WO2007017145A2 - Gsk-3 inhibitors - Google Patents

Gsk-3 inhibitors Download PDF

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Publication number
WO2007017145A2
WO2007017145A2 PCT/EP2006/007520 EP2006007520W WO2007017145A2 WO 2007017145 A2 WO2007017145 A2 WO 2007017145A2 EP 2006007520 W EP2006007520 W EP 2006007520W WO 2007017145 A2 WO2007017145 A2 WO 2007017145A2
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disease
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group
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PCT/EP2006/007520
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French (fr)
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WO2007017145A3 (en
Inventor
Ana MARTÍNEZ GIL
Miguel Medina Padilla
Mercedes Alonso Cascón
Ana Fuertes Huerta
María Luisa NAVARRO RICO
María José PÉREZ PUERTO
Ana Castro Morera
Ester MARTÍN APARICIO
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Noscira SA
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Neuropharma SA
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Priority to JP2008523261A priority Critical patent/JP5484726B2/en
Priority to BRPI0615968-0A priority patent/BRPI0615968B1/en
Priority to CA2616451A priority patent/CA2616451C/en
Priority to US11/996,962 priority patent/US8686042B2/en
Priority to HRP20180109TT priority patent/HRP20180109T1/en
Priority to SI200632241T priority patent/SI1919465T1/en
Priority to LTEP06776492.8T priority patent/LT1919465T/en
Priority to HK09101997.2A priority patent/HK1124761B/en
Priority to KR1020087004188A priority patent/KR101471999B1/en
Priority to ES06776492.8T priority patent/ES2661326T3/en
Priority to DK06776492.8T priority patent/DK1919465T3/en
Priority to PL06776492T priority patent/PL1919465T3/en
Priority to NZ566380A priority patent/NZ566380A/en
Priority to EP06776492.8A priority patent/EP1919465B1/en
Priority to CN2006800275243A priority patent/CN101257900B/en
Priority to AU2006278829A priority patent/AU2006278829B2/en
Application filed by Neuropharma SA filed Critical Neuropharma SA
Publication of WO2007017145A2 publication Critical patent/WO2007017145A2/en
Publication of WO2007017145A3 publication Critical patent/WO2007017145A3/en
Priority to IL189048A priority patent/IL189048A/en
Anticipated expiration legal-status Critical
Priority to NO20081052A priority patent/NO341454B1/en
Priority to CY20181100217T priority patent/CY1119971T1/en
Ceased legal-status Critical Current

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    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/66—Nitrogen atoms not forming part of a nitro radical
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    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated

Definitions

  • the present invention relates to enzyme inhibitors, and more particularly to urea derivatives as inhibitors of glycogen synthase kinase 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.
  • Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase comprised of ⁇ and ⁇ 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 JCe// ScL 2003, 1 16: 1 175-1 186).
  • 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 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 ⁇ -catenin, the translation initiation factor el F2B, as well as ATP citrate lyase, axin, heat shock factor- 1 , c-Jun, c-Myc, c-Myb, CREB, and CEPB ⁇ . These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.
  • GSK-3 may represent a viable strategy to develop novel medicinal entities for the treatment of such unmet diseases (Martinez A, Castro A, Dorronsoro I, Alonso M, Med. Res. Rev., 2002, 22:373-384) through insulin mimicry, tau dephosphorylation and amyloid processing, or transcriptional modulation respectively.
  • 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.
  • GSK-3 inhibitors being both effective and selective, and having good "drugability" properties, i.e. good pha ⁇ naceutical 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.
  • R B IS selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl wherein aryl is selected fiom the group of phenyl, naphthyl, fenanthryl and anthracyl, substituted or unsubstituted aralkyl wherein aralkyl is benzyl, heterocycle selected from the group of azepines, benzimidazole, benzothiazole, furan, imidazole, indole, pipe ⁇ dine, piperazine, purine, thiadiazole, tetrahydrofuran, benzodioxol, thiophene, benzofurane, indazole, quinazohne, py ⁇ dazine, py ⁇ midine, pyrazine, py ⁇ dine, isoxazole, pyrrole, pyrane, -
  • R 7 , R 8 , R9, Rio, Ri 1, Ri2, Ri3, Ri4, Ri5, Ri6, Ri7, Ri8, Ri9 and R 20 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 par
  • Preferred compounds are those wherein R B comprises an aromatic group.
  • R B has at least 10 aromatic carbon atoms.
  • the invention is related to a compound of formula
  • the invention is related to a pharmaceutical composition which comprises a compound of formula (I) as described above or a pharmaceutically acceptable salt, prodrug or solvate thereof and a pharmaceutically acceptable earner, adjuvant or vehicle.
  • the disease or condition mediated by GSK-3 is selected from Alzheimer's disease, type II diabetes, depression and brain injury.
  • the compounds of formula (I) as defined above may be used as reactives for biological assays, preferably as a reactive for GSK-3 inhibition.
  • Figure 1 Represents the IH-NMR and 13C-NMR spectra of l-Benzyl-3-naphtalen-l- yl-urea
  • Figure 2. Represents the the I H-NMR and 13C-NMR spectra of 1 -Benzo[l ,3]dioxol-
  • 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.
  • 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.
  • the present invention is related to the use of compounds of formula (I) 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.
  • R 6 comprises an aromatic group and even more preferably R B has at least 10 aromatic carbon atoms.
  • the compound of formula (1) has an aromatic group which is directly linked to the N atom of the urea group
  • R B is a substituted or unsubstituted naphtyl group, preferably an unsubstituted alpha-naphtyl group
  • R B IS selected from
  • R 3 and R 4 are H
  • GSK-3 mediated disease or condition means any disease or other deleterious condition or state in which GSK-3 is 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 supianuclear 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
  • 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
  • a pharmaceutical composition comprising a compound as defined above, or any pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically 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
  • 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.
  • the invention in another aspect relates to inhibiting GSK-3 activity in a biological sample with the compounds of formula (I), which method comprises contacting the biological sample with a GSK-3 inhibitor of formula (I).
  • biological sample 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.
  • 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.
  • 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 a wherein R d is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc.
  • Alkoxycarbonyl refers to a radical of the formula -C(O)OR 3 where R 1 , is an alkyl radical as defined above, e. g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.
  • Alkylthio refers to a radical of the formula -SR a where R a is an alkyl radical as defined above, e. g., methylthio, ethylthio, propylthio, etc.
  • Amino refers to a radical of the formula-NI-b, -NHR a or -NR 3 R b , wherein R d and R b 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, alky], phenyl, alkoxy, haloalkyl, nitro, cyano, dialkylamino, aminoalkyl, acyl and alkoxycarbonyl, as defined herein.
  • Alkyl 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)-R c and -C(O)-R d where R c is an alkyl radical as defined above and R d is an aryl radical as defined above, e. g., acetyl, propionyl, benzoyl, and the like.
  • Aroylalkyl refers to an alkyl group substituted with -R 3 -C(O)-R d , wherein R a is an alkyl radical as defined above and R d 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.
  • 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.
  • 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.
  • azepines benzimidazole, benzothiazole, furan, isothiazole, imidazole, indole, piperidine, piperazine, purine, quinoline, thiadiazole, tetrahydrofuran, thiadiazole, tetrahydrofuran, be
  • the compounds of the invention aie also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms
  • compounds having the present structures except for the replacement of a hydrogen by a deute ⁇ um or tritium, or the replacement of a carbon by a 13 C- or l 4 C-en ⁇ ched carbon or l 5 N-en ⁇ ched nitrogen are within the scope of this invention
  • pharmaceutically acceptable salts, derivatives, solvates, piodrugs refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound which, upon administration to the recipient is capable of providing (directly or indirectly) a compound as described herein
  • 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
  • salts of compounds provided herein are synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods
  • 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
  • non-aqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonit ⁇ le are preferred
  • 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, malate, mandelate, methanesulphonate and p-toluenesulphonate
  • the alkali addition salts such as, for example,
  • Particularly favoured derivatives or prodrugs aie 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
  • prodrug is used in its bioadest sense and encompasses those de ⁇ vatives that are converted in vivo to the compounds of the invention
  • Such derivatives would readily occui to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the 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.
  • 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.
  • a suitable solvent such as N,N-dimethylformamide, dimethyl sulfoxide, dioxane, dichloromethane or tetrahydrofuran, at a temperature within the range of +20 to +150 0 C.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition.
  • 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.
  • compositions include any solid (tablets, pills, capsules, granules etc.) or liquid (solutions, suspensions or emulsions) composition for oral, topical or parenteral administration.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the GSK-3 ⁇ 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 3 ⁇ was assayed in MOPS 8 mM pH 7.3, EDTA 0.2 mM, MgCl 2 10 mM and sodium orthovanadate 0.25 mM in the presence of 62.5 ⁇ M of Phospho-Glycogen Synthase Peptide-2 (GS-2), 0.5 ⁇ Ci ⁇ - 33 P- ATP and unlabelled ATP at a final concentration of 12.5 ⁇ M.
  • the final assay volume was 20 ⁇ l. After incubation for 30 minutes at 30 0 C, 15 ⁇ l aliquots were spotted onto P81 phosphocellulose papers.
  • the compounds' IC50 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 :

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Abstract

The invention relates to urea derivatives of formula (I) as inhibitors of glycogen synthase kinase 3ß, 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.

Description

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 3β, 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 α 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 JCe// ScL 2003, 1 16: 1 175-1 186). 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 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 β-catenin, the translation initiation factor el F2B, as well as ATP citrate lyase, axin, heat shock factor- 1 , c-Jun, c-Myc, c-Myb, CREB, and CEPBα. 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 I, 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. 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-thiazol- 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 phaπnaceutical 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)
Figure imgf000005_0001
(I)
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 fiom the group of phenyl, naphthyl, fenanthryl and anthracyl, substituted or unsubstituted aralkyl wherein aralkyl is benzyl, heterocycle selected from the group of azepines, benzimidazole, benzothiazole, furan, imidazole, indole, pipeπdine, piperazine, purine, thiadiazole, tetrahydrofuran, benzodioxol, thiophene, benzofurane, indazole, quinazohne, pyπdazine, pyπmidine, pyrazine, pyπdine, 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 5 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, -CC=O)NR9R10, -C=NR1 1, -CN, -OR12, -OC(O)Ri3, -S(O)1-R14, -NRi5R16, -NR17CC=O)R18, -NO2, -N=CRi9R20 Or halogen, wherein R3 and R4 together may form a =O group, and wherein any pair of R3 R'2, R3 R 6, R4 R 2, R4 R e, R 2R "3, R" 3R" 4, R" 4R"5, R'5R'6, Ri5R16 Rι?R|8 or Ri9R20 may form together a cyclic substituent, t is O, 1 , 2, 3 R5 is selected from hydrogen, alkyl, aryl and heterocycle;
R7, R8, R9, Rio, Ri 1, Ri2, Ri3, Ri4, Ri5, Ri6, Ri7, Ri8, Ri9 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 RB comprises an aromatic group.
In a particular embodiment, RB has at least 10 aromatic carbon atoms.
In an additional aspect, the invention is related to a compound of formula
Figure imgf000006_0001
In another aspect, the invention is related to a pharmaceutical composition which comprises a compound of formula (I) as described above or a pharmaceutically acceptable salt, prodrug or solvate thereof and a pharmaceutically acceptable earner, 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 IH-NMR and 13C-NMR spectra of l-Benzyl-3-naphtalen-l- yl-urea
Figure 2.- Represents the the I H-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 (I) 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, R6 comprises an aromatic group and even more preferably RB has at least 10 aromatic carbon atoms. 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
Figure imgf000008_0001
In a particular embodiment, R3 and R4 are H
In another particular embodiment, R"?, R" 3, R 4, R"s and R'6 are independently selected from hydrogen, substituted or unsubstituted alkyl, -C(=O)R7, -C(=O)ORs, - ORi2, -NR|3R|6, or halogen, wherein R7, Rs, R12, Rιs and R|6 are defined as above
Preferably, R" 2, R" 3, R'Λ, R"S and R" 6 aie H
Two preferred compounds of formula (1) are
Figure imgf000008_0002
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 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 supianuclear 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 hyperprohferative 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
According to further aspects of the invention, it is related to a compound of foπnula
Figure imgf000009_0001
and to its use as a medicament.
Another aspect of the present invention is a pharmaceutical composition comprising a compound as defined above, or any pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically 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 (I), 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. 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 -ORa wherein Rd is an alkyl radical as defined above, e. g., methoxy, ethoxy, propoxy, etc.
"Alkoxycarbonyl" refers to a radical of the formula -C(O)OR3 where R1, 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-NI-b, -NHRa or -NR3Rb, wherein Rd 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, alky], 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)-Rd where Rc is an alkyl radical as defined above and Rd is an aryl radical as defined above, e. g., acetyl, propionyl, benzoyl, and the like.
"Aroylalkyl" refers to an alkyl group substituted with -R3-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. Refeiences herein to substituted groups in the compounds of the piesent invention iefer to the specified moiety that may be substituted at one oi moie available positions by one oi more suitable groups, e g , halogen such as fluoio, chloio, biomo and iodo, cyano, hydroxyl, nitro, azido, alkanoyl such as a Cl -6 alkanoyl group such as acyl and the like, carboxamido, alkyl groups including those groups having 1 to about 12 carbon atoms or fiom 1 to about 6 carbon atoms and moie prefeiably 1 -3 carbon atoms, alkenyl and alkynyl groups including groups having one or moie unsaturated linkages and from 2 to about 12 carbon or from 2 to about 6 carbon atoms, alkoxy groups having one or moie 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 otheiwise 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 aie 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 deuteπum or tritium, or the replacement of a carbon by a 13C- or l 4C-enπched carbon or l 5N-enπched nitrogen are within the scope of this invention
The term "pharmaceutically acceptable salts, derivatives, solvates, piodrugs refers to any pharmaceutically acceptable salt, ester, solvate, or any other compound which, upon administration to the recipient is capable of providing (directly or 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 acetonitπle 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, malate, 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 oiganic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylencthanolamine, tπethanolamine, glucamine and basic aminoacids salts
Particularly favoured derivatives or prodrugs aie 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 bioadest sense and encompasses those deπvatives that are converted in vivo to the compounds of the invention Such derivatives would readily occui to those skilled in the art, and include, depending on the functional groups present in the molecule and without limitation, the 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:
Figure imgf000016_0001
in a suitable solvent, such as N,N-dimethylformamide, dimethyl sulfoxide, dioxane, dichloromethane or tetrahydrofuran, at a temperature within the range of +20 to +1500C.
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. 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. EXAMPLES
Preparation of compounds of formula Il
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-Benzyl-3-naphthalen-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:
Figure imgf000018_0001
Figure imgf000018_0002
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 I H- NMR and 13C-NMR spectra are indicated in Figure 1 . They show the white compound to be l -benzyl-3-naphthalen- l -yl-urea. 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:
Figure imgf000019_0001
Figure imgf000019_0002
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 I H-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-3B inhibition
The GSK-3β 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 3β was assayed in MOPS 8 mM pH 7.3, EDTA 0.2 mM, MgCl2 10 mM and sodium orthovanadate 0.25 mM in the presence of 62.5 μM of Phospho-Glycogen Synthase Peptide-2 (GS-2), 0.5 μCi γ-33P- ATP and unlabelled ATP at a final concentration of 12.5 μM. The final assay volume was 20 μl. After incubation for 30 minutes at 30 0C, 15 μl 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. 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' IC50 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
Figure imgf000020_0001

Claims

1.- Use of a compound of formula (I)
Figure imgf000021_0001
(I)
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, benzothiazole. furan, imidazole, indole, pipeπdine, piperazine, purine, thiadiazole, tetrahydrofuran, benzodioxol, thiophene, benzofurane, indazole, quinazohne, pyπdazine, pyπmidine, pyrazine, pyπdine, isoxazole, pyrrole, pyrane, -OR5, and -S(O)t- Rs, 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" 5 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(=0)NR9Rio, -C=NRn, -CN, -ORi2, -OC(=O)R,3, -S(O)1-Ri4, -NRI 5RI 6, -NRi7C(=O)Ri8, -NO2, -N=CRi9R2O or halogen, wherein R3 and R4 together may form a =0 group, and wherein any pair of R3 R'?, R3 R'6, R4 R'2, R4 R'ό, R'2R53, R'3R'4, R^R's, R'5R'6, R15R16, R17R18 or R19R20 may form together a cyclic substituent; t is O, 1 , 2, 3
R5 is selected from hydrogen, alkyl, aryl and heterocycle; R7, R8, R9, R10, Rn, R12, Ri3, Ri4, R15, Ri6, Ri7, Ris, Ri9 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.
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.
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 unsubstituted naphtyl group.
6 - Use according to claim 5, wherein RB IS an unsubstituted alpha-naphtyl group
7 - Use according to claim 1 , wherein RB IS a group selected from
Figure imgf000023_0001
8 - Use according to claim 1 , wherein R3 and R4 are H
9 - Use according to claim 1 , wherein R'2, R-3, R" 4, R"s and R'6 are independently selected from hydrogen, substituted or unsubstituted alkyl, -C(=O)R7, - C(=O)OR8, -ORi2, -NRi5Ri6, or halogen, wherein R7, Rg Ri2, Ri5 and Ri6 are defined as in claim 1
10 - Use according to claim 1 , wherein R'2, R" 3, R 4, R's and R" 6 are H
1 1 - Use according to claim 1 , wherein the compound of foimula (I) is selected from
Figure imgf000023_0002
12 - Use according to claim 1 wherein the disease is Alzheimer's disease
13.- Use according to claim 1 wherein the 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
Figure imgf000024_0001
17.- A compound of formula
Figure imgf000024_0002
for use as a medicament.
18.- A pharmaceutical composition which comprises a compound of formula as defined in any one of claims 1 to 1 1 or a pharmaceutically acceptable salt, prodrug or solvate thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.
19.- A pharmaceutical composition according to claim 18 for oral administration.
20.- Use of a compound of formula (I) as defined in any of claims 1 to 1 1 as reactives for biological assays, preferably as a reactive for GSK-3 inhibition.
21.- Method of treating or preventing an GSK-3 mediated disease or condition with a GSK-3 inhibitor, 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, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula (1) as defined in claims 1 to 1 1 or a pharmaceutical composition thereof.
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KR101471999B1 (en) 2014-12-10
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