WO2010080757A2

WO2010080757A2 - Combinations with an alpha-4beta-2 nicotinic agonist

Info

Publication number: WO2010080757A2
Application number: PCT/US2010/020118
Authority: WO
Inventors: Edwin Johnson; Eva Nordstrom; Samatha Louise Budd Haeberlein; Merouane Bencherif
Original assignee: Astrazeneca Ab; Targacept, Inc.
Priority date: 2009-01-07
Filing date: 2010-01-05
Publication date: 2010-07-15
Also published as: WO2010080757A3

Abstract

The present invention related to a combination of (a) a α4β2 nicotinic agonist and (b) a Second Therapeutic Agent, as defined under group A or group B. 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 cognitive dysfunction in schizophrenia, dementia and/or Alzheimer's disease or those disorders defined below.

Description

COMBINATIONS WITH AN ALPHA-4BETA-2 NICOTINIC AGONIST

FIELD OF THE INVENTION

The present invention relates to a combination of (a) an α4β2 nicotinic agonist and (b) a second therapeutical agent, whereby the second agent may be an agent that may induce cognitive dysfunction. 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 cognitive dysfunction in schizophrenia, dementia and/or Alzheimer's disease.

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 has been shown to restore sensory gating (P50 wave) in both animals and schizophrenics.

Schizophrenia and depression have a well-characterized and unique profile of cognitive deficits or dysfunctions and physical symptoms, which represent a large unmet medical need.

SUMMARY OF THE INVENTION

The nicotinic agonists are those compounds having agonist or partial agonist activity against a subpopulation of nicotine receptors such as the alpha-4/beta-2, or α4β2, 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 amount of a nicotinic agonist 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 disorder, and amelioration of the reoccurrence of a CNS disorder, 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 disclosures of which are incorporated herein by reference in their entirety. It is contemplated that the combination of (a) a therapeutically effective amount of a first therapeutic agent, which is an α4β2 nicotinic agonist and (b) a therapeutically effective amount of a Second Therapeutic Agent, as defined under group A or group B, provide synergistic or additive effects in treating CNS disorders such as neurodegenerative disorders, neuroinflammatory disorders, cognitive disorders, or disorder such as cognitive dysfunction in schizophrenia (CDS), Alzheimer's Disease (AD), attention deficit disorder (ADD), pre-senile dementia (early onset of Alzheimer's Disease), dementia of the Alzheimer's type, mild cognitive impairment, age associated memory impairment, attention deficit hyperactivity disorder (ADHD) or those disorders defined below.

Compositions and methods described herein offer advantages over previous methods for treating CNS disorders. The method of treatment described herein will enhance the effect of either the α4β2 nicotinic agonist or the Second Therapeutic Agent, as defined under group A or group B, when an α4β2 nicotinic agonist is taken in combination with a Second Therapeutic Agent, as defined under group A or group B, and therefore permit reduced quantities of these agents to be used, and therefore permit improved management of disease symptoms. A further advantage of this synergistic/additive effect may be a faster onset of the therapeutic action of the compounds. Other features and advantages will be apparent from the following detailed description and from the claims.

DETAILED DESCRIPTION OF THE INVENTION Combination

A first aspect of the invention relates to a combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is an α4β2 nicotinic agonist and (b) a therapeutically effective amount of a second therapeutic agent, which is a Second Therapeutic Agent as defined under group A or group B. In one embodiment of the invention the combination comprises the compounds (a) and (b) mentioned below.

a4β2 Nicotinic agonists α4β2 Nicotinic agonists useful in the combination of the present invention are those described in US 6,603,011 and US 6,958,399, which are hereby incorporated by reference. Particular nicotinic agonists are compounds N-methyl-5-[3-(5-isopropoxypyridin)yl]-4-penten-2- amine, (4E)-N-methyl-5-[3-(5-isopropoxypyridin)yl]-4-penten-2-amine and (2S)-(4E)-N-methyl- 5-[3-(5-isopropoxypyridin)yl]-4-penten-2-amine, metabolites or pro-drugs and pharmaceutically- acceptable salts, solvates or solvated salts of any of the foregoing. The preparation of these compounds is described in said US patents.

Other α4β2 nicotinic agonists useful in the combination of the present invention are those described in PCT application WO08/057938, which is hereby incorporated by reference. A particular nicotinic agonist is compound N-(5-chlorofuran-2-ylcarbonyl)-3,7- diazabicyclo[3.3.0]octane, and metabolites or pro-drugs and pharmaceutically-acceptable salts, solvates or solvated salts of any of the foregoing. The preparation of this compound is described in said PCT patent application.

Further α4β2 nicotinic agonists useful in the combination of the present invention are those described in PCT application WO04/078752, which is hereby incorporated by reference. Particular nicotinic agonists are the compounds (E)-3-(2-(pyrrolidin-3-yl)vinyl)-5-(tetrahydro- 2H-pyran-4-yloxy)pyridine and (R,E)-3 -(2-(pyrrolidin-3 -yl)vinyl)-5 -(tetrahydro-2H-pyran-4- yloxy)pyridine, and metabolites or pro-drugs and pharmaceutically-acceptable salts, solvates or solvated salts of any of the foregoing. The preparation of these compounds is described in said PCT patent application. Further α4β2 nicotinic agonists useful in the combination of the present invention are those described in PCT application WO08/121686, which is hereby incorporated by reference. A particular nicotinic agonist is compound N-propyl-3-azabicyclo[3.3. l]nonane-7-carboxamide, and metabolites or pro-drugs and pharmaceutically-acceptable salts, solvates or solvated salts of any of the foregoing. The preparation of these compounds is described in said PCT patent application.

Other α4β2 nicotinic agonists useful in the combination of the present invention are ABT-089, ABT-418, ABT-594, ABT-894, (2S)-(4E)-5-[3-(5-isopropoxypyridin)yl]-4-penten-2- amine , TC-2696, TC-6499 and varenicline. For the avoidance of doubt the present invention relates to any combination of any one specific α4β2 nicotinic agonist mentioned above with any one specific Second Therapeutic Agent, as defined under group A or group B.

One embodiment of the invention relates a combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is (2S)-(4E)-N-methyl-5-[3-(5- isopropoxypyridin)yl]-4-penten-2-amine, N-(5-chlorofuran-2-ylcarbonyl)-3,7- diazabicyclo[3.3.0]octane, (R,E)-3-(2-(pyrrolidin-3-yl)vinyl)-5-tetrahydro-2H-pyran-4- yloxy)pyridine, N-propyl-S-azabicyclopj.^nonane-V-carboxamide , and metabolites or prodrugs and pharmaceutically-acceptable salts, solvates or solvated salts of any of the foregoing, and (b) a therapeutically effective amount of a second therapeutic agent, which is a Second

Therapeutic Agent, as defined under group A or group B, as a free base, an isomer, a metabolite or a pro-drug or a pharmaceutically acceptable salt.

Second Therapeutic Agent Group A In one embodiment of the invention the Second Therapeutic Agent Group A comprises of the group selected from:

(i) antidepressants such as amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, reboxetine, robalzotan, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine, Exalon, Chantix, Zyban (buproprion) and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;

(ii) atypical antipsychotics including, for example, quetiapine and pharmaceutically active isomer(s) and metabolite(s) thereof; (iii) antipsychotics including, for example, amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone, haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpiride, suproclone, suriclone, thioridazine, trifluoperazine, trimetozine, valproate, valproic acid, zopiclone, zotepine, ziprasidone and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;

(iv) anxiolytics including for example alnespirone, azapirones,benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, zolazepam or other modulators of 5HT neurotransmitters such as 5HT_IB or/and _ID or 5HTδ,and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;

(v) anticonvulsants including, for example, carbamazepine, valproate, lamotrogine, gabapentin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;

(vi) Alzheimer's therapies including for example donepezil, rivastigmine, tacrine and memantine, dimebon, galantamine, GAM42-, RAGE-, KCNQ2-, or INK.NAC- receptor modulators and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;

(vii) Parkinson's therapies including, for example, deprenyl, L-dopa, Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists and inhibitors of neuronal nitric oxide synthase and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;

(viii) migraine therapies including, for example, almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; (ix) stroke therapies including, for example, abciximab, activase, NXY-059, citicoline, crobenetine, desmoteplase,repinotan, traxoprodil and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;

(x) urinary incontinence therapies including, for example, darafenacin, falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, tolterodine and and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;

(xi) neuropathic pain therapies including, for example, gabapentin, lidoderm, pregablin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;

(xii) nociceptive pain therapies such as celecoxib, etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;

(xiii) insomnia therapies including, for example, allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital, phenobarbital, propofol, roletamide, triclofos,secobarbital, zaleplon, Zolpidem and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;

(xiv) mood stabilizers including, for example, carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, verapamil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;

(xv) statins such as atorvastatin, simvastatin, pravastatin, lovastatin and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof; or

(xvi) nutraceuticals and and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof;

Second Therapeutic Agent Group B

In a second embodiment of the invention the Second Therapeutic Agent Group B comprises of the compounds that may induce cognitive dysfunction. Examples of such compounds may be selected from: (i) anticholinergics, especially antimuscarinics such as Trospium, tolterodine, solifenacin, darifenacin used for indications such as overactive bladder (Eur. Urology 50: 211 (2006);

(ii) antihistamines, such as diphenhydramine used for indications such as allergies (J. Allergy and Clin. Immunol. 105: S622 (2000)); (iii) benzodiazepines such as diazepam, triazolam used for indications such as anxiety, seizures (Allergy and Clin. Immunol. 105: S622 (2000));

(iv) barbiturates such as phenobarbital used for indications such as anxiety, seizures (The Pharmaceut. Jour. 264: #7079, 103);

(v) anticonvulsants such as phenytoin, gabapentin used for indications such as epilepsy; (vi) muscle relaxants such as Baclofen used for indications such as anxiety;

(vii) sedative-hypnotics such as Zolpidem, Zaleplon used for indications such as sleeping disorders; and

(viii) chemotherapeutics such as used for indications such as cancer.

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. 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 both pharmaceutically- acceptable acid addition salts and pharmaceutically-acceptable cationic salts. The expression "pharmaceutically-acceptable cationic salts" is intended to define 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 define 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 α4β2 nicotinic agonist, may be, but are not limited to, tartaric acid, p-hydroxybenzoic acid, phosphoric acid, edisylic acid (1,2-ethanedisulfonic acid), citric acid, orotic acid (uracil-6-carboxylic acid), R-mandelic acid, sulfuric acid, 1,5- naphthalenedisulfonic acid, D-aspartic acid, maleic acid, p-toluenesulfonic acid, and lysine monohydrochloride salts.

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.

Pharmaceutical 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 an α4β2 nicotinic agonist and (b) a therapeutically effective amount of a second therapeutic agent, which is a Second Therapeutic Agent, as defined under group A or group B, together with a pharmaceutically-acceptable vehicle, carrier, excipients 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 (a) and one for (b).

For the avoidance of doubt the present invention relates to this second aspect of the invention comprising any combination of any one specific α4β2 nicotinic agonist mentioned above with any one specific Second Therapeutic Agent, as defined under group A or group B.

The combinations 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, and intramuscular.

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 formulations 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., subcutaneous Iy 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. Other 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 combinations described herein can also be administered in a controlled release formulation (definition) 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.

Kits

A third aspect of the invention relates to a kit comprising a dosage unit of a mixture of a first therapeutic agent, which is an α4β2 nicotinic agonist and a dosage unit of a second therapeutic agent, which is a Second Therapeutic Agent, as defined under group A or group B, optionally with instructions for use.

Methods of treatment A fourth aspect of the invention relates to a method for treating CNS disorders such as neurodegenerative disorders, neuroinflammatory disorders, cognitive disorders, or any disorder mentioned below, in a subject in need thereof comprising administering simultaneously, sequentially or separately, to said subject (a) a therapeutically effective amount of a first therapeutic agent, which is an α4β2 nicotinic agonist and (b) a therapeutically effective amount of a second therapeutic agent, which is a Second Therapeutic Agent, as defined under group A or group B, wherein the amounts of (a) and (b) are together synergistically/additively effective in the treatment.

In one embodiment agent (a) and (b) are administered simultaneously. In another embodiment agent (a) and (b) are administered sequentially. In one embodiment agent (a) and (b) are administered separately.

Neurodegenerative Disorder(s) include, but are not limited to Alzheimer's disease (AD), Dementia, Cognitive Dysfunction in Schizophrenia (CDS), Mild Cognitive Impairment (MCI), Age- Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD), Cognitive Impairment 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.

The invention further relates to therapies for the treatment of: 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). The invention further relates to therapies for the treatment of:

Cognitive Disorder(s) including but 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 Dysfunction in Schizophrenia (CDS); c) Mild Cognitive Impairment (MCI); d) Age-Associated Memory Impairment (AAMI); e) Age-Related Cognitive Decline (ARCD); f) Cognitive Impairment No Dementia (CIND); g) Addictions such as nicotine addiction.

The invention further relates to therapies for the treatment of CNS disorders, such as cognitive dysfunction in schizophrenia (CDS), Alzheimer's Disease (AD), attention deficit disorder (ADD), pre-senile dementia (early onset of Alzheimer's Disease), dementia of the Alzheimer's type, mild cognitive impairment, age associated memory impairment, attention deficit hyperactivity disorder (ADHD), cognitive dysfunction in depression. In another embodiment neurodegenerative disorders, neuroinflammatory disorders, cognitive disorders are selected from the group consisting of cognitive dysfunction in schizophrenia, depression, dementia and/or Alzheimer's disease.

One embodiment of the invention relates to the methods mentioned above wherein the first therapeutic agent (2S)-(4E)-N-methyl-5-[3-(5-isopropoxypyridin)yl]-4-penten-2-amine, N- (5-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane, (R,E)-3-(2-(pyrrolidin-3-yl)vinyl)- 5-tetrahydro-2H-pyran-4-yloxy)pyridine, N-propyl-3-azabicyclo[3.3.1 ]nonane-7-carboxamide, and metabolites or pro-drugs and pharmaceutically-acceptable salts, solvates or solvated salts of any of the foregoing. One embodiment of the invention relates to a method of treating CNS disorders, such as cognitive dysfunction in schizophrenia (CDS), Alzheimer's Disease (AD), attention deficit disorder (ADD), pre-senile dementia (early onset of Alzheimer's Disease), dementia of the Alzheimer's type, mild cognitive impairment, age associated memory impairment, attention deficit hyperactivity disorder (ADHD), cognitive dysfunction in depression or those disorders mentioned 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 cognitive dysfunction in schizophrenia (CDS), Alzheimer's Disease (AD), attention deficit disorder (ADD), pre-senile dementia (early onset of Alzheimer's Disease), dementia of the Alzheimer's type, mild cognitive impairment, age associated memory impairment, attention deficit hyperactivity disorder (ADHD), cognitive dysfunction in depression or those disorders mentioned above, in a subject in need thereof using the pharmaceutical composition of the second aspect of the invention, comprising the combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is an α4β2 nicotinic agonist and (b) a therapeutically effective amount of a second therapeutic agent, which is a Second Therapeutic Agent, as defined under group A or group B.

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 an α4β2 nicotinic agonist and (b) a therapeutically effective amount of a second therapeutic agent, which is a Second Therapeutic Agent, as defined under group A or group B, for the manufacturing of a medicament for use simultaneously, sequentially 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 an α4β2 nicotinic agonist and (b) a therapeutically effective amount of a second therapeutic agent, which is a Second Therapeutic Agent, as defined under group A or group B, for the manufacturing of a medicament for simultaneously, sequentially or separately, treatment of CNS disorders, such as cognitive dysfunction in schizophrenia (CDS), Alzheimer's Disease (AD), attention deficit disorder (ADD), pre-senile dementia (early onset of Alzheimer's Disease), dementia of the Alzheimer's type, mild cognitive impairment, age associated memory impairment, attention deficit hyperactivity disorder (ADHD), cognitive dysfunction in depression or those disorders mentioned above.

Dosages

The effective dose of the α4β2 nicotinic agonist and the Second Therapeutic Agent, as defined under group A or group B, in the combinations of 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.

Typically, the effective dose of nicotinic agonists generally requires administering the compound in a therapeutically effective amount of less than 0.5 mg/kg of patient weight. Often, the nicotinic agonists are administered in an amount from less than about 100 μg/kg of patient weight, and occasionally between about 10 μg/kg to less than 100 μg/kg of patient weight. The foregoing effective doses typically represent that amount administered as a single dose, or as one or more doses administered over a 24 hours period. For human patients, the effective dose of the nicotinic agonists generally requires administering the nicotinic agonist in a therapeutically effective amount of at least about 1 , often at least about 10, and frequently at least about 25 mg/ 24 hr/ patient. For human patients, the effective dose of the nicotinic agonists requires administering the nicotinic agonist which generally does not exceed about 60, often does not exceed about 100, and frequently does not exceed about 100 mg/ 24 hr/ patient. In addition, administration of the effective dose is such that the concentration of the nicotinic agonist within the plasma of the patient normally does not exceed 500 ng/mL, and frequently does not exceed 100 ng/mL.

Typically, the effective dose of nicotinic agonists generally requires administering the compound in a therapeutically effective amount of less than about 10 mg to about 400 mg. More preferably, each dose of the component contains about 50 mg to about 200 mg of the agent, and even more preferably, 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. The term "therapeutically-effective amount" as used herein refers to a sufficient amount of the compound to treat cognitive impairment disorders 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, e.g. a nicotinic agonist.

"Synergy" means an improved effect of the two agents in the combination, which is greater than the additive effect of the two agents.

Examples

EXAMPLE 1

A pharmaceutical composition is prepared by combining a α4β2 nicotinic agonist and a

Second Therapeutic Agent, as defined under group A or group B, in a pharmaceutically- acceptable carrier. The composition contains respective amounts of a α4β2 nicotinic agonist and a Second Therapeutic Agent, as defined under group A or group B, 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: Biological tests for assessing effects of combinations of the α4β2 nicotinic agonist and a Second Therapeutic Agent, as defined under group A or group B.

Interaction design: Interactive effects of drug combinations are tested by coadministering varying doses of the α4β2 nicotinic agonist and Second Therapeutic Agent, as defined under group A or group B, 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 α4β2 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 Second Therapeutic Agent, as defined under group A or group B, the dose range includes doses in which the Second Therapeutic Agent, as defined under group A or group B, is active as well as sub-threshold doses. In vitro testing:

Drug-drug interactive increase in glutamate and GABA function in prefrontal cortex slice from rat. Nicotine increases long range as well as local glutamate signaling in mammalian brain.

Second Therapeutic Agent, as defined under group A or group B, may potentiate local glutamatergic and GABAergic circuit interactions, whereas α4β2 nicotinic agonists act to potentiate signaling through glutamate fiber tracts connecting distinct brain regions. In schizophrenic patients, glutamate and GABA signaling are impaired and γ-band EEG coherence is reduced, indicating a reduction in connectivity between brain regions required for normal cognition. Therefore, compounds that increase glutamate and GABA function in neuronal circuits will improve regional connectivity and cognition.

In vivo testing:

Drug-drug interactive increase in dopamine and serotonin overflow in prefrontal cortex of rat Various drugs, 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 dysfunction of schizophrenia. Therefore, compounds that increase DA overflow in the PFC may improve cognitive function in schizophrenia. In vivo microdialysis method is used to determine concentrations of Second Therapeutic Agent, as defined under group A or group B, and α4β2 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. α4β2 or Second Therapeutic Agent, as defined under group A or group B) 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 or dysfunctions, 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 Second Therapeutic Agent, as defined under group A or group B, and α4β2 nicotinic agonists 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 are 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 which case, mice generally show diminished preference for the novel object. 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. The combinations may result in synergistic/additive action allowing a lower dose of the agents to be administered while achieving at least the same therapeutic effect as achieved with a standard dose of the single compounds (a) or (b). The dosage of the α4β2 nicotinic agonist may be reduced by about 25-90%, for example, about 40-80% and typically about 50-70%. The reduction in amount of the α4β2 nicotinic agonist required will be dependent on the amount of the second therapeutic agent given.

The combinations may also result in synergistic/additive action allowing an improvement in efficacy and reduction in unwanted side effects when the α4β2 nicotinic agonist is administered as a standard dose of the α4β2 nicotinic agonist.

Claims

1. A combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is an α4β2 nicotinic agonist and (b) a therapeutically effective amount of a second therapeutic agent, which is selected from the group of antidepressants, atypical antipsychotics, antipsychotics, anxiolytics, anticonvulsants, Alzheimer's therapies, Parkinson's therapies, migraine therapies, stroke therapies, urinary incontinence therapies, neuropathic pain therapies, insomnia therapies, mood stabilizers, statins, nutraceuticals, anticholinergics, antihistamines, benzodiazepines, barbiturates, anticonvulsants, muscle relaxants, sedative-hypnotics, or chemotherapeutics.

2. A pharmaceutical composition comprising a combination comprising (a) a therapeutically effective amount of a first therapeutic agent, which is an α4β2 nicotinic agonist and (b) a therapeutically effective amount of a second therapeutic agent, which is selected from the group of antidepressants, atypical antipsychotics, antipsychotics, anxiolytics, anticonvulsants, Alzheimer's therapies, Parkinson's therapies, migraine therapies, stroke therapies, urinary incontinence therapies, neuropathic pain therapies, insomnia therapies, mood stabilizers, statins, nutraceuticals, anticholinergics, antihistamines, benzodiazepines, barbiturates, anticonvulsants, muscle relaxants, sedative-hypnotics, or chemotherapeutics; together with together with a pharmaceutically-acceptable vehicle, carrier or diluent.

3. A kit comprising a dosage unit of mixture of a first therapeutic agent, which is an α4β2 nicotinic agonist and a dosage unit of a second therapeutic agent, which is selected from the group of antidepressants, atypical antipsychotics, antipsychotics, anxiolytics, anticonvulsants, Alzheimer's therapies, Parkinson's therapies, migraine therapies, stroke therapies, urinary incontinence therapies, neuropathic pain therapies, insomnia therapies, mood stabilizers, statins, nutraceuticals, anticholinergics, antihistamines, benzodiazepines, barbiturates, anticonvulsants, muscle relaxants, sedative-hypnotics, or chemotherapeutics; optionally with instructions for use.

4. 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 an α4β2 nicotinic agonist and (b) a therapeutically effective amount of a second therapeutic agent, which is selected from the group of antidepressants, atypical antipsychotics, antipsychotics, anxiolytics, anticonvulsants, Alzheimer's therapies, Parkinson's therapies, migraine therapies, stroke therapies, urinary incontinence therapies, neuropathic pain therapies, insomnia therapies, mood stabilizers, statins, nutraceuticals, anticholinergics, antihistamines, benzodiazepines, barbiturates, anticonvulsants, muscle relaxants, sedative-hypnotics, or chemotherapeutics.

5. The method according to claim 4, wherein the CNS disorders are selected from cognitive dysfunction in schizophrenia (CDS), Alzheimer's Disease (AD), attention deficit disorder (ADD), pre-senile dementia (early onset of Alzheimer's Disease), dementia of the Alzheimer's type, mild cognitive impairment, age associated memory impairment and attention deficit hyperactivity disorder (ADHD)

6. The combination according to claim 1, or the pharmaceutical composition according to claim 2, or the kit according to claim 3 or the method according to claims 4 and 5, wherein the first therapeutic agent is (2S)-(4E)-N-methyl-5-[3-(5-isopropoxypyridin)yl]-4-penten-2-amine, N-(5-chlorofuran-2-ylcarbonyl)-3,7-diazabicyclo[3.3.0]octane, (R,E)-3-(2-(pyrrolidin-3- yl)vinyl)-5 -tetrahydro-2H-pyran-4-yloxy)pyridine, N-propyl-3 -azabicyclo [3.3.1 ]nonane-7- carboxamide, and metabolites or pro-drugs and pharmaceutically-acceptable salts, solvates or solvated salts of any of the foregoing.