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Preparation method and application of glutaminylcyclase (QC) inhibitor

A glutaminyl cyclase and inhibitor technology, which is applied in the field of preparation of glutaminyl cyclase inhibitors, can solve the problems of cumbersome synthesis steps, single parent structure, limited activity, etc., and achieve high yield, The process route is simple and feasible, suitable for the effect of large-scale preparation

Active Publication Date: 2016-03-09
SHENZHEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a preparation method and application of a glutaminyl cyclase inhibitor, aiming to solve the existing QC inhibitors which have a single parent structure, poor water solubility, cross-linking Poor membrane performance, limited activity, cumbersome synthesis steps, etc.

Method used

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  • Preparation method and application of glutaminylcyclase (QC) inhibitor
  • Preparation method and application of glutaminylcyclase (QC) inhibitor
  • Preparation method and application of glutaminylcyclase (QC) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Example 1: N-(3-(1H-imidazol-1-yl)propyl)-3',4'-dimethoxy-[1,1'-biphenyl]-2-amine (MQI-1 ), its synthetic route is as follows:

[0041]

[0042] a, 3',4'-dimethoxy-[1,1'-biphenyl]-2-amine: bromoaniline (5.81mmol, 1 equivalent), 3,4-dimethoxyphenylboronic acid (6.98 mmol, 1.2 equivalents) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.35mmol, 0.06 equivalents) were placed in a 50ml round bottom flask , respectively add 10ml of dioxane and 10ml of 2mol / LK 2 CO 3 Solution, 100 ° C, reflux for 3h. Add saturated NaCl solution to quench the reaction, cool to room temperature, extract three times with ethyl acetate, wash once with saturated NaCl solution after combining, anhydrous NaCl 2 SO 4 After drying, the product was collected by silica gel column chromatography with a yield of 90%.

[0043] b. N-(3-bromopropyl)-3',4'-dimethoxy-[1,1'-biphenyl]-2-amine: 3',4'-dimethoxy-[1 ,1'-biphenyl]-2-amine (872.32umol, 1 equivalent)...

Embodiment 2

[0045] Example 2: 4'-fluoro-N-(3-(4-methyl-1H-imidazol-1-yl)propyl)-[1,1'-biphenyl]-2-amine (MQI-31) The synthesis of its synthetic route is as follows:

[0046]

[0047] a, 4'-fluoro-[1,1'-biphenyl]-2-amine: bromoaniline (5.81mmol, 1 equivalent), 4-fluorophenylboronic acid (6.98mmol, 1.2 equivalents) and [1,1' -Bis (diphenylphosphine) ferrocene] palladium dichloride (II) dichloromethane complex (0.35mmol, 0.06 equivalent) is placed in 50ml round bottom flask, solvent is 10ml dioxane and 10ml2mol / LK 2 CO 3 solution, at 100°C, stirred for 3 h, added saturated NaCl solution to quench the reaction, extracted three times with ethyl acetate, combined and washed once with saturated NaCl solution, anhydrous NaCl 2 SO 4 After drying, the product was collected by silica gel column chromatography with a yield of 94%.

[0048] b. N-(3-bromopropyl)-4'-fluoro[1,1'-biphenyl]-2-amine: 4'-fluoro-[1,1'-biphenyl]-2-amine (534.15 umol, 1 equivalent) and 1,3-dibromopropane (3.74mmol, 7 ...

Embodiment 3

[0050] Embodiment 3: QC inhibitor is tested to QC enzyme inhibitory activity

[0051] The schematic diagram of the QC enzyme inhibition activity test principle is as follows: figure 1 shown. The enzyme activity test was carried out in a 96-well microtiter plate, using 200ul pH8.0 Tris buffer system: 0.3mM NADH, 2.0mM freshly prepared Gln-Gln, 14mM α-ketoglutarate, 30U / ml glutamate dehydrogenase, 50mM Tris, pH8 .0 buffer solution, and finally add 0.28 μM recombinant human QC protein and the mixture of different concentrations of inhibitors, shake for 30 seconds, and use a microplate reader to dynamically detect the change in the absorption value of NADH at 340nm wavelength within 15 minutes at 25°C, every 30s Once the data is collected, according to the test results, calculate the IC of the inhibition effect of the inhibitor on the QC enzyme activity 50 Value, the test result for different QC inhibitors is shown in table 1, wherein the structural formula of QC inhibitors is: ...

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Abstract

The invention discloses a preparation method and application of a glutaminylcyclase (QC) inhibitor. The preparation method comprises the of following steps that (1) raw materials of a unit A including a borate group, amino and R1 and raw materials of a unit B including a bromine substituent group and R2 serving as starting materials are subjected to a Suzuki coupling reaction to prepare a unit A and unit B coupled intermediate; (2) the unit A and unit B coupled intermediate and a dibromoalkyl chain serving as raw materials are subjected to an SN2 reaction to prepare an intermediate containing an alkyl chain; and (3) the intermediate containing the alkyl chain and imidazole or substituent-containing imidazole serving as raw materials are subjected to the SN2 reaction to prepare the QC inhibitor. The preparation method can be completed only by means of Suzuki coupling, SN2 reaction and the like, is simple and feasible in process route and high in yield, and is more suitable for large-scale preparation; and the QC inhibitor can be widely applied to development of new high-efficient QC inhibitor drugs, development of drugs, innovative drugs and diagnostic kits for alzheimer disease (AD) and other QC specifically highly expressed related diseases, and the like.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method and application of a glutaminyl cyclase inhibitor. Background technique [0002] Glutaminylcyclase (Glutaminylcyclase, QC, EC2.3.2.5) is an enzyme that can catalyze the intramolecular cyclization reaction of N-terminal glutamine residues such as polypeptides and proteins to generate pyroglutamic acid (pGlu). In 1963, QC was first discovered in the latex of the tropical plant papaya (Caricapapaya), and later studies confirmed that QC is distributed in plants, animals, and microorganisms. Mammalian QC is highly conserved and has no sequence homology with papaya QC, but has significant sequence homology with bacterial aminopeptidase, so animal and plant QC have different evolutionary origins. In plants, the physiological function of QC is not very clear, and it may play a certain role in the process of plant defense against pathogenic microorganisms. QC in a...

Claims

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Application Information

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IPC IPC(8): C07D233/61A61K31/417A61P25/28
CPCC07D233/61
Inventor 吴海强董瑶邹永东郑易之李满满刘志刚贺震旦余熙
Owner SHENZHEN UNIV
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