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Allopurinol derivative and preparation method and application thereof

A compound, N-4- technology, applied in drug combination, bone diseases, organic chemistry, etc., to achieve the effect of inhibiting xanthine oxidase activity, low cost and high yield

Inactive Publication Date: 2014-12-31
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] At present, there are no relevant reports about using allopurinol as a lead compound for anti-tumor after structural modification and transformation

Method used

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  • Allopurinol derivative and preparation method and application thereof
  • Allopurinol derivative and preparation method and application thereof
  • Allopurinol derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1 Synthesis of (4-chloro-1H-pyrazol[3,4-d]pyrimidine-N-1-) ethyl acetate (compound 6 for short)

[0056] Slowly add TEA (1.78g, 17.62mmol) into 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (0.8lg, 5.26mmol) dissolved in 20mL dry DMF, stir at room temperature for 30min, Ethyl bromoacetate (1.06 g, 6.39 mmol) dissolved in 5 mL of dry DMF was slowly added dropwise to the mixture and stirring was continued for 2 h. The reaction solution was detected by TLC and poured into 30mL of water after the reaction was complete. After adjusting the pH value to acidic with dilute hydrochloric acid, it was extracted with ethyl acetate (3×25mL). The organic layer was washed with saturated sodium chloride and concentrated to obtain flocs . The crude product was subjected to silica gel column chromatography and eluted with petroleum ether: ethyl acetate (6:1) to obtain white needle crystals (compound 6).

[0057] Compound 6: white crystal, 83~84℃ 1 H NMR (400MHz, DMSO-d 6 )δ:8.91(s,1H...

Embodiment 2

[0058] Example 2 Synthesis of (N-4-(4-aminophenyl)amino-1H-pyrazol[3,4-d]pyrimidine-N-1-)ethyl acetate (compound 7 for short)

[0059] Compound 6 (1.73g, 7.21mmol) was dissolved in 25mL of acetonitrile, then p-phenylenediamine (0.78g, 7.21mmol) was slowly added to the mixture, the reactant was heated to 80°C and stirred for 3h, detected by TLC to Total response. The reaction solution was concentrated to obtain a solid crude product, which was chromatographed on a silica gel column and eluted with petroleum ether: acetone (2:1) plus a few drops of triethylamine to obtain brown flaky crystals (compound 7).

[0060] Compound 7: Gray solid, 179.8~181.9°C 1 H NMR (400MHz, DMSO-d 6 )δ: 9.76 (br, 1H, NH), 8.27 (s, 2H, CH), 7.37 (s, 2H, ArH), 6.62 (s, 2H, ArH), 5.02~5.18 (m, 4H), 4.14 ( dd, J=7.04Hz, J=14.16Hz, 2H, CH 2 ), 1.19(t, J=7.08Hz, 3H, CH 3 ); 13 C NMR (100MHz, DMSO-d 6 )167.80,155.73,154.30,153.61,132.52,127.41,123.34,113.94,100.76,61.18,47.80,13.94;IR(KBr,ν,cm -1 ):...

Embodiment 3

[0061] The synthesis of embodiment 3 compound 8a~8c

[0062] Compound 7 (0.36g, 1.15mmol) was dissolved in 10mL THF, and NaH (0.069g, 2.88mmol) was slowly added to the mixture under ice conditions, stirred for 30min on ice, and then dissolved in 3mL Bromobenzenesulfonyl chloride (0.34g, 1.34mmol) in THF was slowly added dropwise to the reaction solution. After the dropwise addition was completed, stirring was continued for 1 h, and finally moved to room temperature and stirred overnight. The reaction solution was poured into 15 mL of water, adjusted to a pH of about 3 with dilute hydrochloric acid, extracted with dichloromethane (3×15 mL), the organic layer was washed with saturated sodium chloride, and concentrated to obtain a solid. The crude product was subjected to silica gel column chromatography, eluting with petroleum ether: acetone (2:1), to obtain 8a as a white solid.

[0063] Compound 7 (0.36g, 1.15mmol) was dissolved in 10mL THF, and NaH (0.069g, 2.88mmol) was slow...

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Abstract

The invention provides an allopurinol derivative as shown in Formula I, and a preparation method and application thereof. Tumor growth can be effectively suppressed by the allopurinol derivative provided by the invention, and the allopurinol derivative has good antitumor activity. The activity of xanthine oxidase can be effectively suppressed by the allopurinol derivative, and the allopurinol derivative can be used for treating gout and provides a new drug choice for treating cancer and gout. Additionally, the preparation method of the compound provided by the invention has the advantages of simplicity, lower cost, high yield and good industrial application prospect.

Description

technical field [0001] The present invention relates to allopurinol derivatives and their preparation methods and uses. Background technique [0002] Tumor is one of the most common and serious diseases that threaten human life in the world today. Chemotherapy, radiotherapy, and surgery are currently the main means of treating tumors. However, the number of drugs currently used for tumor treatment is limited, and their prices are high, which brings a greater economic burden to cancer patients. Therefore, it is particularly necessary to develop more effective anti-tumor drugs. [0003] Allopurinol, chemical name: 4-hydroxy-1H-pyrazolo[3,4-d]pyrimidine, its structural formula is as follows: [0004] [0005] It is an isomer of natural hypoxanthine, which can inhibit the activity of xanthine oxidase, prevent the oxidation of xanthine and hypoxanthine to produce uric acid, thereby reducing the concentration of serum uric acid, and is mainly used for the treatment of hyperu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/519A61P35/00A61P19/06
Inventor 尹述凡李财虎陈超肖克毅李颖董林
Owner SICHUAN UNIV
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