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Application of organic amine derivatives as brain-targeting modification group of small-molecule drug

An organic amine and brain-targeting technology, applied in the field of medicine, can solve the problems of low permeability, limited dosage, complicated preparation process, and many blood-brain barrier complications, and achieves easy mass production, simple connection method, good The effect of applying the foreground

Inactive Publication Date: 2010-09-08
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, intrathecal administration is complicated, intracerebral implantation requires surgery, reversible opening of the blood-brain barrier has many complications, and its application is limited.
The administration method of delivering drugs to the brain through nasal administration is simple and feasible, but it is easy to be cleared by nasal cilia after administration and the low permeability of nasal mucosa to polar drugs limits the amount of administration
Although the nanoparticle brain-targeted drug delivery system encapsulated with Tween-like surfactants can make the loaded drug not limited by its molecular weight and fat-soluble size, the amount of pinocytic vesicles in brain capillary endothelial cells is small and pinocytotic The effect is slow, and the amount of drug that can be transported is low. It is usually only suitable for brain administration of drugs with strong effects such as proteins and peptides.
Although the drug delivery system with monoclonal antibody as the guiding group can achieve a relatively ideal brain-targeting effect, due to the species specificity of these substances, the complicated preparation process, the reduced immune activity and their antigenicity in the body, etc. Its prospects for development are limited

Method used

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  • Application of organic amine derivatives as brain-targeting modification group of small-molecule drug
  • Application of organic amine derivatives as brain-targeting modification group of small-molecule drug
  • Application of organic amine derivatives as brain-targeting modification group of small-molecule drug

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Ibuprofen is heated to reflux reaction at 60° C. in excess thionyl chloride solution until no hydrogen chloride gas overflows. After the reaction, excess thionyl chloride was removed by distillation under reduced pressure to obtain ibuprofenyl chloride, which was directly used in the following reaction.

Embodiment 2

[0064] Synthesis of 2-methylaminoethanol-ibuprofen ester (II)

[0065] Dissolve 0.5g (7.0mmol) of 2-(methylamino)ethanol and 0.28g (7.0mmol) of sodium hydroxide in 10.0ml of methanol, add 1.90g (8.6mmol) of BOC anhydride under stirring, and continue stirring at room temperature Reaction 5h, stop the reaction. Spin to dry under reduced pressure, the residue was separated by silica gel H flash column, dichloromethane:methanol (20:1) was eluted, and the collected solution was concentrated under reduced pressure to obtain 0.86 g of a colorless oily liquid, which was N-(methyl)-β - tert-butyl hydroxyethyl carbamate, yield 71.1%.

[0066] Dissolve 0.7g (4.1mmol) tert-butyl N-(methyl)-β-hydroxyethylcarbamate in 10ml of dichloromethane, slowly add 1.10g (4.9mmol) ibuprofenyl chloride dropwise under stirring, dropwise After completion, 0.50 g (4.9 mmol) of triethylamine was added dropwise, and stirring was continued at room temperature for 4.5 h to stop the reaction. Spin to dry und...

Embodiment 3

[0071] Synthesis of 2-dimethylaminoethanol ibuprofen ester (III)

[0072] Dissolve 1.30g (14.6mmol) of N,N-dimethylethanolamine and 5ml of triethylamine in 10ml of dichloromethane, and slowly add 2.24g (10mmol) of ibuprofenyl chloride dropwise under ice-bath conditions, and the addition is complete Afterwards, the reaction was continued at room temperature for 4 h, extracted three times with dichloromethane, and the dichloromethane solution was combined. The organic layer was washed with aqueous sodium bicarbonate and aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Flash column separation, eluting with dichloromethane:methanol (20:1), concentrated the collected solution under reduced pressure to obtain 2.32 g (83.7%) of a colorless oily liquid

[0073] 1HNMR (400MHz, CDCl3): 7.178 (d, 2H, J=8.8Hz, 2'-H, 6'-H), 7.059 (d, 2H, J=8.0Hz, 3'-H, 5'-H) , 4.191-4.107(m, 2H, CH2CH2OCO), 3.660-3.720(m, 1H, COCHCH3), 2.503(...

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Abstract

The invention discloses an application of organic amine derivatives as the brain-targeting modification group of small-molecule drug and further relates to an organic amine compound having the structure thereof as shown in formula (I), and a preparation method thereof, wherein part B is particularly a central-active drug D, and part A is particularly the targeting modification group of organic amine derivatives. The organic amine compound having the structure as shown in formula (I) and targeting on the brain can significantly increase the aggregation concentration of the drug of the part B on the brain, extend the aggregation time thereof at the brain or improve the effect thereof on the brain.

Description

technical field [0001] The present invention relates to the field of medicine, and more specifically relates to the use of organic amine derivatives as small molecular drug brain-targeting modification groups, and further relates to brain-targeting organic amine compounds and their preparations and preparation methods. Background technique [0002] Central nervous system (CNS) diseases, such as brain tumors, Alzheimer's disease, Parkinson's syndrome, etc., are a large class of diseases that threaten human health. However, due to the special anatomical and physiological properties of the brain, there is mainly a blood-brain barrier (blood brain barrier, BBB) between the blood and the brain tissue, so that more than 98% of the drugs cannot reach the brain tissue effectively through the BBB, and drugs can treat CNS diseases. Often the curative effect is unsatisfactory. It is of great scientific significance and practical demand to study new methods and new drugs for the treatm...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K9/00A61K45/00C07C237/08C07C219/10A61P25/00A61P25/28A61P35/00A61P25/16A61K47/54
Inventor 张志荣龚涛孙逊张宣赵栋刘兴
Owner SICHUAN UNIV
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