WO2019120300A1 - 肝递送阿糖胞苷前体药物核苷环磷酸酯化合物及应用 - Google Patents

肝递送阿糖胞苷前体药物核苷环磷酸酯化合物及应用 Download PDF

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WO2019120300A1
WO2019120300A1 PCT/CN2018/122822 CN2018122822W WO2019120300A1 WO 2019120300 A1 WO2019120300 A1 WO 2019120300A1 CN 2018122822 W CN2018122822 W CN 2018122822W WO 2019120300 A1 WO2019120300 A1 WO 2019120300A1
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compound
formula
substituted
unsubstituted
group
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PCT/CN2018/122822
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French (fr)
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席志坚
徐华强
陆春平
伍中山
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浙江柏拉阿图医药科技有限公司
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Application filed by 浙江柏拉阿图医药科技有限公司 filed Critical 浙江柏拉阿图医药科技有限公司
Priority to ES18892537T priority Critical patent/ES2958817T3/es
Priority to JP2020533228A priority patent/JP2021506841A/ja
Priority to CN201880088159.XA priority patent/CN111655703B/zh
Priority to EP18892537.4A priority patent/EP3730504B1/en
Publication of WO2019120300A1 publication Critical patent/WO2019120300A1/zh
Priority to US16/907,215 priority patent/US10899787B2/en

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    • 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
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C07F9/65742—Esters of oxyacids of phosphorus non-condensed with carbocyclic rings or heterocyclic rings or ring systems
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/02—Phosphorylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • 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
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/11—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
    • 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

Definitions

  • the present invention relates to an anticancer prodrug based on liver specific delivery (LSD), a preparation and application of a nucleoside cyclic phosphate compound, or an optical isomer, a hydrate thereof, a solvent Compounds, pharmaceutically acceptable salts, and pharmaceutical compositions.
  • LSD liver specific delivery
  • Liver cancer is a primary malignant tumor that occurs in the liver and is common in patients with cirrhosis or liver fibrosis. According to WHO statistics, more than 700,000 people die of liver cancer every year worldwide, and liver cancer is the second most common cancer. Viral hepatitis is an important cause of liver cancer. In Asia and Africa, the prevalence of hepatitis B and C is the highest incidence of liver cancer. At present, the treatment of liver cancer is a multidisciplinary comprehensive treatment, mainly including surgery, local ablation therapy, interventional therapy, radiotherapy, chemotherapy, targeted therapy.
  • nucleoside chemotherapy drugs for treating liver cancer are limited, and only fluorouracil is used for second-line treatment, and cytarabine is not suitable for solid tumors such as liver cancer.
  • Cytarabine needs to be converted into a monophosphate form by deoxycytidine kinase in cells, and further phosphorylated into a triphosphate form to inhibit DNA replication of tumor cells, resulting in the lack of deoxycytidine kinase in solid tumors.
  • the active ingredient in the tumor is less, and the treatment effect is not good.
  • the present invention utilizes a liver-specific delivery technique that bypasses the deoxycytidine kinase phosphorylation step and successfully increases the concentration of active ingredients in the liver.
  • the cyclic phosphate-modified cytarabine prodrug is metabolized by the CYP3A enzyme in the liver, and does not require deoxycytidine kinase to form a monophosphate compound.
  • the cyclic phosphate (4-aryl-2-oxo-1,3,2-dioxaphosphane) precursor structure has good liver-specific delivery properties, and the mechanism is very clear. That is, the 4-aryl substitution position is specifically catalyzed by CYP3A in the cytochrome P450 isozyme family in hepatocytes to form a hydroxyl group, which is then ring-opened to form a negatively charged phosphate intermediate, which is not easily present through the cell membrane.
  • a nucleotide monophosphate compound is formed, and a nucleotide triphosphate compound is continuously produced under the action of a nucleotide kinase, and at the same time, metabolism
  • the by-product aryl vinyl ketone can be removed by a 1,4-addition reaction with abundant antioxidant and free radical glutathione in hepatocytes, and no side effects of the addition product have been reported.
  • the cytarabine toxic side effects are relatively large, and the use of liver-specific delivery technology to enhance the concentration in the liver is beneficial to reduce toxic side effects.
  • the invention synthesizes an anti-cancer cytarabine cyclic phosphate, and then further modifies its aromatic ring substituent to obtain a class of prodrugs having a liver delivery effect, which has higher curative effect and less toxic side effects. advantage.
  • Each R 1 is independently selected from halogen, nitro, hydroxy, amino, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkane Oxy, substituted or unsubstituted C1-C6 alkylamino, -COOH, substituted or unsubstituted C2-C6 alkylcarboxy, substituted or unsubstituted C2-C6 ester, substituted or unsubstituted C2-C6 alkane
  • R 2 and R 3 are each independently halogen (F or Cl);
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C2-C12 alkanoyl, substituted Or an unsubstituted C2-C11 ester group (ie, -CO-O-C1-C10 alkyl); wherein said substitution has one or more substituents selected from the group consisting of halogen, C1-C3 alkyl , C1-C3 haloalkyl, nitro, hydroxy, -NRaRb, cyano, wherein Ra and Rb are each independently H, C1-C3 alkyl, C3-C6 cycloalkyl, or C1-C3 haloalkyl;
  • n 0, 1, 2 or 3.
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted a C2-C6 ester group, a substituted or unsubstituted C2-C6 alkanoyl group; wherein said substitution has one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl , nitro, hydroxy, amino, cyano.
  • each of the other chiral centers is R-type or S-type;
  • R 2 is Cl and R 3 is F; or R 2 is Cl and R 3 is Cl; or R 2 is F, and R 3 is Cl.
  • the optical isomers include tautomers, cis and trans isomers, conformational isomers, meso compounds, and optical isomers having enantiomeric or diastereomeric relationships. .
  • the compound is selected from the group consisting of:
  • the salt of the compound of Formula I and Formula II is a pharmaceutically acceptable salt of a compound of Formulas I and II with an inorganic or organic acid, or Formula I and
  • the salt of the compound of the formula II is a pharmaceutically acceptable salt formed by reacting a compound of the formula I and formula II with a base.
  • the compound of the formula I and formula II or a salt thereof is an amorphous substance or a crystal.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound as described in the first aspect of the invention, or an optical isomer thereof, a pharmaceutically acceptable salt thereof a hydrate or solvate; and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a third aspect of the invention provides the use of a compound according to the first aspect of the invention, or an optical isomer, pharmaceutically acceptable salt, hydrate or solvate thereof, for the preparation of a medicament for the treatment and/or prevention of cancer In particular, a pharmaceutical composition of liver cancer.
  • a process for the preparation of a compound of formula I according to the first aspect of the invention comprising the steps of:
  • each group is as defined above.
  • the reagent in the step (ia), is selected from the group consisting of dicyclohexylcarbodiimide (DCC), triethylamine, N,N-diisopropylethylamine. Or a combination thereof; preferably DCC and triethylamine.
  • DCC dicyclohexylcarbodiimide
  • N,N-diisopropylethylamine or a combination thereof; preferably DCC and triethylamine.
  • the inert solvent is selected from the group consisting of N,N-dimethylformamide, dichloromethane, tetrahydrofuran or a combination thereof; preferably N, N - dimethylformamide and dichloromethane solvent.
  • reaction temperature of the step (i-a) is from 0 to 100 ° C (preferably at about 25 ⁇ 5 ° C).
  • reaction time of the deprotection reaction of the step (i-a) is from 0.5 to 24 hours, preferably from 0.5 to 8 hours.
  • the de-TBS reagent is selected from the group consisting of TBAF, glacial acetic acid, dilute hydrochloric acid or a combination thereof; preferably an ethanolic hydrochloric acid solution and TBAF.
  • the inert solvent is selected from the group consisting of N,N-dimethylformamide, tetrahydrofuran or a combination thereof; preferably a tetrahydrofuran solvent.
  • reaction temperature of the step (i-b) is -50 to 30 ° C (preferably at about 25 ⁇ 5 ° C).
  • reaction time of the deprotection reaction of the step (i-b) is from 0.5 to 6 hours, preferably from 0.5 to 3 hours, more preferably from 0.5 to 2 hours.
  • the compound of formula IIa is prepared by the following method:
  • the reaction in the step (i-c), is carried out in the presence of a Grignard reagent; preferably, the Grignard reagent is selected from the group consisting of t-butylmagnesium chloride (t-BuMgCl).
  • a Grignard reagent is selected from the group consisting of t-butylmagnesium chloride (t-BuMgCl).
  • the substitution reaction of the step (i-c) is carried out at -50 to 30 ° C (preferably at about 25 ⁇ 5 ° C).
  • reaction time of the substitution reaction of the step (i-c) is from 1 to 72 hours, preferably from 3 to 48 hours, more preferably from 6 to 24 hours.
  • the inert solvent of the step (i-c) is selected from the group consisting of N,N-dimethylformamide, tetrahydrofuran, or a combination thereof; preferably a tetrahydrofuran solvent.
  • ARA-C cytarabine, 4-amino-1-B-D-arabinofuranosyl-2(1H)-pyrimidinone (CAS: 147-94-4)
  • ARA-CMP 4-amino-1-B-D-5'-arabinofuranosyl-2(1H)-pyrimidinone
  • the present inventors After long-term and in-depth research, the present inventors have discovered for the first time through a screening study of a large number of compounds: a class of compounds of formula I and formula II having a specific structure (wherein the 2 and 5 positions of the benzene ring moiety are specific halogens), Surprisingly, it has very excellent anti-liver cancer activity, significantly improved liver delivery, and significantly reduced toxic side effects. Based on the above findings, the inventors completed the present invention.
  • C1-C6 alkyl refers to a straight or branched alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, A sec-butyl group, a tert-butyl group, or the like.
  • C2-C6 alkanoyl refers to a substituent of the structure “linear or branched alkyl-carbonyl having 1 to 6 carbon atoms", such as acetyl, propionyl, butyryl, or Similar group.
  • C1-C6 alkylamino refers to a substituent of the form “linear or branched alkyl-amino" having 1 to 6 carbon atoms, such as methylamino, dimethylamino. , ethylamino, propylamino, diethylamino, or the like.
  • halogen refers to F, Cl, Br and I.
  • the terms "containing”, “comprising” or “including” mean that the various ingredients may be used together in the mixture or composition of the present invention. Therefore, the terms “consisting essentially of” and “consisting of” are encompassed by the term “contains.”
  • the term "pharmaceutically acceptable” ingredient means a substance which is suitable for use in humans and/or animals without excessive adverse side effects (e.g., toxicity, irritation, and allergic reaction), i.e., having a reasonable benefit/risk ratio.
  • the term "effective amount" means an amount of a therapeutic agent that treats, alleviates or prevents a target disease or condition, or an amount that exhibits a detectable therapeutic or prophylactic effect.
  • the precise effective amount for a subject will depend on the size and health of the subject, the nature and extent of the condition, and the combination of therapeutic and/or therapeutic agents selected for administration. Therefore, it is useless to specify an accurate effective amount in advance. However, for a given condition, routine experimentation can be used to determine the effective amount that the clinician can determine.
  • substituted means that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitrate Base, hydroxyl, amino, cyano group.
  • each of the chiral carbon atoms may be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.
  • compound of the invention refers to a compound of formula I and formula II.
  • the term also encompasses various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of Formula I and Formula II.
  • the term "pharmaceutically acceptable salt” refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • solvates of the present invention include stoichiometric solvates such as hydrates and the like, as well as compounds containing variable amounts of water formed upon preparation by low pressure sublimation drying.
  • thermodynamically stable isomers may be present after preparation of the compounds of the invention, such as tautomers, conformers, meso compounds, and optical isomers having enantiomeric or diastereomeric relationships.
  • tautomers such as tautomers, conformers, meso compounds, and optical isomers having enantiomeric or diastereomeric relationships.
  • Each R 1 is independently selected from halogen, nitro, hydroxy, amino, cyano, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 alkane Oxy, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 carboxyl, substituted or unsubstituted C1-C6 ester, substituted or unsubstituted C2-C6 alkanoyl, substituted or not a substituted C2-C6 alkanoamide group; wherein said substituent has one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, hydroxy, amino, Cyano group
  • n 0, 1, 2 or 3;
  • R 2 and R 3 are each independently halogen (F or Cl);
  • R 4 and R 5 are independently selected from hydrogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C1-C6 ester group, substituted or unsubstituted C2 a -C6 alkanoyl group; wherein said substituent has one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, hydroxy, amino, cyano;
  • the other chiral centers are R-type or S-type.
  • the compound may be a racemate or an optical isomer, both of which have certain therapeutic activity against liver cancer.
  • Preferred compounds of formula I have a structure selected from the group consisting of:
  • the P2 and the aromatic group at the 4-position in the phosphate ring structure are cis to each other, and P2 is in the R configuration, and C4 is in the S-form.
  • R 2 is Cl and R 3 is F; or R 2 is Cl and R 3 is Cl; or R 2 is F, and R 3 is Cl.
  • the optical isomers include tautomers, cis and trans isomers, conformational isomers, meso compounds, and optical isomers having enantiomeric or diastereomeric relationships. .
  • the compound is selected from the group consisting of:
  • each of the reactants may be commercially available or may be prepared by a conventional method in the art using commercially available raw materials.
  • the compound of the present invention has excellent inhibitory activity against liver cancer
  • the compound of the present invention and various crystal forms thereof, a pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and a compound containing the present invention are main active ingredients.
  • the pharmaceutical composition can be used to treat, prevent, and alleviate cancer, particularly liver cancer and its associated symptoms. .
  • compositions of the present invention comprise a safe or effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 0.1 to 1000 mg of the compound/agent of the invention, more preferably from 0.5 to 500 mg of the compound/agent of the invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • a particularly preferred mode of administration is oral.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for the compounds of the invention for topical administration include ointments, powders, patches, propellants and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually 0.2 to 1000 mg, preferably 0.5 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the liver is highly deliverable, and the compound can only be specifically catalyzed by CYP3A in the cytochrome P450 isozyme family in hepatocytes to form an active molecule, which has a high negative charge and is not easily discharged outside the liver, so The liver has a higher concentration and achieves liver delivery.
  • the compound PA4101-2 (20.6 g, 35.2 mmol) was dissolved in a 0.5% aqueous solution of hydrochloric acid (610 mL), and the reaction mixture was stirred at room temperature for 4.5 hours (trace by TLC or LCMS, the reaction was completed) and neutralized with saturated NaHCO 3 solution.
  • reaction mixture was stirred at room temperature for 1 hour, and then cooled to 0 ° C, and then added to a solution of PA4107-1 (0.38 g, 0.94 mmol), stirred at room temperature overnight, and then quenched with saturated ammonium chloride solution (10 mL) The extract was extracted with ethyl acetate (3 ⁇ 25 mL), EtOAc (EtOAc)EtOAc.
  • the compound PA4101-4 (200 mg, 0.38 mmol) was dissolved in tetrahydrofuran (10 mL) under a nitrogen atmosphere, cooled to 0 ° C in an ice bath, and a 1 M solution of tert-butylmagnesium chloride (1.4 mL, 1.4 mmol) was slowly added dropwise. After that, the reaction mixture was stirred at room temperature for 1 hour, and then cooled to 0 ° C, and then added to EtOAc (211 mg, 0.57 mmol), and stirred at room temperature overnight.
  • Recombinant human CYP3A4 enzyme was purchased from BD Corporation, batch number 3100772.
  • test compounds PA4101, PA4102, PA4103, PA4104, PA4105, PA4106, PA4107, PA4108, PA4109, PA4110 and PA4111 were synthesized by Zhejiang Plato Pharmaceutical Technology Co., Ltd., dissolved in methanol (national medicine reagent), and stored at a concentration of 100 ⁇ M. liquid.
  • the enzymatic reaction was carried out in a 100 mM KH 2 PO 4 buffer solution (pH 7.4) at a test compound concentration of 100 nM, a human liver microsome concentration of 0.1 nmol/ml, and a NADPH concentration of 2 mM.
  • the reaction was initiated by the last addition of NADPH, sampled in a constant temperature shaking water bath for 1, 5, 10, 20, 30 min, and immediately 1.5 times the volume of methanol was added to terminate the reaction.
  • the ion source is an electrospray ionization source (Turbo Ionspray); positive ion mode; capillary voltage is 3.0 kV; temperature is 500 ° C; desolvation gas flow 1000 L/h; scan time, cone voltage, collision energy and ions for quantitative analysis
  • the reaction is shown in the table below (Table 3):
  • PA4101 492 169 0.1 twenty four twenty two PA4102 441 330 0.1 32 12 PA4103 508 185 0.1 38 twenty two PA4104 476 153 0.1 28 26 PA4105 492 169 0.1 18 20 PA4106 492 169 0.1 28 twenty two PA4107 492 169 0.1 36 18 PA4108 492 169 0.1 32 26 PA4109 508 185 0.1 32 20 PA4110 476 153 0.1 16 twenty two PA4111 476 153 0.1 28 18

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Abstract

一类基于肝脏特异性递送技术（肝递送）（Liver specific Delivery（LSD））的抗癌前体药物核苷环磷酸酯化合物及其应用被公开，具体地，提供了式（I）化合物及其异构体、可药用盐、水合物、溶剂化物、相应的药物组合物以及所述化合物单独或与其它抗癌药物联合在抗癌中的应用，特别是在治疗肝癌（HCC）中的应用。

Description

肝递送阿糖胞苷前体药物核苷环磷酸酯化合物及应用 技术领域
本发明涉及基于肝脏特异性递送技术(肝递送)(Liver Specific Delivery(LSD))的抗癌前体药物，核苷环磷酸酯化合物的制备及应用，或其光学异构体、水合物、溶剂化物、可药用盐以及药物组合物。
背景技术
肝癌是发生在肝脏的原发性恶性肿瘤，常见于发生肝硬化或者肝纤维化的病人。据WHO统计，世界范围内每年因肝癌死亡的人数超过70万，肝癌是第二大致死癌症。病毒性肝炎是导致肝癌的重要诱因，亚洲和非洲因乙型和丙型病毒性肝炎流行成为肝癌最高发的地区。目前，针对肝癌的治疗是多学科的综合治疗，主要有手术、局部消融治疗、介入治疗、放疗、化疗、靶向治疗等。
目前治疗肝癌的核苷类化疗药物有限，只有氟尿嘧啶用于二线治疗，阿糖胞苷不适用于肝癌这样的实体瘤。阿糖胞苷需要在细胞内经过脱氧胞苷激酶的作用转化为单磷酸形式，再进一步磷酸化为三磷酸形式，才能抑制肿瘤细胞的DNA复制，由于实体瘤中缺乏脱氧胞苷激酶，导致实体瘤中活性成分偏少，治疗效果不佳。
本发明利用肝脏特异性递送技术，绕过了脱氧胞苷激酶磷酸化步骤，并且成功提高了肝中活性成分的浓度。
环状磷酸酯修饰的阿糖胞苷前药，在肝中经过CYP3A酶代谢，不需要脱氧胞苷激酶，生成单磷酸化合物。具体而言，环状磷酸酯(4-芳基-2-氧代-1,3,2-二氧杂磷杂环己烷)前体结构有很好的肝脏特异性递送性能，机理非常明确，即4-芳基取代位置被肝细胞中的细胞色素P450同功酶家族中的CYP3A特异性催化，生成羟基，然后开环生成带负电荷的磷酸中间体，该物质不易通过细胞膜而存在细胞内，在磷酸二酯酶催化下，经过水解，β-消除反应，生成核苷酸单磷酸化合物，继续在核苷酸激酶作用下，生成具有生物活性的核苷酸三磷酸化合物，同时，代谢副产物芳基乙烯基酮能与肝细胞中含量丰富的抗氧化和自由基的谷胱甘肽发生1,4-加成反应而被清除，尚未发现该加成产物具有副作用的报道。
阿糖胞苷毒副作用比较大，利用肝脏特异性递送技术，增强肝中浓度，有利于降低毒副作用。
目前尚缺乏活性高、肝递送性强且副作用低的抗肝脏肿瘤药物。因此，本领域迫切需要开发具有更强肝脏特异性且副作用低的高活性抗肿瘤药物。
发明内容
本发明合成了抗癌的阿糖胞苷环状磷酸酯，然后对其芳环取代基进一步的改造，得到一类更具有肝递送作用的前药，使其疗效更高，毒副作用更小的优点。
本发明的第一方面，提供了一种如式I所示的化合物，或其光学异构体、药学上可接受的盐、水合物或溶剂化物：
Figure PCTCN2018122822-appb-000001
其中：
各个R 1独自选自卤素、硝基、羟基、氨基、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基、-COOH、取代或未取代的C2-C6烷基羧基、取代或未取代的C2-C6酯基、取代或未取代的C2-C6烷酰基、取代或未取代的C2-C6烷酰胺基；其中，所述的取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基；
R 2、R 3各自独立地为卤素(F或Cl)；
R 4、R 5各自独立地选自下组：氢、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C2-C12烷酰基、取代或未取代的C2-C11酯基(即-CO-O-C1-C10烷基)；其中，所述的取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、-NRaRb、氰基，其中Ra和Rb各自独立地为H、C1-C3烷基、C3-C6环烷基、或C1-C3卤代烷基；
m为0、1、2或3。
在另一优选例中，R 4、R 5各自独立地选自下组：氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C2-C6酯基、取代或未取代的C2-C6烷酰基；其中，所述的取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基。
且式I和式II中，除已有手性外，其他各个手性中心为R型或S型；
在另一优选例中，R 2为Cl，且R 3为F；或R 2为Cl，且R 3为Cl；或R 2为F，且R 3为Cl。在另一优选例中，所述的光学异构体包括互变异构体，顺反异构体，构象异构体，内消旋化合物和具有对映或非对映关系的光学异构体。
在另一优选例中，所述的化合物选自下组：
Figure PCTCN2018122822-appb-000002
Figure PCTCN2018122822-appb-000003
在另一优选例中，所述式I和式II所示的化合物的盐为式I和式II所示的化合物与无机酸或有机酸所形成的可药用盐，或所述式I和式II所示的化合物的盐为式I和式II所示的化合物与碱反应所形成的可药用盐。所述的式I和式II所示的化合物或其盐为无定形物或晶体。
本发明的第二方面，提供了一种药物组合物，所述的药物组合物包括治疗有效量的如本发明第一方面中所述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂化物；和药学上可接受的辅助剂、稀释剂或载体。
本发明的第三方面，提供了如本发明第一方面所述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂化物的用途，用于制备治疗和/或预防癌症，特别是肝癌的药物组合物。本发明的第四方面，提供了一种如本发明第一方面所述的式I化合物的制备方法，所述方法包括步骤：
Figure PCTCN2018122822-appb-000004
(i-a)在惰性溶剂中，用式II化合物和酸、酰氯、卤代烷基反应，形成式I化合物；
式中，各基团的定义如上文中所述。
在另一优选例中，所述的步骤(i-a)中，所述的试剂选自下组：二环己基碳二亚胺(DCC)、三乙胺、N,N-二异丙基乙胺或其组合；优选为DCC和三乙胺。
在另一优选例中，所述的步骤(i-a)中，所述的惰性溶剂选自下组：N,N-二甲基甲酰胺、二氯甲烷、四氢呋喃或其组合；优选为N,N-二甲基甲酰胺和二氯甲烷溶剂。
在另一优选例中，所述的步骤(i-a)的反应温度为0-100℃(优选在25±5℃左右)。
在另一优选例中，所述的步骤(i-a)的去保护反应的反应时间为0.5-24小时，较佳地为0.5-8小时。
Figure PCTCN2018122822-appb-000005
(i-b)在惰性溶剂中，用式IIa化合物脱除TBS，形成式II化合物；
在另一优选例中，所述的步骤(i-b)中，所述的脱TBS试剂选自下组：TBAF、冰醋酸、稀盐酸或其组合；优选为盐酸乙醇溶液和TBAF。
在另一优选例中，所述的步骤(i-b)中，所述的惰性溶剂选自下组：N,N-二甲基甲酰胺、四氢呋喃或其组合；优选为四氢呋喃溶剂。
在另一优选例中，所述的步骤(i-b)的反应温度为-50-30℃(优选在25±5℃左右)。
在另一优选例中，所述的步骤(i-b)的去保护反应的反应时间为0.5-6小时，较佳地为0.5-3小时，更佳地为0.5-2小时。
在另一优选例中，所述的式IIa化合物是通过以下方法制备的：
Figure PCTCN2018122822-appb-000006
(i-c)在惰性溶剂中，将式Ic化合物与PA4101-4进行取代反应，得到式IIa化合物；
在另一优选例中，在步骤(i-c)中，所述反应在格氏试剂存在下进行；较佳地，所述的格氏试剂选自下组：叔丁基氯化镁(t-BuMgCl)。
在另一优选例中，所述的步骤(i-c)的取代反应在-50-30℃下(优选在25±5℃左右)进行。
在另一优选例中，所述的步骤(i-c)的取代反应的反应时间为1-72小时，较佳地为3-48小时，更佳地为6-24小时。
在另一优选例中，所述的步骤(i-c)的惰性溶剂选自下组：N,N-二甲基甲酰胺、四氢呋喃、或其组合；优选为四氢呋喃溶剂。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
注释：
ARA-C：阿糖胞苷，4-氨基-1-B-D-阿拉伯呋喃糖基-2(1H)-嘧啶酮(CAS：147-94-4)
ARA-CMP：4-氨基-1-B-D-5’-单磷酸阿拉伯呋喃糖基-2(1H)-嘧啶酮
具体实施方式
本发明人经过长期而深入的研究，通过对大量化合物的筛选研究，首次发现：一类具有特定结构的式I和式II化合物(其中苯环部分的2位和5位为特定的卤素)，令人意外地具有非常优异的抗肝癌活性、显著提高的肝递送性以及显著降低的毒副作用。基于上述发现，发明人完成了本发明。
术语
如本文所用，术语“C1-C6烷基”指具有1～6个碳原子的直链或支链烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基，或类似基团。
如本文所用，术语“C2-C6烷酰基”指形如“具有1～6个碳原子的直链或支链烷基-羰基”结构的取代基，如乙酰基、丙酰基、丁酰基，或类似基团。
如本文所用，术语“C1-C6烷胺基”指形如“具有1～6个碳原子的直链或支链烷基-胺基”结构的取代基，如甲胺基、二甲胺基、乙胺基、丙胺基、二乙胺基，或类似基团。
术语“卤素”指F、Cl、Br和I。
本发明中，术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
本发明中，术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反 应(如毒性、刺激和变态反应)，即有合理的效益/风险比的物质。
本发明中，术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量，或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此，预先指定准确的有效量是没用的。然而，对于某给定的状况而言，可以用常规实验来确定该有效量，临床医师是能够判断出来的。
在本文中，除特别说明之处，术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代：卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基。
除非特别说明，本发明中，所有出现的化合物均意在包括所有可能的光学异构体，如单一手性的化合物，或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中，各手性碳原子可以任选地为R构型或S构型，或R构型和S构型的混合物。
如本文所用，术语“本发明化合物”指式I和式II所示的化合物。该术语还包括及式I和式II化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
如本文所用，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸，苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。
本发明中的一些化合物可能用水或各种有机溶剂结晶或重结晶，在这种情况下，可能形成各种溶剂化物。本发明的溶剂合物包括化学计量的溶剂化物如水合物等，也包括在用低压升华干燥法制备时形成的包含可变量水的化合物。
应理解,本发明的化合物制备后可能存在各种热力学稳定的异构体,如互变异构体、构象异构体、内消旋化合物和具有对映或非对映关系的光学异构体等,上述改变形式在阅读了本发明的公开之后,对于本领域技术人员而言是显而易见的。
式I化合物及其制备
为了提供一种能够通过肝递送机制，让抗癌的核苷酸类药物集中在肝细胞中释放的高效、低毒的肝递送前体药物，发明人制备了式I化合物：
Figure PCTCN2018122822-appb-000007
其中：
各R 1独自选自卤素、硝基、羟基、氨基、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基、取代或未取代的C1-C6羧基、取代或未取代的C1-C6酯基、取代或未取代的C2-C6烷酰基、取代或未取代的C2-C6烷酰胺基；其中，所述的取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基；
m为0、1、2或3；
R 2、R 3各自独立地为卤素(F或Cl)；
R 4、R 5独自选自氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6酯基、取代或未取代的C2-C6烷酰基；其中，所述的取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基；
且式I中，除已有手性外，其他各个手性中心为R型或S型。
所述的化合物可以是消旋体，或为光学异构体，两者皆具有一定的肝癌治疗活性。优选的所述的式I化合物具有选自下组的结构：
Figure PCTCN2018122822-appb-000008
在另一优选例中，所述的P2与磷酸酯环结构中4位的芳香基团互为顺式，且P2为R构型，C4为S型。
在另一优选例中，R 2为Cl，且R 3为F；或R 2为Cl，且R 3为Cl；或R 2为F，且R 3为Cl。
在另一优选例中，所述的光学异构体包括互变异构体，顺反异构体，构象异构体，内消旋化合物和具有对映或非对映关系的光学异构体。
在另一优选例中，所述的化合物选自下组：
Figure PCTCN2018122822-appb-000009
通式I化合物的制备方法如下：
在四氢呋喃溶液中，加入PA4101-4化合物，然后0℃下，滴加叔丁基氯化镁，反应30分钟，然后一次性加入Ic化合物，反应过夜，淬灭，硅胶柱层析纯化，得中间体IIa，IIa加入盐酸乙醇溶液，脱去保护基TBS，得通式IIa化合物，II和酸、酰氯、卤代烷基反应得通式I化合物。
Figure PCTCN2018122822-appb-000010
其中，各个反应物可以通过市售途径购得，也可以采用市售的原料，通过本领域常规的方法制备。
药物组合物和施用方法
由于本发明化合物具有优异的对肝癌的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解癌症，特别是肝癌及其相关的症状。。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有0.1-1000mg本发明化合物/剂，更佳地，含有0.5～500mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂
Figure PCTCN2018122822-appb-000011
润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。特别优选的施用方式是口服。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为0.2～1000mg，优选0.5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
(1)肝递送性高，化合物只能被肝细胞中的细胞色素P450同功酶家族中的CYP3A特异性催化，生成活性分子，该活性分子带高负电荷，不容易排出肝外，所以在肝中浓度更高，达到肝递送效果。
(2)活性高，因为肝递送性，所以更多的药物存在肝中，抗癌活性也能大大的提高。
(3)毒副作用低：同等剂量的前药，在肝外代谢成活性分子的量很少，所以对肾脏、骨髓等主要脏器的毒性大大降低。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1 PA4101
合成路线：
Figure PCTCN2018122822-appb-000012
实验部分：
步骤1)化合物PA4101-2的合成：
化合物PA4101-1(Cytarbine，9.5g，39mmol)和咪唑(18g，264mmol)溶于DMF(100mL)中，加入4-二甲氨基吡啶((DMAP，3.8g，31mmol)，在冰浴下慢慢加入叔丁基二甲基氯硅烷(TBSCl，30g，198mmol)，氮气保护下，反应在63℃搅拌过夜,反应结束后，反应液缓慢加入水(400mL)中，乙酸乙酯(3×300mL)萃取，饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，硅胶柱层析分离纯化得PA4101-2(20.6g)，产率90％。
步骤2)化合物PA4101-3的合成：
化合物PA4101-2(20.6g,35.2mmol)溶于0.5％的盐酸乙醇溶液(610mL)中，反应液在室温下搅拌4.5小时后(TLC或LCMS跟踪，反应完全)，用饱和NaHCO 3溶液中和，旋蒸去除乙醇，加入水(200mL)，用乙酸乙酯(3×200mL)萃取，无水硫酸钠干燥，过滤，旋干，硅胶柱层析分离纯化(洗脱剂为：PE：EA：CH 3OH(V:V)＝150:150:4.5)得到白色固体化合物PA4101-3(14.7g)，产率89％。
步骤3)化合物PA4101-4的合成：
化合物PA4101-3(14.7g,31.2mmol)溶于吡啶溶剂(50mL)中，加入N,N-二甲基甲酰胺甲缩醛(4.83g,40.5mmol)，反应在室温下搅拌过夜，旋蒸去除吡啶，得粗品，硅胶柱层析分离纯化(洗脱剂:二氯甲烷:甲醇(V:V)＝100:3)得到白色固体化合物PA4101-4(13.0g)，产率79％。
步骤4)化合物PA4101-6的合成：
化合物PA4101-4(6.7g,12.7mmol)在氮气保护下溶于四氢呋喃(130mL)中，冰浴冷却至0℃，缓慢滴加1M的叔丁基氯化镁溶液(50.0mL,50mmol)，滴加完毕后，反应液在室温下搅拌1小时，再冷却到0℃，加入PA4101-5(6.4g,16.5mmol)，室温下搅拌反应12h，反应结束后用饱和氯化铵溶液(50mL)淬灭，乙酸乙酯(3×200mL)萃取，饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离纯化得白色固体化合物PA4101-6(6.15g)，产率67％。
步骤5)化合物PA4101的合成：
化合物PA4101-6(11.5g,16mmol)溶于12％的盐酸乙醇溶液中，室温下搅拌反应过夜。TLC显示反应完毕后，用氨水调pH值至8-9，旋蒸去除乙醇后加水(100mL)，用乙酸乙酯(3×100mL)萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，通过Combiflash色谱柱纯化，得白色固体PA4101(4.5g)，产率57％。
实施例2 PA4102(对比例)
合成路线：
Figure PCTCN2018122822-appb-000013
实验部分：
步骤1)化合物PA4102-2的合成：
化合物PA4101-4(2.79g,5.3mmol)在氮气保护下溶于四氢呋喃(60mL)中，冰浴冷却至0℃，缓慢滴加1M的叔丁基氯化镁溶液(26.0mL,26.0mmol)，滴加完毕后，反应液在室温下搅拌1小时,再冷却到0℃，加入PA4102-1(2.13g,6.3mmol)，室温下搅拌过夜，反应结束后用饱和氯化铵溶液(30mL)淬灭反应，乙酸乙酯(3×150mL)萃取，饱和食盐水洗， 无水硫酸钠干燥，旋干，硅胶柱层析分离纯化得白色固体化合物PA4102-2(0.68g)，产率19.2％。
步骤2)目标化合物PA4102的合成：
化合物PA4102-2(0.68g,1mmol)溶于3.6％的盐酸乙醇溶液(15mL)中，室温下搅拌反应过夜。TLC显示反应完毕后，用氨水调pH值至8-9，旋蒸去除乙醇后加水(50mL)，用乙酸乙酯(3×50mL)萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，通过Combiflash色谱柱纯化，得白色固体PA4102(300mg)，产率71％。
实施例3 PA4103
合成路线：
Figure PCTCN2018122822-appb-000014
实验部分：
步骤1)化合物PA4103-2的合成：
化合物PA4101-4(0.37g,0.7mmol)在氮气保护下溶于四氢呋喃(10mL)中，冰浴冷却至0℃，缓慢滴加1M的叔丁基氯化镁溶液(2.8mL,2.8mmol)，滴加完毕后，反应液在室温下搅拌1小时，再冷却到0℃，加入PA4103-1(0.38g,0.94mmol)，室温下搅拌过夜，反应结束后用饱和氯化铵溶液(10mL)淬灭反应，乙酸乙酯(3×25mL)萃取，饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离纯化得白色固体化合物PA4103-2(0.17g)，产率32％。
步骤2)目标化合物PA4103的合成：
化合物PA4103-2(0.17g,0.28mmol)溶于3.6％的盐酸乙醇溶液(4mL)中，室温下搅拌反应过夜。TLC显示反应完毕后，用氨水调pH值至8-9，旋蒸去除乙醇后加水(15mL)，用乙酸乙酯(3×50mL)萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，通过Combiflash色谱柱纯化，得白色固体PA4103(46mg)，产率39％。
实施例4 PA4104
合成路线：
Figure PCTCN2018122822-appb-000015
实验部分：
步骤1)化合物PA4104-2的合成：
化合物PA4101-4(0.37g,0.7mmol)在氮气保护下溶于四氢呋喃(10mL)中，冰浴冷却至0℃，缓慢滴加1M的叔丁基氯化镁溶液(2.8mL,2.8mmol)，滴加完毕后，反应液在室温下搅拌1小时，再冷却到0℃，加入PA4104-1(0.38g,0.94mmol)，室温下搅拌过夜，反应结束后用饱和氯化铵溶液(10mL)淬灭反应，乙酸乙酯(3×25mL)萃取，饱和食盐水 洗，无水硫酸钠干燥，旋干，硅胶柱层析分离纯化得白色固体化合物PA4104-2(0.32g)，产率65％。
步骤2)目标化合物PA4104的合成：
化合物PA4104-2(0.32g,0.46mmol)溶于3.6％的盐酸乙醇溶液(7mL)中，室温下搅拌反应过夜。TLC显示反应完毕后，用氨水调pH值至8-9，旋蒸去除乙醇后加水(25mL)，用乙酸乙酯(3×50mL)萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，通过Combiflash色谱柱纯化，得白色固体PA4104(43mg)，产率20％。
实施例5 PA4105
合成路线：
Figure PCTCN2018122822-appb-000016
实验部分：
步骤1)化合物PA4105-2的合成：
化合物PA4101-4(0.33g,0.64mmol)在氮气保护下溶于四氢呋喃(10mL)中，冰浴冷却至0℃，缓慢滴加1M的叔丁基氯化镁溶液(2.5mL,2.5mmol)，滴加完毕后，反应液在室温下搅拌1小时，再冷却到0℃，加入PA4105-1(0.38g,0.94mmol)，室温下搅拌过夜，反应结束后用饱和氯化铵溶液(10mL)淬灭反应，乙酸乙酯(3×25mL)萃取，饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离纯化得白色固体化合物PA4105-2(0.1g)，产率22％。
步骤2)目标化合物PA4105的合成：
化合物PA4105-2(0.1g,0.14mmol)溶于3.6％的盐酸乙醇溶液(3mL)中，室温下搅拌反应过夜。TLC显示反应完毕后，用氨水调pH值至8-9，旋蒸去除乙醇后加水(10mL)，用乙酸乙酯(3×40mL)萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，通过Combiflash色谱柱纯化，得白色固体PA4105(17mg)，产率24.5％。
实施例6 PA4106
合成路线：
Figure PCTCN2018122822-appb-000017
实验部分：
步骤1)化合物PA4106-2的合成：
化合物PA4101-4(0.33g,0.64mmol)在氮气保护下溶于四氢呋喃(10mL)中，冰浴冷却至0℃，缓慢滴加1M的叔丁基氯化镁溶液(2.5mL,2.5mmol)，滴加完毕后，反应液在室温下搅拌1小时，再冷却到0℃，加入PA4106-1(0.38g,0.94mmol)，室温下搅拌过夜，反应结束后用饱和氯化铵溶液(10mL)淬灭反应，乙酸乙酯(3×25mL)萃取，饱和食盐水 洗，无水硫酸钠干燥，旋干，硅胶柱层析分离纯化得白色固体化合物PA4106-2(0.22g)，产率48％。
步骤2)目标化合物PA4106的合成：
化合物PA4106-2(0.22g,0.3mmol)溶于3.6％的盐酸乙醇溶液(5mL)中，室温下搅拌反应过夜。TLC显示反应完毕后，用氨水调pH值至8-9，旋蒸去除乙醇后加水(20mL)，用乙酸乙酯(3×50mL)萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，通过Combiflash色谱柱纯化，得白色固体PA4106(45mg)，产率30％。
实施例7 PA4107
合成路线：
Figure PCTCN2018122822-appb-000018
实验部分：
步骤1)化合物PA4107-2的合成：
化合物PA4101-4(0.35g,0.66mmol)在氮气保护下溶于四氢呋喃(10mL)中，冰浴冷却至0℃，缓慢滴加1M的叔丁基氯化镁溶液(2.7mL,2.7mmol)，滴加完毕后，反应液在室温下搅拌1小时，再冷却到0℃，加入PA4107-1(0.38g,0.94mmol)，室温下搅拌过夜，反应结束后用饱和氯化铵溶液(10mL)淬灭反应，乙酸乙酯(3×25mL)萃取，饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离纯化得白色固体化合物PA4107-2(0.29g)，产率61.7％。
步骤2)目标化合物PA4107的合成：
化合物PA4107-2(0.29g,0.39mmol)溶于3.6％的盐酸乙醇溶液(5mL)中，室温下搅拌反应过夜。TLC显示反应完毕后，用氨水调pH值至8-9，旋蒸去除乙醇后加水(20mL)，用乙酸乙酯(3×50mL)萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，通过Combiflash色谱柱纯化，得白色固体PA4107(90mg)，产率47％。
实施例8 PA4108
合成路线：
Figure PCTCN2018122822-appb-000019
实验部分：
步骤1)化合物PA4108-2的合成：
化合物PA4101-4(380mg,0.72mmol)在氮气保护下溶于四氢呋喃(10mL)中，冰浴冷却至0℃，缓慢滴加1M的叔丁基氯化镁溶液(3mL,3mmol)，滴加完毕后，反应液在室温下搅拌1小时,再冷却到0℃，加入PA4108-1(0.32g,0.86mmol)，室温下搅拌过夜，反应结束后用饱和氯化铵溶液(15mL)淬灭反应，乙酸乙酯(3×150mL)萃取，饱和食盐水洗，无 水硫酸钠干燥，旋干，硅胶柱层析分离纯化得白色固体化合物PA4108-2(140mg)，产率27％。
步骤2)目标化合物PA4108的合成：
化合物PA4108-2(140mg,0.19mmol)溶于3.6％的盐酸乙醇溶液(3mL)中，室温下搅拌反应过夜。TLC显示反应完毕后，用氨水调pH值至8-9，旋蒸去除乙醇后加水(50mL)，用乙酸乙酯(3×50mL)萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，通过Combiflash色谱柱纯化，得白色固体PA4108(35mg)，产率36％。
实施例9 PA4109
合成路线：
Figure PCTCN2018122822-appb-000020
实验部分：
步骤1)化合物PA4109-2的合成：
化合物PA4101-4(380mg,0.72mmol)在氮气保护下溶于四氢呋喃(10mL)中，冰浴冷却至0℃，缓慢滴加1M的叔丁基氯化镁溶液(3mL,3mmol)，滴加完毕后，反应液在室温下搅拌1小时，再冷却到0℃，加入PA4109-1(350mg，0.86mmol)，室温下搅拌过夜，反应结束后用饱和氯化铵溶液(30mL)淬灭反应，乙酸乙酯(3×150mL)萃取，饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离纯化得白色固体化合物PA4109-2(310mg)，产率58.4％。
步骤2)目标化合物PA4109的合成：
化合物PA4109-2(310mg,0.42mmol)溶于3.6％的盐酸乙醇溶液(3mL)中，室温下搅拌反应过夜。TLC显示反应完毕后，用氨水调pH值至8-9，旋蒸去除乙醇后加水(50mL)，用乙酸乙酯(3×50mL)萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，通过Combiflash色谱柱纯化，得白色固体PA4109(110mg)，产率52％。
实施例10 PA4110
合成路线：
Figure PCTCN2018122822-appb-000021
实验部分：
步骤1)化合物PA4110-2的合成：
化合物PA4101-4(330mg,0.6mmol)在氮气保护下溶于四氢呋喃(10mL)中，冰浴冷却至0℃，缓慢滴加1M的叔丁基氯化镁溶液(3mL,3mmol)，滴加完毕后，反应液在室温下搅拌1小时,再冷却到0℃，加入PA4110-1(0.3g,0.8mmol)，室温下搅拌过夜，反应结束 后用饱和氯化铵溶液(30mL)淬灭反应，乙酸乙酯(3×150mL)萃取，饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离纯化得白色固体化合物PA4110-2(200mg)，产率45％。
步骤2)目标化合物PA4110的合成：
化合物PA4110-2(200mg,0.28mmol)溶于3.6％的盐酸乙醇溶液(3mL)中，室温下搅拌反应过夜。TLC显示反应完毕后，用氨水调pH值至8-9，旋蒸去除乙醇后加水(50mL)，用乙酸乙酯(3×50mL)萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，通过Combiflash色谱柱纯化，得白色固体PA4110(70mg)，产率52％。
实施例11 PA4111
合成路线：
Figure PCTCN2018122822-appb-000022
实验部分：
步骤1)化合物PA4111-2的合成：
化合物PA4101-4(200mg,0.38mmol)在氮气保护下溶于四氢呋喃(10mL)中，冰浴冷却至0℃，缓慢滴加1M的叔丁基氯化镁溶液(1.4mL,1.4mmol)，滴加完毕后，反应液在室温下搅拌1小时，再冷却到0℃，加入PA4111-1(211mg,0.57mmol)，室温下搅拌过夜，反应结束后用饱和氯化铵溶液(30mL)淬灭反应，乙酸乙酯(3×150mL)萃取，饱和食盐水洗，无水硫酸钠干燥，旋干，硅胶柱层析分离纯化得白色固体化合物PA4111-2(100mg)，产率34％。
步骤2)目标化合物PA4111的合成：
化合物PA4111-2(230mg,0.31mmol)溶于3.6％的盐酸乙醇溶液(15mL)中，室温下搅拌反应过夜。TLC显示反应完毕后，用氨水调pH值至8-9，旋蒸去除乙醇后加水(50mL)，用乙酸乙酯(3×50mL)萃取，有机相用饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，通过Combiflash色谱柱纯化，得白色固体PA4111(30mg)，产率48％。
表1各个实施例中所制备得到的化合物如下表中所示
Figure PCTCN2018122822-appb-000023
Figure PCTCN2018122822-appb-000024
Figure PCTCN2018122822-appb-000025
表2各个实施例中所制备得到的化合物核磁如下表中所示
Figure PCTCN2018122822-appb-000026
实施例12体外重组人CYP3A4代谢的评价
测定方法：
1)试剂来源
重组人CYP3A4酶购自BD公司，批号3100772。
测试化合物PA4101、PA4102、PA4103、PA4104、PA4105、PA4106、PA4107、PA4108、PA4109、PA4110和PA4111由浙江柏拉阿图医药科技有限公司合成，溶解于甲醇(国药试剂)，制成浓度为100μM的存储液。
2)反应过程
酶促反应在100mM KH 2PO 4缓冲溶液(pH 7.4)中进行，测试化合物浓度为100nM，人肝微粒体浓度为0.1nmol/ml，NADPH浓度为2mM。反应由最后加入的NADPH启动，在恒温震荡水浴锅内反1，5，10，20，30min后取样，立即加入1.5倍体积的甲醇以终止反应。
3)样品处理和分析方法
I样品前处理：
用Eppendorf台式离心机以最大转速13,600rpm离心20分钟。取上清液，用氮吹仪吹干之后重新溶解至流动相A(0.1％甲酸v/v的水溶液)。
II液相梯度：
Figure PCTCN2018122822-appb-000027
分析柱：Waters,Acquity UPLC HSS T3 column
流速：0.5ml/min
柱温：45摄氏度
III质谱条件
离子源为电喷雾电离源(Turbo Ionspray)；正离子模式；毛细管电压为3.0kV；温度为500℃；去溶剂气流1000L/h；扫描时间、锥孔电压、碰撞能量及用于定量分析的离子反应见下表(表3)：
表3，各分析物质谱条件
分析物 Q1(m/z) Q3(m/z) Dwell(s) Cone(V) Collision(V)
PA4101 492 169 0.1 24 22
PA4102 441 330 0.1 32 12
PA4103 508 185 0.1 38 22
PA4104 476 153 0.1 28 26
PA4105 492 169 0.1 18 20
PA4106 492 169 0.1 28 22
PA4107 492 169 0.1 36 18
PA4108 492 169 0.1 32 26
PA4109 508 185 0.1 32 20
PA4110 476 153 0.1 16 22
PA4111 476 153 0.1 28 18
表4体外重组人CYP3A4酶清除速率
Figure PCTCN2018122822-appb-000028
结果表明：在体外，所有化合物均被重组人CYP3A4酶清除，不同化合物的清除速率存在显著差异。出乎意料的是PA4109、PA4108和PA4101清除的速率远远高于PA4102(目前临床三期)。其中PA4109、PA4108和PA4101的转化速率分别约是PA4102的20.6倍、7.24倍和10.7倍(表4)，清除速率越高，生成活性单磷酸代谢产物就越多，就能产生更强的药理活性。
综上，由于本发明式I和式II化合物具有更高的活性，因此治疗时所需的用量更低，具有更高的安全性和更低的毒副作用。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种如下式I所示的化合物，或其光学异构体、药学上可接受的盐、水合物或溶剂化物：
    Figure PCTCN2018122822-appb-100001
    其中：
    各个R 1独自选自卤素、硝基、羟基、氨基、氰基、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C1-C6烷氧基、取代或未取代的C1-C6烷胺基、-COOH、取代或未取代的C2-C6烷基羧基、取代或未取代的C2-C6酯基、取代或未取代的C2-C6烷酰基、取代或未取代的C2-C6烷酰胺基；其中，所述的取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基；
    R 2、R 3各自独立地为卤素(F或Cl)；
    R 4、R 5各自独立地选自下组：氢、取代或未取代的C1-C10烷基、取代或未取代的C3-C10环烷基、取代或未取代的C2-C12烷酰基、取代或未取代的C2-C11酯基(即-CO-O-C1-C10烷基)；其中，所述的取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、-NRaRb、氰基，其中Ra和Rb各自独立地为H、C1-C3烷基、C3-C6环烷基、或C1-C3卤代烷基；
    m为0、1、2或3。
  2. 如权利要求1所述的化合物，其特征在于，R 4、R 5各自独立地选自下组：氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C2-C6酯基、取代或未取代的C2-C6烷酰基；其中，所述的取代指具有一个或多个选自下组的取代基：卤素、C1-C3烷基、C1-C3卤代烷基、硝基、羟基、氨基、氰基。
  3. 如权利要求1所述的化合物，其特征在于，所述的化合物选自下组：
    Figure PCTCN2018122822-appb-100002
  4. 如权利要求1-3任一所述的化合物，或其光学异构体、药学上可接受的盐、水合物或溶剂化物，其特征在于，R 2为Cl，且R 3为F；或R 2为Cl，且R 3为Cl；或R 2为F，且R 3为Cl。
  5. 如权利要求1-4任一所述的化合物，或其光学异构体、药学上可接受的盐、水合物或溶剂化物，其特征在于，所述的化合物选自下组：
    Figure PCTCN2018122822-appb-100003
  6. 如权利要求1-5任一所述的化合物，或其光学异构体、药学上可接受的盐、水合物或溶剂化物，其特征在于，所述式I和式II所示的化合物的盐为式I和式II所示的化合物与无机酸或有机酸所形成的可药用盐，或所述式I和式II所示的化合物的盐为式I和式II所示的化合物与碱反应所形成的可药用盐；所述的式I和式II所示的化合物或其盐为无定形物或晶体。
  7. 一种药物组合物，其特征在于，所述的药物组合物包括治疗有效量的如权利要求1-6任一项中所述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂化物；和药学上可接受的辅助剂、稀释剂或载体。
  8. 如权利要求1-6任一所述的化合物或其光学异构体、药学上可接受的盐、水合物或溶剂化物的用途，其特征在于，用于制备治疗和/或预防癌症(优选为肝癌)的药物组合物。
  9. 如权利要求1所述的式I化合物的制备方法，其特征在于，包括步骤：
    Figure PCTCN2018122822-appb-100004
    (i-a)在惰性溶剂中，用式II化合物和酸、酰氯、卤代烷基反应，形成式I化合物；
    式中，各基团的定义如权利要求1中所述；
  10. 如权利要求9所述的制备方法，其特征在于，所述的式II化合物是通过以下方法制备的：
    Figure PCTCN2018122822-appb-100005
    (i-b)在惰性溶剂中，用式IIa化合物脱除TBS，形成式II化合物；
    式中，各基团的定义如权利要求1中所述；
    优选地，所述的式IIa化合物是通过以下方法制备的：
    Figure PCTCN2018122822-appb-100006
    (i-c)在惰性溶剂中，将式Ic化合物与PA4101-4进行取代反应，得到式IIa化合物。
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JP2021506841A (ja) 2021-02-22
CN111655703A (zh) 2020-09-11
CN109956985A (zh) 2019-07-02
EP3730504A4 (en) 2021-07-28
CN111655703B (zh) 2023-07-25
TW201927308A (zh) 2019-07-16
US20200317711A1 (en) 2020-10-08
EP3730504A1 (en) 2020-10-28
ES2958817T3 (es) 2024-02-15

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