WO2009017454A1 - New therapeutic combination of a gsk3 inhibitor and an a7-nicotinic agonist 960 - Google Patents

New therapeutic combination of a gsk3 inhibitor and an a7-nicotinic agonist 960 Download PDF

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Publication number
WO2009017454A1
WO2009017454A1 PCT/SE2008/050897 SE2008050897W WO2009017454A1 WO 2009017454 A1 WO2009017454 A1 WO 2009017454A1 SE 2008050897 W SE2008050897 W SE 2008050897W WO 2009017454 A1 WO2009017454 A1 WO 2009017454A1
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Prior art keywords
octane
azabicyclo
furo
pyridine
pyrimidin
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PCT/SE2008/050897
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French (fr)
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Hans Basun
Graham Cox
Ingrid Nordgren
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Astrazeneca Ab
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Publication of WO2009017454A1 publication Critical patent/WO2009017454A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to a combination of (a) a GSK3 inhibitor and (b) an ⁇ 7- nicotinic agonist.
  • the invention further relates to pharmaceutical compositions comprising said combination and to methods of treating CNS disorders in mammals by administering said combination.
  • the invention further relates to a kit comprising the combination and use of said kit in treatment of CNS disorders such as cognitivie deficits in schizophrenia, dementia and/or Alzheimer's Disease.
  • Glycogen synthase kinase 3 is a serine / threonine protein kinase composed of two isoforms ( ⁇ and ⁇ ), which are encoded by distinct genes but are highly homologous within the catalytic domain. GSK3 is highly expressed in the central and peripheral nervous system. GSK3 phosphorylates several substrates including tau, ⁇ -catenin, glycogen synthase, pyruvate dehydrogenase and elongation initiation factor 2b (eIF2b). Insulin and growth factors activate protein kinase B, which phosphorylates GSK3 on serine 9 residue and inactivates it.
  • eIF2b elongation initiation factor 2b
  • AD dementias Alzheimer's Disease (AD) dementias, and taupathies.
  • AD Alzheimer's disease
  • Glycogen synthase kinase 3 ⁇ previously known as Tau kinase I selectively phosphorylates the microtubule associated protein Tau at sites that are hyperphosphorylated in AD brains.
  • Hyperphosphorylated tau has lower affinity for microtubules and accumulates as paired helical filaments. This results in depolymerization of microtubules, which leads to dying back of axons and neuritic dystrophy.
  • the paired helical filaments are the main components that constitute neurofibrillary tangles and neuropil threads in AD brains.
  • neurofibrillary tangles are consistently found in other CNS diseases such as amyotrophic lateral sclerosis, parkinsonism-dementia of Gaum, corticobasal degeneration, dementia pugilistica and head trauma, Down's syndrome, postencephalatic parkinsonism, progressive supranuclear palsy, Niemann-Pick's Disease and Pick's Disease.
  • GSK3 has been proposed as the link between the two neuropathological hallmarks of Alzheimer's disease, the extracellular amyloid- ⁇ and the neurofibrillary tangles made of hyperphosphorylated tau. Addition of amyloid- ⁇ to primary hippocampal cultures results in hyperphosphorylation of tau and a paired helical filaments-like state via induction of GSK3 activity, followed by disruption of axonal transport and neuronal death (Imahori and Uchida., J. Biochem 121:179-188, 1997). GSK3 preferentially associates with neurofibrillary tangles and has been shown to accumulate in the cytoplasm ofpre -tangle neurons in AD brains.
  • GSK3 protein levels are also increased by 50% in brain tissue from AD patients (Pei, et al, J. Neuropathol. Exp. Pathol. 58: 1010-1019, 1999). Furthermore, GSK3 phosphorylates pyruvate dehydrogenase, a key enzyme in the glycolytic pathway and prevents the conversion of pyruvate to acetyl-Co-A (Hoshi et al., PNAS 93:2719-2723, 1996). Acetyl-Co-A is critical for the synthesis of acetylcholine, a key neurotransmitter in cognitive functions. Accumulation of amyloid- ⁇ is an early event in AD. GSK3 Tg mice show increased levels of amyloid- ⁇ in brain.
  • GSK3 inhibition may have additional disease modification effects through reduction of amyloid- ⁇ levels as well as the tau pathology associated with AD and the other - diseases referred to above.
  • GSK3 activity is increased in cellular and animal models of neurodegeneration such as cerebral ischemia or after growth factor deprivation.
  • the active site phosphorylation was increased in neurons vulnerable to apoptosis, a type of cell death commonly thought to occur in chronic and acute degenerative diseases such as cognitive disorders, Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, Huntington's Disease and HIV dementia and traumatic brain injury; and as in ischemic stroke.
  • Lithium was neuroprotective in inhibiting apoptosis in cells and in the brain at doses that resulted in the inhibition of GSK3.
  • GSK3 inhibitors could be useful in attenuating the course of neurodegenerative diseases.
  • Bipolar Disorders are characterised by manic episodes and depressive episodes. Lithium has been used to treat BD based on its mood stabilising effects. The disadvantage of lithium is the narrow therapeutic window and the danger of overdosing that can lead to lithium intoxication. The discovery that lithium inhibits GSK3 at therapeutic concentrations has raised the possibility that this enzyme represents a key target of lithium's action in the brain (Stambolic et al., Curr. Biol. 6:1664-1668, 1996; Klein and Melton; PNAS 93:8455-8459, 1996; Gould et al., Neuropsychopharmacology, 1:32-8, 2004).
  • GSK3 inhibitor has been shown to reduce immobilisation time in forced swim test, a model to assess depressive behavior (O'Brien et al., J Neurosci 2004, 24:66791-6798) GSK3 has been associated with a polymorphism found in bipolar II disorder (Szczepankiewicz et al., Neuropsychobiology. 2006;5 3(l):51-6). Inhibition of GSK3 ⁇ may therefore be of therapeutic relevance in the treatment of BD as well as in AD patients that have affective disorders.
  • GSK3 is involved in signal transduction cascades of multiple cellular processes, particularly during neural development.
  • Kozlovsky et al Am J Psychiatry 2000 May; 157(5):831-3 found that GSK3 levels were 41% lower in the schizophrenic patients than in comparison subjects. This study indicates that schizophrenia involves neurodevelopmental pathology and that abnormal GSK3 regulation could play a role in schizophrenia.
  • reduced ⁇ -catenin levels have been reported in patients exhibiting schizophrenia (Cotter et al., Neuroreport 9:1379-1383 (1998)).
  • Atypical antipsychotics such as olanzapine, clozapine, quetiapine, and ziprasidone, inhibits GSK3 by increasing ser9 phosphorylation suggesting that antipsychotics may exert their beneficial effects via GSK3 inhibition (Li X, et al., Int J Neuropsychopharmacol, !0(l): 7- 19 (2007).
  • the nicotinic agonists are those compounds having agonist or partial agonist activity against a subpopulation of nicotine receptors such as the alpha-7, ⁇ -7, receptor.
  • the compounds modulate nicotinic receptors in the patient's brain. As such, such compounds have the ability to express nicotinic pharmacology, and in particular, to act as nicotinic agonists.
  • the nicotinic agonists described herein may be used in methods for preventing and/or treating a central nervous system disorder (CNS) in a subject susceptible to such a disorder.
  • a central nervous system disorder CNS
  • an effective amount of a nicotinic agonists effective for providing some degree of prevention of the progression of a CNS disorder i.e., provide protective effects
  • amelioration of the symptoms of a CNS i.e., provide protective effects
  • amelioration of the symptoms of a CNS i.e., provide protective effects
  • amelioration of the reoccurrence of a CNS can be administered to a patient in need thereof.
  • the nicotinic agonists can be used to treat and/or prevent those types of conditions and disorders for which other types of nicotinic compounds have been proposed as therapeutics. See, for example, Williams et al.
  • the nicotinic agonists are useful in the treatment of a variety of CNS disorders, for example, cognitive disorders, such as Alzheimer's Disease, Cognitive Deficit in Schizophrenia, neurodegenerative disorders, neoroinflammatory disorders, or any disorder mentioned below.
  • the ⁇ -7 receptor has been linked to a deficit in auditory sensory processing in schizophrenics that correlates with cognitive dysfunction.
  • Selective ⁇ -7 agonists are effective in animal models of memory and cognition.
  • compositions comprising a pharmaceutical combination of (a) a GSK3 inhibitor and (b) an ⁇ 7 -nicotinic agonist useful for the treatment of CNS disorders, such as those disorders defined below.
  • the invention also relates to said combination, wherein the GSK3 inhibitor is one of the compounds mentioned below, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof and the ⁇ 7 -nicotinic agonist is one of the compounds mentioned below, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof.
  • the invention also relates to said combination, comprising (a) a first therapeutic agent, which is a GSK3 inhibitor and (b) a second therapeutic agent, which is an ⁇ 7- nicotinic agonist selected from the list herein disclosed.
  • a second aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a combination comprising (a) an amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) an amount of a second therapeutic agent, which is an ⁇ 7 -nicotinic agonist, together with a pharmaceutically-acceptable vehicle, carrier or diluent.
  • a pharmaceutical composition comprising both agents (a) and (b).
  • Another embodiment relates to a two separate pharmaceutical compositions, one for
  • a third aspect of the invention relates to a kit comprising a dosage unit of mixture of a first therapeutic agent, which is a GSK3 inhibitor and a dosage unit of a second therapeutic agent, which is an ⁇ 7 -nicotinic agonist, optionally with instructions for use.
  • a fourth aspect of the invention relates to a method for treating CNS disorders, such as those disorders defined below, in a subject in need thereof comprising administering simultaneously, sequentially, concurrently, separately or adjunct, to said subject (a) an amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) an amount of a second therapeutic agent, which is an ⁇ 7 -nicotinic agonist, wherein the amounts of (a) and
  • a first aspect of the invention relates to a combination comprising (a) an amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) an amount of a second therapeutic agent, which is an ⁇ 7 -nicotinic agonist.
  • the combination comprises the group of compounds (a) and (b) as defined below.
  • GSK3 inhibitors useful in the combination of the present invention and the preparation thereof are described in patent applications WO 03/004472, WO 03/055492, WO 03/082853, WO 06/001754, WO 07/040436, WO 07/040438, WO 07/040439 and WO 07/040440, WO08/002244 and WO08/002245, which are hereby incorporated by reference.
  • GSK inhibitors are compounds selected from the group comprising 3-[7-(2- morpholin-4-ylethoxy)quinazolin-4-yl]-2-oxo-l,3-dihydroindole-5-carbonitrile; 3-[7-(2-methoxyethoxy)quinazolin-4-yl]-2-oxo- 1 ,3-dihydroindole-5-carbonitrile;
  • a particular GSK3 inhibitor is 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH- indole-5-carbonitrile as a free base, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt.
  • the combination may employ any alpha-7 agonist, including but not limited to those disclosed in US Patent Nos. 6,110,914 and 6,569,865; and pending US Application 2008- 0139600 (Al), WO96/06098, WO99/03859, WO00/42044, WO01/060821, WO02/096912, WO03/087103, WP2005/030777, WO2005/030778 and WO2007/133155.
  • alpha-7 agonist including but not limited to those disclosed in US Patent Nos. 6,110,914 and 6,569,865; and pending US Application 2008- 0139600 (Al), WO96/06098, WO99/03859, WO00/42044, WO01/060821, WO02/096912, WO03/087103, WP2005/030777, WO2005/030778 and WO2007/133155.
  • Exemplary alpha-7 agonists include but are not limited to
  • a particularly suitable ⁇ -7 specific nicotinic receptor agonist is S(- )-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one (as a free base, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt.
  • nicotinic receptor agonist is synonymous with the term “nicotine agonist” and both terms refer to agonists of nicotinic acetylcholine receptors. These terms are used interchangeably throughout the description and claims.
  • the second therapeutic agent comprises specific nicotinic receptor agonist which is S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]- 2'-one, a metabolite or prodrug or pharmaceutically-acceptable salt, solvate or solvated salt thereof.
  • This compound interacts specifically with the ⁇ -7 nicotinic acetylcholine.
  • Other compounds having similar specificity are contemplated as being within the scope of the invention.
  • the combination comprises the group of compounds (a) and (b) as defined below:
  • a first therapeutic agent which is a GSK3 inhibitor
  • a second therapeutic agent which is an ⁇ 7 -nicotinic agonist selected from:
  • Suitable pharmaceutically-acceptable salts may be useful in the preparation of the compounds according to the invention.
  • Suitable pharmaceutically-acceptable salts of the compounds described herein include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically-acceptable acid such as hydrochloric acid, sulfuric acid, methanesulphonic acid and fumaric acid.
  • suitable pharmaceutically-acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • pharmaceutically-acceptable salts includes any pharmaceutically acceptable salt, including both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts.
  • pharmaceutically-acceptable cationic salts is intended to include, but is not limited to such salts as the alkali metal salts, (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium), aluminum salts, ammonium salts, and salts with organic amines such as benzathine (N,N'-dibenzylethylenediamine) and choline.
  • the expression “pharmaceutically-acceptable acid addition salts” is intended to include, but is not limited to such salts as the hydrochloride, hydrobromide and sulfate.
  • the pharmaceutically-acceptable cationic salts containing free carboxylic acids can be readily prepared by reacting the free acid form of with an appropriate base.
  • Typical bases are sodium hydroxide, sodium methoxide and sodium ethoxide.
  • the pharmaceutically-acceptable acid addition salts containing free amine groups can be readily prepared by reacting the free base form with the appropriate acid.
  • Suitable salts for the GSK inhibitor may be, but are not limited to, hydrochloride, fumarate, tartrate, citrate, edisylate, phosphate salts.
  • Suitable salts for the ⁇ 7-nicotinic agonist may be, but are not limited to, acid addition salts including salts of mineral acids, for example the hydrochloride and hydrobromide salts; and salts formed with organic acids such as formate, acetate, maleate, benzoate, tartrate, and fumarate salts.
  • Such acid addition salts of any of the compounds herein described may be formed by reacting the free base or a salt, enantiomer or protected derivative thereof, with one or more equivalents of the appropriate acid.
  • the reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, e.g., water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which may be removed in vacuum or by freeze drying.
  • a solvent or medium in which the salt is insoluble e.g., water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which may be removed in vacuum or by freeze drying.
  • the reaction may be a metathetical process or it may be carried out on an ion exchange resin.
  • pharmaceutically-acceptable salts also includes solvates, hydrates or solvated or hydrated salts thereof.
  • the active agents of the composition described herein can be co-administered simultaneously or may be administered separately or sequentially in any order, or as a single pharmaceutical composition.
  • a second aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is GSK3 inhibitor and (b) a therapeutically effective amount of a second therapeutic agent, which is an ⁇ 7 -nicotinic agonist, together with a pharmaceutically-acceptable vehicle, carrier or diluent.
  • One embodiment of the invention relates to one pharmaceutical composition comprising both agents (a) and (b). Another embodiment relates to two separate pharmaceutical compositions, one for agent (a) and one for agent (b).
  • the composition may be administered in a standard manner such as orally, parenterally, transmucosally (e.g., sublingually or via buccal administration), topically, transdermally, rectally, via inhalation (e.g., nasal or deep lung inhalation).
  • Parenteral administration includes, but is not limited to intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal or via a high pressure technique.
  • the composition can be in the form of tablets or lozenges formulated in conventional manner.
  • tablets and capsules for oral administration can contain conventional excipients such as binding agents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (e.g., lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (e.g., magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (e.g., potato starch or sodium starch glycollate), or wetting agents (e.g., sodium lauryl sulfate).
  • binding agents e.g., syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone
  • fillers e.g
  • compositions for inhalation typically can be provided in the form of a solution, suspension, or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant, such as dichlorodifluoromethane or trichlorofluoromethane.
  • a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
  • Typical topical and transdermal formulations comprise conventional aqueous or nonaqueous vehicles, such as eye drops, creams, ointments, lotions, and pastes, or are in the form of a medicated plaster, patch, or membrane.
  • compositions described herein can be formulated for parenteral administration by injection or continuous infusion.
  • Formulations for injection can be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulation agents, such as suspending, stabilizing, and/or dispersing agents.
  • the active ingredient can be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use.
  • a composition in accordance with the present invention also can be formulated as a depot formulation.
  • Such long acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (e.g., an emulsion in an acceptable oil), ion exchange resins, or as sparingly soluble derivatives (e.g., a sparingly soluble salt).
  • suitable polymeric or hydrophobic materials e.g., an emulsion in an acceptable oil
  • ion exchange resins e.g., ion exchange resins
  • sparingly soluble derivatives e.g., a sparingly soluble salt
  • a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.
  • Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc may be used to form tablets.
  • Solid compositions of a similar type are also employed as fillers in soft and hard- filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • composition described herein can be incorporated into oral liquid formulations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example.
  • formulations containing these compounds can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid formulations can contain conventional additives, such as suspending agents, such as sorbitol syrup, synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin, glucose/sugar syrup, gelatin, hydroxyethylcellulose, hydroxypropylmethylcellulose, aluminum stearate gel, emulsifying agents, such as lecithin, sorbitan monooleate, or acacia; nonaqueous vehicles (which can include edible oils), such as almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol; and preservatives, such as methyl or propyl p-hydroxybenzoate and sorbic acid.
  • suspending agents such as sorbitol syrup, synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose
  • aqueous suspensions and/or elixirs are desired for oral administration, the compounds described herein can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • the composition described herein can also be administered in a controlled release formulation such as a slow release or a fast release formulation.
  • controlled release formulations of the combinations described herein may be prepared using methods well known to those skilled in the art. The method of administration will be determined, by the attendant physician or other person skilled in the art after an evaluation of the patient's condition and requirements.
  • a third aspect of the invention relates to a kit comprising a dosage unit of a first therapeutic agent, which is a GSK3 inhibitor and a dosage unit of a second therapeutic agent, which is an ⁇ 7 -nicotinic agonist, optionally with instructions for use.
  • kits as described above wherein the first therapeutic agent is any of the GSK3 inhibiting compounds as herein described and the second therapeutic agent is an ⁇ 7 -nicotinic agonist as herein described, an isomer, metabolite, prodrug or pharmaceutically-acceptable salt thereof of any of these agents.
  • Another embodiment relates to a kit, wherein the GSK3 inhibitor is 2-hydroxy-3-[5-
  • a fourth aspect of the invention relates to a method for treating CNS disorders such as, but not limited to, those discussed herein, including neurodegenerative disorders, neoroinflammatory disorders, cognitive disorders, in a subject in need thereof comprising administering simultaneously, sequentially, concurrently or separately, to said subject (a) a therapeutically effective amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) a therapeutically effective amount of a second therapeutic agent, which is an ⁇ 7- nicotinic agonist, wherein the amounts of (a) and (b) are together synergistically effective in the treatment.
  • a first therapeutic agent which is a GSK3 inhibitor
  • a second therapeutic agent which is an ⁇ 7- nicotinic agonist
  • Neurodegenerative Disorder(s) include, but are but not limited to Alzheimer's Disease (AD), Dementia, Cognitive Deficit in Schizophrenia (CDS), Mild Cognitive Impairment (MCI), Age- Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD), Cognitive Impairement No Dementia (CIND), Multiple Sclerosis, Parkinson's Disease (PD), postencephalitic parkinsonism, Huntington's Disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases (MND), Multiple System Atrophy (MSA), Corticobasal Degeneration, Progressive Supranuclear Paresis, Guillain-Barre Syndrome (GBS), and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP).
  • AD Alzheimer's Disease
  • CDS Cognitive Deficit in Schizophrenia
  • MCI Mild Cognitive Impairment
  • AAMI Age- Associated Memory Impairment
  • ARCD Age-Related Cognitive Decline
  • Dementia includes, but is not limited to, Down syndrome, vascular dementia, dementia with Lewy bodies, HIV dementia, Frontotemporal dementia Parkinson's Type (FTDP), Pick's Disease, Niemann-Pick's Disease, traumatic brain injury (TBI), dementia pugilistica, Creutzfeld- Jacob Disease and prion diseases.
  • FTDP Frontotemporal dementia Parkinson's Type
  • TBI traumatic brain injury
  • dementia pugilistica Creutzfeld- Jacob Disease and prion diseases.
  • Neuroinflammatory Disorder(s) including but not limited to Multiple Sclerosis (MS), Parkinson's disease, Multiple System Atrophy (MSA), Corticobasal Degeneration, Progressive Supranuclear Paresis, Guillain-Barre Syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP).
  • MS Multiple sclerosis
  • RRMS Relapse Remitting Multiple Sclerosis
  • SPMS Secondary Progressive Multiple Sclerosis
  • PPMS Primary Progressive Multiple Sclerosis
  • Cognitive Disorder(s) include, but are not limited to a) Dementia, including but not limited to Alzheimer's Disease (AD), Down syndrome, vascular dementia, Parkinson's Disease (PD), postencephelatic parkinsonism, dementia with Lewy bodies, HIV dementia, Huntington's Disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases (MND), Frontotemporal dementia Parkinson's Type (FTDP), progressive supranuclear palsy (PSP), Pick's Disease, Niemann-Pick's Disease, corticobasal degeneration, traumatic brain injury (TBI), dementia pugilistica, Creutzfeld- Jacob Disease and prion diseases; b) Cognitive Deficit in Schizophrenia (CDS); c) Mild Cognitive Impairment (MCI); d) Age- Associated Memory Impairment (AAMI); e) Age-Related Cognitive Decline (ARCD); f) Cognitive Impairement No Dementia (CIND); g) Addictions such as nicotine
  • the invention further relates to therapies for the treatment of: Attention-Deficit and Disruptive Behavior Disorder(s) including but not limited to attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD) and affective disorders.
  • ADHD attention deficit disorder
  • ADHD attention deficit hyperactivity disorder
  • Alzheimer's Disease cognitive deficit in schizophrenia, mild cognitive impairment and age-associated memory impairment.
  • One embodiment of the invention relates to a method for treating CNS disorders wherein the cognitive disorder is dementia, Cognitive Deficit in Schizophrenia (CDS), Mild Cognitive Impairment (MCI), Age -Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD) or Cognitive Impairement No Dementia (CIND).
  • CDS Cognitive Deficit in Schizophrenia
  • MCI Mild Cognitive Impairment
  • AAMI Age -Associated Memory Impairment
  • ARCD Age-Related Cognitive Decline
  • CIND Cognitive Impairement No Dementia
  • Yet another embodiment of the invention relates to a method for treating CNS disorders, wherein the dementia is Frontotemporal dementia (FTD), Frontotemporal dementia Parkinson's Type (FTDP), progressive supranuclear palsy (PSP), Pick's Disease, Niemann-Pick's Disease, corticobasal degeneration, traumatic brain injury (TBI) or dementia pugilistica.
  • FDD Frontotemporal dementia
  • FTDP Frontotemporal dementia Parkinson's Type
  • PSP progressive supranuclear palsy
  • Pick's Disease Pick's Disease
  • Niemann-Pick's Disease corticobasal degeneration
  • TBI traumatic brain injury
  • dementia pugilistica dementia
  • Yet a further embodiment of the invention relates to a method for treating CNS disorders, wherein the dementia is Alzheimer's Disease (AD), Down's syndrome, vascular dementia, Parkinson's Disease (PD), postencephelatic parkinsonism, dementia with Lewy bodies, HIV dementia, Huntington's Disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases (MND, Creuztfeld- Jacob's disease or prion diseases.
  • AD Alzheimer's Disease
  • PD Parkinson's Disease
  • postencephelatic parkinsonism dementia with Lewy bodies
  • HIV dementia Huntington's Disease
  • ALS amyotrophic lateral sclerosis
  • MND motor neuron diseases
  • One embodiment of the invention relates to a method for treating Alzheimer's Disease.
  • Another embodiment of the invention relates to a method for treating CNS disorders, wherein the use is in the delay of the disease progression of Alzheimer's Disease.
  • Another embodiment of the invention relates to a method for treating Bipolar Disorders.
  • One embodiment of the invention relates to the methods mentioned above wherein the first therapeutic agent is 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5- carbonitrile, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof.
  • the second therapeutic agent is (S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof.
  • One embodiment of the invention relates to a method of treating CNS disorders, such as those disorders defined above, in a subject in need thereof using the kit as described above.
  • Another embodiment of the invention relates to a method of treating CNS disorders, such as those disorders defined above, in a subject in need thereof using the pharmaceutical composition comprising the combination comprising (a) an amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) an amount of a second therapeutic agent, which is an ⁇ 7 -nicotinic agonist.
  • One embodiment of the invention relates to the use of the combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) a therapeutically effective amount of a second therapeutic agent, which is an ⁇ 7- nicotinic agonist, for the manufacturing of a medicament for use simultaneously, sequentially, concurrently or separately, in therapy.
  • a therapeutically effective amount of a first therapeutic agent which is a GSK3 inhibitor
  • a second therapeutically effective amount of a second therapeutic agent which is an ⁇ 7- nicotinic agonist
  • Another embodiment of the invention relates to the use of the combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) a therapeutically effective amount of a second therapeutic agent, which is an ⁇ 7- nicotinic agonist, for the manufacturing of a medicament for use simultaneously, sequentially, concurrently or separately, for the treatment of CNS disorders, such as those disorders defined above.
  • a therapeutically effective amount of a first therapeutic agent which is a GSK3 inhibitor
  • a second therapeutic agent which is an ⁇ 7- nicotinic agonist
  • a further embodiment of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) a therapeutically effective amount of a second therapeutic agent, which is an ⁇ 7 -nicotinic agonist, for use simultaneously, sequentially, concurrently or separately, for treatment of CNS disorders, such as those disorders defined above, particularly for Alzheimer's Disease, Mild Cognitive Impairment and Age- Associated Memory Impairment, and Cognitive Deficit in Schizophrenia.
  • a first therapeutic agent which is a GSK3 inhibitor
  • a second therapeutically effective amount of a second therapeutic agent which is an ⁇ 7 -nicotinic agonist
  • the effective dose of the GSK3 inhibitor and the ⁇ 7 -nicotinic agonist in the combinations according to the present invention may vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder as well as the potency of the selected specific compound, the mode of administration, the age and weight of the patient, and the like. Determining a dose is within the skill of the ordinary artisan.
  • Suitable daily doses of the GSK3 inhibitor in the treatment of a mammal, including man are approximately 0.01 to 250 mg/kg bodyweight at peroral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration.
  • the typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.
  • the effective dose of nicotinic agonists generally requires administering the compound in an amount of less than about 10 mg to about 400 mg.
  • each dose of the ⁇ -7 component contains about 50 mg to about 200 mg of the agent, and in further embodiments, each dose contains from about 20 mg to about 200 mg of the agent.
  • Pediatric dosages may be less such as for example in the range of about 10 mg to about 100 mg daily.
  • doses below those typical of nicotinic agonists generally may be used due to synergistic effects when used in combination with the GSK3 inhibitor.
  • Some ⁇ -7 agonists may be effective in treating cognitive and other disorders in sub-agonistic doses. Such doses are contemplated herein in combination with the GSK3 inhibitor.
  • ⁇ -7 agonist can be administered in agonistic doses, in reduced doses where synergistic effect is seen, or in low-dose, sub- agonistic doses.
  • terapéuticaally-effective amount refers to a sufficient amount of the compound to treat cognitive impairment disorders and psychotic disorders or conditions at a reasonable risk/benefit ratio applicable to any medical treatment.
  • treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
  • treatment refers to the act of "treating” as defined herein.
  • agent means the compounds comprised in the combination of the present invention, i.e. a GSK3 inhibitor or a nicotinic agonist.
  • “Synergy” means an improved effect of the two agents in the combination, which is greater than the expected additive effect of the individual agents.
  • a pharmaceutical composition is prepared by combining a GSK3 inhibitor and and a ⁇ 7- nicotinic agonist in a pharmaceutically-acceptable carrier.
  • the composition contains respective amounts of the GSK3 inhibitor and the ⁇ 7-nicotinic agonist to deliver on a daily basis a therapeutically-effective amount of each ingredient.
  • the composition is administered to a patient on a daily, twice daily, three times daily, or four times daily basis.
  • a pharmaceutical composition is prepared by combining 2-hydroxy-3-[5-(morpholin-4- ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile as a free base or a pharmaceutically acceptable salt thereof, such as the citrate salt thereof, with (S(-)-spiro[l- azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one or a pharmaceutically acceptable salt thereof in a pharmaceutically-acceptable carrier.
  • the composition contains respective amounts of 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile as a free base or a pharmaceutically acceptable salt thereof, such as the citrate salt thereof, and (S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one or a pharmaceutically acceptable salt thereof to deliver on a daily basis a therapeutically-effective amount of each ingredient.
  • the composition is administered to a patient on a daily, twice daily, three times daily, or four times daily basis.
  • Interaction design Interactive effects of drug combinations are tested by co-administering varying doses of the GSK3 inhibitor, for example 2-hydroxy-3-[5-(morpholin-4- ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof, with the ⁇ 7-nicotinic agonist, for example (S(-)-spiro[l-azabicyclo[2.2.2]octane- 3,5'-oxazolidine]-2'-one or a pharmaceutically acceptable salt thereof, and then conducting various biological tests to determine the existence of interactions (positive or negative).
  • the GSK3 inhibitor for example 2-hydroxy-3-[5-(morpholin-4- ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof
  • the ⁇ 7-nicotinic agonist for example (S(-)-spiro[l-azabicyclo[2.2.2]octane
  • the dose range used for combination studies includes doses of the nicotinic agonist known to be active in cognitive-enhancement tests (when tested alone) as well as doses below the threshold for activity (sub-threshold doses).
  • the dose range includes doses in which the GSK3 inhibitor alone is active as well as sub-threshold doses.
  • Drug-drug interactive increase in dopamine and Serotonin overflow in prefrontal cortex of rat.
  • DA dopamine
  • PFC prefrontal cortex
  • NOR novel object recognition
  • Various classes of drugs e.g. a7 nicotinic agonists
  • Drugs that enhance NOR performance may have therapeutic potential in CNS disorders with cognitive deficits including dementias (e.g. Alzheimer's disease) and psychoses (e.g. schizophrenia).
  • Drugs that interact to additively or synergistically improve cognitive performance in NOR in rodents may have surprising activity in human diseases.
  • the interactive effects of a GSK3 inhibitor and a ⁇ 7 agonist on novel object recognition are tested in a mouse NOR model. Mice are allowed to explore first two identical objects (object A) during the sample period.
  • mice were allowed to explore another copy of object A and a second different object (B). Rodents preferentially explore novel objects over familiar objects unless they have forgotten the familiar object. In this version of the test, mice generally show no preference for the novel object by 15minutes. Therefore, drugs that induce preferential exploration of object B over object A supports drug-induced enhancement of memory function. Drugs were administered so that maximal plasma concentrations occurred at the time the sample period.
  • a first therapeutic agent which is a GSK3 inhibitor
  • a second therapeutic agent which is a ⁇ 7- nicotinic agonist
  • CNS disorders such as neurodegenerative disorders, neuroinfiammatory disorders, cognitive disorders, dementia, Alzheimer's Disease, cognitive deficit in schizophrenia, mild cognitive impairment and age-associated memory impairment or any disorder mentioned below.
  • a disease modifying and symptomatic treatment the overall efficiency of the treatment will be enhanced.
  • Compositions and methods described herein may offer advantages over previous methods for treating neuropsychiatric disorders.
  • the method of treatment described herein may permit reduced quantities of these agents to be used and, therefore may permit improved management of disease symptoms such as reduction of disease-related side effects.
  • a further advantage of this synergistic or additive effect may be a faster onset of the therapeutic action of the single compounds.

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Abstract

The present invention related to a combination of (a) a GSK3 inhibitor and (b) an α7- nicotinic agonist. The invention further relates to pharmaceutical compositions comprising said combination and to methods of treating CNS disorders in mammals by administrating said combination. The invention further relates to a kit comprising the combination and use of said kits in treatment of CNS disorders such as dementia and/or Alzheimer's Disease.

Description

NEW THERAPEUTIC COMBINATION OF A GSK3 INHIBITOR AND AN α7- NICOTINIC AGONIST 960
FIELD OF THE INVENTION The present invention relates to a combination of (a) a GSK3 inhibitor and (b) an α7- nicotinic agonist. The invention further relates to pharmaceutical compositions comprising said combination and to methods of treating CNS disorders in mammals by administering said combination. The invention further relates to a kit comprising the combination and use of said kit in treatment of CNS disorders such as cognitivie deficits in schizophrenia, dementia and/or Alzheimer's Disease.
BACKGROUND OF THE INVENTION
Glycogen synthase kinase 3 (GSK3) is a serine / threonine protein kinase composed of two isoforms (α and β), which are encoded by distinct genes but are highly homologous within the catalytic domain. GSK3 is highly expressed in the central and peripheral nervous system. GSK3 phosphorylates several substrates including tau, β-catenin, glycogen synthase, pyruvate dehydrogenase and elongation initiation factor 2b (eIF2b). Insulin and growth factors activate protein kinase B, which phosphorylates GSK3 on serine 9 residue and inactivates it.
Alzheimer's Disease (AD) dementias, and taupathies.
AD is characterized by cognitive decline, cholinergic dysfunction and neuronal death, neurofibrillary tangles and senile plaques consisting of amyloid-β deposits. The sequence of these events in AD is unclear, but are believed to be related. Glycogen synthase kinase 3β (GSK3) previously known as Tau kinase I selectively phosphorylates the microtubule associated protein Tau at sites that are hyperphosphorylated in AD brains. Hyperphosphorylated tau has lower affinity for microtubules and accumulates as paired helical filaments. This results in depolymerization of microtubules, which leads to dying back of axons and neuritic dystrophy. The paired helical filaments are the main components that constitute neurofibrillary tangles and neuropil threads in AD brains. In additiona to AD, neurofibrillary tangles are consistently found in other CNS diseases such as amyotrophic lateral sclerosis, parkinsonism-dementia of Gaum, corticobasal degeneration, dementia pugilistica and head trauma, Down's syndrome, postencephalatic parkinsonism, progressive supranuclear palsy, Niemann-Pick's Disease and Pick's Disease.
GSK3 has been proposed as the link between the two neuropathological hallmarks of Alzheimer's disease, the extracellular amyloid-β and the neurofibrillary tangles made of hyperphosphorylated tau. Addition of amyloid-β to primary hippocampal cultures results in hyperphosphorylation of tau and a paired helical filaments-like state via induction of GSK3 activity, followed by disruption of axonal transport and neuronal death (Imahori and Uchida., J. Biochem 121:179-188, 1997). GSK3 preferentially associates with neurofibrillary tangles and has been shown to accumulate in the cytoplasm ofpre -tangle neurons in AD brains. GSK3 protein levels are also increased by 50% in brain tissue from AD patients (Pei, et al, J. Neuropathol. Exp. Pathol. 58: 1010-1019, 1999). Furthermore, GSK3 phosphorylates pyruvate dehydrogenase, a key enzyme in the glycolytic pathway and prevents the conversion of pyruvate to acetyl-Co-A (Hoshi et al., PNAS 93:2719-2723, 1996). Acetyl-Co-A is critical for the synthesis of acetylcholine, a key neurotransmitter in cognitive functions. Accumulation of amyloid-β is an early event in AD. GSK3 Tg mice show increased levels of amyloid-β in brain. Also, PDAPP mice fed with Lithium show decreased amyloid-β levels in hippocampus and decreased amyloid plaque area (Su et al., Biochemistry 2004, 43:6899-6908). Thus, GSK3 inhibition may have additional disease modification effects through reduction of amyloid-β levels as well as the tau pathology associated with AD and the other - diseases referred to above.
Chronic and Acute Neurodegenerative Diseases
Growth factor mediated activation of the PI3K /Akt pathway has been shown to play a key role in neuronal survival. The activation of this pathway results in GSK3b inhibition. Recent studies (Bhat et. al., PNAS 97:11074-11079 (2000)) indicate that GSK3 activity is increased in cellular and animal models of neurodegeneration such as cerebral ischemia or after growth factor deprivation. For example, the active site phosphorylation was increased in neurons vulnerable to apoptosis, a type of cell death commonly thought to occur in chronic and acute degenerative diseases such as cognitive disorders, Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, Huntington's Disease and HIV dementia and traumatic brain injury; and as in ischemic stroke. Lithium was neuroprotective in inhibiting apoptosis in cells and in the brain at doses that resulted in the inhibition of GSK3. Thus GSK3 inhibitors could be useful in attenuating the course of neurodegenerative diseases.
Bipolar Disorders (BD) Bipolar Disorders are characterised by manic episodes and depressive episodes. Lithium has been used to treat BD based on its mood stabilising effects. The disadvantage of lithium is the narrow therapeutic window and the danger of overdosing that can lead to lithium intoxication. The discovery that lithium inhibits GSK3 at therapeutic concentrations has raised the possibility that this enzyme represents a key target of lithium's action in the brain (Stambolic et al., Curr. Biol. 6:1664-1668, 1996; Klein and Melton; PNAS 93:8455-8459, 1996; Gould et al., Neuropsychopharmacology, 1:32-8, 2004). GSK3 inhibitor has been shown to reduce immobilisation time in forced swim test, a model to assess depressive behavior (O'Brien et al., J Neurosci 2004, 24:66791-6798) GSK3 has been associated with a polymorphism found in bipolar II disorder (Szczepankiewicz et al., Neuropsychobiology. 2006;5 3(l):51-6). Inhibition of GSK3β may therefore be of therapeutic relevance in the treatment of BD as well as in AD patients that have affective disorders.
Schizophrenia Accumulating evidence implicates abnormal activity of GSK3 in mood disorders and schizophrenia. GSK3 is involved in signal transduction cascades of multiple cellular processes, particularly during neural development. Kozlovsky et al (Am J Psychiatry 2000 May; 157(5):831-3) found that GSK3 levels were 41% lower in the schizophrenic patients than in comparison subjects. This study indicates that schizophrenia involves neurodevelopmental pathology and that abnormal GSK3 regulation could play a role in schizophrenia. Furthermore, reduced β-catenin levels have been reported in patients exhibiting schizophrenia (Cotter et al., Neuroreport 9:1379-1383 (1998)). Atypical antipsychotics such as olanzapine, clozapine, quetiapine, and ziprasidone, inhibits GSK3 by increasing ser9 phosphorylation suggesting that antipsychotics may exert their beneficial effects via GSK3 inhibition (Li X, et al., Int J Neuropsychopharmacol, !0(l): 7- 19 (2007).
The nicotinic agonists are those compounds having agonist or partial agonist activity against a subpopulation of nicotine receptors such as the alpha-7, α-7, receptor. The compounds modulate nicotinic receptors in the patient's brain. As such, such compounds have the ability to express nicotinic pharmacology, and in particular, to act as nicotinic agonists.
The nicotinic agonists described herein may be used in methods for preventing and/or treating a central nervous system disorder (CNS) in a subject susceptible to such a disorder. For example, an effective amount of a nicotinic agonists effective for providing some degree of prevention of the progression of a CNS disorder (i.e., provide protective effects), amelioration of the symptoms of a CNS, and amelioration of the reoccurrence of a CNS, can be administered to a patient in need thereof. The nicotinic agonists can be used to treat and/or prevent those types of conditions and disorders for which other types of nicotinic compounds have been proposed as therapeutics. See, for example, Williams et al. DN&P 7(4):205-227 (1994), Arneric et al., CNS Drug Rev. 1(1): 1-26 (1995), Arneric et al., Exp. Opin. Invest. Drugs 5(l):79-100 (1996), Bencherif et al., JPET 279:1413 (1996), Lippiello et al., JPET 279:1422 (1996), Damaj et al., Neuroscience (1997), Holladay et al., J. Med. Chem 40(28): 4169-4194
(1997), Bannon et al., Science 279: 77-80 (1998), PCT WO 94/08992, PCT WO 96/31475, and U.S. Patent Nos. 5,583,140 to Bencherif et al., 5,597,919 to Dull et al., and 5,604,231 to Smith et al. The nicotinic agonists are useful in the treatment of a variety of CNS disorders, for example, cognitive disorders, such as Alzheimer's Disease, Cognitive Deficit in Schizophrenia, neurodegenerative disorders, neoroinflammatory disorders, or any disorder mentioned below.
Studies in both human and experimental animals suggest that nicotine has cognition- enhancing properties. Evidence in the literature suggests that nicotine may improve attentiveness (Levin, E.; 108 Psychopharm. 417-431, 1992). In animal studies, nicotine can reverse deficits in working memory in brain-lesioned rats (Levin et al., Cognitive Brain Research, 137-143, 1993) and also improve performance on serial choice tasks (Muir, et al., 118 Psychopharm., 82-92; 1995). Studies have demonstrated that nicotine can enhance attention and memory in schizophrenics and normal individuals. Nicotine and the α-7 agonist GTS 21 have been shown to restore sensory gating (P50 wave) in both animals and schizophrenics.
The α-7 receptor has been linked to a deficit in auditory sensory processing in schizophrenics that correlates with cognitive dysfunction. Selective α-7 agonists are effective in animal models of memory and cognition.
SUMMARY OF THE INVENTION
This invention relates to compositions comprising a pharmaceutical combination of (a) a GSK3 inhibitor and (b) an α7 -nicotinic agonist useful for the treatment of CNS disorders, such as those disorders defined below.
The invention also relates to said combination, wherein the GSK3 inhibitor is one of the compounds mentioned below, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof and the α7 -nicotinic agonist is one of the compounds mentioned below, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof. Further the invention also relates to said combination, comprising (a) a first therapeutic agent, which is a GSK3 inhibitor and (b) a second therapeutic agent, which is an α7- nicotinic agonist selected from the list herein disclosed. A second aspect of the invention relates to a pharmaceutical composition comprising a combination comprising (a) an amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) an amount of a second therapeutic agent, which is an α7 -nicotinic agonist, together with a pharmaceutically-acceptable vehicle, carrier or diluent. One embodiment of the invention relates to one pharmaceutical composition comprising both agents (a) and (b). Another embodiment relates to a two separate pharmaceutical compositions, one for
(a) and one for (b).
A third aspect of the invention relates to a kit comprising a dosage unit of mixture of a first therapeutic agent, which is a GSK3 inhibitor and a dosage unit of a second therapeutic agent, which is an α7 -nicotinic agonist, optionally with instructions for use.
A fourth aspect of the invention relates to a method for treating CNS disorders, such as those disorders defined below, in a subject in need thereof comprising administering simultaneously, sequentially, concurrently, separately or adjunct, to said subject (a) an amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) an amount of a second therapeutic agent, which is an α7 -nicotinic agonist, wherein the amounts of (a) and
(b) are together synergistically effective in the treatment.
DETAILED DESCRIPTION OF THE INVENTION Combination
A first aspect of the invention relates to a combination comprising (a) an amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) an amount of a second therapeutic agent, which is an α7 -nicotinic agonist. In one embodiment of the invention the combination comprises the group of compounds (a) and (b) as defined below.
Suitable GSK3 inhibitors useful in the combination of the present invention and the preparation thereof are described in patent applications WO 03/004472, WO 03/055492, WO 03/082853, WO 06/001754, WO 07/040436, WO 07/040438, WO 07/040439 and WO 07/040440, WO08/002244 and WO08/002245, which are hereby incorporated by reference.
Particular GSK inhibitors are compounds selected from the group comprising 3-[7-(2- morpholin-4-ylethoxy)quinazolin-4-yl]-2-oxo-l,3-dihydroindole-5-carbonitrile; 3-[7-(2-methoxyethoxy)quinazolin-4-yl]-2-oxo- 1 ,3-dihydroindole-5-carbonitrile;
3-[7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl]-2-oxo-l,3-dihydroindole-5- carbonitrile;
3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-2-oxo-l,3-dihydroindole-5-carbonitrile;
2-hydroxy-3-[5-(4-methylpiperazine-l-carbonyl)pyridin-2-yl]-lH-indole-5-carbonitrile; 1 -[(4-methoxyphenyl)methyl]-3-(5-nitro 1 ,3-thiazol-2-yl)urea;
2-hydroxy-3-[5-[(4-phenylpiperazin-l-yl)methyl]pyridin-2-yl]-lH-indole-5-carbonitrile;
2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile;
2-hydroxy-3-[5-(4-methylpiperazin-l-yl)sulfonylpyridin-2-yl]-lH-indole-5-carbonitrile;
2-hydroxy-3-[5-[(4-methylpiperazin-l-yl)methyl]pyridin-2-yl]-lH-indole-5-carbonitrile; 3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-5-nitro-lH-indol-2-ol;
2-hydroxy-3-[5-(pyrrolidin-l-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile;
[6-(2-hydroxy-5-nitro-lH-indol-3-yl)pyridin-3-yl]-(4-methylpiperazin-l-yl)methanone;
2-hydroxy-3-[5-(l-piperidylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile;
2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-6-carbonitrile; 2-hydroxy-3-[5-(4-methylpiperazin-l-yl)sulfonylpyridin-2-yl]-lH-indole-6-carbonitrile;
3-fluoro-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-2-oxo-lH-indole-6-carbonitrile;
[4-[5-(4-methoxyphenyl)-2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7-tetraen-8-yl]phenyl]-(4- methylpiperazin- 1 -yl)methanone;
3-(4-methoxyphenyl)-N-(2-morpholin-4-ylethyl)-5,7-diazabicyclo[4.3.0]nona-l,3,5,8- tetraene-9-carboxamide;
3-(4-chlorophenyl)-N-(2-morpholin-4-ylethyl)-5,7-diazabicyclo[4.3.0]nona-l,3,5,8- tetraene-9-carboxamide;
5-fluoro-N-[4-(4-methylpiperazin-l-yl)sulfonylphenyl]-4-(2-methyl-3-propan-2-yl- imidazol-4-yl)pyrimidin-2-amine; [4-[[5-fluoro-4-(2-methyl-3-propan-2-yl-imidazol-4-yl)pyrimidin-2-yl]amino]phenyl]-(4- methylpiperazin- 1 -yl)methanone;
[4-[[5-fluoro-4-(2-methyl-3-propan-2-yl-imidazol-4-yl)pyrimidin-2-yl]amino]phenyl]- phenyl-methanone; N-(3-methoxypropyl)-8-[4-(trifluoromethyl)phenyl]-2,7,9-triazabicyclo[4.3.0]nona-
1 ,3,5,7-tetraene-5-carboxamide;
5-(4-methoxyphenyl)-8-[4-(l-piperidylmethyl)phenyl]-2,7,9-triazabicyclo[4.3.0]nona-
1,3,5,7-tetraene;
N-(3-methoxypropyl)-8-[4-(morpholin-4-ylmethyl)phenyl]-2,7,9-triazabicyclo[4.3.0]nona- 1 ,3,5,7-tetraene-5-carboxamide;
[4-[[5-fluoro-4-(2-methyl-3-propan-2-yl-imidazol-4-yl)pyrimidin-2-yl]amino]phenyl]- pyridin-2-yl-methanone;
[4-[[4-(3-cyclohexyl-2-methyl-imidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]phenyl]-(4- methylpiperazin- 1 -yl)methanone; [4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]phenyl]-(4- methylpiperazin- 1 -yl)methanone;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine;
4-(2,3-dimethylimidazol-4-yl)-5-fluoro-N-[4-(morpholin-4-ylmethyl)phenyl]pyrimidin-2- amine;
[4-[5-(4-chlorophenyl)-2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7-tetraen-8-yl]phenyl]-(4- methylpiperazin- 1 -yl)methanone;
N-(3-methoxypropyl)-8-[3-(2,2,3,3-tetrafluoropropoxymethyl)phenyl]-2,7,9- triazabicyclo[4.3.0]nona-l,3,5,7-tetraene-5-carboxamide; [4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]phenyl]- pyridin-2-yl-methanone;
[4-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]phenyl]-pyridin-2-yl- methanone;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine; [4-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]phenyl]-(4- methylpiperazin- 1 -yl)methanone;
4-(2,3-dimethylimidazol-4-yl)-5-fluoro-N-[4-[(4-methylpiperazin-l- yl)methyl]phenyl]pyrimidin-2-amine; 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(4-methylsulfonylphenyl)pyrimidin-
2-amine;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin-2- amine;
[4-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]-2- (trifluoromethoxy)phenyl]-(4-methylpiperazin- 1 -yl)methanone;
5-fluoro-N-[4-(4-methylpiperazin-l-yl)sulfonylphenyl]-4-[3-(oxan-4-yl)-2-
(trifluoromethyl)imidazol-4-yl]pyrimidin-2-amine; azetidin-l-yl-[4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl] amino]phenyl]methanone; 5-fluoro-N-[3-methyl-4-(morpholin-4-ylmethyl)phenyl]-4-[2-methyl-3-(oxan-4- yl)imidazol-4-yl]pyrimidin-2-amine;
5-fluoro-N-[4-(morpholin-4-ylmethyl)phenyl]-4-[3-(oxan-4-yl)-2-
(trifluoromethyl)imidazol-4-yl]pyrimidin-2-amine;
5-fluoro-N-[4-(4-methylpiperazin-l-yl)sulfonylphenyl]-4-[3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-amine;
[4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl] amino]phenyl] -(4-methylpiperazin- 1 -yl)methanone;
5 - [5 -fluoro-2-[ [4-(4-methylpiperazin- 1 -yl)sulfonylphenyl] amino]pyrimidin-4-yl]- 1 -(oxan-
4-yl)imidazole-2-carbonitrile; 5-fluoro-N-[4-(4-methylpiperazin-l-yl)sulfonylphenyl]-4-[3-methyl-2-
(trifluoromethyl)imidazol-4-yl]pyrimidin-2-amine;
5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine;
[4-[[5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2-yl]amino]phenyl]- (4-methylpiperazin- 1 -yl)methanone; N-(2-cyanoethyl)-3-[5-(4-methoxyphenyl)-2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7-tetraen-
8-yl]benzamide;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-methylsulfonyl-3-
(trifluoromethyl)phenyl]pyrimidin-2-amine; azetidin-l-yl-[4-[8-[4-(morpholin-4-ylmethyl)phenyl]-2,7,9-triazabicyclo[4.3.0]nona- l,3,5,7-tetraen-5-yl]phenyl]methanone;
8-[4-(morpholin-4-ylmethyl)phenyl]-N-pyridin-3-yl-2,7,9-triazabicyclo[4.3.0]nona-
1 ,3,5,7-tetraene-5-carboxamide;
2-[3-[8-[4-(4-methylpiperazine-l-carbonyl)phenyl]-2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7- tetraen-5-yl]phenoxy]acetonitrile;
5 -fluoro-N-(4-methylsulfonylphenyl)-4- [3 -propan-2-yl-2-(trifluoromethyl)imidazol-4- yl]pyrimidin-2-amine;
5-fluoro-N-[4-(4-methylpiperazin-l-yl)sulfonylphenyl]-4-[3-propan-2-yl-2-
(trifluoromethyl)imidazol-4-yl]pyrimidin-2-amine; [4-[[5-fluoro-4-[3-propan-2-yl-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl] amino]phenyl] -(4-methylpiperazin- 1 -yl)methanone;
4- [2-methyl-3 -(oxan-4-yl)imidazol-4-yl] -N-(4-methylsulfonylphenyl)pyrimidin-2-amine;
4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine; [4-[[4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]phenyl]-(4- methylpiperazin- 1 -yl)methanone;
4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4-ylmethyl)phenyl]pyrimidin-2- amine;
5-(4-methoxyphenyl)-8-(3-methylsulfonylphenyl)-2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7- tetraene;
[4-[5-(3-fluoro-4-methoxy-phenyl)-2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7-tetraen-8- yl]phenyl]-(4-methylpiperazin- 1 -yl)methanone;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylsulfonylpyridin-3- yl)pyrimidin-2-amine; (2,6-dimethylmorpholin-4-yl)-[4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]phenyl]methanone;
[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]-
(4-methylpiperazin- 1 -yl)methanone; 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(l-morpholin-4- ylethyl)phenyl]pyrimidin-2-amine;
5 -fluoro-N-(4-methylsulfonylphenyl)-4- [3 -(oxan-4-yl)-2-(trifluoromethyl)imidazol-4- yl]pyrimidin-2-amine; azetidin-l-yl-[2-chloro-4-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2- yl]amino]phenyl]methanone; azetidin-l-yl-[4-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]-2- methyl-phenyl]methanone; azetidin-l-yl-[5-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]pyridin-2- yljmethanone; azetidin-l-yl-[4-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]-2-
(trifluoromethoxy)phenyl]methanone; azetidin- 1 -yl- [3 -chloro-5 - [[4-(2,3 -dimethylimidazol-4-yl)-5 -fluoro-pyrimidin-2- yl]amino]pyridin-2 -yljmethanone;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[6-(morpholin-4-ylmethyl)pyridin-3- yl]pyrimidin-2-amine;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine; azetidin- l-yl-[3-chloro-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2 -yljmethanone; N-(6-ethylsulfonylpyridin-3-yl)-5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-amine;
[3-chloro-5-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]-(4-methylpiperazin-l-yl)methanone;
5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N-methyl-N- propan-2-yl-pyridine-2-carboxamide; N-ethyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N- methyl-pyridine-2-carboxamide;
3-[4-[8-[4-(morpholin-4-ylmethyl)phenyl]2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7-tetraene-
5-carbonyl]piperazin-l-yl]propanenitrile; [3-chloro-5-[[5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]-(4-methylpiperazin-l-yl)methanone;
[3-chloro-5-[[5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]-(l-piperidyl)methanone; azetidin- 1 -yl- [3 -chloro-5 -[ [5 -fluoro-4-[3 -methyl-2-(trifluoromethyl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[6-(4-methylpiperazin-l- yl)sulfonylpyridin-3-yl]pyrimidin-2-amine;
N-[6-[(4,4-difluoro-l-piperidyl)methyl]pyridin-3-yl]-5-fluoro-4-[2-methyl-3-(oxan-4- yl)imidazol-4-yl]pyrimidin-2-amine; 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(oxan-4-yl)pyrimidin-2-amine; l-[4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-l- piperidyl]ethanone;
[4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-l-piperidyl]- phenyl-methanone; l-[4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-l- piperidyl]-2-phenyl-ethanone; benzyl 4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]piperidine- 1 -carboxylate;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(l-methylsulfonyl-4- piperidyl)pyrimidin-2-amine;
N-[l-(benzenesulfonyl)-4-piperidyl]-5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-amine;
5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N,N- dimethyl-pyridine-2-sulfonamide; an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof or a solvate or a solvate of a pharmaceutically acceptable salt thereof.
A particular GSK3 inhibitor is 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH- indole-5-carbonitrile as a free base, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt.
The combination may employ any alpha-7 agonist, including but not limited to those disclosed in US Patent Nos. 6,110,914 and 6,569,865; and pending US Application 2008- 0139600 (Al), WO96/06098, WO99/03859, WO00/42044, WO01/060821, WO02/096912, WO03/087103, WP2005/030777, WO2005/030778 and WO2007/133155.
Exemplary alpha-7 agonists include but are not limited to
S-(-)-spiro(l-azabicyclo[2.2.2]octan-3,5'-oxazolindine-2'-one; (R)-spiro[l-azabicyclo[2.2.2]octane-3,2'(3Η)-furo[2,3-b]pyridine;
(øspirofl-azabicycloP^^Joctane-S^'^'^'-dihydrofuroP^-BJpyridine; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-bromospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-phenylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 5'-nitrospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)- furo[2,3-b]pyridine]; l '-chlorospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]isoquinoline];
5'-(phenylcarboxamido)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(phenylaminocarbonylamino)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine]; 5'-(phenylsulfonylamido)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-aminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N-methylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N,N-dimethylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N,N-diethylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 5'-N-ethylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 5'-N-benzylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N-formamidospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N-acetamidospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]isoquinoline]; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]quinoline];
5'-ethenylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(E)-(phenylethenyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(4-morpholino)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(l-azetidinyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 5'-(E)-(2-(4-pyridyl)ethenyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine];
5'-(E)-(2-(2-pyridyl)ethenyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine];
5'-(2-trimethylsilylethynyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine];
5'-ethynylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(2-furyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(3-pyridyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-methylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine-5'carbonitrile]; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine-5'carboxamide];
5'-N'-(3-chlorophenyl)aminocarbonylminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)- furo [2,3 -b]pyridine] ;
5'-N'-(2-nitrophenyl)aminocarbonylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)- furo[2,3-b]pyridine];
4'-chlorospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
4'-methoxyspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
4'-phenylthiospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
4'-(N-2-aminoethyl)aminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 4'-phenylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 4'-methylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
4'-(4-N-methylpiperazin-l-yl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine];
4'-chloro-spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[3,2-c]pyridine]; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[3,2-c]pyridine]; spiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine-7'-oxide]; spiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine-6'-carbonitrile];
6'-chlorospiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine];
6'-fluorospiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine]; N,N-dimethyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridin]-5'- yl] -2-thienyl} methenamine;
N,N-dimethyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridm]-5'- yl] -2-furyl} methenamine;
N,N-dimethyl-l-{4-[(2i?)-3>H-spiro[4-azabicyclo[2.2.2]octane-2,2>-furo[2,3-/)]pyridin]-5>- yl]-2-thienyl}methenamine;
N,N-dimethyl-l-{4-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridm]-5'- yl] -2-furyl} methenamine;
N-methyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridin]-5'-yl]-2- thienyl}methanamine; N-methyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridin]-5'-yl]-2- furyl}methenamine;
(2i?)-5'-[5-(pyrrolidin-l-ylmethyl)-2-furyl]-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'- furo [2,3 -ό]pyridine] ;
(2i?)-5'-[5-(morpholin-4-ylmethyl)-2-furyl]-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'- furo[2,3-ό]pyridine];
N,N-dimethyl-l-{4-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridin]-5'- yl] -2-furyl} methenamine;
(2i?)-5'-[5-(pyrrolidin-l-ylmethyl)-3-furyl]-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'- furo [2,3 -ό]pyridine] ; (2i?)-5'-[5-(morpholin-4-ylmethyl)-3-furyl]-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'- furo [2,3 -ό]pyridine] ;
N-methyl-N-({5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridm]-5'-yl]-
2-furyl}methyl)cyclopropanamine N-methyl-N-({4-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridin]-5'-yl]-
2-furyl}methyl)cyclopropanamine; l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridm]-5'-yl]-2- furyl}methenamine; l-{5-[(2i?)-3>H-spiro[4-azabicyclo[2.2.2]octane-2,2>-furo[2,3-/)]pyridin]-5>-yl]-2- thienyl}methenamine; l-{4-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridm]-5'-yl]-2- furyl}methenamine;
(R)-5-(6-methoxypyridin-3-yl)-3H-r-azaspiro[furo[2,3-b]pyridine-2,3'- bicyclo[2.2.2]octane]; (R)-5-(5-(morpholinomethyl)furan-3-yl)-3H-r-azaspiro[furo[2,3-b]pyridine-2,3'- bicyclo[2.2.2]octane]; an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof or a solvate or a solvate of a pharmaceutically acceptable salt thereof.
A particularly suitable α-7 specific nicotinic receptor agonist (α7 -nicotinic agonists) is S(- )-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one (as a free base, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt.
The term "nicotinic receptor agonist", where used in the description and the claims, is synonymous with the term "nicotine agonist" and both terms refer to agonists of nicotinic acetylcholine receptors. These terms are used interchangeably throughout the description and claims.
The term "specific nicotinic receptor agonist", where used in the description and the claims, is synonymous with the term "specific nicotine agonist" and both terms refer to agonists that interact specifically with the α-7 nicotinic acetylcholine receptor. In one embodiment of the invention the second therapeutic agent comprises specific nicotinic receptor agonist which is S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]- 2'-one, a metabolite or prodrug or pharmaceutically-acceptable salt, solvate or solvated salt thereof. This compound interacts specifically with the α-7 nicotinic acetylcholine. Other compounds having similar specificity are contemplated as being within the scope of the invention.
In one embodiment of the invention the combination comprises the group of compounds (a) and (b) as defined below:
(a) a first therapeutic agent, which is a GSK3 inhibitor and (b) a second therapeutic agent, which is an α7 -nicotinic agonist selected from:
(a) 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile and
(b) S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one; (a) 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile and (b) ((-)-spiro[l-azabicyclo[2.2.2]octane-3,2'-(2',3'-dihydrofuro[2,3-B]pyridine)]; (a) 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile and (b) N-methyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridin]-5'- yl] -2-thienyl} methanamine; (a) 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile and
(b) N,N-dimethyl-l-{5-[(2R)-3Η-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]- 5'-yl]-2-furyl}methenamine;
(a) 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile and
(b) (R)-5-(5-(morpholinomethyl)furan-3-yl)-3H- 1 '-azaspiro[furo[2,3-b]pyridine-2,3'- bicyclo[2.2.2]octane];
(a) 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile and
(b) (R)-5-(6-methoxypyridin-3-yl)-3H-r-azaspiro[furo[2,3-b]pyridine-2,3'- bicyclo[2.2.2]octane]; (a) [4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]phenyl]-(4-methylpiperazin-l-yl)methanone and (b) S(-)-spiro[l- azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one;
(a) [4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]phenyl]-(4-methylpiperazin-l-yl)methanone and (b) ((-)-spiro[l- azabicyclo[2.2.2]octane-3,2'-(2',3'-dihydrofuro[2,3-B]pyridine)]; (a) [4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]phenyl]-(4-methylpiperazin-l-yl)methanone and (b) Λ/-methyl-l-{5-[(2i?)-3'H- spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-ό]pyridin]-5'-yl]-2-thienyl}methanamine; (a) [4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]phenyl]-(4-methylpiperazin-l-yl)methanone and (b) N,N-dimethyl-l-{5-[(2R)- 3Η-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-yl]-2-furyl}methenamine; (a) [4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]phenyl]-(4-methylpiperazin-l-yl)methanone and (b) (R)-5-(5- (morpholinomethyl)furan-3-yl)-3H-r-azaspiro[furo[2,3-b]pyridine-2,3'- bicyclo[2.2.2]octane];
(a) [4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]phenyl]-(4-methylpiperazin-l-yl)methanone and (b) (R)-5-(6-methoxypyridin-3- yl)-3H-r-azaspiro[furo[2,3-b]pyridine-2,3'-bicyclo[2.2.2]octane]; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin- 2-amine and (b) S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin- 2-amine and (b) ((-)-spiro[l-azabicyclo[2.2.2]octane-3,2'-(2',3'-dihydrofuro[2,3- B]pyridine)]; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin- 2-amine and (b) N-methyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3- ό]pyridin]-5'-yl]-2-thienyl}methanamine;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin- 2-amine and (b) N,N-dimethyl-l-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'- furo[2,3-b]pyridin]-5'-yl]-2-furyl}methenamine; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin-
2-amine and (b) (R)-5-(5-(morpholinomethyl)furan-3-yl)-3H-r-azaspiro[furo[2,3- b]pyridine-2,3'-bicyclo[2.2.2]octane];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin- 2-amine and (b) (R)-5-(6-methoxypyridin-3-yl)-3H-r-azaspiro[furo[2,3-b]pyridine-2,3'- bicyclo[2.2.2]octane];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine and (b) S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'- oxazolidine]-2'-one; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine and (b) ((-)-spiro[l-azabicyclo[2.2.2]octane-3,2'-
(2',3'-dihydrofuro[2,3-B]pyridine)];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine and (b) TV-methyl- l-{5-[(2i?)-3'H-spiro[4- azabicyclo[2.2.2]octane-2,2'-furo[2,3-ό]pyridin]-5'-yl]-2-thienyl}methanamine;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine and (b) N,N-dimethyl-l-{5-[(2R)-3'H-spiro[4- azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-yl]-2-furyl} methenamine;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine and (b) (R)-5-(5-(morpholmomethyl)furan-3-yl)-3H- r-azaspiro[furo[2,3-b]pyridine-2,3'-bicyclo[2.2.2]octane];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine and (b) (R)-5-(6-methoxypyridin-3-yl)-3H-r- azaspiro[furo[2,3-b]pyridine-2,3'-bicyclo[2.2.2]octane]; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine and (b) S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'- one;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine and (b) ((-)-spiro[l-azabicyclo[2.2.2]octane-3,2'-(2',3'- dihydrofuro[2,3-B]pyridine)]; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine and (b) Λ/-methyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-
2,2'-furo[2,3-ό]pyridin]-5'-yl]-2-thienyl}methanamine;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine and (b) N,N-dimethyl- 1 - {5-[(2R)-3'H-spiro[4- azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-yl]-2-furyl}methenamine;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine and (b) (R)-5-(5-(morpholinomethyl)furan-3-yl)-3H-r- azaspiro[furo[2,3-b]pyridine-2,3'-bicyclo[2.2.2]octane]; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine and (b) (R)-5-(6-methoxypyridin-3-yl)-3H4'-azaspiro[furo[2,3- b]pyridine-2,3'-bicyclo[2.2.2]octane];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine and (b) S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'- oxazolidine]-2'-one;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine and (b) ((-)-spiro[l-azabicyclo[2.2.2]octane-3,2'-(2',3'- dihy drofuro [2 , 3 -B Jpyridine)] ;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine and (b) TV-methyl- 1 - {5-[(2i?)-3'H-spiro[4- azabicyclo[2.2.2]octane-2,2'-furo[2,3-ό]pyridin]-5'-yl]-2-thienyl}methanamine;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine and (b) N,N-dimethyl-l-{5-[(2R)-3'H-spiro[4- azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-yl]-2-furyl}methenamine; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine and (b) (R)-5-(5-(morpholinomethyl)furan-3-yl)-3H- r-azaspiro[furo[2,3-b]pyridine-2,3'-bicyclo[2.2.2]octane];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine and (b) (R)-5-(6-methoxypyridin-3-yl)-3H-r- azaspiro[furo[2,3-b]pyridine-2,3'-bicyclo[2.2.2]octane]; an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof or a solvate or a solvate of a pharmaceutically acceptable salt thereof.
For use in medicine, pharmaceutically-acceptable salts may be useful in the preparation of the compounds according to the invention. Suitable pharmaceutically-acceptable salts of the compounds described herein include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically-acceptable acid such as hydrochloric acid, sulfuric acid, methanesulphonic acid and fumaric acid. Furthermore, where the compounds carry an acidic moiety, suitable pharmaceutically-acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. The expression "pharmaceutically-acceptable salts" includes any pharmaceutically acceptable salt, including both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts. The expression "pharmaceutically-acceptable cationic salts" is intended to include, but is not limited to such salts as the alkali metal salts, (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium), aluminum salts, ammonium salts, and salts with organic amines such as benzathine (N,N'-dibenzylethylenediamine) and choline. The expression "pharmaceutically-acceptable acid addition salts" is intended to include, but is not limited to such salts as the hydrochloride, hydrobromide and sulfate.
The pharmaceutically-acceptable cationic salts containing free carboxylic acids can be readily prepared by reacting the free acid form of with an appropriate base. Typical bases are sodium hydroxide, sodium methoxide and sodium ethoxide. The pharmaceutically-acceptable acid addition salts containing free amine groups can be readily prepared by reacting the free base form with the appropriate acid.
Suitable salts for the GSK inhibitor may be, but are not limited to, hydrochloride, fumarate, tartrate, citrate, edisylate, phosphate salts. Suitable salts for the α7-nicotinic agonist may be, but are not limited to, acid addition salts including salts of mineral acids, for example the hydrochloride and hydrobromide salts; and salts formed with organic acids such as formate, acetate, maleate, benzoate, tartrate, and fumarate salts. Such acid addition salts of any of the compounds herein described may be formed by reacting the free base or a salt, enantiomer or protected derivative thereof, with one or more equivalents of the appropriate acid. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, e.g., water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which may be removed in vacuum or by freeze drying. The reaction may be a metathetical process or it may be carried out on an ion exchange resin.
In the context of this specification the expression "pharmaceutically-acceptable salts" also includes solvates, hydrates or solvated or hydrated salts thereof.
The active agents of the composition described herein can be co-administered simultaneously or may be administered separately or sequentially in any order, or as a single pharmaceutical composition.
Pharmeceutical compositions
A second aspect of the invention relates to a pharmaceutical composition comprising a combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is GSK3 inhibitor and (b) a therapeutically effective amount of a second therapeutic agent, which is an α7 -nicotinic agonist, together with a pharmaceutically-acceptable vehicle, carrier or diluent.
One embodiment of the invention relates to one pharmaceutical composition comprising both agents (a) and (b). Another embodiment relates to two separate pharmaceutical compositions, one for agent (a) and one for agent (b). The composition may be administered in a standard manner such as orally, parenterally, transmucosally (e.g., sublingually or via buccal administration), topically, transdermally, rectally, via inhalation (e.g., nasal or deep lung inhalation). Parenteral administration includes, but is not limited to intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, intrathecal or via a high pressure technique.
For buccal administration, the composition can be in the form of tablets or lozenges formulated in conventional manner. For example, tablets and capsules for oral administration can contain conventional excipients such as binding agents (e.g., syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone), fillers (e.g., lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol), lubricants (e.g., magnesium stearate, stearic acid, talc, polyethylene glycol or silica), disintegrants (e.g., potato starch or sodium starch glycollate), or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated according to methods well known in the art. Such compositions can also be formulated as suppositories for rectal administration, e.g., containing conventional suppository bases, such as cocoa butter or other glycerides. Compositions for inhalation typically can be provided in the form of a solution, suspension, or emulsion that can be administered as a dry powder or in the form of an aerosol using a conventional propellant, such as dichlorodifluoromethane or trichlorofluoromethane. Typical topical and transdermal formulations comprise conventional aqueous or nonaqueous vehicles, such as eye drops, creams, ointments, lotions, and pastes, or are in the form of a medicated plaster, patch, or membrane. Additionally, compositions described herein can be formulated for parenteral administration by injection or continuous infusion. Formulations for injection can be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulation agents, such as suspending, stabilizing, and/or dispersing agents. Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water) before use. A composition in accordance with the present invention also can be formulated as a depot formulation. Such long acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Accordingly, the compounds of the invention can be formulated with suitable polymeric or hydrophobic materials (e.g., an emulsion in an acceptable oil), ion exchange resins, or as sparingly soluble derivatives (e.g., a sparingly soluble salt). For oral administration a pharmaceutical composition can take the form of solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch and preferably potato or tapioca starch and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc may be used to form tablets. Solid compositions of a similar type are also employed as fillers in soft and hard- filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. Alternatively, the composition described herein can be incorporated into oral liquid formulations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example. Moreover, formulations containing these compounds can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid formulations can contain conventional additives, such as suspending agents, such as sorbitol syrup, synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin, glucose/sugar syrup, gelatin, hydroxyethylcellulose, hydroxypropylmethylcellulose, aluminum stearate gel, emulsifying agents, such as lecithin, sorbitan monooleate, or acacia; nonaqueous vehicles (which can include edible oils), such as almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol; and preservatives, such as methyl or propyl p-hydroxybenzoate and sorbic acid. The liquid forms in which the compositions described herein may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. When aqueous suspensions and/or elixirs are desired for oral administration, the compounds described herein can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. The composition described herein can also be administered in a controlled release formulation such as a slow release or a fast release formulation. Such controlled release formulations of the combinations described herein may be prepared using methods well known to those skilled in the art. The method of administration will be determined, by the attendant physician or other person skilled in the art after an evaluation of the patient's condition and requirements.
Kit
A third aspect of the invention relates to a kit comprising a dosage unit of a first therapeutic agent, which is a GSK3 inhibitor and a dosage unit of a second therapeutic agent, which is an α7 -nicotinic agonist, optionally with instructions for use.
Another embodiment relates to a kit as described above wherein the first therapeutic agent is any of the GSK3 inhibiting compounds as herein described and the second therapeutic agent is an α7 -nicotinic agonist as herein described, an isomer, metabolite, prodrug or pharmaceutically-acceptable salt thereof of any of these agents.
Another embodiment relates to a kit, wherein the GSK3 inhibitor is 2-hydroxy-3-[5-
(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt and the α7- nicotinic agonist is (S)-3?- spiro(l-azabicyclo[2.2.2]octan-3,5'-oxazolidin-2'-one), an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof. Another embodiment relates to a kit as described above wherein the combination is as hereinbefore described in the list.
Method of treatment A fourth aspect of the invention relates to a method for treating CNS disorders such as, but not limited to, those discussed herein, including neurodegenerative disorders, neoroinflammatory disorders, cognitive disorders, in a subject in need thereof comprising administering simultaneously, sequentially, concurrently or separately, to said subject (a) a therapeutically effective amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) a therapeutically effective amount of a second therapeutic agent, which is an α7- nicotinic agonist, wherein the amounts of (a) and (b) are together synergistically effective in the treatment.
Neurodegenerative Disorder(s) include, but are but not limited to Alzheimer's Disease (AD), Dementia, Cognitive Deficit in Schizophrenia (CDS), Mild Cognitive Impairment (MCI), Age- Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD), Cognitive Impairement No Dementia (CIND), Multiple Sclerosis, Parkinson's Disease (PD), postencephalitic parkinsonism, Huntington's Disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases (MND), Multiple System Atrophy (MSA), Corticobasal Degeneration, Progressive Supranuclear Paresis, Guillain-Barre Syndrome (GBS), and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). Dementia includes, but is not limited to, Down syndrome, vascular dementia, dementia with Lewy bodies, HIV dementia, Frontotemporal dementia Parkinson's Type (FTDP), Pick's Disease, Niemann-Pick's Disease, traumatic brain injury (TBI), dementia pugilistica, Creutzfeld- Jacob Disease and prion diseases.
Neuroinflammatory Disorder(s)including but not limited to Multiple Sclerosis (MS), Parkinson's disease, Multiple System Atrophy (MSA), Corticobasal Degeneration, Progressive Supranuclear Paresis, Guillain-Barre Syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP). Multiple sclerosis (MS) includes Relapse Remitting Multiple Sclerosis (RRMS), Secondary Progressive Multiple Sclerosis (SPMS), and Primary Progressive Multiple Sclerosis (PPMS).
Cognitive Disorder(s) include, but are not limited to a) Dementia, including but not limited to Alzheimer's Disease (AD), Down syndrome, vascular dementia, Parkinson's Disease (PD), postencephelatic parkinsonism, dementia with Lewy bodies, HIV dementia, Huntington's Disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases (MND), Frontotemporal dementia Parkinson's Type (FTDP), progressive supranuclear palsy (PSP), Pick's Disease, Niemann-Pick's Disease, corticobasal degeneration, traumatic brain injury (TBI), dementia pugilistica, Creutzfeld- Jacob Disease and prion diseases; b) Cognitive Deficit in Schizophrenia (CDS); c) Mild Cognitive Impairment (MCI); d) Age- Associated Memory Impairment (AAMI); e) Age-Related Cognitive Decline (ARCD); f) Cognitive Impairement No Dementia (CIND); g) Addictions such as nicotine addiction.
The invention further relates to therapies for the treatment of: Attention-Deficit and Disruptive Behavior Disorder(s) including but not limited to attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD) and affective disorders.
Another embodiment of the invention relates to a method for treating dementia in
Alzheimer's Disease, cognitive deficit in schizophrenia, mild cognitive impairment and age-associated memory impairment.
One embodiment of the invention relates to a method for treating CNS disorders wherein the cognitive disorder is dementia, Cognitive Deficit in Schizophrenia (CDS), Mild Cognitive Impairment (MCI), Age -Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD) or Cognitive Impairement No Dementia (CIND). Another embodiment of the invention relates to a method for treating CNS disorders, wherein the disease is Cognitive Deficit in Schizophrenia.
Yet another embodiment of the invention relates to a method for treating CNS disorders, wherein the dementia is Frontotemporal dementia (FTD), Frontotemporal dementia Parkinson's Type (FTDP), progressive supranuclear palsy (PSP), Pick's Disease, Niemann-Pick's Disease, corticobasal degeneration, traumatic brain injury (TBI) or dementia pugilistica.
Yet a further embodiment of the invention relates to a method for treating CNS disorders, wherein the dementia is Alzheimer's Disease (AD), Down's syndrome, vascular dementia, Parkinson's Disease (PD), postencephelatic parkinsonism, dementia with Lewy bodies, HIV dementia, Huntington's Disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases (MND, Creuztfeld- Jacob's disease or prion diseases.
One embodiment of the invention relates to a method for treating Alzheimer's Disease.
Another embodiment of the invention relates to a method for treating CNS disorders, wherein the use is in the delay of the disease progression of Alzheimer's Disease.
Another embodiment of the invention relates to a method for treating Bipolar Disorders.
One embodiment of the invention relates to the methods mentioned above wherein the first therapeutic agent is 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5- carbonitrile, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof. Another embodiment of the invention relates to the methods mentioned above wherein the second therapeutic agent is (S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof.
One embodiment of the invention relates to a method of treating CNS disorders, such as those disorders defined above, in a subject in need thereof using the kit as described above.
Another embodiment of the invention relates to a method of treating CNS disorders, such as those disorders defined above, in a subject in need thereof using the pharmaceutical composition comprising the combination comprising (a) an amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) an amount of a second therapeutic agent, which is an α7 -nicotinic agonist.
One embodiment of the invention relates to the use of the combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) a therapeutically effective amount of a second therapeutic agent, which is an α7- nicotinic agonist, for the manufacturing of a medicament for use simultaneously, sequentially, concurrently or separately, in therapy.
Another embodiment of the invention relates to the use of the combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) a therapeutically effective amount of a second therapeutic agent, which is an α7- nicotinic agonist, for the manufacturing of a medicament for use simultaneously, sequentially, concurrently or separately, for the treatment of CNS disorders, such as those disorders defined above.
A further embodiment of the invention relates to a pharmaceutical composition comprising the combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) a therapeutically effective amount of a second therapeutic agent, which is an α7 -nicotinic agonist, for use simultaneously, sequentially, concurrently or separately, for treatment of CNS disorders, such as those disorders defined above, particularly for Alzheimer's Disease, Mild Cognitive Impairment and Age- Associated Memory Impairment, and Cognitive Deficit in Schizophrenia.
Dosages
The effective dose of the GSK3 inhibitor and the α7 -nicotinic agonist in the combinations according to the present invention may vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder as well as the potency of the selected specific compound, the mode of administration, the age and weight of the patient, and the like. Determining a dose is within the skill of the ordinary artisan.
Suitable daily doses of the GSK3 inhibitor in the treatment of a mammal, including man are approximately 0.01 to 250 mg/kg bodyweight at peroral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration. The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician.
Typically, the effective dose of nicotinic agonists generally requires administering the compound in an amount of less than about 10 mg to about 400 mg. Ins some embodiments, each dose of the α-7 component contains about 50 mg to about 200 mg of the agent, and in further embodiments, each dose contains from about 20 mg to about 200 mg of the agent. Pediatric dosages may be less such as for example in the range of about 10 mg to about 100 mg daily. Additionally, in some embodiments, doses below those typical of nicotinic agonists generally may be used due to synergistic effects when used in combination with the GSK3 inhibitor. Some α-7 agonists may be effective in treating cognitive and other disorders in sub-agonistic doses. Such doses are contemplated herein in combination with the GSK3 inhibitor. Thus, low, sub-agonistic doses, such as about 0.0005mg to about 2mg, of α-7 agonist may be used. Accordingly, an α-7 agonist can be administered in agonistic doses, in reduced doses where synergistic effect is seen, or in low-dose, sub- agonistic doses.
The term "therapeutically-effective amount" as used herein refers to a sufficient amount of the compound to treat cognitive impairment disorders and psychotic disorders or conditions at a reasonable risk/benefit ratio applicable to any medical treatment.
The term "treating" as used herein, refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, refers to the act of "treating" as defined herein.
The term "disorder", unless stated otherwise, has the same meaning as the terms
"condition" and "disease" and are used interchangeably throughout the description and claims. The term "agent" means the compounds comprised in the combination of the present invention, i.e. a GSK3 inhibitor or a nicotinic agonist.
"Synergy" means an improved effect of the two agents in the combination, which is greater than the expected additive effect of the individual agents.
Examples
EXAMPLE 1 (Prophetic)
A pharmaceutical composition is prepared by combining a GSK3 inhibitor and and a α7- nicotinic agonist in a pharmaceutically-acceptable carrier. The composition contains respective amounts of the GSK3 inhibitor and the α7-nicotinic agonist to deliver on a daily basis a therapeutically-effective amount of each ingredient. The composition is administered to a patient on a daily, twice daily, three times daily, or four times daily basis.
EXAMPLE 2 (Prophetic)
A pharmaceutical composition is prepared by combining 2-hydroxy-3-[5-(morpholin-4- ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile as a free base or a pharmaceutically acceptable salt thereof, such as the citrate salt thereof, with (S(-)-spiro[l- azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one or a pharmaceutically acceptable salt thereof in a pharmaceutically-acceptable carrier. The composition contains respective amounts of 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile as a free base or a pharmaceutically acceptable salt thereof, such as the citrate salt thereof, and (S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one or a pharmaceutically acceptable salt thereof to deliver on a daily basis a therapeutically-effective amount of each ingredient. The composition is administered to a patient on a daily, twice daily, three times daily, or four times daily basis.
EXAMPLE 3
Biological tests for assessing effects of combinations of a GSK3 inhibitor and a α7- nicotinic agonist.
Interaction design: Interactive effects of drug combinations are tested by co-administering varying doses of the GSK3 inhibitor, for example 2-hydroxy-3-[5-(morpholin-4- ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile or a pharmaceutically acceptable salt thereof, with the α7-nicotinic agonist, for example (S(-)-spiro[l-azabicyclo[2.2.2]octane- 3,5'-oxazolidine]-2'-one or a pharmaceutically acceptable salt thereof, and then conducting various biological tests to determine the existence of interactions (positive or negative). The dose range used for combination studies includes doses of the nicotinic agonist known to be active in cognitive-enhancement tests (when tested alone) as well as doses below the threshold for activity (sub-threshold doses). Similarly, for the GSK3 inhibitor, the dose range includes doses in which the GSK3 inhibitor alone is active as well as sub-threshold doses. In vivo testing:
Drug-drug interactive increase in dopamine and Serotonin overflow in prefrontal cortex of rat.
Various drugs, including antipsychotics, antidepressants and nicotinic agonists increase dopamine (DA) extracellular levels (overflow) in prefrontal cortex (PFC). In schizophrenia, dopaminergic neurotransmission in the PFC is thought to be decreased and this is thought to be part of the pathophysiology of the cognitive deficits of schizophrenia. Therefore, compounds that increase DA overflow in the PFC may improve cognitive function in schizophrenia. In vivo microdialysis method was used to determine concentrations of dopamine (DA) and serotonin (5-HT) in the prefrontal cortex of the rats injected with α7 agonists.
Interactive effects of drugs on Novel Object Recognition
Potentiation of drug-induced enhancement of novel object recognition (NOR): Various classes of drugs (e.g. a7 nicotinic agonists) have been shown to improve performance of the NOR task in rodents. Drugs that enhance NOR performance may have therapeutic potential in CNS disorders with cognitive deficits including dementias (e.g. Alzheimer's disease) and psychoses (e.g. schizophrenia). Drugs that interact to additively or synergistically improve cognitive performance in NOR in rodents may have surprising activity in human diseases. The interactive effects of a GSK3 inhibitor and a α7 agonist on novel object recognition are tested in a mouse NOR model. Mice are allowed to explore first two identical objects (object A) during the sample period. Then 15 minutes later mice were allowed to explore another copy of object A and a second different object (B). Rodents preferentially explore novel objects over familiar objects unless they have forgotten the familiar object. In this version of the test, mice generally show no preference for the novel object by 15minutes. Therefore, drugs that induce preferential exploration of object B over object A supports drug-induced enhancement of memory function. Drugs were administered so that maximal plasma concentrations occurred at the time the sample period. It is contemplated that the combination of (a) an amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) an amount of a second therapeutic agent, which is a α7- nicotinic agonist provide synergistic or additive effects in treating CNS disorders such as neurodegenerative disorders, neuroinfiammatory disorders, cognitive disorders, dementia, Alzheimer's Disease, cognitive deficit in schizophrenia, mild cognitive impairment and age-associated memory impairment or any disorder mentioned below. Through combination of a disease modifying and symptomatic treatment the overall efficiency of the treatment will be enhanced. Compositions and methods described herein may offer advantages over previous methods for treating neuropsychiatric disorders. The method of treatment described herein may permit reduced quantities of these agents to be used and, therefore may permit improved management of disease symptoms such as reduction of disease-related side effects. A further advantage of this synergistic or additive effect may be a faster onset of the therapeutic action of the single compounds.

Claims

1. A combination comprising (a) a first therapeutic agent, which is a GSK3 inhibitor and
(b) a second therapeutic agent, which is an α7-nicotinic agonist.
2. A pharmaceutical composition comprising a combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) a therapeutically effective amount of a second therapeutic agent, which is an α7- nicotinic agonist, together with a pharmaceutically-acceptable vehicle, carrier or diluent.
3. The pharmaceutical composition according to claim 2, wherein the first therapeutic agent is selected from:
3-[7-(2-morpholin-4-ylethoxy)quinazolin-4-yl]-2-oxo-l,3-dihydroindole-5-carbonitrile;
3-[7-(2-methoxyethoxy)quinazolin-4-yl]-2-oxo-l,3-dihydroindole-5-carbonitrile;
3-[7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-yl]-2-oxo-l,3-dihydroindole-5- carbonitrile;
3-[7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]-2-oxo-l,3-dihydroindole-5-carbonitrile;
2-hydroxy-3-[5-(4-methylpiperazine-l-carbonyl)pyridin-2-yl]-lH-indole-5-carbonitrile;
1 -[(4-methoxyphenyl)methyl]-3-(5-nitro 1 ,3-thiazol-2-yl)urea;
2-hydroxy-3-[5-[(4-phenylpiperazin-l-yl)methyl]pyridin-2-yl]-lH-indole-5-carbonitrile; 2-hydroxy-3- [5 -(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5 -carbonitrile;
2-hydroxy-3- [5 -(4-methylpiperazin-l-yl)sulfonylpyridin-2-yl]-lH-indole-5 -carbonitrile;
2-hydroxy-3-[5-[(4-methylpiperazin-l-yl)methyl]pyridin-2-yl]-lH-indole-5-carbonitrile;
3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-5-nitro-lH-indol-2-ol;
2-hydroxy-3-[5-(pyrrolidin-l-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile; [6-(2-hydroxy-5-nitro-lH-indol-3-yl)pyridin-3-yl]-(4-methylpiperazin-l-yl)methanone;
2-hydroxy-3-[5-(l-piperidylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile;
2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-6-carbonitrile;
2-hydroxy-3-[5-(4-methylpiperazin-l-yl)sulfonylpyridin-2-yl]-lH-indole-6-carbonitrile;
3-fluoro-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-2-oxo-lH-indole-6-carbonitrile; [4-[5-(4-methoxyphenyl)-2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7-tetraen-8-yl]phenyl]-(4- methylpiperazin- 1 -yl)methanone;
3-(4-methoxyphenyl)-N-(2-morpholin-4-ylethyl)-5,7-diazabicyclo[4.3.0]nona-l,3,5,8- tetraene-9-carboxamide; 5 3-(4-chlorophenyl)-N-(2-morpholin-4-ylethyl)-5,7-diazabicyclo[4.3.0]nona-l,3,5,8- tetraene-9-carboxamide;
5-fluoro-N-[4-(4-methylpiperazin-l-yl)sulfonylphenyl]-4-(2-methyl-3-propan-2-yl- imidazol-4-yl)pyrimidin-2-amine;
[4-[[5-fluoro-4-(2-methyl-3-propan-2-yl-imidazol-4-yl)pyrimidin-2-yl]amino]phenyl]-(4- i o methylpiperazin- 1 -yl)methanone;
[4-[[5-fluoro-4-(2-methyl-3-propan-2-yl-imidazol-4-yl)pyrimidin-2-yl]amino]phenyl]- phenyl-methanone;
N-(3-methoxypropyl)-8-[4-(trifluoromethyl)phenyl]-2,7,9-triazabicyclo[4.3.0]nona-
1 ,3,5,7-tetraene-5-carboxamide; is 5-(4-methoxyphenyl)-8-[4-(l-piperidylmethyl)phenyl]-2,7,9-triazabicyclo[4.3.0]nona-
1,3,5,7-tetraene;
N-(3-methoxypropyl)-8-[4-(morpholin-4-ylmethyl)phenyl]-2,7,9-triazabicyclo[4.3.0]nona-
1 ,3,5,7-tetraene-5-carboxamide;
[4-[[5-fluoro-4-(2-methyl-3-propan-2-yl-imidazol-4-yl)pyrimidin-2-yl]amino]phenyl]- 20 pyridin-2-yl-methanone;
[4-[[4-(3-cyclohexyl-2-methyl-imidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]phenyl]-(4- methylpiperazin- 1 -yl)methanone;
[4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]phenyl]-(4- methylpiperazin- 1 -yl)methanone; 25 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin- 1 - yl)sulfonylphenyl]pyrimidin-2-amine;
4-(2,3-dimethylimidazol-4-yl)-5-fluoro-N-[4-(morpholin-4-ylmethyl)phenyl]pyrimidin-2- amine;
[4-[5-(4-chlorophenyl)-2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7-tetraen-8-yl]phenyl]-(4- 30 methylpiperazin- 1 -yl)methanone; N-(3-methoxypropyl)-8-[3-(2,2,3,3-tetrafluoropropoxymethyl)phenyl]-2,7,9- triazabicyclo[4.3.0]nona-l,3,5,7-tetraene-5-carboxamide;
[4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]phenyl]- pyridin-2-yl-methanone; 5 [4-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]phenyl]-pyridin-2-yl- methanone;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine;
[4-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]phenyl]-(4- i o methylpiperazin- 1 -yl)methanone;
4-(2,3-dimethylimidazol-4-yl)-5-fluoro-N-[4-[(4-methylpiperazin-l- yl)methyl]phenyl]pyrimidin-2-amine;
5 -fluoro-4- [2-methyl-3 -(oxan-4-yl)imidazol-4-yl] -N-(4-methylsulfonylphenyl)pyrimidin-
2-amine; is 5 -fluoro-4- [2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin-2- amine;
[4-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]-2-
(trifluoromethoxy)phenyl]-(4-methylpiperazin- 1 -yl)methanone;
5-fluoro-N-[4-(4-methylpiperazin-l-yl)sulfonylphenyl]-4-[3-(oxan-4-yl)-2- 20 (trifluoromethyl)imidazol-4-yl]pyrimidin-2-amine; azetidin-l-yl-[4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]phenyl]methanone;
5-fluoro-N-[3-methyl-4-(morpholin-4-ylmethyl)phenyl]-4-[2-methyl-3-(oxan-4- yl)imidazol-4-yl]pyrimidin-2-amine; 25 5-fluoro-N-[4-(morpholin-4-ylmethyl)phenyl]-4-[3-(oxan-4-yl)-2-
(trifluoromethyl)imidazol-4-yl]pyrimidin-2-amine;
5-fluoro-N-[4-(4-methylpiperazin-l-yl)sulfonylphenyl]-4-[3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-amine;
[4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- 30 yl] amino]phenyl] -(4-methylpiperazin- 1 -yl)methanone; 5 - [5 -fluoro-2-[ [4-(4-methylpiperazin- 1 -yl)sulfonylphenyl] amino]pyrimidin-4-yl]- 1 -(oxan-
4-yl)imidazole-2-carbonitrile;
5 -fluoro-N-[4-(4-methylpiperazin- 1 -yl)sulfonylphenyl] -4- [3 -methyl-2-
(trifluoromethyl)imidazol-4-yl]pyrimidin-2-amine; 5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine;
[4-[[5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2-yl]amino]phenyl]-
(4-methylpiperazin- 1 -yl)methanone;
N-(2-cyanoethyl)-3-[5-(4-methoxyphenyl)-2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7-tetraen- 8-yl]benzamide;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-methylsulfonyl-3-
(trifluoromethyl)phenyl]pyrimidin-2-amine; azetidin- 1 -yl-[4-[8-[4-(morpholin-4-ylmethyl)phenyl]-2,7,9-triazabicyclo[4.3.0]nona- l,3,5,7-tetraen-5-yl]phenyl]methanone; 8-[4-(morpholin-4-ylmethyl)phenyl]-N-pyridin-3-yl-2,7,9-triazabicyclo[4.3.0]nona-
1 ,3,5,7-tetraene-5-carboxamide;
2-[3-[8-[4-(4-methylpiperazine-l-carbonyl)phenyl]-2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7- tetraen-5-yl]phenoxy]acetonitrile;
5 -fluoro-N-(4-methylsulfonylphenyl)-4- [3 -propan-2-yl-2-(trifluoromethyl)imidazol-4- yl]pyrimidin-2-amine;
5-fluoro-N-[4-(4-methylpiperazin-l-yl)sulfonylphenyl]-4-[3-propan-2-yl-2-
(trifluoromethyl)imidazol-4-yl]pyrimidin-2-amine;
[4-[[5-fluoro-4-[3-propan-2-yl-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl] amino]phenyl] -(4-methylpiperazin- 1 -yl)methanone; 4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(4-methylsulfonylphenyl)pyrimidin-2-amine;
4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine;
[4-[[4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]phenyl]-(4- methylpiperazin- 1 -yl)methanone; 4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4-ylmethyl)phenyl]pyrimidin-2- amine;
5-(4-methoxyphenyl)-8-(3-methylsulfonylphenyl)-2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7- tetraene; [4-[5-(3-fluoro-4-methoxy-phenyl)-2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7-tetraen-8- yl]phenyl]-(4-methylpiperazin- 1 -yl)methanone;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylsulfonylpyridin-3- yl)pyrimidin-2-amine;
(2,6-dimethylmorpholin-4-yl)-[4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-yl]amino]phenyl]methanone;
[5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]pyridin-2-yl]-
(4-methylpiperazin- 1 -yl)methanone;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(l-morpholin-4- ylethyl)phenyl]pyrimidin-2-amine; 5-fluoro-N-(4-methylsulfonylphenyl)-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4- yl]pyrimidin-2-amine; azetidin-l-yl-[2-chloro-4-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2- yl] amino]phenyl]methanone; azetidin-l-yl-[4-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]-2- methyl-phenyl]methanone; azetidin-l-yl-[5-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]pyridin-2- yljmethanone; azetidin-l-yl-[4-[[4-(2,3-dimethylimidazol-4-yl)-5-fluoro-pyrimidin-2-yl]amino]-2-
(trifluoromethoxy)phenyl]methanone; azetidin- 1 -yl- [3 -chloro-5 - [[4-(2,3 -dimethylimidazol-4-yl)-5 -fluoro-pyrimidin-2- yl]amino]pyridin-2 -yljmethanone;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[6-(morpholin-4-ylmethyl)pyridin-3- yl]pyrimidin-2-amine;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine; azetidin-l-yl-[3-chloro-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]methanone;
N-(6-ethylsulfonylpyridin-3-yl)-5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-amine; [3-chloro-5-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]-(4-methylpiperazin-l-yl)methanone;
5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N-methyl-N- propan-2-yl-pyridine-2-carboxamide;
N-ethyl-5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N- methyl-pyridine-2-carboxamide;
3-[4-[8-[4-(morpholin-4-ylmethyl)phenyl]2,7,9-triazabicyclo[4.3.0]nona-l,3,5,7-tetraene-
5-carbonyl]piperazin-l-yl]propanenitrile;
[3-chloro-5-[[5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]-(4-methylpiperazin-l-yl)methanone; [3-chloro-5-[[5-fluoro-4-[3-methyl-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]pyridin-2-yl]-(l-piperidyl)methanone; azetidin- 1 -yl- [3 -chloro-5 -[ [5 -fluoro-4-[3 -methyl-2-(trifluoromethyl)imidazol-4- yl]pyrimidin-2-yl]amino]pyridin-2-yl]methanone;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[6-(4-methylpiperazin-l- yl)sulfonylpyridin-3 -yl]pyrimidin-2-amine;
N-[6-[(4,4-difluoro-l-piperidyl)methyl]pyridin-3-yl]-5-fluoro-4-[2-methyl-3-(oxan-4- yl)imidazol-4-yl]pyrimidin-2-amine;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(oxan-4-yl)pyrimidin-2-amine; l-[4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-l- piperidyl]ethanone;
[4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-l-piperidyl]- phenyl-methanone; l-[4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-l- piperidyl]-2-phenyl-ethanone; benzyl 4-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2- yl]amino]piperidine- 1 -carboxylate;
5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(l-methylsulfonyl-4- piperidyl)pyrimidin-2-amine; N-[l-(benzenesulfonyl)-4-piperidyl]-5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4- yl]pyrimidin-2-amine;
5-[[5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]pyrimidin-2-yl]amino]-N,N- dimethyl-pyridine-2-sulfonamide; an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof or a solvate or a solvate of a pharmaceutically acceptable salt thereof.
4. The pharmaceutical composition according to claim 2, wherein the second therapeutic agent is selected from:
S(-)-spiro [ 1 -azabicyclo [2.2.2] octane-3 ,5 ' -oxazolidine]-2 ' -one; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
((-)-spiro[l-azabicyclo[2.2.2]octane-3,2'-(2',3'-dihydrofuro[2,3-B]pyridine)];
5'-bromospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-phenylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-nitrospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)- furo[2,3-b]pyridine]; l '-chlorospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]isoquinoline];
5'-(phenylcarboxamido)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(phenylaminocarbonylamino)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine];
5'-(phenylsulfonylamido)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 5'-aminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N-methylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N,N-dimethylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N,N-diethylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N-ethylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 5'-N-benzylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 5'-N-formamidospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N-acetamidospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]isoquinoline]; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]quinoline]; 5'-ethenylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(E)-(phenylethenyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(4-morpholino)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(l-azetidinyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(E)-(2-(4-pyridyl)ethenyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-fUro[2,3- b]pyridine];
5'-(E)-(2-(2-pyridyl)ethenyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine];
5'-(2-trimethylsilylethynyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine]; 5'-ethynylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(2-furyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(3-pyridyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-methylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine-5'carbonitrile]; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine-5'carboxamide];
5'-N'-(3-chlorophenyl)aminocarbonylminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)- furo [2,3 -b]pyridine] ;
5'-N'-(2-nitrophenyl)aminocarbonylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)- furo [2,3 -b]pyridine] ; 4'-chlorospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
4'-methoxyspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
4'-phenylthiospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
4'-(N-2-aminoethyl)aminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
4'-phenylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 4'-methylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 4'-(4-N-methylpiperazin-l-yl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine];
4'-chloro-spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[3,2-c]pyridine]; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[3,2-c]pyridine]; spiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine-7'-oxide]; spiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine-6'-carbonitrile];
6'-chlorospiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine];
6'-fluorospiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine]; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; spiro[l-azabicyclo[2.2.2]octane-3,2'(3'H)-furo[2,3-b]pyridine-7'-oxide];
5'-bromospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-phenylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-nitrospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)- furo[2,3-b]pyridine];
5'-(phenylcarboxamido)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 5'-(phenylaminocarbonylamino)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3- b]pyridine];
5'-(phenylsulfonylamido)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-aminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N-methylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 5'-N,N-dimethylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N,N-diethylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N-ethylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N-benzylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-N-formamidospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 5'-N-acetamidospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-ethenylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(E)-(phenylethenyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(4-morpholino)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(l-azetidinyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; 5'-(E)-(2-(4-pyridyl)ethenyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3Η)-furo[2,3- b]pyridine];
5'-(E)-(2-(2-pyridyl)ethenyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3Η)-furo[2,3- b]pyridine]; 5'-(2-trimethylsilylethynyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-ethynylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-(2-furyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3Η)-furo[2,3-b]pyridine];
5'-(3-pyridyl)spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine];
5'-methylspiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine]; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine-5'carbonitrile]; spiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)-furo[2,3-b]pyridine-5'carboxamide];
5'-N'-(3-chlorophenyl)aminocarbonylminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)- furo [2,3 -b]pyridine] ;
5'-N'-(2-nitrophenyl)aminocarbonylaminospiro[l-azabicyclo[2.2.2]octane-3,2'-(3'H)- furo[2,3-b]pyridine];
N,N-dimethyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridm]-5'- yl] -2-thienyl} methenamine;
N,N-dimethyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridm]-5'- yl] -2-furyl} methenamine; N,N-dimethyl-l-{4-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridin]-5'- yl] -2-thienyl} methenamine;
N,N-dimethyl-l-{4-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridin]-5'- yl] -2-furyl} methenamine;
N-methyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridin]-5'-yl]-2- thienyl}methanamine;
N-methyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridin]-5'-yl]-2- furyl}methenamine;
(2i?)-5'-[5-(pyrrolidin-l-ylmethyl)-2-furyl]-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'- furo[2,3-ό]pyridine]; (2i?)-5'-[5-(morpholin-4-ylmethyl)-2-furyl]-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'- furo [2,3 -ό]pyridine] ;
N,N-dimethyl-l-{4-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridm]-5'- yl] -2-furyl} methenamine; (2i?)-5'-[5-(pyrrolidin-l-ylmethyl)-3-furyl]-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'- furo [2,3 -ό]pyridine] ;
(2i?)-5'-[5-(morpholin-4-ylmethyl)-3-furyl]-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'- furo[2,3-ό]pyridine];
N-methyl-N-({5-[(2i?)-3>H-spiro[4-azabicyclo[2.2.2]octane-2,2>-furo[2,3-/)]pyridin]-5>-yl]- 2-furyl}methyl)cyclopropanamine
N-methyl-N-({4-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridm]-5'-yl]-
2-furyl}methyl)cyclopropanamine; l-{5-[(2i?)-3>H-spiro[4-azabicyclo[2.2.2]octane-2,2>-furo[2,3-/)]pyridin]-5>-yl]-2- furyl}methenamine; l-{5-[(2i?)-3>H-spiro[4-azabicyclo[2.2.2]octane-2,2>-furo[2,3-/)]pyridin]-5>-yl]-2- thienyl}methenamine; l-{4-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridm]-5'-yl]-2- furyl}methenamine;
(R)-5-(6-methoxypyridin-3-yl)-3H-r-azaspiro[furo[2,3-b]pyridine-2,3'- bicyclo[2.2.2]octane];
(R)-5-(5-(morpholinomethyl)furan-3-yl)-3H-r-azaspiro[furo[2,3-b]pyridine-2,3'- bicyclo[2.2.2]octane]; an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof or a solvate or a solvate of a pharmaceutically acceptable salt thereof.
5. The pharmaceutical composition according to claim 2, wherein (a) the first therapeutic agent and (b) the second therapeutic agent are selected from:
(a) 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile and
(b) S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one; (a) 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile and (b) ((-)-spiro[l-azabicyclo[2.2.2]octane-3,2'-(2',3'-dihydrofuro[2,3-B]pyridine)]; (a) 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile and (b) N-methyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-/)]pyridm]-5'- yl] -2-thienyl} methanamine; (a) 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile and
(b) N,N-dimethyl-l-{5-[(2R)-3Η-spiro[4-azabicyclo[2.2.2]octane-2,2'-fUro[2,3-b]pyridin]- 5'-yl]-2-furyl}methenamine;
(a) 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile and
(b) (R)-5-(5-(morpholinomethyl)furan-3-yl)-3H- 1 '-azaspiro[furo[2,3-b]pyridine-2,3'- bicyclo[2.2.2]octane];
(a) 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile and
(b) (R)-5-(6-methoxypyridin-3-yl)-3H-r-azaspiro[furo[2,3-b]pyridine-2,3'- bicyclo[2.2.2]octane];
(a) [4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]phenyl]-(4-methylpiperazin-l-yl)methanone and (b) S(-)-spiro[l- azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one;
(a) [4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]phenyl]-(4-methylpiperazin-l-yl)methanone and (b) ((-)-spiro[l- azabicyclo[2.2.2]octane-3,2'-(2',3'-dihydrofuro[2,3-B]pyridine)]; (a) [4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]phenyl]-(4-methylpiperazin-l-yl)methanone and (b) Λ/-methyl-l-{5-[(2i?)-3'H- spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-ό]pyridin]-5'-yl]-2-thienyl}methanamine; (a) [4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]phenyl]-(4-methylpiperazin-l-yl)methanone and (b) N,N-dimethyl-l-{5-[(2R)- 3Η-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-yl]-2-furyl}methenamine; (a) [4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]phenyl]-(4-methylpiperazin-l-yl)methanone and (b) (R)-5-(5- (morpholinomethyl)furan-3-yl)-3H-r-azaspiro[furo[2,3-b]pyridine-2,3'- bicyclo[2.2.2]octane]; (a) [4-[[5-fluoro-4-[3-(oxan-4-yl)-2-(trifluoromethyl)imidazol-4-yl]pyrimidin-2- yl]amino]phenyl]-(4-methylpiperazin-l-yl)methanone and (b) (R)-5-(6-methoxypyridin-3- yl)-3H-r-azaspiro[furo[2,3-b]pyridine-2,3'-bicyclo[2.2.2]octane];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin- 2-amine and (b) S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'-one;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin-
2-amine and (b) ((-)-spiro[l-azabicyclo[2.2.2]octane-3,2'-(2',3'-dihydrofuro[2,3-
B]pyridine)];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin- 2-amine and (b) N-methyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'-furo[2,3- ό]pyridin]-5'-yl]-2-thienyl}methanamine;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin-
2-amine and (b) N,N-dimethyl-l-{5-[(2R)-3'H-spiro[4-azabicyclo[2.2.2]octane-2,2'- furo [2,3 -b]pyridin]-5 ?-yl] -2-furyl} methenamine; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin-
2-amine and (b) (R)-5-(5-(morpholinomethyl)furan-3-yl)-3H-r-azaspiro[furo[2,3- b]pyridine-2,3'-bicyclo[2.2.2]octane];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-methylpyridin-3-yl)pyrimidin-
2-amine and (b) (R)-5-(6-methoxypyridin-3-yl)-3H-r-azaspiro[furo[2,3-b]pyridine-2,3'- bicyclo[2.2.2]octane];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine and (b) S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'- oxazolidine]-2'-one;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine and (b) ((-)-spiro[l-azabicyclo[2.2.2]octane-3,2'-
(2',3'-dihydrofuro[2,3-B]pyridine)];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine and (b) Λ/-methyl-l-{5-[(2i?)-3'H-spiro[4- azabicyclo[2.2.2]octane-2,2'-furo[2,3-ό]pyridin]-5'-yl]-2-thienyl}methanamine; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine and (b) N,N-dimethyl-l-{5-[(2R)-3'H-spiro[4- azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-yl]-2-furyl} methenamine;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine and (b) (R)-5-(5-(morpholinomethyl)furan-3-yl)-3H- r-azaspiro[furo[2,3-b]pyridine-2,3'-bicyclo[2.2.2]octane];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(4-methylpiperazin-l- yl)sulfonylphenyl]pyrimidin-2-amine and (b) (R)-5-(6-methoxypyridin-3-yl)-3H-r- azaspiro[furo[2,3-b]pyridine-2,3'-bicyclo[2.2.2]octane]; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine and (b) S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'-oxazolidine]-2'- one;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine and (b) ((-)-spiro[l-azabicyclo[2.2.2]octane-3,2'-(2',3'- dihydrofuro[2,3-B]pyridine)];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine and (b) Λ/-methyl-l-{5-[(2i?)-3'H-spiro[4-azabicyclo[2.2.2]octane-
2,2'-furo[2,3-ό]pyridin]-5'-yl]-2-thienyl}methanamine;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine and (b) N,N-dimethyl- 1 - {5-[(2R)-3'H-spiro[4- azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-yl]-2-furyl}methenamine;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine and (b) (R)-5-(5-(morpholinomethyl)furan-3-yl)-3H-r- azaspiro[furo[2,3-b]pyridine-2,3'-bicyclo[2.2.2]octane]; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-(6-propan-2-ylsulfonylpyridin-3- yl)pyrimidin-2-amine and (b) (R)-5-(6-methoxypyridin-3-yl)-3H4'-azaspiro[furo[2,3- b]pyridine-2,3'-bicyclo[2.2.2]octane];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine and (b) S(-)-spiro[l-azabicyclo[2.2.2]octane-3,5'- oxazolidine]-2'-one; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine and (b) ((-)-spiro[l-azabicyclo[2.2.2]octane-3,2'-(2',3'- dihy drofuro [2 , 3 -B Jpyridine)] ;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine and (b) TV-methyl- 1 - {5-[(2i?)-3'H-spiro[4- azabicyclo[2.2.2]octane-2,2'-furo[2,3-ό]pyridin]-5'-yl]-2-thienyl}methanamine;
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine and (b) N,N-dimethyl-l-{5-[(2R)-3'H-spiro[4- azabicyclo[2.2.2]octane-2,2'-furo[2,3-b]pyridin]-5'-yl]-2-furyl}methenamine; (a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine and (b) (R)-5-(5-(morpholinomethyl)furan-3-yl)-3H- r-azaspiro[furo[2,3-b]pyridine-2,3'-bicyclo[2.2.2]octane];
(a) 5-fluoro-4-[2-methyl-3-(oxan-4-yl)imidazol-4-yl]-N-[4-(morpholin-4- ylmethyl)phenyl]pyrimidin-2-amine and (b) (R)-5-(6-methoxypyridin-3-yl)-3H-r- azaspiro[furo[2,3-b]pyridine-2,3'-bicyclo[2.2.2]octane]; an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof or a solvate or a solvate of a pharmaceutically acceptable salt thereof.
6. A kit comprising a dosage unit of a first therapeutic agent, which is a GSK3 inhibitor and a dosage unit of a second therapeutic agent, which is an α7 -nicotinic agonist, optionally with instructions for use.
7. A method for treating CNS disorders in a subject in need thereof comprising administering to said subject (a) a therapeutically effective amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) a therapeutically effective amount of a second therapeutic agent, which is an α7 -nicotinic agonist.
8. The method according to claim 7, wherein the first therapeutic agent is a compound as defined in claim 3 and the second therapeutic agent is a compound as defined in claim 4.
9. The method according to claim 7, wherein (a) the first therapeutic agent and (b) the second therapeutic agent are selected from the list defined in claim 5.
10. The method according to any one of claims 7 to 9, wherein the CNS disorder is dementia, Alzheimer's Disease, Cognitive Deficit in Schizophrenia, Mild Cognitive Impairment Age- Associated Memory Impairment or Bipolar Disorder.
11. The method according to any one of claims 7 to 10, using the kit according to claim 6.
12. Use of a pharmaceutical composition comprising a combination of (a) an amount of a first therapeutic agent, which is a GSK3 inhibitor and (b) an amount of a second therapeutic agent, which is an α7 -nicotinic agonist for prevention and/or treatment of CNS disorders.
13. Use of a pharmaceutical composition comprising a combination of (a) a therapeutically effective amount of a first therapeutic agent, hich is defined in claim 3 and (b) a therapeutically effective amount of a second therapeutic agent, which is defined in claim 4 for prevention and/or treatment of CNS disorders.
14. Use of a pharmaceutical composition comprising a combination of (a) a therapeutically effective amount of a first therapeutic agent and (b) a therapeutically effective amount of a second therapeutic agent, which are selected from the list defined in claim 5, for prevention and/or treatment of CNS disorders.
15. The use according to any one of claims 12 to 14, wherein the CNS disorders is dementia, Alzheimer's Disease, cognitive deficit in schizophrenia, mild cognitive impairment, age-associated memory impairment or Bipolar Disorder.
PCT/SE2008/050897 2007-07-30 2008-07-29 New therapeutic combination of a gsk3 inhibitor and an a7-nicotinic agonist 960 WO2009017454A1 (en)

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