Derivative of 5-deoxy-5-fluoro cytidine and its preparation process and use

A technology of cytidine and compounds, applied in the field of 5'-deoxy-5-fluorocytidine derivatives, can solve the problems of limited application prospects and achieve good therapeutic selectivity

Inactive Publication Date: 2011-05-11
SHANGHAI RUIGUANG BIOCHEM TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, oral administration of 5'-deoxy-5-fluorouridine has certain intestinal toxicity, so its application prospect is not wide

Method used

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  • Derivative of 5-deoxy-5-fluoro cytidine and its preparation process and use
  • Derivative of 5-deoxy-5-fluoro cytidine and its preparation process and use
  • Derivative of 5-deoxy-5-fluoro cytidine and its preparation process and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Preparation of 5'-deoxy-5-fluoro-N 4 -Methylcytidine (Compound 1)

[0040] A, 2', 3'-di-O-acetyl-5'-deoxy-5-fluorouridine (compound of general formula B, wherein R 6 for acetyl)

[0041] The starting material 5'-deoxy-5-fluorouridine (compound A) was obtained by referring to the literature method (Dong Hui et al., Chinese Journal of Pharmaceutical Industry, 33:108 (2002)). 2 g (8.1 mmol) of compound A was dissolved in 40 ml of anhydrous pyridine, 1.8 ml (18 mmol) of acetic anhydride was added dropwise, and stirred overnight at room temperature. Then 5 ml of methanol was added and stirring was continued for 15 minutes, and the solution was evaporated to dryness. The solid was dissolved in 40ml of dichloromethane, washed with 40ml of 10% aqueous sodium bicarbonate solution, and the aqueous phase was extracted with 10ml×2 of dichloromethane. The dichloromethane liquids were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue...

Embodiment 2

[0047] Preparation of 5'-deoxy-5-fluoro-N 4 -Ethylcytidine (Compound 2)

[0048] Take 3.5g (10 mmol) 1-(2',3'-di-O-acetyl-β-D-5'-deoxyribofuranosyl)-4-(1,2,4-triazole-1- Base)-pyrimidin-2-(1H)-one was added to the mixture of 5ml ethylamine and 30ml dioxane, stirred at room temperature for 1h, and evaporated to dryness. Then 60 ml of tetrahydrofuran, 50 ml of methanol and 12.5 ml of water were added successively. Cool to 0°C, add 12.5ml of 2N sodium hydroxide solution, stir for 10 minutes and neutralize with 732-type cation exchange resin to about pH=7. The resin was filtered off, the solution was evaporated to dryness, and the residue was purified by a silica gel column to obtain 2.3 g of a white solid with a yield of 85% and a melting point of 100 to 102°C. 1 H-NMR (DMSO-d 6 )δ (ppm): 1.10 (3H, t, N-CH 2 CH 3 ), 1.28 (3H, d, 4'-CH 3 ), 3.00 to 3.10 (2H, m, N-CH 2 ), 3.66 (1H, d, 3'-H), 3.80 to 3.83 (1H, m, 4'-H), 3.99 (1H, d, 2'-H), 4.96 (1H, d, OH), 5.24 (1H, d, OH)...

Embodiment 3

[0050] Preparation of 5'-deoxy-5-fluoro-N 4 - Propylcytidine (Compound 3)

[0051] According to the method described in Implementation 2, propylamine was used instead of ethylamine to obtain white solid 5'-deoxy-5-fluoro-N 4 - Propylcytidine. 1 H-NMR (DMSO-d 6 )δ (ppm): 0.90 (3H, t, N-CH 2 CH 2 CH 3 ), 1.27 (3H, d, 4'-CH 3 ), 1.40 to 1.45 (2H, m, N-CH 2 CH 2 CH 3 ), 3.00 to 3.08 (2H, m, N-CH 2 ), 3.65 (1H, d, 3'-H), 3.80 to 3.84 (1H, m, 4'-H), 3.95 (1H, d, 2'-H), 4.96 (1H, d, OH), 5.24 (1H, d, OH), 5.71 (1H, d, 1'-H), 7.72 (1H, d, CHCF), 8.10 (1H, s, NH).

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Abstract

The present invention relates to a compound of the general formula (I) and medicinal salt thereof, wherein R1 and R2 are independently selected from hydrogen, C[1-6] straight-chain or branched-chain alkyl, phenyl and phenyl optionally substituted by C[1-6] alkyl or C[1-6] alkoxy; the condition is that at least one group in the R1 and R2 is not hydrogen; X represents O or S; R3 is selected from hydrogen, C[1-6] straight-chain or branched-chain alkyl, phenyl and phenyl optionally substituted by C[1-6] alkyl or C[1-6] alkoxy; R4 and R5 are independently selected from hydrogen or two (C[1-6]) alkyl amido, the condition is that at least one group in the R4 and R5 is not hydrogen; or R4 and R5 can be combined into a ring and form N-substituted pyrrolidinyl or N-substituted piperdine, and the substituted group is selected from C[1-3] alkyl. The present invention also relates to a preparation process of the compound. The present invention further relates to a medicine composition containing the compound or its medicinal salt and the application of the compound or its medicinal salt in preparation of antitumor medicine.

Description

technical field [0001] The present invention relates to 5'-deoxy-5-fluorocytidine derivatives with anti-tumor and anti-viral activities, and the present invention also relates to the use of the compound described in the preparation method of this type of compound in pharmacy 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 intravenous injection, which is inconvenient to administer. For the convenience of patients, a prodrug of 5-fluorouracil, which is suitable for oral administration, has been developed——5'-deoxy-5-fluorouridine. However, oral administration of 5'-deoxy-5-fluorouridine has certain intestinal toxicity, so its application prospect is not wide. [0003] The technical field requires the development of prodrugs of 5-fluorouracil, which should have no cytotoxicity and can be metabolize...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/06A61K31/7068A61P35/00
Inventor 余建鑫张万年李科吕加国周有骏朱驹姚建忠宋云龙盛春泉张珉陈军
Owner SHANGHAI RUIGUANG BIOCHEM TECH DEV
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