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Glutamine acyl cyclase isoenzyme inhibitor as well as preparation method and application thereof

A technology of glutaminyl cyclase isoenzyme and inhibitor is applied in the field of glutaminyl cyclase isoenzyme inhibitor and preparation thereof, and can solve the problems of poor drugability of leading compounds, insufficient compounds and diverse molecular structures It can solve the problems of limited properties, etc., to achieve the effect of simple and feasible preparation method, easy availability of raw materials, and expansion of molecular structure diversity.

Active Publication Date: 2022-08-09
SHENZHEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a glutaminyl cyclase isoenzyme inhibitor and its preparation method and application, aiming to solve the existing iso-QC inhibitor compound deficiency, molecular structure Issues such as limited diversity, low molecular activity, and poor druggability of lead compounds

Method used

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  • Glutamine acyl cyclase isoenzyme inhibitor as well as preparation method and application thereof
  • Glutamine acyl cyclase isoenzyme inhibitor as well as preparation method and application thereof
  • Glutamine acyl cyclase isoenzyme inhibitor as well as preparation method and application thereof

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preparation example Construction

[0033] In some embodiments, also provide a kind of preparation method of glutaminyl cyclase isoenzyme inhibitor, it comprises the steps:

[0034] added to the reaction solvent Oxalyl chloride solution and DMF are reacted for the first predetermined time to obtain

[0035] Will And the triethylamine solution is added in the reaction solvent, and the reaction is carried out for the second predetermined time to obtain

[0036] added to the reaction solvent Copper acetate monohydrate and triethylamine solution are reacted for a third predetermined time to prepare the glutaminyl cyclase isoenzyme inhibitor.

[0037] In this embodiment, the The preparation includes the following steps: adding to the reaction solvent as well as Reaction for the fourth predetermined time, obtained Will Dissolve in the reaction solvent, add NaOH, react for the fifth predetermined time, add HCl, and prepare added to the reaction solvent AcOH and 30% hydrogen peroxide solution wer...

Embodiment 1

[0044] Preparation of 4-((4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)sulfonyl)-N-phenylaniline:

[0045] a. Add 10.05mmol of 4-(hydrazine carbonyl)piperidine-1-carboxylate tert-butyl ester and 12.03mmol of isothiocyanatomethane to 20mL of anhydrous EtOH, and reflux at 80°C for 3h. , and dried to obtain a white solid which is 4-(2-(methylaminomethylthio)hydrazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester with a yield of 97%.

[0046] b. 9.75mmol of 4-(2-(methylaminomethylthio)hydrazine-1-carbonyl)piperidine-1-carboxylate tert-butyl ester and 19.57mmol of NaOH were added to 20mL of water, and the reaction was carried out under reflux at 100°C for 2h. Let stand for cooling, add 4 mL of concentrated hydrochloric acid dropwise, stir at room temperature for 10 min, suction filtration, and dry the obtained white solid, which is 4-(4-methyl-5-sulfoxy-4,5-dihydro-1H-1,2, 4-Triazol-3-yl)piperidine-1-carboxylate tert-butyl ester, 85% yield.

[0047] c. 20mL CH 2 C...

Embodiment 2

[0053] 3,4-Dimethoxy-N-(4-((4-(4-methyl-4H-1,2,4-triazol-3-yl)piperidin-1-yl)sulfonyl)benzene Base) the preparation of aniline:

[0054] a. Add 10.01 mmol of 4-(hydrazine carbonyl) piperidine-1-carboxylic acid tert-butyl ester and 12.04 mmol of isothiocyanatomethane to 20 mL of anhydrous EtOH, and react at 80° C. for 4 h under reflux. , and dried to obtain a white solid which is 4-(2-(methylaminomethylthio)hydrazine-1-carbonyl)piperidine-1-carboxylic acid tert-butyl ester with a yield of 98%.

[0055] b. 9.81mmol of 4-(2-(methylaminomethylthio)hydrazine-1-carbonyl)piperidine-1-carboxylate tert-butyl ester and 20.23mmol of NaOH were added to 20mL of water, and the reaction was performed under reflux at 100°C for 2h. Let stand for cooling, add 4 mL of concentrated hydrochloric acid dropwise, stir at room temperature for 10 min, suction filtration, and dry the obtained white solid, which is 4-(4-methyl-5-sulfoxy-4,5-dihydro-1H-1,2, 4-Triazol-3-yl)piperidine-1-carboxylate tert-b...

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Abstract

The invention provides a glutamine acyl cyclase isoenzyme inhibitor as well as a preparation method and application thereof, the glutamine acyl cyclase isoenzyme inhibitor is a compound with a novel structural framework, and the preparation method of the novel inhibitor provided by the invention has the advantages that the raw materials are easy to obtain, and the preparation method is simple and feasible. According to the inhibitor provided by the invention, the molecular structure diversity of the glutamine acyl cyclase isoenzyme inhibitor is obviously expanded; the method can be widely applied to preparation of medicines for treating diseases related to high-specificity expression of the glutaminyl cyclase isoenzyme and preparation of kits for diagnosing the diseases related to high-specificity expression of the glutaminyl cyclase isoenzyme.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a glutaminyl cyclase isoenzyme inhibitor and a preparation method and application thereof. technical background [0002] Glutaminyl cyclase (QC) is an enzyme that catalyzes the intramolecular cyclization of N-terminal glutamic acid / glutamine of polypeptides and proteins to generate pyroglutamic acid (pE). Important biological functions such as chemical structure, regulation of biological functions, and enhancement of stability. However, in recent years, many studies have confirmed that the abnormally high expression of QC is directly involved in the occurrence and development of a variety of complex diseases, including neurodegenerative diseases, inflammation, and malignant tumors. [0003] There are two forms of QC in vivo, secretory QC and Golgi QC (iso-enzyme, iso-QC), both of which have similar structural characteristics and substrate selectivity, but abnormal QC...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07D405/14C07D409/14C07D401/14C07D411/14A61P29/00A61P35/00A61K31/454A61K31/4545A61K31/506
CPCC07D401/04C07D405/14C07D409/14C07D401/14C07D411/14A61P29/00A61P35/00
Inventor 吴海强蔡嘉欣魏定钧秦菲霞许晨舒李晨阳熊炜王亦男
Owner SHENZHEN UNIV
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