FR2918371A1 - New substituted naphthalene derivatives are melatonin receptor binders useful e.g. to treat sleep disorders, stress, anxiety, schizophrenia, panic attacks, appetite disorders, obesity, insomnia, epilepsy, diabetes and Parkinson's disease - Google Patents

Abstract

Substituted naphthalene derivatives (I) and their enantiomers, diastereoisomers, or acid or base addition salts, are new. Substituted naphthalene derivatives of formula (I) and their enantiomers, diastereoisomers, or acid or base addition salts, are new. R 11-6C (halo)alkyl, 1-6C alkenyl, polyhalo1-6C alkyl, 3-8C cycloalkyl, cyclo(3-8C)alkyl(1-6C)alkyl, (hetero)aryl or 1-6C (hetero)arylalkyl, where aryl is phenyl, naphthyl or biphenyl, heteroaryl is mono or bicyclic aromatic group containing 1-3 heteroatom of O, S or N, and (hetero)aryl is optionally substituted by 1-3 1-6C alkyl, 1-6C alkoxy, OH, COOH, formyl, nitro, CN, halo(1-6C)alkyl, polyhalo1-6C alkyl, alkyloxycarbonyl or halo; and R 2, R 3H or 1-6C alkyl, preferably CH 3. An independent claim is included for preparation of (I). [Image] ACTIVITY : Hypnotic; Tranquilizer; Antidepressant; Cardiovascular-Gen; Gastrointestinal-Gen; CNS-Gen; Muscular-Gen; Neuroleptic; Anorectic; Anticonvulsant; Antidiabetic; Antiparkinsonian; Nootropic; Antimigraine; Neuroprotective; Endocrine-Gen; Cytostatic; Dermatological; Vasotropic; Immunomodulator; Contraceptive; Analgesic. MECHANISM OF ACTION : Melatonin 1 receptor binder; Melatonin 2 receptor binder; 5-Hydroxytryptamine 2c receptor binder. The ability of (I) to bind melatonin 2 receptor was tested using 2-[ 125>I]-iodomelatonin radioligand. The result showed that inhibitory constant of N-{2-[3-(1-hydroxyethyl)-7-methoxy-1-naphthyl]ethyl}acetamide was 3 nM.

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 shown that melatonin (N-acetyl-5-methoxytryptamine) plays a major role 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. In addition, 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 being novel, 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): embedded image in which:

  R1 represents a linear or branched (C1-C6) alkyl group, linear or branched (C1-C6) alkenyl, linear or branched (C1-C6) haloalkyl, linear or branched (C1-C6) polyhaloalkyl, and (C3-C8) cycloalkyl; ), C3-C8 cycloalkyl (C1-C6) alkyl, the alkyl portion of which may be linear or branched, aryl, (C1-C6) arylalkyl, of which the alkyl part may be linear or branched, heteroaryl or heteroarylalkyl (C1-C6) whose alkyl part can be linear or branched,

  R2 and R3, which may be identical or different, each represent a hydrogen atom or a linear or branched (C1-C6) alkyl group, it being understood that:

  "Aryl" is understood to mean a phenyl, naphthyl or biphenyl group; "heteroaryl" means any aromatic mono or bicyclic group containing 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, the aryl and heteroaryl groups thus defined which may be substituted with 1 to 3 groups selected from linear or branched (C1-C6) alkyl, linear or branched (C1-C6) alkoxy, hydroxy, carboxy, formyl, nitro, cyano, linear or branched (C1-C6) haloalkyl, linear or branched polyhaloalkyl (C1 - C6), alkyloxycarbonyl, or halogen atoms,

  their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base.

  Among the pharmaceutically acceptable acids, mention may be made, without limitation, of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic and methane acids. sulfonic, camphoric, etc.

  Pharmaceutically acceptable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine and the like.

  The preferred compounds of the invention are the compounds of formula (I) for which R1 represents a linear or branched (C1-C6) alkyl group such as, for example, the methyl group.

  Preferred R2 and R3 are hydrogen and methyl.

  Even more particularly, the invention relates to the compounds which are N- {2- [3- (hydroxymethyl) -7-methoxy-1-naphthyl] ethyl} acetamide and N- {2- [3 - (1-hydroxyethyl) ) -7-methoxy-1-naphthyl] ethyl} acetamide. The addition salts with an acid or a pharmaceutically acceptable base of the preferred compounds of the invention form an integral part of the invention.

  The invention also extends to the process for the preparation of the compound of formula (I), characterized in that the compound of formula (II) used is the starting material: NHCOR1 Me in which R1 is as defined in formula (I), which is subjected to the action of the compound of formula RCOC1 in which R represents a linear or branched (C1-C6) alkyl group to give the compound of formula (III): Me in which R and R1 are as defined above, compound of formula (III) which is subjected to - a chemical reduction to yield the compound of formula (Pa), a particular case of compounds of formula (I): (Fa) OH in which R and R 1 are as defined above, or when R represents a methyl group, at an oxidation to give the compound of formula (IV): embedded image in which R 1 is as defined above, which, after conversion into the corresponding ester, is subject to a reduction to drive To the compound of formula (Yb), a particular case of the compounds of formula (I): in which RI is as defined above,

  or to the action of a magnesium of formula R'MgX in which X represents a halogen atom and R 'represents a linear or branched (C1-C6) alkyl group, to give the compound of formula (I / c), a particular case of the compounds of formula (I): in which R 1, R and R 'are as defined previously,

  the compounds of formula (IIa) to (IIc) forming all of the compounds of formula (I) which can be purified according to a conventional separation technique, which are transformed, if desired, into their addition salts with a pharmaceutically acceptable acid or base and from which the isomers are optionally separated by a conventional separation technique.

  The compounds of formula (II) are either commercially available or accessible to those skilled in the art by conventional chemical reactions and described in the literature as for example EPO 447285.

  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 diseases, pathologies of the digestive system, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholy, disorders of the nervous system. appetite, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, e 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, appetite disorders 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, tablets sublinguals, 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 from 0.01 mg to 1 g per 24 hours. hours in one or more takes.

  The following examples illustrate the invention and do not limit it in any way. Example 1: N- {2- [3- (Hydroxymethyl) -7-methoxy-1-naphthyl] ethyl-caetamide Step A: N- [2- (3-Acetyl-7-methoxy-1-naphthyl) ethyl] acetamide

  N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide (82 mmol) is dissolved in 175 ml of dichloromethane. After cooling to 0 ° C., the aluminum trichloride (225 mmol) and the acetyl chloride (106 mmol) are added in small portions and the mixture is left stirring at room temperature for 1 hour. The reaction medium is poured into ice water and then extracted with dichloromethane. After drying over magnesium sulphate and evaporation under reduced pressure of dichloromethane, the product obtained is recrystallized from toluene to yield the title product in the form of a white solid. Melting point: 152-153 ° C. Step B: 4- [2- (acetylamino) ethyl] -6-methoxy-2-naphthoic acid

  The compound obtained in Stage A (3.5 mmol) and potassium iodide (7.7 mmol) are dissolved in 56 ml of a mixture of water and dioxane (1/1). 11 ml of a 9.6% sodium hypochlorite solution and 1.3 g of additional sodium iodide are added at room temperature. 7 ml of additional sodium hypochlorite is added. At the end of the reaction, the iodoform is filtered. The filtrate is treated with sodium thiosulphate solution, acidified with a hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated under reduced pressure. The precipitate obtained is drained and recrystallized from dioxane to yield the title product in the form of a beige solid. Melting point: 248-250 ° C

  Stage C: Methyl 4- [2- (acetylamino) ethyl] -6-methoxy-2-naphthoate

  The compound obtained in Step B (14.6 mmol) is dissolved in 100 ml of methanol and the medium is cooled to 0 ° C. with the aid of an ice bath. The thionyl chloride (22 mmol) is added dropwise and the reaction medium is stirred at room temperature for one hour. The methanol is evaporated under reduced pressure and the residue obtained is taken up in 100 ml of water. The aqueous phase is extracted with 3 times 50 ml of diethyl ether and the organic phase is washed with water, dried over magnesium sulfate and then evaporated. The oil obtained precipitates in petroleum ether. The expected product is filtered off and then recrystallized from acetonitrile to yield the title product in the form of a white solid. Melting point: 168-170 ° C

  Stage D: N- {2- [3- (Hydroxymethyl) -7-methoxy-1-naphthyl] ethyl} acetamide

  In a 250 ml Erlenmeyer flask, the compound obtained in Step C (9.3 mmol) is solubilized in 75 ml of anhydrous tetrahydrofuran. The solution is cooled to 0 ° C. with the aid of an ice bath, then lithium aluminum hydride (18.6 mmol) is added in small portions and the reaction mixture is stirred at this temperature for 2 hours. The solution is hydrolysed with, successively, 0.7 ml of water, 0.7 ml of a 15% sodium hydroxide solution and finally 2.1 ml of water. After stirring for 30 minutes, the mineral precipitate formed is filtered off and washed with twice 50 ml of tetrahydrofuran. The organic phase is dried over magnesium sulphate and evaporated under reduced pressure. The resulting precipitate is filtered off and recrystallized from acetonitrile to yield the title product as a white solid. Melting point: 128-130 ° C

  Example 2: N-12-13- (1-Hydroxyethyl) -7-methoxy-1-naphthyl-ethyl-acetamide

  The compound obtained in Stage A of Example 1 (17.5 mmol) is dissolved in 250 ml of methanol. Sodium borohydride (17.5 mmol) is added in small portions and the solution is stirred at room temperature for 30 minutes. The methanol is evaporated under reduced pressure and the residue obtained is taken up in a 1M aqueous hydrochloric acid solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and evaporated under reduced pressure. The precipitate obtained is recrystallized from acetonitrile to yield the title product as a white solid. Melting point: 128-130 ° C. Elemental microanalysis: C H N Calc'd: 71.06 7.37 16.70 Found: 70.94 7, 61 16, 75 2918371 - 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 swim 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, only 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: Study of binding to the MTI and MT2 receptors of melatonin

  MT1 or MT2 receptor binding experiments were performed using 2- [125 I] -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 tested compounds (K 1).

  Thus, the values of K .; found for the compounds of the invention demonstrate a binding for either melatoninergic binding sites, these values being 10 M. By way of example, the compound obtained in Example 2 has a K (MT1) of 9 nM, and a K (MT2) of 3 nM.

  EXAMPLE D Serotoninergipen 5-HT receptor binding study

  The affinity of the compounds for the human 5-HT2c receptor is assessed on membrane preparations of CHO cells stably expressing this receptor. Incubation was performed in 50 mM TRIS buffer pH 7.4 containing 10 mM MgCl2 and 0.1% BSA in the presence of [3 H] mesulergine (1 nM) and 25 fmol / ml receptor. Nonspecific binding is determined in the presence of 1011M mianserin. The reaction is stopped by the addition of 50 mM TRIS buffer, pH 7.4, followed by a filtration step and 3 successive rinses: the radioactivity bound to the membranes remaining on the filters (0.1% PEI-pretreated GF / B) ) is counted as liquid scintillation.

  The results obtained show that the compounds of the invention are affine for the 5-HT2C receptor with K; <10 M.

  EXAMPLE E Action of the Compounds of the Invention on Circadian Rhythms of Rat Locomotor Activity

  The involvement of melatonin in the training, by the day / night alternation, of most of the circadian physiological, biochemical and behavioral rhythms has made it possible to establish 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. - 13 - EXAMPLE F: Clear / Dark Cages Test

  The compounds of the invention are tested in a behavioral model, the light / dark cages test, 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- [3- (1-hydroxyethyl) -7-methoxy-1-naphthyl] ethyl} acetamide (Example 2) 5 g of wheat starch 20 g of corn starch 20 g of lactose 30 g Magnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g

Claims (10)

  A compound of formula (I): wherein R1 represents a linear or branched (C1-C6) alkyl group, linear or branched (C1-C6) alkenyl or linear or branched (C1-C6) haloalkyl linear or branched polyhaloalkyl (C1-C6), (C3-C8) cycloalkyl, (C3-C8) cycloalkyl (C1-C6) alkyl, the alkyl portion of which may be linear or branched, aryl, (C1-C6) arylalkyl, alkyl part may be linear or branched, heteroaryl or heteroarylalkyl (C1-C6), the alkyl part may be linear or branched, R2 and R3, identical or different, each represent a hydrogen atom or an alkyl group (C1-C6) linear or branched, it being understood that: "aryl" means a phenyl, naphthyl or biphenyl group, - "heteroaryl" means any mono or bicyclic aromatic group containing 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, the aryl and heteroaryl groups thus defined being substituted with 1 to 3 groups selected from linear or branched (C1-C6) alkyl, linear or branched (C1-C6) alkoxy, hydroxy, carboxy, formyl, nitro, cyano, linear or branched (C1-C6) haloalkyl linear or branched polyhaloalkyl (C1-C6), alkyloxycarbonyl, or halogen atoms, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.   2- Compounds of formula (I) according to claim 1 wherein R1 represents a linear or branched (C1-C6) alkyl group, their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable base.   3- compounds of formula (I) according to claim 1 wherein R2 represents a hydrogen atom or a methyl group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable base.   4. Compounds of formula (I) according to claim 1 wherein R3 represents a hydrogen atom or a methyl group, their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable base.   5. Compound of formula (I) according to claim 1 which is N- {2- [3- (hydroxymethyl) -7-methoxy-1-naphthyl] ethyl} acetamide, and its addition salts with a pharmaceutically acceptable base. acceptable.   6. Compound of formula (I) according to claim 1 which is N- {2- [3- (1-hydroxyethyl) -7-methoxy-1-naphthyl] ethyl} acetamide, and its addition salts with a pharmaceutically acceptable base.   7- Process for the preparation of the compound of formula (I) according to claim 1, characterized in that the compound of formula (II) used is the starting material: ## STR5 ## in which R 1 is as defined in US Pat. claim 1, which is subjected to the action of the compound of formula RCOC1 wherein R represents a linear or branched (C1-C6) alkyl group to give the compound of formula (III): in which R and R1 are such that defined above, compound of formula (III) which is subjected - or to a chemical reduction to yield the compound of formula (IIa), a particular case of compounds of formula (I): ## STR1 ## in which R and R 1 are as defined previously, or when R represents a methyl group, to an oxidation to yield the compound of formula (IV): ## STR2 ## in which R 1 is as defined above, which after conversion into the corresponding ester is subjected to a reduction to yield at the co compound of formula (1fb), a particular case of the compounds of formula (I): (Pb) in which R1 is as defined above, or to the action of a magnesium of formula R'MgX in which X represents a halogen atom and R 'represents a linear or branched (C1-C6) alkyl group to give the compound of formula (I / c), a particular case of the compounds of formula (I): wherein R 1, R and R are as defined above, the compounds of formula (Pa) to (I / c) forming all of the compounds of formula (I) which can be purified according to a conventional separation technique, which is transformed, if it is desired, in their addition salts with a pharmaceutically acceptable acid or base and from which the isomers are optionally separated by a conventional separation technique. 2918371 - 18 -   Pharmaceutical compositions containing at least one compound of formula (I) according to any one of claims 1 to 6 or an addition salt thereof with a pharmaceutically acceptable base in combination with one or more pharmaceutically acceptable excipients. 5   9- Pharmaceutical compositions according to claim 8 useful for the manufacture of medicaments for treating disorders of the melatoninergic system.   10- Pharmaceutical compositions according to claim 8 useful 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 sexual dysfunction , as ovulation inhibitors, immunomodulators and in the treatment of cancers.