Sulfur-bearing uridine anticancer drug, intermediate and synthesis method

A technology of anticancer drugs and synthetic methods, which is applied in the direction of drug combinations, chemical instruments and methods, and antineoplastic drugs. The effect of easy access to raw materials

Inactive Publication Date: 2013-12-25
DALIAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although 4-thiothymidine can be used as a new type of nucleoside anticancer drug, the near-ultraviolet wavelength of 4-thiothymidine is at 335nm, which has poor tissue penetration ability, and the ability of light to penetrate tissue is similar to that of photosensitizers. It is related to the excitation wavelength of the light received. The longer the wavelength of the light, the stronger the ability to penetrate the tissue, and it is easier to enter the cells in the inner layer of the tissue.

Method used

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  • Sulfur-bearing uridine anticancer drug, intermediate and synthesis method
  • Sulfur-bearing uridine anticancer drug, intermediate and synthesis method
  • Sulfur-bearing uridine anticancer drug, intermediate and synthesis method

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Experimental program
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Effect test

Embodiment 1

[0056]

[0057] Dissolve uridine (0.55 g, 2 mmol) in 10 mL of 0.3 mol / L dilute nitric acid, add simple iodine (0.504 g, 1.98 mmol), and heat under reflux for 100 min until the raw material is completely reacted (monitored by thin-layer chromatography). . After stopping the reaction, heat filtration to remove excess elemental iodine, the filtrate was extracted with petroleum ether until the solution was clear, and placed at 4°C to obtain a large amount of colorless needle-like crystals of 5-iodouridine, which were weighed to obtain 0.63 g after drying. 75%. m.p. 205-207℃, (literature value m.p. 208-210℃);

[0058] 1 H NMR (400 MHz, DMSO-d 6 ) (ppm): 11.71(br s,1H, N-H), 8.50(s, 1H, 6-H), 5.74(d, 1H, J = 4.0 Hz, 1'-H), 5.10, 5.29, 5.44(d , t, d, 1H, 1H, and 1H, OH), 4.05 (dd, 1H, J = 4.0 Hz, 8.0Hz, 2'-H), 4.00 (dd, 1H, J = 4.0 Hz, 8.0 Hz, 3 '-H), 3.89 (d, 1 H, J =4.0 Hz, 4'-H), 3.54-3.73 (m, 2H, 5'-H); UV-Vis (in CH 3 CN), λmax / nm: 280.0, λmax / nm: 243.0.

[0059] (2)...

Embodiment 2

[0076]

[0077] Dissolve uridine (0.55 g, 2 mmol) in 10 mL of 0.3 mol / L dilute nitric acid, add simple iodine (0.504 g, 1.98 mmol), and heat under reflux for 100 min until the raw material is completely reacted (monitored by thin-layer chromatography). . After stopping the reaction, heat filtration to remove excess elemental iodine, the filtrate was extracted with petroleum ether until the solution was clear, and placed at 4°C to obtain a large amount of colorless needle-like crystals of 5-iodouridine, which were weighed to obtain 0.63 g after drying. 75%. m.p. 205-207℃, (literature value m.p. 208-210℃);

[0078] 1 H NMR (400 MHz, DMSO-d 6 ) (ppm): 11.71(br s,1H, N-H), 8.50(s, 1H, 6-H), 5.74(d, 1H, J = 4.0 Hz, 1'-H), 5.10, 5.29, 5.44(d , t, d, 1H, 1H, and 1H, OH), 4.05 (dd, 1H, J = 4.0 Hz, 8.0 Hz, 2'-H), 4.00 (dd, 1H, J = 4.0 Hz, 8.0 Hz, 3 '-H), 3.89 (d, 1 H, J =4.0 Hz, 4'-H), 3.54-3.73 (m, 2H, 5'-H); UV-Vis (in CH 3 CN), λmax / nm: 280.0, λmax / nm: 243.0.

[0079] (2...

Embodiment 3

[0097]

[0098] In a 100 mL three-necked flask, add 5-iodo-2'-deoxyuridine (1.0 g, 2.82 mmol), anhydrous pyridine (15 mL, 183 mmol), and add purified acetic anhydride after it is fully dissolved (3.0 mL, 32 mmol), reacted under ice bath conditions for 16 h, removed the solvent under reduced pressure, then added 10 mL each of dichloromethane and benzene, removed the solvent again under reduced pressure, and added dichloromethane (20 mL), the solvent was removed under reduced pressure. The crude product was dissolved in dichloromethane (250 mL), and saturated NaHCO 3 (80 mL), extracted three times with dichloromethane. Anhydrous NaSO for organic phase 4 Dry, filter, and remove the solvent from the filtrate under reduced pressure. Add 1.5 mL of 95% ethanol, and then place the mixture in the freezer for 24 h to precipitate a white solid 3',5'-O-dioxoacetyl-5-iodo-2'-deoxyuridine (1.13 g , 2.58 mmol), the yield is 91%, m. p. 156-157 ℃.

[0099] 1 H NMR (400 MHz, DMSO-d 6...

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Abstract

The invention relates to a synthesis method which comprises the steps of taking uridine as a principal raw material, treating with iodine and dilute nitric acid, obtaining 5-iodine uridine, treating with acetic anhydride to form 2',3',5'-O-trioxide acetyl-5-iodine uridine, allowing 2',3',5'-O-trioxide acetyl-5-iodine uridine to react with 2-(tributyl stannane) furan or thiophene by the action of triphenyl phosphine palladium chloride to form an intermediate, deprotecting by stirring in an ammonia methanol saturated solution at the room temperature by the action of phosphorus pentasulfide, and obtaining 5-(2-furyl or thienyl)-4-sulfur-bearing uridine. The compound has absorption at 363nm, and higher sensitivity to ultraviolet A, can enter inner cells of a tissue and act on cancer cells selectively, and overcomes the disadvantages that a photosensitive reagent for optic treatment at present is not gathered in nuclei and cannot selectively act on the cancer cells. The compound belongs to a novel base sulfur-bearing nucleoside compound, absorption light waves of the compound are in a long wavelength region, and the compound can selectively act on the inner cancer cells of the tissue, has a potential pharmaceutical value, and enters the inner cells of the tissue easily.

Description

technical field [0001] The present invention relates to a new compound for treating cancer and its preparation method, in particular, it relates to 5-(2-furyl or thienyl)-4-thiouridine and its analogs, intermediates and synthesis methods, and the synthesized products The ultraviolet spectrum has absorption at 363nm, is sensitive to UVA light, and is a drug suitable for treating cancer. Background technique [0002] Malignant tumors are currently the No. 1 killer threatening human life. Although chemotherapy can reduce cancer mortality, existing anticancer drugs have relatively large side effects on normal cells while killing cancer cells. Radiation therapy focuses rays precisely on target tissue, but high-energy rays can also damage normal cells while killing cancer cells. Surgical treatment is still the most effective treatment for some tumors, but it is not suitable for all malignant tumors. Surgical treatment is basically powerless for advanced cancer. Obviously, chemo...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H19/067C07H1/00A61K41/00A61P35/00
Inventor 张晓辉翟红秀高瑞琦秦建忠
Owner DALIAN UNIVERSITY
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