WO2012168664A1 - 4-{3-[trans-hexahydrocyclopenta[c]pyrrol-2(1h)-yl]propoxy}benzamide, method for preparing same and pharmaceutical compositions that contain same - Google Patents

Abstract

The invention relates to 4-{3-[trans-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide and the enantiomers thereof, as well as to the pharmaceutically acceptable acid or base addition salts thereof.

Description

 4- {3 - [[R] H -VH-HEXAHYDROCYCLOPENTA [qPYRROL-2 (1H-YL]]

 Propoxy} BENZAMIDE,

 ITS PREPARATION METHOD AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING IT

The present invention relates to 4- {3 - [/ - "/ ^ij, -liexariydiOcyclopenta [c] pyri l-2 (lH) - yl] propoxy} benzamide ₅ process for its preparation and pharmaceutical compositions which contain it.

The compound of the present invention is of particular pharmacological interest for its 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., 91, 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 Fiinction, 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, conducted in animals, have shown that the increase in endogenous levels Extra-synaptic histamine helped promote states of alertness, learning and memory processes, and regulate food intake (Brown et al., Prog Neurobiol, 2000, 63, 637-672, Passani et al. Netirosc 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, as well as the treatment of mood disorders, sleep disorders and sleep-wake rhythm, hyperactivity syndrome with attention deficit. 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 hexahydrocyclopenta [c] pyrrol-2-yl derivatives described in WO2005 / 089747 present a cis-type configuration, while the azabicyclic ring of the compound of the present invention has a trans configuration.

At the neurological level, this new compound 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 sleep disorders. 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 mood or sleep disorders, for example.

More particularly, the compound of the present invention corresponds to a racemic mixture of two enantiomers which are 4- [3 - ((3aR, 6aR) -transhexahydiOcyclopenta [c] pyrrol-2 (1H) -yl) pi-poxy] benzamide and 4- [3 - ((3aS, 6aS) -trans ~ hexahydrocyclopenta [c] pyn ^* ol-2 (lH) -yl) propoxy] benzamide. The compound can occur in the form of an addition salt 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, tert-butylamine and the like.

Of the acids, hydrochloric acid is particularly preferred.

The invention also extends to the process for the preparation of 4- {3- [trans-hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide, characterized in that the starting material used is of formula (I):

wherein Hal is a halogen atom and W represents a -CONH ₂ , -COOH, -COOR or -CN function, R being a (C ₁ -C ₆ ) alkyl or benzyl group, on which the octahydiolocyclopenta is condensed; c] pyiTole to lead directly to 4- {3 - ^ / ^d ra-hexahydrocyclopenta [c] pyri l-2 (lH) -yl] propoxy} benzamide when W = - CONH _2, or a homologue thereof acid, ester or nitrile, the latter compounds for which W = ^ - COOH, -COOR or -CN are then converted to their amide homologue to yield 4 ~ {3 ~ [tr m -hexahydrocyclopenta [c] pyiTol-2 (1H ) -yl] propoxy} benzamide, which can be purified by 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 according to a conventional separation technique.

The compound of formula (I) and / or 5'-octahydrocyclopentylpyrrole are either commercially available or accessible to those skilled in the art by conventional chemical reactions and described in the literature.

4- {3 - [(1-Hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzoic acid can be used as a synthetic intermediate and lead to 4- {3- [trans- hexahydiOcyclopenta [cpyrrol-2 (1H) -yl] p-poxybenzamide by coupling with ammonia under standard conditions described in the literature.

Likewise, 4- {3- ^[traf7i, -hexahydiOcyclopenta [c] pynOl-2 (lH) -yl] piOpoxy} benzoic acid can be converted to 4- {3- [traiw iexahydrocyclopenta [c] pyrrol 2 (1H) -yl] propoxy} benzoyl by conventional transformations. The latter compound can be used as a synthetic intermediate and lead to 4- {3- [tram-hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide by coupling with ammonia under standard conditions. described in the literature.

In addition, 4- {3- [t-O-hexahydrocyclopenta [c] pyrol-2 (1H) -yl] propoxy} benzamide can also be obtained by condensation with ammonia, using a 4- {3- [ Alkyl tris - hexahydrocyclopenta [c] pyrol-2 (1H) -yl] propoxy} benzoate or benzyl 4- {3- [trans-hexahydrocyclopenta [c '] pyrrol-2 (1H) -yl] piOpoxy} benzoate these latter compounds can be prepared via the corresponding carboxylic acid or acyl chloride presented above.

Finally, it is also possible to obtain 4- {3 - [/ ram-hexahydiOcyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide by hydrolyzing 4- {3- [tram-hexahydrocyclopenta [c] pynOl-2 (lH) -yl] propoxy} benzonitrile.

At the neurological level, the compound of 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, Lewy body dementia, frontal and subcortical dementia, frontotemporal dementia, vascular dementia, in new treatments for trauma-related cognitive disorders cranial, but also in the treatment of psycho-behavioral disorders associated with these pathologies such as sleep disorders, apathy and anxio-depressive states. Sleep disorders associated with Alzheimer's disease and Parkinson's disease, such as daytime hypersomnolence, are particularly targeted.

At the psychiatric level, the compound may be useful in the treatment of mood disorders, pain, as well as in the treatment of sleep disorders, sleep-wake rhythm and Attention Deficit Hyperactivity Syndrome (ADHD). . Sleep disorders include narcolepsy and sleep apnea. Sleep disorders such as hypersomnias occurring during obstructive sleep apnea syndrome or attention deficit hyperactivity syndrome, as well as daytime sleepiness are also targeted.

The subject of the present invention is also pharmaceutical compositions containing 4- {3 - [(cyclohexahydio) cyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide 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 over 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, lozenges, suppositories, creams, ointments, dermal gels, and oral or injectable ampoules. The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possibly associated treatments and ranges between 0.05 mg and 500 mg per 24 hours. for treatment in 1 to 3 doses per day. The combination of a compound of formula (I) with an acetylcholinesterase inhibitor is also an integral part of the invention, and more particularly the combination of a compound of formula (I) with donepezil, rivastigmine or galantamine. Associations of this type can be used in the treatment of cognitive disorders associated with Alzheimer's disease. 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.).

Preparation 1: 4- (3-Bromopropoxy) benzamide

 A mixture of 16 g of 4-hydroxybenzamide, 59 ml of 1,3-dibromopropane and 38 g of cesium carbonate is stirred in 600 ml of acetonitrile at reflux temperature for 2 hours. The reaction medium is concentrated to dryness. The residue is taken up in a mixture of ethyl acetate and water. The insoluble matter is filtered, the organic phase is decanted, washed again with water and concentrated. The residual oil is purified by chromatography on a silica column with the dichloromethane / methanol eluent system: 9/1. the product of the title is obtained in solid form.

Example 1: 4- {3 - [N] H -Hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide

Stage 1: tram-1, 2-bis- (hydroxymethyl) cyclopentane

In a flask under an argon atmosphere containing 4.0 g of lithium aluminum hydride suspended in 170 mL of anhydrous tetrahydrofuran with stirring at ambient temperature, 8 g of acid / r <my-1 are added in portions, 2-cycIopentanedicarboxylique. The mixture is stirred for one hour at room temperature and then poured into a flask containing 100 ml of ice and 100 ml of ethyl acetate. After half an hour of agitation, the aqueous phase is saturated with sodium chloride. The organic phase is decanted. The aqueous phase is extracted again with ethyl acetate. The organic juices are dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column with a 1/1 ethyl acetate / dichloromethane elution system. The title product is obtained in the form of an oil.

Step 2: trans-1, 2-bis- (Methanesitylonyloxymethyl) cyclopentane

 In a flask under an argon atmosphere containing a solution of 4.5 g of l-trans-1,2-bis (hydroxymethyl) cyclopentane and 7.7 g of triethylamine in 250 ml of dichloromethane at 0 ° C., are added dropwise. drop 5.3 mL of mesyl chloride. The reaction medium is stirred for 3 hours at room temperature. The organic phase is washed with water, dried over sodium sulphate and concentrated. The residual oil is concreted in petroleum ether to yield the title product in the form of a powder.

Step 3: 2-Benzyl-trans-octahydrocyclopenta [c] pyrrole hydrochloride

 A mixture consisting of 2 g of trara-1,2-bis (methanesulfonyloxymethyl) cyclopentane, 3 ml of triethylamine and 0.64 g of benzylamine in 15 ml of tetrahydrofuran is stirred for 50 minutes at 150 ° C. in a microwave oven. . After evaporation of the solvent, the residue is purified by chromatography on a silica column with the elution system dichloromethane / methanol / ammonia 98/2 / 0.5. The product is crystallized in the hydrochloride form in a hydrochloric ethanol solution and then filtered. The title compound is thus obtained in the form of a white powder.

Stage 4: Hydrochloride of lans ~ octahydrocyclopenta [c] pyirole

 A mixture of 1.54 g of 2-benzyl-α-β-octahydrocyclopenta [c] pyrrole hydrochloride and 0.4 g of 10% palladium on carbon in 35 ml of methanol is stirred at room temperature under hydrogen atmosphere. at a pressure of 1.3 bar for 48 hours. After filtration and concentration to dryness, the title product is obtained in solid form.

Step 5: 4- {3- [trans-Hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide

 A mixture of 0.306 g of 4- (3-bromopropoxy) benzamide obtained in the preparation

0.21 g of hydrochloride salt ^, -octahydrocyclopenta [c] pynle, 0.7 ml diisopropylethylamine and 0.036 g of sodium iodide in 15 mL of acetonitrile is heated to the reflux temperature of the solvent. The reaction medium is concentrated to dryness and the solid residue is purified by chromatography on a silica column with the eluent system dichloromethane / methanol / ammonia 28% 90/10/5. After evaporation of the solvents, the title product is obtained in solid form.

Elemental microanalysis:

 % C% N

 Calculated 70.80 8.39 9, 71

Found 70.04 8.32 9.53

PHARMACQLQMIC STUDY

EXAMPLE A Brain Assays of N ^T- 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 H ₃ central histaminergic receptor antagonists. This activity is revealed by the measurement, after oral treatment of the compounds under study, of the central levels of N ^T- methyl-staminate, main metabolite of histamine. An increase in brain levels of N ^T- methyl staminate signifies an increase in the turnover of histamine by blocking H ₃ 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 HCl 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 the brain levels of N ^T- methylhistamine is carried out by capillary electrophoresis. The tissue levels of N ^T- methyl staminate are expressed in μξ / g of fresh brain. The comparison of the brain levels of N ^T- methylhistamine between the vehicle-treated animals (controls) and the animals treated with the compounds of the present invention is carried out by a one-way analysis of variance followed, if necessary, by a complementary analysis (test Dunnett).

The results show that the compound of Example 1 is able to significantly increase the endogenous cerebral concentrations of N ^Î -methylhistamine by 57% at a dose of 1 mg / kg PO, and 67% at a dose of 10 mg / kg PO. These results indicate that the compounds of the present invention are potent H ₃ central histaminergic receptor antagonists. EXAMPLE B Pharmaceutical Compositions

Preparation formula for 1000 tablets dosed at 100 mg:

 4- {3- [trin-1-hexahydrocyclopenta [c] pyiTol-2 (1H) -yl] propoxy} benzamide 100 g

HydiOxypropylcellulose 20 g Polyvinylpyrrolidone 20 g

150 g wheat starch

Lactose 900 g

Magnesium stearate 30 g

Claims

1. 4- {3- [go _"l y-hexahydrocyclopenta [c] pyiTol-2 (lH) -yl] piOpoxy} benzamide and its enantiomers, and addition salts thereof with an acid or with a pharmaceutically acceptable base. 2. Process for the preparation of 4- {3- [iram-hexahydrocycopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide according to claim 1, characterized in that the compound of formula (I):

in which Hal is a halogen atom and W represents a -CONH ₂ , -COOH, -COOR or -CN function, R being a (C ₁ -C ₆ ) alkyl or benzyl group, on which the octahydiOcyclopentafcJpyrrole, to directly lead to 4- {3- [en (7H-hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] piOpoxy} benzamide when W = - CON¾, or to one of its acid counterparts, ester or nitrile, the latter compounds for which W = ^COOH, COOR or CN is then converted into their amide homologous to yield 4- {3- [tr NS-hexahydrocyclopenta [c] pynOl-2 (lH) -yl] pi poxy} benzamide, which can be purified according to a conventional separation technique, which, if desired, is converted into its addition salts with a pharmaceutically acceptable acid or base and the optical isomers are optionally separated therefrom. according to a conventional separation technique. 3. Following compounds:  4- {3- [Fr] -7-hexahydiolopenta [c] pyno] -2 (1H) -yl] propoxy} benzoic acid, - 4- {3- ^[, / - 7w-hexahydrocyclopenta [c] pynOl-2 (lH) -yl] propoxy} benzoyl,  Alkyl 4- [3- [imra-hexahydrocyclopenta [c] pyn-2 (1H) -yl] propoxy} benzoate, - 4- {3 - [/ ra ^"A, -hexahydrocyclopenta [c] pyrrol-2 (lH) -yl] propoxy} benzyl benzoate, 4- {3 - [(1 H) -hexahydrocyclopenta [c] pyrim-2 (1H) -yl] propoxy} benzonitrile. useful as intermediates for the synthesis of 4- {3- [(1 H) -m-hexahydiOcydopenta [c] pyiml-2 (1H) -yl] propoxy} benzamines. A pharmaceutical composition containing as active ingredient the compound of Claim 1, or one of its enantiomers, or an addition salt thereof to a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients. . 5. Pharmaceutical composition according to claim 4 for its use in the treatment of cognitive and psycho-behavioral disorders related to cerebral aging, neurodegenerative diseases or head trauma. 6. Pharmaceutical composition according to claim 5 for use in the treatment of cognitive and psycho-behavioral disorders associated with Alzheimer's disease, Parkinson's disease, Pick's disease, Lewy body dementia, frontal and subacute dementia. cortical, frontotemporal dementia, and vascular dementia. 7. Pharmaceutical compositions according to claim 5 for its use in the treatment of psycho-behavioral disorders such as sleep disorders, apathy and anxio-depressive states. 8. Pharmaceutical compositions according to claim 7 for its use in the treatment of sleep disorders associated with Alzheimer's disease and Alzheimer's disease. Parkinson. 9. Pharmaceutical composition according to claim 4 for its use in the treatment of mood disorders, pain-, as well as in the treatment of sleep disorders, sleep-wake rhythm and hyperactivity syndrome with deficits. attentional. 10. Pharmaceutical composition according to claim 9 for use in 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. . 11. Association of 4- {3 - [/ ₁ rai7 ^s, -hexahydi cyclopenta [c] pyrrol-2 (lH) -yl] propoxy} benzamide according to claim 1 with an inhibitor of acetylcholinesterase. 12. Association of 4- {3 - [/ ri / f ^?,, i'hexahydi-cyclopenta [c] pynOl-2 (lH) -yl] propoxy} benzamide according to claim 1 with donepezil, galantamine or rivastigmine . 13. Association according to claim 1 1 or 12 for its use in the treatment of cognitive disorders associated with neurodegenerative diseases.