Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-06-02
2002-04-30
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S181000
Reexamination Certificate
active
06380230
ABSTRACT:
This application is a 371 of PCT/FR98/02007 filed Sep. 18, 1998.
The present invention relates to cholecystokinin (CCK)-agonist substituted thiazoles and more particularly agonists of the cholecystokinin type A (CCK-A) receptors, to a process for their preparation and to medicines containing them.
CCK is a peptide which, in response to an ingestion of food, is secreted peripherally and participates in regulating many digestive processes (Crawley J. N. et al., Peptides, 1994, 15 (4), 731-735).
CCK has also been identified in the brain, and might be the most abundant neuropeptide acting as a neuromodulator of cerebral functions by stimulation of CCK-B type receptors (Crawley J. N. et al., Peptides, 1994, 15 (4), 731-735). In the central nervous system, CCK interacts with dopamine-mediated neuronal transmission (Crawley J. N. et al., ISIS Atlas of Sci., Pharmac., 1988, 84-90). It also plays a role in mechanisms involving acetylcholine, GABA (&ggr;-aminobutyric acid), serotonin, opioids, somatostatin, and substance P and in ion channels.
Its administration brings about physiological changes: palpebral ptosis, hypothermia, hyperglycaemia, catalepsis; and behaviour changes: hypolocomotion, reduction in searching, analgesia, a change in the learning faculty and a change in sexual behaviour and satiety.
CCK exerts its biological activity via at least two types of receptors: CCK-A receptors located mainly peripherally, and CCK-B receptors essentially present in the cerebral cortex. The CCK-A receptors of peripheral type are also present in certain zones of the central nervous system, including the postrema area, the tractus solitarius nucleus and the interpedoncular nucleus (Moran T. H. et al., Brain Research, 1986, 362, 175-179; Hill D. R. et al., J. Neurosci., 1990, 10, 1070-1081; with, however, specific differences (Hill D. R. et al., J. Neurosci., 1990, 10, 1070-1081); Mailleux P. et al., Neurosci. Lett., 1990, 117, 243-247; Barrett R. W. et al., Mol. Pharmacol., 1989, 36, 285-290; Mercer J. G. et al., Neurosci Lett., 1992, 137, 229-231; Moran T. H. et al., Trends in Pharmacol. Sci., 1991, 12, 232-236).
At the peripheral level, via the CCK-A receptors (Moran T. H. et al., Brain Research, 1986, 362, 175-179), CCK delays gastric drainage, modulates intestinal motility, stimulates vesicle contraction, increases bile secretion and controls pancreatic secretion (McHugh P. R. et al., Fed. Proc., 1986, 45, 1384-1390; Pendleton R. G. et al., J. Pharmacol. Exp. Ther., 1987, 241, 110-116).
The role of CCK in the satiety signal is supported by the fact that the plasmatic concentrations of CCK, which are dependent on the composition of the meals (high concentrations of proteins or lipids) are, after meals, higher than those observed before meals (Izzo R. S. et al., Regul. Pept., 1984, 9, 21-34; Pfeiffer A. et al., Eur. J. Clin. Invest., 1993, 23, 57-62; Lieverse R. J., Gut, 1994, 35, 501). In bulimia sufferers, there is a decrease in the secretion of CCK induced by a meal, (Geraciotti T. D. Jr. et al., N. Engl. J. Med., 1988, 319, 683-688; Deylin M. J. et al., Am. J. Clin. Nutr., 1997, 65, 114-120) and a lowering of the CCK concentrations in the cerebrospinal fluid (Lydiard R. B. et al., Am. J. Psychiatry, 1993, 150, 1099-1101). In the T lymphocytes, which is a cell compartment that may reflect central neuronal secretions, the basal CCK concentrations are significantly lower in patients suffering from bulimia nervosa (Brambilla F. et al., Psychiatry Research, 1995, 37, 51-56). Treatments (for example with L-phenylalanine, or trypsin inhibitors) which increase the secretion of endogenous CCK give rise to a reduction in feeding in several species, including man (Hill A. J. et al., Physiol. Behav., 1990, 48, 241-246; Ballinger A. B. et al., Metabolism, 1994, 43, 735-738). Similarly, the administration of exogenous CCK reduces feeding in many species, including man (Crawley J. N. et al., Peptides, 1994, 15, 731-755).
The inhibition of feeding by CCK is mediated by the CCK-A receptor. Devazepide, an antagonist which is selective for the CCK-A receptors, inhibits the anorexigenic effect of CCK, whereas the selective agonists of these receptors inhibit feeding (Asin K. E. et al., Pharmacol. Biochem. Behav., 1992, 42, 699-704; Elliott R. L. et al., J. Med. Chem., 1994, 37, 309-313; Elliott R. L. et al., J. Med. Chem., 1994, 37, 1562-1568). Furthermore, OLEFT rats, which do not express the CCK-A receptor, are insensitive to the anorexigenic effect of CCK (Miyasaka K. et al., 1994, 180, 143-146).
Based on these lines of evidence of the key role of CCK in the peripheral satiety signal, the use of CCK agonists and antagonists as medicines in the treatment of certain eating behaviour disorders, obesity and diabetes is indisputable. A CCK-receptor agonist can also be used therapeutically in the treatment of emotional and sexual behaviour disorders and memory disorders (Itoh S. et al., Drug. Develop. Res., 1990, 21, 257-276), schizophrenia, psychosis (Crawley J. N. et al., Isis Atlas of Sci., Pharmac., 1988, 84-90 and Crawley J. N., Trends in Pharmacol. Sci., 1991, 12, 232-265), Parkinson's disease (Bednar I. et al., Biogenic amine, 1996, 12 (4), 275-284), tardive dyskinesia (Nishikawa T. et al., Prog. Neuropsychopharmacol. Biol. Psych., 1988, 12, 803-812; Kampen J. V. et al., Eur. J. Pharmacol., 1996, 298, 7-15) and various disorders of the gastrointestinal sphere (Drugs of the Future, 1992, 17 (3), 197-206).
CCK-A receptor agonists of CCK are described in the literature. For example, certain products having such properties are described in EP 383,690 and WO 90/06937, WO 95/28419, WO 96/11701 or WO 96/11940.
Most of the CCK-A receptor agonists described to date are of peptide nature. Thus, FPL 14294 derived from CCK-7 is a powerful, unselective CCK-A receptor agonist towards CCK-B receptors. It has powerful inhibitory activity on feeding in rats and in dogs after intranasal administration (Simmons R. D. et al., Pharmacol. Biochem. Behav., 1994, 47 (3), 701-708; Kaiser E. F. et al., Faseb, 1991, 5, A864). Similarly, it has been shown that A-71623, a tetrapeptide agonist which is selective for CCK-A receptors, is effective in models of anorexia over a period of 11 days and leads to a significant reduction in weight gain when compared with the control in rodents and cynomologous monkeys (Asin K. E. et al., Pharmacol. Biochem. Behav., 1992, 42, 699-704). Similarly, structural analogues of A 71623, which have good efficacy and selectivity for CCK-A receptors, have powerful anorexigenic activity in rats (Elliott R. L. et al., J. Med. Chem., 1994, 37, 309-313; Elliott R. L. et al., J. Med. Chem., 1994, 37, 1562-1568). GW 7823 (Henke B. R. et al., J. Med. Chem., 1996, 39, 2655-2658; Henke B. R. et al., J. Med. Chem., 1997, 40, 2706-2725), a 1,5-benzodiazepine, is an in vitro CCK-A receptor agonist. This molecule is also active orally on the contraction of the bile vesicle in mice and on feeding in rats.
Cholecystokinin-antagonist substituted thiazoles are described in European patent EP 432,040 and European patent application EP 518,731.
European patent application EP 518,731 describes compounds which interact with the gastrin and cholecystokinin receptors, of formula:
in which:
Z
1
can in particular be an indolyl group of formula:
in which X
i
has various meanings and R
z
can be hydrogen; a (C
1
-C
4
)alkyl group; an optionally esterified carboxyalkylene group of formula Z
2
COOR in which Z
2
is a (C
1
-C
4
)alkylene and R is H, a benzyl, a (C
1
-C
6
)alkyl; a carbamoylalkylene group of formula Z
2
CONR
IV
R
V
in which R
IV
and R
V
are each independently hydrogen, a (C
1
-C
6
)alkyl or form a saturated heterocycle with the nitrogen; an acyl group of formula COR
VI
in which R
VI
is a (C
1
-C
4
)alkyl or a phenyl; an alkoxycarbonyl group of formula COOR
VII
in which R
VII
is a tert-butyl or a benzyl.
However, among the compounds of formula 1 described in that application, none contains an indolyl group simultaneously containing groups Xi and R
z
, which are other than hydrogen. The compounds
Bignon Eric
Boigegrain Robert
Brodin Roger
Molimard Jean Charles
Olliero Dominique
Alexander Michael D.
Dupont Paul E.
Gerstl Robert
Sanofi-Synthelabo
LandOfFree
Carboxamidothiazole derivatives, preparation, pharmaceutical... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Carboxamidothiazole derivatives, preparation, pharmaceutical..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Carboxamidothiazole derivatives, preparation, pharmaceutical... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2817062