WO2007120102A1

WO2007120102A1 - New substituted oxindole derivatives

Info

Publication number: WO2007120102A1
Application number: PCT/SE2007/000366
Authority: WO
Inventors: Erwan Arzel; Vern Delisser; Suzanne Iverson; Per Ryberg; Andreas RÅDEVIK
Original assignee: Astrazeneca Ab
Priority date: 2006-04-19
Filing date: 2007-04-18
Publication date: 2007-10-25

Abstract

The present invention relates to new compounds of formula (I). Wherein R1 is hydrogen or hydroxyl, Q is N or N+O- with the proviso that when R1 is hydrogen then Q is N+O- and when R1 is hydroxy then Q is N, as a free base or a pharmaceutically acceptable salt thereof, in an essentially pure and isolated form, pharmaceutical formulations containing said compounds, to the use of said active compounds in therapy, and particularly to GSK3 related disorders, and processes for their preparations as well as new intermediates.

Description

NEW SUBSTITUTED OXINDOLE DERIVATIVES

FIELD OF THE INVENTION

The present invention relates to new compounds of formula (I), as a free base or a pharmaceutically acceptable salt thereof, in an essentially pure and isolated form, to pharmaceutical formulations containing said compounds and to the use of said compounds in therapy. The present invention further relates to processes for the preparation of compounds of formula (I) as well as new intermediates.

BACKGROUND OF THE INVENTION

Glycogen synthase kinase 3 (GSK3) is a serine / threonine protein kinase composed of two isoforms (α and β), which are encoded by distinct genes but are highly homologous within the catalytic domain. GSK3 is highly expressed in the central and peripheral nervous system. GSK3 phosphorylates several substrates including tau, β-catenin, glycogen synthase, pyruvate dehydrogenase and elongation initiation factor 2b (eIF2b). Insulin and growth factors activate protein kinase B, which phosphorylates GSK3 on serine 9 residue and inactivates it.

Alzheimer's Disease (AD) dementias, and taupathies.

AD is characterized by cognitive decline, cholinergic dysfunction and neuronal death, neurofibrillary tangles and senile plaques consisting of amyloid-β deposits. The sequence of these events in AD is unclear, but is believed to be related. Glycogen synthase kinase 3β (GSK3β) or Tau phosphorylating kinase selectively phosphorylates the microtubule associated protein Tau in neurons at sites that are hyperphosphorylated in AD brains. Hyperphosphorylated tau has lower affinity for microtubules and accumulates as paired helical filaments, which are the main components that constitute neurofibrillary tangles and neuropil threads in AD brains. This results in depolymerization of microtubules, which leads to dying back of axons and neuritic dystrophy. Neurofibrillary tangles are consistently found in diseases such as AD, amyotrophic lateral sclerosis, parkinsonism- dementia of Gaum, corticobasal degeneration, dementia pugilistica and head trauma, Down's syndrome, postencephalatic parkinsonism, progressive supranuclear palsy, s Niemann-Pick's Disease and Pick's Disease. Addition of amyloid-β to primary hippocampal cultures results in hyperphosphorylation of tau and a paired helical filaments- like state via induction of GSK3β activity, followed by disruption of axonal transport and neuronal death (Imahori and Uchida, J. Biochem. 1997, 121:179-188). GSK3β preferentially labels neurofibrillary tangles and has been shown to be active in pre-tangle o neurons in AD brains. GSK3 protein levels are also increased by 50% in brain tissue from AD patients. Furthermore, GSK3β phosphorylates pyruvate dehydrogenase, a key enzyme in the glycolytic pathway and prevents the conversion of pyruvate to acetyl-Co-A (Hoshi et al., PNAS 1996, 93: 2719-2723). Acetyl-Co-A is critical for the synthesis of acetylcholine, a neurotransmitter with cognitive functions. Accumulation of amyloid-β is an early event s in AD. GSK Tg mice show increased levels of amyloid-β in brain. Also, PDAPP mice fed with Lithium show decreased amyloid-β levels in hippocampus and decreased amyloid plaque area (Su et al., Biochemistry 2004, 43: 6899-6908). Thus, GSK3β inhibition may have beneficial effects in progression as well as the cognitive deficits associated with Alzheimer's disease and other above-referred to diseases. 0

Chronic and Acute Neurodegenerative Diseases

Growth factor mediated activation of the PI3K /AkX pathway has been shown to play a key role in neuronal survival. The activation of this pathway results in GSK3β inhibition. Recent studies (Bhat et. al., PNAS 2000, 97: 11074-11079) indicate that GSK3β activity is S increased in cellular and animal models of neurodegeneration such as cerebral ischemia or after growth factor deprivation. For example, the active site phosphorylation was increased in neurons vulnerable to apoptosis, a type of cell death commonly thought to occur in chronic and acute degenerative diseases such as cognitive disorders, Alzheimer's Disease, Parkinson's Disease, amyotrophic lateral sclerosis, Huntington's Disease and HIV 0 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 GSK3β. Thus GSK3β inhibitors could be useful in attenuating the course of neurodegenerative diseases.

Bipolar Disorders (BD)

Bipolar Disorders are characterised by manic episodes and depressive episodes. Lithium has been used to treat BD based on its mood stabilising effects. The disadvantage of lithium is the narrow therapeutic window and the danger of overdosing that can lead to lithium intoxication. The discovery that lithium inhibits GSK3 at therapeutic concentrations has raised the possibility that this enzyme represents a key target of lithium's action in the brain (Stambolic et al., Curr. Biol. 1996, 68(12):1664-1668, 1996; Klein and Melton; PNAS 1996, 93:8455-8459; Gould et al., Neuropsychopharmacology, 2005, 30:1223-1237). GSK3 inhibitor has been shown to reduce immobilisation time in forced swim test, a model to assess on depressive behavior (O'Brien et al., J Neurosci 2004, 24(30): 6791-6798). GSK3 has been associated with a polymorphism found in bipolar II disorder (Szczepankiewicz et al., Neuropsychobiology. 2006, 53: 51-56). Inhibition of GSK3β may therefore be of therapeutic relevance in the treatment of BD as well as in AD patients that have affective disorders.

Schizophrenia

Accumulating evidence implicates abnormal activity of GSK3 in mood disorders and schizophrenia. GSK3 is involved in signal transduction cascades of multiple cellular processes, particularly during neural development. (Kozlovsky et al., Am. J. Psychiatry, 2000, 157, 5: 831-833) found that GSK3β levels were 41% lower in the schizophrenic patients than in comparison subjects. This study indicates that schizophrenia involves neurodevelopmental pathology and that abnormal GSK3 regulation could play a role in schizophrenia. Furthermore, reduced β-catenin levels have been reported in patients exhibiting schizophrenia (Cotter et al., Neuroreport 1998, 9(7):1379-1383). Atypical antipsychotic 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.of Neuropsychopharmacol, 2007, 10: 7-19, Epubl. 2006, May 4).

Diabetes s Insulin stimulates glycogen synthesis in skeletal muscles via the dephosphorylation and thus activation of glycogen synthase. Under resting conditions, GSK3 phosphorylates and inactivates glycogen synthase via dephosphorylation. GSK3 is also over-expressed in muscles from Type II diabetic patients (Nikoulina et al., Diabetes 2000 Feb; 49(2): 263- 71). Inhibition of GSK3 increases the activity of glycogen synthase thereby decreasing o glucose levels by its conversion to glycogen. In animal models of diabetes, GSK3 inhibitors lowered plasma glucose levels up to 50 % (Cline et al., Diabetes, 2002, 51: 2903-2910; Ring et al., Diabetes 2003, 52: 588-595). GSK3 inhibition may therefore be of therapeutic relevance in the treatment of Type I and Type II diabetes and diabetic neuropathy. s

Alopecia

GSK3 phosphorylates and degrades β-catenin. β-catenin is an effector of the pathway for keratonin synthesis, β-catenin stabilisation may be lead to increase hair development. Mice expressing a stabilised β-catenin by mutation of sites phosphorylated by GSK3 undergo a 0 process resembling de novo hair morphogenesis (Gat et al., Cell, 1998, 95(5): 605-14)). The new follicles formed sebaceous glands and dermal papilla, normally established only in embryogenesis. Thus GSK3 inhibition may offer treatment for baldness.

Inflammatory disease ₅ The discovery that GSK3 inhibitors provide anti-inflammatory effects has raised the possibility of using GSK3 inhibitors for therapeutic intervention in inflammatory diseases. (Martin et al., Nat. Immunol. 2005, 6(8): 777-784; Jope et al., Neurochem. Res. 2006, DOI 10.1007/s 11064-006-9128-5)). Inflammation is a common feature of a broad range of conditions including Alzheimer's Disease and mood disorders. 0 Cancer

GSK3 is overexpressed in ovarian, breast and prostate cancer cells and recent data suggests that GSK3b may have a role in contributing to cell proliferation and survival pathways in several solid tumor types. GSK3 plays an important role in several signal transduction systems which influence cell proliferation and survival such as WNT, PB Kinase and NFkB. GSK3b deficient MEFs indicate a crucial role in cell survival mediated NFkB pathway (Ougolkov AV and Billadeau DD., Future Oncol. 2006 Feb; 2(1): 91-100.). Thus, GSK3 inhibitors may inhibit growth and survival of solid rumors, including pancreatic, colon and prostate cancer.

Bone-related disorders and conditions

GSK3 inhibitors could be used for treatment of bone-related disorders or other conditions, which involves a need for new and increased bone formation. Remodeling of the skeleton is a continuous process, controlled by systemic hormones such as parathyroid hormone (PTH), local factors (e.g. prostaglandin E2), cytokines and other biologically active substances. Two cell types are of key importance: osteoblasts (responsible for bone formation) and osteoclasts (responsible for bone resorption). Via the RANK, RANK ligand and osteoprotegerin regulatory system these two cell types interact to maintain normal bone turnover (Bell NH, Current Drug Targets - Immune, Endocrine & Metabolic Disorders, 2001, 1:93-102).

Osteoporosis is a skeletal disorder in which low bone mass and deterioration of bone microarchitecture lead to increased bone fragility and fracture risk. To treat osteoporosis, the two main strategies are to either inhibit bone resorption or to stimulate bone formation. The majority of drugs currently on the market for the treatment of osteoporosis act to increase bone mass by inhibiting osteoclastic bone resorption. It is recognized that a drug with the capacity to increase bone formation would be of great value in the treatment of osteoporosis as well as having the potential to enhance fracture healing in patients. Recent in vitro studies suggest a role of GSK3β in osteoblast differentiation. First, it has been shown that glucocorticoids inhibit cell cycle progression during osteoblast differentiation in culture. The mechanism behind this is activation of GSK3β in osteoblasts, resulting in c-Myc down-regulation and impediment of the Gi/S cell cycle transition. The attenuated cell cycle and reduced c-Myc level are returned to normal when GSK3β is inhibited using lithium chloride (Smith et al., J. Biol. Chem., 2002, 277: 18191- 18197). Secondly, inhibition of GSK3β in the pluripotent mesenchymal cell line C3H10T1/2 leads to a significant increase in endogenous β-catenin signaling activity. This, in turn, induces expression of alkaline phosphatase mRNA and protein, a marker of early osteoblast differentiation (Bain et al., Biochem. Biophys. Res. Commun., 2003, 301: 84- 91).

DETAILED DESCRIPTION OF THE INVENTION

The object of the present invention is to provide new compounds having a selective inhibiting effect at GSK3 as well as having a good bioavailability. Accordingly, the present invention provides a compound of formula (I)

wherein Rl is hydrogen or hydroxyl, Q is N or N⁺-O^" with the proviso that when Rl is hydrogen then Q is N⁺-O^" and when Rl is hydroxy then Q is N, as a free base or a pharmaceutically acceptable salt thereof, in an essentially pure and isolated form.

In another aspect of the invention the following compounds are provided: 3-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-2-oxo-lH-indole-5-carbonitrile and 2-hydroxy-3-{5-[(4-oxidomorpholin-4-yl)methyl]pyridin-2-yl}-lH-indole-5- carbonitrile, as a free base or a pharmaceutically acceptable salt thereof, in an essentially pure and isolated form.

2-Hydroxy-3-{5-[(4-oxidomorpholin-4-yl)methyl]pyridin-2-yl}-lH-indole-5-carbonitrile could be in its tautomer form, which is named 3-{5-[(4-oxidomorpholin-4- yl)methyl]pyridin-2-yl}-2-oxoindoline-5-carbonitrile and also is included in this invention.

The compounds of formula (I), 3-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-2- oxo-lH-indole-5-carbonitrile and 2-hydroxy-3-{5-[(4-oxidomorpholin-4- yl)methyl]pyridin-2-yl}-lH-indole-5-carbonitrile have been identified as metabolites from 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]lH-indole-5-carbonitrile in rat, dog and/or man in in-vitro and in-vivo studies.

Thus, a further object of the present invention are metabolite compounds of formula (I) when prepared ex- vivo.

Surprisingly, it has been found that the compound 2-hydroxy-3-{5-[(4-oxidomorpholin-4- yl)methyl]pyridin-2-yl}-lH-indole-5-carbonitrile is reduced in vivo into 2-hydroxy-3-[5- (morpholin-4-ylmethyl)pyridin-2-yl]lH-indole-5-carbonitrile. Accordingly, the compound 2-hydroxy-3-{5-[(4-oxidomorpholin-4-yl)methyl]pyridin-2-yl}-lH-indole-5-carbonitrile is expected to act as a prodrug to the compound 2-hydroxy-3-[5-(morpholin-4- ylmethyl)pyridin-2-yl]lH-indole-5-carbonitrile. In consequence, the compound 2-hydroxy- 3- {5-[(4-oxidomoφholin-4-yl)methyl]pyridin-2-yl} - lH-indole-5-carbonitrile may be useful for the prevention and/or treatment of conditions associated with glycogen synthase kinase-3 (GSK3) in mammals, including man.

The compound 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl] lH-indole-5- carbonitrile is disclosed in WO 03/082853. The present invention also relates to the use of compounds of formula (I) as hereinbefore defined.

Salts for use in pharmaceutical formulations will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I).

In a further aspect of the invention, the following new intermediate is provided: A new compound of formula (VI)

wherein Rl is hydroxyl, R2 is Ci_i2^alkyl or aryl-Cj.g alkyl and Q is N, as a free base or a pharmaceutically acceptable salt thereof.

The new compound of formula (VI) above wherein R2 is Ci.galkyl is of particular interest.

The new compound of formula (VI) wherein Rl is hydroxyl, R2 is ethyl and Q is N, as a free base or a pharmaceutically acceptable salt thereof is of particular interest.

The term C_1-12 alkyl includes both straight and branched chain as well as cyclic alkyl groups having 1 to 12 carbon atoms and may be, but is not limited to, methyl, ethyl, n- propyl, /-propyl, ra-butyl, /-butyl, s-butyl, /-butyl, «-pentyl, z-pentyl, t-pentyl, røeo-pentyl, n- hexyl, /-hexyl cyclohexyl, heptyl, octyl nonyl, decyl, undecyl or odecyl. The term Ci-₆alkyl includes both straight and branched chain having 1 to 6 carbon atoms and may be, but is not limited to, methyl, ethyl, rc-propyl, /-propyl, π-butyl, /-butyl, s-butyl, t-butyl, R-pentyl, /-pentyl, t-pentyl, πeo-pentyl, R-hexyl, /-hexyl or cyclohexyl, particularly methyl, ethyl, isopropyl, and tert-butyl. The term aryl-Cμg alkyl includes both substituted and unsubstituted aryls, and may be, but is not limited to, benzyl and 4-methoxybenzyl.

PHARMACEUTICAL FORMULATIONS

According to one aspect of the present invention there is provided a pharmaceutical formulation comprising the compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof, in an essentially pure and isolated form, for use in the prevention and/or treatment of conditions associated with glycogen synthase kinase-3.

The formulation used in accordance with the present invention may be in a form suitable for oral administration, for example as a tablet, pill, syrup, powder, granule or capsule, for parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion) as a sterile solution, suspension or emulsion, for topical administration as an ointment, patch or cream, for rectal administration as a suppository and for local administration in a body cavity or in a bone cavity.

The formulation may be in a form suitable for oral administration, for example as a tablet, for parenteral injection as a sterile solution or suspension. In general the above formulation may be prepared in a conventional manner using pharmaceutically carriers or diluents.

Suitable daily doses of the compound of formula (I) as a free base and pharmaceutically acceptable salts thereof in the treatment of a mammal, including human, are approximately 0.01 to 250 mg/kg bodyweight at per oral administration and about 0.001 to 250 mg/kg bodyweight at parenteral administration. The typical daily dose of the active ingredients varies within a wide range and will depend on various factors such as the relevant indication, the route of administration, the age, weight and sex of the patient and may be determined by a physician. The compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof, in an essentially pure and isolated form, may be used on its own but will usually be administered in the form of a pharmaceutical formulation in which the active ingredient is in association with pharmaceutically acceptable diluents, excipients or inert carrier. Dependent on the mode of administration, the pharmaceutical formulation may comprise from 0.05 to 99 %w (per cent by weight), for example from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

A diluent or carrier includes water, aqueous poly(ethylene glycol), magnesium carbonate, magnesium stearate, talc, a sugar (such as lactose), pectin, dextrin, starch, tragacanth, macrocrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose or cocoa butter.

A formulation of the invention can be in a unit dosage form such as a tablet or an injectable solution. The tablet may additionally comprise a disintegrant and/or may be coated (for example with an enteric coating or coated with a coating agent such as hydroxypropyl methylcellulose) .

The invention further provides a process for the preparation of a pharmaceutical formulation of the invention which comprises mixing of the compound of formula (I) or a pharmaceutically acceptable salt thereof, a hereinbefore defined, with pharmaceutically acceptable diluents, excipients or inert carriers.

An example of a pharmaceutical formulations of the invention is an injectable solution comprising the compound of formula (I) as a free base or a pharmaceutically acceptable salt thereof, as hereinbefore defined, and sterile water, and, if necessary, either a base or an acid to bring the pH of the final formulation to a pH in the range of about 4 to 6 , particularly about 5, and optionally a surfactant to aid dissolution. A suitable base is sodium hydroxide. A suitable acid is hydrochloric acid. A suitable pharmaceutically acceptable salt of the compound of formula (I) useful in accordance to the invention is, for example, an acid-addition salt, which is sufficiently basic, for example an inorganic or organic acid. In addition a suitable pharmaceutically acceptable salt of the compounds of the invention, which is sufficiently acidic, is an alkali metal salt, an alkaline earth metal salt or a salt with an organic base, which affords a physiologically-acceptable cation.

MEDICAL USES

It has been found that the compounds of formula (I) defined in the present invention, are well suited for inhibiting glycogen synthase kinase-3 (GSK3). Accordingly, said compound of the present invention is expected to be useful in the prevention and/or treatment of conditions associated with glycogen synthase kinase-3 activity, i.e. the compounds may be used to produce an inhibitory effect of GSK3 in mammals, including human, in need of such prevention and/or treatment.

GSK3 is highly expressed in the central and peripheral nervous system and in other tissues. Thus, it is expected that compound of the invention is well suited for the prevention and/or treatment of conditions associated with glycogen synthase kinase-3 in the central and peripheral nervous system. In particular, the compound of the invention is 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 Impairement 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) and dementia pugilistica. One embodiment of the invention relates to the prevention and/or treatment of Alzheimer's Disease, especially the use in the delay of the disease progression of Alzheimer's Disease.

Other conditions are selected from the group consisting of Down's syndrome, vascular dementia, Parkinson's Disease (PD), postencephelatic parkinsonism, dementia with Lewy bodies, HIV dementia, Huntington's Disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases (MND, Creuztfeld-Jacob's disease and prion diseases.

Other conditions are selected from the group consisting of attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD) and affective disorders, wherein the affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, and dysthymia.

Other conditions are selected from the group consisting of Type I diabetes, Type II diabetes, diabetic neuropathy, alopecia, inflammatory diseases and cancer.

One embodiment of the invention relates to the use of a compound of the formula (I), as defined in the present invention, in the prevention and/or treatment of bone-related disorders or conditions in mammals.

One aspect of the invention is directed to the use of a compound of the formula (I) , as defined in the present invention to treat osteoporosis.

One aspect of the invention is directed to the use of a compound of the formula (I), as defined in the present invention to increase and promote bone formation in mammals.

One aspect of the invention is directed to the use of a compound of the formula (I), as defined in the present invention to increase bone mineral density in mammals. Another aspect of the invention is directed to the use of a compound of the formula (I), as defined in the present invention to reduce the rate of fracture and/or increase the rate of fracture healing in mammals.

Another aspect of the invention is directed to the use of a compound of the formula (I), as defined in the present invention to increase cancellous bone formation and/or new bone formation in mammals.

Another aspect of the invention is directed to a method of prevention and/or treatment of bone-related disorders comprising administering to a mammal in need of such prevention and/or treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.

Another aspect of the invention is directed to a method of prevention and/or treatment of osteoporosis comprising administering to a mammal in need of such prevention and/or treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.

Another aspect of the invention is directed to a method of increasing bone formation comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.

Another aspect of the invention is directed to a method of increasing bone mineral density comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.

Another aspect of the invention is directed to a method of reducing the incidence of fracture comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention. Another aspect of the invention is directed to a method of enhancing fracture healing comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a compound of the formula (I) as defined in the present invention.

Another aspect of the invention is directed to said methods and wherein said mammal is a human.

Another aspect of the invention is directed to said methods and wherein said mammal is a vertibrate animal, preferably but not limited to bigger animals such as horses, camels, dromedars but not limited thereto.

The use of the GSK3 inhibitors, the compounds of formula (I) hereinbefore defined, in primary and secondary ostopeorosis, where primary osteoporosis includes postmenopausal osteoporosis and senile osteoporosis in both men and women, and secondary osteoporosis includes cortison induced osteoporosis, as well as any other type of induced secondary osteoporosis, are included in the term osteoporosis. In addition to this, these GSK3 inhibitors may also be used in treatments of myeloma. These GSK3 inhibitors may be administered locally or systemically, in different formulation regimes, to treat these conditions.

The promotion and increasing of bone formation makes the compounds of the formula (I) hereinbefore defined, suitable to reducing the incidence of fracture, to reduce the rate of fracture and/or increase the rate of fracture healing, to increase cancellous bone formation and/or new bone formation in mammals.

The use to promote and increase new bone formation may be in connection with surgery. This invention can be used during surgery, where the treating surgeon will place the invention locally in an appropriate formulation, near the deficient bone and/or in the body cavity. The bone may for instance have been broken, and utilizing the invention as described and claimed herein will then be placed in or near the fracture during open fracture repair. In some instances bone pieces may be missing (e.g. after tumour removal or severe casualties), and utilizing the invention as described and claimed herein will then be placed near the site of constructive bone surgery.

The present invention relates also to the use of the compound of formula (I) as as defined in the present invention in the manufacture of a medicament for the prevention and/or treatment of conditions associated with glycogen synthase kinase-3.

The invention also provides for a method of treatment and/or prevention of conditions associated with glycogen synthase kinase-3 comprising administering to a mammal, including human in need of such treatment and/or prevention a therapeutically effective amount of the compound of formula (I) as as defined in the present invention.

The dose required for the therapeutic or preventive treatment of a particular disease will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated.

For veterinary use the amounts of different components, the dosage form and the dose of the medicament may vary and will depend on various factors such as, for example the individual requirement of the animal treated.

In the context of the present specification, the term "therapy" also includes "prevention" unless there are specific indications to the contrary. The terms "therapeutic" and "therapeutically" should be construed accordingly.

In the context of the present specification, the term "disorder" also includes "condition" unless there are specific indications to the contrary. METHODS OF PREPARATION

The present invention also relates to processes for preparing the compound of formula (I)

wherein Rl is hydrogen or hydroxyl, Q is N or N⁺-O with the proviso that when Rl is hydrogen then Q is N⁺-O and when Rl is hydroxy then Q is N, as a free base or a pharmaceutically acceptable salt thereof, in an essentially pure and isolated form, which comprises:

A. a process for preparing the compound of formula (I) wherein Rl is hydroxyl and Q is N, by ai) reacting a compound of formula (II)

(H)

with morpholine to form a compound of formula (III) wherein Q is N,

(IN) followed by aii) reacting the compound of formula (III) with an organic carbonate in the presence of a base in a polar aprotic solvent to obtain a compound of formula (IV), wherein R2 is an C\.

12alkyl, particularly ethyl and Q is N

(IV) followed by aiii) reacting the compound of formula (IV) with a compound of formula (V), wherein R3 is a hydrogen or a halogen, where the halogen is fiuoro, chloro, bromo or iodo,

(V) in the presence of a base in a polar aprotic solvent and in the presence of air/oxygen to give a compound of formula (VI), wherein Rl is a hydroxy and Q is N and R2 is an Ci_i2 alkyl, particularly ethyl

followed by aiv) cyclisation of the compound of formula (VI) with a reducing agent.

hi said process the compound of formula (VI) wherein Rl is hydroxy, R2 is ethyl and Q is N is of particular interest.

Non-limiting examples of bases, particularly organic bases,that may be used are: organic amine base such as C^alkyl lithium such as n, sec or tert butyl lithium; alkali metal hydrides such as sodium hydride and lithium hydride; alkali metal amides such as lithium diisopropylamide, sodium diisopropylamide or sodium amide; or alkoxides such as lithium tert-butoxide, particularly lithium diisopropylamide and lithium butoxide.

Suitable reducing agent may be iron in acetic acid, zinc in acetic acid, titanium trichloride, s sodium dithionite, hydrogenation using a metal catalyst e.g. palladium, platinium/vanadium, Raney-nickel, particularly iron in acetic acid. Further reducing agent are disclosed in "Comprehensive Organic Transformation;" R.C. Larock., VCH publishers; ISBN 0-89573-710-8, Edition 2, page 823;

o B. a process for preparing the compound of formula (I) wherein Rl is hydrogen and Q is

N⁺-O-, by oxidation of the morpholine nitrogen of the compound of formula (I) wherein Rl is hydrogen or hydroxyl and Q is N, using an oxidation agent in a chlorinated solvent or a polar protic solvent. s

Non-limiting examples of a suitable oxidation agent include peracids such as 3- chloroperbenzoic acid (metøchloroperbenzoic acid), tert-bntyl hydroperoxide (/-BuOOH) or Caro's acid (H₂SO₅), particularly røetøchloroperbenzoic acid.

0 Examples of chlorinated solvents are chloroform and dichloromethane and of polar protic solvents are acetic acid, water and methanol.

Suitable polar aprotic solvents are sulpholane, tetramethylurea or l,3-dimethyl-2- imidazolidinone or ethers such as tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, tert- 5 butlymethyl ether, or diethyleneglycol dimethyl ether or aromatics such as toluene, xylene, or mixtures thereof, particularly tetrahydrofuran.

A compound of formula (I) wherein Rl is hydrogen and Q is N⁺-O-, 2-hydroxy-3-{5-[(4- oxidomorpholin-4-yl)methyl]pyridin-2-yl}-lH-indole-5-carbonitrile may be prepared by o reacting 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH^'-indole-5-carbonitrile with røetø-chloroperbenzoic acid in a chlorinated solvent such as chloroform or dichloromethane.

Where necessary converting the resultant compound of formula (I), or another salt thereof, into a pharmaceutically acceptable salt thereof, or converting the resultant compound of formula (I) into a further compound of formula (I).

Preparation of Starting materials and Intermediates

Starting materials used were available from commercial sources, or prepared according to literature procedures.

(6-methyl-3-pyridyl)-rnethanol may be prepared in a known manner described in the prior art in, for example J. Med. Chem, 1996, 39 (26), 5053

5-chloromethyl-2-methyl- pyridine may be prepared in a known manner described in the prior art in, for example J. Med. Chem, 2004, 47(11), 4787

3-Fluoro-4-nitrobenzonitrile may be prepared according to the procedure described in WO 00/73313.

WORKING EXAMPLES

The following working example will describe, but not limit, the invention.

Example 1 2-Hydroxy-3-{5-r(^'4-oxidomorpholm-4-yl)methyllpyridin-2-yl}-lH-indole-5-carbonitrile

2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile (prepared as described in Example 58 of WO 03/082853; 1.26 g, 3.75 mmol) was dispersed in 40 niL chloroform. A solution of meta-chloroperbenzoic acid (80%) (716 mg, 4.16 mmol) in chloroform (10 mL) was added dropwise and the mixture was stirred for 10 minutes. The solvent was evaporated in vacuo and the crude product was purified by preparative ΗPLC (column: XTerra® prep MSC₈, gradient 05-45%B, 20mL/min, 40°C, (A-O. IM ammonium acetate in 0.1% acetonitrile aqueous solution, B-acetonitrile)) to give the title compound (750 mg, yield: 57%).

2-Ηydroxy-3-{5-[(4-oxidomorpholm-4-yl)methyl]pyridin-2-yl}-lH-indole-5-carbonitrile (2 mg) was mixed with 1 mL of trifiuoroacetic acid and the mixture was concentrated in vacuo. This trifiuoroacetic acid adduct was then analysed as follows: Η NMR (400 MHz, Acetonitrile-^) δ ppm 9.18 (s, 1 H), 8.14 (s, 1 H), 7.86 (dd, J=9.3, 2.0 Hz, 1 H), 7.74 (s, 1 H), 7.60 (d, J=9.3 Hz, 1 H), 7.35 (dd, J=8.1, 1.5 Hz, 1 H), 7.13 (d, J=8.3 Hz, 1 H), 4.77 (s, 2 H), 4.05 - 4.19 (m, 2 H), 3.84 - 3.99 (m, 2 H), 3.46 - 3.74 (m, 4 H); MS (ESI) m/z 351 (M+l)⁺.

Example 2

3-Hvdroxy-3-|^"5-(^'moφholin-4-ylmethvDpyridin-2-yl^'|-2-oxo-lH-indole-S-carbonitrile

Iron powder (52mg, 0.93 mmol) was added to a solution of ethyl 2-(5-cyano-2-nitro- phenyl)-2-hydroxy-2-[5-(morpholin-4-ylmethyl)pyridin-2-yl]acetate (O.lg, 0.23mmol) (described below) in acetic acid (3ml) at 6O⁰C and the mixture was stirred for 30 minutes. The dark brown reaction mixture was cooled to room temperature and Celite added. The

(S) mixture was filtered off and the Celite washed with acetic acid. The filtrate was then concentrated and purified by silica gel column chromatography eluting with dichloromethane/methanol (1%) ammonium hydroxide (15:1- 10:1) to give 3-hydroxy-3- [5-(morpholin-4-ylmethyl)pyridin-2-yl]-2-oxo-lH-indole-5-carbonitrile as an oil (13mg; yield: 16%).

¹H NMR (SOOMHZ; d6-OMSO): δ 10.91 (s,lH), 8.2 (d, IH, J= 1.08Hz), 7.80 (m, 2H); 7.7 (dd, IH, J= 1.68, 8.12), 7.42 (d, IH, J= 1.43), 7.06 (s, IH), 7.02 (d, IH, J= 8.12Hz), 3.55 (br t,4H,), 3.45 (s, 2H), 3.34 (s, IH), 2.33 (br s,4H) ppm. MS (ESI) m/z 351 (M+l)⁺.

The ethyl 2-(5-cyano-2-nitro-phenyl)-2-hydroxy-2-[5-(morpholin-4-ylmethyl)pyridin-2- yl]acetate was prepared according to the following steps: a^ 4-rC6-methylpyridin-3-yDmethyl1morpholine To a solution of (6-methyl-3-pyridyl)-methanol (5Og, 0.506mol) in toluene (500ml) and water (9ml) heated to 35°C was added thionyl chloride (66.9 ml, 1.06mol) dropwise. After stirring at 35°C over night 300ml was distilled off under vacuum and rediluted with toluene (250ml) and water (lθml)to give a solution of 5 ^'-chloromethyl-2-methyl- pyridine (J.MedChem, 2004, 47(11), 4787). The mixture was then heated to 40°C and morpholine (112.2ml, 1.29mol) added and the slurry heated to 80°C for 3 hrs. After cooling to room temperature saturated sodium carbonate solution (150ml) was added and the aqueous phase separated and extracted with toluene (200ml). The combined organic layer was washed with brine and concentrated to give an oil. The oil was dissolved in iso-octane (300ml) at 40°C then cooled to -5°C overnight. Two crops were obtained which gave 4-[(6- methylpyridin-3-yl)methyl]morpholine as a solid (53.65g, yield: 72%). H NMR

(400MHz;CDCl₃): δ 8.4 (d, J=1.72Hz, IH), 7.54 (dd, 1=2.1, 1.9 IHz, IH), 7.1 (d, J=7.92Ηz, IH), 3.68 (apparent t, J=4.6, 9.28Hz, 4H), 3.4 (s, 2H), 2.5 (s, 3H), 2.4 (apparent t, J=4.5,8.93Hz, 4H); MS (ESI) m/z 193 (M+l)⁺; Melting point: 51-52°C.

b) Ethyl 2-r5-(morpholin-4-ylmethyl')pyridin-2-yllacetate

4-[(6-Methyl-pyridin-3-ylmethyl]morpholine (30g, 156mmol) and diethylcarbonate (23.96g, 202.9mmol) were dissolved in tetrahydrofuran (150ml). The solution was cooled down to -13 ⁰C and lithium diisopropylamide solution (190.8ml, 1.8M, 343.3mmol) was added dropwise over lhr 45min. After stirring for an additional 35 min the reaction mixture was added to a cold aqueous solution of ammonium chloride (204.5ml, 4.58M, 936.2mmol) at O⁰C. The biphasic mixture was warm to +30°C and separated. The aqueous layer was extracted twice with toluene (120ml) and the combined organic layers were concentrated by distillation to give ethyl 2-[5-(morpholin-4-ylmethyl)pyridin-2-yl]acetate as a toluene solution (204ml) (55.38g, yield: 92% (based on assay). An aliquot was removed and purified by column chromatography eluting with dichloromethane/methanol (40:1) to give ethyl 2-[5-(moφholin-4-ylmethyl)pyridin-2-yl]acetate as a yellow oil. ¹H NMR (400MHz;CDCl_3i): δ 8.45 (d, J=I.88Hz, IH), 7.65 (dd, J=2.21,7.93Hz, IH), 7.25 (d, J=6.12Hz, IH), 4.15 (q, 1=1.11, 14.29Hz, 2H), 3.82 (s, 2H), 3.69 (t, 1=4.61, 9.28Hz, 4H), 3.45 (s, 2H), 2.42 (t, J= 4.52, 9JHz, 4Η), 1.25 (t, J=7.13,14.29Hz, 3H); MS (ESI) m/z 265 (M+l)⁺.

c) Ethyl 2-f 5-cvano-2-nitro-phenylV2-hydroxy-2- r5-Cmoφholin-4-ylmethyl)pyridm-2- yl]acetate

A solution of ethyl 2-[5-(moφholin-4-ylmethyl)pyridin-2-yl]acetate (1.3g, 4.92mmol) and 3-fluoro-4-nitrobenzonitrile (0.9g, 5.41mmol) in tetrahydrofuran (30ml) was cooled down to -10 °C and lithium tert-butoxide solution in tetrahydrofuran (4.92ml, 20w/w%, 10.82mmol) was added dropwise whilst bubbling air through the solution. The resulting dark purple solution was then allowed to stir at room temperature overnight under air. Saturated ammonium chloride solution was then added to the reaction solution followed by

5 Celite . The Celite was then filtered off and washed with ethylacetate. The aqueous layer was separated and extracted with ethylacetate and the combined organic layers washed with brine and dried with anhydrous sodium sulphate. After concentration the dark brown oil was dissolved in ethylacetate (15ml) and stand overnight at room temperature. The resulting suspension was filtered and washed with heptane; after drying in an oven at o +50⁰C under vacuum gave ethyl 2-(5-cyano-2-nitro-phenyl)-2-hydroxy-2-[5-(morpholin-4- ylmethyl)pyridin-2-yl]acetate as a solid (1.0 Ig, yield 48%). ¹H NMR (400MHz;CDCl₃,): δ 8.40 (s, IH), 8.1 (s, IH), 7.85 (d, J=7.96Hz, IH), 7.63 (d, J=8.12Hz, IH), 7.44 (s, IH), 4.2 (m, 2H), 3.57 (br s, 4H), 3.53 (br s, 4H), 2.36 (br s, 4H), 1.15 (t, J=7.09,14.09Hz, 3H); MS (ESI) m/z 427 (M+l)⁺. 5

General Methods

¹H NMR spectra were recorded in the indicated deuterated solvent at 400 MHz or 500MHz. The 400MHz spectra were obtained using a Bruker av400 NMR spectrometer equipped with a 3mm flow injection SEI ¹HZD-¹³C probe head with Z-gradients, using a 0 BEST 215 liquid handler for sample injection, or using a Bruker DPX400 NMR or Bruker 500MHz ultrashield spectrometer equipped with a 4-nucleus probehead with Z-gradients. Chemical shifts are given in ppm down- and upfield from TMS. Resonance multiplicities are denoted s, d, t, q, m and br for singlet, doublet, triplet, quartet, multiplet, and broad respectively. 5 LC-MS analyses were recorded on a Waters LCMS equipped with a Waters X-Terra MS, C8-column, (3.5 μm, 100 mm x 3.0 mm i.d.). The mobile phase system consisted of A: 10 mM ammonium acetate in water/acetonitrile (95:5) and B: acetonitrile. A linear gradient was applied running from 0% to 100% B in 4-5 minutes with a flow rate of 1.0 niL/min. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a o positive or negative ion mode. The capillary voltage was 3 kV and the mass spectrometer was typically scanned between m/z 100-700. Alternative, LC-MS HPLC conditions were as follows: Column: Agilent Zorbax SB-C8 ( 5 μm, 50mm x 2mm i.d) Flow: 1.0 mL/minGradient: 95% A to 100% B in 5 min. A = 5% acetonitrile in water with 0.1% formic acid and B = acetonitrile with 0.1% formic acid. UV-DAD 210-400 nm Alternative, LC-MS analyses were recorded on a Waters 2790 LCMS equipped with a Phenomenex Luna Cl 8 (5 μm, 5Ox 4.6mm i.d.) The mobile phase system consisted of A: 10 mM ammonium formate( pH 4) in water and B: acetonitrile. A linear gradient was applied running from 95% to 5% B in 5 minutes with a flow rate of 2.0 mL/min. The mass spectrometer was equipped with an electrospray ion source (ESI) operated in a positive or negative ion mode. The capillary voltage was 3 kV and the mass spectrometer was typically scanned between m/z 100-700.

Mass spectra (MS) were run using an automated system with atmospheric pressure chemical (APCI or CI) or electrospray (+ESI) ionization. Generally, only spectra where parent masses are observed are reported. The lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks (for example when chlorine is present).

HPLC assays were performed using an Agilent HPl 100 Series system equipped with a Waters X-Terra MS, C₈ column (3.0 x 100 mm, 3.5 μm). The column temperature was set to 40 °C and the flow rate to 1.0 mL/min. The Diode Array Detector was scanned from 200-300 nm. A linear gradient was applied, run from 0% to 100% B in 4 min. Mobile phase A: 10 mM ammonium acetate in water/acetonitrile (95:5), mobile phase B: acetonitrile.

HPLC purities were performed using a Dionex P680 Series system equipped with a Genesis AQ, (100 x 4.6 mm, 4 μm) column. The column temperature was set to 25 ⁰C and the flow rate to 1.5 mL/min. The Diode Array Detector was scanned from 200-300 nm. The mobile phase system comprise of A: 10/90 (v/v) acetonitrile/ phosphate buffer (25mM, pH 6.8) and B: 70/30 (v/v) acetonitrile/ phosphate buffer (25mM, pH 6.8).A gradient was applied according to the table below:

Preparative HPLC was performed on a Waters Auto purification HPLC-UV system with a diode array detector using a Waters XTerra® MS C₈ column (19x300 mm, 7 μm) with the gradient described. Compounds have been named using ACD/Name, version 8.08, software from Advanced Chemistry Development, Inc. (ACD/Labs), Toronto ON, Canada, www.acdlabs.com, 2004 or are according to IUPAC convention.

PHARMACOLOGY

Determination of ATP competition in Scintillation Proximity GSK3β Assay. GSK3β scintillation proximity assay.

The competition experiments were carried out in duplicate with 10 different concentrations of the inhibitors in clear-bottom microtiter plates (Wallac, Finland). A biotinylated peptide substrate, Biotin-Ala-Ala-Glu-Glu-Leu-Asp-Ser-Arg-Ala-Gly-Ser(PO₃H₂)-Pro-Gln-Leu (AstraZeneca, Lund), was added at a final concentration of 1 μM in an assay buffer containing 1 mU recombinant human GSK3β (Dundee University, UK), 12 mM morpholinepropanesulfonic acid (MOPS), pH 7.0, 0.3 mM EDTA, 0.01% β- mercaptorethanol, 0.004 % Brij 35 (a natural detergent), 0.5 % glycerol and 0.5 μg BSA/25 μl. The reaction was initiated by the addition of 0.04 μCi [γ-³³P]ATP (Amersham, UK) and unlabelled ATP at a final concentration of 1 μM and assay volume of 25 μl. After incubation for 20 minutes at room temperature, each reaction was terminated by the addition of 25 μl stop solution containing 5 mM EDTA, 50 μM ATP, 0.1 % Triton X-100 and 0.25 mg streptavidin coated Scintillation Proximity Assay (SPA) beads (Amersham, UK). After 6 hours the radioactivity was determined in a liquid scintillation counter (1450 MicroBeta Trilux, Wallac). The inhibition curves were analysed by non-linear regression using GraphPad Prism, USA. The K_m value of ATP for GSK3β, used to calculate the inhibition constants (Kj) of the various compounds, was 20 μM.

The following abbreviations have been used: MOPS Morpholinepropanesulfonic acid

EDTA Ethylenediaminetetraacetic acid

BSA Bovin Serum Albumin

ATP Adenosine Triphosphate

SPA Scintillation Proximity Assay GSK3 Glycogen synthase kinase 3

Results

The K; value for the compounds of formula (I) of the present invention are in the range of 0.001 nM to lOμM.

Formation of 2-hydroxy-3- [5-(morpholin-4-ylmethyl)pyridin~2~yl] lH-indole-5- carbonitrile after iv dosing of 2-hydroxy-3-{5-[(4-oxidomorpholin~4- yl)methyl]pyridin-2-yl}-lH-indole-5-carbonitrile

One male Sprague-Dawley rat received 2-hydroxy-3-{5-[(4-oxidomorpholin-4- yl)methyl]pyridin-2-yl}-lH-indole-5-carbonitrile by a single intravenous (iv) dose at a dose level of 1 mg/kg (3 μmol/kg in saline adjusted to pΗ 3 with 0.5M HCl). Blood samples were collected at 5 min, 30 min, 1, 2, 4 and 8 hours after dosing. The determination of the total plasma concentration of 2-hydroxy-3-[5-(morpholin-4- ylmethyl)pyridin-2-yl]lH-indole-5-carbonitrile was performed by ultrafiltration (96 well plate Multiscreen Ultracell, Millipore Corp., USA), the UF plate was centrifuged for 45 minutes at 2000 g and 20 °C, followed by reversed-phase liquid chromatography (Ηypersil Gold Cl 8, 50x2.1 mm, Thermo Electron Corp, Bellefonte, PA, USA) and electrospray ionisation tandem mass spectrometry (TSQ Quantum, Thermo Electron Corp., San Jose, CA, USA). The mobile phase system consisted of A: 5 % acetonitrile in 0.01 M ammonium formate and 0.1 % formic acid and B: 70 % acetonitrile in 0.01 M ammonium formate and 0.1 % formic acid the gradient was applied according to table below:

The flow-rate was 0.25 mL/min. The mass spectrometer is operated in the positive ion electrospray mode. The responses are measured using multiple reaction monitoring of the product ion transitions (m/z 335->248) for 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin- 2-yl] lH-indole-5-carbonitrile. The result is shown in Figure 1.

Figure 1 shows that the compound 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2- yl]lH-indole-5-carbonitrile was formed after a single iv dose of the compound 2-hydroxy- 3-{5-[(4-oxidomorpholin-4-yl)methyl]pyridin-2-yl}-lH-indole-5-carbonitrile in a rat.

In consequence, the compound 2-hydroxy-3-{5-[(4-oxidomoφholin-4-yl)methyl]pyridin- 2-yl}-lH-indole-5-carbonitrile is transformed into the compound 2-hydroxy-3-[5- (morpholin-4-ylmethyl)pyridin-2-yl]lH-indole-5-carbonitrile and thus the compound 2- hydroxy-3- {5-[(4-oxidomorpholin-4-yl)methyl]pyridin-2-yl} - lH-mdole-5-carbonitrile may act as a prodrug to the compound 2-hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]lH- indole-5-carbonitrile.

Claims

1. A compound of formula (I)

wherein Rl is hydrogen or hydroxyl, Q is N or N⁺-O with the proviso that when Rl is hydrogen then Q is N⁺O^" and when Rl is hydroxy then Q is N, as a free base or a pharmaceutically acceptable salt thereof, in an essentially pure and isolated form.

2. A compound according to claim 1, which is 3-hydroxy-3-[5-(morpholin-4- ylmethyl)pyridin-2-yl]-2-oxo-lH-indole-5-carbonitrile.

3. A compound according to claim 1, which is 2-hydroxy-3-{5-[(4-oxidomorpholin-4- yl)methyl]pyridin-2-yl}-lH-indole-5-carbonitrile.

4. A pharmaceutical formulation comprising as active ingredient a therapeutically effective amount of the compound according to any one of claims 1 to 3, optionally in association with diluents, excipients or inert carriers.

5. An injectable solution comprising the compound of formula (I) as defined in any one of claims 1 to 3, sterile water, and, if necessary, either a base, particularly sodium hydroxide, or an acid, particularly hydrochloric acid, to bring the pH of the final formulation to a pH in the range of about 4 to 6, and optionally a surfactant.

6. An injectable solution according to claim 5, where the pH is about 5.

7. A compound as defined in any one of claims 1 to 3 for use in therapy.

8. Use of a compound as defined in any one of claims 1 to 3 in the manufacture of a medicament for prevention and/or treatment of conditions associated with glycogen synthase kinase-3.

9. Use of a compound as defined in any one of claims 1 to 3 in the manufacture of a medicament for prevention and/or treatment of cognitive disorders.

10. The use according to claim 9, wherein the cognitive disorder is dementia, Cognitive Deficit in Schizophrenia (CDS), Mild Cognitive Impairment (MCI), Age-Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD) or Cognitive Impairement No Dementia (CIND).

11. The use according to claim 10, wherein the disease is Cognitive Deficit in Schizophrenia.

12. The use according to claim 10, wherein the dementia is associated with neurofibrillar tangle pathologies.

13. The use according to claim 10, wherein the dementia is Frontotemporal dementia (FTD), Frontotemporal dementia Parkinson's Type (FTDP), progressive supranuclear palsy (PSP), Pick's Disease, Niemann-Pick's Disease, corticobasal degeneration, traumatic brain injury (TBI) or dementia pugilistica.

14. The use according to claim 10, wherein the dementia is Alzheimer's Disease (AD), Down's syndrome, vascular dementia, Parkinson's Disease (PD), postencephelatic parkinsonism, dementia with Lewy bodies, HIV dementia, Huntington's Disease, amyotrophic lateral sclerosis (ALS), motor neuron diseases (MND, Creuztfeld- Jacob's disease or prion diseases.

15. The use according to claim 14, wherein the dementia is Alzheimer's Disease.

16. The use according to claim 15, wherein the use is in the delay of the disease progression of Alzheimer's Disease.

17. Use of a compound as defined in any one of claims 1 to 3 in the manufacture of a medicament for prevention and/or treatment of attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD) or affective disorders.

18. The use according to claim 17, wherein the affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, or dysthymia.

19. Use of a compound as defined in any one of claims 1 to 3 in the manufacture of a medicament for prevention and/or treatment of Type I diabetes, Type II diabetes, diabetic neuropathy, alopecia, inflammatory diseases or cancer.

20. Use of a compound as defined in any one of claims 1 to 3 in the manufacture of a medicament for prevention and/or treatment of bone related disorders or conditions in mammals.

21. The use of a compound as defined in any one of claims 1 to 3 in the manufacture of a medicament for prevention and/or treatment of osteoporosis in mammals.

22. The use of a compound as described in any one of claims 1 to 3, in the manufacturing of a medicament for increasing bone formation in mammals.

23. The use of a compound as described in any one of claims 1 to 3, in the manufacturing of a medicament for increasing cancellous bone formation and/or new bone formation in mammals.

24. The use of a compound as described in any one of claims 1 to 3, in the manufacturing of a medicament for increasing bone mineral density in a mammal.

25. The use of a compound as described in any one of claims 1 to 3, in the manufacturing of a medicament for reducing the incidence of fracture in a mammal.

26. The use of a compound as described in any one of claims 1 to 3, in the manufacturing of a medicament for enhancing fracture healing in a mammal.

27. The use according to any one of claims 20 to 27, wherein said mammal is a human.

28. A method of prevention and/or treatment of conditions associated with glycogen synthase kinase-3, comprising administering to a mammal, including human in need of such prevention and/or treatment, a therapeutically effective amount of a compound as defined in any one of claims 1 to 4.

29. A method of prevention and/or treatment of cognitive disorders, comprising administering to a mammal, including human in need of such prevention and/or treatment, a therapeutically effective amount of a compound as defined in any one of claims 1 to 4.

30. The method according to claim 29, wherein the cognitive disorder is dementia, Cognitive Deficit in Schizophrenia (CDS), Mild Cognitive Impairment (MCI), Age- Associated Memory Impairment (AAMI), Age-Related Cognitive Decline (ARCD) or Cognitive Impairement No Dementia (CIND).

31. The method according to claim 30, wherein the disease is Cognitive Deficit in Schizophrenia.

32. The method according to claim 31, wherein the dementia is associated with neurofibrillar tangle pathologies.

33. The method according to claim 31, wherein the dementia is Frontotemporal dementia (FTD), Frontotemporal dementia Parkinson's Type (FTDP), progressive supranuclear palsy (PSP), Pick's Disease, Niemann-Pick's Disease, corticobasal degeneration, traumatic brain injury (TBI) or dementia pugilistica.

34. The method according to claim 31, wherein the dementia is 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), Creuztfeld- Jacob's disease or prion diseases.

35. The method according to claim 34, wherein the dementia is Alzheimer's Disease.

36. The method according to claim 35, wherein the treatment is in the delay of the disease progression of Alzheimer's Disease.

37. A method of prevention and/or treatment of attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD) or affective disorders, comprising administering to a mammal, including human in need of such prevention and/or treatment, a therapeutically effective amount of a compound as defined in any one of claims 1 to 3.

38. The method according to claim 37, wherein the affective disorders are Bipolar Disorder including acute mania, bipolar depression, bipolar maintenance, major depressive disorders (MDD) including depression, major depression, mood stabilization, schizoaffective disorders including schizophrenia, or dysthymia.

39. A method of prevention and/or treatment of Type I diabetes, Type II diabetes, diabetic neuropathy, alopecia, inflammatory diseases or cancer, comprising administering to a mammal, including human in need of such prevention and/or treatment, a therapeutically effective amount of a compound as defined in any one of claims 1 to 3.

40. A method of prevention and/or treatment of bone related disorders or conditions comprising administering to a mammal, in need of such prevention and/or treatment, a therapeutically effective amount of a compound as defined in any one of claims 1 to 3.

41. A method of prevention and/or treatment of osteoporosis comprising administering to a mammal, in need of such prevention and/or treatment, a therapeutically effective amount of a compound as described in any one of claims 1 to 3.

42. A method of increasing bone formation comprising administering to a mammal, in need of such prevention and/or treatment, a therapeutically effective amount of a compound as described in any one of claims 1 to 3.

43. A method of increasing cancellous bone formation and/or new bone formation comprising administering to a mammal, in need of such prevention and/or treatment, a therapeutically effective amount of a compound as described in any one of claims 1 to 3.

44. A method of increasing bone mineral density comprising administering to a mammal, in need of such prevention and/or treatment, a therapeutically effective amount of a compound as described in any one of claims 1 to 3.

45. A method of reducing the incidence of fracture comprising administering to a mammal in need of such prevention and/or treatment, a therapeutically effective amount of a compound as described in any one of claims 1 to 3.

46. A method of enhancing fracture healing comprising administering to a mammal, in need of such prevention and/or treatment, a therapeutically effective amount of a compound as described in any one of claims 1 to 3.

47. A method according to any one of claims 28 to 46, wherein said mammal is a human.

48. A process for the preparation of a compound of formula (I) wherein Rl is hydroxyl and Q is N according to any one of claims 1 to 3, by reacting a compound of formula (IV) wherein R2 is an C χ_i2 alkyl

(IV) with a compound of formula (V), wherein R3is a hydrogen or a halogen, where the halogen is fluoro, chloro, bromo or iodo,

(V) in the presence of a base in a polar aprotic solvent and in the presence of air/oxygen to give a compound of formula (VI), wherein Rl is a hydroxy and Q is N and R2 an C \.\2 alkyl,

followed by cyclisation of the compound of formula (VI) with a reducing agent.

49. A process according to claim 48 wherein R2 is ethyl.

50. A process according to claim 48 wherein the base is selected from the group: Cμgalkyl lithium such as n, sec or tert butyl lithium; alkali metal hydrides such as sodium hydride and lithium hydride; alkali metal amides such as lithium diisopropylamide, sodium diisopropylamide or sodium amide or alkoxides such as lithium tert-butoxide.

51. A process according to claim 50 wherein the base is lithium tert-butoxide.

52. A process according to claim 48 wherein the reducing agent is selected from the group: iron in acetic acid, zinc in acetic acid, titanium trichloride, sodium dithionite, hydrogenation using a metal catalyst e.g. palladium, platinium/vanadium, Raney-nickel.

53. A process according to claim 52 wherein the reducing agent is iron in acetic acid

54. A process for the preparation of a compound of formula (I) wherein Rl is hydrogen and Q is N⁺O^" according to any one of claims 1 to 3, which comprises oxidation of a compound of formula (I) wherein Rl is hydrogen and Q is N, with an oxidation agent such as a peracid in a chlorinated solvent or a polar protic solvent.

55. A process according to claim 54 wherein the oxidation agent is meta-chloroperbenzoic acid.

56. A process for the preparation of a compound of formula (I) wherein Rl is hydrogen and Q is N⁺-O^" according to any one of claims 1 to 4, which comprises reacting 2-hydroxy- 3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-lH-indole-5-carbonitrile with meta- chloroperbenzoic acid in a chlorinated solvent such as chloroform.

57. A new compound of formula (VI)

wherein Rl is hydroxyl, R2 is Ci.^alkyl and Q is N, as a free base or a pharmaceutically acceptable salt thereof.

58. A compound according to claim 57 wherein Rl is hydroxy and R2 is ethyl and Q is

N.