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Water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative and preparation and application methods thereof

A nuclear oxygen alkyl group and shikonin technology, which is applied in the field of water-soluble shikonin naphthalene oxyalkylated derivatives and its preparation and application, can solve the problem of water solubility of toxic side effects, increase water solubility, poor Limiting clinical application and other issues to achieve the effect of inhibiting tumor growth

Inactive Publication Date: 2013-05-01
SHANGHAI JIAOTONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The antitumor effect of shikonin has been confirmed by many research reports, but its clinical application is limited due to its toxic side effects and poor water solubility
[0003] After searching the literature of the prior art, it was found that the Chinese invention patent application with the publication number CN1420111A disclosed a class of naphthalene derivatives and their preparation methods and uses, and reported the inhibitory effect and anti-tumor effect of this type of compound on telomerase , these compounds are side chain hydroxy acylated derivatives of shikonin; previously applied for patents (application number 201010127297.X) reported naphthalene (5,8-dihydroxy-1 , 4-Naphthoquinone) structure after alkylation significantly decreased cytotoxicity, but did not involve the issue of increasing its water solubility

Method used

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  • Water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative and preparation and application methods thereof
  • Water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative and preparation and application methods thereof
  • Water-soluble shikonin naphthazarin oxygen nucleus alkyl derivative and preparation and application methods thereof

Examples

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Embodiment 1

[0039] The preparation of 1,4,5,8-tetramethoxy-2-[1-(N,N-dimethylaminoacetoxy)-4-methyl-3-pentenyl]naphthalene, as figure 1 As shown, this embodiment includes the following steps:

[0040] Step 1: Add shikonin (144mg, 0.50mmol), dried potassium carbonate (690mg, 5.0mmol), DMF (15ml), KI (20mg), methyl iodide (0.16ml, 2.5mmol) into a 25ml reaction vial . Under nitrogen protection, react at room temperature (25°C) for 24h. After the reaction, add water (10ml) to dilute, extract with ethyl acetate (20ml×3), wash the extract with water (15ml×2), dry over anhydrous magnesium sulfate, filter, and concentrate to dryness to obtain 139mg of crude product, which is analyzed by PTLC After separation, 121.0 mg of orange-red solid 5,8-dimethoxy-2-(1-hydroxy-4-methyl-3-pentenyl)-1,4-naphthoquinone was obtained, with a yield of 76.6%. Melting point: 56~59℃, IR(KBr): 3457, 2930, 1652, 1571, 1475, 826cm -1 . 1 HNMR (300MHz, CDCl 3 , δppm): δ7.32(s, 2H, ArH), 6.79(s, 1H, H quin ), 5.17(t...

Embodiment 2

[0044] Preparation of 1,4,5,8-tetramethoxy-2-[1-(N,N-diethylaminoacetoxy)-4-methyl-3-pentenyl]naphthalene (Ⅱ2), like figure 2 As shown, this embodiment includes the following steps:

[0045] Step one, step two, with embodiment 1 step one, step two.

[0046] Step 3 is the same as in Example 1, except that bromoacetic acid is replaced by N,N-dimethylaminoacetic acid. Obtain light yellow 1,4,5,8-tetramethoxy-2-[1-(2-bromoacetoxy)-4-methyl-3-pentenyl]naphthalene semi-cured substance 55.57mg, yield 85%.

[0047] 1 HNMR (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 H OCOCH 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 2 Br), 3.84(s, 3H, OCH 3 ), 2.66~2.54 (m, 2H, C H 2 CH=(CH 3 ) 2 ), 1.67 (s, 3H, C H 3 ), 1.58(s, 3H, C H 3 ).

[0048] Step 4: Dissolve 1,4,5,8-tetramethoxy-2-[1-(2-bromoacetoxy)-4-methyl-3-pentenyl]naphthalen...

Embodiment 3

[0051] 1,4,5,8-Tetramethoxy-2-{1-[2-(1-piperidinyl)acetoxy]-4-methyl-3-pentenyl}naphthalene (Ⅱ-3) preparation, such as image 3 As shown, this embodiment includes the following steps:

[0052] Step one, step two, with embodiment 1 step one, step two.

[0053] Step 3 is the same as Step 3 in Example 2.

[0054] Step 4 was the same as Step 4 of Example 2, except that piperidine was substituted for diethylamine to obtain 26.67 mg of the target compound (II-3) with a yield of 63%.

[0055] 1 HNMR (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 H OCO), 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 2 N(C H 2 CH 2 ) 2 CH 2 , C H 2 CH=(CH 3 ) 2 ), 1.66(s, 3H, C H 3 ), 163~1.58(t, 6H, COCH 2 N(CH 2 C H 2 ) 2 C H 2 ), 1.57(s, 3H, C H 3 ).

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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 [0001] The invention relates to a compound in the technical field of traditional Chinese medicine and a preparation and application method thereof, in particular to a water-soluble shikonin naphthalene oxyalkylated derivative and its preparation and application. Background technique [0002] Comfrey is a commonly used clinical traditional Chinese medicine recorded in the Pharmacopoeia of the People's Republic of China. It can be divided into Lithospermumerythrohizon, also known as Northeast Comfrey and Soft Comfrey (A.euchroma Johnst), also known as Xinjiang Comfrey. The main active ingredients in hard comfrey are shikonin and its derivatives, while soft comfrey contains akanin and its derivatives, shikonin and akanin are enantiomers of each other, and shikonin is R Configuration, Akanin is S configuration. These ingredients all have antibacterial, anti-inflammatory, anti-cancer, and treatment of burns and scalds. The antitumor effect of shikonin has been c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C229/12C07C227/18C07C227/08C07D493/06C07D295/15A61K31/223A61K31/4453A61K31/495A61K31/357A61P35/02A61P35/00A61P35/04
Inventor 李绍顺周文王汝冰彭瑛
Owner SHANGHAI JIAOTONG UNIV