Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-10-11
1998-04-07
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546124, 546125, 546132, A61K 3144, C07D45102, C07D45110
Patent
active
057365563
DESCRIPTION:
BRIEF SUMMARY
The present application is a U.S. national application filed under 35 USC 371 of PCT/EP95/01358, filed Apr. 12, 1995, which in turn is based upon the priority of Danish applications 0447/94, filed Apr. 19, 1994 and 1338/94, filed Nov. 24, 1994.
The present invention relates to novel oxime derivatives which are monoamine neurotransmitter, i.e dopamine, serotonin and noradrenalin, reuptake inhibitors. The present invention especially relates to novel oxime derivatives which are potent dopamine-reuptake inhibitors, and as such have pronounced anti-parkinsonian, antidepressant, anti-obesity, anti-narcolepsy and anti-drug-abuse activity and, at the same time, a low degree of undesired side effects; methods for the preparation of the novel oxime derivatives; pharmaceutical compositions containing the novel oxime derivatives; and methods for the treatment of parkinsonism, depression, obesity, narcolepsy and drug abuse, by administering a therapeutically effective amount of one or more of the novel oxime derivatives to a living animal body, including a human.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide novel oxime derivatives having anti-parkinsonian, antidepressant, anti-obesity, anti-narcolepsy and anti drug abuse activity.
Another object of the invention is to provide novel pharmaceutical compositions containing the novel oxime derivatives which are useful for the treatment of parkinsonism, depression, obesity, narcolepsy and drug abuse.
Still another object of the invention is to provide a method of treating parkinsonism, depression, obesity, narcolepsy and drug abuse by administering a therapeutically effective amount of one or more of the novel oxime derivatives to a living animal body, including a human.
Other objects will become apparent hereinafter to one skilled in the art.
BRIEF DESCRIPTION OF THE DRAWINGS
Reference is now made to the drawings for a better understanding of the invention, wherein:
FIG. 1 is a graph showing that a compound of the invention identified as NS2214, at doses ranging from 0.1 to 2.5 mg/kg, causes a dose-dependent decrease in disability scores.
FIG. 2 is a graph showing that a compound of the invention identified as NS2214, at doses ranging from 0.1 to 2.5 mg/kg, causes a dose dependent increase in locomotor activity.
The column identified as "VEH", in each case identifies the results obtained when testing only the vehicle employed, the test being conducted as described in the Specification under the heading "Antagonism of MTPT-induced Parkinsonism in Marmoset Monkeys".
BACKGROUND OF THE INVENTION
Dopamine is released into the synaptic cleft in order to stimulate postsynaptic dopaminergic receptors. The removal of dopamine occurs normally by a reuptake mechanism into presynaptic terminals. By inhibiting this uptake an enhancement of the physiological dopaminergic activity occurs. Compounds capable of inhibiting dopamine-reuptake are predicted to be useful in the treatment of Parkinson's disease, depression, cocaine addiction, obesity and narcolepsy.
A well known substance with both powerful dopamine releasing and dopamine-reuptake inhibiting properties, is cocaine. Cocaine has a variety of pharmacological actions, primarily a strong CNS stimulation and local anesthetic action. These effects are accompanied by high toxicity and dependence liability. (See for example R. L. Clarke et al in Journal of Medicinal Chemistry 16(11), 1261-1267 (1973)). The dependence liability is thought to be related to a combination of cocaine's powerful stimulant activity, short term of action, and rapid onset of action together with its strong dopamine releasing properties. It is believed, that compounds having long lasting selective dopamine reuptake-inhibiting properties, and being devoid of dopamine releasing properties, will be extremely useful as a novel type of anti-parkinsonian, antidepressant, anti-obesity and anti-narcolepsy agents. Furthermore such compounds will be extremely useful in the treatment of drug addiction, and especially in the treatment
REFERENCES:
Journal of Medicinal Chemistry, vol. 34, No. 3, Mar. 1991 Washington US, pp. 883-886, F. Ivy Carroll et al., "Synthesis and ligand binding of cocaine isomers at the cocaine receptor".
Journal of Medicinal Chemistry, vol. 36, No. 24, Nov. 26, 1993 Washington US, pp. 3975-3977, Daniele Simoni et al., "Methoxylation of cocaine . . . ".
Moldt Peter
Scheel-Kruger J.o slashed.rgen
Watjen Frank
NeuroSearch A/S
Rotman Alan L.
LandOfFree
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