WO2005012229A1 - Novel bicyclic alkyl derivatives method for production of and pharmaceutical compositions comprising the same - Google Patents

Abstract

Compounds of formula (I), where R<1> = straight-chain or branched C1-C6 alkyl, R<2> is as defined in the description and n = 1 or 2. The invention also relates to medicaments.

Description

 NOVEL ALKYLATED BICYCLIC DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to new alkylated bicyclic derivatives, their preparation process and the pharmaceutical compositions containing them.

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

Numerous studies have highlighted over the past ten years the crucial role of melatonin (N-acetyl-5-methoxytryptamine) in many pathophysiological phenomena as well as in controlling the circadian rhythm. However, it has a fairly short half-life due to rapid metabolism. It is therefore very advantageous to be able to make available to the clinician analogues of melatonin, metabolically more stable and having an agonist or antagonist character, from which one can expect a therapeutic effect greater than that of the hormone itself.

In addition to their beneficial action on circadian rhythm disorders (J. Neurosurg. 1985, 63, pp. 321-341) and sleep (Psychopharmacology, 1990, 100, pp. 222-226), the ligands of the melatoninergic system have interesting pharmacological properties on the central nervous system, in particular 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 diseases of

Parkinson (J. Neurosurg. 1985, 63, pp. 321-341) and Alzheimer's (Brain Research, 1990, 528, pp. 170-174). Likewise, these compounds have shown 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 exerted via specific receptors of the melatonin. Molecular biology studies have shown the existence of several receptor subtypes that can bind this hormone (Trends Pharmacol. Sci., 1995, 16, p. 50; WO 97.04094). Some of these receptors could be located and characterized for different species, including mammals. In order to be able to better understand the physiological functions of these receptors, it is of great interest to have selective ligands.

In addition, such compounds, by interacting selectively with one or the other of these receptors, can be, for the clinician, excellent drugs for the treatment of pathologies linked 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 strong affinity for the melatonin receptors and / or a selectivity for one or the other of the melatoninergic binding sites.

The present invention relates more particularly to the compounds of formula (I):

dans laquelle :

in which :

* R ¹ represents an alkyl _(Cι-C6) linear or branched, R ² represents an alkyl _(Cι-C6) linear or branched, an alkenyl group (C ₂ -C ₆₎ linear or branched cycloalkyl (C -C ₈ ), a cycloalkyl (C ₃ -C ₈ ) alkyl (Cι-C ₆ ) group in which the alkyl part can be linear or branched, aryl, arylalkyl (Cι-C ₆ ) in which the alkyl part can be linear or branched, heteroaryl, heteroarylalkyl (Cι-C ₆ ), the alkyl part of which can be linear or branched, or a linear or branched alkyl group (C Cβ) substituted by one or more halogen atoms, n is 1 or 2,

Being heard 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 can be substituted by 1 to 3 groups chosen from linear or branched (Cι-C ₆ ) alkyl, linear or branched alkoxy (CrC ₆ ), hydroxy, carboxy, formyl, nitro, cyano, polyhaloalkyl (Cι -C ₆ ) linear or branched, 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, non-limiting mention may be made of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane acids. sulfonic, camphoric, etc.

Among the pharmaceutically acceptable bases, non-limiting mention may be made of sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.

The preferred compounds of the invention are the compounds of formula (I) for which R ¹ represents a methyl, ethyl, "-propyl or w-butyl group and more particularly" -butyl.

The preferred value of n is 1.

R ² advantageously represents an alkyl group such as, for example, methyl, ethyl, "-propyl, isopropyl, w-butyl, or isobutyl groups.

Even more particularly, the invention relates to N - [(4-butyl-2,3-dihydro-1H-inden-1-yl) methyl] butanamide. The enantiomers, diastereoisomers as well as the addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention.

The invention also extends to the process for preparing the compounds of formula (I) characterized in that the compound of formula (II) is used as starting material:

dans laquelle n est tel que défini dans la formule (I), que l'on soumet à l'action d'un agent de déméthylation comme BBr₃, pour conduire au composé de formule (III) :

in which n is as defined in formula (I), which is subjected to the action of a demethylating agent such as BBr ₃ , to yield the compound of formula (III):

in which n is defined as above, which is subjected to the action of triflic anhydride to yield the compound of formula (IV):

dans laquelle n est tel que défini précédemment, sur lequel on condense l'acide boronique de formule R^!B(OH)₂ dans laquelle R¹ est tel que défini dans la formule (I) pour conduire au composé de formule (V) :

dans laquelle n et R¹ sont tels que définis précédemment,

in which n is as defined above, on which the boronic acid of formula R is condensed ^! B (OH) ₂ in which R ¹ is as defined in formula (I) to yield the compound of formula (V):

in which n and R ¹ are as defined above,

compound of formula (V) on which we condense, in the presence of Raney nickel, ll''aannhhyyddririddee ddee ffoorrmmuullee ((RR ²² CCOO)) ₂₂ OO ddaannss 1which R ² is as defined in formula (I) to lead to compound of formula (I)

dans laquelle n, R¹ et R² sont tels que définis précédemment,

in which n, R ¹ and R ² are as defined above,

which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with an acid or a pharmaceutically acceptable base and from which the isomers are optionally separated according to a conventional separation technique .

The compounds of formula (II) are either commercial or accessible to a person skilled in the art by conventional chemical reactions and described in the literature.

The pharmacological study of the derivatives of the invention has shown that they are non-toxic, endowed with a strong selective affinity for the melatonin receptors and have important activities on the central nervous system and, in particular, it has been noted therapeutic properties for sleep disorders, antidepressant, anxiolytic, antipsychotic, analgesic properties as well as for microcirculation, which make it possible to establish that the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal depressions or major depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jetlag, schizophrenia, panic attacks, melancholy, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders linked to normal or pathological aging, migraine, memory loss, Alzheimer's disease, as well as in cerebral circulation disorders. 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 inhibitors of ovulation, of immunomodulators and that they are likely to be used in the treatment of cancer.

The compounds will preferably be used in the treatment of major depression, seasonal depressions, 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 seasonal depressions, major 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, there may be mentioned, more particularly those which are suitable for oral, parenteral, nasal, per or transcutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets , sachets, packages, capsules, lollipops, tablets, 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 any treatments combined and ranges from 0.01 mg to 1 g per 24 hours in one or more doses.

The following examples illustrate the invention and do not limit it in any way.

Example 1: N-14-Butyl-2,3-dihydro-1Z / -inden-1-yl) methyllbutanamide

Stage A: 4-Hydroxy-l-indane carbonitrile

In a flask, 1.3 g of 4-methoxy-1-indane carbonitrile is placed in solution in ethanol. 10 mg of Palladium on carbon are added thereto. The medium is purged with argon and then placed under a hydrogen atmosphere. The reaction is left for 16 hours at room temperature. At the end of the reaction, the medium is filtered through celite and then evaporated to yield the title compound in the form of a beige powder. Melting point: 164 ° C

Stage B: 1-Cyano-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate

In a three-necked flask, the compound obtained in stage A is placed in 2 eq. of pyridine. The reaction medium is brought to 0 ° C. and 2 eq. of triflic anhydride are added. Stirring is maintained at room temperature for 45 minutes then the pyridine is evaporated under reduced pressure. The residue is then taken up in dichloromethane and treated successively with a 1Ν HCl solution, water and then with a ΝaOH 2Ν solution. The organic phase is recovered, dried over MgSO ₄ and then evaporated under reduced pressure to yield the title compound in the form of a colorless oil.

Stage C: 4-Butyl-1-indane carbonitrile

In a three-necked flask, 150 mg of the compound obtained in stage B are placed in toluene. Butylboronic acid (1.5 eq.), Lithium chloride (2 eq.) As well as potassium carbonate (1.5 eq.) Dissolved in water are then added. The reaction medium is purged several times with argon before the addition of Pd (PPh ₃ ) ₄ (5%). Stirring is maintained at 60 ° C for 6 hours. The residue is then taken up in ether and washed successively with a 2N NaOH solution and with a saturated NaCl solution. The organic phase is recovered, dried over MgSO ₄ and then evaporated under reduced pressure to conduct, after purification, by chromatography on a column of silica gel (eluent: CH ₂ C1 ₂ / petroleum ether: 6/4) to the title compound in the form of an oil colorless.

Stage D: N - [(4-Butyl-2,3-dihydro-1H-inden-1-yl) methyl] butanamide

In a three-necked flask, 80 mg of the compound obtained in stage C are dissolved in anhydrous THF. Butanoic anhydride (5 eq.) As well as Raney nickel (10 mg) are added. The reaction medium is then purged with argon and then placed under a hydrogen atmosphere. After 16 hours of reaction at room temperature, the reaction mixture is filtered through celite. To the filtrate is added a 20% ammonia solution. After extraction, the organic phase is washed successively with an IN HCl solution, water and an IN NaOH solution. The organic phase is recovered and then evaporated under reduced pressure. The crude reaction product is then purified by chromatography on a column of silica gel (eluent: CH ₂ C1 ₂ / petroleum ether: 6/4) to yield the title compound in the form of a colorless oil.

Example 2: N - [(5-Butyl-1,2,3-4-tetrahvdro-1-naphthaienyl) methyπbutanamide

Stage A: 5-Hydroxy-1,2,3,4-tetrahydro-l-naphthalene carbonitrile

The procedure is carried out as in Stage A of Example 1, replacing 4-methoxy-1-indane carbonitrile with 5-methoxy-1,2,3,4-tetrahydro-1-naphthalene carbonitrile. The title product is obtained after purification by chromatography on silica gel (eluent: CH ₂ Cl ₂ / MeOH: 99/1) in the form of a colorless oil.

Stage B: 5-Cyano-5,6,7,8-tetrahydro-1-naphthalenyl trifluoromethanesulfonate

The procedure is carried out as in stage B of Example 1 starting from the compound obtained in stage A. The title product is obtained after purification by chromatography on silica gel (eluent: CH ₂ C1 ₂ / petroleum ether: 4/6) in the form of a colorless oil. Stage C: 5-Butyl-1,2,3,4-tetrahydro-1-naphthalene carbonitrile

The procedure is carried out as in stage C of Example 1 starting from the compound obtained in stage B.

Stage D: N - [(5-Butyl-1,2,3,4-tetrahydro-1-naphthalenyl) methyl] butanamide

The procedure is carried out as in stage D of Example 1 starting from the compound obtained in stage C. PHARMACOLOGICAL STUDY

EXAMPLE A Study of acute toxicity

Acute toxicity was assessed after oral administration in groups of 8 mice (26 ± 2 grams). The animals were observed at regular intervals during the first day and daily during the two weeks following the 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 device consists of a plexiglass cylinder filled with water. The animals are tested individually during a 6 minute session. At the start of each test, the animal is placed in the center of the cylinder. The downtime is recorded. Each animal is judged immobile when it stops struggling, and remains on the surface of the water, immobile, only making the movements allowing it to keep the head above water.

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

1. Study of binding to the MTi and MT ₂ melatonin receptors

MTi or MT ₂ receptor binding experiments are performed using 1177

22 - [[II]] - iiooddoommééllaattoonniinnee ccoommmmee rraaddiioolliiggaanndd ddee rrééfféérréence. The radioactivity retained is determined using a liquid scintillation counter

Competitive binding experiments are then carried out in triplicate, with the different compounds to be tested. A range of different concentrations is tested for each compound. The results are used to determine the binding affinities of the compounds tested (IC ₅ o).

2. Study of binding to the -T site? melatonin

The binding experiments on the MT ₃ sites are carried out on hamster brain membranes using 2- [ ¹²⁵ I] iodomelatonin as radioligand. The membranes are incubated for 30 minutes with 2- [ ¹²⁵ I] iodomelatonin at a temperature of 4 ° C. and different concentrations of the compounds to be tested. After incubation, the membranes are quickly filtered and then washed with cold buffer using a filtration system. The fixed radioactivity is measured by a scintillation counter. The values of IC ₅ o (concentration inhibiting by 50% the specific binding) are calculated from competition curves using a nonlinear regression model.

Thus, the IC ₅ o values found for the compounds of the invention attest to a bond for one or the other of the melatoninergic binding sites, these values being <10 μM.

By way of example, the compound of Example 1 has an IC ₅ o (MTi) of 4.10 ^"8 M and an IC ₅₀ (MT ₂ ) of 3.10 ^{" 9} M.

EXAMPLE D 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 physiological, biochemical and behavioral circadian 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 the circadian rhythms of locomotor activity which represent a reliable marker of the activity of the endogenous circadian clock.

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 one month old are subjected as soon as they arrive at the laboratory to a light cycle of 12 hours of light per 24 hours (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 follow the nycthemeral (LD) or circadian (DD) rhythms ).

As soon as the recorded rhythms show a stable training by the light cycle

LD 12:12, the rats are placed in permanent darkness (DD).

Two to three weeks later, when free flow (rhythm reflecting that of the endogenous clock) is clearly established, the rats receive a daily administration of the test molecule.

The observations are made by visualizing the activity rhythms:

- training of activity rhythms by the light rhythm,

- disappearance of the training of rhythms in permanent darkness,

- training through daily administration of the molecule; transient or lasting effect. Software allows:

- to measure the duration and intensity of the activity, the period of the rhythm in the animals in free course and during the treatment,

- possibly highlighting by spectral analysis the existence of circadian and non-circadian components (ultradians for example).

Results

It is clear that the compounds of the invention make it possible to act powerfully on the circadian rhythm via the melatoninergic system.

EXAMPLE E: Light / dark cage test

The compounds of the invention are tested in a behavioral model, the test of light / dark cages, which makes it possible to reveal the anxiolytic activity of the molecules.

The device consists of two polyvinyl boxes covered with Plexiglas. One of these boxes is obscure. A lamp is placed above the other box giving a light intensity in the center thereof of approximately 4000 lux. An opaque plastic tunnel separates the light 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 start of each test, the mouse is placed in the tunnel, facing the dark box. The time spent by the mouse in the lit 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 lighted cage as well as the number of transitions, which shows the anxiolytic activity of the derivatives of the invention.

EXAMPLE F Activity of the Compounds of the Invention on the Caudal Artery of the Rat

The compounds of the invention were tested in vitro on the rat caudal artery. Melatoninergic receptors are present on these vessels which makes them a significant pharmacological model for studying the activity of melatoninergic ligands. The receptor stimulation can induce either vasoconstriction or vasodilation depending on the arterial segment studied.

Protocol

1 month old rats are accustomed for 2 to 3 weeks to a 12h / 12h light / dark cycle.

After sacrifice, the caudal artery is isolated and maintained in a richly oxygenated environment. The arteries are then cannulated at both ends, suspended vertically in an organ chamber in an appropriate medium and perfused via their proximal end. Changes in pressure in the infusion rate allow the vasoconstrictor or vasodilator effect of the compounds to be assessed.

The activity of the compounds is evaluated on segments pre-contracted by phenylephrine (1 μM). A concentration-response curve is determined in a non-cumulative manner by adding a concentration of the compound studied on the pre-contracted segment. When the observed effect has reached equilibrium, the medium is changed and the preparation left 20 minutes before the addition of the same concentration of phenylephrine and a new concentration of the compound studied.

Results

The compounds of the invention significantly modify the diameter of the caudal arteries preconstructed by phenylephrine.

EXAMPLE G Pharmaceutical composition: Tablets

1000 tablets containing 5 mg of N - [(4-butyl-2,3-dihydro-1H-inden-1-yl) methyl] butanamide

(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

1- Compounds of formula (I):

in which: * R ¹ represents a linear or branched alkyl group (CrC ₆ ), R ² represents a linear or branched alkyl group (Cι-C ₆ ), a linear or branched alkenyl group (C ₂ -C ₆ ), a group cycloalkyl (C ₃ -C ₈ ), a cycloalkyl (C ₃ -C ₈ ) alkyl (Cι-C ₆ ) group in which the alkyl part can be linear or branched, aryl, arylalkyl (Cι-C ₆ ) in which the alkyl part can be linear or branched, heteroaryl, heteroarylalkyl ^ -C _ό ) the alkyl part of which can be linear or branched, or an alkyl group (dC ₆ ) linear or branched substituted by one or more halogen atoms, n is 1 or 2, 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 can be substituted by 1 to 3 groups chosen from linear or branched alkyl (dC ₆ ), linear or branched alkoxy (Cι-C ₆ ), hydroxy, carboxy, formyl, nitro, cyano, polyhaloalkyl (Cι -C ₆ ) linear or branched, alkyloxycarbonyl, or halogen atoms, their enantiomers and diastereoisomers, as well as their addition salts with an acid or a pharmaceutically acceptable base. 2- Compounds of formula (I) according to claim 1 for which R ¹ represents a methyl, ethyl, n-propyl or w-butyl group, their enantiomers and diastereoisomers as well as their addition salts with an acid or a pharmaceutically base acceptable. 3- Compounds of formula (I) according to claim 1 for which n is 1, their enantiomers and diastereoisomers, as well as their addition salts with an acid or with a pharmaceutically acceptable base. 4- Compounds of formula (I) according to claim 1 for which R ² represents an alkyl group, their enantiomers and diastereoisomers, as well as their addition salts with an acid or with a pharmaceutically acceptable base. 5- Compound of formula (I) according to claim 1 which is N - [(4-butyl-2,3-dihydro-1H- inden-1-yl) methyl] butanamide, its enantiomers as well as its addition salts to a pharmaceutically acceptable acid or base. 6- A process for preparing the compounds of formula (I) according to claim 1 characterized in that the compound of formula (II) is used as starting material:

in which n is as defined in formula (I), which is subjected to the action of a demethylating agent such as BBr, to yield the compound of formula (III):

in which n is defined as above, which is subjected to the action of triflic anhydride to yield the compound of formula (IV):

in which n is as defined above, on which the boronic acid of formula R'B (OH) ₂ is condensed in which R ¹ is as defined in formula (I) to yield the compound of formula (V):

in which n and R are as defined above, compound of formula (V) on which is condensed, in the presence of Raney nickel, the anhydride of formula (R CO) O in which R is as defined in formula (I), to lead to the compound of formula (I ):

in which n, R ¹ and R ² are as defined above, which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with an acid or a pharmaceutically acceptable base and from which the isomers are optionally separated according to a conventional separation technique . 7- Pharmaceutical compositions containing at least one compound of formula (I) according to any one of claims 1 to 5 or one of their addition salts with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients. 8- Pharmaceutical compositions according to claim 7 useful for the manufacture of medicaments for treating disorders of the melatoninergic system. 9- Pharmaceutical compositions according to claim 7 useful for the manufacture of medicaments for the treatment of sleep disorders, stress, anxiety, major depression or seasonal depressions, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jetlag, 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, disorders of the cerebral circulation, as well as in sexual dysfunctions , as ovulation inhibitors, immunomodulators and in the treatment of cancer.