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Sarsasapogenin derivative and preparation method as well as application thereof

A technology of smilagenin and derivatives, which is used in the application field of treating neurodegenerative diseases

Inactive Publication Date: 2018-06-05
SHENYANG PHARMA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

So far, there is no report about it and its derivatives treating neurodegenerative diseases

Method used

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  • Sarsasapogenin derivative and preparation method as well as application thereof
  • Sarsasapogenin derivative and preparation method as well as application thereof
  • Sarsasapogenin derivative and preparation method as well as application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: Synthesis of (22R,25S)-3β-benzyloxy-26-piperidinyl-5β-furostane (ZA-3-6)

[0055] Synthesis of A.a: Add smilagenin (4.16g, 0.01mol) and NaH (0.48g, 0.02mol) to a 250mL eggplant-shaped bottle, add benzyl bromide (3.42g, 0.02mol) to 40mL DMF while stirring at room temperature, 40 °C and the reaction was stirred until the reaction was complete. After the reaction was complete, let it cool, then add about 10 times the amount of water, stir, and filter with suction to obtain a solid, which was recrystallized from ethanol to obtain a white solid ZA-1 (3.8 g, yield 75%). 1 H NMR (300MHz, CDCl 3 ,δ):7.35(m,2H,H-2′,6′),7.33(m,2H,H-3′,5′),7.28(m,1H,H-4′),4.51(d, J=12.3Hz, 1H, Ar-CH 2 ), 4.46 (d, J=12.3Hz, 1H, Ar-CH 2 ),4.40(m,1H,H-16),3.96(dd,J=2.6,11.0Hz,1H,H-26),3.71(br.s,1H,H-3),3.30(d,J= 11.0Hz, 1H, H-26), 1.08(d, J=7.1Hz, 3H, 27-CH 3 ),0.99(d,J=6.8Hz,3H,21-CH 3 ),0.97(s,3H,19-CH 3 ),0.76(s,3H,18-CH 3 ). 13 C NMR (100MHz, CDCl 3 ,δ):139.6,128.4,128.4,127...

Embodiment 2

[0059] Example 2: Synthesis of (22R,25S)-3β-benzyloxy-26-diethylamino-5β-furostane (ZA-3-2)

[0060] The preparation steps were the same as in Example 1, except that the reaction reagent in step D was replaced with diethylamine to obtain oil ZA-3-2 (0.34 g, 60.6%). 1 H NMR (300MHz, CDCl 3 ,δ):7.35(m,2H,H-2′,6′),7.32(m,2H,H-3′,5′),7.26(m,1H,H-4′),4.50(d, J=12.3Hz, 1H, Ar-CH 2 ), 4.45 (d, J=12.3Hz, 1H, Ar-CH 2 ),4.28(td,J=7.7&5.0Hz,1H,H-16),3.70(br.s,1H,H-3),3.30(m,1H,H-22),2.46(m,4H, N-CH 2 ),1.00(s,3H,19-CH 3 ),0.97(m,9H,3×CH 3 ), 0.90 (d, J=6.3Hz, 3H, 27-CH 3 ),0.79(s,3H,18-CH 3 ). 13 C NMR (100MHz, CDCl 3 ,δ):139.5,128.3,128.3,127.3,127.3,127.2,90.5,83.3,73.8,69.5,65.6,60.2,57.0,47.6,47.6,41.1,40.2,40.0,37.9,37.1,35.5,35.1,32.3, 31.8, 31.0, 30.8, 30.5, 26.7, 26.5, 24.7, 23.9, 20.8, 19.2, 18.5, 16.6, 11.7, 11.7. ESI-HRMS: m / z 564.4765 [M+H] + (Calcd for C 38 h 62 NO 2 ,564.4775).

Embodiment 3

[0061] Example 3: Synthesis of (22R,25S)-3β-benzyloxy-26-di-n-propylamino-5β-furostane (ZA-3-3)

[0062] The preparation steps were the same as in Example 1, except that the reaction reagent in step D was replaced with di-n-propylamine to obtain oil ZA-3-3 (0.43 g, 73.2%). 1 H NMR (400MHz, CDCl 3 ,δ):7.35(m,2H,H-2′,6′),7.32(m,2H,H-3′,5′),7.26(m,1H,H-4′),4.50(d, J=12.2Hz, 1H, Ar-CH 2 ), 4.46 (d, J=12.2Hz, 1H, Ar-CH 2 ),4.29(td,J=5.1,7.7Hz,1H,H-16),3.70(br.s,1H,H-3),3.30(m,1H,H-22),2.32(m,4H, N-CH 2 ), 0.99 (d, J=6.7Hz, 3H, 21-CH 3 ),0.97(s,3H,19-CH 3 ), 0.90 (d, J=6.4Hz, 3H, 27-CH 3 ), 0.86(t, J=7.3Hz, 6H, 2×CH 3 ),0.78(s,3H,18-CH 3 ). 13 C NMR (100MHz, CDCl 3 ,δ):139.5,128.3,128.3,127.3,127.3,127.2,90.5,83.2,73.8,69.5,65.6,61.6,57.0,56.8,56.8,41.1,40.2,40.0,37.8,37.0,35.5,35.1,32.2, 32.1, 31.8, 30.9, 30.8, 30.5, 26.7, 26.5, 24.7, 23.9, 20.8, 20.1, 20.1, 19.2, 18.4, 16.6, 12.0, 12.0. ESI-HRMS: m / z 592.5095 [M+H] + (Calcd for C 40 h 66 NO 2 ,592.5088).

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Abstract

The invention belongs to the technical field of medicinal chemistry and particularly relates to a sarsasapogenin derivative and a preparation method as well as application thereof. The compound has structures shown in formulae I, II, III, IV, V, VI and VII as shown in the specification. Through the proof of a molecular level experiment, a cellular level experiment, and an APP transgenic mouse place navigation and space exploration experiment, the compound can improve the spatial learning memory capability of model mice, and has a good effect of treating degenerative diseases of nervous systems.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to smilagenin derivatives, pharmaceutical compositions using them as active ingredients, their preparation methods and their application in treating neurodegenerative diseases. Background technique [0002] Neurodegenerative diseases are caused by the loss of neurons or their myelin, which worsen with age and eventually lead to dysfunction, such as Alzheimer's disease (AD), Parkinson's disease (PD), muscular dystrophy Lateral sclerosis (ALS) and Huntington's disease (HD), etc. Neurodegenerative diseases mainly affect the cognitive and motor functions of patients, causing disability and high mortality, which bring great psychological and economic burdens to patients' families and society. However, due to unclear etiology and complicated pathogenesis, the current Some therapeutic drugs and methods can only temporarily improve the symptoms, and there is still a...

Claims

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Application Information

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IPC IPC(8): C07J71/00A61K31/58A61P25/00
CPCC07J71/00
Inventor 宋少江王文豹李明华李明杰彭缨王泽丹王绍杰
Owner SHENYANG PHARMA UNIVERSITY
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