Amantadine nitrate compound with neuroprotective effect, and preparation therefor and medical application thereof

An amantadine nitrate, neuroprotective technology, applied in the field of medicine, can solve the problems of not being able to fundamentally cure diseases, blocking the process of neurodegeneration and the like

Pending Publication Date: 2016-02-03
GUANGZHOU MAGPIE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These drug molecules acting on a single target can only alleviate the clinical symptoms of a c...

Method used

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  • Amantadine nitrate compound with neuroprotective effect, and preparation therefor and medical application thereof
  • Amantadine nitrate compound with neuroprotective effect, and preparation therefor and medical application thereof
  • Amantadine nitrate compound with neuroprotective effect, and preparation therefor and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Embodiment 1, the synthesis of compound NM-002a

[0058] Compound AD-003e1.48g (5mmol) was dissolved in 30mL of dry dichloromethane and cooled in an ice-water bath. Add 3 mL of a mixture of acetic anhydride and fuming nitric acid (the volume ratio of acetic anhydride: fuming nitric acid is equal to 3:2). Maintain an ice-water bath and react for 10-15 minutes. The reaction solution was poured into 30 mL of 1N sodium bicarbonate solution, and the dichloromethane was separated, and the aqueous layer was extracted with dichloromethane (20 mL×3). The dichloromethane was combined, washed with 30 mL of water, dried over anhydrous sodium sulfate, filtered, and the dichloromethane was distilled under reduced pressure to obtain a colorless oily crude product. Silica gel column separation (petroleum ether:dichloromethane=10:1) yielded 1.07 g (62.9%) of colorless oil NM-002a. ESI-MS: m / z340.2 ([M] + ). 1 H-NMR(DMSO-d6,ppm):0.83(s,3H),1.15-1.24(m,2H),1.26-1.47(m,14H),1.56-1.80(...

Embodiment 2

[0059] Embodiment 2, the synthesis of compound NM-002

[0060] To compound NM-002a 680mg (2mmol), add 5mL of hydrogen chloride-saturated ether solution, react at room temperature, and spot plate monitoring. At the end of the reaction, a white solid precipitated out. Filter and wash the white solid with anhydrous ether to obtain 390 mg (70.7%) of pure NM-002. ESI-MS: m / z341.0 ([M+H] + ). 1 H-NMR(DMSO-d6,ppm):0.88(s,3H),1.19-1.29(m,2H),1.30-1.38(m,2H),1.38-1.52(m,4H),1.54-1.64(m ,2H), 1.66-1.73(m,2H), 2.18-2.24(m,1H), 4.29(s,2H), 8.11(s,3H).

Embodiment 3

[0061] Embodiment 3, the synthesis of compound NM-004a

[0062] Take a 50mL round-bottom flask and place it in an ice-water bath to cool it, and add 20mL of concentrated sulfuric acid, 2mL of n-hexane and 970mg (4mmol) of compound NM-003a into the round-bottom flask. Maintaining the ice-water bath, formic acid (1.8 mL) was slowly added dropwise. After dropping, continue to react in ice-water bath for 3 hours. The reaction solution was poured into 100 mL of ice water, and a solid was precipitated. After standing still, a light yellow solid was obtained after suction filtration. After the solid was dried, it was dissolved in ethyl acetate, and the aqueous sodium hydroxide solution was basified to a pH of about 9-10, and the aqueous layer was separated. The organic layer was extracted with aqueous sodium hydroxide solution (30 mL×3), the aqueous solutions were combined, and the aqueous layer was acidified with dilute hydrochloric acid solution to a pH of about 3. Suction filt...

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Abstract

The invention relates to an amantadine nitrate compound with a neuroprotective effect, and preparation therefor and medical application thereof. The compound has a structure of a general formula (I) as shown in the specification, has multimechanisms, comprises NMDA receptor inhibition, NO releasing and inhibition of inward flow of calcium ions, and has a good protection effect on cells, particularly on neurons. The compound can be used for preparing drugs with a cytoprotection effect, and the drugs are used for preventing or treating diseases related to increasing of NMDA receptors, calcium ions in cells and the like, such as diseases related to neurodegeneration including senile dementia, parkinson's disease, brain stroke, glaucoma and the like, diseases related to a cardio-cerebrovascular system including parkinsonism combined with cerebral arteriosclerosis, and respiratory tract infectivity caused by influenza viruses.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to an amantadine derivative with neuroprotective effect, its synthesis method, pharmaceutical use and application in preventing or treating diseases. Background technique [0002] Amantadine and its derivatives have various biological activities and are widely used in the field of medicine. Rimantadine (1-aminoethyl adamantane, Rimantadine) is a drug widely used clinically to prevent and treat influenza. Amantadine is widely used in the treatment of influenza and Parkinson's Disease (PD) (Schwabetal., J. Am. Med. Assoc. 1969, 208: 1168). Memantine (1,3-dimethylamantadine, Memantine) is currently the only NMDA receptor antagonist approved by the US FDA for the treatment of moderate to severe Alzheimer's disease (Alzheimer's Disease, AD). NMDA receptor is a subtype of an important excitatory amino acid ionotropic glutamate receptor in the central nervous system, and is an important c...

Claims

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Application Information

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IPC IPC(8): C07C211/38C07C209/76A61K31/21A61P9/10A61P39/06A61P25/16A61P25/28A61P25/00A61P9/00A61P25/14A61P27/06A61P27/02A61P25/08A61P7/02A61P3/06A61P11/00A61P3/10A61P1/18A61P1/16A61P13/12A61P35/00
CPCA61K31/21C07C209/76C07C211/38A61K31/04A61P1/16A61P1/18A61P11/00A61P13/12A61P21/02A61P25/00A61P25/08A61P25/14A61P25/16A61P25/28A61P27/02A61P27/06A61P35/00A61P3/06A61P39/06A61P43/00A61P7/02A61P9/00A61P9/10A61P9/14A61P3/10
Inventor 王玉强刘正于沛孙业伟张在军张高小单璐琛易鹏吉米·莱雷克
Owner GUANGZHOU MAGPIE PHARMA
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