Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-03-12
1999-09-28
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514299, 546112, 546132, C07D45104, C07D45114, A61K 31435, A61K 3144
Patent
active
059589450
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel azabicyclonaphthalenecarboxamide derivatives, to a process for their preparation and to their use as drugs.
These compounds are antidopaminergic and antiserotoninergic agents and are thus used as antipsychotic drugs for treating schizophrenia, its positive and negative symptoms, or disorders of the central nervous system that are sensitive to antidopaminergic and antiserotoninergic treatment, such as, for example, compulsive obsessive disorders, anxiety, depression, drug addiction, tardive dyskinesia and gastrointestinal disorders.
The need to have antidopaminergic activity, in particular on the dopaminergic receptors of the subclass D.sub.2, constitutes a standard approach in the treatment of schizophrenia (Carlsson A., Am. J. Psychiatry, 135, 164, 1978). However, most of the compounds having such a mechanism of action have the drawback of possessing undesirable clinical side effects, in particular extrapyramidal side effects (see Acta Psychiatr. Scand. 1995, 91 (Suppl 388): 24-30).
It has been seen that the fact of combining with powerful antidopaminergic activity, in the same molecule, antagonist activity towards the serotoninergic receptors of the 5-HT.sub.2 subclass might constitute a condition for avoiding these extrapyramidal side effects (H. Y. Meltzer J.P.E.T. 1989, 251, 238).
U.S. Pat. No. 5,395,835 describes naphthamides of formula ##STR2## in which the naphthalene ring-system is variously substituted with variable groups R, these products being antidopaminergic agents of the D.sub.3 subclass, which are useful as antipsychotic agents for the treatment of schizophrenia or other pathologies which respond to blocking of the dopaminergic receptors.
Patent EP 539,281 describes naphthamides of formula ##STR3## in which Z represents a residue derived from 2-aminomethyl-N-alkylpyrrolidine, 2-aminoethyl-N,N-diethylamine, 2-aminoethylmorpholine, 2-aminoethyl-N,N-dibutylamine or 4-amino-N-butyl (or N-benzyl) piperidine, which are active on the dopaminergic system, in particular the D.sub.3 receptor subclass, and are useful as antipsychotic agents, psychostimulants, antiautistic agents, antidepressants, anti-Parkinson agents and antihypertensive agents. The compound which is structurally most similar to the compounds of the present invention corresponds to the above structure in which R=H, Y=CH.sub.3, X=H, and Z=4-amino-N-benzylpiperidine, and will be referred to hereinbelow as: patent EP 539,281 compound.
Patent EP 585,116 describes 1-alkoxynaphthalene-2-carboxamides, with a high degree of affinity for the 5-HT.sub.1A serotoninergic receptors, of formula ##STR4##
U.S. Pat. No. 4,536,580 describes nortropane benzamide derivatives with neuroleptic properties, of formula ##STR5## where A represents a variously substituted pyrimidine or benzene ring, the most powerful product being compound No. 64 (tropapride) (Drug of the Future, Vol. 9, No. 9, 673).
Patent EP 416,521 describes compounds of naphthamide tropane type, of structure: ##STR6## where R.sub.2 may be a naphthalene ring-system, which is either unsubstituted or substituted with an alkyl group of 1 to 10 carbon atoms. These compounds are active in the cardiovascular field.
Patent WO 84/03281 describes compounds of azabicyclo-alkylbenzamide type, of formula ##STR7## where R.sub.4 may be a tropane skeleton and the ring formed by the junction A--E may be a heterocycle and form a quinoline.
However, it does not appear, or is not suggested in the abovementioned patents, that the fact of combining a 3-.beta.-aminotropane skeleton with an aromatic 1-alkoxy-2-naphthamide system can give compounds having this double activity: simultaneously dopaminergic antagonist and agonist on the D.sub.2 subclass, and simultaneously serotoninergic antagonist and agonist, this being the basis of the present invention.
The best balance represented by the derivatives of the invention between the serotoninergic receptors, in particular, but not exclusively, the 5-HT.sub.2 receptors, in comparison with the dopaminergic D.sub.2 receptors, make
REFERENCES:
patent: 5395835 (1995-03-01), Glase
Imbert Thierry
Koek Wouter
Monse Barbara
Pierre Fabre Medicament
Rotman Alan L.
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