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16-site substituted double functional group huperzine b derivative, preparation method and use thereof

A technology of huperzine B and derivatives, which is applied in the fields of medicinal chemistry and pharmacotherapeutics to achieve the effects of high therapeutic index, strong inhibitory effect and small side effects

Inactive Publication Date: 2008-06-04
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the acetylcholinesterase inhibitor drugs currently on the market for the treatment of AD have certain side effects, the development of new acetylcholinesterase inhibitors is still an interesting research goal for drug workers around the world.

Method used

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  • 16-site substituted double functional group huperzine b derivative, preparation method and use thereof
  • 16-site substituted double functional group huperzine b derivative, preparation method and use thereof
  • 16-site substituted double functional group huperzine b derivative, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1: Preparation of N, N'-dimethyl-N-(p-fluorobenzyl)-N'-(16-huperzine B)-1,12-dodecanediamine (I B -4)

[0062] a step reaction:

[0063] 512mg of HupB, 12ml of dichloromethane, and 1.2ml of pyridine were added to a 25ml round bottom flask, and 1.2ml of trifluoroacetic anhydride was added dropwise at 0°C. After several hours, the reaction was stopped, and a small amount of water was added to decompose the excess trifluoroacetic anhydride, the layers were separated, and the aqueous layer was washed twice with dichloromethane (5ml×2). Combine dichloromethane, wash with water, and dry over anhydrous sodium sulfate. Silica gel column chromatography. The product N-(trifluoroacetyl)-huperzine B was 700mg, and the yield was 99%.

[0064] IR (KBr): 3398, 2960, 2890, 1697, 1654, 1604, 1432, 1228, 1195, 1105, 833, 644.

[0065] Step b reaction:

[0066] Add 719 mg of N-(trifluoroacetyl)-huperzine ethyl chloroform solution in a 50 ml round bottom flask, add 600 mg of ...

Embodiment 2

[0082] Example 2: Preparation of N, N'-dimethyl-N-(p-fluorobenzyl)-N'-(16-huperzine B)-1,10-decanediamine (I B -3)

[0083] N,N'-Dimethyl-N-(p-fluorobenzyl)-1,10-decanediamine and 16-formyl huperzine II C According to the conditions of step d, the compound N, N'-dimethyl-N-(p-fluorobenzyl)-N'-(O-methyl-16-huperzine B)-1,10-decane Diamine, react according to the conditions of step e to obtain N, N'-dimethyl-N-(p-fluorobenzyl)-N'-(16-huperzine B)-1,10-decanediamine.

[0084] [α] D 20 =-31.2 (c=0.48, CHCl 3 ).

[0085]IR (KBr): 2926, 2852, 2789, 1658, 1616, 1508, 1456, 1221, 1095, 833, 663.

[0086] 1 HNMR (400MHz, CDCl 3 ): 8.02 (1H, d, J = 9.5Hz), 7.36-7.32 (2H, m), 7.03-7.00 (2H, m), 6.50 (1H, d, J = 9.4Hz), 5.70 (1H, d, J=4.5Hz), 3.64(2H, s), 3.07(1H, d, J=11.0Hz), 2.95(1H, dd, J=17.7Hz, J=4.5Hz), 2.88(1H, d, J= 12.9Hz), 2.75(1H, d, J=12.8Hz), 2.58-2.46(5H, m), 2.30(3H, s), 2.18(2H, br), 2.10(1H, J=12.0Hz), 2.02 (3H, s), 1.86 (1H, br), 1.69-1.55 (5H, m), 1.39-1.14 ...

Embodiment 3

[0088] Example 3: Preparation of N, N'-dimethyl-N-(p-fluorobenzyl)-N'-(16-huperzine B)-1,8-octacarbondiamine (I B -2)

[0089] N, N'-dimethyl-N-(p-fluorobenzyl)-1,8-octacarbondiamine and 16-formyl huperzine II C Reaction according to the conditions of step d, the compound N, N'-dimethyl-N-(p-fluorobenzyl)-N'-(O-methyl-16-huperzine B)-1,8-octacarbon Diamine, react according to the conditions of step e to obtain N, N'-dimethyl-N-(p-fluorobenzyl)-N'-(16-huperzine ethyl)-1,8-octacarbon diamine.

[0090] [α] D 20 =-45.1 (c=1.5, CHCl 3 ).

[0091] IR (KBr): 2927, 2854, 2789, 1658, 1616, 1508, 1458, 1221, 1097, 833, 756.

[0092] 1 HNMR (400MHz, CDCl 3 ): 7.79 (1H, d, J = 9.6Hz), 7.28-7.24 (2H, m), 7.00-6.59 (2H, m), 6.64 (1H, d, J = 9.4Hz), 5.23 (1H, d, J=5.2Hz), 3.46(2H, s), 2.90(1H, dd, J=17.9Hz, J=5.2Hz), 2.83(1H, d, J=12.4Hz), 2.76(1H, d, J= 12.6Hz), 2.69(1H, d, J=12.5Hz), 2.63(1H, d, J=12.6Hz), 2.49(1H, d, J=17.8Hz), 2.43(1H, br) 2.37-2.30( 3H, m), 2.16 (3H, s), 2.15...

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Abstract

The invention relates to a huperzine B derivative with 16 substituted dual function groups and the preparation method and application thereof. The derivative adopts the huperzine B as a lead compound and is obtained by the steps that 16-methyl is first oxidated to aldehyde group and then treated with reductive amination with substitution amine compounds. The derivative provided in the invention also expresses higher inhibitory activity of acetylcholinesterase than that of the lead compound of the huperzine B in a test of vitro bioactivity. The huperzine B derivative with 16 substituted dual function groups has relatively strong inhibiting effect on butyrylcholine esterase and is expected to become a candidate drug with high therapeutic index and little side effect to treat degenerative brain disorder after further optimization and screening.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry and pharmacotherapeutics, and relates to a dual inhibitor of acetylcholinesterase and butyrylcholinesterase. More specifically, the invention relates to a 16-position substituted bifunctional group huperzine B derivative, Its preparation method and its use. Background technique [0002] Alzheimer's disease (AD), also known as Alzheimer's disease, is a progressive cognitive impairment whose incidence increases with age. According to statistics, the prevalence rate of the elderly over the age of 65 is 5%, while the prevalence rate of the elderly over the age of 80 is as high as 20%. The degeneration of the cerebral cortex in patients leads to loss of normal activities, including memory and judgment decline, lack of reasoning ability and slow behavior. Once the ability to live independently is lost, it will bring a heavy mental and economic burden to the family. [0003] AD is a disease caused b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/08A61K31/439A61K31/497A61P25/28C07D211/00
Inventor 何煦昌白东鲁施玉芳唐希灿傅燕
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI