CN1844084A - Beta-elemene amino acid or carboxylic acid derivatives and preparation process and use thereof - Google Patents
Beta-elemene amino acid or carboxylic acid derivatives and preparation process and use thereof Download PDFInfo
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Abstract
The invention discloses a A-elemene amino acid or carboxylic acid derivants, Process for preparing, usage and preparation; the structural formula of derivant is III. Wherein R represent C2-C20 every kinds of alpha-, beta-, gamma- amino acids; Every kinds of amino acids of C1-C20; wherein cyclohexane skeleton has three chirality center. This derivant is used to improve water-solubility and anticancer active of A-elemene amino acid, introducing amino acid which contains synthetic compounds of amidol or carboxy group, this derivant has stronger physiologically active and larger polarity, reaching the purpose of improving water-solubility.
Description
Technical field:
The present invention relates to new beta-elemene amino acid or carboxylic acid derivative and preparation method thereof, relate to intermediate of synthetic described beta-elemene amino acid or carboxylic acid derivative and preparation method thereof, and relate to the application of described beta-elemene amino acid or carboxylic acid derivative.
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 is main component (the Guo Yong TOOLING of the broad-spectrum anti-cancer drug Elemenum Emulsion developed voluntarily of China, 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, do not have tangible liver, renal toxicity, have " double effect " that selectivity suppresses tumor cell proliferation and improves immunologic function, clinically kinds of tumors is had definite curative effect, be wide spectrum antitumor characteristics (Wang XW.Elemene[J] .Drugs Fut, 1998,23, (3): 266-270.[3] 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 than the strong (Cheng Baoguo of beta-elemene, Hu Jiehan, Dong Jinhua. elemene derivatives containing nitrogen and as cancer therapy drug [P]. China: CN1066444C.2001,5,30; Cheng Baoguo, Hu Jiehan, Dong Jinhua is etc. elemene hydroxyls derivs and as cancer therapy drug [P]. China: CN 1052716C.200,5,24).Cell mitogen is at G
1Phase, tumour cell was because fast breeding makes its demand to nutritive substances such as amino acid be far longer than normal cell to the demand maximum of nutritive substances such as amino acid.And the beta-elemene inducing apoptosis of tumour cell is just by acting on tumour cell G
0/ G
1Phase, hinder tumour cell and enter G from the S phase
2, the M phase, reach the purpose that suppresses growth of tumour cell (Zou Lijuan, Li Jie, Yu Limin, etc. beta-elemene antitumous effect and induced tumor Study of apoptosis [J]. Dalian Medical Univ's journal, 1998,20 (2): 9-12).Therefore our imagination is passed through beta-elemene is combined with amino acid, makes its amino acid transport system that can optionally act on tumour cell, thereby strengthens beta-elemene to tumour cell G
0/ G
1The effect of phase.Introducing the amino acid structure fragment simultaneously in medicines structure also can strengthen water-soluble.
Summary of the invention:
The purpose of this invention is to provide a kind of beta-elemene amino acid or carboxylic acid derivative and preparation method and purposes and preparation method thereof.It is in the structure of beta-elemene, introduce contain amino and (or) structure fragment of carboxyl, more synthetic water-soluble better, the derivative that anti-tumor activity is strong than beta-elemene, and it has been carried out the antitumour activity screening.By this compounds structure activity relationship is inquired into, seek novel structure, good water solubility, active high beta-elemene amino acid or carboxylic acid derivative, and its preparation method is provided; Be applied to the cancer therapy drug field, initiative beta-elemene class PTS.
The invention provides beta-elemene amino acid or the following formula III of carboxylic acid derivative structure:
Wherein R represent the various α of C2-C20-, β-, the gamma-amino acidic group is in formula III a mode.
Or the various α of C2-C20-, β-, the gamma-amino acid methoxycarbonyl is in formula III b mode.
Or the various α of C2-C20-, β-, the gamma-amino acidic group, or the various acyloxy of C1-C20 are in formula III c mode.
Wherein the hexanaphthene skeleton has three chiral centres.
Preferably, the invention provides the beta-elemene amino acid or the carboxylic acid derivative of formula III, wherein R represents various DL, D, and the L configuration is amino acid based in formula III a mode.As: glycine base, alaninyl, phenylalanine amino, methionine(Met) base, leucine base, isoleucine, the proline(Pro) base, tryptophane base, L-glutamic acid base, Serine base, halfcystine base, Gelucystine base, the Threonine base, a word used in person's names propylhomoserin base, tyrosine-based, asparagine acidic group, arginine base, Methionin base.
R represents various DL, D, and L configuration amino acid methyl ester base is in formula III b mode.As: glycine methyl ester base, alanine methyl ester base, phenylalanine methyl ester base, the methyl methionine base, leucine methoxycarbonyl, Isoleucine methoxycarbonyl, the proline methyl ester base, tryptophan methyl ester base, glutamic acid methyl ester base, the serine methylester base, acthiol-J base, Gelucystine methoxycarbonyl, the Threonine methoxycarbonyl, a word used in person's names propylhomoserin methoxycarbonyl, L-Tyrosine methyl ester base, the aspartic acid methoxycarbonyl, arginine methyl esters base, lysine methyl ester base.
R represents various DL, D, and the L configuration is amino acid based in formula III c mode.As: glycine base, alaninyl, phenylalanine amino, methionine(Met) base, leucine base, isoleucine, the proline(Pro) base, tryptophane base, L-glutamic acid base, Serine base, halfcystine base, Gelucystine base, the Threonine base, a word used in person's names propylhomoserin base, tyrosine-based, asparagine acidic group, arginine base, Methionin base; Or the various acyloxy of C1-C10.
Wherein the hexanaphthene skeleton has three chiral centres.
More preferably, the invention provides the beta-elemene amino acid or the carboxylic acid derivative of formula III, wherein R represents various DL, D, and the L configuration is amino acid based in formula III a mode.As: glycine base, alaninyl, phenylalanine amino, methionine(Met) base, leucine base, isoleucine, proline(Pro) base, tryptophane base, L-glutamic acid base.
R represents various DL, D, and L configuration amino acid methyl ester base is in formula III b mode.As: glycine methyl ester base, alanine methyl ester base, phenylalanine methyl ester base, methyl methionine base, leucine methoxycarbonyl, Isoleucine methoxycarbonyl, proline methyl ester base, tryptophan methyl ester base, glutamic acid methyl ester base.
R represents various DL, D, and the L configuration is amino acid based in formula III c mode.As: glycine base, alaninyl, phenylalanine amino, methionine(Met) base, leucine base, isoleucine, proline(Pro) base, tryptophane base, L-glutamic acid base; Or 3-carboxyl propionyloxy, 3-carboxyl-2-acryloxy.
Wherein the hexanaphthene skeleton has three chiral centres.
The invention provides and contain above-mentioned beta-elemene amino acid or carboxylic acid derivative " pharmaceutical salts " and refer to conventional acid salt or base addition salt, 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 or organic bases or mineral alkali.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.Base addition salt comprises the salt that is derived from sodium, potassium, ammonium.In the present invention, the particularly preferred pharmaceutical salts of The compounds of this invention is hydrochloride, maleate, sodium salt, sylvite.
The invention provides and contain above-mentioned beta-elemene amino acid or carboxylic acid derivative and pharmaceutical composition that pharmaceutically can received vehicle.
Beta-elemene amino acid of the present invention or carboxylic acid derivative or composition can be used to prepare various anti-tumor drugs.
Particularly the invention provides beta-elemene amino acid of the present invention or the carboxylic acid acid derivative purposes in the various anti-tumor drugs of preparation.
The present invention provides the preparation method of above-mentioned beta-elemene amino acid or carboxylic acid derivative in addition, it is characterized in that: obtain corresponding nitrogen containing derivative by chloro beta-elemene intermediate formula II and amino acid or carboxylic acid reaction.
Provide the synthetic route that is used for synthetic beta-elemene amino acid or carboxylic acid derivative as follows among the present invention:
Solvent for use is a common solvent in above-mentioned beta-elemene amino acid of the present invention or the carboxylic acid derivative preparation process; As ethanol, ethyl acetate, sherwood oil, N, dinethylformamide, methylene dichloride etc.
Advantage of the present invention is: described beta-elemene amino acid or carboxylic acid derivative, be for improving the water-soluble of beta-elemene and improving antitumour activity, and in its molecule, introduce the group institute synthetic compound that amino acid etc. contains amino or carboxyl, these derivatives may have stronger physiologically active and than high polarity, its amino or carboxyl are convenient to reach the water miscible purpose of improvement with acid or alkali salify.
Embodiment:
Embodiment 1 chloro beta-elemene intermediate
With
Preparation
In being housed, the three-necked bottle of mechanical stirrer adds beta-elemene 51.0g (0.25mol), Glacial acetic acid 35mL (0.61mol), be cooled to about 5 ℃ with ice-water bath, under agitation drip 180mL (1.41mol/L from constant pressure funnel, 0.254mol) chlorine bleach liquor, about 4h dropwises, and continues reaction 1h.Then reaction solution is transferred in the separating funnel of 1L,, merges organic phase, be washed to neutrality, anhydrous sodium sulfate drying with 50mL sherwood oil (60-90 ℃) extracting twice.Concentrate, get 52.5g oyster oily matter, separate through silica gel column chromatography, getting monochloro is the mixture 20.5g of 13-chloro-beta-elemene and 14-chloro-beta-elemene for Elemenum.
Method is led in the preparation of embodiment 2 amino acid methyl ester hydrochlorides
In the 100mL three-necked bottle of drying tube and device for absorbing tail gas is housed, add 22mmol amino acid, the dry methyl alcohol of 15mL, feed the exsiccant hydrogen chloride gas under the stirring at room fast, after dissolving fully to amino acid, under the reflux state, continue logical hydrogenchloride 2h again, concentrate, get white solid.With 1: 3 methyl alcohol-ether mixed solvent recrystallization.
Method is led in the preparation of embodiment 3 beta-elemene amino acid methyl ester derivations
With 10mmol amine, monochloro is for beta-elemene 5mmol, and triethylamine 10mmol is dissolved in 5mL N, in the dinethylformamide, and backflow 8-20h.Leach the triethylamine hydrochloride needle crystal of generation, filtrate adds 10mL water, uses sherwood oil-extracted with diethyl ether 4 times, and extraction liquid is dry to be concentrated, and uses the preparation of silica gel Thin-layer separation.
Embodiment 4
Synthetic
With the glycine is raw material, is equipped with glycine methyl ester hydrochloride by the logical legal system of the preparation of embodiment 2 amino acid methyl ester hydrochlorides, presses the logical method preparation of preparation of embodiment 3 beta-elemene amino acid methyl ester derivations again.MS(m/z)：292(M+1)；
1H-NMR(CDCl
3)δ(ppm)：1.00(3H，s)，1.42-1.74(9H，m)，1.99-2.01(2H，m)，3.24(2H，s)，3.40(2H，s)，3.73(3H，s)，4.58-4.96(6H，m)，5.77-5.86(1H，dd)
Embodiment 5
Synthetic
With the DL-L-Ala is raw material, is equipped with the alanine methyl ester hydrochloride by the logical legal system of the preparation of embodiment 2 amino acid methyl ester hydrochlorides, presses the logical method preparation of preparation of embodiment 3 beta-elemene amino acid methyl ester derivations again.MS(m/z)：306(M+1)；
1H-NMR(CDCl
3)δ(ppm)：0.99(3H，s)，1.31(3H，d)，1.45-1.74(9H，m)，2.00(2H，m)，3.12(1H，d)，3.23(1H，d)，3.36(1H，q)，3.73(3H，s)，4.58-4.96(6H，m)，5.77-5.86(1H，dd)
Embodiment 6
Synthetic
With the DL-phenylalanine is raw material, is equipped with phenylalanine methyl ester hydrochloride by the logical legal system of the preparation of embodiment 2 amino acid methyl ester hydrochlorides, presses the logical method preparation of preparation of embodiment 3 beta-elemene amino acid methyl ester derivations again.MS(m/z)：382(M+1)；
1H-NMR(CDCl
3)δ(ppm)：0.94(3H，s)，1.34-1.61(6H，m)，1.70(3H，s)，1.87-1.91(2H，m)，2.90-2.97(2H，dd)，3.03(1H，d)，3.28(1H，d)，3.51(1H，t)，3.67(3H，s)，4.56-4.91(6H，m)，5.74-5.84(1H，dd)，7.12-7.25(2H，m)，7.26-7.31(3H，m)
Embodiment 7
Synthetic
With the DL-tryptophane is raw material, is equipped with the tryptophan methyl ester hydrochloride by the logical legal system of the preparation of embodiment 2 amino acid methyl ester hydrochlorides, presses the logical method preparation of preparation of embodiment 3 beta-elemene amino acid methyl ester derivations again.EI-MS?m/z：420(M
+)；
1H-NMR(CDCl
3)δ：0.93(3H，s)，1.22-1.53(6H，m)，1.61-1.87(5H，m)，3.05-3.27(4H，m)，3.60-3.66(1H，m)，3.66(3H，s)，4.53-4.92(6H，m)，5.76(1H，dd)，7.02-7.62(5H，m)
Embodiment 8
Synthetic
With the L-leucine is raw material, is equipped with the leucine methyl ester hydrochloride by the logical legal system of the preparation of embodiment 2 amino acid methyl ester hydrochlorides, presses the logical method preparation of preparation of embodiment 3 beta-elemene amino acid methyl ester derivations again.EI-MS?m/z：347(M
+)；
1H-NMR(CDCl
3)δ：0.99(9H，s)，1.13-2.13(14H，m)，3.84(6H，brs)，4.57-5.30(6H，m)，5.82(1H，m)
Embodiment 9
Synthetic
With the L-Isoleucine is raw material, is equipped with the Isoleucine methyl ester hydrochloride by the logical legal system of the preparation of embodiment 2 amino acid methyl ester hydrochlorides, presses the logical method preparation of preparation of embodiment 3 beta-elemene amino acid methyl ester derivations again.ESI-MS?m/z：348(M+1)；
1H-NMR(CDCl
3).δ：0.90(6H，m)，1.00(3H，s)，1.45-1.74(12H，m)，2.03(2H，m)，3.00-3.25(3H，m)，3.72(3H，s)，4.58-4.97(6H，m)，5.82(1H，dd)
Embodiment 10
Synthetic
With the DL-methionine is raw material, is equipped with hydrochloride methyl methionine by the logical legal system of the preparation of embodiment 2 amino acid methyl ester hydrochlorides, presses the logical method preparation of preparation of embodiment 3 beta-elemene amino acid methyl ester derivations again.ESI-MS?m/z：366(M+1)；
1H-NMR(CDCl
3)δ：0.98(3H，s)，1.44-1.98(13H，m)，2.10(3H，s)，2.60(2H，t)，2.94-3.10(2H，m)，3.35(1H，m)，3.70(3H，s)，4.58-4.95(6H，m)，5.82(1H，dd)
Embodiment 11
Synthetic
With the L-proline(Pro) is raw material, is equipped with proline methyl ester hydrochloride by the logical legal system of the preparation of embodiment 2 amino acid methyl ester hydrochlorides, presses the logical method preparation of preparation of embodiment 3 beta-elemene amino acid methyl ester derivations again.EI-MS?m/z：331(M
+)；
1H-NMR(CDCl
3)δ：1.00(3H，s)，1.25-2.10(17H，m)，3.02(3H，m)，3.69(3H，s)，4.15-4.92(6H，m)，5.80(1H，m)
Embodiment 12
Synthetic
With L-L-glutamic acid is raw material, is equipped with the glutamic acid methyl ester hydrochloride by the logical legal system of the preparation of embodiment 2 amino acid methyl ester hydrochlorides, presses the logical method preparation of preparation of embodiment 3 beta-elemene amino acid methyl ester derivations again.ESI-MS?m/z：402(M+K)；
1H-NMR(CDCl
3)δ：0.99(3H，s)，1.44-1.74(7H，m)，1.97-2.53(8H，m)，3.38(1H，d)3.75(3H，s)，4.13(1H，dd)，4.50(1H，d)，4.59-4.98(6H，m)，5.80(1H，dd)
The logical method of preparation preparation of embodiment 13 beta-elemene amino acid derivatives:
1: 4 in molar ratio ratio of beta-elemene amino acid methyl ester derivation is added the 10%NaOH aqueous solution and 2mL acetone, 50-60 ℃ stir 5-6 hour down after, pH5-6 promptly separates out solid with 2M hydrochloric acid accent, filter the beta-elemene amino acid derivative.
Embodiment 14
Synthetic
Product with embodiment 4 is a raw material, presses the logical method preparation of preparation of embodiment 13 beta-elemene amino acid derivatives.ESI-MS?m/z：278(M+1)，300(M+Na)；
1H-NMR(CDCl
3)δ(ppm)：0.98(3H，s)，1.25-1.56(6H，m)，1.69(3H，s)，2.03(2H，m)，3.49(2H，s)，3.64(2H，s)，4.56-5.84(6H，m)，5.75-5.84(1H，dd)
Embodiment 15
Synthetic
Product with embodiment 5 is a raw material, presses the logical method preparation of preparation of embodiment 13 beta-elemene amino acid derivatives.ESI-MS?m/z：292(M+1)，314(M+Na)；
1H-NMR(DMSO)δ(ppm)：0.94(3H，d)，1.25(3H，d)，1.35-1.58(6H，m)，1.70(3H，d)，1.99(1H，m)，2.20(1H，m)，3.17-3.40(3H，m)，4.58-5.21(6H，m)，5.77-5.87(1H，dd)
Embodiment 16
Synthetic
Product with embodiment 6 is a raw material, presses the logical method preparation of preparation of embodiment 13 beta-elemene amino acid derivatives.ESI-MS?m/z：368(M+1)，390(M+Na)；
1H-NMR(CDCl
3)δ(ppm)：0.92(3H，m)，1.25-6.17(6H，m)，1.85(1H，m)，1.87(3H，s)，1.95(1H，m)，3.25(5H，m)，4.53-4.99(6H，m)，5.78(1H，dd)，7.32(5H，s)
Embodiment 17
Synthetic
Product with embodiment 7 is a raw material, presses the logical method preparation of preparation of embodiment 13 beta-elemene amino acid derivatives.EI-MS?m/z：394(M
+)；
1H-NMR(CDCl
3)δ：0.90(3H，s)，1.42-1.91(11H，m)，3.00(1H，m)，3.38-3.50(2H，m)，4.00(2H，m)，4.60-5.37(6H，m)，5.76-5.90(1H，dd)，7.06-7.55(5H，m)
Embodiment 18
Synthetic
Product with embodiment 8 is a raw material, presses the logical method preparation of preparation of embodiment 13 beta-elemene amino acid derivatives.EI-MS?m/z：333(M
+)；
1H-NMR(CDCl
3)，δ：9.01(3H，s)，0.97(6H，s)，1.16-1.60(6H，m)，1.62-1.82(6H，m)1.99(2H，m)，3.35-3.60(3H，m)，4.56-5.39(6H，m)，5.72(1H，dd)
Embodiment 19
Synthetic
Product with embodiment 9 is a raw material, presses the logical method preparation of preparation of embodiment 13 beta-elemene amino acid derivatives.ESI-MS?m/z：334(M+1)；
1H-NMR(CDCl
3)δ：0.90(3H，s)，0.99(6H，s)，1.45-1.70(11H，m)，2.01(3H，brs)，3.30-3.56(3H，m)，4.57-5.20(6H，m)，5.79(1H，m)
Method is led in the preparation of embodiment 20 uncle's N-fourth oxygen acylamino acids:
With 4mmol amino acid, 0.7mL (4.8mmol) triethylamine, 7mLDMF, stir, be heated to 45 ℃, drip 1.9g (8.8mmol) (BOC)
2O (two dimethyl dicarbonate butyl esters) keeps this temperature and is stirred to amino acid and dissolves fully, and room temperature continues reaction 0.5-1h.Add 10mL distilled water and 10mL ethyl acetate, separate organic phase and water, organic phase merges water with distilled water (10mL * 5) extraction, with the hydrochloric acid adjust pH to 3 of 6mol/L.Use ethyl acetate (10mL * 4) extraction again, merge organic phase, anhydrous sodium sulfate drying.Filter, concentrate, get faint yellow oily thing.
Method is led in the preparation of embodiment 21 [(uncle's N-fourth oxygen acyl group)-amino acid]-(beta-elemene-13-yl) ester:
With the beta-elemene monochloro for thing (2.5mmol), uncle's N-fourth oxygen acylamino acid (5mmol), triethylamine 1.4mL (10mol), 10mLDMF, 90 ℃ of reactions of oil bath.After the cooling, add 10mL distilled water and 10mL ethyl acetate, separate organic phase and water, water merges organic phase, anhydrous sodium sulfate drying with ethyl acetate (10mL * 4) extraction.Filter, concentrate, separate with thin-layer chromatography, get brown oil through column chromatography.
Method is led in the preparation of embodiment 22 amino acid-(beta-elemene-13-yl) ester:
With the product of embodiment 21, the ethyl acetate solution 15mL's (2.5mol/L) of adding hydrogenchloride, disappear in 45 ℃ of stirring reaction 24h to raw material point.Cooling is regulated pH value to 8 with the aqueous sodium carbonate of 3mol/L, separates organic phase and water, and water merges organic phase, anhydrous sodium sulfate drying with ethyl acetate (10mL * 4) extraction.Filter, concentrate,, get yellow oil through column chromatography for separation.Again to wherein slowly dripping saturated ether solution of hydrogen chloride while stirring, to the pH value be 6, white precipitate is separated out, filter, washing, white powder hydrochloric acid inflammation.
Embodiment 23
With the DL-tryptophane is raw material; the logical legal system of the preparation of embodiment uncle 20N-fourth oxygen acylamino acid gets uncle's N-fourth oxygen acyl group tryptophane; again according to the logical method preparation of the preparation of embodiment 21 [(uncle's N-fourth oxygen acyl group)-amino acid]-(beta-elemene-13-yl) ester; then according to the logical method of the preparation of embodiment 22 amino acid-beta-elemene base-13-ester; slough protecting group BOC, make tryptophane-beta-elemene base-13-ester.MS?m/z：406(M
+)，
1H-NMR(CDCl
3)δ：0.99(3H，s)，1.45-1.70(9H，m)，1.97(2H，m)，3.39(2H，m)，4.02(1H，brs)，4.46(2H，s)，4.59-5.01(6H，m)，5.80(1H，dd)，7.00-7.38(5H，m)
Embodiment 24
Synthetic
With the L-leucine is raw material, is prepared according to embodiment 23 steps.EI-MS?m/z：86(100)，304(5)，288(2)，203(8)；
1H-NMR(CDCl
3)δ：0.92-0.96(6H，t)，1.01(3H，s)，1.44-1.74(12H，m)，1.98-2.03(2H，m)，3.51(1H，dd)，4.58-5.06(8H，m)，5.82(1H，dd)
Embodiment 25
Synthetic
With the different ammonia amino acid of L-is raw material, is prepared according to embodiment 23 steps.ES?I-MS?m/z：355[M-H+Na]
+，203；
1H-NMR(CDCl
3)δ：0.92-0.96(6H，m)，1.01(3H，s)，1.47-1.74(12H，m)，1.98-2.03(2H，m)，3.51(1H，dd)，4.59-5.06(8H，m)，5.82(1H，dd)
Embodiment 26
Synthetic
With the DL-methionine is raw material, is prepared according to embodiment 23 steps.EI-MS?m/z：352(M+1)；
1H-NMR(CDCl
3)δ：1.01(3H，s)，1.48-1.71(11H，m)，2.2-2.10(2H，m)，2.11(3H，s)，2.64(2H，t)，3.64(1H，dd)，4.59-5.06(8H，m)，5.82(1H，dd)
Embodiment 27
Synthetic
With the DL-L-Ala is raw material, is prepared according to embodiment 23 steps.EI-MS?m/z：276(1)，262(9)，203(2)，44(100)；
1H-NMR(CDCl
3)δ：1.01(3H，s)，1.34-1.70(12H，m)，1.98-2.03(2H，m)，3.61(1H，dd)，4.59-5.07(8H，m)，5.74-5.86(1H，m)
Embodiment 28
Synthetic
With the DL-phenylalanine is raw material, is prepared according to embodiment 23 steps.EI-MS?m/z：368(M+1)；
1H-NMR(CDCl
3)δ：1.02(3H，s)，1.50-1.75(9H，m)，1.99-2.04(2H，m)，2.91-3.11(2H，m)，3.76-3.80(1H，m)，4.60-5.82(8H，m)，5.81(1H，dd)，7.20-7.32(5H，m)
Embodiment 29
Synthetic
With Succinic Acid 10mmol, triethylamine 10mmol, monochloro is dissolved in 5mLN for beta-elemene 5mmol, in the dinethylformamide, backflow 8-20h.Leach the triethylamine hydrochloride needle crystal of generation, filtrate adds 10mL water, uses sherwood oil-extracted with diethyl ether 4 times, and extraction liquid is dry to be concentrated, and uses the preparation of silica gel Thin-layer separation.In acetone, become sodium salt with yellow soda ash.EI-MS?m/z：343(M+Na)；H-NMR(CDCl
3)δ(ppm)1.00(3H，s，-CH
3)，1.47-1.68(6H，m)，1.70(3H，s)，1.98-2.04(2H，m)，2.68(4H，s)，4.51-5.00(8H，m)，5.77-5.86(1H，dd)
Embodiment 30
Synthetic
With the toxilic acid is raw material, according to preparation of embodiment 29 methods and one-tenth sodium salt.EI-MS?m/z：317(M-1)；
1H-NMR(CDCl
3)δ(ppm)：1.01(3H，s)，1.48-1.75(9H，m)，1.99-2.18(2H，m)，4.59-5.18(8H，m)，5.77-5.87(1H，dd)，6.88(1H，d)，7.00(1H，d)。
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 the present invention.
Embodiment 31
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 50 μ L4 ℃ precoolings, making its final concentration is 16%; Attached cell then needs every hole to add the 50%TCA of 50 μ L4 ℃ precoolings, 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).
Measured the inhibited proliferation of 25 compounds among the embodiment with aforesaid method, calculated the half-inhibition concentration (IC of medicine three-type-person's cancer cells HL-60, Hela, SGC-7901 cell
50) as shown in table 1.Wherein the majority of compounds activity is higher than lead compound beta-elemene (III), the result shows by introduce amino acid or organic acid structure in the beta-elemene structure, can strengthen the external antitumour activity of beta-elemene.
Table 1 target compound is to the half-inhibition concentration (IC of cancer cells
50)
Claims (7)
1, beta-elemene amino acid or carboxylic acid derivative is characterized in that: the following formula III of described derivant structure:
Wherein R represent the various α of C2-C20-, β-, the gamma-amino acidic group; The various acyloxy of C1-C20;
Wherein the hexanaphthene skeleton has three chiral centres.
2, according to described beta-elemene amino acid of claim 1 or carboxylic acid derivative, it is characterized in that: wherein R represents various DL-configurations, D-form, and the L-configuration is amino acid based, the glycine base, alaninyl, phenylalanine base, methionine(Met) base, the leucine base, isoleucine, proline(Pro) base, tryptophane base, the L-glutamic acid base, Serine base, halfcystine base, Gelucystine base, the Threonine base, a word used in person's names propylhomoserin base, tyrosine-based, the asparagine acidic group, arginine base, Methionin base; The various acyloxy of C1-C10;
Wherein the hexanaphthene skeleton has three chiral centres.
3, according to claim 1 or 2 described beta-elemene amino acid or carboxylic acid derivative, it is characterized in that: wherein R represents various DL, D, the L configuration is amino acid based, glycine base, alaninyl, the phenylalanine base, methionine(Met) base, leucine base, isoleucine, the proline(Pro) base, tryptophane base, L-glutamic acid base, 3-carboxyl propionyloxy, 3-carboxyl-2-acryloxy;
Wherein the hexanaphthene skeleton has three chiral centres.
4, the preparation method of a kind of beta-elemene amino acid according to claim 1 or carboxylic acid derivative, it is characterized in that: obtain corresponding beta-elemene amino acid derivative by chloro beta-elemene intermediate formula (II) and amino acid or carboxylic acid reaction, solvent for use is a common solvent in beta-elemene amino acid or the carboxylic acid derivative preparation process, ethanol, ethyl acetate, sherwood oil, N, dinethylformamide, methylene dichloride
The synthetic route of synthetic beta-elemene amino acid or carboxylic acid derivative is as follows:
So-called amino acid is glycine, L-Ala, and phenylalanine, methionine(Met), leucine, Isoleucine, proline(Pro), tryptophane, L-glutamic acid, so-called carboxylic acid are succsinic acid, toxilic acid, fumaric acid, oxysuccinic acid;
Wherein the hexanaphthene skeleton has three chiral centres.
5, beta-elemene amino acid or carboxylic acid derivative " pharmaceutical salts ", it is characterized in that: refer to conventional acid salt or base addition salt, 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 or organic bases or mineral alkali.
6, the composition of a kind of beta-elemene amino acid or carboxylic acid derivative is characterized in that: said composition is by beta-elemene amino acid or carboxylic acid derivative and pharmaceutically can form by received vehicle.
7, the purposes of beta-elemene amino acid or carboxylic acid derivative is characterized in that: the application in the preparation cancer therapy drug of described beta-elemene amino acid or carboxylic acid derivative.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101225049B (en) * | 2006-10-20 | 2011-06-01 | 中国科学院上海应用物理研究所 | Beta-elemene amino acid derivatives as well as synthetic method and use thereof |
| CN102746212A (en) * | 2011-04-18 | 2012-10-24 | 沈阳药科大学 | Beta-elemene indole derivative, preparation and application thereof |
| CN104119221A (en) * | 2014-08-01 | 2014-10-29 | 大连远大医药科技开发有限公司 | Beta-elemene 14-site ramification and application of beta-elemene 14-site ramification in treating atherosclerosis |
| CN104130124A (en) * | 2014-08-01 | 2014-11-05 | 大连远大医药科技开发有限公司 | Beta-elemene 13-site derivative and use thereof in treatment of atherosclerosis |
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| CN115010642A (en) * | 2022-06-17 | 2022-09-06 | 沈阳药科大学 | Beta-elemene imide derivatives and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101225049B (en) * | 2006-10-20 | 2011-06-01 | 中国科学院上海应用物理研究所 | Beta-elemene amino acid derivatives as well as synthetic method and use thereof |
| CN102746212A (en) * | 2011-04-18 | 2012-10-24 | 沈阳药科大学 | Beta-elemene indole derivative, preparation and application thereof |
| CN102746212B (en) * | 2011-04-18 | 2014-04-30 | 沈阳药科大学 | Beta-elemene indole derivative, preparation and application thereof |
| CN104119221A (en) * | 2014-08-01 | 2014-10-29 | 大连远大医药科技开发有限公司 | Beta-elemene 14-site ramification and application of beta-elemene 14-site ramification in treating atherosclerosis |
| CN104130124A (en) * | 2014-08-01 | 2014-11-05 | 大连远大医药科技开发有限公司 | Beta-elemene 13-site derivative and use thereof in treatment of atherosclerosis |
| WO2016015480A1 (en) * | 2014-08-01 | 2016-02-04 | 大连远大医药科技开发有限公司 | Β-elemene 14-position derivative and application of same in the treatment of atherosclerosis |
| WO2016015479A1 (en) * | 2014-08-01 | 2016-02-04 | 大连远大医药科技开发有限公司 | Β-elemene 13-position derivative and application of same in the treatment of atherosclerosis |
| CN112707833A (en) * | 2019-10-24 | 2021-04-27 | 沈阳药科大学 | Histone deacetylase inhibitor and preparation and application thereof |
| CN115010642A (en) * | 2022-06-17 | 2022-09-06 | 沈阳药科大学 | Beta-elemene imide derivatives and application thereof |
| CN115010642B (en) * | 2022-06-17 | 2023-05-26 | 沈阳药科大学 | Beta-elemene imide derivative and application thereof |
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