Classifications

• • 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
  • A61P25/28—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 novel hexahydrocyclopenta [ô] 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.
• 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).
• 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.
• the potential therapeutic indications for compounds capable of increasing turnover or the release of histamine at the central level are the treatment of cognitive deficits associated with cerebral aging, acute and chronic neurodegenerative diseases, schizophrenia and that treatment of mood disorders, Tourette's syndrome (Gulhan Ercan-Sencicek et al., New England Journal of Medicine, May 20, 2010, 1901-1908), schizophrenia, sleep disorders and sleep rhythm -sleep, hyperactivity syndrome with attention deficit.
• Tourette's syndrome Gulhan Ercan-Sencicek et al., New England Journal of Medicine, May 20, 2010, 1901-1908
• schizophrenia, sleep disorders and sleep rhythm -sleep hyperactivity syndrome with attention deficit.
• studies have shown that a histamine injection into the central hypothalamic nuclei involved in the regulation of satiety attenuates the diet in the rat.
• hypofunctioning of histaminergic transmission has been demonstrated in genetically obese rats (Machidori et al., Brain Research, 1992, 590, 180-186). Accordingly, eating disorders
• the present invention relates to novel azabicyclic derivatives which are distinguished from the compounds exemplified in WO2005 / 089747 by the presence of a hexahydrocyclopenta [6] pyrrol-1-yl ring.
• these new compounds open the way not only to new treatments for cognitive disorders related 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 Tourette's syndrome, schizophrenia, mood or sleep disorders, for example.
• the present invention relates more particularly to the compounds of formula (I):
• ⁇ ALK represents an alkylene chain
• ⁇ W represents a group - ⁇ - R 0 u -
• R and R ' represent, independently of one another, a hydrogen atom or an alkyl group (CJ O-C) -straight or branched optionally substituted by one or more groups selected from halogen, hydroxy and alkoxy being heard that:
• alkylene denotes a bivalent radical, linear or branched, containing from 2 to 6 carbon atoms
• alkoxy denotes an alkyl-oxy group whose linear or branched alkyl chain contains from 1 to 6 carbon atoms, their enantiomers and diastereoisomers, and also their addition salts with an acid or a pharmaceutically acceptable base.
• pharmaceutically acceptable acids mention may be made, without limitation, of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic and methane acids. sulfonic, camphoric, etc.
• pharmaceutically acceptable bases mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, and the like.
• ALK represents a linear divalent radical containing from 2 to 6 carbon atoms such as, for example, the ethylene or propylene 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
• Another particular aspect of the invention relates to the compounds of formula (I) for which W represents the group N- ⁇ - R.
• R and R ' represent, independently of one another, the hydrogen atom, the methyl group or the ethyl group, these groups being optionally substituted by a methoxy.
• W represents the group -CO-NH-CH 3 , -CO-N (CH 3 ) 2 , -CO-NH 2 , -CO-N (CH 2 CH 3 ) 2 , -NH-CO-CH 3 , -N (CH 3 ) -CO-CH 3 or -NH-CO-CH 2 -OCH 3 .
• the preferred compounds of the invention are those for which the hexahydro-cyclopenta [Z] pyrrol-1-yl ring is of cis configuration.
• the hydrochloride, oxalate and citrate are more particularly preferred.
• the invention also extends to the process for preparing the compounds of formula (I), characterized in that the compound of formula (II) used is the starting material:
• ALK group in which the ALK group is as defined above, can be used as synthetic intermediates for the compounds of formula (I / a), in particular cases of 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).
• the ALK group in which the ALK group is as defined above, can be used as synthetic intermediates for the compounds of formula (I / a), in particular cases of 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).
• the compounds of formula (I / a), particular cases of the compounds of formula (I) for which W represents a group -CONRR ' can also be obtained by condensation of the amine NHRR ', where R and R' have the same meaning as in formula (I), using the compounds of formula (VIII):
• ALK group is as defined above and R "represents a linear or branched (C 1 -C 6 ) alkyl group or a benzyl group
• the compounds of formula (VIII) being prepared via the carboxylic acid (VI) or the corresponding acyl chloride (VII) presented above.
• 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, new treatments for cognitive disorders related to head trauma, but also in the treatment of disorders psycho-behaviors 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.
• these compounds may be useful in the treatment of mood disorders, and more particularly the treatment of anxio-depressive states, Tourette's syndrome, schizophrenia and cognitive disorders associated with it, 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 present invention also relates to pharmaceutical compositions containing a compound of formula (I) 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 any associated treatments and ranges from 0.05mg to 500mg 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 compounds below correspond to racemates of cis or trans configuration.
• the compounds below correspond, respectively, to racemic mixtures of (3 ⁇ , 6 ⁇ ) -hexahydrocyclopenta [2 ⁇ ] pyrrol-1 (2H) -yl skeletons and (3 ⁇ S, 6 ⁇ S) backbones.
• hexahydrocyclopenta [)] pyrrol-1 (2H) -yl and racemic mixtures of (3 ⁇ , 6 ⁇ S) -hexahydrocyclopenta [ ⁇ ] pyrrol-1 (2H) -yl backbones and backbones (3 ⁇ S, 6 ⁇ ) - hexahydrocyclopenta [è] pyrrol-1 (2H) -yl.
• racemic mixtures can be separated to obtain the pure enantiomers by HPLC chiral separation techniques, for example of CHIRALCEL OF, CHIRALPACK AS-H or CHIRALPACK AD-H.
• Step 1 4- ⁇ 3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy ⁇ benzonitrile
• Step 2 4- ⁇ 3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2Yl) -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 18 h.
• 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.
• Stage 1 Methyl 4- ⁇ 3- [cis-HexahydrocyclopentaPo] pyrrol-1 (2H) -yl] propoxy ⁇ benzoate
• the experimental procedure is identical to that of Example 1, synthesis route A, replacing at Stage 1 the 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 Stage I compound, 12.7 ml of 2 N sodium hydroxide and 8 ml of methanol is refluxed for one hour.
• In the reaction medium cooled in an ice bath are added 12.7 ml of 2N HCl. The precipitate is washed with water and dried under vacuum.
• Step 3 4- ⁇ 3- [cis, -hexahydrocyclopenta [b] pyrrol-1 (2Yi) -yl] propoxy ⁇ chloride
• Step 4 4- ⁇ 3- [cis-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy ⁇ benzamide
• the enantiomer 1 was obtained by preparative separation on a chiral column CHIRALCEL OF 4.6 x 250 mm 10 ⁇ , 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.
• Example 1b 4- ⁇ 3- [cw-HexahydrocycIopenta [b] pyrrol-1 (2H) -yl] propoxy ⁇ benzamide
• the enantiomer 2 was obtained by preparative separation on a chiral CHIRALCEL OF 4.6 x 250 mm 10 ⁇ column, elution at room temperature, eluent mixture: n-heptane / n-propanol / diethylamine (60/40 / 0.1) , flow rate 1 ml / min, UV detection at 255 nm
• the enantiomer 1 was obtained by preparative separation on a CHIRALCEL OF 60X chiral column (600 mm 20 ⁇ ), 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.
• the enantiomer 2 was obtained by preparative separation on a CHIRALCEL OF 60X chiral column (600 mm 20 ⁇ ), 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.
• the enantiomer 1 was obtained by preparative separation on a chiral column CHIRALPAK AS-H 4.6 x 250 mm 5 ⁇ , elution at ambient temperature, eluent mixture: acetonitrile / diethylamine (100 / 0.1) flow rate 0.6 ml / min, UV detection at 240 nm.
• the enantiomer 2 was obtained by preparative separation on a chiral column CHIRALPAK AS-H 4.6 x 250 mm 5 ⁇ , elution at ambient temperature, eluent mixture: acetonitrile / diethylamine (100 / 0.1) flow rate 0.6 ml / min, UV detection at 240 nm.
• Example 6 4- ⁇ 3- [cw-Hexahydrocyclopenta [6] pyrrol-1 (2H) -yl] propoxy ⁇ -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.
• Example 7a 4- ⁇ 3- [c / s-hexahydrocyclopenta [Z]] pyrrol-1 (2H) -yl] propoxy ⁇ -7V-methylbenzamide hydrochloride (enantiomer 1)
• Enantiomer 1 was obtained by preparative separation on a chiral column CHIRALPACK AS-H 4.6 x 250 mm 5 ⁇ , elution at room temperature, eluent mixture: acetonitrile / diethylamine (100 / 0.1) flow rate 1 ml / min, UV detection at 250 nm.
• Example 7b 4- ⁇ 3- [cis-Hexahydrocyclopenta [6] pyrrol-1 (2H) -yl] propoxy ⁇ -N-methylbenzamide Hydrochloride (Enantiomer 2)
• the enantiomer 2 was obtained by preparative separation on a chiral column CHIRALPACK AS-H 4.6 x 250 mm 5 ⁇ , elution at room temperature, eluent mixture: acetonitrile / diethylamine (100 / 0.1) flow rate 1 ml / min, UV detection at 250 nm.
• Example 8 N- (4- ⁇ 3- [c-Hexahydrocyclopenta [6] pyrrol-1 (2H) -yl] propoxy ⁇ phenyl) -N-methylacetamide hydrochloride
• Example 8a N- (4- ⁇ 3- [c-Hexahydrocyclopenta [e] pyrrol-1 (2H) -yl] propoxy ⁇ phenyl) -N-methylacetamide Hydrochloride (Enantiomer 1)
• the enantiomer 1 was obtained by preparative separation on a chiral column CHIRALPAK AD-H 4.6 x 250 mm 5 ⁇ , elution at room temperature, eluent mixture: ethanol / acetonitrile / diethylamine (15/85 / 0.1) flow rate 1 , 0 ml / min, UV detection at 280 nm.
• Enantiomer 2 was obtained by preparative chiral column separation CHIRALPAK AD-H 4.6 x 250 mm 5 ⁇ m, elution at room temperature, eluent mixture: ethanol / acetonitrile / diethylamine (15/85 / 0.1) flow rate 1 , 0 ml / min, UV detection at 280 nm.
• Example 9 N- (4- ⁇ 3- [c-hexahydrocyclopenta [ ⁇ ] pyrrol-1 (2H) -yl] propoxy ⁇ phenyl) -2-methoxyacetamide hydrochloride
• the enantiomer 1 was obtained by preparative separation on a chiral column CHIRALPAK AD-H 4.6 x 250 mm 5 ⁇ , elution at room temperature, eluent mixture: ethanol / acetonitrile / diethylamine (5/95 / 0.1) flow rate 1 , 0 ml / min, UV detection at 250 nm.
• the enantiomer 2 was obtained by preparative separation on a chiral column CHIRALPAK AD-H 4.6 x 250 mm 5 ⁇ , elution at room temperature, eluent mixture: ethanol / acetonitrile / diethylamine (5/95 / 0.1) flow rate 1 , 0 ml / min, UV detection at 250 nm.
• Route A 4- ⁇ 3 - [/ rans-hexahydrocyclopenta [6] pyrrol-1 (2H) -yl] propoxy ⁇ benzamide hydrochloride
• Step 2 4- ⁇ 3- [trans-Hexahydrocyclopenta] [P-pyrrol-1 (2H) -yl] propoxy ⁇ benzamide
• Step 1 In the reaction medium of Step 1 at room temperature are added 0.004 moles of tr-octahydrocyclopenta [ ⁇ ] pyrrole, the synthesis of which 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- [tmns-hexahydrocyclopentaPoJpyrrol-1 (2H) -yl] propoxy ⁇ benzamide hydrochloride
• the product obtained in Stage 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.
• Step 1 4- ⁇ 3- [trans-Hexahydrocyclopenta] pyrrol-1 (2K) -yl] propoxy ⁇ benzonitrile
• the experimental procedure is identical to that of Example 10, Synthetic Route A, Stages 1 and 2, replacing at Step 1 4-hydroxybenzamide with 4-hydroxybenzonitrile.
• Step 2 4- ⁇ 3- [trans-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy ⁇ benzamide
• the compound obtained in the above Step (2.2 g) is dissolved in 90 ml of ethanol and refluxed 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-hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy ⁇ benzamide hydrochloride
• the product obtained in Stage 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.
• Step 1 methyl 4- [3- [trans-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy] benzoate
• Step 3 4- ⁇ 3- [trans-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy ⁇ chloride
• Step 4 4- ⁇ 3- [trans-Hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy) benzamide
• Step 5 4- ⁇ 3- [trans-hexahydrocyclopenta [b] pyrrol-1 (2H) -yl] propoxy ⁇ benzamide hydrochloride
• Step 4 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.
• Example 16 4- ⁇ 3 - [// * a is-hexahydrocyclopenta [6] pyrrol-l (2H) -yl] propoxy ⁇ -N-methylbenzamide
• the animals were sacrificed, brains removed, frozen in liquid nitrogen, weighed and homogenized in 0.1 N HC10 4 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- methylhistamine are expressed in ⁇ g / 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 compounds of the present invention are capable, at a dose of 3 mg / kg PO, of significantly increasing the endogenous brain concentrations of N T- methylhistamine by more than 140%.
• the compounds of Examples 7, 8 and 9 administered at 3 mg / kg PO respectively increase the endogenous cerebral concentrations of ⁇ ⁇ - Methylhistamine 145%, 143% and 190%.
• the compounds of the present invention are potent H 3 central histaminergic receptor antagonists.
• the objective is to measure the affinity of compounds of the present invention for type murine histamine H 3 receptor transfected into CHO cells.
• the compounds are incubated at different concentrations in the presence of transfected CHO cells, a radiolabeled ligand, iodoproxifan, specific for H 3 receptors and scintillating beads for 24 hours at room temperature.
• the displacement of the specific binding of the ligand by the test compounds is measured, and the affinity constants of these compounds for the mouse H 3 receptors are determined.

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