HK1028351B - Use of a specific antagonist of 5ht2 receptors for preparing medicines useful for treating sleep-disordered breathing - Google Patents

Description

The present invention relates to a new use of a specific 5HT2A receptor antagonist.

1- ((2-fluorophenyl) -3- ((4-hydroxyphenyle) -prop-2-ene-1-one-O-2-dimethylaminoethyl) -oxyme of formula (I) and its pharmaceutically acceptable salts are described in European Patent 0 373 998 B1 as antagonists of the 5HT2 receptor: - What?

In particular, (1Z,2E)-1-(2-fluorophenyl) -3- ((4-hydroxyphenyl) -prop-2-en-1-one-O-(2-dimethylaminoethyl) oxime, known as SR 46349 B and hereinafter referred to as compound A, has been studied for its biochemical and pharmacological properties. Compound A is a specific antagonist of the 5HT2A receptor, i.e. it has no affinity for the 5HT1A, 5HT1B and 5HT1D receptors and a low affinity for the 5HT2C receptor; in isolated brain tissue studies, the absence of activity of the compound A on the stomach receptor has been shown to be a specific indicator of the 5HT2A receptor (Thermothermother, 1993; J.M., 1992, 5HT2A, 5HT2A, 5HT2A, 5HT2A, 5HT2A, 5HT2A, and 5HT2A, 1992; and in the rat tissues, the absence of activity of this compound on the stomach receptor has been shown to be a major fundamental factor in the formation of RHT2A and RHT2A (R.M., 1992, 5HT2A., 5HT2A., 5HT2A., 5HT2A., 5HT2A., 5HT2A., 5HT2A., 5HT2A., 5M., 5HT2A., 5HT2A., 26), and R.M., 26).

Studies on sleep have shown that certain 5HT2 antagonists such as ritanserin, amoxapine, and ICI 169 369 alter the architecture of sleep and regulate or increase the time of slow-wave sleep (G. Loas, L'encéphale, 1991, XVII, 423-425).

The central mechanisms by which serotonin modulates respiratory activity have been studied and it has been found that among the different receptor families, only 5HT1 and 5HT2 receptors affect respiratory activity at the central level (R. Monteau et al., Eur. J. Pharmacol., 1994, 259, 71-74).

In the same paper, the authors study in vitro on preparations of newborn rat tissue, using compound A, which receptor subtypes are involved in modulating respiratory activity. They note that pretreatment with compound A significantly prevents or reduces cervical tonic activity induced by 5-hydroxytryptamine and attributed to activation of 5HT2 spinal receptors; it also inhibits the depressant effect of 5-hydroxytryptamine on the activity of the nerf in the hypoglossal space. Furthermore, the authors suggest that compound A could be used for in vivo study of the mechanisms responsible for obstructive sleep apnea.

The use of L-tryptophan, a serotonin precursor, in sleep respiratory disorders has been studied (H.S. Schmidt, Bull. Eur. Physiopathol. Respir., 1983, 19, 625-629) and 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, to treat various conditions including sleep apnea.

A paper by Yoshioka et al. in J. Pharmacol. Exp. Ther., 1992, 260 (2), 917-924 deals with the pharmacological characterization of 5-HT-induced apnea in rats; it reports that 5-HT2 receptor antagonists such as ketanserin and methysergidine inhibit 5-HT-induced apnea, suggesting that 5-HT-induced apnea is mediated by inhibition of related phrenic nerve activity.

In a recent paper, S.C. Veasey et al. (Am. J. Respirat. Critic. Care Med., 1996, 153, 776-786) investigated the effects of two serotonin antagonists on an animal model of sleep respiratory disorders: the English bulldog. They concluded that ritanserin and methysergide, which antagonize 5HT2 receptors in particular, when given systemically, lead to marked decreases in upper respiratory dilatory muscle activity and small decreases in diaphragm activity, these decreases coinciding with dissatisfactions in oxyhemoglobin. The authors suggest that serotonin may play a role in increasing upper respiratory dilatory activity in the sleep disorders known to occur.

D. Rose et al. (Fundam. Clin. Pharmacol., 1996, 10 (1), 80) report the results of in vivo studies in newborn decerebrate animals (rats and cats). In the cat, they observed that high doses of 5-hydroxytryptamine induced prolonged central apnea associated with active expiration periods. In the rat, they observed no apnea after administration of 5-hydroxytryptamine, which is in contradiction with the in vitro results in the newborn rat.

The observed interspecies differences in respiratory mechanisms and the differences between the results of in vivo and in vitro studies in rats do not give any indication to the scientific community as to the possible effect of the compound (I) on sleep apnea.

Unexpectedly, the compound of formula (I), particularly compound A, a serotonin 5HT2A receptor antagonist, has now been found to be effective in treating sleep apnea syndrome.

Thus the present invention relates to the use of a compound of formula (I) for the preparation of medicinal products useful in the treatment of sleep apnea syndrome, in particular obstructive sleep apnea-hypopnea syndrome.

Sleep apnea syndrome is defined as a stop (apnea) or decrease (hypopnea) in breathing that occurs recurrently during sleep. Hypnea and apnea occur both during REM sleep and slow sleep. Repeated stops of breathing induce a decrease in oxygen hemoglobin saturation (SaO2) and awakenings, leading to fragmentation of sleep and the disappearance of stages 3 and 4 corresponding to slow deep sleep. (i) an increased susceptibility to cardiovascular complications such as pulmonary hypertension, heart failure, hypertension, cardiac arrhythmias, strokes and myocardial infarction;

In addition, fragmented sleep and nighttime desaturation of oxyhemoglobin lead to fatigue, irritability, morning headaches, memory problems, and/or personality disorders.

Recent epidemiological data indicate that this syndrome affects 2 to 4 percent of the adult population or more, with men and obese people being particularly affected (New Engl. J. Med., 1993, 328 (17), 1230-1235).

The main treatment currently prescribed, apart from weight loss and surgery, is mechanical ventilation with continuous positive pressure (PPC). The principle of this latter treatment (PPC) is based on the nasal administration of positive inhalation and expiratory pressure to suppress collapse of the upper airways. This treatment is cumbersome, noisy and constricting, requiring the patient to wear a nasal mask every night; it also has side effects such as dry nose, sneezing, mouth bleeding or aerophagy. To date, no treatment with a pharmacological agent is known (D.W. Hudgel, Chest, 1996, 109/465, 1335-18).

It has now been found that the compound of formula (I), particularly compound A, is active in humans in the treatment of sleep apnea syndrome.

In healthy young subjects (18 to 35 years of age), administration of compound A was observed to induce a doubling of the duration of stages 3 and 4 of slow-wave sleep at the 1 mg dose, with stages 1 and 2 of slow-wave sleep slightly reduced and REM sleep not altered.

The effect of compound A on patients with sleep apnea was determined in a double-blind clinical trial against placebo.

Patients in this study have an apnea-hypopnea index greater than 25 and also have symptoms such as daytime sleepiness, hypertension, fatigue, morning headache, nocturia, etc.

Apnea is defined as the absence of nasobucal airflow for at least 10 seconds. Hypopnea is defined as a reduction of at least 50% of nasobucal airflow for at least 10 seconds. The apnea-hypopnea index (AHI) is the number of apneas and hypopneas occurring per hour. This index is obtained by polysomnographic recording also measuring ventilation rate, esophageal pressure and oxygen hemoglobin saturation (SaO2).

A capsule containing 5 mg of compound A was given with an evening meal every day for 14 days.

Thus, the present invention is intended to use a compound of formula (I) for the preparation of medicinal products useful in the treatment of sleep apnea syndrome.

The compound of formula (I) and its pharmaceutically acceptable salts are prepared according to the description given in European Patent 0 373 998 B1.

In pharmaceutical formulations for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active substance alone or in combination with another active substance may be administered as a unit dose, in combination with conventional pharmaceutical media, to animals and humans.The appropriate unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral dosage forms, aerosols, implants, subcutaneous, intramuscular, intramuscular, intranasal and recital dosage forms.

In pharmaceutical formulations, the active substance is generally formulated in dosage units, the dosage unit containing 0.05 to 50 mg, preferably 0.1 to 10 mg, preferably 0.5 to 5 mg 5HT2A receptor antagonist per dosage unit for daily administration.

When preparing a solid composition in tablet form, a wetting agent may be added to the micronized or unmicronized active substance and mixed with a pharmaceutical vehicle such as silica, starch, lactose, magnesium stearate, talc or analogues.

A capsule preparation is obtained by mixing the active substance or active substances with a diluent by incorporating the resulting mixture into soft or hard capsules.

A preparation in the form of a syrup or elixir may contain the active substance or active substances together with a sweetener, preferably a non-caloric sweetener, methylparaben and propylparaben as antiseptics, as well as a flavouring agent and an appropriate colouring.

Water-dispersible powders or granules may contain the active substance mixed with dispersion agents or wetting agents, or suspension agents such as polyvinylpyrrolidone or polyvidone, as well as sweeteners or flavour enhancers.

For rectal administration, suppositories are used which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile solutions for injection containing dispersion agents and/ or pharmacologically compatible solubilisers, e. g. propylene glycol or butylene glycol, are used.

For example, to prepare an aqueous solution for intravenous injection, a co-solvent can be used: an alcohol such as ethanol, a glycol such as polyethylene glycol or propylene glycol and a hydrophilic surfactant such as polysorbate 80.

For transdermal administration, multi-laminated or tank-like patches in which the active substance is in an alcoholic solution may be used.

The active substance may also be formulated in the form of microcapsules or microspheres, possibly with one or more media or additives.

The active substance may also be presented as a complex with a cyclodextrin, e.g. α-, β- or γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.

Implants are one of the long-release forms useful in the case of chronic treatments, which can be prepared as an oil suspension or as a microsphere suspension in an isotonic medium.

According to the present invention, oral forms of administration are preferred.

The test chemical is a chemical that is used to produce a substance that is capable of producing a specific chemical.

Composé A	0,118 mg
Lactose monohydrate extra-fin cristallisé	99,132 mg
Amidon de maïs modifié	25 mg
Silice colloïdale anhydre	0,11 mg
Stéarate de magnésium	0,64 mg
Pour une gélule blanc opaque de taille 0, terminée à

The test chemical is a mixture of two or more of the following:

Composé A	1,18 mg
Lactose monohydrate extra-fin cristallisé	451,42 mg
Amidon de maïs modifié	114 mg
Silice colloïdale anhydre	0,5 mg
Stéarate de magnésium	2,9 mg
Pour une gélule blanc opaque de taille 0, terminée à

The test chemical is a 5 mg capsule of (1Z,2E)-1- ((2-fluorophenyl) -3- ((4-hydroxyphenyle) -prop-2-en-1-one-O- ((2-dimethylaminoethyl) -oxyme.

Composé A	5,9 mg
Lactose monohydrate extra-fin cristallisé	446,7 mg
Amidon de maïs modifié	114 mg
Silice colloïdale anhydre	0,5 mg
Stéarate de magnésium	2,9 mg
Pour une gélule blanc opaque de taille 0, terminée à

The test chemical is a mixture of two or more of the following:

Composé A	11,8 mg
Lactose monohydrate extra-fin cristallisé	440,8 mg
Amidon de maïs modifié	114 mg
Silice colloïdale anhydre	0,5 mg
Stéarate de magnésium	2,9 mg
Pour une gélule blanc opaque de taille 0, terminée à

Claims (4)

1. Use of 1-(2-fluorophenyl)-3-(4-hydroxyphenyl)-prop-2-en-1-one-O-(2-dimethylaminoethyl)oxime, or of one of its pharmaceutically acceptable salts, for the preparation of medicines useful in the treatment of sleep apnoea syndrome.
2. Use, according to Claim 1, of the hemifumarate of (1Z, 2E)-1- (2-fluorophenyl)-3- (4-hydroxyphenyl)prop-2-en-1-one-O-(2-dimethylaminoethyl)oxime.
3. Use of 1-(2-fluorophenyl)-3-(4-hydroxyphenyl)-prop-2-en-1-one-O-(2-dimethylaminoethyl)oxime, or of one of its pharmaceutically acceptable salts, for the preparation of medicines useful in the treatment of sleep obstructive apnoea-hypoapnoea syndrome.
4. Use, according to Claim 3, of the hemifumarate of (1Z, 2E)-1-(2-fluorophenyl)-3-(4-hydroxyphenyl)prop-2-en-1-one-O-(2-dimethylaminoethyl)-oxime.