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Compound with anti-alzheimer's disease activity and preparation method thereof

A technology for Alzheimer's disease and compounds, which is applied in the field of drug synthesis, can solve the problems of difficult preparation, structural modification of C-5 position-structure-activity relationship research has not been carried out, etc., and achieves the effect of simple process route.

Inactive Publication Date: 2015-12-23
NORTHWEST A & F UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although many units have carried out a lot of research, unfortunately due to many factors such as the difficulty of its preparation, the structural modification of its C-5 position-structure-activity relationship research has not yet been carried out

Method used

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  • Compound with anti-alzheimer's disease activity and preparation method thereof
  • Compound with anti-alzheimer's disease activity and preparation method thereof
  • Compound with anti-alzheimer's disease activity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Synthesis of (R)-3-((R)-4,5-bis(tert-butyldimethylsilyloxy)pentanol)-4-phenyloxazolidin-2-one (Compound 2)

[0044] Dissolve compound 1 (10.0g, 26.5mmol) in 120mL tetrahydrofuran and 40mL water, add lithium hydroxide monohydrate (3.4g, 79.6mmol), stir at room temperature for 12 hours, extract with ethyl acetate, concentrate, dissolve in 100mL tetrahydrofuran , cooled to -78°C, added triethylamine (7.3mL, 53mmol), pivaloyl chloride (3.8g, 31.8mmol), oxazolidinone (4.7g, 26.5mmol) and anhydrous lithium chloride (3.4g, 79.6 mmol), reacted at natural temperature for 10 hours, quenched with water, extracted with ethyl acetate, dried, concentrated, and purified by silica gel column to obtain white solid 2 (9.6 g, 69%).

[0045] 1 HNMR (400MHz, CDCl 3 )δ7.38-7.22(m,5H),4.72-4.65(m,1H),4.25-4.15(m,2H),3.84-3.77(m,1H),3.61(dd,J=10.0,5.2Hz, 1H), 3.48(dd, J=10.0, 6.4Hz, 1H), 3.35(dd, J=13.2, 3.2Hz, 1H), 3.14-2.97(m, 2H), 2.77(dd, J=13.2, 9.6Hz ,1H),2.10-2.00(m,1H),1.82-1.72(m,...

Embodiment 2

[0069] The preparation method of compound 1b refers to the preparation method of L-685-4581a.

[0070] tert-Butyl

[0071] (1S,2R,4R)-4-(((S)-1-((S)-1-amino-1-oxo-3-phenylpropan-2-ylamino)-4-methyl-1-oxopentan-2- yl)carbamoyl)-2-hydroxy-1,5-diphenylpentylcarbamate (1b)

[0072] 1 HNMR (400MHz, CD 3 OD)δ7.32-7.13(m,15H),4.63-4.59(m,1H),4.58-4.47(m,2H),4.22(dd,J=10.0,5.6Hz,1H),3.90-3.80(m ,1H),3.14(dd,J=14.0,6.0Hz,1H),2.90-2.76(m,3H),2.70-2.62(m,1H),1.72-1.56(m,2H),1.54-1.34(m ,11H),1.33-1.25(m,1H),0.92-0.86(m,3H),0.86-0.78(m,3H)ppm.

Embodiment 3

[0074] The preparation method of compound 1c refers to the preparation method of L-685-4581a.

[0075] tert-Butyl

[0076] (1S,2R,4R)-5-((S)-1-((S)-1-amino-1-oxo-3-phenylpropan-2-ylamino)-4-methyl-1-oxopentan-2-ylamino )-4-benzyl-1-cyclopropyl-2-hydroxy-5-oxopentylcarbamate (1c)

[0077] 1 HNMR (400MHz, CD 3 OD)δ7.10-6.96(m,10H),4.43-4.38(m,1H),4.34(dd,J=8.4,6.0Hz,1H),4.00(dd,J=8.6,5.6Hz,1H), 3.50-3.40(m,1H),2.95(dd,J=14.0,6.0Hz,1H),2.74-2.62(m,3H),2.58-2.47(m,2H),1.74-1.55(m,2H), 1.37-1.07(m,13H),0.76-0.65(m,4H),0.64-0.57(m,3H),0.24-0.10(m,2H),0.05--0.04(m,1H),-0.05-- 0.14(m,1H)ppm.

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Abstract

The invention discloses a compound with anti-alzheimer's disease activity which has a structure in formula (I), and the substituent R of the compound represents C1-C6 alkyl group, cycloalkyl group or aryl group. By structurally transforming the C-5 site of L-685-458, the method is adopted for the first time to successfully prepare the L-685-458, synthesize five types of new L-685-458 analogues, which have the advantages of high yield, easiness in separation, low cost, convenient production expansion and the like. Inferred according to the activity of the compound L-685-458, the five types of new L-685-458 analogues ought to have the anti-alzheimer's disease activity, and therefore have the prospect of being developed into anti-alzheimer's disease medicines.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and specifically relates to various compounds with anti-senile dementia activity. The invention also provides the preparation methods of these compounds. Background technique [0002] Alzheimer's disease, also known as Alzheimer's disease (Alzheimer's disease, AD), is a heterogeneous disease with multiple pathogenesis, a neurodegenerative disease with characteristic neuropathological and neurochemical changes. The etiology and pathogenesis of Alzheimer's disease have not been clarified so far. The current research is mainly on the abnormal phosphorylation of tubulin TAU to form double helix fiber tangles, the abnormal hydrolysis and misfolding of amyloid precursor (APP) in the membrane, and the formation of abnormalities on chromosomes. Caused by mutations in certain genes. The American Psychiatric Association defines dementia in the Diagnostic and Statistical Manual as an organic mental...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07K1/10C07K1/02A61P25/28
Inventor 杜振亭司长梅毛卓亚韩盼魏邦国
Owner NORTHWEST A & F UNIV
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