Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-01-20
1998-08-04
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544357, A61K 31495, C07D40114, C07D40312
Patent
active
057894124
DESCRIPTION:
BRIEF SUMMARY
The present application is a U.S. National Application filed under 35 USC 371 of PCT/FR95/00975, filed Jul. 20, 1995 based upon a French application Ser. No. 94/08981 filed Jul. 20, 1994.
The present invention relates to novel piperazides derived from arylpiperazine, as well as to a process for their preparation, to pharmaceutical compositions containing them and to their use as medicaments.
Serotonin or 5-hydroxytryptamine (5-HT) is a neurotransmitter and a neuromodulator of the central nervous system involved in many physiological and pathological processes. Serotonin plays an important role not only in the nervous system but also in the cardiovascular and gastrointestinal systems. At the central level, serotonin controls functions as varied as sleep, locomotion, feeding, learning and memory, endocrine modulations, sexual behavior and temperature regulation. In the spinal column, serotonin plays an important role in the control systems of the afferent peripheral nociceptors (cf. A. Moulignier, Rev. Neurol. (Paris), 150, 3-15, 1994).
Serotonin may play an important role in various types of pathological conditions such as certain psychiatric disorders (anxiety, depression, aggressiveness, panic attacks, obsessive compulsive disorders, schizophrenia, suicidal tendency), certain neurodegenerative disorders (Alzheimer-type dementia, Parkinsonism, Huntington'chorea), anorexia, bulimia, disorders associated with alcoholism, cerebral vascular accidents, migraine or various headaches (R. Glennon, Neurosci. Biobehavioral Reviews, 14, 35, 1990).
Many recent pharmacological studies have demonstrated the diversity of the serotonin receptors and their respective involvement in these various modes of action (cf. E. Zifa, G. Fillion, Pharm Reviews, 44, 401, 1992; S. Langer, N. Brunello, G. Racagni, J. Mendlecvicz, "Serotonin receptor subtypes: pharmacological significance and clinical implications", Karger Ed. (1992); B. E. Leonard, Int. Clin. Psycho-pharmacology, 7, 13-21 (1992); R. W. Fuller, J. Clin. Psychiatry, 53, 36-45 (1992); D. G. Grahame-Smith, Int. Clin. Psychopharmacology, 6, suppl. 4, 6-13, (1992). These receptors are mainly subdivided into 4 major classes (5HT.sub.1, 5HT.sub.2, 5HT.sub.3 and 5HT.sub.4) which themselves contain subclasses, such as the 5HT.sub.1 receptors which are mainly divided into 5HT.sub.1A, 5HT.sub.1B and 5HT.sub.1D (cf. G. R. Martin, P. A. Humphrey, Neuropharmacol., 33, 261, 1994; P. R. Saxena, Exp. Opin. Invest. Drugs, 3 (5), 513, 1994). The 5HT.sub.1D receptors themselves contain several receptor subtypes; thus, the 5HT.sub.1Da and 5HT.sub.1Db receptors have been cloned and then identified in man (cf. for example E. Hamel et al., Mol. Pharmacol., 44, 242, 1993; G. W. Rebeck et al., Proc. Natl. Acad. Sci. USA, 91, 3666, 1994). Moreover, it has recently been demonstrated that the 5HT.sub.1B self-receptors in rodents and 5HT.sub.1D in other species were capable of controlling the release of serotonin in nerve endings (cf. M. Briley, C. Moret, Cl. Neuropharm. 16, 387, 1993; B. E. Leonard, Int. Clin. Psychopharmacol., 9, 7, 1994) as well as the release of other neurotransmitters such as norepinephrine, dopamine or acetylcholine (M. Harrigton, J. Clin. Psychiatry, 53, 10, 1992).
Compounds having a selective antagonist activity towards the central 5HT.sub.1D receptors, such as the novel compounds described in the present invention, can thus exert a beneficial effect on individuals suffering from central nervous system disorders. In particular, such compounds are useful in the treatment of pain, cancer, locomotion disorders, depression, anxiety, panic attacks, agoraphobia, obsessive compulsive disorders, memory disorders including dementia, amnesia, appetite disorders, sexual dysfunctioning, Alzheimer's disease and Parkinson's disease. 5HT.sub.1D antagonists are also useful in the treatment of endocrine disorders such as hyperprolactinaemia, the treatment of vasospasms, of hypertension and of gastrointestinal disorders in which changes in motility and in secretion are involved.
The compounds
REFERENCES:
Popescu, Chemical Abstracts, vol. 68, No. 105151, 1968.
Pestellini et al, Chemical Abstracts, vol. 90 No. 132586, 1979.
Millan et al, Journal of Pharmacology and Experimental Therapeutics, 262, pp. 451-463, 1992.
Buzzl et al, Chephalagia 15, pp. 277-280, 1995.
Halazy Serge
Jorand Catherine
Pauwels Peter
Bernhardt Emily
Pierre Fabre Medicament
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