CN1844105A - Beta-elemene derivatives containing nitrogen and their preparation method and use - Google Patents
Beta-elemene derivatives containing nitrogen and their preparation method and use Download PDFInfo
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Abstract
The invention discloses an A-elemene nitrogenous derivant, it providing the preparation and usage of A-elemene nitrogenous derivant, the structural formula is as picture shows, wherein R represent aliphatic amido of C1-C20, aromatic amido; amido of C1-C20 containing heterocycle; wherein cyclohexane skeleton has three chirality center. This derivant may has some physiologically active like alkaloid; meanwhile, it can increase polarity and making the synthesized derivant has certain alkalinity and it can reach the purpose of improving water-solubility salt-forming with inorganic acid or organic acid.
Description
Technical field:
The present invention relates to new beta-elemene derivatives containing nitrogen and preparation method thereof, relate to intermediate of synthetic described beta-elemene derivatives containing nitrogen and preparation method thereof, and relate to the application of described beta-elemene derivatives containing nitrogen.
Background technology:
From zingiberaceous plant RADIX CURCUMAE (Curcuma wenyujin Y.H.Chen et C.Ling), claim again in the volatile oil of warm curcuma zedoary, isolated beta-elemene (I) is the main component of the broad-spectrum anti-cancer drug Elemenum Emulsion developed voluntarily of China, (Guo Yong TOOLING, Wu Xiuying, Chen Yuren. the isolation identification of Elemenum [J] in the warm Rhizoma Curcumae volatile oil. bulletin of Chinese materia medica, 1983,8 (30): 31-33.) beta-elemene has higher selectivity to tumour cell, no bone marrow inhibition, there are not tangible liver, renal toxicity, has the double effect that selectivity suppresses tumor cell proliferation and improves immunologic function, clinically kinds of tumors there is definite curative effect, is the antitumor characteristics of wide spectrum, (Wang XW.Elemene[J] .DrugsFut, 1998,23 (3): 266-270; Money army. the pharmacology of PTS Elemenum and clinical .[J]. Chinese clinical tumor, 1996,23 (6): 453-455; Chen Jianqun, Wu Kejian. injection liquid is to the influence [J] of malignant tumor patient T lymphocyte subsets. Chinese clinical tumor, 1996,23 (4): 299-301).At present Elemenum Emulsion be applied to as the two wires cancer therapy drug clinical, its antitumous effect than 5 FU 5 fluorouracil, cis-platinum etc. a little less than, not obvious to some solid tumor curative effect.And the Elemenum poorly water-soluble, the formulation of clinical use has only emulsion, less stable, and intravenous administration has tangible blood vessel irritation, is difficult to arrive site of action, has limited its clinical application.Once found also in early-stage Study that some were beta-element nitrogenous, the antitumour activity of containing oxygen derivative and water-soluble all strong than beta-elemene, (Cheng Baoguo, Hu Jiehan, Dong Jinhua. elemene derivatives containing nitrogen and as cancer therapy drug [P]. China: CN 1066444C.2001,5,30, Cheng Baoguo, Hu Jiehan, Dong Jinhua, Deng. elemene hydroxyls derivs and as cancer therapy drug [P]. China: CN 1052716C.200,5,24.)
Nitrogen-containing heterocycle compound plays the important physical effect in animal and plant body, all contain this class formation in the base of most of medium-height grass the effective elements of the medicines, nucleic acid; In modern medicines, nitrogen-containing heterocycle compound has also accounted for quite great proportion.This research and design is introduced amido or heterocycle amido in the beta-elemene structure, expectation can improve the hydrophilic while, strengthens with human body interacting and the raising antitumour activity, finds to have the PTS of Elemenum effect characteristics.
Summary of the invention:
The object of the present invention is to provide the beta-elemene derivatives containing nitrogen of novel structure, this compounds structure activity relationship is inquired into, seek the beta-elemene derivatives containing nitrogen of good water solubility, active height, novel structure, and provide its preparation method, be applied to the cancer therapy drug field, initiative beta-elemene PTS.
The invention provides the following formula III of beta-elemene derivatives containing nitrogen structure:
Wherein R represents fatty amido, the aromatic amino of C1-C20; C1-C20 contains the heterocyclic amido.
Wherein the hexanaphthene skeleton has three chiral centres.
Preferably, the invention provides the beta-elemene derivatives containing nitrogen of formula III, wherein:
Wherein R represents 2,3, and 4,5,6 randomly have one or several substituent piperazinyl (2,3,4,5,6 substituting group is the C1-C20 alkyl, C1-C20 alkoxyl group, C6-C20 aryl, C1-C20 ester group, C1-C20 acyl group, C1-C20 amide group); 2,3,4,5,6 randomly have one or several substituent piperidyl (substituting group is the C1-C20 alkyl, C1-C20 alkoxyl group, C6-C20 aryl, C1-C20 ester group, C1-C20 acyl group, C1-C20 amide group); 2,3,5,6, the position randomly has one or several substituent morpholinyl, and (substituting group is the C1-C20 alkyl, C1-C20 alkoxyl group, C6-C20 aryl, the C1-C20 ester group, C1-C20 acyl group, C1-C20 amide group), Pyrrolidine base and 2,3,4,5 randomly have one or several substituent Pyrrolidine base (substituting group are the C1-C20 alkyl, C1-C20 alkoxyl group, C6-C20 aryl, the C1-C20 ester group, C1-C20 acyl group, C1-C20 amide group); The substituted imidazole base.
Wherein the hexanaphthene skeleton has three chiral centres.
More preferably, the invention provides the beta-elemene derivatives containing nitrogen of formula III, wherein:
On behalf of C1-C20, R contain the heterocyclic secondary amine; 2,3,4,5,6 randomly have one or several substituent piperazinyl (2,3,4,5,6 substituting group is the C1-C20 alkyl, C1-C20 alkoxyl group, C6-C20 aryl, C1-C20 acyl group); 2,3,4,5,6 randomly have one or several substituent piperidyl (substituting group is the C1-C20 alkyl, C1-C20 alkoxyl group, C6-C20 aryl, C1-C20 acyl group); 2,3,5; 6, the position randomly has one or several substituent morpholinyl, and (substituting group is the C1-C20 alkyl, the C1-C20 alkoxyl group; the C6-C20 aryl, the C1-C20 acyl group), Pyrrolidine base and 2; 3; 4,5 randomly have one or several substituent Pyrrolidine base (substituting group are the C1-20 alkyl, the C1-C20 alkoxyl group; the C6-C20 aryl, the C1-C20 acyl group).
Wherein the hexanaphthene skeleton has three chiral centres.
In the most preferred embodiment of the present invention, the R of formula III represents 3,5-dimethyl-1-piperazinyl; 4-methyl isophthalic acid-piperazinyl, 4-ethyl-1-piperazinyl, 4-sec.-propyl-1-piperazinyl; 4-isobutyl--1-piperazinyl, 4-benzyl-1-piperazinyl, 4-(3-chloro-phenyl-)-1-piperazinyl; 4-(2-p-methoxy-phenyl)-1-piperazinyl, 4-(4-p-methoxy-phenyl)-1-piperazinyl, 4-(1; 4-benzdioxan-2-formyl radical)-the 1-piperazinyl; 1-Pyrrolidine base, 2-(2-thienyl) ethylamino-, N-cyclohexylamino.
Beta-elemene derivatives containing nitrogen pharmaceutical salts of the present invention refers to conventional acid salt, and it has kept the biological effectiveness and the characteristic of formula III, and the salt that becomes with suitable non-toxicity organic acid or mineral acid.Example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, phosphoric acid, nitric acid, acetate, tartrate, Whitfield's ointment, methylsulfonic acid, Succinic Acid, citric acid, oxysuccinic acid, lactic acid, fumaric acid, toxilic acid etc.In the present invention, the particularly preferred pharmaceutical salts of The compounds of this invention is hydrochloride or maleate.
Wherein the hexanaphthene skeleton has three chiral centres.
The invention provides and contain above-mentioned beta-elemene derivatives containing nitrogen and pharmaceutical composition that pharmaceutically can received vehicle.
Beta-elemene derivatives containing nitrogen of the present invention or composition can be used to prepare various anti-tumor drugs.
Particularly the invention provides the purposes of beta-elemene derivatives containing nitrogen of the present invention in the various anti-tumor drugs of preparation.
The present invention provides the preparation method of above-mentioned beta-elemene derivatives containing nitrogen in addition, it is characterized in that: obtain corresponding nitrogen containing derivative by dichloro-beta-elemene intermediate formula II and itrogenous organic substance reaction.So-called itrogenous organic substance is aliphatic amide, the aromatic amine of C1-C20; C1-C20 contains heterocyclic amine.
Provide the synthetic route that is used for synthetic beta-elemene derivatives containing nitrogen as follows in the invention:
Solvent for use is a common solvent in the above-mentioned beta-elemene derivatives containing nitrogen preparation process of the present invention, as ethanol, sherwood oil, N, dinethylformamide, methylene dichloride or the like.
Advantage of the present invention is: described beta-elemene derivatives containing nitrogen, be for improving the water-soluble of beta-elemene and improving antitumour activity, and in its molecule, introduce nitrogen-containing group, as institute's synthetic compounds such as nitrogen heterocyclic rings, these derivatives may have the physiologically active of some analogous alkaloid, simultaneously can increase polarity, and make institute's synthetic derivative present certain alkalescence, be convenient to reach the water miscible purpose of improvement with mineral acid or organic acid salify.
Embodiment:
The preparation of embodiment 1 dichloro-beta-elemene intermediate (II)
Add beta-elemene 26.0g (0.127mol) in the three-necked bottle of mechanical stirrer is housed, Glacial acetic acid 38mL (0.67mol) is cooled to about 5 ℃ with ice-water bath, under agitation drip chlorine bleach liquor 198mL (1.41mol/L, 0.275mol), about 4h dropwises, and continues reaction 1h.Reaction solution is transferred in the separating funnel of 1L, with 50mL sherwood oil (60-90 ℃) extracting twice, merges organic phase, water Xian is to neutrality, anhydrous sodium sulfate drying.Steam to remove sherwood oil and get the 30.5g brown oil, GC shows and contains monochloro in the product for Elemenum 15.0%, dichloro-Elemenum 54.6%.Through silica gel column chromatography, separate with the sherwood oil wash-out.
2 couples of embodiment replace the logical method of preparation of beta-elemene derivatives containing nitrogen
With 16mmol amine, two chloro beta-elemene 4mmol, triethylamine 16mmo is dissolved in 10mL N, and 8-20h refluxes in the dinethylformamide.Leach the triethylamine hydrochloride needle crystal of generation, filtrate adding 10mL water is used sherwood oil-extracted with diethyl ether 4 times, and extraction liquid is dry to be concentrated, and separates with silica gel column chromatography, gets product.
Embodiment 3
Synthetic
With 3, the 5-lupetazin is a raw material, presses 2 couples of embodiment and replaces the logical method preparation of beta-elemene derivatives containing nitrogen preparation.Drip the toxilic acid acetone soln and become maleate, get white crystal, mp192.0-194.5 ℃.MS(m/z)：429(M+1)；
1H-NMR(CDCl
3)δ(ppm)：1.00(15H，m)，1.40-1.65(8H，m)，2.09(4H，m)，2.60-2.98(12H，m，)，4.78-5.03(6H，m)，5.76-5.82(1H，dd)
Embodiment 4
Synthetic
With 13, two [1-(3,5-lupetazin base)]-beta-elemene 0.3g (0.7mmol) of 14-are dissolved in formalin 0.55mL (7mmol) solution, be warming up to 60-70 ℃ under stirring, slowly drip formic acid 0.35g (8mmol), at 80 ℃ of reaction 12h, putting cold back transfers pH to be about 11 with 10M sodium hydroxide, use extracted with diethyl ether, combining extraction liquid, washing, anhydrous sodium sulfate drying, concentrate,, get light yellow oily product through column chromatography for separation.MS(m/z)：457(M+1)；
1H-NMR(CDCl
3)δ(ppm)：1.00(3H，s)，1.10(12H，m)，1.44-1.57(6H，m)，1.61-2.00(6H，m)，2.31(9H，s)，2.60-3.70(9H，m)，4.80-5.04(6H，m)，5.74-5.84(1H，dd)
Embodiment 5
Synthetic
With the N-ethyl piperazidine is raw material, presses the preparation of embodiment 3 methods and becomes maleate, gets white crystal, mp.179.0-181.5 ℃.MS(m/z)：429(M+1)；
1H-NMR(CDCl
3)δ(ppm)：0.96(3H，s)，1.99(6H，t)，1.39-1.43(4H，m)，1.61(2H，m)，2.08-2.50(6H，m)，2.73-3.13(16H，m)，3.25(4H，m)，4.85-5.10(6H，m)，5.77(1H，dd)
Embodiment 6
Synthetic
With N-sec.-propyl piperazine is raw material, presses the preparation of embodiment 3 methods and becomes maleate, gets white crystal, mp185.5-187.0 ℃ of MS (m/z): 457 (M+1);
1H-NMR (CDCl
3) δ (ppm): 1.04 (3H, s), 1.00 (12H, d), 1.36-1.79 (6H, m), 2.02-2.78 (20H, m), 2.94-3.17 (4H, m), 4.72-5.15 (6H, m), 5.85 (1H, dd)
Embodiment 7
Synthetic
With the N-isobutyl piperazine is raw material, presses the preparation of embodiment 3 methods and becomes maleate, gets white crystal, mp184.5-187.0 ℃ of MS (m/z): 485 (M+1);
1H-NMR (CDCl
3) δ (ppm): 0.93 (12H, d), 0.95 (3H, s), 1.23-1.42 (4H, m), 1.61-1.65 (2H, m), 1.99 (4H, m), 2.50-3.66 (24H, m), 4.84-5.14 (6H, m), 5.77-5.86 (1H, dd)
Embodiment 8
Synthetic
With the N-benzyl diethylenediamine is raw material, presses the preparation of embodiment 3 methods and becomes maleate, gets white crystal, mp103.4-107.6 ℃.MS(m/z)：553(M+1)；
1H-NMR(CDCl
3)δ(ppm)：0.98(3H，s)，1.39-1.60(6H，m)，1.72(2H，s，-CH＜)，2.45(16H，br s)，2.65(1H，d)，2.90(2H，s，＞N-CH
2-)，3.02(1H，d)，3.51(4H，s)，4.76-5.03(6H，m)，5.76-5.85(1H，dd)，7.24-7.31(10H，m)
Embodiment 9
Synthetic
With N-(2-chloro-phenyl-) piperazine hydrobromide is raw material, presses 2 couples of embodiment and replaces the logical method preparation of beta-elemene derivatives containing nitrogen preparation.MS(m/z)：592(M-1)；
1H-NMR(CDCl
3)δ(ppm)：1.05(3H，s)，1.50-1.69(8H，m)，2.23(1H，d)，2.24-2.59(8H，m)，2.73(1H，d)，3.00(2H，s)，3.15(8H，brs)，4.85-5.11(6H，m)，5.75-5.85(1H，dd)，6.74-6.88(6H，m)，7.12-7.19(2H，m)
Embodiment 10
Synthetic
With N-(2-p-methoxy-phenyl) piperazine is raw material, presses embodiment: 2 pairs replace the logical method preparation of beta-elemene derivatives containing nitrogen preparation.MS(m/z)：585(M+1)；
1H-NMR(CDCl
3)δ(ppm)：1.07(3H，s)，1.47-1.72(6H，m)，2.22-2.34(3H，m)，2.65-2.82(9H，m)，3.03-3.18(10H，m)；3.89-3.90(6H，s)，4.87-5.14(6H，m)，5.85-5.91(1H，dd)，6.88-7.05(8H，m)
Embodiment 11
Synthetic
With N-(4-p-methoxy-phenyl) piperazine is raw material, presses 2 couples of embodiment and replaces the logical method preparation of beta-elemene derivatives containing nitrogen preparation.MS(m/z)：584(M
+)；
1H-NMR(CDCl
3)δ(ppm)：1.02(3H，s)，1.51-1.78(6H，m)，2.11-2.26(2H，m)，2.26-2.73(10H，m)，2.99-3.07(10H，m)，3.76(6H，s)，4.28-5.08(6H，m)，5.80(1H，dd)，6.81-6.85(8H，m)
Embodiment 12
Synthetic
With N-(1,4-benzdioxan diformyl) piperazine hydrochloride is raw material, presses 2 couples of embodiment and replaces the logical method preparation of beta-elemene derivatives containing nitrogen preparation.MS(m/z)：697(M+1)；
1H-NMR(CDCl
3)δ(ppm)：1.02(3H，s)，1.49-1.74(8H，m)，2.48(8H，brs)，2.88-3.11(4H，m)，3.60(4H，brs)，3.73(4H，brs)，4.28-4.50(5H，m)，4.81-5.30(7H，m)，5.77-5.80(1H，dd)，6.89(8H，d)
Embodiment 13
Synthetic
With the Pyrrolidine is raw material, by embodiment 3 methods preparations and become into maleate, white crystal, 121.0-123.5mp ℃.MS(m/z)：343(M+1)；
1H-NMR(CDCl
3)δ(ppm)：1.00(3H，s)，1.40-1.60(6H，m)，1.76(7H，brs)，2.06-2.30(4H，m)，2.46(7H，brs)，2.70(1H，d)，3.03(1H，d)，3.06(1H，d)，3.23(1H，d)，4.70-5.07(6H，m)，5.77-5.86(1H，dd)
Embodiment 14
Synthetic
With the 2 thiophene ethyl amine is raw material, presses 2 couples of embodiment and replaces the logical method preparation of beta-elemene derivatives containing nitrogen preparation, and logical hydrogen chloride gas becomes hydrochloride in ether.Get white crystals, mp210.5-212.3 ℃.MS(m/z)：455(M+1)；
1H-NMR(CDCl
3)δ(ppm)：0.98(3H，s)，1.35(1H，m)，1.54-1.68(4H，m)，2.09(1H，d)，2.30(1H，brs)，2.55(1H，d)，3.18-3.61(11H，m)，4.01(1H，d)，4.89-5.58(6H，m)，5.70-5.79(1H，dd)，6.93(4H，s)，7.16(2H，s)
Embodiment 15
Synthetic
Product with embodiment 14 is a raw material, and the method for pressing embodiment 4 is synthetic.MS(m/z)：483(M+1)；
1H-NMR(CDCl
3)δ(ppm)：1.00(3H，s)，1.41-1.58(8H，m)，2.20(6H，m)，2.60-2.66(5H，m)，2.98(7H，m)，4.77-5.04(6H，m)，5.77(1H，dd)，6.80(2H，m)，6.91(2H，m)，7.11(2H，m)
Embodiment 16
Synthetic
With the hexahydroaniline is raw material, presses the preparation of embodiment 14 methods and becomes hydrochloride.mp241.0-245.3℃。MS(m/z)：399(M
+)；
1H-NMR(CDCl
3)δ(ppm)：1.01(3H，s)，1.24-1.35(7H，m)，1.56-1.69(13H，m)，2.14-2.35(7H，m)，2.54(1H，d)，2.96(2H，m)，3.40(1H，m)，3.52(1H，m)，3.69(1H，m)，3.88(1H，m)，4.96-5.86(6H，m)，5.73-5.83(1H，dd)
Embodiment 17
Synthetic
Product with embodiment 16 is a raw material, and the method for pressing embodiment 4 is synthetic.MS(m/z)：427(M+1)；H-NMR(CDCl
3)δ(ppm)：0.99(3H，s)，1.15-1.25(11H，m)，1.43-1.63(9H，m)，1.77(8H，m)，2.15(6H，m)，2.40(2H，m)，2.77(1H，d)，3.02(2H，d)，3.14(1H，d)，4.80-5.07(6H，m)，5.76-5.86(1H，dd)
Following embodiment is an anticancer pharmacology activity experiment of the present invention, also can select the cancer cells of other kind the following examples that experimentize not limit that this is anti-bright.
Embodiment 18
Measured the inhibited proliferation of target compound with srb assay to three-type-person's cancer cells.The Hela that takes the logarithm vegetative period, SGC-7901, HL-60 three-type-person cancer cells are with 4 * 10
4Cell/mL is inoculated in 96 orifice plates.At 37 ℃, 5%CO
2The saturated humidity incubator in cultivate 12h, after 48h was handled in dosing, the cell HL-60 that swims needed every hole to add the 80%TCA of 4 ℃ of precoolings of 50 μ L, making its final concentration is 16%; Attached cell then needs every hole to add the 50%TCA of 4 ℃ of precoolings of 50 μ L, and making its final concentration is 10%.Behind 4 ℃ of refrigerator fixed cell 1h, add 0.4%SRB, 50 μ L/well, room temperature dyeing 30min.Add 10mMTris alkali at last, 150 μ L/well, the 15min that vibrates on micro oscillator all dissolves until dyestuff, utilizes microplate reader to survey the absorbance (OD value) of every hole solution at the 540nm place, deducts the blank well absorbance.Calculate as follows medicine to the inhibiting rate of tumour cell in-vitro multiplication (Inhibition Rate, IR%):
IR％＝(1-OD
sample/OD
control)×100％
Half-inhibition concentration (IC with ICP1.0.0 computed in software medicine
50).
Measure 15 compounds among the embodiment 3-17 to three-type-person's cancer cells HL-60, Hela, SGC-7901 cells in vitro inhibited proliferation with aforesaid method, calculated the half-inhibition concentration (IC of medicine
50) as shown in table 1.Wherein 13 compound activities are higher than lead compound beta-elemene (I); The IC that 3 compounds are arranged
50Value is than low 2 orders of magnitude of beta-elemene.The result shows and improve by the polar group of in the beta-elemene structure, introducing nitrogen atom that it is water-soluble, strengthened the external antitumour activity of beta-elemene really.
Table 1 target compound is to the half-inhibition concentration (IC of cancer cells
50)
| Structural formula of compound | IC 50(μM) | ||
| SGC-7901 | Hela | HL-60 |
Embodiment 19
Mtt assay has been measured the inhibited proliferation of part target compound to breast cancer cell line mcf-7 and adriamycin-resistant breast cancer cell line mcf-7/Adr and K562 cell.The cell of taking the logarithm vegetative period is inoculated in 96 orifice plates with the cell density of every 2000/mL in hole, and every hole 100 μ l place 37 ℃, 5%CO
2Hatched in the incubator 24 hours, and made it adherent.Then variant concentration test-compound is added in 96 orifice plates, continue to cultivate after 4 days, every hole adds 50 μ lMTT solution (2mg/mL), hatched 4 hours for 37 ℃, the sucking-off supernatant liquor, every hole adds 200 μ lDMSO, after the room temperature micro oscillation made the bluish voilet crystallization fully dissolve in 10 minutes, measures every hole absorbance in microplate reader 570nm place.Be subjected to the absorbance of reagent thing to compare the growth inhibition ratio of trying to achieve the medicine pair cell not add.Calculate as follows medicine to the inhibiting rate of tumour cell in-vitro multiplication (Inhibition Rate, IR%):
IR％＝(1-OD
sample/OD
control)×100％
Half-inhibition concentration (IC with ICP1.0.0 computed in software medicine
50).
The results are shown in Table 2, show that beta-elemene and these target compounds suppress the IC of breast cancer cell line mcf-7 and these two kinds of cells of adriamycin-resistant breast cancer cell line mcf-7/Adr
50Be worth basic identically, illustrate that adriamycin-resistant breast cancer cell line mcf-7/Adr does not have resistance to these 13 beta-elemene derivatives.Therefore this compounds is expected to develop the medicine that becomes the treatment drug-resistant tumor.
Table 2 target compound is to the half-inhibition concentration (IC of cancer cells
50)
Claims (9)
1. beta-elemene derivatives containing nitrogen, it is characterized in that: its structural formula is as follows
Wherein R represents fatty amido, the aromatic amino of C1-C20; C1-C20 contains the heterocyclic amido;
Wherein the hexanaphthene skeleton has three chiral centres.
2, a kind of beta-elemene derivatives containing nitrogen according to claim 1, it is characterized in that: wherein R represents 2,3,4,5,6 randomly have one or several substituent piperazinyl, 2,3,4,5,6 substituting group is the C1-C20 alkyl, the C1-C20 alkoxyl group, the C6-C20 aryl, the C1-C20 ester group, C1-C20 acyl group, C1-C20 amide group; 2,3,4,5,6 randomly have one or several substituent piperidyl, and substituting group is the C1-C20 alkyl, C1-C20 alkoxyl group, C6-C20 aryl, C1-C20 ester group, C1-C20 acyl group, C1-C20 amide group; 2,3,5,6, the position randomly has one or several substituent morpholinyl, and substituting group is the C1-C20 alkyl, C1-C20 alkoxyl group, C6-C20 aryl, the C1-C20 ester group, C1-C20 acyl group, C1-C20 amide group, Pyrrolidine base and 2,3,4,5 randomly have one or several substituent Pyrrolidine base, substituting group is the C1-C20 alkyl, C1-C20 alkoxyl group, C6-C20 aryl, the C1-C20 ester group, C1-C20 acyl group, C1-C20 amide group; The substituted imidazole base;
Wherein the hexanaphthene skeleton has three chiral centres.
3, a kind of beta-elemene derivatives containing nitrogen according to claim 2 is characterized in that: wherein on behalf of C1-C20, R contain the heterocyclic secondary amine; 2,3,4,5,6 randomly have one or several substituent piperazinyl, and 2,3,4,5,6 substituting group is the C1-C20 alkyl, C1-C20 alkoxyl group, C6-C20 aryl, C1-C20 acyl group; 2,3,4,5,6 randomly have one or several substituent piperidyl, and substituting group is the C1-C20 alkyl, C1-C20 alkoxyl group, C6-C20 aryl, C1-C20 acyl group; 2,3,5,6, the position randomly has one or several substituent morpholinyl, and substituting group is the C1-C20 alkyl, the C1-C20 alkoxyl group, C6-C20 aryl, C1-C20 acyl group, Pyrrolidine base and 2,3,4,5 randomly have one or several substituent Pyrrolidine base, and substituting group is the C1-C20 alkyl, the C1-C20 alkoxyl group, the C6-C20 aryl, the C1-C20 acyl group;
Wherein the hexanaphthene skeleton has three chiral centres.
4, a kind of beta-elemene derivatives containing nitrogen according to claim 3, it is characterized in that: wherein R represents 3,5-dimethyl-1-piperazinyl, 4-methyl isophthalic acid-piperazinyl, 4-ethyl-1-piperazinyl, 4-sec.-propyl-1-piperazinyl, 4-isobutyl--1-piperazinyl, 4-benzyl-1-piperazinyl, 4-(3-chloro-phenyl-)-1-piperazinyl, 4-(2-p-methoxy-phenyl)-1-piperazinyl, 4-(4-p-methoxy-phenyl)-1-piperazinyl, 4-(1,4-benzdioxan-2-formyl radical)-the 1-piperazinyl, 1-Pyrrolidine base, 2-(2-thienyl) ethylamino-, N-cyclohexylamino;
Wherein the hexanaphthene skeleton has three chiral centres.
5,, a kind of beta-elemene derivatives containing nitrogen pharmaceutical salts according to claim 1 is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, phosphoric acid, nitric acid, acetate, tartrate, Whitfield's ointment, methylsulfonic acid, Succinic Acid, citric acid, oxysuccinic acid, lactic acid, fumaric acid, toxilic acid.
6, beta-elemene derivatives containing nitrogen pharmaceutical salts according to claim 1 is a hydrochloric acid, fumaric acid, toxilic acid.
7, a kind of preparation method of a kind of beta-elemene derivatives containing nitrogen according to claim 1 is characterized in that: obtain corresponding nitrogen containing derivative by dichloro-beta-elemene intermediate and itrogenous organic substance reaction, the structural formula of intermediate is:
The synthetic route of beta-elemene derivatives containing nitrogen is as follows:
Solvent for use is a common solvent in the above-mentioned beta-elemene derivatives containing nitrogen preparation process, and as ethanol, sherwood oil, N, dinethylformamide, methylene dichloride, so-called itrogenous organic substance are aliphatic amide, the aromatic amine of C1-C20; C1-C20 contains heterocyclic amine.
8, a kind of right that contains requires 1 described beta-elemene derivatives containing nitrogen, it is characterized in that: said composition is by olive β-fragrant alkene nitrogen containing derivative and pharmaceutical composition that pharmaceutically can received vehicle.
9, the purposes of beta-elemene derivatives containing nitrogen is characterized in that: the application of described beta-elemene derivatives containing nitrogen in the preparation cancer therapy drug.
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