WO2024183772A1 - 肝递送调节胆固醇代谢药物环状磷酸酯化合物及应用 - Google Patents

肝递送调节胆固醇代谢药物环状磷酸酯化合物及应用 Download PDF

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WO2024183772A1
WO2024183772A1 PCT/CN2024/080399 CN2024080399W WO2024183772A1 WO 2024183772 A1 WO2024183772 A1 WO 2024183772A1 CN 2024080399 W CN2024080399 W CN 2024080399W WO 2024183772 A1 WO2024183772 A1 WO 2024183772A1
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formula
compound
pharmaceutically acceptable
unsubstituted
substituted
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French (fr)
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席志坚
陆春平
曹建新
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浙江柏拉阿图医药科技有限公司
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Priority claimed from CN202310199083.0A external-priority patent/CN118580274A/zh
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Publication of WO2024183772A1 publication Critical patent/WO2024183772A1/zh

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    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • 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

Definitions

  • Non-alcoholic fatty liver disease is the most common chronic liver disease in the world.
  • the prevalence of NAFLD in ordinary adults ranges from 6.3% to 28.7%, of which 10% to 30% are non-alcoholic steatohepatitis.
  • the prevalence of NAFLD is highest in the Middle East and South America, lowest in Africa, and at an upper-middle level in most Asian countries, including China. With the global prevalence of obesity and metabolic syndrome, NAFLD has grown rapidly in Asian countries in the past 20 years and is showing a trend of younger onset.
  • the prevalence of NAFLD in adults in developed regions such as Shanghai, Guangzhou and Hong Kong in China is around 15%.
  • Thyroid dysfunction can lead to obesity, inadequate lipid metabolism, and insulin resistance, which are elements of the metabolic syndrome that also occur in NAFLD.
  • Hypothyroidism may directly or indirectly lead to NAFLD through three known mechanisms of NFALD: hepatic lipid accumulation, inflammation with oxidative stress, and subsequent defects in liver repair and regeneration responses.
  • Thyroid hormone (TH) is mainly divided into two major subtypes, ⁇ and ⁇ .
  • THR- ⁇ has a more significant regulatory effect on body temperature and basal metabolic rate (BMR).
  • Thyroid hormone receptor ⁇ plays a minor role in the regulation of basal metabolic rate (BMR), but is the main subtype of thyrotropin-releasing hormone (TRH) expressed in the liver and is considered to be the main target of thyroid hormone (TH) replacement therapy to improve lipid metabolism characteristics.
  • BMR basal metabolic rate
  • TRH thyrotropin-releasing hormone
  • TH thyroid hormone
  • Sobetirom can prevent fat accumulation by increasing fatty acid ⁇ -oxidation
  • Eproxime can significantly reduce serum cholesterol levels
  • MGL-3196 can increase ⁇ -oxidation and mitochondrial respiration rate and reduce liver triglycerides
  • Remdesivir can reduce lipids that cause atherosclerosis.
  • VK2809 is a novel liver-selective thyroid receptor ⁇ agonist that can significantly reduce LDL-C and liver fat content.
  • cyclic phosphate (4-aryl-2-oxo-1,3,2-dioxaphosphinane) has excellent liver-specific delivery performance and a very clear mechanism.
  • the 4-aryl substitution position is specifically catalyzed by CYP3A in the cytochrome P450 isoenzyme family in hepatocytes to generate a hydroxyl group, which then opens the ring to generate a negatively charged phosphate intermediate. This substance does not easily pass through the cell membrane and exists inside the cell to exert its pharmacological effect, thereby achieving high tissue selectivity.
  • the metabolic byproduct aromatic vinyl ketone can undergo a 1,4-addition reaction with glutathione, which is rich in antioxidants and free radicals in hepatocytes, and is cleared. No reports of side effects of the addition product have been found.
  • VK2809A As the active ingredient, a meta-chloro-substituted aromatic ring, VK2809, is synthesized. Under the action of CYP3A enzyme, it is metabolized into VK2809A. This drug has shown good ability to lower liver lipids in clinical 2a (CN110198719A).
  • the present invention synthesizes a drug cyclic phosphate for regulating fat metabolism, and then further transforms its aromatic ring substituent to obtain a class of prodrugs with liver-specific delivery (liver delivery) effect, so that the efficacy is higher and the toxic side effects are smaller.
  • 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 alkoxy, 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 unsubstituted C2-C6 alkanoylamide;
  • substitution refers to having one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, hydroxyl, amino, and cyano;
  • each chiral center is in the R form or the S form.
  • P2 and the aromatic group at position 4 are cis to each other, and P2 is R-type and C4 is S-type.
  • the compound has the structure shown below:
  • R 2 and R 3 are halogen
  • n 0, 1, 2, 3.
  • the compound is a compound of formula I-a and formula II-a.
  • R 2 is halogen
  • R 3 is F, Br, or I
  • R 3 ⁇ R 5 is a preferred embodiment
  • R 2 is Cl
  • R 3 is F
  • the compound is selected from the following group:
  • the salt of the compound represented by Formula I and Formula II is a pharmaceutically acceptable salt formed by the compound represented by Formula I and Formula II and an inorganic acid or an organic acid, or the salt of the compound represented by Formula I and Formula II is a pharmaceutically acceptable salt formed by the reaction of the compound represented by Formula I and Formula II and a base.
  • the compound represented by Formula I and Formula II or its salt is an amorphous substance or a crystal.
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises a therapeutically effective amount of the compound as described in the first aspect of the present invention or its optical isomer, pharmaceutically acceptable salt, hydrate or solvate; and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the third aspect of the present invention provides a use of the compound described in the first aspect of the present invention or its optical isomers, pharmaceutically acceptable salts, hydrates or solvates, or the compound described in the second aspect of the present invention.
  • the use of the pharmaceutical composition is to prepare a pharmaceutical composition for treating and/or preventing acute or chronic diseases related to hyperlipidemia, hypercholesterolemia, hepatic fatty lesions, cardiomegaly, hepatomegaly, fatty liver, liver fibrosis and cirrhosis.
  • the fourth aspect of the present invention provides a method for preparing the compound of formula I according to the first aspect of the present invention, the method comprising the steps of:
  • a compound of formula Va is subjected to a condensation reaction with compounds of formula Vc and Vd to obtain compounds of formula I and formula II.
  • step i the reaction is carried out in the presence of a condensation agent.
  • the condensing agent is selected from the following group: dicyclohexylcarbodiimide (DCC).
  • condensation reaction is carried out at 60-100°C (about 80°C).
  • reaction time of the condensation reaction is 1-72 hours, preferably 3-48 hours, and more preferably 6-24 hours.
  • the inert solvent is selected from the following group: N,N-dimethylformamide, pyridine, or a combination thereof; preferably a mixed solvent of N,N-dimethylformamide and pyridine in a ratio of 20:1 to 1:5 (v/v) (preferably 10:1 to 1:2 (v/v)).
  • the compounds of formula Vc and Vd are prepared by the following method:
  • an amphoteric solvent such as EtOH
  • a reducing agent such as NaBH 4
  • Reaction e.g. 1-5h
  • the It is prepared by any one of methods 1-3 selected from the following group:
  • S-configuration cis If there is no special statement, it means that C4 in the phosphate ring structure is S-configuration, and P2 and its 4-position aromatic group are cis-configuration to each other.
  • the inventors After long and in-depth research, the inventors have found for the first time through screening and research of a large number of compounds that a class of compounds of formula I and formula II with specific structures (e.g., different halogens at positions 3 and 5 of the benzene ring, or different halogens at positions 2 and 5 of the benzene ring) surprisingly have very excellent antiviral activity, significantly improved liver-specific delivery (liver delivery) and significantly reduced toxic side effects. Based on the above findings, the inventors have completed the present invention.
  • specific structures e.g., different halogens at positions 3 and 5 of the benzene ring, or different halogens at positions 2 and 5 of the benzene ring
  • C1-C6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
  • C2-C6 alkanoyl refers to a substituent of a "straight or branched alkyl-carbonyl having 1 to 6 carbon atoms" structure, such as acetyl, propionyl, butyryl, or the like.
  • C1-C6 alkylamino refers to a substituent having a structure of "a straight-chain or branched alkyl-amino group having 1 to 6 carbon atoms", such as methylamino, dimethylamino, ethylamino, propylamino, diethylamino, or a similar group.
  • halogen refers to F, Cl, Br and I.
  • the terms “comprising”, “including” or “comprising” indicate that various components can be used together in the mixture or composition of the present invention. Therefore, the terms “consisting mainly of” and “consisting of” are included in the term “comprising”.
  • the term "pharmaceutically acceptable” ingredient refers to a substance that is suitable for use in humans and/or animals without excessive adverse side effects (such as toxicity, irritation and allergic reaction), that is, has a reasonable benefit/risk ratio.
  • the term "effective amount" refers to the amount of a therapeutic agent to treat, alleviate or prevent a target disease or condition, or the amount that exhibits a detectable therapeutic or preventive effect.
  • the exact effective amount for a subject depends on the subject's size and health, the nature and extent of the condition, and the therapeutic agent and/or combination of therapeutic agents selected for administration. Therefore, it is useless to specify the exact effective amount in advance. However, for a given condition, the effective amount can be determined by routine experiments, which a clinician is able to judge.
  • substituted means that one or more hydrogen atoms on a group are replaced by a substituent selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, hydroxy, amino, and cyano.
  • each chiral carbon atom can be optionally in R configuration or S configuration, or a mixture of R configuration and S configuration.
  • compound of the present invention refers to compounds of Formula I and Formula II.
  • the term also includes 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 formed by a compound of the present invention and an acid or base that is suitable for use as a drug.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred class of salts is a salt formed by a compound of the present invention and an acid.
  • Suitable acids for forming salts include, but are not limited to, inorganic 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, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, and acidic amino acids such as aspartic acid and glutamic acid.
  • inorganic 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, maleic acid, lactic acid, malic acid, tartaric acid, citric
  • Some compounds of the present invention may be crystallized or recrystallized with water or various organic solvents, in which case various solvates may be formed.
  • the solvates of the present invention include stoichiometric solvates such as hydrates, and also include compounds containing variable amounts of water formed when prepared by low-pressure sublimation drying.
  • the compounds of the present invention may exist in various thermodynamically stable isomers after preparation, such as tautomers, conformational isomers, meso compounds and optical isomers with enantiomeric or diastereomeric relationships, etc.
  • thermodynamically stable isomers after preparation such as tautomers, conformational isomers, meso compounds and optical isomers with enantiomeric or diastereomeric relationships, etc.
  • R1 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 alkoxy, 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 unsubstituted C2-C6 alkanoylamide;
  • R 2 and R 3 are different halogens
  • n 0, 1, 2, or 3;
  • substitution refers to having one or more substituents selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, nitro, hydroxyl, amino, and cyano;
  • each chiral center is R-type or S-type.
  • a preferred class of compounds of formula I has the structure shown in formula I below:
  • the compound of formula I is a compound of formula I-a.
  • the aromatic groups at positions P2 and 4 in the phosphate ring structure are cis-type relative to each other, and P2 is R-type, and C4 is S-type.
  • R 2 is Cl and R 3 is F; or R 2 is Cl and R 3 is Br.
  • the optical isomers include tautomers, cis-trans isomers, conformational isomers, meso compounds and optical isomers with enantiomeric or diastereomeric relationships.
  • the compound is selected from the following group:
  • Another preferred class of compounds of formula II has the following structure:
  • the compound of formula II is a compound of formula II-a.
  • the P2 and the aromatic group at position 4 in the phosphate ring structure are cis-type relative to each other, and P2 is R-type and C4 is S-type.
  • R 2 is Cl and R 3 is F; or R 2 is Cl and R 3 is Br.
  • the optical isomers include tautomers, cis-trans isomers, conformational isomers, meso compounds and optical isomers with enantiomeric or diastereomeric relationships.
  • the compound is selected from the following group:
  • the various reactants can be purchased from commercial sources, or prepared using commercially available raw materials by conventional methods in the art.
  • the 1,3-propylene glycol derivative Vc (preferably a chiral 1,3-propylene glycol derivative) is prepared by the following method:
  • an amphoteric solvent such as EtOH
  • a reducing agent such as NaBH 4
  • Reaction e.g. 1-5h
  • the It is prepared by any one of methods 1-3 selected from the following group:
  • compositions and methods of administration are provided.
  • the compounds of the present invention have excellent activity in regulating fat metabolism
  • the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat and prevent acute or chronic diseases related to hyperlipidemia, hypercholesterolemia, hepatic fatty lesions, cardiac hypertrophy, hepatomegaly, fatty liver, liver fibrosis and cirrhosis.
  • the pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier.
  • safe and effective amount means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 0.1-1000 mg of the compound of the present invention per dose, and more preferably, contains 0.5-500 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • administrations include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • a particularly preferred 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 with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for
  • Solid dosage forms such as tablets, pills, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifiers, and the release of the active compound or compounds in such compositions may be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into 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 tinctures.
  • the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottons
  • composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and perfumes.
  • Suspensions in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of the invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 0.2 to 1000 mg, preferably 0.5 to 500 mg.
  • the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.
  • Liver-specific delivery technology is highly effective.
  • the compound can only be specifically catalyzed by CYP3A in the cytochrome P450 isoenzyme family in liver cells to generate active molecules.
  • the active molecules carry a high negative charge and are not easily excreted from the liver. Therefore, the concentration in the liver is higher, achieving a specific delivery effect.
  • PA7010-P1 (2S, 4S) -4- (5-chloro-2-fluorophenyl) -2- ((4- (4-hydroxy-3-isopropylbenzyl) -3,5-dimethylphenoxy) methyl) -1,3,2-dioxophosphine-2-oxide
  • PA7010-P2 (2R, 4R) -4- (5-chloro-2-fluorophenyl) -2- ((4- (4-hydroxy-3-isopropylbenzyl) -3,5-dimethylphenoxy) methyl) -1,3,2-dioxophosphine-2-oxide
  • PA7010-P3 (2S, 4R) -4- (5-chloro-2-fluorophenyl) -2- ((4- (4-hydroxy-3-isopropylbenzyl) -3,5-dimethylphenoxy) methyl) -1,3,2-dioxophosphine-2-oxide
  • PA7010-P4 (2R, 4S) -4- (5-chloro-2-fluorophenyl) -2- ((4- (4-hydroxy-3-isopropylbenzyl) -3,5-dimethylphenoxy) methyl) -1,3,2-dioxophosphine-2-oxide (off-white solid, 1616.5 mg), 1 H NMR (400 MHz, DMSO-d 6 ) ⁇ : 8.98(s,1H),7.48-7.58(m,2H),7.32-7.37(m,1H),6.85(m,1H),6.78(m,2H),6.61-6.63(m,1H),6.46-6.49(m,1H),5.96-5.99(m,1H),4.68-4 .71(m,1H),4.35-4.67(m,3H),3.83-3.84(m,2H),3.32-3.39(m,1H),2.38-2.42(m,1H),2.19-2.35(m,7
  • the rough sample is split into peak1, peak2+3, peak4:
  • peak2+3 is split into peak2 and peak3:
  • Ultra-high performance liquid chromatography Vanquish Flex (Thermo Scientific) system consisting of a binary pump F, split sampler FT, diode array detector FG, and column compartment H;
  • High-resolution mass spectrometer Q Exactive HF-X quadrupole tandem electrostatic field orbital trap high-resolution mass spectrometer (Thermo Scientific); analysis software: Xcalibur (Thermo Scientific, version 4.2SP1), Compound Discoverer (Thermo Scientific, version 3.1).
  • the chromatographic column was Waters: ACQUITY UPLC BEH C18 Column (2.1 ⁇ 50 mm I.D., 1.7 ⁇ m particle size); the column temperature was 40°C; the flow rate was 0.4 mL/min; the UV detection wavelength was 190-400 nm.
  • test compounds were metabolized to PA7010-3 in human liver microsomes in vitro.
  • the results are summarized as follows:
  • Table 2 Amount of test compounds metabolized to PA7010-3 by human liver microsomes in vitro

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Abstract

本发明提供基于肝脏特异性递送技术(肝递送)(Liver Specific Delivery(LSD))的调节胆固醇代谢药物环状磷酸酯化合物及应用，具体地，本发明提供了式I和式II化合物及其异构体、可药用盐、水合物、溶剂化物，以及相应的药物组合物。本发明还提供了本发明化合物单独或与其它药物联合在治疗高血脂、高胆固醇血症、肝性脂肪病变、心脏肥大、肝肿大、脂肪肝、肝纤维化和肝硬化的应用。

Description

肝递送调节胆固醇代谢药物环状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))的调节胆固醇药物环状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
非酒精性脂肪肝(NAFLD)是全球最常见的慢性肝病，普通成人NAFLD患病率介于6.3％～28.7％，其中10％～30％为非酒精性脂肪性肝炎。中东地区和南美洲NAFLD患病率最高，非洲最低，包括中国在内的亚洲多数国家NAFLD患病率处于中上水平。随着肥胖症和代谢综合征在全球的流行，近20年亚洲国家NAFLD增长迅速且呈低龄化发病趋势，在中国上海、广州和香港等发达地区成人NAFLD患病率在15％左右。
甲状腺功能障碍可导致肥胖、脂质代谢不足和胰岛素抵抗，这是NAFLD中也会出现的代谢综合征的要素。通过NFALD的三种已知机制：肝脏脂质积聚、伴随氧化应激的炎症以及随后的肝脏修复和再生反应缺陷，甲状腺功能减退可能直接或间接导致NAFLD。甲状腺激素(TH)主要分为α和β两大亚型。后期通过动物实验证明，甲状腺激素补充疗法的心脏毒性是由甲状腺激素受体的单一亚型甲状腺激素受体α(THR-α)引起的。除心率外，THR-α对体温和基础代谢率(BMR)的调节作用更为显著。甲状腺激素受体β(THR-β)在基础代谢率(BMR)调节中则是起次要作用，但却是促甲状腺激素释放激素(TRH)肝脏表达的主要亚型，且被认为是甲状腺激素(TH)补充疗法改善脂代谢特性的主要作用靶点。甲状腺激素受体β(THR-β)的特性提示THR-β选择性激动剂具有肝脏脂质代谢多重调控，且避免体重减轻，降低心脏毒性，平衡有效性和安全性的潜力。
已经开发了多种能够以充当THR-β选择性激动剂的化合物：索贝蒂罗姆(GC-1)能通过增加脂肪酸β氧化来防止脂肪堆积；依普罗肟(KB-2115)能显著性降低血清胆固醇的水平；MGL-3196能增加β氧化和线粒体呼吸速率，降低肝脏甘油三酯；瑞米替仑(MGL-3196)能降低导致动脉粥样硬化的脂质 和脂蛋白；VK2809是新型肝脏选择性甲状腺受体β激动剂，能显著降低LDL-C和肝脏脂肪含量。
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，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于细胞内，发挥药效作用，从而能够实现高组织选择性，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。
以VK2809A为活性成分，合成间氯取代的芳环，VK2809，在CYP3A酶作用下，代谢成VK2809A，该药物在临床2a中，展现出不错的降肝脂能力(CN110198719A)。
然而，目前尚缺乏活性高、肝脏特异性递送性强、且毒副作用低的调节脂肪代谢的化合物，因此，本领域迫切需要开发具有活性高、肝脏特异性递送性强、且毒副作用低等优点的新型调节脂肪代谢的化合物。
发明内容
本发明合成了调节脂肪代谢的药物环状磷酸酯，然后对其芳环取代基进一步的改造，得到一类具有肝脏特异性递送(肝递送)作用的前药，使其疗效更高，毒副作用更小。
在本发明的第一方面，提供了一种如下式I和式II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：

其中：
各R1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；
式I和式II中，各个手性中心为R型或S型。
在另一优选例中，所述的磷酸酯环结构中P2与其4位的芳香基团互为顺式，且P2为R型，C4为S型。
在另一优选例中，所述的选自下组：
在另一优选例中，所述的化合物具有如下所示的结构：

其中，R2，R3为卤素；
n为0、1、2、3。
在另一优选例中，所述的化合物为式I-a和式II-a化合物。
在另一优选例中，R2为卤素，R3为F、Br、或I，且R3≠R5。
在另一优选例中，R2为Cl，且R3为F。
在另一优选例中，所述的化合物选自下组：
在另一优选例中，所述的式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，提供了一种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，或如本发明第二方面所 述的药物组合物的用途，用于制备治疗和/或预防高血脂、高胆固醇血症、肝性脂肪病变、心脏肥大、肝肿大、脂肪肝、肝纤维化和肝硬化相关的急性或慢性疾病的药物组合物。
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：
i.在惰性溶剂中，将式Va化合物和式Vc和Vd化合物进行缩合反应，得到式I和式II化合物。
在另一优选例中，在步骤i中，所述反应在缩合剂存在下进行。
在另一优选例中，所述的缩合剂选自下组：二环己基碳二亚胺(DCC)。
在另一优选例中，所述的缩合反应在60-100℃下(80℃左右)进行。
在另一优选例中，所述的缩合反应的反应时间为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，所述的惰性溶剂选自下组：N,N-二甲基甲酰胺、吡啶、或其组合；优选为N,N-二甲基甲酰胺和吡啶的20：1至1：5(v/v)(较佳地10：1-至1：2(v/v))的混合溶剂。
在另一优选例中，所述的式Vc和Vd化合物(优选为手性的1,3-丙二醇衍生物)是通过以下方法制备的：
ii.在惰性溶剂(如DMF)中，在HCOOH、Et3N和(S,S)-N-(对甲苯磺酰)-1,2- 二苯基乙二胺(二氯)(对甲基异丙基苯)钌(II)存在下，在40～80℃下对进行还原反应(如1-5h)，从而得到
iii.在两性溶剂(如EtOH)中，用还原剂(如NaBH4)与 反应(如1-5h)，从而得到
在另一优选例中，所述的是通过选自下组的方法1-3中任一制备的：
方法1
i.在两性溶剂(如EtOH)中，用SOCl2与反应，得到化合物；
ii.在惰性溶剂(如THF)中，在碱(如LiHMDS)存在下，用乙酸乙酯和在-60～-20℃下反应(如10～30min)，得到化合物；
方法2
i.在惰性溶剂(如DCM)中，在SnCl2存在下，在室温下用 与反应，得到 化合物；
方法3
i.在惰性溶剂(如THF)中，在碱(如叔丁醇钾)存在下，用 在回流温度下反应过夜，得到 化合物。
应理解，在本发明范围内，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。
说明
S构型顺式：如无特殊表述，指磷酸酯环结构中C4为S构型，P2与其4位的芳香基团互为顺式
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(例如苯环部分的3位和5位为不同的卤素，或苯环部分的2位和5位为不同的卤素)，令人意外地具有非常优异的抗病毒活性、显著提高的肝脏特异性递送性(肝递送)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和式II化合物及其制备
为了提供一种能够通过肝脏特异性递送机制，让调节胆固醇代谢的药物集中在肝细胞中释放的高效、低毒的前体药物，发明人制备了式I和式II的优选化合物：
其中：
R1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，R2，R3分别为不同的卤素；
n为0、1、2、3；
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，各个手性中心为R型或S型。
优选的实施例中，所述的选自下组：
一类优选的式I化合物具有如下式I所示的结构：

在另一优选例中，所述的式I化合物为式I-a化合物。
在另一优选例中，所述的磷酸酯环结构中P2与4位的芳香基团互为顺式，且P2为R型，C4为S型。
在另一优选例中，R2为Cl，且R3为F；或R2为Cl，且R3为Br。
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：
另一类优选的式II化合物具有如下结构：

其中，各基团的定义如上文中所示。
在另一优选例中，所述的式II化合物为式II-a化合物。
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型，C4为S型。
在另一优选例中，R2为Cl，且R3为F；或R2为Cl，且R3为Br。
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：
化合物的制备方法(以式I化合物为例)：
在N,N-二甲基甲酰胺和吡啶(10:1)溶液中，加入单磷酸衍生物Va，1,3-丙二醇衍生物Vc和二环己基碳二亚胺，升温至80℃左右，反应16h，反应完毕，将反应液减压旋蒸，去除有机溶剂，粗产物溶于乙酸乙酯，用饱和食盐水洗涤，无水硫酸钠干燥，减压蒸除溶剂，硅胶柱层析，得到通式I化合物。
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。
在本发明的优选实施例中，所述的1,3-丙二醇衍生物Vc(优选为手性的1,3-丙二醇衍生物)是通过以下方法制备的：
i.在惰性溶剂(如DMF)中，在HCOOH、Et3N和(S,S)-N-(对甲苯磺酰)-1,2-二苯基乙二胺(二氯)(对甲基异丙基苯)钌(II)存在下，在40～80℃下对进行还原反应(如1-5h)，从而得到
ii.在两性溶剂(如EtOH)中，用还原剂(如NaBH4)与反应(如1-5h)，从而得到
在另一优选例中，所述的是通过选自下组的方法1-3中任一制备的：
方法1
i.在两性溶剂(如EtOH)中，用SOCl2与反应，得到化合物；
ii.在惰性溶剂(如THF)中，在碱(如LiHMDS)存在下，用乙酸乙酯和在-60～-20℃下反应(如10～30min)，得到化合物；
方法2
i.在惰性溶剂(如DCM)中，在SnCl2存在下，在室温下用与反应，得到化合物；
方法3
i.在惰性溶剂(如THF)中，在碱(如叔丁醇钾)存在下，用 在回流温度下反应过夜，得到化合物。
应理解，上述制备方法仅为以式I化合物为例，本领域技术人员可以方便地 替换相应的原料从而制备其他的式II化合物。
药物组合物和施用方法
由于本发明化合物具有优异的调节脂肪代谢的活性，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、预防高血脂、高胆固醇血症、肝性脂肪病变、心脏肥大、肝肿大、脂肪肝、肝纤维化和肝硬化相关的急性或慢性疾病。
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(如吐温)、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、娇味剂和香料。
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)肝脏特异性递送技术(肝递送)性强，化合物只能在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，达到特异性递送效果。
(2)活性高，因为肝脏特异性递送性，所以更多的药物存在肝中，调节脂肪代谢的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，所以对全身的毒性能大大的降低。
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 PA7001(对比例)(4S)-4-(3-氯苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(100mg，0.27mmol)溶于N,N-二甲基甲酰胺(10ml)和吡啶(1ml)中，分别加入二环己基碳亚胺(170mg，0.82mmol)和(S)-1-(3-氯苯基)丙烷-1,3-二醇(51mg，0.27mmol)，反应混合物加热到80度左右，反应16小时，反应完毕，反应体系加乙酸乙酯和水，体系分液，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压蒸出溶剂，硅胶柱层析(二氯甲烷：甲醇＝60:1到30:1)，得到白色固体20mg，收率：14％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.01(s,1H),7.36-7.52(m,4H),6.87(s,1H),6.77-6.85(m,2H),6.62-6.64(m,1H),6.46-6.49(m,1H),5.77-5.89(m,1H),4.42-4.76(m,4H),3.84(s,2H),3.11-3.36(m,1H),2.29-2.36(m,2H),2.19-2.24(m,6H),1.11-1.13(m,6H)ppm.
实施例2 PA7002(4S)-4-(3,5-二氯苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(130mg，0.36mmol)，二环己基碳亚胺(221mg，1.07mmol)和(S)-1-(3,5-二氯苯基)丙烷-1,3-二醇(79mg，0.36mmol)反应完毕，得到白色固体25mg，收率：13％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.03(s,1H),7.61-7.67(m,1H),7.49-7.54(m,2H),6.77-6.87(m,3H),6.62-6.64(m,1H),6.47-6.49(m,1H),5.79-5.91(m,1H),4.47-4.74(m,4H),3.83(s,2H),3.11-3.37(m,1H),2.28-2.36(m,2H),2.10-2.21(m,6H),1.11-1.13(m,6H)ppm.
实施例3 PA7003(4S)-4-(3-氯-5-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(150mg，0.41mmol)，二环己基碳亚胺(254mg，1.23mmol)和(S)-1-(3-氯-5-氟苯基)丙烷-1,3-二醇(84mg，0.41mmol)反应完毕，得到白色固体38mg，收率：17％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.01(s,1H),7.43-7.49(m,1H),7.40-7.42(m, 1H),7.23-7.37(m,1H),6.74-6.85(m,3H),6.60-6.61(m,1H),6.43-6.46(m,1H),5.77-5.90(m,1H),4.41-4.76(m,4H),3.81-3.82(m,2H),3.09-3.21(m,1H),2.29-2.37(m,2H),2.21-2.25(m,6H),1.09-1.11(m,6H)ppm.
实施例4 PA7004(4S)-4-(3-氯-2-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(150mg，0.41mmol)，二环己基碳亚胺(254mg，1.23mmol)和(S)-1-(3-氯-2-氟苯基)丙烷-1,3-二醇(84mg，0.41mmol)反应完毕，得到白色固体36mg，收率：16％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.02(s,1H),7.53-7.65(m,1H),7.33-7.45(m,1H),7.18-7.21(m,1H),6.85(m,1H),6.84-6.85(m,1H),6.74-6.81(m,2H),6.60-6.62(m,1H),5.98-6.12(m,1H),4.42-4.82(m,4H),3.81-3.82(m,2H),3.10-3.15(m,1H),2.32-2.40(m,2H),2.10-2.21(m,6H),1.10-1.11(m,6H)ppm.
实施例5 PA7005(4S)-4-(3-氯-4-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(150mg，0.41mmol)，二环己基碳亚胺(254mg，1.23mmol)和(S)-1-(3-氯-4-氟苯基)丙烷-1,3-二醇(84mg，0.41mmol)反应完毕，得到白色固体40mg，收率：18％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.01(s,1H),7.62-7.66(m,1H),7.47-7.49(m,1H),7.40-7.41(m,1H),6.84-6.86(m,1H),6.83-6.84(m,2H),6.60-6.62(m,1H),6.45-6.47(m,1H),5.75-5.87(m,1H),4.41-4.73(m,4H),3.81(s,2H),3.11-3.15(m,1H),2.25-2.37(m,2H),2.22-2.24(m,6H),1.09-1.11(m,6H)ppm.
实施例6 PA7006(4S)-4-(2,3-二氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(150mg，0.41mmol)，二环己基碳亚胺(254mg，1.23mmol)和(S)-1-(2,3-二氟苯基)丙烷-1,3-二醇(77mg，0.41mmol)反应完毕，得到白色固体30mg，收率：14％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.04(s,1H),7.18-7.50(m,3H),6.84-6.85(m,1H),6.81-6.84(m,2H),6.62-6.74(m,1H),6.46-6.60(m,1H),5.99-6.14(m,1H),4.42-4.83(m,4H),3.81-3.82(m,2H),3.11-3.15(m,1H),2.35-2.41(m,2H),2.19-2.22(m,6H),1.09-1.11(m,6H)ppm.
实施例7 PA7007(4S)-4-(2,4-二氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(150mg，0.41mmol)，二环己基碳亚胺(254mg，1.23mmol)和(S)-1-(2,4-二氟苯基)丙烷-1,3-二醇(77mg，0.41mmol)反应完毕，得到白色固体23mg，收率：11％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.03(s,1H),7.37-7.67(m,1H),7.05-7.34(m,2H),6.76-6.87(m,3H),6.62-6.64(m,1H),6.46-6.48(m,1H),5.92-6.09(m,1H),4.42-4.83(m,4H),3.83(s,2H),3.11-3.18(m,1H),2.35-2.42(m,1H),2.16-2.20(m,7H),1.10-1.13(m,6H)ppm.
实施例8 PA7008(4S)-4-(3,4-二氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(150mg，0.41mmol)，二环己基碳亚胺(254mg，1.23mmol)和(S)-1-(3,4-二氟苯基)丙烷-1,3-二醇(78mg，0.41mmol)反应完毕，得到白色固体69mg，收率：33％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.01(s,1H),7.39-7.54(m,2H),7.24-7.30(m,1H),6.74-6.86(m,3H),6.60-6.62(m,1H),6.44-6.47(m,1H),5.74-5.86(m,1H),4.42-4.73(m,4H),3.81(s,2H),3.10-3.15(m,1H),2.22-2.27(m,8H),1.09-1.10(m,6H)ppm.
实施例9 PA7009(4S)-4-(2,3-二氯苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(150mg，0.41mmol)，二环己基碳亚胺(254mg，1.23mmol)和(S)-1-(2,3-二氯苯基)丙烷-1,3-二醇(91mg，0.41mmol)反应完毕，得到白色固体49mg，收率：22％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.03(s,1H),7.31-7.72(m,3H),6.77-6.85(m,3H),6.61-6.62(m,1H),6.44-6.47(m,1H),5.98-6.19(m,1H),4.41-4.83(m,4H),3.82(s,2H),3.10-3.15(m,1H),2.26-2.37(m,2H),2.21-2.24(m,6H),1.09-1.10(m,6H)ppm.
实施例10 PA7010(4S)-4-(5-氯-2-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(130mg，0.36mmol)，二环己基碳亚胺(221mg，1.07mmol)和(S)-1-(5-氯-2-氟苯基)丙烷-1,3-二醇(73mg，0.36mmol)反应完毕，得到白色固体25mg，收率：13％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.01-9.02(m,1H),7.50-7.62(m,2H),7.33-7.49 (m,1H),6.79-6.87(m,3H),6.63-6.64(m,1H),6.61-6.62(m,1H),5.97-6.10(m,1H),4.46-4.84(m,4H),3.83(s,2H),3.13-3.16(m,1H),2.36-2.43(m,1H),2.19-2.24(m,7H),1.11-1.10(m,6H)ppm.
实施例11 PA7011(4S)-4-(2,4-二氯苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(130mg，0.36mmol)，二环己基碳亚胺(221mg，1.07mmol)和(S)-1-(2,4-二氯苯基)丙烷-1,3-二醇(79mg，0.36mmol)反应完毕，得到白色固体22mg，收率：13％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.03(s,1H),7.40-7.73(m,3H),6.79-6.87(m,3H),6.63-6.65(m,1H),6.49-6.51(m,1H),5.94-6.17(m,1H),4.43-4.88(m,4H),3.84(s,2H),3.12-3.19(m,1H),2.04-2.36(m,8H),1.12-1.13(m,6H)ppm.
实施例12 PA7012(4S)-4-(3,4-二氯苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(130mg，0.36mmol)，二环己基碳亚胺(221mg，1.07mmol)和(S)-1-(3,4-二氯苯基)丙烷-1,3-二醇(79mg，0.36mmol)反应完毕，得到白色固体63mg，收率：32％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.02(s,1H),7.44-7.74(m,2H),7.38-7.41(m,1H),6.84-6.87(m,2H),6.75(s,1H),6.62-6.64(m,1H),6.47-6.49(m,1H),5.78-5.91(m,1H),4.42-4.75(m,4H),3.83(s,2H),3.11-3.18(m,1H),2.25-2.35(m,2H),2.19-2.21(m,6H),1.11-1.13(m,6H)ppm.
实施例13 PA7013(4S)-4-(2-氯-5-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(130mg，0.36mmol)，二环己基碳亚胺(221mg，1.07mmol)和(S)-1-(2-氯-5-氟苯基)丙烷-1,3-二醇(73mg，0.36mmol)反应完毕，得到白色固体5mg，收率：3％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.03(s,1H),7.40-7.61(m,1H),7.30-7.39(m,2H),6.80-6.86(m,3H),6.62-6.64(m,1H),6.47-6.49(m,1H),5.95-6.16(m,1H),4.43-4.86(m,4H),3.84(s,2H),3.11-3.18(m,1H),2.25-2.36(m,2H),2.19-2.23(m,6H),1.11-1.13(m,6H)ppm.
实施例14 PA7014(4S)-4-(2,5-二氯苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5- 二甲基苯氧基)甲基)膦酸(100mg，0.27mmol)，二环己基碳亚胺(170mg，0.82mmol)和(S)-1-(2,5-二氯苯基)丙烷-1,3-二醇(61mg，0.27mmol)反应完毕，得到白色固体15mg，收率：10％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.00(s,1H),7.47-7.64(m,3H),6.81-6.84(m,3H),6.61-6.79(m,1H),6.44-6.60(m,1H),5.95-6.13(m,1H),4.41-4.55(m,4H),3.81(s,2H),3.09-3.35(m,1H),2.24-2.64(m,2H),2.21-2.23(m,6H),1.09-1.18(m,6H)ppm.
实施例15 PA7015(4S)-4-(2,5-二氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(100mg，0.27mmol)，二环己基碳亚胺(170mg，0.82mmol)和(S)-1-(2,5-二氟苯基)丙烷-1,3-二醇(52mg，0.27mmol)反应完毕，得到白色固体28mg，收率：20％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.02(s,1H),7.24-7.41(m,3H),6.76-6.86(m,3H),6.60-6.62(m,1H),6.44-6.46(m,1H),5.94-6.09(m,1H),4.41-4.82(m,4H),3.81(s,2H),3.10-3.15(m,1H),2.21-2.40(m,1H),2.18-2.29(m,7H),1.09-1.11(m,6H)ppm.
实施例16 PA7016(4S)-4-(3,5-二氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(130mg，0.36mmol)，二环己基碳亚胺(221mg，1.07mmol)和(S)-1-(3,5-二氟苯基)丙烷-1,3-二醇(67mg，0.36mmol)反应完毕，得到白色固体17mg，收率：9％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.01(s,1H),7.14-7.32(m,3H),6.85-6.87(m,2H),6.76(s,1H),6.62-6.64(m,1H),6.46-6.48(m,1H),5.78-5.92(m,1H),4.42-4.76(m,4H),3.83-3.84(m,2H),3.11-3.18(m,1H),2.27-2.36(m,2H),2.18-2.24(m,6H),1.11-1.13(m,6H)ppm.
实施例17 PA7017(4S)-4-(4-氯-3-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
采用与对比例PA7001类似的方法制备，将(4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)膦酸(150mg，0.41mmol)，二环己基碳亚胺(254mg， 1.23mmol)和(S)-1-(4-氯-3-氟苯基)丙烷-1,3-二醇(84mg，0.41mmol)反应完毕，得到白色固体43mg，收率：20％，Rf＝0.4(二氯甲烷：甲醇＝20：1)，1H NMR(400MHz,DMSO-d6)δ：9.02(s,1H),7.52-7.71(m,1H),7.42-7.50(m,1H),7.27-7.34(m,1H),6.74-6.87(m,3H),6.62-6.64(m,1H),6.47-6.49(m,1H),5.78-5.92(m,1H),4.42-4.75(m,4H),3.83(s,2H),3.11-3.18(m,1H),2.25-2.36(m,2H),2.19-2.21(m,6H),1.11-1.13(m,6H)ppm.
实施例18 PA7010-P1(2S,4S)-4-(5-氯-2-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物,PA7010-P2(2R,4R)-4-(5-氯-2-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物,PA7010-P3(2S,4R)-4-(5-氯-2-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物和PA7010-P4(2R,4S)-4-(5-氯-2-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物的制备
4-(5-氯-2-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物(5097.8mg)通过手性柱，在以下的条件下，得到4个异构体：
PA7010-P1(2S,4S)-4-(5-氯-2-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物(类白色固体，754.8mg)，1H NMR(400MHz,DMSO-d6)δ：8.99(s,1H),7.53-7.61(m,2H),7.34-7.39(m,1H),6.86-6.87(m,1H),6.82(m,2H),6.62-6.64(m,1H),6.45-6.48(m,1H),6.06-6.09(m,1H),4.77-4.83(m,1H),4.65-4.68(m,2H),4.48-4.56(m,1H),3.83(m,2H),3.11-3.18(m,1H),2.39-2.42(m,1H),2.35-2.38(m,7H),1.06-1.13(m,6H)ppm.
PA7010-P2(2R,4R)-4-(5-氯-2-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物(类白色固体，736.5mg)，1H NMR(400MHz,DMSO-d6)δ：8.98(s,1H),7.53-7.61(m,2H),7.34-7.39(m,1H),6.86-6.87(m,1H),6.82(m,2H),6.62-6.64(m,1H),6.45-6.48(m,1H),6.06-6.09(m,1H),4.77-4.83(m,1H),4.65-4.68(m,2H),4.48-4.55(m,1H),3.83(m,2H),3.11-3.18(m,1H),2.39-2.42(m,1H),2.35-2.38(m,7H),1.06-1.13(m,6H)ppm.
PA7010-P3(2S,4R)-4-(5-氯-2-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物(类白色固体，1442.1mg)，1H NMR(400MHz,DMSO-d6)δ：8.98(s,1H),7.48-7.58(m,2H),7.33-7.37(m,1H),6.85 (m,1H),6.78(m,2H),6.61-6.63(m,1H),6.46-6.49(m,1H),5.96-5.99(m,1H),4.66-4.71(m,1H),4.36-4.52(m,3H),3.83(m,2H),3.34-3.36(m,1H),2.32-2.41(m,1H),2.19-2.31(m,7H),1.06-1.12(m,6H)ppm.
PA7010-P4(2R,4S)-4-(5-氯-2-氟苯基)-2-((4-(4-羟基-3-异丙基苄基)-3,5-二甲基苯氧基)甲基)-1,3,2-二氧代膦-2-氧化物(类白色固体，1616.5mg)，1H NMR(400MHz,DMSO-d6)δ：8.98(s,1H),7.48-7.58(m,2H),7.32-7.37(m,1H),6.85(m,1H),6.78(m,2H),6.61-6.63(m,1H),6.46-6.49(m,1H),5.96-5.99(m,1H),4.68-4.71(m,1H),4.35-4.67(m,3H),3.83-3.84(m,2H),3.32-3.39(m,1H),2.38-2.42(m,1H),2.19-2.35(m,7H),1.06-1.16(m,6H)ppm.
粗样拆分为peak1、peak2+3、peak4：
柱子：CHIRALPAK IH(IH00CD-VK010)
流动相：正己烷：乙醇＝20：80(V/V)
流速：1.0ml/min
波长：UV 210nm
温度：35℃
peak2+3拆分为peak2、peak3：
柱子：CHIRALPAK IB N-5(IBN5CD-VD005)
流动相：正己烷：乙醇＝70：30(V/V)
流速：1.0ml/min
波长：UV 210nm
温度：35℃
表1各个实施例中所制备得到的化合物如下表中所示：


实施例11体外CYP3A4酶代谢成活性分子评价
试验过程：
1.取10μL的20mM待测物储备液加入到40μL ACN中，稀释成4mM供试品中间溶液。
2. 5分钟时间点加辅酶试验方法(N＝2)：
将1μL 4mM待测物加入到10μL 20mg/mL肝微粒体溶液中，再加入89μL的PBS缓冲液，在37℃恒温振荡器中预热5分钟，最后加入100μL预热的还原型辅酶II溶液开始反应。根据孵育时间在37℃恒温振荡器中反应5分钟，加入300μL的甲醇终止反应。
3.样品前处理
所有样品终止反应后，涡旋混匀后放入离心机中，离心(18,000×g)10分钟去除蛋白。取400μL上清液至氮气流下吹干，加入200μL的40％乙腈水(含0.1％甲酸)复溶，涡旋5min，离心(18,000×g)样品 10min，取2μL上清液在LC-UV-HRMS系统下进行分析。
4.分析仪器和条件
超高效液相色谱：由液相泵(Binary Pump F)、分流进样器(Split Sampler FT)、二极管阵列检测器(Diode Array Detector FG)、柱温箱(Column Compartment H)组成的Vanquish Flex(Thermo Scientific)系统；
高分辨质谱仪：Q Exactive HF-X四级杆串联静电场轨道阱高分辨质谱(Thermo Scientific)；分析软件：Xcalibur(Thermo Scientific，4.2SP1版本)，Compound Discoverer(Thermo Scientific，3.1版本)。
5.色谱条件
色谱柱为Waters:ACQUITY UPLC BEH C18Column(2.1×50mm I.D.，1.7μm粒径)；柱温为40℃；流速为0.4mL/min；紫外检测波长190～400nm。流动相：A(水/0.1％甲酸)和B(乙腈/0.1％甲酸)。
洗脱程序：
6.质谱条件：HESI(+)
Scan type:Full MS/ddMS2
Spray Voltage(KV):3.5
Temperature(℃)
Aux gas heater temp:350
Capillary temperature:320
Gas Flows(L/h)
Sheath gas:40
Aux gas:15
Sweep gas:1
S-lens RF level:40
7.试验结果
测试化合物在体外人肝微粒体中代谢成PA7010-3的量，汇总结果如下：
表2测试化合物在体外由人肝微粒体代谢成PA7010-3的量
结果表明，在体外，化合物PA7010、PA7013、PA7014、PA7016、PA7003和PA7015被人肝微粒体活化成单磷酸代谢产物PA7010-3的效率显著大于对照化合物PA7001(VK2809，目前在临床II期)，分别是PA7001的2.98倍、5.45倍、3.10倍、3.20倍、2.11倍和4.81倍。
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 (9)

  1. 一种如下式I和式II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：
    其中：
    R1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，R2，R3分别为不同的卤素；
    n为0、1、2、3；
    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，各个手性中心为R型或S型。
  2. 如权利要求1所述的化合物，其特征在于，所述的 选自下组：
  3. 如权利要求2所述的化合物，其特征在于，所述的化合物具有如下所示的结构：
  4. 如权利要求3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，R2为Cl，且R3为F，或R2为F，且R3为Cl，或R2为Cl，且R3为Cl，或R2为F，且R3为F。
  5. 如权利要求3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：
  6. 如权利要求1-5所述的式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，或如权利要求7所述的药物组合物的用途，其特征在于，用于制备治疗和/或预防高血脂、高胆固醇血症、肝性脂肪病变、心脏肥大、肝肿大、脂肪肝、肝纤维化和肝硬化相关的急性或慢性疾病的药物组合物。
  9. 如权利要求1所述的式I和式II化合物的制备方法，其特征在于，包括步骤：
    i.在惰性溶剂中，将式Va化合物和式Vc及Vd化合物进行缩合反应，得到式I和式II化合物。
PCT/CN2024/080399 2023-03-03 2024-03-06 肝递送调节胆固醇代谢药物环状磷酸酯化合物及应用 WO2024183772A1 (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1882327A (zh) * 2003-11-19 2006-12-20 症变治疗公司 含磷的新的拟甲状腺素药
CN101189248A (zh) * 2005-05-26 2008-05-28 症变治疗公司 新型含磷拟甲状腺素药
US20090232879A1 (en) * 2005-05-26 2009-09-17 Metabasis Therapeutics, Inc. Thyromimetics for the Treatment of Fatty Liver Diseases

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1882327A (zh) * 2003-11-19 2006-12-20 症变治疗公司 含磷的新的拟甲状腺素药
CN101189248A (zh) * 2005-05-26 2008-05-28 症变治疗公司 新型含磷拟甲状腺素药
US20090232879A1 (en) * 2005-05-26 2009-09-17 Metabasis Therapeutics, Inc. Thyromimetics for the Treatment of Fatty Liver Diseases

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