Indian Patents. 268584:GSK-3 INHIBITORS

Title of Invention	GSK-3 INHIBITORS
Abstract	The invention relates to urea derivatives of formula (I) as inhibitors of glycogen synthase kinase 36, GSK-3, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use for the treatment and or prophylaxis of a disease in which GSK-3 is involved, such as Alzheimer's disease or non-insulin dependent diabetes mellitus.

Full Text	WO 2007/017145 PCT/EP2006/007520 GSK-3 INHIBITORS FIELD OF THE INVENTION The present invention relates to enzyme inhibitors, and more particularly to urea derivatives as inhibitors of glycogen synthase kinase 3(3, GSK-3, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use for the treatment and or prophylaxis of a disease in which GSK-3 is involved, such as Alzheimer's disease or non-insulin dependent diabetes mellitus. BACKGROUND OF THE INVENTION The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of enzymes and other biomolecules associated with target diseases. One important class of enzymes that has been the subject of extensive study is the protein kinases. Many diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-related diseases. Accordingly, there has been a substantial effort in medicinal chemistry to find protein kinase inhibitors that are effective as therapeutic agents. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of a and β isoforms that are each encoded by distinct genes (Coghlan et al., Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)). The threonine/serine kinase glycogen synthase kinase-3 (GSK-3) fulfills a pivotal role in various receptor-linked signalling pathways (Doble, BW, Woodgett, JR J.Cell Sci. 2003, 116:1175-1186). Dysregulation within these pathways is considered a crucial event in the development of several prevalent human disorders, such as type II diabetes (Kaidanovich O, Eldar-Finkelman H, Expert Opin. Ther. Targets, 2002, 6:555-561), Alzheimer's disease (Grimes CA, Jope RS, Prog.Neurobiol. 2001, 65:391-426) , CNS disorders such as manic depressive disorder and neurodegenerative diseases, and chronic inflammatory disorders (Hoeflich KP, Luo WO 2007/017145 PCT/EP2006/007520 2 J, Rubie EA, Tsao MS, Jin O, Woodgett J, Nature 2000, 406:86-90). These diseases may be caused by, or result in, the abnormal operation of certain cell signalling pathways in which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase which is the rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein Tau, the gene transcription factor P-catenin, the translation initiation factor elF2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBa. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development. Currently, inhibition of GSK-3 may represent a viable strategy to develop novel medicinal entities for the treatment of such unmet diseases (Martinez A, Castro A, Dorronsoro 1, Alonso M, Med. Res. Rev., 2002, 22:373-384) through insulin mimicry, tau dephosphorylation and amyloid processing, or transcriptional modulation respectively. In the State of the Art, some compounds containing an urea group have already been described as having GSK-3 inhibitory properties. This is the case, for example, of publications WO03/004472, WO03/004475 and WO03/089419. These publications refer each one to a very broad number of compounds defined by a Markush structure, said structure being big and complex, this circumstance making their preparation more complicated and increasing the probability of reactivity of the compounds. Particularly, these compounds pertain to structural subgroups such as substituted thiazole compounds and heterocyclic amines. These compounds may contain, among many other groups, an urea functional group. These compounds are generally said to have inhibitory effects on GSK-3, and thus potential activity in the treatment and prevention of a series of diseases related to GSK-3, such as dementias, diabetes and mood disorders. Nevertheless, no results regarding GSK-3 inhibition for any particular compounds are included in any of the above-mentioned publications; that is, neither for those comprising an urea functional group any results really proving any activity of these urea derivatives are shown. WO 2007/017145 PCT/EP2006/007520 3 On the other hand, Publication WO03/004478 and article "Structural Insights and Biological Effects of GSK-3 specific Inhibitor AR-A014418", J. Biol. Chem., 278 (46), 2003 deal with one particular urea, 4-(4-methoxybenzyl)-N'-(5-nitro-l,3-thiazo!- 2-yl)urea; this urea indeed has a much smaller and simpler structure than the above mentioned ureas. It is described as having GSK-3 inhibitory properties, and thus as having potential activity for treating and/or preventing numerous conditions associated with glycogen synthase kinase 3. Nevertheless, it is not clear whether the GSK-3 inhibitory effect is due to the urea itself or to the nitro-thiazole, as heterocyclic compounds have been described as having GSK-3 inhibitory properties, see for example above-mentioned WO03/089419. Some other ureas have been described in relation to the treatment of neurological disorders, but in relation with completely different methods of action, for example WO00/06156, wherein the disclosed ureas are described to be potentiators of glutamate receptor function. There is therefore still a need to find good GSK-3 inhibitors, being both effective and selective, and having good "drugability:' properties, i.e. good pharmaceutical properties related to administration, distribution, metabolism and excretion. An additional advantage would be to find compounds with simple, stable structures, being easy to be prepared by ordinary proceedings known to the skilled person. DESCRIPTION OF THE INVENTION It has now been found that a group of stable and small urea derivatives shows inhibitory effects on GSK-3 enzyme. Use of a compound of formula (1) WO 2007/017145 PCT/EP2006/007520 4 or any pharmaceutically acceptable salt, prodrug or solvate thereof, wherein: RB is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl wherein aryl is selected from the group of phenyl, naphthyl, fenanthryl and anthracyl, substituted or unsubstituted aralkyl wherein aralkyl is benzyl, heterocycle selected from the group of azepines, benzimidazole, benzofhiazole, furan, imidazole, indole, piperidine, piperazine, purine, thiadiazole, tetrahydrofuran, benzodioxol, thiophene, benzofurane, indazole, quinazoline, pyridazine, pyrimidine, pyrazine, pyridine, isoxazole, pyrrole, pyrane, -OR5, and -S(O)t- R5, wherein RB comprises from 8 to 15 atoms selected from C, O, N, and S, with the proviso that RB is not a heterocycle substituted by a heterocycle, R3, R4, R'2, R'3, R'4, R's y R'6 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, - C(=O)R7; -C(=O)OR8, -C(=O)NR9R,0, -C=NR,,, -CN, -OR,2, -OC(=O)R,3, -S(O),-RI4, -NR15R16, -NRI7C(=O)R18, -NO2, -N=CR\|9R2oor halogen, wherein R3 and R4 together may form a =0 group, and wherein any pair of R3 R'2, R3 R:6, R4 R'2, R4 R:6, R^R'3, R'3R54, R^RN, R'sR'6, R15R16, R17R18 or R19R20 may form together a cyclic substituent; t is 0, 1, 2, 3 WO 2007/017145 PCT/EP2006/007520 5 R5 is selected from hydrogen, alkyl, aryl and heterocycle; R7, Rg. R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted alkoxy, substituted or unsubstituted ariloxy, halogen, in the manufacture of a medicament for the treatment and/or prevention of a GSK-3 mediated disease or condition wherein the disease or condition is selected from the group of diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia, Huntington's Disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding such as due to solitary cerebral amyloid angiopathy, hair loss, obesity, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, brain injury, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases as hyperplasias and immunodeficiency. Preferred compounds are those wherein R8 comprises an aromatic group. In a particular embodiment, R8 has at least 10 aromatic carbon atoms. In an additional aspect, the invention is related to a compound of formula WO 2007/017145 PCT/EP2006/007520 6 In another aspect, the invention is related to a pharmaceutical composition which comprises a compound of formula (I) as described above or a pharmaceutical!;/ acceptable salt, prodrug or solvate thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. Preferably, the disease or condition mediated by GSK-3 is selected from Alzheimer's disease, type II diabetes, depression and brain injury. According to another aspect, the compounds of formula (I) as defined above may be used as reactives for biological assays, preferably as a reactive for GSK-3 inhibition. BRIEF DESCRIPTION OF THE FIGURES Figure 1.- Represents the 1H-NMR and 13C-NMR spectra of l-Benzyl-3-naphtalen-l- yl-urea Figure 2- Represents the the 1H-NMR and 13C-NMR spectra of 1-Benzo[l,3]dioxol- 5-yl-3-benzyl-urea Figure 3.- Diagram showing GSK-3 activity of l-Benzyl-3-naphtalen-l-yl-urea measured at different concentrations. The results are reflected in comparison with the control. Figure 4.- Diagram showing GSK-3 activity of l-Benzo[l,3]dioxol-5-yl-3-benzyl-urea measured at different concentrations. The results are reflected in comparison with the control. DETAILED DESCRIPTION OF THE INVENTION The urea derivatives of formula (I) according to the present invention are chemical entities which surprisingly have shown good inhibitory effects on GSK-3 enzyme, together with a good stability and low toxicity. As indicated above, in a first aspect the present invention is related to the use of compounds of formula (1) or any pharmaceutically acceptable salt, prodrug or solvate thereof, in the preparation of a medicament for the treatment of a disease or condition mediated by GSK-3. Preferably, RB comprises an aromatic group and even more preferably RB has at least 10 aromatic carbon atoms. WO 2007/017145 PCT/EP2006/007520 7 In a preferred embodiment, the compound of formula (1) has an aromatic group which is directly linked to the N atom of the urea group. According to another particular embodiment, RB is a substituted or unsubstituted naphtyl group, preferably an unsubstituted alpha-naphtyl group. Preferably, RB is selected from: In another particular embodiment, R'2, R3, R'4, R:5 and R56 are independently selected from hydrogen, substituted or unsubstituted alkyl, -C(=O)R7, -C(=O)OR8, - OR\|2, -NR\|5R\|6, or halogen, wherein R7, R8, R12, R15 and Ri6 are defined as above. Preferably, RS, R'3, R'4, R's and R\ are H. Two preferred compounds of formula (I) are: Within the present invention, the expression "GSK-3 mediated disease or condition" means any disease or other deleterious condition or state in which GSK-3 is WO 2007/017145 PCT/EP2006/007520 8 known to play a role. This disease or condition may be, but is not limited to, diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia, Huntington's Disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding such as due to solitary cerebral amyloid angiopathy, hair loss, obesity, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, brain injury, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases as hyperplasias and immunodeficiency. Preferably, the GSK-3 mediated disease or condition is either Alzheimer's Disease, type II diabetes, depression or brain injury. Another aspect of the present invention is a pharmaceutical composition comprising a compound as defined above, or any pharmaceutically acceptable salt, According to further aspects of the invention, it is related to a compound of formula WO 2007/017145 PCT/EP2006/007520 9 prodrug or solvate thereof, and a phannaceutically acceptable carrier adjuvant or vehicle; preferably, said pharmaceutical composition is for oral administration. Preferred diseases or conditions which may be treated with this pharmaceutical composition may be, but are not limited to, diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia, Huntington's Disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding such as due to solitary cerebral amyloid angiopathy, hair loss, obesity, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, brain injury, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases as hyperplasias and immunodeficiency. Another aspect of this invention relates to a method of treating or preventing an GSK-3 mediated disease or condition with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula (I) as defined above or a pharmaceutical composition thereof. In another aspect the invention relates to inhibiting GSK-3 activity in a biological sample with the compounds of formula (1), which method comprises contacting the biological sample with a GSK-3 inhibitor of formula (I). The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Thus, in one aspect the invention is directed to the use of compounds of formula 1 as reactives for biological assays, in particular as a reactive for GSK-3 inhibition. WO 2007/017145 PCT/EP2006/007520 10 In the above definition of compounds of formula (I) the following terms have the meaning indicated: "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no saturation, having one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc. Alkyl radicals may be optionally substituted by one or more substituents such as halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio. "Alkoxy" refers to a radical of the formula -OR;1 wherein Ra is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc. "Alkoxycarbonyl" refers to a radical of the formula -C(O)ORa where Ra is an alkyl radical as defined above, e. g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc. "Alkylthio" refers to a radical of the formula -SRa where Ra is an alkyl radical as defined above, e. g., methylthio, ethylthio, propylthio, etc. "Amino" refers to a radical of the formula-Nhb, -NHRa or -NRaRb, wherein Ra and Rb are independently a radical alkyl as defined above. "Aryl" refers to a phenyl, naphthyl, indenyl, fenanthryl or anthracyl radical, preferably phenyl or naphthyl radical. The aryl radical may be optionally substituted by one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl, as defined herein. "Aralkyl" refers to an aryl group linked to an alkyl group. Preferred examples include benzyl and phenethyl. "Acyl" refers to a radical of the formula-C(O)-Rc and -C(O)-Rti where Rc is an WO 2007/017145 PCT/EP2006/007520 11 alkyl radical as defined above and Rj is an aryl radical as defined above, e. g., acetyl, propionyl, benzoyl, and the like. "Aroylalkyl" refers to an alky] group substituted with -Ra-C(O)-Rd, wherein Ra is an alkyl radical as defined above and Rd is a radical aryl as defined above. Preferred examples include benzoylmethyl. "Carboxy" refers to a radical of the formula -C(O)OH. "Cycloalkyl" refers to a stable 3-to 10-membered monocyclic or bicyclic radical which is saturated or partially saturated, and which consist solely of carbon and hydrogen atoms. Unless otherwise stated specifically in the specification, the term "cycloalkyl" is meant to include cycloalkyl radicals which are optionally substituted by one or more such as alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl. "Halo" refers to bromo, chloro, iodo or fluoro. "Heterocycle" refers to a heterocyclyl radical. The heterocycle refers to a stable 3-to 15 membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, preferably a 4-to 8-membered ring with one or more heteroatoms, more preferably a 5- or 6-membered ring with one or more heteroatoms. For the purposes of this invention, the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidised; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be partially or fully saturated or aromatic. Examples of such heterocycles include, but are not limited to, azepines, benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, thiadiazole, tetrahydrofuran, benzodioxol, thiophene, benzofurane, indazole, quinazoline, pyridazine, pyrimidine, pyrazine, pyridine, isoxazole, pyrrole, pyrazole, pyrane. WO 2007/017145 PCT/EP2006/007520 12 References herein to substituted groups in the compounds of the present invention refer to the specified moiety that may be substituted at one or more available positions by one or more suitable groups, e. g., halogen such as fluoro, chloro, bromo and iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a C1-6 alkanoyl group such as acyl and the like; carboxamido; alkyl groups including those groups having 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; alkylsulfonyl groups including those moieties having one or more sulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to about 12 carbon atoms or from 1 to about 6 carbon atoms; unsubstituted cycloalkyl, wherein cycloalkyl is as it was described above; unsubstituted aryl, wherein cycloalkyl is as it was described above, particularly phenyl or naphthyl; and aralkyl such as benzyl. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and each substitution is independent of the other. Unless otherwise stated, the compounds of the invention are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a I3C- or l4C-enriched carbon or 15N-enriched nitrogen are within the scope of this invention. The term "pharmaceutically acceptable salts, derivatives, solvates, prodrugs" refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound which, upon administration to the recipient is capable of providing (directly or WO 2007/017145 PCT/EP2006/007520 13 indirectly) a compound as described herein. However, it will be appreciated that non- pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts, prodrugs and derivatives can be carried out by methods known in the art. For instance, pharmaceutically acceptable salts of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of the acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, maiate, mandelate, methanesulphonate and p-toluenesulphonate. Examples of the alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium, ammonium, magnesium, aluminium and lithium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glucamine and basic aminoacids salts. Particularly favoured derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Any compound that is a prodrug of a compound of formula (I) is within the scope of the invention. The term "prodrug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the WO 2007/017145 PCT/EP2006/007520 14 following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known methods of producing a prodrug of a given acting compound are known to those skilled in the art and can be found e.g. in Krogsgaard-Larsen et al. "Textbook of Drugdesign and Discovery" Taylor & Francis (April 2002). The compounds of the invention may be in crystalline form either as free compounds or as solvates (e.g. hydrates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art. Suitable solvates are pharmaceutically acceptable solvates. In a particular embodiment the solvate is a hydrate. The compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels. Purity levels for the drug substance are preferably above 50%, more preferably above 70%, most preferably above 90%. In a preferred embodiment it is above 95% of the compound of formula (I), or of its salts, solvates or prodrugs. The compounds of the present invention represented by the above described formula (1) may include enantiomers depending on the presence of chiral centres or isomers depending on the presence of multiple bonds (e.g. Z, E). The single isomers, enantiomers or diastereoisomers and mixtures thereof fall within the scope of the present invention. The compounds of formula (I) defined above can be obtained by available synthetic procedures, for example by reacting: in a suitable solvent, such as N,N-dimethylformamide, dimethyl sulfoxide, dioxane, dichloromethane or tetrahydrofuran, at a temperature within the range of+20 to +150°C. One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition. In the case of salts and solvates the additional ionic and solvent moieties must also be non-toxic. The compounds of the invention may present different polymorphic forms, it is intended that the invention encompasses all such forms. Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration. In a preferred embodiment the pharmaceutical compositions are in oral form. Suitable dose forms for oral administration may be tablets and capsules and may contain conventional excipients known in the art such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate. The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art. The tablets may for example be prepared by wet or dry granulation and optionally coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. WO 2007/017145 PCT/EP2006/007520 16 The pharmaceutical compositions may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the appropriate unit dosage form. Adequate excipients can be used, such as bulking agents, buffering agents or surfactants. The mentioned formulations will be prepared using standard methods such as those described or referred to in the Spanish and US Pharmacopoeias and similar reference texts. Administration of the compounds or compositions of the present invention may be by any suitable method, such as intravenous infusion, oral preparations, and intraperitoneal and intravenous administration. Oral administration is preferred because of the convenience for the patient and the chronic character of many of the diseases to be treated. Generally an effective administered amount of a compound of the invention will depend on the relative efficacy of the compound chosen, the severity of the disorder being treated and the weight of the sufferer. However, active compounds will typically be administered once or more times a day for example 1, 2, 3 or 4 times daily, with typical total daily doses in the range of from 0.1 to 1000 mg/kg/day. The compounds and compositions of this invention may be used with other drugs to provide a combination therapy. The other drugs may form part of the same composition, or be provided as a separate composition for administration at the same time or at different time. In the following, the present invention is further illustrated by examples. They should in no case be interpreted as a limitation of the scope of the invention as defined in the claims. WO 2007/017145 PCT/EP2006/007520 17 EXAMPLES Preparation of compounds of formula II The compounds of formula II according to the present invention where prepared by reacting a convenient isocyanate with a convenient amine in order to obtain the corresponding urea, as described above. Example 1 Preparation of l-BenzyI-3-naphthaIen-l-yl-urea 0.44 ml (4 mmol) benzylamine are reacted with 0.58 ml (4 mmol) 2-Isocyanato- naphthalene in dichloromethane at room temperature during night: The resulting white precipitate is filtered and washed with diethylether. 1.18 gr of a white powder with a molecular weight of 276 are obtained. Corresponding 1H- NMR and 13C-NMR spectra are indicated in Figure 1. They show the white compound to be l-benzyl-3-naphthalen-l-yl-urea. WO 2007/017145 PCT/EP2006/007520 18 Example 2 Preparation of l-Benzo[l,3\|dioxol-5-yl-3-benzyl-urea 0.44 ml (4 mmol) benzylamine are reacted with 654.5 mg (4 mmol) 5- isocyanato-benzo[l,3]dioxole in dichloromethane at room temperature during night: The resulting white precipitate is filtered and washed with diethylether. 1 gr of a white powder with a molecular weight of 276 is obtained. Corresponding 1H-NMR and 13C-NMR spectra are shown in Figure 2. They show the white compound to be 1- benzyl-3-naphthalen-1 -yl-urea. Biological Methods GSK-3(3 inhibition The GSK-3P activity was determined by incubation of a mixture of recombinant human GSK-3 enzyme, a phosphate source and GSK-3 substrate in the presence and in the absence of the corresponding test compound, and by measuring the GSK-3 activity of this mixture. Recombinant human glycogen synthase kinase 38 was assayed in MOPS 8 mM pH 7.3, EDTA 0.2 mM, MgCl? 10 mM and sodium orthovanadate 0.25 mM in the presence of 62.5 uM of Phospho-Glycogen Synthase Peptide-2 (GS-2), 0.5 uCi y-33P- ATP and unlabclled ATP at a final concentration of 12.5 uM. The final assay volume was 20 ul After incubation for 30 minutes at 30 °C, 15 ul aliquots were spotted onto P81 phosphocellulose papers. Filters were washed four times for at least 10 minutes each and counted with 1.5 ml of scintillation cocktail in a scintillation counter. WO 2007/017145 PCT/EP2006/007520 19 The values for GSK-3 activity in the presence of the compounds according to the present invention were measured at different concentrations; the results, reflected in comparison with the control, are shown in Figures 3 and 4. The compounds' 1C50 values were calculated analyzing inhibition curves by non-linear regression using GraphPad Prism. The IC50 (concentration at which 50 % of enzyme inhibition is shown) values are gathered in table 1: Table 1 Compound IC50 1 -BenzyI-3-naphthalen-l-yl-urea 17.1 l-Benzo\|l,31dioxol-5-yl-3-benzyl-urea 38.4 20 AMENDED CLAIMS 1.- Use of a compound of formula (1) or any pharmaceutically acceptable salt, prodnxg or solvatc thereof, wherein: RB is selected from substituted or unsubstitutcd alkyl, substituted or unsubstituted cyeloalkyl, substituted or unsubstituted aryl wherein aryl is selected from the group of phenyl, naphthyl, fenaathryl and aathracy], substituted or unsubstituted aralkyl wherein aralkyl is benzyl, heterocyclc selected -from the group of azepines, benzimidazole, benzothiazole, ftran, imidazole, indole, piperidinc, piperazine, purine, thiadiazole, tetrahydrofiiran, benzodioxol, thiophene, ben2ofurane, indazole, quinazoline, pyridazine, pyrimidine, pyrazine, pyridine, isoxazole, pyrrole, pyrane, -OR5, and -S(O)f R5, wherein RB comprises from 8 to 15 atoms selected from C, O, N, and S, with the proviso that RB is not a heterocyclc substituted by a heterocyclc, R3, R4, R'2, R3. R'4, R's y R's are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted^aryl, substituted ^or ^lnsubstitutcd heterocycle, G(^O)R7, -U=^)OK8, -C(=0)NR9Rto, -C=NRnj -CN, -ORI2, -OC(=O)R]3, -S(O)t-Ru, -NR]3Ri6, -NRi7C(=O)R\|g, -NO2, -N«CRi9ll2o or halogen, wherein R3 and R4 together AMENDED SHEET 21 may form a -O group, and wherein any pair of R3 R'2, R3 R'6, R4 R'2, R4 R'6, R'2 R'3, R'3R'4, R'4R'5, R'5R'6, R15R16, R17R18 or R19R20 may form together a cyclic substituent; tisO, 1,2,3 R5 is selected from hydrogen, alkyl, aryl and heterocycle; f7, R8, R9, R10, R11, R13, R14, R15, R16, R17, R18, R19 and R20 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitutcd cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstitutcd heterocycle, substituted or unsubstitutcd alkoxy, substituted or unsubstituted ariloxy, halogen, R12 is selected from hydrogen, unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstitutcd alkenyl, substituted or unsubstituted aryl, substituted or unsubstitutcd heterocycle, substituted or unsubstitutcd alkoxy, substituted or unsubstituted ariioxy, halogen, in the manufacture of a medicament for the treatment and/or prevention of a GSK-3 mediated disease or condition wherein the disease or condition is selecled from the group of diabetes, conditions associated with diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guarn paricinson ism-dementia complex, Pick's disease, corticobasal degeneration, frontotemporal dementia, Huntrngton's Disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and ncurotrauroatic diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding such as due to solitary cerebral amyloid angiopathy, hair loss, obesity, hypertension, polycystic ovary syndrome, syndrome X, ischacmia, brain injury, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, chronic inflammatory diseases, cancer and hyperprolifcrative diseases as hyperplasias and immunodeficiency, 2.- Use according to claim 1, wherein RB comprises an aromatic group. 3.- Use according to claim 1, wherein RB has at least 10 aromatic carbon atoms. AMENDED SHEET 22 4.- Use according to claim 2, wherein the aromatic group is directly linked to the N atom of the urea group. 5.- Use according to claim 3, wherein RB is a substituted or unsubstituled naphtyl group. 6.- Use according to claim 5, wherein RB is an unsubstituted aJpha-naphtyl group. 7.- Use according to claim 1, wherein R8 is a group selected from: 9.- Use according to claim 1, wherein R'2, R'3, R4, R's and R*6 arc independently selected from hydrogen, substituted or unsubstituted alkyl, -C(iO)R'/, - CO-COORn, -OR12, -NRi5R.i6, or halogen, wherein R7, Rg, Rj2, Rjs and Ri6 are defined as an claim 1. 10.- Use according to claim 1, wherein R'2j R'3j R%, R'5 and R'6 arc H. 11.- Use according to claim 1, wherein the compound of formula (I) is selected from: AMENDED SHEET 23 12.- Use according to claim 1 wherein the disease is Alzheimer's disease. 13.- Use according to claim 1 wherein tie disease is type II diabetes. 14.- Use according to claim 1 wherein the disease is depression. 15.- Use according to claim 1 wherein the disease is brain injury. 16.- A compound of formula 24 for use as a medicament 18.- A pharmaceutical composition which comprises a compound of formula as defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceuticaily acceptable carrier, adjuvant or vehicle. 19.- A pharmaceutical composition according to claim 18 for oral administration. 20.- Use of a compound of formula (1) as defined in any of claims 1 to 11 as reactives for biological assays, preferably as a reactive for GSK-3 inhibition. 21.- Method of treating or preventing au GSK-3 mediated disease or condition with a GSK-3 inhibitor, wherein the disease or condition is selected from flic group of diabetes, conditions associated with diabetes, chronic neurodegeneralive conditions including dementias such as Alzheimer's disease, Parkinson's disease, progressive supraimclear palsy, subacute sclerosing panencephatttic parkuisom'sm, postencephalitic parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration, frontotcinporal dementia, Huntington's Disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatjc diseases such as acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar disorders, promotion of functional recovery post stroke, cerebral bleeding such as due to solitary cerebral amyloid angiopathy, hair Joss, obesity, hypertension, polycystie ovary syndrome, syndrome X, ischaemia, brain injury, traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease, inflammation, chronic inflammatory diseases, cancer and hyperproliferativc diseases as hyperplasias and immunodeficiency, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula (I) as defined in claims 1 to 11 or a pharmaceutical composition thereof. AMENDED SHEET The invention relates to urea derivatives of formula (I) as inhibitors of glycogen synthase kinase 36, GSK-3, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use for the treatment and or prophylaxis of a disease in which GSK-3 is involved, such as Alzheimer's disease or non-insulin dependent diabetes mellitus.

Full Text

WO 2007/017145 PCT/EP2006/007520
GSK-3 INHIBITORS
FIELD OF THE INVENTION
The present invention relates to enzyme inhibitors, and more particularly to urea
derivatives as inhibitors of glycogen synthase kinase 3(3, GSK-3, to processes of
preparation of such compounds, to pharmaceutical compositions comprising them, and
to their use for the treatment and or prophylaxis of a disease in which GSK-3 is
involved, such as Alzheimer's disease or non-insulin dependent diabetes mellitus.
BACKGROUND OF THE INVENTION
The search for new therapeutic agents has been greatly aided in recent years by
better understanding of the structure of enzymes and other biomolecules associated with
target diseases. One important class of enzymes that has been the subject of extensive
study is the protein kinases. Many diseases are associated with abnormal cellular
responses triggered by protein kinase-mediated events. These diseases include
autoimmune diseases, inflammatory diseases, neurological and neurodegenerative
diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or
hormone-related diseases. Accordingly, there has been a substantial effort in medicinal
chemistry to find protein kinase inhibitors that are effective as therapeutic agents.
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase
comprised of a and β isoforms that are each encoded by distinct genes (Coghlan et al.,
Chemistry & Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics
Dev., 10, 508-514 (2000)). The threonine/serine kinase glycogen synthase kinase-3
(GSK-3) fulfills a pivotal role in various receptor-linked signalling pathways (Doble,
BW, Woodgett, JR J.Cell Sci. 2003, 116:1175-1186). Dysregulation within these
pathways is considered a crucial event in the development of several prevalent human
disorders, such as type II diabetes (Kaidanovich O, Eldar-Finkelman H, Expert Opin.
Ther. Targets, 2002, 6:555-561), Alzheimer's disease (Grimes CA, Jope RS,
Prog.Neurobiol. 2001, 65:391-426) , CNS disorders such as manic depressive disorder
and neurodegenerative diseases, and chronic inflammatory disorders (Hoeflich KP, Luo

WO 2007/017145 PCT/EP2006/007520
2
J, Rubie EA, Tsao MS, Jin O, Woodgett J, Nature 2000, 406:86-90). These diseases
may be caused by, or result in, the abnormal operation of certain cell signalling
pathways in which GSK-3 plays a role.
GSK-3 has been found to phosphorylate and modulate the activity of a number
of regulatory proteins. These proteins include glycogen synthase which is the rate
limiting enzyme necessary for glycogen synthesis, the microtubule associated protein
Tau, the gene transcription factor P-catenin, the translation initiation factor elF2B, as
well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and
CEPBa. These diverse protein targets implicate GSK-3 in many aspects of cellular
metabolism, proliferation, differentiation and development.
Currently, inhibition of GSK-3 may represent a viable strategy to develop novel
medicinal entities for the treatment of such unmet diseases (Martinez A, Castro A,
Dorronsoro 1, Alonso M, Med. Res. Rev., 2002, 22:373-384) through insulin mimicry,
tau dephosphorylation and amyloid processing, or transcriptional modulation
respectively.
In the State of the Art, some compounds containing an urea group have already
been described as having GSK-3 inhibitory properties. This is the case, for example, of
publications WO03/004472, WO03/004475 and WO03/089419. These publications
refer each one to a very broad number of compounds defined by a Markush structure,
said structure being big and complex, this circumstance making their preparation more
complicated and increasing the probability of reactivity of the compounds. Particularly,
these compounds pertain to structural subgroups such as substituted thiazole compounds
and heterocyclic amines. These compounds may contain, among many other groups, an
urea functional group. These compounds are generally said to have inhibitory effects on
GSK-3, and thus potential activity in the treatment and prevention of a series of diseases
related to GSK-3, such as dementias, diabetes and mood disorders. Nevertheless, no
results regarding GSK-3 inhibition for any particular compounds are included in any of
the above-mentioned publications; that is, neither for those comprising an urea
functional group any results really proving any activity of these urea derivatives are
shown.

WO 2007/017145 PCT/EP2006/007520
3
On the other hand, Publication WO03/004478 and article "Structural Insights
and Biological Effects of GSK-3 specific Inhibitor AR-A014418", J. Biol. Chem., 278
(46), 2003 deal with one particular urea, 4-(4-methoxybenzyl)-N'-(5-nitro-l,3-thiazo!-
2-yl)urea; this urea indeed has a much smaller and simpler structure than the above
mentioned ureas. It is described as having GSK-3 inhibitory properties, and thus as
having potential activity for treating and/or preventing numerous conditions associated
with glycogen synthase kinase 3. Nevertheless, it is not clear whether the GSK-3
inhibitory effect is due to the urea itself or to the nitro-thiazole, as heterocyclic
compounds have been described as having GSK-3 inhibitory properties, see for example
above-mentioned WO03/089419.
Some other ureas have been described in relation to the treatment of
neurological disorders, but in relation with completely different methods of action, for
example WO00/06156, wherein the disclosed ureas are described to be potentiators of
glutamate receptor function.
There is therefore still a need to find good GSK-3 inhibitors, being both
effective and selective, and having good "drugability:' properties, i.e. good
pharmaceutical properties related to administration, distribution, metabolism and
excretion. An additional advantage would be to find compounds with simple, stable
structures, being easy to be prepared by ordinary proceedings known to the skilled
person.
DESCRIPTION OF THE INVENTION
It has now been found that a group of stable and small urea derivatives shows
inhibitory effects on GSK-3 enzyme.
Use of a compound of formula (1)

WO 2007/017145 PCT/EP2006/007520
4

or any pharmaceutically acceptable salt, prodrug or solvate thereof,
wherein:
RB is selected from substituted or unsubstituted alkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted aryl wherein aryl is selected from the group of
phenyl, naphthyl, fenanthryl and anthracyl, substituted or unsubstituted aralkyl wherein
aralkyl is benzyl, heterocycle selected from the group of azepines, benzimidazole,
benzofhiazole, furan, imidazole, indole, piperidine, piperazine, purine, thiadiazole,
tetrahydrofuran, benzodioxol, thiophene, benzofurane, indazole, quinazoline,
pyridazine, pyrimidine, pyrazine, pyridine, isoxazole, pyrrole, pyrane, -OR5, and -S(O)t-
R5, wherein RB comprises from 8 to 15 atoms selected from C, O, N, and S,
with the proviso that RB is not a heterocycle substituted by a heterocycle,
R3, R4, R'2, R'3, R'4, R's y R'6 are independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, -
C(=O)R7; -C(=O)OR8, -C(=O)NR9R,0, -C=NR,,, -CN, -OR,2, -OC(=O)R,3, -S(O),-RI4,
-NR15R16, -NRI7C(=O)R18, -NO2, -N=CR|9R2oor halogen, wherein R3 and R4 together
may form a =0 group, and wherein any pair of R3 R'2, R3 R:6, R4 R'2, R4 R:6, R^R'3,
R'3R54, R^RN, R'sR'6, R15R16, R17R18 or R19R20 may form together a cyclic substituent;
t is 0, 1, 2, 3

WO 2007/017145 PCT/EP2006/007520
5
R5 is selected from hydrogen, alkyl, aryl and heterocycle;
R7, Rg. R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 are independently
selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl,
substituted or unsubstituted heterocycle, substituted or unsubstituted alkoxy, substituted
or unsubstituted ariloxy, halogen, in the manufacture of a medicament for the treatment
and/or prevention of a GSK-3 mediated disease or condition wherein the disease or
condition is selected from the group of diabetes, conditions associated with diabetes,
chronic neurodegenerative conditions including dementias such as Alzheimer's disease,
Parkinson's disease, progressive supranuclear palsy, subacute sclerosing panencephalitic
parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis, guam
parkinsonism-dementia complex, Pick's disease, corticobasal degeneration,
frontotemporal dementia, Huntington's Disease, AIDS associated dementia,
amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as
acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar
disorders, promotion of functional recovery post stroke, cerebral bleeding such as due to
solitary cerebral amyloid angiopathy, hair loss, obesity, hypertension, polycystic ovary
syndrome, syndrome X, ischaemia, brain injury, traumatic brain injury, cancer,
leukopenia, Down's syndrome, Lewy body disease, inflammation, chronic inflammatory
diseases, cancer and hyperproliferative diseases as hyperplasias and immunodeficiency.
Preferred compounds are those wherein R8 comprises an aromatic group.
In a particular embodiment, R8 has at least 10 aromatic carbon atoms.
In an additional aspect, the invention is related to a compound of formula

WO 2007/017145 PCT/EP2006/007520
6
In another aspect, the invention is related to a pharmaceutical composition
which comprises a compound of formula (I) as described above or a pharmaceutical!;/
acceptable salt, prodrug or solvate thereof and a pharmaceutically acceptable carrier,
adjuvant or vehicle.
Preferably, the disease or condition mediated by GSK-3 is selected from
Alzheimer's disease, type II diabetes, depression and brain injury.
According to another aspect, the compounds of formula (I) as defined above
may be used as reactives for biological assays, preferably as a reactive for GSK-3
inhibition.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1.- Represents the 1H-NMR and 13C-NMR spectra of l-Benzyl-3-naphtalen-l-
yl-urea
Figure 2- Represents the the 1H-NMR and 13C-NMR spectra of 1-Benzo[l,3]dioxol-
5-yl-3-benzyl-urea
Figure 3.- Diagram showing GSK-3 activity of l-Benzyl-3-naphtalen-l-yl-urea
measured at different concentrations. The results are reflected in comparison with the
control.
Figure 4.- Diagram showing GSK-3 activity of l-Benzo[l,3]dioxol-5-yl-3-benzyl-urea
measured at different concentrations. The results are reflected in comparison with the
control.
DETAILED DESCRIPTION OF THE INVENTION
The urea derivatives of formula (I) according to the present invention are
chemical entities which surprisingly have shown good inhibitory effects on GSK-3
enzyme, together with a good stability and low toxicity.
As indicated above, in a first aspect the present invention is related to the use of
compounds of formula (1) or any pharmaceutically acceptable salt, prodrug or solvate
thereof, in the preparation of a medicament for the treatment of a disease or condition
mediated by GSK-3. Preferably, RB comprises an aromatic group and even more
preferably RB has at least 10 aromatic carbon atoms.

WO 2007/017145 PCT/EP2006/007520
7
In a preferred embodiment, the compound of formula (1) has an aromatic group
which is directly linked to the N atom of the urea group.
According to another particular embodiment, RB is a substituted or unsubstituted
naphtyl group, preferably an unsubstituted alpha-naphtyl group.
Preferably, RB is selected from:

In another particular embodiment, R'2, R3, R'4, R:5 and R56 are independently
selected from hydrogen, substituted or unsubstituted alkyl, -C(=O)R7, -C(=O)OR8, -
OR|2, -NR|5R|6, or halogen, wherein R7, R8, R12, R15 and Ri6 are defined as above.
Preferably, RS, R'3, R'4, R's and R\ are H.
Two preferred compounds of formula (I) are:

Within the present invention, the expression "GSK-3 mediated disease or
condition" means any disease or other deleterious condition or state in which GSK-3 is

WO 2007/017145 PCT/EP2006/007520
8
known to play a role. This disease or condition may be, but is not limited to, diabetes,
conditions associated with diabetes, chronic neurodegenerative conditions including
dementias such as Alzheimer's disease, Parkinson's disease, progressive supranuclear
palsy, subacute sclerosing panencephalitic parkinsonism, postencephalitic
parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's
disease, corticobasal degeneration, frontotemporal dementia, Huntington's Disease,
AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and
neurotraumatic diseases such as acute stroke, epilepsy, mood disorders such as
depression, schizophrenia and bipolar disorders, promotion of functional recovery post
stroke, cerebral bleeding such as due to solitary cerebral amyloid angiopathy, hair loss,
obesity, hypertension, polycystic ovary syndrome, syndrome X, ischaemia, brain injury,
traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease,
inflammation, chronic inflammatory diseases, cancer and hyperproliferative diseases as
hyperplasias and immunodeficiency.
Preferably, the GSK-3 mediated disease or condition is either Alzheimer's
Disease, type II diabetes, depression or brain injury.

Another aspect of the present invention is a pharmaceutical composition
comprising a compound as defined above, or any pharmaceutically acceptable salt,
According to further aspects of the invention, it is related to a compound of
formula

WO 2007/017145 PCT/EP2006/007520
9
prodrug or solvate thereof, and a phannaceutically acceptable carrier adjuvant or
vehicle; preferably, said pharmaceutical composition is for oral administration.
Preferred diseases or conditions which may be treated with this pharmaceutical
composition may be, but are not limited to, diabetes, conditions associated with
diabetes, chronic neurodegenerative conditions including dementias such as Alzheimer's
disease, Parkinson's disease, progressive supranuclear palsy, subacute sclerosing
panencephalitic parkinsonism, postencephalitic parkinsonism, pugilistic encephalitis,
guam parkinsonism-dementia complex, Pick's disease, corticobasal degeneration,
frontotemporal dementia, Huntington's Disease, AIDS associated dementia,
amyotrophic lateral sclerosis, multiple sclerosis and neurotraumatic diseases such as
acute stroke, epilepsy, mood disorders such as depression, schizophrenia and bipolar
disorders, promotion of functional recovery post stroke, cerebral bleeding such as due to
solitary cerebral amyloid angiopathy, hair loss, obesity, hypertension, polycystic ovary
syndrome, syndrome X, ischaemia, brain injury, traumatic brain injury, cancer,
leukopenia, Down's syndrome, Lewy body disease, inflammation, chronic inflammatory
diseases, cancer and hyperproliferative diseases as hyperplasias and immunodeficiency.
Another aspect of this invention relates to a method of treating or preventing an
GSK-3 mediated disease or condition with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a therapeutically effective amount
of a compound of formula (I) as defined above or a pharmaceutical composition thereof.
In another aspect the invention relates to inhibiting GSK-3 activity in a
biological sample with the compounds of formula (1), which method comprises
contacting the biological sample with a GSK-3 inhibitor of formula (I). The term
"biological sample", as used herein, includes, without limitation, cell cultures or extracts
thereof; preparations of an enzyme suitable for in vitro assay; biopsied material
obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen,
tears, or other body fluids or extracts thereof. Thus, in one aspect the invention is
directed to the use of compounds of formula 1 as reactives for biological assays, in
particular as a reactive for GSK-3 inhibition.

WO 2007/017145 PCT/EP2006/007520
10
In the above definition of compounds of formula (I) the following terms have the
meaning indicated:
"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting of
carbon and hydrogen atoms, containing no saturation, having one to eight carbon atoms,
and which is attached to the rest of the molecule by a single bond, e. g., methyl, ethyl,
n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc. Alkyl radicals may be optionally
substituted by one or more substituents such as halo, hydroxy, alkoxy, carboxy, cyano,
carbonyl, acyl, alkoxycarbonyl, amino, nitro, mercapto and alkylthio.
"Alkoxy" refers to a radical of the formula -OR;1 wherein Ra is an alkyl radical as
defined above, e. g., methoxy, ethoxy, propoxy, etc.
"Alkoxycarbonyl" refers to a radical of the formula -C(O)ORa where Ra is an
alkyl radical as defined above, e. g., methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, etc.
"Alkylthio" refers to a radical of the formula -SRa where Ra is an alkyl radical as
defined above, e. g., methylthio, ethylthio, propylthio, etc.
"Amino" refers to a radical of the formula-Nhb, -NHRa or -NRaRb, wherein Ra
and Rb are independently a radical alkyl as defined above.
"Aryl" refers to a phenyl, naphthyl, indenyl, fenanthryl or anthracyl radical,
preferably phenyl or naphthyl radical. The aryl radical may be optionally substituted by
one or more substituents such as hydroxy, mercapto, halo, alkyl, phenyl, alkoxy,
haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl, as defined
herein.
"Aralkyl" refers to an aryl group linked to an alkyl group. Preferred examples
include benzyl and phenethyl.
"Acyl" refers to a radical of the formula-C(O)-Rc and -C(O)-Rti where Rc is an

WO 2007/017145 PCT/EP2006/007520
11
alkyl radical as defined above and Rj is an aryl radical as defined above, e. g., acetyl,
propionyl, benzoyl, and the like.
"Aroylalkyl" refers to an alky] group substituted with -Ra-C(O)-Rd, wherein Ra is
an alkyl radical as defined above and Rd is a radical aryl as defined above. Preferred
examples include benzoylmethyl.
"Carboxy" refers to a radical of the formula -C(O)OH.
"Cycloalkyl" refers to a stable 3-to 10-membered monocyclic or bicyclic radical
which is saturated or partially saturated, and which consist solely of carbon and
hydrogen atoms. Unless otherwise stated specifically in the specification, the term
"cycloalkyl" is meant to include cycloalkyl radicals which are optionally substituted by
one or more such as alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy and
alkoxycarbonyl.
"Halo" refers to bromo, chloro, iodo or fluoro.
"Heterocycle" refers to a heterocyclyl radical. The heterocycle refers to a stable
3-to 15 membered ring which consists of carbon atoms and from one to five
heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
preferably a 4-to 8-membered ring with one or more heteroatoms, more preferably a 5-
or 6-membered ring with one or more heteroatoms. For the purposes of this invention,
the heterocycle may be a monocyclic, bicyclic or tricyclic ring system, which may
include fused ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl
radical may be optionally oxidised; the nitrogen atom may be optionally quaternized;
and the heterocyclyl radical may be partially or fully saturated or aromatic. Examples of
such heterocycles include, but are not limited to, azepines, benzimidazole,
benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine,
quinoline, thiadiazole, tetrahydrofuran, thiadiazole, tetrahydrofuran, benzodioxol,
thiophene, benzofurane, indazole, quinazoline, pyridazine, pyrimidine, pyrazine,
pyridine, isoxazole, pyrrole, pyrazole, pyrane.

WO 2007/017145 PCT/EP2006/007520
12
References herein to substituted groups in the compounds of the present
invention refer to the specified moiety that may be substituted at one or more available
positions by one or more suitable groups, e. g., halogen such as fluoro, chloro, bromo
and iodo; cyano; hydroxyl; nitro; azido; alkanoyl such as a C1-6 alkanoyl group such as
acyl and the like; carboxamido; alkyl groups including those groups having 1 to about
12 carbon atoms or from 1 to about 6 carbon atoms and more preferably 1-3 carbon
atoms; alkenyl and alkynyl groups including groups having one or more unsaturated
linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms; alkoxy
groups having one or more oxygen linkages and from 1 to about 12 carbon atoms or 1 to
about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those
moieties having one or more thioether linkages and from 1 to about 12 carbon atoms or
from 1 to about 6 carbon atoms; alkylsulfinyl groups including those moieties having
one or more sulfinyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6
carbon atoms; alkylsulfonyl groups including those moieties having one or more
sulfonyl linkages and from 1 to about 12 carbon atoms or from 1 to about 6 carbon
atoms; aminoalkyl groups such as groups having one or more N atoms and from 1 to
about 12 carbon atoms or from 1 to about 6 carbon atoms; unsubstituted cycloalkyl,
wherein cycloalkyl is as it was described above; unsubstituted aryl, wherein cycloalkyl
is as it was described above, particularly phenyl or naphthyl; and aralkyl such as benzyl.
Unless otherwise indicated, an optionally substituted group may have a substituent at
each substitutable position of the group, and each substitution is independent of the
other.
Unless otherwise stated, the compounds of the invention are also meant to
include compounds which differ only in the presence of one or more isotopically
enriched atoms. For example, compounds having the present structures except for the
replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by
a I3C- or l4C-enriched carbon or 15N-enriched nitrogen are within the scope of this
invention.
The term "pharmaceutically acceptable salts, derivatives, solvates, prodrugs"
refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound
which, upon administration to the recipient is capable of providing (directly or

WO 2007/017145 PCT/EP2006/007520
13
indirectly) a compound as described herein. However, it will be appreciated that non-
pharmaceutically acceptable salts also fall within the scope of the invention since those
may be useful in the preparation of pharmaceutically acceptable salts. The preparation
of salts, prodrugs and derivatives can be carried out by methods known in the art.
For instance, pharmaceutically acceptable salts of compounds provided herein
are synthesized from the parent compound which contains a basic or acidic moiety by
conventional chemical methods. Generally, such salts are, for example, prepared by
reacting the free acid or base forms of these compounds with a stoichiometric amount of
the appropriate base or acid in water or in an organic solvent or in a mixture of the two.
Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol or
acetonitrile are preferred. Examples of the acid addition salts include mineral acid
addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide,
sulphate, nitrate, phosphate, and organic acid addition salts such as, for example,
acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, maiate, mandelate,
methanesulphonate and p-toluenesulphonate. Examples of the alkali addition salts
include inorganic salts such as, for example, sodium, potassium, calcium, ammonium,
magnesium, aluminium and lithium salts, and organic alkali salts such as, for example,
ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine,
glucamine and basic aminoacids salts.
Particularly favoured derivatives or prodrugs are those that increase the
bioavailability of the compounds of this invention when such compounds are
administered to a patient (e.g., by allowing an orally administered compound to be more
readily absorbed into the blood) or which enhance delivery of the parent compound to a
biological compartment (e.g., the brain or lymphatic system) relative to the parent
species.
Any compound that is a prodrug of a compound of formula (I) is within the
scope of the invention. The term "prodrug" is used in its broadest sense and
encompasses those derivatives that are converted in vivo to the compounds of the
invention. Such derivatives would readily occur to those skilled in the art, and include,
depending on the functional groups present in the molecule and without limitation, the

WO 2007/017145 PCT/EP2006/007520
14
following derivatives of the present compounds: esters, amino acid esters, phosphate
esters, metal salts sulfonate esters, carbamates, and amides. Examples of well known
methods of producing a prodrug of a given acting compound are known to those skilled
in the art and can be found e.g. in Krogsgaard-Larsen et al. "Textbook of Drugdesign
and Discovery" Taylor & Francis (April 2002).
The compounds of the invention may be in crystalline form either as free
compounds or as solvates (e.g. hydrates) and it is intended that both forms are within
the scope of the present invention. Methods of solvation are generally known within the
art. Suitable solvates are pharmaceutically acceptable solvates. In a particular
embodiment the solvate is a hydrate.
The compounds of formula (I) or their salts or solvates are preferably in
pharmaceutically acceptable or substantially pure form. By pharmaceutically acceptable
form is meant, inter alia, having a pharmaceutically acceptable level of purity excluding
normal pharmaceutical additives such as diluents and carriers, and including no material
considered toxic at normal dosage levels. Purity levels for the drug substance are
preferably above 50%, more preferably above 70%, most preferably above 90%. In a
preferred embodiment it is above 95% of the compound of formula (I), or of its salts,
solvates or prodrugs.
The compounds of the present invention represented by the above described
formula (1) may include enantiomers depending on the presence of chiral centres or
isomers depending on the presence of multiple bonds (e.g. Z, E). The single isomers,
enantiomers or diastereoisomers and mixtures thereof fall within the scope of the
present invention.
The compounds of formula (I) defined above can be obtained by available
synthetic procedures, for example by reacting:

in a suitable solvent, such as N,N-dimethylformamide, dimethyl sulfoxide, dioxane,
dichloromethane or tetrahydrofuran, at a temperature within the range of+20 to +150°C.
One preferred pharmaceutically acceptable form is the crystalline form,
including such form in a pharmaceutical composition. In the case of salts and solvates
the additional ionic and solvent moieties must also be non-toxic. The compounds of the
invention may present different polymorphic forms, it is intended that the invention
encompasses all such forms.
Examples of pharmaceutical compositions include any solid (tablets, pills,
capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for
oral, topical or parenteral administration.
In a preferred embodiment the pharmaceutical compositions are in oral form.
Suitable dose forms for oral administration may be tablets and capsules and may contain
conventional excipients known in the art such as binding agents, for example syrup,
acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example
lactose, sugar, maize starch, calcium phosphate, sorbitol or glycine; tabletting
lubricants, for example magnesium stearate; disintegrants, for example starch,
polyvinylpyrrolidone, sodium starch glycolate or microcrystalline cellulose; or
pharmaceutically acceptable wetting agents such as sodium lauryl sulfate.
The solid oral compositions may be prepared by conventional methods of
blending, filling or tabletting. Repeated blending operations may be used to distribute
the active agent throughout those compositions employing large quantities of fillers.
Such operations are conventional in the art. The tablets may for example be prepared by
wet or dry granulation and optionally coated according to methods well known in
normal pharmaceutical practice, in particular with an enteric coating.

WO 2007/017145 PCT/EP2006/007520
16
The pharmaceutical compositions may also be adapted for parenteral
administration, such as sterile solutions, suspensions or lyophilized products in the
appropriate unit dosage form. Adequate excipients can be used, such as bulking agents,
buffering agents or surfactants.
The mentioned formulations will be prepared using standard methods such as
those described or referred to in the Spanish and US Pharmacopoeias and similar
reference texts.
Administration of the compounds or compositions of the present invention may
be by any suitable method, such as intravenous infusion, oral preparations, and
intraperitoneal and intravenous administration. Oral administration is preferred because
of the convenience for the patient and the chronic character of many of the diseases to
be treated.
Generally an effective administered amount of a compound of the invention will
depend on the relative efficacy of the compound chosen, the severity of the disorder
being treated and the weight of the sufferer. However, active compounds will typically
be administered once or more times a day for example 1, 2, 3 or 4 times daily, with
typical total daily doses in the range of from 0.1 to 1000 mg/kg/day.
The compounds and compositions of this invention may be used with other
drugs to provide a combination therapy. The other drugs may form part of the same
composition, or be provided as a separate composition for administration at the same
time or at different time.
In the following, the present invention is further illustrated by examples. They
should in no case be interpreted as a limitation of the scope of the invention as defined
in the claims.

WO 2007/017145 PCT/EP2006/007520
17
EXAMPLES
Preparation of compounds of formula II
The compounds of formula II according to the present invention where prepared
by reacting a convenient isocyanate with a convenient amine in order to obtain the
corresponding urea, as described above.
Example 1
Preparation of l-BenzyI-3-naphthaIen-l-yl-urea
0.44 ml (4 mmol) benzylamine are reacted with 0.58 ml (4 mmol) 2-Isocyanato-
naphthalene in dichloromethane at room temperature during night:

The resulting white precipitate is filtered and washed with diethylether. 1.18 gr
of a white powder with a molecular weight of 276 are obtained. Corresponding 1H-
NMR and 13C-NMR spectra are indicated in Figure 1. They show the white compound
to be l-benzyl-3-naphthalen-l-yl-urea.

WO 2007/017145 PCT/EP2006/007520
18
Example 2
Preparation of l-Benzo[l,3|dioxol-5-yl-3-benzyl-urea
0.44 ml (4 mmol) benzylamine are reacted with 654.5 mg (4 mmol) 5-
isocyanato-benzo[l,3]dioxole in dichloromethane at room temperature during night:

The resulting white precipitate is filtered and washed with diethylether. 1 gr of a
white powder with a molecular weight of 276 is obtained. Corresponding 1H-NMR and
13C-NMR spectra are shown in Figure 2. They show the white compound to be 1-
benzyl-3-naphthalen-1 -yl-urea.
Biological Methods
GSK-3(3 inhibition
The GSK-3P activity was determined by incubation of a mixture of recombinant
human GSK-3 enzyme, a phosphate source and GSK-3 substrate in the presence and in
the absence of the corresponding test compound, and by measuring the GSK-3 activity
of this mixture.
Recombinant human glycogen synthase kinase 38 was assayed in MOPS 8 mM
pH 7.3, EDTA 0.2 mM, MgCl? 10 mM and sodium orthovanadate 0.25 mM in the
presence of 62.5 uM of Phospho-Glycogen Synthase Peptide-2 (GS-2), 0.5 uCi y-33P-
ATP and unlabclled ATP at a final concentration of 12.5 uM. The final assay volume
was 20 ul After incubation for 30 minutes at 30 °C, 15 ul aliquots were spotted onto
P81 phosphocellulose papers. Filters were washed four times for at least 10 minutes
each and counted with 1.5 ml of scintillation cocktail in a scintillation counter.

WO 2007/017145 PCT/EP2006/007520
19
The values for GSK-3 activity in the presence of the compounds according to
the present invention were measured at different concentrations; the results, reflected in
comparison with the control, are shown in Figures 3 and 4.
The compounds' 1C50 values were calculated analyzing inhibition curves by
non-linear regression using GraphPad Prism. The IC50 (concentration at which 50 % of
enzyme inhibition is shown) values are gathered in table 1:
Table 1

Compound IC50
1 -BenzyI-3-naphthalen-l-yl-urea 17.1
l-Benzo|l,31dioxol-5-yl-3-benzyl-urea 38.4

20
AMENDED CLAIMS
1.- Use of a compound of formula (1)

or any pharmaceutically acceptable salt, prodnxg or solvatc thereof,
wherein:
RB is selected from substituted or unsubstitutcd alkyl, substituted or unsubstituted
cyeloalkyl, substituted or unsubstituted aryl wherein aryl is selected from the group of
phenyl, naphthyl, fenaathryl and aathracy], substituted or unsubstituted aralkyl wherein
aralkyl is benzyl, heterocyclc selected -from the group of azepines, benzimidazole,
benzothiazole, ftran, imidazole, indole, piperidinc, piperazine, purine, thiadiazole,
tetrahydrofiiran, benzodioxol, thiophene, ben2ofurane, indazole, quinazoline,
pyridazine, pyrimidine, pyrazine, pyridine, isoxazole, pyrrole, pyrane, -OR5, and -S(O)f
R5, wherein RB comprises from 8 to 15 atoms selected from C, O, N, and S,
with the proviso that RB is not a heterocyclc substituted by a heterocyclc,
R3, R4, R'2, R*3. R'4, R's y R's are independently selected from hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted^aryl, substituted ^or ^lnsubstitutcd heterocycle,
G(^O)R7, -U=^)OK8, -C(=0)NR9Rto, -C=NRnj -CN, -ORI2, -OC(=O)R]3, -S(O)t-Ru,
-NR]3Ri6, -NRi7C(=O)R|g, -NO2, -N«CRi9ll2o or halogen, wherein R3 and R4 together
AMENDED SHEET

21
may form a -O group, and wherein any pair of R3 R'2, R3 R'6, R4 R'2, R4 R'6, R'2 R'3,
R'3R'4, R'4R'5, R'5R'6, R15R16, R17R18 or R19R20 may form together a cyclic substituent;
tisO, 1,2,3
R5 is selected from hydrogen, alkyl, aryl and heterocycle;
f7, R8, R9, R10, R11, R13, R14, R15, R16, R17, R18, R19 and R20 are independently selected
from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstitutcd
cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl,
substituted or unsubstitutcd heterocycle, substituted or unsubstitutcd alkoxy, substituted
or unsubstituted ariloxy, halogen,
R12 is selected from hydrogen, unsubstituted alkyl, substituted or unsubstituted
cycloalkyl, substituted or unsubstitutcd alkenyl, substituted or unsubstituted aryl,
substituted or unsubstitutcd heterocycle, substituted or unsubstitutcd alkoxy, substituted
or unsubstituted ariioxy, halogen,
in the manufacture of a medicament for the treatment and/or prevention of a GSK-3
mediated disease or condition wherein the disease or condition is selecled from the
group of diabetes, conditions associated with diabetes, chronic neurodegenerative
conditions including dementias such as Alzheimer's disease, Parkinson's disease,
progressive supranuclear palsy, subacute sclerosing panencephalitic parkinsonism,
postencephalitic parkinsonism, pugilistic encephalitis, guarn paricinson ism-dementia
complex, Pick's disease, corticobasal degeneration, frontotemporal dementia,
Huntrngton's Disease, AIDS associated dementia, amyotrophic lateral sclerosis, multiple
sclerosis and ncurotrauroatic diseases such as acute stroke, epilepsy, mood disorders
such as depression, schizophrenia and bipolar disorders, promotion of functional
recovery post stroke, cerebral bleeding such as due to solitary cerebral amyloid
angiopathy, hair loss, obesity, hypertension, polycystic ovary syndrome, syndrome X,
ischacmia, brain injury, traumatic brain injury, cancer, leukopenia, Down's syndrome,
Lewy body disease, inflammation, chronic inflammatory diseases, cancer and
hyperprolifcrative diseases as hyperplasias and immunodeficiency,
2.- Use according to claim 1, wherein RB comprises an aromatic group.
3.- Use according to claim 1, wherein RB has at least 10 aromatic carbon atoms.
AMENDED SHEET

22
4.- Use according to claim 2, wherein the aromatic group is directly linked to the
N atom of the urea group.
5.- Use according to claim 3, wherein RB is a substituted or unsubstituled
naphtyl group.
6.- Use according to claim 5, wherein RB is an unsubstituted aJpha-naphtyl
group.
7.- Use according to claim 1, wherein R8 is a group selected from:

9.- Use according to claim 1, wherein R'2, R'3, R*4, R's and R*6 arc
independently selected from hydrogen, substituted or unsubstituted alkyl, -C(iO)R'/, -
CO-COORn, -OR12, -NRi5R.i6, or halogen, wherein R7, Rg, Rj2, Rjs and Ri6 are defined as
an claim 1.
10.- Use according to claim 1, wherein R'2j R'3j R%, R'5 and R'6 arc H.
11.- Use according to claim 1, wherein the compound of formula (I) is selected
from:
AMENDED SHEET

23

12.- Use according to claim 1 wherein the disease is Alzheimer's disease.
13.- Use according to claim 1 wherein tie disease is type II diabetes.
14.- Use according to claim 1 wherein the disease is depression.
15.- Use according to claim 1 wherein the disease is brain injury.
16.- A compound of formula

24
for use as a medicament
18.- A pharmaceutical composition which comprises a compound of formula as
defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt, prodrug or
solvate thereof, and a pharmaceuticaily acceptable carrier, adjuvant or vehicle.
19.- A pharmaceutical composition according to claim 18 for oral
administration.
20.- Use of a compound of formula (1) as defined in any of claims 1 to 11 as
reactives for biological assays, preferably as a reactive for GSK-3 inhibition.
21.- Method of treating or preventing au GSK-3 mediated disease or condition
with a GSK-3 inhibitor, wherein the disease or condition is selected from flic group of
diabetes, conditions associated with diabetes, chronic neurodegeneralive conditions
including dementias such as Alzheimer's disease, Parkinson's disease, progressive
supraimclear palsy, subacute sclerosing panencephatttic parkuisom'sm, postencephalitic
parkinsonism, pugilistic encephalitis, guam parkinsonism-dementia complex, Pick's
disease, corticobasal degeneration, frontotcinporal dementia, Huntington's Disease,
AIDS associated dementia, amyotrophic lateral sclerosis, multiple sclerosis and
neurotraumatjc diseases such as acute stroke, epilepsy, mood disorders such as
depression, schizophrenia and bipolar disorders, promotion of functional recovery post
stroke, cerebral bleeding such as due to solitary cerebral amyloid angiopathy, hair Joss,
obesity, hypertension, polycystie ovary syndrome, syndrome X, ischaemia, brain injury,
traumatic brain injury, cancer, leukopenia, Down's syndrome, Lewy body disease,
inflammation, chronic inflammatory diseases, cancer and hyperproliferativc diseases as
hyperplasias and immunodeficiency, which method comprises administering to a patient
in need of such a treatment a therapeutically effective amount of a compound of
formula (I) as defined in claims 1 to 11 or a pharmaceutical composition thereof.
AMENDED SHEET

The invention relates to urea derivatives of formula (I) as inhibitors of glycogen synthase kinase 36, GSK-3, to
processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use for the treatment
and or prophylaxis of a disease in which GSK-3 is involved, such as Alzheimer's disease or non-insulin dependent diabetes mellitus.

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=05tOOOSz5mYa3mrOOEIlaA==&loc=wDBSZCsAt7zoiVrqcFJsRw==

« Previous Patent

Next Patent »

Patent Number

268584

Indian Patent Application Number

885/KOLNP/2008

PG Journal Number

37/2015

Publication Date

11-Sep-2015

Grant Date

04-Sep-2015

Date of Filing

28-Feb-2008

Name of Patentee

NEUROPHARMA, S.A.

Applicant Address

AVENIDA DE LA INDUSTRIA, 52 E-28760 TRES CANTOS (MADRID)

Inventors:

#	Inventor's Name	Inventor's Address
1	PEREZ PUERTO MARIA JOSE	JULIO LOPEZ 5-2˚ B, E-28008 MADRID
2	CASTRO MORERA ANA	FRANCISCO SILVELA 21 - ESC 1-4˚ 4˚, E-28028 MADRID
3	MARTIN APARICIO ESTER	MIGUEL DE CERVANTES 13, E-28411 MORALZARZAL-MADRID
4	MARTINEZ GIL ANA	SANTA TERESA 12-2˚ I, E-28004 MADRID
5	ALONSO CASCON MERCEDES	AVENIDA DE BURGOS, 16A-8˚ E, E-28036 MADRID
6	FUERTES HUERTA ANA	ALENZA 9 5˚ DERECHA, E-28003 MADRID
7	NAVARRO RICO MARIA LUISA	DOCTOR VELASCO 12 2˚ D, E-28014, MADRID
8	MEDINA PADILLA MIGUEL	LA BANEZA 42-C-6˚D, E-28029 MADRID

PCT International Classification Number

A61K 31/17,A61P 3/10

PCT International Application Number

PCT/EP2006/007520

PCT International Filing date

2006-07-28

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	05380176.7	2005-07-29	EUROPEAN UNION