Patent Application
20060063789
The present invention concerns a novel group of compounds, their use as a medicine, their use for the manufacture of a medicament for the treatment of diseases mediated through glycogen synthase kinase 3, in particular glycogen synthase kinase 3β; processes for their preparation and pharmaceutical compositions comprising them.
WO 00/62778 describes cyclic protein tyrosine kinase inhibitors.
WO 91/18887 concerns diaminopyrimidine derivatives having gastric acid secretion inhibiting properties.
U.S. Pat. No. 5,691,364 concerns benzamidine derivatives as anti-coagulants.
WO 98/41512 concerns substituted 2-anilinopyrimidines useful as inhibitors of src-family protein kinase.
WO 00/78731 discloses 5-cyano-2-aminopyrimidines as KDR and/or FGFr kinase inhibitors.
WO 99/50250 and WO 00/27825 concern HIV inhibiting aminopyrimidine derivatives.
WO 95/09853 describes N-phenyl-2-pyrimidineamine derivatives for the treatment of tumor diseases.
WO 98/18782 concerns 2-pyrimidineamine derivatives as selective protein tyrosine kinase inhibitors.
EP 0,337,943 discloses N-phenyl-N-pyrimidin-2-yl derivatives having herbicidal plant growth regulating activity.
EP 0,164,204 concerns 2-aminopyrimidines which augment the immune response.
EP 0,233,461 relates to 4,5,6-substituted 2-pyrimidineamines having anti-asthmatic activity.
U.S. Pat. No. 5,516,775 concerns the use of 2-anilinopyrimidines as protein kinase C inhibitors.
The present invention relates to compounds which are distinguishable from the prior art in structure, pharmacological activity, potency or selectivity.
The present invention concerns a compound of formula (I)
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein
The present invention also relates to the use of a compound for the manufacture of a medicament for the prevention or the treatment of diseases mediated through GSK3, said compound being a compound of formula of formula (I′)
a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine and a stereochemically isomeric form thereof, wherein
As used herein C1-3alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as methyl, ethyl, propyl, 1-methylethyl; C1-4alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as the groups defined for C1-3alkyl and butyl; C1-6alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for C1-4alkyl and pentyl, hexyl, 2-methylbutyl and the like; C1-10alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 10 carbon atoms such as the groups defined for C1-6alkyl and heptyl, octyl, nonyl, decyl and the like; C1-6alkanediyl as a group or part of a group defines bivalent straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as methylene, 1,2-ethane-diyl or 1,2-ethylidene, 1,3-propanediyl or 1,3-propylidene, 1,4-butanediyl or 1,4-butylidene and the like; C2-6alkenyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing a double bond such as ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like; C2-10alkenyl defines straight and branched chain hydrocarbon radicals having from 2 to 10 carbon atoms containing a double bond such as the groups defined for C2-6alkenyl and heptenyl, octenyl, nonenyl, decenyl and the like; C2-6alkenediyl defines bivalent straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing one or more double bonds such as ethenediyl, propenediyl, butenediyl, pentenediyl, hexenediyl and the like; C2-6alkynyl defines straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing a triple bond such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like; C2-10alkynyl defines straight and branched chain hydrocarbon radicals having from 2 to 10 carbon atoms containing a triple bond such as the groups defined for C2-6alkynyl and heptynyl, octynyl, nonynyl, decynyl and the like; C2-6alkynediyl defines bivalent straight and branched chain hydrocarbon radicals having from 2 to 6 carbon atoms containing a triple bond such as ethynediyl, propynediyl, butynediyl, pentynediyl, hexynediyl and the like; C3-6cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; C3-7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; a monocyclic, bicyclic or tricyclic saturated carbocycle represents a ring system consisting of 1, 2 or 3 rings, said ring system being composed of only carbon atoms and said ring system containing only single bonds; a monocyclic, bicyclic or tricyclic partially saturated carbocycle represents a ring system consisting of 1, 2 or 3 rings, said ring system being composed of only carbon atoms and comprising at least one double bond provided that the ring system is not an aromatic ring system; a monocyclic, bicyclic or tricyclic aromatic carbocycle represents an aromatic ring system consisting of 1, 2 or 3 rings, said ring system being composed of only carbon atoms; the term aromatic is well known to a person skilled in the art and designates cyclically conjugated systems of 4n′+2 electrons, that is with 6, 10, 14 etc. π-electrons (rule of Hüickel; n′ being 1, 2, 3 etc.); a monocyclic, bicyclic or tricyclic saturated heterocycle represents a ring system consisting of 1, 2 or 3 rings and comprising at least one heteroatom selected from O , N or S, said ring system containing only single bonds; a monocyclic, bicyclic or tricyclic partially saturated heterocycle represents a ring system consisting of 1, 2 or 3 rings and comprising at least one heteroatom selected from O, N or S, and at least one double bond provided that the ring system is not an aromatic ring system; a monocyclic, bicyclic or tricyclic aromatic heterocycle represents an aromatic ring system consisting of 1, 2 or 3 rings and comprising at least one heteroatom selected from O, N or S.
Particular examples of monocyclic, bicyclic or tricyclic saturated carbocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4,2,0]octanyl, cyclononanyl, cyclodecanyl, decahydronapthalenyl, tetradecahydroanthracenyl.
Particular examples of monocyclic, bicyclic or tricyclic partially saturated carbocycles are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[4,2,0]octenyl, cyclononenyl, cyclodecenyl, octahydronaphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,2,3,4,4a,9,9a, 10-octahydroanthracenyl.
Particular examples of monocyclic, bicyclic or tricyclic aromatic carbocycles are phenyl, naphthalenyl, anthracenyl.
Particular examples of monocyclic, bicyclic or tricyclic saturated heterocycles are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl, thiadiazolidinyl, pyrazolidinyl, piperidinyl, hexahydropyrimidinyl, hexahydropyrazinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, decahydroquinolinyl, octahydroindolyl.
Particular examples of monocyclic, bicyclic or tricyclic partially saturated heterocycles are pyrrolinyl, imidazolinyl, pyrazolinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, indolinyl and the like.
Particular examples of monocyclic, bicyclic or tricyclic aromatic heterocycles are azetyl, oxetylidenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, naphthiridinyl, pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl, isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl, imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl, imidazoimidazolyl, isoxazolotriazinyl, isothiazolotriazinyl, pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl, triazolotriazinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl.
As used herein before, the term (═O) forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom and a sulfonyl moiety when two of said terms are attached to a sulfur atom.
The term halo is generic to fluoro, chloro, bromo and iodo. As used in the foregoing and hereinafter, polyhalomethyl as a group or part of a group is defined as mono- or polyhalosubstituted methyl, in particular methyl with one or more fluoro atoms, for example, difluoromethyl or trifluoromethyl; polyhaloC1-6alkyl as a group or part of a group is defined as mono- or polyhalosubstituted C1-6alkyl, for example, the groups defined in halomethyl, 1,1-difluoro-ethyl and the like. In case more than one halogen atoms are attached to an alkyl group within the definition of polyhalomethyl or polyhaloC1-6alkyl, they may be the same or different.
The term heterocycle as in the definition of for instance R2, R5, R6, R8 or R15 is meant to include all the possible isomeric forms of the heterocycles, for instance, pyrrolyl also includes 2H-pyrrolyl.
The hereinabove-mentioned carbocycles may be attached to the remainder of the molecule of formula (I) or (I′) through any ring carbon as appropriate, if not otherwise specified. Thus, for example, when the partially saturated bicyclic carbocycle is 1,2,3,4-tetrahydronaphthalenyl, it may be 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl and the like.
The hereinabove-mentioned heterocycles may be attached to the remainder of the molecule of formula (I) or (I′) through any ring carbon or heteroatom as appropriate, if not otherwise specified. Thus, for example, when the aromatic monocyclic heterocycle is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.
When any variable (eg. R5, R6 etc.) occurs more than one time in any constituent, each definition is independent.
Lines drawn into ring systems from substituents indicate that the bond may be attached to any of the suitable ring atoms.
For therapeutic use, salts of the compounds of formula (I) or (I′) are those wherein the counterion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) or (I′) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by-treatment with alkali into the free base form.
The compounds of formula (I) or (I′) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline, the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.
The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) or (I′) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term “quaternary amine” as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) or (I′) are able to form by reaction between a basic nitrogen of a compound of formula (I) or (I′) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
It will be appreciated that some of the compounds of formula (I) or (I′) and their N-oxides, addition salts, quaternary amines and stereochemically isomeric forms may contain one or more centers of chirality and exist as stereochemically isomeric forms.
The term “stereochemically isomeric forms” as used hereinbefore defines all the possible stereoisomeric forms which the compounds of formula (I) or (I′), and their N-oxides, addition salts, quaternary amines or physiologically functional derivatives may possess. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure as well as each of the individual isomeric forms of formula (I) or (I′) and their N-oxides, salts, solvates or quaternary amines substantially free, i.e. associated with less than 10%, preferably less than 5%, in particular less than 2% and most preferably less than 1% of the other isomers. In particular, stereogenic centers may have the R- or S-configuration; substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration. Compounds encompassing double bonds can have an E or Z-stereochemistry at said double bond. Stereochemically isomeric forms of the compounds of formula (I) or (I′) are obviously intended to be embraced within the scope of this invention.
The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several tertiary nitrogen atoms are oxidized to the so-called N-oxide.
Some of the compounds of formula (I) or (I′) may also exist in their tautomeric form (e.g. keto-enol tautomerie). Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term “compounds of formula (I)” or “compounds of formula (I) or (I′)” is meant to also include their N-oxide forms, their salts, their quaternary amines and their stereochemically isomeric forms. Of special interest are those compounds of formula (I) or (I′) which are stereochemically pure.
Particular compounds are those compounds of formula (I) or (I′) as defined hereinabove provided that the molecular mass of the compounds is at most 1000 u, in particular at most 800 u, more in particular at most 700 u (u stands for unified atomic mass unit and equals 1.66×10−27 kg).
Also particular interesting compounds are those compounds of formula (I) or (I′) as defined hereinabove, their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, wherein
Further interesting compounds are those compounds of formula (I) or (I′) as defined hereinabove wherein
Yet further particular interesting compounds are those compounds of formula (I) or (I′) as defined hereinabove provided that the compound is other than
R2 is hydrogen, trifluoromethyl, C1-4alkyl; R3 is hydrogen, C1-4alkyl, hydroxyC1-4alkyl, amino, C1-4alkylcarbonyl, or phenylC1-4alkyl wherein phenyl may optionally be substituted or R2 is NR2′R2″ with R2′ and R2″ each independently representing hydrogen or C1-4alkyl or optionally substituted phenyl; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle, provided that when R2 is a monocyclic, bicyclic or tricyclic saturated heterocycle or a monocyclic, bicyclic or tricyclic partially saturated heterocycle or a monocyclic, bicyclic or tricyclic aromatic heterocycle then at least one N atom is present and R2 is bound to the pyrimidinyl ring via a nitrogen atom; R1 is hydrogen or C1-4alkyl and s is defined as hereinabove;
wherein R1 is hydrogen, C1-4alkyl or optionally substituted phenyl; R1′ is hydrogen or C1-4alkyl; R2 is optionally substituted phenyl; R3 is hydrogen, C1-4alkyl, hydroxyC1-4alkyl, amino, C1-4alkylcarbonyl, or phenylC1-4alkyl wherein phenyl may optionally be substituted and s is as defined hereinabove;
R4a and R4b each independently are as defined hereinabove; R2 is C1-10alkyl; C2-10alkenyl; C2-10alkynyl; monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle, each of said groups representing R2 may optionally be substituted; R1 is hydrogen or C1-6alkyl; R3 and s are as defined hereinabove;
R1 is as defined hereinabove; R4a and R4b each independently are hydrogen or methyl; X is a direct bond, —C1-6alkyl-, —NR1—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)—, —S(═O)2—, —O—C1-4alkyl-, —NR1—C1-4alkyl-, —S—C1-4alkyl-; R2 is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-7cycloalkyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, said groups representing R2 may optionally be substituted; R3a represents hydrogen, hydroxy, halo, C1-6alkyl, C3-7cycloalkyl, C2-6alkenyl optionally substituted with one or more halogen atoms, C2-6alkynyl optionally substituted with one or more halogen atoms, C1-6alkyl substituted with cyano or —C(═O)R7, C1-6alkyloxy, C1-6alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C1-6alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)pR7, —NH—S(═O)pR7, —C(═O)R7, —NHC(═O)H, —C(═O)NHNH2, —NHC(═O)R7, —C(═NH)R7 or aryl; R3b is hydroxy, cyano, carboxyl, halo, cyanoC1-6alkyl, hydroxyC1-6alkyl, aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, C1-6alkyloxy, C1-6alkylthio, C1-6alkyl-S(═O)p, C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkylcarbonyloxy, C2-6alkenyl, C2-6alkynyl, polyhaloC1-6alkyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, triazolyl, tetrazolyl optionally substituted with imino, a 5-membered heteroaromatic ring, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl optionally substituted with hydroxy, isoxazolidinone, or a radical of formula
Further preferred compounds are those compounds of formula (I) or (I′) wherein one or where possible more of the following restrictions apply:
Also preferred are those compounds of formula (I) or (I′) wherein the compounds are compounds of the following formula:
Also preferred are those compounds of formula (I) or (I′) wherein the compounds are compounds of the following formula
Also preferred are those compounds of formula (a-1) wherein one or where possible more of the following restrictions apply:
Also preferred are those compounds of formula (a-2) wherein the following restriction applies:
Particular preferred compounds are those compounds of formula (a-1) wherein
Further particular preferred compounds are those compounds of formula (a-2) wherein
Also preferred are those compounds of formula (a-1) or (a-2) wherein
Also preferred are those compounds of formula (a-1) or (a-2) as defined hereinabove wherein R2 is other than hydrogen or C1-6alkyl.
Another preferred group of compounds of formula (I) or (I′) are those compounds having the following formula
with R1, R2, R3, R4a, R4b and X as defined for the compounds of formula (I) and wherein both —X—R2 and R3 are other than hydrogen.
Particular preferred are those compounds of formula (a-3) wherein one or where possible more of the following restrictions apply:
Particular preferred compounds of formula (I) or (I′) are those compounds selected from
Further preferred compounds of formula (I) or (I′) are those compounds selected from
Compounds of formula (I) can be prepared by reacting an intermediate of formula (II) with an intermediate of formula (III) wherein W1 represents a suitable leaving group, such as for example a halo atom, e.g. chloro, bromo, or C1-6alkyl-S—, in the presence of a suitable solvent, such as for example N,N-dimethylacetamide, N,N-dimethylformamide, methylene chloride, diglyme, tetrahydrofuran, water, an alcohol, e.g. ethanol, isopropanol and the like, and optionally in the presence of a suitable acid, such as for example hydrochloric acid, or a suitable base, such as for example sodium carbonate, N,N-diethylethanamine or NN-diisopropylethanamine.
Compounds of formula (I) can also be prepared by reacting an intermediate of formula (IV) wherein W2 represents a suitable leaving group, such as for example a halo atom, e.g. chloro, bromo and the like, with an intermediate of formula (V) optionally in the presence of a suitable solvent, such as for example CH3OCH2CH2OH.
Compounds of formula (I) wherein Z is O, said compounds being represented by formula (I-a) can be prepared by reacting an intermediate of formula (VI) wherein W3 represents a suitable leaving group, such as for example a halo atom, e.g. chloro, bromo and the like, or C1-6alkyloxy, with an intermediate of formula (VII) in the presence of a suitable solvent, such as for example tetrahydrofuran or an alcohol, e.g. methanol, ethanol and the like.
Compounds of formula (I) wherein Z is O and R4a and R4b are hydrogen, said compounds being represented by formula (I-a-1), can be prepared by reacting an intermediate of formula (VIII) with a suitable oxidizing agent, such as for example H2O2 or NaBO3, in the presence of a suitable solvent, such as for example water, dimethylsulfoxide or an alcohol, e.g. methanol, ethanol and the like, and optionally in the presence of a suitable base, such as for example dipotassium carbonate.
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, distillation, trituration and chromatography.
The compounds of formula (I) may further be prepared by converting compounds of formula (I) into each other according to art-known group transformation reactions.
The compounds of formula (I) may be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. t.butyl hydro-peroxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Compounds of formula (I) wherein R3 is halo, or wherein R2 is substituted with halo, can be converted into a compound of formula (I) wherein R3 is cyano, or wherein R2 is substituted with cyano, by reaction with a suitable cyano-introducing agent, such as sodium cyanide or CuCN, optionally in the presence of a suitable catalyst, such as for example tetrakis(triphenylphosphine)palladium and a suitable solvent, such as N,N-dimethylacetamide or N,N-dimethylformamide. A compound of formula (I) wherein R3 is cyano, or wherein R2 is substituted with cyano, can further be converted into a compound of formula (I) wherein R3 is aminocarbonyl, or wherein R2 is substituted with aminocarbonyl, by reaction with HCOOH, in the presence of a suitable acid, such as hydrochloric acid. A compound of formula (I) wherein R3 is cyano, or wherein R2 is substituted with cyano, can also further be converted into a compound of formula (I) wherein R3 is tetrazolyl, or wherein R2 is substituted with tetrazolyl, by reaction with sodium azide in the presence of ammonium chloride and N,N-dimethylacetoacetamide.
Compounds of formula (I) wherein R2 is substituted with halo, can also be converted into a compound of formula (I) wherein R2 is substituted with mercapto, by reaction with disodium sulfide in the presence of a suitable solvent, such as, for example, 1,4-dioxane.
Compounds of formula (I) wherein R2 is substituted with halo, can also be converted into a compound of formula (I) wherein R2 is substituted with C1-6alkylthio, by reaction with a reagent of formula alkaline metal+ −S—C1-6alkyl, e.g. Na+ −S—C1-6alkyl, in the presence of a suitable solvent, such as dimethylsulfoxide. The latter compounds can further be converted into a compound of formula (I) wherein R2 is substituted with C1-6alkyl-S(═O)—, by reaction with a suitable oxidizing agent, such as a peroxide, e.g. 3-chlorobenzenecarboperoxoic acid, in the presence of a suitable solvent, such as an alcohol, e.g. ethanol.
Compounds of formula (I) wherein R3 is halo, or wherein R2 is substituted with halo, can also be converted into a compound of formula (I) wherein R3 is C1-6alkyloxy, or wherein R2 is substituted with C1-6alkyloxy, by reaction with alcoholate salt, such as, for example, LiOC1-6alkyl, in the presence of a suitable solvent, such as an alcohol, e.g. methanol.
Compounds of formula (I) wherein R3 is halo, or wherein R2 is substituted with halo, can also be converted into a compound of formula (I) wherein R3 is hydroxy, or wherein R2 is substituted with hydroxy, by reaction with a suitable carboxylate, e.g. sodium acetate, in a suitable reaction-inert solvent, such as, for example, dimethylsulfoxide, followed by treating the obtained reaction product with a suitable base, such as pyridine, and acetyl chloride.
Compounds of formula (I) wherein R3 is halo, or wherein R2 is substituted with halo, can also be converted into a compound of formula (I) wherein R3 is a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle, or wherein R2 is substituted with a monocyclic, bicyclic or tricyclic saturated carbocycle; a monocyclic, bicyclic or tricyclic partially saturated carbocycle; a monocyclic, bicyclic or tricyclic aromatic carbocycle; a monocyclic, bicyclic or tricyclic saturated heterocycle; a monocyclic, bicyclic or tricyclic partially saturated heterocycle; a monocyclic, bicyclic or tricyclic aromatic heterocycle, said substituents being represented by -L, by reaction with H-L in the presence of a suitable base, such as for example sodium hydroxide, dipotassium carbonate, sodium hydride, in the presence of a suitable solvent, such as, for example, 1,4-dioxane, N,N-dimethylacetamide, N,N-dimethylformamide.
Compounds of formula (I) wherein R3 is chloro, or wherein R2 is substituted with chloro, can be converted into a compound of formula (I) wherein R3 is fluoro, or wherein R2 is substituted with fluoro, by reaction with a suitable fluoride salt, such as for example potassium fluoride, in the presence of a suitable solvent, e.g. sulfolane.
Compounds of formula (I) wherein X—R2 is hydrogen and wherein the R3 substituent positioned at the meta position compared to the NR1 linker, is halo, can be converted into a compound of formula (I) wherein said R3 substituent. is replaced by X—R2 wherein X is other than a direct bond when R2 is hydrogen, by reaction with H—X—R in the presence of a suitable solvent, such as N,N-dimethylacetamide or N,N-dimethylformamide optionally in the presence of a suitable base, such as for example
N,N-diisopropylethanamine.
Compounds of formula (I) wherein R2 is substituted with C1-4alkyloxyC1-6alkyl, can be converted into a compound of formula (I) wherein R2 is substituted with hydroxyC1-6alkyl, by dealkylating the ether in the presence of a suitable dealkylating agent, such as, for example, tribromoborane, and a suitable solvent, such as methylene chloride.
Compounds of formula (I) wherein R3 or X—R2 are C1-6alkyloxycarbonyl, or wherein R2 is substituted with C1-6alkyloxycarbonyl, can be converted into a compound of formula (I) wherein R3 or X—R2 are aminocarbonyl, or wherein R2 is substituted with aminocarbonyl or mono- or di(C1-6alkyl)aminocarbonyl by reaction with a suitable agent such as ammonia, NH2(C1-6alkyl), AlCH3[N(C1-6alkyl)2]Cl optionally in the presence of a suitable acid, such as for example hydrochloric acid, and in the presence of a suitable solvent such as an alcohol, e.g. methanol; tetrahydrofuran; N,N-diisopropylethane.
Compounds of formula (I) wherein R3 is hydrogen or wherein R2 is unsubstituted, can be converted into a compound wherein R3 is halo or wherein R2 is substituted with halo, by reaction with a suitable halogenating agent, such as, for example Br2 or 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2,2,2]octane bis[tetrafluoroborate], in the presence of a suitable solvent, such as tetrahydrofuran, water, acetonitrile, chloroform and optionally in the presence of a suitable base such as N,N-diethylethanamine.
Compounds of formula (I) wherein R3 or —X—R2 are C1-6alkyloxycarbonyl or wherein R2 is substituted with C1-6alkyloxycarbonyl, can be converted into a compound of formula (I) wherein R3 or X—R2 are hydroxymethyl or wherein R2 is substituted with hydroxymethyl by reaction with a suitable reducing agent, such as for example LiAlH4.
Compounds of formula (I) wherein —X—R2 is —O—CH2-(optionally substituted)phenyl may be converted into a compound of formula (I) wherein —X—R2 represents OH by reaction with a suitable reducing agent, such as H2, in the presence of a suitable catalyst, such as for example palladium on charcoal, and a suitable solvent, such as for example an alcohol, e.g. methanol, ethanol and the like, or N,N-dimethylacetamide. Compounds of formula (I) wherein —X—R2 represents OH may be converted into a compound of formula (I) wherein —X—R2 represents —O—X1-—R2 by reaction with W1—X1—R2 wherein W1 represents a suitable leaving group, such as for example a halo atom, e.g. chloro, and wherein —O—X1 represents those linkers falling under the definition of X which are attached to ring A via a O atom (in said definition X1 represents that part of the linker wherein the O atom is not included), in the presence of a suitable base, such as for example dipotassium carbonate, and a suitable solvent, such as for example N,N-dimethylacetamide.
Compounds of formula (I) wherein R3 is nitro, or wherein R2 is substituted with nitro, may be converted into a compound of formula (I) wherein R3 is amino or wherein R2 is substituted with amino, by reaction with a suitable reducing agent, such as for example H2, in the presence of a suitable catalyst, such as for example palladium on charcoal, a suitable catalyst poison, such as for example a thiophene solution, and a suitable solvent, such as for example an alcohol, e.g. methanol, ethanol and the like.
Compounds of formula (I) wherein R2 is substituted with NH2, can be converted into a compound of formula (I) wherein R2 is substituted with NH—S(═O)2—NR5R6, by reaction with W1—S(═O)2—NR5R6 wherein W1 represents a suitable leaving group such as for example a halo atom, e.g. chloro, in the presence of a suitable solvent, such as for example N,N-dimethylacetamide and a suitable base, such as for example N,N-diethylethanamine.
Some of the compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically.
An alternative manner of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to art-known procedures, such as those described in WO 99/50250, WO 00/27825 or EP 0,834,507.
Intermediates of formula (III) can be prepared by reacting an intermediate of formula (IX) wherein W1 is as defined hereinabove, with an intermediate of formula (X) in the presence of a suitable solvent, such as for example acetonitrile or dioxane, and in the presence of a suitable base, such as for example N,N-diisopropylethanamine.
Intermediates of formula (VI) can be prepared by reacting an intermediate of formula (V) with an intermediate of formula (XI) wherein W4 represents a suitable leaving group, such as for example a halo atom, e.g. chloro and the like, in the presence of a suitable solvent, such as for example CH3OCH2CH2OH.
Intermediates of formula (VI) wherein R1 is hydrogen, said intermediates being represented by formula (VI-a), can be prepared by reacting an intermediate of formula (XI) with an intermediate of formula (XII) in the presence of a suitable salt such as for example dipotassium carbonate and CuI.
Intermediates of formula (XII) can be prepared by reacting an intermediate of formula (V) wherein R1 is hydrogen, said intermediate being represented by formula (V-a), with formic acid.
Intermediates of formula (VI) wherein X—R2 is OH, said intermediates being represented by formula (VI-b), can be prepared by reducing an intermediate of formula (XIII) in the presence of a suitable reducing agent, such as for example H2, a suitable catalyst, such as palladium on charcoal, and a suitable solvent, such as an alcohol, e.g. ethanol and the like.
Intermediates of formula (VIII) can be prepared by reacting an intermediate of formula (III) with an intermediate of formula (XIV) in the presence of a suitable solvent, such as for example dioxane and diethylether, and a suitable acid, such as for example hydrochloric acid.
Intermediates of formula (VIII) wherein X is —O—C1-6alkyl, said intermediates being represented by formula (VIII-a), can be prepared by reacting an intermediate of formula (XV) with an intermediate of formula (XVI) in the presence of sodium hydride, and a suitable solvent, such as for example tetrahydrofuran.
The compounds of formula (I) or (I′) inhibit Glycogen synthase kinase 3 (GSK3), in particular glycogen synthase kinase 3 beta (GSK3β). They are selective Glycogen synthase kinase 3 inhibitors. Specific inhibitory compounds are superior therapeutic agents since they are characterized by a greater efficacy and lower toxicity by virtue of their specificity.
Synonyms for GSK3 are tau protein kinase I (TPK I), FA (Factor A) kinase, kinase FA and ATP-citrate lysase kinase (ACLK).
Glycogen synthase kinase 3 (GSK3), which exists in two isoforms, i.e. GSK3α and GSK3β, is a proline-directed serine/threonine kinase originally identified as an enzyme that phosphorylates glycogen synthase. However, it has been demonstrated that GSK3 phosphorylates numerous proteins in vitro such as glycogen synthase, phosphatase inhibitor I-2, the type-II subunit of cAMP-dependent protein kinase, the G-subunit of phosphatase-1, ATP-citrate lyase, acetyl coenzyme A carboxylase, myelin basic protein, a microtubule-associated protein, a neurofilament protein, an N-CAM cell adhesion molecule, nerve growth factor receptor, c-Jun transcription factor, JunD transcription factor, c-Myb transcription factor, c-Myc transcription factor, L-Myc transcription factor, adenomatous polyposis coli tumor supressor protein, tau protein and β-catenin.
The above-indicated diversity of proteins which may be phosphorylated by GSK3 implies that GSK3 is implicated in numerous metabolic and regulatory processes in cells.
GSK3 inhibitors may therefore be useful in the prevention or treatment of diseases mediated through GSK3 activity such as bipolar disorder (in particular manic depression), diabetes, Alzheimer's disease, leukopenia, FTDP-17 (Fronto-temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, Pick's disease, Niemann Pick's disease type C, Dementia Pugilistica, dementia with tangles only, dementia with tangles and calcification, Down syndrome, myotonic dystrophy, Parkinsonism-dementia complex of Guam, aids related dementia, Postencephalic Parkinsonism, prion diseases with tangles, subacute sclerosing panencephalitis, frontal lobe degeneration (FLD), argyrophilic grains disease, subacute sclerotizing panencephalitis (SSPE) (late complication of viral infections in the central nervous system), inflammatory diseases, cancer, dermatological disorders such as baldness, neuronal damage, schizophrenia, pain, in particular neuropathic pain. GSK3 inhibitors can also be used to inhibit sperm motility and can therefore be used as male contraceptives.
In particular, the compounds of the present invention are useful in the prevention or treatment of Alzheimer's disease, diabetes, especially type 2 diabetes (non insulin dependent diabetes).
The major neuropathological landmarks in Alzheimer's disease are neuronal loss, the deposition of amyloid fibers and paired helical filaments (PHF) or neurofibrillary tangles (NFT). Tangle formation appears to be the consequence of accumulation of aberrantly phosphorylated tau protein. This aberrant phosphorylation destabilizes neuronal cytoskeleton, which leads to reduced axonal transport, deficient functioning and ultimately neuronal death. The density of neurofibrillary tangles has been shown to parallel duration and severity of Alzheimer's disease. Reduction of the degree of tau phosphorylation can provide for neuroprotection and can prevent or treat Alzheimer's disease or can slow the progression of the disease. As mentioned hereinabove, GSK3 phosphorylates tau protein. Thus compounds having an inhibitory activity for GSK3 may be useful for the prevention or the treatment of Alzheimer's disease.
Insulin regulates the synthesis of the storage polysaccharide glycogen. The rate-limiting step in the glycogen synthesis is catalyzed by the enzym glycogen synthase. It is believed that glycogen synthase is inhibited by phosphorylation and that insulin stimulates glycogen synthase by causing a net decrease in the phosphorylation of this enzym. Thus, in order to activate glycogen synthase, insulin must either activate phosphatases or inhibit kinases, or both.
It is believed that glycogen synthase is a substrate for glycogen synthase kinase 3 and that insulin inactivates GSK3 thereby promoting the dephosphorylation of glycogen synthase.
In addition to the role of GSK3 in insulin-induced glycogen synthesis, GSK3 may also play a role in insulin resistance. It is believed that GSK3 dependent Insulin Receptor Substrate-1 phosphorylation contributes to insulin resistance.
Therefore, GSK3 inhibition may result in the increased deposition of glycogen and a concomitant reduction of blood glucose, thus mimicing the hypoglycemic effect of insulin. GSK3 inhibition provides an alternative therapy to manage insulin resistance commonly observed in non insulin dependent diabetes mellitus and obesity. GSK3 inhibitors may thus provide a novel modality for the treatment of type 1 and type 2 diabetes.
GSK3 inhibitors, in particular GSK3β inhibitors, may also be indicated for use in the prevention or the treatment of pain, in particular neuropathic pain.
After axotomy or chronic constriction injury, neuronal cells die through an apoptotic pathway and the morphological changes correlate with the onset of hyperalgesia and/or allodynia.
The induction of apoptosis is probably triggered by a reduced supply of neurotrophic factors as the time course of neuronal loss is positively altered by administration of neurotrophins. GSK, in particular GSK3β, has been shown to be involved in the initiation of the apoptotic cascade and trophic factor withdrawal stimulates the GSK3β apoptosis pathway.
In view of the above, GSK3β inhibitors might reduce signals of and even prevent levels of neuropathic pain.
Due to their GSK3 inhibitory properties, particularly their GSK30β inhibitory properties, the compounds of formula (I) or (I′), their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms thereof, are useful to prevent or treat GSK3 mediated diseases, in particular GSK30β mediated diseases, such as bipolar disorder (in particular manic depression), diabetes, Alzheimer's disease, leukopenia, FTDP-17 (Fronto-temporal dementia associated with Parkinson's disease), cortico-basal degeneration, progressive supranuclear palsy, multiple system atrophy, Pick's disease, Niemann Pick's disease type C, Dementia Pugilistica, dementia with tangles only, dementia with tangles and calcification, Down syndrome, myotonic dystrophy, Parkinsonism-dementia complex of Guam, aids related dementia, Postencephalic Parkinsonism, prion diseases with tangles, subacute sclerosing panencephalitis, frontal lobe degeneration (FLD), argyrophilic grains disease, subacute sclerotizing panencephalitis (SSPE) (late complication of viral infections in the central nervous system), inflammatory diseases, cancer, dermatological disorders such as baldness, neuronal damage, schizophrenia, pain, in particular neuropathic pain. The present compounds are also useful as male contraceptives. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals suffering from disease mediated through GSK3, in particular GSK3β, or they may be useful to prevent warm-blooded animals to suffer from disease mediated through GSK3, in particular GSK3β. More in particular, the compounds of the present invention may be useful in the treatment of warm-blooded animals suffering from Alzheimer's disease, diabetes, especially type 2 diabetes, cancer, inflammatory diseases or bipolar disorder.
In view of the above described pharmacological properties, the compounds of formula (I) or any subgroup thereof, their N-oxides, pharmaceutically acceptable addition salts, quaternary amines and stereochemically isomeric forms, may be used as a medicine. In particular, the present compounds can be used for the manufacture of a medicament for treating or preventing diseases mediated through GSK3, in particular GSK3β. More in particular, the present compounds can be used for the manufacture of a medicament for treating or preventing Alzheimer's disease, diabetes, especially type 2 diabetes, cancer, inflammatory diseases or bipolar disorder.
In view of the utility of the compounds of formula (I) or (I′), there is provided a method of treating warm-blooded animals, including humans, suffering from or a method of preventing warm-blooded animals, including humans, to suffer from diseases mediated through GSK3, in particular GSK30β, more in particular a method of treating or preventing Alzheimer+s disease, diabetes, especially type 2 diabetes, cancer, inflammatory diseases or bipolar disorder. Said method comprises the administration, preferably oral administration, of an effective amount of a compound of formula-(I) or (I′), a N-oxide form, a pharmaceutically acceptable addition salt, a quaternary amine or a possible stereoisomeric form thereof, to warm-blooded animals, including humans.
The present invention also provides compositions for preventing or treating diseases mediated through GSK3, in particular GSK30β, comprising a therapeutically effective amount of a compound of formula (I) or (I′) and a pharmaceutically acceptable carrier or diluent.
The compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. The compounds of the present invention may also be administered via inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder. Any system developed for the delivery of solutions, suspensions or dry powders via oral or nasal inhalation or insufflation are suitable for the administration of the present compounds.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
The present compounds are orally active compounds, and are preferably orally administered.
The exact dosage, the therapeutically effective amount and frequency of administration depends on the particular compound of formula (I) or (I′) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention.
When used as a medicament to prevent or treat Alzheimer's disease, the compounds of formula (I) or (I′) may be used in combination with other conventional drugs used to combat Alzheimer's disease, such as galantamine, donepezil, rivastigmine or tacrine. Thus, the present invention also relates to the combination of a compound of formula (I) or (I′) and another agent capable of preventing or treating Alzheimer's disease. Said combination may be used as a medicine. The present invention also relates to a product containing (a) a compound of formula (I) or (I′), and (b) another agent capable of preventing or treating Alzheimer's disease, as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of Alzheimer's disease. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
When used as a medicament to prevent or treat type 2 diabetes, the compounds of formula (I) or (I′) may be used in combination with other conventional drugs used to combat type 2 diabetes, such as glibenclamide, chlorpropamide, gliclazide, glipizide, gliquidon, tolbutamide, metformin, acarbose, miglitol, nateglinide, repaglinide, acetohexamide, glimepiride, glyburide, tolazamide, troglitazone, rosiglitazone, pioglitazone, isaglitazone.
Thus, the present invention also relates to the combination of a compound of formula (I) or (I′) and another agent capable of preventing or treating type 2 diabetes. Said combination may be used as a medicine. The present invention also relates to a product containing (a) a compound of formula (I) or (I′), and (b) another agent capable of preventing or treating type 2 diabetes, as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of type 2 diabetes. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
When used as a medicament to prevent or treat cancer, the compounds of formula (I) or (I′) may be used in combination with other conventional drugs used to combat cancer such as platinum coordination compounds for example cisplatin or carboplatin; taxane compounds for example paclitaxel or docetaxel; camptothecin compounds for example irinotecan or topotecan; anti-tumour vinca alkaloids for example vinblastine, vincristine or vinorelbine; anti-tumour nucleoside derivatives for example 5-fluorouracil, gemcitabine or capecitabine; nitrogen mustard or nitrosourea alkylating agents for example cyclophosphamide, chlorambucil, carmustine or lomustine; anti-tumour anthracycline derivatives for example daunorubicin, doxorubicin or idarubicin; HER2 antibodies for example trastzumab; and anti-tumour podophyllotoxin derivatives for example etoposide or teniposide; and antiestrogen agents including estrogen receptor antagonists or selective estrogen receptor modulators preferably tamoxifen, or alternatively toremifene, droloxifene, faslodex and raloxifene; aromatase inhibitors such as exemestane, anastrozole, letrazole and vorozole; differentiating agents for example retinoids, vitamin D and DNA methyl transferase inhibitors for example azacytidine; kinase inhibitors for example flavoperidol and imatinib mesylate or farnesyltransferase inhibitors for example R115777.
Thus, the present invention also relates to the combination of a compound of formula (I) or (I′) and another agent capable of preventing or treating cancer. Said combination may be used as a medicine. The present invention also relates to a product containing (a) a compound of formula (I) or (I′), and (b) another agent capable of preventing or treating cancer, as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of cancer. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
When used as a medicament to prevent or treat bipolar disorder, the compounds of formula (I) or (I′) may be used in combination with other conventional drugs used to combat bipolar disorder such as atypical antipsychotics, anti-epileptica, benzodiazepines, lithium salts, for example olanzapine, risperidone, carbamazepine, valproate, topiramate.
Thus, the present invention also relates to the combination of a compound of formula (I) or (I′) and another agent capable of preventing or treating bipolar disorder. Said combination may be used as a medicine. The present invention also relates to a product containing (a) a compound of formula (I) or (I′), and (b) another agent capable of preventing or treating bipolar disorder, as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of bipolar disorder. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
When used as a medicament to prevent or treat inflammatory diseases, the compounds of formula (I) or (I′) may be used in combination with other conventional drugs used to combat inflammatory diseases such as steroids, cyclooxygenase-2 inhibitors, non-steroidal-anti-inflammatory drugs, TNF-α antibodies, such as for example acetyl salicylic acid, bufexamac, diclofenac potassium, sulindac, diclofenac sodium, ketorolac trometamol, tolmetine, ibuprofen, naproxen, naproxen sodium, tiaprofen acid, flurbiprofen, mefenamic acid, nifluminic acid, meclofenamate, indomethacin, proglumetacine, ketoprofen, nabumetone, paracetamol, piroxicam, tenoxicam, nimesulide, fenylbutazon, tramadol, beclomethasone dipropionate, betamethasone, beclamethasone, budesonide, fluticasone, mometasone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, celecoxib, rofecoxib, infliximab, leflunomide, etanercept, CPH 82, methotrexate, sulfasalazine.
Thus, the present invention also relates to the combination of a compound of formula (I) or (I′) and another agent capable of preventing or treating inflammatory diseases. Said combination may be used as a medicine. The present invention also relates to a product containing (a) a compound of formula (I) or (I′), and (b) another agent capable of preventing or treating inflammatory diseases, as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of inflammatory disorders. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
Hereinafter, “DMF” is defined as N,N-dimethylformamide, “THF” is defined as tetrahydrofuran, “DMSO” is defined as dimethylsulfoxide, “TFA” is defined as trifluoroacetic acid.
A. Preparation of the Intermediate Compounds
a) Reaction under Argon atmosphere. 2,4,6-Trimethylaniline (0.0678 mol) was added to 2,4-dichloropyrimidine (0.0664 mol) in 1,4-dioxane (100 ml). N,N-di(1-methylethyl)-ethaneamine (N,N-diisopropylethanamine) (0.0830 mol) was added. The reaction mixture was stirred and refluxed for 4 days and the solvent was evaporated. The residue was dissolved in CH2Cl2, washed with a saturated NaHCO3 solution, then dried (Na2SO4), filtered and the solvent was evaporated to give 17.1 g solid residue. This solid was dissolved in CH2Cl2:hexane (1:1; 150 ml), and the resulting solution was concentrated to 100 ml, then filtered. The residue was purified by column chromatography on KP-Sil (eluent: CH2Cl2). The desired fractions were collected and the solvent was evaporated. The less polar fraction was stirred in CH2Cl2 for 3 hours and filtered, yielding 0.44 g 4-chloro-N-(2,4,6-trimethylphenyl)-2-pyrimidinamine. A second fraction was recrystallized from acetonitrile, filtered off and dried, yielding 2-chloro-N-(2,4,6-trimethyl-phenyl)-4-pyrimidinamine (intermediate 1) (mp. 182-183° C).
b) A mixture of intermediate 1 (1.06 mol) and 5.4 N HCl/2-propanol (1.15 mol) in water (4000 ml) was stirred and warmed to 40-45° C. over 30 minutes. 4-Aminobenzonitrile (1.29 mol) was added at 40-45° C. The reaction mixture was stirred and refluxed for 3.5 hours, then cooled to room temperature. EtOAc (1000 ml) was added and the mixture was alkalized by portionwise addition of NaHCO3. EtOAc (1000 ml) was added and the mixture was stirred vigorously for 10 minutes. The whole was filtered off to give precipitate (I) and filtrate (I). The filtrate's (I) layers were separated. The organic layer was washed with brine, dried (MgSO4), filtered and the solvent was evaporated. The residue was stirred in ethanol (300 ml), filtered off, then dried (vacuum, 40° C.), yielding: 50 g of fraction 1. Precipitate (I) was stirred in EtOAc (1000 ml), filtered off and dried (vacuum, 40° C.). This fraction was stirred in ethanol (400 ml), filtered off and dried (vacuum, 40° C.). Yielding: 248 g of fraction 2. Fractions 1 and 2 were combined, stirred for 45 minutes in boiling ethanol (2000 ml, p.a.), then allowed to cool while stirring overnight. The precipitate was filtered off, washed with ethanol, and dried (vacuum, 40° C., 24 hours), yielding 271 g of 4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (intermediate 2) (mp. 217.1-218.2° C.).
Compound 8 (prepared according to B4) (0.0162 mol) and POCl3 (25 ml) were heated in an oil bath at 125-135° C., and stirred for 12 minutes. The sample was poured over ice, stirred, and filtered. The resulting solid was dried at room temperature for 3 days at 200 mm Hg, yielding 4.86 g of intermediate 3 (yellow solid, 97%)
NaH (0.00808 mol), THF (0.00808 mol) and benzenemethanol (0.00808 mol) were stirred for 5 minutes under Ar. Intermediate 3 (0.00646 mol) was added, and the sample was refluxed overnight. The sample was evaporated. More THF, water, and CH3CN were added. The mixture was stirred for 60 minutes, then filtered to produce 2.49 g solid. The solid was dried at 65° C. for 3 days in 200 mm Hg, then 1 day at 80° C. and 0.2 mm Hg. A 0.26 g sample was purified by flash column chromatography in CH2Cl2, then dried at 80° C. for 16 hours at 0.2 mm Hg, yielding 0.23 g of intermediate 4 (88%) (mp. 156-157° C.).
B. Preparation of the Final Compounds
A solution of 2-chloro-5-nitro-N-(phenylmethyl)-4-pyrimidinamine (0.012 mol), 3-aminobenzamide (0.012 mol) and Et3N (0.012 mol) in DMF (50 ml) was stirred for 2 hours at 60° C. The mixture was allowed to cool to room temperature and methanol (10 ml) was added. The mixture was stirred for 10 minutes and the resulting precipitate was filtered off, washed and dried, yielding 3.3 g of compound 1 (77%).
4,5-Diamino-6-methyl-2(1H)-pyrimidinethione (0.0704 mol), 3-aminobenzamide (0.106 mol), and (CH3OCH2CH2)2O (20 ml) were refluxed under Ar for 3 hours, then stirred overnight at room temperature. The sample was heated to reflux, filtered, and washed with hot (CH3OCH2CH2)2O (2×) then filtered, yielding 15.25 g of compound 2.
A mixture of MeOH (4 ml), H2O (4 ml) and HCl/2-propanol (0.2 ml) was added to a mixture of intermediate 1 (0.000242 mol) and 4-amino-N-methyl-benzamide (0.000242 mol). The reaction mixture was stirred overnight at 60° C. The desired compound was isolated and purified by high performance liquid chromatography over RP C-18 (eluent: (0.5% NH4OAc in H2O/CH3CN 90/10)/CH3OH/CH3CN 70/15/15; 0/50/50; 0/0/100). The desired fractions were collected and the solvent was evaporated, yielding 0.017 g of compound 3.
30% H2O2 (7.3 ml) was added dropwise to intermediate 4 (0.00378 mol) and K2CO3 (1.22 g) in DMSO (17.5 ml) in a water bath at 16-17° C. More DMSO (20 ml) was added, and the reaction was stirred and warmed to room temperature for 4 hours. More DMSO (20 ml) was added to reduce foam, and the mixture was stirred for 1 hour. Water was added, and the sample was filtered to 2.56 g solid. The solid was partitioned between CHCl3 and water, stirred overnight, then filtered to 1.11 g white solid, and the filtrate was evaporated to 0.17 g. The filtrate solid was recrystallized with methanol. The sample was dried at 80° C. for 16 hours at 0.2 mm Hg, yielding 0.08 g of compound 4 (mp.: 216-217° C.).
A mixture of 0.0127 mol of compound 6
(prepared according to B1a) in DMF (80 ml)) was treated with 3-(1-methyl-1H-imidazol-2-yl)benzeneamine (0.0127 mol) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.0127 mol). The reaction mixture was stirred for 4 hours at 60° C., then cooled to room temperature, yielding compound 5 (100%).
The mixture of 0.0127 mol of compound 5 in DMF (80 ml) was hydrogenated (H166-080) at 50° C. with Pd/C, 10% (2 g) as a catalyst in the presence of thiophene solution (2 ml) and extra DMF (20 ml). After uptake of H2 (3 equiv), the catalyst was filtered off, washed and the filtrate was evaporated under reduced pressure, yielding compound 7 (100%).
N2 was bubbled through a solution of compound 2 (prepared according to B1b) (0.0663 mol), DMSO (800 ml) and Et3N (0.0729 mol) under Ar for 0.5 hours. Br2 (0.0729 mol) was added. The reaction was stirred at room temperature overnight. Water (11) was added dropwise. Filtration produced 17.5 g solid. The sample was refluxed in MeOH (1 l) for 60 minutes, then cooled, filtered, and dried at 80° C. for 3 days at 200 mm Hg, yielding 11.51 g of compound 8 (55%).
Compound 4 (prepared according to B2) (0.00226 mol), CuCN (0.03383 mol), and DMF (27 ml) were added to a pressure vessel under Argon. The mixture was stirred at 110-120° C. for 2 days. The mixture was filtered, and the solvent was evaporated for 2 days. The mixture was sonicated and stirred in 10% MeOH: CH2Cl2 (250 ml). The sample was purified by column chromatography, washing with 10% MeOH: CH2Cl2 to produce 0.05 g solid. The sample was purified by Gilson prep HPLC (gradient of 0.1% TFA in H2O and 0.1 % TFA in CH3CN), lyophilized, then dried at 80° C. for 16 hours at 0.2 mm Hg, yielding 0.02 g of compound 9 (mp.: 260-261° C.).
Tables 1 to 3 list the compounds of formula (I) which were prepared according to one of the above examples.
The pharmacological activity of the present compounds was examined using the following test.
GSK3beta assays were performed at 25° C. in a 100 μl reaction volume of 25 mM Tris (pH 7.4) containing 10 mM MgCl2, 1 mM DTT, 0.1 mg/ml BSA, 5% glycerol and containing 19 nM GSK3β, 5 μM biotinylated phosphorylated CREB peptide, 1 μM ATP, 2 nM ATP-P33 and a suitable amount of a test compound of formula (I) or (I′). After one hour, the reaction was terminated by adding 70 μl of Stop mix (1 mM ATP, 18 mg/ml streptavidin coated PVT SPA bead pH 11.0). The beads to which the phosphorylated CREB peptide is attached were allowed to settle for 30 minutes and the radioactivity of the beads was counted in a microtiterplate scintillation counter and compared with the results obtained in a control experiment (without the presence of a test compound) in order to determine the percentage of GSK3β inhibition. The IC50 value, i.e. the concentration (M) of the test compound at which 50 % of GSK3β is inhibited, was calculated from the dose response curve obtained by performing the above-described GSK3β assay in the presence of different amounts of the test compound.
Table 4 lists pIC50 values (−log IC50 (M)) obtained in the above-described test for the present compounds.
| Number | Date | Country | Kind |
|---|---|---|---|
| 0120492.7 | Nov 2001 | EP | regional |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP02/12079 | 10/29/2002 | WO | 3/9/2005 |
