Substituted 4-phenylaminothiazoles, their process of preparation

Details Substituted 4-phenylaminothiazoles, their process of preparation Substituted 4-phenylaminothiazoles, their process of preparation

1997-12-22

1999-03-09

Davis, Zinna Northington

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514310, 514311, 514313, 514394, 514249, 514257, 514414, 514370, 546143, 546148, 546159, 546167, 548190, 5483047, 548465, 544235, 544353, 544356, C07D27742, C07D41712, A61K 31425

Patent

active

058801359

DESCRIPTION:

BRIEF SUMMARY
This application is a .sctn.371 of PCT/FR96/00941, filed Jun. 18, 1996.


SUMMARY

The invention relates to substituted aminothiazoles of formula: ##STR2## in which R.sub.1 to R.sub.6, n and Z are as defined in claim 1.
The subject of the present invention is new substituted branched aminothiazoles, and a process for their preparation. These new substituted compounds generally have an antagonist activity with respect to CRF (corticotropin releasing factor) and can therefore 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 regulation of the hypothalamohypophysosuprarenal axis (release of adrenocorticotropic hormone: ACTH) and its pathologies, as well as in the depressive syndromes which result therefrom. CRF also causes secretion of .beta.-endorphin, of .beta.-lipotropin and of corticosterone.
CRF is therefore the physiological regulator of the secretion of adrenocorticotropic hormone (ACTH) and more generally of peptides derived from pro-opiomelano-cortin (POMC). Although located in the hypothalamus, CRF is also widely distributed in the central nervous system (limbic area), in which it plays the role of neurotransmitter and/or of neuromodulator, independently of its effects on the hypothalamohypophysosuprarenal axis.
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 causes modifications in gastric dumping, in intestinal transit time, in faecal excretion and in acid secretion, as well as tensional effects. The specific involvement of CRF in these effects was demonstrated by 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), which makes it possible to confirm the role of this peptide in the development of endocrinal and behavioural disorders related to stress.
Indeed, these experiments show that CRF plays an important role 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), such as: possible to show the modification in the ACTH response in depressive patients (Breier A. et al., Am. J. Psychiatry, 1987, 144, 1419-1425). for example a high level of CRF in the cephalorhachidian 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). pathologies of 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 with time, these effects can result in various pathologies, such as: fatigue syndrome, hypertension, heart disorders, modification in gastric dumping and in faec

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