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Multiple target point type Tamibarotene derivative as well as preparation method and application thereof

A tamibarotene, multi-target technology, applied in the preparation of urea derivatives, the preparation of organic compounds, chemical instruments and methods, etc., can solve the problems of low drug resistance, toxic and side effects that limit clinical use, etc.

Active Publication Date: 2015-12-23
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with all-trans retinoic acid (ATRA), it has higher efficacy and lower drug resistance, but its side effects include hypertriglyceridemia, hypercholesterolemia, skin rash, bone pain , retinoic acid syndrome and teratogenic effects limit its clinical use

Method used

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  • Multiple target point type Tamibarotene derivative as well as preparation method and application thereof
  • Multiple target point type Tamibarotene derivative as well as preparation method and application thereof
  • Multiple target point type Tamibarotene derivative as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-((ureaoxy)carbonyl)benzamide ( 1) Preparation

[0064] Tamibarotene (AM80) (0.35g, 1mmol) was dissolved in anhydrous tetrahydrofuran, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.1mmol), adding pentafluorophenol (0.20g, 1.1mmol) dissolved in N,N-dimethylformamide in advance. The reaction was carried out at room temperature for 12 h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was distilled off for further use. First, hydroxyurea (0.08g, 1mmol) was dissolved in N,N-dimethylformamide, N-methylmorpholine (12mL) was added to dissolve the upper pentafluorophenol ester in anhydrous dioxane, Drop into the N,N-dimethylformamide reaction solution. Reaction at room temperature for 12h. Directly passed through column (EA / PE=5 / 1) to obtain white solid 1 (0.11 g, 27%). ESI-MSm / z:410.5(M+H) + , 1 H-NMR (600MHzDMSO-d 6 ): δ1.24-1.25(m,12H), 1...

Embodiment 2

[0065] Example 2: (5-fluoro-2,4-dioxy-3,4-dihydropyrimidin-1(2H)-yl)methyl-4-((5,5,8,8-tetramethyl Preparation of -5,6,7,8-tetrahydro-2-naphthyl)carbamoyl)benzoate (3)

[0066] 5-Fluorouracil (5-FU) (1.3g, 10mmol) was mixed with 3mL of 37% by volume formaldehyde solution, stirred at 60°C for 2h, and evaporated under reduced pressure to obtain a colorless viscous oil. The obtained oil was dissolved in anhydrous acetonitrile, and AM80 (3.51g, 10mmol), dicyclohexylcarbodiimide (2.3g, 11mmol), and an appropriate amount of 4-dimethylaminopyridine were added. After 24 hours, TLC monitored that the reaction was complete, evaporated the solvent, added ethyl acetate to dissolve, and washed the organic phase with water, 1M hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride, respectively. After drying with anhydrous magnesium sulfate, the solvent was evaporated by filtration, and the residue was separated by silica gel column (dichloromethane / methanol 60:1) t...

Embodiment 3

[0067] Example 3: N 1 -(2-(2,6-Piperidinedione-3-yl)-1-oxoisoindoline-4-yl)-N 4 Preparation of (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)terephthalamide (5)

[0068] Tamibarotene (AM80) (0.35 g, 1 mmol) was dissolved in 20 mL of thionyl chloride, two drops of DMF was added dropwise, and stirred and refluxed at 75° C. for 2 h. The solvent was distilled off to obtain compound 4 as a yellow oil. Lenalidomide (0.26 g, 1 mmol) was dissolved in pyridine solution, and compound 4 in tetrahydrofuran was added dropwise under ice-cooling. Remove from the ice room and warm the reaction. After 24 hours, TLC monitored that the reaction was complete. The solvent was evaporated, ethyl acetate was added for dissolution, and the organic phase was washed with water, 1M hydrochloric acid and saturated sodium chloride respectively. After drying with anhydrous magnesium sulfate, the solvent was evaporated by filtration, and the residue was separated on a silica gel column (petroleum et...

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PUM

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Abstract

The invention provides a multiple target point type Tamibarotene derivative as well as a preparation method and an application thereof. Particularly, RAR (retinoic acid receptor) agonist Tamibarotene is connected with antineoplastic drug hydroxycarbamide, fluorouracil and lenalidomide on sales through ester bonds or amido bonds respectively to obtain three multiple target point mutual prodrugs. The invention provides a method for preparing the compound and the application of the compound in preparing antineoplastic drugs, particularly drugs for curing various leukemias. The invention further relates to a drug combination of the compound.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to multi-target tamibarotene derivatives and preparation methods thereof, and the medical application of these compounds, especially the application in the preparation of antitumor drugs. Background technique [0002] Retinoic acid receptors are a subfamily of the nuclear receptor (nuclear receptors, NR) superfamily, which consists of two types of receptors, retinoic acid receptors (retinoic acid receptors, RARs) and retinoid X receptors (retinoid X receptors, RXRs) , RARs and RXRs include three subtypes of α, β and γ, respectively. Retinoids are a general term for more than 4,000 natural and synthetic compounds, which are related to the metabolite of vitamin A (retinol): all-trans-retinoic acid (ATRA) in structure and function. . Retinoic acid compounds have a wide range of biological effects, and play an important role in maintaining normal body functions, anti-tumor, treating...

Claims

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Application Information

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IPC IPC(8): C07C275/64C07C273/18C07D239/553C07D401/04A61K31/513A61K31/4439A61K31/175A61P35/02
Inventor 张颖杰徐文方江余祺李晓杨侯金宁丁永正
Owner SHANDONG UNIV
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