CN116120327A - Beta-elemene 13, 14-position symmetrical disubstituted derivative and preparation method and application thereof - Google Patents

Beta-elemene 13, 14-position symmetrical disubstituted derivative and preparation method and application thereof Download PDF

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CN116120327A
CN116120327A CN202310169653.1A CN202310169653A CN116120327A CN 116120327 A CN116120327 A CN 116120327A CN 202310169653 A CN202310169653 A CN 202310169653A CN 116120327 A CN116120327 A CN 116120327A
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elemene
beta
compound
derivative
pharmaceutically acceptable
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谢恬
党夏雯
杜晓莉
白仁仁
戚香
章映茜
毛晴
高园
叶向阳
王丽薇
卓晓韬
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Hangzhou Normal University
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Abstract

The invention discloses a beta-elemene 13, 14-position symmetrical double-substituted derivative, a preparation method and application thereof. The structural formula of the beta-elemene 13, 14-symmetrical disubstituted derivative is shown as formula (I). By connecting polar amino substituent groups on the small-molecule elemene, the integral drug-like characteristics of the molecule can be remarkably improved, the original three carbon-carbon double bond parts of the elemene are reserved, 1 to a plurality of hetero atoms are introduced, the integral component force is small, the capability of the drug for penetrating through the blood brain barrier is improved, the blood brain barrier can be penetrated, and the novel anti-glioma drug is hopefully developed.

Description

Beta-elemene 13, 14-position symmetrical disubstituted derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of preparation of beta-elemene derivatives, and particularly relates to a beta-elemene 13, 14-position symmetrical disubstituted derivative, and a preparation method and application thereof.
Background
Elemene is a kind of small molecule volatile oil compounds, and is mainly extracted from radix Curcumae tubers. The elemene reported in the current literature mainly comprises alpha-elemene, (±) -beta-elemene, gamma-elemene and delta-elemene, wherein (-) -beta-elemene is a main active ingredient which plays an anti-tumor role, has broad-spectrum anti-tumor activity and has certain curative effects on various cancers, such as liver cancer, breast cancer, lung cancer and the like. At present, various preparations taking elemene as a main component have a certain anticancer curative effect clinically.
However, the elemene has low polarity, poor water solubility and low bioavailability, which limits the clinical application thereof. Therefore, the elemene derivative which has good water solubility, higher biological oral utilization degree, better biological activity than the elemene and less toxic and side effect needs to be obtained by structural modification of the elemene.
In the past 20-30 years, scientific researchers have performed a great deal of structural modification and activity research work on beta-elemene. On the premise of not damaging the elemene skeleton and double bonds thereof, most of researches mainly focus on modification of beta-elemene at 13-sites, and some researches report that the beta-elemene is modified at 13 and 14 sites by the same substituent, and relatively few reports relate to unique double-amination structural modification of beta-elemene at 13 and 14 sites.
Glioma is a primary malignant tumor of the intracranial central nervous system of neuroepithelial origin, which is the most refractory malignancy in humans. The effect of a large number of anti-tumor drugs on treating the Brain glioma is not obvious, and a Blood-Brain Barrier (BBB) exists between the central nervous system and the peripheral Blood circulation, so that a plurality of drugs cannot pass through the Barrier and cannot exert the anti-Brain glioma activity. The BBB is composed of endothelial cells, continuous basement membrane, and Astrocytes (AS) that are tightly connected and are overlaid on each other. The multi-layer membranous structure forms a protective barrier of brain tissue, strictly limits the exchange of substances between blood and brain tissue, and fully protects the brain from being injured by external chemical substances. However, for diseased brain, the BBB also prevents the drug from entering brain tissue, thereby severely affecting the treatment of the brain disease with the drug. Researches show that nearly 100% of macromolecules and 98% of small molecular medicines cannot pass through the BBB, which directly results in poor curative effects of common antitumor medicines such as pazopanib, paclitaxel and doxorubicin on brain glioma. The anti-tumor drug which can effectively pass through the BBB can exert better curative effect in the treatment of brain glioma, such as Temozolomide (TMZ), and has been widely used as an anti-brain glioma drug clinically in spite of the fact that the anti-brain glioma cell proliferation activity is not strong in vitro.
In the process of researching and developing targeted drugs for treating gliomas, how to improve the ability of drugs to penetrate the blood brain barrier is still a challenge to be solved by scientists. In contrast, it is much easier to increase the in vitro bioactivity of the drug (inhibit proliferation of gliomas). Therefore, modifying drugs (e.g., introducing functional groups containing nitrogen atoms, adjusting the physicochemical properties of the molecule) by suitable methods to enhance the ability of the drug to penetrate the blood brain barrier has been a research hotspot for pharmaceutical scientists for many years.
Elemene is a sesquiterpene compound extracted from Curcuma wenyujin Y.H.Chen et C.Ling. Its molecular weight is very small (MW 204), and it has broad-spectrum anti-tumor cell activity. The document shows that elemene has the capacity of penetrating the blood brain barrier itself, but the degree of penetration is still limited. In addition, the document shows that the elemene has a certain inhibiting effect on glioma. Elemene itself has a certain ability to penetrate the blood brain barrier, but this ability is weaker.
By connecting polar amino substituent groups on the small molecule elemene, the overall drug-like properties (such as good solubility, lipophilicity, membrane penetrability, metabolic stability, ideal pharmacokinetic and pharmacodynamic properties and the like) of the molecule can be significantly improved. Therefore, the 13-position and 14-position of the beta-elemene are connected with nitrogen-containing amino substituent groups with smaller molecular weight, and an elemene double-amino substituent compound with novel structure is formed. The novel molecular entity reserves three original carbon-carbon double bond parts of elemene (the three carbon-carbon double bonds are main contribution elements of the antitumor activity of the elemene), simultaneously introduces a compound containing 1 to a plurality of hetero atoms, has smaller whole component force, makes the penetration of blood brain barrier possible, and is expected to develop a novel anti-glioma drug.
Disclosure of Invention
The first object of the invention is to provide a class of beta-elemene 13, 14-symmetrical disubstituted derivatives aiming at the defects of the prior art.
The beta-elemene 13, 14-symmetrical double-substituted derivative, or optical isomer, racemate, single enantiomer, possible diastereoisomer, or pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate and solvate thereof, is characterized in that the structural formula of the beta-elemene 13, 14-symmetrical double-substituted derivative is shown as the formula (I):
Figure SMS_1
Figure SMS_2
in formula (I):
R 1 、R 2 each independently selected from the following structural fragments: H. c (C) 1-6 Alkyl group of (C),
Figure SMS_3
-SO 2 R 3 、-COR 3 、-CO(O)R 3 And R is 1 、R 2 Not simultaneously H, methyl, ethyl and isopropyl;
or R is 1 And R is 2 Together with the N atom to which they are attached, form a mono-or polyheterocyclic structure optionally containing an additional 0 to 3 heteroatoms selected from N, O, S;
R 3 selected from C 1-6 Alkyl, C of (2) 2-6 Alkenyl, C 3-6 Alkynyl, C 3-6 Cycloalkyl or 3-to 7-membered heterocyclyl;
preferably, the R 1 And R is 2 Together with the N atom to which they are attached, form a mono-or polyheterocyclic structure selected from one of the following structural fragments:
Figure SMS_4
wherein R is 4 Selected from hydrogen, C 1-6 Alkyl, C of (2) 3-6 Alkenyl, C 3-6 Alkynyl, C 2-6 Cycloalkyl, 3-to 7-membered heterocyclyl, -C (O) R 3 or-SO 2 R 3 。
Preferably, the method comprises
Figure SMS_5
Selected from one of the following structural fragments:
Figure SMS_6
in another preferred embodiment, the beta-elemene 13, 14-position symmetrical disubstituted derivative (I) is any one of the compounds 1 to 20 shown in the following structures:
Figure SMS_7
the second object of the invention is to provide a preparation method of the beta-elemene 13, 14-symmetrical disubstituted derivative.
For R 1 Or R is 2 The beta-elemene 13, 14-symmetrical double-substituted derivative with the structure of formula (I) is hydrogen, and can be synthesized by adopting a synthetic route I:
Figure SMS_8
wherein R is 1 And R is 2 Is defined as above;
the method specifically comprises the following steps:
(1) Performing 13-position and 14-position allylic dichloro reaction on the beta-elemene A-1 to obtain an intermediate beta-elemene dichloro compound A-2;
(2) Will contain R 1 、R 2 The nitrogen heteroatom functional group structural fragment A-3 of the substituent is connected to the 13-position and the 14-position of the beta-elemene through nucleophilic substitution reaction to obtain the symmetrical double-substituted derivative of the 13, 14-position of the beta-elemene shown in the formula (I).
In addition, for R 1 And R is 2 The beta-elemene 13, 14-position symmetrical disubstituted derivatives of structural formula (I) which are not hydrogen and do not form a mono-or multi-heterocyclic structure can be prepared by adopting a second synthetic route:
Figure SMS_9
the method specifically comprises the following steps:
(1) Performing 13-position and 14-position allylic dichloro reaction on the beta-elemene A-1 to obtain an intermediate beta-elemene dichloro compound A-2;
(2) Will contain R 2 Substituents and P 1 The nitrogen heteroatom functional group structural fragment A-4 of the protecting group is connected to the 13-position and the 14-position of the beta-elemene through nucleophilic substitution reaction to obtain a compound A-5;
(3) Removing the protecting group in compound A-5 and reacting the resulting amine intermediate with R 1 -X is subjected to substitution under basic conditions to obtain the compound of formula (I).
For R 1 And R is 2 Beta-elemene 13, 14-position symmetrical disubstituted derivatives of formula (I) which are not hydrogen and do not form mono-or polyheterocycles, can also be prepared using synthetic route three:
Figure SMS_10
specifically, intermediate A-5 of scheme II is deprotected to give an amine with an appropriate R-containing group 1 And (3) carrying out reductive amination reaction on the aldehyde to obtain the compound shown in the formula (I).
The compound of formula (I) of the present invention can be produced by the method as described above, however, the conditions of the method, such as reactants, solvents, amounts of compounds used, reaction temperature, time required for the reaction, etc., are not limited to the above explanation. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.
Step (1) of each synthetic route of the present invention may employ the prior art, such as the method disclosed in publication No. CN110683932 a.
The third object of the invention is to provide the application of the beta-elemene 13, 14-symmetrical disubstituted derivative, or optical isomer, racemate, single enantiomer, possible diastereoisomer, or pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate and solvate thereof in preparing antitumor drugs.
A fourth object of the present invention is to provide an antitumor drug comprising a safe and effective amount of the β -elemene 13, 14-position symmetrical disubstituted derivative, or an optical isomer, racemate, single enantiomer, possible diastereomer thereof, or pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof.
Preferably, the antitumor drug may further comprise a pharmaceutically acceptable carrier or excipient.
Preferably, in the application and the antitumor drug, the tumor comprises colon cancer, lung cancer, prostate cancer and brain glioma.
Because the compounds of the present invention have activity in inhibiting proliferation of various tumor cell lines, the compounds of the present invention and various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates thereof, and pharmaceutical compositions containing the compounds of the present invention as a main active ingredient are useful for treating, preventing and alleviating various diseases, including various cancers.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically 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 compositions contain 1-2000mg of the compound of the invention per dose, more preferably 5-1000mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, and the like), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, and the like), polyols (e.g., propylene glycol, glycerol, mannitol, sorbitol, and the like), emulsifiers (e.g.
Figure SMS_11
) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, 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 admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or solubilisers, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, such as glycerin; (d) Disintegrants, 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 amine compounds; (g) humectants, such as cetyl alcohol and glycerol monostearate; (h) adsorbents such as kaolin; (i) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, 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 with 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 released in a delayed manner in a certain location within the gut. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used 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 these substances and the like.
In addition to these inert diluents, the compositions can also include 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, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, 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 excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredients are mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
Preferably, the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 5000mg, preferably 5 to 2000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are 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 13, 14-symmetrical double-substituted derivative with a structure shown in a formula (I), a pharmaceutical composition and hydrate containing the compound shown in the formula (I), and isotope derivatives, chiral isomers, allosteric isomers, different salts, prodrugs, preparations and the like of the compound. The invention also provides a preparation method and application of the beta-elemene 13, 14-site symmetrical disubstituted derivative, and the proliferation activity of the compound on various tumor cell strains. The beta-elemene 13, 14-symmetrical double-substituted derivative is expected to become an anti-tumor candidate medicament for treating glioma and the like.
Detailed Description
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The methods of operation, under which specific conditions are not noted in the examples below, are generally in accordance with conventional conditions, or in accordance with the conditions recommended by the manufacturer.
Example 1: preparation of Compound 1
Figure SMS_12
Intermediate 1-b
Beta-elemene 1-a (3.8 g,18.6 mmoL) was dissolved in a mixed solution of dichloromethane (25 mL) and glacial acetic acid (22 mL). A catalytic amount of TBAF was added and an aqueous solution of NaClO (m=3.0, 28ml,84 mmol) was slowly dropped under ice bath, which took 5 hours, and stirring was continued at 0 ℃ for 1 hour after dropping. The reaction was quenched by the addition of 10% aqueous sodium sulfite (30 mL) and saturated aqueous sodium bicarbonate (20 mL). The reaction mixture was extracted with ethyl acetate (3X 50 mL). The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to silica gel column chromatography (100% petroleum ether) to give compound 1-b (1.84 g, yield 37%) as a colorless liquid. 1 H NMR(400MHz,CDCl 3 )δ5.80(dd,J＝17.1,11.1Hz,1H),5.29(d,J＝1.0Hz,1H),5.18(d,J＝1.0Hz,1H),5.05(s,1H),4.98–4.90(m,3H),4.14–4.08(dd,J＝11.6,0.8Hz,1H),4.11(s,2H),3.98(dd,J＝11.6,0.8Hz,1H),2.37–2.22(m,2H),1.79–
1.63(m,2H),1.59–1.43(m,4H),0.99(s,3H)。
Intermediate 1-d
Compound 1-b (783 mg,2.88 mmoL) was dissolved in dry DMF (1 mL). Cesium carbonate (250 mg,1.8 mmoL) and diamine 1-c (349 mg,1.65 mmoL) were added at room temperature and stirred at 70℃for 10 hours. DMF was removed under reduced pressure, the residue diluted with ethyl acetate (40 mL) and washed with water (20 mL) and the aqueous phase back extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the crude product obtained after concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=1:1) to give a colorless liquid compound 1-d (220 mg, yield 63%). 1 HNMR(500MHz,CDCl 3 )δ5.77(dd,J＝17.5,10.8Hz,1H),5.05(d,J＝1.6Hz,1H),4.93(d,J＝1.7Hz,1H),4.91–4.80(m,3H),4.72(d,J＝1.7Hz,1H),3.54(s,4H),3.18(s,4H),2.91(dd,J＝231.9,13.9Hz,2H),3.07–2.88(m,2H),2.75(dt,J＝8.6,4.1Hz,4H),2.62–2.45(m,4H),2.41–2.25(m,4H),2.15(dd,J＝12.6,3.3Hz,1H),2.04(d,J＝7.4Hz,1H),1.66–1.55(m,2H),1.54–1.45(m,2H),1.44(s,18H),1.44–1.35(m,2H),0.97(s,3H).
Compound 1
Compound 1-d (220 mg,0.35 mmoL) was dissolved in dry dichloromethane (2 mL) and CF was added 3 COOH (1 mL), gradually warmed to room temperature and stirred for 3 hours. Saturated sodium bicarbonate solution (10 mL) was adjusted to ph=9, dichloromethane (3×10 mL) was extracted, the organic phase was washed with saturated brine, 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=1:10) to give compound 1 (97.8 mg, yield 65%) as a colorless oil. 1 HNMR(500MHz,MeOH)δ5.70(dd,J＝17.5,10.8Hz,1H),5.37(s,1H),5.25(d,J＝6.4Hz,2H),5.15(s,1H),4.94–4.84(m,4H),4.28–3.65(m,5H),3.51(s,4H),3.40(t,J＝10.7Hz,5H),3.35–3.23(m,8H),3.21(s,2H),3.15(s,3H),2.12(dd,J＝10.9,4.9Hz,1H),2.01(dq,J＝12.4,5.9,5.2Hz,1H),1.60(dd,J＝11.9,6.0Hz,2H),1.50–1.33(m,4H),0.91(s,3H).
Example 2: preparation of Compound 2
Figure SMS_13
Compound 2
Compound 1 (157.8 mg,0.35 mmoL) was dissolved in dry methylene chloride (2 mL), formaldehyde (105 mg,3.5 mmoL) and sodium triacetoxyborohydride (440 mg,2.0 mmoL) were added to the reaction solution, the reaction solution was stirred at room temperature for 8 hours, an aqueous potassium carbonate solution was added to the reaction solution to adjust pH=9, methylene chloride was extracted, the organic phase was washed with saturated brine, 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 (methylene chloride: methanol=15:1) to give Compound 2 (62 mg, yield 39%) as a colorless oil. 1 H NMR(500MHz,MeOH)δ5.74(dd,J＝17.6,10.8Hz,1H),4.97(d,J＝1.7Hz,1H),4.85(d,J＝1.6Hz,1H),4.81(dd,J＝5.6,1.6Hz,2H),4.78(dd,J＝3.2,1.4Hz,1H),4.69(d,J＝1.8Hz,1H),3.13(d,J＝13.4Hz,1H),2.95(s,2H),2.73–2.65(m,4H),2.65–2.57(m,5H),2.41(dd,J＝9.3,6.5Hz,1H),2.34(dd,J＝5.6,3.8Hz,4H),2.30–2.27(m,2H),2.26(d,J＝3.3Hz,1H),2.24(d,J＝3.0Hz,1H),2.22(s,3H),2.22(s,3H),2.21–2.18(m,2H),2.18–2.12(m,4H),2.02(ddq,J＝11.8,7.5,3.8Hz,1H),1.67–1.51(m,2H),1.45(dddd,J＝15.7,9.9,6.1,2.6Hz,3H),1.40–1.28(m,2H),1.28–1.12(m,2H),0.92(s,3H).
Example 3: preparation of Compound 3
Figure SMS_14
Compound 3
Compound 1-b (100 mg,0.36 mmoL) was dissolved in dry DMF (1.5 mL). DIPEA (298 mg,2.31 mmoL) and Compound 2-a (119 mg,1.10 mmoL) were added at room temperature, and stirred at 100℃for 8 hours. DMF was removed under reduced pressure, the residue was diluted with ethyl acetate (20 mL) and washed with water (20 mL), and the aqueous phase was concentrated under reduced pressure. The crude product obtained after concentration was subjected to silica gel column chromatography (dichloromethane/methanol=40:1) to give compound 3 (30 mg, yield 31%) as a colorless oil. 1 H NMR(500MHz,CDCl 3 )δ5.81–5.69(m,1H),5.04–4.69(m,6H),3.30(d,J＝13.2Hz,1H),3.13(d,J＝13.0Hz,1H),3.03(d,J＝13.0Hz,1H),2.72(d,J＝13.3Hz,1H),2.17(d,J＝9.9Hz,7H),2.01(qd,J＝9.9,3.4Hz,1H),1.69–1.31(m,9H),0.96(s,3H),0.48–0.32(m,8H).
Example 4: preparation of Compound 4
Figure SMS_15
Intermediate 3-b
NaH (48.5 mg,1.2 mmol) was dissolved in dry DMF (1.5 mL) under ice-bath conditions, and after stirring for 15min compound 2-b was added and stirred at 70℃for 8 hours. After completion of the conversion, the reaction mixture was quenched by adding water (10 mL) and extracted with ethyl acetate (3X 15 mL). The combined organic phases were washed with saturated brine (2X 15 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=15:1) to give compound 4 (115 mg) as a colorless oilYield 62%). 1 H NMR(500MHz,CDCl 3 )δ5.85–5.77(m,1H),4.97–4.72(m,6H),3.76(dq,J＝50.4,16.4Hz,4H),2.50(d,J＝8.3Hz,2H),1.88(dd,J＝11.6,4.5Hz,2H),1.71–1.55(m,4H),1.47(d,J＝3.0Hz,22H),1.01(s,3H),0.72–0.46(m,9H).
Compound 4
Compound 3-b (115 mg,0.22 mmoL) was dissolved in dry methanol (2 mL). A solution of HCl in dioxane (2 mL,0.5 mmol) was added at 0deg.C and the mixture was gradually warmed to room temperature and stirred for 3 hours. Methanol was removed under reduced pressure, and the mixture was diluted with ethyl acetate and extracted (10 mL), and the aqueous phase was dried under reduced pressure to give Compound 4 (68 mg, yield 100%) as a white solid. 1 HNMR(500MHz,MeOH)δ5.88(dd,J＝17.5,10.8Hz,1H),5.41(s,1H),5.28(d,J＝5.0Hz,2H),5.20(s,1H),5.03–4.95(m,2H),3.86–3.74(m,2H),3.64(s,2H),2.76(dtt,J＝18.8,7.5,3.9Hz,2H),2.42(dd,J＝12.8,3.0Hz,1H),2.27(td,J＝10.2,8.7,6.0Hz,1H),1.79(dq,J＝13.4,2.8Hz,1H),1.73(ddd,J＝15.0,6.2,3.2Hz,1H),1.69–1.63(m,1H),1.63–1.57(m,1H),1.53(ddd,J＝14.8,7.8,3.6Hz,2H),1.08–0.96(m,7H),0.89(tq,J＝5.9,3.6,2.9Hz,4H).
Example 5: preparation of Compound 5
Figure SMS_16
Referring to the synthetic procedure of compound 3 in example 3, compound 5 (45 mg, yield 36%) was obtained as a yellow oil. 1 H NMR(500MHz,CDCl 3 )δ5.75(dd,J＝17.5,10.8Hz,1H),5.05(q,J＝1.5Hz,1H),4.94–4.88(m,4H),4.80(dt,J＝11.3,6.8Hz,5H),4.49–4.38(m,4H),3.94(dddd,J＝20.2,13.1,7.0,6.1Hz,2H),3.17(s,2H),3.09(dt,J＝2.5,1.2Hz,2H),2.05(td,J＝11.6,11.2,5.8Hz,2H),1.67–1.40(m,8H),0.99(s,3H).
Example 6: preparation of Compound 6
Figure SMS_17
Intermediate 5-b
Compound 5-a (74.5 mg,0.33 mmoL) was dissolved in dryDMF (1.0 mL). K is added at room temperature 2 CO 3 (50 mg,0.36 mmoL) and compound 2-b (30 mg,0.11 mmoL) were stirred at 80℃for 8 hours. DMF was removed under reduced pressure, the residue diluted with ethyl acetate (20 mL) and washed with water (20 mL) and the aqueous phase back extracted with ethyl acetate (20 mL). The combined organic phases were washed with saturated brine (2X 15 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product obtained after concentration was subjected to silica gel column chromatography (dichloromethane/methanol=40:1) to give compound 5-b (70 mg, yield 98%) as a colorless oil. 1 HNMR(500MHz,MeOH)δ5.85–5.77(m,1H),4.97–4.92(m,2H),4.90(dt,J＝3.3,1.6Hz,2H),4.84(s,1H),3.36(q,J＝5.2,4.8Hz,8H),3.17(s,2H),3.11(d,J＝7.4Hz,7H),3.05(d,J＝7.8Hz,2H),2.01(ddt,J＝14.9,11.8,3.2Hz,2H),1.71(ddd,J＝11.7,7.2,4.4Hz,8H),1.67–1.42(m,25H).
Compound 6
Referring to the synthetic procedure of compound 4 in example 4, compound 6 (18 mg, yield 60%) was obtained as a white solid. 1 H NMR(500MHz,MeOH)δ5.87(dd,J＝17.4,10.7Hz,1H),5.54(s,1H),5.37(d,J＝18.5Hz,2H),5.24(s,1H),5.03–4.96(m,2H),4.27(t,J＝9.2Hz,2H),4.16(dd,J＝24.0,11.4Hz,3H),4.00(td,J＝24.1,9.2Hz,5H),3.88(d,J＝12.6Hz,1H),3.77(d,J＝12.6Hz,1H),3.28(s,4H),3.20(d,J＝6.4Hz,4H),2.44–2.31(m,5H),2.20(t,J＝10.3Hz,5H),1.80–1.70(m,2H),1.70–1.56(m,3H),1.54(d,J＝7.3Hz,2H),1.05(s,3H).
Example 7: preparation of Compound 7
Figure SMS_18
Intermediate 6-b
Referring to the procedure for the synthesis of intermediate 5-b in example 6, compound 6-b (78 mg, yield 40%) was obtained as a yellow oil. 1 H NMR(500MHz,MeOH)δ5.72(dd,J＝17.5,10.8Hz,1H),4.98(s,1H),4.87(d,J＝1.5Hz,1H),4.82–4.77(m,2H),3.78–3.68(m,8H),3.22–3.13(m,3H),2.97(s,2H),2.65–2.58(m,3H),2.56(s,1H),2.53–2.39(m,5H),1.95(q,J＝6.8Hz,4H),1.33(s,21H),0.92(s,2H).
Compound 7
Compound 6-b (40 mg,0.06 mmoL) was dissolved in dry methanol (1 mL). A solution of HCl in dioxane (1 mL,0.5 mmol) was added at 0deg.C, and the mixture was gradually warmed to room temperature and stirred for 3 hours. Methanol was removed under reduced pressure, and the mixture was diluted with ethyl acetate and extracted (10 mL). The aqueous phase was concentrated under reduced pressure, and the crude product obtained after the concentration was subjected to C18 column chromatography (acetonitrile: water=0:1) to give compound 7 (23 mg, yield 67%) as a colorless oil. 1 H NMR(500MHz,CDCl 3 )δ5.87(dd,J＝17.5,10.7Hz,1H),5.56(s,1H),5.40(s,1H),5.35(s,1H),5.28(s,1H),5.03–4.93(m,3H),4.57–4.26(m,6H),4.15(dd,J＝19.4,10.7Hz,7H),3.83(t,J＝14.2Hz,4H),3.71–3.36(m,8H),2.58(tt,J＝7.9,3.9Hz,4H),2.48(dd,J＝12.7,2.9Hz,1H),2.32(d,J＝12.0Hz,1H),1.89(d,J＝13.0Hz,1H),1.78(dd,J＝12.7,5.3Hz,1H),1.70–1.53(m,4H),1.04(s,3H).
Example 8: preparation of Compound 8
Figure SMS_19
Intermediate 7-b
Referring to the synthetic procedure of compound 3 in example 3, compound 7-b (247 mg, yield 51.6%) was obtained as a yellow oil. 1 H NMR(500MHz,CDCl 3 )δ5.79(dd,J＝17.5,10.7Hz,1H),5.02(s,1H),4.94–4.80(m,4H),4.77(s,1H),3.74–3.49(m,8H),2.98(d,J＝13.9Hz,1H),2.89(d,J＝13.4Hz,1H),2.82(d,J＝13.4Hz,1H),2.57(d,J＝13.8Hz,1H),2.47–2.11(m,8H),2.10–1.95(m,2H),1.44(s,24H),0.99(s,3H).
Compound 8
Referring to the synthetic procedure for compound 3 in example 3, compound 7-b (22 mg, 51.6%) was obtained as a yellow oil. 1 H NMR(500MHz,MeOH)δ5.87(dd,J＝17.5,10.8Hz,1H),5.51(s,1H),5.44–5.37(m,2H),5.35(s,1H),5.04–4.93(m,2H),4.08–4.00(m,5H),3.91(s,4H),3.70(dd,J＝13.0,10.4Hz,2H),3.66(s,4H),3.42(d,J＝12.8Hz,1H),3.10(qd,J＝9.8,7.8,3.5Hz,2H),3.01(s,2H),2.98–2.85(m,2H),2.54(dd,J＝12.5,2.7Hz,1H),2.40–2.28(m,8H),2.01(d,J＝4.6Hz,2H),1.91–1.85(m,1H),1.75(d,J＝11.8Hz,1H),1.66(dd,J＝14.7,11.5Hz,1H),1.61(dd,J＝11.8,2.7Hz,1H),1.58–1.49(m,2H),1.25–1.15(m,2H),1.03(s,3H).
Example 9: preparation of Compound 9
Figure SMS_20
Referring to the synthetic procedure for compounds 1-d in example 1, compound 9 (87 mg, yield 73%) was obtained as a colorless oil. 1 H NMR(500MHz,DMSO)δ7.65(d,J＝2.3Hz,1H),7.58(d,J＝2.3Hz,1H),7.43(d,J＝1.8Hz,2H),6.25(dt,J＝4.1,2.1Hz,2H),5.84(dd,J＝17.4,10.8Hz,1H),5.02–4.88(m,3H),4.77(d,J＝31.0Hz,3H),4.62(d,J＝6.2Hz,4H),1.82(ddd,J＝67.2,12.3,3.3Hz,2H),1.59–1.29(m,6H),0.97(s,3H).
Example 10: preparation of Compound 10
Figure SMS_21
Referring to the synthetic procedure of compound 3-b in example 4, compound 10 (170 mg, yield 71.7%) was obtained as a colorless oil. 1 H NMR(500MHz,CDCl 3 )δ5.83(dd,J＝17.4,10.7Hz,1H),5.14(s,1H),5.04(d,J＝9.5Hz,2H),4.97–4.87(m,3H),3.98(d,J＝14.5Hz,1H),3.79–3.67(m,2H),3.28(d,J＝14.5Hz,1H),2.83(s,3H),2.80(s,3H),2.76(s,3H),2.73(s,3H),2.14(dd,J＝12.5,3.6Hz,1H),2.11–2.04(m,2H),1.68(d,J＝5.9Hz,1H),1.63(s,1H),1.61–1.54(m,3H),1.54–1.46(m,2H),1.02(s,3H).
Example 11: preparation of Compound 11
Figure SMS_22
Intermediate 10-b
Referring to the synthetic procedure of compound 3 in example 3, compound 10-b (170 mg, yield 54%) was obtained as a yellow oil. 1 H NMR(500MHz,CDCl 3 )δ5.73(dd,J＝17.6,10.8Hz,1H),4.98(s,1H),4.87(s,1H),4.84(d,J＝6.1Hz,1H),4.80(d,J＝3.1Hz,1H),4.72(s,1H),3.47–3.24(m,8H),2.96(d,J＝13.8Hz,1H),2.84(q,J＝13.4Hz,2H),2.58(d,J＝13.9Hz,1H),2.33–2.21(m,6H),2.15(t,J＝15.1Hz,3H),1.39(d,J＝1.5Hz,24H),0.93(s,3H).
Compound 11
Compound 10-b (115 mg,0.22 mmoL) was dissolved in dry dichloromethane (2 mL), CF3COOH was added at room temperature, and stirred for 3 hours. The reaction was diluted with DCM (20 mL), washed with water, aqueous saturated sodium bicarbonate solution adjusted to ph=9, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure to give compound 11 (80 mg, yield 98%) as a colourless oil. 1 H NMR(500MHz,DMSO)δ5.81(dd,J＝17.5,10.7Hz,1H),5.02(s,1H),4.91(s,2H),4.90–4.83(m,2H),4.78(s,1H),2.97(d,J＝13.7Hz,1H),2.93–2.68(m,9H),2.61(t,J＝15.4Hz,2H),2.41–2.14(m,8H),2.04(q,J＝16.8,14.1Hz,2H),1.67–1.60(m,1H),1.57(d,J＝12.1Hz,1H),1.52–1.39(m,3H),1.35(d,J＝10.8Hz,1H),0.97(s,3H).
Example 12: preparation of Compound 12
Figure SMS_23
Referring to the synthetic procedure of compound 1-d in example 1, compound 12 (66 mg, yield 91%) was obtained as a colorless oil. 1 H NMR(500MHz,DMSO)δ5.86–5.76(m,1H),4.99(d,J＝5.8Hz,1H),4.94–4.84(m,4H),4.77(d,J＝2.0Hz,1H),3.00(d,J＝13.4Hz,1H),2.87(s,2H),2.45–2.18(m,16H),2.15(s,6H),2.05(tt,J＝11.8,3.5Hz,2H),1.65–1.33(m,7H),0.97(s,3H).
Example 13: preparation of Compound 13
Figure SMS_24
Intermediate 12-b
Referring to the synthetic procedure of compound 1-d in example 1, compound 12-b (426 mg, yield 91%) was obtained as a yellow oil. 1 H NMR(400MHz,CDCl 3 )δ5.82(dd,J＝17.8,10.5Hz,1H),4.97–4.93(m,1H),4.92(q,J＝1.3Hz,1H),4.86(s,2H),4.76–4.72(m,2H),4.25(d,J＝17.1Hz,1H),4.16(d,J＝2.9Hz,2H),3.89(d,J＝17.1Hz,1H),1.99–1.87(m,2H),1.71–1.65(m,1H),1.64(s,4H),1.63–1.58(m,2H),1.46(d,J＝2.9Hz,35H),1.01(s,3H).
Compound 13
Referring to the synthetic procedure of compound 5-b in example 6, compound 13 (20 mg, yield 12%) was obtained as a colorless oil. 1 H NMR(500MHz,CDCl 3 )δ8.26(dd,J＝7.8,4.8Hz,4H),6.51(dt,J＝7.7,4.7Hz,2H),5.83(dd,J＝17.4,10.9Hz,1H),5.09(d,J＝1.3Hz,1H),4.98(q,J＝1.4Hz,1H),4.97–4.94(m,2H),4.92–4.89(m,1H),4.79(s,1H),4.11–4.01(m,3H),3.90(ddt,J＝16.1,5.2,1.4Hz,1H),2.04(td,J＝10.5,9.0,4.6Hz,2H),1.73–1.65(m,3H),1.52–1.45(m,3H),1.02(s,3H).
Example 14: preparation of Compound 14
Figure SMS_25
Intermediate 13-b
Referring to the synthetic procedure of compound 2 in example 2, compound 13 (214 mg, yield 100%) was obtained as a colorless oil. 1 H NMR(500MHz,CDCl 3 )δ4.03(s,2H),2.99(d,J＝68.6Hz,2H),2.79(d,J＝11.0Hz,2H),2.35(s,4H),1.44(s,9H).
Intermediate 14
Referring to the synthetic procedure of compound 3 in example 3, compound 14 (31 mg, yield 35%) was obtained as a yellow oil. 1 H NMR(500MHz,MeOH)δ5.85–5.78(m,1H),4.95–4.87(m,4H),4.82(d,J＝13.7Hz,3H),3.51(d,J＝6.1Hz,2H),3.48(t,J＝7.0Hz,2H),3.14–2.97(m,3H),2.87(d,J＝3.6Hz,5H),2.85–2.78(m,5H),2.41(s,5H),2.40(s,3H),2.08–2.00(m,2H),1.94(dd,J＝8.4,5.3Hz,2H),1.70–1.58(m,2H),1.58–1.50(m,3H),1.50–1.40(m,2H),1.01(s,3H).
Example 15: preparation of Compound 15
Figure SMS_26
Compound 15
Compound 14-a (27.6 mg,0.19 mmoL), HATU (82.1 mg,0.21 mmoL), DIPEA (46.4 mg,0.36 mmoL) were dissolved in DMF (1 mL), and Compound 12-c (30 mg,0.09 mmoL) was added thereto and stirred at room temperature for 8 hours. The reaction was extracted with DCM (2X 10 mL), and the organic phase was washed with saturated brine (2X 10 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=4:1) to give compound 1 (30 mg, yield 69%) as a colorless oil. 1 H NMR(500MHz,CDCl 3 )δ7.73(ddd,J＝8.5,5.1,2.5Hz,4H),7.11–6.95(m,4H),5.74(dd,J＝17.3,10.9Hz,1H),4.98(s,1H),4.93–4.83(m,4H),4.75(s,1H),4.07–3.91(m,3H),3.81(dd,J＝15.9,5.2Hz,1H),2.02–1.89(m,3H),1.83(s,1H),1.68–1.50(m,3H),1.50–1.38(m,3H),0.94(s,3H).
Example 16: preparation of Compound 16
Figure SMS_27
Compound 15-b
Compound 15-a (176 mg,0.538 mmoL) was dissolved in dry ethanol (2 mL) and Et was added 3 N (113 mg,1.12 mmoL) and Compound 11 (100 mg,0.224 mmoL) were stirred at 60℃for 4 hours. The reaction mixture was extracted with dichloromethane (2X 10 mL), and the organic phase was washed with saturated brine (2X 10 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 15-b (135 mg, yield 48%) as a yellow oil. 1 H NMR(500MHz,CDCl 3 )δ7.70(dd,J＝8.8,3.3Hz,2H),5.86–5.78(m,1H),5.38(d,J＝1.5Hz,4H),5.10(s,1H),5.00–4.97(m,2H),4.94(d,J＝1.3Hz,1H),4.92–4.89(m,1H),4.84(s,1H),3.88–3.61(m,8H),3.26–3.00(m,4H),3.00–2.82(m,4H),2.52(s,8H),1.34–1.19(m,8H),1.02(d,J＝3.2Hz,3H),0.99–0.94(m,4H).
Compound 16
Compound 15-b (135 mg,0.141 mmoL) was dissolved in dry dichloromethane (1 mL),adding CF 3 COOH (0.5 mL), stirred at room temperature for 3 hours. Saturated NaHCO was used as the reaction solution 3 The solution (10 mL) was washed, extracted with dichloromethane (2X 10 mL), and the organic phase was washed with saturated brine (2X 10 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to give compound 16 (35.7 mg, yield 36%) as a yellow oil. 1 H NMR(500MHz,CDCl 3 )δ7.69(dd,J＝5.7,3.4Hz,2H),5.79(dd,J＝17.5,10.7Hz,1H),5.44(d,J＝1.6Hz,3H),4.96(d,J＝4.1Hz,2H),4.92(d,J＝1.3Hz,1H),4.90–4.84(m,2H),4.83(s,1H),3.44(t,J＝5.5Hz,8H),3.10(d,J＝13.8Hz,1H),3.02–2.88(m,2H),2.70(d,J＝13.8Hz,1H),2.59–2.47(m,6H),2.40(d,J＝13.4Hz,2H),2.20(dd,J＝12.9,3.2Hz,1H),2.11–2.03(m,1H),1.62(td,J＝18.0,15.3,9.7Hz,2H),1.47(dtd,J＝17.8,13.6,4.5Hz,4H),0.99(s,4H).
Tumor cell proliferation inhibition assay
Evaluation of in vitro antitumor Activity
1. Experimental device and reagent
1.1 instruments
Biosafety cabinets (Shanghai hundred Biotechnology Co., ltd.), constant temperature carbon dioxide incubator (THERMO), enzyme linked immunosorbent assay (Spark), inverted microscope (Nikon), pipette kit (eppendorf) and centrifuge (beckman coulter).
1.2 reagents
DMEM (zhejiang seny biotechnology limited), RPMI 1640 (zhejiang seny biotechnology limited), mcCoy' S5A (zhejiang seny biotechnology limited), fatal Bovine Serum (BI), PBS (zhejiang seny biotechnology limited), trypsin (zhejiang seny biotechnology limited), DMSO (Coolaber) and CCK-8 (Coolaber).
1.3 cell lines
Human colon cancer cells (HCT 116), human lung cancer cells (A549), human prostate cancer cells PC-3, human glioma cells U87MG, and human glioma cells U251.
2. Experimental method
1) Taking test cells in logarithmic growth phase, passing through pancreatinAfter digestion and counting, the sample was taken at 5X 10 4 A concentration of 100. Mu.L per well (5X 10 per well) was inoculated into 96-well empty culture plates 3 Individual cells), at 37 ℃,5% co 2 Culturing in an incubator for 24 hours;
2) The test drugs were diluted to different concentrations with 10% FBS/DMEM or RPMI 1640 or McCoy' S5A complete medium. The experimental group changed the culture solution containing different concentration of the tested sample, the control group changed the culture solution containing the equal volume of solvent (DMSO), each group was set 3 parallel holes, at 37 ℃,5% CO 2 Culturing in an incubator for 48 hours;
wherein, PC-3 cells and A549 cells use RPMI 1640 complete medium, U87MG cells and U251 cells use DMEM complete medium, and HCT116 cells use McCoy' S5A complete medium.
3) Adding 10 mu L of CCK-8 solution into each well, culturing at 37 ℃ for 1-4 hours, and measuring the absorbance value (OD value) of each well at 490nm by an enzyme-labeled instrument;
4) The survival and inhibition were calculated using the following formula
Cell viability = [ (a) s -A b )/(A c -A b )]×100％
Inhibition ratio = [ (A) c -A s )/(A c -A b )]×100％
Using GraphPad Prism 7.0 software, an S-type dose-survival curve was drawn using a nonlinear regression model and IC was calculated 50 Values.
A s : absorbance of experimental wells (cell-containing medium, CCK-8, test drug)
A c : control wells (absorbance of cell-containing Medium, CCK-8, vehicle (DMSO))
A b : absorbance of blank wells (medium without cells and drug to be tested, CCK-8)
3. Experimental results
The proliferation inhibition of two tumor cells by the target compounds was measured by the above-described experimental methods, and the results are shown in table 1.
TABLE 1 Single concentration inhibition of target Compounds on U87 and U251 cells
Figure SMS_28
Figure SMS_29
Note that: wherein "A" represents that the inhibition rate is greater than or equal to 70%, "B" represents that the inhibition rate is between 20% and 70%, and "C" represents that the inhibition rate is below 20%.
The test results show that the inhibition effect of the compounds 1,2,6,7,9 and 10 on U87 and U251 cells is better than that of beta-elemene.
Further, it will be understood that various changes and modifications may be made by those skilled in the art after reading the foregoing description of the invention, and such equivalents are intended to fall within the scope of the claims appended hereto.
The above embodiments are not intended to limit the present invention, and the present invention is not limited to the above embodiments, and falls within the scope of the present invention as long as the present invention meets the requirements.

Claims (10)

1. A beta-elemene 13, 14-position symmetrical double-substituted derivative, or an optical isomer, a racemate, a single enantiomer, a possible diastereoisomer, or a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate and a solvate thereof, which is characterized in that the structure of the beta-elemene 13, 14-position symmetrical double-substituted derivative is shown as a formula (I):
Figure QLYQS_1
in formula (I):
R 1 、R 2 each independently selected from the following structural fragments: H. c (C) 1-6 Alkyl group of (C),
Figure QLYQS_2
-SO 2 R 3 、-COR 3 、-CO(O)R 3 And R is 1 、R 2 Not simultaneously H, methyl, ethyl and isopropyl;
R 3 selected from C 1-6 Alkyl, C of (2) 2-6 Alkenyl, C 3-6 Alkynyl, C 3-6 Cycloalkyl or 3-to 7-membered heterocyclyl;
or R is 1 And R is 2 Together with the N atom to which they are attached, 0-3 heteroatoms selected from N, O, S form a mono-or multi-heterocyclic structure.
2. The beta-elemene 13, 14-symmetrical disubstituted derivative according to claim 1, or an optical isomer, racemate, single enantiomer, possible diastereoisomer, or a pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein R is 1 And R is 2 Together with the N atom to which they are attached, 0 to 3 heteroatoms selected from N, O, S form a mono-or polyheterocyclic structure selected from one of the following structural fragments:
Figure QLYQS_3
wherein R is 4 Selected from hydrogen, C 1-6 Alkyl, C of (2) 3-6 Alkenyl, C 3-6 Alkynyl, C 2-6 Cycloalkyl, 3-to 7-membered heterocyclyl, -C (O) R 3 or-SO 2 R 3 。
3. The beta-elemene 13, 14-symmetrical disubstituted derivatives according to claim 1, or optical isomers, racemates, single enantiomers, possible diastereomers thereof, or pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates thereof, wherein the
Figure QLYQS_4
Selected from one of the following structural fragments: />
Figure QLYQS_5
4. The beta-elemene 13, 14-position symmetrical disubstituted derivative according to claim 1, or an optical isomer, racemate, single enantiomer, possible diastereoisomer, or a pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, wherein the beta-elemene 13, 14-position symmetrical disubstituted derivative is any one of compounds 1 to 25 shown in the following structures:
Figure QLYQS_6
5. a preparation method of a beta-elemene 13, 14-position symmetrical disubstituted derivative is characterized by adopting a synthesis route I:
Figure QLYQS_7
in formula (I):
R 1 、R 2 one of them is selected from C 1-6 Alkyl group of (C),
Figure QLYQS_8
-SO 2 R 3 、-COR 3 、-CO(O)R 3 And the other is H; wherein R is 3 Selected from C 1-6 Alkyl, C of (2) 2-6 Alkenyl, C 3-6 Alkynyl, C 3-6 Cycloalkyl or 3-to 7-membered heterocyclyl;
or R is 1 And R is 2 Together with the N atom to which they are attached, 0-3 heteroatoms selected from N, O, S form a mono-or multi-heterocyclic ring structure;
the method specifically comprises the following steps:
(1) Performing 13-position and 14-position allylic dichloro reaction on the beta-elemene A-1 to obtain an intermediate beta-elemene dichloro compound A-2;
(2) Will contain R 1 、R 2 The nitrogen heteroatom functional group structural fragment A-3 of the substituent is connected to the 13-position and the 14-position of the beta-elemene through nucleophilic substitution reaction to obtain the symmetrical double-substituted derivative of the 13, 14-position of the beta-elemene shown in the formula (I).
6. A preparation method of a beta-elemene 13, 14-position symmetrical disubstituted derivative is characterized by adopting a second synthesis route:
Figure QLYQS_9
wherein R is 1 、R 2 Each independently selected from the following structural fragments: c (C) 1-6 Alkyl group of (C),
Figure QLYQS_10
-SO 2 R 3 、-COR 3 、-CO(O)R 3 And R is 1 、R 2 Methyl, ethyl and isopropyl are not simultaneously present; r is R 3 Selected from C 1-6 Alkyl, C of (2) 2-6 Alkenyl, C 3-6 Alkynyl, C 3-6 Cycloalkyl or 3-to 7-membered heterocyclyl; or R is 1 And R is 2 Together with the N atom to which they are attached, 0-3 heteroatoms selected from N, O, S form a mono-or multi-heterocyclic ring structure;
the method specifically comprises the following steps:
(1) Performing 13-position and 14-position allylic dichloro reaction on the beta-elemene A-1 to obtain an intermediate beta-elemene dichloro compound A-2;
(2) Will contain R 2 Substituents and P 1 The nitrogen heteroatom functional group structural fragment A-4 of the protecting group is connected to the 13-position and the 14-position of the beta-elemene through nucleophilic substitution reaction to obtain a compound A-5;
(3) Removing the protecting group in compound A-5 and reacting the resulting amine intermediate with R 1 -X is subjected to substitution under basic conditions to obtain the compound of formula (I).
7. A preparation method of a beta-elemene 13, 14-position symmetrical disubstituted derivative is characterized by adopting a synthesis route III:
Figure QLYQS_11
wherein R is 1 、R 2 Each independently selected from the following structural fragments: c (C) 1-6 Alkyl group of (C),
Figure QLYQS_12
-SO 2 R 3 、-COR 3 、-CO(O)R 3 And R is 1 、R 2 Methyl, ethyl and isopropyl are not simultaneously present; r is R 3 Selected from C 1-6 Alkyl, C of (2) 2-6 Alkenyl, C 3-6 Alkynyl, C 3-6 Cycloalkyl or 3-to 7-membered heterocyclyl; or R is 1 And R is 2 Together with the N atom to which they are attached, 0-3 heteroatoms selected from N, O, S form a mono-or multi-heterocyclic ring structure;
the method specifically comprises the following steps:
(1) Performing 13-position and 14-position allylic dichloro reaction on the beta-elemene A-1 to obtain an intermediate beta-elemene dichloro compound A-2;
(2) Will contain R 2 Substituents and P 1 The nitrogen heteroatom functional group structural fragment A-4 of the protecting group is connected to the 13-position and the 14-position of the beta-elemene through nucleophilic substitution reaction to obtain a compound A-5;
(3) Removing the protecting group in compound A-5 and reacting the resulting amine intermediate with a catalyst containing R 1 Is subjected to reductive amination to obtain the compound of formula (I).
8. Use of a β -elemene 13, 14-symmetrical disubstituted derivative according to any one of claims 1 to 4, or an optical isomer, racemate, single enantiomer, possible diastereoisomer thereof, or a pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof, for the preparation of an antitumor drug.
9. An antitumor agent comprising a safe and effective amount of the beta-elemene 13, 14-position symmetrical disubstituted derivative according to any one of claims 1 to 4, or an optical isomer, racemate, single enantiomer, possible diastereomer thereof, or a pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate thereof.
10. An antitumor drug according to claim 9, further comprising a pharmaceutically acceptable carrier or excipient.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1153167A (en) * 1995-12-26 1997-07-02 中国科学院大连化学物理研究所 Nitrogenous derivs. of elemene and their use as anticancer drugs
US20060014987A1 (en) * 2003-07-07 2006-01-19 Lan Huang Synthesis of beta-elemene, intermediates thereto, analogues and uses thereof
CN1844105A (en) * 2006-05-07 2006-10-11 沈阳药科大学 Beta-elemene derivatives containing nitrogen and their preparation method and use
CN113698401A (en) * 2021-09-14 2021-11-26 杭州师范大学 Beta-elemene macrocyclic derivatives, preparation method and application thereof
CN114573459A (en) * 2022-02-28 2022-06-03 杭州师范大学 Beta-elemene diamine substituted derivative and preparation method and application thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1153167A (en) * 1995-12-26 1997-07-02 中国科学院大连化学物理研究所 Nitrogenous derivs. of elemene and their use as anticancer drugs
US20060014987A1 (en) * 2003-07-07 2006-01-19 Lan Huang Synthesis of beta-elemene, intermediates thereto, analogues and uses thereof
CN1844105A (en) * 2006-05-07 2006-10-11 沈阳药科大学 Beta-elemene derivatives containing nitrogen and their preparation method and use
CN113698401A (en) * 2021-09-14 2021-11-26 杭州师范大学 Beta-elemene macrocyclic derivatives, preparation method and application thereof
CN114573459A (en) * 2022-02-28 2022-06-03 杭州师范大学 Beta-elemene diamine substituted derivative and preparation method and application thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
COLUMBUS, OHIO, US: "REGISTRY[online]", 《STN检索报告 US REGISTRY》, 22 November 1999 (1999-11-22), pages 1 - 2 *
徐莉英: "β-榄香烯衍生物的合成及抗癌活性研究", 《中国博士学位论文全文数据库 医药卫生科技辑》, no. 04, 15 April 2012 (2012-04-15), pages 079 - 3 *
罗带暄: "《化学试剂与精细化学品合成基础》", 31 May 1991, 高等教育出版社, pages: 507 *

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