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Blood brain barrier high-permeability hexokinase inhibitor as well as synthesis method and application thereof

A technology of compounds and hydrates, applied in the directions of organic active ingredients, chemical instruments and methods, active ingredients of heterocyclic compounds, etc., to achieve the effect of improving the permeability of the blood-brain barrier

Pending Publication Date: 2022-05-27
福建金兰厚普生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there have been reports about PKM inhibitors in the treatment of tumors, but there have been no relevant reports in the field of research on the treatment of central nervous system diseases

Method used

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  • Blood brain barrier high-permeability hexokinase inhibitor as well as synthesis method and application thereof
  • Blood brain barrier high-permeability hexokinase inhibitor as well as synthesis method and application thereof
  • Blood brain barrier high-permeability hexokinase inhibitor as well as synthesis method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0098] Specifically, the synthetic method of the present invention comprises:

[0099] The serine methyl ester hydrochloride is reacted with hydrazine hydrate in an alcohol solvent to obtain the amine transesterified compound IM1 serine hydrazide hydrochloride. The reaction time is 12-72h, preferably 24-72h.

[0100] In an inert solvent, the 3,4-position phenolic hydroxyl groups on compound S4 and S3 are ketalized under the catalyst of acid to form a ring to form compound IM3, and then the 2-position phenolic hydroxyl group in compound IM3 is reacted with acid chloride or its analogs. The esterification reaction is carried out to obtain compound IM4 in which all three hydroxyl groups at positions 2, 3, and 4 are protected.

[0101] Compound IM4 and IM1 undergo condensation reaction in alcohol solvent to prepare compound of formula II.

[0102] The compound of formula II undergoes a hydrogenation reaction under the action of a catalyst and hydrogen to obtain a benserazide der...

Embodiment 1

[0133] The synthetic route of the present embodiment is as follows:

[0134]

[0135] Preparation of compound IM1: react serine methyl ester hydrochloride and hydrazine hydrate in methanol solvent for 2 days, and a white solid is precipitated to obtain compound IM1, 1 H NMR (400MHz, D2O) δ3.83 (dt, J=5.6, 4.1Hz, 1H), 3.74–3.73 (m, 1H), 3.71–3.70 (m, 1H), 3.68 (d, J=0.6Hz, 1H), 3.67(d, J=0.6Hz, 1H), 3.65(d, J=0.6Hz, 1H), 3.64(d, J=0.6Hz, 1H).

[0136] Preparation of compound IM2: using trimethyl orthoacetate (80 mmol) as a solvent, p-toluenesulfonic acid monohydrate (4 mmol) as a catalyst, 2,3,4 trihydroxybenzaldehyde (40 mmol) and trimethyl orthoacetate at 110 The reaction was refluxed in a round-bottomed flask at ℃ for 2 days, and a solid was precipitated. The product was subjected to suction filtration, and washed with the filtrate to obtain a white solid, weighing 3.18 g, and the yield was 38% to obtain compound IM2, 1 H NMR (400MHz, CHLOROFORM-D)δ11.03-10.89(m,1H),9.8...

Embodiment 2

[0141] The synthetic route of the present embodiment is as follows:

[0142]

[0143] Preparation of compound IM1: react serine methyl ester hydrochloride and hydrazine hydrate in methanol solvent for 2 days, and a white solid is precipitated to obtain compound IM1, 1 H NMR (400MHz, D2O) δ3.83 (dt, J=5.6, 4.1Hz, 1H), 3.74–3.73 (m, 1H), 3.71–3.70 (m, 1H), 3.68 (d, J=0.6Hz, 1H), 3.67(d, J=0.6Hz, 1H), 3.65(d, J=0.6Hz, 1H), 3.64(d, J=0.6Hz, 1H).

[0144] Compound IM2 was prepared by using trimethyl orthoacetate as a solvent and p-toluenesulfonic acid monohydrate (4 mmol) as a catalyst. The reaction was refluxed in the bottom flask for 2 days, and a solid was precipitated. The product was filtered with suction and washed with the filtrate to obtain a white solid, which weighed 3.18 g and the yield was 38% to obtain compound IM2, 1 H NMR (400MHz, CHLOROFORM-D)δ11.03-10.89(m,1H),9.80-9.68(m,1H),7.48-7.05(m,1H),6.64-6.43(m,1H),3.48-2.91 (m,3H),1.89–1.76(m,3H).

[0145] Preparat...

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Abstract

The invention discloses a blood-brain barrier high-permeability hexokinase inhibitor as well as a synthesis method and application thereof. Wherein the inhibitor has a structure as shown in a formula I. The compound provided by the invention can solve the problems that benserazide molecules have high polarity and have a plurality of phenolic hydroxyl groups, so that the bioavailability is low and the benserazide is difficult to penetrate through a blood-brain barrier. Therefore, the inhibitor disclosed by the invention has the advantages that the cell permeability and bioavailability are remarkably improved, so that the effect of treating the Alzheimer's disease, the Parkinson's disease and the multiple sclerosis is achieved by penetrating through the blood brain barrier, and the inhibitor has a wide application prospect in the field of central nervous system diseases.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a blood-brain barrier high-permeability hexokinase inhibitor and a synthesis method and application thereof. Background technique [0002] Hexokinase (HK) is the first rate-limiting enzyme in glycolysis, and its main function is to catalyze glucose to glucose 6-phosphate, thereby providing a substrate for the generation of glucose 1,6-diphosphate. There are four main subtypes of HK in mammalian cells, namely HK1, HK2, HK3 and HK4. There are some differences in the respective functions of these different subtypes of HK. For example, in human and mouse cells, the phosphorylation of glucose to glucose 6-phosphate is mainly mediated by HK1 and HK2. For different subtypes of HK, the researchers have also screened a variety of inhibitors, some selectively inhibit only one of the HK, and some can inhibit all HK at the same time. [0003] Pyruvate kinase PKM (PKM) is the second key rate-limi...

Claims

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Application Information

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IPC IPC(8): C07D317/46C07D295/205C07C241/04C07C243/34C07C269/00C07C271/44A61P25/00A61P25/28A61P25/16A61K31/5377A61K31/36
CPCC07D317/46C07D295/205C07C241/04C07C243/34C07C269/04C07C269/06C07C271/44A61P25/00A61P25/28A61P25/16
Inventor 袁增强廖亚金宋梦文潘瑞远李硕硕
Owner 福建金兰厚普生物科技有限公司
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