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Parazole and isoxazole derivative, preparation method for same and application thereof

A technology of isoxazole and derivatives, applied in the field of pharmaceutical compounds, can solve the problems of poor specificity and low activity

Inactive Publication Date: 2012-03-21
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] In 2005, G.Gupta et al. reported a kind of acrosome inhibitor in "Journal of Human Reproduction". However, the technology reported in this document has defects such as low activity and low specificity.

Method used

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  • Parazole and isoxazole derivative, preparation method for same and application thereof
  • Parazole and isoxazole derivative, preparation method for same and application thereof
  • Parazole and isoxazole derivative, preparation method for same and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1～5

[0125] Synthesis of 5-(4-substituted arylamide)-1H-pyrazole-3-carboxylic acid ethyl ester II compound (compound II-1);

[0126] (1) Synthesis of 4-(4-nitro)phenyl-2,4-dioxo-butyric acid ethyl ester (intermediate 2)

[0127] In a dry reaction flask, add 400 mL of absolute ethanol and 2.3 g of sodium metal to prepare a sodium ethoxide solution. Add 8.3g of p-nitroacetophenone to the sodium ethoxide solution, stir at room temperature until the solid is completely dissolved, then add 15.74g of diethyl oxalate, react for 6 hours, add acetic acid to adjust the pH to 6.5, and filter with suction to obtain a yellow solid, which is Intermediate 2, dried to obtain 11.7g;

[0128] (2) Synthesis of ethyl 5-(4-nitrophenyl)-1H-pyrazole-3-carboxylate (intermediate 3)

[0129] Intermediate 2 (11.7g, 0.044mol) and hydrazine hydrate (2.6mL, 0.044mol) with a weight concentration of 85% were added to 400% ethanol solution, refluxed for 6 hours, allowed to stand, and filtered to obtain Intermedi...

Embodiment 6～16

[0136] Preparation of Compound II-8:

[0137] Intermediates 2-4 were prepared according to steps (1)-(3) in Example 1, except for step (4);

[0138] (4) Synthesis of target compound 5-(4-benzamidophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (II-8)

[0139] Compound 4 (0.58g, 2.5mol) was added to 50mL of anhydrous ethyl acetate solution, stirred at room temperature until the solid was completely dissolved, then 1.5g of triethylamine was added, and benzoyl chloride (2.5 mol) was reacted for 6 hours, washed with water, and recrystallized from methanol to obtain 0.25 g of a white solid.

[0140] In the 5-(4-substituted arylamide)-1H-pyrazole-3-carboxylic acid ethyl ester compounds of the present invention, II-3, II-4, II-8, II-9 to II-21 are all according to the above prepared in the same way, only using different acid chlorides in step (4), the acid chlorides are respectively n-butyryl chloride, n-pentanoyl chloride, benzoyl chloride, p-fluorobenzoyl chloride, 2,6-difluoro...

Embodiment 17～33

[0142] Synthesis of 5-(4-substituted arylamide)-isoxazole-3-carboxylic acid ethyl ester III compound (III-1):

[0143] (1) Synthesis of 4-(4-nitro)phenyl-2,4-dioxo-butyric acid ethyl ester (intermediate 2)

[0144] In a dry reaction flask, add 400 mL of absolute ethanol and 2.3 g of sodium metal to prepare a sodium ethoxide solution. Add 8.3g of p-nitroacetophenone to the sodium ethoxide solution, stir at room temperature until the solid is completely dissolved, then add 15.74g of diethyl oxalate, react for 6 hours, add acetic acid to adjust the pH to 6, and filter with suction to obtain a yellow solid, which is the intermediate Body 2, dried to obtain 11.7g;

[0145] (2) Synthesis of ethyl 5-(4-nitrophenyl)-1H-pyrazole-3-carboxylate (intermediate 31)

[0146] Intermediate 2 (11.7g, 0.044mol) and hydroxylamine hydrochloride (3.1g, 0.044mol) were added to 400mL of absolute ethanol, refluxed for 6 hours, and filtered to obtain intermediate 3' (7.2g);

[0147] (3) Synthesis of...

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Abstract

The invention discloses a parazole and isoxazole derivative, a preparation method for same and application thereof. The parazole and isoxazole derivative prepared by the method is higher in survivability and specificity and is a novel candidate drug for male contraception in clinic, thereby having higher application value. The parazole and isoxazole derivative is a compound with the general constitutional formula I.

Description

technical field [0001] The invention relates to pharmaceutical compounds, in particular to pyrazole and isoxazole derivatives and their preparation methods and applications. Especially related to 5-(4-substituted aryl amides)-1H-pyrazole-3-carboxylic acid ethyl esters and 5-(4-substituted aryl amides)-isoxazole-3-carboxylic acid ethyl esters and their synthesis and apply. Background technique [0002] At present, the commonly used contraceptive methods in clinical practice are mainly steroidal contraceptives, contraceptive devices, surgical blockade of fallopian tubes or vas deferens, and external contraceptives. For many years, hormonal contraceptives used by women have been used the most. This kind of drugs will interfere with women's normal physiological functions and have many side effects. However, currently available contraceptive methods for men have almost no other effective contraceptives except condoms and vasectomy means. Therefore, it is necessary to speed up ...

Claims

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Application Information

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IPC IPC(8): C07D231/14C07D261/18A61K31/415A61K31/42A61P15/16
Inventor 吕加国祁晶晶朱驹周有骏盛春泉郑灿辉宋云龙章玲刘雪飞丁莉莉韩广乾赵军涛陈倩倩田巍
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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