Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
2000-03-27
2000-11-07
O'Sullivan, Peter
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
564256, A61K 3115, C07C25158
Patent
active
061437921
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel use of a specific 5HT.sub.2A receptor antagonist.
1-(2-fluorophenyl)-3-(4-hydroxyphenyl)-prop-2-en-1-one-O-2-dimethylamino ethyl)-oxime of formula (I) and its pharmaceutically acceptable salts are described in the European patent 0 373 998 Bi as 5HT.sub.2 receptor to antagonists: ##STR1##
More particularly, the hemifumarate of (1Z, 2E)-1-(2-fluorophenyl)-3-(4-hydroxyphenyl)-prop-2-en-1-one-O-(2-dimethylam inoethyl)-oxime, known under the code name SR 46349 B and hereafter designated compound A, has been studied with respect to its pharmacological and biochemical properties. Compound A is a specific 5HT.sub.2A receptor antagonist, in that it has no affinity for the 5HT.sub.1A, 5HT.sub.1B and 5HT.sub.1D receptors and a slight affinity for the 5HT.sub.2C receptor; in studies on isolated tissues, the absence of activity of compound A on the stomachal fundus of the rat indicates a 5HT.sub.2A versus 5HT.sub.2B specificity (M. Rinaldi-Carmona et al., J. Pharmacol. Exp; Ther., 1992, 262, 2, 759-768). In the rodent, it has been shown that this compound binds mainly to the brain regions containing the 5HT.sub.2 receptor (M. Rinaldi-Carmona et al., Life Sciences, 1993, 54, 119-127).
Studies on sleep have shown that certain 5HT.sub.2 receptor antagonists like ritanserin, amoxapine and ICI 169 369 modify the architecture of sleep and regulate or increase the time of slow-wave sleep (G. Loas, L'encephale, 1991, XVII, 423-425)
The central mechanisms by which serotonin modulates respiratory activity have been studied and it was found that, among the different families of receptors, only the 5HT.sub.1 receptors and the 5HT.sub.2 receptors have a central effect on respiratory activity (R. Monteau et al., Eur. J. Pharmacol., 1994, 259, 71-74).
In the same article, these authors studied, in vitro, on tissue preparations from newborn rats, with the aid of compound A, which receptor subtypes are implicated in the modulation of respiratory activity. They observed that pretreatment with compound A prevents or significantly reduces the cervical tonic activity induced by 5-hydroxytryptamine and attributed to the activation of the 5HT.sub.2 spinal receptors; similarly, it inhibits the depressor effect of 5-hydroxytryptamine on the activity of the hypoglossal nerve. Moreover, the authors suggest that compound A might be used for the in vivo study of the mechanisms responsible for obstructive apnea.
The use of L-tryptophan, a precursor of serotonin, in the respiratory disorders of sleep has been studied (H. S. Schmidt, Bull. Eur. Physiopathol. Respir., 1983, 19, 625-629) as well as that of fluoxetine, a selective inhibitor of serotonin recapture (Hanzel D. A., Chest, 1991, 100, 416-421).
The European patent application EP 449 561 A indicates the use of (R)-fluoxetine for the treatment of different diseased states, including sleep apneas.
An article by M. Yoshioka et al. in J. Pharmacol. Exp. Ther., 1992, 260 (2), 917-924 relates to the pharmacological characterization of the apnea induced by 5-HT in the rat; it reports that 5HT.sub.2 receptor antagonists such as ketanserin and methysergide inhibit apnea induced by 5-HT, suggesting that the apnea induced by 5-HT is mediated by the inhibition of the afferent phrenic nerve activity.
In a recent article, S. C. Veasey et al. (Am; J. Respirat. Critic. Care Med., 1996, 153, 776-786) studied the effects of two serotonin antagonists in an animal model of respiratory disorders of sleep : the English bulldog. They conclude that ritanserin and methysergide, which antagonize 5HT.sub.2 receptors in particular, when administered systemically, lead to a marked diminution of the dilating muscle activity of the upper airways and to a slight diminution of the activity of the diaphragm, these diminutions coinciding with oxyhemoglobin desaturations. The authors suggest that serotonin might play a role in increasing the dilating activity of the upper airways which is known to be implicated in the sleep apnea syndrome.
D. Rose et al. (Fundam. Clin. Pharmacol.,1996, 1
REFERENCES:
patent: 5166416 (1992-11-01), Congy et al.
patent: 5290951 (1994-03-01), Congy et al.
M. Yoshioka et al., J. Pharmacol. and Exp. Therapeutics, vol. 260, No. 2 pp. 917-924 (1992).
S. Veasey et al. Am. J. of Resp. and Critical Care Med., vol. 153, No. 2, pp. 776-786 (1996).
M. Rinaldi-Carmona et al., Life Sciences, vol. 54, pp. 119-127 (1993).
G. Loas, L'Encephale, XVII, pp. 423-425 (1991).
R. Monteau, European Journal of Pharmacology, vol. 259, pp. 71-74 (1994).
H. S. Schmidt, Bulletin European Physiopath. Resp., vol. 19, pp. 625-629, (1983).
D. Hanzel, et al., Chest, vol. 100, No. 2, pp. 416-421 (1991).
M. Rinaldi-Carmona et al., J. Pharmacol. and Exp. Thera., vol. 262, No. 2, pp. 759-768 (1992).
D. Rose et al., Fundamental and Clinical Pharmacology, vol. 10, No. 1, p. 80 (1996).
T. Young et al., The New England Journal of Med., vol. 328, No. 17, pp. 1230-1235 (1993).
D. Hudgel, Chest, vol. 109, No. 5, pp. 1346-1358, (1996).
Alexander Michael D.
DuPont Paul E.
O'Sullivan Peter
Sanofi-Synthelabo
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