Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-11
2004-06-15
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Reexamination Certificate
active
06750221
ABSTRACT:
The present invention relates to the use of binding partners for 5-HT5 receptors for the treatment of neuropathological disorders and associated indications, symptoms and dysfunctions and to processes for the identification and characterization of binding partners of this type.
At least seven different receptor classes mediate the manifold physiological activities which are ascribed to an involvement of the neurotransmitter serotonin (5-hydroxytryptamine, abbreviated 5-HT). According to an internationally recognized classification, they are designated by 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7. Most of these classes moreover include receptor types which can be differentiated further. Thus the 5-HT1 class includes receptors which can be divided into at least five subclasses, which are designated by 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D and 5-HT1E (Boess F. G. and Martin I. L., Neuropharmacology 33:275-317 (1994)).
The 5-HT5 class was described for the first time by Plassat et al., The EMBO Journal Vol. 11 No. 13, pp. 4779-4786 (1992). 5-HT5A and 5-HT5B receptors are differentiated (Erlander et al., Proc. Natl. Acad. Sci. USA 90:3452-3456 (1993)). Only small sequence homologies exist between 5-HT5 and other 5-HT receptors. The pharmacological profile of these receptors differs markedly. Using molecular biology techniques, the localization of 5-HT5 receptors was possible in the olfactory bulb, in the hippocampus, in the cortex, in the cerebral ventricles, in the corpus callosum and in the cerebellum. By means of immunohistochemical methods, it was possible to show that 5-HT5 receptors are principally expressed on astrocytes (Carson et al., GLIA 17:317-326 (1996)). Astrocytes are directly adjacent to the basal membrane of brain capillaries of the blood-brain barrier. An abnormal astrocyte endothelium structure accompanies a loss of the blood-brain barrier. The exact significance of the astrocytes is unclear. They appear to look after transport tasks and connective functions. Reactive astrocytes were observed in connection with reactive gliosis in a number of pathological brain changes and neuropsychiatric disorders. As a result of brain injuries, they change their morphologies. The protein expression pattern changes and growth factors are produced. In vitro investigations on cultured astrocytes have allowed the detection of 5-HT5 receptor-mediated responses. It is thus to be suspected on the one hand that they are involved in recovery processes of the brain after disorders, but on the other hand it is also not to be excluded that they contribute to the creation of damage or even to an increase in damage.
CNS disorders nowadays concern large sections of the population. In particular on account of the increase in elderly people, the numbers of patients are increasing continuously. Neuropathological conditions such as cerebral ischemia, stroke, epilepsy and attacks in general, chronic schizophrenia, other psychotic disorders, dementia, in particular Alzheimer's dementia, demyelinizing disorders, in particular multiple sclerosis, and brain tumors lead to damage to the brain and the neuronal deficits associated therewith.
Therapeutic treatments of the neurodegenerative and neuropsychiatric disorders outlined were up to now directed at various membrane receptors with the aim of compensating deficits in neurotransmission processes. Indeed, it was possible to achieve neuroprotective effects with serotonogic compounds in animal models of neuropathological conditions, such as ischemia, cerebral stroke and excitotoxicity. In some cases, it was also possible to observe favorable effects on emotional disturbances, such as depression or anxiety states. Mention may be made here, for example, of 5-HT1A agonists, such as buspirone or the compound 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), which is characterized as a selective 5-HT1A receptor ligand. These active compounds, however, only decrease neurological deficits to a limited extent. There is still no effective therapy at present.
It is therefore an object of the present invention to make possible the treatment of neuropathological disorders with adequate efficacy and minor side effects.
Surprisingly, it has now been found that treatment of the above disease conditions and associated indications, symptoms and dysfunctions is made possible by specific use of substances having binding affinities for 5-HT5 receptors.
One subject of the present invention is therefore the use of binding partners for 5-HT5 receptors for the preparation of an agent for the treatment of neuropathological disorders and associated indications, symptoms and dysfunctions.
Neuropathological disorders are understood according to the invention as meaning disorders which are accompanied by neurological deficits, i.e. a condition characterized by neurological deficiency symptoms. The term “disorder” in the sense according to the invention designates anomalies which, as a rule, are regarded as pathological conditions and can reveal themselves in the form of certain signs, symptoms and/or dysfunctions. The treatment according to the invention can be directed at individual disorders, viz. anomalies or pathological conditions, but a number of anomalies which are causally connected to one another can be combined to give patterns, i.e. syndromes, which can be treated according to the invention.
This condition can exist temporarily, progressively or persistently.
According to the invention, the treatment of neurodegenerative and/or neuropsychiatric disorders is preferred. These disorders occur, in particular, in neuropathological syndromes, as a rule syndromes caused by brain damage, for example cerebral ischemia, stroke, epilepsy and seizures in general, chronic schizophrenia, other psychotic disorders, dementia, in particular Alzheimer dementia, demyelinizing disorders, in particular multiple sclerosis, and brain tumors. The invention in particular also relates to the use of 5-HT5 binding partners for the treatment of those forms of the abovementioned disorders in whose formation and/or course 5-HT5 receptors are involved, i.e. disorders which are modulated by a 5-HT5 receptor activity.
According to a further aspect of the present invention, neuropathological disorders are treated which accompany a glial reaction. The use according to the invention relates in particular to the modulation of a glial reaction.
An advantageous action of the binding partners is seen in the preventive or acute treatment of neurological deficits, which are observed in patients who suffer from psychiatric disorders, such as epilepsy, psychosis, e.g. psychoses of the acute exogenous reaction type or concomitant psychoses of organic or exogenous cause, e.g. after trauma, especially brain lesions and diffuse brain damage, in metabolic disorders, infections, and endocrinopathies; endogenous psychoses, such as schizophrenia, and schizotypic and delusional disorders; effective disorders, such as depression, mania and manic depressive conditions; and mixed forms of the psychoses described above; senile dementia and senile dementia of the Alzheimer type, and in the treatment or prevention of demyelinization processes.
The binding partners according to the invention are efficacious, in particular with respect to the treatment of ischemic damage, e.g. as a result of brain and spinal cord trauma and vascular occlusion or heart failure.
Especially to be mentioned here is stroke (synonym: cerebral apoplexy, cerebral or apoplectic insult, cerebral stroke). Transitory ischemic attacks, reversible ischemic neurological deficits, prolonged reversible ischemic neurological deficits, partially reversible ischemic neurological symptoms and also persistent complete cerebral infarcts can be treated according to the invention. The treatment of acute forms is particularly advantageous according to the invention.
One or more of the changes in nerve tissues listed below underlie the forms of neuropathological disorders which can be preferably treated according to the invention: degeneration or death of neurons,
Garcia-Ladona Francisco Javier
Hofmann Hans-Peter
Steiner Gerd
Szabo Laszlo
BASF - Aktiengesellschaft
Henley III Raymond
Keil & Weinkauf
LandOfFree
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