Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

• the present invention relates to compounds, compositions and methods for the treatment of conditions associated with enhancement or improvement of cognitive ability or to counteract cognitive decline.
• n is equal to 1 , 2 or 3;
• This reaction may be performed for example at room temperature in absolute methanol in the presence of an acid such as HCI, or according to any method known to the person skilled in the art.
• R 1 , R 2 , R 3 and n have the same definitions as defined above.
• aldehyde VI may be prepared according to procedures described in Bioorg. Med. Chem. Letters (2009), 19(1 1 ), 31 18-3121 , or according to any other method known to the person skilled in the art.
• the synthesis of aldehyde VI may be performed in a two-steps procedure involving the protection of 4-bromo-1 H-pyrazole-5-carbonitrile with a protecting group, for example with tetrahydro-2H-pyran-2-yl under acidic conditions, followed by a carbonylation, using for example ethyl formate and n-butyl lithium. These steps may be performed according to any method known to the person skilled in the art.
• Alcohol of formula IV may be obtained by reduction at room temperature of aldehyde of formula VI using sodium borohydride, or according to any other method known to the person skilled in the art.
• the present invention includes the synthesis of the following intermediates:
• compositions of formula I include therapeutically active, non-toxic acid or base salt forms which the compounds of formula I are able to form.
• the acid addition salt form of a compound of formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like; or an organic acid, such as, for example, acetic, trifluoroacetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p- aminosalicylic, pamoic and the like.
• an appropriate acid such as an inorganic acid, for example, a hydrohalic such as hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like
• the compounds of formula I containing acidic protons may be converted into their therapeutically active, non-toxic base addition salt forms, e.g. metal or amine salts, by treatment with appropriate organic and inorganic bases.
• Appropriate base salt forms include, for example, ammonium salts, alkali and earth alkaline metal salts, e.g. lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. N-methyl-D- glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
• salt forms can be converted into the free forms by treatment with an appropriate base or acid.
• Compounds of the formula i and their saits can be in the form of a solvate, which is included within the scope of the present invention.
• Such solvates include for example hydrates, alcoholates and the like.
• Compounds of formula I and some of their intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem., 45 (1976) 11-30.
• the invention also relates to all enantiomeric forms of the compounds of formula I or mixtures thereof (including all possible mixtures of stereoisomers).
• the methods of the invention comprise administration to a mammal (preferably a human) suffering from above mentioned conditions or disorders, of a compound according to the invention in an amount sufficient to alleviate or prevent the disorder or condition.
• treatment of conditions associated with enhancement or improvement of cognitive ability or “to counteract cognitive decline” or “treatment of a cognitive disorder” or “improving the cognitive function” or “counteracting the decline of the cognitive function” used throughout this specification shall mean promoting cognitive function (affecting impaired cognitive function in the subject so that it more closely resembles the function of an aged-matched normal, unimpaired subject, including affecting states in which cognitive function is reduced compared to a normal subject) and preserving cognitive function (affecting normal or impaired cognitive function such that it does not decline or does not fall below that observed in the subject upon first presentation or diagnosis, e.g. to the extent of expected decline in the absence of treatment).
• the suitability of the compounds according to the present invention for conditions associated with enhancement or improvement of cognitive ability may be tested through assays that are well known in the art.
• assays include in particular the novel object recognition test (NOR) set out in Example 3 as well as the Y-maze test set out in Example 4.
• the mammal has normal cognitive function which is improved.
• the mammal exhibits cognitive impairment associated with aging.
• the mammal is a human with cognitive impairment associated with a disease or disorder such as autism, dyslexia, attention deficit hyperactivity disorder, schizophrenia, obsessive compulsive disorders, psychosis, bipolar disorders, depression, Tourette's syndrome and disorders of learning in children, adolescents and adults, Age Associated Memory Impairment, Age Associated Cognitive Decline, Parkinson's Disease, Down's Syndrome, traumatic brain injury Huntington's Disease, Progressive Supranuclear Palsy (PSP), HIV, stroke, vascular diseases, Pick's or Creutzfeldt-Jacob diseases, multiple sclerosis (MS), other white matter disorders and drug-induced cognitive worsening.
• a disease or disorder such as autism, dyslexia, attention deficit hyperactivity disorder, schizophrenia, obsessive compulsive disorders, psychosis, bipolar disorders, depression, Tourette's syndrome and disorders of learning in children, adolescents and adults, Age Associated Memory Impairment, Age Associated Cognitive Decline, Parkinson's Disease, Down's Syndrome, traumatic brain injury Huntington
• the impairment of cognitive function is caused by, or attributed to, Alzheimer's disease. In another embodiment, the impairment of cognitive function is caused by, or attributed to, mild cognitive impairment (MCI).
• MCI mild cognitive impairment
• compositions for the treatment of a cognitive disorder or for improving the cognitive function or counteracting the decline of the cognitive function.
• Such compositions typically contain the active pharmaceutical ingredient and a pharmaceutically acceptable excipient.
• Suitable diluents and carriers may take a wide variety of forms depending on the desired route of administration, e.g., oral, rectal, parenteral or intranasal.
• compositions comprising compounds according to the invention can, for example, be administered orally, parenterally, i.e., intravenously, intramuscularly or subcutaneously, intrathecally, transdermal ⁇ (patch), by inhalation or intranasally.
• compositions suitable for oral administration can be solids or liquids and can, for example, be in the form of tablets, pills, dragees, gelatin capsules, solutions, syrups, chewing-gums and the like.
• active ingredient may be mixed with an inert diluent or a non-toxic pharmaceutically acceptable carrier such as starch or lactose.
• these pharmaceutical compositions can also contain a binder such as microcrystalline cellulose, gum tragacanth or gelatine, a disintegrant such as alginic acid, a lubricant such as magnesium stearate, a glidant such as colloidal silicon dioxide, a sweetener such as sucrose or saccharin, or colouring agents or a flavouring agent such as peppermint or methyl salicylate.
• a binder such as microcrystalline cellulose, gum tragacanth or gelatine
• a disintegrant such as alginic acid
• a lubricant such as magnesium stearate
• a glidant such as colloidal silicon dioxide
• a sweetener such as sucrose or saccharin
• colouring agents or a flavouring agent such as peppermint or methyl salicylate.
• compositions which can release the active substance in a controlled manner are in conventional form such as aqueous or oily solutions or suspensions generally contained in ampoules, disposable syringes, glass or plastics vials or infusion containers.
• compositions containing the compound of the present invention in the form of a pharmaceutically acceptable co-crystal are also comprised by the present invention.
• Such pharmaceutical compositions may furthermore contain known or marketed therapeutic agents used in the treatment of cognitive or a neurological disorders (AD) including donepezil (Aricept®), galanthamine (Razadyne®, Razadyne ER®, Reminyl®, Nivalin®), rivastigmine tartrate (Exelon®), memantine (Axura®, Akatinol®, Namenda®, Ebixa®).
• AD cognitive or a neurological disorders
• the pro-cognitive activity of the compounds according to the present invention in particular of formula I, or their pharmaceutically acceptable salts may be determined by a variety of preclinical tests and models known to a skilled person in the art. Such tests may challenge the efficacy on multiple memory phases and types. In contrast to challenging a particular memory type or phase, the cognitive models test the ability of a compound to prevent or reverse a memory deficit in a given brain pathway, system, or function.
• the compounds according to the present invention show a strong efficacy to improve two phases of memory: acquisition, and consolidation. They improve the acquisition phase of short and long term memory as seen by reversing the scopolamine induced deficit in the novel object recognition and passive avoidance, respectively. They improve the consolidation of spatial reference learning as seen by improved amyloid-induced memory deficit in the Morris water maze. Efficacy to improve retention might also be found in the inhibitory avoidance or active avoidance test.
• NMR spectra are recorded on a BRUKER AVANCE 400 NMR Spectrometer fitted with a Linux workstation running XWIN NMR 3.5 software and a 5 mm inverse 1 H/BB probehead, or BRUKER DRX 400 NMR fitted with a SG Fuel running XWIN NMR 2.6 software and a 5 mm inverse geometry 1 H/ 1 3 C/ 1 9F triple probehead.
• the compound is studied in d6-dimethylsulfoxide (or d3-chloroform) solution at a probe temperature of 313 K or 300 K and at a concentration of 10 mg/ml.
• the instrument is locked on the deuterium signal of ds-dimethylsulfoxide (or d3-chloroform). Chemical shifts are given in ppm downfield from TMS (tetramethylsilane) taken as internal standard.
• HPLC analyses are performed using one of the following systems:
• the gradient runs from 100 % solvent A (acetonitrile, water, trifluoroacetic acid (10/90/0.1 , v/v/v)) to 100 % solvent B (acetonitrile, water, trifluoroacetic acid (90/10/0.1 , v/v/v)) in 7 min with a hold at 100 % B of 4 min.
• the flow rate is set at 2.5 ml/min and a split of 1/25 is used just before API source.
• API spectra (+ or -) are performed using a FINNIGAN LCQ ion trap mass spectrometer.
• APCI source operated at 450°C and the capillary heater at 160°C.
• ESI source operated at 3.5 kV and the capillary heater at 210°C.
• Mass spectrometric measurements in DIP/EI mode are performed as follows: samples are vaporized by heating the probe from 50°C to 250°C in 5 min. El (Electron Impact) spectra are recorded using a FINNIGAN TSQ 700 tandem quadrupole mass spectrometer. The source temperature is set at 150°C.
• Mass spectrometric measurements on a TSQ 700 tandem quadrupole mass spectrometer (Finnigan MAT) in GC/MS mode are performed with a gas chromatograph model 3400 (Varian) fitted with a split/splitless injector and a DB-5MS fused-silica column (15 m x 0.25 mm I.D., 1 ⁇ ) from J&W Scientific. Helium (purity 99.999 %) is used as carrier gas.
• the injector (CTC A200S autosampler) and the transfer line operate at 290 and 250°C, respectively.
• Sample (1 ⁇ ) is injected in splitless mode and the oven temperature is programmed as follows: 50°C for 5 min., increasing to 280°C (23°C/min) and holding for 10 min.
• the TSQ 700 spectrometer operates in electron impact (El) or chemical ionization (CI/CH4) mode (mass range 33 - 800, scan time 1.00 sec).
• the source temperature is set at 150°C.
• High resolution mass spectrometry measurements are run on a Waters LCT Time of flight mass spectrometer equipped with an ESI source and a Waters Acquity UPLC (column: BEH C18 (1 .7 ⁇ , 2.1 x 50 mm)) with diode array detector.
• the gradient runs from 98 % solvent A (aqueous ammonium formate (63 mg/l), 30% aqueous ammonia (50 ⁇ / ⁇ )) to 95 % acetonitrile and back in 6 min.
• the source parameters are as follows: ESI capillary voltage 2.5 kV, cone voltage 135 V, source block temperature 135°C, desolvation temperature 350°C, cone gas flow 20 IJHr (Nitrogen), desolvation Gas flow 800 UHr.
• the detector is set with a flight tube at 7.2 KV and an MCP detector at 2,500 V. Specific rotation is recorded on a Perkin-Elmer 341 polarimeter. The angle of rotation is recorded at 25°C on 1 % solutions in methanol, at 589 nm.
• Melting points are determined on a Btichi 535 or 545 Tottoli-type fusionometre, and are not corrected, or by the onset temperature on a Perkin Elmer DSC 7.
• Preparative chromatographic separations are performed on silicagel 60 Merck, particle size 15-40 ⁇ , reference 1 .1511 1.9025, using Novasep axial compression columns (80 mm i.d.), flow rates between 70 and 150 ml/min. Amount of silicagel and solvent mixtures as described in individual procedures. Reverse phase separations are carried out using 500 g of either Kromasil C18 10 ⁇ silicagel (acidic or neutral conditions) or Phenomenex Gemini C18 10 ⁇ (basic conditions) in 8-cm ID columns with a flow rate of 150 ml/min. Products are detected at 215 nm unless otherwise specified.
• the mixture is stirred at -90°C for 20 min then decomposed by the addition of a THF/water mixture (10 mL, 1 :1 ). The cooling bath is removed. The reaction mixture is allowed to heat up to room temperature and diluted with ethyl acetate (25 mL). Solid NaCI is added.
• 3,4,5-Trifluorobenzaldehyde a5 (700 g, 4.37 mol, 1 eq) is dissolved in THF (1 L). The temperature of the mixture is brought to 5°C by the use of an ice bath.
• carbethoxymethylene triphenyl phosphorane (1550 g, 4.44 mol, 1.017 eq) is dissolved in dichloromethane (3 L). This yellow solution is added to the reaction mixture in 1.5 h (T° ⁇ 16°C). After 1 h at 5°C, the starting product is completely consumed and the solution is concentrated to dryness at 45°C.
• Hexane (5 L) is added to the white residue and the suspension is stirred for 4h at room temperature.
• Nitromethane (1 L) is placed in the reaction vessel and cooled to -19°C.
• DBU 1095 mL, 1 eq
• 2E 3-(3,4,5-trifluorophenyl)prop-2-enoate a6 (1656 g, 7.20 mol) is added while keeping the temperature below -12°C.
• the reaction mixture is stirred at -15°C for 2 h. A small quantity of solid stays in suspension so the mixture is brought to 0°C until completion of the reaction.
• Water (2 L) is added while maintaining the temperature around 10°C.
• the pH is brought to 1 by adding HCI 6N (1.6 L). The color turns from orange to yellow.
• alpha D (MeOH, 25°C): +15.1 °.
• the enantiomers are resolved by chiral chromatography (chiralpak IC, 80 * 380 mm, eluent: heptane/ethanol 70/30 v/v) to afford the 2.88 g of enantiomer A a12-A (first eluted) and 3.1 g of enantiomer B a12-B (second eluted) as white solids.
• 4-(3,4,5-trifluorophenyl)pyrrolidin-2-one and enantiomers may be synthesized according to the same method.
• Solution A at 0°C, DIPEA (6.6 mL, 39.8 mmol) and methanesulfonyl chloride (0.7 mL, 8.7 mmol) are added to a solution of 4-(hydroxymethyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H- pyrazole-5-carbonitrile a9 (1.65 g, 7.96 mmol) in CH2CI2 (20 mL). The mixture is stirred for 30 minutes at 0°C.
• Example 3 In vivo model for assessing the efficacy of a test compound in learning and memory disorders (novel object recognition test; NOR)
• the purpose of the study is to evaluate the ability of test compounds to reverse the experimental deficit induced by scopolamine.
• the experiments was carried out using male C57BIJ6J mice (Centre d'Elevage R. Janvier, BP. 55, 53940 Le Genest-Saint-lsle, F.), weighing 20-35 g (10-14 weeks old) at their arrival that should meet inclusion criteria described in the experimental procedure.
• the experimental arena is a square wooden box (40x40x40 cm) painted in dark blue, with 8 * 8 cm black painted squares under a clear plexiglass floor.
• the arena was placed in a dark room illuminated only by lamps giving a uniform dim light in the box (around 60 lux).
• mice were habituated to the environment for a maximum of 30 min.
• mice were submitted to two trials spaced by an intertrial interval of 60 min.
• T1 mice were placed in the arena containing 2 identical objects and time required by each animal to complete 20 s of object exploration was determined with a cut-off time of 12 min. Exploration was considered to be directing the nose at a distance less than 2 cm from the object and/or touching the object.
• mice were placed back in the arena for 5 min and exploration of each object together with locomotor activity was determined.
• a criterion of minimal level of object exploration was used in the study to exclude animals with naturally low levels of spontaneous exploration: only animals having a minimal level of object exploration of 3 s during the testing trial (Novel + Familiar > 3 s ) were included in the study.
• test compounds displayed typically an activity at 30 mg/kg or less.

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• 2012
  • 2012-07-20 WO PCT/EP2012/003077 patent/WO2014012563A1/fr not_active Ceased

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