Acyclic nucleoside phosphonate compounds or pharmaceutically acceptable salts thereof, preparation method, application, intermediate compounds thereof, and medicinal composition containing same

A compound, nucleoside phosphine technology, applied in the direction of drug combination, chemical instruments and methods, compounds of group 5/15 elements of the periodic table, etc., can solve problems such as inhibition and hemorrhagic enteritis, large toxic and side effects, and patient-patient differences

Inactive Publication Date: 2010-06-30
WUJIANG XINKAI MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Tegafur and its similar carmofur are representative 5-fluorouracil prodrugs, but there are still many shortcomings in clinical use: such as irregular oral administration, large individual differences; large toxic and side effects, can cause bone marrow suppression and Hemorrhagic enteritis; low fat solubility, poor penetration of drugs into tissue cells, etc., which have a certain impact on clinical efficacy
The non-linearity of drug elimination leads to obvious differences between patients and patients, which limits the further application of this kind of 5-fluorouracil prodrugs

Method used

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  • Acyclic nucleoside phosphonate compounds or pharmaceutically acceptable salts thereof, preparation method, application, intermediate compounds thereof, and medicinal composition containing same
  • Acyclic nucleoside phosphonate compounds or pharmaceutically acceptable salts thereof, preparation method, application, intermediate compounds thereof, and medicinal composition containing same
  • Acyclic nucleoside phosphonate compounds or pharmaceutically acceptable salts thereof, preparation method, application, intermediate compounds thereof, and medicinal composition containing same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] Example 1 Preparation of 1-[bis(2,2,2-trifluoroethyl)-phosphonooxy]-5-fluoro-N 4 -Methylcytosine (compound 1)

[0085] A, 1-[bis(2,2,2-trifluoroethyl)-phosphonooxy]-5-fluoro-uracil (compound H)

[0086] The key intermediate [bis(2,2,2-trifluoroethyl)-phosphonomethyl Oxy]ethyl iodide (compound F). Dissolve 1.46g (11.2mmol) of 5-fluorouracil in 30mL of DMF, add 1.77ml (12.11mmol) of DBU and react at 80°C for 1h. Then add 4g (9.3mmol) [bis(2,2,2-trifluoroethyl)-phosphonomethoxy]ethyl iodide, and stir at 100°C for 5h. The organic solvent was evaporated, the residue was dissolved in 100 mL of dichloromethane, and the organic phase was washed with 50 mL of saturated Na 2 CO 3 aqueous solution and 50mL saturated brine. The organic phase was dried (Na 2 SO 4 ), filtered, evaporated to dryness and purified by silica gel column, developing solvent: chloroform:methanol=10:0.4 to obtain 2g of white solid, yield: 50%, mp118~120°C. 1 H-NMR (CDCl 3 )δ (ppm): 3.84 ~ 3.86 (2H,...

Embodiment 2

[0091] Example 2 Preparation of 1-[bis(2,2,2-trifluoroethyl)-phosphonooxy]-5-fluoro-N 4 -Ethylcytosine (compound 2)

[0092] Take 4.8g (10mmol) 1-[bis(2,2,2-trifluoroethyl)-phosphonooxy]-5-fluoro-4-(1,2,4-triazol-1-yl)- Pyrimidin-2-(1H)-one was added to a mixture of 5ml ethylamine and 30ml dioxane, stirred at room temperature for 1h, and evaporated to dryness. The residue was dissolved in 50ml of dichloromethane, and the organic phase was washed with 50ml of saturated sodium bicarbonate and saturated brine, and dried (MgSO 4 ), filtered and evaporated to dryness, and the residue was purified by silica gel column to obtain 2.3 g of white solid, yield: 50%, melting point 102-104°C. 1 H-NMR (CDCl 3 )δ (ppm): 1.10 (3H, t, N-CH 2 CH 3 ), 3.00~3.10 (2H, m, N- CH 2 CH 3 ), 3.66~3.69 (2H, m, N- CH 2 CH 2 -O), 3.77~3.80(2H, m, N- CH 2 CH 2 -O), 4.01 (2H, s, O- CH 2 P-), 4.20~4.23 (4H, m, 2XCF 3 CH 2 -O), 7.34 (1H, d, 6-H), 8.90 (1H, br, NH).

Embodiment 3

[0093] Example 3 Preparation of 1-[bis(2,2,2-trifluoroethyl)-phosphonooxy]-5-fluoro-N 4 -Propylcytosine (Compound 3)

[0094] According to the method described in Example 2, propylamine was used instead of ethylamine to obtain white solid compound 3, yield: 45%. 1 H-NMR (CDCl 3 )δ (ppm): 0.90 (3H, t, N-CH 2 CH 2 CH 3 ), 1.40~1.45 (2H, m, N-CH 2 CH 2 CH 3 ), 3.00~3.08 (2H, m, N- CH 2 CH 2 CH 3 ), 3.44~3.47 (2H, m, N- CH 2 CH 2 -O), 3.67~3.70 (2H, m, N-CH 2 CH 2 -O), 3.89 (2H, s, O- CH 2 P-), 4.20~4.22 (4H, m, 2XCF 3 CH 2 -O), 7.25 (1H, d, 6-H), 8.90 (1H, br, NH).

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Abstract

The invention discloses acyclic nucleoside phosphonate compounds or pharmaceutically acceptable salts thereof shown in the formula (I), a preparation method, application, intermediate compounds thereof, and a medicinal composition containing the same. The acyclic nucleoside pyrimidine phosphonate compounds per se have no cytotoxicity, high activity of tumor and virus resistance and high selectivity; and the preparation method has low cost and high product yield.

Description

technical field [0001] The present invention relates to a compound or its pharmaceutically acceptable salt, its preparation method and application, its intermediate and its pharmaceutical composition, in particular to a ring-opening nucleoside phosphinate compound or its pharmaceutically acceptable salt and its preparation Methods and applications, intermediates thereof, and pharmaceutical compositions containing them. Background technique [0002] Since 5-fluorouracil was synthesized in 1957, it has been widely used in the treatment of various tumors because of its good selectivity and low adverse reactions. However, most of 5-fluorouracil is administered intravenously, and a prodrug 5'-deoxy-5-fluorouridine suitable for oral administration has been developed for the convenience of patients. However, oral administration of 5'-deoxy-5-fluorouridine has certain intestinal toxicity. [0003] Tegafur, the precursor of 5-fluorouracil, combines with uracil to form UFT, and then...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6512C07F9/6558A61K31/675A61P31/12A61P35/00
Inventor 余建鑫夏广新王征翟富民陈玉林魏海洋孙增铭
Owner WUJIANG XINKAI MEDICAL TECH
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