WO2009017453A1 - Nouvelle combinaison thérapeutique d'antipsychotique et d'inhibiteur de gsk3 958 - Google Patents

Nouvelle combinaison thérapeutique d'antipsychotique et d'inhibiteur de gsk3 958 Download PDF

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WO2009017453A1
WO2009017453A1 PCT/SE2008/050896 SE2008050896W WO2009017453A1 WO 2009017453 A1 WO2009017453 A1 WO 2009017453A1 SE 2008050896 W SE2008050896 W SE 2008050896W WO 2009017453 A1 WO2009017453 A1 WO 2009017453A1
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pyrimidin
fluoro
imidazol
methyl
oxan
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PCT/SE2008/050896
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English (en)
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Hans Basun
Graham Cox
Ingrid Nordgren
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Astrazeneca Ab
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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
    • A61K31/44—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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • 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) an antipsychotic and (b) a GSK3 inhibitor.
  • the invention further relates to pharmaceutical compositions comprising said combination and to methods of treating CNS disorders, such as psychiatric disorders; particularly, cognitive impairment disorders in psychotic 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 psychiatric disorders; particularly, cognitive impairment disorders in psychotic disorders.
  • Exemplary conventional antipsychotics may include but are not limited to chlorpromazine, haloperidol, fiupenthixol and perphenazine.
  • Examples of atypical antipsychotics include but are not limited to clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, amisulpride, sulpride, zotepine, sertindole, paliperidone, bifeprunox and asenapine.
  • Atypical antipsychotics offer several clinical benefits over the conventional antipsychotics. The distinct advantages over traditional antipsychotic medications include greater improvement in negative symptoms, such as social withdrawal, and lower risk of Parkinsonian side effects and tardive dyskinesia.
  • Quetiapine the international nonproprietary name for 1 l-[4-[2-(2hydroxyethoxy)ethyl]-l- piperazinyl]dibenzo-[b,f][l,4]thiazepine, is an atypical antipsychotic and is on the market as Seroquel ® for: 1) treatment of schizophrenia; 2) depressive episodes associated with bipolar disorder, and 3) treatment of acute manic episodes associated with bipolar I disorder, as either monotherapy or adjunct therapy to lithium or divalproex. Quetiapine has also shown promise for the management of depressive disorders.
  • Quetiapine and its pharmaceutically acceptable salts are described in U.S. Patent Number 4,879,288, which is incorporated herein by reference. A preparation of these compounds is also described in said US patent.
  • Cognitive dysfunction is also an integral feature of depression and schizophrenia (Psychol Med. 24:829, 1994; Am. J. Psychiatry 161:25, 2004). Significant deficits have been found in a range of neuropsychological measures covering aspects of language function, memory, both recall and recognition, attention and behavioral regulation.
  • cognitive impairment disorders may be associated with the following psychiatric disorder or condition selected from the group consisting of 1) Schizophrenia and other Psychotic Disorders including but not limited to Psychotic Disorder, Schizophreniform Disorder, Schizoaffective Disorder, Delusional Disorder, Brief
  • Psychia and other Cognitive Disorders including but not limited to Panic Disorder Without Agoraphobia, Panic Disorder With Agoraphobia, Agoraphobia Without History of Panic Disorder, Specific Phobia, Social Phobia, Obsessive-Compulsive Disorder, Postraumatic Stress Disorder, Acute Stress Disorder, Generalized Anxiety Disorder and Generalized Anxiety Disorder Due to a General Medical Condition; 4) Mood Disorders including but not limited to a) Depressive Disorders, including but not limited to Major Depressive Disorder and Dysthymic Disorder and b) Bipolar Depression and/or Bipolar mania including but not limited to Bipolar I Disorder, including but not limited to those with manic, depressive or mixed episodes, and Bipolar II Disorder, c) Cyclothymic Disorder, d) Mood Disorder Due to a General Medical Condition; 5) Sleep Disorders including but not limited to a) Dyssomnia Disorders including but not
  • Quetiapine has demonstrated an ability to treat both the positive (hallucinations, delusions) and negative symptoms (emotional withdrawal, apathy) of psychosis and is associated with fewer neurological and endocrine related side effects compared to earlier agents. Quetiapine has also been associated with a reduction in hostility and aggression. Quetiapine is associated with fewer side effects such as EPS, acute dystonia, acute dyskinesia, as well as tardive dyskinesia. Quetiapine has also helped enhance patient compliance with treatment, ability to function and overall quality of life, while reducing recidivism (P. Weiden et al., Atypical antipsychotic drugs and long-term outcome in schizophrenia, J. Clin.
  • 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 is characterized by cognitive decline, cholinergic dysfunction and neuronal death, neurofibrillary tangles and senile plaques consisting of amyloid- ⁇ deposits. The sequenceof these events in AD is unclear, but are believed to be related.
  • Glycogen synthase kinase 3 ⁇ (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.
  • 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, postencephalitic 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.
  • 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).
  • 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.
  • PDAPP mice fed with Lithium show decreased amyloid- ⁇ levels in hippocampus and decreased amyloid plaque area (Su et al., Biochemistry 2004, 43:6899-6908).
  • 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.
  • 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
  • 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, 10(l);7- 19 (2007)).
  • GSK3 inhibitors are well suited for the prevention and/or treatment of conditions associated with glycogen synthase kinase-3 in the central and peripheral nervous system.
  • GSK3 inhibitors are expected to be suitable for prevention and/or treatment of conditions associated with cognitive disorders and predemented states, especially dementia, Alzheimer's Disease (AD), Cognitive Deficit in Schizophrenia (CDS), Mild Cognitive Impairment (MCI), Age-Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD) and Cognitive Impairment No Dementia (CIND), diseases associated with neurofibrillar tangle pathologies, Frontotemporal dementia (FTD), Frontotemporal dementia Parkinson's Type (FTDP), progressive supranuclear palsy (PSP), Pick's Disease, Niemann-Pick's Disease, corticobasal degeneration (CBD), traumatic brain injury (TBI), dementia pugilistica, Down's syndrome, vascular dementia, Parkinson's Disease (PD),
  • AD Alzheimer's
  • the present invention relates to the combination of (a) an amount of a first therapeutic agent, which is an antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor. Particularly, the synergistic combination of (a) and (b).
  • the combinations described herein are contemplated to provide synergistic or additive effects in treating psychiatric disorders; particularly, cognitive impairment disorders in psychotic disorders. Described combinations are contemplated to provide symptomatic relief of psychiatric disorders; particularly, cognitive impairment disorders in psychotic disorders, are contemplated to have fewer side effects, are contemplated to permit a reduction in use of these agents as compared to independent administration, are contemplated to complement sedatives and mood stabilizers such as lithium, and are contemplated to prophylactically address progression of psychotic conditions and/or decline of cognitive function in psychotic conditions. Compositions and methods described herein are contemplated to offer advantages over previous methods for treating neuropsychiatric disorders.
  • compositions comprising (a) an amount of a first therapeutic agent, which is an antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor. Also disclosed herein are combinations of an antipsychotic and a GSK3 inhibitor described as useful for the simultaneous, sequential, concurrent, separate or adjunct treatment of said disorders. Particularly, compositions comprising a pharmaceutical combination of an atypical antipsychotic and a GSK3 inhibitor are described as useful for the simultaneous, sequential, concurrent, separate or adjunct treatment of said disorders.
  • the invention also relates to said combination, wherein the atypical antipsychotic agent is quetiapine and wherein the GSK3 inhibitor is one of the compounds mentioned below or an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt of any of these agents. Further the invention also relates to said combination, wherein the atypical antipsychotic agent is quetiapine and wherein the 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 thereof of any of these agents.
  • a second aspect of the invention relates to pharmaceutical compositions comprising a combination of (a) an amount of a first therapeutic agent, which is an antipsychotic agent, particularly an atypical antipsychotic agent and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor, together with a pharmaceutically acceptable vehicle, carrier or diluent.
  • a first therapeutic agent which is an antipsychotic agent, particularly an atypical antipsychotic agent
  • a second therapeutic agent which is a GSK3 inhibitor
  • a third aspect of the invention relates to a kit comprising a dosage unit of a first therapeutic agent, which is an antipsychotic and a dosage unit of a second therapeutic agent, which is a GSK3 inhibitor, optionally with instructions for use.
  • a fourth aspect of the invention relates to a method for treating CNS disorders such as psychiatric disorders; particularly, cognitive impairment disorders in psychotic disorders 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 an antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor, wherein the amounts of (a) and (b) are together synergistically effective in the treatment.
  • a first therapeutic agent which is an antipsychotic
  • a second therapeutic agent which is a GSK3 inhibitor
  • Another embodiment relates to said method wherein (a) an amount of a first therapeutic agent, which is an antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor, are administered simultaneously, sequentially, concurrently, separately or adjunct to the subject in a pharmaceutical composition additionally comprising a pharmaceutically acceptable vehicle, carrier or diluent, by a method selected from the group consisting of oral, transmucosal, transdermal, nasal, pulmonary, buccal, parenteral rectal, and sublingual administration.
  • a further embodiment relates to said method wherein, (a) an amount of a first therapeutic agent, which is an antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor are administered simultaneously, sequentially, concurrently, separately or adjunct, to the subject in a pharmaceutical composition additionally comprising a pharmaceutically acceptable vehicle, carrier or diluent, by a method selected from the group consisting of 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, intradermal, intramuscular, intrathecal or via a high-pressure technique.
  • Another embodiment relates to said methods mentioned above wherein the antipsychotic is quetiapine and the 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 thereof of any of these agents.
  • a first aspect of the invention relates to a combination comprising (a) an amount of a first therapeutic agent, which is an antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor.
  • the combination comprises the group of compounds (a) and (b) as defined below.
  • Suitable conventional antipsychotics useful in the combination of the present invention may include but are not limited to chlorpromazine, haloperidol, flupenthixol and perphenazine.
  • Suitable atypical antipsychotics useful in the combination of the present invention include but are not limited to clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, amisulpride, sulpride, zotepine, sertindole, paliperidone, bifeprunox and asenapine, as a free base, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof.
  • a particular atypical antipsychotic is quetiapine, as free base, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt.
  • 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,
  • GSK inhibitors are compounds selected from the group comprising 3-[7-(2- morpholin-4-ylethoxy)quinazolin-4-yl]-2-oxo- 1 ,3-dihydroindole-5-carbonitrile; 3-[7-(2-methoxyethoxy)quinazolin-4-yl]-2-oxo-l,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 , a prodrug or a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salts also includes solvates, hydrates or solvated or hydrated salts thereof.
  • 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 an antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor, 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 first therapeutic agent comprises of compounds selected from chlorpromazine, haloperidol, flupenthixol and perphenazine.
  • atypical antipsychotics include but are not limited to clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, amisulpride, sulpride, zotepine, sertindole, paliperidone, bifeprunox and asenapine, isomers, metabolites, prodrugs or pharmaceutically acceptable salts thereof.
  • the first therapeutic agent is an atypical antipsychotic, which is quetiapine, isomers, metabolites, prodrugs or pharmaceutically acceptable salts thereof.
  • the second therapeutic agent comprises compounds which are GSK3 inhibitors having binding action at the glycogen synthase kinase 3 receptor, such as compounds specifically described herein, for example 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 thereof.
  • GSK3 inhibitors having binding action at the glycogen synthase kinase 3 receptor, such as compounds specifically described herein, for example 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 thereof.
  • GSK3 inhibitior having binding action at the glycogen synthase kinase 3 receptor may be useful in the combinations, pharmaceutical compositions, methods, uses and kits described herein.
  • a first therapeutic agent which is an antipsychotic and (b) a second therapeutic agent, which is a GSK3 inhibitor selected from:
  • 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 both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts.
  • 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.
  • 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 with an appropriate base.
  • Typical bases include 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 an appropriate acid.
  • the salts of the antipsychotic compound may be prepared according to the process described in US 4,879,288 and are preferably pharmaceutically acceptable salts, but other salts may also be prepared. Such other salts may, for example, find use in the preparation of the antipsychotic compound or the pharmaceutically acceptable salts thereof.
  • Convenient salts may be selected from those pharmaceutically acceptable salts known in the art. These may be obtained, for example, by reacting the antipsychotic compound with a convenient acid, such as for example, hydrochloric acid, maleic acid, fumaric acid, citric acid, phosphoric acid, methane sulfonic acid, and sulfuric acid.
  • a preferred salt is the hemi-fumarate salt.
  • Suitable salts for the for the GSK inhibitor may be, but are not limited to, hydrochloride, fumarate, tartrate, citrate, edisylate, phosphate salt.
  • compositions described herein can be co-administered simultaneously or may be administered separately, concurrently or sequentially in any order, or as a single pharmaceutical composition comprising, for example, an antipsychotic and GSK3 inhibitor described herein.
  • the antipsychotic is an atypical antipsychotic.
  • a GSK3 inhibitor such as 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 thereof, may be co-administered simultaneously or may be administered separately or sequentially in any order, or as a single pharmaceutical composition with an atypical antipsychotic such as quetiapine to produce a synergistic benefit over and above that obtained by administration of either compound alone.
  • an atypical antipsychotic such as quetiapine
  • the combinations described herein can be administered in a standard manner for the treatment of psychiatric disorders; particularly, cognitive impairment disorders in psychotic disorders 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). Tablets may be coated according to methods known in the art.
  • binding agents e.g., syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone
  • fillers e.g., lactose, sugar
  • 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 compositions may comprise conventional aqueous or nonaqueous vehicles, such as eye drops, creams, ointments, lotions, and pastes, or may be in the form of a medicated plaster, patch, or membrane.
  • compositions described herein can be formulated for parenteral administration by injection or continuous infusion.
  • Compositions for injection can be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain composition 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 preparation.
  • Such long acting compositions 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).
  • 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, for example potato or tapioca starch, and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia.
  • 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; examples of materials in this connection may also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • composition described herein can be incorporated into oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example.
  • oral liquid preparations such as aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, for example.
  • compositions containing these compounds can be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations can contain conventional additives, such as suspending agents, for example 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 for example 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 may 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 composition such as a slow release, fast release composition or delayed release.
  • a controlled release composition such as a slow release, fast release composition or delayed release.
  • Such controlled release compositions of the combinations described herein may be prepared using methods 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 mixture of a first therapeutic agent, which is a antipsychotic, preferably an atypical antipsychotic and a dosage unit of a second therapeutic agent, which is a GSK3 inhibitor, optionally with instructions for use.
  • a first therapeutic agent which is a antipsychotic, preferably an atypical antipsychotic
  • a second therapeutic agent which is a GSK3 inhibitor
  • Examples of atypical antipsychotics include but are not limited to clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, amisulpride, sulpride, zotepine, sertindole, paliperidone, bifeprunox and asenapine, isomers, metabolites or prodrugs and pharmaceutically acceptable salts, solvates or solvated salts thereof.
  • a further embodiment relates to a kit wherein the atypical antipsychotic is quetiapine, an isomer, a metabolite or a prodrug or a pharmaceutically acceptable salt thereof .
  • Another embodiment relates to a kit as described above wherein the second therapeutic agent 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 thereof.
  • Another embodiment relates to a kit as described above wherein the combination is as hereinbefore described in the list.
  • a fourth aspect of the invention relates to a method for treating CNS disorders such as, but not limited to, those discussed herein, including psychiatric disorders; particularly, cognitive impairment disorders in psychotic disorders 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 an antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor, wherein the amounts of (a) and (b) are together synergistically effective in the treatment.
  • a first therapeutic agent which is an antipsychotic
  • a second therapeutic agent which is a GSK3 inhibitor
  • One embodiment relates to a method for treating psychiatric disorders; particularly, cognitive impairment disorders in psychotic disorders 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 an atypical antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor, wherein the amounts of (a) and (b) are together synergistically effective in the treatment.
  • a first therapeutic agent which is an atypical antipsychotic
  • a second therapeutic agent which is a GSK3 inhibitor
  • the cognitive impairment disorder is selected from the group consisting of Alzheimer's disease, age related memory disorder, memory disorder, dementia senile dementia, dementia of the Alzheimer's type, vascular dementia, vascular dementia, cognitive impairment caused by traumatic brain injury, dementia due to other general medical conditions, substance-induced persisting dementia, dementia due to multiple etiologies, dementia not otherwise specified, attention deficit disorder, mild cognitive impairment and age-associated memory impairment, cognitive deficit in schizophrenia, cognitive deficit in Bipolar Disorders, and cognitive disorder not otherwise specified.
  • a particular embodiment is the cognitive impairment disorders: Alzheimer's Disease, Cognitive Deficit in Schizophrenia, Mild Cognitive Impairment, Age- Associated Memory Impairment and Cognitive Deficit in Bipolar Disorders.
  • the psychotic disorder or condition is selected from the group consisting of Bipolar Disorders, depressive episodes associated with bipolar disorder, and treatment of acute manic episodes associated with bipolar I disorder.
  • the psychotic disorder or condition is selected from the group consisting of schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, treatment-resistant shared psychotic disorder, psychotic disorder due to a medical condition, and psychotic disorder not otherwise specified.
  • the combination of the invention containing an atypical antipsychotic, for example quetiapine, and a GSK3 inhibitor described herein are believed to be particularly useful for the prevention of, reducing the development of, or reversal of, psychotic disorders, conditions or symptoms and are therefore particularly useful in the treatment of schizophrenia, schizophreniform disorder, schizoaffective disorder or delusional disorder, dementia and Alzheimers' Disease.
  • One embodiment relates to method for treating psychotic disorder 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 an antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor, wherein the amounts of (a) and (b) are together synergistically effective in the treatment.
  • the first therapeutic agent (a) comprises of compounds selected from chlorpromazine, haloperidol, flupenthixol and perphenazine.
  • atypical antipsychotics include but are not limited to clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, amisulpride, sulpride, zotepine, sertindole, paliperidone, bifeprunox and asenapine.
  • Another embodiment of the invention relates to the methods mentioned above wherein the first therapeutic agent is quetiapine and pharmaceutically acceptable salts thereof.
  • Another embodiment of the invention relates to the methods mentioned above wherein the combination hereinbefore described are used.
  • One embodiment of the invention relates to a method of treating psychiatric disorders; particularly, cognitive impairment disorders in psychotic disorders in a subject in need thereof using the kit as described above.
  • Another embodiment of the invention relates to a method of treating psychiatric disorders; particularly, cognitive impairment disorders in psychotic disorders in a subject in need thereof using a pharmaceutical composition comprising the combination comprising (a) an amount of a first therapeutic agent, which is an antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor.
  • One embodiment of the invention relates to the use of the combination comprising (a) an amount of a first therapeutic agent, which is an antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor, for the manufacturing of a medicament for use simultaneously, sequentially, separately or adjunct, in therapy.
  • a first therapeutic agent which is an antipsychotic
  • a second therapeutic agent which is a GSK3 inhibitor
  • Another embodiment of the invention relates to the use of the combination comprising (a) an amount of a first therapeutic agent, which is an atypical antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor, for the manufacturing of a medicament for use simultaneously, sequentially or separately, for the treatment of psychiatric disorders; particularly, cognitive impairment disorders in psychotic disorders.
  • a first therapeutic agent which is an atypical antipsychotic
  • a second therapeutic agent which is a GSK3 inhibitor
  • a further embodiment of the invention relates to an agent comprising the combination comprising (a) an amount of a first therapeutic agent, which is an antipsychotic and (b) an amount of a second therapeutic agent, which is a GSK3 inhibitor, for use simultaneously, sequentially, separately or adjunct, for treatment of psychiatric disorders; particularly, cognitive impairment disorders in psychotic disorders.
  • the effective dose of an antipsychotic and a GSK3 inhibitor 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.
  • the daily dose of the combination contains from about 1 mg to about 1200 mg.
  • each dose of the first component contains about 25 mg to about 1000 mg of the quetiapine, and even more preferably, each dose contains from about 150 mg to about 800 mg or 300 mg to about 800 mg or 400 mg to about 800 mg of quetiapine.
  • the first component contains about 150-300 or 300-600 mg of the quetiapine.
  • Pediatric dosages may be less such as for example in the range of about 0.5 mg to about 40 mg daily. These dosages may be administered in one, two or more oral doses, for example: quetiapine: from about 1.0 to about 40 mg/kg given once daily or in divided doses.
  • One embodiment relates to a method wherein the quetiapine or pharmaceutically acceptable salt thereof is administered at a dosage of between about 5 mg to about 800 mg daily. Another embodiment relates to a method wherein the quetiapine or pharmaceutically acceptable salt thereof is administered at a dosage of between about 10 mg to about 600 mg daily.
  • a further embodiment relates to a method wherein the quetiapine or pharmaceutically acceptable salt thereof is administered at a dosage of between about 25 mg to about 300 mg daily.
  • One embodiment relates to a method wherein the quetiapine or pharmaceutically acceptable salt thereof is administered at a dosage of between about 400 mg to about 800 mg daily.
  • Another embodiment of the invention relates to a method wherein the quetiapine or quetiapine salt is administered at a dosage of between about 150 mg to about 300 mg daily.
  • 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.
  • terapéuticaally-effective amount refers to a sufficient amount of the compound to treat psychiatric disorders; particularly, cognitive impairment disorders in 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. an antipsychotic or a GSK3 inhibitor.
  • Cognitive impairment includes but is not limited to an acquired deficit in one or more of memory function, problem solving, orientation and abstraction.
  • “Cognitive function testing” may fall into the categories of attention related tasks such as simple reaction time, choice reaction time, and digit vigilance; categories of working memory such as numeric working memory and spatial working memory; categories of secondary episodic recognition memory testing, such as word recognition, picture recognition, immediate word recall, and delayed word recall; as well as other tasks such as visual tracking.
  • Other examples of standard tests for measuring cognitive impairment may include but are not limited to, the Mini Mental State Examination, the Global Deterioration Scale and Geriatric Depression Scale, the Randt Memory Test and the Alzheimer's Disease Assessment Scale.
  • Cognitive impairment which may be treated by the methods described herein may include, inter alia, dementia, cognitive impairments caused by major depression, bipolar disease, schizophrenia, fibromyalgia, traumatic brain injury, Alzheimer's disease, age- related memory disorder, vascular dementia, dementia due to other general medical conditions (e.g., Human Immunodeficiency Virus disease, head trauma, Parkinson's disease, Huntington's disease), substance-induced persisting dementia (e.g., due to drug abuse, a medication, or toxin exposure), dementia due to multiple etiologies, or dementia not otherwise specified, and cognitive disorder not otherwise specified.
  • Other conditions having associated cognitive impairment which may be treated by the methods described herein appear in DSM-IV, 4.sup.th ed., pp. 135-180.
  • “Dementia” refers to global deterioration of intellectual functioning in clear consciousness, and is characterized by one or more symptoms of disorientation, impaired memory, impaired judgment, and/or impaired intellect. The symptoms of “dementia” are generally worse than, and can encompass, the symptoms of "cognitive impairment.”
  • “Cognitive impairments caused by traumatic brain injury” refers to cognitive impairments, as defined herein, that are associated with or caused by traumatic brain injuries, and other traumas to the head, such as, for example, traumas caused by accidents and/or sports injuries.
  • “Cognitive impairments caused by traumatic brain injury” includes dementia pugilistica, which is severe brain damage caused by repeated blows to the head (e.g., from boxing).
  • “Dementia pugilistica” is a chronic and progressive clinical syndrome characterized by neurological evidence of damage to pyramidal, extrapyramidal, and cerebellar systems with associated psychosis, dementia, personality change and impaired social functioning and/or prominent signs/symptoms of Parkinsonism (e.g., tremors, dysarthria, rigidity, bradykinesia, other extrapyramidal signs).
  • Associated physical symptoms may include inflammation-related aspects commonly associated with schizophrenia and may include conditions associated with elevated levels of inflammatory cytokines thought to modulate the symptomatology of schizophrenia, over-activation of the immune system by increases in the level of circulating monocytes or increased levels of Interleukin-6 (IL-6), necrotizing colitis, inflammation, edema and hemorrhage.
  • IL-6 Interleukin-6
  • “Synergy” means an improved effect of the two agents in the combination, which is greater than the expected additive effect of the two individual agents.
  • a pharmaceutical composition is prepared by combining an antipsychotic with a GSK3 inhibitor in a pharmaceutically acceptable carrier.
  • the composition contains respective amounts of antipsychotic and the GSK3 inhibitor to deliver on a daily basis a therapeutically-effective amount of each ingredient.
  • the composition is administered to a patient for the treatment of cognitive impairment in association with schizophrenia on a daily, twice daily, three times daily, or four times daily basis.
  • a pharmaceutical composition is prepared by combining quetiapine with 2-hydroxy-3-[5- (morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile as free base or a pharmaceutically acceptable salt thereof, such as the citrate salt thereof, in a pharmaceutically acceptable carrier.
  • the composition contains respective amounts of quetiapine and 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5- carbonitrile as free base or a pharmaceutically acceptable salt thereof, such as 2-hydroxy- 3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile citrate to deliver on a daily basis a therapeutically-effective amount of each ingredient.
  • the composition is administered to a patient for the treatment of cognitive impairment in association with schizophrenia on a daily, twice daily, three times daily, or four times daily basis.
  • Biological tests for assessing effects of combinations of a GSK3 inhibitor and an antipsychotic Interaction design Interactive effects of drug combinations are tested by co-administering varying doses of the GSK3 inhibitor with the atypical antipsychotic drug and then conducting various biological tests (e.g. antipsychotic tests) to determine the existence of interactions (positive or negative).
  • the dose range used for combination studies includes doses of a GSK3 inhibitor 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 antipsychotic alone is active as well as sub-threshold doses.
  • Quetiapine-induced sedation can induce sedation in rats as manifested as reductions in spontaneous LMA. Test compounds that increase LMA in quetiapine treated rats may reduce drug-induced sedation. Test compound are administered 30 minutes before quetiapine and then spontaneous activity measured at various time points.
  • Various drugs including antipsychotics, antidepressants and nicotinic agonists increase dopamine (DA) extracellular levels (overflow) in prefrontal cortex (PFC).
  • DA dopamine
  • PFC prefrontal cortex
  • DA dopamine
  • 5-HT serotonin
  • Quetiapine catalepsy Although quetiapine is generally well tolerated with respect to extrapyramidal symptoms (EPS) in humans at therapeutic doses, it can induce catalepsy in rats when administered at high doses. Test compounds that reduce catalepsy in quetiapine- treated rats may reduce drug-induced EPS-like effects. Test compound are administered 30 minutes before quetiapine and then catalepsy is measured at various time points.
  • EPS extrapyramidal symptoms
  • Background noise (white noise) is set at 7OdB.
  • Each session begins with a 3 -minute apparatus-habituation period followed by 3 blocks of trials.
  • white-noise startle stimuli are presented for 40 ms with an inter-trial interval that varies between 10- 15s.
  • Block 1 consists of 12 trials at each of 6 white noise stimuli with intensities of 74, 84, 94, 104, 114, or 124 dB to be presented in an ascending then descending order. This block of trials serves as the startle-habituation component of the assay.
  • Block 2 consists of 48 startle trials, 8 trials at each of 6 stimulus intensities (74, 84, 94, 104, 114, and 124 dB).
  • Block 3 consists of 10 startle (124 dB) and 30 prepulse (10 trials at each of 3 intensities) trials to be presented randomly. For prepulse trials a brief (20 ms) lower intensity (74, 84, or 94 dB) is presented prior to the startle stimulus.
  • D-amphetamine or phencyclidine are used to disrupt PPI. Reversal of drug-induced PPI-deficits is considered to be evidence of potential antipsychotic efficacy in schizophrenic patients.
  • D-amphetamine model LMA is assessed in male Long Evans rats using a paradigm that includes a habituation phase followed by administration of D-amphetamine at various doses. Animals are allowed to acclimatize to the testing room for 1 hour before being weighed and placed into activity chambers. Thirty minutes after LMA measurement is initiated animals are briefly removed, dosed with an antipsychotic drug or vehicle at 1 ml/kg and returned to the chambers. After a further 30 minutes animals are again removed and dosed with vehicle or D-amphetamine at 1 mg/kg via the sub-cutaneous route. After returning animals to the activity chambers, LMA is assessed for a further 60 minutes. Statistical analysis is made of total distance traveled after D-amphetamine administration using ANOVA and Tukey's post hoc analysis where appropriate. All values are expressed as Mean and SD.
  • PCP model In addition to the D-amphetamine model, reversal of PCP-induced increases in LMA is also assessed. Some atypical antipsychotics (e.g. clozapine) are more active in this preclinical model than in reversal of D-amphetamine-induced PPI deficits. The methods for the PCP model are the same as those for the D-amphetamine model. Reversal of PCP-induced increases in LMA is considered to be evidence of potential antipsychotic efficacy in schizophrenic patients.
  • the combinations are contemplated to result in synergistic 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 an antipsychotic may be reduced by about 25-90%, for example, about 40-80% and typically about 50-70%. The reduction in amount of an antipsychotic required will be dependent on the amount of the second therapeutic agent given.
  • the combinations may also result in synergistic action allowing an improvement in efficacy and reduction in unwanted side effects when the antipsychotic is administered as a standard dose of the an antipsychotic.

Abstract

L'invention concerne une combinaison (a) d'un antipsychotique et (b) d'un inhibiteur de GSK3, ainsi que des compositions pharmaceutiques qui renferment cette combinaison et des procédés de traitement de troubles psychiatriques; en particulier les handicaps cognitifs liés aux troubles psychotiques chez les mammifères, traités par administration d'une telle combinaison. L'invention concerne également un kit comprenant ladite combinaison et l'utilisation d'un tel kit pour le traitement de troubles psychiatriques; en particulier les handicaps cognitifs liés aux troubles psychotiques.
PCT/SE2008/050896 2007-07-30 2008-07-29 Nouvelle combinaison thérapeutique d'antipsychotique et d'inhibiteur de gsk3 958 WO2009017453A1 (fr)

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