WO2014083003A1 - Pro-cognitive compound - Google Patents

Abstract

The invention relates generally to a compound according to formula I - more in particular la or lb, a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof-, for use as a cognitive enhancement (pro-cognitive) agent and pharmaceutical compositions and combinations thereof. The compound and compositions according to this invention are in particular suitable for the treatment (or prevention) of disorders which are associated with cognitive impairment by improving one or more of cognition, memory, executive functions, learning, behavior and the like. Furthermore, the compounds and compositions are useful agents for the treatment of non-cognitive psychopathological symptoms associated with cognitive impairment such as, but not limited to, irritability, tension, neurovegetative symptoms, sleep problems, concentration difficulties, loneliness, depression symptoms and slowing. These symptoms could all be the joint manifestation of a cognitive disorder making the compounds and compositions also useful for the improvement of these non-cognitive symptoms.

Description

PRO-COGNITIVE COMPOUND

FIELD OF THE INVENTION The invention relates generally to a compound according to formula I - more in particular la or lb, a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof-, for use as a cognitive enhancement (pro-cognitive) agent and pharmaceutical compositions and combinations thereof. The compound and compositions according to this invention are in particular suitable for the treatment (or prevention) of disorders which are associated with cognitive impairment by improving one or more of cognition, memory, executive functions, learning, behavior and the like. Furthermore, the compounds and compositions are useful agents for the treatment of non-cognitive psychopathological symptoms associated with cognitive impairment such as, but not limited to, irritability, tension, neurovegetative symptoms, sleep problems, concentration difficulties, loneliness, depression symptoms and slowing. These symptoms could all be the joint manifestation of a cognitive disorder making the compounds and compositions also useful for the improvement of these non-cognitive symptoms. BACKGROUND TO THE INVENTION

Cognitive disorders are among the most challenging and life-changing disorders, since they can really change the personality of a patient. They can limit a patient's success in work, interfere with friendships, impair the ability to care for themselves, etc. These disorders can manifest during any developmental stage and in adult life and are often associated with a broad range of neurological and psychiatric conditions. In fact, cognitive disorders represent some of the most complex, heterogeneous and common clinical entities. It is therefore highly desirable to provide compounds and compositions for preventing and/or treating cognitive disorders in patients and/or which are suitable as pro-cognitive agents for improving cognitive aspects such as cognition, memory, executive functions, learning, and the like.

5-HT₄ receptors are seven transmembrane-spanning domain receptors that are positively coupled to adenylyl cyclase. Their activation thus results in increased cAMP levels. In the brain, relatively high expression of 5-HT₄ receptors are found in the limbic system, mainly in the hippocampus and frontal cortex and amygdale (Bonaventure et al. 2000. Synapse 36, 35-46), which are area's that are vulnerable to the development of Alzheimer's Disease (AD) pathology. The synchronous appearance of 5-HT4 receptors and cholinergic markers suggests a close connection between 5-HT4 receptors and cholinergic signaling which supports the view that 5-HT4 receptor agonists could have a positive effect on symptoms associated with disorders with impaired cholinergic transmission, related to as well as unrelated to cognition. In addition to their expression in the brain, 5-HT₄ receptors are expressed in peripheral tissues such as the gastrointestinal (Gl) tract and atrium. Activation of the 5-HT₄R in the Gl tract is the mechanism of action of prucalopride, a compound used to treat constipation.

We have now identified two structurally related 5-HT₄R agonists, hereinafter referred to as compounds N°1 and N°2, that have a set of unique properties that translate into an unexpected high efficacy in behavioral tests relevant for cognitive function, and this in combination with limited peripheral effects. Furthermore, their effects are also considered relevant for non-cognitive psychiatric symptoms associated with cognitive impairment. Pharmacological studies in animals have previously shown that activation of 5-HT₄ receptors has a procognitive effect (Moser, et al., 2002. J Pharmacol Exp Ther 302, 731 -741 ). Accordingly, several suggested 5-HT₄ receptor agonists (e.g. SL65.0155, PRX-03140 and PF-04995274) have been developed and reached clinical testing phase. However, and with reference to the experimental part hereinafter, we found that at low physiological receptor densities, these agents in fact behave like 5-HT₄R antagonists, and not like 5-HT₄R agonists and are therefore clearly distinct from compounds N°1 and N°2.

Apart from these antagonists, the centrally active 5-HT₄R partial agonist RS67333 has also shown a pro-cognitive effect in animal behavioral experiments (Fontana et al., 1997. Neuropharmacology. 36: 689-96; Lelong et al., 2001. Neuropharmacology 41 : 517-22; Orsetti et al., 2003 Learn Mem. 10: 420-6). However, compounds N°1 and N°2, also being partial 5-HT₄R agonists, appear to have a set of unique properties that translate into a unexpected high efficacies as cognition enhancers in comparison with RS67333. Finally, prucalopride and velusetrag (TD-5108) being 5-HT₄R agonists with a high intrinsic activity, i.e. full 5-HT₄R agonists, are expected to have a high effect in the CNS and also in the periphery, as exemplified by the fact that both are being developed for the treatment of constipation. Compounds N°1 and N°2, which are structurally related to each other, appear to have unique properties because, their effects in the periphery are markedly lower than those of known 5-HT₄R agonists like prucalopride, while they show a clearly higher pro-cognitive effect in animal models. This makes the compounds particularly useful for the treatment of CNS disorders, in particular for the treatment of disorders in which cognitive function is impaired.

SUMMARY OF THE INVENTION

We thus identified two structurally related 5-HT₄R agonists, falling under the general formula I and hereinafter referred to as compounds N°1 and N°2, with a set of unexpected unique properties that translate into an unexpected high efficacy in behavioral tests relevant for cognitive function in combination with a low peripheral efficacy making them particularly useful for the treatment of CNS disorders, in particular disorders in which cognitive function is impaired.

Furthermore, their effects are also considered relevant for non-cognitive psychiatric symptoms associated with cognitive impairment.

This finding is evidenced in the experimental data provided in the examples hereinafter, and is summarized in the following arguments:

1 . Compounds N°1 and N°2 unexpectedly show superior cognition-enhancing properties compared to other 5-HT₄R agonists that had been suggested in the literature to be able to enhance cognition and that have higher intrinsic activity and/or better brain penetrating potential (see example 1 ). In extension, Compounds N°1 and N°2 show superior efficacy in reversing cholinergic deficits in the brain in comparison to the literature references.

2. In contrast to the results obtained in the behavioral assays relevant for cognition and/or cholinergic impairment, but in line with the intrinsic activity differences, Compounds N°1 and N°2 behave as a partial agonists in peripheral assays compared to prucalopride, a 5-HT₄R agonist used to treat gastrointestinal disorders. This profile results in reduced efficacy at peripheral 5-HT₄R receptors and thus limited peripheral effects (see example 2).

3. The unique properties of Compounds N°1 and N°2 are underscored by the fact that compounds N°1 and N°2 show splice variant-specific behaviour, something which has never been reported before for a 5-HT₄R agonist (see example 3). 4. As illustrated for Compound N°1 , the compounds act synergistically with cholinesterase inhibitors in behavioral assays relevant for cognition and/or cholinergic impairment (see example 4).

Therefore, in a first aspect, the present invention provides a compound according to formula I, a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

wherein R-i and R₂ are each independently selected from the list comprising -

H and Me;

Preferably, the compound according to this invention, represented by formula I, is selected from the compounds represented by formula la or lb.

Thus, in a particular embodiment, the present invention provides a compound according to formula la or lb, a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

The present invention further provides a combination of a compound according to this invention and an acetylcholinesterase inhibitor.

In particular, the present invention provides a combination of a compound according to this invention and an acetylcholinesterase inhibitor for use in medicine; more specifically, for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

The present invention further provides a pharmaceutical composition comprising a compound according to this invention, for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

The present invention also provides a pharmaceutical composition comprising a combination according to this invention for use in medicine; more specifically for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

This invention also provides the use of a compound according to this invention, as a pro-cognitive agent. Further, it provides the use of a combination according to this invention, as a pro-cognitive combination; and the use of a pharmaceutical composition according to this invention, as a pro-cognitive composition. In a further aspect, the present invention provides a method for improving cognition; said method comprising administering to a subject in need thereof a compound, a combination or a pharmaceutical composition according to this invention.

The present invention provides a method for improving cognitive symptoms such as executive function, cognitive symptoms, long term memory, delayed memory, working memory, attention, learning, visual learning, verbal learning, speed of processing, vigilance, visual motor function, social cognition or neuropsychiatric symptoms, REM sleep, visual motor skills; said method comprising administering to a subject in need thereof a compound, a combination or a pharmaceutical composition according to this invention.

In a specific embodiment according to this invention, the disorder in which cognitive function is impaired is selected from the non-limiting list comprising amnesia, dementia, delirium, Alzheimer's disease, vascular dementia, Pick's disease, mild cognitive impairment (MCI), schizophrenia, post coronary bypass cognitive symptoms, multiple scleroses, CADASIL syndrome, Down syndrome, frontal lobe dementia, fragile X syndrome, Parkinson's disease dementia (PDD), cognitive impairment in depression and bipolar disorders, alcoholism with Wernicke's encephalopathy, attention-deficit/hyperactivity disorder, autism, bipolar disorder, Creutzfeldt-Jakob disease, dementia pugilistica, dementia with Lewy bodies, semantic dementia, Olivopontocerebellar atrophy, complex of Guam, progressive supranuclear palsy, Sleep disorders, Subacute sclerosing panencephalitis, traumatic brain injury, and the like.

These disorders are characterized by cognitive symptoms as well as non-cognitive psychopathological symptoms associated with the cognitive impairment such as, but not limited to, irritability, tension, neurovegetative symptoms, sleep problems, concentration difficulties, loneliness, depression symptoms and slowing. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. Bar graph representation of the effect of different doses of (A) compound N°1 and compound N°2 and (B) prucalopride and RS67333 on % spontaneous alternation of mice in the T-maze. Groups where scopolamine is administered are indicated by a line. Results represented as mean ± SEM (n=10 CD1 mice, 20 for control groups; all compounds administered i.p. 30 min. prior to test). *P<0. 001 vs. scopolamine + placebo (grey bar); # P<0.05 versus control (Dunnett). Figure 2. Bar graph representation of the effect of compound N°1 , in the absence and presence of the 5-HT₄ receptor antagonist GR125487, on % spontaneous alternation of mice in the T-maze. Groups where scopolamine is administered are indicated by a line. Results represented as mean ± SEM (n=10 CD1 mice; all compounds administered i.p. 30 min. prior to test). * P<0.05 vs. scopolamine water/saline; # P<0.05 versus control (Fisher).

Figure 3. Bar graph representation of the entrance latency in the retention phase in a passive avoidance test. Mice were treated before the acquisition test (not shown) with solvent or scopolamine (0.5 mg/kg; s.c) in combination with saline, or increasing doses of compound N°1 (A), compound N°2 (B) or prucalopride (C).. 24h later, retention memory was assessed in a drug-free state. Results represented as mean ± SEM (n=1 1 -14 C57BI6 mice; all compounds administered 30 min. before acquisition). * PO.05, *** P<0.001 vs. scopolamine/saline (Dunnett). Figure 4. Escape latency over time during training sessions (A) and time spent in each quadrant (target, opposite, adjacentl and 2) during the 100 seconds probe trial after 72 hours (B) in a Morris Water Maze assay. Before acquisition training trials animals were either treated or not (control) with scopolamine, in case of the former in the presence of solvent (placebo), prucalopride (7.5 mg/kg p.o.) or compound N°1 (7.5 mg/kg p.o.). Probe trials were performed 72h later in drug-free conditions. Results are represented as mean ± S.E.M; N= 13-14 C57BL/6 mice, control versus placebo (*** P<0.001 ); compound N°1 versus placebo (# PO.05, ## P<0.01 , ### P<0.001 ); prucalopride versus placebo (+ P< 0.05, ++ P<0.01 ); significantly above chance level (^ΛΛΡ<0.01 , ^ΛΛΛΡ<0.001 ). Figure 5. (A). Compound N°1 plasma and brain ECF concentrations following 2.5 mg/kg i.v. dose to freely moving female Wistar rats (n=4). Data are means ± SEM. (B). Compound N°2 plasma and brain ECF concentrations following a 10 mg/kg i.p. dose administered to freely moving female Wistar rats (n=6-7). Data are means ± SEM. (C). Prucalopride plasma and brain ECF concentrations following 2.5 mg/kg i.v. dose to freely moving female Wistar rats (n=6). Data are means ± SEM

Figure 6. Bar graph representation of an ineffective dose of compound N°1 , an ineffective dose of galantamine and the combination of both ineffective doses on % spontaneous alternation of mice in the T-maze. Groups where scopolamine is administered are indicated by a line. Results are represented as mean ± SEM (n=10 CD1 mice; all compounds administered i.p. 30 min. prior to test). * P<0.05 vs. scopolamine water/saline; # P<0.05 versus control (Fisher).

DETAILED DESCRIPTION OF THE INVENTION

This invention relates in general to a compound according to formula I, a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof

(I) wherein

Ri and R₂ are each independently selected from the list comprising - H and Me;

for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

In a particular embodiment, the present invention provides a compound according to formula la or lb, a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

The term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of this invention.

More specifically, the present invention relates to the trans-isomer of compounds according to formula (I), (la) or (lb), which are represented by formulae (II), (Ma), and (Mb) respectively.

For example, the trans-isomer of a compound according to formula (la) is represented by formula (Ma) and hereinafter referred to as Compound N° 1 . The trans-isomer of a compound according to formula (lb) is represented by formula (Mb) and hereinafter referred to as Compound N° 2. In both instances, still including the 3S and 3R- configuration for the 3-hydroxy substituent to the piperidinyl moiety. In a particular embodiment of the present invention, the 3-hydroxy substituent to the piperidinyl moiety is in the 3S configuration, and the invention accordingly provides the compounds according to any one of formulas (I), (la), (lb), (Ma) or (lib) wherein the 3- hydroxy substituent to the piperidinyl moiety is in the 3S configuration.

Disorders in which cognitive function is impaired as used herein are a category of mental health disorders that primarily affect learning, memory, perception, executive function, and problem solving; and in particular includes cognitive disorders such as amnesia, dementia and delirium. The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) describes cognitive disorders, as disorders with a "significant impairment of cognition or memory that represents a marked deterioration from a previous level of function." The three main areas outlined by the DSM-IV-TR of cognitive disorders are delirium, dementia, and amnesia, however, there are many sub categories in each to these areas as well. Thus in a particular embodiment, a disorder in which cognitive function is impaired, as defined herein is selected from the list comprising amnesia, dementia and delirium. Dementia is a disorder characterized by loss of global cognitive ability. Although dementia is far more common in the geriatric population (about 5% of those over 65 are said to be involved), it can occur before the age of 65, in which case it is termed "early onset dementia". Dementia is not a single disease, but a non-specific syndrome (i.e., set of signs and symptoms). Affected cognitive areas include memory, attention, language, executive functioning and problem solving. Especially in later stages of the condition, subjects may be disoriented in time (not knowing the day, week, or even year), in place (not knowing where they are), and in person (not knowing who they and/or others around them are). Some of the most common forms of dementia are: Alzheimer's disease, vascular dementia, frontotemperal dementia, semantic dementia and dementia with Lewy bodies.

Amnesia patients have trouble retaining long term memories. Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. Retrograde amnesia is caused by damage to the hippocampus with memories that were encoded or in the process of being encoded in long term memory are erased. Delirium, or acute confusional state, is a syndrome that presents as severe confusion and disorientation, developing with relatively rapid onset and fluctuating in intensity. Delirium itself is not a disease, but rather a clinical syndrome (a set of symptoms), which result from an underlying disease, from medications administered during treatment of that disease in a critical phase, from abuse of medications, drugs or alcohol, drug withdrawals, mental illness, severe pain, immobilization, and sleep deprivation. Delirium can also be accompanied by a shift in attention, mood swings, violent or unordinary behaviors, and hallucinations. It can also be fatal if it is caused by a preexisting medical condition. In a specific embodiment according to this invention, the disorder in which cognitive function is impaired is selected from the non-limiting list comprising amnesia, dementia, delirium, Alzheimer's disease, vascular dementia, Pick's disease, mild cognitive impairment (MCI), schizophrenia, post coronary bypass cognitive symptoms, multiple scleroses, CADASIL syndrome, Down syndrome, frontal lobe dementia, fragile X syndrome, Parkinson's disease dementia (PDD), cognitive impairment in depression and bipolar disorders, alcoholism with Wernicke's encephalopathy, attention-deficit/hyperactivity disorder, autism, bipolar disorder, Creutzfeldt-Jakob disease, dementia pugilistica, dementia with Lewy bodies, semantic dementia, Olivopontocerebellar atrophy, complex of Guam, progressive supranuclear palsy, Sleep disorders, Subacute sclerosing panencephalitis, traumatic brain injury, and the like.

These disorders are characterized by cognitive symptoms as well as non-cognitive psychopathological symptoms associated with the cognitive impairment such as, but not limited to, irritability, tension, neurovegetative symptoms, sleep problems, concentration difficulties, loneliness, depression symptoms and slowing.

This invention further provides a combination of a compound as defined herein above, and an acetylcholinesterase inhibitor.

An acetylcholinesterase inhibitor (AChEi) or anti-cholinesterase as used herein, is a compound that inhibits the acetylcholinesterase enzyme from breaking down acetylcholine, thereby increasing both the level and duration of action of the neurotransmitter acetylcholine. Exemplary acetylcholinesterase inhibitors for use in the present invention include but are not limited to physostigmine, neostigmine, pyridostigmine, rivastigmine, ambenonium, demarcarium, galantamine and donepezil,

Further, compounds according to this invention, more in particular compounds N°1 and N°2 may be useful when co-administered with one or more agents designed to provide symptomatic therapy to patients having a disorder in which cognitive function is impaired. For example, the claimed compounds may be useful in combination with memantine (Namenda(R)), an NMDA receptor antagonist. Additional agents that may be used in combination with compounds of the invention, in particular compounds N° 1 or N°2 include 5-HT6 antagonists such as Lu AE58054, DMXB-anabaseine, GSK- 742457, SUVN-502, PRX-07034, and SAM-531 (WAY-262531 ); nicotinic receptor agonists, such as ABT-089, SSR-18071 1 , AZD-0328, and EVP-6124; muscarinic agonists, such as NGX-267, AF-102B (Cevimeline), and WAL 2014 FU (talsaclidine); histamine H3 antagonists such as GSK- 189254 and PF-365474; and dimebon; alpha7 nicotine potentiators, GABA modulators. Also, the claimed compounds may be beneficial in combination with disease modifying therapies such as for example for Alzheimer's disease with amyloid-beta and tau aggregation inhibitors, and beta secretase inhibitors or gamma secretase inhibitors, such as BMS-708163. When used in combination therapy, the compounds according to this invention, more in particular the compounds N°1 or N°2 are either physically mixed with the other therapeutic agent(s) to form a composition containing the active ingredients; or each agent is present in separate and distinct compositions which are administered to the patient simultaneously or sequentially in any order. Combination therapy includes administration of the agents, when formulated separately, substantially at the same time, as well as administration of each agent at a different time. For example, the compounds according to this invention, more in particular compound N°1 or N°2 can be combined with a second therapeutic agent using conventional procedures and equipment to form a composition comprising said compound and one or more second therapeutic agent. Additionally, the therapeutic agents may be combined with a pharmaceutically acceptable carrier to form a pharmaceutical composition comprising a compound according to this invention, such as compound N°1 or N°2, one or more second therapeutic agent, and a pharmaceutically acceptable carrier. In this embodiment, the components of the composition are typically mixed or blended to create a physical mixture. The physical mixture is then administered in a therapeutically effective amount using any of the routes described below. Alternatively, the therapeutic agents may remain separate and distinct before administration to the patient. In this embodiment, the agents are not physically mixed together before administration but are administered simultaneously or at separate times as separate compositions. Such compositions can be packaged separately or may be packaged together as a kit. The two therapeutic agents in the kit may be administered by the same route of administration or by different routes of administration. The present invention further provides a combination of a compound as defined herein and an acetylcholinesterase inhibitor for use in medicine; more in particular, for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

The present invention further provides a pharmaceutical composition comprising a compound as defined in herein, for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

The invention further provides a pharmaceutical composition comprising a combination as defined herein above for use in medicine; more in particular for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

The compounds according to the invention can be prepared and formulated into pharmaceutical compositions by methods known in the art and in particular according to the methods described in the published patent specification WO9902156 mentioned herein and incorporated by reference.

Within said specification Compound N°1 of the present invention, is specifically disclosed as compound No. 3 in Table F-1 , made in accordance with example B1 of said specification. Furthermore, Compound N°2 of the present invention is specifically disclosed as compound No. 38 in Table F-3, made in accordance with example B1 of said specification. The S- and R- configuration for compound N°2 of the present invention are specifically disclosed as compounds 39 and 40 in Table F-3, and made in accordance with example B4 of said specification. To prepare the aforementioned pharmaceutical compositions, a therapeutically effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for systemic administration such as oral, percutaneous, or parenteral administration; or topical administration such as via inhalation, a nose spray, eye drops or via a cream, gel, shampoo or the like.

The pharmaceutical compositions of the present invention can be prepared by any known or otherwise effective method for formulating or manufacturing the selected product form. Methods for preparing the pharmaceutical compositions according to the present invention can be found in "Remington^'s Pharmaceutical Sciences", Mid. Publishing Co., Easton, Pa., USA. For example, the compound can be formulated along with common excipients, diluents, or carriers, and formed into oral tablets, capsules, sprays, mouth washes, lozenges, treated substrates (e. g. oral or topical swabs, pads, or disposable, non- digestible substrate treated with the compositions of the present invention) ; oral liquids (e. g. , suspensions, solutions, emulsions), powders, or any other suitable dosage form.

Non-limiting examples of suitable excipients, diluents, and carriers can be found in "Handbook of Pharmaceutical Excipients", Second edition, American Pharmaceutical Association, 1994 and include: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as acetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite ; carriers such as propylene glycol and ethyl alcohol, and lubricants such as talc, calcium and magnesium stearate, and solid polyethyl glycols.

In a further embodiment, the present invention provides the use of a compound or composition as defined herein, as a pro-cognitive agent or composition respectively.

The present invention also provides a method for improving cognition, said method comprising administering to a subject in need thereof a compound, a combination, or a pharmaceutical composition as defined herein.

The invention further provides a method for improving one or more of REM sleep, visual motor skills, executive function, long term memory, delayed memory, working memory, attention, learning, visual learning, verbal learning, speed of processing, vigilance, visual motor function, or social cognition; said method comprising administering to a subject in need thereof a compound, a combination, or a pharmaceutical composition as defined herein.

Furthermore, the invention provides a method for the prevention and/or treatment of a cognitive disorder; said method comprising administering to a subject in need thereof a compound, a combination, or a pharmaceutical composition as defined herein. EXAMPLES

This invention will be better understood by reference to the Experimental Details that follow, but those skilled in the art will readily appreciate that these are only illustrative of the invention as described more fully in the claims that follow thereafter. Additionally, throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains. Introduction: Compounds N°1 and N°2 behave as true partial agonists

Selective 5-HT₄R ligands (SL65.0155, PRX-03140 and PF-04995274), previously suggested to be 5-HT₄R agonists, which have been described to affect CNS functioning are listed in Table 1 . However, as shown in Table 1 , these compounds behave as 5-HT₄R antagonists (i.e. bind to the receptor but do not activate it) in a recombinant cell line expressing physiological levels of 5-HT₄R. They are thus substantially different from Compound N°1 , Compound N°2, prucalopride or RS67333 which are partial 5-HT₄R agonists. Given this important difference, examples 1 , 2 and 3 are aimed at comparing Compounds N°1 and N°2, being partial agonists, with prucalopride and/or RS-67333. Prucalopride is a 5-HT₄R agonist able to enter the brain with a higher intrinsic activity than Compounds N°1 and N°2. RS67333 has a similar profile as Compound N°1 and N°2 and is the reference 5-HT₄R agonist used in the literature to study 5-HT₄ receptor-mediated effects in the brain. Table 1 : Affinity (pKi or pKB), potency (pEC50) and efficacy (max effect) of 5-HT₄R ligands in a recombinant cell line stably expressing 5-HT₄R at low densities (21 fmol/m , allowing comparison of efficacy between the agonists.

pKB values are obtained in functional inhibition experiments with 30nM 5-HT as stimulus. pKi values are obtained in radioligand (3[H]GR1 13808) displacement studies. All data are obtained in a cell line stably expressing human 5-HT₄R at low densities (21 fmol/mg) with the exception of (a): from De Maeyer et al., 2008 Neurogastroenterol Motil. 20: 99-1 12 and (b): from Mohler et al., 2007. Neuropharmacology. 53:563-73.

N.D.: not determined; N.C.: EC50 value not calculable;

Example 1. Superior cognition-enhancing properties

In several in vivo cognitive assays, Compounds N°1 and N°2 showed to have superior cognition enhancing properties in comparison to other 5-HT₄R agonists:

A. COMPOUND N°1 and COMPOUND N°2 were superior in their ability to reverse scopolamine-induced cognitive deficits in a working memory test (See

1 .A).

B. COMPOUND N°1 and COMPOUND N°2 were superior in their ability to reverse scopolamine-induced cognitive deficit in a fear-motivated memory test (see 1 .B)

C. COMPOUND N°1 was superior in its ability to reverse scopolamine-induced cognitive deficits in a spatial memory test (COMPOUND N°2 not tested) (see 1 .C)

This pro-cognitive effect of COMPOUND N°1 is not believed to be a consequence of non-specific interaction(s) of COMPOUND N°1 , because it could be blocked with the selective 5-HT₄R antagonist GR125487. Because COMPOUND N°2 is similar to COMPOUND N°1 , highly selective for 5-HT₄Rs, a non-specific interaction is not expected to be involved in its pro-cognitive effect. A reasonable explanation for the superior cognition enhancing properties of COMPOUNDS N°1 and N°2 in comparison to other 5-HT₄R agonists would have been (i) that they have a better brain penetration or (ii) that they have a much higher intrinsic activity. However, these arguments appear to be invalid in view of the following: (i) The cognitive enhancement provided by COMPOUNDS N°1 and N°2, but not RS67333 or prucalopride, is not caused by a better brain penetration of COMPOUNDS N°1 and N°2, because COMPOUNDS N°1 and N°2 have a lower brain penetration than prucalopride (See Fig. 5). Furthermore, RS67333 is well described in scientific literature as a good brain penetrating compound. (ii) The intrinsic activity of COMPOUNDS N°1 and N°2 at 5-HT₄ receptors is equal to that of RS67333, so similar efficacies in cognitive assays would have been expected (Table 1 ). The intrinsic activities of COMPOUNDS N°1 and N°2 at 5- HT₄ receptors is lower than that of prucalopride, making it much weaker agonists for which it would be expected to be less efficacious in cognitive assays.

In summary:

Table 2

+, ++, +++ represent a discrete qualitative scale with + referring to "low", ++ to "medium" and +++ to '"high".

1.A. Spontaneous alternation (working memory)

The T-maze continuous alternation task in mice evaluates the spatial exploratory performance in mice. This test is based on the willingness of rodents to explore a new environment, i.e. their preference to visit a new arm of the maze rather than a familiar arm. Many parts of the brain - including the hippocampus, septum, basal forebrain, and prefrontal cortex - are involved in this task and it relies on spatial and working memory and is sensitive to various pharmacological manipulations affecting memory processes. When used in conjunction with pharmacological tools such as scopolamine, the system allows inducing memory deficit useful as model for evaluating compounds with cognitive enhancing properties. Scopolamine is a muscarinic antagonist that blocks the activity of the muscarinic acetylcholine receptor, thereby causing impairment of cholinergic and cognitive function, in mice treated therewith.

Compound N°1 dose-dependently reversed the scopolamine-induced cognitive deficits in the spontaneous alternation task (Figure 1A), an effect that could be blocked by the 5-HT₄ receptor antagonist GR125487, illustrating that the effect of Compound N°1 is 5- HT₄ receptor-mediated (Figure 2). The structurally related Compound N°2 showed a similar dose-dependent reversal of the scopolamine-induced cognitive deficits (Figure 1A).

In the same experimental setup, the 5-HT₄R agonist prucalopride did not reverse the scopolamine-induced deficit on spontaneous alternation, while the commercially available reference agonist RS67333 induced a partial reversal of the scopolamine deficit, whilst only at the 1.5 mg/kg dose (Figure 1 B). This result for RS67333 is in line with Lelong et al., Naunyn Schmiedebergs Arch Pharmacol. 2003 Jun;367(6):621 -8. 1.B. Passive avoidance (fear motivated memory test)

Passive avoidance is a fear-motivated test classically used to assess short-term or long-term memory in mice. In these experiments, mice were placed in the light compartment of a shuttle box containing a light and a dark compartment. Entry into the dark compartment is accompanied with a mild inescapable electrical shock. The time that the animal takes to move from the light compartment to the dark is recorded (acquisition phase) and 24h later, the test is repeated (retention phase). An increase in entrance latency is a measure of memory to the aversive stimulus, a behavior clearly shown in control animals (Figure 3). All treatments are done 30 min before the acquisition phase, with the retention phase being performed drug-free.

Animals that had been treated with scopolamine showed a marked decrease in escape latency compared to control animals. This amnesic effect of scopolamine was reversed by 7.5 mg/kg Compound N°1 (Figure 3) but not by prucalopride at a wide range of doses tested (Figure 3). Also Compound N°2 was able to partially reverse the scopolamine-induced deficits.

1.C. Morris water maze (spatial memory) The Morris Water Maze is a tool to assess spatial learning and memory. The subject is placed in a round tank of translucent water. The room in which the tank sits is decorated with visual cues to serve as reference points. The mouse must swim around the pool until by chance it discovers the hidden platform just below the surface that it can climb up onto. This procedure is repeated during daily training sessions on several consecutive days. The time needed to locate the platform decreases with increased training, as can be seen for control animals (Figure 4). 72 h after the last training sessions, animals are placed in the same water tank but the platform is removed (probe trial). The time spent in the quadrant where the platform was previously located is a measure of retention memory, clearly demonstrated for the control animals (Figure 4). Pre-treatment of the animals with scopolamine on each training day impaired this learning and retention behavior, while Compound N°1 partially restored the scopolamine-impaired spatial memory while prucalopride did not restore the scopolamine-impaired spatial memory acquisition (Figure 4).

Example 2. Partial agonism in peripheral assays

As shown in Table 1 , Compounds N°1 and N°2 have a lower intrinsic activity than prucalopride, a 5-HT₄R agonist which is clinically used to treat gastrointestinal disorders (Table 2). In line with this, but in contrast to the results obtained in the cognitive assay's, Compounds N°1 and N°2 behave as a partial agonist in peripheral assays, with a lower intrinsic activity compared to prucalopride.. As shown in Table 3, the efficacies of Compound N°1 and Compound N°2 in peripheral assays is systematically lower to equal than that of prucalopride illustrating their partial agonistic behaviour in the periphery. Table 3: Intrinsic activity of Compound N°1 and prucalopride in various peripheral assays

unit N°1 N°2 Pru

In vitro

Human right atrium % force increase vs. 5-HT 20 14 47

Porcine left atrium inotropy % force increase vs. 33 52 64 (IBMX present)¹ isoprenaline

Porcine right atrium % rate increase vs. 26 16 28 chronotropy ¹ isoprenaline

Porcine stomach¹ % increase in contraction 55 61 92

Guinea pig ileum % increase 29 38 39

Guinea pig colon (NANC % increase off-response 64 38 87 stimulation)

Guinea pig colon (tone) % increase in contraction nt 49 88

vs. 5-HT

Rat oesophagus % relaxation vs. 5-HT 63 60 73

Dog antrum % increase 81 nt 1 15

In vivo

Dog antrum (p.o.) % increase vs. MMC 17 20 28

Dog colon (p.o.) % motility index 73 80 98

Heart rate in anaesthesized % increase 14 12 29 pig 1 : De Maeyer et al., 2006. Pharmacol Exp Ther. 317: 955-64

Nt : not tested The structurally related Compounds N°1 and N°2 clearly differentiate themselves from the 5-HT₄ receptor ligands that have reached clinical development phases. These have been described as being particularly useful to treat cognitive disorders because they were claimed as being partial agonists that do not have effects in the periphery (Moser, et al., 2002. J Pharmacol Exp Ther 302, 731-741 ; Mohler et al., 2007. Neuropharmacology. 53: 563-73). However, as shown in Table 1 , these compounds behave as antagonists (bind to the receptor without activating it) in a recombinant cell system while Compounds N°1 and N°2 are true partial agonists. As far as we know, a 5-HT4R antagonist is indeed devoid of any effect in the periphery, making the argument for the absence of peripheral effects obvious. These compounds are thus substantially different from Compounds N°1 and N°2, since a 5-HT₄R antagonist blocks the receptor while a partial agonist does activate the receptor.

In fact, SL65.0155, PRX-03140 and PF-04995274 have been described as being antagonists at 5-HT₄ receptors in peripheral tissues. These compounds were classified as being partial agonists based on data obtained in overexpressing recombinant cell lines (Moser, et al., 2002. J Pharmacol Exp Ther 302, 731 -741 ; Mohler et al., 2007. Neuropharmacology. 53: 563-73; Brodney MA et al., 2012. J Med Chem; 55: 9240-54). It is therefore important to note that the results shown in table 1 are obtained with a recombinant cell line that stably expresses the 5-HT₄R at low densities (21 fmol/mg). This allows a true differentiation between full agonists, partial agonists and antagonists. Recombinant cells with higher expression levels of the 5-HT₄R do not always allow a clear differentiation between full and partial agonists. Furthermore, in these cells, antagonists often behave as "partial agonists". A series of compounds that behave as neutral antagonists in mouse colliculi neurons, one of the most studied endogenous 5-HT₄ receptor-expressing cells, displayed partial agonistic properties in COS-7 cells transiently transfected with 5-HT₄Rs (100-8000 fmol/mg) (Claeysen S, Sebben M, Becamel C, Eglen RM, Clark RD, Bockaert J, Dumuis A. Pharmacological properties of 5-Hydroxytryptamine(4) receptor antagonists on constitutively active wild- type and mutated receptors. Mol Pharmacol. 2000. 58: 136-44).

To further support this hypothesis, the compounds from table 1 were also evaluated in a recombinant cell expressing higher densities of the same 5-HT₄ receptor splice variant. In line with our hypothesis, the compounds that behaved as antagonist in the experiment with low 5-HT₄R levels, now appeared to be agonists (Table 4). We can thus conclude that Compounds N°1 and N°2 clearly differentiate from SL65.0155, PRX-0314 and PF-04995274, the 5-HT₄ receptor ligands that have reached clinical development phases.

Table 4: Potency (pEC50) and efficacy (max effect) of 5-HT₄R ligands in recombinant cell line stably expressing 5-HT₄R at higher densities

Example 3. Splice variant-specific behaviour

In functional assays, performed with HEK293 cells expressing different human 5-HT₄ receptor splice variants, the order of potency of COMPOUND N°1 at the different splice variants was 5-HT₄(g) > 5-HT₄(b) > 5-HT₄(c) > 5-HT₄(a) (Table 5). This contrasts with prucalopride which has a totally different order of potency at these splice variants: 5-HT₄(a) = 5-HT₄(b) > 5-HT₄(c) > 5-HT₄(g).

While prucalopride has a very low potency at this 5-HT₄(g) receptor, COMPOUND N°1 was extremely potent at this variant. In other words, Compound N°1 is 800-fold more potent than prucalopride at the 5-HT₄(g) receptor while the potency ratio is only 2 at the 5-HT₄(a) receptor. Though less pronounced, this difference also shows for Compound N°2 which is 63-fold more potent than prucalopride at 5-ΗΤ₄₍₉₎ while the ratio is only 2 at the 5-HT_4(a) receptor. Table 5: Characterization of COMPOUND N°1 and N°2 in a functional cAMP assay and comparison to prucalopride.

* max: % of 5-HT response; ** this splice variant is named 5-HT_4e by CEREP (reference is made to Mialet et al. (2000), Brit. J . Pharmacol ., 129: 771 -781 , but this variant has been renamed to 5-HT_4g); nt: not tested.

Example 4. Interaction with cholinesterase inhibitors (AChEi)

When co-administering Compound N°1 and the cholinesterase inhibitor galantamine, at doses that are ineffective by themselves, the cognitive impairment induced by scopolamine could be partially reversed (Fig. 6). This synergistic effect is not caused by an interaction at the PK level (results not shown).

These results show that Compound N°1 has the potential to increase the efficacy of sub-effective doses of a cholinesterase inhibitor. Based on these results, combining Compound N°1 with an AChEi results in improved effects at lower doses, leaving room for augmentation therapy in a clinical setting.

Claims

1 . A compound according to formula I, a stereochemical^ isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof

(I)

wherein R-i and R₂ are each independently selected from the list comprising - H and Me;

for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

2. A compound according to formula la or lb, a stereochemically isomeric form thereof, an N-oxide form thereof, or a pharmaceutically acceptable acid or base addition salt thereof

for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

3. A combination of a compound as defined in anyone of claims 1 or 2 and an acetylcholinesterase inhibitor.

4. A combination of a compound as defined in anyone of claims 1 or 2 and an acetylcholinesterase inhibitor for use in medicine.

5. A combination of a compound as defined in anyone of claims 1 or 2 and an acetylcholinesterase inhibitor for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

6. A pharmaceutical composition comprising a compound as defined in anyone of claims 1 or 2, for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

7. A pharmaceutical composition comprising a combination as defined in any one of claims 3 to 5 for use in medicine.

8. A pharmaceutical composition comprising a combination as defined in any one of claims 3 to 5 for use in the prevention and/or treatment of a disorder in which cognitive function is impaired.

9. The compound for use as defined in anyone of claims 1 or 2; the combination for use as defined in claim 5; or the pharmaceutical composition for use as defined in claim 8; wherein the disorder in which cognitive function is impaired is selected from the list comprising amnesia, dementia and delirium; in particular dementia.

10. The compound for use as defined in anyone of claims 1 or 2; the combination for use as defined in claim 5; or the pharmaceutical composition for use as defined in claim 8; wherein the disorder in which cognitive function is impaired is selected from the list comprising: amnesia, dementia, delirium, Alzheimer's disease, vascular dementia, Pick's disease, mild cognitive impairment (MCI), schizophrenia, post coronary bypass cognitive symptoms, multiple scleroses, CADASIL syndrome, Down syndrome, frontal lobe dementia, fragile X syndrome, Parkinson's disease dementia (PDD), cognitive impairment in depression and bipolar disorders, alcoholism with Wernicke's encephalopathy, attention-deficit/hyperactivity disorder, autism, bipolar disorder, Creutzfeldt- Jakob disease, dementia pugilistica, dementia with Lewy bodies, semantic dementia, Olivopontocerebellar atrophy, complex of Guam, progressive supranuclear palsy, Sleep disorders, Subacute sclerosing panencephalitis, traumatic brain injury; and .non-cognitive psychopathological symptoms associated with the cognitive impairment such as, but not limited to, irritability, tension, neurovegetative symptoms, sleep problems, concentration difficulties, loneliness, depression symptoms and slowing.

1 1. Use of a compound as defined in anyone of claims 1 or 2 as a pro-cognitive agent.

12. Use of a combination as defined in claim 3 as a pro-cognitive combination.

13. Use of a pharmaceutical composition as defined in claim 6 as a pro-cognitive composition.

14. A method for improving cognition; said method comprising administering to a subject in need thereof a compound as defined in anyone of claims 1 or 2, a combination as defined in claim 3; or a pharmaceutical composition as defined in claim 6.

15. A method for improving one or more of REM sleep, visual motor skills, executive function, long term memory, delayed memory, working memory, attention, learning, visual learning, verbal learning, speed of processing, vigilance, visual motor function, or social cognition; said method comprising administering to a subject in need thereof a compound as defined in anyone of claims 1 or 2; a combination as defined claim 3; or a pharmaceutical composition as defined in claim 6.

16. A method for the prevention and/or treatment of a disorder in which cognitive function is impaired such as a cognitive disorder; said method comprising administering to a subject in need thereof a compound as defined in anyone of claims 1 or 2; a combination as defined in claim 3; or a pharmaceutical composition as defined in claim 6.

17. The method according to claim 16; wherein the disorder in which cognitive function is impaired is selected from the list comprising amnesia, dementia and delirium; in particular dementia.

18. The method according to claim 17; wherein the disorder in which cognitive function is impaired is selected from the list comprising amnesia, dementia, delirium, Alzheimer's disease, vascular dementia, Pick's disease, mild cognitive impairment (MCI), schizophrenia, post coronary bypass cognitive symptoms, multiple scleroses, CADASIL syndrome, Down syndrome, frontal lobe dementia, fragile X syndrome, Parkinson's disease dementia (PDD), cognitive impairment in depression and bipolar disorders, alcoholism with Wernicke's encephalopathy, attention-deficit/hyperactivity disorder, autism, bipolar disorder, Creutzfeldt-Jakob disease, dementia pugilistica, dementia with Lewy bodies, semantic dementia, Olivopontocerebellar atrophy, complex of Guam, progressive supranuclear palsy, Sleep disorders, Subacute sclerosing panencephalitis, traumatic brain injury; and non-cognitive psychopathological symptoms associated with the cognitive impairment such as, but not limited to, irritability, tension, neurovegetative symptoms, sleep problems, concentration difficulties, loneliness, depression symptoms and slowing.