Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1988-11-30
1990-06-26
Shen, Cecilia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514218, 5142358, 540481, 540575, 540598, 544121, 544295, 544360, 544364, A61K 31495, A61K 31505, C07D40106, C07D40306
Patent
active
049372459
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND
There is an urgent need for novel drugs in the treatment of mental disorders which are more effective and which have fewer side effects than the drugs in clinical use today. Antipsychotic drugs in current use produce a range of troublesome extrapyramidal movement disorders (e.g. acute dystonic reactions and tardive dyskinesia) and are poor in ameliorating the negative symptoms (e.g. restricted or blunted emotional arousal) of schizophrenia. The main disadvantage of the antidepressants is that they fail to alleviate depression in 30 to 40% of patients. Anxiolytics are commonly associated with addictive properties.
PRIOR ART
Various pyridyl- and pyrimidyl-piperazine derivatives pharmacologically active in the central nervous system are known in the art. Some representative examples can be mentioned. Azaperone, a neuroleptic drug of the butyrophenone series, is a sedative for pigs. Buspirone is an anxiolytic. The anxiolytic effect is thought to be mediated via effects on the 5HT-receptors. ##STR2##
DESCRIPITON OF THE INVENTION
Pyridyl- and pyrimidyl-piperazines substituted in the 4-position of the piperazine ring with a highly lipophilic diphenyl-butyl group have unexpectedly been found to exhibit pharmacological properties superior to compounds known in the art.
According to the invention there are provided novel compounds having the general formula (I). ##STR3## wherein R.sub.1 and R.sub.2 are the same or different and selcted from hydrogen and halogen; and lower alkyl; ##STR4## wherein R.sub.5 is selected from hydrogen, lower alkyl or halogen; R.sub.6 and R.sub.7 are the same or different and selected from hydrogen, halogen, lower alkyl, electron donor groups such as lower alkoxy or hydroxy, electron acceptor groups such as cyano, nitro, trifluoromethyl, COOR.sub.8, CONR.sub.9 R.sub.10 or CO--B; wherein R.sub.8 is hydrogen or lower alkyl; R.sub.9 and R.sub.10 are the same or different and selected from hydrogen, lower alkyl and cycloalkyl; ##STR5## wherein m is 1, 2, 3 or 4. R.sub.11 is selected from hydrogen or lower alkyl, and the pharmacologically active salts thereof, include straight and branched, saturated and unsaturated hydrocarbon groups having from 1 to 5 carbon atoms; hydrocarbon groups having from 3 to 8 carbon atoms; or unsaturated alkoxy groups having from 1 to 5 carbon atoms;
It is preferred that one of R.sub.1 and R.sub.2 is different from hydrogen and when one or both of R.sub.1 and R.sub.2 are halogen fluoro is preferred.
As regards R.sub.3 and R.sub.4 hydrogen or methyl are preferred, especially hydrogen.
As regards R.sub.5 hydrogen, methyl, or halogen, especially fluoro, is preferred.
As regards R.sub.6 hydrogen, methyl, alkoxy, amide, nitro, trifluoromethyl, halogen or cyano is preferred.
It is preferred that R.sub.7 is hydrogen, methyl, alkoxy, nitro, halogen, cyano or an amide group.
Compounds wherein A is 2-substituted pyridyl are of special interest, especially those carrying an methoxy, amide, cyano or hydrogen substituent in the 3-position.
The compounds of formula (I) have basic properties and, consequently, they may be converted to their therapeutically active acid addition salts by treatment with appropriated acids; e.g. inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid, or organic acids such as acetic, propanoic, glycolic, lactic, malonic, oxalic, succinic, fumaric, tartaric, citric and pamoic acid.
Conversely, the salt form can be converted into the free base form by treatment with alkali.
The compounds of formula (I) and their pharmaceutically acceptable salts have valuable pharmacological properties, making them useful for the treatment of mental disorders such as psychoses, depression and anxiety. Stress and anxiety in animals can also be treated.
It has been assumed that the antipsychotic actions of neuroleptic drugs are inextricably linked to their ability to produce extrapyramidal side-effects, possibly by an action at a common site. This assumption is now being questioned since antipsychotic drugs nowadays exist
REFERENCES:
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Fex et al, CA 110-95280t (1989).
Leysen, J. E., et al., "[.sup.3 H]ketanserin, A Selective .sup.3 H-Ligand for Serotonin.sub.2 Receptor Binding Sites: Binding Properties, Brain Distribution, and Functional Role," Mol. Pharmacol. 21: 301-314, 1982.
Abramo Aina L.
Christensson Erik G.
Fex Tomas
Lundstedt Torbjorn E.
Olsson Knut G.
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