CN114573504A - Beta-elemene derivative containing N-OH bond and preparation method and application thereof - Google Patents

Beta-elemene derivative containing N-OH bond and preparation method and application thereof Download PDF

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CN114573504A
CN114573504A CN202210205994.5A CN202210205994A CN114573504A CN 114573504 A CN114573504 A CN 114573504A CN 202210205994 A CN202210205994 A CN 202210205994A CN 114573504 A CN114573504 A CN 114573504A
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elemene
beta
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CN114573504B (en
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谢恬
叶向阳
高园
白仁仁
罗欣雨
陈玉
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Hangzhou Normal University
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Abstract

The invention discloses a beta-elemene derivative containing N-OH bonds, a preparation method and application thereof. The invention provides a beta-elemene derivative containing N-OH bonds and having a novel structure shown in a formula (I), a pharmaceutical composition containing the compound shown in the formula (I), a hydrate, an isotope derivative, a chiral isomer, a variant, different salts, a prodrug, a preparation and the like of the compound. The invention also provides a preparation method and application of the beta-elemene derivatives containing N-OH bonds and having novel structures, and the activities of the compounds on proliferation inhibition of various tumor cell strains. The beta-elemene derivatives containing N-OH bonds and having novel structures are expected to become anti-tumor candidate medicines for treating lung cancer.
Figure DDA0003523349460000011

Description

Beta-elemene derivative containing N-OH bond and preparation method and application thereof
Technical Field
The invention belongs to the field of preparation and application of beta-elemene derivatives, and particularly relates to a beta-elemene derivative containing an N-OH bond, and a preparation method and application thereof.
Background
Elemene is a sesquiterpene compound extracted from Curcuma wenyujin Y.H.Chen et C.Ling of Zingiberaceae, and has broad-spectrum antitumor activity. At present, elemene oral emulsion/injection is approved by the country as a new class-two anti-cancer drug and is widely applied clinically. However, the structure of the terpene volatile oil only contains two elements of carbon and hydrogen, belongs to terpene volatile oil, has the defects of poor water solubility, difficult absorption by organisms, low bioavailability, limited activity of inhibiting the proliferation of tumor cells in vitro and the like, and limits the maximum clinical application of the terpene volatile oil. Therefore, it is necessary to modify the structure of (-) -beta-elemene, the main active ingredient in elemene, to improve water solubility, to improve bioactivity and bioavailability, and to enhance the clinical antitumor effect.
The literature reports that the derivatization of beta-Elemene (beta-Elemene, abbreviated as beta-Ele) is mainly to synthesize beta-Elemene chloride through allyl halogenation and then perform bimolecular nucleophilic substitution reaction (SN)2Reaction), and introducing polar groups such as hydroxyl, amino and the like on the premise that the beta-elemene skeleton and double bonds thereof are not damaged. Currently, β -elemene derivatives are broadly classified into amines, esters, amino acids, ethers, alcohols, glycosides, and organometallic complexes according to the difference of substituents. Although there are many studies on the modification of β -elemene structure, the studies have been conducted since β -elemene derivatives having N-OH bonds have not been reported. The development of this work: (1) hopefully, the anti-tumor mechanism of beta-elemene which confuses people for a long time is clear; (2) is expected to develop a new generation of new anticancer drugs with the antitumor effect superior to that of beta-elemene; (3) compared with the prior art that only simple structural modification is carried out on the beta-elemene, the research work is pioneering.
Disclosure of Invention
The first purpose of the present invention is to provide a beta-elemene derivative containing N-OH bond, which is suitable for overcoming the disadvantages of the prior art.
The beta-elemene derivative containing N-OH bonds, or optical isomers, racemates, single enantiomers, possible diastereoisomers, or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates and solvates thereof is characterized in that the structure of the derivative is shown as the formula (I):
Figure BDA0003523349440000011
in formula (I):
n is 0, 1, 2, 3;
-L-bond is
Figure BDA0003523349440000021
Figure BDA0003523349440000022
Is a 5-to 10-membered aryl, 5-to 10-membered heteroaryl;
R1selected from the following structural fragments: hydrogen, C1-6Alkyl radical, C3-6Cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, -OC1-6Alkyl, -CF3、-CN、-NH2；
When n is 2, 3, adjacent R1And 0-3 heteroatoms selected from O, S, N.
Further, the beta-elemene derivative containing the N-OH bond is any one of compounds 1-44 shown in the following structures:
Figure BDA0003523349440000031
Figure BDA0003523349440000041
the second object of the present invention is to provide a process for preparing beta-elemene derivatives containing N-OH bonds.
The synthesis route of the beta-elemene derivative with the structure of formula (I) and a novel structure and containing N-OH bond is as follows:
Figure BDA0003523349440000051
the method specifically comprises the following steps:
(1) firstly, the catalyst contains L,
Figure BDA0003523349440000052
And R1Acids A-1 and H of the structural fragment2Carrying out amide condensation reaction on NOTHP (A-2) to obtain an intermediate A-3;
(2) then, allylic bromination reaction is carried out on the beta-elemene A-4 to obtain an intermediate beta-elemene 13-bit bromination product A-5;
(3) then connecting the intermediate A-3 to a beta-elemene 13-bit bromo-product A-5 through a nucleophilic substitution reaction to obtain an intermediate A-6;
(4) finally, the intermediate A-6 is deprotected to obtain the final product of formula (I).
The compound represented by the formula (I) of the present invention can be produced by the above-mentioned method, however, the conditions of the method, such as reactants, solvent, amount of the compound used, reaction temperature, time required for the reaction, and the like are not limited to the above-mentioned explanation. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
Step (2) of the synthetic route of the present invention may be carried out by the methods known in the art, for example, as disclosed in publication No. CN 110683932A.
The third purpose of the invention is to provide the application of the beta-elemene derivatives containing N-OH bonds with novel structures, or optical isomers, racemates, single enantiomers, possible diastereoisomers, or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates and solvates thereof in preparing antitumor drugs.
The fourth purpose of the invention is to provide an anti-tumor drug, which contains safe and effective dose of the beta-elemene derivatives containing N-OH bonds and novel structures, or optical isomers, racemes, single enantiomers and possible diastereoisomers thereof, or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates and solvates thereof.
Preferably, the anti-tumor drug can also comprise a pharmaceutically acceptable carrier.
Preferably, in the use and the anti-tumor medicament, the tumor comprises lung cancer.
The compound has the activity of inhibiting the proliferation of various tumor cell strains, so the compound, various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof and a pharmaceutical composition containing the compound as a main active ingredient can be used for treating, preventing and relieving various diseases, including various cancers.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 5-1000mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), and the like
Figure BDA0003523349440000061
) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or solubilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders such as hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, such as glycerol; (d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, such as kaolin; (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms, such as tablets, dragees, capsules, pills, and granules, can be prepared using coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be delayed in release at a site within the digestive tract. Examples of embedding components which can be used are polymeric substances and wax-like substances. If desired, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration, including pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly employed in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like.
In addition to these inert diluents, the compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these materials, and the like.
Compositions for parenteral injection may comprise 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 nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms for topical administration of the compounds of the present invention include ointments, powders, patches, sprays, and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When the pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is suitable for mammals (such as human beings) to be treated, wherein the administration dose is a pharmaceutically-considered effective administration dose, and for a human body with a weight of 60kg, the daily administration dose is usually 1 to 5000mg, preferably 5 to 2000 mg. Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
Compared with the prior art, the invention has the main advantages that: the invention provides a beta-elemene derivative containing N-OH bonds and having a novel structure shown in a formula (I), a pharmaceutical composition containing the compound shown in the formula (I), a hydrate, an isotope derivative, a chiral isomer, a variant, different salts, a prodrug, a preparation and the like of the compound. The invention also provides a preparation method and application of the beta-elemene derivatives containing N-OH bonds and having novel structures, and the activities of the compounds on proliferation inhibition of various tumor cell strains. The beta-elemene derivatives containing N-OH bonds and having novel structures are expected to become anti-tumor candidate drugs for treating lung cancer.
Drawings
The compound of figure 1 induces the apoptosis result of H460 cells; wherein (a) is blank group, (b) is compound 1, (c) is positive control drug beta-elemene (beta-Ele, 1d), and (d) is positive control drug Vorinostat (SAHA).
FIG. 2 Effect of the compound on tumor volume of human Lung cancer cell NCI-H460 nude mice transplanted tumors.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The following examples are conducted under conditions not specified, usually according to conventional conditions, or according to conditions recommended by the manufacturer.
Example 1: preparation of Compound 1
Figure BDA0003523349440000071
Intermediate 1c
To a solution of Compound 1a (398.9mg, 2.43mmol) in DMF (5mL) at room temperature was added NH in sequence2OTHP (1b, 219.1mg, 1.87mmol), DIPEA (362.5mg, 2.81mmol), 1-ethyl-3- (3-dimethylpropylamine) carbodiimide hydrochloride (EDCI, 931.7mg, 4.86mmol) and 1-hydroxybenzotriazole (HOBT, 328.3mg, 2.43 mmol). The reaction was stirred at room temperature for 5 h. After complete conversion, water (20mL) was added to the reaction mixture to terminate the reaction, followed by extraction with ethyl acetate (3X 15 mL). The combined organic phases were washed with saturated brine (2X 15mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (methanol: dichloromethane ═ 13: 87) to obtain 1c (350mg, yield 71.1%) as a yellow solid.1H NMR(400MHz,CDCl3)δ9.29(s,1H),8.19(s,1H),7.60(d,J＝14.7Hz,2H),6.49(d,J＝8.6Hz,1H),6.23(s,1H),4.96(d,J＝41.5Hz,3H),3.99(t,J＝10.2Hz,1H),3.66(dd,J＝10.9,5.5Hz,1H),1.96–1.77(m,4H),1.68–1.62(m,1H),1.60–1.54(m,1H).[M+H]+:264.4.
Intermediate 1e
To a solution of β -Ele (1d, 210.1mg, 1.03mmol) in acetic acid (3mL) under ice-bath was added N-bromosuccinimide (NBS, 183.3mg, 1.03 mmol). Stirring for 6h under ice-bath conditions. TLC monitored incomplete reaction of starting material, so the reaction was warmed to room temperature and stirred overnight (25-28 ℃). After complete conversion, saturated sodium bicarbonate solution was slowly added dropwise to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate (3 × 10 mL). The combined organic phases were washed with saturated brine (2 × 10mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: n-hexane) to give colorless oily liquid 1e (72mg, yield 25.4%).1H NMR(400MHz,CDCl3)δ5.89–5.76(m,1H),5.21(s,1H),5.04(t,J＝1.1Hz,1H),4.97–4.81(m,3H),4.59(dt,J＝1.9,0.9Hz,1H),4.04(d,J＝0.7Hz,2H),2.33–2.17(m,1H),2.06(dd,J＝12.6,3.5Hz,1H),1.74–1.70(m,3H),1.69–1.39(m,6H),1.01(s,3H)。
Intermediate 1f
To a solution of intermediate 1e (367.9mg, 1.30mmol) in DMF (5mL) at room temperature was added intermediate 1c (410.7mg, 1.56mmol) and cesium carbonate (Cs) in that order2CO3990.5mg, 3.04 mmol). The reaction was stirred at 60 ℃ for 6 h. After complete conversion, water (20mL) was added to the reaction mixture to terminate the reaction, followed by extraction with ethyl acetate (3X 15 mL). The combined organic phases were washed with saturated brine (2X 15mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 1: 3) to obtain compound 1f (121.7mg, yield 20.1%) as a colorless oily compound.1H NMR(400MHz,CDCl3)δ8.17(d,J＝2.3Hz,1H),7.62–7.49(m,2H),6.85(d,J＝15.7Hz,1H),6.44(d,J＝8.6Hz,1H),5.74(dd,J＝17.4,10.9Hz,1H),4.96–4.79(m,5H),4.77–4.59(m,4H),4.51(t,J＝2.9Hz,1H),4.22(dd,J＝19.6,16.5Hz,1H),3.98–3.87(m,1H),3.52(dd,J＝11.5,6.5Hz,1H),1.97–1.86(m,2H),1.82–1.64(m,4H),1.63(d,J＝3.5Hz,3H),1.59–1.46(m,5H),1.46–1.33(m,3H),0.93(s,3H).[M+H]+:466.8.
Compound 1
To a solution of intermediate 1f (110.3mg, 0.24mmol) in methanol (3mL) at room temperature was added p-toluenesulfonic acid monohydrate (TsOH. H)2O, 137.0mg, 0.72 mmol). The reaction was stirred at room temperature for 8 h. After complete conversion, the reaction was quenched by addition of saturated sodium bicarbonate solution and water (10mL) and extracted with dichloromethane (3X10 mL). The combined organic phases were washed with saturated brine (2X10mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by C18 column chromatography (acetonitrile: water ═ 1: 1) to obtain a white solid (64.2mg, yield 70.3%).1H NMR(500MHz,DMSO-d6)δ9.74(s,1H),8.12(d,J＝2.4Hz,1H),7.73(dd,J＝8.7,2.5Hz,1H),7.39(d,J＝15.7Hz,1H),6.99(d,J＝15.8Hz,1H),6.46(q,J＝8.0,7.4Hz,3H),5.85–5.75(m,1H),4.99–4.84(m,4H),4.78(t,J＝1.9Hz,1H),4.59(d,J＝2.2Hz,1H),4.26(s,2H),1.97(dt,J＝13.8,6.9Hz,2H),1.70–1.52(m,6H),1.50–1.32(m,3H),0.96(s,3H).13C NMR(126MHz,DMSO-d6)δ161.12,150.54,150.48,149.02,147.56,139.70,135.30,119.71,112.71,112.40,110.49,108.77,52.39,41.54,32.79,27.04,25.07,16.78.[M+H]+:381.2.
Example 2: preparation of Compound 2
Figure BDA0003523349440000091
Intermediate 2b
Reference was made to the procedure for the synthesis of intermediate 1c in example 1 to give 2b as a white solid (711.1mg, yield 66.6%).1H NMR(500MHz,CDCl3)δ9.22(s,1H),8.77(s,1H),8.59(s,1H),7.92–7.60(m,2H),7.32(dd,J＝7.9,4.8Hz,1H),6.49(s,1H),5.06(s,1H),3.99(t,J＝9.5Hz,1H),3.66(dtd,J＝11.2,4.2,2.0Hz,1H),1.96–1.82(m,3H),1.74–1.56(m,3H).[M+H]+:249.0.
Intermediate 2c
Referring to the procedure for the synthesis of intermediate 1f in example 1, colorless oily liquid 2c (102mg, yield 16%) was obtained.1H NMR(500MHz,CDCl3)δ8.80(s,1H),8.58(d,J＝3.8Hz,1H),7.82(dt,J＝8.0,2.0Hz,1H),7.70(d,J＝15.9Hz,1H),7.33(dd,J＝7.9,4.8Hz,1H),7.21(d,J＝15.8Hz,1H),5.81(dd,J＝17.3,11.0Hz,1H),5.03–4.87(m,5H),4.82(q,J＝1.5Hz,1H),4.69(dd,J＝33.3,16.3Hz,1H),4.58(s,1H),4.34(dd,J＝23.1,16.4Hz,1H),4.00(dt,J＝11.2,4.8Hz,1H),3.63–3.54(m,1H),2.04–1.94(m,2H),1.91–1.72(m,5H),1.69–1.55(m,7H),1.53–1.41(m,3H),1.01(s,3H).
Compound 2
Referring to the procedure for the synthesis of compound 1 in example 1, colorless oily liquid 2(70.6mg, yield 91.7%) was obtained.1H NMR(500MHz,DMSO-d6)δ9.97(s,1H),8.84(d,J＝2.2Hz,1H),8.57(dd,J＝4.8,1.6Hz,1H),8.12(dt,J＝8.0,2.0Hz,1H),7.57(d,J＝15.9Hz,1H),7.48–7.36(m,2H),5.81(dd,J＝17.8,10.5Hz,1H),5.02–4.84(m,4H),4.78(s,1H),4.59(s,1H),4.28(s,2H),2.04–1.91(m,2H),1.74–1.33(m,10H),0.97(s,3H).13C NMR(126MHz,DMSO-d6)δ150.81,150.45,149.99,147.54,138.36,134.68,131.21,124.42,119.81,112.72,110.94,110.51,52.39,52.14,41.58,32.78,27.03,25.06,16.78.[M+H]+:389.2.
Example 3: preparation of Compound 3
Figure BDA0003523349440000092
Intermediate 3b
Reference was made to the procedure for the synthesis of intermediate 1c in example 1 to give 3b as a yellow solid (522.4mg, yield 65.0%).1H NMR(500MHz,CDCl3)δ8.43(s,1H),7.65(d,J＝15.6Hz,1H),7.34(d,J＝8.2Hz,2H),6.72–6.58(m,2H),6.26(s,1H),4.99(s,1H),4.17–3.73(m,3H),3.66(ddt,J＝9.4,5.2,2.7Hz,1H),1.93–1.79(m,3H),1.74–1.61(m,3H).
Intermediate 3c
Reference was made to the procedure for the synthesis of intermediate 1f in example 1 to give 3c as a pale yellow solid (107.3mg, yield 20.2%).1H NMR(500MHz,CDCl3)δ7.65(d,J＝15.7Hz,1H),7.39–7.34(m,2H),6.91–6.83(m,1H),6.68–6.63(m,2H),5.80(dd,J＝17.4,10.9Hz,1H),5.03–4.86(m,5H),4.84–4.70(m,2H),4.61–4.56(m,1H),4.27(dd,J＝22.5,16.5Hz,1H),4.00(tt,J＝8.3,1.8Hz,1H),3.91(s,2H),3.62–3.56(m,1H),2.00(tdd,J＝14.7,12.1,8.3Hz,2H),1.89–1.71(m,5H),1.67–1.54(m,7H),1.51–1.41(m,3H),1.00(s,3H).[M+H]+:381.0.
Compound 3
Reference was made to the procedure for the synthesis of compound 1 in example 1 to give 3 as a yellow solid (25mg, yield 50.6%).1H NMR(500MHz,DMSO-d6)δ9.73(s,1H),7.43–7.32(m,3H),6.96(d,J＝16.1Hz,1H),6.60(d,J＝8.5Hz,2H),5.85(dd,J＝17.9,10.4Hz,1H),5.65(d,J＝8.4Hz,1H),5.01–4.87(m,4H),4.85–4.80(m,1H),4.62(d,J＝2.3Hz,1H),4.28(s,2H),2.09–1.94(m,2H),1.77–1.35(m,9H),1.00(s,3H).13C NMR(126MHz,DMSO-d6)δ155.96,155.24,153.88,152.33,147.47,134.73,127.54,118.89,118.85,117.46,115.79,115.23,57.14,46.29,37.54,31.78,29.83,21.53.[M+H]+:381.2.
Example 4: preparation of Compound 6
Figure BDA0003523349440000101
Intermediate 6b
Reference was made to the procedure for the synthesis of intermediate 1c in example 1 to give off-white gummy solid 6b (959.3mg, 84.4% yield).1H NMR(500MHz,CDCl3)δ8.45(s,1H),7.71(d,J＝15.6Hz,1H),7.41(d,J＝7.8Hz,2H),7.18(d,J＝7.8Hz,2H),6.41(s,1H),5.01(s,1H),3.98(t,J＝9.6Hz,1H),3.67(dtd,J＝11.3,4.2,1.8Hz,1H),2.37(s,3H),1.93–1.79(m,3H),1.72–1.62(m,2H),1.59–1.52(m,1H).[M+H]+:262.0.
Intermediate 6c
Reference is made to the procedure for the synthesis of intermediate 1f in example 1, giving a colorless oily compoundProduct 6c (126.7mg, yield 20.3%).1H NMR(500MHz,CDCl3)δ7.71(d,J＝15.8Hz,1H),7.44(d,J＝7.9Hz,2H),7.18(d,J＝7.8Hz,2H),7.03(d,J＝15.7Hz,1H),5.81(dd,J＝17.4,10.9Hz,1H),5.04–4.87(m,5H),4.85–4.70(m,2H),4.58(d,J＝3.8Hz,1H),4.30(dd,J＝22.6,16.5Hz,1H),4.05–3.95(m,1H),3.59(m,1H),2.37(s,3H),2.05–1.96(m,2H),1.90–1.72(m,5H),1.69–1.41(m,10H),1.00(s,3H).[M+H]+:464.5.
Compound 6
Reference was made to the procedure for the synthesis of Compound 1 in example 1 to give Compound 6 as a white solid (40.1mg, yield 70.8%).1H NMR(500MHz,DMSO-d6)δ9.83(s,1H),7.58–7.46(m,3H),7.23(d,J＝7.9Hz,3H),5.81(dd,J＝17.9,10.5Hz,1H),4.97(s,1H),4.94–4.84(m,3H),4.80–4.77(m,1H),4.59(d,J＝2.3Hz,1H),4.27(s,2H),2.33(s,3H),1.98(dt,J＝13.8,7.1Hz,2H),1.71–1.52(m,6H),1.49–1.33(m,3H),0.97(s,3H).
Example 5: preparation of Compound 7
Figure BDA0003523349440000111
Intermediate 7b
Reference was made to the procedure for the synthesis of intermediate 1c in example 1 to give 7b as a white solid (1.07g, yield 70.5%).1H NMR(500MHz,CDCl3)δ9.00(s,1H),7.71(d,J＝15.7Hz,1H),7.31(d,J＝6.4Hz,2H),7.24(t,J＝7.9Hz,1H),7.17(d,J＝7.5Hz,1H),6.42(s,1H),5.03(s,1H),4.00(t,J＝9.1Hz,1H),3.66(ddt,J＝9.6,5.5,2.9Hz,1H),2.34(s,3H),1.85(dq,J＝12.7,4.7,4.1Hz,3H),1.71–1.55(m,3H).[M+H]+:262.0.
Intermediate 7c
Referring to the procedure for the synthesis of intermediate 1f in example 1, colorless oily liquid 7c (100mg, yield 15.4%) was obtained.1H NMR(500MHz,CDCl3)δ7.70(d,J＝15.8Hz,1H),7.38–7.31(m,2H),7.27(t,J＝7.6Hz,1H),7.18(d,J＝7.4Hz,1H),7.06(d,J＝15.5Hz,1H),5.81(dd,J＝17.4,10.9Hz,1H),5.04–4.86(m,5H),4.84–4.69(m,2H),4.59(dd,J＝4.9,2.0Hz,1H),4.30(dd,J＝22.4,16.5Hz,1H),4.04–3.95(m,1H),3.62–3.56(m,1H),2.37(s,3H),2.06–1.94(m,2H),1.89–1.72(m,5H),1.69–1.53(m,7H),1.53–1.39(m,3H),1.01(s,3H).
Compound 7
Referring to the procedure for the synthesis of compound 1 in example 1, colorless oily liquid 7(74mg, yield 94.0%) was obtained.1H NMR(500MHz,DMSO-d6)δ9.91(s,1H),7.56–7.43(m,3H),7.37–7.20(m,3H),5.82(dd,J＝17.9,10.5Hz,1H),4.99(s,1H),4.95–4.85(m,3H),4.80(t,J＝1.9Hz,1H),4.60(s,1H),4.29(s,2H),2.35(s,3H),1.99(dt,J＝13.7,6.8Hz,2H),1.75–1.53(m,6H),1.52–1.34(m,3H),0.98(s,3H).[M+H]+:380.2.
Example 8: preparation of Compound 8
Figure BDA0003523349440000121
Intermediate 8b
Reference was made to the procedure for the synthesis of intermediate 1c in example 1 to give 8b as a white solid (1.35g, yield 83.8%).1H NMR(500MHz,CDCl3)δ8.01(d,J＝15.8Hz,1H),7.50(d,J＝7.3Hz,1H),7.40–7.08(m,4H),6.33(s,1H),5.03(s,1H),3.99(t,J＝9.3Hz,1H),3.66(dtd,J＝11.3,4.1,1.8Hz,1H),2.42(s,3H),1.92–1.78(m,3H),1.73–1.55(m,3H).
Intermediate 8c
Referring to the procedure for the synthesis of intermediate 1f in example 1, colorless oily liquid 8c (186.0mg, yield 24.5%) was obtained.1H NMR(500MHz,CDCl3)δ8.01(d,J＝15.7Hz,1H),7.56(d,J＝7.3Hz,1H),7.28–7.24(m,1H),7.21(t,J＝6.8Hz,2H),7.00(d,J＝16.0Hz,1H),5.81(dd,J＝17.4,10.9Hz,1H),5.07–4.86(m,5H),4.84–4.68(m,2H),4.60–4.57(m,1H),4.30(dd,J＝21.2,16.5Hz,1H),4.05–3.95(m,1H),3.59(ddt,J＝12.9,6.7,3.1Hz,1H),2.45(s,3H),2.05–1.95(m,2H),1.91–1.71(m,5H),1.69–1.55(m,7H),1.54–1.41(m,3H),1.01(s,3H).
Compound 8
Referring to the procedure for the synthesis of compound 1 in example 1, colorless oily liquid 8(95.7mg, yield 73.1%) was obtained.1H NMR(500MHz,Methanol-d4)δ7.92(d,J＝15.8Hz,1H),7.59(d,J＝7.6Hz,1H),7.26–7.16(m,4H),5.80(dd,J＝17.5,10.8Hz,1H),4.99(d,J＝24.1Hz,2H),4.92–4.76(m,5H),4.58(s,1H),4.35(s,2H),2.41(s,3H),2.01(dp,J＝13.5,6.8,6.0Hz,2H),1.74–1.60(m,6H),1.55–1.39(m,3H),1.00(s,3H).13C NMR(126MHz,Methanol-d4)δ150.13,148.09,147.45,140.18,137.31,133.87,130.40,129.44,126.07,125.89,117.05,111.37,110.30,109.03,52.62,52.02,42.04,39.79,39.46,32.88,26.86,24.00,18.45,15.74.[M+H]+:380.0.
Example 7: preparation of Compound 9
Figure BDA0003523349440000131
Intermediate 9b
Reference was made to the procedure for the synthesis of intermediate 1c in example 1 to give 9b as a yellow solid (733.7mg, yield 85.6%).1H NMR(500MHz,CDCl3)δ8.96(s,1H),7.86–7.39(m,5H),6.66–6.34(m,1H),5.04(s,1H),3.98(q,J＝10.6Hz,1H),3.72–3.62(m,1H),1.86(qt,J＝10.6,7.6,3.5Hz,3H),1.64(ddd,J＝32.1,10.6,6.9Hz,3H).
Intermediate 9c
Referring to the procedure for the synthesis of intermediate 1f in example 1, colorless oily liquid 9c (110.0mg, yield 17.3%) was obtained.1H NMR(500MHz,CDCl3)δ7.78–7.56(m,5H),7.21(d,J＝15.2Hz,1H),5.80(dd,J＝17.3,11.0Hz,1H),5.09–4.78(m,6H),4.75–4.56(m,2H),4.35(dd,J＝23.1,16.4Hz,1H),4.00(dt,J＝11.1,5.1Hz,1H),3.58(dd,J＝11.9,5.6Hz,1H),2.07–1.92(m,2H),1.90–1.60(m,12H),1.54–1.42(m,3H),1.01(s,3H).[M+H]+:475.2.
Compound 9
Reference was made to the procedure for the synthesis of compound 1 in example 1 to give 9(68.0mg, 83.2% yield) as a yellow oily liquid.1H NMR(500MHz,DMSO-d6)δ9.99(s,1H),7.87(s,4H),7.59(d,J＝15.9Hz,1H),7.42(d,J＝15.9Hz,1H),5.80(dd,J＝17.8,10.5Hz,1H),5.06–4.74(m,5H),4.58(s,1H),4.28(s,2H),2.07–1.87(m,2H),1.76–1.31(m,9H),0.96(s,3H).
Example 8: preparation of Compound 12
Figure BDA0003523349440000132
Intermediate 12b
Reference was made to the procedure for the synthesis of intermediate 1c in example 1 to give 12b as a white solid (967.2mg, 91.3% yield).1H NMR(500MHz,CDCl3)δ8.89(s,1H),7.75(d,J＝15.8Hz,1H),7.62(s,4H),6.67–6.29(m,1H),5.03(s,1H),3.98(d,J＝11.8Hz,1H),3.76–3.60(m,1H),2.01–1.47(m,6H).
Intermediate 12c
Referring to the procedure for the synthesis of intermediate 1f in example 1, light yellow oily liquid 12c (108.0mg, yield 14.4%) was obtained.1H NMR(500MHz,CDCl3)δ7.72(d,J＝15.8Hz,1H),7.63(s,4H),7.18(d,J＝12.3Hz,1H),5.81(dd,J＝17.3,11.0Hz,1H),5.06–4.79(m,6H),4.78–4.56(m,2H),4.34(dd,J＝23.1,16.4Hz,1H),4.03–3.97(m,1H),3.59(dq,J＝9.3,4.1,3.0Hz,1H),2.08–1.93(m,2H),1.90–1.59(m,12H),1.53–1.42(m,3H),1.01(s,3H).
Compound 12
Referring to the procedure for the synthesis of compound 1 in example 1, yellow oily liquid 12(65.7mg, yield 79.1%) was obtained.1H NMR(500MHz,DMSO-d6)δ9.96(s,1H),7.91(d,J＝8.1Hz,2H),7.78(d,J＝8.0Hz,2H),7.63(d,J＝16.0Hz,1H),7.44(d,J＝15.9Hz,1H),5.82(dd,J＝17.6,10.7Hz,1H),5.05–4.84(m,4H),4.80(s,1H),4.60(s,1H),4.30(s,2H),1.99(dt,J＝11.5,5.6Hz,2H),1.75–1.34(m,9H),0.98(s,3H).
Example 9: preparation of Compound 15
Figure BDA0003523349440000141
Intermediate 15b
Reference was made to the procedure for the synthesis of intermediate 1c in example 1 to give 15b as a white solid (1.38g, 88.8% yield).1H NMR(400MHz,CD3OD)δ8.36(d,J＝2.4Hz,1H),7.82(dd,J＝8.8,2.4Hz,1H),6.57(d,J＝8.8Hz,1H),5.02–4.99(m,1H),4.11(td,J＝10.9,3.1Hz,1H),3.69–3.57(m,1H),1.96–1.56(m,6H).[M+H]+:238.3。
Intermediate 15c
Referring to the procedure for the synthesis of intermediate 1f in example 1, oil-free liquid 15c (210.3mg, yield 31.0%) was obtained.1H NMR(400MHz,CDCl3)δ8.52(d,J＝2.2Hz,1H),7.83(dd,J＝8.6,2.3Hz,1H),6.48(d,J＝8.6Hz,1H),5.80(dd,J＝17.8,10.5Hz,1H),5.09–4.71(m,8H),4.58(dd,J＝6.9,2.0Hz,1H),4.32(dd,J＝16.4,13.3Hz,1H),3.79(tdd,J＝10.9,6.8,2.8Hz,1H),3.58–3.47(m,1H),2.08–1.94(m,2H),1.81–1.35(m,15H),1.00(s,3H).[M+H]+:440.2。
Compound 15
Reference was made to the procedure for the synthesis of compound 1 in example 1 to give 15(170mg, yield 80.3%) as a white solid.1H NMR(500MHz,DMSO-d6)δ9.72(s,1H),8.37(d,J＝2.4Hz,1H),7.73(dd,J＝8.7,2.4Hz,1H),6.53–6.32(m,3H),5.81(dd,J＝17.8,10.5Hz,1H),5.06–4.83(m,4H),4.78(t,J＝1.9Hz,1H),4.58(d,J＝2.3Hz,1H),4.26(s,2H),2.00(ddd,J＝12.0,9.9,3.7Hz,2H),1.72–1.32(m,9H),0.96(s,3H).13C NMR(126MHz,DMSO-d6)δ167.52,161.24,150.46,150.16,148.93,147.56,138.35,118.29,112.71,110.72,110.50,106.69,53.33,52.41,41.78,39.94,32.86,27.04,25.08,16.79.[M+H]+:356.5。
Example 10: evaluation of antitumor Activity in vitro of the Compound prepared in example 1
1. Experimental materials and instruments
Experimental materials: DMEM (seirui biotechnology limited, zhejiang); RPMI 1640 (zhejiang senri biotechnology limited); fatal bone Serum (BI); PBS (zhejiang senri biotechnology limited); trypsin (zhejiang senri biotechnology limited); dmso (coolaber); CCK-8 (Coolaber).
An experimental instrument: biosafety cabinets (shanghai baiji biotechnology limited); a thermostated carbon dioxide incubator (THERMO); enzyme linked immunoassay (Spark); inverted microscope (Nikon); a set of pipette guns (Eppendorf); centrifuge (Beckman coulter).
Different types of human lung cancer cell lines: h1975, H460 and a 549.
2. Experimental procedure
1) Taking test cells in logarithmic growth phase, digesting with pancreatin, counting, diluting the tumor cell suspension to 5 × 104Each/mL of the cells was inoculated in a 96-well plate, and 100. mu.L of cell-containing medium (5X 10 per well) was added to each well except for the blank group and 100. mu.L of cell-free medium3Individual cells);
2) at a wet content of 5% CO2After incubation at 37 ℃ for 8h in an incubator, the original medium in the 96-well plate was aspirated off, 100. mu.L of medium containing no test compound was added to each of the wells except for the control and blank groups, and 100. mu.L of medium containing the test compound was added to each of the other wells (using 10% FBS/RPMI 1640 complete medium), 6 duplicate wells were set for each concentration, the wells containing no test compound were used as the blank group, the wells containing no test compound were used as the control group, and the wells containing cells and test compound were used as the experimental group. beta-Ele and SAHA are selected as positive controls in the experiment;
3) at 37 ℃ with 5% CO2Continuously culturing for 72h in a humid incubator;
4) adding 10 μ L of CCK-8 solution into each well in dark condition, and adding 5% CO at 37 deg.C2Continuously culturing for 1-4h in a humid incubator, and measuring the absorbance value (OD value) of each hole at 450nm of an enzyme-labeling instrument;
5) the survival and inhibition rates were calculated using the following formulas
The cell survival rate is [ (As-Ab)/(Ac-Ab) ]. times.100%
The inhibition rate is [ (Ac-As)/(Ac-Ab) ]. times.100%
Calculating the single concentration inhibition rate by using Excel; sigmoidal dose-survival curves were plotted using a non-linear regression model using GraphPad Prism 7.0 software and IC calculated50The value is obtained.
As: absorbance of test well (cell-containing medium, CCK-8, drug to be tested)
Ac: absorbance of control wells (cell-containing Medium, CCK-8, vehicle (DMSO))
Ab: absorbance of blank wells (cell-free Medium, CCK-8, vehicle (DMSO)))
3. Results of the experiment
The proliferation inhibitory effects of the compound prepared in example 1, as well as the positive control drugs β -Ele and SAHA on 3 lung cancer cell lines were determined according to the above experimental methods, and the results are shown in table 1.
TABLE 1 results of antiproliferative Activity of target Compounds on solid tumor cell lines in vitro
Figure BDA0003523349440000151
aThe values in the table are the average values of three tests, and the value after "+ -" represents the standard deviation;bwhen the concentration is 10 μm, the inhibition rate is less than 10% as expressed by "n.a. -stationary".
4. Discussion of results
At the cellular level: 1) compound 1 exhibited significantly greater cell proliferation inhibitory activity than the positive control β -Ele; 2) compound 1 showed comparable inhibitory activity to the positive control SAHA.
Example 11: apoptosis assay was performed on the compound prepared in example 1
1. Experimental materials and instruments
Experimental materials: DMEM (zhejiang senri biotechnology limited); RPMI 1640 (zhejiang senri biotechnology limited); fatal bone Serum (BI); PBS (zhejiang senri biotechnology limited); trypsin (zhejiang senri biotechnology limited); dmso (coolaber); apoptosis kits (synbiotics); double distilled water.
An experimental instrument: biosafety cabinets (shanghai baiji biotechnology limited); a thermostated carbon dioxide incubator (THERMO); enzyme linked immunoassay analyzer (Spark); inverted microscope (Nikon); a set of pipette guns (Eppendorf); a centrifuge (Beckman coulter); a flow cytometer.
Human lung cancer cell line: H460.
2. experimental procedure
1) GetTest cells in logarithmic growth phase are trypsinized and counted, and the tumor cell suspension is diluted to 5 x104The seeds are inoculated in 46 cm culture dishes at the concentration of one/mL;
2) at a wet content of 5% CO2After incubation in an incubator at 37 ℃ for 8h, the original medium in the 6cm dish was aspirated, 4mL of medium without test compound was added to the blank group, and 4mL of medium with test compound was added to the remaining three groups (complete medium using 10% FBS/RPMI 1640; test compound concentration 10. mu.M). beta-Ele and SAHA are selected as positive controls in the experiment;
3) at 37 ℃ with 5% CO2Continuously culturing for 72h in a humid incubator to induce apoptosis;
4) after culturing for 72h, transferring all the original cell culture solution into a 10mL centrifuge tube, then digesting the cells in the culture dish with pancreatin until the cells are completely digested, transferring the pancreatin containing the cells into the 10mL centrifuge tube together, centrifuging for 5min at 1000r, and removing the supernatant;
5) adding 1 XPBS for centrifugal washing, and then removing the PBS;
6) diluting 5 × Binding Buffer in the apoptosis kit with double distilled water to be 1 × Binding Buffer, and taking 500 μ L of 1 × Binding Buffer to resuspend cells;
7) adding 5 mu L of annexin V and 10 mu L of PI in the apoptosis kit into each tube;
8) after gentle vortex mixing, incubating for 5min at room temperature in the dark;
9) annexin V-FITC was detected by the FITC channel and PI was detected by the PI channel on a flow cytometer.
3. Results of the experiment
The effect of the compound prepared in example 1, as well as the positive control drug β -Ele and SAHA on inducing apoptosis in lung cancer cell line H460 was determined according to the above experimental method, and the results are shown in fig. 1(a) - (d).
4. Discussion of results
1) Compared with the blank group and the positive control beta-Ele group, the compound 1 can obviously induce H460 cell apoptosis; 2) compared with the positive control SAHA group, the compound 1 has equivalent effect of inducing H460 cell apoptosis.
Example 12: evaluation of antitumor Activity in vivo on the Compound prepared in example 1
1. Preparation of the model
Collecting cultured human lung cancer NCI-H460 cell suspension at a concentration of 1 × 107one/mL, 0.1mL each, was inoculated subcutaneously into the right axilla of nude mice.
2. Grouping and administration of drugs
Measuring the diameter of the transplanted tumor of the nude mouse by using a vernier caliper, wherein the tumor volume reaches 80-100mm 18 days after inoculation3Animals were randomly grouped into groups of 5 animals each. Meanwhile, each group of nude mice starts to be dosed, the dosing scheme is shown in the group and the dosing scheme, and the antitumor effect of the tested sample is dynamically observed by using a method for measuring the tumor size. After the experiment, the nude mice were sacrificed immediately, and the tumor mass was removed by surgery and weighed.
3. Observation index
The formula for Tumor Volume (TV) is:
TV＝1/2×a×b2wherein a and b represent length and width, respectively.
Calculating Relative Tumor Volume (RTV) according to the measurement result, wherein the calculation formula is as follows:
RTV＝Vt/V0
wherein V0When administered separately from the cage (i.e. d)0) Measurement of the resulting tumor volume, VtFor the tumor volume at each measurement. Evaluation indexes of antitumor activity: the relative tumor proliferation rate T/C (%) was calculated as follows:
T/C(％)＝(TRTV/CRTV)×100％
wherein T isRTV: treatment group RTV; cRTV: model set RTV.
Evaluation indexes of antitumor activity: the tumor growth inhibition (%) is calculated as follows:
the tumor growth inhibition rate was ═ [ (average tumor weight in model group-average tumor weight in administration group)/average tumor species in model group ] × 100%
4. Statistical processing
The mean values are represented by X + -SD, the analysis between groups is statistically processed by t-test, and the results are statistically analyzed using SPSS (statistical Package for the Social science) 17.0.
5. Results of the experiment
The effect of Compound 1 prepared in example 1, as well as the positive control drugs β -Ele and SAHA on the tumor volume of transplanted tumors in nude mice with human lung cancer cells NCI-H460 was determined according to the above experimental method, and the results are shown in FIG. 2.
TABLE 1 specific experimental protocol
(X±SD，n＝5)
Figure BDA0003523349440000171
In comparison with the blank set, the results,*P＜0.05，**P＜0.01
TABLE 2 Effect of test Compounds on tumor growth of human Lung cancer cell NCI-H460 nude mice transplanted tumors
(X±SD，n＝5)
Figure BDA0003523349440000172
P < 0.05, P < 0.01, compared to blank
6. Discussion of results
On a human lung cancer cell NCI-H460 nude mouse transplantation tumor model, the compound 1 shows a remarkably stronger tumor proliferation inhibition effect than that of the positive controls beta-Ele and SAHA.
Furthermore, it should be understood that various changes and modifications can be made by one skilled in the art after reading the above description of the present invention, and equivalents also fall within the scope of the invention as defined by the appended claims.

Claims (9)

1. The beta-elemene derivative containing N-OH bonds, or optical isomers, racemates, single enantiomers, possible diastereoisomers, or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates and solvates thereof is characterized in that the structure of the derivative is shown as the formula (I):
Figure FDA0003523349430000011
in formula (I):
n is 0, 1, 2, 3;
-L-bond is
Figure FDA0003523349430000012
Figure FDA0003523349430000013
Is a 5-to 10-membered aryl, 5-to 10-membered heteroaryl;
R1selected from the following structural fragments: hydrogen, C1-6Alkyl radical, C3-6Cycloalkyl, 5-10 membered aryl, 5-10 membered heteroaryl, -OC1-6Alkyl, -CF3、-CN、-NH2。
2. The N-OH bond-containing β -elemene derivative of claim 1, wherein when N is 2, 3, adjacent R is selected from the group consisting of optical isomers, racemates, single enantiomers, possible diastereomers, and pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, and solvates thereof1Forming a cyclic structure containing 0-3 heteroatoms selected from O, S, N.
3. The N-OH bond-containing β -elemene derivative of claim 1, or an optical isomer, racemate, single enantiomer, or possible diastereomer thereof, or a pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof, wherein the N-OH bond-containing β -elemene derivative of a novel structure is any one of compounds 1 to 44 represented by the following structures:
Figure FDA0003523349430000021
Figure FDA0003523349430000031
4. a process for the preparation of β -elemene derivatives containing N-OH bond as claimed in any one of claims 1-3, characterized by the following synthetic route:
Figure FDA0003523349430000041
the method specifically comprises the following steps:
(1) firstly, the catalyst contains L,
Figure FDA0003523349430000042
And acid A-1 and A-2 of the R structural fragment are subjected to amide condensation reaction to obtain an intermediate A-3;
(2) then carrying out allylic bromination reaction on the beta-elemene A-4 to obtain an intermediate beta-elemene 13-site bromination product A-5;
(3) then connecting the intermediate A-3 to a beta-elemene 13-bit bromo-product A-5 through a nucleophilic substitution reaction to obtain an intermediate A-6;
(4) finally, the intermediate A-6 is deprotected to obtain the final product (I).
5. Beta-elemene derivatives containing an N-OH bond as claimed in any one of claims 1 to 3, or optical isomers, racemates, single enantiomers, possible diastereomers, or pharmaceutically acceptable salts thereof,
The prodrug, the deuterated derivative, the hydrate and the solvate are applied to the preparation of antitumor drugs.
6. The use of claim 5, wherein the tumor comprises lung cancer.
7. An antitumor agent characterized by comprising a safe and effective amount of the N-OH bond-containing β -elemene derivative of claim 1 or 2, or an optical isomer, racemate, single enantiomer, or possible diastereomer thereof, or a pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof.
8. The antitumor drug as claimed in claim 7, further comprising a pharmaceutically acceptable carrier.
9. An anti-tumor medicament as claimed in claim 7 or 8, wherein said tumor comprises lung cancer.
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