FR2953515A1 - NOVEL HEXAHYDROCYCLOPENTA [B] PYRROLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME - Google Patents

Abstract

Compounds of formula (I): in which: - ALK represents an alkylene chain, - W represents a group where R and R 'are as defined in the description. Drug.

Description

The present invention relates to novel hexahydrocyclopenta [b] pyrrole derivatives, process for their preparation and pharmaceutical compositions containing them.

The compounds of the present invention are particularly valuable from a pharmacological point of view for their interaction with central histaminergic systems in vivo.

The aging of the population, as a result of the increase in life expectancy at birth, has also led to a large increase in the incidence of age-related neuropathologies, including Alzheimer's disease. The main clinical manifestations of cerebral aging and especially age-related neuropathologies are deficits in memory and cognitive functions that can lead to dementia.

In the central nervous system, neuropharmacological studies have shown that histamine via central histaminergic systems plays a role of neurotransmitter or neuromodulator in physiological or physiopathological situations (Pell and Green, Annu Rev. Neurosci., 1986, 9, 209 Schwartz et al., Physiol Rev., 1991, 71, 1-51). Thus, it has been shown that histamine is involved in various physiological and behavioral processes such as thermoregulation, neuroendocrine regulation, nociception, circadian rhythm, cataleptic states, motor skills, aggressiveness, eating behavior, learning and memorization, as well as synaptic plasticity (Hass et al., Histaminergic neurons: morphology and function, Boca Raton, FL: CRC Press, 1991, pp. 196-208, Brown et al., Prog Neurobiology, 2001, 63, 637-672, Smith et al., Neuroimmunomodulation 2007, 14, pp. 317-325).

Studies in animals have shown that the increase in endogenous extra-synaptic levels of histamine can promote states of alertness, learning and memory processes and regulate food intake (Brown et al. Prog Neurobiol., 2000, 63, 637-672, Passani et al., Neurosci, Biobehav, Rev., 2000, 24, 107-113). Consequently, the potential therapeutic indications for compounds capable of increasing the turnover or histamine release at the central level are the treatment of cognitive deficits associated with cerebral aging, acute and chronic neurodegenerative diseases, schizophrenia, as well as as the treatment of mood disorders, schizophrenia, sleep disorders and sleep-wake rhythm, attention deficit hyperactivity syndrome. In addition, studies have shown that a histamine injection into the central hypothalamic nuclei involved in the regulation of satiety attenuates the diet in the rat. In addition, hypofunctioning of histaminergic transmission has been demonstrated in genetically obese rats (Machidori et al., Brain Research, 1992, 590, 180-186). Accordingly, eating disorders and obesity are also potential therapeutic indications for the compounds of the present invention.

The present invention relates to novel azabicyclic derivatives which are distinguished from the compounds exemplified in WO2005 / 089747 by the presence of a hexahydrocyclopenta [b] pyrrol-1-yl ring.

Surprisingly, this structural difference with respect to the compounds of application WO2005 / 089747 confers on the compounds of the invention not only remarkable procognitive properties, but also powerful awakening, anti-sedative, anti-hypnotic, anxiolytic and antidepressant properties.

At the neurological level, this combination of activities opens the way not only to new treatments for cognitive disorders linked to cerebral aging, neurodegenerative diseases or head trauma, but also to the treatment of psycho-behavioral disorders associated with these pathologies such as disorders of the brain. sleep, apathy and / or depressive states. Moreover, the pharmacological profile of the compounds of the invention also makes it possible to envisage new treatments in the psychiatric field, for schizophrenia, mood or sleep disorders, for example. The present invention relates more particularly to the compounds of formula (I): (I) in which:

ALK represents an alkylene chain; W represents a group -R or II R 'OOR' where R and R 'represent, independently of one another, a hydrogen atom or a (C1-C6) alkyl group; linear or branched optionally substituted with one or more groups chosen from halogen, hydroxy and alkoxy,

it being understood that: the term alkylene denotes a bivalent radical, linear or branched, containing from 2 to 6 carbon atoms, the term alkoxy denotes an alkyl-oxy group whose linear or branched alkyl chain contains from 1 to 6 atoms of carbon,

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

The preferred compounds of formula (I) are those for which the group W is located in the para position.

Preferably, ALK represents a linear divalent radical containing from 2 to 6 carbon atoms such as, for example, the ethylene, propylene or butylene group, and more preferably still a propylene group.

A particular aspect of the invention relates to the compounds of formula (I) for which W represents the group II i ùR. Another particular aspect of the invention relates to the compounds of formula (I) for which W represents the group IIIRR 'O. Advantageously, R and R' represent, independently of one another, the atom of hydrogen, the methyl group or the ethyl group, these groups being optionally substituted by a methoxy.

More particularly, W represents the -CO-NH-CH 3 group, -CO-N (CH 3) 2, -CO-NH 2, -CO-N (CH 2 CH 3) 2, -NH-CO-CH 3, -N (CH 3) - CO-CH3 or -NH-CO-CH2-OCH3.

Preferred compounds of the invention are those for which the hexahydrocyclopenta [b] pyrrol-1-yl ring is of cis configuration. Other preferred compounds are those for which the core configuration is trans.

Even more particularly, the invention relates to the compounds of formula (I) which are: 4- {3- [cis-hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} benzamide, N- (4- {2- [cis-hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} phenyl) acetamide, 4- {3- [cis -hexahydrocyclopenta [b] pyrrol-1 (21)) - yl] propoxy N, N-dimethylbenzamide, 4- {3- [cis -hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} -N, N -diethylbenzamide, 4- {3- [ cis-hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} -N-methyl benzamide, N- (4- {3- [cis-hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy } phenyl) -N-methylacetamide, N- (4- {3- [cis -hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} phenyl) -2-methoxyacetamide, 3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} -N, N-diethylbenzamide; N- (4- {3- [trans-hexahydro-cyclopenta [b] pyrrol); Propoxy (phenyl) -N-methylacetamide, N- (4- {3- [-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} phenyl) -2-methoxyacetamide, 4 - {3- [tr ans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} benzamide, N- (4- {3 - [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} phenyl) acetamide, 4 - {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} -N, N-dimethyl benzamide, 4- {3- [trans-hexahydro-cyclopenta [b] pyrrol-1- yl] propoxy} -N-methylbenzamide,

and their enantiomers and addition salts thereof with a pharmaceutically acceptable acid or base.

Among the addition salts with a pharmaceutically acceptable acid, the hydrochloride, oxalate and citrate are more particularly preferred.

The invention also extends to the process for the preparation of compounds of formula (I), characterized in that the compound of formula (II): OH (II) in which W is as defined is used as starting material in formula (I),

compound of formula (II) on which the compound of formula (III) is condensed in basic medium: BruALK CI (III)

in which ALK is as defined in formula (I), to obtain the compound of formula (IV):

WhereALK CI

in which W and ALK are as defined above, on which the compound of formula (V): (V) is condensed to yield the compound of formula (I) as defined above: (I) which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and optionally separated optical isomers according to a conventional separation technique.

The compounds of formulas (II) and (III) are either commercially available or accessible to those skilled in the art by conventional chemical reactions and described in the literature. The compounds of formulas (V) of cis or trans configuration are also either commercially available or accessible to those skilled in the art by conventional chemical reactions and described in the literature.

Alternatively, the compounds of formula (VI): OH in which the ALK group is as defined above,

may be used as synthetic intermediates for the compounds of formula (Ua), in particular the compounds of formula (I) for which W represents a group -CONRR ', by coupling with an amine of formula NHRR', where R and R 'have the same meaning as in formula (I). Similarly, the compounds of formula (VII): ## STR2 ## in which the ALK group is as defined above,

may be used as synthetic intermediates for the compounds of formula (I / a), in particular the compounds of formula (I) for which W represents a group -CONRR ', by coupling with an amine of formula NHRR', where R and R 'have the same meaning as in formula (I).

In addition, the compounds of formula (I / a), in particular the compounds of formula (I) for which W represents a group -CONRR ', can also be obtained by the condensation of the amine NHRR', where R and R have the same meaning as in formula (I), using the compounds of formula (VIII): (VIII) OR "in which the ALK group is as defined above and R" represents an (C1-C6) alkyl group linear or branched or a benzyl group,

The compounds of formula (VIII) being prepared via the corresponding carboxylic acid (VI) or acyl chloride (VII) presented above. Finally, it is also possible to obtain the compounds of formula (I / a) by hydrolyzing compounds of formula (IX): in which the ALK group is as defined above.

The pharmacological study of the compounds of formula (I) has shown that they have procognitive properties by facilitating the processes of memorization and learning, awake, anti-sedative, anti-hypnotic, anxiolytic and antidepressant properties.

At the neurological level, the compounds according to the invention may be useful in the treatment of cognitive disorders related to cerebral aging or to neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Pick's disease, body dementia. Lewy, frontal and subcortical dementia, frontotemporal dementia, vascular dementia, Huntington's disease, multiple sclerosis, in new treatments for cognitive disorders related to head trauma, but also in the treatment of psycho-behavioral disorders associated with these pathologies such as sleep disorders, apathy and anxio-depressive states.

At the psychiatric level, these compounds may be useful in the treatment of mood disorders, and more particularly the treatment of anxio-depressive states, schizophrenia and cognitive disorders associated with it, as well as in the treatment of disorders of the body. sleep, sleep-wake rhythm and Attention Deficit Hyperactivity Syndrome (ADHD). Sleep disorders include narcolepsy and sleep apnea. 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.

In the pharmaceutical compositions according to the invention, the mass fraction of active ingredient (mass of the active ingredient on the total mass of the composition) is between 1 and 50%.

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, 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 possibly associated treatments and ranges between 0.05 mg and 500 mg per 24 hours. for treatment in 1 to 3 doses per day.

The following examples illustrate the invention and do not limit it in any way. The structures of the compounds, described in the examples, were determined according to the usual spectrophotometric techniques (infrared, NMR, mass spectrometry, etc.).

By way of information, the compounds below correspond to racemates of cis or trans configuration. In other words, the compounds below correspond, respectively, to racemic mixtures of backbones (3aR, 6aR) -hexahydrocyclopenta [b] pyrrol-1 (2H) -yl and backbones (3aS, 6aS) -hexahydrocyclopenta [ b] pyrrol-1 (2H) -yl, and racemic mixtures of backbones (3aR, 6aS) -hexahydrocyclopenta [b] pyrrol-1 (2H) -yl and backbones (3aS, 6aR) - hexahydrocyclopenta [b] pyrrol 1 (211) -yl. As mentioned in some examples below, the racemic mixtures can be separated to obtain the pure enantiomers by HPLC chiral separation techniques, for example, CHIRALCEL OF, CHIRALPACK AS-H or CHIRALPACK AD. -H.

Example 1 Synthetic Route A: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (211) -yl] propoxy} benzamide

Step 1: 4- (3-Chloropropoxy) benzamide A mixture of 0.004 moles of 4-hydroxybenzamide, 0.004 moles of 1-bromo-3-chloropropane and 0.006 moles of cesium carbonate in 10 ml of acetonitrile is heated. at reflux for 5 hours.

Stage 2: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) yl] propoxy} benzamide In the reaction medium of stage 1 at room temperature are added 0.004 mole of cis-octahydrocyclopenta [b] pyrrole, of which the synthesis is described in the publication J Org. Chem. 1996, 61, 5813-5817, and 0.002 moles of sodium iodide. The refluxing heating is then resumed for 16 hours. The precipitate is filtered and rinsed with acetonitrile. The filtrate is concentrated to dryness. The residue is taken up in dichloromethane. This solution is extracted with sodium hydroxide and then with water, before being dried over magnesium sulphate and concentrated to dryness. The residue is purified by preparative chromatography technique on Lichroprep RP-18 phase.

Elemental Microanalysis% C% H% N 20 Calculated 70.80 8.39 9.71 Found 70.80 8.29 9.70

Example 1, Route B: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (211) -yl] propoxy} benzamide

Step 1: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) yl] propoxy} benzonitrile The experimental procedure is identical to that of Example 1, synthetic route A, replacing Stage 1 4-hydroxybenzamide by 4-hydroxybenzonitrile.

Stage 2: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) yl] propoxy} benzamide The compound obtained in the preceding stage (2.2 g) is dissolved in 90 ml of ethanol and heated under reflux. in the presence of 5.1 g of KOH for 18h. The medium is poured into 90 ml of water and then concentrated to half volume under vacuum. The solid obtained is filtered, rinsed with isopropyl ether and dried. % C% H% N Calculated 70.80 8.39 9.71 Found 70.32 8.28 9.40 Example 1, Route C: 4-13- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) - ylJpropoxy} benzamide

Stage 1: Methyl 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) yl] propoxy} benzoate The experimental procedure is identical to that of Example 1, synthetic route A, replacing at Step 1 4-hydroxybenzamide with methyl 4-hydroxybenzoate.

Step 2: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) yl} propoxy} benzoic acid A mixture of 3.5 g of the Step 1 compound, 12.7 ml of 2 N sodium hydroxide and 8 ml of methanol is refluxed for one hour. 12.7 ml of 2N HCl are added to the reaction medium cooled in an ice bath. The precipitate is washed with water and dried in vacuo.

Step 3: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) yl] propoxy} benzoyl chloride, hydrochloride A mixture of 1.8 g of the product described in Step 2 and 20 ml of thionyl chloride is refluxed for 2 hours. The reaction medium is concentrated under vacuum, coevaporated twice with toluene. The solid residue is homogenized in ethyl ether, filtered and dried under vacuum. Elemental Microanalysis: Step 4: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) yl] propoxy} benzamide In a solution of 1 g of the product described in Step 3 in the dichloromethane at room temperature. At 0 ° C., 4 ml of 2N ammoniacal methanol are added dropwise. The mixture is then stirred for 1 hour at room temperature, washed with a 2N sodium hydroxide solution and then with water. The organic phase is dried over magnesium sulfate and concentrated. The solid obtained is filtered, rinsed with isopropyl ether and dried.

Elemental Microanalysis:% C% H% N Calculated 70.80 8.39 9.71 Found 70.69 8.46 9.41 Example 1a: 4- {2- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} benzamide (enantiomer 1) Enantiomer 1 was obtained by preparative chiral column separation CHIRALCEL OF 4.6 x 250 mm 10 μm, elution at room temperature, eluent mixture: n-heptane / 15 n-propanol / diethylamine (60/40 / 0.1), flow rate 1 ml / min, UV detection at 255 nm.

Rotatory power: [aD] 589r, 25 = + 38, 72 "c = 1.0; MeOH)

Example lb: 4- {2- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} benzamide (enantiomer 2)

The enantiomer 2 was obtained by preparative separation on a chiral CHIRALCEL 20 OF 4.6 x 250 mm 10 μm column, elution at ambient temperature, eluent mixture: n-heptane / n-propanol / diethylamine (60/40 / 0.1 ), flow rate 1 ml / min, UV detection at 255 nm

Rotatory power: [aD] 589nm25 ° = - 36.53 "c = 0.9; MeOH) Example 2: 4- {2- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] ethoxy} benzamide

The experimental procedure is identical to that of Example 1, synthesis route A, replacing in Step 1 1-bromo-3-chloropropane by 1-bromo-2-chloroethane.

Elemental Microanalysis% C% H% N Calculated 70.04 8.08 10.21 Found 69.98 8.16 9.98

Example 3 N- (4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} phenyl) acetamide The experimental procedure is identical to that of Example 1, synthetic route A, replacing in Step 1 the 4-hydroxybenzamide with N- (4-hydroxyphenyl) acetamide.

Elemental Microanalysis:% C% H% N Calculated 71.49 8.67 9.26 Found 70.89 8.79 8.90 Example 3a: N- (4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} phenyl) acetamide (enantiomer 1) Enantiomer 1 was obtained by preparative chiral column separation CHIRALCEL OF 60X (600 mm 20 μm), elution at room temperature, eluent mixture: n-heptane / N-propanol / diethylamine (100/5 / 0.1), flow rate 50 ml / min, UV detection at 255 nm. 0 Rotatory power: [aDJss9nm s = + 41.90 "c = 1.0; Example 3b: N- (4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} phenyl) acetamide (Enantiomer 2) The enantiomer 2 was obtained by preparative separation on a CHIRALCEL OF 60X chiral column (600 mm 20 μm), elution at ambient temperature, eluent mixture: n-heptane / 5 n-propanol / diethylamine (100/5 / 0.1), flow rate 50 ml / min, UV detection at 255 nm. 0 Rotatory power: [aD] 5s9nm 5 = - 42.21 "c = 1.0; MeOH) Example 4: N- (4- {2- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] ethoxy} phenyl) acetamide Oxalate The experimental procedure is identical to that of Example 2, replacing at the Stade 1

4-hydroxybenzamide with N- (4-hydroxyphenyl) acetamide. 0.36 g of oxalic acid is then added to 0.38 g of the compound thus obtained in 6 ml of ethanol. The product obtained is filtered, rinsed with ethyl ether and then dried under vacuum. Elemental microanalysis

% C% H% N 15 Calculated 60.31 6.92 7.40

Found 59.82 6.79 7.71 Example 5: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} -N, N-dimethylbenzamide hydrochloride The experimental procedure is identical to that of Example 1, synthesis route A, replacing in Step 1 the 4-hydroxybenzamide with 4-hydroxy-N, N-dimethylbenzamide. The product thus obtained is dissolved in 10 ml of ethanol to which 2 ml of 2N hydrochloric ether are added. The crystallized product is filtered off, rinsed with ethanol and dried under vacuum. 2953515 - 16 - Elemental Microanalysis

% C% H% N% Cl% CI-Calculated 64.67 8.28 7.94 10.05 10.05

Found 64.54 8.25 7.85 9.75 9.76 Example 5a: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} -N, N- hydrochloride dimethylbenzamide (enantiomeric) Enantiomer 1 was obtained by preparative chiral column separation CHIRALPAK AS-H 4.6 x 250 mm 5 μm, elution at room temperature, eluent mixture: acetonitrile / diethylamine (100 / 0.1) flow rate 0 , 6 ml / min, UV detection at 240 nm. 0 10 Rotatory power: [aDJ589n2 = - 32.66 "c = 0.6; MeOH) Example 5b: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} -N, N-dimethylbenzamide hydrochloride (enantiomer 2) The enantiomer 2 was obtained by preparative separation on CHIRALPAK AS-H chiral column 4.6 x 250 mm 5 μm, elution at room temperature, eluent mixture: acetonitrile / diethylamine (100 / 0.1) flow rate 0.6 ml / min, UV detection at 240 nm. Rotatory power: [aDJ589n ,,, = + 34.93 "c = 0.8; MeOH) Example 6: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} -N, N-diethylbenzamide Dioxalate The experimental procedure is identical to that of Example 4, replacing in Step 1, N- (4-hydroxyphenyl) acetamide with 4-hydroxy-N, N-diethylbenzamide. 2953515 -17- Elemental Microanalysis

% C% H% N

Calculated 57.24 6.92 5.34

Found 57.74 6.84 4.72 Example 7: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (211) -yl] propoxy} -N-methylbenzamide hydrochloride The experimental procedure is identical to that of Example 5, replacing in Step 1 4-hydroxy-N, N-dimethylbenzamide with 4-hydroxy-N-methylbenzamide. Elemental microanalysis

10 C% H% N% Cl% Cl-

Calculated 63.80 8.03 8.27 10.46 10.46

Found 63.40 8.02 8.23 9.68 10.12 Example 7a: 4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (211) -yl] propoxy} -N-methylbenzamide hydrochloride (enantiomer) 1) The enantiomer 1 was obtained by preparative chiral column separation CHIRALPACK AS-H 4.6 x 250 mm 5 μm, elution at room temperature, eluent mixture: acetonitrile / diethylamine (100 / 0.1) flow rate 1 ml / min, UV detection at 250 nm. Rotatory power: [αD] 589n, = -35.97 ° C = 0.98; MeOH) Example 7b: 4- {3- [cis-hexahydrocyclopenta [b] pyrrol-1 (211) -yl] hydrochloride

Propoxy-N-methylbenzamide (enantiomer 2) Enantiomer 2 was obtained by preparative chiral column separation CHIRALPACK AS-H 4.6 x 250 mm 5 μm eluting at room temperature, eluent mixture: acetonitrile / diethylamine (100 / 0,1) flow rate 1 ml / min, UV detection at 250 nm. - 18 - Rotatory power [aDJ589nm20 ° = + 36.41 "c = 0.94; MeOH) Example 8: N- (4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} phenyl) -N-methylacetamide hydrochloride The experimental procedure is identical to that of the Example By replacing in Step 1 the 4-hydroxy-N, N-dimethylbenzamide with N- (4-hydroxyphenyl) -N-methylacetamide. Elemental Microanalysis% C% H% N% Cl-

Calculated 64.67 8.28 7.94 10.05 Found 64.22 8.14 7.73 10.07 Example 8a: N- (4- {3- [cis-hexahydrocyclopenta [b] pyrrol-1 hydrochloride (2H) -yl] propoxy} phenyl) -N-methylacetamide (enantiomer 1) The enantiomer 1 was obtained by preparative separation on a chiral column CHIRALPAK AD-H 4.6 x 250 mm 5μm, elution at room temperature, eluent mixture : ethanol / acetonitrile / diethylamine (15/85 / 0.1) flow rate 1.0 ml / min, UV detection at 280 nm. Rotatory power [α D] 589n, 20 = - 28.36 ° C = 0.53; DMSO) Example 8b: N- (4- {3- [cis-hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} phenyl) -N-methylacetamide hydrochloride (enantiomer 2) The enantiomer 2 was obtained by preparative separation on a chiral column CHIRALPAK AD-H 4.6 x 250 mm 5μm, elution at room temperature, eluent mixture: ethanol / acetonitrile / diethylamine (15/85 / 0.1) flow rate 1.0 ml / min, detection UV at 280 nm. Rotatory power [aD] 589 nm 2 O = + 29.38 ° (c = 0.50, DMSO) Example 9: N- (4- {3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) hydrochloride ) -yl] p -oxyphenyl) -2-methoxyacetamide

The experimental procedure is identical to that of Example 5, replacing in Stage 1 4-hydroxy-N, N-dimethylbenzamide by N- (4-hydroxyphenyl) -2-methoxyacetamide.

Elemental Microanalysis:% C% H% N% Cl- Calculated 61.86 7.92 7.59 9.61 Found 62, 09 7, 69 7, 80 10, 46

Example 10, Route A: 4- {3- [Crans-hexahydro-cyclopenta [b] pyrrol-1-10-yl] propoxy} benzamide hydrochloride

Step 1: 4- (3-Chloropropoxy) benzamide A mixture consisting of 0.004 moles of 4-hydroxybenzamide, 0.004 moles of 1-bromo-3-chloropropane and 0.006 moles of cesium carbonate in 10 ml of acetonitrile is heated to room temperature. reflux for 5 hours.

Step 2: 4- {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl} propoxy} benzamide In the Stage 1 reaction medium at room temperature, 0.004 moles of trans-octahydro-cyclopenta [b] pyrrole are added, of which the synthesis is described in J Chem. Soc. 1959, 1050-1054, and 0.002 moles of sodium iodide. The refluxing heating is then resumed for 16 hours. The precipitate is filtered and rinsed with acetonitrile. The filtrate is concentrated to dryness. The residue is taken up in dichloromethane. This solution is extracted with sodium hydroxide and then with water, before being dried over magnesium sulphate and concentrated to dryness. The residue is purified by preparative chromatography technique on Lichroprep RP-18 phase.

Step 3: 4- {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl} propoxy} benzamide hydrochloride The product obtained in Step 2 is dissolved in 10 ml of ethanol to which 2 ml of ether are added. 2N hydrochloric acid. The crystallized product is filtered, rinsed with ethanol and dried under vacuum.

Elemental Microanalysis: C% H% N% Cl-5 Calculated 62.86 7.66 10.91 Found 61.89 7.70 8.29 10.63

Example 10, Route B: 4- {3- [trans-Hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} benzamide hydrochloride

Stage 1: 4- {3- [trans-Hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} benzonitrile The experimental procedure is identical to that of Example 10, synthetic route at stages 1 and 2, replacing in Step 1 4-hydroxybenzamide by 4-hydroxybenzonitrile.

Stage 2: 4- {3- [trans-Hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} benzamide The compound obtained in the preceding Stage (2.2 g) is dissolved in 90 ml of ethanol and heated to 80.degree. reflux in the presence of 5.1 g of KOH for 18 hours. The medium is poured into 90 ml of water and then concentrated to half volume under vacuum. The solid obtained is filtered, rinsed with isopropyl ether and dried.

Step 3: 4- {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} benzamide hydrochloride

The product obtained in Step 2 is dissolved in 10 ml of ethanol to which 2 ml of 2N hydrochloric ether are added. The crystallized product is filtered, rinsed with ethanol and dried under vacuum.

Elemental Microanalysis: C% H% N% Cl-Calculated 62.86 7.66 10.91 Found 62.59 7.69 8.30 10.75 2953515 Example 10, Route C: Hydrochloride 4- {3- [trans-Hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} benzamide

Step 1: Methyl 4- {3- [trans-Hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} benzoate The experimental procedure is identical to that of Example 10, synthesis route at stages 1 and 2, replacing in Stage 1 4-hydroxybenzamide with methyl 4-hydroxybenzoate.

Step 2: 4- {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl} propoxy} benzoic acid A mixture of 3.5 g of the compound of the above Step, 12.7 ml of 2 N sodium hydroxide and 8 ml of methanol is refluxed for one hour. 12.7 ml of 2N HCl are added to the reaction medium cooled in an ice bath. The precipitate is washed with water and dried under vacuum.

Step 3: 4- {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} benzoyl chloride, hydrochloride A mixture of 1.8 g of the product described in Step 2 and 20 ml of thionyl chloride is refluxed for 2 hours. The reaction medium is concentrated under vacuum, coevaporated twice with toluene. The solid residue is homogenized in ethyl ether, filtered and dried under vacuum.

Step 4: 4- {3- [trans-Hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} benzamide In a solution of 1 g of the product described in Step 3 in dichloromethane at 0 ° C., are added dropwise 4 ml of 2N ammonia methanol. The mixture is then stirred for 1 hour at ambient temperature, washed with a 2N sodium hydroxide solution and then with water. The organic phase is dried over magnesium sulfate and concentrated. The solid obtained is filtered, rinsed with isopropyl ether and dried. Step 5: 4- {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} benzamide hydrochloride

The product obtained in Step 4 is dissolved in 10 ml of ethanol to which 2 ml of 2N hydrochloric ether are added. The crystallized product is filtered, rinsed with ethanol and dried under vacuum.

Elemental Microanalysis:% C% H% N% Cl- Calculated 62.86 7.66 8.62 10.91 Found 62.40 7.50 8.41 10.67 Example 11: 4- {2- [HCl trans-hexahydro-cyclopenta [b] pyrrol-1-yl] ethoxy} benzamide

The experimental procedure is identical to that of Example 10, synthesis route A, by replacing in Step 1 1-bromo-3-chloropropane by 1-bromo-2-chloroethane.

Elemental Microanalysis: Calculated 61.83 7.46 9.01 11.41 Found 61.30 7.38 8.80 10.97 Example 12: N- (4- {3HCl) hydrochloride - [trams-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} phenyl) acetamide The experimental procedure is identical to that of Example 10, synthesis route A, replacing in Step 1 the 4-hydroxybenzamide by N- (4-hydroxyphenyl) acetamide. 2953515 - 23 Elemental microanalysis. % C% H% N% Cl- Calculated 63.80 8.03 8.27 10.46 Found 63.53 7.86 7.83 10.14

Example 13: N- (4- {2- [Irans-hexahydro-cyclopenta [b] pyrrol-1-yl] ethoxy} phenyl) acetamide hydrochloride

The experimental procedure is identical to that of Example 11, replacing in Step 1 the 4-hydroxybenzamide by N- (4-hydroxyphenyl) acetamide.

Elemental Microanalysis 10% C% H% N% Cl- Calculated 62.86 7.66 10.91 Found 61.87 7.58 8.49 10.29

Example 14: 4- {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} -N, N-dimethylbenzamide hydrochloride

The experimental procedure is identical to that of Example 10, synthesis route A, replacing in Step 1 4-hydroxybenzamide by 4-hydroxy-N, N-dimethylbenzamide.

Elemental Microanalysis: C% H% N% Cl-Calculated 64.67 8.28 7.94 10.05 20 Found 64.64 7.97 7.64 10.35

Example 15: 4- {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] p-oxy} -N, N-diethylbenzamide hydrochloride

The experimental procedure is identical to that of Example 10, synthetic route A, replacing in Step 1 the 4-hydroxybenzamide with 4-hydroxy-N, N-diethylbenzamide. Elemental Microanalysis: C% H% N% Cl- Calculated 66.21 8.73 7.35 9.31 Found 66.42 8.61 7.26 9.22

Example 16: 4- {34 Trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} -N-methylbenzamide hydrochloride

The experimental procedure is identical to that of Example 10, synthesis route A, replacing in Stage 1 the 4-hydroxybenzamide by 4-hydroxy-N-methylbenzamide. Elemental Microanalysis C% H% N% Cl% Cl- Calculated 63.80 8.03 8.27 10.46 10.46 Found 63.63 7.94 7.99 10.02 10.11 Example 17: Hydrochloride N- (4- {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} phenyl) -N-methylacetamide

The experimental procedure is identical to that of Example 10, synthesis route A, replacing in Step 1 the 4-hydroxybenzamide by N- (4-hydroxyphenyl) -N-methylacetamide.

Elemental Microanalysis% C% H% N% Cl-20 Calculated 64.67 8.28 7.94 10.05 Found 64.10 8.15 7.91 10.01 2953515 - Example 18: N- Hydrochloride ( 4- {3- [trams-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} phenyl) -2-methoxyacetamide

The experimental procedure is identical to that of Example 10, synthesis route A, replacing in Step 1 the 4-hydroxybenzamide by N- (4-hydroxyphenyl) -2-5 methoxyacetamide.

Elemental Microanalysis:% C% H% N% Cl- Calculated 61.86 7.92 7.59 9.61 Found 61.31 7.86 7.56 9.60 2953515 - 26 - PHARMACOLOGICAL STUDY

EXAMPLE A Brain Assays of Nt-Methylhistamine in the NMRI Mouse

This study carried out according to the method of Taylor et al. (Biochem Pharm., 1992, 44, 1261-1267), aims to evaluate the ex vivo activity of the compounds of the present invention as H3 central histamine receptor antagonists. This activity is revealed by the measurement, after oral treatment of the compounds under study, of the central levels of NT-methylhistamine, the main metabolite of histamine. An increase in brain levels of NT-Methylhistamine leads to an increase in histamine turnover by blocking H3-type central histaminergic receptors.

NMRI mice (18-20 g) are orally treated with the compounds of the present invention or their vehicle (20 ml / kg). One hour after the pharmacological treatment, the animals are sacrificed, the brains are removed, frozen in liquid nitrogen, weighed and homogenized in 0.1 N HC1O4 at 4 ° C. The homogenates are centrifuged (15000 g, 17 min, 4 ° C). The supernatants are recovered and aliquoted. The aliquots are frozen in liquid nitrogen and stored at -80 ° C until analyzed. The determination of brain levels of NT-methylhistamine is carried out by capillary electrophoresis. The tissue levels of NT-methylhistamine are expressed in gg / g of fresh brain. Comparison of brain levels of NT-methylhistamine between vehicle-treated (control) animals and animals treated with the compounds of the present invention is performed by one-way analysis of variance followed, if necessary, by further analysis (test). Dunnett).

The results show that the compounds of the present invention are capable, at a dose of 3 mg / kg PO, of significantly increasing the endogenous brain concentrations of Nt-methylhistamine by more than 140%.

By way of example, the compounds of Examples 7, 8 and 9 administered at 3 mg / kg respectively increase the endogenous brain concentrations of Nt-methylhistamine by 145%, 143% and 190%. These results indicate that the compounds of the present invention are potent H3 histamine central histamine receptor antagonists.

EXAMPLE B Pharmaceutical Compositions

Preparation formula for 1000 tablets dosed at 100 mg: Compound of Example 7 100 g Hydroxypropylcellulose 20 g Polyvinylpyrrolidone 20 g 10 Wheat starch 150 g Lactose 900 g Magnesium stearate 30 g

Claims (20)

REVENDICATIONS1. Compounds of formula (I): (I) in which: • ALK represents an alkylene chain, • W represents a group IIR or R 'O where R and R' represent, independently of one another, an atom of hydrogen or a linear or branched (C1-C6) alkyl group optionally substituted by one or more groups chosen from halogen, hydroxy and alkoxy, it being understood that: the term alkylene denotes a bivalent radical, linear or branched, containing from 2 to 6 carbon atoms, the term alkoxy denotes an alkyl-oxy group in which the linear or branched alkyl chain contains from 1 to 6 carbon atoms, their enantiomers and diastereoisomers, as well as their addition salts with an acid or with a pharmaceutically acceptable base. 2. Compounds of formula (I) according to claim 1 for which the group W is located in the para position. He o ùR R '2953515 - 29 - 3. Compounds of formula (I) according to claim 1 wherein ALK represents a linear divalent radical containing from 2 to 6 carbon atoms, their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. 5 4. Compounds of formula (I) according to claim 1 wherein ALK represents a propylene group, their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to claim 1 wherein W represents a group Ii ùR, their enantiomers and diastereoisomers and their addition salts with a pharmaceutically acceptable acid or base. 6. Compounds of formula (I) according to claim 1 wherein W represents a group II R, their enantiomers and diastereoisomers and their salts R 'O addition to a pharmaceutically acceptable acid or base. 7. Compounds of formula (I) according to claim 1, for which R and R 'represent, independently of one another, a hydrogen atom, a methyl group or an ethyl group, these groups being optionally substituted by a methoxy, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base 8. Compounds of formula (I) according to claim 1 wherein W represents a group -CO-NH2, -CO-NH-CH3, -CO-N (CH3) 2, -CO-N (CH2CH3) 2, -NH -CO-CH3, -N (CH3) -CO-CH3 or -NH-CO-CH2-OCH3, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 2953515 -30- 9. Compounds of formula (I) according to claim 1 which are: 4- {3- [cis-hexahydrocyclopenta [b] pyrrol-1 (211) -yl] propoxy} benzamide, - N- (4- { 2- [cis-hexahydrocyclopenta [b] pyrrol-1 (21)) - yl] propoxy} phenyl) acetamide, 5- {3- [cis-hexahydrocyclopenta [b] pyrrol-1 (211) -yl] propoxy N, N-dimethylbenzamide, 4- {3- [cis -hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} -N, N -diethylbenzamide, 4- {3- [ cis-hexahydrocyclopenta [b] pyrrol-1 (21) -yl] propoxy} -N-methylbenzamide, N- (4- {3- [cis -hexahydrocyclopenta [b] pyrrol-1 (2H) -yl} ] propoxyphenyl) -N-methylacetamide, N- (4- {3- [cis -hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy} phenyl) -2-methoxyacetamide, - 4 - {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} -N, N-diethylbenzamide; N- (4- {3- [trans-hexahydro-cyclopenta [b] pyrrol); 1-yl] propoxy} phenyl) -N-methylacetamide, N- (4- {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} phenyl) -2-methoxyacetamide, 4- {3- [trans-hexahydro-cyclo penta [b] pyrrol-1-yl] propoxy} benzamide, N- (4- {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} phenyl) acetamide, - 4- {3 [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} -N, N-dimethylbenzamide, 4- {3- [trans-hexahydro-cyclopenta [b] pyrrol-1-yl] propoxy} -N-methylbenzamide, and their enantiomers as well as their addition salts with a pharmaceutically acceptable acid or base. 10. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that the compound of formula (II) used is the starting material: ## STR2 ## in which W is as defined in claim 1, compound of formula (II) on which is condensed in basic medium the compound of formula (III): BruALK Cl (III) wherein ALK is as defined in formula (I), to obtain the compound of formula (IV): where ALK CI in which W and ALK are as defined above, on which the compound of formula (V): (V) is condensed to yield the compound of formula (I) as defined above: -32 - (I) which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and from which the optical isomers are optionally separated. a classic separation technique. 11. Compounds of formula (VI) below: (VI) OH in which the ALK group is as defined in claim 1, useful as synthesis intermediates of the compounds of formula (IIa), a particular case of compounds of formula (I) according to claim 1 wherein W represents a group -CONRR ', since W, R and R' are as defined in claim 1. 12. Compounds of the following formula (VII): (VII) in which the ALK group is as defined in claim 1, useful as synthetic intermediates for the compounds of formula (IIa), a particular case compounds of formula (I) according to claim 1 wherein W represents a group -CONRR ', since W, R and R' are as defined in claim 1. 13. Compounds of formula (VIII) below: (VIII) OR "in which the ALK group is as defined in claim 1 and R" is a linear or branched (C1-C6) alkyl group or a benzyl group, Io useful as synthesis intermediates of the compounds of formula (Iia), a particular case of the compounds of formula (I) according to claim 1 for which W represents a group -CONRR ', since W, R and R' are such that defined in claim 1. 14. Compounds of formula (IX) below: in which the ALK group is as defined in claim 1, useful as synthesis intermediates for compounds of formula (IIa), a particular case of compounds of formula (I) according to claim 1 wherein W represents a -CONRR 'group, since W, R and R' are as defined in claim 1. 15. Pharmaceutical compositions containing as active ingredient at least one compound of formula (I) according to any one of claims 1 to 9, or one of its addition salts with a pharmaceutically acceptable acid or base, alone or in combination with one or more pharmaceutically acceptable excipients. 16. Pharmaceutical compositions according to claim 15 for the treatment of cognitive and psycho-behavioral disorders related to cerebral aging, neurodegenerative diseases or head trauma. 17. Pharmaceutical compositions according to claim 16 for the treatment of cognitive and psycho-behavioral disorders associated with Alzheimer's disease, Parkinson's disease, Pick's disease, Lewy body dementia, frontal and subcortical dementia, frontotemporal dementia, vascular dementia, Huntington's disease, and multiple sclerosis. 18. Pharmaceutical compositions according to claim 16 useful for the treatment of psycho-behavioral disorders such as sleep disorders, apathy and anxio-depressive states. 19. Pharmaceutical compositions according to claim 15, useful for the treatment of mood disorders, anxiety-depressive states, schizophrenia and cognitive disorders associated with it, as well as in the treatment of sleep disorders, rhythm disorders sleep-wake and hyperactivity syndrome with attention deficit. 20. Pharmaceutical compositions according to claim 19 useful for the treatment of sleep disorders such as narcolepsy, hypersomnias occurring during obstructive sleep apnea syndrome or attention deficit hyperactivity syndrome, as well as daytime sleepiness. 25