Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-07-17
2000-02-22
Huang, Evelyn Mei
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514312, 546144, 546148, 546155, A61K 3147, C07D21522, C07D21704
Patent
active
060280808
DESCRIPTION:
BRIEF SUMMARY
The invention relates to quinolin-2-(1H)-one derivatives of the formula I ##STR2## in which R.sup.1, R.sup.2 --(CH.sub.2).sub.5 --, adjacent ring B or D or, together with R.sup.6, --(CH.sub.2).sub.4 -- or --(CH.sub.2).sub.5 --, meaning --(CH.sub.2).sub.m --NR.sup.6 R.sup.7 or --(CH.sub.2).sub.n --NR.sup.6 R.sup.7, and their salts and solvates.
This invention also relates to the use of these compounds and their physiologically acceptable salts for the treatment of neurodegenerative changes in CNS functions.
The Patent Applications WO 93/11115 A1 and EP 0 481 676 A1 disclose quinolin-2-(1H)-one derivatives which act as antagonists of glutamate receptors, in particular of NMDA receptors. On account of these properties, the compounds are described as suitable for the treatment of acute neurodegenerative disorders which are caused by stroke or hypoglycaemia, cerebral palsy, transient cerebral ischaemic attacks, cerebral ischaemias during surgical heart-lung interventions or cardiac arrests, perinatal asphyxia, epilepsy, Huntington's chorea, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, atrophy of the cerebellum, anoxias due to drowning, bone marrow and head injuries, intoxification due to exogenous and endogenous NMDA receptor agonists or neurotoxins, including those in the environment.
Additionally, appropriate compounds should also be suitable for the prevention of neurodegenerative disorders or, on account of their NMDA receptor-antagonistic properties, employable as antispasmodics, analgesics, antiemetics, or for the prevention or reduction of the dependence potential of narcotics.
It was not known until now and was therefore surprising that the quinolin-2-(1H)-ones, substituted in the in [sic] 3-position by various phenyl groups, of the present invention exhibit this activity for the indications mentioned. This applies in particular to the use of these medicaments in liquid form; to be precise particularly if they are administered in an infusion solution. This type of administration is necessary in the case of unconsciousness of the patient to be treated.
It was therefore an object of the present invention to provide compounds having improved neuroprotective action.
It was furthermore an object of this invention to make available processes by means of which the appropriate compounds can be prepared in the highest possible yields and high purities.
This object is achieved by the present invention.
It has now been found that compounds of the formula I, in which the radicals R.sup.1 to R.sup.7, A, Hal, X, m and n have the given meanings, and their physiologically acceptable salts have useful pharmacological properties. In particular, these compounds are selective antagonists of N-methyl-D-aspartate receptors (NMDA receptor antagonists). The compounds according to the invention have proved in particular to be selective ligands of the strychnine-insensitive glycine receptor, which modulates the NMDA receptor. They are therefore suitable for the treatment of neurodegenerative disorders, including cerebrovascular diseases. They are particularly highly suitable for the treatment of acute neurodegenerative disorders which are caused by stroke or hypoglycaemia, cerebral palsy, transient cerebral ischaemic attacks, cerebral ischaemias during surgical heart-lung interventions or cardiac arrest, perinatal asphyxia, anoxias due to drowning, bone marrow and head injuries, intoxification by exogenous and endogenous NMDA receptor agonists or by neurotoxins, but also due to epileptic attacks or due to Huntington's chorea.
Experiments have shown that the compounds according to the invention are particularly effective in the case of an infarct. They can therefore be administered to the patient, for example in the unconscious state, in the form of infusion solutions.
The compounds according to the invention, however, are also suitable for the prevention of appropriate neurodegenerative disorders, such as occur in Alzheimer's disease, Parkinson's disease, atrophy of the cerebellum, an amyotrophic late
REFERENCES:
patent: 5268378 (1993-12-01), Baker et al.
patent: 5348962 (1994-09-01), Kulagowski
patent: 5614532 (1997-03-01), Carling et al.
English abstract for EP 685466.
Ackermann Karl-August
Gottschlich Rudlof
Holzemann Gunter
Leibrock Joachim
Rautenberg Wilfried
Huang Evelyn Mei
Merck Patent Gesellschaft mit beschrankter Haftung
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