FR2918368A1 - NOVEL NAPHTHALENIC DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME - Google Patents

Abstract

Compound of formula (I): Drugs.

Description

The present invention relates to novel naphthalenic derivatives,

  their preparation process and the pharmaceutical compositions containing them.

  The compounds of the present invention are novel and have very interesting pharmacological characteristics concerning melatoninergic receptors.

  Numerous studies have highlighted over the last ten years the important role of melatonin (N-acetyl-5-methoxytryptamine) in many physiopathological phenomena as well as in the control of circadian rhythms. However, it has a relatively low half-life due to rapid metabolism. It is therefore very interesting to be able to provide the clinician with melatonin analogues, which are metabolically more stable and have an agonist or antagonist character, which can be expected to have a therapeutic effect greater than that of the hormone itself.

  In addition to their beneficial effect on circadian rhythm disorders (J. Neurosurg, 1985, 63, pp. 321-341) and sleep (Psychopharmacology, 1990, 100, pp. 222-226), the melatoninergic system ligands possess interesting pharmacological properties on the central nervous system, including anxiolytics and antipsychotics (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272), analgesics (Pharmacopsychiat., 1987, 20, pp. 222-223) as well as for the treatment of Parkinson's disease (J. Neurosurg, 1985, 63, pp. 321-341) and Alzheimer's (Brain Research, 1990, 528, pp. 170-174). Similarly, these compounds showed activity on certain cancers (Melatonin Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), on ovulation (Science 1987, 227, pp. 714-720), on diabetes (Clinical Endocrinology, 1986, 24, pp. 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp. 443-446). These different effects are mediated through specific receptors for melatonin. Molecular biology studies have shown the existence of several receptor subtypes capable of binding this hormone (Trends Pharmacol Sci., 1995, 16, p.50, WO 97.04094). Some of these receptors could be localized and characterized for different species, including mammals. In order to better understand the physiological functions of these receptors, it is of great interest to have selective ligands. Moreover, such compounds, by selectively interacting with one or other of these receptors, may be for the clinician excellent drugs for the treatment of pathologies related to the melatoninergic system, some of which have been mentioned previously. .

  The compounds of the present invention in addition to their novelty, show a very high affinity for melatonin receptors.

  They also have a high affinity for the 5-HT2c receptor, which has the effect of reinforcing the properties observed with melatoninergic receptors, particularly in the field of depression.

  The present invention relates more particularly to the compound of formula (I): O or N- [2- (7-fluoro-1-naphtyl) ethyl] acetamide, as well as its addition salts with a pharmaceutically acceptable base.

  Among the pharmaceutically acceptable bases, mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.

  The invention also extends to the process for the preparation of the compound of formula (I), characterized in that the compound of formula (II) is used as starting material: -3 NHCOMe which is subjected to demethylation for to give the compound of formula (III): NHCOMe HO which is subjected to the action of trifluoromethanesulfonic anhydride to yield the compound of formula (IV): CF3SOZO NHCOMe that is subjected to the action of the 4 -methoxybenzylamine to give the compound of formula (V): OMe NHCOMe (V) HN which is subjected to the action of palladium on charcoal to yield the compound of formula 10 (VI): -4 NHCOMe HZN that one subject to the action of tetrafluoroboric acid to yield the compound of formula (I), which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts at a temperature of pharmaceutically acceptable base.

  The compound of formula (II) and its synthesis are described in the literature, for example in patent EPO447285.

  The pharmacological study of the derivatives of the invention has shown that they are atoxic, endowed with a high selective affinity for melatonin receptors and have important activities on the central nervous system and, in particular, have been noted. therapeutic properties on sleep disorders, antidepressant, anxiolytic, antipsychotic, analgesic and microcirculation properties, which make it possible to establish that the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal depression or major depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholy, disorders of the appetite, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, as well as disorders of the cerebral circulation. In another field of activity, it appears that in the treatment, the products of the invention can be used in sexual dysfunctions, that they have properties of ovulation inhibitors, immmunomodulators and that they are likely to be used in the treatment of cancers. The compounds will preferably be used in the treatment of major depression, seasonal depression, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, disorders of the appetite and obesity.

  For example, the compounds will be used in the treatment of major depression, seasonal depression and sleep disorders.

  The present invention also relates to pharmaceutical compositions containing at least one compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients.

  Among the pharmaceutical compositions according to the invention, mention may be made, more particularly, of those which are suitable for oral, parenteral, nasal, percutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets. , sachets, packets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and oral or injectable ampoules.

  The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possibly associated treatments and ranges between 0.01 mg and 1 g per 24 hours. in one or more takes.

  The following examples illustrate the invention and do not limit it in any way. Example 1: N [2- (7-fluoro-1-naphthyl) ethyl] acetamide Step A: N- [2- (7-Hydroxy-1-naphthyl) ethyl] acetamide

  N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide (35 mmol) is dissolved in 250 ml of dichloromethane and the reaction mixture is cooled to 0 ° C. with the aid of an ice bath -salt. Boron tribromide (70 mmol) is added dropwise and the reaction mixture is stirred cold for 2 hours. The reaction medium is poured into water and stirred vigorously until 2 clear phases are obtained. The organic phase is dried over magnesium sulfate and the dichloromethane is evaporated under reduced pressure. The product obtained is recrystallized from toluene to yield the title product as a white solid. Melting point: 123-125 ° C

  Stage B: 8- [2- (Acetylamino) ethyl] -2-naphthyl trifluoromethanesulfonate

  The compound obtained in Step A (33 mmol) is solubilized in 30 ml of dichloromethane, and then the triethylamine (100 mmol) is added. The solution is cooled to -20 ° C. using a cold plate. The trifluoromethanesulfonic anhydride (35 mmol) is added slowly and the reaction medium is allowed to return to ambient temperature. The latter is poured into the water. The organic phase is washed twice with 1M sodium hydroxide solution and with water, dried over magnesium sulphate and evaporated under reduced pressure. The oil obtained is purified on silica gel (eluent: acetone / cyclohexane 3/7) to yield the title product in the form of a white solid after recrystallization in cyclohexane. Melting point: 81-830C

  Stage C: N- (2- {7 - [(4-Methoxybenzyl) amino] -1-naphthyl} ethyl) acetamide hydrochloride

  In a 100 ml flask, the compound obtained in Step B (2.8 mmol), palladium acetate (0.3 mmol), X-Phos (0.3 mmol), cesium carbonate ( 2.8 mmol) and 4-methoxybenzylamine (2.8 mmol) are dissolved in 10 ml of dimethylformamide. Placed in a microwave, this solution is irradiated with a power of 100 W for 10 minutes. The reaction medium is allowed to return to room temperature, then poured into 100 ml of water and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue obtained is purified on silica gel (eluent: acetone / cyclohexane 5/5). The residue obtained is taken up in ether and then ether saturated with hydrochloric acid is added dropwise. The precipitate formed is filtered off and recrystallized from acetonitrile to yield the title product as a yellow solid. Melting point: 194-196 C

  Stage D: N- [2- (7-Amino-1-naphthyl) ethyl] acetamide The compound obtained in Stage C (8.5 mmol) in base form is solubilized in 50 ml of methanol and 0.3 g of palladium 10% on activated charcoal are added to the solution. The reaction medium is put under hydrogen at atmospheric pressure and left stirring for 12 hours at room temperature. The catalyst is filtered and the methanol is evaporated under reduced pressure to yield the title product as a brown oil.

  Stage E: N- [2- (7-fluoro-1-naphthyl) ethyl] acetamide

  The compound obtained in Stage D (8.9 mmol) is dissolved in 30 ml of 0.4 M hydrochloric acid. This solution is cooled to 0.degree. C. with the aid of an ice bath, the nitrite of sodium (8.9 mmol), previously dissolved in 5 ml of water, is added over a period of 15 minutes and then 48% tetrafluoroboric acid (37.1 mmol) is added all at once. The precipitate formed is filtered off and heated in refluxing xylene. After cooling, the reaction medium is poured into water and extracted with 50 ml of dichloromethane. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is purified on silica gel (eluent: acetone / cyclohexane 4/6) to conduct after recrystallization from cyclohexane to the title product in the form of a white solid. Melting Point: 136-138 C-8 PHARMACOLOGICAL STUDY EXAMPLE A: Acute Toxicity Study

  Acute toxicity was assessed after oral administration to batches of 8 mice (26 2 grams). The animals were observed at regular intervals during the first day and daily for two weeks after treatment. The LD 50, resulting in the death of 50% of the animals, was evaluated and showed the low toxicity of the compounds of the invention.

EXAMPLE B: Forced Swimming Test

  The compounds of the invention are tested in a behavioral model, the forced swimming test. The apparatus consists of a Plexiglas cylinder filled with water. The animals are tested individually during a 6-minute session. At the beginning of each test, the animal is placed in the center of the cylinder. The downtime is recorded. Each animal is judged immobile when it ceases to struggle, and remains on the surface of the water, motionless, making only the movements allowing it to keep its head out of the water.

  After administration 40 minutes before the start of the test, the compounds of the invention significantly reduce the duration of immobilization attesting to their antidepressant activity.

  EXAMPLE C Melatonin MT1 and MT Receptor Binding Study The MT1 or MT2 receptor binding experiments were performed using 2- [125I] -iodomelatonin as a reference radioligand. The retained radioactivity is determined using a liquid scintillation counter. Competitive binding experiments are then performed in triplicate, with the various compounds to be tested. A range of different concentrations is tested for each compound. The results make it possible to determine the binding affinities of the compounds tested (Ki).

  By way of example, the compound obtained in Example 1 has a K (MT1) of 7 nM and a K (MT2) of 0.6 nM.

  EXAMPLE D Study of Serotoninergic Receptor Binding 5-HTk

  The affinity of the compounds for the human 5-HT2c receptor is evaluated on membrane preparations of CHO cells stably expressing this receptor.

  Incubation was performed in 50 mM TRIS buffer pH 7.4 containing 10 mM MgCl 2 and 0.1% BSA in the presence of [3 H] mesulergine (1 nM) and 25 fmol / ml receptor. The non-specific binding is determined in the presence of 10 M mianserine. The reaction is stopped by the addition of 50 mM TRIS buffer, pH 7.4 followed by a filtration step and 3 successive rinses: membrane-bound radioactivity remaining on the filters (GF / B pretreated with 0.1% PEI) is counted as liquid scintillation.

  The result obtained with the compound of Example 1 shows that it is affine for the 5-HT2C receptor with a K; from 6 to 11M.

  EXAMPLE E Action of the Compounds of the Invention on the Circadian Rhythms of Rat Locomotor Activity The involvement of melatonin in the training, by day / night alternation, of most of the circadian physiological, biochemical and behavioral rhythms has established a pharmacological model for the search for melatoninergic ligands. The effects of the molecules are tested on many parameters and, in particular, on circadian circulations of locomotor activity which represent a reliable marker of endogenous circadian clock activity. In this study, we evaluate the effects of such molecules on a particular experimental model, namely the rat placed in temporal isolation (permanent darkness).

  Experimental protocol Male rats aged one month are subjected to a light cycle of 12 hours of light per day as soon as they arrive at the laboratory (LD 12:12). After 2 to 3 weeks of adaptation, they are placed in cages equipped with a wheel connected to a recording system in order to detect the phases of locomotor activity and thus to follow the diurnal (LD) or circadian (DD) rhythms. ).

  As soon as the recorded rhythms show steady training by the LD 12: 12 light cycle, the rats are put in permanent darkness (DD). Two to three weeks later, when the free-course (rhythm reflecting that of the endogenous clock) is clearly established, the rats receive a daily administration of the molecule to be tested.

  The observations are made thanks to the visualization of the rhythms of activity: - entrainment of the rhythms of activity by the luminous rhythm, - disappearance of the training of the rhythms in permanent darkness, - entrainment by the daily administration of the molecule; transient or lasting effect.

  Software allows: - to measure the duration and the intensity of the activity, the period of the rhythm in the animals in free course and during the treatment, - to possibly highlight by spectral analysis the existence of circadian and non circadian components circadians (ultradians for example).

  Results It is clear that the compounds of the invention allow to act in a powerful way on the circadian rhythm via the melatoninergic system. EXAMPLE F: Clear / Dark Cages Test

  .............. ... DTD: The compounds of the invention are tested in a behavioral model, the test of clear / dark cages, which reveals the anxiolytic activity of the molecules .

  The device consists of two polyvinyl boxes covered with Plexiglas. One of these boxes is obscure. One lamp is placed above the other box giving a luminous intensity in the center of it of approximately 4000 lux. An opaque plastic tunnel separates the clear box from the dark box. The animals are tested individually during a 5 min session. The floor of each box is cleaned between each session. At the beginning of each test, the mouse is placed in the tunnel, facing the dark box. The time spent by the mouse in the lighted box and the number of transitions through the tunnel are recorded after the first entry in the dark box. After administration of the compounds 30 min before the start of the test, the compounds of the invention significantly increase the time spent in the illuminated cage and the number of transitions, which shows the anxiolytic activity of the derivatives of the invention.

  EXAMPLE G: Pharmaceutical Composition: Tablets

  1000 tablets dosed with 5 mg of N- [2- (7-fluoro-1-naphthyl) ethyl] acetamide (Example 1) 5 g Wheat starch 20 g corn starch 20 g lactose 30 g magnesium stearate 2 g silica 1 g Hydroxypropylcellulose 2 g

Claims (5)

1- Compound of formula (I): O or N- [2- (7-fluoro-1-naphthyl) ethyl] acetamide, as well as its addition salts with a pharmaceutically acceptable base.   2- A method of preparing the compound of formula (I) according to claim 1 characterized in that the starting material used is the compound of formula (II): NHCOMe that is subjected to a demethylation to yield the compound of formula (III): NHCOMe HO 10 which is subjected to the action of trifluoromethanesulfonic anhydride to yield the compound of formula (IV): - 13 - CF3SO2O NHCOMe which is subjected to the action of 4- methoxybenzylamine to give the compound of formula (V): OMe NHCOMe (V) HN which is subjected to the action of palladium on charcoal to yield the compound of formula (VI): NHCOMe H2N which is subjected to the action of tetrafluoroboric acid to yield the compound of formula (I), which can be purified by a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable base.   3- Pharmaceutical compositions containing the compound of formula (I) according to claim 1 or one of its addition salts with a pharmaceutically acceptable base in combination with one or more pharmaceutically acceptable excipients.   4- Pharmaceutical compositions according to claim 3 useful for the manufacture of medicaments for treating disorders of the melatoninergic system.   5. Pharmaceutical compositions according to claim 3 for the manufacture of medicaments for the treatment of sleep disorders, stress, anxiety, major depression or seasonal depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholy, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes , Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, cerebral circulation disorders, as well as dysfunctions as ovulation inhibitors, immunomodulators and in the treatment of cancers.