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Dual binding site acetylcholinesterase inhibitors for the treatment of alzheimer's disease

A technology of ethyl and compound, applied in the field of a new family of compounds, which can solve the problems of increased neurotoxicity of βA fibrils, changes in enzyme biochemical and pharmacological properties, etc.

Inactive Publication Date: 2005-11-30
NEUROPHARMA SA (ES)
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These complexes are capable of altering the biochemical and pharmacological properties of the enzyme, resulting in increased neurotoxicity of βA fibrils

Method used

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  • Dual binding site acetylcholinesterase inhibitors for the treatment of alzheimer's disease
  • Dual binding site acetylcholinesterase inhibitors for the treatment of alzheimer's disease
  • Dual binding site acetylcholinesterase inhibitors for the treatment of alzheimer's disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 15

[0125] Example 1.5,6-dimethoxy-2-{[7-(1,2,3,4-tetrahydro-acridin-9-ylamino)heptylamino]-methyl}-2,3- Dihydro-inden-1-one

[0126]

[0127]To a stirred solution of 9-(7-aminoheptylamino)-1,2,3,4-tetrahydroacridine (134mg, 0.43mmol) in a mixture of ethanol:water 3:1 (3.5ml) at room temperature Paraformaldehyde (26 mg, 0.86 mmol) and 5,6-dimethoxy-2,3-dihydro-inden-1-one (83 mg, 0.43 mmol) were added. The pH was adjusted to 3 with 35% hydrochloric acid, and the mixture was refluxed for 24 hours. At the end of this period, the reaction mixture was cooled (25 °C), the solvent was removed under vacuum pressure, and the 2 CO 3 The residue was treated with saturated solution (3.5ml) and dichloromethane (5ml). The organic layer was washed with water (5ml) and dried (anhydrous Na 2 SO 4 ). The solvent was removed in vacuo and the residue was purified by preparative centrifugal thin layer chromatography. Elution with 5:1 ethyl acetate:methanol containing 1% aqueous ammonia pro...

Embodiment 25

[0131] Example 2.5,6-dimethoxy-2-{[6-(1,2,3,4-tetrahydro-acridin-9-ylamino)-hexylamino]-methyl}-2,3- Dihydro-inden-1-one

[0132]

[0133] According to the general method of Example 1, 9-(6-aminohexylamino)-1,2,3,4-tetrahydroacridine (96mg, 0.32mmol), paraformaldehyde (19mg, 0.64mmol), 5, 6-Dimethoxy-2,3-dihydro-inden-1-one (62 mg, 0.32 mmol) and 35% hydrochloric acid (pH=3) were refluxed for 24 hours. Purification by two preparative centrifugal thin layer chromatography using 10:1 ethyl acetate:methanol with 2% ammonia provided the title compound as a yellow slurry (8 mg, 5%).

[0134] 1 H-NMR (CDCl 3 , 300MHz, δ): 7.97(dd, 2H, J=8.1Hz), 7.56(ddd, 1H, J=8.1, 1.2Hz), 7.34(ddd, 1H, J=8.2, 1.2Hz), 7.13( s, 1H), 6.85(s, 1H), 3.94(s, 3H), 3.88(s, 3H), 3.55(t, 2H, J=7.0Hz), 3.30-3.19(m, 1H), 3.10-3.07 (m, 2H), 2.90-2.60(m, 7H), 1.89-1.68(m, 4H), 1.40-1.35(m, 2H), 1.28-1.11(m, 6H).

[0135] 13 C-NMR (CDCl 3 , 300MHz, δ): 207.1, 155.7, 151.2, 149.4, 149.3, 129.3, 128.7, 12...

Embodiment 3

[0137] Example 3.2-[6-(1,2,3,4-tetrahydro-acridin-9-ylamino)-hexylamino]-2,3-dihydro-indene-1,3-dione

[0138]

[0139] Add oxalic acid (1,2,3,4-tetrahydro-acridin-9-yl)-hexane-1,6-diamine (339mg, 0.87mmol) in ethanol:water 3:1 (3.5ml ) was added paraformaldehyde (26.4 mg, 0.88 mmol) and 2,3-dihydro-indene-1,3-dione (129 mg, 0.88 mmol). The pH was adjusted to 3 with 35% hydrochloric acid, and the mixture was refluxed for 24 hours. At the end of this period, the reaction mixture was cooled (25 °C), the solvent was removed under vacuum pressure, and the 2 CO 3 The residue was treated with saturated solution (3.5ml) and dichloromethane (5ml). The organic layer was washed with water (5ml) and dried (anhydrous Na 2 SO 4 ). The solvent was removed in vacuo and the residue was purified by preparative centrifugal thin layer chromatography. Elution with 10:1 to 3:1 ethyl acetate:methanol containing 1% aqueous ammonia provided the title compound as a yellow slurry (17 mg, 4.4%...

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Abstract

A family of compounds of formula (I) wherein: X is one of the following radicals: which behaves as dual site acetylcholinesterase inhibitors and which are especially useful for the treatment of cognitive disorders as senile dementia, cerebrovascular dementia, mild cognition impairment, attention deficit disorder, and / or neurodegenerative dementing disease with aberrant protein aggregations as specially Alzheimer's disease, Parkinson disease, ALS, or prion diseases, as Creutzfeldt-Jakob disease or Gerstmann-Straussler-Scheinher disease.

Description

technical field [0001] The present invention relates to a new family of compounds that act as two-site acetylcholinesterase inhibitors, and to the synthesis and biological evaluation of said family of compounds. These compounds are particularly useful in the treatment of cognitive disorders such as senile dementia, cerebrovascular dementia, mild cognitive impairment, attention deficit disorder, and / or neurodegenerative dementia with abnormal protein aggregation, such as especially Alzheimer's disease disease, Parkinson's disease, ALS, or prion diseases such as Creutzfeldt-Jakob disease or Ger-Sch-Sarr disease. [0002] Accordingly, the present invention also relates to pharmaceutical compositions containing said compounds. Background technique [0003] Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is one of the most common causes of mental decline in the elderly, accounting for approximately 50-60% of all dementia cases in persons over the age of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/473C07D219/12C07D401/12C07D417/12
CPCC07D401/12C07D219/12C07D417/12A61P25/16A61P25/28A61P43/00A61P9/10
Inventor A·马丁内斯希尔I·多龙索罗·迪亚斯L·鲁维奥阿列塔D·阿隆索戈迪略A·富埃尔特斯韦尔塔S·莫拉莱斯-阿尔塞莱M·德尔蒙特米莲E·加西亚帕洛梅罗P·乌桑埃赫亚C·德奥斯特里M·梅迪纳帕迪利亚
Owner NEUROPHARMA SA (ES)
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