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Preparation and application of a 5-fluorouracil substituted carboxylic acid derivative

A technology for fluorouracil carboxylic acid and derivatives, which is applied in the field of medicinal chemistry to achieve the effects of reducing toxic side effects, improving oral bioavailability, and having a broad anti-tumor spectrum

Active Publication Date: 2020-08-07
浙江方锘制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although both CA4 and 5-fluorouracil have good therapeutic effects on tumors, their respective defects also exist objectively. By comparing the advantages and disadvantages of their anti-tumor effects, we found that they have the possibility of complementarity

Method used

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  • Preparation and application of a 5-fluorouracil substituted carboxylic acid derivative
  • Preparation and application of a 5-fluorouracil substituted carboxylic acid derivative
  • Preparation and application of a 5-fluorouracil substituted carboxylic acid derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 Preparation of 3'-amino-3,4,4',5-tetramethoxystilbene (Ⅱa)

[0035]

[0036] Step 1: Synthesis of 3'-nitro-3,4,4',5-tetramethoxystilbene

[0037] Under the protection of nitrogen, suspend and dissolve 3,4,5-trimethoxybenzyl bromidetriphenylphosphine salt (4.42g, 8.5mmol) in anhydrous tetrahydrofuran (50mL), cool down to -20°C, and slowly add dropwise under stirring n-Butyllithium solution (8mL, 2.5M), gradually dissolved after adding, and continued to stir for 3h, dissolved 3-nitro-4-methoxybenzaldehyde (1.5g, 8.3mmol) in 10mL of anhydrous tetrahydrofuran, Add dropwise to the reaction solution through the dropping funnel, after the addition is complete, react for 5 hours and then rise to room temperature, and stir the reaction overnight. TLC detected that the reaction was complete, and 50 mL was added to quench the reaction, and the liquid was separated. Re-extract with 50mL ethyl acetate, combine the organic phases, continue to wash with water for 2-3 ti...

Embodiment 2

[0040] Example 2 Synthesis of 3'-amino-3,4,4',5-tetramethoxydiphenylethane (Ⅱb)

[0041]

[0042] Dissolve the 3'-nitro-3,4,4',5-tetramethoxystilbene (1.4g, 4.0mmol) prepared in Step 1 of Example 1 in 30mL ethyl acetate, add 10% Palladium carbon catalyst (200mg), replaced with hydrogen three times, hydrogenated at room temperature for 4h, TLC detected the reaction was complete, filtered, spin-dried, and purified by column chromatography to obtain IIb (1g, 78.0%). 1 H NMR (500MHz, CDCl 3 )δ6.76(d, J=5Hz 2H), 6.65(d, J=5Hz, 1H), 6.41(s, 2H), 3.87(s, 3H), 3.85(s, 9H), 2.82(s, 4H ).

Embodiment 3

[0043] Example 3 3,4,5-trimethoxy-3'-amino-4'-ethoxystilbene (Ⅱc)

[0044]

[0045] Step 1: Preparation of 3,4,5-trimethoxyphenyl-3'-nitro-4'-ethoxystilbene

[0046] Under the protection of argon, suspend trimethoxyphenylmethylenetriphenylphosphine bromide (15g, 28.7mmol) in anhydrous tetrahydrofuran (300mL), cool to about -15°C, drop n-butyl lithium cyclohexyl Alkane solution (1.6mol / L, 22mL), after adding, react for 1 hour, dissolve 4-ethoxy-3-nitrobenzaldehyde (5.7g, 29mmol) in anhydrous tetrahydrofuran (24mL), and drop The funnel was slowly added dropwise into the above reaction solution, after the addition was completed, it was stirred for 1 h and then raised to room temperature, and stirred overnight, TLC detection showed that the reaction was complete, adding water to quench the reaction, separating the organic layer, removing 3 / 4 of the solvent, and adding 4 of the remaining mother liquor. The mixture was doubled with absolute ethanol, cooled in an ice bath for cry...

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Abstract

The invention discloses a preparation and an application for a compound compounded from stilbene and diphenylethane antitumor drugs and 5-fluorouracil antitumor drugs. The compound provided by the invention has a general structural formula (I) as described in the specification.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to stilbene / diphenylethane tubulin inhibitor antineoplastics and antimetabolite antineoplastics. Background technique [0002] In 1971, Folkman first proposed the theory of angiogenesis, and believed that the vascular system of tumors plays an important role in the process of tumor growth, development and metastasis. Inhibiting tumor angiogenesis can lead to partial death of tumor cells due to ischemia and hypoxia, thereby delaying tumor progression. Growth and inhibition of tumor metastasis (Folkman J.er al., J.Med 1971,285,1182-1186) [0003] Pharmacological studies have confirmed that tumor growth must depend on angiogenesis, which provides a new target for tumor therapy, and the development of tumor vascular-targeted drugs has become a research hotspot for anti-tumor drugs. In the 1980s, American scientists reported that a series of stilbene compounds with anti-tumor activity...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/553A61K31/505A61P35/00A61P35/02
CPCC07D239/553
Inventor 吴范宏周九九庞婉赵磊马中林张志凯俞晓东吴建越黄金文
Owner 浙江方锘制药有限公司
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