Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-06-12
2004-10-19
Solola, Taofiq (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S264800
Reexamination Certificate
active
06806282
ABSTRACT:
A subject-matter of the present invention is novel branched substituted amino derivatives of 3-amino-1-phenyl-1H-[1,2,4]triazole, processes for their preparation and the pharmaceutical compositions comprising them.
These novel triazole derivatives have an antagonistic activity with respect to CRF (corticotropin releasing factor) and can thus constitute active principles of pharmaceutical compositions.
Corticotropin releasing factor (CRF) is a peptide whose sequence of 41 amino acids was characterized by Vale W. et al. in 1981 (Science, 1981, 213, 1394-1397). CRF is the main endogenous factor involved in the regulation of the hypothalamohypophysosuprarenal axis (release of adrenocorticotropic hormone: ACTH) and its pathologies, and also in the depressive syndromes which result from its dysfunctioning. CRF also causes the secretion of &bgr;-endorphin, of &bgr;-lipotropin and of corticosterone. CRF is therefore the physiological regulator of the secretion of adrenocorticotropic hormone (ACTH) and of cortisol by the effect of ACTH at the suprarenal level and more generally of peptides derived from proopiomelanocortin (POMC). In addition to its location in the hypothalamus, CRF is widely distributed in the central nervous system but also in extraneuronal tissues, such as the suprarenal glands and the testicles. The presence of CRF has also been demonstrated during inflammatory processes.
Numerous animal experiments have shown that the central administration of CRF causes varied anxiogenic effects, such as modification of the behaviour in general: for example neophobia, reduction in sexual receptivity and decrease in food consumption and slow-wave sleep in the rat. The intracerebroventricular injection of CRF also increases the excitation of the noradrenergic neurons of the locus coeruleus which is often associated in animals with a state of anxiety. In the rat, the central or peripheral administration of CRF or of related peptides (for example urocortin, sauvagine) induces, in addition to central effects, such as increase in alertness and in emotional reactivity to the surroundings, modifications in gastric dumping, in acid secretion, in intestinal transit time and in faecal excretion, as well as tensional effects. CRF is also involved in the complex regulation of inflammatory responses, on the one hand with a pro-inflammatory role in some animal models (degranulation of mastocytes resulting in the release of inflammatory molecules, such as histamine, prostaglandins, and the like) and, on the other hand, as inhibitor of the effects brought about by the increase in the vascular permeability as a result of the inflammation.
The use of a peptide antagonist, &agr;-helical CRF(9-41) (&agr;H-CRF), or of specific antibodies (Rivier J. et al., Science, 1984, 224, 889-891) has made it possible to confirm the role of this peptide in all these effects. These experiments have also confirmed the important role of CRF in man in the integration of the complex responses observed during physiological, psychological or immunological stress, simultaneously at the neuroendocrinal, visceral and behavioural levels (Morley J. E. et al., Endocrine Review, 1987, 8, 3, 256-287; Smith M. A. et al., Horm. Res., 1989, 31, 66-71). In addition, clinical data militate in favour of the effective involvement of CRF in many disorders resulting from a condition of stress (Gulley L. R. et al., J. Clin. Psychiatry, 1993, 54, 1, (suppl.), 16-19), for example:
the existence of the CRF test (i.v. administration) in man has made it possible to show the modification in the ACTH response in depressive patients (Breier A. et al., Am. J. Psychiatry, 1987, 144, 1419-1425).
the discovery of an endogenous CRF hypersecretion in certain pathologies, for example a high level of CRF in the cephalorrhachidian fluid in non-medicated patients who are depressed or affected by dementia of Alzheimer's disease type (Nemeroff C. B. et al., Science 1984, 226, 4680, 1342-1343; Regul. Pept., 1989, 25, 123-130) or a decreased density of CRF receptors in the cortex of suicide victims (Nemeroff C. B. et al., Arch. Gen. Psychiatry, 1988, 45, 577-579).
the dysfunctioning of CRF-dependent neurons is even suggested in the severe pathologies which are Alzheimer's and Parkinson's diseases, Huntington's chorea and amyotrophic lateral sclerosis (De Souza E. B., Hospital Practice, 1988, 23, 59).
The central administration of CRF in many animal species produces behavioural effects similar to those obtained in man in stress situations. When they are repeated over time, these effects can result in various pathologies, such as: fatigue, hypertension, heart and tensional disorders, modification in gastric dumping and in faecal excretion (colitis, irritable bowel), modification in acid secretion, hyperglycaemia, retarded growth, anorexia, neophobia, migraines, reproductive disorders, immunosuppression (inflammatory processes, multiple infections and cancers) and varied neuropsychiatric disorders (depression, anorexia or bulimia nervosa and anxiety).
The injection via the intracerebroventricular route of the reference peptide antagonist, &agr;H-CRF (9-41), prevents the effects obtained either by the administration of exogenous CRF or by the use of stress-inducing agents (ether, restraint, noise, electric shock, weaning from ethanol or surgery) capable by themselves of inducing an increase in the level of endogenous CRF. These results are confirmed by the study of many antagonist peptide molecules which are structurally related to CRF and which have a prolonged duration of action with respect to &agr;H-CRF (9-41) (Rivier J. et al., J. Med. Chem., 1993, 36, 2851-2859; Menzaghi F. et al., J. Pharmacol. Exp. Ther., 1994, 269, 2, 564-572; Hernandez J. F. et al., J. Med. Chem., 1993, 36, 2860-2867).
Such CRF-antagonist peptide compounds are disclosed, for example, in U.S. Pat. No. 5,109,111, U.S. Pat. No. 5,132,111 and U.S. Pat. No. 5,245,009 and in patent applications WO 92/22 576 and WO 96/19 499.
In addition, preliminary studies have shown that tricyclic anti-depressants can modulate the level of CRF and the number of rCRF receptors in the brain (Grigoriadis D. E. et al., Neuropsychopharmacology, 1989, 2, 53-60). Likewise, benzodiazepine anxiolytics are capable of inhibiting the effect of CRF (Britton K. T. et al., Psychopharmacology, 1988, 94, 306), without the mechanism of action of these substances being entirely elucidated. These results confirm, if necessary, the growing need for non-peptide antagonist molecules for CRF receptors.
It is also important to point out three possible consequences of conditions of chronic stress, which are immunodepression, fertility disorders and the development of diabetes.
CRF exerts such effects by interacting with specific membrane receptors which have been characterized in the pituitary gland and the brain of numerous species (mouse, rat and man), as well as in the heart, the squelettal muscle (rat, mouse) and in the myometrium and the placenta during pregnancy.
The 3-amino-1-phenyl-1H-[1,2,4]triazole compounds are not represented to any great extent. Mention may be made in particular of compounds carrying a phenyl at the 5-position as disclosed by Ebenreth A. et al. (Pharmazie, 1992, 47(7), 556-7) and by Bozo E., Szilagil G. and Janaky J. (Arch. Pharm., 1989, 322(10), 583-7, Patents Nos. HU44522, HU195791, 1986), who claim antiinflammatory-antirheumatic properties. In two Japanese patents (JP 02091061 and JP 2729810, 1988), Inamori et al. claim the preparation of 3-amino-1-phenyl-1H-[1,2,4]triazoles as insecticides.
In the Neurocrine patent application published under the number WO 96/39 400, 3-amino-5-phenyl-1H-[1,2,4]triazole compounds are disclosed as antagonists of CRF receptors.
It has now been found, according to the present invention, that some 3-amino-1-phenyl-1H-[1,2,4]triazole derivatives which are a subject-matter of the present invention have an excellent affinity with respect to CRF receptors. Furthermore, due to their structure, these molecule
Geslin Michel
Gully Danielle
Maffrand Jean-Pierre
Roger Pierre
Alexander Michael D.
Dupont Paul E.
Sanofi-Synthelabo
Solola Taofiq
LandOfFree
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