8-pyrazole substituted xanthine A2B adenosine receptor antagonist and synthesis method and application thereof

An adenosine receptor and a synthesis method technology, applied in the field of drug synthesis, can solve the problems of complex meta-trifluoromethylbenzyl synthesis conditions, severe reaction conditions, long reaction time and the like, and achieve easy industrial production, few reaction steps, Yield-enhancing effect

Inactive Publication Date: 2012-07-04
JINZHOU MEDICAL UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method requires more severe reaction conditions, and the reaction time is long, especially the m-trifluoromethylbenzyl synthesi

Method used

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  • 8-pyrazole substituted xanthine A2B adenosine receptor antagonist and synthesis method and application thereof
  • 8-pyrazole substituted xanthine A2B adenosine receptor antagonist and synthesis method and application thereof
  • 8-pyrazole substituted xanthine A2B adenosine receptor antagonist and synthesis method and application thereof

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Experimental program
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Effect test

Embodiment 1

[0069] R 1 , R 2 for hydrogen, R 3 For o-nitrobenzylpyrazole—synthesis of 8-(o-nitrobenzyl-1H-pyrazole)-xanthine

[0070] (1) Synthetic raw material o-nitrobenzyl-1H-pyrazole-4-carboxylic acid

[0071] ①Synthesis of ethyl pyrazole-4-carboxylate

[0072]

[0073] In a 250mL reaction flask equipped with a stirrer, a thermometer, a dropping funnel and a fractionating column, add 0.12mol of triethyl orthoformate, 0.10mol of ethyl cyanoethyl ester, 0.4g of acetic anhydride and 0.1g of a zinc chloride catalyst, and stir , reflux at 110°C for 1 hour, continue to heat up to 132°C, and distill off the low boiling point substances generated during the reaction from the top of the fractionating column; the reaction solution is cooled to precipitate crystals, filtered and washed with ethanol to obtain light yellow crystalline ethoxymethylene Ethyl cyanoacetate, Mp: 50~51°C; 0.1mol ethoxymethylene ethyl cyanoacetate and 0.10mol hydrazine hydrate were stirred in 400mL ethanol for 12h...

Embodiment 2

[0081] R 1 , R 2 for hydrogen, R 3 For m-nitrobenzylpyrazole—synthesis of 8-(m-nitrobenzyl-1H-pyrazole)-xanthine

[0082]

[0083] Dissolve 1.0mmol of m-nitrobenzyl-4-pyrazolecarboxylic acid and 1.0mmol of carbodiimide hydrochloride in 22mL of methanol, add 1.0mmol of 5,6-diaminouracil in 5 times under stirring, and stir for 12 hours , filter, remove solvent, wash with water, dissolve it in 15mL methanol and 15mL sodium hydroxide solution, react in microwave (360 W) for 30 min, cool to room temperature, acidify to pH with 6mol / L hydrochloric acid in ice bath =4, 8-(m-nitrobenzyl-1H-pyrazole)-xanthine was precipitated as a yellow solid, mass: 31.5 g, yield 89.3%., Mp: 196-198°C, purity: >95%. 1 H NMR (DMSO-d6): 13.39 (s,1H), 10.01(s,1H), 7.99-8.03 (m,2H), 7.81 (s,1H),7.62 (s,1H) 7.45-7.40 (m, 2H), 6.08 (s,1H), 5.01 (s, 2H) (eg image 3 ); LC-MS(m / z): 354 [M+] (eg Figure 4 ).

Embodiment 3

[0085] R 1 , R 2 for hydrogen, R 3 For p-nitrobenzylpyrazole—synthesis of 8-(p-nitrobenzyl-1H-pyrazole)-xanthine

[0086]

[0087] Dissolve 1.0mmol p-nitrobenzyl-4-pyrazolecarboxylic acid and 1.0mmol carbodiimide hydrochloride in 22mL methanol, add 1.0mmol 5,6-diaminouracil in 5 times under stirring, and stir for 10 hours , filter, remove solvent, wash with water, dissolve it in 15mL methanol and 15mL sodium hydroxide solution, react in microwave (350 W) for 20 min, cool to room temperature, acidify to pH with 6mol / L hydrochloric acid in ice bath =2, 8-(p-nitrobenzyl-1H-pyrazole)-xanthine was precipitated as a light yellow solid, mass: 28.4g, yield 82.8%, Mp: 208-210°C, purity: 97.4%. 1 H NMR (DMSO-d6): 13.39 (s,1H), 10.02(s,1H), 8.07(m,2H) ,7.61 (s, 1H),7.32 (m,2H), 7.43 (s,1H), 6.08 (s,1H), 5.01 (s,2H) (eg Figure 5 ); LC-MS(m / z):354 [M+] (eg Figure 6 ).

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Abstract

The invention relates to a 8-pyrazole substituted xanthine A2B adenosine receptor antagonist and a synthesis method and an application thereof. The structural formula of the A2B adenosine receptor antagonist is shown in the specifications, and the antagonist is synthesized by taking 1,3-dialkyl-5,6-diaminouracil and nitrobenzyl pyrazole-4-formic acid as raw materials and improving a Traube reaction. The synthesis method disclosed by the invention has mild conditions, low cost and high yield, is easy to operate, and is suitable for industrial production. As proved by a pharmacological experiment, the affinity and selectivity of an A2B receptor are enhanced due to substitution of the 8-position of xanthine in 8-pyrazole substituted xanthine with nitrobenzyl pyrazole, the secretion of IL-8 can be suppressed, and the release of inflammatory factors is reduced. The receptor antagonist is suitable for treating bronchial asthma.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to an 8-pyrazole substituted xanthine A 2B Adenosine receptor antagonist and its synthesis method and application. Background technique [0002] Bronchial asthma is the most common chronic respiratory disease in the world. Its main features are chronic airway inflammation and increased airway reactivity to various stimuli. It often recurs clinically and seriously threatens people's health. It is a recognized medical science worldwide. Asthma is listed as one of the four major persistent diseases by the World Health Organization. According to investigations, there are at least 100 million people in the world suffering from asthma. In recent years, studies have found that adenosine is an effective bronchoconstrictor, through the interaction with specific A 2B Adenosine receptor interaction can contract bronchial smooth muscle, promote inflammatory cells to release inflammatory factors,...

Claims

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Application Information

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IPC IPC(8): C07D473/04C07D473/08A61K31/522A61P11/06
Inventor 贾云宏马玉梅蔡东
Owner JINZHOU MEDICAL UNIV
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