Tacrine-ferulaic acid hetero-blend, preparation method and pharmaceutical compositions thereof

A technology for drugs and compounds, applied in the field of medicine, can solve the problems of elevated transaminases, frequent oral administration, water solubility and poor human tolerance.

Inactive Publication Date: 2008-10-15
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] As the first drug approved to treat AD, tacrine has been found to have obvious deficiencies: (1) hepatotoxic side effects are relatively large, and about 25% of patients taking the drug have elevated transaminases. Strict monitoring of transaminases must be carried out when patients take the drug
(2) The dosage is too high, generally reaching 80mg / d or even higher in the later stage
(3) Too many times of oral medicine
Although the activity and efficacy of improved derivatives such as A7A are obviously better than tacrine, their water solubility and human tolerance are poor, so the research on improved derivatives such as A7A is still in the phase I clinical stage.

Method used

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  • Tacrine-ferulaic acid hetero-blend, preparation method and pharmaceutical compositions thereof
  • Tacrine-ferulaic acid hetero-blend, preparation method and pharmaceutical compositions thereof
  • Tacrine-ferulaic acid hetero-blend, preparation method and pharmaceutical compositions thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044]

[0045] 3-Methoxy-4-hydroxy-ferulic acid-{N-(2-[2-(1,2,3,4-tetrahydro-acridin-9-amino)-ethyl]-methyl -amino]}-amide.

[0046] Reagents: Ferulic acid (170mg, 8.3mmol), anhydrous THF (35ml), BOP (770mg, 17mmol), and {N-(1,2,3,4-tetrahydro-acridin-9-amino) -N'-methyl}-1.2-bisethylenediamine (200 mg, 6.7 mmol).

[0047] Method: Dissolve ferulic acid in anhydrous THF, add triethylamine, stir at room temperature, then add BOP dropwise, and finally add {N-(1,2,3,4-tetrahydro-acridine-9-amino )-N'-methyl}-1.2-bisethylenediamine, stirred overnight at room temperature. After concentration, it was directly separated by silica gel column chromatography, eluent: dichloromethane:methanol=11:3.

[0048] Purification: silica gel column chromatography using DCM / MeOH (12:1). White solid, yield: 110 mg (35%)

[0049] 1 H NMR results are:

[0050] 1 HNMR (DMSO, 400MHz, δppm): 9.38(s, 1H), 7.90-7.84(m, 2H), 7.80(m, 1H), 7.78-7.77(m, 1H), 7.60-7.56(m, 1H), 7.30-7.56(d, 1H), 7.09...

Embodiment 2

[0054]

[0055] 3-Methoxy-4-hydroxy-ferulic acid-{N-(2-[2-(6-chloro-1,2,3,4-tetrahydro-acridine-9-amino)-ethyl ]-methyl-amino]}-amide.

[0056] Reagents: Ferulic acid (170 mg, 8.3 mmol), anhydrous THF (35 ml), BOP (770 mg, 17 mmol), and {N-(6-chloro-1,2,3,4-tetrahydro-acridine-9 -amino)-N'-methyl}-1.2-diethylenediamine (200 mg, 6.0 mmol).

[0057] Purification: silica gel column chromatography using dichloromethane:methanol DCM / MeOH (12:1). White solid, yield: 106 mg (34%).

[0058] Except that the reagents and purification columns are different, the rest of the preparation and purification steps are the same as in Example 1.

[0059] 1 HNMR (DMSO, 400MHz, δppm): 9.38(s, 1H), 7.90-7.84(m, 1H), 7.80(m, 1H), 7.78-7.77(m, 1H), 7.60-7.56(m, 1H), 7.30-7.56(d, 1H), 7.09(d, 1H), 6.97-6.95(d, 1H), 6.79-6.77(d, 1H), .6.42-6.39(d, 1H), 3.73(s, 6H) , 3.63-3.60 (m, 2H), 3.34-3.30 (m, 2H), 2.97 (br, 2H), 2.65 (br, 2H), 1.83 (br, 4H), 1.75-1.31 (m, 4H).

[0060] 13 C NMR (DMSO, 1...

Embodiment 3

[0062]

[0063] 3-Methoxy-4-hydroxy-ferulic acid-{N-[(1,2,3,4-tetrahydro-acridin-9-amino)-pentyl-3-one]}-amide

[0064] Reagents: Ferulic acid (170mg, 8.3mmol), anhydrous THF (35ml), BOP (770mg, 17mmol), and {N-[(1,2,3,4-tetrahydro-acridin-9-amino )-3-keto]}-pentamethylenediamine (200 mg, 6.1 mmol).

[0065] Purification: silica gel column chromatography using DCM / MeOH (12:1). Yellow solid, yield: 105 mg (30%).

[0066] Except that the reagents and purification columns are different, the rest of the preparation and purification steps are the same as in Example 1.

[0067] 1HNMR (DMSO, 400MHz, δppm): 9.38(s, 1H), 7.90-7.84(m, 2H), 7.80(m, 1H), 7.78-7.77(m, 1H), 7.60-7.56(m, 1H), 7.30-7.56(d, 1H), 7.09(d, 1H), 6.97-6.95(d, 1H), 6.79-6.77(d, 1H), .6.42-6.39(d, 1H), 3.73(s, 3H) , 3.63-3.60 (m, 2H), 3.34-3.30 (m, 2H), 2.97 (br, 2H), 2.65 (br, 2H), 1.83 (br, 4H), 1.60-1.41 (m, 4H).

[0068] 13 C NMR (DMSO, 100MHz, δppm): δ210.8, 168.8, 161.4, 158.3, 150.1, 151.2, 148.2, 14...

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Abstract

The invention relates to a cross-linked body of Tacrine and ferulic acid or a dynamic isomer, medicine salts, a pro-drug or a solvate thereof, wherein, the structural formula is shown in formula (I). The invention also relates to a method for making the same, a combination taking the formula (I) compound as active composition, and application of the compound and the combination thereof taken as the medicine for preventing and curing AChE-mediated diseases, in particular the application in preparation of the medicine for preventing Alzheimer diseases and dementia, in which other oxidative stresses take part.

Description

【Technical field】 [0001] The invention relates to a tacrine-ferulic acid hybrid, a preparation method thereof, a pharmaceutical composition containing them, and their application in the preparation of cholinesterase (AChE)-mediated diseases, belonging to the field of medicine. 【Background technique】 [0002] Alzheimer's disease (AD) is a neurodegenerative disease characterized clinically by gradual deterioration of cognitive and memory functions, progressive decline in activities of daily living, and accompanied by various neuropsychiatric symptoms and behavioral disturbances. disease. Its pathological features are brain regions, especially the neocortex and hippocampus, the appearance of senile plaques (SP) outside nerve cells, abnormal phosphorylation of tau protein in neurons to form neurofibrillary tangles (neurofibrillary tangles, NFT), and neurite Loss of haptic and pyramidal cells. The 2006 International Conference on the Prevention of Dementia pointed out that ther...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D219/12A61K31/473A61P25/28
Inventor 皮荣标叶敏忠成志毅刘培庆
Owner SUN YAT SEN UNIV
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