WO2023169372A1 - Cucurbitacin b derivative, preparation method therefor, and use thereof - Google Patents

Cucurbitacin b derivative, preparation method therefor, and use thereof Download PDF

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WO2023169372A1
WO2023169372A1 PCT/CN2023/079902 CN2023079902W WO2023169372A1 WO 2023169372 A1 WO2023169372 A1 WO 2023169372A1 CN 2023079902 W CN2023079902 W CN 2023079902W WO 2023169372 A1 WO2023169372 A1 WO 2023169372A1
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substituted
unsubstituted
group
alkylene
alkyl
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PCT/CN2023/079902
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French (fr)
Chinese (zh)
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南发俊
李静雅
卓宁
曹磊
孙新宇
马杰
孔祥荣
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中国科学院上海药物研究所
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Publication of WO2023169372A1 publication Critical patent/WO2023169372A1/en

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0088—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing unsubstituted amino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Definitions

  • the present invention relates to a class of cucurbitacin B derivatives, preparation methods thereof, and the use of such cucurbitacin B derivatives or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing any of them in anti-tumor, anti-inflammatory, etc. aspects of use.
  • Cucurbitacins are a class of cucurbitacin-type tetracyclic triterpenoids with bitter taste and toxicity. They are mainly found in Cucurbitaceae plants, such as Trichosanthes melon, pumpkin, cucumber and watermelon. Others include Scrophulariaceae and Brassicaceae. , Primulaceae, Rubiaceae and other plants are also found. According to structural characteristics, cucurbitacins are divided into 12 categories, including cucurbitacins A-T, etc., with more than 200 derivatives, of which cucurbitacins B and E are the main types.
  • cucurbitacin B has been widely studied due to its rich sources and multiple powerful physiological activities. It has been proven to have therapeutic effects on various cancers, AIDS, and inflammation.
  • Current research on cucurbitacin B and its derivatives mainly focuses on anti-tumor activity.
  • Cucurbitacin B has been found to be effective against breast cancer, lung cancer, skin cancer, brain cancer, liver cancer, leukemia, gastric cancer, prostate cancer, cervical cancer cells, etc. It has anti-proliferative effects, and a large number of related mechanisms and molecular targets have been discovered. This area still needs further research.
  • the object of the present invention is to provide various derivatives of cucurbitacin B and their salts as well as preparation methods and uses of such derivatives.
  • a first aspect of the present invention provides a compound represented by general formula (I), or its enantiomers, diastereomers, racemates, tautomers, and optical isomers. , stereoisomers or pharmaceutically acceptable salts thereof:
  • R1 is selected from the following group: unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted C6 -C10 aryl, unsubstituted or substituted C3-C8 cyclic hydrocarbyl, unsubstituted or substituted 3-8 membered heterocyclic hydrocarbyl, unsubstituted or substituted 5-8 membered heteroaryl; the substitution is by Substituted with one or more substituents selected from the following group: C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1- C8 haloalkoxy, cyano, azido, biotin ester, biotin
  • R c and R d are each independently selected from: hydrogen, unsubstituted or substituted C1-C8 alkyl group, unsubstituted or substituted -(C1-C6 alkylene)C3-C8 heterocyclic hydrocarbon group, unsubstituted Substituted or substituted C6-C10 aryl group, unsubstituted or substituted C3-C8 cyclic hydrocarbon group, unsubstituted or substituted 3-8 membered heterocyclic hydrocarbon group, unsubstituted or substituted 5-8 membered heteroaryl group , C1-C8 alkylene biotinamide, (C1-C8 alkylene) 5-8 membered heteroaryl (C1-C8 alkylene) biotin amide; the substitution is by One or more substituents selected from the following group are substituted: C1-C8 alkyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-
  • R 1 is selected from the following group: unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, Unsubstituted or substituted C6 aryl group, unsubstituted or substituted C4-C7 cyclic hydrocarbon group, unsubstituted or substituted 4-7 membered heterocyclic hydrocarbon group, unsubstituted or substituted 4-7 membered heteroaryl group;
  • the substitution is one or more substituents selected from the following group: C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 Haloalkyl, C1-C6 haloalkoxy, cyano, azido, biotin ester, biotin amide, -COOR d
  • R c and R d are each independently selected from: hydrogen, unsubstituted or substituted C1-C6 alkyl group, unsubstituted or substituted -(C1-C6 alkylene)C4-C7 heterocyclic hydrocarbon group, unsubstituted Substituted or substituted C6 aryl, unsubstituted or substituted C3-C8 cyclic hydrocarbyl, unsubstituted or substituted 3-8 membered heterocyclic hydrocarbyl, unsubstituted or substituted 5-8 membered heteroaryl, ( C1-C6 alkylene) 5-8 membered heteroaryl (C1-C6 alkylene) biotinamide, C1-C6 alkylene biotinamide; the substitution is one or more selected from the group Substituent substitution: C1-C6 alkyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalk
  • R 1 is selected from the following group: unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C2-C4 alkenyl, unsubstituted or substituted C2-C4 alkynyl, Unsubstituted or substituted C6 aryl group, unsubstituted or substituted C4-C6 cycloalkyl group, unsubstituted or substituted 4-6 membered heterocyclic hydrocarbyl group, unsubstituted or substituted 4-6 membered heteroaryl group;
  • the substitution is one or more substituents selected from the following group: C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 Haloalkyl, C1-C4 haloalkoxy, cyano, azido, biotin ester, biotin amide, -CO
  • R c and R d are each independently selected from: hydrogen, unsubstituted or substituted C1-C4 alkyl group, unsubstituted or substituted -(C1-C4 alkylene)C4-C6 heterocyclic hydrocarbon group, unsubstituted Substituted or substituted C6 aryl group, unsubstituted or substituted C3-C6 cycloalkyl group, unsubstituted or substituted 3-6 membered heterocyclic hydrocarbyl group, unsubstituted or substituted 5-6 membered heteroaryl group, C2 -C5 alkylene biotinamide, (C1-C4 alkylene)5-8 membered heteroaryl (C1-C4 alkylene) biotinamide; the substitution is one or more selected from the group consisting of: Substituent substitution: C1-C4 alkyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-
  • the compound has the following structure:
  • R1 is defined as above.
  • R 1 is unsubstituted or substituted phenyl, and the substitution is substituted by one or more substituents selected from the following group: C1-C4 alkyl, C1-C4 alkoxy, Halogen, hydroxyl, -NR c R d , azido group, biotin ester, biotin amide, -OCOR d , -NHCOR d , -COOR d , C1-C6 haloalkoxy group, cyano group;
  • R c and R d are each independently selected from: hydrogen, C1-C4 alkyl group, C1-C6 alkylene biotinamide.
  • the compound is selected from: C1-C49.
  • a second aspect of the present invention provides a pharmaceutical composition comprising:
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here refers to the ability of each component in the composition to interact with the active ingredient of the present invention (the compound represented by the general formula (I), or its enantiomers, diastereomers, exogenous racemates, tautomers, optical isomers, stereoisomers or pharmaceutically acceptable salts thereof) and blending with each other without significantly reducing the efficacy of the active ingredients.
  • the active ingredient of the present invention the compound represented by the general formula (I), or its enantiomers, diastereomers, exogenous racemates, tautomers, optical isomers, stereoisomers or pharmaceutically acceptable salts thereof
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, 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, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • the administration mode of the active ingredients or pharmaceutical compositions of the present invention is not particularly limited.
  • Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the active ingredient, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • compositions for parenteral injection may contain 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.
  • the compounds of the present invention can be administered alone or in combination with other therapeutic drugs (such as anti-tumor drugs).
  • 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, and the dosage when administered is a pharmaceutically effective dosage.
  • a mammal such as a human
  • the daily dose is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • the third aspect of the present invention provides the compound represented by the general formula (I) described in the first aspect, or its enantiomers, diastereomers, racemates, tautomers, Optical isomers, stereoisomers or pharmaceutically acceptable salts thereof or the use of pharmaceutical compositions described in the second aspect are used to prepare drugs for preventing and/or treating tumors or inflammation.
  • the tumor is selected from the group consisting of lung cancer, liver cancer, breast cancer, ovarian cancer, cervical cancer, colon cancer, melanoma, prostate cancer, gastric cancer, and hematological tumors.
  • the inflammation is inflammation caused by activation of the intracellular NF- ⁇ B signaling pathway.
  • novel cucurbitacin B derivatives of the present invention are easy to synthesize and have good anti-tumor and anti-inflammatory activities, and some of the derivatives have stronger anti-tumor and anti-inflammatory activities than cucurbitacin B.
  • the inventor of the present application carried out structural modification of the C25 acetoxy group of cucurbitacin B through a palladium-catalyzed coupling method without introducing a protecting group, and obtained a series of cucurbitacins.
  • B derivatives have good anti-tumor and anti-inflammatory activities, and have anti-proliferative effects on a variety of tumor cell lines, with better activity than cucurbitacin B.
  • the present invention was completed.
  • the halogen is F, Cl, Br or I.
  • C1-C6 means having 1, 2, 3, 4, 5 or 6 carbon atoms
  • C1-C8 means having 1, 2, 3, 4, 5, 6, 7 Or 8 carbon atoms, and so on.
  • 3-8 membered means having 3, 4, 5, 6, 7 or 8 ring atoms, and so on.
  • alkyl refers to a saturated linear or branched hydrocarbon moiety.
  • C1-C8 alkyl refers to a saturated linear or branched hydrocarbon moiety having 1, 2, 3, 4, 5, 6, Straight-chain or branched alkyl groups of 7 or 8 carbon atoms, including without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , pentyl and hexyl, etc.; preferably ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
  • alkoxy means -O-alkyl.
  • C1-C6 alkoxy refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy base and butoxy group, etc.
  • alkylene refers to a linear or branched saturated aliphatic group having a specified number of carbon atoms and connected to at least two other groups, that is, a divalent hydrocarbon group.
  • the two groups attached to the alkylene group may be attached to the same or different atoms on the alkylene group.
  • a linear alkylene group may be a divalent group -(CH2)n-, where n is 1, 2, 3, 4, 5, or 6.
  • Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene.
  • alkenyl refers to a straight-chain or branched hydrocarbon moiety containing at least one double bond.
  • C2-C6 alkenyl refers to a straight-chain or branched hydrocarbon moiety having 2 to 6 carbon atoms and containing one double bond.
  • Chain or branched alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.
  • alkynyl refers to a linear or branched chain alkynyl group containing one triple bond, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl. Alkynyl etc.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon moiety.
  • C3-C8 cycloalkyl refers to a cyclic hydrocarbon group having 3 to 8 carbon atoms in the ring.
  • Hydrocarbyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclodecanyl, and the like.
  • C3-C6 cycloalkyl has a similar meaning.
  • Polycyclic cyclic hydrocarbon groups include spirocyclic, condensed and bridged cyclic hydrocarbon groups.
  • heterocyclyl or “heterocyclic hydrocarbyl” means a saturated or partially unsaturated cyclic group containing at least one ring heteroatom (such as N, O or S).
  • heteroatom such as N, O or S.
  • 3-8 membered heterocyclyl refers to a saturated or unsaturated 3-8 membered cyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, such as dioxetane Pentyl, tetrahydropyridyl, dihydropyridyl, dihydrofuryl, dihydrothienyl, oxanyl, wait.
  • 3-6 membered heterocyclyl has a similar meaning.
  • 3-7 membered nitrogen-containing heterocycle refers to a cycloalkyl ring having 3-7 ring atoms and containing 1, 2 or 3 N atoms, including without limitation cycloazidine ring , azobutane ring, azoheptane ring, etc.
  • biotin ester refers to Biotinamide (also known as biotinamide) is
  • alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups described herein are substituted and unsubstituted groups.
  • Possible substituents on alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl include, but are not limited to: hydroxyl, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkene Base, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl base, heteroaryloxy, C1-C10 alkylamino, C1-C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfamoyl, arylsulfam
  • the substitution is mono-substitution or poly-substitution
  • the poly-substitution is disubstitution, tri-substitution, tetra-substitution or penta-substitution.
  • the disubstituted means having two substituents, and so on.
  • the structural formulas described in the present invention are intended to include all tautomeric, optical isomers and stereoisomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers).
  • Conformation For example, the R and S configurations containing asymmetric centers, the (Z) and (E) isomers of double bonds and the conformational isomers of (Z) and (E).
  • individual stereochemical isomers, tautomers or mixtures of enantiomers, diastereomers or geometric isomers or conformational isomers or tautomers thereof of the compounds of the invention All belong to the scope of the present invention.
  • tautomers means that structural isomers with different energies can cross a low energy barrier and thus convert into each other.
  • proton tautomers i.e. proton transfer
  • interconversion through proton migration such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole
  • valency tautomers include interconversion through some bonding electron recombination.
  • the pharmaceutically acceptable salts are not particularly limited and preferably include: inorganic acid salts, organic acid salts, alkyl sulfonates and aryl sulfonates;
  • the inorganic acid salts include hydrochlorides , hydrobromide, nitrate, sulfate, phosphate, etc.;
  • the organic acid salts include formate, acetate, propionate, benzoate, maleate, fumarate, Succinate, tartrate, citrate, etc.;
  • the alkyl sulfonate includes methyl sulfonate, ethyl sulfonate, etc.;
  • the aryl sulfonate includes benzene sulfonate, p-toluene sulfonate, etc. Salt etc.
  • the cucurbitacin B derivative of the present invention can be prepared using the following route.
  • the reaction is carried out in dichloromethane or tetrahydrofuran; the palladium catalyst used is tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ) or palladium chloride (PdCl 2 ); the base used is potassium fluoride or potassium carbonate ;
  • the other reactant is substituted boric acid or substituted boric acid pinacol ester; the reaction temperature is room temperature; the reaction time takes about 12 to 24 hours; the solvent is removed from the reaction, and the concentrate is subjected to column chromatography to obtain the target product, and the obtained product is analyzed by NMR Wait for a way to confirm.
  • R is defined as shown above.
  • MR was measured with AVANCE III 400M instrument produced by Bruker, NMR calibration: ⁇ H 7.26ppm (CDCl3), 2.50ppm (DMSO-d6); mass spectrometry was measured with Agilent 1200 Quadrupole LC/MS. Or SHIMADZU GCMS-QP5050A determination; reagents are mainly provided by Shanghai Chemical Reagent Company; TLC thin layer chromatography silica gel plate is produced by Shandong Yantai Huiyou Silica Gel Development Co., Ltd., model HSGF 254; compound purification used Normal phase column chromatography silica gel is produced by Qingdao Marine Chemical Plant Branch in Shandong province, model zcx-11, 200-300 mesh.
  • DMAP 4-dimethylaminopyridine
  • DCM dichloromethane
  • DMF N,N-dimethylformamide
  • THF tetrahydrofuran
  • Cucurbitacin B (50mg, 0.090mmol), (4-[(trimethylsilyl)alkyne]phenyl)boronic acid (39.09mg, 0.18mmol), potassium fluoride (10.41mg, 0.18mmol), tris( Dibenzylideneacetone) dipalladium (4.10 mg, 0.045 mmol) was dissolved in dry DCM (4 mL) and stirred at room temperature overnight. TLC showed that the reaction was complete the next day. The DCM was rotated out, and 17.8 mg (0.026 mmol) of the intermediate was obtained by column chromatography.
  • Example 10 Anti-proliferation test (MTS test) of compounds on A549 (human non-small cell lung cancer) and PLC/PRF/5 (human liver cancer) cell lines
  • Sample treatment Dissolve the sample with DMSO and store it at low temperature.
  • concentration of DMSO in the final system is controlled within a range that does not affect the detection activity.
  • MTS method was used to detect cell survival rate.
  • adherent cells were digested with 0.025% trypsin and counted; A549 cells were counted at 3000/well, and PLC/PRF/5 cells were counted at 5000/well (all Inoculate 80ul into a 96-well plate at a density of 10% FBS (culture plating) and place it in a 37°C incubator with 5% CO 2 for overnight growth.
  • Each test compound was diluted in a three-fold concentration gradient, and eight concentrations were tested. Three replicate wells were set up for each concentration; 20ul of the diluted compounds were added to the corresponding cell wells, and the adherent cells were incubated in 5% CO 2 at 37°C.
  • the anti-tumor cell proliferation results of the compounds are shown in Tables 1 (A549 cells) and 2 (PLC/PRF/5 cells).
  • the tested compounds have good anti-proliferation activity (IC 50 ⁇ 100nM).
  • IC 50 is half inhibition or 50% inhibition concentration. “*”: 1-10 ⁇ M; “**”: 0.1-1 ⁇ M; “***”: 100-1nM
  • TNF ⁇ is used to stimulate NF- ⁇ B transcriptional activity
  • PS-341 Bossezomib, bortezomib
  • TNF ⁇ Positive compounds or compounds to be tested were co-treated with TNF ⁇ .
  • luciferase substrate containing cell lysis solution was added to fully lyse the cells. Detect the luminescence signal intensity and evaluate the effect of the compound on NF- ⁇ B transcriptional activity.
  • Sample processing Dissolve the sample with DMSO and store it at low temperature.
  • concentration of DMSO in the final system is controlled so as not to affect within the range of detectable activity.
  • TNF ⁇ stimulation After the cells grow on the wall for 24 hours, add 50 ⁇ l of complete culture medium (containing 10% FBS) containing 20ng/ml TNF ⁇ , that is, the final concentration of TNF ⁇ is 10ng/ml.
  • Compound treatment Take 1 ⁇ L of compound from the compound master plate and the control compound master plate and add it to the 96-well screening plate.
  • Detection Add CellTiter-Blue after 4 hours and incubate in the dark. After a total of 6 hours, EnVisionTM detection was carried out; immediately after the end, 90 ⁇ L of liquid was removed from the 96-well screening plate, and 20 ⁇ L of Luciferace substrate was added, and the Luciferase signal intensity was measured using 2101 Multilabel Reader.
  • the tested compounds all have inhibitory activity on the NF- ⁇ B signaling pathway, and most of the compounds have good NF- ⁇ B inhibitory activity (IC 50 ⁇ 1 ⁇ M).
  • NF- ⁇ B signaling pathway inhibitory activity results Note: IC 50 is half inhibition or 50% inhibition concentration. "*”: 10-100 ⁇ M; “**”: 1-10 ⁇ M; “***”: 0.1-1 ⁇ M

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Abstract

A cucurbitacin B derivative, a preparation method therefor and a use thereof. The structure of the compound is shown in formula I. The cucurbitacin B derivative is easy to synthesize, has good anti-tumor and anti-inflammatory activity, and can be used for preparing anti-tumor and anti-inflammatory drugs.

Description

一类葫芦素B衍生物及其制备方法和用途A class of cucurbitacin B derivatives and preparation methods and uses thereof 技术领域Technical field
本发明涉及一类葫芦素B衍生物，及其制备方法，以及该类葫芦素B衍生物或其药学上可接受的盐或含有它们中任何一种的药物组合物在抗肿瘤和抗炎等方面的用途。The present invention relates to a class of cucurbitacin B derivatives, preparation methods thereof, and the use of such cucurbitacin B derivatives or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing any of them in anti-tumor, anti-inflammatory, etc. aspects of use.
背景技术Background technique
葫芦素(Cucurbitacins)是一类具有苦味和毒性的葫芦烷型四环三萜类化合物，主要存在于葫芦科植物，如瓜蒌、南瓜、黄瓜和西瓜等，其他如玄参科、十字花科、报春花科、茜草科等植物中也有发现。根据结构特点，葫芦素分为12大类，包括葫芦素A-T等，其衍生物多达200多种，其中葫芦素B和E是主要类型。Cucurbitacins are a class of cucurbitacin-type tetracyclic triterpenoids with bitter taste and toxicity. They are mainly found in Cucurbitaceae plants, such as Trichosanthes melon, pumpkin, cucumber and watermelon. Others include Scrophulariaceae and Brassicaceae. , Primulaceae, Rubiaceae and other plants are also found. According to structural characteristics, cucurbitacins are divided into 12 categories, including cucurbitacins A-T, etc., with more than 200 derivatives, of which cucurbitacins B and E are the main types.
在多种葫芦素亚型中，葫芦素B因其丰富的来源和多种强大的生理活性被广泛研究，已被证明对多种癌症、艾滋病、炎症均有治疗作用。目前对葫芦素B及其衍生物的研究主要集中在抗肿瘤活性上，已经发现葫芦素B对乳腺癌、肺癌、皮肤癌、脑癌、肝癌、白血病、胃癌、前列腺癌、宫颈癌细胞等均有抗增殖作用，并且发现了大量相关的机制和分子靶标。本领域尚需对其进行深入研究。Among various cucurbitacin subtypes, cucurbitacin B has been widely studied due to its rich sources and multiple powerful physiological activities. It has been proven to have therapeutic effects on various cancers, AIDS, and inflammation. Current research on cucurbitacin B and its derivatives mainly focuses on anti-tumor activity. Cucurbitacin B has been found to be effective against breast cancer, lung cancer, skin cancer, brain cancer, liver cancer, leukemia, gastric cancer, prostate cancer, cervical cancer cells, etc. It has anti-proliferative effects, and a large number of related mechanisms and molecular targets have been discovered. This area still needs further research.
发明内容Contents of the invention
本发明的目的在于提供葫芦素B的多种衍生物和它们的盐以及该类衍生物的制备方法和用途。The object of the present invention is to provide various derivatives of cucurbitacin B and their salts as well as preparation methods and uses of such derivatives.
本发明的第一方面，提供一种通式(I)所示的化合物，或其对映异构体、非对映异构体、外消旋体、互变异构体、光学异构体、立体异构体或其药学上可接受的盐：
A first aspect of the present invention provides a compound represented by general formula (I), or its enantiomers, diastereomers, racemates, tautomers, and optical isomers. , stereoisomers or pharmaceutically acceptable salts thereof:
其中，各独立地为单键或双键；Among them, each Independently a single bond or a double bond;
R1选自下组：未取代的或取代的C1-C8烷基、未取代的或取代的C2-C8烯基、未取代的或取代的C2-C8炔基、未取代的或取代的C6-C10芳基、未取代的或取代的C3-C8环烃基、未取代的或取代的3-8元杂环烃基、未取代的或取代的5-8元杂芳基；所述取代是被选自下组的一个或多个取代基取代：C1-C8烷基、C1-C8烷氧基、卤素、羟基、C2-C8烯基、C2-C8炔基、C1-C8卤代烷基、C1-C8卤代烷氧基、氰基、叠氮基、生物素酯、生物素酰胺、-COORd、-CONHRd、-OCORd、-OCOORd、-NRcRd、-NHCORd、-NHCOORd、-NHCONHRd， R1 is selected from the following group: unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted C6 -C10 aryl, unsubstituted or substituted C3-C8 cyclic hydrocarbyl, unsubstituted or substituted 3-8 membered heterocyclic hydrocarbyl, unsubstituted or substituted 5-8 membered heteroaryl; the substitution is by Substituted with one or more substituents selected from the following group: C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1- C8 haloalkoxy, cyano, azido, biotin ester, biotin amide, -COOR d , -CONHR d , -OCOR d , -OCOOR d , -NR c R d , -NHCOR d , -NHCOOR d , -NHCONHRd ,
其中Rc、Rd各自独立地选自：氢、未取代的或取代的C1-C8的烷基、未取代的或取代的-(C1-C6亚烷基)C3-C8杂环烃基、未取代的或取代的C6-C10芳基、未取代的或取代的C3-C8环烃基、未取代的或取代的3-8元杂环烃基、未取代的或取代的5-8元杂芳基、C1-C8亚烷基生物素酰胺、(C1-C8亚烷基)5-8元杂芳基(C1-C8亚烷基)生物素酰胺；所述取代是被 选自下组的一个或多个取代基取代：C1-C8烷基、C2-C8炔基、C1-C8卤代烷基、C1-C8卤代烷氧基、5-8元杂芳基(C1-C8亚烷基)生物素酰胺。Wherein R c and R d are each independently selected from: hydrogen, unsubstituted or substituted C1-C8 alkyl group, unsubstituted or substituted -(C1-C6 alkylene)C3-C8 heterocyclic hydrocarbon group, unsubstituted Substituted or substituted C6-C10 aryl group, unsubstituted or substituted C3-C8 cyclic hydrocarbon group, unsubstituted or substituted 3-8 membered heterocyclic hydrocarbon group, unsubstituted or substituted 5-8 membered heteroaryl group , C1-C8 alkylene biotinamide, (C1-C8 alkylene) 5-8 membered heteroaryl (C1-C8 alkylene) biotin amide; the substitution is by One or more substituents selected from the following group are substituted: C1-C8 alkyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, 5-8 membered heteroaryl (C1-C8 substituent) Alkyl) biotinamide.
在另一优选例中，R1选自下组：未取代的或取代的C1-C6烷基、未取代的或取代的C2-C6烯基、未取代的或取代的C2-C6炔基、未取代的或取代的C6芳基、未取代的或取代的C4-C7环烃基、未取代的或取代的4-7元杂环烃基、未取代的或取代的4-7元杂芳基；所述取代是被选自下组的一个或多个取代基取代：C1-C6烷基、C1-C6烷氧基、卤素、羟基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6卤代烷氧基、氰基、叠氮基、生物素酯、生物素酰胺、-COORd、-CONHRd、-OCORd、-OCOORd、-NRcRd、-NHCORd、-NHCOORd、-NHCONHRd，In another preferred embodiment, R 1 is selected from the following group: unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, Unsubstituted or substituted C6 aryl group, unsubstituted or substituted C4-C7 cyclic hydrocarbon group, unsubstituted or substituted 4-7 membered heterocyclic hydrocarbon group, unsubstituted or substituted 4-7 membered heteroaryl group; The substitution is one or more substituents selected from the following group: C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 Haloalkyl, C1-C6 haloalkoxy, cyano, azido, biotin ester, biotin amide, -COOR d , -CONHR d , -OCOR d , -OCOOR d , -NR c R d , -NHCOR d , -NHCOOR d , -NHCONHR d ,
其中Rc、Rd各自独立地选自：氢、未取代的或取代的C1-C6的烷基、未取代的或取代的-(C1-C6亚烷基)C4-C7杂环烃基、未取代的或取代的C6芳基、未取代的或取代的C3-C8环烃基、未取代的或取代的3-8元杂环烃基、未取代的或取代的5-8元杂芳基、(C1-C6亚烷基)5-8元杂芳基(C1-C6亚烷基)生物素酰胺、C1-C6亚烷基生物素酰胺；所述取代是被选自下组的一个或多个取代基取代：C1-C6烷基、C2-C6炔基、C1-C6卤代烷基、C1-C6卤代烷氧基、5-8元杂芳基(C1-C4亚烷基)生物素酰胺。Wherein R c and R d are each independently selected from: hydrogen, unsubstituted or substituted C1-C6 alkyl group, unsubstituted or substituted -(C1-C6 alkylene)C4-C7 heterocyclic hydrocarbon group, unsubstituted Substituted or substituted C6 aryl, unsubstituted or substituted C3-C8 cyclic hydrocarbyl, unsubstituted or substituted 3-8 membered heterocyclic hydrocarbyl, unsubstituted or substituted 5-8 membered heteroaryl, ( C1-C6 alkylene) 5-8 membered heteroaryl (C1-C6 alkylene) biotinamide, C1-C6 alkylene biotinamide; the substitution is one or more selected from the group Substituent substitution: C1-C6 alkyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, 5-8 membered heteroaryl (C1-C4 alkylene) biotinamide.
在另一优选例中，R1选自下组：未取代的或取代的C1-C4烷基、未取代的或取代的C2-C4烯基、未取代的或取代的C2-C4炔基、未取代的或取代的C6芳基、未取代的或取代的C4-C6环烃基、未取代的或取代的4-6元杂环烃基、未取代的或取代的4-6元杂芳基；所述取代是被选自下组的一个或多个取代基取代：C1-C4烷基、C1-C4烷氧基、卤素、羟基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4卤代烷氧基、氰基、叠氮基、生物素酯、生物素酰胺、-COORd、-CONHRd、-OCORd、-OCOORd、-NRcRd、-NHCORd、-NHCOORd、-NHCONHRd，In another preferred embodiment, R 1 is selected from the following group: unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C2-C4 alkenyl, unsubstituted or substituted C2-C4 alkynyl, Unsubstituted or substituted C6 aryl group, unsubstituted or substituted C4-C6 cycloalkyl group, unsubstituted or substituted 4-6 membered heterocyclic hydrocarbyl group, unsubstituted or substituted 4-6 membered heteroaryl group; The substitution is one or more substituents selected from the following group: C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 Haloalkyl, C1-C4 haloalkoxy, cyano, azido, biotin ester, biotin amide, -COOR d , -CONHR d , -OCOR d , -OCOOR d , -NR c R d , -NHCOR d , -NHCOOR d , -NHCONHR d ,
其中Rc、Rd各自独立地选自：氢、未取代的或取代的C1-C4的烷基、未取代的或取代的-(C1-C4亚烷基)C4-C6杂环烃基、未取代的或取代的C6芳基、未取代的或取代的C3-C6环烃基、未取代的或取代的3-6元杂环烃基、未取代的或取代的5-6元杂芳基、C2-C5亚烷基生物素酰胺、(C1-C4亚烷基)5-8元杂芳基(C1-C4亚烷基)生物素酰胺；所述取代是被选自下组的一个或多个取代基取代：C1-C4烷基、C2-C4炔基、C1-C4卤代烷基、C1-C4卤代烷氧基、5-6元杂芳基(C1-C4亚烷基)生物素酰胺。Wherein R c and R d are each independently selected from: hydrogen, unsubstituted or substituted C1-C4 alkyl group, unsubstituted or substituted -(C1-C4 alkylene)C4-C6 heterocyclic hydrocarbon group, unsubstituted Substituted or substituted C6 aryl group, unsubstituted or substituted C3-C6 cycloalkyl group, unsubstituted or substituted 3-6 membered heterocyclic hydrocarbyl group, unsubstituted or substituted 5-6 membered heteroaryl group, C2 -C5 alkylene biotinamide, (C1-C4 alkylene)5-8 membered heteroaryl (C1-C4 alkylene) biotinamide; the substitution is one or more selected from the group consisting of: Substituent substitution: C1-C4 alkyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, 5-6 membered heteroaryl (C1-C4 alkylene) biotinamide.
在另一优选例中，所述化合物具有以下结构：
In another preferred embodiment, the compound has the following structure:
R1定义同前。 R1 is defined as above.
在另一优选例中，R1为未取代的或取代的苯基，所述取代是被选自下组的一个或多个取代基取代：C1-C4烷基、C1-C4烷氧基、卤素、羟基、-NRcRd、叠氮基、生物素酯、生物素酰胺、-OCORd、-NHCORd、-COORd、C1-C6卤代烷氧基、氰基；In another preferred embodiment, R 1 is unsubstituted or substituted phenyl, and the substitution is substituted by one or more substituents selected from the following group: C1-C4 alkyl, C1-C4 alkoxy, Halogen, hydroxyl, -NR c R d , azido group, biotin ester, biotin amide, -OCOR d , -NHCOR d , -COOR d , C1-C6 haloalkoxy group, cyano group;
Rc、Rd各自独立地选自：氢、C1-C4的烷基、C1-C6亚烷基生物素酰胺。 R c and R d are each independently selected from: hydrogen, C1-C4 alkyl group, C1-C6 alkylene biotinamide.
在另一优选例中，所述化合物选自：C1-C49。In another preferred embodiment, the compound is selected from: C1-C49.
本发明的第二方面，提供一种药物组合物，包含：A second aspect of the present invention provides a pharmaceutical composition comprising:
第一方面所述的通式(I)所示的化合物，或其对映异构体、非对映异构体、外消旋体、互变异构体、光学异构体、立体异构体或其药学上可接受的盐；和The compound represented by the general formula (I) described in the first aspect, or its enantiomers, diastereomers, racemates, tautomers, optical isomers, and stereoisomers body or a pharmaceutically acceptable salt thereof; and
药学上可接受的载体。Pharmaceutically acceptable carrier.
“药学上可接受的载体”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活性成分(通式(I)所示的化合物，或其对映异构体、非对映异构体、外消旋体、互变异构体、光学异构体、立体异构体或其药学上可接受的盐)以及它们之间相互掺和，而不明显降低活性成分的药效。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。"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility" here refers to the ability of each component in the composition to interact with the active ingredient of the present invention (the compound represented by the general formula (I), or its enantiomers, diastereomers, exogenous racemates, tautomers, optical isomers, stereoisomers or pharmaceutically acceptable salts thereof) and blending with each other without significantly reducing the efficacy of the active ingredients. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, 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, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
本发明的活性成分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、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。The administration mode of the active ingredients or pharmaceutical compositions of the present invention is not particularly limited. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.
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。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
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。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1，3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredients, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. Besides these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
除了活性成分外，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。Suspensions may contain, in addition to the active ingredient, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
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。Compositions for parenteral injection may contain 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.
本发明化合物可以单独给药，或者与其他治疗药物(如抗肿瘤药)联合给药。The compounds of the present invention can be administered alone or in combination with other therapeutic drugs (such as anti-tumor drugs).
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1～2000mg，优选20～500mg。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。When using the pharmaceutical composition, 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, and the dosage when administered is a pharmaceutically effective dosage. For a person weighing 60 kg, the daily dose is The dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
本发明的第三方面，提供第一方面所述的通式(I)所示的化合物，或其对映异构体、非对映异构体、外消旋体、互变异构体、光学异构体、立体异构体或其药学上可接受的盐或第二方面所述的药物组合物用途，用于制备预防和/或治疗肿瘤或炎症的药物。The third aspect of the present invention provides the compound represented by the general formula (I) described in the first aspect, or its enantiomers, diastereomers, racemates, tautomers, Optical isomers, stereoisomers or pharmaceutically acceptable salts thereof or the use of pharmaceutical compositions described in the second aspect are used to prepare drugs for preventing and/or treating tumors or inflammation.
在另一优选例中，所述肿瘤选自下组：肺癌、肝癌、乳腺癌、卵巢癌、宫颈癌、结肠癌、黑色素瘤、前列腺癌、胃癌、血液瘤。 In another preferred embodiment, the tumor is selected from the group consisting of lung cancer, liver cancer, breast cancer, ovarian cancer, cervical cancer, colon cancer, melanoma, prostate cancer, gastric cancer, and hematological tumors.
在另一优选例中，所述炎症是由细胞内NF-κB信号通路激活引起的炎症。In another preferred embodiment, the inflammation is inflammation caused by activation of the intracellular NF-κB signaling pathway.
本发明新型的葫芦素B衍生物，合成简便，具有较好的抗肿瘤和抗炎活性，其中部分衍生物具有比葫芦素B更强的抗肿瘤和抗炎活性。The novel cucurbitacin B derivatives of the present invention are easy to synthesize and have good anti-tumor and anti-inflammatory activities, and some of the derivatives have stronger anti-tumor and anti-inflammatory activities than cucurbitacin B.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。说明书中所揭示的各个特征，可以被任何提供相同、均等或相似目的的替代性特征取代。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification may be replaced by any alternative feature serving the same, equivalent or similar purpose. Due to space limitations, they will not be described one by one here.
具体实施方式Detailed ways
本申请的发明人经过广泛而深入地研究，通过一种钯催化偶联的方法，在不引入保护基的情况下，对葫芦素B的C25位乙酰氧基进行结构改造，得到一系列葫芦素B衍生物，具有良好的抗肿瘤和抗炎活性，对多种肿瘤细胞系均有抗增殖作用，活性优于葫芦素B。在此基础上，完成了本发明。After extensive and in-depth research, the inventor of the present application carried out structural modification of the C25 acetoxy group of cucurbitacin B through a palladium-catalyzed coupling method without introducing a protecting group, and obtained a series of cucurbitacins. B derivatives have good anti-tumor and anti-inflammatory activities, and have anti-proliferative effects on a variety of tumor cell lines, with better activity than cucurbitacin B. On this basis, the present invention was completed.
术语the term
在本发明中，所述卤素为F、Cl、Br或I。In the present invention, the halogen is F, Cl, Br or I.
在本发明中，术语“C1-C6”是指具有1、2、3、4、5或6个碳原子，“C1-C8”是指具有1、2、3、4、5、6、7或8个碳原子，依此类推。“3-8元”是指具有3、4、5、6、7或8个环原子，依此类推。In the present invention, the term "C1-C6" means having 1, 2, 3, 4, 5 or 6 carbon atoms, and "C1-C8" means having 1, 2, 3, 4, 5, 6, 7 Or 8 carbon atoms, and so on. "3-8 membered" means having 3, 4, 5, 6, 7 or 8 ring atoms, and so on.
在本发明中，术语“烷基”表示饱和的线性或支链烃部分，例如术语“C1-C8烷基”是指具有1个、2个、3个、4个、5个、6个、7个或8个碳原子的直链或支链烷基，非限制性地包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基和已基等；优选乙基、正丙基、异丙基、正丁基、异丁基、仲丁基和叔丁基。In the present invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon moiety. For example, the term "C1-C8 alkyl" refers to a saturated linear or branched hydrocarbon moiety having 1, 2, 3, 4, 5, 6, Straight-chain or branched alkyl groups of 7 or 8 carbon atoms, including without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl , pentyl and hexyl, etc.; preferably ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
在本发明中，术语“烷氧基”表示-O-烷基。例如术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、正丙氧基、异丙氧基和丁氧基等。In the present invention, the term "alkoxy" means -O-alkyl. For example, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy base and butoxy group, etc.
在本发明中，术语“亚烷基”是指具有指定的碳原子数并连接至少两个其他基团的直链或支链饱和脂肪族基团，即二价烃基团。连接到亚烷基的两个基团可以连接到亚烷基上相同的或不同原子。例如，直链亚烷基可以是-(CH2)n-的二价基团，其中n是1、2、3、4、5或6。代表性的亚烷基包括但不限于亚甲基、亚乙基、亚丙基、亚异丙基、亚丁基、亚异丁基、亚仲丁基、亚戊基和亚己基。In the present invention, the term "alkylene" refers to a linear or branched saturated aliphatic group having a specified number of carbon atoms and connected to at least two other groups, that is, a divalent hydrocarbon group. The two groups attached to the alkylene group may be attached to the same or different atoms on the alkylene group. For example, a linear alkylene group may be a divalent group -(CH2)n-, where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene.
在本发明中，术语“烯基”表示包含至少一个双键的直链或支链烃基部分，例如术语“C2-C6烯基”是指具有2至6个碳原子的含有一个双键的直链或支链烯基，非限制性地包括乙烯基、丙烯基、丁烯基、异丁烯基、戊烯基和己烯基等。In the present invention, the term "alkenyl" refers to a straight-chain or branched hydrocarbon moiety containing at least one double bond. For example, the term "C2-C6 alkenyl" refers to a straight-chain or branched hydrocarbon moiety having 2 to 6 carbon atoms and containing one double bond. Chain or branched alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.
在本发明中，术语“炔基”是指含有一个三键的直链或支链炔基，非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基、戊炔基和己炔基等。In the present invention, the term "alkynyl" refers to a linear or branched chain alkynyl group containing one triple bond, including, but not limited to, ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl. Alkynyl etc.
在本发明中，术语“环烃基”表示饱和或者部分不饱和单环或多环环状烃基部分，例如术语“C3-C8环烃基”是指在环上具有3至8个碳原子的环状烃基，非限制性地包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环庚烯基、环辛基和环癸基等。术语“C3-C6环烃基”具有类似的含义。多环环烃基包括螺环、稠环和桥环的环烃基。 In the present invention, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon moiety. For example, the term "C3-C8 cycloalkyl" refers to a cyclic hydrocarbon group having 3 to 8 carbon atoms in the ring. Hydrocarbyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclodecanyl, and the like. The term "C3-C6 cycloalkyl" has a similar meaning. Polycyclic cyclic hydrocarbon groups include spirocyclic, condensed and bridged cyclic hydrocarbon groups.
本发明中，术语“杂环基”或“杂环烃基”表示包含至少一个环杂原子(例如N,O或S)的饱和或者部分不饱和环状基团。例如术语“3-8元杂环基”是指在环上含有1～3个选自氧、硫和氮中的杂原子的饱和或不饱和的3-8元环基，例如二氧杂环戊基、四氢吡啶基、二氢吡啶基、二氢呋喃基、二氢噻吩基、氧杂环己烯基、等。术语“3-6元杂环基”具有类似的含义。In the present invention, the term "heterocyclyl" or "heterocyclic hydrocarbyl" means a saturated or partially unsaturated cyclic group containing at least one ring heteroatom (such as N, O or S). For example, the term "3-8 membered heterocyclyl" refers to a saturated or unsaturated 3-8 membered cyclic group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen in the ring, such as dioxetane Pentyl, tetrahydropyridyl, dihydropyridyl, dihydrofuryl, dihydrothienyl, oxanyl, wait. The term "3-6 membered heterocyclyl" has a similar meaning.
在本发明中，术语“3-7元含氮杂环”是指具有3-7个环原子且包含1、2或3个N原子的环烷基环，非限制性地包括环氮丙烷环、环氮丁烷环、环氮庚烷环等。In the present invention, the term "3-7 membered nitrogen-containing heterocycle" refers to a cycloalkyl ring having 3-7 ring atoms and containing 1, 2 or 3 N atoms, including without limitation cycloazidine ring , azobutane ring, azoheptane ring, etc.
在用作取代基时，生物素酯是指生物素酰胺(也称为生物素胺)是指 When used as a substituent, biotin ester refers to Biotinamide (also known as biotinamide) is
在本发明中除非另外指出，表示连接位点。In the present invention, unless otherwise indicated, Indicates the connection site.
除非另外说明，本文所述的烷基、烷氧基、环烷基、杂环基和芳基为取代的和未取代的基团。烷基、烷氧基、环烷基、杂环基和芳基上可能的取代基包括，但不限于：羟基、氨基、硝基、腈基、卤素、C1-C6烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C6烷氧基、芳基、杂芳基、杂芳氧基、C1-C10烷基氨基、C1-C20二烷基氨基、芳基氨基、二芳基氨基、C1-C10烷基氨磺酰基、芳基氨磺酰基、C1-C10烷基亚氨基、C1-C10烷基磺基亚氨基、芳基磺基亚氨基、巯基、C1-C10烷硫基、C1-C10烷基磺酰基、芳基磺酰基、酰基氨基、氨酰基、氨基硫代酰基、胍基、脲基、氰基、酰基、硫代酰基、酰氧基、羧基和羧酸酯基。另一方面，环烷基、杂环烷基、杂环烯基、芳基和杂芳基也可互相稠合。Unless otherwise stated, alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups described herein are substituted and unsubstituted groups. Possible substituents on alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl include, but are not limited to: hydroxyl, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkene Base, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl base, heteroaryloxy, C1-C10 alkylamino, C1-C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfamoyl, arylsulfamoyl, C1-C10 alkyl Cylimino, C1-C10 alkylsulfonylimino, arylsulfonylimino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, amino Thioacyl, guanidine, ureido, cyano, acyl, thioacyl, acyloxy, carboxyl and carboxylate groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl groups may also be fused to each other.
本发明中，所述取代为单取代或多取代，所述多取代为二取代、三取代、四取代、或五取代。所述二取代就是指具有两个取代基，依此类推。In the present invention, the substitution is mono-substitution or poly-substitution, and the poly-substitution is disubstitution, tri-substitution, tetra-substitution or penta-substitution. The disubstituted means having two substituents, and so on.
除非特别说明，本发明所描述的结构式意在包括所有的互变异构、光学异构和立体异构形式(如对映异构体、非对映异构体，几何异构体或构象异构体)：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体和(Z)、(E)的构象异构体。因此本发明的化合物的单个立体化学异构体、互变异构体或其对映异构体、非对映异构体或几何异构体或构象异构体或互变异构体的混合物都属于本发明的范围。Unless otherwise stated, the structural formulas described in the present invention are intended to include all tautomeric, optical isomers and stereoisomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers). Conformation): For example, the R and S configurations containing asymmetric centers, the (Z) and (E) isomers of double bonds and the conformational isomers of (Z) and (E). Thus individual stereochemical isomers, tautomers or mixtures of enantiomers, diastereomers or geometric isomers or conformational isomers or tautomers thereof of the compounds of the invention All belong to the scope of the present invention.
术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑、1H-苯并[d]咪唑与3H-苯并[d]咪唑，化合价互变异构体包括通过一些成键电子重组而进行互变。The term "tautomers" means that structural isomers with different energies can cross a low energy barrier and thus convert into each other. For example, proton tautomers (i.e. proton transfer) include interconversion through proton migration, such as 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole , valency tautomers include interconversion through some bonding electron recombination.
在本文中，所述的药学上可接受的盐没有特别的限制，优选包括：无机酸盐、有机酸盐、烷基磺酸盐和芳基磺酸盐；所述无机酸盐包括盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐等；所述有机酸盐包括甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、 琥珀酸盐、酒石酸盐、柠檬酸盐等；所述烷基磺酸盐包括甲基磺酸盐、乙基磺酸盐等；所述芳基磺酸盐包括苯磺酸盐、对甲苯磺酸盐等。In this article, the pharmaceutically acceptable salts are not particularly limited and preferably include: inorganic acid salts, organic acid salts, alkyl sulfonates and aryl sulfonates; the inorganic acid salts include hydrochlorides , hydrobromide, nitrate, sulfate, phosphate, etc.; the organic acid salts include formate, acetate, propionate, benzoate, maleate, fumarate, Succinate, tartrate, citrate, etc.; the alkyl sulfonate includes methyl sulfonate, ethyl sulfonate, etc.; the aryl sulfonate includes benzene sulfonate, p-toluene sulfonate, etc. Salt etc.
制备方法Preparation
本发明的葫芦素B衍生物，能够采用以下路线进行制备。
The cucurbitacin B derivative of the present invention can be prepared using the following route.
反应在二氯甲烷或四氢呋喃中进行；所用钯催化剂为三(二亚苄基丙酮)二钯(Pd2(dba)3)或氯化钯(PdCl2)；所用碱为氟化钾或碳酸钾；另一反应物为取代的硼酸或取代的硼酸频哪醇酯；反应温度为室温；反应时间约需12～24h；反应旋去溶剂，浓缩物经柱层析得目标产物，所得产物用NMR等方法来确认。其中，R的定义如前所示。

The reaction is carried out in dichloromethane or tetrahydrofuran; the palladium catalyst used is tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ) or palladium chloride (PdCl 2 ); the base used is potassium fluoride or potassium carbonate ; The other reactant is substituted boric acid or substituted boric acid pinacol ester; the reaction temperature is room temperature; the reaction time takes about 12 to 24 hours; the solvent is removed from the reaction, and the concentrate is subjected to column chromatography to obtain the target product, and the obtained product is analyzed by NMR Wait for a way to confirm. Among them, R is defined as shown above.

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(如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the invention and are not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples are usually carried out according to conventional conditions (such as conditions described in Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or according to manufacturing Conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all technical and scientific terms used herein have the same meaning as familiar to one skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the method of the present invention. The preferred implementation methods and materials described in this article are for demonstration purposes only.
下述制备实施例中，MR用Bruker生产的AVANCE III 400M仪器测定，NMR定标：δH 7.26ppm(CDCl3)，2.50ppm(DMSO-d6)；质谱用Agilent 1200 Quadrupole LC/MS液质联用仪或SHIMADZU GCMS-QP5050A测定；试剂主要由上海化学试剂公司提供；TLC薄层层析硅胶板由山东烟台会友硅胶开发有限公司生产，型号HSGF 254；化合物纯化使用的 正相柱层析硅胶为山东青岛海洋化工厂分厂生产，型号zcx-11，200-300目。In the following preparation examples, MR was measured with AVANCE III 400M instrument produced by Bruker, NMR calibration: δH 7.26ppm (CDCl3), 2.50ppm (DMSO-d6); mass spectrometry was measured with Agilent 1200 Quadrupole LC/MS. Or SHIMADZU GCMS-QP5050A determination; reagents are mainly provided by Shanghai Chemical Reagent Company; TLC thin layer chromatography silica gel plate is produced by Shandong Yantai Huiyou Silica Gel Development Co., Ltd., model HSGF 254; compound purification used Normal phase column chromatography silica gel is produced by Qingdao Marine Chemical Plant Branch in Shandong Province, model zcx-11, 200-300 mesh.
本文缩写所对应的的中文如下：The Chinese corresponding to the abbreviations in this article are as follows:
DMAP:4-二甲氨基吡啶；DCM:二氯甲烷；DMF：N,N-二甲基甲酰胺；THF：四氢呋喃。DMAP: 4-dimethylaminopyridine; DCM: dichloromethane; DMF: N,N-dimethylformamide; THF: tetrahydrofuran.
实施例1
Example 1
将葫芦素B(30mg,0.054mmol)，苯硼酸(13.11mg,0.11mmol)，氟化钾(6.24mg，0.11mmol)，三(二亚苄基丙酮)二钯(2.46mg，0.027mmol)，溶于干燥DCM(4mL)中，室温下搅拌过夜，次日TLC显示反应完全。旋出DCM，柱层析分离得产物C1 16.0mg(0.028mmol)，收率：51.44％。1H NMR(400MHz,Chloroform-d)δ7.32–7.28(m,4H),7.25–7.19(m,2H),6.41(d,J＝15.6Hz,1H),5.80–5.78(m,1H),4.44–4.34(m,4H),3.61(d,J＝4.0Hz,1H),3.23(d,J＝14.8Hz,1H),2.74(d,J＝10.8Hz,1H),2.69(dd,J＝14.8,2.4Hz,1H),2.53(d,J＝6.8Hz,1H),2.41(ddt,J＝19.2,8.0,2.8Hz,1H),2.30(ddd,J＝12.4,6.0,3.2Hz,1H),2.04–1.94(m,3H),1.86(dd,J＝13.6,8.8Hz,1H),1.74(s,1H),1.66–1.58(m,5H),1.49(s,3H),1.48(s,3H),1.43(s,3H),1.35(s,3H),1.34(s,3H),1.28(s,3H),1.07(s,3H),0.98(s,3H).Combine cucurbitacin B (30mg, 0.054mmol), phenylboronic acid (13.11mg, 0.11mmol), potassium fluoride (6.24mg, 0.11mmol), tris(dibenzylideneacetone) dipalladium (2.46mg, 0.027mmol), Dissolve in dry DCM (4 mL) and stir at room temperature overnight. TLC showed that the reaction was complete the next day. The DCM was rotated out, and the product C1 was separated by column chromatography to obtain 16.0 mg (0.028 mmol), yield: 51.44%. 1 H NMR(400MHz,Chloroform-d)δ7.32–7.28(m,4H),7.25–7.19(m,2H),6.41(d,J＝15.6Hz,1H),5.80–5.78(m,1H) ,4.44–4.34(m,4H),3.61(d,J＝4.0Hz,1H),3.23(d,J＝14.8Hz,1H),2.74(d,J＝10.8Hz,1H),2.69(dd, J＝14.8,2.4Hz,1H),2.53(d,J＝6.8Hz,1H),2.41(ddt,J＝19.2,8.0,2.8Hz,1H),2.30(ddd,J＝12.4,6.0,3.2Hz ,1H),2.04–1.94(m,3H),1.86(dd,J＝13.6,8.8Hz,1H),1.74(s,1H),1.66–1.58(m,5H),1.49(s,3H), 1.48(s,3H),1.43(s,3H),1.35(s,3H),1.34(s,3H),1.28(s,3H),1.07(s,3H),0.98(s,3H).
用实施例1中类似的方法，葫芦素B与不同的取代硼酸或取代硼酸频哪醇酯反应可得到以下化合物：






Using a similar method in Example 1, the following compounds can be obtained by reacting cucurbitacin B with different substituted boric acids or substituted boric acid pinacol esters:






实施例2
Example 2
将C13(20mg,0.036mmol)溶于甲醇(5mL)中，换氮气后，迅速加入Pd/C,再换氮气后换氢气，室温下搅拌。2小时后TLC检测反应完全。换氮气后滤去Pd/C，旋干溶剂后，柱层析分离得产物C30 17.3mg(0.031mmol)，收率：86.12％。Dissolve C13 (20 mg, 0.036 mmol) in methanol (5 mL). After replacing nitrogen, quickly add Pd/C, then replace nitrogen and then hydrogen, and stir at room temperature. After 2 hours, TLC detected that the reaction was complete. After replacing with nitrogen, filter out the Pd/C. After spinning the solvent to dryness, column chromatography separates the product C30 17.3 mg (0.031 mmol), yield: 86.12%.
1H NMR(400MHz,Chloroform-d)δ5.78(d,J＝5.6Hz,1H),4.43–4.38(m,2H),4.31(t,J＝8.0Hz,1H),3.60(d,J＝4.0Hz,1H),3.26(d,J＝14.4Hz,1H),2.75–2.62(m,3H),2.53(d,J＝6.8Hz,1H),2.47–2.37(m,2H),2.33–2.28(m,1H),2.00–1.93(m,2H),1.84(dd,J＝13.2,8.8Hz,1H),1.63(s,2H),1.55–1.50(m,2H),1.41(s,4H),1.36(s,3H),1.34(s,3H),1.28(s,3H),1.12(d,J＝5.6Hz,2H),1.07(s,3H),0.97(s,3H),0.91(s,3H),0.89(s,3H),0.87(s,6H). 1 H NMR (400MHz, Chloroform-d) δ5.78(d,J＝5.6Hz,1H),4.43–4.38(m,2H),4.31(t,J＝8.0Hz,1H),3.60(d,J ＝4.0Hz,1H),3.26(d,J＝14.4Hz,1H),2.75–2.62(m,3H),2.53(d,J＝6.8Hz,1H),2.47–2.37(m,2H),2.33 –2.28(m,1H),2.00–1.93(m,2H),1.84(dd,J＝13.2,8.8Hz,1H),1.63(s,2H),1.55–1.50(m,2H),1.41(s ,4H),1.36(s,3H),1.34(s,3H),1.28(s,3H),1.12(d,J＝5.6Hz,2H),1.07(s,3H),0.97(s,3H) ,0.91(s,3H),0.89(s,3H),0.87(s,6H).
实施例3
Example 3
将C19(15mg,0.025mmol)，氢氧化钾(14.22mg,0.25mmol)，溶于2mL甲醇：DMF＝1：1混合溶液中，室温下搅拌1h，TLC显示反应完全。用乙酸乙酯(3×50mL)萃取，将合并的有机层分别用去离子水和饱和食盐水洗涤，经硫酸钠干燥浓缩，柱层析分离得产物C31 8.2mg(0.014mmol)，收率：55.59％。Dissolve C19 (15 mg, 0.025 mmol) and potassium hydroxide (14.22 mg, 0.25 mmol) in 2 mL of methanol:DMF=1:1 mixed solution, and stir at room temperature for 1 hour. TLC shows that the reaction is complete. Extract with ethyl acetate (3×50mL), wash the combined organic layers with deionized water and saturated brine respectively, dry and concentrate over sodium sulfate, and separate by column chromatography to obtain product C31 8.2mg (0.014mmol), yield: 55.59%.
1H NMR(400MHz,Chloroform-d)δ7.22–7.15(m,2H),6.86(d,J＝7.6Hz,1H),6.71(d,J＝2.0Hz,1H),6.69(dd,J＝8.2,2.0Hz,1H),6.42(d,J＝15.6Hz,1H),6.18(s,1H),5.94–5.93(m,2H),5.75(t,J＝3.2Hz,1H),4.46(t,J＝8.0Hz,1H),4.41(s,1H),3.49(s,1H),3.19(d,J＝14.4Hz,1H),2.71(d,J＝14.4Hz,1H),2.55(d,J＝6.8Hz,1H),2.37(dd,J＝20.4,8.8Hz,1H),2.32–2.26(m,1H),2.04–2.01(m,2H),1.98–1.85(m,5H),1.47(s,1H),1.46(s,3H),1.44(s,3H),1.43(s,3H),1.36(s,3H),1.35(s,3H),1.25(s,2H),1.23(s,3H),1.02(s,3H),0.99(s,3H). 1 H NMR (400MHz, Chloroform-d) δ7.22–7.15 (m, 2H), 6.86 (d, J = 7.6Hz, 1H), 6.71 (d, J = 2.0Hz, 1H), 6.69 (dd, J ＝8.2,2.0Hz,1H),6.42(d,J＝15.6Hz,1H),6.18(s,1H),5.94–5.93(m,2H),5.75(t,J＝3.2Hz,1H),4.46 (t,J＝8.0Hz,1H),4.41(s,1H),3.49(s,1H),3.19(d,J＝14.4Hz,1H),2.71(d,J＝14.4Hz,1H),2.55 (d,J＝6.8Hz,1H),2.37(dd,J＝20.4,8.8Hz,1H),2.32–2.26(m,1H),2.04–2.01(m,2H),1.98–1.85(m,5H ),1.47(s,1H),1.46(s,3H),1.44(s,3H),1.43(s,3H),1.36(s,3H),1.35(s,3H),1.25(s,2H) ,1.23(s,3H),1.02(s,3H),0.99(s,3H).
实施例4
Example 4
将C18(47.2mg,0.080mmol)，DMAP(19.48mg,0.16mmol)，EDCI(30.57mg,0.16mmol)，2-(3-丁炔基氮二丙啶-3-基)乙酸(13.34mg,0.088mmol)溶于干燥DCM(4mL)中，室温下避光搅拌3h，TLC显示反应完全。用乙酸乙酯(3×50mL)萃取，将合并的有机层分别用饱和氯化铵溶液，去离子水和饱和食盐水洗涤，经硫酸钠干燥浓缩，柱层析分离得产物C32 29.5mg(0.041mmol)，收率：50.79％。Combine C18 (47.2mg, 0.080mmol), DMAP (19.48mg, 0.16mmol), EDCI (30.57mg, 0.16mmol), 2-(3-butynylaziridin-3-yl)acetic acid (13.34mg, 0.088 mmol) was dissolved in dry DCM (4 mL), and stirred in the dark at room temperature for 3 h. TLC showed that the reaction was complete. Extract with ethyl acetate (3 × 50 mL), wash the combined organic layers with saturated ammonium chloride solution, deionized water and saturated brine respectively, dry and concentrate over sodium sulfate, and separate by column chromatography to obtain product C32 29.5 mg (0.041 mmol), yield: 50.79%.
1H NMR(400MHz,Methanol-d4)δ7.36(t,J＝8.0Hz,1H),7.27(dt,J＝8.0,1.2Hz,1H),7.10(t,J＝2.0Hz,1H),7.05(d,J＝15.6Hz,1H),6.98(ddd,J＝8.0,2.4,1.2Hz,1H),6.70(d,J＝15.6Hz,1H),5.82(dt,J＝5.6,2.4Hz,1H),4.57(dd,J＝12.8,6.0Hz,1H),4.49(t,J＝7.6Hz, 1H),3.44(d,J＝14.8Hz,1H),2.99(d,J＝12.8Hz,1H),2.71(s,1H),2.66(s,1H),2.63–2.59(m,2H),2.45–2.37(m,1H),2.34(t,J＝2.4Hz,1H),2.13(td,J＝7.2,2.4Hz,2H),2.10–2.05(m,2H),2.02–1.97(m,2H),1.87–1.83(m,1H),1.80(td,J＝7.2,2.0Hz,2H),1.50(s,3H),1.49(s,3H),1.45(s,1H),1.41(s,3H),1.37(s,3H),1.30(s,3H),1.29(s,3H),1.05(s,3H),0.91(s,3H). 1 H NMR (400MHz, Methanol-d 4 ) δ7.36 (t, J = 8.0 Hz, 1H), 7.27 (dt, J = 8.0, 1.2 Hz, 1H), 7.10 (t, J = 2.0 Hz, 1H) ,7.05(d,J＝15.6Hz,1H),6.98(ddd,J＝8.0,2.4,1.2Hz,1H),6.70(d,J＝15.6Hz,1H),5.82(dt,J＝5.6,2.4 Hz,1H),4.57(dd,J＝12.8,6.0Hz,1H),4.49(t,J＝7.6Hz, 1H),3.44(d,J＝14.8Hz,1H),2.99(d,J＝12.8Hz,1H),2.71(s,1H),2.66(s,1H),2.63–2.59(m,2H), 2.45–2.37(m,1H),2.34(t,J＝2.4Hz,1H),2.13(td,J＝7.2,2.4Hz,2H),2.10–2.05(m,2H),2.02–1.97(m, 2H),1.87–1.83(m,1H),1.80(td,J＝7.2,2.0Hz,2H),1.50(s,3H),1.49(s,3H),1.45(s,1H),1.41(s ,3H),1.37(s,3H),1.30(s,3H),1.29(s,3H),1.05(s,3H),0.91(s,3H).
用实施例4中类似的方法，C18与不同的羧酸缩合可得到以下化合物：

Using a similar method in Example 4, the following compounds can be obtained by condensing C18 with different carboxylic acids:

实施例5
Example 5
将C32(29.5mg,0.041mmol)，N-(3-叠氮丙基)生物素胺(13.26mg,0.041mmol)，五 水硫酸铜(5.07mg,0.020mmol)，抗坏血酸钠(8.05mg,0.041mmol)溶于4mL甲醇：水＝3：1的混合溶液中，室温下避光搅拌过夜，TLC显示反应完全。用乙酸乙酯(3×50mL)萃取，将合并的有机层分别用去离子水和饱和食盐水洗涤，经硫酸钠干燥浓缩，柱层析分离得产物C34 27.7mg(0.026mmol)，收率：64.16％。Combine C32 (29.5mg, 0.041mmol), N-(3-azidopropyl)biotinamine (13.26mg, 0.041mmol), five Water copper sulfate (5.07 mg, 0.020 mmol) and sodium ascorbate (8.05 mg, 0.041 mmol) were dissolved in 4 mL of a mixed solution of methanol: water = 3:1, and stirred overnight in the dark at room temperature. TLC showed that the reaction was complete. Extract with ethyl acetate (3×50 mL), wash the combined organic layers with deionized water and saturated brine respectively, dry and concentrate over sodium sulfate, and separate by column chromatography to obtain product C34 27.7 mg (0.026 mmol), yield: 64.16%.
1H NMR(400MHz,Methanol-d4)δ7.82(s,1H),7.36(t,J＝8.0Hz,1H),7.27(dt,J＝8.0,1.2Hz,1H),7.09(t,J＝2.0Hz,1H),7.04(d,J＝15.6Hz,1H),6.97(ddd,J＝8.0,2.4,0.8Hz,1H),6.71(d,J＝15.6Hz,1H),5.81(dt,J＝6.0,2.4Hz,1H),4.56(dd,J＝13.0,6.0Hz,1H),4.51–4.46(m,2H),4.39(t,J＝7.2Hz,2H),4.29(dd,J＝7.8,4.8Hz,1H),3.43(d,J＝14.8Hz,1H),3.21–3.17(m,3H),2.98(d,J＝12.8Hz,1H),2.91(dd,J＝12.6,5.2Hz,1H),2.71(d,J＝2.4Hz,1H),2.67(d,J＝6.4Hz,1H),2.62–2.57(m,5H),2.40(dd,J＝19.4,8.0Hz,1H),2.20(t,J＝7.6Hz,2H),2.08(d,J＝6.8Hz,2H),2.05–2.02(m,2H),2.00–1.96(m,2H),1.84(dd,J＝13.4,8.8Hz,1H),1.76–1.55(m,5H),1.49(s,3H),1.48(s,3H),1.40(s,3H),1.37(s,3H),1.30(s,3H),1.28(s,3H),1.04(s,3H),0.91(s,3H). 1 H NMR (400MHz, Methanol-d 4 ) δ7.82 (s, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.27 (dt, J = 8.0, 1.2 Hz, 1H), 7.09 (t, J＝2.0Hz,1H),7.04(d,J＝15.6Hz,1H),6.97(ddd,J＝8.0,2.4,0.8Hz,1H),6.71(d,J＝15.6Hz,1H),5.81( dt,J＝6.0,2.4Hz,1H),4.56(dd,J＝13.0,6.0Hz,1H),4.51–4.46(m,2H),4.39(t,J＝7.2Hz,2H),4.29(dd ,J＝7.8,4.8Hz,1H),3.43(d,J＝14.8Hz,1H),3.21–3.17(m,3H),2.98(d,J＝12.8Hz,1H),2.91(dd,J＝ 12.6,5.2Hz,1H),2.71(d,J＝2.4Hz,1H),2.67(d,J＝6.4Hz,1H),2.62–2.57(m,5H),2.40(dd,J＝19.4,8.0 Hz,1H),2.20(t,J＝7.6Hz,2H),2.08(d,J＝6.8Hz,2H),2.05–2.02(m,2H),2.00–1.96(m,2H),1.84(dd ,J＝13.4,8.8Hz,1H),1.76–1.55(m,5H),1.49(s,3H),1.48(s,3H),1.40(s,3H),1.37(s,3H),1.30( s,3H),1.28(s,3H),1.04(s,3H),0.91(s,3H).
实施例6
Example 6
将C19(34.8mg,0.059mmol)，HOBt(11.93mg,0.088mmol)，EDCI(16.93mg,0.088mmol)，2-(3-丁炔基氮二丙啶-3-基)乙酸(7.17mg,0.047mmol)，DIPEA(15.22mg,0.12mmol)，溶于干燥DCM(4mL)中，室温下避光搅拌3h，TLC显示反应完全。用乙酸乙酯(3×50mL)萃取，将合并的有机层分别用饱和氯化铵溶液，去离子水和饱和食盐水洗涤，经硫酸钠干燥浓缩，柱层析分离得产物C35 13.6mg(0.019mmol)，收率：31.79％。C19 (34.8mg, 0.059mmol), HOBt (11.93mg, 0.088mmol), EDCI (16.93mg, 0.088mmol), 2-(3-butynylazidipropidin-3-yl)acetic acid (7.17mg, 0.047mmol), DIPEA (15.22mg, 0.12mmol), dissolved in dry DCM (4mL), stirred in the dark at room temperature for 3h, TLC showed that the reaction was complete. Extract with ethyl acetate (3 × 50 mL), wash the combined organic layers with saturated ammonium chloride solution, deionized water and saturated brine respectively, dry and concentrate over sodium sulfate, and separate by column chromatography to obtain product C35 13.6 mg (0.019 mmol), yield: 31.79%.
1H NMR(400MHz,Chloroform-d)δ7.64(s,1H),7.46(dd,J＝8.0,2.0Hz,1H),7.33(t,J＝2.0Hz,1H),7.29(t,J＝8.0Hz,1H),7.19(d,J＝15.2Hz,1H),7.11(dd,J＝6.6,2.0Hz,1H),6.48(d,J＝16.0Hz,1H),5.81(dt,J＝6.0,2.0Hz,1H),4.44–4.38(m,3H),3.61(d,J＝4.0Hz,1H),3.25(d,J＝14.4Hz,1H),2.75–2.68(m,2H),2.57(d,J＝6.8Hz,1H),2.47–2.39(m,2H),2.32–2.26(m,3H),2.13–2.08(m,2H),2.02–1.97(m,2H),1.96–1.90(m,1H),1.88–1.80(m,2H),1.65(s,5H),1.50(s,3H),1.46(s,3H),1.46(s,3H),1.35(s,3H),1.34(s,3H),1.28(s,3H),1.08(s,3H),0.99(s,3H). 1 H NMR (400MHz, Chloroform-d) δ7.64 (s, 1H), 7.46 (dd, J = 8.0, 2.0Hz, 1H), 7.33 (t, J = 2.0Hz, 1H), 7.29 (t, J ＝8.0Hz,1H),7.19(d,J＝15.2Hz,1H),7.11(dd,J＝6.6,2.0Hz,1H),6.48(d,J＝16.0Hz,1H),5.81(dt,J ＝6.0,2.0Hz,1H),4.44–4.38(m,3H),3.61(d,J＝4.0Hz,1H),3.25(d,J＝14.4Hz,1H),2.75–2.68(m,2H) ,2.57(d,J＝6.8Hz,1H),2.47–2.39(m,2H),2.32–2.26(m,3H),2.13–2.08(m,2H),2.02–1.97(m,2H),1.96 –1.90(m,1H),1.88–1.80(m,2H),1.65(s,5H),1.50(s,3H),1.46(s,3H),1.46(s,3H),1.35(s,3H ),1.34(s,3H),1.28(s,3H),1.08(s,3H),0.99(s,3H).
用实施例6中类似的方法，C19与不同的羧酸缩合可得到以下化合物：

Using a similar method in Example 6, the following compounds can be obtained by condensing C19 with different carboxylic acids:

实施例7
Example 7
将C29(50mg,0.074mmol)溶于DCM(4mL)中，加入三氟乙酸(0.5mL)室温下搅拌2h，TLC显示反应完全。旋去溶剂，柱层析分离得产物C37 24.7mg(0.040mmol)，收率：54.71％。C29 (50 mg, 0.074 mmol) was dissolved in DCM (4 mL), trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 2 h. TLC showed that the reaction was complete. The solvent was removed and the product C37 was separated by column chromatography 24.7 mg (0.040 mmol), yield: 54.71%.
1H NMR(400MHz,Methanol-d4)δ8.01(t,J＝2.0Hz,1H),7.88(dt,J＝8.0,1.2Hz,1H),7.59(ddd,J＝7.8,2.0,1.2Hz,1H),7.42(t,J＝8.0Hz,1H),7.06(d,J＝15.6Hz,1H),6.77(d,J＝15.6Hz,1H),5.81(dt,J＝5.6,2.0Hz,1H),4.57(dd,J＝13.0,5.6Hz,1H),4.52(t,J＝8.0Hz,1H),3.41(d,J＝14.8Hz,1H),2.98(d,J＝13.2Hz,1H),2.63–2.62(m,1H),2.59(d,J＝5.2Hz,1H),2.44–2.38(m,1H),2.10(ddd,J＝12.4,5.6,3.6Hz,1H),2.05(d,J＝5.6Hz,1H),1.98(d,J＝8.4Hz,1H),1.86(dd,J＝13.6,8.4Hz,1H),1.52(s,6H),1.42(s,3H),1.38(s,3H),1.30(s,3H),1.28(s,3H),1.04(s,3H),0.91(s,3H). 1 H NMR (400MHz, Methanol-d 4 ) δ8.01 (t, J = 2.0 Hz, 1H), 7.88 (dt, J = 8.0, 1.2 Hz, 1H), 7.59 (ddd, J = 7.8, 2.0, 1.2 Hz,1H),7.42(t,J＝8.0Hz,1H),7.06(d,J＝15.6Hz,1H),6.77(d,J＝15.6Hz,1H),5.81(dt,J＝5.6,2.0 Hz,1H),4.57(dd,J＝13.0,5.6Hz,1H),4.52(t,J＝8.0Hz,1H),3.41(d,J＝14.8Hz,1H),2.98(d,J＝13.2 Hz,1H),2.63–2.62(m,1H),2.59(d,J＝5.2Hz,1H),2.44–2.38(m,1H),2.10(ddd,J＝12.4,5.6,3.6Hz,1H) ,2.05(d,J＝5.6Hz,1H),1.98(d,J＝8.4Hz,1H),1.86(dd,J＝13.6,8.4Hz,1H),1.52(s,6H),1.42(s, 3H),1.38(s,3H),1.30(s,3H),1.28(s,3H),1.04(s,3H),0.91(s,3H).
实施例8
Example 8
将葫芦素B(50mg,0.090mmol)，(4-[(三甲基甲硅烷基)炔]苯基)硼酸(39.09mg,0.18mmol)，氟化钾(10.41mg，0.18mmol)，三(二亚苄基丙酮)二钯(4.10mg，0.045mmol)，溶于干燥DCM(4mL)中，室温下搅拌过夜，次日TLC显示反应完全。旋出DCM，柱层析分离得中间体17.8mg(0.026mmol)。将中间体(17.8mg,0.026mmol)溶于THF(3mL)中，加入TBAF的THF溶液(1mol/L，79.46μL，0.079mmol)和冰醋酸(4.54μL，0.079mmol)，搅拌2h，TLC显示反应完全。用乙酸乙酯(3×50mL)萃取，将合并的有机层分别用饱和氯化铵溶液，去离子水和饱和食盐水洗涤，经硫酸钠干燥浓缩，柱层析分离得产物C38 15.4mg(0.026mmol)，收率：28.52％。Cucurbitacin B (50mg, 0.090mmol), (4-[(trimethylsilyl)alkyne]phenyl)boronic acid (39.09mg, 0.18mmol), potassium fluoride (10.41mg, 0.18mmol), tris( Dibenzylideneacetone) dipalladium (4.10 mg, 0.045 mmol) was dissolved in dry DCM (4 mL) and stirred at room temperature overnight. TLC showed that the reaction was complete the next day. The DCM was rotated out, and 17.8 mg (0.026 mmol) of the intermediate was obtained by column chromatography. Dissolve the intermediate (17.8mg, 0.026mmol) in THF (3mL), add TBAF THF solution (1mol/L, 79.46μL, 0.079mmol) and glacial acetic acid (4.54μL, 0.079mmol), stir for 2h, TLC shows Complete reaction. Extract with ethyl acetate (3 × 50 mL), wash the combined organic layers with saturated ammonium chloride solution, deionized water and saturated brine respectively, dry and concentrate over sodium sulfate, and separate by column chromatography to obtain product C38 15.4 mg (0.026 mmol), yield: 28.52%.
1H NMR(400MHz,Chloroform-d)δ7.42(d,J＝8.4Hz,2H),7.25–7.23(m,2H),7.19(d,J＝15.6Hz,1H),6.34(d,J＝15.6Hz,1H),5.80–5.78(m,1H),4.44–4.38(m,3H),3.60(d,J＝3.6Hz,1H),3.22(d,J＝14.8Hz,1H),3.04(s,1H),2.73(d,J＝12.8Hz,1H),2.68(d,J＝14.4Hz,1H),2.49(d,J＝6.8Hz,1H),2.41(dd,J＝19.2,7.6Hz,1H),2.33–2.27(m,1H),2.01–1.94(m,2H),1.85(dd,J＝12.8,9.6Hz,1H),1.61(s,4H),1.48(s,3H),1.47(s,3H),1.41(s,3H),1.35(s,6H),1.29(s,3H),1.07(s,3H),0.98(s,3H).. 1 H NMR (400MHz, Chloroform-d) δ7.42 (d, J = 8.4Hz, 2H), 7.25–7.23 (m, 2H), 7.19 (d, J = 15.6Hz, 1H), 6.34 (d, J ＝15.6Hz,1H),5.80–5.78(m,1H),4.44–4.38(m,3H),3.60(d,J＝3.6Hz,1H),3.22(d,J＝14.8Hz,1H),3.04 (s,1H),2.73(d,J＝12.8Hz,1H),2.68(d,J＝14.4Hz,1H),2.49(d,J＝6.8Hz,1H),2.41(dd,J＝19.2, 7.6Hz,1H),2.33–2.27(m,1H),2.01–1.94(m,2H),1.85(dd,J＝12.8,9.6Hz,1H),1.61(s,4H),1.48(s,3H ),1.47(s,3H),1.41(s,3H),1.35(s,6H),1.29(s,3H),1.07(s,3H),0.98(s,3H)..
实施例9
Example 9
将C19(15.7mg,0.027mmol)溶于干燥乙腈(2mL)中，0℃下加入亚硝酸叔丁酯(8.22mg,0.80mmol)，叠氮基三甲基硅烷(9.18mg，0.80mmol)，搅拌1h。TLC显示反应完全。旋出溶剂，柱层析分离得产物C39 10.3mg(0.017mmol)，收率：61.82％。Dissolve C19 (15.7mg, 0.027mmol) in dry acetonitrile (2mL), add tert-butyl nitrite (8.22mg, 0.80mmol) and azidotrimethylsilane (9.18mg, 0.80mmol) at 0°C. Stir for 1h. TLC showed the reaction was complete. The solvent was spun off, and product C39 was separated by column chromatography to obtain 10.3 mg (0.017 mmol), yield: 61.82%.
1H NMR(400MHz,Chloroform-d)δ7.30(t,J＝8.0Hz,1H),7.18(d,J＝15.6Hz,1H),7.06(d,J＝8.0Hz,1H),6.91–6.88(m,2H),6.40(d,J＝15.6Hz,1H),5.79(t,J＝3.2Hz,1H),4.43–4.37(m,3H),3.60(d,J＝4.0Hz,1H),3.24(d,J＝14.8Hz,1H),2.75–2.68(m,2H),2.52(d,J＝6.8Hz,1H),2.41(dd,J＝19.6,7.6Hz,1H),2.33–2.28(m,1H),2.01–1.95(m,2H), 1.86(dd,J＝13.2,8.8Hz,1H),1.61(s,4H),1.48(s,3H),1.47(s,3H),1.43(s,3H),1.36(s,3H),1.34(s,3H),1.28(s,3H),1.08(s,3H),0.99(s,3H). 1 H NMR (400MHz, Chloroform-d) δ7.30(t,J＝8.0Hz,1H),7.18(d,J＝15.6Hz,1H),7.06(d,J＝8.0Hz,1H),6.91– 6.88(m,2H),6.40(d,J＝15.6Hz,1H),5.79(t,J＝3.2Hz,1H),4.43–4.37(m,3H),3.60(d,J＝4.0Hz,1H ),3.24(d,J＝14.8Hz,1H),2.75–2.68(m,2H),2.52(d,J＝6.8Hz,1H),2.41(dd,J＝19.6,7.6Hz,1H),2.33 –2.28(m,1H),2.01–1.95(m,2H), 1.86(dd,J＝13.2,8.8Hz,1H),1.61(s,4H),1.48(s,3H),1.47(s,3H),1.43(s,3H),1.36(s,3H),1.34 (s,3H),1.28(s,3H),1.08(s,3H),0.99(s,3H).
实施例10化合物对A549(人非小细胞肺癌)和PLC/PRF/5(人肝癌)细胞系抗增殖测试(MTS实验)Example 10 Anti-proliferation test (MTS test) of compounds on A549 (human non-small cell lung cancer) and PLC/PRF/5 (human liver cancer) cell lines
实验原理：用CellTiterAQueous One Solution Cell Proliferation Assay(MTS)比色法检测细胞增殖。该分析方法以四唑化合物(3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺基苯基)-2H-四唑,内盐；MTS]为基础。黄色的MTS到蓝紫色水溶性甲臜的转化由脱氢酶催化，而脱氢酶存在于有代谢活性的活细胞中；死细胞不能完成MTS到甲臜的转化。由490nm处吸光度确定的甲臜(Formazan)的量与培养中活细胞的数量直接成正比。Experimental principle: using CellTiter AQueous One Solution Cell Proliferation Assay (MTS) colorimetric method detects cell proliferation. This analytical method uses the tetrazole compound (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H -tetrazole, internal salt; MTS] as the basis. The conversion of yellow MTS to blue-violet water-soluble formazan is catalyzed by dehydrogenase, and dehydrogenase exists in metabolically active living cells; dead cells cannot complete the conversion of MTS to blue-violet water-soluble formazan. Conversion of formazan. The amount of formazan, determined by absorbance at 490 nm, is directly proportional to the number of viable cells in culture.
实验方法：样品处理：样品用DMSO溶解，低温保存。DMSO在最终体系中的浓度控制在不影响检测活性的范围内。Experimental method: Sample treatment: Dissolve the sample with DMSO and store it at low temperature. The concentration of DMSO in the final system is controlled within a range that does not affect the detection activity.
用MTS法检测细胞存活率，即将生长在对数生长期的细胞，贴壁细胞经0.025％的胰酶消化，计数；A549细胞以3000/well，PLC/PRF/5细胞以5000/well(均以10％FBS条件培养铺板)的密度接种到96孔板中80ul,置于5％CO2 37℃培养箱过夜生长。测试化合物每个以三倍浓度梯度进行稀释，测试八个浓度，每个浓度设置三复孔；稀释后的化合物分别取20ul加到对应的细胞孔中，贴壁细胞在5％CO2 37℃培养箱中培养72小时；分别加入20ul的MTS，在5％CO2 37℃培养箱中孵育2小时。使用Molecular Device VersaMax测试490nm(L1)的光吸收值，参考波长690nm(L2)，将(L1-L2)值对抑制剂不同浓度作图，经公式拟合得到IC50。MTS method was used to detect cell survival rate. For cells growing in the logarithmic growth phase, adherent cells were digested with 0.025% trypsin and counted; A549 cells were counted at 3000/well, and PLC/PRF/5 cells were counted at 5000/well (all Inoculate 80ul into a 96-well plate at a density of 10% FBS (culture plating) and place it in a 37°C incubator with 5% CO 2 for overnight growth. Each test compound was diluted in a three-fold concentration gradient, and eight concentrations were tested. Three replicate wells were set up for each concentration; 20ul of the diluted compounds were added to the corresponding cell wells, and the adherent cells were incubated in 5% CO 2 at 37°C. Cultivate in the incubator for 72 hours; add 20ul of MTS respectively, and incubate for 2 hours in a 5% CO 2 37°C incubator. Use Molecular Device VersaMax to test the light absorption value at 490nm (L1), refer to the wavelength 690nm (L2), plot the (L1-L2) value against different concentrations of the inhibitor, and obtain the IC 50 by fitting the formula.
实验结果(以表中化合物为例，但不局限于这些化合物)Experimental results (taking the compounds in the table as examples, but not limited to these compounds)
化合物的抗肿瘤细胞增殖结果如表1(A549细胞)和2(PLC/PRF/5细胞)所示，被测化合物在A549和PLC/PRF/5细胞上均有较好的抗增殖活性(IC50<100nM)。The anti-tumor cell proliferation results of the compounds are shown in Tables 1 (A549 cells) and 2 (PLC/PRF/5 cells). The tested compounds have good anti-proliferation activity (IC 50 <100nM).
表1化合物对A549细胞系的抗增殖结果


注：IC50为半数抑制即50％抑制浓度。
“*”：1-10μM；“**”：0.1-1μM；“***”：100-1nMTable 1 Anti-proliferation results of compounds on A549 cell line


Note: IC 50 is half inhibition or 50% inhibition concentration.
“*”: 1-10μM; “**”: 0.1-1μM; “***”: 100-1nM
表2化合物对PLC/PRF/5细胞系的抗增殖结果

注：IC50为半数抑制即50％抑制浓度。
“*”：1-10μM；“**”：0.1-1μM；“***”：100-1nMTable 2 Anti-proliferation results of compounds on PLC/PRF/5 cell lines

Note: IC 50 is half inhibition or 50% inhibition concentration.
“*”: 1-10μM; “**”: 0.1-1μM; “***”: 100-1nM
实施例11 NF-κB信号通路抑制活性测试Example 11 NF-κB signaling pathway inhibitory activity test
实验原理：利用TNFα刺激NF-κB转录活性，PS-341(Bortezomib,硼替佐米)作为阳性对照，评价待测化合物对NF-κB信号通路的作用。阳性化合物或待测化合物与TNFα共处理细胞，6h后加入含细胞裂解液的荧光素酶底物，充分裂解。检测luminescence信号强度，评价化合物对NF-κB转录活性的影响。Experimental principle: TNFα is used to stimulate NF-κB transcriptional activity, and PS-341 (Bortezomib, bortezomib) is used as a positive control to evaluate the effect of the test compound on the NF-κB signaling pathway. Positive compounds or compounds to be tested were co-treated with TNFα. After 6 hours, luciferase substrate containing cell lysis solution was added to fully lyse the cells. Detect the luminescence signal intensity and evaluate the effect of the compound on NF-κB transcriptional activity.
实验过程experiment procedure
样品处理：样品用DMSO溶解，低温保存，DMSO在最终体系中的浓度控制在不影响 检测活性的范围之内。Sample processing: Dissolve the sample with DMSO and store it at low temperature. The concentration of DMSO in the final system is controlled so as not to affect within the range of detectable activity.
接板：生长状态良好的293T细胞以2万/孔/50μL的密度接入CulturPlateTM-96孔细胞板。Plate connection: 293T cells in good growth status are connected to the CulturPlateTM-96-well cell plate at a density of 20,000/well/50μL.
TNFα刺激：细胞贴璧生长24h后，加入含20ng/ml TNFα的完全培养基(含10％FBS)50μl，即TNFα终浓度为10ng/ml。TNFα stimulation: After the cells grow on the wall for 24 hours, add 50 μl of complete culture medium (containing 10% FBS) containing 20ng/ml TNFα, that is, the final concentration of TNFα is 10ng/ml.
化合物处理：从化合物母板和对照化合物母板取1μL化合物加入96孔筛选板。Compound treatment: Take 1 μL of compound from the compound master plate and the control compound master plate and add it to the 96-well screening plate.
检测：4h后加入CellTiter-Blue避光孵育。共6h后，EnVisionTM检测；结束后立即从96孔筛选板中取走90μL液体，再加入20μL的Luciferace底物，2101 Multilabel Reader读数检测Luciferase信号强度。Detection: Add CellTiter-Blue after 4 hours and incubate in the dark. After a total of 6 hours, EnVisionTM detection was carried out; immediately after the end, 90 μL of liquid was removed from the 96-well screening plate, and 20 μL of Luciferace substrate was added, and the Luciferase signal intensity was measured using 2101 Multilabel Reader.
实验结果(以表中化合物为例，但不局限于这些化合物)Experimental results (taking the compounds in the table as examples, but not limited to these compounds)
被测化合物均对NF-κB信号通路具有抑制活性，其中多数化合物具有较好的NF-κB抑制活性(IC50<1μM)。The tested compounds all have inhibitory activity on the NF-κB signaling pathway, and most of the compounds have good NF-κB inhibitory activity (IC 50 <1μM).
表3 NF-κB信号通路抑制活性结果

注：IC50为半数抑制即50％抑制浓度。
“*”：10-100μM；“**”：1-10μM；“***”：0.1-1μMTable 3 NF-κB signaling pathway inhibitory activity results

Note: IC 50 is half inhibition or 50% inhibition concentration.
"*": 10-100μM; "**": 1-10μM; "***": 0.1-1μM
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。 All documents mentioned in this application are incorporated by reference in this application to the same extent as if each individual document was individually incorporated by reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims (11)

  1. 一种通式(I)所示的化合物，或其对映异构体、非对映异构体、外消旋体、互变异构体、光学异构体、立体异构体或其药学上可接受的盐：
    A compound represented by general formula (I), or its enantiomers, diastereomers, racemates, tautomers, optical isomers, stereoisomers or its pharmaceutical Acceptable salt:
    其中，各独立地为单键或双键；Among them, each Independently a single bond or a double bond;
    R1选自下组：未取代的或取代的C1-C8烷基、未取代的或取代的C2-C8烯基、未取代的或取代的C2-C8炔基、未取代的或取代的C6-C10芳基、未取代的或取代的C3-C8环烃基、未取代的或取代的3-8元杂环烃基、未取代的或取代的5-8元杂芳基；所述取代是被选自下组的一个或多个取代基取代：C1-C8烷基、C1-C8烷氧基、卤素、羟基、C2-C8烯基、C2-C8炔基、C1-C8卤代烷基、C1-C8卤代烷氧基、氰基、叠氮基、生物素酯、生物素酰胺、-COORd、-CONHRd、-OCORd、-OCOORd、-NRcRd、-NHCORd、-NHCOORd、-NHCONHRd， R1 is selected from the following group: unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted C6 -C10 aryl, unsubstituted or substituted C3-C8 cyclic hydrocarbyl, unsubstituted or substituted 3-8 membered heterocyclic hydrocarbyl, unsubstituted or substituted 5-8 membered heteroaryl; the substitution is by Substituted with one or more substituents selected from the following group: C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1- C8 haloalkoxy, cyano, azido, biotin ester, biotin amide, -COOR d , -CONHR d , -OCOR d , -OCOOR d , -NR c R d , -NHCOR d , -NHCOOR d , -NHCONHRd ,
    其中Rc、Rd各自独立地选自：氢、未取代的或取代的C1-C8的烷基、未取代的或取代的-(C1-C6亚烷基)C3-C8杂环烃基、未取代的或取代的C6-C10芳基、未取代的或取代的C3-C8环烃基、未取代的或取代的3-8元杂环烃基、未取代的或取代的5-8元杂芳基、C1-C8亚烷基生物素酰胺、(C1-C8亚烷基)5-8元杂芳基(C1-C8亚烷基)生物素酰胺；所述取代是被选自下组的一个或多个取代基取代：C1-C8烷基、C2-C8炔基、C1-C8卤代烷基、C1-C8卤代烷氧基、5-8元杂芳基(C1-C8亚烷基)生物素酰胺。Wherein R c and R d are each independently selected from: hydrogen, unsubstituted or substituted C1-C8 alkyl group, unsubstituted or substituted -(C1-C6 alkylene)C3-C8 heterocyclic hydrocarbon group, unsubstituted Substituted or substituted C6-C10 aryl group, unsubstituted or substituted C3-C8 cyclic hydrocarbon group, unsubstituted or substituted 3-8 membered heterocyclic hydrocarbon group, unsubstituted or substituted 5-8 membered heteroaryl group , C1-C8 alkylene biotinamide, (C1-C8 alkylene) 5-8 membered heteroaryl (C1-C8 alkylene) biotinamide; the substitution is one selected from the group below or Multiple substituents: C1-C8 alkyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, 5-8 membered heteroaryl (C1-C8 alkylene) biotinamide.
  2. 一种通式(I)所示的化合物，或其对映异构体、非对映异构体、外消旋体、互变异构体、光学异构体、立体异构体或其药学上可接受的盐：
    A compound represented by general formula (I), or its enantiomers, diastereomers, racemates, tautomers, optical isomers, stereoisomers or its pharmaceutical Acceptable salt:
    其中，各独立地为单键或双键；Among them, each Independently a single bond or a double bond;
    R1选自下组：未取代的或取代的C1-C8烷基、未取代的或取代的C2-C8烯基、未取代的或取代的C2-C8炔基、未取代的或取代的C6-C10芳基、未取代的或取代的C3-C8环烃基、未取代的或取代的3-8元杂环烃基、未取代的或取代的5-8元杂芳基；所述取代是被选 自下组的一个或多个取代基取代：C1-C8烷基、C1-C8烷氧基、卤素、羟基、C2-C8烯基、C2-C8炔基、C1-C8卤代烷基、C1-C8卤代烷氧基、氰基、-COORd、-CONHRd、-OCORd、-OCOORd、-NRcRd、-NHCORd、-NHCOORd、-NHCONHRd， R1 is selected from the following group: unsubstituted or substituted C1-C8 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted C6 -C10 aryl, unsubstituted or substituted C3-C8 cyclic hydrocarbyl, unsubstituted or substituted 3-8 membered heterocyclic hydrocarbyl, unsubstituted or substituted 5-8 membered heteroaryl; the substitution is by select Substituted with one or more substituents from the following group: C1-C8 alkyl, C1-C8 alkoxy, halogen, hydroxyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 Haloalkoxy, cyano, -COOR d , -CONHR d , -OCOR d , -OCOOR d , -NR c R d , -NHCOR d , -NHCOOR d , -NHCONHR d ,
    其中Rc、Rd各自独立地选自：氢、未取代的或取代的C1-C8的烷基、未取代的或取代的-(C1-C6亚烷基)C3-C8杂环烃基、未取代的或取代的C6-C10芳基、未取代的或取代的C3-C8环烃基、未取代的或取代的3-8元杂环烃基、未取代的或取代的5-8元杂芳基；所述取代是被选自下组的一个或多个取代基取代：C1-C8烷基、C2-C8炔基、C1-C8卤代烷基、C1-C8卤代烷氧基、5-8元杂芳基(C1-C8亚烷基)生物素酰胺。Wherein R c and R d are each independently selected from: hydrogen, unsubstituted or substituted C1-C8 alkyl group, unsubstituted or substituted -(C1-C6 alkylene)C3-C8 heterocyclic hydrocarbon group, unsubstituted Substituted or substituted C6-C10 aryl group, unsubstituted or substituted C3-C8 cyclic hydrocarbon group, unsubstituted or substituted 3-8 membered heterocyclic hydrocarbon group, unsubstituted or substituted 5-8 membered heteroaryl group ; The substitution is one or more substituents selected from the following group: C1-C8 alkyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, 5-8 yuan heteroaryl (C1-C8 alkylene) biotinamide.
  3. 如权利要求1或2所述的化合物，其特征在于，所述化合物具有以下结构：
    The compound of claim 1 or 2, wherein the compound has the following structure:
  4. 如权利要求1或2所述的化合物，其特征在于，所述化合物具有以下结构：
    The compound of claim 1 or 2, wherein the compound has the following structure:
  5. 如权利要求1或2所述的化合物，其特征在于，R1选自下组：未取代的或取代的C1-C6烷基、未取代的或取代的C2-C6烯基、未取代的或取代的C2-C6炔基、未取代的或取代的C6芳基、未取代的或取代的C4-C7环烃基、未取代的或取代的4-7元杂环烃基、未取代的或取代的4-7元杂芳基；所述取代是被选自下组的一个或多个取代基取代：C1-C6烷基、C1-C6烷氧基、卤素、羟基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6卤代烷氧基、氰基、叠氮基、生物素酯、生物素酰胺、-COORd、-CONHRd、-OCORd、-OCOORd、-NRcRd、-NHCORd、-NHCOORd、-NHCONHRd，The compound of claim 1 or 2, wherein R 1 is selected from the group consisting of unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or Substituted C2-C6 alkynyl, unsubstituted or substituted C6 aryl, unsubstituted or substituted C4-C7 cycloalkyl, unsubstituted or substituted 4-7 membered heterocyclic hydrocarbyl, unsubstituted or substituted 4-7 membered heteroaryl; the substitution is one or more substituents selected from the following group: C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxyl, C2-C6 alkenyl, C2 -C6 alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, cyano, azido, biotin ester, biotin amide, -COOR d , -CONHR d , -OCOR d , -OCOOR d , - NR c R d , -NHCOR d , -NHCOOR d , -NHCONHR d ,
    其中Rc、Rd各自独立地选自：氢、未取代的或取代的C1-C6的烷基、未取代的或取代的-(C1-C6亚烷基)C4-C7杂环烃基、未取代的或取代的C6芳基、未取代的或取代的C3-C8环烃基、未取代的或取代的3-8元杂环烃基、未取代的或取代的5-8元杂芳基、(C1-C6亚烷基)5-8元杂芳基(C1-C6亚烷基)生物素酰胺、C1-C6亚烷基生物素酰胺；所述取代是被选自下组的一个或多个取代基取代：C1-C6烷基、C2-C6炔基、C1-C6卤代烷基、C1-C6卤代 烷氧基、5-8元杂芳基(C1-C4亚烷基)生物素酰胺。Wherein R c and R d are each independently selected from: hydrogen, unsubstituted or substituted C1-C6 alkyl group, unsubstituted or substituted -(C1-C6 alkylene)C4-C7 heterocyclic hydrocarbon group, unsubstituted Substituted or substituted C6 aryl, unsubstituted or substituted C3-C8 cyclic hydrocarbyl, unsubstituted or substituted 3-8 membered heterocyclic hydrocarbyl, unsubstituted or substituted 5-8 membered heteroaryl, ( C1-C6 alkylene) 5-8 membered heteroaryl (C1-C6 alkylene) biotinamide, C1-C6 alkylene biotinamide; the substitution is one or more selected from the group Substituent substitution: C1-C6 alkyl, C2-C6 alkynyl, C1-C6 haloalkyl, C1-C6 halo Alkoxy, 5-8 membered heteroaryl (C1-C4 alkylene) biotinamide.
  6. 如权利要求1或2所述的化合物，其特征在于，R1选自下组：未取代的或取代的C1-C4烷基、未取代的或取代的C2-C4烯基、未取代的或取代的C2-C4炔基、未取代的或取代的C6芳基、未取代的或取代的C4-C6环烃基、未取代的或取代的4-67元杂环烃基、未取代的或取代的4-6元杂芳基；所述取代是被选自下组的一个或多个取代基取代：C1-C4烷基、C1-C4烷氧基、卤素、羟基、C2-C4烯基、C2-C4炔基、C1-C4卤代烷基、C1-C4卤代烷氧基、氰基、叠氮基、生物素酯、生物素酰胺、-COORd、-CONHRd、-OCORd、-OCOORd、-NRcRd、-NHCORd、-NHCOORd、-NHCONHRd，The compound of claim 1 or 2, wherein R 1 is selected from the group consisting of unsubstituted or substituted C1-C4 alkyl, unsubstituted or substituted C2-C4 alkenyl, unsubstituted or Substituted C2-C4 alkynyl, unsubstituted or substituted C6 aryl, unsubstituted or substituted C4-C6 cycloalkyl, unsubstituted or substituted 4-67 membered heterocyclic hydrocarbyl, unsubstituted or substituted 4-6 membered heteroaryl; the substitution is one or more substituents selected from the following group: C1-C4 alkyl, C1-C4 alkoxy, halogen, hydroxyl, C2-C4 alkenyl, C2 -C4 alkynyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, cyano, azido, biotin ester, biotin amide, -COOR d , -CONHR d , -OCOR d , -OCOOR d , - NR c R d , -NHCOR d , -NHCOOR d , -NHCONHR d ,
    其中Rc、Rd各自独立地选自：氢、未取代的或取代的C1-C4的烷基、未取代的或取代的-(C1-C4亚烷基)C4-C6杂环烃基、未取代的或取代的C6芳基、未取代的或取代的C3-C6环烃基、未取代的或取代的3-6元杂环烃基、未取代的或取代的5-6元杂芳基、C2-C5亚烷基生物素酰胺、(C1-C4亚烷基)5-8元杂芳基(C1-C4亚烷基)生物素酰胺；所述取代是被选自下组的一个或多个取代基取代：C1-C4烷基、C2-C4炔基、C1-C4卤代烷基、C1-C4卤代烷氧基、5-6元杂芳基(C1-C4亚烷基)生物素酰胺。Wherein R c and R d are each independently selected from: hydrogen, unsubstituted or substituted C1-C4 alkyl group, unsubstituted or substituted -(C1-C4 alkylene)C4-C6 heterocyclic hydrocarbon group, unsubstituted Substituted or substituted C6 aryl group, unsubstituted or substituted C3-C6 cycloalkyl group, unsubstituted or substituted 3-6 membered heterocyclic hydrocarbyl group, unsubstituted or substituted 5-6 membered heteroaryl group, C2 -C5 alkylene biotinamide, (C1-C4 alkylene)5-8 membered heteroaryl (C1-C4 alkylene) biotinamide; the substitution is one or more selected from the group consisting of: Substituent substitution: C1-C4 alkyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 haloalkoxy, 5-6 membered heteroaryl (C1-C4 alkylene) biotinamide.
  7. 如权利要求1或2所述的化合物，其特征在于，所述化合物为：







    The compound according to claim 1 or 2, characterized in that, the compound is:







  8. 一种药物组合物，其特征在于，包含：A pharmaceutical composition, characterized in that it contains:
    如权利要求1-7任一项所述的通式(I)所示的化合物，或其对映异构体、非对映异构体、外消旋体、互变异构体、光学异构体、立体异构体或其药学上可接受的盐；和The compound represented by the general formula (I) according to any one of claims 1 to 7, or its enantiomers, diastereomers, racemates, tautomers, and optical isomers conformation, stereoisomer or pharmaceutically acceptable salt thereof; and
    药学上可接受的载体。Pharmaceutically acceptable carrier.
  9. 如权利要求1-7任一项所述的通式(I)所示的化合物，或其对映异构体、非对映异构体、外消旋体、互变异构体、光学异构体、立体异构体或其药学上可接受的盐或权利要求8所述的药物组合物用途，其特征在于，用于制备预防和/或治疗肿瘤或炎症的药物。The compound represented by the general formula (I) according to any one of claims 1 to 7, or its enantiomers, diastereomers, racemates, tautomers, and optical isomers The conformation, stereoisomer or pharmaceutically acceptable salt thereof or the use of the pharmaceutical composition according to claim 8, characterized in that it is used to prepare drugs for preventing and/or treating tumors or inflammation.
  10. 如权利要求9所述的用途，其特征在于，所述肿瘤选自下组：肺癌、肝癌、乳腺癌、卵巢癌、宫颈癌、结肠癌、黑色素瘤、前列腺癌、胃癌、血液瘤。The use according to claim 9, wherein the tumor is selected from the group consisting of lung cancer, liver cancer, breast cancer, ovarian cancer, cervical cancer, colon cancer, melanoma, prostate cancer, gastric cancer, and hematological tumors.
  11. 如权利要求9所述的用途，其特征在于，所述炎症是由细胞内NF-κB信号通路激活引起的炎症。 The use according to claim 9, characterized in that the inflammation is inflammation caused by activation of the intracellular NF-κB signaling pathway.
PCT/CN2023/079902 2022-03-09 2023-03-06 Cucurbitacin b derivative, preparation method therefor, and use thereof WO2023169372A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002078617A2 (en) * 2001-03-28 2002-10-10 University Of South Florida Materials and methods for treatment of cancer and identification of anti-cancer compounds
WO2009024103A2 (en) * 2007-08-22 2009-02-26 Ustav Organicke Chemie A Biochemie Akademie Ved Ceske Republiky, V.V.I. Natural brassinosteroids for use for treating hyperproliferation, treating proliferative diseases and reducing adverse effects of steroid dysfunction in mammals, pharmaceutical composition and its use
CN102659888A (en) * 2012-03-02 2012-09-12 张南 Cucurbitacin derivatives and preparation method thereof
CN103360452A (en) * 2012-04-04 2013-10-23 浙江大学 Preparation and application of pedicellus melo tetracyclic triterpenoid cucurbitacin type compound
US20190144492A1 (en) * 2016-04-29 2019-05-16 Fernando Thome Kreutz Nanoemulsions and methods for cancer therapy

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002078617A2 (en) * 2001-03-28 2002-10-10 University Of South Florida Materials and methods for treatment of cancer and identification of anti-cancer compounds
WO2009024103A2 (en) * 2007-08-22 2009-02-26 Ustav Organicke Chemie A Biochemie Akademie Ved Ceske Republiky, V.V.I. Natural brassinosteroids for use for treating hyperproliferation, treating proliferative diseases and reducing adverse effects of steroid dysfunction in mammals, pharmaceutical composition and its use
CN102659888A (en) * 2012-03-02 2012-09-12 张南 Cucurbitacin derivatives and preparation method thereof
CN103360452A (en) * 2012-04-04 2013-10-23 浙江大学 Preparation and application of pedicellus melo tetracyclic triterpenoid cucurbitacin type compound
US20190144492A1 (en) * 2016-04-29 2019-05-16 Fernando Thome Kreutz Nanoemulsions and methods for cancer therapy

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Doctoral Dissertation", 1 June 2022, UNIVERSITY OF CHINESE ACADEMY OF SCIENCES (SHANGHAI INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF SCIENCES), CN, article ZHUO, NING: "Design and Synthesis of Intestinal-restricted TGR5 Agonists Based on Pentacyclic Triterpene Skeleton and Diversified Transformation of Cucurbitacin B", pages: 1 - 181, XP009548963, DOI: 10.27880/d.cnki.gksyw.2022.000021 *

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