WO2024078387A1 - 取代3-氟苯丙酸酯类化合物及其制备方法、药物组合及用途 - Google Patents

取代3-氟苯丙酸酯类化合物及其制备方法、药物组合及用途 Download PDF

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WO2024078387A1
WO2024078387A1 PCT/CN2023/123222 CN2023123222W WO2024078387A1 WO 2024078387 A1 WO2024078387 A1 WO 2024078387A1 CN 2023123222 W CN2023123222 W CN 2023123222W WO 2024078387 A1 WO2024078387 A1 WO 2024078387A1
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formula
compound
optionally
acid
pain
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PCT/CN2023/123222
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French (fr)
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高清志
刘胜男
孙子茹
刘阳
杜金平
韩建斌
李扬
张顺杰
赵富平
高香倩
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天津谷堆生物医药科技有限公司
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Definitions

  • the present invention relates to a 3-fluorophenylpropionic acid ester compound, a preparation method, a pharmaceutical composition and application thereof.
  • Non-Steroidal Anti-Inflammatory Drug is a class of drugs with antipyretic, analgesic, anti-inflammatory and anti-rheumatic effects.
  • NSAIDs with different structural formulas, but they all have similar mechanisms of action, mainly by inhibiting the activity of cyclooxygenase (COX), thereby preventing arachidonic acid from generating prostacyclin (PGI2), prostaglandins (PGE1, PGE2) and thromboxane A2 (TXA2), ultimately achieving anti-inflammatory and analgesic effects.
  • COX cyclooxygenase
  • PGE1, PGE2 prostaglandins
  • TXA2 thromboxane A2
  • NSAIDs are widely used in many clinical diseases, and their total consumption worldwide is second only to antibiotics. In the treatment of various rheumatic diseases, the prescription volume of NSAIDs ranks first, so NSAIDs has always been one of the hot spots for research and development.
  • Flurbiprofen is currently recognized as one of the NSAIDs with the strongest anti-inflammatory and analgesic effects.
  • Most of the flurbiprofen preparations on the market are oral preparations, which are prone to cause adverse reactions such as gastrointestinal dysfunction.
  • Upper gastrointestinal intolerance is also a major factor restricting flurbiprofen.
  • flurbiprofen's irritation and side effects on the gastrointestinal tract mainly come from the carboxylic acid group on its molecule.
  • Flurbiprofen axetil developed by Japan Science and Pharmaceutical Co., Ltd. is a prodrug of flurbiprofen, which has the advantages of long analgesic effect, targeted effect, and reduced gastrointestinal irritation.
  • flurbiprofen axetil is unstable in the gastrointestinal environment, it cannot be administered orally and requires intravenous injection, which greatly limits its wide application.
  • the present invention provides a 3-fluorophenylpropionic acid ester compound, such as a compound shown in the following formula (I), or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof (such as a hydrate), or an inclusion compound thereof, or a racemate thereof, or a cocrystal thereof, or an isotope-labeled substance thereof, or a nitrogen oxide thereof.
  • the compound has good anti-inflammatory activity and can effectively treat and/or prevent the growth and reproduction of multiple myeloma.
  • a preparation method, a pharmaceutical composition and use thereof containing the compound are also provided.
  • X is an alkylene group
  • P is selected from:
  • Y is selected from a single bond, -O-, -S-, or -NH-;
  • W is a single bond or an alkylene group
  • R1 and R2 are the same or different and are independently selected from -H, an optionally substituted alkyl group, an optionally substituted aryl group, or R1 and R2 are connected to each other and together with the nitrogen atom to which they are connected form an optionally substituted alicyclic group or
  • R 5 is one or two, each independently selected from -H, alkyl
  • R 3 is an optional group
  • R 3 is one or more, each independently alkyl, hydroxy, carboxyl, alkyl substituted with hydroxy, alkoxy, -N(R 5 )(R 6 ), R 5 and R 6 are the same or different, and each independently alkyl;
  • R4 is selected from -H, alkyl, alkanoyl
  • R 3 and -OR 4 are connected to each other to form an aliphatic heterocycle
  • optionally substituted refers to being unsubstituted or substituted by one or more substituents, wherein the substituents in the "optionally substituted alkyl", “optionally substituted aryl” and “optionally substituted alicyclic group” are each independently selected from hydroxyl, amino, carboxyl, halogen, nitro, cyano, alkyl, alkylthio, alkanoyl and hydroxy-substituted aryl;
  • alkyl moieties in the “alkyl”, “alkanoyl”, “hydroxy-substituted alkyl”, “alkoxy” and “alkylthio” are each independently C 1-20 straight or branched chain alkyl, optionally C 1-17 straight or branched chain alkyl, optionally C 1-10 straight or branched chain alkyl, optionally C 1-7 straight or branched chain alkyl, optionally methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl, heptyl, n-octyl, n-nonyl, n-decyl, undecyl, dodecyl, tridecyl,
  • the "alkylene” is a C 1-20 straight or branched alkylene, optionally a C 1-17 straight or branched alkylene, optionally a C 1-10 straight or branched alkylene, optionally a C 1-8 straight or branched alkylene, optionally a C 1-6 straight or branched alkylene, optionally a C 1-3 straight or branched alkylene, optionally a methylene, ethylene, isoethylidene, n-propylene, isopropylene, n-butylidene, isobutylidene, tert-butylidene, sec-butylidene, n-pentylidene, isopentylidene, neopentylidene, tert-pentylidene, n-hexylidene, isohexylidene, heptylidene, n-octylidene, n-nony
  • the alicyclic ring in the "alicyclic ring” or “alicyclic group” is a C 3-8 (preferably C 4-6 ) alicyclic ring containing 1-3 heteroatoms selected from O, N, and S on the ring, and is optionally a dioxolane, aziridine, azetidine, tetrahydropyrrolyl, morpholinyl, piperidinyl, or piperazinyl;
  • aryl or “hydroxy-substituted aryl” is a 6-10-membered monocyclic or bicyclic condensed aromatic ring group; optionally, phenyl or naphthyl;
  • the present invention relates to the aforementioned compound and any attendant definitions, wherein the 3-fluorophenylpropionic acid ester moiety is in the S configuration or the R configuration.
  • R1 and R2 are the same or different and are independently selected from -H, n-propyl, isopropyl, Alternatively, R1 and R2 are connected to each other and together with the nitrogen atom to which they are connected form the following group: heterocyclopropane-1-yl, azetidin-1-yl, tetrahydropyrrol-1-yl, morpholin-1-yl, piperidin-1-yl, or piperazin-1-yl,
  • the aliphatic heterocyclic ring is a dioxolane ring.
  • Another aspect of the present invention relates to the following compound, or its optical isomer, or its solvate (such as hydrate), or its inclusion compound, or its racemate, or its co-crystal, or its isotope label, or its nitrogen oxide:
  • the present invention provides a method for preparing the compound of formula (I) or its optical isomer, or its pharmaceutically acceptable salt, or its solvate (e.g., hydrate), or its inclusion compound, or its racemate, or its cocrystal, or its isotope-labeled substance, or its nitrogen oxide;
  • P is selected from The method comprises the steps of obtaining a compound of formula (II) by reacting a compound of formula (A) and a compound of formula (B) through method A:
  • Formula (A) is selected from R configuration, S configuration or racemate
  • D is selected from Cl, Br, I, OTs, OMs;
  • Each Y is selected from -O-, -S-, or -NH-, wherein R1 and R2 are as described in formula (I).
  • the compound of formula (II) can be prepared by a substitution reaction of the compound of formula (A) and the compound of formula (B) in a suitable solvent at a suitable temperature under base catalysis.
  • the base used in the substitution reaction is one or more selected from pyridine, or triethylamine, or N,N-diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene, or potassium carbonate, or cesium carbonate, or sodium hydride, or lithium bistrimethylsilylamide;
  • the solvent of the substitution reaction is one or more selected from DMF, or DMAC, or dimethyl sulfoxide, or NMP, or DCM, or tetrahydrofuran, or acetonitrile, or ethyl acetate, or isopropyl acetate, or dioxane, or acetone; optionally, the temperature of the substitution reaction is 0°C to 100°C.
  • formula (B) can adopt one of the following steps 1-3, but is not limited to the following method:
  • step 1
  • the chlorination reagent and sodium iodide (or potassium iodide) are refluxed in acetonitrile (or acetone). After the reaction is completed, the solvent is removed under reduced pressure, an organic solvent and water are added, the layers are separated, the organic phase is collected, dried over anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain the corresponding iodinated compound of formula (B).
  • step 3 is used to synthesize formula (B);
  • formula (A), formula (C) and formula (M) are subjected to method B to obtain formula (II);
  • Method B 1 Formula (A) and formula (C) are subjected to condensation reaction to obtain formula (D); 2 Formula (D) is deprotected to obtain formula (E); 3 Formula (E) and formula (M) are condensed to obtain formula (II).
  • Y is a single bond
  • X, R1 and R2 are as described in formula (I);
  • Formula (A) is selected from R configuration, S configuration or racemate
  • R7 is selected from methyl, ethyl, tert-butyl, benzyl, or p-methoxybenzyl; and E is -OH.
  • A is selected from a single bond, and X, R 3 and R 4 are as described in formula (I);
  • Z is selected from -OH, -NH 2 , -SH, -NH-;
  • the condensation agent of the condensation reaction is selected from one or more of DCC, DIC, EDCI, HATU, HBTU, CDI, HCTU, TBTU, TSTU, TNTU, HAPyU, HBPyU, BOP, PyBOP, PyAOP, DPPCl, DECP, DPPA, MPTA, or BOPCl; optionally, the solvent of the condensation reaction is selected from one or more of dichloromethane, dimethyl sulfoxide, N,N-dimethylformamide, hexamethylphosphoric triamide, or acetonitrile; optionally, the temperature of the condensation reaction is 0°C-100°C.
  • the method comprises subjecting the compound of formula (A) to obtain the compound of formula (III) by method D:
  • A is selected from a single bond, and X, R 3 , R 4 and Z are as described above;
  • the method comprises reacting the compounds of formula (A) and formula (H) by method E to obtain the compound of formula (III):
  • formula (B) in method A can be prepared by (but not limited to) one of methods a-e:
  • formula (B1) is prepared by the following method a:
  • the chloromethyl reagent and silver methanesulfonate are refluxed in acetonitrile. After the reaction is completed, the solvent is removed under reduced pressure, an organic solvent and water are added, the layers are separated, the organic phase is collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the corresponding methylsulfonyloxy-substituted compound (B4).
  • the chloromethyl reagent and silver p-toluenesulfonate are refluxed in acetonitrile. After the reaction is completed, the solvent is removed under reduced pressure, an organic solvent and water are added, the layers are separated, the organic phase is collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the corresponding p-toluenesulfonyloxy-substituted compound (B5).
  • formula (H) in method E is prepared by (but not limited to) one of methods f-k:
  • Or (H1) can be prepared by the following method:
  • Formula (H1) and sodium bromide (or potassium bromide) are refluxed in acetonitrile (or acetone). After the reaction is completed, the solvent is removed under reduced pressure, an organic solvent and water are added, the layers are separated, the organic phase is collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain formula (H2).
  • Formula (H1) and sodium iodide (or potassium iodide) are refluxed in acetonitrile (or acetone). After the reaction is completed, the solvent is removed under reduced pressure, an organic solvent and water are added, the layers are separated, the organic phase is collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain formula (H3).
  • Formula (H1) and silver methanesulfonate are refluxed in acetonitrile (or acetone). After the reaction is completed, the solvent is removed under reduced pressure, an organic solvent and water are added, the layers are separated, the organic phase is collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain formula (H4).
  • Formula (H1) and silver p-toluenesulfonate are refluxed in acetonitrile (or acetone). After the reaction is completed, the solvent is removed under reduced pressure, an organic solvent and water are added, the layers are separated, the organic phase is collected, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain formula (H5).
  • the pharmaceutically acceptable salt is an inorganic acid salt or an organic acid salt, preferably, selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, methanesulfonic acid, tartaric acid, formic acid, acetic acid, salicylic acid, citric acid, succinic acid, fumaric acid, or benzoic acid.
  • the present invention provides a pharmaceutical composition, which comprises the compound of formula (I) above or its optical isomer, or its pharmaceutically acceptable salt, or its solvate (e.g., hydrate), or its inclusion compound, or its racemate, or its co-crystal or its isotope-labeled substance, or its nitrogen oxide and pharmaceutically acceptable excipients.
  • a pharmaceutical composition which comprises the compound of formula (I) above or its optical isomer, or its pharmaceutically acceptable salt, or its solvate (e.g., hydrate), or its inclusion compound, or its racemate, or its co-crystal or its isotope-labeled substance, or its nitrogen oxide and pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are selected from: fillers, disintegrants, lubricants, glidants, effervescent agents, flavoring agents, preservatives, solubilizers, cosolvents, antioxidants, anti-photolysis agents, pH regulators, emulsifiers, antibacterial preservatives, local analgesics, chelating agents, non-aqueous solvents, coating materials or other excipients.
  • the pharmaceutically acceptable excipients whose filler includes one or more of lactose, mannitol, and calcium carbonate;
  • the binder includes one or more of sucrose, starch, povidone, and sodium carboxymethyl cellulose;
  • the disintegrant includes one or more of starch, cross-linked povidone, cross-linked sodium carboxymethyl cellulose, and an effervescent disintegrant;
  • the non-aqueous solvent includes one or more of soybean oil, castor oil, and peanut oil;
  • the solubilizer includes one or more of Tween 80, Tween 60, and poloxamer 68;
  • the cosolvent includes one or more of sodium benzoate, sodium salicylate, and sodium p-aminobenzoate.
  • the pharmaceutical composition may be administered orally (e.g., buccal), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppository or lotion), transdermally (skin electroporation, transdermal preparations, such as creams, gels, lotions, and transdermal patches, etc.), or by inhalation (e.g., aerosol), and in the form of solid, liquid, or gaseous dosage forms, including tablets and suspensions.
  • Administration may be performed in a single unit dosage form, or in a random single dose treatment, under continuous treatment.
  • the therapeutic composition may also be in the form of an oil emulsion or dispersion, combined with a lipophilic salt such as pamoic acid, or in the form of a biodegradable sustained release composition, for subcutaneous or intramuscular administration.
  • the pharmaceutical composition can be made into a solid oral preparation, a liquid oral preparation, an injection or a transdermal preparation.
  • the solid and liquid oral preparations include: tablets, dispersible tablets, sugar-coated tablets, granules, dry powders, capsules, syrups and solutions.
  • the injections include: small needles, large infusions, freeze-dried powder injections, etc.
  • the transdermal preparations include: ointments, plasters, liniments, aerosols, traditional plasters, adhesive dispersion patches, peripheral adhesive skeleton patches, reservoir patches and papuam, etc.
  • the present invention provides a use of a compound of formula (I) or its optical isomer, or a pharmaceutically acceptable salt, or a solvate (such as a hydrate), or an inclusion compound, or a racemate, or a cocrystal, or an isotope-labeled substance, or a nitrogen oxide, or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and/or treating inflammation, pain, fever, cancer, Alzheimer's disease, etc.; preferably, the inflammation is selected from rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, scapulohumeral periarthritis, tendon and tenosynovitis, peritenosynovitis, lateral epicondylitis (tennis elbow), postoperative anti-inflammatory, and swelling and inflammation caused by trauma; preferably, the pain is selected from mild to moderate pain, post-traumatic or post-strain pain, dysmenorrhea and post-operative pain,
  • the cancer cells include human esophageal cancer cell Eca-109, human multiple myeloma cell MM.1S, human gastric cancer cell NUGC-4, human brain astrocyte glioblastoma U87, human glioma cell U251, and large cell lung cancer cell H460.
  • the present invention provides a compound of formula (I) or its optical isomer, or a pharmaceutically acceptable salt, or a solvate (e.g., a hydrate), or an inclusion compound, or a racemate, or a cocrystal, or an isotope-labeled compound, or a nitrogen oxide, or the above-mentioned pharmaceutical composition, for use in combination with one or more other active drugs ("second active compounds") in the preparation of a medicament for preventing and/or treating inflammation, pain, fever, cancer, or Alzheimer's disease; preferably, the inflammation is selected from rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, scapulohumeral periarthritis, tendon and tenosynovitis, peritenosynovitis, lateral epicondylitis (tennis elbow), postoperative anti-inflammatory, and swelling and inflammation caused by trauma; the pain is selected from mild to moderate pain, post-traumatic or post-strain pain, dys
  • the cancer cells include human esophageal cancer cells Eca-109, human multiple myeloma cells MM.1S, human gastric cancer cells NUGC-4, human brain astrocytes U87, human glioma cells U251, and large cell lung cancer cells H460.
  • the second active compound examples of the present invention may include one or more of the following substances: sufentanil, dexmedetomidine, formoterol, isoproterenol, salbutamol, bambuterol, procaterol, fenoterol, arformoterol, tulobuterol, clenbuterol, salmeterol, salmeterol casone, terbutaline, metaprenaline, chlorprenaline, etc.
  • treating refers to alleviating or reducing the severity of symptoms associated with the disease or condition being treated, such as pain, inflammation, rheumatism, etc.
  • preventing includes inhibiting the symptoms of a particular disease or condition, such as pain, inflammation, rheumatism.
  • the compounds of the present invention may exist in isotopically traced or enriched form, containing one or more atoms whose atomic weight or mass number is different from the atomic weight or mass number of the largest amount of atoms found in nature.
  • Isotopes may be radioactive or non-radioactive isotopes.
  • Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine and iodine include, but are not limited to: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl and 125 I.
  • Compounds containing other isotopes of these and/or other atoms are within the scope of the present invention.
  • optical isomer refers to a substance having identical molecular structure, similar physicochemical properties, but different optical activity. It includes optical isomer mixtures in any proportion.
  • the compound of formula (I) may contain one or more asymmetric carbon atoms, and its existence form may be an optically pure enantiomer, such as an enantiomeric mixture of a racemate, an optically pure diastereomer, a diastereomeric mixture, a racemate of a diastereomer, or a mixture of a racemate of a diastereomer.
  • Optically active forms can be obtained, for example, by resolution of a racemate, by asymmetric synthesis or asymmetric chromatography (chromatography using a chiral adsorbent or eluent). The present invention includes all these forms.
  • solvate refers to a compound that is further bound by a chemical or non-chemical amount of a solvent through non-covalent intermolecular forces.
  • the solvent is water
  • the solvate is a hydrate.
  • BOPCl Bis(2-oxo-3-oxazolidinyl)phosphoryl chloride
  • HAPyU O-(7-azabenzotriazol-1-yl)-bis(tetrahydropyrrolyl)carbonium hexafluorophosphate
  • HATU 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HBTU Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HBPyU O-(Benzotriazol-1-yl)-bis(tetrahydropyrrolyl)carbonium hexafluorophosphate
  • CDI N,N-Carbonyldiimidazole
  • HCTU 6-Chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate
  • TBTU Benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate borate
  • TSTU O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate
  • DMAC N,N-dimethylacetamide
  • DCM dichloromethane
  • DIPEA N,N-diisopropylethylamine
  • TNTU 2-(endo-5-norbornene-2,3-dicarboximide)-1,1,3,3-tetramethyluronium tetrafluoroborate
  • Eca-109 human esophageal cancer cells
  • MM.1S human multiple myeloma cells
  • NUGC-4 Human gastric cancer cells
  • Figure 4 is the mechanical withdrawal reflex threshold of the left lower limb of rats in each group after 13 days of intervention with each test drug in Experimental Example 4 (Mean ⁇ SD)
  • the compound was prepared by general synthesis method 1 to obtain a colorless liquid with a yield of 47.9%.
  • the product was prepared by general synthesis method 1 to obtain a colorless liquid with a yield of 41.3%.
  • the product was prepared by general synthesis method 1 to obtain a colorless liquid with a yield of 52.6%.
  • the compound was prepared by general synthesis method 1 to obtain a colorless liquid with a yield of 59.6%.
  • Formula (M) (1.0 equivalent) or formula (M) protected by a protecting group (Boc, tert-butyl) (1.0 equivalent) is dissolved in DCM, chloromethyl chloroformate or 1-chloroethyl chloroformate (1.1-1.5 equivalent) and pyridine (1.6 equivalent) or triethylamine (0.6-1.6 equivalent) are added dropwise at 0°C, and stirred at -78°C to room temperature for 1 hour. After the reaction is completed, DCM and water are added for extraction, the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless transparent compound.
  • Formula (A) (1.0 equivalent) was dissolved in anhydrous DMF, potassium carbonate (1.6-2.0 equivalent) was added, and then the above product was dissolved in DMF and added dropwise to the reaction solution, and the temperature was raised to 40-50°C and stirred for 4 hours. After the reaction was completed, ethyl acetate was added, and the organic phase was washed with saturated aqueous ammonium chloride solution, water, and saturated aqueous sodium chloride solution in sequence, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the product.
  • the product of formula (M) protected by a protecting group is deprotected by hydrochloric acid or trifluoroacetic acid to obtain the final product.
  • the product was prepared by general synthesis method 2 to obtain a colorless liquid with a yield of 64.7%.
  • the compound was prepared by general synthesis method 2 to obtain a white solid with a yield of 44.6%.
  • the compound was prepared by general synthesis method 2 to obtain a white solid with a yield of 36.4%.
  • the general synthetic method 2 was used to prepare the product as a colorless oil with a yield of 38.3%.
  • the general synthetic method 2 was used to prepare the product as a colorless oil with a yield of 46.7%.
  • the general synthetic method 2 was used to prepare the product as a colorless oil with a yield of 42.2%.
  • the compound was prepared by general synthesis method 2 to obtain a white solid with a yield of 45.2%.
  • the compound was prepared by general synthesis method 2 to obtain a colorless oily liquid with a yield of 38.6%.
  • the product was prepared by general synthesis method 2 to obtain a colorless liquid with a yield of 61.4%.
  • Formula (A) (1.0 equivalent) was dissolved in anhydrous DCM, oxalyl chloride (3.0 equivalent) or acetyl chloride (1.2-1.5 equivalent) and a catalytic amount of DMF were added dropwise, and the mixture was stirred at room temperature for 0.5 h. The solution was drained to obtain formula (G).
  • Formula (G) was dissolved in a mixed solution of ethyl acetate: water (2:1) or a DCM solution, and added dropwise to a mixed system of formula (F) (2.0 equivalent) and potassium carbonate (6.0 equivalent) or triethylamine (1.5 equivalent), and stirred at -20-25°C for 4-12 h.
  • the compound was prepared by general synthesis method 3 to obtain a white solid with a yield of 42.7%.
  • the compound was prepared by general synthetic method 3 to obtain a colorless oil with a yield of 56.5%.
  • Formula (J) (1 equivalent) is dissolved in dry DCM, oxalyl chloride (1.5 equivalents) is added under nitrogen protection, then 1 drop of DMF is added, stirred at room temperature for 1 hour, and distilled under reduced pressure to obtain an acyl chloride compound, which is dissolved in DCM, zinc chloride (0.02 equivalents) is added, and then acetaldehyde (1 equivalent) is added at -15°C under nitrogen protection.
  • the reaction is carried out at room temperature for 16 hours, and after concentrating under reduced pressure, the residue is dissolved in 20 mL of ethyl acetate, washed with water (20 mL), saturated sodium bicarbonate solution (20 mL), and saturated sodium chloride aqueous solution (20 mL) in sequence, and the organic phase is collected, dried over anhydrous sodium sulfate, filtered, and the filtrate is evaporated to dryness under reduced pressure to obtain a compound of Formula (H).
  • Formula (A) (1.0 equivalent) is dissolved in DMF, triethylamine (1.5 equivalent) or potassium carbonate (1.6-2.0 equivalent), with or without sodium iodide (1.1 equivalent), and stirred at 20-50°C.
  • Formula (H) or formula (H) protected by a protecting group (1.2 equivalent) is dissolved in DMF, slowly added to the above reaction solution, and reacted for 3-4 hours.
  • the compound of formula (III) protected by the protecting group is reduced with hydrogen or de-tert-butyldimethylsilylated with acid, base or tetrabutylammonium fluoride to obtain the compound of formula (III).
  • the compound was prepared by general synthetic method 4 to obtain a colorless oil with a yield of 20.0%.
  • the compound was prepared by general synthetic method 4 to obtain a colorless oil with a yield of 38.7%.
  • the compound was prepared by general synthesis method 4 to give a white solid with a yield of 47.4%.
  • the compound was prepared by general synthetic method 4 to obtain a colorless oil with a yield of 47.6%.
  • the compound was prepared by general synthetic method 4 to obtain a colorless oil with a yield of 43.4%.
  • the compound was prepared by general synthetic method 4 to obtain a colorless oil with a yield of 59.2%.
  • the compound was prepared by general synthetic method 4 to obtain a colorless oil with a yield of 61.4%.
  • the compound was prepared by general synthetic method 4 to obtain a colorless oil with a yield of 46.7%.
  • the compound was prepared by general synthetic method 4 to obtain a colorless oil with a yield of 56.35%.
  • the compound was prepared by general synthetic method 4 to obtain a colorless oil with a yield of 58.6%.
  • the compound was prepared by general synthetic method 3 to obtain a colorless oil with a yield of 62.5%.
  • the compound was prepared by general synthetic method 3 to obtain a colorless oil with a yield of 69.4%.
  • the compound was prepared by general synthetic method 5 to give a colorless oil with a yield of 51.7%.
  • the compound was prepared by general synthesis method 4 to obtain a white solid with a yield of 92.9%.
  • the compound was prepared by general synthesis method 3 to obtain a white solid with a yield of 40.7%.
  • the product was prepared by general synthesis method 3 to obtain a colorless liquid with a yield of 77.5%.
  • the compound was prepared by general synthesis method 5 to obtain a colorless liquid with a yield of 60.3%.
  • the product was prepared by general synthesis method 3 to obtain a colorless liquid with a yield of 48.3%.
  • Step 1 (Synthesized using step 1)
  • Step 2 (Synthesized using step 2)
  • the compound was prepared by general synthesis method 6 to obtain a colorless liquid with a yield of 65.32%.
  • the compound was prepared by general synthetic method 6 to give a colorless liquid with a yield of 12.33%.
  • the compound was prepared by general synthesis method 6 to give a colorless liquid with a yield of 19.87%.
  • the compound was prepared by general synthesis method 6 to obtain a colorless liquid with a yield of 21.66%.
  • the compound was prepared by general synthesis method 6 to obtain a colorless liquid with a yield of 35.37%.
  • the compound was prepared by general synthesis method 6 to obtain a colorless liquid with a yield of 55.78%.
  • the compound was prepared by general synthesis method 6 to obtain a colorless liquid with a yield of 56.65%.
  • the compound was prepared by general synthesis method 6 to obtain a colorless liquid with a yield of 89.25%.
  • the compound was prepared by general synthesis method 6 to obtain a colorless liquid with a yield of 51.38%.
  • the compound was prepared by general synthesis method 6 to obtain a colorless liquid with a yield of 55.51%.
  • the compound was prepared by general synthesis method 6 to obtain a colorless liquid with a yield of 56.93%.
  • the compound was prepared by general synthetic method 2 to obtain a colorless oil with a yield of 30.98%.
  • the compound was prepared by general synthetic method 2 to obtain a colorless oil with a yield of 29.75%.
  • the general synthetic method 2 was used to prepare the product, and a colorless oil was obtained with a yield of 77.35%.
  • the general synthetic method 2 was used to prepare the product, and a colorless oil was obtained with a yield of 76.59%.
  • the compound was prepared by general synthetic method 2 to obtain a colorless oil with a yield of 81.27%.
  • the compound was prepared by general synthetic method 2 to obtain a colorless oil with a yield of 80.52%.
  • mice Male female Sprague Dawley rats aged 8-10 weeks, weighing 200 ⁇ 20g, were randomly divided into groups, 3 rats in each group. Each group was administered by gavage, with a dose of 50mg/kg flurbiprofen and other embodiment groups with an equimolar dose of 50mg/kg flurbiprofen.
  • blood was collected at 0.0833h, 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, 9h, 12h, and 24h after drug administration, and heparin sodium anticoagulation was performed.
  • the blood collection method was to collect 250 ⁇ L of blood from the orbital venous plexus of the rat. The collected blood samples were centrifuged at 12000rpm for 5min in a centrifuge, and all plasma was drawn into a 1.5mL centrifuge tube, and the plasma was stored in a -80°C refrigerator.
  • Test Example 2 Anti-inflammatory effect on experimental rat toe swelling
  • mice Male SD rats weighing 150-160g were randomly divided into groups, with 10 rats in each group.
  • Physiological saline, the compounds of the present invention, and control drugs flurbiprofen or flurbiprofen axetil were intraperitoneally injected, respectively, at a dose of 10 mg/kg and a volume of 10 ⁇ L/g.
  • 100 ⁇ L of 1% ⁇ -carrageenan was injected into the plantar of the right hind paw of each rat to induce inflammation.
  • the paw volume was measured every 1 hour using a foot volume meter to calculate the swelling inhibition rate.
  • the results showed that the compounds of the present invention in Table 2 all had better anti-inflammatory effects than flurbiprofen.
  • * represents P value less than 0.05
  • ** represents P value less than 0.01
  • *** represents P value less than 0.001.
  • Test Example 3 Effects of dry yeast on fever in rats
  • mice Male SD rats, 4 weeks old, were randomly divided into groups, 10 rats in each group.
  • the ambient temperature was 20-21°C, the humidity was 40-70%, and the body temperature screening was performed.
  • the average body temperature was about 37.4°C, and the elimination rate was about 10%.
  • Physiological saline, the compound of the present invention, or the control drug flurbiprofen were injected intraperitoneally, the dose was 10 mg/kg, and the administration volume was 10 ⁇ L/g. 20 minutes after administration, 20% active dry yeast suspension was injected subcutaneously, and the rectal temperature was measured at 4h and 8h after modeling.
  • Test Example 4 Analgesic and anti-inflammatory effects on collagen-induced rheumatoid arthritis (CIA)
  • mice Female Lewis rats, 6-8 weeks old, were randomly divided into groups, 8 rats in each group. The ambient temperature was 20.5-24.5°C, the humidity was 40-70%, and the light cycle was 12 hours light and 12 hours dark.
  • Type II collagen was mixed with Freund's incomplete adjuvant (IFA) at a ratio of 1:1 and fully emulsified on ice before use. 100 ⁇ L of the mixture was injected intradermally at 2-3 cm from the base of the rat's tail, and 50 ⁇ L of the mixture was injected into the base of both hind limbs. The blank control group was injected with an equal volume of saline. IFA was used for re-immunization 7 days later. The rats were observed for disease development every day after the second immunization.
  • IFA Freund's incomplete adjuvant
  • Rats with a total score of more than 2 points on both sides of the hind limb were selected and randomly divided into model group, flurbiprofen, compound 33, compound 2, compound 13, compound 20, compound 35 group according to body weight, score and foot volume.
  • a blank control group was also set up, with 8 rats in each group.
  • the administration volume was 10 mg/kg, and the administration time was 14 days.
  • the model group and the blank control group were given the corresponding volume of solvent.
  • each test drug showed a significant effect in reducing the volume of the left hind limb foot of CIA rats (P ⁇ 0.05 or 0.01). Compared with the model group, the volume of the left lower limb foot of CIA rats was significantly reduced during the test drug treatment (Figure 3).
  • Compound 33, Compound 2, Compound 13, Compound 20, and Compound 35 showed better effects than the flurbiprofen group.
  • MTT method was used for testing. Tumor cells in the logarithmic phase were collected, the concentration of the cell suspension was adjusted, 100 ⁇ L was added to each well, and the cell density to be tested was adjusted to 1000-10000 cells/well by plating (the edge wells were filled with sterile PBS). Incubate at 5% CO 2 and 37°C until the cells adhered to the wall (96-well flat-bottom plate), add drugs of different concentration gradients, 100 ⁇ L per well, and set up 4 replicate wells. Incubate at 5% CO 2 and 37°C for 72 hours and observe under an inverted microscope.
  • the inhibitory rate of the drug on tumor cell growth was calculated according to the following formula:

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Abstract

一种式（I）所示的取代3-氟苯丙酸酯类化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物（例如水合物）、或其包合物、或其消旋体、或其共晶体、或其同位素标记物、或其氮氧化物，及它们的药物组合物和用途。该化合物具有显著提高的药物活性，能够有效治疗和/或预防炎症、疼痛、发热、癌症或老年痴呆症。

Description

取代3-氟苯丙酸酯类化合物及其制备方法、药物组合及用途 技术领域
本发明涉及一种3-氟苯丙酸酯类化合物、其制备方法、药物组合物及用途。
 背景技术
非甾体抗炎药(Non-Steroidal Anti-Inflammatory Drug，NSAID)是一类具有解热、镇痛、抗炎和抗风湿作用的药物。NSAIDs种类繁多，结构式各不相同，但都有相似的作用机制，主要是通过抑制环氧化酶(Cyclooxygenase，COX)的活性，从而阻止花生四烯酸生成前列环素(PGI2)，前列腺素(PGE1，PGE2)和血栓素A2(TXA2)，最终达到抗炎镇痛的效果。目前，NSAIDs广泛应用于临床诸多疾病，全球范围内总消耗量仅次于抗生素，在各种风湿病的治疗中，NSAIDs的处方量位居第一，因此NSAIDs一直是研究与开发的热点之一。
不同的NSAIDs由于结构差异很大，因此在理化性质、药效及生物利用度、代谢、半衰期等药动学方面均存在明显差别。氟比洛芬是目前公认抗炎镇痛痛作用最强的NSAIDs药物之一。目前市场上的氟比洛芬制剂多为口服制剂，易引起胃肠道功能紊乱等不良反应，上消化道的不耐受也是制约氟比洛芬的主要因素。作为芳基丙酸类药物，氟比洛芬对胃肠道的刺激及副作用主要源于其分子上的羧酸基团。科学家们通过将其进行结构修饰及衍生，以期获得毒副作用小且具有较高生物利用度的前体药物，提高患者的顺应性。日本科研制药株式会社开发的氟比洛芬酯即为氟比洛芬的前药，具有镇痛作用时间长、靶向化作用、减轻胃肠道刺激等优点。然而，由于氟比洛芬酯在胃肠道环境中不稳定，无法口服给药，需静脉注射，极大限制了其广泛应用。
因此，研制稳定性更高、半衰期更长、效果更优、毒副作用更小的NSAIDs，是新型抗炎镇痛药物的开发需求。
发明内容
本发明提供一种3-氟苯丙酸酯类化合物，如下式(I)所示的化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体、或其同位素标记物、或其氮氧化物。该化合物具有良好的抗炎活性，能够有效治疗和/或预防多发性骨髓瘤的生长繁殖。还提供了包含所述化合物的制备方法、药物组合物和用途。
一种式(I)所示的化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物(可选地，所述溶剂化物为水合物)、或其包合物、或其消旋体、或其共晶体、或其同位素标记物、或其氮氧化物，
其中：
X为亚烷基；
P选自：
式(a)中，
Y选自单键、-O-，-S-，或-NH-；
W为单键或亚烷基；
R1和R2相同或者不同，各自独立地选自-H，任选取代的烷基，任选取代的芳基，或者，R1和R2相互连接、且与它们连接的氮原子共同形成任选取代的脂杂环基或
R5为一个或两个，各自独立地选自-H，烷基；
式(c)中，虚线表示单键或不存在；
式(b)中，
A选自单键、-O-(C＝O)-或-O-(C＝O)-亚烷基；
R3为任选存在的基团；
R3存在时，为一个或多个，各自独立地为烷基、羟基、羧基、羟基取代的烷基、烷氧基、-N(R5)(R6)，R5、R6相同或不同，各自独立地为烷基；
R4选自-H，烷基，烷酰基；
或者R3与-OR4相互连接形成脂杂环；
所述“任选取代的”是指未取代或被一个或多个取代基取代，其中所述“任选取代的烷基”、“任选取代的芳基”、“任选取代的脂杂环基”中的取代基各自独立地选自羟基、氨基、羧基、卤素、硝基、氰基、烷基、烷硫基、烷酰基、羟基取代的芳基；
可选地，所述“烷基”，“烷酰基”、“羟基取代的烷基”、“烷氧基”、“烷硫基”中的烷基部分各自独立地为C1-20直链或支链烷基，可选地，为C1-17直链或支链烷基，可选地，为C1-10直链或支链烷基，可选地，为C1-7直链或支链烷基，可选地，为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基，异戊基、新戊基、叔戊基、正己基、异己基、庚基、正辛基、正壬基、正癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、或十六烷基；
可选地，所述“亚烷基”为C1-20直链或支链亚烷基，可选地，为C1-17直链或支链亚烷基，可选地，为C1-10直链或支链亚烷基，可选地，为C1-8直链或支链亚烷基，可选地，为C1-6直链或支链亚烷基，可选地，为C1-3直链或支链亚烷基，可选地，为亚甲基、亚乙基、亚异乙基、亚正丙基、亚异丙基、亚正丁基、亚异丁基、亚叔丁基、亚仲丁基、亚正戊基，亚异戊基、亚新戊基、亚叔戊基、亚正己基、亚异己基、亚庚基、亚正辛基、亚正壬基、亚正癸基；
可选地，所述“脂杂环”、“脂杂环基”中的脂杂环为环上含有选自O、N、S的1-3个杂原子的C3-8(优选为C4-6)脂杂环，可选地，为二氧戊环、氮杂环丙烷基、氮杂环丁烷基、四氢吡咯基、吗啉基、哌啶基、或哌嗪基；
可选地，所述“芳基”、“羟基取代的芳基”为6-10元单环或双环稠合芳香环基团；可选地为苯基或萘基；
可选地，本发明涉及前述化合物和任何附属的定义，其中3-氟苯丙酸酯部分为S构型或R构型。
可选地，R1和R2相同或者不同，各自独立地选自-H，正丙基，异丙基， 或者，R1和R2相互连接、且与它们连接的氮原子共同形成下述基团：杂环丙烷-1-基、氮杂环丁烷-1-基、四氢吡咯-1-基、吗啉-1-基、哌啶-1-基、或哌嗪-1-基，
可选地，R3与-OR4相互连接形成脂杂环时，所述脂杂环为二氧戊环。
本发明的另一方面涉及下述化合物，或其光学异构体、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体、或其同位素标记物、或其氮氧化物：
又一方面，本发明提供一种如上述式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体或其同位素标记物、或其氮氧化物的制备方法；
其式(I)中，P选自包括将式(A)化合物和式(B)化合物通过方法A得到式(II)的步骤：
方法A：将式(A)和式(B)通过取代反应制得式(II)；
其中，
式(A)选自R构型、S构型或消旋体；
式(B)和式(II)中X、Y、W、R1和R2如式(I)中所述；
式(B)中D选自Cl，Br，I，OTs，OMs；
各个Y选自-O-，-S-，或-NH-，其中R1和R2如式(I)所述。
可选地，将式(A)和式(B)在碱催化下，在合适溶剂中，于适当温度下，通过取代反应制得式(II)。
可选地，所述方法A中，所述取代反应所用的碱为选自吡啶、或三乙胺、或N，N-二异丙基乙胺、或1,8-二氮杂二环[5.4.0]十一碳-7-烯、或碳酸钾、或碳酸铯、或氢化钠、或双三甲基硅基胺基锂中的一种或多种；可选地，所述取代反应的溶剂为选自DMF、或DMAC、或二甲基亚砜、或NMP、或DCM、或四氢呋喃、或乙腈、或乙酸乙酯、或乙酸异丙酯、或二氧六环、或丙酮中的一种或多种；可选地，所述取代反应的温度为0℃至100℃。
可选地，式(B)可以采用如下步骤1-3中的一种，但并不限于以下方法：
步骤1：
在室温下，向剧烈搅拌的酸的二氯甲烷溶液中加入饱和碳酸氢钠溶液和催化量四丁基硫酸氢铵，然后加入氯磺酸氯甲酯，反应完成后，分层，收集有机相，无水硫酸钠干燥，减压旋干，柱层析纯化后得式(B)化合物。
和/或步骤2：
将氯代试剂和碘化钠(或碘化钾)在乙腈(或丙酮)中回流，反应完成后，减压除去溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压除去溶剂，得相应的碘代式(B)化合物。
可选的，W不存在，使用步骤3合成式(B)；
或步骤3：
0℃下，向氯甲酸氯甲酯的二氯甲烷溶液中加入相应的仲胺，反应完成后，过滤，有机相用1N盐酸洗，无水硫酸钠干燥，减压除去溶剂，得式(B)化合物。
或者，W为单键时，包括将式(A)、式(C)和式(M)通过方法B得到式(II)；
方法B：①将式(A)和式(C)通过缩合反应制得式(D)；②将式(D)进行脱保护得式(E)；③式(E)与式(M)缩合得式(II)。
其中，
Y为单键，X、R1和R2如式(I)所述；
式(A)选自R构型、S构型或消旋体；
式(C)中R7选自甲基、乙基、叔丁基、苄基、或对甲氧基苄基；E为-OH。
或者，P选自包括式(A)化合物和式(F)化合物通过方法C得到式(III)；
方法C：将式(A)和式(F)通过缩合反应制得式(III)；
其中，
式(F)中，A选自单键，X、R3和R4如式(I)中所述；
式(F)中，Z选自-OH，-NH2，-SH，-NH-；
可选地，所述方法B和方法C中，所述缩合反应的缩合剂选自DCC，DIC，EDCI，HATU，HBTU，CDI，HCTU，TBTU，TSTU，TNTU，HAPyU，HBPyU，BOP，PyBOP，PyAOP，DPPCl，DECP，DPPA，MPTA，或BOPCl中的一种或多种，可选地，所述缩合反应的溶剂选自二氯甲烷，二甲亚砜，N,N-二甲基甲酰胺，六甲基磷酰三胺，或乙腈中的一种或多种；可选地，所述缩合反应的温度为0℃-100℃。
或者，包括将式(A)通过方法D得到式(III)化合物：
方法D：
其中，
式(F)中，A选自单键，X、R3、R4和Z如上所述；
或者，包括将式(A)和式(H)通过方法E得到式(III)化合物：
方法E：
其中，
式(H)中，A为-O-(C＝O)-；G选自Cl，Br，I，OMs，或OTs；X、R3和R4如式(I)中所述；
可选地，方法A中式(B)可采取(但并不限于)方法a-e中的一种制得：
当式(B)中D为Cl时，采用下述方法a制得式(B1)：
低温下，向式(M)中加入碱，然后加入氯甲酸氯甲酯或氯甲酸氯乙酯，反应完成后，有机相使用1N柠檬酸淋洗，无水硫酸钠干燥，减压蒸馏，得式(B1)；
或当式(B)中D为Br时，采用下述方法b制得式(B2)：将氯甲基试剂和溴化钠(或溴化钾)在乙腈(或丙酮)中回流，反应完成后，减压除去溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压蒸馏得相应的溴代化合物式(B2)；
或当式(B)中D为I时，采用下述方法c制得式(B3)：
将氯甲基试剂和碘化钠(或碘化钾)在乙腈(或丙酮)中回流，反应完成后，减压除去溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压蒸馏得相应的碘代化合物式(B3)；
或当式(B)中D为OMs时，采用下述方法d制得式(B4)：
将氯甲基试剂和甲磺酸银在乙腈中回流，反应完成后，减压除去溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压蒸馏得相应的甲磺基氧基取代的化合物式(B4)。
或当式(B)中D为OTs时，采用下述方法e制得(B5)：
将氯甲基试剂和对甲苯磺酸银在乙腈中回流，反应完成后，减压除去溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压蒸馏得相应的对苯磺基氧基取代的式(B5)。
可选地，方法E中式(H)采取(但并不限于)方法f-k中的一种制得：
当式(H)中，G为Cl时，采用下述方法f制得(H1)：
在室温下，向式(J)二氯甲烷酸溶液中加入饱和碳酸氢钠溶液和催化量四丁基硫酸氢铵，然后加入式(K)，反应完成后，分层，收集有机相，无水硫酸钠干燥，减压旋干，柱层析纯化后得式(H1)。
或采用下述方法g制得(H1)：
或当式(H)中，G为Br时，采用下述方法h制得(H2)：
将式(H1)和溴化钠(或溴化钾)在乙腈(或丙酮)中回流，反应完成后，减压除去溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压蒸馏得式(H2)。
或当式(H)中，G为I时，采用下述方法i制得(H3)：
将式(H1)和碘化钠(或碘化钾)在乙腈(或丙酮)中回流，反应完成后，减压除去溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压蒸馏得式(H3)。
或当式(H)中，G为OMs时，采用下述方法j制得(H4)：
将式(H1)和甲磺酸银在乙腈(或丙酮)中回流，反应完成后，减压除去溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压蒸馏得式(H4)。
或当式(H)中，G为OTs时，采用下述方法k制得(H5)：
将式(H1)和对甲苯磺酸银在乙腈(或丙酮)中回流，反应完成后，减压除溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压蒸馏得式(H5)。
所述药学上可接受的盐为无机酸盐或有机酸盐，优选地，选自盐酸、硫酸、磷酸、硝酸、甲磺酸、酒石酸、甲酸、乙酸、水杨酸、柠檬酸、琥珀酸、富马酸、或苯甲酸。
又一方面，本发明提供一种药物组合物，所述药物组合物包括上述式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体或其同位素标记物、或其氮氧化物和药学上可接受的辅料。
可选地，所述的药学上可接受辅料选自：填充剂、崩解剂、润滑剂、助流剂、泡腾剂、矫味剂、防腐剂、增溶剂、助溶剂、抗氧剂、抗光解剂、pH调节剂、乳化剂、抑菌防腐剂、局部止痛剂、络合剂、非水溶剂、包衣材料或其它赋形剂。
可选地，所述的药学上可接受的辅料，其填充剂包括乳糖、甘露醇、碳酸钙中的一种或几种的组合物；所述的粘合剂包括蔗糖、淀粉、聚维酮、羧甲基纤维素钠中的一种或几种的组合物；所述的崩解剂包括淀粉、交联聚维酮、交联羧甲基纤维素钠、泡腾崩解剂中的一种或几种的组合物；非水溶剂包括大豆油、蓖麻油、花生油中的一种或几种的组合物；增溶剂包括吐温80、吐温60、泊洛沙姆68中的一种或几种的组合物；助溶剂包括苯甲酸钠、水杨酸钠、对氨基苯甲酸钠中的一种或几种的组合物。
可选地，所述药物组合物的给药方式包括：经口给药(例如，口腔)、舌下给药、肠胃外给药(例如，肌肉内、静脉内或者皮下)、直肠给药(例如，由栓剂或洗剂)、透皮给药(皮肤电穿孔，透皮制剂等，如乳膏、凝胶、涂剂和透皮贴片等)或者通过吸入给药(例如，气雾剂)，并且以固体、液体或气态剂量的形式，包括片剂和混悬剂给药等。可以在连续治疗下，以单一单位剂量形式，或以随意的单一剂量治疗，进行给药。治疗组合物还可以为油乳剂或分散剂的形式，结合有亲脂性盐如双羟萘酸，或者为可生物降解的持续释放组合物的形式，用于皮下或者肌肉内给药。
可选地，所述药物组合物可以制成固体口服制剂、液体口服制剂、注射剂或透皮制剂。所述固体及液体口服制剂包括：片剂、分散片、糖衣剂、颗粒剂、干粉剂、胶囊剂、糖浆剂和溶液剂。所述的注射剂包括：小针、大输液、冻干粉针等。所述的透皮制剂包括：软膏剂、硬膏剂、搽剂、气雾剂、传统贴膏、黏胶分散型贴剂、周边黏胶骨架型贴剂、储库型贴剂和巴布膏剂等。
又一方面，本发明提供一种式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体或其同位素标记物、或其氮氧化物或上述药物组合物在制备用于预防和/或治疗炎症、疼痛、发热、癌症、老年痴呆等药物中的用途；优选地，所述炎症选自类风湿性关节炎、骨关节炎、强直性脊椎炎、肩周炎、肌腱及腱鞘炎、腱鞘周围炎、肱骨外上髁炎(网球肘)、术后抗炎、外伤所致肿胀炎症；优选地，所述疼痛选自轻度至中度疼痛、创伤后或劳损后疼痛、痛经和手术后疼痛、牙痛及癌痛、成人急性疼痛等；所述发热包括普通感冒或流行性感冒引起的发热；所述癌症选自胃癌、食管癌、多发性骨髓瘤、脑胶质瘤、肺癌。优选地，所述癌症细胞包括人食管癌细胞Eca-109，人多发性骨髓瘤细胞MM.1S，人胃癌细胞NUGC-4，人脑星形胶质母细胞U87，人胶质瘤细胞U251，大细胞肺癌细胞H460。
又一方面，本发明提供一种前述式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体或其同位素标记物、或其氮氧化物或上述药物组合物与其他一种或多种活性药物(“第二活性化合物”)联合用药，在制备用于预防和/或治疗炎症、疼痛、发热、癌症或老年痴呆症的药物中的用途；优选地，所述炎症选自类风湿性关节炎、骨关节炎、强直性脊椎炎、肩周炎、肌腱及腱鞘炎、腱鞘周围炎、肱骨外上髁炎(网球肘)、术后抗炎、外伤所致肿胀炎症；所述疼痛选自轻度至中度疼痛、创伤后或劳损后疼痛、痛经和手术后疼痛、牙痛及癌痛、成人急性疼痛等；所述发热包括普通感冒或流行性感冒引起的发热；所述癌症选自胃癌、食管癌、多发性骨髓瘤、脑胶质瘤、肺癌。优选地，所述癌症细胞包括人食管癌细胞Eca-109，人多发性骨髓瘤细胞MM.1S，人胃癌细胞NUGC-4，人脑星形胶质母细胞U87，人胶质瘤细胞U251，大细胞肺癌细胞H460。本发明所述第二活性化合物实例可包括以下物质中的一种或多种：舒芬太尼、右美托咪定、福莫特罗、异丙肾上腺素、沙丁胺醇、班布特罗、丙卡特罗、非诺特罗、阿福特罗、妥洛特罗、克伦特罗、沙美特罗、沙美特罗卡松、特布他林、奥西那林、氯丙那林等。
如本文中所用，除非另有说明，否则术语“治疗”是指减轻或减少与所治疗的疾病或病患例如疼痛、炎症、风湿病等相关的症状的严重性。术语“预防”包括抑制特定疾病或病症例如疼痛、炎症、风湿病的症状。
本发明的化合物可以以同位素示踪或富集形式存在，含有一个或多个原子，这些原子的原子量或质量数不同于自然界中发现的最大量的原子的原子量或质量数。同位素可以是放射性或非放射性的同位素。原子例如氢、碳、磷、硫、氟、氯和碘的同位素包括但不局限于：2H，3H，13C，14C，15N，18O，32P，35S，18F，36Cl和125I。含有这些和/或其它原子的其它同位素的化合物在本发明范围之内。
本文使用的术语“光学异构体”指的是分子结构完全相同，物理化学性质相近，但旋光性不同的物质。包括任意比例光学异构混合物。式(I)化合物可以含有一个或多个不对称碳原子，并且其存在形式可以是旋光纯对映异构体，例如外消旋物的对映异构体混合物、旋光纯非对映异构体、非对映异构体混合物、非对映异构体的外消旋物或非对映异构体的外消旋物的混合物。可以通过例如外消旋物的拆分，通过不对称合成或不对称色谱法(使用手性吸附剂或洗脱剂的色谱法)，获得旋光活性形式。本发明包括所有这些形式。
本文所使用的术语“溶剂化物”是指进一步通过非共价分子间力结合的化学量或非化学量的溶剂的化合物。例如当溶剂为水时，该溶剂化物为水合物。
缩略语
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BOP：六氟磷酸苯并三唑-1-氧基三(二甲氨基)磷
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BOPCl：二(2-氧-3-唑烷基)磷酰氯
DCC：二环己基碳二亚胺
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DECP：氰代磷酸二乙酯
DIC：N,N'-二异丙基碳二亚胺
EDCI：1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐
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HAPyU：O-(7-氮杂苯并三氮唑-1-基)-二(四氢吡咯基)碳鎓六氟磷酸盐
HATU：2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
HBTU：苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐
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HBPyU：O-(苯并三氮唑-1-基)-二(四氢吡咯基)碳鎓六氟磷酸盐
CDI：N,N-碳酰二咪唑
HCTU：6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯
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MPTA：硫代二甲基磷酰基叠氮
TBTU：苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐硼酸酯
TSTU：O-(N-琥珀酰亚胺)-1,1,3,3-四甲基脲四氟硼酸酯
DMAP：4-二甲氨基吡啶
DMF：N,N-二甲基甲酰胺
DMAC：N，N-二甲基乙酰胺DCM：二氯甲烷DIPEA：N,N-二异丙基乙胺
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DPPCl：二苯基次膦酰氯
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DPPA：叠氮磷酸二苯酯
NMP：N-甲基吡咯烷酮
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PyAOP：(7-氮杂苯并三唑-1-氧)三吡咯磷六氟磷酸盐
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PyBOP：六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷
TNTU：2-(内-5-降冰片烯-2,3-二羧酰亚胺)-1,1,3,3-四甲基脲四氟硼酸盐
Eca-109：人食管癌细胞
MM.1S：人多发性骨髓瘤细胞
NUGC-4：人胃癌细胞
U87：人脑星形胶质母细胞
U251：人胶质瘤细胞
H460：大细胞肺癌细胞
 附图说明
图1是试验例4给药期间各组大鼠体重变化图(n＝8，Mean±SD)
图2是试验例4各受试药干预14天后CIA大鼠关节炎评分图(n＝8，Mean±SD)
图3是试验例4各受试药干预14天后CIA大鼠左后肢足体积变化图(n＝8，Mean±SD)
图4是试验例4各受试药干预13天后各组大鼠左下肢机械缩足反射阈值(Mean±SD)
 具体实施方式
除非另有定义，否则本文使用的所有技术和科学术语具有与本领域普通技术人员通常理解的相同的含义。如果本文的术语有多个定义，除非另有说明，否则以本部分为主。
本发明的实施例详细说明如下，但所提供的实施例不以任何方式限制本发明。
实施例
通用合成方法1：
采用方法B合成。
第一步：
将式(A)(1.0当量)、2-乙醇酸叔丁酯(1.1当量)、EDCI(1.5当量)和DMAP(0.1当量)加入到5mL DMF中，室温搅拌12h。加入乙酸乙酯，再依次用饱和氯化铵水溶液、水、饱和氯化钠水溶液洗涤有机相，收集有机相无水硫酸钠干燥，过滤得到滤液减压蒸干，将产物溶解于DCM中，加入三氟乙酸(2mL)，搅拌4h后减压浓缩得白色固体。
第二步：
将上述产物(1.0当量)、和式(M)(1.1～2当量)、HATU(1.2～1.5当量)和DIPEA(5.0当量)加入到5mL DMF中，室温搅拌4h。待反应完成后，加入乙酸乙酯，再依次用饱和氯化铵水溶液、水、饱和氯化钠水溶液洗涤有机相，收集有机相无水硫酸钠干燥，减压浓缩，采用硅胶柱层析纯化，得产物。
实施例1：化合物1的制备
采用通用合成方法1制备，得无色液体，收率47.9％。
1H NMR(400MHz,DMSO-d6)δ7.57–7.44(m,5H),7.43–7.38(m,1H),7.34–7.26(m,2H),4.90–4.77(m,2H),4.00(q,J＝7.2Hz,1H),3.55(t,J＝4.8Hz,4H),3.41(d,J＝5.0Hz,2H),3.35(s,2H),1.47(d,J＝7.1Hz,3H).
实施例2：化合物10的制备
采用通用合成方法1制备，得无色液体，收率41.3％。
1H NMR(400MHz,DMSO-d6)δ7.57–7.52(m,2H),7.52–7.45(m,3H),7.43–7.38(m,1H),7.34–7.26(m,2H),4.90(d,J＝5.7Hz,2H),4.00–3.94(m,1H),3.67–3.58(m,1H),3.52(q,J＝5.3Hz,2H),3.46(q,J＝5.9Hz,2H),3.33(s,4H),3.18–3.10(m,1H),1.46(d,J＝7.1Hz,3H).
实施例3：化合物11的制备
采用通用合成方法1制备，得无色液体，收率52.6％。
1H NMR(400MHz,DMSO-d6)δ7.56–7.45(m,5H),7.43–7.38(m,1H),7.35–7.26(m,2H),4.94–4.80(m,2H),4.00(q,J＝7.1Hz,1H),3.42(m,8H),2.01(s,3H),1.47(d,J＝7.1Hz,3H).
实施例4：化合物12的制备
采用通用合成方法1制备，得无色液体，收率59.6％。
1H NMR(400MHz,DMSO-d6)δ7.57–7.45(m,5H),7.43–7.37(m,1H),7.34–7.23(m,2H),4.61–4.48(m,2H),4.09(td,J＝7.8,3.5Hz,2H),3.99(q,J＝7.1Hz,1H),3.87(t,J＝7.7Hz,2H),2.21(p,J＝7.6Hz,2H),1.45(d,J＝7.1Hz,3H).
通用合成方法2：
采用方法A合成。
第一步：
将式(M)(1.0当量)或保护基(Boc、叔丁基)保护的式(M)(1.0当量)溶于DCM中，0℃下逐滴加入氯甲酸氯甲酯或1-氯乙基氯甲酸酯(1.1～1.5当量)和吡啶(1.6当量)或三乙胺(0.6～1.6当量)，-78℃～室温搅拌1h。反应完毕后，加入DCM和水萃取，收集有机相，无水硫酸钠干燥，过滤后减压浓缩得无色透明化合物。
第二步：
将式(A)(1.0当量)溶于无水DMF中，加入碳酸钾(1.6～2.0当量)，然后将上述产物溶于DMF中，并逐滴加入反应液中，升温至40～50℃搅拌4h。反应完毕后，加入乙酸乙酯，再依次用饱和氯化铵水溶液、水、饱和氯化钠水溶液洗涤有机相，收集有机相无水硫酸钠干燥，过滤后减压浓缩，用硅胶柱层析进行纯化得产物。
保护基保护的式(M)得产物后经盐酸或三氟乙酸脱保护后得终产物。
实施例5：化合物2的制备
采用通用合成方法2制备，得无色液体，收率64.7％。
1H NMR(400MHz,DMSO-d6)δ7.54(dt,J＝8.2,1.6Hz,2H),7.51–7.45(m,3H),7.43–7.38(m,1H),7.27–7.18(m,2H),5.78–5.68(m,2H),3.97(q,J＝7.1Hz,1H),3.48(d,J＝14.3Hz,4H),3.30(s,4H),1.43(d,J＝7.1Hz,3H).
实施例6：化合物13的制备
采用通用合成方法2制备，得无色液体，收率50.9％。
1H NMR(400MHz,DMSO-d6)δ7.56–7.44(m,5H),7.43–7.37(m,1H),7.25–7.18(m,2H),5.74(d,J＝5.9Hz,1H),5.65(s,1H),3.94(q,J＝7.1Hz,1H),3.13–2.99(m,4H),1.42(t,J＝6.5Hz,5H),1.33(q,J＝7.4Hz,2H),0.73(dt,J＝20.5,7.4Hz,6H).
实施例7：化合物14的制备
采用通用合成方法2制备，得无色液体，收率32.4％。
1H NMR(400MHz,DMSO-d6)δ7.57–7.43(m,5H),7.43–7.38(m,1H),7.27–7.14(m,2H),6.71(dt,J＝14.6,5.4Hz,1H),3.89(qd,J＝7.0,2.3Hz,1H),3.17–2.89(m,4H),1.45(d,J＝19.0Hz,2H),1.43–1.37(m,6H),1.36–1.21(m,2H),0.83–0.63(m,6H).
实施例8：化合物15的制备
采用通用合成方法2制备，得无色液体，收率56.4％。
1H NMR(400MHz,DMSO-d6)δ7.54–7.44(m,5H),7.43–7.37(m,1H),7.28–7.19(m,2H),5.78–5.68(m,2H),3.97(q,J＝7.1Hz,1H),3.45(s,4H),3.28(s,4H),1.95(s,3H),1.44(d,J＝7.1Hz,3H).
实施例9：化合物16的制备
采用通用合成方法2制备，得白色固体，收率44.6％。
1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),7.57–7.46(m,4H),7.44–7.39(m,1H),7.28–7.18(m,2H),5.74(s,2H),3.97(q,J＝7.0Hz,1H),3.54(m,4H),3.09(m,4H),1.44(d,J＝7.1Hz,3H).
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1H NMR(400MHz,DMSO-d6)δ8.75(s,2H),7.56-7.38(m,6H),7.26-7.20(m,2H),5.75(d,J＝8.0Hz,2H),3.97(q,J＝7.1Hz,1H),3.58-3.51(m,4H),3.09(s,4H),1.44(d,J＝7.1Hz,3H).
实施例10：化合物18制备
采用通用合成方法2制备，得白色固体，收率36.4％。
1H NMR(600MHz,DMSO-d6)δ9.15(d,J＝10.8Hz,1H),8.52(d,J＝11.1Hz,1H),7.56–7.46(m,5H),7.44–7.38(m,1H),7.26–7.20(m,2H),5.75(d,J＝12.7Hz,2H),4.07(m,1H),3.97(q,J＝7.1Hz,2H),3.25(s,2H),2.78(m,2H),1.44(d,J＝7.1Hz,3H),1.19(d,J＝6.4Hz,6H).
实施例11：化合物20的制备
采用通用合成方法2制备，得无色油状产物，收率38.3％。
1H NMR(400MHz,DMSO-d6)δ7.56–7.45(m,5H),7.43–7.38(m,1H),7.27–7.18(m,2H),5.75–5.65(m,2H),4.76(d,J＝3.9Hz,1H),3.96(q,J＝7.1Hz,1H),3.61(s,3H),3.09–2.99(m,2H),1.70–1.57(m,2H),1.43(d,J＝7.1Hz,3H),1.24(s,2H).
实施例12：化合物21的制备
采用通用合成方法2制备，得无色油状产物，收率46.7％。
1H NMR(400MHz,DMSO-d6)δ7.57–7.43(m,5H),7.39(t,J＝7.2Hz,1H),7.27–7.16(m,2H),6.71(dq,J＝12.9,5.4Hz,1H),3.90(q,J＝7.1Hz,1H),3.32–3.05(m,4H),1.52(q,J＝5.6Hz,1H),1.48–1.29(m,11H).
实施例13：化合物22的制备
采用通用合成方法2制备，得无色油状产物，收率42.2％。
1H NMR(400MHz,DMSO-d6)δ7.60–7.44(m,5H),7.43–7.37(m,1H),7.28–7.15(m,2H),6.71(dq,J＝10.9,5.4Hz,1H),3.91(q,J＝7.1Hz,1H),3.25(t,J＝5.2Hz,2H),3.17(q,J＝6.0Hz,2H),1.85–1.66(m,4H),1.49–1.32(m,6H).
实施例14：化合物23的制备
采用通用合成方法2制备，得无色液体，收率34.9％。
1H NMR(600MHz,DMSO-d6)δ12.29(s,1H),7.55–7.45(m,5H),7.40(t,J＝7.3Hz,1H),7.25–7.18(m,2H),5.74–5.68(m,2H),3.96(q,J＝7.1Hz,1H),3.80(d,J＝40.6Hz,2H),2.89(s,2H),2.42(s,1H),1.78(d,J＝13.9Hz,2H),1.43(d,J＝7.1Hz,3H),1.41–1.33(m,2H).
实施例15：化合物24的制备
采用通用合成方法2制备，得无色液体，收率46.6％。
1H NMR(400MHz,DMSO-d6)δ7.54–7.45(m,5H),7.41(d,J＝6.8Hz,1H),7.21(d,J＝11.3Hz,2H),5.75(s,1H),5.67(d,J＝5.9Hz,1H),3.96(d,J＝7.1Hz,2H),3.68(s,1H),1.43(d,J＝7.1Hz,3H),1.05(m,12H).
[援引加入（细则20.6）21.11.2023]
1H NMR(400MHz,DMSO-d6)δ7.54-7.45(m,5H),7.43-7.38(m,1H),7.25-7.18(m,2H),5.75(d,J＝5.9Hz,1H),5.67(d,J＝5.9Hz,1H),3.96(q,J＝7.1Hz,1H),3.89(s,1H),3.68(s,1H),1.43(d,J＝7.1Hz,3H),1.05(d,J＝18.9Hz,12H).
实施例16：化合物25的制备
采用通用合成方法2制备，得无色液体，收率43.6％。
1H NMR(400MHz,DMSO-d6)δ7.56–7.45(m,5H),7.43–7.38(m,1H),7.26–7.19(m,2H),5.72–5.67(m,2H),4.75(td,J＝5.4,3.4Hz,2H),3.96(q,J＝7.1Hz,1H),3.46(q,J＝6.0Hz,2H),3.39(q,J＝6.0Hz,2H),3.25(m,4H),1.43(d,J＝7.1Hz,3H).
实施例17：化合物3的制备
采用通用合成方法2制备，得无色液体，收率42.1％。
1H NMR(400MHz,DMSO-d6)δ7.55–7.51(m,2H),7.51–7.45(m,3H),7.44–7.38(m,1H),7.28–7.18(m,2H),5.75(t,J＝4.8Hz,1H),5.69(d,J＝5.9Hz,1H),3.96(q,J＝7.1Hz,1H),3.77(d,J＝13.4Hz,1H),3.64(d,J＝13.1Hz,1H),3.41–3.34(m,1H),3.26(s,1H),2.49–2.34(m,2H),1.44(d,J＝7.1Hz,3H),1.02(d,J＝6.6Hz,6H).
[援引加入（细则20.6）21.11.2023]
1H NMR(400MHz,DMSO-d6)δ7.55-7.51(m,2H),7.51-7.45(m,3H),7.44-7.38(m,1H),7.25-7.21(m,2H),5.74(d,J＝4.8Hz,1H),5.69(d,J＝5.9Hz,1H),3.96(q,J＝7.1Hz,1H),3.77(d,J＝13.4Hz,1H),3.64(d,J＝13.1Hz,1H),3.41-3.34(m,1H),3.26(s,1H),2.49-2.34(m,2H),1.44(d,J＝7.1Hz,3H),1.02(d,J＝6.6Hz,6H).
实施例18：化合物4的制备
采用通用合成方法2制备，得白色固体，收率45.2％。
1H NMR(600MHz,DMSO-d6)δ9.89(s,1H),9.18(s,1H),7.53(d,J＝8.4Hz,2H),7.47(q,J＝8.1Hz,4H),7.41–7.35(m,4H),7.30(d,J＝9.2Hz,2H),6.67(d,J＝8.9Hz,2H),3.85(q,J＝7.0Hz,1H),1.44(d,J＝6.9Hz,3H).
实施例19：化合物5的制备
采用通用合成方法2制备，得无色液体，收率51.7％。
1H NMR(400MHz,DMSO)δ7.55(d,J＝7.6Hz,2H),7.51–7.43(m,3H),7.40(t,J＝7.3Hz,1H),7.30–7.18(m,2H),6.77(s,1H),5.65(ddd,J＝15.7,6.0,3.4Hz,2H),3.95(q,J＝7.1Hz,1H),3.62(d,J＝5.2Hz,1H),2.36(dd,J＝12.9,4.5Hz,2H),1.98(t,J＝9.6Hz,3H),1.86(s,1H),1.78–1.72(m,1H),1.43(dd,J＝7.1,1.7Hz,3H).
[援引加入（细则20.6）21.11.2023]
1H NMR(400MHz,DMSO-d6)δ7.55(d,J＝7.6Hz,2H),7.51-7.43(m,3H),7.40(t,J＝7.3Hz,1H),7.30-7.18(m,2H),6.77(s,1H),5.65(ddd,J＝15.7,6.0,3.4Hz,2H),3.95(q,J＝7.1Hz,1H),3.62(d,J＝5.2Hz,1H),2.36(dd,J＝12.9,4.5Hz,2H),1.98(t,J＝9.6Hz,3H),1.86(s,1H),1.78-1.72(m,1H),1.43(dd,J＝7.1,1.7Hz,3H).
实施例20：化合物6的制备
采用通用合成方法2制备，得无色液体，收率40.8％。
1H NMR(400MHz,DMSO-d6)δ12.61(s,1H),7.89(dd,J＝8.1,3.8Hz,1H),7.57–7.52(m,2H),7.48(td,J＝8.1,2.2Hz,3H),7.44–7.36(m,1H),7.28–7.17(m,2H),5.68(qd,J＝6.1,3.7Hz,2H),3.94(ddd,J＝13.0,8.3,3.3Hz,2H),1.65–1.46(m,3H),1.43(d,J＝7.2Hz,3H),0.89–0.76(m,6H).
实施例21：化合物7的制备
采用通用合成方法2制备，得无色液体，收率48.2％。
1H NMR(400MHz,DMSO-d6)δ12.75(s,1H),9.22(d,J＝3.1Hz,1H),7.93(dd,J＝8.3,4.0Hz,1H),7.54(dd,J＝8.4,1.5Hz,2H),7.50–7.45(m,3H),7.43–7.40(m,1H),7.26–7.17(m,2H),7.05–6.98(m,2H),6.66–6.62(m,2H),5.66–5.56(m,2H),4.10(q,J＝5.3Hz,2H),4.08–4.03(m,1H),3.92(dd,J＝7.2,4.8Hz,1H),1.41(dd,J＝7.1,1.5Hz,3H).
实施例22：化合物8的制备
采用通用合成方法2制备，得无色液体，收率42.3％。
1H NMR(400MHz,DMSO-d6)δ7.95(d,J＝8.3Hz,1H),7.56–7.52(m,2H),7.48(t,J＝8.0Hz,3H),7.43–7.37(m,1H),7.28–7.19(m,2H),5.72–5.64(m,2H),4.32(td,J＝8.1,5.4Hz,1H),3.96(q,J＝7.1Hz,1H),2.76–2.68(m,1H),2.58–2.51(m,1H),1.44(d,J＝7.1Hz,3H).
实施例23：化合物9的制备
采用通用合成方法2制备，得无色油状液体，收率38.6％。
1H NMR(400MHz,DMSO-d6)δ7.57–7.45(m,5H),7.44–7.37(m,1H),7.29–7.20(m,2H),6.71(q,J＝5.4Hz,1H),3.92(q,J＝7.1Hz,1H),3.54(d,J＝11.3Hz,4H),3.39–3.30(m,4H),1.45–1.36(m,6H).
实施例24：化合物26的制备
采用通用合成方法2制备，得无色液体，收率61.4％。
1H NMR(600MHz,DMSO)δ7.50(ddd,J＝15.3,13.6,7.9Hz,5H),7.41(t,J＝7.3Hz,1H),7.26–7.19(m,2H),5.73(dd,J＝21.7,6.7Hz,2H),3.96(q,J＝7.1Hz,1H),3.50(s,4H),2.51(s,4H),1.44(t,J＝8.1Hz,3H).
实施例25：化合物27的制备
采用通用合成方法2制备，得无色液体，收率64.1％。
1H NMR(600MHz,DMSO)δ7.50(dd,J＝21.8,13.5Hz,5H),7.40(t,J＝6.8Hz,1H),7.21(s,2H),5.74(d,J＝6.5Hz,1H),5.71(d,J＝5.9Hz,1H),3.97(q,J＝7.1Hz,1H),3.50(s,4H),2.52(s,4H),1.44(d,J＝7.1Hz,3H).
实施例26：化合物28的制备
采用通用合成方法2制备，得无色液体，收率63.4％。
1H NMR(400MHz,DMSO)δ7.53–7.46(m,5H),7.42–7.38(m,1H),7.21(d,J＝9.4Hz,2H),5.70(dd,J＝33.6,5.9Hz,2H),3.94(q,J＝7.1Hz,1H),3.07(ddd,J＝23.6,14.1,6.9Hz,4H),1.46–1.23(m,7H),0.79–0.63(m,6H).
实施例27：化合物29的制备
采用通用合成方法2制备，得无色液体，收率62.5％。
1H NMR(400MHz,DMSO)δ7.56–7.37(m,6H),7.21(d,J＝9.4Hz,2H),5.70(dd,J＝33.7,5.9Hz,2H),3.94(q,J＝7.1Hz,1H),3.12–2.99(m,4H),1.43(d,J＝7.1Hz,3H),1.41–1.22(m,4H),0.73(dt,J＝20.2,7.4Hz,6H).
实施例28：化合物30的制备
采用通用合成方法2制备，得无色液体，收率67.6％。
1H NMR(600MHz,DMSO)δ7.56–7.37(m,6H),7.21(t,J＝8.2Hz,2H),5.70(dd,J＝20.6,5.9Hz,2H),4.72(d,J＝3.7Hz,1H),3.96(q,J＝7.1Hz,1H),3.62(s,3H),3.05(s,2H),1.67–1.61(m,2H),1.43(d,J＝7.1Hz,2H),1.25(s,3H).
实施例29：化合物31的制备
采用通用合成方法2制备，得无色液体，收率59.4％。
1H NMR(600MHz,DMSO)δ7.59–7.37(m,6H),7.22(t,J＝8.2Hz,2H),5.70(dd,J＝20.6,5.9Hz,2H),4.72(d,J＝3.7Hz,1H),3.96(q,J＝7.1Hz,1H),3.62(s,3H),3.05(s,2H),1.67–1.61(m,2H),1.43(d,J＝7.1Hz,3H),1.24(s,2H).
通用合成方法3：
采用方法D合成。
将式(A)(1.0当量)溶解到无水DCM中，滴加草酰氯(3.0当量)或者乙酰氯(1.2～1.5当量)，和催化量的DMF，室温搅拌0.5h，将溶液抽干得到式(G)。将式(G)溶解到乙酸乙酯：水(2:1)的混合溶液或DCM溶液中，逐滴加至式(F)(2.0当量)和碳酸钾(6.0当量)或三乙胺(1.5当量)的混合体系中，-20～25℃搅拌4～12h。加入乙酸乙酯10mL，用水(10mL)洗涤有机相，收集有机相无水硫酸钠干燥，过滤减压浓缩，柱层析得产物。
实施例30：化合物32的制备
采用通用合成方法3制备，得白色固体，收率42.7％。
1H NMR(400MHz,DMSO-d6)δ13.20(s,1H),7.94(dd,J＝7.8,1.7Hz,1H),7.63(td,J＝7.7,1.8Hz,1H),7.60–7.53(m,3H),7.52–7.46(m,2H),7.44–7.33(m,4H),7.14(dd,J＝8.1,1.2Hz,1H),4.19(q,J＝7.2Hz,1H),1.59(d,J＝7.2Hz,3H).
实施例31：化合物33的制备
采用通用合成方法3制备，得无色油状物，收率56.5％。
1H NMR(400MHz,DMSO-d6)δ8.55(s,1H),7.56–7.52(m,2H),7.48(t,J＝7.6Hz,3H),7.43–7.38(m,1H),7.27(t,J＝8.0Hz,2H),7.00(s,1H),6.73(s,1H),5.31(t,J＝5.3Hz,1H),5.15–5.05(m,2H),4.53(d,J＝4.0Hz,2H),3.95(q,J＝7.1Hz,1H),2.12(s,3H),1.46(d,J＝7.1Hz,3H).
通用合成方法4：
采用方法E合成。
第一步：
将式(J)(1.0当量)、碳酸氢钠(3.8当量)和四正丁基硫酸氢铵(0.1当量)溶于二氯甲烷：水(1:1)的混合溶液中，室温下搅拌5分钟。将氯甲基氯磺酸酯(1.1～2当量)溶于DCM中，逐滴加入上述反应液中，室温搅拌1h。用水(20mL)洗有机相，无水硫酸钠干燥，过滤减压浓缩得式(H)。
或将式(J)(1当量)溶于DMF中，向溶液中依次加入咪唑(2当量)、叔丁基二甲基氯硅烷(2当量)或苄基溴(2当量)，室温下搅拌1h，将混合物倒入15mL水中，用乙酸乙酯萃取(10mL*3),有机相用饱和氯化钠水溶液(20mL)洗涤三次，收集有机相，无水硫酸钠干燥，减压蒸馏得保护基保护的式(J)。然后进行第一步反应得式保护基保护的(H)。
或将式(J)(1当量)溶于干燥的DCM中，在氮气保护下加入草酰氯(1.5当量)，然后加入1滴DMF，室温下搅拌1h，减压蒸馏得酰氯化合物，并溶于DCM中，加入氯化锌(0.02当量)，然后在氮气保护下于-15℃下加入乙醛(1当量)。室温反应16小时，减压浓缩后将剩余物溶于20mL乙酸乙酯，依次用水(20mL)、饱和碳酸氢钠溶液(20mL)、饱和氯化钠水溶液(20mL)洗涤，收集有机相，无水硫酸钠干燥，过滤得到滤液减压蒸干，得式(H)化合物。
第二步：
将式(A)(1.0当量)溶于DMF中，加入三乙胺(1.5当量)或碳酸钾(1.6～2.0当量)，加或不加碘化钠(1.1当量)，20～50℃下搅拌。将式(H)或保护基保护的式(H)(1.2当量)溶于DMF，缓慢加入上述反应液中，反应3～4h。加入乙酸乙酯20mL，再依次用水(20mL)、饱和氯化钠水溶液(20mL)洗涤有机相，收集有机相无水硫酸钠干燥，过滤减压浓缩，用硅胶柱层析进行纯化得产物式(III)或含保护基的式(III)。
保护基保护的式(III)经氢气还原或酸或碱或四丁基氟化铵脱叔丁基二甲基硅基后得式(III)。
实施例32：化合物34的制备
采用通用合成方法4制备，得无色油状物，收率20.0％。
1H NMR(400MHz,DMSO-d6)δ7.56–7.44(m,5H),7.41(td,J＝7.0,1.6Hz,1H),7.23–7.12(m,2H),7.12–7.01(m,4H),5.81–5.61(m,2H),3.90(p,J＝7.1Hz,1H),3.76(p,J＝6.9Hz,1H),2.36(t,J＝7.2Hz,2H),1.75(dh,J＝13.2,6.6Hz,1H),1.34(ddd,J＝19.4,11.2,7.2Hz,6H),0.81(dd,J＝6.6,4.4Hz,6H).
实施例33：化合物35的制备
采用通用合成方法4制备，得无色油状物，收率38.7％。
1H NMR(600MHz,DMSO-d6)δ10.48(s,1H),7.80–7.75(m,2H),7.46(d,J＝4.6Hz,4H),7.43–7.37(m,2H),7.25–7.18(m,2H),6.88–6.82(m,2H),5.96–5.89(m,2H),3.99(q,J＝7.1Hz,1H),1.44(d,J＝7.1Hz,3H).
实施例34：化合物36的制备
采用通用合成方法4制备，得白色固体，收率47.4％。
1H NMR(600MHz,DMSO-d6)δ7.88(dd,J＝7.8,1.7Hz,1H),7.75–7.69(m,1H),7.51–7.37(m,7H),7.28–7.20(m,3H),5.96–5.90(m,2H),4.01(q,J＝7.1Hz,1H),2.24(s,3H),1.46(d,J＝7.1Hz,3H).
实施例35：化合物37的制备
采用通用合成方法4制备，得无色油状物，收率47.6％。
1H NMR(400MHz,DMSO-d6)δ7.88(dd,J＝7.8,1.7Hz,1H),7.75–7.69(m,1H),7.49–7.38(m,7H),7.28–7.20(m,3H),5.95–5.91(m,1H),4.02(dd,J＝7.1,5.8Hz,1H),2.24(s,3H),1.46(d,J＝7.1Hz,3H).
实施例36：化合物38的制备
采用通用合成方法4制备，得无色油状物，收率43.4％。
1H NMR(600MHz,DMSO-d6)δ10.29(s,1H),7.67(dd,J＝7.9,1.8Hz,1H),7.55–7.38(m,7H),7.27–7.20(m,2H),6.99(d,J＝8.4Hz,1H),6.91(t,J＝7.6Hz,1H),6.04–5.95(m,2H),4.02(q,J＝7.1Hz,1H),1.46(d,J＝7.1Hz,3H).
实施例37：化合物39的制备
采用通用合成方法4制备，得无色油状物，收率59.2％。
1H NMR(400MHz,DMSO-d6)δ7.51–7.37(m,6H),7.30–7.15(m,2H),7.09–6.95(m,3H),5.91(q,J＝6.0Hz,2H),4.00(q,J＝7.1Hz,1H),2.88(s,6H),2.18(s,3H),1.45(d,J＝7.1Hz,3H).
实施例38：化合物40的制备
采用通用合成方法4制备，得无色油状物，收率61.4％。
1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),7.48–7.38(m,6H),7.37–7.30(m,3H),7.26–7.18(m,2H),7.06(ddd,J＝7.4,2.7,1.7Hz,1H),5.95(q,J＝5.9Hz,2H),4.01(q,J＝7.1Hz,1H),1.45(d,J＝7.1Hz,3H).
实施例39：化合物41的制备
采用通用合成方法4制备，得无色油状物，收率46.7％。
1H NMR(400MHz,DMSO-d6)δ10.35(s,1H),7.46(d,J＝5.4Hz,4H),7.44–7.36(m,3H),7.22(dd,J＝11.9,1.7Hz,1H),7.19(dd,J＝7.9,1.8Hz,1H),6.28(dd,J＝9.2,2.5Hz,1H),6.07(d,J＝2.5Hz,1H),5.97–5.89(m,2H),3.99(t,J＝7.1Hz,1H),2.97(s,6H),1.44(d,J＝7.1Hz,3H).
实施例40：化合物42的制备
采用通用合成方法4制备，得无色油状物，收率56.35％。
1H NMR(600MHz,DMSO)δ10.48(s,1H),7.78(d,J＝8.6Hz,2H),7.45(t,J＝11.3Hz,4H),7.42–7.36(m,2H),7.21(t,J＝11.3Hz,2H),6.85(d,J＝8.6Hz,2H),5.92(dd,J＝16.2,5.9Hz,2H),3.99(q,J＝7.1Hz,1H),1.44(d,J＝7.1Hz,3H).
实施例41：化合物43的制备
采用通用合成方法4制备，得无色油状物，收率58.6％。
1H NMR(600MHz,DMSO)δ10.48(s,1H),7.78(d,J＝8.6Hz,2H),7.45(t,J＝11.3Hz,4H),7.42–7.36(m,2H),7.21(t,J＝11.3Hz,2H),6.85(d,J＝8.6Hz,2H),5.92(dd,J＝16.2,5.9Hz,2H),3.99(q,J＝7.1Hz,1H),1.44(d,J＝7.1Hz,3H).
实施例42：化合物44的制备
采用通用合成方法3制备，得无色油状物，收率62.5％。
1H NMR(600MHz,DMSO)δ8.51(s,1H),7.56–7.43(m,6H),7.40(t,J＝7.3Hz,1H),7.26(t,J＝8.4Hz,2H),6.99(s,1H),6.72(s,1H),5.27(t,J＝5.3Hz,1H),5.09(q,J＝12.7Hz,2H),4.52(d,J＝4.8Hz,2H),2.11(s,3H),1.45(d,J＝7.1Hz,3H).
实施例43：化合物45的制备
采用通用合成方法3制备，得无色油状物，收率69.4％。
1H NMR(600MHz,DMSO)δ8.52(s,1H),7.57–7.45(m,5H),7.40(t,J＝7.4Hz,1H),7.26(t,J＝8.4Hz,2H),6.99(s,1H),6.72(s,1H),5.28(t,J＝5.3Hz,1H),5.09(q,J＝12.7Hz,2H),4.52(d,J＝5.1Hz,2H),3.95(q,J＝7.0Hz,1H),2.11(s,3H),1.45(d,J＝7.1Hz,3H).
通用合成方法5：
采用方法C合成。
将式(A)(1.0当量)、式(F)(1.2当量)、EDCI(1.5当量)和DMAP(0.1当量)加入到5mL DMF中，室温搅拌12h。加入乙酸乙酯50mL，再依次用饱和氯化铵水溶液(50mL*2)、水(50mL)、饱和氯化钠水溶液(50mL)洗涤有机相，收集有机相无水硫酸钠干燥，过滤减压浓缩，柱层析纯化得产物。
实施例44：化合物46的制备
采用通用合成方法5制备，得无色油状物，收率51.7％。
1H NMR(400MHz,DMSO-d6)δ7.57–7.44(m,5H),7.44–7.37(m,1H),7.27–7.18(m,4H),6.95–6.85(m,2H),5.11–5.00(m,2H),3.92(q,J＝7.1Hz,1H),3.73(s,3H),1.43(d,J＝7.1Hz,3H).
实施例45：化合物47的制备
采用通用合成方法4制备，得白色固体，收率92.9％。
1H NMR(600MHz,DMSO-d6)δ7.59–7.45(m,5H),7.40(t,J＝7.3Hz,1H),7.26(t,J＝10.2Hz,2H),6.40(m,3H),5.07(d,J＝22.8Hz,2H),3.99(d,J＝7.1Hz,1H),3.67(s,6H),1.47(d,J＝7.1Hz,3H).
实施例46：化合物48的制备
采用通用合成方法3制备，得白色固体，收率40.7％。
1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),7.57–7.38(m,6H),7.27–7.19(m,2H),7.13(m,2H),6.83(dd,J＝8.1,1.1Hz,1H),6.75(td,J＝7.5,1.2Hz,1H),5.08(d,J＝3.8Hz,2H),3.94(q,J＝7.1Hz,1H),1.45(d,J＝7.1Hz,3H).
实施例47：化合物49的制备
采用通用合成方法3制备，得无色液体，收率77.5％。
1H NMR(600MHz,CDCl3)δ7.53(d,J＝7.8Hz,2H),7.43(t,J＝7.6Hz,2H),7.36(m,2H),7.15–7.07(m,2H),6.80–6.70(m,3H),5.93(m,2H),5.08–4.93(m,2H),3.77(q,J＝7.2Hz,1H),1.53(d,J＝7.1Hz,3H).
实施例48：化合物50的制备
采用通用合成方法5制备，得无色液体，收率60.3％。
1H NMR(600MHz,DMSO-d6)δ7.58–7.52(m,2H),7.48(m,3H),7.45–7.37(m,1H),7.31(td,J＝7.9,1.8Hz,1H),7.27–7.14(m,3H),7.00(d,J＝8.2Hz,1H),6.90(t,J＝7.4Hz,1H),5.54–4.86(m,2H),3.94(q,J＝7.1Hz,1H),3.74(s,3H),1.45(d,J＝7.1Hz,3H).
实施例49：化合物51的制备
采用通用合成方法3制备，得无色液体，收率48.3％。
1H NMR(400MHz,DMSO-d6)δ7.55–7.45(m,5H),7.45–7.37(m,1H),7.30–7.24(m,2H),6.55(s,2H),5.14–5.00(m,2H),3.99(q,J＝7.1Hz,1H),3.68(s,6H),3.62(s,3H),1.47(d,J＝7.2Hz,3H).
实施例50：化合物52的制备
采用通用合成方法5制备，得无色液体，收率5.6％。
1H NMR(600MHz,DMSO-d6)δ9.46(s,1H),7.63–7.32(m,6H),7.24–7.05(m,4H),6.71(d,J＝8.4Hz,2H),5.00(q,J＝12.0Hz,2H),3.91(q,J＝7.1Hz,1H),1.43(d,J＝7.1Hz,3H).
通用合成方法6：
采用方法A合成。
第一步：(采用步骤1合成)
将酸(1当量)分散在DCM中，加入催化剂四丁基硫酸氢铵和碳酸氢钠(4当量)的水溶液，搅拌下加入氯磺酸氯甲酯(1.2当量)，室温反应4小时，静置分层，收集有机相，无水硫酸钠干燥，减压浓缩经硅胶柱层析得氯代式(B)。
第二步：(采用步骤2合成)
将氯代式(B)溶于乙腈，加入碘化钠(1.2当量)，40℃反应1小时得碘代式(B)。
第三步：
在碘代式(B)中加入式(A)(1当量)，碳酸钾(1.2当量)，继续反应10小时，减压除去溶剂，加入乙酸乙酯和饱和氯化钠萃取，收集有机相，无水硫酸钠干燥，浓缩分离得产物式(II)。
实施例51：化合物53的制备
采用通用合成方法6制备，得无色液体，收率65.32％。
1H NMR(400MHz,Chloroform-d)δ7.53(dt,J＝8.0,1.5Hz,2H),7.48–7.34(m,4H),7.17–7.08(m,2H),6.67(s,2H),5.75(q,J＝5.6Hz,2H),3.80(q,J＝7.2Hz,1H),3.47(t,J＝7.2Hz,2H),2.30(t,J＝7.5Hz,2H),1.67–1.50(m,8H),1.34–1.23(m,3H).
[援引加入（细则20.6）21.11.2023]
1H NMR(400MHz,Chloroform-d)δ7.53(dt,J＝8.0,1.5Hz,2H),7.48-7.34(m,4H),7.17-7.08(m,2H),6.67(s,2H),5.75(q,J＝5.6Hz,2H),3.80(q,J＝7.2Hz,1H),3.47(t,J＝7.2Hz,2H),2.30(t,J＝7.5Hz,2H),1.67-1.50(m,7H),1.34-1.23(m,2H).
实施例52：化合物54的制备
采用通用合成方法6制备，得无色液体，收率12.33％。
1H NMR(400MHz,Chloroform-d)δ7.55(d,J＝7.6Hz,2H),7.48–7.36(m,4H),7.16–7.09(m,2H),5.84–5.76(m,2H),5.74(s,2H),3.81(q,J＝7.1Hz,1H),2.80(s,3H),1.58(s,2H).
实施例53：化合物55的制备
采用通用合成方法6制备，得无色液体，收率19.87％。
1H NMR(400MHz,Chloroform-d)δ7.54(dt,J＝6.8,1.5Hz,2H),7.47–7.34(m,4H),7.17–7.09(m,2H),5.77–5.70(m,2H),3.88–3.77(m,4H),2.76–2.71(m,3H),2.65(td,J＝7.0,0.9Hz,2H),1.57(s,3H).
实施例54：化合物56的制备
采用通用合成方法6制备，得无色液体，收率21.66％。
1H NMR(400MHz,Chloroform-d)δ7.56–7.52(m,2H),7.48–7.34(m,4H),7.17–7.09(m,2H),6.68(s,2H),5.79–5.70(m,2H),3.81(td,J＝7.1,3.5Hz,3H),2.69–2.64(m,2H),1.56(d,J＝7.2Hz,3H).
实施例55：化合物57的制备
采用通用合成方法6制备，得无色液体，收率35.37％。
1H NMR(400MHz,Chloroform-d)δ7.53(dt,J＝8.2,1.5Hz,2H),7.50–7.33(m,4H),7.19–7.06(m,2H),6.66(s,2H),5.84–5.70(m,2H),3.81(q,J＝7.1Hz,1H),3.55(t,J＝6.8Hz,2H),2.33(d,J＝7.4Hz,2H),1.89(p,J＝7.1Hz,2H),1.56(d,J＝7.2Hz,3H).
实施例56：化合物58的制备
采用通用合成方法6制备，得无色液体，收率55.78％。
1H NMR(400MHz,Chloroform-d)δ7.53(dt,J＝8.1,1.5Hz,2H),7.48–7.32(m,4H),7.18–7.07(m,2H),6.68(s,2H),5.80–5.72(m,2H),3.79(q,J＝7.2Hz,1H),3.54–3.46(m,2H),2.34–2.26(m,2H),1.62–1.50(m,7H),1.24(dt,J＝11.6,3.6Hz,12H).
实施例57：化合物59的制备
采用通用合成方法6制备，得无色液体，收率56.65％。
1H NMR(400MHz,Chloroform-d)δ7.53(dt,J＝8.0,1.5Hz,2H),7.48–7.32(m,4H),7.15(d,J＝1.8Hz,1H),7.14–7.07(m,1H),6.29(q,J＝1.8Hz,1H),5.75(q,J＝5.6Hz,2H),3.80(q,J＝7.1Hz,1H),3.45(t,J＝7.2Hz,2H),2.30(t,J＝7.5Hz,2H),2.07(d,J＝1.9Hz,3H),1.65–1.49(m,6H),1.34–1.21(m,3H).
实施例58：化合物60的制备
采用通用合成方法6制备，无色液体，收率54.53％。
1H NMR(400MHz,Chloroform-d)δ7.53(dt,J＝8.1,1.5Hz,2H),7.48–7.32(m,4H),7.15(d,J＝1.8Hz,1H),7.14–7.07(m,1H),5.80–5.71(m,2H),3.80(q,J＝7.2Hz,1H),3.44(t,J＝7.2Hz,2H),2.30(t,J＝7.5Hz,2H),1.95(s,6H),1.64–1.45(m,6H),1.28(dtd,J＝10.7,7.6,7.2,4.8Hz,3H).
实施例59：化合物61的制备
采用通用合成方法6制备，得无色液体，收率89.25％。
1H NMR(400MHz,Chloroform-d)δ7.53(dt,J＝8.2,1.5Hz,2H),7.49–7.32(m,4H),7.17–7.07(m,2H),6.67(s,2H),5.75(q,J＝5.6Hz,2H),3.80(q,J＝7.1Hz,1H),3.48(t,J＝7.2Hz,2H),2.30(t,J＝7.5Hz,2H),1.67–1.50(m,8H),1.32–1.21(m,3H).
[援引加入（细则20.6）21.11.2023]
1H NMR(400MHz,Chloroform-d)δ7.53(dt,J＝8.2,1.5Hz,2H),7.49-7.32(m,4H),7.17-7.07(m,2H),6.67(s,2H),5.75(q,J＝5.6Hz,2H),3.80(q,J＝7.1Hz,1H),3.48(t,J＝7.2Hz,2H),2.30(t,J＝7.5Hz,2H),1.67-1.50(m,7H),1.32-1.21(m,2H).
实施例60：化合物62的制备
采用通用合成方法6制备，得无色液体，收率51.38％。
1H NMR(400MHz,Chloroform-d)δ7.58–7.49(m,2H),7.45(dt,J＝6.9,1.3Hz,1H),7.44–7.32(m,3H),7.18–7.07(m,2H),6.67(s,2H),5.75(q,J＝5.6Hz,2H),3.80(q,J＝7.2Hz,1H),3.48(t,J＝7.2Hz,2H),2.30(t,J＝7.5Hz,2H),1.67–1.59(m,3H),1.59–1.52(m,5H),1.34–1.22(m,3H).
[援引加入（细则20.6）21.11.2023]
1H NMR(400MHz,Chloroform-d)δ7.58-7.49(m,2H),7.45(dt,J＝6.9,1.3Hz,1H),7.44-7.32(m,3H),7.18-7.07(m,2H),6.67(s,2H),5.75(q,J＝5.6Hz,2H),3.80(q,J＝7.2Hz,1H),3.48(t,J＝7.2Hz,2H),2.30(t,J＝7.5Hz,2H),1.67-1.59(m,2H),1.59-1.52(m,5H),1.34-1.22(m,2H).
实施例61：化合物63的制备
采用通用合成方法6制备，得无色液体，收率55.51％。
1H NMR(400MHz,Chloroform-d)δ7.57–7.49(m,2H),7.49–7.32(m,4H),7.18–7.07(m,2H),6.67(s,2H),5.80–5.73(m,2H),3.79(q,J＝7.1Hz,1H),3.52–3.43(m,2H),2.36–2.25(m,2H),1.63–1.51(m,8H),1.35–1.19(m,3H).
实施例62：化合物64的制备
采用通用合成方法6制备，得无色液体，收率56.93％。
1H NMR(400MHz,Chloroform-d)δ7.57–7.49(m,2H),7.48–7.33(m,4H),7.14(dd,J＝7.9,1.8Hz,1H),7.11(dd,J＝11.3,1.8Hz,1H),6.67(s,2H),5.80–5.71(m,2H),3.80(q,J＝7.1Hz,1H),3.53–3.46(m,2H),2.39–2.31(m,2H),1.59(s,3H),1.55(d,J＝7.0Hz,4H).
实施例63：化合物65的制备
采用通用合成方法2制备，得无色油状物，收率30.98％。
1H NMR(600MHz,Chloroform-d)δ7.52(dd,J＝7.1,1.5Hz,2H),7.43(t,J＝7.6Hz,2H),7.41–7.35(m,2H),7.17–7.10(m,2H),5.79(s,2H),3.79(q,J＝7.1Hz,1H),3.28–3.08(m,4H),1.55(d,J＝7.1Hz,3H),1.49(p,J＝7.6Hz,2H),1.39(p,J＝7.4Hz,2H),1.29(p,J＝7.4Hz,2H),1.25–1.18(m,2H),0.91(m,6H).
实施例64：化合物66的制备
采用通用合成方法2制备，得无色油状物，收率29.75％。
1H NMR(600MHz,Chloroform-d)δ7.52(dt,J＝8.1,1.4Hz,2H),7.42(dd,J＝8.5,6.9Hz,2H),7.39–7.33(m,2H),7.16–7.10(m,2H),5.78(s,2H),3.79(q,J＝7.1Hz,1H),3.27–3.16(m,2H),3.11(td,J＝7.3,4.6Hz,2H),1.54(d,J＝7.2Hz,3H),1.49(p,J＝7.5Hz,2H),1.39(p,J＝7.5Hz,2H),1.28(q,J＝7.5Hz,2H),1.21(h,J＝7.5Hz,2H),0.88(dt,J＝22.8,7.4Hz,6H).
实施例65：化合物67的制备
采用通用合成方法2制备，得无色油状物，收率77.35％。
1H NMR(600MHz,Chloroform-d)δ7.52(dt,J＝8.0,1.5Hz,2H),7.43(dd,J＝8.5,6.9Hz,2H),7.41–7.33(m,2H),7.15(dd,J＝7.9,1.9Hz,1H),7.11(dd,J＝11.5,1.8Hz,1H),5.81–5.75(m,2H),3.82–3.77(m,1H),3.26–3.20(m,1H),3.15(h,J＝6.9Hz,1H),2.85(d,J＝45.8Hz,3H),1.54(d,J＝7.0Hz,4H),1.49(t,J＝7.2Hz,1H),1.42(t,J＝7.2Hz,1H),1.26(s,4H),1.21(s,1H),0.86(t,J＝6.8Hz,3H).
实施例66：化合物68的制备
采用通用合成方法2制备，得无色油状物，收率76.59％。
1H NMR(600MHz,Chloroform-d)δ7.52(dt,J＝8.1,1.4Hz,2H),7.46–7.33(m,4H),7.18–7.09(m,2H),5.82–5.73(m,2H),3.78-3.80(m,1H),3.25–3.20(m,1H),3.15(d,J＝8.0Hz,1H),2.85(d,J＝45.8Hz,3H),1.42(t,J＝7.2Hz,1H),1.26(s,7H),0.87(t,J＝6.5Hz,3H).
[援引加入（细则20.6）21.11.2023]
1H NMR(600MHz,Chloroform-d)δ7.52(dt,J＝8.1,1.4Hz,2H),7.46-7.33(m,4H),7.18-7.08(m,2H),5.84-5.72(m,2H),3.79(dd,J＝7.4,3.2Hz,1H),3.25-3.08(m,2H),2.85(d,J＝45.8Hz,3H),1.55(d,J＝7.1Hz,3H),1.51-1.39(m,2H),1.24(d,J＝23.8Hz,6H),0.86(t,J＝6.5Hz,3H).
实施例67：化合物69的制备
采用通用合成方法2制备，得无色油状物，收率81.27％。
1H NMR(600MHz,DMSO-d6)δ7.52(dt,J＝8.2,1.5Hz,2H),7.50–7.45(m,3H),7.44–7.39(m,1H),7.23–7.19(m,2H),5.75(d,J＝5.7Hz,1H),5.67(d,J＝5.9Hz,1H),3.93(q,J＝7.1Hz,1H),3.02–2.90(m,4H),1.86(dt,J＝13.8,7.0Hz,1H),1.76(dt,J＝13.8,6.9Hz,1H),1.43(d,J＝7.1Hz,3H),0.74(dt,J＝33.3,6.4Hz,12H).
实施例68：化合物70的制备
采用通用合成方法2制备，得无色油状物，收率80.52％。
1H NMR(600MHz,DMSO-d6)δ7.54–7.46(m,5H),7.42–7.38(m,1H),7.23–7.19(m,2H),5.75(d,J＝5.7Hz,1H),5.67(d,J＝5.9Hz,1H),3.93(q,J＝7.1Hz,1H),3.03–2.90(m,4H),1.86(dt,J＝13.6,6.9Hz,1H),1.75(dq,J＝13.7,6.9Hz,1H),1.43(d,J＝7.1Hz,3H),0.74(dt,J＝33.3,6.5Hz,12H).
试验例
试验例1：大鼠体内药代动力学试验
实验方法：取8-10周龄的成年雌性Sprague Dawley大鼠，体重200±20g，随机分组，每组3只。各组均通过灌胃给药，剂量分别为50mg/kg氟比洛芬，和与50mg/kg氟比洛芬等摩尔剂量的其他实施例组，灌胃给药后分别于药后0.0833h、0.25h、0.5h、1h、2h、3h、4h、6h、9h、12h、24h采集血液于肝素钠抗凝，采血方式为大鼠眼眶静脉丛取血250μL，采集完的血样于离心机中12000rpm、离心5min，吸取全部血浆于1.5mL离心管中，血浆存放于-80℃冰箱中保存。
按照外标标准曲线法测定。样品处理：取冻存的样品恢复室温后，涡旋均匀后用甲醇稀释2倍，加入含0.5％甲酸的乙腈：甲醇＝7:3的混合提取剂稀释5倍，涡旋振荡1min后，于4℃、12000rpm、离心10min后取上清液进样5μL分析，利用Winnonlin软件计算各实施例的药代动力学参数。结果见表1。
结果显示：本发明中的上述化合物的代谢产物在大鼠血浆中的暴露量或半衰期较氟比洛芬相比均显著提高。
表1.受试药物的药代动力学参数
试验例2：对实验性大鼠足趾肿胀的抗炎作用
实验方法：体重150～160g的SD大鼠，雄性，随机分组，每组10只。分别腹腔注射生理盐水、本发明化合物、对照药物氟比洛芬或氟比洛芬酯，剂量均为10mg/kg，给药体积10μL/g。于给药后1h，在每鼠右后足跖注射1％λ-角叉菜胶100μL致炎后，每隔1h用足容积测量仪测量爪体积，计算肿胀抑制率。结果显示：表2中的本发明化合物较氟比洛芬相比均具有更好的抗炎效果。
表2.对λ-角叉菜胶致大鼠足肿胀的抗炎作用
其中，*代表P值小于0.05，**代表P值小于0.01，***代表P值小于0.001。
试验例3：对干酵母致大鼠发热的影响
实验方法：雄性SD大鼠，4周龄，随机分组，每组10只。环境温度为20～21℃，湿度为40～70％，进行体温筛选，平均体温约37.4℃，淘汰率约为10％。分别腹腔注射生理盐水、本发明化合物或对照药物氟比洛芬，剂量均为10mg/kg，给药体积10μL/g。于给药后20min后，皮下注射20％的活性干酵母混悬液，造模后于4h、8h测量肛温。
结果显示：表3中的本发明化合物较氟比洛芬相比均具有更好的解热效果。
表3.对干酵母致大鼠发热模型的解热作用
试验例4：对胶原诱导型类风湿关节炎(CIA)疾病的镇痛、抗炎作用
实验方法：雌性Lewis大鼠，6～8周龄，随机分组，每组8只。环境温度为20.5-24.5℃，湿度为40～70％，光照周期12小时明12小时暗。将II型胶原与弗氏不完全佐剂(IFA)按照1:1混合，冰上进行充分乳化后使用。大鼠尾根部2～3cm处皮内注射100μL混合液，两侧后肢根部各50μL混合液，空白对照组注射等体积生理盐水。7天后采用IFA进行再次免疫。第二次免疫后每天观察大鼠发病情况。选择两侧后肢评分总分2分以上的大鼠，依据体重，评分以及足体积随机分组，分为模型组，氟比洛芬、化合物33、化合物2、化合物13、化合物20、化合物35组，另设一组空白对照组，每组8只。给药体积10mg/kg，给药时间14天。模型组及空白对照组给予相应体积的溶媒。
检测指标：体重、关节炎评分、后肢足体积、机械足反射阈值(MWT)。
关节炎评分标准：0＝正常；1＝踝关节可观察到红斑和轻微肿胀；2＝踝关节至跖关节或掌关节可观察到红斑和轻微肿胀；3＝踝关节至跖趾关节或掌关节可观察到红斑和中度肿胀；4＝踝关节至趾关节可观察到红斑和重度肿胀；计算所有(4只)足爪的评分总和，每只大鼠关节炎指数总和最多16。
试验结果：
1、受试药对CIA大鼠体重的影响：
结果表明试验期间各组大鼠体重无显著变化，受试药物对大鼠体重无显著影响(Mean±SD)，结果见图1。
2、受试药对CIA大鼠关节炎评分的影响：
结果显示，给药期间模型组大鼠评分显著高于空白对照组，并且经各受试药干预14天后能够显著降低CIA大鼠关节炎评分(图2，P＜0.01)，提示受试药物能够显著降低CIA大鼠关节炎评分。
3、受试药对CIA大鼠后肢足体积的影响：
各受试药物干预14天后均表现出显著降低CIA大鼠左后肢足体积的作用(P＜0.05或0.01)。与模型组相比，受试药物治疗期间显著降低CIA大鼠左下肢足体积(图3)。化合物33、化合物2、化合物13、化合物20、化合物35较氟比洛芬组相比，显示出更优效果。
4、受试药对CIA大鼠后肢机械缩足反射阈值(MWT)的影响：
造模成功后，与空白对照组相比，CIA大鼠左下肢机械缩足反射阈值(MWT)显著降低。受试药物干预治疗13天后，各受试药均表现出显著增加MWT的作用(图4，P＜0.05)，其中化合物33、化合物2、化合物13、化合物20、化合物35较氟比洛芬组相比，显示出略优或更优效果。
试验5：抗肿瘤药效
实验方法：采用MTT法测试。收集对数期肿瘤细胞，调整细胞悬液浓度，每孔加入100μL，铺板调整待测细胞密度至1000-10000个/孔，(边缘孔用无菌PBS填充)。在5％CO2，37℃孵育，至细胞贴壁(96孔平底板)，加入不同浓度梯度的药物，每孔100μL，设4个复孔。在5％CO2，37℃条件下孵育72小时，倒置显微镜下观察。向96孔板中加入配制好的MTT溶液(5mg/mL),每孔20μL，混匀，在37℃，5％CO2条件下孵育4h后，弃掉板内液体，每孔加入150μL DMSO，酶标仪振荡3分钟，在490nm处检测OD值(光密度值)。
按下列公式计算药物对肿瘤细胞生长的抑制率：
细胞存活率(％)＝(治疗组OD值/对照组OD值)×100％
实验结果：
表4.抗肿瘤试验结果(IC50值，单位：微摩尔)

Claims (9)

  1. [根据细则91更正 13.12.2023]
    一种式(I)所示的化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体、或其同位素标记物、或其氮氧化物，
    其中：
    X为亚烷基；
    P选自：
    式(a)中，
    Y选自单键、-O-，-S-，或-NH-；
    W为单键或亚烷基；
    R1和R2相同或者不同，各自独立地选自-H，任选取代的烷基，任选取代的芳基，或者，R1和R2相互连接、且与它们连接的氮原子共同形成任选取代的脂杂环基或
    R5为一个或两个，各自独立地选自-H，烷基；
    式(c)中，虚线表示单键或不存在；
    式(b)中，
    A选自单键、-O-(C＝O)-或-O-(C＝O)-亚烷基；
    R3为任选存在的基团；
    R3存在时，为一个或多个，各自独立地为烷基、羟基、羧基、羟基取代的烷基、烷氧基、-N(R5)(R6)，R5、R6相同或不同，各自独立地为烷基；
    R4选自-H，烷基，烷酰基；
    或者R3与-OR4相互连接形成脂杂环；
    所述“任选取代的”是指未取代或被一个或多个取代基取代，其中所述“任选取代的烷基”、“任选取代的芳基”、“任选取代的脂杂环基”中的取代基各自独立地选自羟基、氨基、羧基、卤素、硝基、氰基、烷基、烷硫基、烷酰基、羟基取代的芳基。
  2. [根据细则91更正 13.12.2023]
    根据权利要求1所述的式(I)所示的化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体、或其同位素标记物、或其氮氧化物，其特征在于，
    所述“烷基”，“烷酰基”、“羟基取代的烷基”、“烷氧基”、“烷硫基”中的烷基部分各自独立地为C1-20直链或支链烷基，可选地，为C1-17直链或支链烷基，可选地，为C1-10直链或支链烷基，可选地，为C1-7直链或支链烷基，可选地，为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基，异戊基、新戊基、叔戊基、正己基、异己基、庚基、正辛基、正壬基、正癸基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、或十六烷基；
    可选地，所述“亚烷基”为C1-20直链或支链亚烷基，可选地，为C1-17直链或支链亚烷基，可选地，为C1-10直链或支链亚烷基，可选地，为C1-8直链或支链亚烷基，可选地，为C1-6直链或支链亚烷基，可选地，为C1-3直链或支链亚烷基，可选地，为亚甲基、亚乙基、亚异乙基、亚正丙基、亚异丙基、亚正丁基、亚异丁基、亚叔丁基、亚仲丁基、亚正戊基，亚异戊基、亚新戊基、亚叔戊基、亚正己基、亚异己基、亚庚基、亚正辛基、亚正壬基、亚正癸基；
    可选地，所述“脂杂环”、“脂杂环基”中的脂杂环为环上含有选自O、N、S的1-3个杂原子的C3-8(优选为C4-6)脂杂环，可选地，为二氧戊环、氮杂环丙烷基、氮杂环丁烷基、四氢吡咯基、吗啉基、哌啶基、或哌嗪基；
    可选地，所述“芳基”、“羟基取代的芳基”为6-10元单环或双环稠合芳香环基团；可选地为苯基或萘基；
    可选地，本发明涉及前述化合物和任何附属的定义，其中3-氟苯丙酸酯部分为S构型或R构型。
  3. [根据细则91更正 13.12.2023]
    根据权利要求1或2所述的式(I)所示的化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或2其消旋体、或其共晶体、或其同位素标记物、或其氮氧化物，其特征在于，R1和R2相同或者不同，各自独立地选自-H，正丙基，异丙基，或者，R1和R2相互连接、且与它们连接的氮原子共同形成下述基团：杂环丙烷-1-基、氮杂环丁烷-1-基、四氢吡咯-1-基、吗啉-1-基、哌啶-1-基、或哌嗪-1-基，
    可选地，R3与-OR4相互连接形成脂杂环时，所述脂杂环为二氧戊环。
  4. [根据细则91更正 13.12.2023]
    根据权利要求1-3任一项所述的式(I)所示的化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体、或其同位素标记物、或其氮氧化物，其特征在于，
    所述药学上可接受的盐为无机酸盐或有机酸盐，优选地，选自盐酸、硫酸、磷酸、硝酸、甲磺酸、酒石酸、甲酸、乙酸、水杨酸、柠檬酸、琥珀酸、富马酸、或苯甲酸。
  5. [根据细则91更正 13.12.2023]
    根据权利要求1-4任一项所述的式(I)所示的化合物，或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体、或其同位素标记物、或其氮氧化物，其特征在于，选自下述化合物，或其光学异构体、或其溶剂化物、或其包合物、或其消旋体、或其共晶体、或其同位素标记物、或其氮氧化物：
  6. [根据细则91更正 13.12.2023]
    权利要求1-5任一项所述式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体或其同位素标记物、或其氮氧化物的制备方法；
    其式(I)中，P选自时，包括将式(A)化合物和式(B)化合物通过方法A得到式(II)的步骤：
    方法A：将式(A)和式(B)通过取代反应制得式(II)；
    其中，
    式(A)选自R构型、S构型或消旋体；
    式(B)和式(II)中X、Y、W、R1和R2如式(I)中所述；
    式(B)中D选自Cl，Br，I，OTs，OMs；
    各个Y选自-O-，-S-，或-NH-，其中R1和R2如式(I)所述；
    可选地，将式(A)和式(B)在碱催化下，在合适溶剂中，于适当温度下，通过取代反应制得式(II)；
    可选地，所述方法A中，所述取代反应所用的碱为选自吡啶、或三乙胺、或N，N-二异丙基乙胺、或1,8-二氮杂二环[5.4.0]十一碳-7-烯、或碳酸钾、或碳酸铯、或氢化钠、或双三甲基硅基胺基锂中的一种或多种；可选地，所述取代反应的溶剂为选自DMF、或DMAC、或二甲基亚砜、或NMP、或DCM、或四氢呋喃、或乙腈、或乙酸乙酯、或乙酸异丙酯、或二氧六环、或丙酮中的一种或多种；可选地，所述取代反应的温度为0℃至100℃；
    可选地，式(B)可以采用如下步骤1-3中的任一种，但并不限于以下方法：
    步骤1：
    在室温下，向剧烈搅拌的酸的二氯甲烷溶液中加入饱和碳酸氢钠溶液和催化量四丁基硫酸氢铵，然后加入氯磺酸氯甲酯，反应完成后，分层，收集有机相，无水硫酸钠干燥，减压旋干，柱层析纯化后得式(B)化合物。
    和/或步骤2：
    将氯代试剂和碘化钠(或碘化钾)在乙腈(或丙酮)中回流，反应完成后，减压除去溶剂，加入有机溶剂和水，分层，收集有机相，无水硫酸钠干燥，减压除去溶剂，得相应的碘代式(B)化合物。
    可选的，W不存在，使用步骤3合成式(B)；
    或步骤3：
    0℃下，向氯甲酸氯甲酯的二氯甲烷溶液中加入相应的仲胺，反应完成后，过滤，有机相用1N盐酸洗，无水硫酸钠干燥，减压除去溶剂，得式(B)化合物。
    或者，W为单键时，包括将式(A)、式(C)和式(M)通过方法B得到式(II)；
    方法B：①将式(A)和式(C)通过缩合反应制得式(D)；②将式(D)进行脱保护得式(E)；③式(E)与式(M)缩合得式(II)；
    其中，
    Y为单键，X、R1和R2如式(I)所述；
    式(A)选自R构型、S构型或消旋体；
    式(C)中R7选自甲基、乙基、叔丁基、苄基、或对甲氧基苄基；E为-OH；
    或者，P选自时，包括式(A)化合物和式(F)化合物通过方法C得到式(III)；
    方法C：将式(A)和式(F)通过缩合反应制得式(III)；
    其中，
    式(F)中，A选自单键，X、R3和R4如式(I)中所述；
    式(F)中，Z选自-OH，-NH2，-SH，-NH-；
    可选地，所述方法B和方法C中，所述缩合反应的缩合剂选自DCC，DIC，EDCI，HATU，HBTU，CDI，HCTU，TBTU，TSTU，TNTU，HAPyU，HBPyU，BOP，PyBOP，PyAOP，DPPCl，DECP，DPPA，MPTA，或BOPCl中的一种或多种，可选地，所述缩合反应的溶剂选自二氯甲烷，二甲亚砜，N,N-二甲基甲酰胺，六甲基磷酰三胺，或乙腈中的一种或多种；可选地，所述缩合反应的温度为0℃-100℃；
    或者，包括将式(A)通过方法D得到式(III)化合物：
    方法D：
    其中，
    式(F)中，A选自单键，X、R3、R4和Z如上所述；
    或者，包括将式(A)和式(H)通过方法E得到式(III)化合物：
    方法E：
    其中，
    式(H)中，A为-O-(C＝O)-；G选自Cl，Br，I，OMs，或OTs；X、R3和R4如式(I)中所述。
  7. [根据细则91更正 13.12.2023]
    一种药物组合物，所述药物组合物包括上述式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体或其同位素标记物、或其氮氧化物和药学上可接受的辅料，
    可选地，所述的药学上可接受辅料选自：填充剂、崩解剂、润滑剂、助流剂、泡腾剂、矫味剂、防腐剂、增溶剂、助溶剂、抗氧剂、抗光解剂、pH调节剂、乳化剂、抑菌防腐剂、局部止痛剂、络合剂、非水溶剂、包衣材料或其它赋形剂；
    可选地，所述的药学上可接受的辅料，其填充剂包括乳糖、甘露醇、碳酸钙中的一种或几种的组合物；所述的粘合剂包括蔗糖、淀粉、聚维酮、羧甲基纤维素钠、中的一种或几种的组合物；所述的崩解剂包括淀粉、交联聚维酮、交联羧甲基纤维素钠、泡腾崩解剂中的一种或几种的组合物；非水溶剂包括大豆油、蓖麻油、花生油中的一种或几种的组合物；增溶剂包括吐温80、吐温60、泊洛沙姆68中的一种或几种的组合物；助溶剂包括苯甲酸钠、水杨酸钠、对氨基苯甲酸钠中的一种或几种的组合物；
    可选地，所述药物组合物的给药方式包括：经口给药(例如，口腔)、舌下给药、肠胃外给药(例如，肌肉内、静脉内或者皮下)、直肠给药(例如，由栓剂或洗剂)、透皮给药(皮肤电穿孔，透皮制剂等，如乳膏、凝胶、涂剂和透皮贴片等)或者通过吸入给药(例如，气雾剂)；
    可选地，在连续治疗下，以单一单位剂量形式，或以随意的单一剂量治疗，进行给药；
    可选地，所述药物组合物还可以为油乳剂或分散剂的形式，其结合有亲脂性盐如双羟萘酸，或者为可生物降解的持续释放组合物的形式，其用于皮下或者肌肉内给药；
    可选地，所述药物组合物可以制成固体口服制剂、液体口服制剂、注射剂、或透皮制剂；
    可选地，所述固体及液体口服制剂包括：片剂、分散片、糖衣剂、颗粒剂、干粉剂、胶囊剂、糖浆剂和溶液剂；
    可选地，所述的注射剂包括：小针、大输液、冻干粉针；
    可选地，所述的透皮制剂包括：软膏剂、硬膏剂、搽剂、气雾剂、传统贴膏、黏胶分散型贴剂、周边黏胶骨架型贴剂、储库型贴剂和巴布膏剂。
  8. [根据细则91更正 13.12.2023]
    权利要求1-5任一项所述式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体或其同位素标记物、或其氮氧化物或权利要求7所述的药物组合物在制备用于预防和/或治疗炎症、疼痛、发热、癌症、老年痴呆等药物中的用途；
    可选地，所述炎症选自类风湿性关节炎、骨关节炎、强直性脊椎炎、肩周炎、肌腱及腱鞘炎、腱鞘周围炎、肱骨外上髁炎(网球肘)、术后抗炎、外伤所致肿胀炎症；
    可选地，所述疼痛选自轻度至中度疼痛、创伤后或劳损后疼痛、痛经和手术后疼痛、牙痛及癌痛、成人急性疼痛等；
    可选地，所述发热包括普通感冒或流行性感冒引起的发热；
    可选地，所述癌症选自胃癌、食管癌、多发性骨髓瘤、脑胶质瘤、肺癌。
    可选地，所述癌症的细胞包括人食管癌细胞Eca-109，人多发性骨髓瘤细胞MM.1S，人胃癌细胞NUGC-4，人脑星形胶质母细胞U87，人胶质瘤细胞U251，大细胞肺癌细胞H460。
  9. [根据细则91更正 13.12.2023]
    权利要求1-5任一项所述式(I)化合物或其光学异构体、或其药学上可接受的盐、或其溶剂化物(例如水合物)、或其包合物、或其消旋体、或其共晶体或其同位素标记物、或其氮氧化物或权利要求7所述药物组合物与其他一种或多种第二活性化合物联合用药，在制备用于预防和/或治疗炎症、疼痛、发热、癌症、老年痴呆症的药物中的用途；
    可选地，所述炎症选自类风湿性关节炎、骨关节炎、强直性脊椎炎、肩周炎、肌腱及腱鞘炎、腱鞘周围炎、肱骨外上髁炎(网球肘)、术后抗炎、外伤所致肿胀炎症；
    可选地，所述疼痛选自轻度至中度疼痛、创伤后或劳损后疼痛、如痛经和手术后疼痛、牙痛及癌痛、成人急性疼痛等；
    可选地，所述发热包括普通感冒或流行性感冒引起的发热；
    可选地，所述癌症选自胃癌、食管癌、多发性骨髓瘤、脑胶质瘤、肺癌；
    可选地，所述癌症的细胞包括人食管癌细胞Eca-109，人多发性骨髓瘤细胞MM.1S，人胃癌细胞NUGC-4，人脑星形胶质母细胞U87，人胶质瘤细胞U251，或大细胞肺癌细胞H460；
    可选地，所述其他一种或多种活性药第二活性化合物实例选自以下物质中的一种或多种：舒芬太尼、右美托咪定、福莫特罗、异丙肾上腺素、沙丁胺醇、班布特罗、丙卡特罗、非诺特罗、阿福特罗、妥洛特罗、克伦特罗、沙美特罗、沙美特罗卡松、特布他林、奥西那林、氯丙那林。
PCT/CN2023/123222 2022-10-09 2023-10-07 取代3-氟苯丙酸酯类化合物及其制备方法、药物组合及用途 WO2024078387A1 (zh)

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