EP1912940A1 - Substituted isoindolones and their use as metabotropic glutamate receptor potentiators - Google Patents

Substituted isoindolones and their use as metabotropic glutamate receptor potentiators

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Publication number
EP1912940A1
EP1912940A1 EP06720759A EP06720759A EP1912940A1 EP 1912940 A1 EP1912940 A1 EP 1912940A1 EP 06720759 A EP06720759 A EP 06720759A EP 06720759 A EP06720759 A EP 06720759A EP 1912940 A1 EP1912940 A1 EP 1912940A1
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EP
European Patent Office
Prior art keywords
alkyl
dihydro
benzyl
isoindol
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06720759A
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German (de)
English (en)
French (fr)
Inventor
Bradford Van Wagenen
Radhakrishnan Ukkiramapandian
Joshua Clayton
Ian Egle
James Empfield
Methvin Isaac
Fupeng Ma
Abdelmalik Slassi
Gary Steelman
Rebecca Urbanek
Sally Walsh
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AstraZeneca AB
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AstraZeneca AB
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Publication date
Priority claimed from PCT/US2005/028760 external-priority patent/WO2006020879A1/en
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of EP1912940A1 publication Critical patent/EP1912940A1/en
Withdrawn legal-status Critical Current

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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to novel compounds that function as potentiators of glutamate receptors, methods for their preparation, pharmaceutical compositions containing them and their use in therapy.
  • the metabotropic glutamate receptors constitute a family of GTP-binding-protein (G-protein) coupled receptors that are activated by glutamate, and have important roles in synaptic activity in the central nervous system, including neural plasticity, neural development and neurodegeneration.
  • Activation of mGluRs in intact mammalian neurons elicits one or more of the following responses: activation of phospholipase C; increases in phosphoinositide (PI) hydrolysis; intracellular calcium release; activation of phospholipase D; activation or inhibition of adenyl cyclase; increases or decreases in the formation of cyclic adenosine monophosphate (cAMP); activation of guanylyl cyclase; increases in the formation of cyclic guanosine monophosphate (cGMP); activation of phospholipase A 2 ; increases in arachidonic acid release; and increases or decreases in the activity of voltage- and ligand-gated ion channels (Schoepp et ah, 1993, Trends Pharmacol.
  • PI phosphoinositide
  • Group-I includes mGluRl and mGluR5, which activate phospholipase C and the generation of an intracellular calcium signal.
  • the Group-II mGluR2 and mGluR3
  • Group-Ill mGluR4, mGluR ⁇ , mGluR7, and mGluR8 mGluRs mediate an inhibition of adenylyl cyclase activity and cyclic AMP levels.
  • mGluR family receptors are implicated in a number of normal processes in the mammalian CNS, and are important targets for compounds for the treatment of a variety of neurological and psychiatric disorders. Activation of mGluRs is required for induction of hippocanipal long-term potentiation and cerebellar long-term depression (Bashir et ah, 1993, Nature, 363:347 ; Bortolotto et al, 1994, Nature, 368:740 ; Aiba et al., 1994, Cell, 79:365 ; Aiba et ah, 1994, Cell, 79:377).
  • mGluR activation has been suggested to play a modulatory role in a variety of other normal processes including synaptic transmission, neuronal development, apoptotic neuronal death, synaptic plasticity, spatial learning, olfactory memory, central control of cardiac activity, waking, motor control and control of the vestibulo-ocular reflex (Nakanishi, 1994, Neuron, 13:1031; Pin et ah, 1995, Neuropharmacology, supra; Knopfel et ah, 1995, J. Med. Chem., 38:1417).
  • R 1 is a 3- to 7-membered ring that may contain one or more heteroatoms independently selected from the group consisting of N, O and S, wherein said ring may be substituted by one or more A;
  • R 2 and R 3 are independently selected from the group consisting of H, Ci_ 6 -alkyl, C 2-6 -alkenyl, C 2-6 -alkynyl, aryl, heteroaryl, heterocycloalkyl, C 3-8 -cycloalkyl, C 1-6 -alkyl-aryl, Ci -6 -alkyl- heteroaryl, C i -6 -alkyl -heterocycloalkyl, and Ci -6 -alkyl-C 3 - 8 -cycloalkyl, wherein R 2 and R 3 may be substituted by one or more A;
  • R and R 6 are independently selected from the group consisting of H, hydroxy, F, Cl, Br, I, nitro, cyano, C 1-6 -alkyl, Ci -6 -alkylhalo, OC 1-6 alkyl, OCi -6 -alkylhalo, C 2-6 -alkenyl, OC 2-6 - alkenyl, C 2-6 -alkynyl, OC 2-6 -alkynyl, C 3 , 8 -cycloalkyl, C] -6 -alkyl-C 3-8 -cycloalkyl, OC 0-6 -alkyl- C 3-8 -cycloalkyl, aryl, C 1-6 -alkylaryl, OC 0-6 -alkylaryl, (CO)R 10 , O(CO)R 10 , 0(CO)OR 10 , C(O)OR 10 , O(CNR 10 )OR n , C 1-6 -alkylOR 10
  • R 5 is selected from the group consisting of CN, OCo -6 -alkyl, C 3 - 8 -cycloalkyl, Ci -6 -alkyl-C 3-8 - cycloalkyl, OCo -6 -alkyl-C 3-8 -cycloalkyl, Co -6 -alkylaryl, OC 0-6 -alkylaryl, C 0-6 -alkylheteroaryl, OCo- 6 -alkylheteroaryl, lieterocycloalkyl, Ci- ⁇ -alkylheterocycloalkyl, OC 0-6 - alkylheterocycloalkyl and C(O)R 10 , wherein any cyclic moiety is substituted by one or more B;
  • R 7 is selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, OC 1-4 -alkyl, Ci -6 - alkyl, Ci -6 -alkylhalo, OC 1-6 -alkylhalo, C 2-6 -alkenyl, OC 2-6 -alkenyl, C 2-6 -alkynyl, OC 2-6 - alkynyl, and C 3-8 -cycloalkyl;
  • R 8 and R 9 are independently selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, C 1-6 -alkyl, C] -6 -alkylhalo, OC 1-6 alkyl, OCi -6 -alkylhalo, C 2-6 -alkenyl, OC 2-6 -alkenyl, C 2-
  • R 10 and R 11 are independently selected from the group consisting of H, hydroxy, oxo, F, Cl, Br, I, nitro, cyano, C 1-6 -alkyl, C 1-6 -alkylhalo, OCi -6 alkyl, OCi -6 -alkylhalo, C 2-6 -alkenyl, OC 2- 6 -alkenyl, C 2-6 -alkynyl, OC 2-6 -alkynyl, C 3 .
  • B is selected from the group consisting of Co- ⁇ -alkyl-Cs-s-cycloalkyl, OC 0-6 -alkyl-C 3-8 - cycloalkyl, C 0-6 -alkylaryl, OCo -6 -alkylaryl, C ⁇ -alkylheterocycloalkyl, OC 0-6 - alkylheterocycloalkyl, C 1-6 -alkylheteroaryl and OC 1-6 -alkylheteroaryl, wherein any cyclic moiety is substituted with at least one substituent selected from the group consisting of halo, alkyl, alkylhalo, alkoxy, oxo, COR 5 CO 2 R, SO 2 R and CN;
  • R is selected from the group consisting of H and alkyl
  • n is selected from the group consisting of 1 , 2, 3, 4, 5, 6, 7, and 8;
  • the invention also provides processes for the preparation of compounds of formula I.
  • the invention further provides a pharmaceutical composition comprising a compound according to formula I together with a pharmaceutically acceptable carrier or excipient; in another aspect the invention provides a method for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction in an animal in need of such treatment.
  • the method comprises the step of administering to the animal a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof.
  • the invention also provides for the use of a compound according to formula I, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for the treatment of any of the conditions discussed herein. Further, the invention provides a compound of formula I 5 or a pharmaceutically acceptable salt or solvate thereof, for use in therapy.
  • the present invention is based upon the discovery of compounds that exhibit activity as pharmaceuticals, in particular as modulators of metabotropic glutamate receptors. More particularly, the compounds of the present invention exhibit activity as potentiators of the mGluR2 receptor, and are useful in therapy, in particular for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction.
  • alkyl as used herein means a straight- or branched-chain hydrocarbon radical having, for example, from one to six carbon atoms, and includes methyl, ethyl, propyl, isopropyl, t-butyl and the like.
  • alkenyl as used herein means a straight- or branched-chain alkenyl radical having, for example, from two to six carbon atoms, and includes ethenyl, 1-propenyl, 1-butenyl and the like.
  • alkynyl as used herein means a straight- or branched-chain alkynyl radical having, for example, from two to six carbon atoms, and includes 1-propynyl (propargyl), 1- butynyl and the like.
  • cycloalkyl as used herein means a cyclic group (which may be unsaturated) having, for example, from three to seven carbon atoms, and includes cyclopropyl, cyclohexyl, cyclohexenyl and the like.
  • heterocycloalkyl as used herein means, for example, a three- to seven-membered cyclic group (which may be unsaturated) having at least one heteroatom selected from the group consisting of N, S and O, and includes piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl and the like.
  • alkoxy as used herein means a straight- or branched-chain alkoxy radical having, for example, from one to six carbon atoms and includes methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.
  • halo as used herein means halogen and includes fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms.
  • aryl as used herein means an aromatic group having, for example, five to twelve atoms, and includes phenyl, naphthyl and the like.
  • heteroaryl means an aromatic group which includes at least one heteroatom selected from the group consisting of N, S and O, and includes groups and includes pyridyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl and the like.
  • alkanoyl as used herein means a straight- or branched-chain alkanoyl radical having, for example, from two to seven atoms, and includes acetyl, propionyl, butyryl and the like.
  • cycloalkenyl as used herein means an unsaturated cylcloaklyl group having, for example, from four to seven carbon atoms, and includes cyclopent-1-enyl, cyclohex-1-enyl and the like.
  • alkylaryl refers to an alkyl radical substituted with an aryl, heteroaryl or cycloalkyl group, and includes 2-phenethyl, 3- cyclohexyl propyl and the like.
  • the term "5- to 7-membered ring that may contain one or more heteroatoms independently selected from N, O and S” includes aromatic and heteroaromatic rings, as well as carbocyclic and heterocyclic rings which may be saturated or unsaturated, and includes furyl, isoxazolyl, oxazolyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, triazolyl, morpholinyl, piperazinyl, piperidinyl, homopiperidinyl, tetrahydropyranyl, phenyl, cyclohexyl, cycloheptyl, cyclopentyl, cyclohexanyl and the like.
  • pharmaceutically acceptable salt means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients.
  • a "pharmaceutically acceptable acid addition salt” is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids.
  • Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid.
  • Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form.
  • the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection criteria for the appropriate salt will be known to one skilled in the art.
  • Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • a "pharmaceutically acceptable basic addition salt” is any non-toxic organic or inorganic base addition salt of the acid compounds represented by Formula I or any of its intermediates.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxides.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia.
  • the selection of the appropriate salt may be important so that an ester functionality, if any, elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
  • Solidvate means a compound of Formula I or the pharmaceutically acceptable salt of a compound of Formula I wherein molecules of a suitable solvent are incorporated in a crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered as the solvate.
  • suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a hydrate.
  • stereoisomers is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).
  • treat or “treating” means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.
  • terapéuticaally effective amount means an amount of the compound which is effective in treating the named disorder or condition.
  • pharmaceutically acceptable carrier means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient.
  • a pharmaceutical composition i.e., a dosage form capable of administration to the patient.
  • a pharmaceutically acceptable oil typically used for parenteral administration.
  • R 1 is a 3- to 7-membered ring that may contain one or more heteroatoms independently selected from the group consisting of N, O and S, wherein said ring may be substituted by one or more A;
  • R 2 and R 3 are independently selected from the group consisting of H, Ci -6 -alkyl, C 2 - 6 -alkenyl, C 2-6 -alkynyl, aryl, heteroaryl, heterocycloalkyl, C 3 .
  • R 4 and R 6 are independently selected from the group consisting of H, hydroxy, F, Cl 5 Br, I, nitro, cyano, C 1-6 -alkyl, Q- ⁇ -alkylhalo, OCi -6 alkyl, OC ⁇ -alkylhalo, C 2 - 6 -alkenyl, OC 2-6 - alkenyl, C 2-6 -alkynyl, OC 2-6 -alkynyl, C 3-8 -cycloalkyl, Cj- ⁇ -alkyl-Cs-s-cycloalkyl, OC 0-6 -alkyl- C 3-8 -cycloalkyl, aryl, C 1-6 -alkylaryl, OC 0-6 -alkylaryl, (CO)R 10 , 0(CO)R 10 , 0(CO)OR 10 , C(O)OR 10 , 0(CNR 10 PR 11 , Ci -6 -alkylOR 10 ,
  • R 5 is selected from the group consisting of CN, OC 0-6 -alkyl, C 3-8 -cycloalkyl, Ci -6 -alkyl-C 3-8 - cycloalkyl, OC 0-6 -alkyl-C 3-8 -cycloalkyl, C 0-6 -alkylaryl, OCo- 6 -alkylaryl, Co- 6 -alkylheteroaryl, OCo -6 -alkylheteroaryl, heterocycloalkyl, Ci-o-alkylheterocycloalkyl, OC 0-6 - alkylheterocycloalkyl and C(O)R 10 , wherein any cyclic moiety is substituted by one or more B; R 7 is selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, OC] -4 -alkyl, Ci -6 - alkyl, Ci -6 -alkylhal
  • R and R are independently selected from the group consisting of H, F, Cl, Br, I, nitro, cyano, C 1-6 -alkyl, Ci -6 -alkylhalo, OC 1-6 alkyl, OCi -6 -alkylhalo, C 2-6 -alkenyl, OC 2-6 -alkenyl, C 2 .
  • R 10 and R 11 are independently selected from the group consisting of H, hydroxy, oxo, F, Cl, Br, I, nitro, cyano, C 1-6 -alkyl, C 1-6 -alkylhalo, OC 1-6 alkyl, OC 1-6 -alkylhalo, C 2-6 -alkenyl, OC 2- 6 -alkenyl, C 2-6 -alkynyl, OC 2-6 -alkynyl, C 3-8 -cycloalkyl, Ci -6 -alkyl-C 3-8 -cycloalkyl, OCo -6 - alkyl-C 3-8 -cycloalkyl, aryl, C 1-6 -alkylaryl, OC 0-6 -alkylaryl, Co ⁇ -alkyl-heterocycloalkyl, OCi -6 - alkyl-heterocycloalkyl, heteroaryl, Ci -6 alkylheteroaryl,
  • A is selected from the group consisting of H, hydroxy, F, Cl, Br, I, nitro, cyano, oxo, Cj -6 - alkyl, C 1-6 -alkylhalo, OC 1-6 alkyl, OCi -6 -alkylhalo 5 C 2 - 6 -alkenyl, OC 2-6 -alkenyl, C 2 .
  • B is selected from the group consisting of C 0-6 -alkyl-C 3-8 -cycloalkyl, OC 0-6 -alkyl-C 3-8 - cycloalkyl, Co -6 -alkylaryl, OCo- ⁇ -alkylaryl, Ci-o-alkylheterocycloalkyl, OCo -6 - alkylheterocycloalkyl, C 1-6 -alkylheteroaryl and OC 1-6 -alkylheteroaryl, wherein any cyclic moiety is substituted with at least one substituent selected from the group consisting of halo, alkyl, alkylhalo, alkoxy, oxo, COR, CO 2 R, SO 2 R and CN;
  • R is selected from the group consisting of H and alkyl
  • n is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8;
  • the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture.
  • the present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of formula I.
  • the optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.
  • a corresponding alkali metal such as sodium, potassium, or lithium
  • an alkaline earth metal such as a calcium
  • a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques.
  • a suitably acidic proton such as a carboxylic acid or a phenol
  • an alkali metal or alkaline earth metal hydroxide or alkoxide such as the ethoxide or methoxide
  • a suitably basic organic amine such as choline or meglumine
  • the compound of formula I may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or jD-toluenesulphonate.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or jD-toluenesulphonate.
  • R 5 is selected from the group consisting of heterocycloalkyl and Ci -6 alkylheterocycloalkyl.
  • B is selected from the group consisting of Co- aalkylaryl, Ci ⁇ alkylheteroaryl and Co -6 alkylheterocycloalkyl.
  • the compounds of the present invention may be formulated into conventional pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, in associaton with a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include, but are not limited to, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or table disintegrating agents.
  • a solid carrier can also be an encapsulating material.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided compound of the invention, or the active component.
  • the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized moulds and allowed to cool and solidify.
  • Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low-melting wax, cocoa butter, and the like.
  • composition is also intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component (with or without other carriers) is surrounded by a carrier which is thus in association with it. Similarly, cachets are included.
  • Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • Liquid form compositions include solutions, suspensions, and emulsions.
  • sterile water or water propylene glycol solutions of the active compounds may be liquid preparations suitable for parenteral administration.
  • Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
  • Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
  • Exemplary compositions intended for oral use may contain one or more coloring, sweetening, flavoring and/or preservative agents.
  • the pharmaceutical composition will include from about 0.05%w (percent by weight) to about 99%w, more particularly, from about 0.10%w to 50%w, of the compound of the invention, all percentages by weight being based on the total weight of the composition.
  • a therapeutically effective amount for the practice of the present invention can be determined by one of ordinary skill in the art using known criteria including the age, weight and response of the individual patient, and interpreted within the context of the disease which is being treated or which is being prevented.
  • the compounds of the present invention exhibit activity as pharmaceuticals, in particular as modulators of metabotropic glutamate receptors. More particularly, the compounds of the present invention exhibit activity as potentiators of the mGluR2 receptor, and are useful in therapy, in particular for the treatment of neurological and psychiatric disorders associated with glutamate dysfunction in an animal.
  • the neurological and psychiatric disorders include, but are not limited to, disorders such as cerebral deficit subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, cerebral deficits secondary to prolonged status epilepticus, migraine (including migraine headache), urinary incontinence, substance tolerance, substance withdrawal (including, substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, social phobia, obsessive compulsive
  • the invention thus provides a use of any of the compounds according to formula I, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of any of the conditions discussed above.
  • the invention provides a method for the treatment of a subject suffering from any of the conditions discussed above, whereby an effective amount of a compound according to formula I or a pharmaceutically acceptable salt or solvate thereof, is administered to a patient in need of such treatment.
  • the invention also provides a compound of formula I or pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the term “therapeutic” and “therapeutically” should be construed accordingly.
  • the term “therapy” within the context of the present invention further encompasses the administration of an effective amount of a compound of the present invention, to mitigate either a pre-existing disease state, acute or chronic, or to mitigate a recurring condition.
  • This definition also encompasses prophylactic therapies for prevention of recurring conditions and continued therapy for chronic disorders.
  • the compounds of the present invention may be administered in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
  • the route of administration is oral, intravenous, or intramuscular.
  • the dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, who determines the individual regimen and dosage level for a particular patient.
  • the compounds described herein may be provided or delivered in a form suitable for oral use, for example, in a tablet, lozenge, hard and soft capsule, aqueous solution, oily solution, emulsion, and suspension.
  • the compounds may be formulated into a topical administration, for example, as a cream, ointment, gel, spray, or aqueous solution, oily solution, emulsion or suspension.
  • the compounds described herein also may be provided in a form that is suitable for nasal administration, for example, as a nasal spray, nasal drops, or dry powder.
  • the compounds can be administered to the vagina or rectum in the form of a suppository.
  • the compounds described herein also may be administered parentally, for example, by intravenous, intravesicular, subcutaneous, or intramuscular injection or infusion.
  • the compounds can be administered by insufflation (for example as a finely divided powder).
  • the compounds may also be administered transdermally or sublingually.
  • the compounds of formula I, or salts thereof are useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of mGluR-related activity in laboratory animals as part of the search for new therapeutics agents.
  • Such animals include, for example, cats, dogs, rabbits, monkeys, rats and mice.
  • a compound of formula Ib is then cross-coupled with a suitable reagent containing R 5 to yield a a compound according to formula Ic:
  • 5-substituted-7-chloro isoindolones are synthesized as depicted in Scheme 2 below.
  • 4-bromo-2-methylbenzoic acid is chlorinated ortho to the acid using N-chlorosuccinimide and a palladium catalyst.
  • this acid was then esterified, brominated, and cyclized to yield the isoindolone intermediate.
  • Substituent R 5 is introduced similarly.
  • isoindolones that are substituted with an amide at C5 can be prepared as depicted in Scheme 3 below.
  • an appropriately substituted 5- bromoisoindolone is converted to the corresponding nitrile using zinc cyanide in the presence of a palladium catalyst.
  • the nitrile is then hydrolyzed under basic conditions to provide the benzoic acid, which was then coupled with various amines using methodologies that are well- known in the art to provide the final compounds.
  • the process as described above can be adapted for the preparation of amino-propargyl and amino-alkyl isoindolones.
  • suitable 5- bromoisoindolones are first subjected to Sonogashira coupling conditions with various propargyl amines as shown in Scheme 4.
  • the resulting alkyne then can be hydrogenated using routine methodologies to provide the amino-alkyl substituted product.
  • R and R' correspond to substituents as defined herein for R 10 and R 1 '.
  • R 1 preferably is an aryl group.
  • a compound of formula Ie is then cross-coupled with a reagent comprising R 5 , thereby yielding a compound according to formula If:
  • Another process of the invention contemplates the preparation of compounds of formula I that are unsubstituted on the isoindolone aromatic ring.
  • This subset of compounds are be straightforwardly prepared as depicted below in Scheme 6.
  • phthalimide is reduced, for example with tin under acidic conditions, to provide isoindolinone.
  • This intermediate is alkylated with various electrophiles under basic conditions to provide the desired final products.
  • X can be any suitable leaving group such as, for example, halo, such as bromo and iodo; and tosylate.
  • the mass spectrometer was equipped with an electrospray ion source operated in a positive and/or negative ion mode.
  • the ion spray voltage was ⁇ 3 kV and the mass spectrometer was scanned from m/z 100-700 at a scan time of 0.8 s.
  • X-Terra MS, Waters, C8, 2.1 x 50mm, 3.5 mm was applied a linear gradient from 5 % to 100% acetonitrile inlO mM ammonium acetate (aq.), or in 0.1% TFA (aq.).
  • Microwave heating was performed in a Smith Synthesizer Single-mode microwave cavity producing continuous irradiation at 2450 MHz (Personal Chemistry AB, Uppsala, Sweden).
  • the pharmacological properties of the compounds of the invention can be analyzed using standard assays for functional activity.
  • glutamate receptor assays are well known in the art as described in, for example, Aramori et ah, 1992, Neuron, 8:757; Tanabe et ah, 1992, Neuron, 8:169; Miller et ah, 1995, J. Neuroscience, 15:6103; Balazs, et ah, 1997, J. Neurochemistry, 1997,69:151.
  • the methodology described in these publications is incorporated herein by reference.
  • the compounds of the invention can be studied by means of an assay that measures the mobilization of intracellular calcium, [Ca 2+ ] j in cells expressing mGluR2.
  • Fluorometric Imaging Plate Reader FLIPR analysis was used to detect allosteric activators of mGluR2 via calcium mobilization.
  • FLIPR Fluorometric Imaging Plate Reader
  • the cells were trypsinized and plated in DMEM at 100,000 cells/well in black sided, clear-bottom, collagen I coated, 96-well plates. The plates were incubated under 5% CO 2 at 37 0 C overnight. Cells were loaded with 6 ⁇ M fluo-3 acetoxymethylester (Molecular Probes, Eugene Oregon) for 60 minutes at room temperature.
  • FLIPR experiments were done using a laser setting of 0.8 W and a 0.4 second CCD camera shutter speed. Extracellular fluo-3 was washed off and cells were maintained in 160 ⁇ L of buffer and placed in the FLIPR. An addition of test compound (O.Ol ⁇ M to 30 ⁇ M in duplicate) was made after 10 seconds of baseline fluorescent readings were recorded on FLIPR. Fluorescent signals were then recorded for an additional 75 seconds at which point a second addition of DCG-IV (0.2 ⁇ M) was made and fluorescent signals were recorded for an additional 65 seconds. Fluorescent signals were measured as the peak height of the response within the sample period. Data was analyzed using Assay Explorer, and EC 5 O and E ma ⁇ values (relative to maximum DCG-IV effect) were calculated using a four parameter logistic equation.
  • a [ 35 S]-GTPyS binding assay was used to functionally assay mGluR2 receptor activation.
  • the allosteric activator activity of compounds at the human mGluR2 receptor were measured using a [ 35 S]-GTPyS binding assay with membranes prepared from CHO cells which stably express the human mGluR2.
  • the assay is based upon the principle that agonists bind to G- protein coupled receptors to stimulate GDP-GTP exchange at the G-protein. Since [ 35 S]- GTP ⁇ S is a non-hydrolyzable GTP analog, it can be used to provide an index of GDP-GTP exchange and, thus, receptor activation.
  • the GTP ⁇ S binding assay therefore provides a quantitative measure of receptor activation.
  • Membranes were prepared from CHO cells stably transfected with human mGluR2. Membranes (30 ⁇ g protein) were incubated with test compound (3nM to 300 ⁇ M) for 15 minutes at room temperature prior to the addition of 1 ⁇ M glutamate, and incubated for 30 min at 3O 0 C in 500 ⁇ l assay buffer (20 mM HEPES, 10OmM NaCl, 1OmM MgCl 2 ), containing 30 ⁇ M GDP and O.lnM [ 35 S]-GTPyS (1250 Ci/mmol). Reactions were carried out in triplicate in 2 ml polypropylene 96- well plates.
  • the compounds of the present invention were active in assays described herein at concentrations (or with EC 50 values) less than 10 ⁇ M.
  • concentrations or with EC 50 values
  • Example 6 7-Chloro-5-[5-(chloromethyl)-l ,2,4-oxadiazol-3-yl]-2-[(4,4-difluoro-cyclohexyl) methyl] isoindolin- 1 -one
  • 3-Amino-l-benzyl-pyrrolidine (57mg, 0.325mmol), 5-Bromo-7-methyl-2-(4- trifluoromethoxybenzyl)-2,3-dmydro-isoindol-l-one (lOOmg, 0.25mmol), NaO 1 Bu (168mg, 1.75mmol), BINAP (16mg, 0.025mmol) and Pd 2 (dba) 3 (23mg, 0.025 mmol) were dissolved in anhydrous toluene (5mL). The mixture was immersed in a 110°C oil bath. After eighteen hours, the reaction was cooled and poured into water and extracted with ethyl acetate.
  • Example 16.1 7-Methyl-5- [5-(4-methyl-piperazin- 1 -ylmethyl)-pyridin-3 -yl] -2-(4- rifluoromethoxybenzyl)-2,3-dihydro-isoindol-l-one
  • Methanesulfonic acid 5-[7-methyl-l-oxo-2-(4-tri£luoromethoxy-benzyl)-2,3-dihydro-lH- isoindol-5-yl]-pyridin-3-ylmethyl ester ( 36mg, 0.071mmol) was dissolved in THF (5mL). N- Methyl piperazine (24uL, 0.213mmol) was added and the mixture stirred at 5O 0 C for 18hrs. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated.
  • Example 17.1 4- ⁇ 4-[7-Chloro-l-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-lH- isoindol-5-ylmethyl]-piperidin- 1 -ylmethyl ⁇ -benzonitrile
  • Example 18.1 4- ⁇ 4-[7-Chloro-l -oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro- 1 H- isoindol-5 -ylmethyl] -piperazin- 1 -methyl ⁇ -nicotinonitrile

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