CN101863786B - Water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative and preparation and application methods thereof - Google Patents
Water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative and preparation and application methods thereof Download PDFInfo
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Abstract
The invention relates to a water-soluble shikonin naphthazarin oxygen nucleus alkyl side chain alkali-containing nitrogen atom derivative in the technical field of the medicine and chemical industry, and a preparation method thereof; the structural formula of the derivative is as follows: wherein the molecular formula of R is CO(CH2)Nn(R5R6), wherein: n=1-3, R5 and R6 are alkanes, alkenes, cycloalkanes or cycloolefines with 1 to 5 carbon atoms, the structure of R1, R2, R3 and R4 is the same, i.e. CH3, C2H5 or CH2, which is correspondingly and respectively as follows: 1,4,5,8-O-tetramethyl shikonin side chain alkali-containing nitrogen ester derivative, 1,4,5,8-O-tetraethyl shikonin side chain alkali-containing nitrogen ester derivative and 1:8, 4:5-O-dimethylene shikonin side chain alkali-containing nitrogen ester derivative. The preparation method has the advantages of easily available raw materials, short synthesis route and higher reaction yield, and the prepared compound can serveas a prodrug for curing malignant tumors.
Description
Technical field
What the present invention relates to is a kind of compound and Application and preparation method thereof of technical field of traditional Chinese medicines, specifically a kind of water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative and preparation thereof and application.
Background technology
Asian puccoon is the clinical conventional Chinese medicine that the Pharmacopoeia of the People's Republic of China records, and can be divided into gromwell root (Lithospermumerythrohizon), has another name called RADIX LITHOSPERMI from Northeast and Radix Arnebiae (A.euchroma Johnst), has another name called lithospermum euchromum Royle.Main effective constituent in the gromwell root is Shikonin and derivative thereof, contains AK and derivative thereof in the Radix Arnebiae, and Shikonin and AK be enantiomer each other, and Shikonin is the R configuration, and AK is the S configuration.The effects such as that these compositions all have is antibiotic, anti-inflammatory, anticancer, treatment burn and scald.The antitumor action of Shikonin is confirmed by many research reports, but because its toxic side effect and poorly water-soluble limit its clinical application.
Find through the literature search to prior art, publication number is that the Chinese invention patent application of CN1420111A has disclosed naphthalene alizarin derivatives and its production and use, reported restraining effect and the antitumor action of this compounds opposite end granzyme, these compounds are pendant hydroxyl group acylated derivatives of Shikonin; The patent (application number is 201010127297.X) of application obviously makes cytotoxicity descend after having reported naphthazarin (5,8-dihydroxyl-1,4-naphthoquinone) structure alkylation to Shikonin and derivative thereof before this, increases its water-soluble problem but relate to.Introducing hydrophilic basic nitrogen atom at the Shikonin side chain, can increase water-solublely, and can be to solve one of water-soluble problem effective ways of alkannin derivant with the acceptable sour salify of some physiology.
Summary of the invention
The present invention is directed to the prior art above shortcomings, a kind of water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative and preparation thereof and application are provided, with the relatively reduction of tumor cell in vitro inhibition test showed cell toxic action or disappearance of Shikonin, water-soluble obvious increase, the test of animal anti-tumor in vivo demonstrates certain inhibition tumor growth effect, can be used as the treatment that prodrug is used for malignant tumour.Simultaneously, the required raw material of the preparation method who the present invention relates to is easy to get, and synthetic route is short.
The present invention is achieved by the following technical solutions:
The present invention relates to a kind of water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative, its structural formula is as follows:
Wherein: the molecular formula of R is CO (CH
2)
nN(R5R6), wherein: n=1-3, R5 and R6 are alkane, alkene, naphthenic hydrocarbon or the cycloolefin of 1-5 carbon atom, R
1, R
2, R
3And R
4Structure is identical and be CH
3, C
2H
5Or CH
2, correspondence is respectively: Isosorbide-5-Nitrae, 5,8-O-tetramethyl-Shikonin side chain contains basic nitrogen ester derivative, Isosorbide-5-Nitrae, 5,8-O-tetraethyl-Shikonin side chain contains basic nitrogen ester derivative and 1:8, and 4:5-O-dimethylene Shikonin side chain contains the basic nitrogen ester derivative, and its structural formula is followed successively by:
The present invention relates to the preparation method of above-mentioned water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative, comprise in three kinds of modes any one:
1, preparation Isosorbide-5-Nitrae, 5,8-O-tetramethyl-Shikonin side chain contains the basic nitrogen ester derivative, and its structural formula is:
Wherein: n=1-3, R
5, R
6Be alkane, alkene, naphthenic hydrocarbon or the cycloolefin of 1～5 carbon atom:
Step 1 is mixed Shikonin with Anhydrous potassium carbonate, be dissolved in anhydrous N, in the N-diformamide, adds methyl iodide, gets 5,8-O-dimethyl Shikonin;
Step 2 is dissolved in 5,8-O-dimethyl Shikonin in the aqueous solution of tetrahydrofuran (THF), adds successively afterwards Sodium Hydrosulphite, sodium hydroxide and methyl-sulfate, gets Isosorbide-5-Nitrae, 5,8-O-tetramethyl-Shikonin;
Step 3, with 1,4,5,8-O-tetramethyl-Shikonin is dissolved in the methylene dichloride, at DMAP, N, the N'-dicyclohexylcarbodiimide exists lower, gets Isosorbide-5-Nitrae with nitrogenous organic acid or brominated organic acid condensation esterification, 5,8-O-tetramethyl-Shikonin side chain contains basic nitrogen ester derivative or brominated ester derivative;
Step 4, with Isosorbide-5-Nitrae, 5,8-O-tetramethyl-Shikonin side chain contains the bromo-ester class and is dissolved in the dry methylene dichloride, splashes into aminated compounds behind the adding Anhydrous potassium carbonate, gets Isosorbide-5-Nitrae, and 5,8-O-tetramethyl-Shikonin side chain contains the basic nitrogen ester derivative.
Above-mentioned steps one to step 4 is all implemented under nitrogen protection.
2, preparation Isosorbide-5-Nitrae, 5,8-O-tetraethyl-Shikonin side chain contains the basic nitrogen ester derivative, and its structural formula is:
Step 1 is mixed Shikonin with Anhydrous potassium carbonate, be dissolved in anhydrous N, in the N-diformamide, adds iodoethane, gets 5,8-O-diethyl Shikonin;
Step 2 is dissolved in 5,8-O-diethyl Shikonin in the aqueous solution of tetrahydrofuran (THF), adds successively afterwards Sodium Hydrosulphite, sodium hydroxide and ethyl sulfate, gets Isosorbide-5-Nitrae, 5,8-O-tetraethyl-Shikonin;
Step 3, with 1,4,5,8-O-tetraethyl-Shikonin is dissolved in the methylene dichloride, at DMAP, N, the N'-dicyclohexylcarbodiimide exists lower, gets Isosorbide-5-Nitrae with nitrogenous organic acid or bromo organic acid condensation esterification, 5,8-O-tetraethyl-Shikonin side chain contains basic nitrogen ester derivative or brominated ester derivative;
Step 4, with Isosorbide-5-Nitrae, the brominated ester derivative of 5,8-O-tetraethyl-Shikonin is dissolved in the dry methylene dichloride, splashes into aminated compounds behind the adding Anhydrous potassium carbonate, gets Isosorbide-5-Nitrae, and 5,8-O-tetraethyl-Shikonin side chain contains the basic nitrogen ester derivative.
Above-mentioned steps one to step 4 is all implemented under nitrogen protection.
3, preparation 1:8,4:5-O-dimethylene Shikonin side chain contains the basic nitrogen ester derivative, and its structural formula is:
Step 1 is mixed Shikonin with Anhydrous potassium carbonate, be dissolved in anhydrous N, in the N-diformamide, adds methylene bromide and potassiumiodide and reacting by heating, obtains 1:8,4:5-O-dimethylene Shikonin;
Step 2, at DMAP, N, the N'-dicyclohexylcarbodiimide exists lower, with 1:8,4:5-O-dimethylene Shikonin gets 1:8 with nitrogenous organic acid or brominated organic acid condensation esterification, and 4:5-O-dimethylene Shikonin side chain contains basic nitrogen ester derivative or brominated ester derivative;
Step 3, with 1:8, the brominated ester derivative of 4:5-dimethylene Shikonin is dissolved in the dry methylene dichloride, splashes into aminated compounds behind the adding Anhydrous potassium carbonate, gets 1:8, and 4:5-O-dimethylene Shikonin side chain contains the basic nitrogen ester derivative.
Above-mentioned steps one to step 3 is all implemented under nitrogen protection;
Described reacting by heating refers to: be warming up to 160 ℃ and reacted 20 minutes.
The present invention relates to the application method of above-mentioned water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative, be used for suppressing human leukemia cell's growth, be specially: with 1,4,5,8-O-tetramethyl-Shikonin side chain contains the basic nitrogen ester derivative and dissolves in and contain 2% tween 80 physiological saline or prepare injection liquid after directly salify is dissolved in physiological saline, can be used in the inhibition tumor growth, can be used as prodrug and is applied to treat malignant tumour.
In sum, the water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative that the present invention prepares can be used in preparation injection type medicine or preparation type medicine, as injection liquid, ready-made be the administrations such as available oral dry powder, vein, subcutaneous, intraperitoneal, to realize suppressing the effect of tumor growth.
Description of drawings
Fig. 1 is the water-soluble shikonin Isosorbide-5-Nitrae, the syntheti c route figure of 5,8-tetramethyl ether derivant (structural formula II).
Fig. 2 is the water-soluble shikonin Isosorbide-5-Nitrae, the syntheti c route figure of 5,8-tetrem ether derivant (structural formula III).
Fig. 3 is water-soluble shikonin 1:8, the syntheti c route figure of 4:5-two methylene ether derivants (structural formula IV).
Embodiment
The below elaborates to embodiments of the invention, and present embodiment is implemented under take technical solution of the present invention as prerequisite, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-[1-(N, N-dimethylamino acetoxyl group)-4-methyl-3-pentenyl] preparation of naphthalene, as shown in Figure 1, present embodiment may further comprise the steps:
Step 1 in the 25ml reaction flask, adds Shikonin (144mg, 0.50mmol), dry salt of wormwood (690mg, 5.0mmol), DMF (15ml), KI(20mg), methyl iodide (0.16ml, 2.5mmol).Under nitrogen protection, room temperature (25 ℃) reaction 24h.After reaction finishes, add entry (10ml) dilution, with ethyl acetate (20ml * 3) extraction, extraction liquid water (15ml * 2) washing, anhydrous magnesium sulfate drying filters, and is concentrated into dried, get crude product 139mg, separate through PTLC, get 5,8-dimethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)-1, the orange red solid 121.0mg of 4-naphthoquinones, yield is 76.6%.Fusing point: 56～59 ℃, IR (KBr): 3457,2930,1652,1571,1475,826cm
-1.
1HNMR (300MHz, CDCl
3, δ ppm): δ 7.32 (s, 2H, ArH), 6.79 (s, 1H, H
Quin), 5.17 (t, 1H, J=7.80Hz, C
H=), 4.75 (t, 1H, J=7.20Hz, C
HO), 3.98 (s, 6H, 2 * OC
H 3), 2.45 ~ 2.31 (m, 2H, C
H 2C (CH
3)
2), 1.72 (s, 3H, C
H 3), 1.62 (s, 3H, C
H 3).
13CNMR (75MHz, CDCl
3, δ ppm): δ 185.5,185.1,154.2,153.8,150.6,136.7,133.9,120.9,120.4,119.1,69.2,57.1,57.0,35.7,29.4,26.1,18.3.MS (ESI, %): 339 (M
++ Na
+, 31), 371 (M
++ NaOCH
3, 100);
Step 2; under nitrogen protection; with 5; 8-dimethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)-Isosorbide-5-Nitrae naphthoquinones (157mg, 0.5mmol) is water-soluble/tetrahydrofuran (THF) (1:4; V/V; 8ml), add respectively the sodium hydroxide of 5 times of equivalent Sodium Hydrosulphitees, 10 equivalents, the methyl-sulfate of 10 equivalents under 25 ℃, fully stir.After half an hour, temperature rising reflux 12h is cooled to room temperature, adds methylene dichloride in reaction solution, and dichloromethane layer is water and saturated common salt water washing respectively, anhydrous MgSO
4Drying, the pressure reducing and steaming methylene dichloride.Use silica gel column chromatography, ethyl acetate: sherwood oil (1:4, V/V) wash-out gets Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) faint yellow oily compound of naphthalene 121.1mg, yield 70.4%.
1H?NMR(300MHz，CDCl
3，δppm):δ7.02(s，1H，ArH)，6.82(s，2H，ArH)，5.33(m，2H，CHO，C
H=CH
2C(CH
3)
2)，3.95(s，6H，2×OC
H 3)，3.93(s，3H，OC
H 3)，3.76(s，3H，OCH
3)，2.55~2.51(m，2H，C
H 2C(CH
3)
2)，1.72(s，3H，C
H 3)，1.65(s，3H，C
H 3).
13CNMR(75MHz，CDCl
3，δppm):δ153.6，151.7，150.5，146.8，135.4，134.2，122.9，120.5，108.6，108.1，106.4，68.8，63.0，58.6，58.1，57.4，57.2，37.4，25.1，18.2.MS(ESI，%):369(M
++Na
+，100)，401(M
++NaOCH
3，38)。
Step 3; under nitrogen protection; with 1; 4,5,8-tetramethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) naphthalene (50mg; 0.14mmol) be dissolved in the dry methylene dichloride; add the dicyclohexylcarbodiimide of 2 times of molar weights and 4-dimethylamino pyridine and 2 times of amount N of catalytic amount, N-dimethylamino acetic acid, stirring at room 12h.Add short heavy filtration of an amount of sherwood oil in the reaction solution, filtrate is through concentrating under reduced pressure, the residue silica gel column chromatography, and sherwood oil: (2/1, V/V) wash-out gets light yellow semicure material (II-1) 51.89mg to ethyl acetate, and productive rate is 86%.
1HNMR（300MHz，CDCl
3，δppm）:6.89(s，1H，ArH)，6.84(s，2H，ArH)，6.42(m，1H，C
H=C(CH
3)
2)，5.16(t，1H，J＝5.7Hz，C
HOCO)，3.94(s，3H，OCH
3)，3.93(s，3H，OCH
3)，3.90(s，3H，OCH
3)，3.85(s，3H，OCH
3)，3.24(d，2H，J＝2.7Hz，COC
H 2)，2.63~2.58(m，2H，C
H 2CH=(CH
3)
2)，2.36(s，6H，COCH
2N(C
H 3)
2)，1.67(s，3H，CH
2CH=(C
H 3)
2)，1.58(s，3H，CH
2CH=(C
H 3)
2).
Embodiment 2
Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-[1-(N, N-diethylamino acetoxyl group)-4-methyl-3-pentenyl] preparation of naphthalene (II 2), as shown in Figure 2, present embodiment may further comprise the steps:
Step 1, step 2 are with embodiment 1 step 1, step 2.
Step 3 with embodiment 1, only replaces N with bromoacetic acid, N-dimethylamino acetic acid.Get light yellow Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-[1-(2-acetobrom oxygen base)-4-methyl-3-pentenyl] naphthalene semicure material 55.57mg, productive rate 85%.
1HNMR（300MHz，CDCl
3，δppm）:6.88(s，1H，ArH)，6.83(s，2H，ArH)，6.42(q，1H，J＝5.4，5.7Hz，C
H=C(CH
3)
2)，5.16(t，1H，J＝7.5Hz，C
HOCOCH
2)，3.94(s，3H，OCH
3)，3.93(s，3H，OCH
3)，3.88(s，3H，OCH
3)，3.85(d，2H，J＝6.9Hz，COC
H 2Br)，3.84(s，3H，OCH
3)，2.66~2.54(m，2H，C
H 2CH=(CH
3)
2)，1.67(s，3H，C
H 3)，1.58(s，3H，C
H 3).
Step 4: with Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-[1-(2-acetobrom oxygen base)-4-methyl-3-pentenyl] naphthalene (50mg, 0.10mmol) dissolves in the 15ml anhydrous methylene chloride, adds respectively Anhydrous potassium carbonate (69mg, 0.5mmol), 5 diethylamine solutions, backflow is spent the night, filter, filtrate decompression is concentrated, the residue silica gel column chromatography, sherwood oil: ethyl acetate (2/1, V/V) wash-out gets light yellow semicure material (II-2) 36.26mg, and yield is 79%.
1H?NMR（300MHz，CDCl
3，δppm）:6.88(s，1H，ArH)，6.83(s，2H，ArH)，6.42(m，1H，C
H=C(CH
3)
2)，5.16(t，1H，J＝6.9，7.2Hz，C
HOCO)，3.94(s，3H，OCH
3)，3.93(s，3H，OCH
3)，3.90(s，3H，OCH
3)，3.85(s，3H，OCH
3)，3.42(d，2H，J＝3.3Hz，COC
H 2)，2.70(q，4H，J＝6.9，6.6Hz，COCH
2N(C
H 2CH
3)
2)，2.57(m，2H，C
H 2CH=(CH
3)
2)，1.67(s，3H，C
H 3)，1.57(s，3H，C
H 3)，1.06(t，6H，J＝7.2Hz，CH
2N(CH
2C
H 3)
2).
Embodiment 3
Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-{1-[2-(1-piperidyl) acetoxyl group]-the 4-methyl-3-pentenyl } preparation of naphthalene (II-3), as shown in Figure 3, present embodiment may further comprise the steps:
Step 1, step 2 are with embodiment 1 step 1, step 2.
Step 3 is with embodiment 2 step 3.
Step 4 with embodiment 2 step 4, just replaces diethylamine with piperidines, obtains target compound (II-3) 26.67mg, and productive rate is 63%.
1HNMR（300MHz，CDCl
3，δppm）:6.86(s，1H，ArH)，6.83(s，2H，ArH)，6.36(q，1H，J＝5.4，2.1Hz，C
H=C(CH
3)
2)，5.17(t，1H，J＝6.0Hz，C
HOCO)，3.94(s，3H，OCH
3)，3.93(s，3H，OCH
3),3.92(s，3H，OCH
3)，3.85(s，3H，OCH
3)，3.28(d，2H，J＝6.9Hz，COC
H 2)，2.61~2.50(m，6H，CH
2N(C
H 2CH
2)
2CH
2，C
H 2CH=(CH
3)
2)，1.66(s，3H，C
H 3)，163~1.58(t，6H，COCH
2N(CH
2C
H 2)
2C
H 2)，1.57(s，3H，C
H 3).
Embodiment 4
Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-{1-[2-(N-methyl isophthalic acid-piperazinyl) acetoxyl group]-the 4-methyl-3-pentenyl } preparation of naphthalene (II 4)
Step 1, step 2 are with embodiment 1 step 1, step 2.
Step 3 is with embodiment 2 step 3.
Step 4 with embodiment 2 step 4, just replaces diethylamine with methylpiperazine, obtains target compound (II 4) 36.93mg, and productive rate is 76%.
1HNMR（300MHz，CDCl
3，δppm）:6.88(s，1H，ArH)，6.86(s，2H，ArH)，6.41(m，1H，C
H=C(CH
3)
2)，5.15(t，1H，J＝6.9Hz，C
HOCO)，3.96(s，3H，OCH
3)，3.95(s，3H，OCH
3)，3.92(s，3H，OCH
3)，3.87(s，3H，OCH
3)，3.27(d，2H，COC
H 2)，2.64~2.50(m，10H，COCH
2N(C
H 2C
H 2)
2N，C
H 2CH=(CH
3)
2)，2.31(s，3H，NCH
3)，1.68(s，3H，C
H 3)，1.59(m，3H，C
H 3).
Embodiment 5
Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-{1-[3-(N, N-dimethylamino) propionyloxy]-the 4-methyl-3-pentenyl } preparation of naphthalene (II-5)
Step 1, step 2 are with embodiment 1 step 1, step 2.
Step 3, with embodiment 3, just with N, N-dimethylamino propionic acid replaces N, and N-dimethylamino acetic acid gets white semicure thing 48.58mg, and productive rate is 78%.
1HNMR（300MHz，CDCl
3，δppm）:6.86(s，1H，ArH)，6.82(s，2H，ArH)，6.32(t，1H，J＝6.3，6.9Hz，C
H=C(CH
3)
2)，5.15(t，1H，J＝6.3，6.9Hz，C
HOCO)，3.93(s，3H，OCH
3)，3.92(s，3H，OCH
3)，3.89(s，3H，OCH
3)，3.84(s，3H，OCH
3)，2.61~2.51(m，6H，C
H 2CH=(CH
3)
2，COC
H 2C
H 2N(CH
3)
2)，2.24(s，6H，COCH
2CH
2N(C
H 3)
2)，1.66(s，3H，C
H 3)，1.55(s，3H，C
H 3).
Embodiment 6
Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-{1-[3-(N, N-diethylin) propionyloxy]-the 4-methyl-3-pentenyl } preparation of naphthalene (II-6)
Step 1, step 2 are with embodiment 1 step 1, step 2.
Step 3 with embodiment 3, just replaces N with 3-(N, N-diethylin) propionic acid, and N-dimethylamino acetic acid gets white semicure thing 47.01mg, and productive rate is 71%.
1H?NMR（300MHz，CDCl
3，δppm）:6.88(s，1H，ArH)，6.85(s，2H，ArH)，6.37(m，1H，C
H=C(CH
3)
2)，5.17(t，1H，J＝6.0，7.2Hz，C
HOCO)，3.96(s，3H，OCH
3)，3.95(s，3H，OCH
3)，3.88(s，3H，OCH
3)，3.86(s，3H，OCH
3)，2.85(t，2H，J＝7.5，7.2Hz，COC
H 2)，2.55(m，8H，C
H 2CH=(CH
3)
2，COCH
2C
H 2N(C
H 2CH
3)
2)，1.68(s，3H，C
H 3)，1.58(s，3H，C
H 3)，1.04(t，6H，J＝6.9，7.5Hz，CH
2N(CH
2C
H 3)
2).
Embodiment 7
Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-{1-[3-(1-piperidyl) propionyloxy]-the 4-methyl-3-pentenyl } preparation of naphthalene (II-7)
Step 1, step 2 are with embodiment 1 step 1, step 2.
Step 3 with embodiment 3, just replaces N with 3-piperidines propionic acid, and N-dimethylamino acetic acid gets white semicure thing 44.13mg, and productive rate is 65%.
1H?NMR（300MHz，CDCl
3，δppm）:6.86(s，1H，ArH)，6.83(d，2H，J＝1.5Hz，ArH)，6.36(t，1H，J＝5.7，6.6Hz，C
H=C(CH
3)
2)，5.15(t，1H，J＝6.6Hz，C
HOCO)，3.89(s，6H，2×OCH
3)，3.85(s，3H，OCH
3)，3.79(s，3H，OCH
3)，2.74~2.43(m，10H，COC
H 2C
H 2N(C
H 2CH
2)
2CH
2，C
H 2CH=(CH
3)
2)，1.62(s，3H，C
H 3)，1.54~1.51(m，9H，C
H 3，COCH
2N(CH
2C
H 2)
2C
H 2).
Embodiment 8
Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-{1-[3-(N-methyl isophthalic acid-piperazinyl) propionyloxy]-the 4-methyl-3-pentenyl } preparation of naphthalene (II-8)
Step 1, step 2 are with embodiment 1 step 1, step 2.
Step 3 is with embodiment 3, just with 3-(N-methyl isophthalic acid-piperazine) propionic acid replacement N, N-dimethylamino acetic acid gets white semicure thing 50.40mg, and productive rate is 72%.
1HNMR（300MHz，CDCl
3，δppm）:6.85(s，1H，ArH)，6.83(s，2H，ArH)，6.39(t，1H，J＝6.3，7.2Hz，C
H=C(CH
3)
2)，5.15(t，1H，J＝6.3Hz，C
HOCO)，3.94(s，3H，OCH
3)，3.93(s，3H，OCH
3)，3.90(s，3H，OCH
3)，3.84(s，3H，OCH
3)，2.74~2.00(m，17H，COC
H 2C
H 2N(C
H 2C
H 2)
2 NC
H 3，C
H 2CH=(CH
3)
2)，1.66(s，3H，C
H 3)，1.61(s，3H，C
H 3).
Embodiment 9
Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-[1-(N, N-dimethylamino acetoxyl group)-4-methyl-3-pentenyl] preparation of naphthalene (III-1)
Step 1, step 2, with embodiment 1 step 1, step 2, just the methyl iodide with step 1 replaces with iodoethane, and the methyl-sulfate of step 2 replaces with ethyl sulfate.
Step 3 is with embodiment 1 step 3, with Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) naphthalene replaces Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) naphthalene gets light yellow semicure material 51.48mg, and productive rate is 84%.
1H?NMR（300MHz，CDCl
3，δppm）:6.87(s，1H，ArH)，6.80(d，2H，J＝1.8Hz，ArH)，6.40(t，1H，J＝6.0，1.5Hz，C
H=C(CH
3)
2)，5.15(t，1H，J＝5.7，1.5Hz，C
HOCO)，4.08(m，8H，4×OC
H 2CH
3)，3.23(d，2H，J＝3.9Hz，COC
H 2)，2.61~2.54(m，2H，C
H 2CH=(CH
3)
2)，2.35(s，6H，N(CH
3)
2)，1.67(s，3H，C
H 3)，1.61(s，3H，C
H 3)，1.54~1.47(m，12H，4×OCH
2C
H 3).
Embodiment 10
Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-[1-(N, N-diethylin acetoxyl group)-4-methyl-3-pentenyl] preparation of naphthalene (III-2)
Step 1, step 2, with embodiment 1 step 1, step 2, just the methyl iodide with step 1 replaces with iodoethane, and the methyl-sulfate of step 2 replaces with ethyl sulfate.
Step 3 is with embodiment 1 step 3, only respectively with bromoacetic acid and Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) naphthalene replaces N, N-dimethylamino acetic acid and 1,4,5,8-tetramethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) naphthalene.Get light yellow Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-[1-(2-acetobrom oxygen base)-4-methyl-3-pentenyl] the light yellow semicure thing of naphthalene.
1H?NMR（300MHz，CDCl
3，δppm）:6.89(s，1H，ArH)，6.81(s，2H，ArH)，6.35(t，1H，J＝7.2，6.0Hz，C
H=C(CH
3)
2)，5.15(m，1H，C
HOCO)，4.05(m，8H，4×OC
H 2CH
3)，3.85(t，2H，J＝3.9Hz，COC
H 2Br)，2.60(m，2H，C
H 2CH=(CH
3)
2)，1.69(s，3H，C
H 3)，1.62(s，3H，C
H 3)，1.55~1.42(m，12H，4×OCH
2C
H 3).
Step 4 is with Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-[1-(2-acetobrom oxygen base)-4-methyl-3-pentenyl] naphthalene (50mg, 0.09mmol) dissolves in the 15ml anhydrous methylene chloride, add respectively Anhydrous potassium carbonate (62mg, 0.45mmol), 5 diethylamine solutions, backflow is spent the night, and filters, and filtrate decompression is concentrated, the residue silica gel column chromatography, sherwood oil: ethyl acetate (2/1, V/V) wash-out, get light yellow semicure material (III-2) 36.26mg, yield is 79%.
1HNMR（300MHz，CDCl
3，δppm）:6.88(s，1H，ArH)，6.80(d，2H，J＝1.5Hz，ArH)，6.39(t，1H，J＝5.7，7.5Hz，C
H=C(CH
3)
2)，5.15(t，1H，J＝2.1，5.7Hz，C
HOCO)，4.07(m，8H，4×OC
H 2CH
3)，3.41(d，2H，J＝3.0Hz，COC
H 2)，2.71(q，4H，J＝6.9Hz，COCH
2N(C
H 2CH
3)
2)，2.57(m，2H，C
H 2CH=(CH
3)
2)，1.67(s，3H，C
H 3)，1.61(s，3H，C
H 3)，1.50(m，12H，4×OCH
2C
H 3)，1.07(t，6H，J=7.2Hz，CH
2N(CH
2C
H 3)
2).
Embodiment 11
Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-{1-[2-(1-piperidyl) acetoxyl group]-the 4-methyl-3-pentenyl } preparation of naphthalene (III-3)
Step 1, step 2, with embodiment 1 step 1, step 2, just the methyl iodide with step 1 replaces with iodoethane, and the methyl-sulfate of step 2 replaces with ethyl sulfate.
Step 3, step 4 with embodiment 10 step 3, step 4, just replace to piperidines with diethylamine solution in the step 4, get light yellow semicure thing 28.77mg, and yield is 57%.
1H?NMR（300MHz，CDCl
3，δppm）:6.87(s，1H，ArH)，6.80(d，2H，J＝1.5Hz，ArH)，6.37(t，1H，J＝6.0，7.52Hz，C
H=C(CH
3)
2)，5.15(t，1H，J＝6.6，6.9Hz，C
HOCO)，4.06(m，8H，4×OC
H 2CH
3)，3.26(d，2H，J＝6.9Hz，COC
H 2)，2.54(m，6H，COCH
2N(C
H 2CH
2)
2CH
2，C
H 2CH=(CH
3)
2)，1.67(s，3H，C
H 3)，1.61~1.43(m，21H，C
H 3，4×OCH
2C
H 3，COCH
2N(CH
2C
H 2)
2C
H 2).
Embodiment 12
Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-{1-[2-(N-methyl isophthalic acid-piperazinyl) acetoxyl group]-the 4-methyl-3-pentenyl } preparation of naphthalene (III-4)
Step 1, step 2, with embodiment 1 step 1, step 2, just the methyl iodide with step 1 replaces with iodoethane, and the methyl-sulfate of step 2 replaces with ethyl sulfate.
Step 3, step 4 with embodiment 10 step 3, step 4, just replace to N methyl piperazine with diethylamine solution in the step 4.Get light yellow semicure thing 37.94mg, yield is 74%.
1HNMR（300MHz，CDCl
3，δppm）:6.86(s，1H，ArH)，6.79(d，2H，J＝1.8Hz，ArH)，6.37(t，1H，J＝5.7，7.2Hz，C
H=C(CH
3)
2)，5.14(t，1H，J=5.7，7.2Hz，C
HOCO)，4.09(m，8H，4×OC
H 2CH
3)，3.26(d，2H，J＝4.5Hz，COC
H 2)，2.59(m，10H，J＝6.9Hz，COCH
2N(C
H 2C
H 2)
2N，C
H 2CH=(CH
3)
2)
2)，2.30(s，3H，NC
H 3)1.66(s，3H，C
H 3)，1.61(s，3H，C
H 3)，1.49(m，12H，4×OCH
2C
H 3).
Embodiment 13
Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-{1-[3-(N, N-dimethylamino) propionyloxy]-the 4-methyl-3-pentenyl } preparation of naphthalene (III-5)
Step 1, step 2, with embodiment 1 step 1, step 2, just the methyl iodide with step 1 replaces with iodoethane, and the methyl-sulfate of step 2 replaces with ethyl sulfate.
Step 3 is with embodiment 1 step 3, respectively with 1,4,5,8-tetraethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) naphthalene and 3-(N, N-dimethylamino) propionic acid replaces 1,4,5,8-tetramethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) naphthalene and N, N-dimethylamino acetic acid, get light yellow semicure thing 65.83mg, yield is 73%.
1HNMR（300MHz，CDCl
3，δppm）:6.85(s，1H，ArH)，6.80(d，2H，J＝1.5Hz，ArH)，6.31(t，1H，J＝6.0，6.3Hz，C
H=C(CH
3)
2)，5.15(t，1H，J＝6.3，6.6Hz，C
HOCO)，4.07(m，8H，4×OC
H 2CH
3)，2.67~2.52(m，6H，C
H 2CH=(CH
3)
2，COC
H 2C
H 2N(CH
3)
2)，2.25(s，6H，COCH
2CH
2N(C
H 3)
2)，1.66(s，3H，C
H 3)，1.59(s，3H，C
H 3)，1.56(m，12H，4×OCH
2C
H 3).
Embodiment 14
Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-{1-[3-(N, N-diethylin) propionyloxy]-the 4-methyl-3-pentenyl } preparation of naphthalene (III-6)
Step 1, step 2, with embodiment 1 step 1, step 2, just the methyl iodide with step 1 replaces with iodoethane, and the methyl-sulfate of step 2 replaces with ethyl sulfate.
Step 3 is with embodiment 1 step 3, respectively with 1,4,5,8-tetraethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) naphthalene and 3-(N, the N-diethylin) propionic acid replaces 1,4,5,8-tetramethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) naphthalene and N, N-dimethylamino acetic acid,, getting light yellow semicure thing 65.79mg, yield is 67%.
1HNMR（300MHz，CDCl
3，δppm）:6.86(s，1H，ArH)，6.80(s，2H，ArH)，6.31(t，1H，J＝6.3，6.9Hz，C
H=C(CH
3)
2)，5.15(t，1H，J=6.3，6.9Hz，C
HOCO)，4.05(m，8H，4×OC
H 2CH
3)，2.85(t，2H，J＝7.2，7.5Hz，COC
H 2)，2.54(m，8H，C
H 2CH=(CH
3)
2，COCH
2C
H 2N(C
H 2CH
3)
2)，1.68(s，3H，C
H 3)，1.61(s，3H，C
H 3)，1.53(m，12H，4×OCH
2C
H 3)，1.05(t，6H，J＝6.9，7.5Hz，CH
2N(CH
2C
H 3)
2).
Embodiment 15
Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-{1-[3-(1-piperidyl) propionyloxy]-the 4-methyl-3-pentenyl } preparation of naphthalene (III-7)
Step 1, step 2, with embodiment 1 step 1, step 2, just the methyl iodide with step 1 replaces with iodoethane, and the methyl-sulfate of step 2 replaces with ethyl sulfate.
Step 3, with embodiment 1 step 3, respectively with Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) naphthalene and 3-piperidines propionic acid replace Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) naphthalene and N, N-dimethylamino acetic acid gets light yellow semicure thing 37.00mg, and yield is 55%.
1HNMR（300MHz，CDCl
3，δppm）:6.83(s，1H，ArH)，6.78(d，2H，ArH)，6.31(t，1H，J=6.0，6.6Hz，C
H=C(CH
3)
2)，5.12(t，1H，J=6.6，6.9Hz，C
HOCO)，4.11~3.96(m，8H，4×OC
H 2CH
3)，2.69~2.21(m，10H，COC
H 2C
H 2N(C
H 2CH
2)
2CH
2，C
H 2CH=(CH
3)
2)，1.65~1.24(m，24H，2×C
H 3，4×OCH
2C
H 3，CH
2N(CH
2C
H 2)
2C
H 2).
Embodiment 16
Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-{1-[3-(N-methyl isophthalic acid-piperazinyl) propionyloxy]-the 4-methyl-3-pentenyl } preparation of naphthalene (III-8)
Step 1, step 2, with embodiment 1 step 1, step 2, just the methyl iodide with step 1 replaces with iodoethane, and the methyl-sulfate of step 2 replaces with ethyl sulfate.
Step 3, with embodiment 1 step 3, respectively with Isosorbide-5-Nitrae, 5,8-tetraethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) naphthalene and 3-(methylpiperazine base) propionic acid replacement Isosorbide-5-Nitrae, 5,8-tetramethoxy-2-(1-hydroxy-4-methyl-3-pentenyl) naphthalene and N, N-dimethylamino acetic acid gets light yellow semicure thing 42.01mg, and yield is 61%.
1HNMR（300MHz，CDCl
3，δppm）:6.97(s，1H，ArH)，6.2(s，2H，ArH)，6.37(t，1H，J=6.3，6.6Hz，C
H=C(CH
3)
2)，5.14(t，1H，J＝5.7，7.2Hz，C
HOCO)，4.24~4.10(m，8H，4×OC
H 2CH
3)，2.84(t，2H，7.5，6.6Hz，COC
H 2CH
2)，2.78~2.35(m，15H，C
H 2N(C
H 2C
H 2)
2NC
H 3，C
H 2CH=(CH
3)
2))1.97~1.21(m，18H，4×OCH
2C
H 3H，2×C
H 3).
Embodiment 17
2-[1-(N, N-dimethylamino acetoxyl group)-4-methyl-3-pentenyl]-1,8:4, the preparation of 5 pairs of (methylene-dioxy) naphthalenes (IV-1)
Step 1 in the 25ml reaction flask, adds Shikonin (100mg, 0.35mmol), Anhydrous potassium carbonate (239.6mg 1.74mmol), potassiumiodide (10mg) and N, dinethylformamide (5ml) slowly adds methylene bromide (0.5ml), after dropwising, at 160 ℃ of reaction 20min, remove DMF under reduced pressure, add entry and ethyl acetate, tell ethyl acetate layer, be concentrated into driedly, get crude product 125.3mg.Through the PTLC purifying, get 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene radical dioxy base) the light yellow semi-solid material of naphthalene 78.9mg of 5-, yield 76.3%.
1H?NMR(300MHz，CDCl
3，δppm):δ7.04(s，1H，ArH)，6.82(s，2H，J＝3.0Hz，ArH)，5.59~5.53(t，2H，J＝4.8Hz，ArOC
H 2OAr)，5.49~5.47(t，2H，J＝3.6Hz，ArOC
H 2OAr)，5.21~5.11(m，2H，C
HOH，C
H=C(CH
3)
2)，2.53~2.35(m，2H，C
H 2CH=C(CH
3)
2)，1.73(s，3H，CH
3)，1.63(s，3H，CH
3).MS(EI，m/e):314[M
+].
13C?NMR(75MHz，CDCl
3，δppm):δ144.7，144.6，144.6，140.6，136.1，125.3，119.6，115.1，114.6，109.1，108.4，107.0，92.0，91.78，68.07，37.13，26.15，18.23。
Step 2; under nitrogen protection; temperature is controlled in 0 ~ 5 ℃; with 2-(1-hydroxy-4-methyl-3-pentenyl)-1,8:4, two (methylene-dioxy) naphthalene (100mg of 5-; 0.32mmol) dissolve in the anhydrous methylene chloride (5ml); the N that adds 1.5 equivalents, the DCC of N-dimethylamino acetic acid, 1.1 equivalents and the DMAP of catalytic amount, uniform temp stirs 2h.Add sherwood oil (4ml) and make precipitation, filter, concentrating under reduced pressure methylene dichloride and sherwood oil get thick product.Thick product silica gel column chromatography, ethyl acetate: (1/2, V/V) wash-out obtains pale yellow oily matter (IV-1) 78.78mg, yield 62%. to sherwood oil
1HNMR（300MHz，CDCl
3，δppm）:6.89(s，1H，ArH)，6.82(d，2H，J＝1.2Hz，ArH)，6.27(t，1H，J＝6.9，7.2Hz，C
H=C(CH
3)
2)，5.56(m，4H，2×ArOC
H 2OAr)，5.06(t，1H，J＝6.0，7.2Hz，C
HOCO)，3.21(s，2H，COC
H 2)，2.66~2.49(m，2H，C
H 2CH=(CH
3)
2)，2.34(s，6H，COCH
2N(C
H 3)
2)，1.64(s，3H，C
H 3)，1.59(s，3H，C
H 3).
Embodiment 18
1, tumor cell in vitro inhibition test
Present embodiment adopts the MTT colorimetry, test tumor cell line: the Leukemia K562 cell (impact of Emodin on Human chronic granulocytic leukemia K562 Cell apoptosis and proliferation and cmyc genetic expression, China's treatment and prevention of tumour magazine, 16(20): 1541,2009).Cell is cultivated to contain 10% calf serum, and attached cell makes cell be in logarithmic phase with 0.05% pancreas enzyme-EDTA Digestive system digestion when going down to posterity.Cell is inoculated in 96 well culture plates during test, and 200 μ l are inoculated in every hole, and concentration is 5 * 10
4The cell suspension of cells/ml.In 37 ℃, CO
2The incubator preculture is spent the night.After the preculture, every hole adds 2 μ l drug solutions.Drug effect cell 2 days.After drug effect finished, adding concentration in the every hole of 96 well culture plates when mtt assay is measured was the MTT working fluid 20 μ l of 5mg/ml, hatches 4 hours for 37 ℃, abandons supernatant liquor, adds 200 μ l DMSO, measures the OD value with microplate reader under the 570nm wavelength.
Method for estimating curative effect:
Inhibitory rate of cell growth=(contrast class value-test class value)/contrast class value * 100%
Dosage arranges: during to cytosis, establish 4 concentration, mainly in 0.1～100 μ M/ml scope.
Biometrics: the inhibiting rate according to trial drug cell growth under different concns calculates IC with the Logit method
50Value.
Experimental control: positive control drug is used 5-FU (5-Fu)
Test-results: see Table 1.
Table 1
2, animal anti-tumor in vivo embodiment
(the acetylshikonin injection liquid is to the research of S180 tumor-bearing mice tumor-inhibiting action, Chinese medicines with mouse S180 transplanted tumor for present embodiment
Reason is with clinical, 24(1): 22,2008) be model, with the positive contrast of 5-FU.
Compound method: grind with tween-80 first during the sample preparation, use physiological saline solution again, tween-80 content is 2%.Reference substance: use physiological saline solution during preparation.
Animal and knurl strain: kunming mice, female, body weight 18-20g, limited liability company provides conformity certification by Si Laike embodiment animal: SCXK(Shanghai) 2007-0005.The knurl strain: 2 of mouse S180 ascites sarcomas, gone down to posterity by pharmaceutical college of Shanghai Communications University and to keep.
Test method: get 2 of the mouse S180 ascites sarcomas of growth animated period, extract ascites under the aseptic condition, with normal saline dilution to 2 * 10
7, press 0.2ml/ only to the subcutaneous vaccination of mouse armpit.Next day is with at random all groupings of mouse, 8 every group.Be respectively blank group, positive controls 5-FU 25mg/kg and sample sets 12mg/kg, intraperitoneal injection.
Mouse inoculation begins by the body weight administration next day, and wherein sample sets and positive controls successive administration are 8 days, inoculate execution in the 9th day, gets the knurl piece and weighs, and calculates tumour inhibiting rate.
Tumour inhibiting rate=(control group knurl weight-administration group knurl is heavy)/control group knurl heavy * 100%
The result: the sample abdominal injection sees Table 2 to the tumour inhibiting rate of mouse S180 transplanted tumor.
Table 2
| Sample number into spectrum | Inhibiting rate (%) | Animals survived number of elements (beginning/finish) |
| Ⅱ-1 | 36 | 8/8 |
| Ⅱ-2 | 34 | 8/8 |
| Ⅱ-5 | 28 | 8/8 |
| Ⅲ-1 | 36 | 8/8 |
| Ⅲ-5 | 42 | 8/8 |
| Ⅳ-1 | 28 | 8/8 |
| Shikonin | - | 8/0 |
| 5-FU | 44 | 8/8 |
Claims (1)
1. a water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative is characterized in that, its structural formula is as follows:
Wherein: the molecular formula of R is CO (CH
2)
nN(R
5R
6), wherein: n=1-3, R
5And R
6Be the alkyl of 1-5 carbon atom, R
1, R
2, R
3And R
4Structure is identical and be CH
3, C
2H
5Or CH
2, correspondence is respectively: Isosorbide-5-Nitrae, 5,8-O-tetramethyl-Shikonin side chain contains basic nitrogen ester derivative, Isosorbide-5-Nitrae, 5,8-O-tetraethyl-Shikonin side chain contains basic nitrogen ester derivative and 1:8, and 4:5-O-dimethylene Shikonin side chain contains the basic nitrogen ester derivative, and its structural formula is followed successively by:
、
、
。
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| CN101066919A (en) * | 2007-06-14 | 2007-11-07 | 上海交通大学 | Process of synthesizing shikolin dimethyl ether derivative |
| CN101139287A (en) * | 2007-10-11 | 2008-03-12 | 上海交通大学 | Method for synthesizing alkannin dimethyl ether derivative |
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| CN101066919A (en) * | 2007-06-14 | 2007-11-07 | 上海交通大学 | Process of synthesizing shikolin dimethyl ether derivative |
| CN101139287A (en) * | 2007-10-11 | 2008-03-12 | 上海交通大学 | Method for synthesizing alkannin dimethyl ether derivative |
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