CN1844084B - 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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- 0 CC(C)C(CC1)C[C@@](C(*)CCl)C1(C)C=C Chemical compound CC(C)C(CC1)C[C@@](C(*)CCl)C1(C)C=C 0.000 description 3
- CGATWPMWHPRADL-MJBXVCDLSA-N CCC([C@H](CC[C@@H]1C)C[C@H]1C(C)=C)=C Chemical compound CCC([C@H](CC[C@@H]1C)C[C@H]1C(C)=C)=C CGATWPMWHPRADL-MJBXVCDLSA-N 0.000 description 1
- YENYNMDBEXVRLB-PCKAHOCUSA-O C[C@@H](CC[NH+]=C)C(C)(CCC(C)C(C)=C)C=C Chemical compound C[C@@H](CC[NH+]=C)C(C)(CCC(C)C(C)=C)C=C YENYNMDBEXVRLB-PCKAHOCUSA-O 0.000 description 1
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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 midbody of synthetic said beta-elemene amino acid or carboxylic acid derivative and preparation method thereof, and relate to the application of said beta-elemene amino acid or carboxylic acid derivative.
Background technology:
From Zingiberaceae turmeric (Curcuma? Wenyujin? YHChen? Et? C.Ling), also known as volatile oil of Curcuma, the isolated β-elemene is our own developed a broad-spectrum anti-tumor drugs Elemene Milk is the main component (Guo TOOLING, Wu Xiuying, Chen Yuren. volatile oil of Curcuma Elemene Isolation and Identification [J]. Chinese Bulletin, 1983,8 (30) :31-33).Beta-elemene has higher selectivity to tumour cell, and no bone marrow inhibition does not have tangible liver, renal toxicity; Have selectivity and suppress tumor cell proliferation and " double effect " that improve immunologic function, clinically kinds of tumors is had definite curative effect, be antitumor characteristics (Wang XW.Elemene [J] the .Drugs Fut of wide spectrum; 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: CN1052716C.200,5,24).Cell mitogen is at G
1Phase is maximum to the demand of nutritive substances such as amino acid, and tumour cell is because fast breeding makes its demand to nutritive substances such as amino acid be far longer than normal cell.And the beta-elemene inducing apoptosis of tumour cell is just through acting on tumour cell G
0/ G
1Phase, hinder tumour cell and get into 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.In medicines structure, introducing the amino acid structure fragment simultaneously 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 with (or) structure fragment of carboxyl, more synthetic water-soluble better, the verivate that anti-tumor activity is strong than beta-elemene, and it has been carried out the antitumour activity screening.Through 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 present 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 with formula III a mode.
Or the various α of C2-C20-, β-, the gamma-amino acid methoxycarbonyl is with 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 with formula III c mode.
Wherein the hexanaphthene skeleton has three chiral centres.
Preferably, the present invention provides the beta-elemene amino acid or the carboxylic acid derivative of formula III, and wherein R represents various DL, D, and the L configuration is amino acid based with formula III a mode.As: the glycocoll base, alaninyl, phenylalanine(Phe) is 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, l-arginine base, Methionin base.
R represents various DL, D, and L configuration amino acid methyl ester base is with formula III b mode.As: glycine methyl ester base, alanine methyl ester base, phenylalanine methyl ester base, methyl methionine base, leucine methoxycarbonyl; The Isoleucine methoxycarbonyl, proline methyl ester base, tryptophan methyl ester base, glutamic acid methyl ester base, serine methylester base; The acthiol-J base, Gelucystine methoxycarbonyl, Threonine methoxycarbonyl, a word used in person's names propylhomoserin methoxycarbonyl; The L-Tyrosine methyl ester base, aspartic acid methoxycarbonyl, arginine methyl esters base, lysine methyl ester base.
R represents various DL, D, and the L configuration is amino acid based with formula III c mode.As: the glycocoll base, alaninyl, phenylalanine(Phe) is 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, l-arginine base, Methionin base; Or the various acyloxy of C1-C10.
Wherein the hexanaphthene skeleton has three chiral centres.
More preferably, the present invention provides the beta-elemene amino acid or the carboxylic acid derivative of formula III, and wherein R represents various DL, D, and the L configuration is amino acid based with formula III a mode.As: the glycocoll base, alaninyl, phenylalanine(Phe) is 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 with 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 with formula III c mode.As: the glycocoll base, alaninyl, phenylalanine(Phe) is 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, Hydrocerol A, 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 preferred especially pharmaceutical salts of The compounds of this invention is hydrochloride, PHENRAMINE 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 according to the invention or carboxylic acid derivative or compsn 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 through chloro beta-elemene midbody 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 following among the present invention:
Above-mentioned beta-elemene amino acid of the present invention or carboxylic acid derivative prepare that solvent for use is a common solvent in the process, like ethanol, ETHYLE ACETATE, and 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 verivates possibly 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:
The preparation of embodiment 1 chloro beta-elemene midbody
and
, the three-necked bottle of mechanical stirrer adds beta-elemene 51.0g (0.25mol) in being housed; Glacial acetic acid min. 99.5 35mL (0.61mol); Be cooled to about 5 ℃ with ice-water bath, under agitation drip 180mL (1.41mol/L, 0.254mol) chlorine bleach liquor from constant pressure funnel; About 4h dropwises, and continues reaction 1h.Then reaction solution is transferred in the separating funnel of 1L, with 50mL sherwood oil (60-90 ℃) extracted twice, merges organic phase, washing is to neutrality, anhydrous sodium sulfate drying.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 5mLN, in the dinethylformamide, refluxes 8
-20h.Leach the triethylamine hydrochloride needle crystal of generation, filtrating adds 10mL water, and with sherwood oil-extracted with diethyl ether 4 times, extraction liquid is dry concentrated, uses the preparation of silica gel Thin-layer separation.
Embodiment's 4
is synthetic
With the glycocoll 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's 5
is 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's 6
is synthetic
With the DL-phenylalanine(Phe) 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's 7
is 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's 8
is 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，br?s)，4.57-5.30(6H，m)，5.82(1H，m)
Embodiment's 9
is 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's 10
is 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's 11
is 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's 12
is 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 verivates:
With the beta-elemene amino acid methyl ester derivation in molar ratio the ratio of 1:4 add the 10%NaOH aqueous solution and 2mL acetone, 50
-60 ℃ are stirred 5 down
-After 6 hours, transfer pH5 with 2M hydrochloric acid
-6 promptly separate out solid, cross to filter the beta-elemene amino acid verivate.
Embodiment's 14
is synthetic;
Product with embodiment 4 is a raw material, presses the logical method preparation of preparation of embodiment 13 beta-elemene amino acid verivates.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's 15
is synthetic
Product with embodiment 5 is a raw material, presses the logical method preparation of preparation of embodiment 13 beta-elemene amino acid verivates.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's 16
is synthetic
Product with embodiment 6 is a raw material, presses the logical method preparation of preparation of embodiment 13 beta-elemene amino acid verivates.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's 17
is synthetic
Product with embodiment 7 is a raw material, presses the logical method preparation of preparation of embodiment 13 beta-elemene amino acid verivates.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's 18
is synthetic
Product with embodiment 8 is a raw material, presses the logical method preparation of preparation of embodiment 13 beta-elemene amino acid verivates.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's 19
is synthetic
Product with embodiment 9 is a raw material, presses the logical method preparation of preparation of embodiment 13 beta-elemene amino acid verivates.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 uncle 20N-fourth oxygen acylamino acid:
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 zero(ppm) water and 10mL ETHYLE ACETATE, separate organic phase and water, organic phase merges water, with the hydrochloric acid adjust pH to 3 of 6mol/L with zero(ppm) water (10mL * 5) extraction.Use ETHYLE 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 zero(ppm) water and 10mL ETHYLE ACETATE, separate organic phase and water, water merges organic phase, anhydrous sodium sulfate drying with ETHYLE 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 ETHYLE 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 is scorching.
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; According to the logical method of the preparation of embodiment 22 amino acid-beta-elemene base-13-ester, slough the basic BOC of protection then, make tryptophane-beta-elemene base-13-ester.MSm/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's 24
is synthetic
With the L-leucine is raw material, prepares according to embodiment 23 steps.EI-MSm/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's 25
is synthetic
With the different ammonia amino acid of L-is raw material, prepares according to embodiment 23 steps.ESI-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's 26
is synthetic
With the DL-methionine is raw material, prepares 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's 27
is synthetic
With the DL-L-Ala is raw material, prepares 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's 28
is synthetic
With the DL-phenylalanine(Phe) is raw material, prepares 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's 29
is synthetic
With Succinic Acid 10mmol, triethylamine 10mmol, monochloro is dissolved in 5mLN for beta-elemene 5mmol, in the dinethylformamide, refluxes 8
-20h.Leach the triethylamine hydrochloride needle crystal of generation, filtrating adds 10mL water, and with sherwood oil-extracted with diethyl ether 4 times, extraction liquid is dry concentrated, uses the preparation of silica gel Thin-layer separation.In acetone, become sodium salt with yellow soda ash.EI-MSm/z：343(M+Na)；
1H-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's 30
is synthetic
With the toxilic acid is raw material, according to preparation of embodiment 29 methods and one-tenth sodium salt.EI-MSm/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 following embodiment that experimentizes 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 on micro oscillator, vibrates all dissolves until dyestuff, utilizes ELIASA to survey the absorbance (OD value) of every hole solution at the 540nm place, deducts the blank well absorbance.By following formula calculate 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 through in the beta-elemene structure, introducing amino acid or organic acid 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. a beta-elemene amino acid or carboxylic acid derivative and pharmaceutical salts thereof, it is selected from following compound:
Compound 1 compound 2
Compound 3 compounds 4
Compound 5 compounds 6
Compound 7 compounds 8
Compound 9 compounds 10
Compound 11 compounds 12
Compound 13 compounds 14
Compound 15 compounds 16
Compound 17 compounds 18
Compound 19 compounds 20
Compound 21 compounds 22
Compound 23
2. the preparation method of a beta-elemene amino acid as claimed in claim 1 or carboxylic acid derivative and pharmaceutical salts thereof is characterized in that: described compound 1-7, and 9 synthetic route is following:
R
1＝H，CH
3，CH
2Ph，CH
2CH(CH
3)
2，CH(CH
3)CH
2CH
3，CH
2CH
2SCH
3，CH
2CH
2COOH，
3. the preparation method of a beta-elemene amino acid as claimed in claim 1 or carboxylic acid derivative and pharmaceutical salts thereof, it is characterized in that: the synthetic route of described compound 10-15 is following:
R
1＝H，CH
3，CH
2Ph，CH
2CH(CH
3)
2，CH(CH
3)CH
2CH
3，
4. the preparation method of a beta-elemene amino acid as claimed in claim 1 or carboxylic acid derivative and pharmaceutical salts thereof, it is characterized in that: the synthetic route of described compound 17-21 is following:
R
1＝CH
3，CH
2Ph，CH
2CH(CH
3)
2，CH(CH
3)CH
2CH
3，CH
2CH
2SCH
3。
5. the preparation method of a beta-elemene amino acid as claimed in claim 1 or carboxylic acid derivative and pharmaceutical salts thereof; It is characterized in that: wherein; Compound 22 and 23 preparation method are following: obtain through chloro beta-elemene midbody formula (II) and carboxylic acid reaction; Solvent for use is ethanol, ETHYLE ACETATE, sherwood oil, N in the preparation process, dinethylformamide, methylene dichloride, and the structural formula of said chloro beta-elemene midbody formula (II) is:
6. a pharmaceutical composition is characterized in that, said compsn is by described beta-elemene amino acid of claim 1 or carboxylic acid derivative and pharmaceutically can form by received vehicle.
7. described beta-elemene amino acid of claim 1 or carboxylic acid derivative or the described pharmaceutical composition of claim 6 application in the preparation cancer therapy drug.
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| 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 |
| CN112707833B (en) * | 2019-10-24 | 2022-11-25 | 沈阳药科大学 | Histone deacetylase inhibitor and preparation 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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Non-Patent Citations (3)
| Title |
|---|
| C. ZDERO et al.FURTHER ISOCEDRENE DERIVATIVES AND OTHER CONSTITUENTS FROM PEREZZA SPECIES.《Pkytockemistry》.1988,第27卷(第3期),849-853. |
| STN.STN.《STN》.1999,1-5. |
| STN.STN.《STN》.1999,1-5.;C. ZDERO et al.FURTHER ISOCEDRENE DERIVATIVES AND OTHER CONSTITUENTS FROM PEREZZA SPECIES.《Pkytockemistry》.1988,第27卷(第3期),849-853. * |
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