CN1690044A - 5,8-menadiol diacetate derivatives and their preparing process and use - Google Patents
5,8-menadiol diacetate derivatives and their preparing process and use Download PDFInfo
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Abstract
The present invention provides one kind of 5, 8-dihydro naphthoquinone derivatives with the given general expressions, and their preparation process and application as antitumor medicine.
Description
Technical field
The present invention relates to a kind of active dihydronaphthalene quinone derivative of good biological that has, be specifically related to 5 of side chain nitrogen replacement, 8-dihydronaphthalene quinone derivative and preparation method and they purposes as antitumor drug.
Background technology
Shikonin (A) is 5, most typical representative in the 8-dihydronaphthalene quinones, and Shikonin can separate from each kind of plant of Boraginaceae and obtains.Shikonin has wide biological activity, as anti-inflammatory, antibiotic, immunomodulatory, anti-AIDS, antitumor, promote to scald wound healing etc., be subjected to the extensive concern of medical research circle, be widely used as a kind of extract of traditional Chinese medicine.
The anti-tumor activity of Shikonin own is more weak and difficult to be absorbed in vivo, and people have studied the derivative of its a lot of 1 '-positions hydroxyl modified for this reason, find that these derivatives have good antineoplastic activity more than Shikonin itself.Wherein exemplary compounds is 1 '-O-acetylshikonin [2-(1-acetyl oxygen-4-methyl-3-pentenyl)-5; 8-dihydroxyl-1; 4-naphthoquinones]; 1 '-O-isobutyryl shikonin [2-(1-isobutyl acyl-oxygen-4-methyl-3-pentenyl)-5,8-dihydroxyl-1,4-naphthoquinones] and 1 '-O-(3; the 3-dimethyl) acryl Shikonin [2-(1-3; the 3-dimethyl) acryloxy-4-methyl-3-pentenyl]-5,8-dihydroxyl-1,4-naphthoquinones].
With the close compound of the present invention patent WO9703940, WO9502572, CN1420111A are arranged.
Further finding in the research, 5,8-dihydronaphthalene quinone structure is that Shikonin has the active key of good biological, a lot of synthetic 5,8-dihydronaphthalene quinone derivative all has and the similar biological activity of Shikonin, these derivatives have often kept the hydroxyl of 1 ' of side chain or with its esterification, wherein the compound of esterification generally has better biological activity than nonesterified parent.
1.H.Brockmann，Justus?Liebigs?Ann.Der?Chem.，1935，2-47.
2.R.H.thomason，Naturally?Occurring?Quinones.III，Recent?Advances，Chapman?and?Hall.New?York，1987，pp.219-223.
3.M.Hayashi，Nippon?Yakurigaku?Zasshi?1977，73，193.
4.V.P.Papageorgiou，Planta?Med.1980，193.
5.G.Honda，F.Sakakibara，K.Yazaki，M.Tabata，J.Nat.Prod.1988，51，152.
6.B.Z.Ahn，K.U.Baik，G.R.Kweon，K.Lim，B.D.Hwang，J.Med.Chem.1995，38，1044.
7.Q.Lu，W.J.Liu，J.Ding，J.C.Cai，W.H.Duan，Bioorg?Med.Chem.Lett.2002，12，1375.
8.X.Chen，L.Yang，N.Zhang，J.A.Turpin，R.W.Buckheit，C.Osterling，Joost.J.Oppenheim，O.M.Z.Howard，Antimicrob.Agents.Chemother.，2003，47，2810.
9.Y.-S.Chang，S.-C.Kuo，S.-H.Weng，S.-C.Jan，F.-N.Ko，C.-M.Teng，Planta?Med.1993，59，401.
10.H.Wagner，B.Kreher，K.Jurcic，Arzeim.-Forsch./Drug?Res.1988，38，273.
11.M.Hayashi.Nippon?Yakurigaku?Zasshi?1977，73，205.
12.V.P.Papageorgiou，A.N.Assimopoulou，E.A.Couladouros，D.Hepworth，K.C.Nicolaou，Angew.Chem.Int.Ed，1999，38，270.
But because therefore the metabolism hydrolysis easily in vivo of the derivative of these acylated hydroxies causes active decline.
For searching has good biological active 5 more, 8-dihydronaphthalene naphtoquinone compounds, our design and prepared that side chain nitrogen replaces 5,8-dihydronaphthalene quinone derivative, we find that this compounds has very strong anti-tumor activity, and this compounds does not also have bibliographical information at present.
Summary of the invention
An object of the present invention is to provide have to tumour cell have that the side chain nitrogen of strong cytotoxic activity replaces 5,8-dihydronaphthalene quinone derivative.
Another object of the present invention provides the preparation method of this analog derivative.
A further object of the present invention provides this analog derivative as the application on the antitumor drug.
The invention provides 5 of the side chain nitrogen replacement shown in following general formula (I), (II), (III), (IV), 8-dihydronaphthalene quinone derivative:
Wherein R1=C1-C6 straight or branched alkyl, aromatic base or aromatic base alkyl;
R2=alkyl, aromatic base or aromatic base alkyl, wherein aromatic base comprises fragrant heterocyclic radical;
R3=hydrogen atom or C1-C3 alkyl or alkyl acyl;
R4=connects the alkyl of C and X, X=O or NH;
R5=alkyl or aromatic base or alkyl acyl.
Substituting group of the present invention, except that indicating especially, alkyl refers to saturated and undersaturated straight chain and alkane chain side chain, preferable methyl, ethyl, sec.-propyl, the tertiary butyl, amyl group, 3-methyl butyl; Aryl-heterocyclic and non-heterocyclic aromatic group, preferred phenyl, tolyl, furyl, pyridyl, thienyl.
Preferred compound is:
| Numbering | ????R 1 | ????R 2 | ????R 3 |
| ????SHN-1 | ????CH 2CH 2CH(CH 3) 2 | ????C(O)OC(CH 3) 3 | ????CH 3 |
| ????SHN-2 | ????CH(CH 3) 2 | ????C(O)OC(CH 3) 3 | ????CH 3 |
| ????SHN-3 | ????CH 3 | ????C(O)OC(CH 3) 3 | ????CH 3 |
| ????SHN-4 | ????CH 2Ph | ????C(O)OC(CH 3) 3 | ????CH 3 |
| ????SHN-5 | ????CH 2CH 2CH(CH 3) 2 | ????C(O)OC(CH 3) 3 | ????H |
| ????SHN-6 | ????CH(CH 3) 2 | ????C(O)OC(CH 3) 3 | ????H |
| ????SHN-7 | ????CH 3 | ????C(O)OC(CH 3) 3 | ????H |
| ????SHN-8 | ????CH 2Ph | ????C(O)OC(CH 3) 3 | ????H |
| ????SHN-9 | ????CH 2CH 2CH(CH 3) 2 | ????C(O)CH 3 | ????H |
| ????SHN-10 | ????CH 2CH 2CH(CH 3) 2 | ????C(O)CH(CH 3) 2 | ????H |
| ????SHN-11 | ????CH 2CH 2CH(CH 3) 2 | ????C(O)CH 2Ph | ????H |
| ????SHN-12 | ????CH(CH 3) 2 | ????C(O)CH 3 | ????H |
| ????SHN-13 | ????CH(CH 3) 2 | ????C(O)CH(CH 3) 2 | ????H |
| ????SHN-14 | ????CH(CH 3) 2 | ????C(O)CH 2Ph | ????H |
| ????SHN-15 | ????CH 3 | ????C(O)CH 3 | ????H |
| ????SHN-16 | ????CH 3 | ????C(O)CH(CH 3) 2 | ????H |
| ????SHN-17 | ????CH 3 | ????C(O)CH 2Ph | ????H |
| ????SHN-18 | ????CH 2Ph | ????C(O)CH 3 | ????H |
| ????SHN-19 | ????CH 2Ph | ????C(O)CH(CH 3) 2 | ????H |
| ????SHN-20 | ????CH 2Ph | ????C(O)CH 2Ph | ????H |
| ????SHN-21 | ????CH 2CH 2CH(CH 3) 2 | C (O) (α-Fu Nan) | ????H |
| ????SHN-22 | ????CH 2CH 2CH(CH 3) 2 | C (O) (α-thiophene) | ????H |
| ????SHN-23 | ????CH 2CH 2CH(CH 3) 2 | C (O) (α-pyridine) | ????H |
| ????SHN-24 | ????CH 2CH 2CH(CH 3) 2 | ????C(O)(CH 2) 4CH 3 | ????H |
| ????SHN-25 | ????CH 2CH 2CH(CH 3) 2 | ????C(O)CH 2OPh | ????H |
| ????SHN-26 | ????CH 2CH 2CH(CH 3) 2 | ????C(O)CH 2NHAc | ????H |
| ????SHN-27 | ????CH(CH 3) 2 | C (O) (α-Fu Nan) | ????H |
| ????SHN-28 | ????CH(CH 3) 2 | C (O) (α-thiophene) | ????H |
| ????SHN-29 | ????CH(CH 3) 2 | C (O) (α-pyridine) | ????H |
| ????SHN-30 | ????CH(CH 3) 2 | ????C(O)(CH 2) 4CH 3 | ????H |
| ????SHN-31 | ????CH(CH 3) 2 | ????C(O)CH 2NHAc | ????H |
| ????SHN-32 | ????CH 3 | C (O) (α-Fu Nan) | ????H |
| ????SHN-33 | ????CH 3 | C (O) (α-thiophene) | ????H |
| ????SHN-34 | ????CH 3 | C (O) (α-pyridine) | ????H |
| ????SHN-35 | ????CH 3 | ????C(O)CH 2NHAc | ????H |
| ????SHN-36 | ????CH 2Ph | C (O) (α-Fu Nan) | ????H |
| ????SHN-37 | ????CH 2Ph | C (O) (α-thiophene) | ????H |
| ????SHN-38 | ????CH 2Ph | C (O) (α-pyridine) | ????H |
| ????SHN-39 | ????CH 2Ph | ????C(O)(CH 2) 4CH 3 | ????H |
| ????SHN-40 | ????CH 2Ph | ????C(O)CH 2NHAc | ????H |
| ????SHN-41 | ????CH 2CH 2CH(CH 3) 2 | ????C(O)OCH 3 | ????H |
| ????SHN-42 | ????CH 2CH 2CH(CH 3) 2 | ????C(O)OCH 2CH 3 | ????H |
| ????SHN-43 | ????CH 2CH 2CH(CH 3) 2 | ????C(O)OCH 2CH(CH 3) 2 | ????H |
| ????SHN-44 | ????CH 2CH 2CH(CH 3) 2 | ????C(O)OCH 2Ph | ????H |
| ????SHN-45 | ????CH(CH 3) 2 | ????C(O)OCH 3 | ????H |
| ????SHN-46 | ????CH(CH 3) 2 | ????C(O)OCH 2CH 3 | ????H |
| ????SHN-47 | ????CH(CH 3) 2 | ????C(O)OCH 2CH(CH 3) 2 | ????H |
| ????SHN-48 | ????CH 3 | ????C(O)OCH 3 | ????H |
| ????SHN-49 | ????CH 3 | ????C(O)OCH 2CH 3 | ????H |
| ????SHN-50 | ????CH 2Ph | ????C(O)OCH 3 | ????H |
| ????SHN-51 | ????CH 2Ph | ????C(O)OCH 2CH 3 | ????H |
| ????SHN-52 | ????CH 2CH 2CH(CH 3) 2 | ????S(O) 2Ph(4-CH 3) | ????H |
| ????SHN-53 | ????CH 2CH 2CH(CH 3) 2 | ?S(O) 2CH 3 | ????H |
| ????SHN-54 | ????CH(CH 3) 2 | ?S(O) 2Ph(4-CH 3) | ????H |
| ????SHN-55 | ????CH 3 | ?S(O) 2Ph(4-CH 3) | ????H |
| ????SHN-56 | ????CH 2Ph | ?S(O) 2Ph(4-CH 3) | ????H |
| ????SHN-57 | ????CH(CH 3) 2 | ?C(O)OC(CH 3) 3 | ????Ac |
| ????SHN-58 | ????CH 3 | ?C(O)OC(CH 3) 3 | ????Ac |
| ????SHN-59 | ????CH 2Ph | ?C(O)OC(CH 3) 3 | ????Ac |
| ????SHN-60 | ????CH 3 | ?C(O)Ph | ????Ac |
| ????SHN-61 | ????CH 2Ph | ?C(O)CH 3 | ????Ac |
The present invention also provides 5 shown in above-mentioned general formula (I), (II), (III), (IV), and seven kinds of preparation methods of 8-dihydronaphthalene quinones can obtain by following one or several reaction:
At first by following flow preparation intermediate X II:
Hydroxyl R with dihydronaphthalene quinone derivative V
11-Br or R
11-Cl or R
11Protections such as-I; under the effect of Grignard reagent, generate VII again with N, O-dimethyl oxyammonia; compound VI I with Grignard reagent reacting generating compound VIII; the VIII deprotection can be obtained IX; generate X with the oxammonium hydrochloride effect again; reduction then obtains compounds X I, introduces R2 and obtain XII under the organic bases effect.
In above synthetic route, R1, R2, as defined above, R3 represents alkyl, and R10 represents alkyl, and R11 represents allyl group or methoxyl group methylene radical.
Below further openly seven kinds of preparation methods of general formula (I), (II), (III), (IV) compound.
Method one:
In suitable solvent, be that formula (XII) compound of alkyl obtains general formula compound (II) with two acetic acid iodosobenzenes or two (trifluoracetic acid) iodosobenzene oxidation R3, the preferred polar solvent of solvent that uses in this reaction is as the mixed solvent of acetonitrile, dimethyl formamide etc. and water.
In the preferred embodiment scheme of the inventive method one, two acetic acid iodosobenzenes or two (trifluoracetic acid) iodosobenzene at first are dissolved in the solvent, gained solution cooling then, preferred 0-5 ℃.With respect to formula (XII) compound, two acetic acid iodosobenzenes or two (trifluoracetic acid) iodosobenzene are its 1-50 times of molar weight, preferred 2-5 times of molar weight, the solution that then adds compound (XII), in 10 minutes-10 hours, add, preferably in 30 minutes-2 hours, add, it is reacted several hrs at 0-30 ℃, when reacting completely, adding distil water is to mixture, the product of gained extracts with The suitable solvent, as ethyl acetate etc., separates then and by post-processing step such as recrystallization or column chromatography purification.
As giving an example of formula (II) compound that passes through the inventive method-preparation, can obtain following compound: SHN-1, SHN-2, SHN-3, SHN-4.
Method two:
R3 is that general formula (II) compound of hydrogen is general formula (II) the compound dealkylation preparation by the R3=alkyl, takes off the preferred AgO/ nitric acid of alkyl reagent.
In the preferred embodiment of embodiment the inventive method two, formula R
3For the compound (II) of alkyl is dissolved in reactionlessness organic solvent such as acetone, benzene, the toluene etc., be cooled to 0-5 ℃ and in gained solution, add 1-50 times of molar weight, especially the dealkylation agent of 2-6 molar weight (with respect to formula (I) compound) then.Reaction mixture stirred 10 minutes-4 hours at 0-30 ℃ then, and preferred 20 minutes-1 hour, then with extractions such as suitable extraction agent such as methylene dichloride.The extracting solution desiccant dehydration,, concentrate then.As needs, separablely go out products therefrom and step such as recrystallization routinely, purifying such as column chromatography.
R by the inventive method two preparations
3Giving an example of the general formula of=H (II) compound can obtain following compound: SHN-5, SHN-6, SHN-7, SHN-8.
Method three:
R3 is that general formula (II) compound of alkyl acyl is to be general formula (II) compound prepared in reaction in the presence of organic bases and organic acid anhydride or acyl chlorides of hydrogen by R3.
In the preferred embodiment according to preparation the inventive method three, formula R
3For the compound (II) of hydrogen is dissolved in the organic solvent such as methylene dichloride, toluene etc. of reactionlessness, at-15 ℃-55 ℃ organic basess that add 1-50 times of molar weight such as pyridine, triethylamine, the organic acid anhydride or the organic acid acyl chlorides that under agitation add 1-50 times of molar weight stirred 0.5-50 hour.Then with suitable extraction agent dilution, organic phase washing, organic acid anhydride that the saturated sodium bicarbonate flush away is excessive or acyl chlorides, saturated sodium-chloride washing.The organic phase desiccant dehydration that extracts concentrates.Purified products such as available if needed recrystallization or column chromatography.
By the inventive method three preparation R
3The exemplary of the general formula of=alkyl acyl (II) compound is: SHN-57, SHN-58, SHN-59.
Method four:
A) under appropriate condition, slough R in order to last method one, method two, method three prepared general formula (II) dihydronaphthalene quinone derivatives
2(being generally acidic conditions) obtains the compound of general formula for (XIV).
General formula (II) compound is dissolved in inert solvent such as methylene dichloride, ethyl acetate etc., at 0 ℃-40 ℃ hydrochloric acid soln or organic acid such as the trifluoroacetic acids that add ethyl acetate.Stirred 30 minutes-8 hours, and waited to react completely, under reduced pressure concentrate, solvent evaporated obtains the salt of compound (XIV).
B): with general formula is that the compound and the organic acid of (XIV) reacts in the presence of organic bases and dicyclohexyl carbodiimide or other condensing agents, perhaps reacts preparation general formula (I) compound in the presence of organic bases with organic acid anhydride or acyl chlorides.
At 0-30 ℃ with dissolved compounds such as organic solvent such as methylene dichloride (XIV), the compound bad to some solvability will add the triethylamine of 1-3 times of molar weight, adds the organic acid R2COOH of 1-20 times of molar weight, the condensing agent of 1-20 times of molar weight stirred 30 minutes-4 hours.Finish Deng reaction, filter, filtrate concentrates, and with column chromatography or recrystallization purifying, obtains general formula (I) compound.
When the preparation of part general formula (I) compound, after the salt that obtains compound (XIV), after dissolvings such as methylene chloride, add 1-20 times of molar weight organic acid acyl chlorides or acid anhydrides, the organic bases that adds 1-20 times of molar weight again, reaction obtains general formula (I) compound.
Exemplary by general formula (I) compound of present method four preparation is: SHN-9, SHN-10, SHN-11, SHN-12, SHN-13, SHN-14, SHN-15, SHN-16, SHN-17, SHN-18, SHN-19, SHN-20, SHN-21, SHN-22, SHN-23, SHN-24, SHN-27, SHN-28, SHN-29, SHN-30, SHN-32, SHN-33, SHN-34, SHN-36, SHN-37, SHN-38, SHN-39, SHN-60, SHN-61.
Method five:
After obtaining the salt of compound (XIV), with dissolvings such as inert solvent such as methylene dichloride, at 0 ℃-30 ℃ chloro-formic ester R that add 1-2 times of molar weight according to method four
2OCOCl, organic bases such as triethylamine, the pyridine etc. of 1-3 times of molar weight of adding stirred 30 minutes-5 hours, concentrated, and column chromatography or recrystallization purifying obtain general formula (II) compound.
Exemplary by formula (II) compound of the inventive method five preparation is: SHN-41, SHN-42, SHN-43, SHN-44, SHN-45, SHN-46, SHN-47, SHN-48, SHN49, SHN50, SHN51.
Method six:
After obtaining the salt of compound (XIV) according to method four, be used in dissolving such as 0-30 ℃ of methylene chloride after, add the organic acid R of 1-20 times of molar weight
5XR
4COOH, the condensing agent of 1-20 times of molar weight stirred 30 minutes-4 hours.Finish Deng reaction, filter, filtrate concentrates, and with column chromatography or recrystallization purifying, obtains general formula (III) compound.
Exemplary by general formula (III) compound of present method preparation is: SHN-25, SHN-26, SHN-31, SHN-31, SHN-35, SHN40.
Method seven:
After obtaining compound (XIV), add inert solvent such as methylene dichloride equal solvent, 0 ℃-30 ℃ organic SULPHURYL CHLORIDE that add 2-10 times of molar weight according to method four, the organic bases of 2-10 times of molar weight stirred 1-24 hour, concentrated, column chromatography or recrystallization purifying obtain compound (IV).
Exemplary by general formula (IV) compound of present method preparation has: SHN-52, SHN-53, SHN-54, SHN-55, SHN-56.
Formula (I), (II), (III), (IV) compound by aforesaid method one-seven preparation of the present invention, finding in cellulotoxic experiment has had strong inhibitory effects to tumor cell line, and this class new compound tool antitumor action can be used in preparation prevention and medicine for treating tumor thing.
Antitumor cytolytic activity:
Use sulphonyl rhodamine B protein staining method (sulforhodamine B respectively, SRB) and tetrazolium (microculture tetrozolium, MTT) reduction method is carried out the research (Cancer Res.1988,48 (3), 589) of anti-tumor activity to the synthetic compound.
SRB is a kind of protein binding dyestuff, can combine with the basic aminoacids in the biomacromolecule, and its optical density(OD) at 515nm (OD) reading becomes good linear relationship with cell count, so can be used as the quantitative of cell count.Human lung carcinoma cell A-549 cultivates with the RPMI-1640 that contains 10% calf serum, and the cell with logarithmic phase during mensuration is made into cell suspension, is inoculated on 96 well culture plates.The every hole of experimental group adds the compound of 10 μ l different concns respectively, control group adds the RPMI-1640 nutrient solution that equal-volume contains maximum concentration solvent (methyl-sulphoxide), at 37 ℃, cultivate after 72 hours under 5% carbon dioxide conditions, fix with trichoroacetic acid(TCA), every hole adds 100 μ lSRB liquid, and the unconjugated SRB of flush away measures the OD value with the dull and stereotyped reader of automatic spectrophotometric.With the tumour cell group that does not add medicine is contrast, calculates the growth inhibition ratio of medicine to this tumour cell.
Inhibiting rate=[(control group-administration group)/control group] * 100%
Have the desaturase relevant with NADP in the plastosome of viable cell, xanchromatic MTT can be reduced to insoluble blue material (formazan), dead cell does not then have this function.With measuring the OD value at the 550nm place with microplate reader behind the methyl-sulphoxide dissolving formazan, can be to viable count.This law adopts mouse leukemia P388 and human leukemia HL-60 cell system, and experimental technique srb assay, incubation time are 48 hours, the same srb assay of data analysis.
Result evaluation: invalid: 10-5mol/L＜85%;
The weak effect: 10-5mol/L 〉=85% or 10-6mol/L＞50%;
Potent: 10-6mol/L 〉=85% or 10-7mol/L＞50%.
The part of compounds activity data of measuring is as follows:
Table 1:(structured data is seen embodiment)
| Concentration (M) P388 * | Estimate | |||||
| Sample number into spectrum | ????10 -4 | ??10 -5 | ??10 -6 | ??10 -7 | ??10 -8 | |
| SHN-25 SHN-26 SHN-41 SHN-42 SHN-43 SHN-44 SHN-52 SHN-53 alkannin | ????100 ????97.3 ????98.5 ????100 ????98.4 ????100 ????100 ????93.7 ????83.1 | ??100 ??100 ??100 ??100 ??100 ??100 ??100 ??100 ??97.8 | ??20.2 ??100 ??54.9 ??37.4 ??55.4 ??26.6 ??51.3 ??100 ??100 | ??3.1 ??2.6 ??0.9 ??9.5 ??5.9 ??5.3 ??17.7 ??23.3 ??15.4 | ??1.6 ??0 ??0 ??3.9 ??8.7 ??0.4 ??0 ??18.6 ??0 | The weak effect of the weak effect weak effect of the weak effect of the weak effect of potent weak effect is potent |
Table 2:
| Concentration (M) HL-60 | Estimate | |||||
| Sample number into spectrum | ????10 -4 | ??10 -5 | ??10 -6 | ??10 -7 | ?10 -8 | |
| SHN-5 SHN-9 SHN-10 SHN-11 SHN-21 SHN-22 SHN-23 SHN-24 alkannin | ????91.9 ????95.4 ????100 ????72.0 ????86.8 ????97.2 ????85.1 ????77.3 ????85.6 | ??100 ??100 ??100 ??92.2 ??88.0 ??100 ??87.5 ??99.8 ??100 | ??100 ??94.9 ??97.0 ??82.5 ??23.7 ??100 ??90.1 ??92.4 ??76.4 | ??13.0 ??47.4 ??2.9 ??4.6 ??9.8 ??0 ??521 ??3.6 ??3.1 | ?0 ?19.2 ?0.8 ?8.4 ?0 ?0 ?20.4 ?0 ?0 | The potent potent weak effect of the weak effect of potent potent weak effect |
Table 3:
| Concentration (M) A-549 | Estimate | |||||
| Sample number into spectrum | ????10 -4 | ??10 -5 | ??10 -6 | ????10 -7 | ??10 -8 | |
| SHN-5 SHN-9 SHN-10 SHN-11 SHN-21 SHN-22 SHN-23 SHN-24 SHN-25 SHN-26 SHN-41 SHN-42 SHN-43 SHN-44 SHN-52 SHN-53 alkannin | ????100 ????100 ????100 ????99.4 ????100 ????100.0 ????99.7 ????99.2 ????93.4 ????91.0 ????95.0 ????95.1 ????91.6 ????93.9 ????99.0 ????92.3 ????96.4 | ??100 ??100 ??100 ??100 ??100 ??100 ??100 ??100 ??28.0 ??64.7 ??95.3 ??93.0 ??84.9 ??46.4 ??90.8 ??97.1 ??96.8 | ??99.2 ??100 ??98.6 ??63.6 ??44.6 ??99.1 ??92.8 ??71.3 ??0 ??0.6 ??46.3 ??37.8 ??0 ??0 ??49.3 ??47.0 ??71.7 | ????11 ????20.1 ????1.2 ????10.3 ????0.5 ????6.8 ????4.2 ????2.0 ????0 ????0 ????14.6 ????8.1 ????0 ????0 ????7.0 ????3.8 ????10.8 | ??12.1 ??0 ??4.1 ??8.2 ??1.2 ??10.9 ??1.4 ??11.2 ??0 ??0 ??1.4 ??0 ??0 ??0 ??1.2 ??0 ??3.2 | The weak effect of the invalid weak effect of the potent weak effect of the weak effect of the potent potent weak effect weak effect weak effect of invalid weak effect |
It is as shown in the table, and this compounds has the intensive cytotoxic activity to tumor cell line, is promising antitumor drug.
Embodiment
In the following example, will be described more specifically 5 of representational formulas (I) more of the present invention, (II), (III), (IV), 8-dihydronaphthalene quinone derivative and their preparation method.
Embodiment 1
2-(1-(1-tert.-butoxy) formyl nitrogen base-4-methyl amyl)-5,8-dimethoxy-1, the preparation of 4-naphthoquinones (SHN-1)
2.58g (6mmol) two (trifluoracetic acid) iodosobenzene is dissolved in the distilled water mixed solvent of the acetonitrile of 125ml and 62ml, be cooled to 0 ℃, dropping is dissolved with 0.806g (2mmol) 3-(1-(1-tert.-butoxy) formyl nitrogen base-4-methyl amyl)-5, the 125ml acetonitrile solution of 8-dimethoxy-1-naphthols dripped off at 45 minutes.Dripping off the back keeps 0 ℃ to stir 2 hours.Add ethyl acetate and water in reactant, tell organic phase, the water ethyl acetate extraction merges organic phase.Organic phase saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate concentrates.The resistates column chromatography purification obtains 0.673g (yield: 65%) have the title compound of following structure.
1H-NMR(CDCl
3，400Hz，δppm)：7.30(s，2H)，6.66(s，1H)，5.22(d，J＝8.7Hz，1H)，4.54(q，J＝8.5Hz，1H)，3.97(s，3H)，3.96(s，3H)，1.45-4.85(m，3H)，1.40(s，9H)，1.12-1.30(m，2H)，0.86(d，J＝6.6Hz，6H)
Embodiment 2
2-(1-(1-tert.-butoxy) formyl nitrogen base-2-methyl-propyl)-5,8-dimethoxy-1, the preparation of 4-naphthoquinones (SHN-2)
2.58g (6mmol) two (trifluoracetic acid) iodosobenzene is dissolved in the distilled water mixed solvent of the acetonitrile of 125ml and 62ml, be cooled to 0 ℃, dropping is dissolved with 0.75g (2mmol) 3-(1-(1-tert.-butoxy) formyl nitrogen base-2-methyl-propyl)-5, the 125ml acetonitrile solution of 8-dimethoxy-1-naphthols dripped off at 45 minutes.Dripping off the back keeps 0 ℃ to stir 2 hours.Add ethyl acetate and water in reactant, tell organic phase, the water ethyl acetate extraction merges organic phase.Organic phase saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate concentrates.The resistates column chromatography obtains 0.467g (yield: 60%) have the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：7.31(s，2H)，6.63(s，1H)，5.32(d，J＝9.1，1H)，4.28(t，J＝8.9Hz，1H)，3.96(s，3H)，3.95(s，3H)，2.11-2.20(m，1H)，1.40(s，9H)，0.94(d，J＝6.8Hz，3H)，0.88(d，J＝6.7Hz，3H)
Embodiment 3
2-(1-(1-tert.-butoxy) formyl nitrogen base ethyl)-5,8-dimethoxy-1, the preparation of 4-naphthoquinones (SHN-3)
2.58g (6mmol) two (trifluoracetic acid) iodosobenzene is dissolved in the distilled water mixed solvent of the acetonitrile of 125ml and 62ml, be cooled to 0 ℃, dropping is dissolved with 0.694g (2mmol) 3-(1-(1-tert.-butoxy) formyl nitrogen base ethyl)-5, the 125ml acetonitrile solution of 8-dimethoxy-1-naphthols.Dripping off the back keeps 0 ℃ to stir 2 hours.Add ethyl acetate and water in reactant, tell organic phase, the water ethyl acetate extraction merges organic phase.Organic phase saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate concentrates.The resistates column chromatography obtains 0.469g (yield: 65%) have the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：7.31(s，2H)，6.68(s，1H)，5.16(bs，1H)，4.70-4.81(m，1H)，3.96(s，3H)，3.95(s，3H)，1.40(bs，12H)
Embodiment 4
2-(1-(1-tert.-butoxy) formyl nitrogen base-2-phenylethyl)-5,8-dimethoxy-1, the preparation of 4-naphthoquinones (SHN-4)
2.58g (6mmol) two (trifluoracetic acid) iodosobenzene is dissolved in the distilled water mixed solvent of the acetonitrile of 125ml and 62ml, be cooled to 0 ℃, dropping is dissolved with 0.847g (2mmol) 3-(1-(1-tert.-butoxy) formyl nitrogen base-2-phenylethyl)-5, the 125ml acetonitrile solution of 8-dimethoxy-1-naphthols.Dripping off the back keeps 0 ℃ to stir 2 hours.Add ethyl acetate and water in reactant, tell organic phase, the water ethyl acetate extraction merges organic phase.Organic phase saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate concentrates.The resistates column chromatography obtains 0.536g (yield: 64%) have the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：7.33(s，2H)，7.14-7.27(m，5H)，6.42(s，1H)，5.30(bs，1H)，4.88(q，J＝7.8Hz，1H)，4.00(s，3H)，3.96(s，3H)，3.17(dd，J＝6.8Hz，13.6Hz，1H)，3.00(dd，J＝6.7Hz，13.5Hz，1H)，1.35(s，9H)。
Embodiment 5
2-(1-(1-tert.-butoxy) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-5)
0.834g (2mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-4-methyl amyl)-5,8-dimethoxy-1,4-naphthoquinones (SHN-1) is dissolved in the 65ml acetone, be cooled to 0 ℃, add 2.6g (0.02mol) AgO, drip 6M nitric acid 3.9ml (0.023mol), drip off the back and stirred 30 minutes, add the dilution of 400ml methylene dichloride.Organic phase washes with water successively, and 10% hypo solution is washed, the saturated sodium-chloride water solution washing, and anhydrous sodium sulfate drying concentrates the resistates column chromatography.Obtain the title compound that 0.389g (yield 50%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.65(s，1H)，12.45(s，1H)，7.19(s，2H)，6.94(s，1H)，5.13(d，J＝8.1Hz，1H)，4.70-4.80(m，1H)，1.50-1.78(m，3H)，1.43(s，9H)，1.15-1.34(m，2H)，0.88(d，J＝9.2Hz，6H)
Embodiment 6
2-(1-(1-tert.-butoxy) formyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-6)
0.778g (2mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-methyl-propyl)-5,8-dimethoxy-1,4-naphthoquinones (SHN-2) is dissolved in the 65ml acetone, be cooled to 0 ℃, add 2.6g (0.02mol) AgO, drip 6M nitric acid 3.9ml (0.023mol), drip off the back and stirred 30 minutes, add the dilution of 400ml methylene dichloride.Organic phase washes with water successively, and 10% hypo solution is washed, the saturated sodium-chloride water solution washing, and anhydrous sodium sulfate drying concentrates the resistates column chromatography.Obtain the title compound that 0.289g (yield 40%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.66(s，1H)，12.45(s，1H)，7.20(AB，J＝9.6Hz，2H)，6.92(s，1H)，5.22(d，J＝8.7Hz，1H)，4.51(t，J＝8.5Hz，1H)，2.10-2.23(m，1H)，1.42(s，9H)，0.98(d，J＝6.gHz，3H)，0.93(d，J＝6.6Hz，3H)
Embodiment 7
2-(1-(1-tert.-butoxy) formyl nitrogen base-ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-7)
0.722g (2mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-ethyl)-5,8-dimethoxy-1,4-naphthoquinones (SHN-3) is dissolved in the 65ml acetone, be cooled to 0 ℃, add 2.6g (0.02mol) AgO, drip 6M nitric acid 3.9ml (0.023mol), drip off the back and stirred 30 minutes, add the methylene dichloride dilution.Organic phase washes with water successively, and 10% hypo solution is washed, the saturated sodium-chloride water solution washing, and anhydrous sodium sulfate drying concentrates the resistates column chromatography.Obtain the title compound that 0.3g (yield 45%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.63(s，1H)，12.44(s，1H)，7.20(s，2H)，6.98(s，1H)，5.07(s，1H)，4.93(m，1H)，1.41-1.44(m，12H)
Embodiment 8
2-(1-(1-tert.-butoxy) formyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-8)
0.875g (2mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-phenylethyl)-5,8-dimethoxy-1,4-naphthoquinones (SHN-4) is dissolved in the 65ml acetone, be cooled to 0 ℃, add 2.6g (0.02mol) AgO, drip 6M nitric acid 3.9ml (0.023mol), drip off the back and stirred 30 minutes, add the methylene dichloride dilution.Organic phase washes with water successively, and 10% hypo solution is washed, the saturated sodium-chloride water solution washing, and anhydrous sodium sulfate drying concentrates the resistates column chromatography.Obtain the title compound that 0.335g (yield 41%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.70(s，1H)，12.40(s，1H)，7.14-7.30(m，7H)，6.74(s，1H)，5.2(bs，1H)，5.02-5.10(m，1H)，3.22(dd，J＝6.5Hz，13.8Hz，1H)，2.99(dd，J＝7.9Hz，13.7Hz，1H)，1.38(s，9H)
Embodiment 9
2-(1-acetyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-9) 39mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-5) is dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stirs 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 12mg (0.15mmol) Acetyl Chloride 98Min., stirring at room 2 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 25mg (yield 75%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.64(s，1H)，12.41(s，1H)，7.17(AB，J＝9.8Hz，2H)，6.92(s，1H)，6.22(d，J＝8.6Hz，1H)，4.95(q，J＝8.4Hz，1H)，2.00(s，3H)，1.48-1.88(m，3H)，1.1-1.30(m，2H)，0.854(d，J＝6.6Hz，3H)，0.847(d，J＝6.6Hz，3H)
Embodiment 10
2-(1-(2-methyl propionyl) nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-10)
Operation is just used the isobutyric anhydride replacing acetyl chloride, the title compound that obtains having following structure with example 9.
1H-NMR(CDCl3，400Hz，δppm)：12.67(s，1H)，12.43(s，1H)，7.19(AB，J＝9.6Hz，2H)，6.94(s，1H)，6.27(d，J＝8.5Hz，1H)，4.96-5.02(m，1H)，2.34-2.44(m，1H)，1.70-1.90(m，2H)，1.51-1.60(m，1H)，1.12-1.32(m，8H)，0.88(d，J＝6.6Hz，3H)，0.87(d，J＝6.6Hz，3H)
Embodiment 11
2-(1-phenylacetyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-11) is operated with example 9, just uses the phenyllacetyl chloride replacing acetyl chloride, the title compound that obtains having following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.53(s，1H)，12.42(s，1H)，7.25-7.40(m，5H)，7.18(AB，J＝9.6Hz，2H)，6.83(s，1H)，6.07(d，J＝8.3Hz，1H)，4.91-4.98(m，1H)，4.59(AB，J＝16Hz，2H)，1.42-1.80(m，3H)，1.04-1.14(m，2H)，0.82(d，J＝6.6Hz，6H)
Embodiment 12
2-(1-acetyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-12) 36mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-6) is dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stirs 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 12mg (0.15mmol) Acetyl Chloride 98Min., stirring at room 2 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 22mg (yield 72%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.67(s，1H)，12.43(s，1H)，7.19(AB，J＝9.6Hz，2H)，6.94(s，1H)，4.71(t，J＝8.9Hz，1H)，2.17-2.26(m，1H)，2.00(s，3H)，1.01(d，J＝6.7Hz，3H)，0.88(d.J＝6.8Hz，3H)
Embodiment 13
2-(1-(2-methyl propionyl) nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-13)
Operation is just used the isobutyric anhydride replacing acetyl chloride, the title compound that obtains having following structure with example 12.
1H-NMR(CDCl3，400Hz，δppm)：12.68(s，1H)，12.44(s，1H)，7.20(AB，J＝9.6Hz，2H)，6.93(s，1H)，6.32(d，J＝10.3Hz，1H)，4.70(t，J＝9Hz，1H)，2.36-2.42(m，1H)，2.17-2.25(m，1H)，1.17(d，J＝6.8Hz，3H)，1.13(d，J＝6.9Hz，3H)，1.00(d，J＝8.7Hz，3H)，0.89(d，J＝6.6Hz，3H)
Embodiment 14
2-(1-phenylacetyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-14)
Operation is just used the phenyllacetyl chloride replacing acetyl chloride, the title compound that obtains having following structure with example 12.
1H-NMR(CDCl3，400Hz，δppm)：12.52(s，1H)，12.42(s，1H)，7.24-7.40(m，5H)，7.18(AB，J＝9.6Hz，2H)，6.82(s，1H)，6.19(d，J＝8.7Hz，1H)，4.70(t，J＝8.5Hz，1H)，3.60(AB，J＝16Hz，2H)，2.01-2.12(m，1H)，0.82(d，J＝6.7Hz，6H)
Embodiment 15
2-(1-acetyl nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-15)
33mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-7) are dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 12mg (0.15mmol) Acetyl Chloride 98Min., stirring at room 2 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 18mg (yield 65%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.65(s，1H)，12.42(s，1H)，7.19(AB，J＝9.7Hz，2H)，6.96(s，1H)，6.20(d，J＝7.7Hz，1H)，5.05-5.19(m，1H)，2.02(s，3H)，1.50(d，J＝7.0Hz，3H)
Embodiment 16
2-(1-(2-methyl propionyl) nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-16)
Operation is just used the isobutyric anhydride replacing acetyl chloride, the title compound that obtains having following structure with example 15.
1H-NMR(CDCl3，400Hz，δppm)：12.66(s，1H)，12.42(s，1H)，7.19(AB，J＝9.8Hz，2H)，6.93(s，1H)，6.15(d，J＝8.2Hz，1H)，5.13-5.18(m，1H)，2.36-2.43(m，1H)，1.50(d，J＝7.0Hz，3H)，1.14-1.18(m，6H)
Embodiment 17
2-(1-phenylacetyl nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-17)
Operation is just used the phenylacetic anhydride replacing acetyl chloride, the title compound that obtains having following structure with example 15.
1H-NMR(CDCl3，400Hz，δppm)：12.54(s，1H)，12.41(s，1H)，7.27-7.41(m，5H)，7.19(s，2H)，6.82(s，1H)，6.04(d，J＝7.8Hz，1H)，5.09-5.18(m，1H)，3.59(s，2H)，1.39(d，J＝6.9，3H)
Embodiment 18
2-(1-acetyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-18)
41mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-phenylethyl base)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-7) are dissolved in the ethyl acetate solution of hydrogenchloride of 10ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 12mg (0.15mmol) Acetyl Chloride 98Min., stirring at room 2 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 18mg (yield 65%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.72(s，1H)，12.38(s，1H)，7.20-7.35(m，7H)，6.71(s，1H)，5.32(q，J＝7.8Hz，1H)，3.23(dd，J＝7.3Hz，J＝13.8Hz，1H)，3.07(dd，J＝7.6Hz，J＝13.8Hz，1H)，1.96(s，3H)
Embodiment 19
2-(1-(2-methyl propionyl) nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-19)
Operation is just used the isobutyric anhydride replacing acetyl chloride, the title compound that obtains having following structure with example 18.
1H-NMR(CDCl3，400Hz，δppm)：12.73(s，1H)，12.39(s，1H)，7.14-7.31(m，7H)，6.72(s，1H)，6.20(d，J＝8.1Hz，1H)，5.32(q，J＝7.7Hz，1H)，3.24(dd，J＝6.7Hz，13.6Hz，1H)，3.04(dd，J＝8Hz，13.8Hz，1H)，2.32(m，1H)，1.07(d，J＝6.8Hz，3H)，1.05(d，J＝6.8Hz，3H)
Embodiment 20
2-(1-phenylacetyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-20) is operated with example 18, just uses the phenyllacetyl chloride replacing acetyl chloride, the title compound that obtains having following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.61(s，1H)，12.39(s，1H)，7.12-7.38(m，10H)，6.81-6.95(m，2H)，4.06(s，1H)，6.00(d，J＝7.3Hz，1H)，5.27-5.32(m，1H)，3.53(s，2H)，3.10(dd，J＝6Hz，13.7Hz，1H)，2.85(dd，J＝7.7Hz，13.6Hz，1H)
Embodiment 21
2-(1-(2-furoyl) nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-21)
39mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-5) are dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 10mg (0.1mmol) triethylamine, the dicyclohexylcarbodiimide (DCC) of 23mg (0.11mmol) then adds 12mg (0.1mmol) 2-furancarboxylic acid, stirring at room 2 hours, reactant is concentrated the resistates column chromatography.Obtain the title compound that 29mg (yield 76%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.7(s，1H)，12.43(s，1H)，7.49(dd，J＝0.8Hz，1.8Hz，1H)，7.19(s，2H)，7.12(dd，J＝0.8Hz，3.6Hz，1H)，7.30(d，J＝8.5Hz，1H)，7.01(s，1H)，6.51(dd，J＝1.7Hz，3.5Hz，1H)，5.16(q，J＝8.5Hz，1H)，1.61-2.00(m，3H)，1.18-1.40(m，2H)，0.89(d，J＝6.6Hz，3H)，0.88(d，J＝6.6Hz，3H)
Embodiment 22
2-(1-(2-thenoyl) nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-22)
Operation just changes the 2-furancarboxylic acid into the 2-thiophenic acid with example 21, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.71(s，1H)，12.44(s，1H)，7.54(dd，J＝1.1Hz，3.7Hz，1H)，7.50(dd，J＝1.1Hz，4.9Hz，1H)，7.20(AB，J＝9.6Hz，2H)，7.09(dd，J＝3.9Hz，5.1Hz，1H)，7.02(s，1H)，6.84(d，J＝8.5Hz，1H)，5.34(q，J＝8.3Hz，1H)，1.86-1.98(m，2H)，1.54-1.64(m，1H)，1.18-1.38(m，2H)，0.90(d，J＝6.6Hz，3H)，0.89(d，J＝6.6Hz，3H)
Embodiment 23
2-(1-(2-pyridine formyl) nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-23)
Operation just changes the 2-furancarboxylic acid into the 2-pyridine carboxylic acid with example 21, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.71(s，1H)，12.43(s，1H)，8.60(d，J＝5.2Hz，1H)，8.15(d，J＝7.8Hz，1H)，7.86(t，J＝7.7Hz，1H)，7.46(dd，J＝4.8Hz，7.5Hz，1H)，7.18(s，2H)，7.02(s，1H)，5.26(q，J＝8.3Hz，1H)，1.80-2.10(m，2H)，1.65-1.64(m，1H)，1.24-1.41(m，2H)，0.90(d，J＝6.6Hz，3H)，0.89(d，J＝6.6Hz，3H)
Embodiment 24
2-(1-hexanoyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-24)
Operation just changes the 2-furancarboxylic acid into caproic acid with example 21, obtains having the title compound of following structure.
1H-NMR(CDCl
3，400Hz，δppm)：12.68(s，1H)，12.45(s，1H)，7.2(AB，J＝9.6Hz，2H)，6.94(s，1H)，6.18(d，J＝8.4Hz，1H)，5.00(q，J＝8.4Hz，1Hz)，2.22(t，J＝7.1Hz，2H)，1.14-1.90(m，11H)，0.84-0.92(m，9H)
Embodiment 25
2-(1-(2-benzene oxygen acetyl) nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-25)
Operation just changes the 2-furancarboxylic acid into the 2-phenoxy acetic acid with example 21, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.59(s，1H)，12.41(s，1H)，6.90-7.32(m，8H)，5.02-5.10(m，1H)，4.53(AB，J＝15.3Hz，2H)，1.72-1.92(m，2H)，1.48-1.59(m，1H)，1.10-1.24(m，2H)，0.853(d，J＝6.6Hz，3H)，0.850(d，J＝6.7Hz，3H)
Embodiment 26
2-(1-(2-acetyl nitrogen base acetyl) nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-26)
Operation just changes the 2-furancarboxylic acid into acetyl-glycine with example 21, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.40-12.80(bs，2H)，7.35(d，J＝8.2Hz，1H)，7.18(s，2H)，6.95(s，1H)，6.68(bs，1H)，5.00-5.08(m，1H)，3.98(d，J＝5.3Hz，2H)，2.07(s，3H)，1.50-1.90(m，3H)，1.18-1.30(m，2H)，0.9(d，J＝2.2，3H)，0.8(d，J＝2.2，3H)
Embodiment 27
2-(1-(2-furoyl) nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-27)
36mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-6) are dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 10mg (0.1mmol) triethylamine, the dicyclohexylcarbodiimide (DCC) of 23mg (0.11mmol) then adds 12mg (0.1mmol) 2-furancarboxylic acid, stirring at room 2 hours, reactant is concentrated the resistates column chromatography.Obtain the title compound that 23mg (yield 70%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.72(s，1H)，12.43(s，1H)，7.48(dd，J＝0.6Hz，1.5Hz，1H)，7.11-7.19(m，4H)，7.00(s，1H)，6.05(dd，J＝1.8Hz，3.5Hz，1H)，4.88(t，J＝8.8Hz，1H)，2.32-2.38(m，1H)，1.07(d，J＝6.5Hz，3H)，0.95(d，J＝6.8Hz，3H)
Embodiment 28
2-(1-(2-thenoyl) nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-28)
Operation just changes the 2-furancarboxylic acid into the 2-thiophenic acid with example 27, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.73(s，1H)，12.45(s，1H)，7.53(dd，J＝1.1Hz，3.7Hz，1H)，7.50(dd，J＝1.1Hz，4.9Hz，1H)，7.20(AB，J＝9.7Hz，2H)，7.09(dd，J＝3.7Hz，5Hz，1H)，7.02(s，1H)，6.94(d，J＝9.3Hz，1H)，4.83(t，J＝9.2Hz，1H)，2.32-2.38(m，1H)，1.10(d，J＝6.8Hz，3H)，0.94(d，J＝6.8Hz，3H)
Embodiment 29
2-(1-(2-pyridine formyl) nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-29)
Operation just changes the 2-furancarboxylic acid into the 2-pyridine carboxylic acid with example 27, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.72(s，1H)，12.42(s，1H)，8.77(d，J＝8.9Hz，1H)，8.61(d，J＝4.2，1H)，8.16(d，J＝8.1Hz，1H)，7.84-7.88(m，1H)，7.47(dd，J＝5.5Hz，7.2Hz，1H)，7.18(s，2H)，7.02(s，1H)，5.05(t，J＝8.5Hz，1H)，2.40-2.44(m，1H)，1.07(d，J＝6.8Hz，3H)，1.02(d，J＝6.7Hz，3H)
Embodiment 30
2-(1-hexanoyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-30)
Operation just changes the 2-furancarboxylic acid into caproic acid with example 27, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.68(s，1H)，12.44(s，1H)，7.20(AB，J＝9.5Hz，2H)，6.94(s，1H)，6.26(d，J＝9.5Hz，1H)，4.71(t，J＝9.1Hz，1H)，1.58-1.65(m，2H)，1.22-1.35(m，4H)，1.0(d，J＝6.8Hz，3H)，0.83-0.90(m，6H)
Embodiment 31
2-(1-(2-acetyl nitrogen base acetyl) nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-31)
Operation just changes the 2-furancarboxylic acid into acetyl-glycine with example 27, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.66(s，1H)，12.43(s，1H)，7.34(d，J＝8.4Hz，1H)，7.19(s，2H)，6.96(s，1H)，4.86(t，J＝8.5Hz，1H)，4.00(m，2H)，2.22(m，1H)，2.06(s，1H)，0.97(d，J＝6.9Hz，3H)，0.93(d，J＝6.6Hz，3H)
Embodiment 32
2-(1-(2-furoyl) nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-32) 33mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-7) is dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stirs 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 10mg (0.1mmol) triethylamine, the dicyclohexylcarbodiimide (DCC) of 23mg (0.11mmol) then adds 12mg (0.1mmol) 2-furancarboxylic acid, stirring at room 2 hours, reactant is concentrated the resistates column chromatography.Obtain the title compound that 23mg (yield 69%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.68(s，1H)，12.42(s，1H)，7.48(dd，J＝0.9Hz，1.8Hz，1H)，7.20(s，2H)，7.13(dd，J＝0.7Hz，3.5Hz，1H)，7.03(s，1H)，6.99(dd，J＝1.7Hz，3.5Hz，1H)，5.30-5.38(m，1H)，1.61(d，J＝7.1Hz，3H)
Embodiment 33
2-(1-(2-thenoyl) nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-33)
Operation just changes the 2-furancarboxylic acid into the 2-thiophenic acid with example 32, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.70(s，1H)，12.43(s，1H)，7.54(dd，J＝1.2Hz，3.7Hz，1H)，7.51(dd，J＝1.2Hz，5.0Hz，1H)，7.21(s，2H)，7.09(dd，J＝3.8Hz，5.1Hz，1H)，7.04(s，1H)，6.75(d，J＝8.4Hz，1H)，5.32(m，1H)，1.62(d，J＝6.9Hz，3H)
Embodiment 34
2-(1-(2-pyridine formyl) nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-34)
Operation just changes the 2-furancarboxylic acid into the 2-pyridine carboxylic acid with example 32, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.65(s，1H)，12.39(s，1H)，8.58(d，J＝4.6Hz，1H)，8.53(d，J＝7.1Hz，1H)，8.14(d，J＝8.1Hz，1H)，7.80-7.90(m，1H)，7.45(dd，J＝2.1Hz，7.9Hz，1H)，7.17(s，2H)，7.01(s，1H)，5.39(m，1H)，1.62(d，J＝7Hz，3H)
Embodiment 35
2-(1-(2-acetyl nitrogen base acetyl) nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-35)
Operation just changes the 2-furancarboxylic acid into acetyl-glycine with example 32, obtains having the title compound of following structure.
1H-NMR(CD3OD，400Hz，δppm)：7.17(s，2H)，6.91(s，1H)，5.15(q，J＝6.9Hz，1H)，3.85(s，2H)，2.00(s，3H)，1.45(d，J＝7Hz，3H)
Embodiment 36
2-(1-(2-furoyl) nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-36)
41mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-8) are dissolved in the ethyl acetate solution of hydrogenchloride of 10ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 10mg (0.1mmol) triethylamine, the dicyclohexylcarbodiimide (DCC) of 23mg (0.11mmol) then adds 12mg (0.1mmol) 2-furancarboxylic acid, stirring at room 2 hours, reactant is concentrated the resistates column chromatography.Obtain the title compound that 30mg (yield 74%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.76(s，1H)，12.38(s，1H)，7.47(d，J＝0.8Hz，1H)，7.08-7.47(m，9H)，6.76(s，1H)，6.49(dd，J＝1.7Hz，3.5Hz，1H)，5.49(q，J＝7.5Hz，1H)，3.33(dd，J＝7.2Hz，13.8Hz，1H)，3.18(dd，J＝7.4Hz，13.7Hz，1H)
Embodiment 37
2-(1-(2-thenoyl) nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-37)
Operation just changes the 2-furancarboxylic acid into the 2-thiophenic acid with example 36, obtains having the title compound of following structure.
1H-NMR(CDCl
3，400Hz，δppm)：12.76(s，1H)，12.38(s，1H)，7.49(dd，J＝1.1Hz，5Hz，1H)，7.46(dd，J＝1.01Hz，3.9Hz，1H)，7.16-7.45(m，8H)，6.83(d，J＝8.1Hz，1H)，6.75(s，1H)，5.46(q，J＝7.5Hz，1H)，3.32(dd，J＝7.3Hz，13.8Hz，1H)，3.20(dd，J＝7.3Hz，13.6Hz，1H)
Embodiment 38
2-(1-(2-pyridine formyl) nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-38)
Operation just changes the 2-furancarboxylic acid into the acid of 2-pyridine carboxylic acid, the title compound that obtains having following structure with example 36.
1H-NMR(CDCl3，400Hz，δppm)：12.76(s，1H)，12.38(s，1H)，8.58(d，J＝4.6Hz，1H)，8.53(d，J＝7.1Hz，1H)，8.14(d，J＝8.1Hz，1H)，7.80-7.90(m，1H)，7.16-7.45(m，8H)，6.88(d，J＝8.1Hz，1H)，6.72(s.1H)，5.48(q，J＝7.5Hz，1H)，3.33(dd，J＝7.5Hz，13.8Hz，1H)，3.21(dd，J＝7.5Hz，13.6Hz，1H)
Embodiment 39
2-(1-hexanoyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-39)
Operation just changes the 2-furancarboxylic acid into caproic acid with example 36, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.72(s，1H)，12.39(s，1H)，7.13-7.31(m，7H)，6.73(s，1H)，6.44(d，J＝8.4Hz，1H)，5.34(q，J＝7.8Hz，1H)，3.23(dd，J＝6.9Hz，13.7Hz，1H)，3.04(dd，J＝7.8Hz，13.7Hz，1H)，2.12-2.15(m，2H)，1.50-1.59(m，2H)，1.16-1.29(m，4H)，0.84(t，J＝7.2Hz，3H)
Embodiment 40
2-(1-(acetyl nitrogen base acetyl) nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-40)
Operation just changes the 2-furancarboxylic acid into acetyl glycine with example 36, obtains having the title compound of following structure.
1H-NMR(CD3OD，400Hz，δppm)：7.14-7.26(m，7H)，6.80(s，1H)，5.30(dd，J＝5.5Hz，8.9Hz，1H)，3.72(AB，J＝16.5，2H)，3.17(dd，J＝5.7Hz，13.3Hz，1H)，2.85(dd，J＝8.6Hz，14Hz，1H)，1.93(s，3H)
Embodiment 41
2-(1-(1-methoxyl group) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-41)
39mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-5) are dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 14mg (0.15mmol) methyl-chloroformate, stirring at room 2 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 23mg (yield 45%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.64(s，1H)，12.43(s，1H)，7.21(s，2H)，6.96(s，1H)，5.35(d，J＝8.2Hz，1H)，4.70-4.78(m，1H)，3.67(s，3H)，1.50-1.90(m，3H)，1.16-13.4(m，2H)，0.88(d，J＝6.6Hz，6H)
Embodiment 42
2-(1-(1-oxyethyl group) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-42)
Operation just changes methyl-chloroformate into Vinyl chloroformate with example 41, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.64(s，1H)，12.43(s，1H)，7.19(s，2H)，6.95(s，1H)，5.30(d，J＝7.6Hz，1H)，4.75(q，J＝7.9Hz，1H)，4.03-4.15(m，2H)，1.50-1.89(m，3H)，1.17-1.30(m，5H)，0.88(d，J＝6.7Hz，6H)
Embodiment 43
2-(1-(1-isobutyl-) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-43)
Operation just changes methyl-chloroformate into isobutyl chlorocarbonate with example 41, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.65(s，1H)，12.44(s，1H)，7.19(s，2H)，6.96(s，1H)，5.30(s，1H)，4.71-4.79(m，1H)，3.78-3.89(m，2H)，1.51-1.93(m，3H)，1.16-1.35(m，2H)，0.80-0.95(m，12H)
Embodiment 44
2-(1-(1-benzyl) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-44)
Operation just changes methyl-chloroformate into chloroformic acid benzyl ester with example 41, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.64(s，1H)，12.43(s，1H)，7.35(s，5H)，7.18(s，2H)，6.96(s，1H)，5.42(d，J＝8.6Hz，1H)，5.08(AB，J＝12.1Hz，2H)，4.78(q，J＝8.2Hz，1H)，1.48-1.90(m，3H)，1.15-1.34(m，2H)，0.88(d，J＝6.6Hz，6H)
Embodiment 45
2-(1-(1-methoxyl group) formyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-45)
36mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-6) are dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 14mg (0.15mmol) methyl-chloroformate, stirring at room 2 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 14mg (yield 42%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.66(s，1H)，12.45(s，1H)，7.20(AB，J＝9.7Hz，2H)，6.94(s，1H)，5.43(d，9Hz，1H)，4.47(t，8.7Hz，1H)，3.66(s，3H)，2.18-2.26(m，1H)，1.00(d，J＝6.7Hz，3H)，0.92(d，J＝6.7Hz，3H)
Embodiment 46
2-(1-(1-oxyethyl group) formyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-46)
Operation just changes methyl-chloroformate into Vinyl chloroformate with 45, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.67(s，1H)，12.45(s，1H)，7.19(s，1H)，6.93(s，1H)，5.39(d，J＝9.2Hz，1H)，4.49(t，J＝8.6Hz，1H)，4.01-4.06(m，2H)，2.05-2.10(m，1H)，1.24(t，J＝7.3Hz，3H)，1.00(d，J＝6.7Hz，3H)，0.92(d，J＝6.8Hz，3H)
Embodiment 47
2-(1-(1-isobutoxy) formyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-47)
Operation just changes methyl-chloroformate into isobutyl chlorocarbonate with 45, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.67(s，1H)，12.44(s，1H)，7.19(s，2H)，6.93(s，1H)，5.41(d，J＝8.8Hz，1H)，4.49(t，J＝8.4Hz，1H)，3.76-3.89(m，2H)，2.05-2.10(m，1H)，1.91-1.95(m，1H)，0.91-1.01(m，12H)
Embodiment 48
2-(1-(1-methoxyl group) formyl nitrogen base-ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-48)
33mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-7) are dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 14mg (0.15mmol) methyl-chloroformate, stirring at room 2 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 13mg (yield 43%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.63(s，1H)，12.43(s，1H)，7.20(s，2H)，6.99(s，1H)，5.29(bs，1H)，4.95(m，1H)，3.66(s，3H)，1.5(d，J＝7.1Hz，3H)
Embodiment 49
2-(1-(1-oxyethyl group) formyl nitrogen base-ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-49)
Operation just changes methyl-chloroformate into Vinyl chloroformate with example 48, obtains as having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.64(s，1H)，12.44(s，1H)，7.20(s，2H)，6.99(s，1H)，5.24(d，J＝6.9Hz，1H)，4.93-5.00(m，1H)，4.02-4.20(m，2H)，1.49(d，J＝7Hz，3H)，1.23(t，J＝7.2，3H)
Embodiment 50
2-(1-(1-methoxyl group) formyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-50)
41mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-8) are dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 14mg (0.15mmol) methyl-chloroformate, stirring at room 2 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 17mg (yield 45%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.70(s，1H)，12.40(s，1H)，7.12-7.32(m，7H)，6.76(s，1H)，5.37(d，J＝7.5Hz，1H)，5.07-5.13(m，1H)，3.60(s，3H)，3.23(q，J＝7Hz，14Hz，1H)，3.00(q，J＝7.4Hz，14Hz，1H)
Embodiment 51
2-(1-(1-oxyethyl group) formyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-51)
Operation just changes methyl-chloroformate into Vinyl chloroformate with example 50, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.71(s，1H)，12.40(s，1H)，7.13-7.32(m，7H)，6.76(s，1H)，5.34(d，J＝7.6Hz，1H)，5.07-5.13(m，1H)，4.05(q，J＝7.2Hz，2H)，3.23(q，J＝6.9Hz，14Hz，1H)，3.01(q，J＝6.9Hz，14Hz，1H)，1.20(t，J＝7.2Hz，3H)
Embodiment 52
2-(1-tolysulfonyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-52)
39mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-5) are dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 36mg (0.2mmol) Tosyl chloride, stirring at room 12 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 10mg (yield 22%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.43(s，1H)，12.33(s，1H)，7.57(d，J＝8.2Hz，2H)，7.16(AB，J＝9.8Hz，2H)，7.05(d，J＝8.0Hz，2H)，6.68(s，1H)，5.46(d，J＝9.8Hz，1H)，4.20(q，J＝8.1Hz，1H)，2.19(s，3H)，1.66-1.86(m，2H)，1.42-1.52(m，1H)，0.98-1.31(m，2H)，0.82(d，J＝6.6Hz，3H)，0.80(d，J＝6.6Hz，3H)
Embodiment 53
2-(1-methylsulfonyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-53)
Operation just changes Tosyl chloride into methylsulfonyl chloride with example 52, obtains having the title compound of following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.67(s，1H)，12.41(s，1H)，7.19(s，2H)，7.06(s，1H)，5.26(d，J＝9.3Hz，1H)，4.48(q，J＝7.7Hz，1H)，2.91(s，3H)，1.78-1.90(m，2H)，1.52-1.64(m，1H)，1.31-1.40(m，1H)，1.15-1.26(m，11H)，0.78(d，J＝6.5Hz，6H)
Embodiment 54
2-(1-tolysulfonyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-54)
36mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-6) are dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 36mg (0.2mmol) Tosyl chloride, stirring at room 12 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 7mg (yield 17%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.45(s，1H)，12.33(s，1H)，7.54(d，J＝8Hz，2H)，7.18(AB，J＝9.6Hz，2H)，7.02(d，J＝8Hz，2H)，6.60(s，1H)，5.49(d，J＝9.5Hz，1H)，3.87(t，J＝8.8Hz，1H)，2.08-2.17(m，4H)，1.06(d，J＝6.5Hz，3H)，0.76(d，J＝6.5Hz，3H)
Embodiment 55
2-(1-tolysulfonyl nitrogen base-ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-55)
33mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-7) are dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 36mg (0.2mmol) Tosyl chloride, stirring at room 12 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 7mg (yield 18%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.44(s，1H)，12.34(s，1H)，7.59(d，J＝8Hz，2H)，7.17(AB，J＝9.7Hz，2H)，7.08(d，J＝8Hz，2H)，6.76(s，1H)，5.47(d，J＝9.3，1H)，4.40-4.51(m，1H)，2.20(s，3H)，1.49(d，J＝7.1，3H)
Embodiment 56
2-(1-tolysulfonyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-56)
41mg (0.1mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-8) are dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 36mg (0.2mmol) Tosyl chloride, stirring at room 12 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 7mg (yield 15%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：12.54(s，1H)，12.32(s，1H)，7.45(d，J＝8.0Hz，2H)，7.16-7.21(m，5H)，7.03(d，J＝8.0)，6.95-7.00(m，2H)，6.65(s，1H)，5.33(d，J＝8.Hz，1H)，4.50-4.61(m，1H)，3.13(q，J＝7Hz，13.9Hz，1H)，2.96(q，J＝7.1Hz，13.7Hz，1H)，2.23(s，3H)
Embodiment 57
2-(1-(1-tert.-butoxy) formyl nitrogen base-2-methyl-propyl)-5,8-diacetoxy-1,4-naphthoquinones (SHN-57)
90mg (0.25mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-6) is dissolved in the 2ml pyridine, at room temperature adds the 1ml diacetyl oxide, stirs 4 hours, add the methylene dichloride dilution, organic phase washes with water successively, the pickling of 2M salt, and saturated sodium bicarbonate solution is washed, the 10ml saturated nacl aqueous solution is washed, anhydrous sodium sulfate drying.Solution concentration, the resistates column chromatography obtains the title compound that 90mg (yield 81%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：7.38(s，2H)，6.62(s，1H)，5.05(d，J＝8.8Hz，1H)，4.36(t，J＝8.1Hz，1H)，2.41(s，6H)，2.06(m，1H)，1.37(s，9H)，0.92(d，J＝6.7Hz，3H)，0.90(d，J＝6.7Hz，3H)
Embodiment 58
2-(1-(1-tert.-butoxy) formyl nitrogen base-ethyl)-5,8-diacetoxy-1,4-naphthoquinones (SHN-58)
90mg (0.25mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-ethyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-7) is dissolved in the 2ml pyridine, at room temperature adds the 1ml diacetyl oxide, stirs 4 hours, add the methylene dichloride dilution, organic phase washes with water successively, the pickling of 2M salt, and saturated sodium bicarbonate solution is washed, saturated nacl aqueous solution is washed, anhydrous sodium sulfate drying.Solution concentration, the resistates column chromatography obtains the title compound that 115mg (yield 95%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：7.37(s，2H)，6.68(s，1H)，4.91(bs，1H)，4.75-4.80(m，1H)，2.43(s，6H)，1.45(s，9H)，1.38(d，J＝10.4Hz，3H)
Embodiment 59
2-(1-(1-tert.-butoxy) formyl nitrogen base-2-styroyl)-5,8-diacetoxy-1,4-naphthoquinones (SHN-59)
90mg (0.25mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-styroyl)-5,8-dihydroxyl-1,4-naphthoquinones (SHN-8) is dissolved in the 2ml pyridine, at room temperature adds the 1ml diacetyl oxide, stirs 4 hours, add the dilution of 30ml methylene dichloride, organic phase washes with water successively, the pickling of 2M salt, and saturated sodium bicarbonate solution is washed, saturated nacl aqueous solution is washed, anhydrous sodium sulfate drying.Solution concentration, the resistates column chromatography obtains the title compound that 98mg (yield 85%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：7.38(s，2H)，7.12-7.28(m，5H)，6.43(s，1H)，5.30(s，1H)，5.03(d，J＝8.1Hz，1H)，4.90-4.98(m，1H)，3.11(dd，J＝6.3Hz，14Hz，1H)，2.89(dd，J＝8.3Hz，13.7Hz，1H)，2.47(s，3H)，2.43(s，3H)，1.47(s，9H)
Embodiment 60
2-(1-benzoyl nitrogen base-ethyl)-5,8-diacetoxy-1,4-naphthoquinones (SHN-60)
30mg (0.072mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-ethyl)-5,8-diacetoxy-1,4-naphthoquinones (SHN-58) are dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 17mg (0.108mmol) Benzoyl chloride, stirring at room 12 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 13mg (yield 46%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：7.76(d，J＝7.4Hz，2H)，7.51(t，J＝7.4Hz，1H)，7.44(t，J＝7.6Hz，2H)，7.37(s，2H)，7.25(s，1H)，6.72(s，1H)，6.69(d，J＝7.8Hz，1H)，5.20-5.25(m，1H)，2.44(s，3H)，2.41(s，3H)，1.53(d，J＝7.3Hz，3H)
Embodiment 61
2-(1-benzoyl nitrogen base-2-styroyl)-5,8-diacetoxy-1,4-naphthoquinones (SHN-60)
30mg (0.061mmol) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-styroyl)-5,8-diacetoxy-1,4-naphthoquinones (SHN-59) are dissolved in the ethyl acetate solution of hydrogenchloride of 5ml 1.5M, stir 2 hours.Reaction solution is concentrated into dried, adds the 10ml methylene dichloride, 20mg (0.2mmol) triethylamine, 10mg (0.092mmol), stirring at room 12 hours concentrates reactant the resistates column chromatography.Obtain the title compound that 12mg (yield 41%) has following structure.
1H-NMR(CDCl3，400Hz，δppm)：7.38(s，2H)，7.11-7.28(m，5H)，6.40(s，1H)，6.04(d，J＝8.5Hz，1H)，5.17(q，J＝7.6Hz，1H)，3.12(q，J＝7.5Hz，13.8Hz，1H)，2.73(q，J＝7.6Hz，14.0Hz，1H)，2.48(s，3H)，2.40(s，3H)，1.94(s，3H)
Claims (13)
1,5 of the replacement of the side chain nitrogen shown in general formula as described below (I), (II), (III), (IV), 8-dihydronaphthalene quinone derivative:
R wherein
1=C
1-C
6Straight or branched alkyl, aromatic base or aromatic base alkyl;
R
2=alkyl, aromatic base or aromatic base alkyl, wherein aromatic base comprises fragrant heterocyclic radical;
R
3=hydrogen atom or C
1-C
3Alkyl or alkyl acyl;
R
4The alkyl of=connection C and X, X=O or NH;
R
5=alkyl or aromatic base or alkyl acyl.
2,5 of side chain nitrogen replacement according to claim 1,8-dihydronaphthalene quinone derivative is characterized in that, works as R
1=C
1-C
6Straight or branched alkyl, aromatic base or aromatic base alkyl;
R
2=alkyl, aromatic base or aromatic base alkyl, wherein aromatic base comprises fragrant heterocyclic radical;
R
4The alkyl of=connection C and X, X=O or NH;
R
5When=alkyl or aromatic base or alkyl acyl;
R
3=C
1-C
3The straight or branched alkyl.
3,5 of side chain nitrogen replacement according to claim 1,8-dihydronaphthalene quinone derivative is characterized in that, works as R
1=C
1-C
6Straight or branched alkyl, aromatic base or aromatic base alkyl;
R
2=alkyl, aromatic base or aromatic base alkyl, wherein aromatic base comprises fragrant heterocyclic radical;
R
4The alkyl of=connection C and X, X=O or NH;
When R5=alkyl or aromatic base or alkyl acyl;
The R3=hydrogen atom.
4,5 of side chain nitrogen replacement according to claim 1,8-dihydronaphthalene quinone derivative is characterized in that, works as R
1=C
1-C
6Straight or branched alkyl, aromatic base or aromatic base alkyl;
R
2=alkyl, aromatic base or aromatic base alkyl, wherein aromatic base comprises fragrant heterocyclic radical;
R
4The alkyl of=connection C and X, X=O or NH;
R
5When=alkyl or aromatic base or alkyl acyl;
R
3=alkyl acyl.
5, according to claim 15,8-dihydronaphthalene quinone derivative is characterized in that described compound is selected from:
1) 2-(1-(1-tert.-butoxy) formyl nitrogen base-4-methyl amyl)-5,8-dimethoxy-1,4-naphthoquinones;
2) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-methyl-propyl)-5,8-dimethoxy-1,4-naphthoquinones;
3) 2-(1-(1-tert.-butoxy) formyl nitrogen base ethyl)-5,8-dimethoxy-1,4-naphthoquinones;
4) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-phenylethyl)-5,8-dimethoxy-1,4-naphthoquinones;
5) 2-(1-(1-tert.-butoxy) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
6) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones;
7) 2-(1-(1-tert.-butoxy) formyl nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
8) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
9) 2-(1-acetyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
10) 2-(1-(2-methyl propionyl) nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
11) 2-(1-hexanoyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
12) 2-(1-phenylacetyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
13) 2-(1-(2-furoyl) nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
14) 2-(1-(2-thenoyl) nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
15) 2-(1-(2-pyridine formyl) nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
16) 2-(1-(2-acetyl nitrogen base acetyl) nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
17) 2-(1-(2-phenoxy group acetyl) nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
18) 2-(1-acetyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones;
19) 2-(1-(2-methyl propionyl) nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones;
20) 2-(1-phenylacetyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones;
21) 2-(1-hexanoyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones;
22) 2-(1-(2-furoyl) nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones;
23) 2-(1-(2-thenoyl) nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones;
24) 2-(1-(2-pyridine formyl) nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones;
25) 2-(1-(2-acetyl nitrogen base acetyl) nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones;
26) 2-(1-acetyl nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
27) 2-(1-(2-methyl propionyl) nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
28) 2-(1-phenylacetyl nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
29) 2-(1-(2-furoyl) nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
30) 2-(1-(2-thenoyl) nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
31) 2-(1-(2-pyridine formyl) nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
32) 2-(1-(2-acetyl nitrogen base) acetyl nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
33) 2-(1-acetyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
34) 2-(1-(2-methyl propionyl) nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
35) 2-(1-hexanoyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
36) 2-(1-phenylacetyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
37) 2-(1-(2-furoyl) nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
38) 2-(1-(2-thenoyl) nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
39) 2-(1-(2-pyridine formyl) nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
40) 2-(1-(2-acetyl nitrogen base acetyl) nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
41) 2-(1-(1-methoxyl group) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
42) 2-(1-(1-oxyethyl group) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
43) 2-(1-(1-isobutyl-oxygen base) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
44) 2-(1-(1-benzyloxy) formyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
45) 2-(1-(1-isobutoxy) formyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones;
46) 2-(1-(1-methoxyl group) formyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones;
47) 2-(1-(1-oxyethyl group) formyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones;
48) 2-(1-(1-methoxyl group) formyl nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
49) 2-(1-(1-oxyethyl group) formyl nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
50) 2-(1-(1-methoxyl group) formyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
51) 2-(1-(1-oxyethyl group) formyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
52) 2-(1-methylsulfonyl acyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
53) 2-(1-tolysulfonyl nitrogen base-4-methyl amyl)-5,8-dihydroxyl-1,4-naphthoquinones;
54) 2-(1-tolysulfonyl nitrogen base-2-methyl-propyl)-5,8-dihydroxyl-1,4-naphthoquinones;
55) 2-(1-tolysulfonyl nitrogen base ethyl)-5,8-dihydroxyl-1,4-naphthoquinones;
56) 2-(1-tolysulfonyl nitrogen base-2-phenylethyl)-5,8-dihydroxyl-1,4-naphthoquinones.
57) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-methyl-propyl)-5,8-diacetoxy-1,4-naphthoquinones;
58) 2-(1-(1-tert.-butoxy) formyl nitrogen base ethyl)-5,8-diacetoxy-1,4-naphthoquinones;
59) 2-(1-(1-tert.-butoxy) formyl nitrogen base-2-phenylethyl)-5,8-diacetoxy-1,4-naphthoquinones;
60) 2-(1-benzoyl nitrogen base ethyl)-5,8-diacetoxy-1,4-naphthoquinones;
61) 2-(1-acetyl nitrogen base-2-phenylethyl)-5,8-diacetoxy-1,4-naphthoquinones.
6. the preparation method of general formula as claimed in claim 1 (II) compound, at 0-30 ℃ with the inferior allusion quotation acyl benzene of two acetic acid or two (trifluoracetic acid) iodosobenzene oxidation R
3For formula (XII) compound of alkyl obtains general formula compound (II), the preferred polar solvent of reaction solvent, the mixed solvent of acetonitrile, dimethyl formamide and water.
7. according to claim 15, the preparation method of 8-dihydronaphthalene quinone derivative is general formula (II) the compound dealkylation preparation of alkyl by R3, temperature of reaction 0-30 ℃, take off the preferred AgO/ nitric acid of alkyl reagent, the preferred acetone of reaction solvent, acetonitrile, dimethyl formamide etc.R1, the R2 definition is the same.
8. according to claim 15, the preparation method of 8-dihydronaphthalene quinone derivative, general formula (II) compound that by R3 is hydrogen exists down in-15-55 ℃ prepared in reaction by organic bases and organic acid anhydride or acyl chlorides, reacting preferred solvent is inert solvents such as methylene dichloride, toluene, R6 represents alkyl, and R1, R2 definition is the same.
9. according to 5 of the described general formula of claim 1 (I), the preparation method of 8-dihydronaphthalene quinone derivative, this method may further comprise the steps:
A) general formula (II) dihydronaphthalene quinone derivative compound is sloughed R under 0-40 ℃ and appropriate condition
2(be generally acidic conditions, use strong acid such as example hydrochloric acid, trifluoroacetic acid), the reaction solvent ethyl acetate obtains the compound of general formula for (XIV);
B) with general formula (XIV) compound and organic acid in the presence of organic bases and dicyclohexyl carbodiimide or other condensing agents 0-30 ℃ of reaction, perhaps in the presence of organic bases, react with organic acid anhydride or acyl chlorides, preparation compound (I), reaction solvent is generally used inert solvents such as methylene dichloride, tetrahydrofuran (THF), and preferred methylene dichloride is made solvent.
10. according to 5 of the described general formula of claim 1 (II), the preparation method of 8-dihydronaphthalene quinone derivative, dihydronaphthalene quinone derivative (XIV) and chloro-formic ester compound are obtained 0-30 ℃ of prepared in reaction in the presence of organic bases, the solvent of reaction is inert solvents such as methylene dichloride, tetrahydrofuran (THF), and preferred methylene dichloride is made solvent.
11. according to 5 of the described general formula of claim 1 (III), the preparation method of 8-dihydronaphthalene quinone derivative, with dihydronaphthalene quinone derivative (XIV) and organic acid in the presence of organic bases and dicyclohexyl carbodiimide or other condensing agents at 0-30 ℃ of prepared in reaction compound (III), reaction solvent is inert solvents such as tetrahydrofuran (THF), methylene dichloride, and preferred methylene dichloride is made solvent.
12. according to 5 of the described general formula of claim 1 (IV), the preparation method of 8-dihydronaphthalene quinone derivative, with dihydronaphthalene quinone derivative (XIV) and sulfonyl chloride compound in the presence of organic bases 0-30 ℃ of reaction, preparation compound (IV), the solvent of reaction is inert solvents such as tetrahydrofuran (THF), methylene dichloride, and preferred methylene dichloride is made solvent.
13, as claimed in claim 15, the purposes of 8-dihydronaphthalene quinone derivative is used in the preparation antitumor drug.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101265212B (en) * | 2008-03-27 | 2010-07-28 | 上海交通大学 | Antineoplastic alkanna tinctoria ketoximes derivatives |
| CN102659661A (en) * | 2012-04-20 | 2012-09-12 | 南京大学 | Synthetic method and application of shikonin derivative |
| CN105272891A (en) * | 2015-10-19 | 2016-01-27 | 吉林大学 | Compound with neuroprotective effect and medical applications |
| CN105541676A (en) * | 2016-01-25 | 2016-05-04 | 黑龙江八一农垦大学 | 2-butyl sulfoxide-1,4-naphthoquinone compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2144518A1 (en) * | 1993-07-14 | 1995-01-26 | Kyong Up Baik | Process for preparing 5,8-dihydronaphtoquinone derivatives, novel 5,8-dihydronaphtoquinone derivatives and their use as anticancer agent |
| KR0180791B1 (en) * | 1995-07-24 | 1999-05-15 | 김용옥 | 6-substituted-5,8-dioxy-1,4-naphthoquinone derivative, its preparation process and the usage as anticancer drug |
| CN1206403A (en) * | 1996-02-16 | 1999-01-27 | 教堂山北卡罗莱纳州大学 | Naphthoquinone antitumor compound and method |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101265212B (en) * | 2008-03-27 | 2010-07-28 | 上海交通大学 | Antineoplastic alkanna tinctoria ketoximes derivatives |
| CN102659661A (en) * | 2012-04-20 | 2012-09-12 | 南京大学 | Synthetic method and application of shikonin derivative |
| CN105272891A (en) * | 2015-10-19 | 2016-01-27 | 吉林大学 | Compound with neuroprotective effect and medical applications |
| CN105541676A (en) * | 2016-01-25 | 2016-05-04 | 黑龙江八一农垦大学 | 2-butyl sulfoxide-1,4-naphthoquinone compound |
| CN105541676B (en) * | 2016-01-25 | 2017-08-04 | 黑龙江八一农垦大学 | A kind of naphthoquinone compound of 2 fourth sulfoxide 1,4 |
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