Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-02
2002-02-05
Gerstl, Robert (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S190000
Reexamination Certificate
active
06344470
ABSTRACT:
The subject of the present invention is new branched amino derivatives of thiazole, a process for preparing them and pharmaceutical compositions containing them. These new thiazole derivatives are endowed with CRF (corticotropin releasing factor) antagonizing activity and can therefore constitute active ingredients in pharmaceutical compositions.
Corticotropin releasing factor (CRF) is a peptide whose sequence of 41 amino acids has been characterized by Vale W. et al. in 1981 (Science, 1981, 213, 1394-1397). CRF is the principal endogenous factor involved in the regulation of the hypothalamohypophysoadrenal axis (release of the adrenocorticotropic hormone: ACTH) and its pathologies, as well as in the depressive syndromes which result therefrom, CRF also causes the secretion of &bgr;-endorphin, &bgr;lipotropin and corticosterone. CRF is therefore the physiological regulator of the secretion of the adrenocorticotropic hormone (ACTH) and more generally of the peptides derived from pro-opiomelanocortin (POMC). In addition to its hypothalamic localization, CRF is widely distributed in the central nervous system, but also in extraneuronal tissues such as the adrenal 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 various anxiogenic effects such as the modification of behaviour in general: for example neophobia, reduction in sexual receptivity, decrease in food consumption and lingering 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 related peptides (for example urocortin, sauvagin) induces, in addition to central effects such as an increase in wakefulness and in emotional reactivity towards the surroundings, modifications in the emptying of the stomach, in acid secretion, in intestinal transit and in faecal excretion as well as tensional effects. CRF is also involved in the complex regulation of the inflammatory responses, on the one hand with a pro-inflammatory role in certain animal models, on the other hand as inhibitor of the effects induced by the increase in vascular permeability following the inflammation.
The use of a peptide antagonist, alpha-helical CRF (
9-41
) (ah-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 of these effects. These experiments have also confirmed the important role of CRF in humans in the integration of the complex responses observed during a physiological, psychological or immunological stress both from the neuroendocrinal, visceral and behavioural point of view (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 numerous disorders resulting from a state of stress (Gulley L. R. et al., J. Clin. Psychiatry, 1993, 54, 1, (suppl.), 16-19) for example:
the existence of the CRF-based test (i.v. administration) in humans 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 hypersecretion of endogenous CRF in certain pathologies, for example of a high CRF level in the cephalorachidien fluid in non medicated patients, depressed patients or patients suffering from dementia of the Alzheimer's disease type (Nemeroff C. B. et al., Science, 1984, 226, 4680, 1342-1343; Regul. Pept., 1989, 25, 123-130), or of a reduced density of CRF receptors in the cortex of victims of suicide (Nemeroff C. B. et al., Arch. Gen. Psychiatry, 1988, 45, 577-579);
the dysfunction of the CRF-dependent neurons is even suggested in severe pathologies such as Alzheimer's disease, Parkinson's disease, Huntingdon's chorea and amyotrophic lateral sclerosis (De Souza, E. B., Hospital Practice, 1988, 23, 59).
The central administration of CRF in numerous animal species produces behavioural effects similar to those obtained in man in situations of stress. When they are repeated over time, these effects can cause various pathologies such as fatigue, hypertension, cardiac disorders, modification in the emptying of the stomach, in faecal exretion (colitis, irritable colon), modification in acid secretion, hyperglycaemia, retarded growth, anorexia, neophobia, reproductive disorders, immunosuppression (inflammatory processes, multiple infections and cancers) and various neuropsychiatric disorders (depression, nervous anorexia and anxiety).
The injection, by the intracerebroventricular route, of the reference peptide antagonist, ah-CRF, prevents the effects obtained either by the administration of exogenous CRF, or by the use of stress-causing agents (ether, constraint, noise, electric shock, alcohol withdrawal, surgery) which are capable, by themselves, of inducing an increase in the endogenous CRF level. These results are confirmed by the study of numerous antagonist peptide molecules which are structurally related to CRF and which possess a prolonged duration of action compared with ah-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-antagonizing peptide compounds are described, for example, in U.S. Pat. Nos. 5,109,111, 5,132,111, 5,245,009 and in Patent Applications WO 92 22576 and WO 96 19499.
In addition, preliminary studies have shown that tricyclic antidepressants could modulate the CRF level as well as the number of CRF receptors in the brain. (Grigoriadis D. E., et al, Neuropsychopharmacology, 1989, 2, 53-60). Likewise, benzodiazepine anxiolytics are capable of reversing the effect of CRF (Britton K. T. et al., Psychopharmacology, 1988, 94, 306), without the mechanism of action of these substances being completely elucidated. These results strengthen, if necessary, the increasing need for molecules which are nonpeptide antagonists of the CRF receptors.
It is important to also report three possible consequences of the states of chronic stress which are immunodepression, fertility disorders as well as the appearance of diabetes.
CRF exerts such effects by interacting with specific membrane receptors which have been characterized in the hypophysis and the brain of numerous species (mice, rats and humans) as well as in the heart, the skeletal muscle (rats, 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 whose tertiary amine in the 2 position comprises two substituents each having at least one heteroatom including one amine derivative. These compounds are antagonists of the platelet activating factor (PAF-acether) and find applications in the treatment of asthma, of certain allergic or inflammatory states, of cardiovascular diseases, of hypertension and of various renal pathologies or alternatively as contraceptive agents.
Application GB 2 022 285 describes compounds possessing an activity which regulates the immune response and having anti-inflammatory properties. They are thiazole derivatives which are substituted at the 2 position with secondary amine groups.
Some 2-acylaminothiazole derivatives have been described in Patent Application EP 432 040. These compounds are antagonists of cholecystokinin and of gastrin.
2-Amino-4, 5-diphenylthiazole derivatives having anti-inflammatory properties are also known (Patent Application JP-01 75 475).
2-Amino-4-(4-hydroxyphenyl)thiazole derivatives which are useful as synthesis intermediates for the preparation of 2,2-diarylchromenothiazole derivatives are also known (Patent Application EP 205 069). 2-(N-methyl-N-benzylamino)thiazo
Fontaine Evelyne
Gully Danielle
Roger Pierre
Wermuth Camille Georges
Alexander Michael D.
Gerstl Robert
Sanofi-Synthelabo
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