Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-17
2003-07-01
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S181000, C548S190000, C548S193000
Reexamination Certificate
active
06586456
ABSTRACT:
The present invention relates to novel branched aminothiazole derivatives, to a process for preparing them and to pharmaceutical compositions containing them. These novel thiazole derivatives have antagonist activity towards CRF (corticotropin releasing factor) and can thus constitute active principles for pharmaceutical compositions.
Corticotropin releasing factor (CRF) is a peptide whose sequence of 41 amino acids was characterized by W. Vale et al. in 1981 (Science, 1981, 213, 1394-1397). CRF is the main endogenous factor involved in regulating the hypothalamo-hypophysoadrenal axis (release of adrenocorticotropic hormone: ACTH) and its pathologies, as well as in the depressive syndromes arising therefrom. CRF also brings about the secretion of &bgr;-endorphin, &bgr;-lipotropin and corticosterone. CRF is thus the physiological regulator of the secretion of adrenocorticotropic hormone (ACTH) and more generally of peptides derived from propiomelanocortin (POMC). Besides its location in the hypothalamus, CRF is also widely distributed in the central nervous system, as well as in extra-neuronal tissues such as the adrenal glands and the testicles. The presence of CRF has also been demonstrated in the course of inflammatory processes.
Numerous animal experiments have shown that the central administration of CRF causes various anxiogenic effects such as modification of the behaviour in general: for example neophobia, reduction in sexual receptivity, decrease in food consumption and in slow-wave sleep in rats. 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 rats, the central or peripheral administration of CRF or of similar peptides (for example urocortine or sauvagine) induces, in addition to central effects such as heightening consciousness and emotional reactivity towards the environment, modifications in gastric drainage, in acid secretion, in intestinal transit and in faecal excretion, as well as tension effects. CRF is also involved in the complex regulation of inflammatory responses, firstly with a pro-inflammatory role in certain animal models, and secondly as an inhibitor of the effects induced by increasing the vascular permeability following inflammation.
The use of a peptide antagonist, alpha-helical CRF(9-41) (&agr;-CRF) or of specific antibodies (Rivier J. et al., Science, 1984, 224, 889-891) confirms the role of this peptide in all of these effects. These experiments also confirmed the important role of CRF in man in the integration of the complex responses observed during a physiological, psychological or immunological stress both in neuroendocrinal and visceral as well as behavioural terms (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 argue in favour of the effective involvement of CRF in the 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 demonstrate the modification of the ACTH response in depressive patients (Breier A. et al., Am. J. Psychiatry, 1987, 144, 1419-1425),
the discovery of a hypersecretion of endogenous CRF in certain pathologies, for example an elevated level of CRF in the cephalorrachidian fluid in non-medicated patients who are depressed or suffering from a dementia such as Alzheimer's disease (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 severe pathologies such as Alzheimer's disease, Parkinson's disease, 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 under stress conditions. When they are repeated over time, these effects may result in various pathologies such as: fatigue, hypertension, cardiac and tension disorders, modification of gastric drainage or of faecal excretion (colitis, irritable bowel), modification of acid secretion, hyperglycaemia, retarded growth, anorexia, neophobia, migraines, reproductive disorders, immunosuppression (inflammatory processes, multiple infections and cancers) and various neuropsychiatric disorders (depression, anorexia nervosa and anxiety).
The intracerebroventricular injection of the reference peptide antagonist, &agr;-CRF, prevents the effects obtained either by administration of exogenous CRF or by the use of stress-inducing agents (ether, restraint, noise, electric shock, ethanol withdrawal symptoms or surgery) which are 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 that are structurally similar to CRF and that have a prolonged duration of action relative to &agr;-CRF (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 described, for example, in U.S. Pat. Nos. 5,109,111, 5,132,111 and 5,245,009 and in patent applications WO 92/22576 and WO 96/19499.
In addition, preliminary studies have shown that tricyclic antidepressants can modulate the level of CRF as well as the number of CRF receptors in the brain (Grigoriadis D. E. et al., Neuropsychopharmacology, 1989, 2, 53-60). Similarly, benzodiazepine anxiolytic agents are capable of reversing the effect of CRF (Britton K. T. et al., Psychopharmacology, 1988, 94, 306), although the mechanism of action of these substances has not been entirely elucidated. These results reinforce, 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, namely 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 many species (mice, rats and man) as well as in the heart, the skeletal muscle (rats and mice) and in the myometrium and the placenta during pregnancy.
A large number of 2-aminothiazole derivatives are already known. Patent application EP 462 264 describes 2-aminothiazole derivatives, in which the tertiary amine in position 2 comprises two substituents each containing at least one hetero atom including an amine derivative. These compounds are platelet activation factor antagonists (PAF-acether) and find their applications in the treatment of asthma, certain allergic or inflammatory conditions, cardiovascular diseases, hypertension and various renal pathologies, or alternatively as contraceptive agents.
Patent application GB 2 022 285 describes compounds with regulatory activity on the immune response and with anti-inflammatory properties. These are thiazole derivatives substituted in position 2 with secondary amine groups.
Certain 2-acylaminothiazole derivatives have been described in patent application EP 432 040. These compounds are antagonists of cholecystokinin and gastrin.
2-Amino-4,5-diphenylthiazole derivatives with anti-inflammatory properties are also known (patent application JP-01 75 475).
2-Amino-4-(4-hydroxyphenyl)thiazole derivatives which are useful as synthetic intermediates for the preparation of 2,2-diarylchromenothiazole derivatives are also known (patent application EP 205 069).
2-(N-Methyl-N-benzylamino)thiazole derivatives are also described in J. Chem. Soc. Perkin, Trans. 1, 1984, 2, 147-153 and in J. Chem. Soc. Perkin, Trans. 1, 1983, 2, 341-347.
Fontaine Evelyne
Geslin Michel
Gully Danielle
Pradines Antoine
Roger Pierre
Alexander Michael D.
Dupont Paul E.
Sanofi-Synthelabo
Stockton Laura L.
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