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

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

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WO2012168664A1
WO2012168664A1 PCT/FR2012/051287 FR2012051287W WO2012168664A1 WO 2012168664 A1 WO2012168664 A1 WO 2012168664A1 FR 2012051287 W FR2012051287 W FR 2012051287W WO 2012168664 A1 WO2012168664 A1 WO 2012168664A1
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propoxy
hexahydrocyclopenta
benzamide
treatment
pyrrol
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PCT/FR2012/051287
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French (fr)
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Alain Dhainaut
Anne-Marie Chollet
Patrick Casara
Pierre Lestage
Fany Panayi
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Les Laboratoires Servier
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • 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 has also led to a large increase in the incidence of age-related neuropathologies, including Alzheimer's disease.
  • 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.
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • hydrochloric hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic and methane acids. sulfonic, camphoric, etc.
  • 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):
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the mass fraction of active ingredient is between 1 and 50%.
  • 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.).
  • Step 2 trans-1, 2-bis- (Methanesitylonyloxymethyl) cyclopentane
  • Step 5 4- ⁇ 3- [trans-Hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy ⁇ benzamide
  • NMRI mice (18-20 g) are orally treated with the compounds of the present invention or their vehicle (20 ml / kg).
  • 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 ⁇ / 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).
  • HydiOxypropylcellulose 20 g Polyvinylpyrrolidone 20 g

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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-[rR^iVS-HEXAHYDROCYCLOPENTA[qPYRROL-2(lH -YL]  4- {3 - [[R] H -VH-HEXAHYDROCYCLOPENTA [qPYRROL-2 (1H-YL]]
PROPOXY}BENZAMIDE,  Propoxy} BENZAMIDE,
SON PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES QUI LE CONTIENNENT  ITS PREPARATION METHOD AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING IT
La présente invention concerne le 4-{3-[/;-«/ïj,-liexariydiOcyclopenta[c]pyri l-2(lH)- yl]propoxy}benzamide5 son procédé de préparation et les compositions pharmaceutiques qui le contiennent. 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.
Le composé de la présente invention est particulièrement intéressant d'un point de vue pharmaco logique pour son interaction avec les systèmes histaminergiques centraux in vivo. The compound of the present invention is of particular pharmacological interest for its interaction with central histaminergic systems in vivo.
Le vieillissement de la population, du fait de l'augmentation de l'espérance de vie à la naissance, a entraîné parallèlement un large accroissement de l'incidence des neuropathologies liées à l'âge, et notamment de la maladie d'Alzheimer. Les principales manifestations cliniques du vieillissement cérébral et surtout des neuropathologies liées à l'âge, sont les déficits des fonctions mnésiques et cognitives qui peuvent conduire à la démence. 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.
Au niveau du système nerveux central, des études neuropharmacologiques ont montré que l'histamine via les systèmes histaminergiques centraux jouait un rôle de neurotransmetteur ou neuromodulateur en situations physiologiques ou physiopathologiques (Pell et Green, Annu, Rev. Neurosci., 1986, 9, 209-254; Schwartz et al., Physiol. Rev., 1 91, 71, 1-51). Ainsi, il a été montré que l'histamine intervenait dans divers processus physiologiques et comportementaux tels que la thermorégulation, la régulation neuroendocrinienne, la nociception, le rythme circadien, les états cataleptiques, la motricité, l'agressivité, le comportement alimentaire, l'apprentissage et la mémorisation, ainsi que la plasticité synaptique (Hass et al., Histaminergic neurones : 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). 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).
Des études, réalisées chez l'animal, ont montré que l'augmentation des taux endogènes extra-synaptiques d'histamine permettait de promouvoir les états de vigilance, les processus d'apprentissage et de mémoire et de réguler la prise alimentaire (Brown et al., Prog. Neurobiol , 2000, 63, 637-672; Passani et al., NetiroscL Biobehav. Rev., 2000, 24, 107-1 13). En conséquence, les indications thérapeutiques potentielles pour des composés capables d'augmenter le turn-over ou la libération d'histamine au niveau central sont le traitement des déficits cognitifs associés au vieillissement cérébral, aux maladies neurodégénératives aiguës et chroniques, ainsi que le traitement des troubles de l'humeur, des troubles du sommeil et du rythme veille-sommeil, du syndrome d'hyperactivité avec déficits attentionnels. Par ailleurs, des travaux ont montré qu'une injection d'histamine au niveau des noyaux centraux hypothalamiques impliqués dans la régulation de la satiété atténue l'alimentation chez le rat. De plus, un hypofonctionnement de la transmission histaminergique a été mis en évidence chez des rats génétiquement obèses (Machidori et al., Brain Research, 1992, 590, 180-186). En conséquence, les troubles du comportement alimentaire et l'obésité sont également des indications thérapeutiques potentielles pour les composés de la présente invention. 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.
Les dérivés de type hexahydrocyclopenta[c]pyrrol-2-yl décrits dans la demande WO2005/089747 présentent une configuration de type cis, alors que le noyau azabicyclique du composé de la présente invention a une configuration trans. 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.
Au niveau neurologique, ce nouveau composé ouvre la voie non seulement à de nouveaux traitements des troubles cognitifs liés au vieillissement cérébral, aux maladies neurodégénératives ou aux traumatismes crâniens, mais également au traitement des troubles psychocomportementaux associés à ces pathologies tels que les troubles du sommeil, l'apathie et/ou les états dépressifs. Par ailleurs, le profil pharmacologique des composés de l'invention permet aussi d'envisager de nouveaux traitements dans le domaine psychiatrique, pour les troubles de l'humeur ou du sommeil par exemple. 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.
Plus particulièrement, le composé de la présente invention correspond à un mélange racémique de deux énantiomères qui sont le 4-[3~((3aR,6aR)-trans- hexahydiOcyclopenta[c]pyrrol-2(ÎH)-yl)pi poxy]benzamide et le 4-[3-((3aS,6aS)-trans~ hexahydrocyclopenta[c]pyn*ol-2(lH)-yl)propoxy]benzamide. Le composé peut se présenter sous la forme d'un sel d'addition à un acide ou à une base pharmaceutiquement acceptable. 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.
Parmi les acides pharmaceutiquement acceptables, on peut citer à titre non limitatif les acides chlorhydrique, bromhydrique, sulfurique, phosphonique, acétique, trifiuoroacétique, lactique, pyruvique, malonique, succinique, glutarique, fumarique, tartrique, maléique, citrique, ascorbique, oxalique, méthane sulfonique, camphorique, etc. 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.
Parmi les bases pharmaceutiquement acceptables, on peut citer à titre non limitatif l'hydroxyde de sodium, l'hydroxyde de potassium, la triéthylamine, la tertbuty lamine, etc. Among the pharmaceutically acceptable bases, mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine and the like.
Parmi les acides, l'acide chlorhydrique est particulièrement préféré. Of the acids, hydrochloric acid is particularly preferred.
L'invention s'étend également au procédé de préparation du 4-{3-[trans- hexahydrocyclopenta[c]pyrrol-2(lH)-yl]propoxy}benzamide caractérisé en ce que l'on utilise comme produit de départ le composé de formule (I) : 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):
Figure imgf000004_0001
Figure imgf000004_0001
dans laquelle Hal est un atome d'halogène et W représente une fonction -CONH2, - COOH, -COOR ou -CN, R étant un groupement (CrC6)alkyle ou benzyle, sur lequel on condense le tra«s-octahydiOcyclopenta|c]pyiTole, pour conduire directement au 4-{3-^/j ra-hexahydrocyclopenta[c]pyri l-2(lH)-yl]propoxy}benzamide lorsque W=- CONH2, ou à l'un de ses homologues acide, ester ou nitrile, ces derniers composés pour lesquels W=^-COOH, -COOR ou -CN étant ensuite transformés en leur homologue amide pour conduire au 4~{3~[tr m- hexahydrocyclopenta[c]pyiTol-2(lH)-yl]propoxy}benzamide, qui peut être purifié selon une technique classique de séparation, que l'on transforme, si on le souhaite, en ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable et dont on sépare éventuellement les isomères optiques selon une technique classique de séparation. 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.
Le composé de formule (I) et le //vm5'-octahydrocyclopentajc]pyrrole sont soit commerciaux, soit accessibles à l'homme du métier par des réactions chimiques classiques et décrites dans la littérature, 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.
L ' acide 4- { 3 - [ ra '-hexahydrocyclopenta[c]pyrrol-2( 1 H)-yl]propoxy } benzoïque peut être utilisé en tant qu'intermédiaire de synthèse et conduire au 4-{3-[trans- hexahydiOcyclopenta[cjpyrrol-2(lH)-yl]pi poxy}benzamide par couplage avec l'ammoniac dans des conditions classiques décrites dans la littérature. 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.
De même, l'acide 4-{3-[traf7i,-hexahydiOcyclopenta[c]pynOl-2(lH)-yl]piOpoxy} benzoïque peut être transformé en chlorure de 4-{3-[traiw iexahydrocyclopenta[c]pyrrol- 2(lH)-yl]propoxy}benzoyle par des transformations classiques. Ce dernier composé peut être utilisé en tant qu'intermédiaire de synthèse et conduire au 4-{3-[tram- hexahydrocyclopenta[c]pyrrol-2(lH)-yl]propoxy}benzamide par couplage avec l'ammoniac dans des conditions classiques décrites dans la littérature. 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.
De plus, le 4-{3-[t/OOi-hexahydrocyclopenta[c]pyriOl-2(lH)-yl]propoxy}benzamide peut aussi être obtenu par condensation avec l'ammoniac, en utilisant un 4-{3-[tra - hexahydrocyclopenta[c]pyiTol-2(lH)-yl]propoxy}benzoate d'alkyle ou un 4-{3-[trans- hexahydrocyclopenta[c']pyrrol-2(lH)-yl]piOpoxy}benzoate de benzyle, ces derniers composés pouvant être préparés via l'acide carboxylique ou le chlorure d'acyle correspondant présentés précédemment. 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.
Enfin, il est également possible d'obtenir le 4-{3-[/ram-hexahydiOcyclopenta[c]pyrrol- 2(lH)-yl]propoxy}benzamide en hydroîysant le 4-{3-[tram- hexahydrocyclopenta[c]pynOl-2(lH)-yl]propoxy}benzonitrile. 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.
Au niveau neurologique, le composé de l'invention peut être utile dans le traitement des troubles cognitifs liés au vieillissement cérébral ou aux maladies neurodégénératives telles que la maladie d 'Alzheimer, la maladie de Parkinson, la maladie de Pick, les démences à corps de Lewy, les démences frontales et sous-corticales, les démences frontotemporales, les démences vasculaires, dans de nouveaux traitements des troubles cognitifs liés aux traumatismes crâniens, mais également dans le traitement des troubles psychocomportementaux associés à ces pathologies tels que les troubles du sommeil, l'apathie et les états anxio-dépressifs. Les troubles du sommeil associés à la maladie d'Alzheimer et à la maladie de Parkinson, tels que les hypersomnolences diurnes, sont particulièrement visés. 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.
Au niveau psychiatrique, le composé peut être utile dans le traitement des troubles de l'humeur, de la douleur, ainsi que dans le traitement des troubles du sommeil, du rythme veille-sommeil et du syndrome d'hyperactivité avec déficits attentionnels (ADHD). Parmi les troubles du sommeil, on peut citer plus particulièrement la narcolepsie et l'apnée du sommeil. Les troubles du sommeil tels que les hypersomnies survenant lors du syndrome d'apnée obstructive du sommeil ou du syndrome d'hyperactivité avec déficits attentionnels, ainsi que les somnolences diurnes sont également visés. 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.
La présente invention a également pour objet les compositions pharmaceutiques contenant le 4- { 3 - [/rara-hexahydiOcyclopenta[c]pyrrol-2( 1 H)-yl]propoxy} benzamide en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables. 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.
Dans les compositions pharmaceutiques selon l'invention, la fraction massique en principe actif (masse du principe actif sur la masse totale de la composition) est comprise entre 1 et 50 %. 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%.
Parmi les compositions pharmaceutiques selon l'invention, on pourra citer, plus particulièrement celles qui conviennent pour l'administration orale, parentérale, nasale, per ou transcutanée, rectale, perlinguale, oculaire ou respiratoire et notamment les comprimés simples ou dragéifiés, les comprimés sublinguaux, les sachets, les paquets, les gélules, les glossettes, les tablettes, les suppositoires, les crèmes, les pommades, les gels dermiques, et les ampoules buvables ou injectables. La posologie varie selon le sexe, l'âge et le poids du patient, la voie d'administration, la nature de l'indication thérapeutique, ou des traitements éventuellement associés et s'échelonne entre 0,05 mg et 500 mg par 24 heures pour un traitement en 1 à 3 prises par jour. L'association d'un composé de formule (I) avec un inhibiteur de l'acétylcholinesterase fait aussi partie intégrante de l'invention, et plus particulièrement encore l'association d'un composé de formule (I) avec le donépézil, la rivastigmine ou la galantamine. Les associations de ce type peuvent être utilisées dans le traitement des troubles cognitifs associés à la maladie d'Alzheimer. Les exemples suivants illustrent l'invention et ne la limitent en aucune façon. Les structures des composés, décrits dans les exemples, ont été déterminées selon les techniques spectrophotométriques usuelles (infrarouge, RMN, spectrométrie de masse...). 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.).
Préparation 1 : 4-(3-Bromopropoxy)benzamide Preparation 1: 4- (3-Bromopropoxy) benzamide
Un mélange de 16 g de 4-hydroxybenzamide, 59 mL de 1,3-dibromopropane et 38 g de carbonate de césium est agité dans 600 mL d'acétonitrile à la température du reflux pendant 2 heures. Le milieu réactionnel est concentré à sec. Le résidu est repris dans un mélange d'acétate d'éthyle et d'eau. L'insoluble est filtré, la phase organique est décantée, relavée avec de l'eau et concentrée. L'huile résiduelle est purifiée par chromatographie sur colonne de silice avec le système d'éluant dichlorométhane/méthanol : 9/1. le produit du titre est obtenu sous forme solide.  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.
Exemple 1 : 4-{3-[//Y///i-Hexahydrocyclopenta[c]pyrrol-2(lH)-yl]propoxy}benzamide Example 1: 4- {3 - [N] H -Hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide
Stade 1 : tram -l,2-bis-(Hydroxyméthyl)cyclopentane Stage 1: tram-1, 2-bis- (hydroxymethyl) cyclopentane
Dans un ballon sous atmosphère d'argon contenant 4,0 g d'hydrure d'aluminium lithium en suspension dans 170 mL de tétrahydrofuranne anhydre sous agitation à température ambiante, sont ajoutés par portions 8 g d'acide /r<my- 1,2-cycIopentanedicarboxylique. Le mélange est agité pendant une heure à température ambiante, puis versé dans un flacon contenant 100 mL de glace et 100 mL d'acétate d'éthyle. Après un demi-heure d'agitation, la phase aqueuse est saturée avec du chlorure de sodium. La phase organique est décantée. La phase aqueuse est extraite à nouveau avec de l'acétate d'éthyle. Les jus organiques sont séchés sur sulfate de magnésium et concentrés. Le résidu est purifié par chromato graphie sur colonne de silice avec un système d'élution acétate d'éthyle/dichlorométhane 1/1. Le produit du titre est obtenu sous la forme d'une huile. 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.
Stade 2 : trans-1, 2-bis-(Méthanesitlfonyloxyméthyl)cyclopentane Step 2: trans-1, 2-bis- (Methanesitylonyloxymethyl) cyclopentane
Dans un ballon sous atmosphère d'argon contenant une solution de 4,5 g de lrans-l ,2-bis- (hydroxyméthyl)cyclopentane et 7,7 g de triéthylamine dans 250 mL de dichlorométhane à 0 °C, sont ajoutés goutte à goutte 5,3 mL de chlorure de mésyle. Le milieu réactionnel est agité 3 heures à température ambiante. La phase organique est lavée à l'eau, séchée sur sulphate de sodium et concentrée. L'huile résiduelle est concrétée dans l'éther de pétrole pour conduire au produit du titre sous la forme d'une poudre.  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.
Stade 3 : Chlorhydrate de 2-benzyl-trans-octahydrocyclopenta[c]pyrrole Step 3: 2-Benzyl-trans-octahydrocyclopenta [c] pyrrole hydrochloride
Un mélange composé de 2 g de trara-l,2-bis-(méthanesulfonyloxyméthyl)cyclopentane, 3 mL de triéthylamine et 0,64 g de benzylamine dans 15 mL de tétrahydrofuranne est agité pendant 50 minutes à 150 °C dans un four à microondes. Après évaporation du solvant, le résidu est purifié par chromatographie sur colonne de silice avec le système d'élution dichlorométhane/méthanol/ammoniaque 98/2/0,5. Le produit est cristallisé sous forme de chlorhydrate dans une solution d'éthanol chlorhydrique, puis filtré. Le composé du titre est ainsi obtenu sous la forme d'une poudre blanche.  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.
Stade 4 : Chlorhydrate de lrans~octahydrocyclopenta[c]pyirole Stage 4: Hydrochloride of lans ~ octahydrocyclopenta [c] pyirole
Un mélange de 1,54 g de chlorhydrate de 2-benzyl-tra/w-octahydrocyclopenta[c]pyrrole et 0,4 g de palladium sur charbon à 10% dans 35 mL de méthanol est agité à température ambiante sous atmosphère d'hydrogène à la pression d'1,3 bar pendant 48 heures. Après filtration et concentration à sec, le produit du titre est obtenu sous forme solide.  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.
Stade 5 : 4-{3-[trans-Hexahydrocyclopenta[c]pyrrol-2(lH)-yl]propoxy}benzamide Step 5: 4- {3- [trans-Hexahydrocyclopenta [c] pyrrol-2 (1H) -yl] propoxy} benzamide
Un mélange de 0,306 g de 4-(3-bromopropoxy)benzamide obtenu dans la Préparation A mixture of 0.306 g of 4- (3-bromopropoxy) benzamide obtained in the preparation
0,21 g de chlorhydrate de /ra»i,-octahydrocyclopenta[c]pyn le, 0,7 mL diisopropyléthylamine et 0,036 g d'iodure de sodium dans 15 mL d'acétonitrile, est chauffé à la température de reflux du solvant. Le milieu réactionnel est concentré à sec et le résidu solide est purifié par chromatographie sur colonne de silice avec le système d'éluant dichlorométhane/méthanol/ammoniaque 28% 90/10/5. Après évaporation des solvants, on obtient le produit du titre sous forme solide. 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.
Microanalyse élémentaire : Elemental microanalysis:
% C % N  % C% N
Calculé 70,80 8,39 9, 71  Calculated 70.80 8.39 9, 71
Trouvé 70,04 8,32 9,53 Found 70.04 8.32 9.53
ETUDE PHARMACQLQGIQUE PHARMACQLQMIC STUDY
EXEMPLE A : Dosages cérébraux de la NT-Méthylhistamine chez la souris NMRI EXAMPLE A Brain Assays of N T- Methylhistamine in the NMRI Mouse
Cette étude réalisée selon la méthode de Taylor et Coll. (Biochem. Pharm., 1992, 44, 1261- 1267), a pour objectif d'évaluer l'activité ex vivo des composés de la présente invention en tant qu'antagonistes des récepteurs histaminergiques centraux de type H3. Cette activité est révélée par la mesure, après traitement par voie orale des composés sous étude, des taux centraux de NT-Méthylhi staminé, métabolite principal de l'histamine. Une augmentation des concentrations cérébrales de NT-Méthylhi staminé signe une augmentation du turn-over de l'histamine par blocage des récepteurs histaminergiques centraux de type H3. 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.
Des souris NMRI (18-20 g) sont traitées par voie orale par les composés de la présente invention ou par leur véhicule (20 ml/kg). Une heure après le traitement pharmacologique, les animaux sont sacrifiés, les cerveaux sont prélevés, congelés dans l'azote liquide, pesés et homogénéisés dans HC10 0,1 N à 4 °C. Les homogénats sont centrifugés (15000 g, 17 min, 4 °C). Les surnageants sont récupérés et aliquotés. Les aliquotes sont congelés dans l'azote liquide et stockés à -80 °C jusqu'à leur analyse. 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.
La détermination des taux cérébraux de NT-Méthylhistamine est réalisée par électrophorèse capillaire. Les taux tissulaires de NT-Méthylhi staminé sont exprimés en μξ/g de cerveau frais. La comparaison des taux cérébraux de NT-Méthylhistamine entre les animaux traités par le véhicule (témoins) et les animaux traités par les composés de la présente invention est effectuée par une analyse de variance à un facteur suivie si nécessaire par une analyse complémentaire (test de Dunnett). 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).
Les résultats montrent que le composé de l'Exemple 1 est capable d'augmenter de façon significative les concentrations cérébrales endogènes de NÎ-Méthylhistamine de 57% à la dose de 1 mg/kg PO, et de 67% à la dose de 10 mg/kg PO. Ces résultats indiquent que les composés de la présente invention sont de puissants antagonistes des récepteurs histaminergiques centraux de type H3. EXEMPLE B : Compositions pharmaceutiques 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
Formule de préparation pour 1000 comprimés dosés à 100 mg : Preparation formula for 1000 tablets dosed at 100 mg:
4-{3-[trw?i-hexahydrocyclopenta[c]pyiTol-2(lH)-yl]propoxy}benzamide 100 g 4- {3- [trin-1-hexahydrocyclopenta [c] pyiTol-2 (1H) -yl] propoxy} benzamide 100 g
HydiOxypropylcellulose 20 g Polyvinylpyrrolidone 20 gHydiOxypropylcellulose 20 g Polyvinylpyrrolidone 20 g
Amidon de blé 150 g150 g wheat starch
Lactose 900 gLactose 900 g
Stéarate de magnésium 30 g Magnesium stearate 30 g

Claims

REVENDICATIONS
1. 4-{3-[ira«ly-hexahydrocyclopenta[c]pyiTol-2(lH)-yl]piOpoxy}benzamide et ses énantiomères, ainsi que leurs sels d'addition à un acide ou à une base pharmaceutiquement acceptable. 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. Procédé de préparation du 4-{3-[iram-hexahydrocycïopenta[c]pyrrol-2(lH)- yl]propoxy}benzamide selon la revendication 1 caractérisé en ce que l'on utilise comme produit de départ le composé de formule (I) : 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):
Figure imgf000012_0001
Figure imgf000012_0001
dans laquelle Hal est un atome d'halogène et W représente une fonction -CONH2, - COOH, -COOR ou -CN, R étant un groupement (Ci-C6)alkyle ou benzyle, sur lequel on condense le /ram'-octahydiOcyclopentafcJpyrrole, pour conduire directement au 4-{3-[fr(7/îi-hexahydrocyclopenta[c]pyrrol-2(lH)-yl]piOpoxy}benzamide lorsque W=- CON¾, ou à l'un de ses homologues acide, ester ou nitrile, ces derniers composés pour lesquels W=^COOH, -COOR ou CN étant ensuite transformés en leur homologue amide pour conduire au 4-{3-[tr ns- hexahydrocyclopenta[c]pynOl-2(lH)-yl]pi poxy}benzamide, qui peut être purifié selon une technique classique de séparation, que l'on transforme, si on le souhaite, en ses sels d'addition à un acide ou à une base pharmaceutiquement acceptable et dont on sépare éventuellement les isomères optiques selon une technique classique de séparation. 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. Composés suivants : 3. Following compounds:
- acide 4-{3-[fra/7.y-hexahydiOcyclopenta[c]pynOl-2(lH)-yl]propoxy}benzoïque, 4- {3- [Fr] -7-hexahydiolopenta [c] pyno] -2 (1H) -yl] propoxy} benzoic acid,
- chlorure de 4-{3-[ ,/--7w-hexahydrocyclopenta[c]pynOl-2(lH)-yl]propoxy} benzoyle, - 4- {3- [, / - 7w-hexahydrocyclopenta [c] pynOl-2 (lH) -yl] propoxy} benzoyl,
- 4-{3-[imra-hexahydrocyclopenta[c]pyn l-2(lH)-yl3propoxy}benzoate d'alkyle, Alkyl 4- [3- [imra-hexahydrocyclopenta [c] pyn-2 (1H) -yl] propoxy} benzoate,
- 4-{3-[/ra«A,-hexahydrocyclopenta[c]pyrrol-2(lH)-yl]propoxy}benzoate de benzyle,- 4- {3 - [/ ra "A, -hexahydrocyclopenta [c] pyrrol-2 (lH) -yl] propoxy} benzyl benzoate,
- 4- {3 -[/ri//7^-hexahydrocyclopenta[c]pyri l-2( 1 H)-yl]propoxy}benzonitrile. utiles en tant qu'intermédiaires de synthèse du 4-{3-[tra/M-hexahydiOcydopenta[c]pyiml- 2( 1 H) -yl] propoxy } benzami de . 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.
4. Composition pharmaceutique contenant comme principe actif le composé de la revendication 1 , ou l'un de ses énantiomères, ou un de ses sels d'addition à un acide ou à une base phamiaceutiquement acceptables, en combinaison avec un ou plusieurs excipients pharmaceutiquement acceptables. 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. Composition pharmaceutique selon la revendication 4 pour son utilisation dans le traitement des troubles cognitifs et psychocomportementaux liés au vieillissement cérébral, aux maladies neurodégénératives ou aux traumatismes crâniens. 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. Composition pharmaceutique selon la revendication 5 pour son utilisation dans le traitement des troubles cognitifs et psychocomportementaux associés à la maladie d'Alzheimer, la maladie de Parkinson, la maladie de Pick, les démences à corps de Lewy, les démences frontales et sous-corticales, les démences frontotemporales, et les démences vasculaires. 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. Compositions pharmaceutiques selon la revendication 5 pour son utilisation dans le traitement des troubles psychocomportementaux tels que les troubles du sommeil, l'apathie et les états anxio-dépressifs. 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. Compositions pharmaceutiques selon la revendication 7 pour son utilisation dans le traitement des troubles du sommeil associés à la maladie d'Alzheimer et à la maladie de Parkinson. 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. Composition pharmaceutique selon la revendication 4 pour son utilisation dans le traitement des troubles de l'humeur, de la douleur-, ainsi que dans le traitement des troubles du sommeil, du rythme veille-sommeil et du syndrome d'hyperacti ité avec déficits attentionnels. 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. Composition pharmaceutique selon la revendication 9 pour son utilisation dans le traitement des troubles du sommeil tels que la narcolepsie, les hypersomnies survenant lors du syndrome d'apnée obstructive du sommeil ou du syndrome d'hyperactivité avec déficits attentionnels, ainsi que les somnolences diurnes. 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 du 4-{3-[/rai71s,-hexahydi cyclopenta[c]pyrrol-2(lH)-yl]propoxy} benzamide selon la revendication 1 avec un inhibiteur de Pacétylcholinesterase. 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 du 4-{3-[/ri/f?,,i'-hexahydi cyclopenta[c]pynOl-2(lH)-yl]propoxy} benzamide selon la revendication 1 avec le donépézil, la galantamine ou la rivastigmine. 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 selon la revendication 1 1 ou 12 pour son utilisation dans le traitement des troubles cognitifs associés aux maladies neurodégénératives. 13. Association according to claim 1 1 or 12 for its use in the treatment of cognitive disorders associated with neurodegenerative diseases.
PCT/FR2012/051287 2011-06-08 2012-06-08 4-{3-[trans-hexahydrocyclopenta[c]pyrrol-2(1h)-yl]propoxy}benzamide, method for preparing same and pharmaceutical compositions that contain same WO2012168664A1 (en)

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US9789102B2 (en) 2012-04-06 2017-10-17 Sanofi H3 receptor antagonist for use in the treatment of alzheimer's disease

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WO2015032966A1 (en) * 2013-09-09 2015-03-12 Sanofi An h3 receptor antagonist combined with a cholinesterase inhibitor for use in the treatment of alzheimer's disease

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