Smilax sapogenin derivative and preparation and applications thereof

Abstract

The invention relates to a synthetic method and medical applications of a natural medicine rhizoma anemarrhenae smilax sapogenin structure derivative for resisting senile dementia. The high-purity rhizoma anemarrhenae sapogenin is used as a prodrug, and is subjected to structural modification methods such as inversion of configuration, oxidation, ammoniation, different degrees and locations of ring opening to increase the druggability, and pharmacology proves that the rhizoma anemarrhenae sapogenin has activity resisting senile dementia. The new application of the rhizoma anemarrhenae sapogenin and derivatives thereof in preparation of the medicine for resisting senile dementia is developed through the pharmacological activity.

Description

technical field

[0001] The invention belongs to the technical field of medicine, and relates to smilagenin derivatives and a preparation method and application thereof, in particular to the application of smilagenin derivatives in anti-senile dementia and antidepressant drugs. Background technique

[0002] Alzheimer's disease (Alzheimer's disease) is the so-called senile dementia. It is a fatal neurodegenerative disease with progressive development. The clinical manifestations are deteriorating cognitive and memory functions, progressive decline in daily life ability, and various neuropsychiatric symptoms and behavioral disturbances.

[0003] It is a group of primary degenerative brain diseases of unknown etiology. Most of the onsets are in old age, the onset is insidious, the course of the disease is slow and irreversible, and the main clinical manifestation is intellectual impairment. The main pathological changes are diffuse atrophy of the cortex, widening of the sulci,...

Examples

Embodiment 1

[0037] Example 1 Preparation of Epismilagenin

[0038] (1) Add smilagenin (4.16g, 10mmol), benzoic acid (2.44g, 20mmol), Ph 3 P (5.24g, 20mmol), 50ml of dry THF, DIAD (4.04g, 20mmol) dissolved in 20ml of dry THF was added dropwise with stirring at room temperature, and the reaction was completed at room temperature for 24h. After the reaction was completed, evaporate to dryness under reduced pressure, add water, stir, filter with suction, put on a silica gel column, wash away impurities with petroleum ether, and wash with petroleum ether: ethyl acetate (80:1) to obtain an intermediate product, the structure identification data is as follows:

[0039] m / z: [M+H] + =521.3620, 1 H-NMR (300MHz, CDCl 3 ): δ 8.05(2H, m, H-2',6'), 7.54 (1H, m, H-4'), 7.43 (2H, m, H-3',5'), 4.98 (1H, m , H-3), 4.42 (1H, m, H-26), 3.96 (1H, dd, J=2.52 Hz, J=11.04 Hz, H-26), 3.31 (1H, d, J=11.04 Hz H- 16), 1.08 (3H, d, J=7.11Hz, CH 3 -21), 1.00 (3H, d, J=6.72 Hz, CH 3 -27), 0.98 (3H, s,...

Embodiment 2

[0041] Example 2 Amination of the 3-position of timogenin

[0042]

[0043] (1) Add 0.8g (0.0045mol) NBS, 5ml dichloromethane (or THF) into a 50ml eggplant-shaped bottle, add dropwise triphenylphosphine dissolved in 5ml dichloromethane (or THF) at room temperature under nitrogen protection, After the dropwise addition, stir at 0-30°C for 0.5h, then add 1.2g (0.003mol) of smilagenin dissolved in 10ml of dichloromethane (or THF) dropwise and stir at 10-30°C until the reaction is complete. Add saturation The brine was extracted with dichloromethane (×2), and the organic layer was concentrated under reduced pressure to obtain a solid, which was applied to a silica gel column and washed with petroleum ether: ethyl acetate 100:1-50:1 to obtain a white solid (1.1 g, yield 78 %)[M+H] + =479.25.

[0044] (2) Add 0.96g (0.002mol) of white solid, 10ml DMF (or acetonitrile, acetone, etc.) and 1.62g dimethylamine hydrochloride to a 50ml eggplant-shaped bottle, and react at reflux at 6...

Embodiment 3

[0045] Example 3 Amination of the 3-position of timogenin

[0046]

[0047] Add 0.96g A (0.002mol), 10ml DMF (or acetonitrile, acetone, etc.), 1.7g hexahydropyridine into a 50ml eggplant-shaped flask, and react at reflux at 60°C for 12h. Add water and filter with suction to obtain a white solid, silica gel column, petroleum ether: ethyl acetate (20:1) plus triethylamine to wash the product, and obtain a white solid C (0.38g, yield about 40%) [M+H] + =484.4151, 1 H-NMR (600MHz, CDCl 3 )δ4.4 0(1H,m,J=7.5Hz,J=14.7Hz,H-26),3.96(1H,dd,J=2.58Hz,10.98Hz,H-26),3.30(1H,d, J=10.92Hz,H-16),2.34(4H,br.s,N-2CH 2 ),2.17(1H,br.s,H-3),1.08(3H,d,J=7.08Hz,CH 3 -21),0.99(3H,d,J=6.9Hz,CH 3 -27),0.95(3H,s,CH 3 -19),0.76(3H,s,CH 3 -18).

technical field

[0001] The invention belongs to the technical field of medicine, and relates to smilagenin derivatives and a preparation method and application thereof, in particular to the application of smilagenin derivatives in anti-senile dementia and antidepressant drugs. Background technique

[0002] Alzheimer's disease (Alzheimer's disease) is the so-called senile dementia. It is a fatal neurodegenerative disease with progressive development. The clinical manifestations are deteriorating cognitive and memory functions, progressive decline in daily life ability, and various neuropsychiatric symptoms and behavioral disturbances.

[0003] It is a group of primary degenerative brain diseases of unknown etiology. Most of the onsets are in old age, the onset is insidious, the course of the disease is slow and irreversible, and the main clinical manifestation is intellectual impairment. The main pathological changes are diffuse atrophy of the cortex, widening of the sulci,...

Examples

Embodiment 1

[0037] Example 1 Preparation of Epismilagenin

[0038] (1) Add smilagenin (4.16g, 10mmol), benzoic acid (2.44g, 20mmol), Ph 3 P (5.24g, 20mmol), 50ml of dry THF, DIAD (4.04g, 20mmol) dissolved in 20ml of dry THF was added dropwise with stirring at room temperature, and the reaction was completed at room temperature for 24h. After the reaction was completed, evaporate to dryness under reduced pressure, add water, stir, filter with suction, put on a silica gel column, wash away impurities with petroleum ether, and wash with petroleum ether: ethyl acetate (80:1) to obtain an intermediate product, the structure identification data is as follows:

[0039] m / z: [M+H] + =521.3620, 1 H-NMR (300MHz, CDCl 3 ): δ 8.05(2H, m, H-2',6'), 7.54 (1H, m, H-4'), 7.43 (2H, m, H-3',5'), 4.98 (1H, m , H-3), 4.42 (1H, m, H-26), 3.96 (1H, dd, J=2.52 Hz, J=11.04 Hz, H-26), 3.31 (1H, d, J=11.04 Hz H- 16), 1.08 (3H, d, J=7.11Hz, CH 3 -21), 1.00 (3H, d, J=6.72 Hz, CH 3 -27), 0.98 (3H, s,...

Embodiment 2

[0041] Example 2 Amination of the 3-position of timogenin

[0042]

[0043] (1) Add 0.8g (0.0045mol) NBS, 5ml dichloromethane (or THF) into a 50ml eggplant-shaped bottle, add dropwise triphenylphosphine dissolved in 5ml dichloromethane (or THF) at room temperature under nitrogen protection, After the dropwise addition, stir at 0-30°C for 0.5h, then add 1.2g (0.003mol) of smilagenin dissolved in 10ml of dichloromethane (or THF) dropwise and stir at 10-30°C until the reaction is complete. Add saturation The brine was extracted with dichloromethane (×2), and the organic layer was concentrated under reduced pressure to obtain a solid, which was applied to a silica gel column and washed with petroleum ether: ethyl acetate 100:1-50:1 to obtain a white solid (1.1 g, yield 78 %)[M+H] + =479.25.

[0044] (2) Add 0.96g (0.002mol) of white solid, 10ml DMF (or acetonitrile, acetone, etc.) and 1.62g dimethylamine hydrochloride to a 50ml eggplant-shaped bottle, and react at reflux at 6...

Embodiment 3

[0045] Example 3 Amination of the 3-position of timogenin

[0046]

[0047] Add 0.96g A (0.002mol), 10ml DMF (or acetonitrile, acetone, etc.), 1.7g hexahydropyridine into a 50ml eggplant-shaped flask, and react at reflux at 60°C for 12h. Add water and filter with suction to obtain a white solid, silica gel column, petroleum ether: ethyl acetate (20:1) plus triethylamine to wash the product, and obtain a white solid C (0.38g, yield about 40%) [M+H] + =484.4151, 1 H-NMR (600MHz, CDCl 3 )δ4.4 0(1H,m,J=7.5Hz,J=14.7Hz,H-26),3.96(1H,dd,J=2.58Hz,10.98Hz,H-26),3.30(1H,d, J=10.92Hz,H-16),2.34(4H,br.s,N-2CH 2 ),2.17(1H,br.s,H-3),1.08(3H,d,J=7.08Hz,CH 3 -21),0.99(3H,d,J=6.9Hz,CH 3 -27),0.95(3H,s,CH 3 -19),0.76(3H,s,CH 3 -18).

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