1. Field of the Invention
The invention relates to derivatives of β-carbolines, preferably 9-alkyl-β-carbolines (9-alkyl-BC), the production thereof and their use for prophylaxis and treatment of neurodegenerative diseases and pharmaceutical compositions containing these derivatives.
2. Description of the Relevant Art
The compounds according to the invention shall be used in particular in Parkinson's disease. Parkinson's disease, also known as Parkinson's syndrome or PD, counts among the chronic diseases which are still incurable. The course of the disease is characterized by dying neurons in the brain. Predominantly such neurons substantia nigra, literally “black substance”, neurons are affected which contain the neurotransmitter dopamine. Therefore, the formation of the neurotransmitter dopamine to a sufficient extent is no longer ensured. Changes (i.e. Lewy bodies, dying of other neuron types) can be found also in other parts of the brain, i.e. in the nucleus coeruleus, the Raphe nuclei, the Nucleus Basalis of Meynert, the nucleus of the vagus nerve and the hippocampus. Dopamine is a neurotransmitter essential for the control of the locomotor system; its lack leads to movement disorders such as trembling (resting tremor), involuntary muscular rigidity (rigor) and a deceleration of movement (hypokinesia). In advanced stades further movement disorders occur such as the inability to initiate a movement (freezing) and the incapability of maintaining an upright posture with the risk of falling. Further, cogitation, memory and the circulatory control are affected and feelings change involving depressions and at the final stage dementia.
Parkinson's disease is divided into a sporadic form (about 95% of the affected) and a familial form. In the latter, the main cause is the inheritance of the disease risk. Besides, many diseases are described in which movement disorders occur, but their ethology is based on other causes. They are referred to as secondary parkinsonism. These forms can be caused by drugs such as neuroleptics and reserpine and its derivatives. In addition, a hemiparkinsonism hemiatrophy syndrome is known. A Parkinson's syndrome is also described for hydrocephalus, oxygen deficiency, cerebral infections (encephalitis), manganese intoxications, carbon monoxide (CO), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and cyanide. Further causes are parathyroid diseases, a brain tumor, a brain lesion and multiple occlusions (infarctions) of cerebral vessels. Further diseases involving movement disorders are Alzheimer's disease, diffuse Lewy bodies disease, frontotemporal dementia, Lytico-Bodig disease (Parkinsonism-dementia-amyotrophic lateral sclerosis), striatonigral degeneration, sporadic olivo-ponto-cerebellar degeneration, progressive pallidal atrophy, progressive supranuclear palsy, Huntington's disease, X chromosome-linked dystonia (Lubag disease), mitochondrial cytopathy with striatal necrosis, neuroacanthocytosis and Wilson's disease. A reduced function of dopaminergic neurons is also involved in the so-called restless legs syndrome.
Currently, the dopamine precursor L-DOPA is applied for compensating the lack of dopamine and drugs are used which directly stimulate dopamine receptors as well as drugs which inhibit the degradation of dopamine. However, soon there occurred side effects of a long-term treatment with L-DOPA which range from dyskinesia (abnormal, involuntary movements) to dystonia (painful muscular cramps) and abrupt alternating movement-freezing-stages. Moreover, it was recognized that L-DOPA can lead to an accelerated loss of dopaminergic neurons in the brain.
In Germany, one to two percent of the people over 60 years suffer from Parkinson's disease. Thus, there is the urgent need to provide drugs which are suitable for the treatment of Parkinson's disease and other movement disorders, particularly well-tolerated substances and pharmaceutical formulations which can be used for prophylaxis and treatment of neurodegenerative diseases and movement disorders.
USPTO Backgrounds
USPTO Backgrounds