫代-2’-氟代核苷磷酰胺化合物的固体形式及其制备方法和用途
JP2020502043A (ja) * 2016-12-22 2020-01-23 シチュアン ケルン−バイオテック バイオファーマシューティカル カンパニー リミテッド ４’−チオ−２’−フルオロヌクレオシドホスファミド化合物の固体形態及びそのための調製方法及びその使用
WO2018113592A1 (zh) * 2016-12-22 2018-06-28 四川科伦博泰生物医药股份有限公司 4'-硫代-2'-氟代核苷磷酰胺化合物的固体形式及其制备方法和用途
CN109952307B (zh) * 2016-12-22 2022-03-25 四川科伦博泰生物医药股份有限公司 4’-硫代-2’-氟代核苷磷酰胺化合物的固体形式及其制备方法和用途
US10787477B2 (en) 2016-12-22 2020-09-29 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Solid form of 4′-thio-2′-fluoronucleoside phosphamide compound and preparation method therefor and use thereof
CN110573521B (zh) * 2017-06-29 2023-04-21 四川科伦博泰生物医药股份有限公司 4’-硫代核苷的新型化合物的制备方法和此制备方法中的中间体
CN110573521A (zh) * 2017-06-29 2019-12-13 四川科伦博泰生物医药股份有限公司 4’-硫代核苷的新型化合物的制备方法和此制备方法中的中间体
WO2019001292A1 (zh) * 2017-06-29 2019-01-03 四川科伦博泰生物医药股份有限公司 4'-硫代核苷的新型化合物的制备方法和此制备方法中的中间体
CN110831604A (zh) * 2017-09-01 2020-02-21 四川科伦博泰生物医药股份有限公司 用于肿瘤治疗或预防的药物组合物、方法及其用途
US11266674B2 (en) 2017-09-01 2022-03-08 Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd. Pharmaceutical composition for tumor treatment or prevention, method, and use thereof
WO2019042226A1 (zh) 2017-09-01 2019-03-07 四川科伦博泰生物医药股份有限公司 用于肿瘤治疗或预防的药物组合物、方法及其用途
US11141421B2 (en) 2018-01-29 2021-10-12 Fujifilm Corporation Antitumor agent for biliary tract cancer and method for treating biliary tract cancer
WO2019146130A1 (ja) * 2018-01-29 2019-08-01 富士フイルム株式会社 胆道がん用抗腫瘍剤および胆道がんの処置方法
JP2021522197A (ja) * 2018-04-19 2021-08-30 サウザーン リサーチ インスチチュート 癌の治療のための４’−チオ−ヌクレオチドおよび−ヌクレオシドプロドラッグ
JP7419259B2 (ja) 2018-04-19 2024-01-22 サウザーン リサーチ インスチチュート 癌の治療のための４’－チオ－ヌクレオチドおよび－ヌクレオシドプロドラッグ
CN112770731A (zh) * 2018-11-28 2021-05-07 四川科伦博泰生物医药股份有限公司 以4’-硫代核苷类化合物为活性成分的口服药物组合物、其制备方法及其用途
WO2020108343A1 (zh) * 2018-11-28 2020-06-04 四川科伦博泰生物医药股份有限公司 以4'-硫代核苷类化合物为活性成分的口服药物组合物、其制备方法及其用途

Also Published As

Publication number Publication date
HK1232229A1 (zh) 2018-01-05
EP3279207A1 (en) 2018-02-07
EA201791535A1 (ru) 2018-01-31
US20180079770A1 (en) 2018-03-22
CN106661077A (zh) 2017-05-10
AU2016240117C1 (en) 2020-11-26
JP2018513832A (ja) 2018-05-31
US20200262860A1 (en) 2020-08-20
CN109553651A (zh) 2019-04-02
EA034375B1 (ru) 2020-01-31
EP3279207A4 (en) 2018-11-14
CN109553651B (zh) 2021-08-06
HK1243424A1 (zh) 2018-07-13
AU2016240117A1 (en) 2017-08-24
AU2016240117B2 (en) 2020-08-06
EP3279207B1 (en) 2024-01-24
JP6769000B2 (ja) 2020-10-14
US10662214B2 (en) 2020-05-26
CA2975990A1 (en) 2016-10-06
CN106661077B (zh) 2019-02-12

Similar Documents

Publication Publication Date Title
WO2016155593A1 (zh) 4'-硫代核苷的新型化合物及其制备方法、药物组合物和应用
AU2015349390B2 (en) New type of cytidine derivative and application thereof
PL167682B1 (pl) (1H) -plrymidyn-2-onu PL PL PL PL PL PL PL PL PL PL PL
JP2010202655A (ja) チオアラビノフラノシル化合物の製造方法
EP3560921B1 (en) Quinazoline compound, preparation method, application as pi3k inhibitor for the treatment of cancer, and pharmaceutical compostion thereof
CA3097003A1 (en) 4'-thio-nucleotide and -nucleoside prodrugs for the treatment of cancer
CN101787064B (zh) 阿糖胞苷衍生物及其在抗癌抗肿瘤中的用途
US10500224B2 (en) Mutual prodrug comprising short chain fatty acids and zebularine or 1'-cyano-cytarabine for cancer treatment
TW201734028A (zh) 抑制癌症及病毒之化合物
KR20060127906A (ko) 4'-치환된 카보버와 아바카비어 유도체 및 ｈｉｖ와 ｈｃｖ항바이러스 활성을 갖는 관련 화합물
TWI477508B (zh) 用以治療癌症之組成物及方法
CN113366008A (zh) 一种cd73抑制剂，其制备方法和应用
WO2019080724A1 (zh) 核苷磷酸类化合物及其制备方法和用途
TWI794576B (zh) 一類含氟取代的苯并噻吩類化合物及其藥物組合物及應用
CN111655710B (zh) 吉西他滨含磷前药
CN101787065B (zh) 阿糖胞苷前药衍生物及其在抗癌抗肿瘤中的用途
KR0137763B1 (ko) 항종양 6-술펜아미드, 6-술핀아미드 및 6-술폰아미드퓨린, 퓨린 뉴클레오시드, 퓨린 뉴클레오티드 및 관련 화합물
AU2022339679A1 (en) 2'-chloro-2'-fluoro-n2-amino-n6-methylamino purine nucleotides for flavivirus treatment
WO2023034617A1 (en) 2'-chloro-2'-fluoro-n2-amino-n6-methylamino purine nucleotides for flavivirus treatment
KR20220050181A (ko) 아민, 아미드 및 페놀 전달에 유용한 프로드러그 플랫폼

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16771348

Country of ref document: EP

Kind code of ref document: A1

REEP Request for entry into the european phase

Ref document number: 2016771348

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2975990

Country of ref document: CA

Ref document number: 2017541855

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 201791535

Country of ref document: EA

ENP Entry into the national phase

Ref document number: 2016240117

Country of ref document: AU

Date of ref document: 20160328

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 15558620

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE