Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-06-19
2003-06-10
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06576670
ABSTRACT:
The present invention relates to a novel use of antagonists of various serotonin receptors, namely the antagonists of the 5HT
2A
and 5HT
2A-2C
receptors for serotonin, preferably antagonists which are specific for said receptors. Among these antagonists specific for the 5HT
2A
and 5HT
2A-2C
receptors, it is possible to distinguish several compounds or families of compounds.
1-(2-Fluorophenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one-O-2-dimethylaminoethyl)oxime of formula (I) and its pharmaceutically acceptable salts are described in European Patent 0 373 998 B1 as 5HT
2
receptor antagonists:
More particularly, (1Z,2E)-1-(2-fluorophenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one-O-(2-dimethylaminoethyl)oxime hemifumarate, known under the code name SR 46349B and called hereinafter compound A, has been studied for its biochemical and pharmacological properties. Compound A is an antagonist which is specific for the 5HT
2A
receptor, that is to say it has no affinity for the 5HT
1A
, 5HT
1B
, and 5HT
1D
receptors, and has a moderate affinity for the 5HT
2C
receptor; in studies on isolated tissues, the absence of activity of compound A on rat stomach fundus indicates a 5HT
2A
specificity versus 5HT
2B
(M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Ther., 1992, 262, 2, 759-768). In rodents, it has been shown that this compound predominantly binds to the regions of the brain containing the 5HT
2
receptor (M. Rinaldi-Carmona et al., Life Sciences, 1993, 54, 119-127).
(+)-(R)-&agr;-(2,3-Dimethoxyphenyl)(1-[2-(4-fluorophenyl)ethyl]-4-piperidin-4-yl)methanol of formula (II) whose code name is MDL 100907 is known to be a 5HT
2A
receptor antagonist (J. Pharmacol. Exp. Therap., 1996, 277, 968-981).
International Patent Application WO 98/38189 describes oxazolidine derivatives of formula (III) having 5HT
2A
receptor-antagonizing properties:
(S)-2-[[(7-Fluoro-2,3-dihydro-1H-inden-4-yl)-oxy]methyl]morpholine hydrochloride whose code name is YM 992 is a 5HT
2A
receptor antagonist described by Takeuchi H. et al. in Eur. J. Pharmacol. 1997, 329, 27-35.
Fananserin of formula:
is also a 5HT
2A
receptor antagonist described by Doble A. et al., in Br. J. Pharmacol., 1992, 105, 27-36.
Studies on sleep have shown that some 5HT
2
receptor antagonists such as ritanserin, amoxapine and ICI 169 369 modify the architecture of sleep and regulate or increase slow wave sleep time (G. Loas, L'encéphale, 1991, XVII, 423-425).
The central mechanisms by which serotinin modulates the respiratory activity have been studied and it has been found that among the various families of receptors, only the 5HT
1
receptors and the 5HT
2
receptors affect the nerve control of the respiratory muscles (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 sub-types of receptors are involved in the modulation of the respiratory activity. They observed that pretreatment with compound A prevents or significantly reduces the tonic cervical activity induced by 5-hydroxytryptamine and attributed to the activation of the spinal 5HT
2
receptors; likewise, it inhibits the depressant effect of 5-hydroxytryptamine on the activity of the hypoglossal nerve. Moreover, the authors suggest that compound A could be used for the in vivo study of the mechanisms responsible for obstructive apnea.
The use of L-tryptophan, a precursor of serotonin, in respiratory disorders of sleep has been studied in humans (H. S. Schmidt, Bull. Eur. Physiopathol. Respir., 1983, 19, 625-629) as well as that of fluoxetine, a selective inhibitor of serotonin reuptake (Hanzel D. A., Chest, 1991, 100, 416-421).
European Patent Application EP 449 561 A indicates the use of (R)-fluoxetine for treating various conditions 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 apnea induced by 5-HT in rats; it reports that 5HT
2
receptor antagonists such as ketanserin and methysergide inhibit apnea and the increase in pulmonary resistance induced by 5-HT, and shows that a 5HT
2
agonist inhibits respiration in a manner identical to 5-HT. This article suggests that 5-HT-induced apnea is in part mediated by the vagal system.
S. C. Veasey et al., (Am. J. Respir. Crit. Care Med., 1996, 153, 776-786) have studied the effects of two serotonin antagonists on an animal model (the English bulldog) of respiratory disorders of sleep occurring during rapid-eye-movement sleep. They concluded that ritanserin and methysergide which antagonize in particular the 5HT
2
receptors, when administered systemically, lead to a marked reduction in the activity of the dilatory muscle of the upper respiratory tracts and to a slight reduction in the activity of the diaphragm, these reductions coinciding with oxyhemoglobin desaturations. The authors suggest that serotonin could play a role in the increase in dilatory activity for the upper respiratory tracts during rapid-eye-movement sleep.
D. Rose et al., (Fundam. Clin. Pharmacol., 1996, 10 (1), 80) have reported the results of studies carried out in vivo on decerebrated newborn animals (rats and cats). In cats, they observed that the administration of high doses of 5-hydroxytryptamine induced prolonged central apneas linked to periods of active expiration. In rats, they observed no apnea after administration of 5-hydroxytryptamine, which is in contradiction with the results observed in vitro in newborn rats.
The interspecies differences observed on the respiratory mechanisms as well as the differences between the results of the studies in vivo and in vitro in rats give no indication to persons skilled in the art on the potential effect of the antagonists specific for the 5HT
2A
or 5HT
2A-2C
receptors on respiratory disorders linked to sleep in humans.
Unexpectedly, it has now been found that the 5HT
2A
or 5HT
2A-2C
receptor antagonists, in particular the compounds of formula (I), in particular compound A, and the compound of formula (II), are effective in the treatment of snoring and of upper airway high resistance or resistance syndrome.
Thus, the present invention relates to the use of a 5HT
2A
or 5HT
2A-2C
receptor antagonist, in particular a compound of formula (I) and the compound of formula (II), for the preparation of medicines useful in the treatment of snoring and of upper airway high resistance or resistance syndrome.
The present invention also relates to a pharmaceutical composition for the treatment of snoring and of upper airway high resistance or resistance syndrome comprising a 5HT
2A
or 5HT
2A-2C
receptor antagonist.
Furthermore, the invention relates to a method of treating snoring and upper airway high resistance or resistance syndrome comprising the administration of an effective quantity of a 5HT
2A
or 5HT
2A-2C
receptor antagonist.
Upper airway high resistance or resistance syndrome has been described by C. Guilleminault et al., in Chest, 1993, 104 (3), 781-787. It consists of repeated wakefulness visible on the electroencephalogram and accompanied by an increase in respiratory effort, indicated by a negative esophageal pressure.
The clinical consequences of upper airway resistance syndrome may include:
i) excessive somnolence during the day and secondarily loss of productivity, or even risks of accidents;
ii) chronic fatigue, irritability, nycturia, morning headaches, memory and/or personality disorders; an increase in susceptibility to cardiovascular complications such as pulmonary hypertension, cardiac insufficiency, systemic arterial hypertension, cardiac arrhythmias, stroke and myocardial infarction.
It has now been found that the 5HT
2A
or 5HT
2A-2C
receptor antagonists, preferably the antagonists specific for said receptors, in particular the compound of formula (I), in particular compound A and the compound of formula (II) are active in humans in the treatment of the abovementioned sleep disorders.
In young (18 to 35 years ol
Alexander Michael D.
Dupont Paul E.
Fay Zohreh
Kwon Brian-Yong S.
Sanofi
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