Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1986-11-26
1988-10-18
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514211, 514212, 514218, 514255, 5142358, 540484, 540544, 540575, 540607, 540609, 540612, 544107, 544121, 544357, 544365, 544372, 544390, 544391, A61K 31495, C07D24104, C07D29500
Patent
active
047787899
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Drugs in use today for the treatment of mental disorders most often are associated with serious side effects. Antipsychotic drugs commonly cause disturbing extrapyramidal symptoms, and long term treatment may result in tardive dyskinesia. Antidepressants often exhibit cardiotoxicity, and anxiolytic drugs have addicting properties. As a result of these drawbacks efforts are being made to fine new pharmacologically active drugs which have fewer side effects.
The present invention relates to novel piperazine- and homopiperazinecarboxamides bearing a phenoxyalkyl or thiophenoxyalkyl side chain, which exhibit valuable pharmacological properties, and which have a low tendency to cause side effects.
Pharmacologically valuable piperazine carboxamides are previously known from British patent application No. 2,037,745. However, the compounds according to the British application differ from the compounds according to the present invention in being substituted in the 4-position with a very lipophilic 4,4-diphenylbutyl group. Furthermore, these previous compounds are very active in pharmacological models which may indicate potentation of noradrenaline and serotonine (e.g inhibition of muricide behaviour), which in turn may cause unwanted side effects, e.g. aneroxigenic. The compounds of the present invention are considerably less active in these pharmacological models indicating that fewer side effects are to be expected when compounds according to the present invention are used.
Piperazinecarboxamides substituted the 4-position with a butyrophenone side chain are known from Collect. Czech. Chem. Commun 1975, 40(4), 1218-30. The butyrophenone side chain is chemically distinctly different from a phenoxyalkyl or thiophenoxyalkyl group. Besides, the authors state that their compounds display CNS-activity only at high doses.
The French patent application 2367067 and the Swedish patent application 8100852-6 describe piperazine derivatives having a phenoxyalkyl side chain but in neither case are the compounds piperazinecarboxamides. The compounds according to the French patent application are chracterized by an analgesic effect that is not accompanied by any secondary effects (cf. the French application page 1, lines 20-24).
DESCRIPTION OF THE INVENTION
According to the invention there are provided novel compounds having the general formula: ##STR1## wherein R.sub.1 is selected from hydrogen, halogen or trifluoromethyl; X is oxygen or sulfur; lower alkyl; ##STR2## wherein R.sub.4 and R.sub.5 are the same or different and selected from hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, hydroxy-alkyl, alkoxyalkyl, alkanoyloxyalkyl: phenyl or phenyl-alkyl, wherein the phenyl groups may be unsubstituted or monosubstituted with halogen or CF.sub.3 ; lower alkyl, hydroxy, lower alkoxy or lower alkanoyloxy; lower alkyl; pharmaceutically active salts thereof, include straight and branched, saturated and unsaturated hydrocarbon groups having 1 to 10 carbon atoms; hydrocarbon groups having from 3 to 8 carbon atoms; the term alkoxy is meant to include straight and branched, saturated or unsaturated alkoxy groups having from 1 to 10 carbon atoms; and unsaturated alkanoyloxy groups having from 1 to 10 carbon atoms; carbon atoms and
The compounds of formula (I) have basic properties and consequently they may be converted to their therapeutically active acid addition salts by treatment with appropriate 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.
In the compounds of the general formula (I) it is preferred that R.sub.1 is halogen or CF.sub.3 and that R.sub.1 is situated in the m- or p-position.
If selected from halogen it is preferred that R.sub.1 is F or Cl, especially F.
When R.sub.1 is CF.sub.3 it is preferably situated in the m-posit
REFERENCES:
patent: 3000892 (1961-09-01), Janssen
patent: 3962249 (1976-06-01), Irikura
patent: 4219551 (1980-08-01), Seidelmann et al.
patent: 4413006 (1983-11-01), Kanno et al.
Chemical Abstract, vol. 38, 6830b, 1962, "Hypoglycemic Agent".
Chemical Abstracts, vol. 102, 95674j; 1985, "Substituted Piperazin-1-yl-Acetic-Acid Amides and their Use".
Chemical Abstracts, 83, Abs. No. 131539u, (1975) p. 503.
Chemical Abstracts, 85, Abs. No. 33082m (1976) p. 407.
Abramo Aina L.
Christensson Erik G.
Fex Tomas
Olsson Knut G.
Aktiebolaget Leo
Covington Raymond
Raymond Richard L.
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