CN102146026A - Protosappanin A derivative and preparation method and application thereof - Google Patents
Protosappanin A derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a protosappanin A derivative and a preparation method and application thereof, in particular to a compound with a general formula I and a chemical synthesis method thereof and application of the compound in immunologic rejection response after anti-organ transplantation. The protosappanin A derivative with higher purity and better stability is obtained by the chemical synthesis method, the defects of high workload and low yield in natural extraction of protosappanin A are overcome, and the method is more favorable for batch production of effective compounds and cost reduction and is also more favorable for exploration of a later medicament acting mechanism and research and development of future new medicaments. The general formula I is shown in the specification.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to have the protosappanin A derivative of immunosuppressive activity, its chemical synthesis process and the application in the immunological rejection after anti-organ transplantation of these derivatives.
Background technology
Organ transplantation has become the effective treatment means of the depleted patient of end-organ as 20th century one of clinical medical significant achievement.At present, the survival rate and the quality of life of transplant patient all are greatly improved, and this mainly has benefited from the immunosuppressive action of medicine mediation.Though immunosuppressant therapy has experienced the development in a century, from the radioactive rays of indiscriminate destruction all cells, chemicals participates in immunoreactive cell to an inhibition ciclosporin A (Cyclosporin A, CsA), tacrolimus, mycophenlate mofetil, mizoribine and leflunomide etc., make a lot of progress, but rejection is still the major cause of transplant organ loss of function, present most immunosuppressor toxic side effects is big, costing an arm and a leg, is one of filed of organ transplantation problem demanding prompt solution.
Bush has another name called lignum sappan.Be the dry duramen of leguminous plants bush (caesalpinia sappan L.), sweet, the one-tenth of distinguishing the flavor of, property is flat, mainly contains flavonoid compound and phytosterin compound, comprises Hematorylin, bush cinnamophenone, brazilin, former Hematorylin etc.The traditional Chinese medical science thinks that it has the effect of removing heat from blood, stagnation resolvation blood, menstruation regulating, is used for dysmenorrhoea, rheumatalgia, liver blood increases diseases such as Sheng, is the class medicine that typically activates blood circulation and disperses blood clots.Graft-rejection often can cause the infringement of a series of small vessel disease reason such as vascular endothelial cell swelling, inner membrance oedema and fibrosis, vessel wall thickening, luminal stenosis, thrombosis, and these pathological changes belong to " blood stasis symptom " category of the traditional Chinese medical science.Research also shows, use drug for invigorating blood circulation and eliminating stasis and can improve blood circulation, suppress platelet aggregation, thereby improve the oxygen ability of taking the photograph in the transplant organ blood, quicken its repair process, the function of transplant organ is improved, and some drug for invigorating blood circulation and eliminating stasis itself just have the immunoreactive function of adjusting simultaneously, and this just uses drug for invigorating blood circulation and eliminating stasis for graft-rejection reliable argument is provided.Effects such as pharmacology and clinical further confirmation bush are antitumor in addition in recent years, adjusting is immune, hypoglycemic.Once bush and other Chinese prescriptions were carried out the treatment of autoimmune disorder (as scleroderma) clinically.
Confirmed that bush has the effect of anti-heart transplant rejection.By detecting three kinds of different extracts of bush: the immunosuppressive activity of water extract, alcohol extract and ester extract.Discover that dosage group and heavy dose of group all can influence T lymphocyte transformation function and Mf cell activity in the alcohol extract, the heavy dose of group of alcohol extract also can influence B lymphocyte transformation function (p＜0.05), but to the not influence of NK cell activity.Heavy dose of group of alcohol extract and the heavy dose of group of water extract can reduce the generation of the IL-2 in the mixed lymphocytes culture supernatant.Bush various purification thing, especially alcohol extracts can influence the panimmunity cell activity, and the bush alcohol extract also can influence the function that B drenches to be changeed, and CsA does not then influence the B cell activity.In experiment made on the living, have been found that, use rat dystopy of the same race abdominal cavity heart transplantation model, the bush alcohol extract is the survival time of prolong rats heart transplant effectively, is extended to 17.43 ± 2.48 days of test group by the average survival fate (6.32 ± 1.58 days) of control group.Detect the rising of CD4+/CD8+ ratio in the effective suppressor T cell subgroup by flow cytometer, the production of cytokines of minimizing peripheral blood IL-2, INF-r, TNF-a etc. alleviates the pathological lesion of heart transplant.Can infer that thus bush may participate in resisting transplant rejection from a plurality of links, a plurality of angle.
In order to further investigate the effective constituent of bush alcohol extract, three kinds of monomers that content is more the bush alcohol extract have further been isolated: brazilin, protosappanin A, high different flavanone.Wherein protosappanin A can alleviate the graft pathological lesion, and brazilin and high different flavanone can not alleviate the graft pathological lesion.The experiment confirm protosappanin A can prolong the heart transplant survival time, reduces peripheral blood CD4+/CD8+T lymphocyte ratio, reduces peripheral blood IFN-γ and TNF-a level but not obvious for serum il-2 effect; Also can reduce the expression level of cardiac muscular tissue's granzyme B and pore-forming protein gene mRNA.Therefore protosappanin A has the effect of anti-heart transplantation acute rejection.
Yet not only workload is big for the method for employing natural extract protosappanin A, and resulting output is less; Adopt the method for chemosynthesis on the other hand because this compound itself is the structure of polyhydric biphenyl octatomic ring, on synthetic, has very big difficulty, except that Masahiro Nagal applying biological method was synthetic, its chemical complete synthesis work did not also have bibliographical information at present.Thereby limited it in scientific research and application clinically.
Summary of the invention
The object of the present invention is to provide Hematorylin A derivative, promptly
The compound of following general formula I,
It is characterized in that: R
1Be C
1-4Alkyl, preferable methyl; R
2Be C
1-4Alkyl, preferable methyl.
Described compound is: 1-(2 ', 4,4 ', 5-tetramethoxy-2-xenyl) acetone.
Another object of the present invention has been to provide a kind of easy chemical synthesis process synthesising property to stablize, have the active described compound of immunosuppression pharmacology, thereby solves the shortcoming that chemosynthesis step of the prior art is many, difficulty is big.
A kind of method for preparing described compound may further comprise the steps:
(1) with Resorcinol through etherificate, halogenation and with the compound of the following general formula of nucleophilic substitution reaction preparation of boronating agent
(2) with 1, the compound of the following general formula of 2-dialkoxy-4 (2-oxo) alkylbenzene halogenation preparation
Wherein, R
1Be C
1-4Alkyl; R
2Be C
1-4Alkyl;
(3) compound with general formula I I carries out linked reaction with the compound with general formula III in the presence of metal catalyst, and preparation has the compound of general formula I.
Wherein, halogenation is to carry out bromination with the N-bromo-succinimide described in the step (1); Halogenation described in the step (2) is to carry out bromination with the liquid bromine.
Described boronating agent is boric acid isopropyl ester, the positive butyl ester of boric acid or trimethyl borate, the preferred boric acid isopropyl ester; Use n-Butyl Lithium or grignard reagent as alkali in the described affine substitution reaction, preferred n-Butyl Lithium.
Described metal catalyst is four (triphenyl phosphorus) palladium or palladium, preferred four (triphenyl phosphorus) palladium.
Another purpose of the present invention provides the application of described compound on the preparation immunosuppressive drug.
By compound of the present invention is used for anti-organ transplant rejection, confirmed that the protosappanin A derivative is the effective immunosuppressive drug of a class, and do not had obvious toxic-side effects, be the resisting transplant rejection medicine that DEVELOPMENT PROSPECT is arranged very much.
Description of drawings
Fig. 1 is the influence diagram of compound (1) to acceptor spleen competence for added value;
Fig. 2 is that compound (1) illustrates the influence that is subjected to CD4/CD8 ratio in the peripheral body;
Fig. 3 is the influence diagram that compound (1) changes IL-2 in the acceptor serum;
Fig. 4 is the influence diagram that compound (1) changes IFN-r in the acceptor serum;
Fig. 5 is the influence diagram that compound (1) changes IL-10 in the acceptor serum;
Fig. 6 is that different concns compound (1) is to the active influence diagram of dendritic cell;
Fig. 7 is the influence diagram that compound (1) is expressed the dendritic cell surface molecular;
Fig. 8 is that compound (1) is handled the influence diagram of back dendritic cell to xenogenesis T cell proliferation;
Fig. 9 is the influence diagram of compound (1) to dendritic cell IL-12 secretion level;
Figure 10 is the influence diagram of compound (1) to dendritic cell IL-10 secretion level;
Figure 11 is the influence diagram of compound (1) to post-transplantation acceptor routine blood test;
Figure 12 is the influence diagram of compound (1) to post-transplantation acceptor blood biochemistry;
Figure 13 is the nuclear-magnetism figure of compound (1).
Embodiment
With preferred following compounds is that embodiment further specifies the present invention, it should be understood that these embodiment only are used for the purpose of illustration, never limit protection scope of the present invention.
Compound (1)
Compound (1) 1-(2 ', 4,4 ', 5-tetramethoxy-2-xenyl) acetone
The preparation of embodiment 1 1-(2 ', 4,4 ', 5-tetramethoxy-2-xenyl) acetone
1-(2 ', 4,4 ', 5-tetramethoxy-2-xenyl) acetone synthetic route is as follows:
The preparation method of 1-(2 ', 4,4 ', 5-tetramethoxy-2-xenyl) acetone is as follows:
Synthesizing of m-dimethoxybenzene (3)
With Resorcinol (2) (5; 5g; 0.05mol), methyl-sulfate (15; 75g; 0.125mol), salt of wormwood (17,25g, 0.125mol) and 120ml acetone join in the 250ml four-hole bottle; nitrogen protection refluxed 2 hours down; steam acetone behind the cold filtration, get yellow oil, add 100ml KOH (20%) solution backflow 30min again; divide three extractions with the 60ml methylene dichloride; obtain yellow liquid 5.4g after steaming methylene dichloride, productive rate 71%, fusing point-52 ℃; boiling point 85-87 ℃ (7mmHg), density 1.055.
1-bromo-2,4-dimethoxy benzene (4) synthetic
Will between phenylene dimethyl ether (3) (12.4g, 0.09mol), 3A molecular sieve 45g joins in the 390ml carbon tetrachloride solution, adds NBS (17.1g again, 0.096nmol), stirring at room 150min filters, hypo solution washing back separatory, anhydrous sodium sulfate drying steams most of solvent, and decompression is purified and obtained safran liquid 16.2g, yield 83%, fusing point 25-26 ℃, boiling point 153-155 ℃ (18mmHg), density 1.507.
2,4-dimethoxy phenylo boric acid (5) synthetic
With 1-bromo-2, and 4-dimethoxy benzene (4) (9g, 0.0414mol), boric acid isopropyl ester (20ml), tetrahydrofuran (THF) 100ml join (anhydrous and oxygen-free processing) in the four-hole bottle, and low temperature (50 ℃) drips the hexane solution 40ml of n-Butyl Lithium, dripped off in two hours, and slowly rose to room temperature, stirring is spent the night, the dilute hydrochloric acid acidifying is alkalized behind the extracted with diethyl ether diluted sodium hydroxide solution, divides water-yielding stratum, solid is separated out in acidifying again, filtering drying obtains the 5.3g white solid, productive rate 70%, fusing point 125-127 ℃.
2-bromo-3,4-dimethoxy Propiophenone (7) synthetic
With 3, (19.4g 0.1mol) places the 1L there-necked flask to 4-dimethoxy Propiophenone (6), adds entry (200ml) and acetate (200ml), dropping liquid bromine (16.5g) (being dissolved in the 100ml acetate) under the ice-water bath, dripped off in 2 hours, and in the impouring 2000ml water, separated out white flocks behind the continuation stirring 30min, filtering roars of laughter does, obtain the 12.5g white solid, yield 45.7%, fusing point 61.5-63 ℃.
Synthesizing of compound (1) 1-(2 ', 4,4 ', 5-tetramethoxy-2-xenyl) acetone
With 2-bromo-3, and 4-dimethoxy Propiophenone (7) (2g, 7.3mmol), phenylo boric acid 4 (2.5g, 13.7mmol), toluene 20ml, water 20ml, yellow soda ash (1.7g), a little four (triphenyl phosphorus) palladium is put into the 100ml four-hole bottle, nitrogen replacement three times, and reflux stopped in 12 hours.Product is through column chromatography for separation (sherwood oil: ethyl acetate=3: 1).Get white solid 2.2g, productive rate 94%, 95 ℃ of fusing points.
IR(KBr)cm-1：3050，2999，2964，2832，1708，1614，1504，1207，1159。
HNMRδpmm：1.96(3H，s，CH
3)，3.46(2H，s，CH
2)，
3.71(3H，s，5-OCH
3)，3.85(3H，s，2’-OCH
3)，3.85(3H，s，4’-OCH
3)，3.89(3H，s，4-OCH
3)，6.54(1H，d，J＝7.8，5’-H)，6.53(1H，s，3’-H)，6.72(1H，s，3-H)，6.73(1H，s，6-H)，7.05(1H，d，J＝7.8，6’-H)。
The present invention has abandoned traditional through traditional Chinese medicine extraction and isolating method, and adopt simple chemical synthesis process, this method is simple to operate, it is higher to obtain purity, stability is the protosappanin A derivative better, be more conducive to the batch process of active compound and reduce cost, solved the different problem of monomer purity that the different batches that runs into extracts in pharmacodynamic study, solved the systematic error that causes by leaching process difference.
The application of The compounds of this invention in immunosuppression, following examples all adopt the compound of embodiment 1 to experimentize
Experimental technique:
1, sets up rat allogeneic heart transplantation model
The Rats of Allogeneic Transplantation art adopts Ono improvement art formula, will for heart aorta ascendens and pulmonary artery respectively with the aorta abdominalis and the capable end-to-side anastomosis of postcava of acceptor, postoperative is determined heart transplant dancing intensity and frequency by abdominal touch every day.
2, animal grouping and administration
The postoperative animal gives different medicines and irritates stomach, is divided into seven groups at random: 1, control group: only do heart transplant operation, do not give any medicine.2, compound (1) group: give with compound (1) and (25mg/kg/d) irritate stomach; 3, Ciclosporin A group: the heart transplantation postoperative is given and Ciclosporin A (10mg/kg/d).More than each treated animal by postoperative administration on the secondth.
3, the observation of postoperative general state and heart transplantation postoperative graft survival
The postoperative general state is observed the observation that comprises phenomenons such as the mental status, active situation, diet situation, body weight increase and decrease, stool proterties.Observe beating of heart transplant by the abdominal cavity palpation, stop jumping standard as graft death with heart transplant.
4, experimental specimen collection
Each is organized the rat implantation medication and anaesthetizes after 7 days, opens abdomen, and postcava blood sampling 4-5ml collects serum, and-80 ℃ store for future use.Cut heart transplant, 4% Paraformaldehyde 96 is fixed, and is used for pathology and detects.
| Grouping | The example number | Mean ± standard deviation |
| Contrast | 6 | 6.833±1.472 |
| CsA* | 6 | 16.167±3.869 |
| Compound * | 6 | 13.000±4.858 |
Table 1 is respectively organized the graft survival fate
Annotate: it is p＜0.05 that each group is compared * with control group
| Grouping | The example number | Classification |
| Contrast | 7 | 3，4，4，3，3，4，4 |
| CsA* | 7 | 2-3，2，3，3，2，2-3，3-4 |
| Compound * | 7 | 3，2，2-3，2，2-3，2-3，3-4 |
Table 2 is respectively organized graft stdn cardiac muscle biopsy in 7 days classification
Annotate: it is p＜0.05 that each group is compared * with control group
Experimental result is as shown in Figure 1 and Figure 2: survival time of compound (1) significant prolongation rat implantation heart, and alleviated the pathology damage degree of graft, compare with control group and have significant difference.Confirm that compound (1) is the compound of effective resisting transplant rejection.
Experimental technique:
BrdU ELISA method detects its allogene by 96h mixed lymphocyte reacion (MLR) stimulates ability: reacting cells is 7 days splenocyte of each group SD acceptor mouse post-transplantation, after the erythrocyte cracked liquid splitting erythrocyte, the rat lymphocyte parting liquid separates the T cell that obtains, irritation cell comes from the splenic t-cell of normal Wistar rats, mix in varing proportions, cumulative volume is 200 μ L, place at the bottom of 96 hole circles behind the culture plate co-cultivation 96h, detect the multiplication capacity of T cell with BrdU ELISA method.Detect the step by specification: 20h before finishing to cultivate, every hole adds BrdU marking fluid 20 μ L (i.e. 200 μ mol/L), after finishing to cultivate, add FixDenat and make the DNA sex change, every then hole adds 100 μ L anti--BrdU-POD working fluid, washings are washed 3 times, every hole adds 100 μ L tmb substrate liquid, adds 1mol/L H behind the 20min
2SO
4Stop buffer is with the absorbance of automatic microplate reader (Bio-Rad) with dual wavelength pattern (450nm and 690nm) mensuration sample.
Experimental result as shown in Figure 1, to compare * with control group be p＜0.05 to each group:
After using compound (1), the acceptor splenic t-cell is subjected to remarkable inhibition to the multiplication capacity of heterostimulation, compares with control group to have significant difference, has further confirmed the immunosuppressive action of this compounds.
Experimental technique:
(1) flow cytometer detects the T cell subsets
Take EDTA anti-freezing rat vein blood 0.1ml, under the normal temperature respectively with mouse anti rat CD4
+, mouseanti rat CD8
+, mouse anti rat CD3
+0.1ml, add 0.1ml CD monoclonal antibody (1: 1000) in each experiment tube, 30 ℃ hatch 45 minutes after, add cell washing lotion 3ml, centrifugal 2 minutes of 1000r/min, twice repeatedly.Add the fluorescently-labeled mouse anti rat of 0.1ml IgG, hatched 45 minutes for 30 ℃.Behind the splitting erythrocyte haemolysis, centrifugal 2 minutes of 1000r/min abandons supernatant, adds PBS washing 2 times, adds stationary liquid to 0.5ml.Get 20ul and monitor 5 * 10 with flow cytometer (BD FACS Calibur)
5CD3 in the individual cell
+, CD4
+, CD8
+, the per-cent that the T cell respectively accounts for.
(2) mensuration of serum cytokines
Post-transplantation was got peripheral blood in 7 days, centrifuging and taking serum-80 ℃ preservation, and interleukin-22 (IL-2), interferon-r (IFN-r) and interleukin-11 0 (IL-10) detect and operate according to enzyme-linked immunosorbent assay (ELISA) test kit specification sheets.
Experimental result:
As shown in Figure 2, to compare * with control group be p＜0.05 to each group.Use compound (1) and suppressed 7 days peripheral blood CD4/CD8 ratio of acceptor postoperative.
As Fig. 3, Fig. 4, shown in Figure 5, in each figure, it is p＜0.05 that each group is compared * with control group.Use this compounds and suppressed the secretion of peripheral blood Th1 type IFN-r, and increased the secretion of Th2 type IL-10.IL-2 there is restraining effect, but does not reach statistical significance.
The external immunosuppressant experimental study experimental technique of embodiment 5 The compounds of this invention:
1, rat marrow source dendritic cell (Dendritic Cell, preparation DC) and cultivation
The Wistar rat, the 180-200 gram, the cleaning level is purchased in Beijing dimension tonneau China laboratory animal company.The cervical vertebra dislocation method is put to death animal, 75% alcohol whole body soaking disinfection, and careful separation femur and shin bone place aseptic culture fluid.5ml asepsis injector syringe needle is inserted in the medullary space, and (PhosphateBuffered Saline, PBS) flushing repeatedly obtains medullary cell with phosphate buffer soln.The ammonium chloride splitting erythrocyte, PBS washing 3 times, the RPMl RPMI-1640 that contains 10% foetal calf serum is resuspended, is inoculated on 6 well culture plates, and cell density is 2 * 10
6/ ml.(rmGM-CSF, 10ng/ml) (rmIL-4 1000U/ml) puts 37 ℃, 5%CO with recombined small-mouse interleukin 4 to add mGM-CSF
2Cultivate under the condition.Half amount is changed liquid every other day, and supplies rmGM-CSF and rmIL-4 by the concentration of 10ng/ml.
2, the tetrazolium bromide staining detects The compounds of this invention to cultivating the influence of DC vigor
Be incubated at the DC in 96 orifice plates, contain 1640 culture medium culturing 5 days of 10% foetal calf serum, random packet: 1. immature DC group (im-DC): (Lipopolysaccharides LPS) handles not use The compounds of this invention and lipopolysaccharides; 2. LPS-DC:LPS (1mg/ml)+compound (0nmol/L); 3. 5-DC:LPS (1mg/ml)+compound (5hmol/L); 4. 20-DC:LPS (1mg/ml)+compound (20nmol/L); 5. 40-DC:LPS (1mg/ml)+compound (40nmol/L).After each organizes medicine irritation 24h, and every hole adding tetrazolium bromide (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT) solution 20 μ (15mg/mL), 37 ℃ are continued to hatch 4h.Supernatant liquor in the careful absorption hole, every hole add 150 μ l dimethyl sulfoxide (DMSO), and (Dimethyl sulfoxide, DMSO), vibration 10min dissolves crystallisate fully.Select the 490nm wavelength, microplate reader detects each hole absorbance.According to of the influence of different concns compound to the DC cell viability, determine the optimum concn of compound treatment, carry out the mensuration of following index.
3, cell phenotype analysis
Flow cytometer (BD FACS Calibur) detects respectively organizes rat DC specific surfaces mark OX62 and costimulatory molecules CD80, the expression of CD86.
Collecting cell, the PBS washing, resuspended, the antibody that adds Fluoresceine isothiocyanate (FITC) or Phycoerythrin (PE) mark detects with flow cytometer behind the 30min, counts 5 respectively, 000 cell, the result represents with each antigen reactive positive rate.
4, mixed lymphocyte reacion (Mixed Leukocyte Reaction, MLR)-BrdU ELISA
BrdU ELISA method detects its allogene by 96h MLR stimulates ability: irritation cell comes from DC and the sophisticated DC of control group that the Wistar rat is handled through compound (1), and reacting cells is the splenocyte of SD rat, the T cell that obtains through separation.Its concrete grammar is the same.
5, ELISA method
Collect nutrient solution, culture supernatant to be measured-80 ℃ preservation, rat interleukin 12 (IL-12), IL-10 detect and press the operation of ELISA test kit specification sheets.
Experimental result:
As shown in Figure 6, it is p＜0.05 that each group is compared * with control group, and the maximum concentration that does not influence cytoactive with compound (1) processing DC is 20nM.
As shown in Figure 7, compound (1) can significantly reduce the surface molecular CD80 of rat marrow source DC, the expression of CD86, suppresses the maturation of DC.
As shown in Figure 8, compound (1) can suppress the lymphopoietic ability of DC activation xenogenesis T.
As Fig. 9, shown in Figure 10, in each figure, it is p＜0.05 that each group is compared * with control group.Can reduce the secretion of cytokine IL-12 behind compound (1) the processing DC, increase the secretion of cytokine IL-10 simultaneously.
The toxic side effect of embodiment 6 The compounds of this invention
Experimental technique:
The postoperative general state is observed the observation that comprises phenomenons such as the mental status, active situation, diet situation, body weight increase and decrease, stool proterties.Each is organized the rat implantation medication and anaesthetizes after 7 days, opens abdomen, and postcava blood sampling 4-5ml carries out routine blood test and biochemical analysis, gets liver and kidney and carries out the pathology detection.
Experimental result:
As Figure 11, shown in Figure 12, use compound (1) back rat serum routine and biochemical indicator are not made significant difference.
Compound (1) does not make significant difference to the change of liver-kidney diseases reason.
The present invention has confirmed that The compounds of this invention has the effect of anti-transplantation immunity, and toxic side effect is little, is a kind of resisting transplant rejection medicine that DEVELOPMENT PROSPECT is arranged very much.Exploitation Chinese medicine, the immunosuppressor that screening makes new advances from Chinese medicine is with Chinese characteristics, and meets China's actual conditions, is an opportunity motherland's Chinese medicine being pushed to the world.Chinese medicine has aboundresources, and toxic side effect is light, lower-price characteristic.Seek out the Chinese medicine of certain immunosuppressive action and further investigate its mechanism of action, substitute or the alternative immunosuppressive action that is using of part, not only can alleviate patient's misery and economical load, make more patient can accept the life that transplantation treatment prolongs the patient, improve life quality, also can be country and save a large amount of foreign exchanges, crucial meaning is arranged.
Claims (10)
1. the compound of following general formula,
It is characterized in that: R
1Be C
1-4Alkyl; R
2Be C
1-4Alkyl.
2. according to the described compound of claim 1, it is characterized in that: R
1Be methyl, ethyl or propyl group, R
2Be methyl, ethyl or propyl group.
3. according to claim 1 or 2 described compounds, it is characterized in that: R
1Be methyl or ethyl, R
2Be methyl or ethyl.
4. according to the described compound of claim 3, it is characterized in that: R
1Be methyl, R
2It is methyl.
5. according to each described compound among the claim 1-4, it is: 1-(2 ', 4,4 ', 5-tetramethoxy-2-xenyl) acetone.
6. a method for preparing each described compound among the claim 1-5 is characterized in that, may further comprise the steps:
(1) with Resorcinol through etherificate, halogenation and with the compound of the following general formula of nucleophilic substitution reaction preparation of boronating agent
(2) with 1, the compound of the following general formula of 2-dialkoxy-4-(2-oxo) alkylbenzene halogenation preparation
Wherein, R
1Be C
1-4Alkyl; R
2Be C
1-4Alkyl;
(3) compound with general formula I I carries out linked reaction with the compound with general formula III in the presence of metal catalyst, and preparation has the compound of general formula I.
7. in accordance with the method for claim 6, it is characterized in that halogenation described in the step (1) is to carry out bromination with the N-bromo-succinimide; Halogenation described in the step (2) is to carry out bromination with the liquid bromine.
8. in accordance with the method for claim 6, it is characterized in that described boronating agent is boric acid isopropyl ester, the positive butyl ester of boric acid or trimethyl borate, the preferred boric acid isopropyl ester; Use n-Butyl Lithium or grignard reagent as alkali in the described affine substitution reaction, preferred n-Butyl Lithium.
9. in accordance with the method for claim 6, it is characterized in that described metal catalyst is four (triphenyl phosphorus) palladium or palladium, preferred four (triphenyl phosphorus) palladium.
10. the application of the described compound of claim 1 in the preparation immunosuppressive drug.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104016959A (en) * | 2014-05-29 | 2014-09-03 | 黑龙江大学 | Biochemical total synthetic method for protosappanin A and derivatives thereof |
| CN107496390A (en) * | 2017-09-05 | 2017-12-22 | 哈尔滨医科大学 | Application of the protosappanin A derivative in caused by chemotherapeutic medicines heart injury is protected |
| CN109288835A (en) * | 2018-08-08 | 2019-02-01 | 北京大学 | Application of the compound in the drug of preparation treatment acute pulmonary embolism |
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| CN101045046A (en) * | 2006-03-31 | 2007-10-03 | 上海安普生物科技有限公司 | Use of Brazil hemoatoxy type compound for preparing antineoplastic |
| CN101603068A (en) * | 2009-06-23 | 2009-12-16 | 山东省医学科学院基础医学研究所 | The application of Hematorylin in measuring cell-proliferation activity and medicine pair cell toxic effect |
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| CN104016959A (en) * | 2014-05-29 | 2014-09-03 | 黑龙江大学 | Biochemical total synthetic method for protosappanin A and derivatives thereof |
| CN107496390A (en) * | 2017-09-05 | 2017-12-22 | 哈尔滨医科大学 | Application of the protosappanin A derivative in caused by chemotherapeutic medicines heart injury is protected |
| CN107496390B (en) * | 2017-09-05 | 2020-10-27 | 哈尔滨医科大学 | Application of hematoxylin A derivative in protecting heart damage caused by chemotherapeutic drugs |
| CN109288835A (en) * | 2018-08-08 | 2019-02-01 | 北京大学 | Application of the compound in the drug of preparation treatment acute pulmonary embolism |
| CN109288835B (en) * | 2018-08-08 | 2020-09-25 | 北京大学 | Application of compound in preparation of medicine for treating acute pulmonary embolism |
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