1. Field of the Invention
The present invention relates to bis(styryl)pyrimidine or bis(styryl)benzene compounds, pharmaceutically acceptable salts thereof, a method for the preparation thereof, and a pharmaceutical composition for the prevention and treatment of diseases associated with beta-amyloid deposition, that is, amyloidosis-associated diseases.
2. Description of the Related Art
With the increase in the average longevity of human beings all over the world and the entry into an aging society, there has been a great increase in the incidence of degenerative brain disorders such as senile dementia including Alzheimer's disease, apoplexy, Parkinson's disease, etc. Reports from the Korea Institute for Health and Social Affairs discloses that the number of senile persons was about 7% of the total population in 2000, the beginning stage of the aging society in Korea, and this increased to 3.97 million in 2003 with a population ratio of 8.3%, and will amount to about 14.4% in 2019 with the entry of Korea into an aged society. In Korea, dementia is reported in about 15% of senile adults in the ages of 75 to 79 and in as many as about 39% of adults of more than 80 years of age. Females are known to have a twice or three times higher rate of incidence of dementia than do males.
Dementia is a generic term for a set of symptoms accompanying an abnormal decline in the general cognitive functions of language, learning and memory and higher mental functions as a result of the injury or destruction of a normally developed brain by external factors such as postnatal damage or disease. Progressive memory impairment is accompanied by behavior impairments such as disorientation in language, person and place, incurring social and occupational impairments. Dementia is caused largely by Alzheimer's disease, vascular dementia, particular cerebral diseases and systemic diseases with over 50% of the cases resulting from Alzheimer's disease.
Alzheimer's disease is anatomically characterized by the decline and loss of neurons responsible for memory and cognition. The pathophysiological features of Alzheimer's disease are associated with both senile plaque and neurofibrillary tangles in the brain. Research indicates that the pathological features of Alzheimer's disease are associated with both amyloid plaque and neurofibrillary tangles in the brain. Among various causes including immunological factors, genetic factors, viral infection, environmental factors such as toxic compounds, damage to the brain, etc., the deposition of beta-amyloid protein and the formation of neurofibrillary tangles are known to play the most important roles in the incidence of Alzheimer's disease. Amyloid plaque results from the deposition of amyloid-beta peptide, and neurofibrillary tangles are pathological protein aggregates formed by hyperphosphorylation of a microtubule-associated protein known as tau, causing it to aggregate in an insoluble form which leads to neurodegeneration.
Beta amyloid is a peptide of 40 amino acids (beta amyloid 1-40) or 42 amino acids (beta amyloid 1-42) that appear to be the main constituent of amyloid plaque in the brains of Alzheimer's disease patients. Beta amyloid is formed after sequential cleavage of the amyloid precursor protein by β and γ secretases. Beta amyloid fibril formation, which is known to have direct influence on the formation of plaque, occurs via a complex multi-step nucleated polymerization mechanism that involves discrete soluble oligomeric intermediates termed protofibrils, which disappear upon fibril formation. Recent studies have reported that the oligomers are more potential in neurotoxicity than are fibrils, thus making the prevention or inhibition of oligomer formation an attractive therapy for Alzheimer's disease.
Most of the therapeutic agents developed so far have been cholinergic drugs which are designed to increase the level of acetylcholine in the brain or the activity of cholinergic neurons on the basis of the fact that acetylcholine levels in the brains of Alzheimer's disease patients are lower than in those of healthy persons. Currently available cholinergic drugs, such as Donepezil, Rivastigmin, Galantamin, Memantine, etc., however, aim to improve memory impairment only, with limitations to the fundamental medical treatment of Alzheimer's disease and the production of side effects.
Leading to the present invention, intensive and thorough research into therapies for Alzheimer's disease, conducted by the present inventors, resulted in the finding that novel bis(styryl)pyrimidine or bis(styryl)benzene compounds inhibit the deposition of beta amyloid and reduce the toxicity of beta amyloid, thus being useful in the treatment of diseases featuring amyloids, such as Alzheimer's disease.