EP2509947A1 - Derives azabicyclo [3.1.0]hex- 2 -yl, leur procede de preparation et les compositions pharmaceutiques qui les contiennent - Google Patents

Derives azabicyclo [3.1.0]hex- 2 -yl, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

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Publication number
EP2509947A1
EP2509947A1 EP10799080A EP10799080A EP2509947A1 EP 2509947 A1 EP2509947 A1 EP 2509947A1 EP 10799080 A EP10799080 A EP 10799080A EP 10799080 A EP10799080 A EP 10799080A EP 2509947 A1 EP2509947 A1 EP 2509947A1
Authority
EP
European Patent Office
Prior art keywords
formula
compounds
group
azabicyclo
hex
Prior art date
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Withdrawn
Application number
EP10799080A
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German (de)
English (en)
French (fr)
Inventor
Patrick Casara
Anne-Marie Chollet
Alain Dhainaut
Jean-Michel Henlin
Pierre Lestage
Fany Panayi
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Laboratoires Servier SAS
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Laboratoires Servier SAS
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Application filed by Laboratoires Servier SAS filed Critical Laboratoires Servier SAS
Publication of EP2509947A1 publication Critical patent/EP2509947A1/fr
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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to novel azabicyclo [3.1.0] hex-2-yl 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.
  • rhistamine is involved in various physiological and behavioral processes such as thermoregulation, neuroendocrine regulation, nociception, circadian rhythm, cataleptic states, motor skills, aggression, eating behavior, learning and memorization, as well as synaptic plasticity (Hass et al., Histaminergic Neurons: Morphology and Function, Boca Raton, FL: CRC Press, 1991, pp. 196-208, Brown et al., Prog Neurobiology, 2001, 63, 637-672, Smith et al., Neuroimmunomodulation 2007, 14, pp. 317-325).
  • 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 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 an injection of Wstamine in 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 2-azabicyclo [3.1.0] hexane 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 and R ' represent, independently of one another, a hydrogen atom or a linear or branched (Ci-C e) alkyl group optionally substituted with one or more groups chosen from halogen, hydroxy and alkoxy, being understood than :
  • 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 a pharmaceutically acceptable acid or 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 rj--.
  • 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 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).
  • ALK group is as defined above and R "represents a linear or branched (C 1 -C e) alkyl group or a benzyl group
  • the compounds of formula (VIII) being prepared via the corresponding carboxylic acid (VI) or 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, in new treatments for cognitive disorders related to head trauma, but also in the treatment of psycho-behavioral disorders associated with these pathologies such as sleep disorders, apathy and anxio-depressive states. 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 hypersomnia occurring during obstructive sleep apnea syndrome or attention deficit hyperactivity syndrome, as well as that daytime sleepiness is 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 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.
  • racemic mixtures can be separated to obtain the pure enantiomers by chiral HPLC separation techniques, for example, CHIRALCEL OF, CHIRALPACK AS-H, CHIRALPACK T304, or CHIRALPACK AD -H.
  • Step 3 4- [3- (cis-2-azabicyclo [3.1.0] hex-2-yl) propoxy] benzamide hydrochloride
  • the product obtained in Step 2 is dissolved in 10 ml of ethanol to which 2 ml of 2N hydrochloric ether.
  • the product thus obtained is filtered, rinsed with ethanol and dried under vacuum.
  • Step 1 4- ⁇ 3- (cis-2-azabicyclo [3.1.0] hex-2-yl) propoxy ⁇ benzonitrile
  • 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 off, rinsed with isopropyl ether and then dissolved in 10 ml of ethanol to which 2 ml of 2N hydrochloric ether are added.
  • the product thus obtained is filtered off, rinsed with ethanol and dried under reduced pressure. empty.
  • Step 2 4- ⁇ 3- (cis-2-azabicyclo [3.1.0] hex-2-yl) propoxy ⁇ benzoic acid
  • a mixture of 3.5 g of the Step 1 compound, 12.7 ml of sodium hydroxide 2 N and 8 ml of methanol is refluxed for one hour.
  • 12.7 ml of 2N HCl are added to the reaction medium cooled in an ice bath. The precipitate is washed with water and dried under vacuum.
  • Step 3 4- ⁇ 3- (cis-2-azabicyclo [3.1.0] hex-2-yl) propoxy ⁇ benzoyl chloride
  • Step 4 4- [3- (c-S-2-azabicyclo [3.1.0] hex-2-yl) propoxy] benzamide hydrochloride
  • a solution of 1 g of the product described in Step 3 in dichloromethane at 0 ° 4 ml of 2N ammoniacal methanol are added dropwise thereto.
  • the mixture is then stirred for 1 hour at ambient temperature, washed with a 2N sodium hydroxide solution and then with water.
  • the organic phase is dried over magnesium sulfate and concentrated.
  • the solid obtained is filtered off, rinsed with isopropyl ether and then dissolved in 10 ml of ethanol to which 2 ml of 2N hydrochloric ether are added.
  • the product thus obtained is filtered off, rinsed with ethanol and dried under vacuum.
  • Elemental microanalysis :
  • Example 2 4- ⁇ 2- (c) -5-azabicyclo [3.1.0] hex-2-yl) ethoxy ⁇ benzamide hydrochloride
  • the experimental procedure is identical to that of Example 1, synthetic route A, substituting 1-bromo-2-chloroethane for 1-bromo-3-chloropropane in Step 1
  • Example 4 N- (4- ⁇ 2- (cis-2-azabicyclo [3.1.0] hex-2-yl) ethoxy ⁇ phenyl) acetamide hydrochloride
  • the experimental procedure is identical to that of Example 2, replacing Stage 1 4-hydroxybenzamide with N- (4-hydroxyphenyl) acetamide.
  • Step 1 4- [3- (cis-2-Azabicyclo [3.1.0] hex-2-yl) propoxy] -N, N-dimethylbenzamide
  • the experimental method is identical to that of Example 1, synthetic route at stages 1 and 2, replacing in Step 1 the 4-hydroxybenzamide with 4-hydroxy-N, N-dimethylbenzamide.
  • Step 2 4- [3- (cis-2-azabicyclo [3.1.0] hex-2-yl) propoxy] -N, N-dimethylbenzamide hydrochloride
  • Step 1 4- [3- (c-2-Azabicyclo [3.1.0] hex-2-yl) propoxy] -N, N-diethylbenzamide
  • Step 2 4- [3- (cis-2-azabicyclo [3.1.0] hex-2-yl) propoxy] -N, N-diethylbenzamide hydrochloride
  • Example 6a 4- ⁇ 3- ( ⁇ -azabicyclo [3.1.0] hex-2-yl) propoxy ⁇ -AVV-diethylbenzamide hydrochloride (enantiomer 1)
  • the enantiomer 1 was obtained by separation prepared on CHIRALPACK T304 chiral column loaded to 1 g / kg, eluent mixture: acetonitrile / diethylamine (100 / 0.1), flow rate 100 ml / min, UV detection at 270 nm.
  • Example 6b 4- ⁇ 3- ( ⁇ -2-azabicyclo [3.1.0] hex-2-yl) propoxy ⁇ -NyV-diethylbenzamide hydrochloride (enantiomer 2)
  • the enantiomer 2 was obtained by preparative separation on a CHIRALPACK T304 chiral column loaded to 1 g / kg, eluent mixture: acetonitrile / diethylamine (100 / 0.1), flow rate 100 ml / min, UV detection at 270 nm.
  • Example 7 4- ⁇ 3- (m-2-azabicyclo [3.1.0] hex-2-yl) propoxy ⁇ -N-methylbenzamide hydrochloride Step 1: 4- [3- (cis-2-Azabicyclo [3.1. 0] hex-2-yl) propoxy] -N-methylbenzamide
  • Example 7a 4- ⁇ 3- (m-2-azabicyclo [3.1.0] hex-2-yl) propoxy ⁇ -N-methylbenzamide hydrochloride (enantiomer 1)
  • the enantiomer 1 was obtained by preparative separation on a CHIRALPACK LA 20 ⁇ chiral column loaded to 0.3 g / 650 g, eluent mixture: acetonitrile / diethylamine (100 / 0.1), flow rate 100 ml / min, UV detection at 280 nm.
  • Example 7b 4- ⁇ 3- ( ⁇ -azabicyclo [3.1.0] hex-2-yl) propoxy ⁇ -N-methylbenzamide hydrochloride (enantiomer 2)
  • the enantiomer 2 was obtained by preparative separation on a CHIRALPACK IA 20 ⁇ chiral column loaded to 0.3 g / 650 g, eluent mixture: acetonitrile / diethylamine (100 / 0.1), flow rate 100 ml / min, UV detection at 280 nm.
  • Example 8b N- (4- ⁇ 3- (cis-2-azabicyclo [3.1.0] hex-2-yl) propoxy ⁇ hydrochloride
  • the enantiomer 2 was obtained by preparative separation on CHIRALPACK IA chiral column 20 ⁇ loaded at 0.5g / 650g, eluent mixture: acetonitrile / diethylamine (100 / 0.1), flow 1 OOml / min, UV detection at 295nm.
  • 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 HClO4 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 Examples 4, 9, 8, 7, 6 and 3, administered at 3 mg / kg PO increase the endogenous brain concentrations of N T -methylhistamine, respectively of:
  • the objective is to measure the affinity of the compounds of the present invention for transfected hist-type murine histaminergic receptors in 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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Neurosurgery (AREA)
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  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Rheumatology (AREA)
  • Anesthesiology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP10799080A 2009-12-09 2010-12-08 Derives azabicyclo [3.1.0]hex- 2 -yl, leur procede de preparation et les compositions pharmaceutiques qui les contiennent Withdrawn EP2509947A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR0905953A FR2953521B1 (fr) 2009-12-09 2009-12-09 Nouveaux derives azabicyclo[3.1.0]hex-2-yl, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
PCT/FR2010/000823 WO2011070253A1 (fr) 2009-12-09 2010-12-08 Derives azabicyclo [3.1.0] hex- 2 -yl, leur procede de preparation et les compositions pharmaceutiques qui les contiennent

Publications (1)

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EP2509947A1 true EP2509947A1 (fr) 2012-10-17

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US (1) US20120283245A1 (enrdf_load_stackoverflow)
EP (1) EP2509947A1 (enrdf_load_stackoverflow)
JP (1) JP2013513589A (enrdf_load_stackoverflow)
KR (1) KR20120102763A (enrdf_load_stackoverflow)
CN (1) CN102652127A (enrdf_load_stackoverflow)
AP (1) AP2012006352A0 (enrdf_load_stackoverflow)
AR (1) AR079265A1 (enrdf_load_stackoverflow)
AU (1) AU2010329762B2 (enrdf_load_stackoverflow)
BR (1) BR112012013666A2 (enrdf_load_stackoverflow)
CA (1) CA2782469C (enrdf_load_stackoverflow)
CL (1) CL2012001479A1 (enrdf_load_stackoverflow)
CO (1) CO6541535A2 (enrdf_load_stackoverflow)
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CU (1) CU20120091A7 (enrdf_load_stackoverflow)
EA (1) EA201200849A1 (enrdf_load_stackoverflow)
EC (1) ECSP12011950A (enrdf_load_stackoverflow)
FR (1) FR2953521B1 (enrdf_load_stackoverflow)
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IN (1) IN2012DN04966A (enrdf_load_stackoverflow)
MA (1) MA33882B1 (enrdf_load_stackoverflow)
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PH (1) PH12012501053A1 (enrdf_load_stackoverflow)
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TW (1) TW201200499A (enrdf_load_stackoverflow)
UA (1) UA102950C2 (enrdf_load_stackoverflow)
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WO (1) WO2011070253A1 (enrdf_load_stackoverflow)
ZA (1) ZA201203943B (enrdf_load_stackoverflow)

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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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FR2866647B1 (fr) * 2004-02-20 2006-10-27 Servier Lab Nouveaux derives azabicycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
GB0507680D0 (en) * 2005-04-15 2005-05-25 Glaxo Group Ltd Compounds
ATE466007T1 (de) * 2005-11-30 2010-05-15 Hoffmann La Roche 5-substituierte indol-2-carbonsäureamidderivate

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UA102950C2 (ru) 2013-08-27
BR112012013666A2 (pt) 2016-04-19
SA110320011B1 (ar) 2013-10-01
MA33882B1 (fr) 2013-01-02
US20120283245A1 (en) 2012-11-08
AU2010329762B2 (en) 2013-10-03
ZA201203943B (en) 2013-08-28
WO2011070253A8 (fr) 2012-08-02
CU20120091A7 (es) 2012-07-31
CA2782469C (fr) 2014-04-08
FR2953521B1 (fr) 2011-11-18
IN2012DN04966A (enrdf_load_stackoverflow) 2015-09-25
FR2953521A1 (fr) 2011-06-10
CL2012001479A1 (es) 2013-02-08
PH12012501053A1 (en) 2013-02-04
AR079265A1 (es) 2012-01-04
CA2782469A1 (fr) 2011-06-16
MX2012006578A (es) 2012-06-25
JP2013513589A (ja) 2013-04-22
EA201200849A1 (ru) 2013-01-30
KR20120102763A (ko) 2012-09-18
CN102652127A (zh) 2012-08-29
SG181082A1 (en) 2012-07-30
WO2011070253A1 (fr) 2011-06-16
PE20121475A1 (es) 2012-10-20
CO6541535A2 (es) 2012-10-16
AP2012006352A0 (en) 2012-08-31
CR20120286A (es) 2012-08-20
NI201200099A (es) 2012-11-09
TW201200499A (en) 2012-01-01
AU2010329762A1 (en) 2012-06-21
ECSP12011950A (es) 2012-07-31
UY33072A (es) 2011-05-31
GEP20156227B (en) 2015-01-26
TN2012000267A1 (fr) 2013-12-12

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