WO2009047303A2

WO2009047303A2 - Metabotropic glutamate receptor modulators for the treatment of pervasive developmental disorder

Info

Publication number: WO2009047303A2
Application number: PCT/EP2008/063553
Authority: WO
Inventors: Daniel Umbricht; Baltazar Gomez-Mancilla
Original assignee: Novartis Ag
Priority date: 2007-10-12
Filing date: 2008-10-09
Publication date: 2009-04-16
Also published as: WO2009047303A3

Abstract

The invention concerns the use an mGluR modulator, e.g. an mGluR5 modulator, for the treatment, prevention or delay of progression of a pervasive developmental disorder. The invention further concerns the use of an mGluR modulator for the treatment, prevention or delay of progression of a disorder is selected from Fragile X syndrome and fragile X- associated tremor/ataxia syndrome (FXTAS).

Description

Organic Compounds

The present invention relates to new pharmaceutical uses of compounds acting as modulators of metabotropic glutamate receptors ("mGluR modulators"), including antagonists of metabotropic glutamate receptors ("mGluR antagonists"). In particular, the present invention relates new uses of modulators e.g. antagonists of metabotropic glutamate type-5 receptors ("mGluRδ antagonists").

WO 2005/079802, WO 2003/047581 , WO 2004/000316, WO 2005/044265, WO 2005/044266, WO 2005/044267, WO 2006/114262 and WO 2007/071358 disclose mGluRδ antagonists and their use as pharmaceuticals.

It has been surprisingly found that compounds having mGluR modulating activity, in particular antagonistic activity, may be used to treat pervasive developmental disorders (PDD), for example, disorders which are associated with the Fragile X mental retardation I gene (FMR1 ). In particular, it has been found that mGluRδ modulators, e.g. mGluRδ antagonists, may be used to treat for example Fragile X syndrome. Disorders which are treatable by the compounds described herein include those which result from a mutation of the FMR1 gene which may result in abnormal expression of the FMR1 gene product, the FMR protein.

Accordingly, a first aspect of the invention concerns the use of an mGluR modulator for the treatment, prevention and/or delay of progression of a pervasive developmental disorder (PDD), for example, a disorder associated with the Fragile X mental retardation I gene (FMR1 ). In one embodiment, the mGluR modulator is for the treatment, prevention and/or delay of progression of Fragile X syndrome. In one embodiment, the invention concerns the use of an mGluR modulator for the treatment, prevention and/or delay of progression of fragile X-associated tremor/ataxia syndrome (FXTAS).

A further aspect of the invention relates to a method for the treatment, prevention or delay of progression of a pervasive developmental disorder (PDD) in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of an mGluR, e.g. mGluRδ, modulator. In one embodiment, the method is for the treatment, prevention or delay of progression of a disorder associated with the Fragile X mental retardation I gene (FMR1), e.g. Fragile X syndrome, in a subject in need of such treatment, wherein the method comprises administering to said subject a therapeutically effective amount of an mGluR, e.g. mGluR5, modulator. In one embodiment, the method is for the treatment, prevention and/or delay of progression of fragile X-associated tremor/ataxia syndrome (FXTAS) in a subject in need of such treatment, wherein the method comprises administering to said subject a therapeutically effective amount of an mGluR, e.g. mGluR5, modulator. In one embodiment, the method is for the treatment, prevention or delay of progression of a disorder associated with Fragile X syndrome in a subject in need of such treatment, which method comprises administering to said subject a therapeutically effective amount of an mGluR, e.g. mGluR5, modulator.

A further aspect of the invention relates to a pharmaceutical composition comprising an mGluR, e.g. mGluR5, modulator for the treatment, prevention or delay of progression of a pervasive developmental disorder (PDD). In one embodiment, the disorder is, for example, a disorder associated with the Fragile X mental retardation I gene (FMR1) e.g. Fragile X syndrome. In one embodiment, the pharmaceutical composition is for the treatment, prevention or delay of progression of Fragile X syndrome. In one embodiment, the pharmaceutical composition is for the treatment, prevention or delay of progression of fragile X-associated tremor/ataxia syndrome (FXTAS).

A further aspect of the invention relates to the use of an mGluR, e.g. mGluR5, modulator for the manufacture of a medicament for the treatment, prevention or delay of progression of a a pervasive developmental disorder (PDD), for example, a disorder associated with the Fragile X mental retardation I gene (FMR1) e.g. Fragile X syndrome. In one embodiment, the medicament is for the treatment, prevention or delay of progression of Fragile X syndrome. In one embodiment, the medicament is for the treatment, prevention or delay of progression of fragile X-associated tremor/ataxia syndrome (FXTAS).

The mGluR modulator may be an mGluR5 modulator. In certain embodiments, the mGluR modulator is an mGluR, e.g. mGluR5, antagonist. In the present specification, the following definitions shall apply if no specific other definition is given:

"Alkyl" represents a straight-chain or branched-chain alkyl group, preferably represents a straight-chain or branched-chain C_1-12 alkyl, particularly preferably represents a straight-chain or branched-chain C_1-6 alkyl; for example, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert- butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, with particular preference given to methyl, ethyl, n-propyl and iso-propyl.

"Alkandiyl" represents a straight-chain or branched-chain alkandiyl group bound by two different carbon atoms to the molecule, it preferably represents a straight-chain or branched- chain C_1-12 alkandiyl, particularly preferably represents a straight-chain or branched-chain C_1- ₆ alkandiyl; for example, methandiyl (-CH₂-), 1 ,2-ethanediyl (-CH₂-CH₂-), 1 ,1-ethanediyl ((- CH(CH₃)-), 1 ,1-, 1 ,2-, 1 ,3-propanediyl and 1 ,1-, 1 ,2-, 1 ,3-, 1 ,4-butanediyl, with particular preference given to methandiyl, 1 ,1-ethanediyl, 1 ,2-ethanediyl, 1 ,3-propanediyl or 1 ,4- butanediyl.

Each alkyl part of "alkoxy", "alkoxyalkyl", "alkoxycarbonyl", "alkoxycarbonylalkyl" and "halogenalkyl" shall have the same meaning as described in the above-mentioned definition of "alkyl".

"Alkenyl" represents a straight-chain or branched-chain alkenyl group, preferably C_2-6 alkenyl, for example, vinyl, allyl, 1-propenyl, isopropenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, etc. and preferably represents C_2-4 alkenyl.

"Alkendiyl" represents a straight-chain or branched-chain alkendiyl group bound by two different carbon atoms to the molecule, it preferably represents a straight-chain or branched- chain C_2-6 alkandiyl; for example, -CH=CH-, -CH=C(CH₃)-, -CH=CH-CH₂-, -C(CH₃)=CH-CH₂-, -CH=C(CH₃)-CH₂-, -CH=CH-C(CH₃)H-, -CH=CH-CH=CH-, -C(CH₃)=CH-CH=CH-, -CH=C(CHa)-CH=CH-, with particular preference given to -CH=CH-CH₂-, -CH=CH-CH=CH-.

"Alkynyl" represents a straight-chain or branched-chain alkynyl group, preferably C_2-6 alkynyl, for example, ethenyl, propargyl, 1-propynyl, isopropenyl, 1- (2- or 3) butynyl, 1- (2- or 3) - A -

pentenyl, 1- (2- or 3) hexenyl, etc. .preferably represents C_2-4 alkynyl and particularly preferably represents ethynyl.

"Aryl" represents an aromatic hydrocarbon group, preferably a C_6-io aromatic hydrocarbon group; for example phenyl, naphthyl, especially phenyl.

"Aralkyl" denotes an "aryl" bound to an "alkyl" (both as defined above) an represents, for example benzyl, α-methylbenzyl, 2-phenylethyl, α,α-dimethylbenzyl, especially benzyl.

"Heterocycle" represents a saturated, partly saturated or aromatic ring system containing at least one hetero atom. Preferably, heterocycles consist of 3 to 11 ring atoms of which 1-3 ring atoms are hetero atoms. Heterocycles may be present as a single ring system or as bicyclic or tricyclic ring systems; preferably as single ring system or as benz-annelated ring system. Bicyclic or tricyclic ring systems may be formed by annelation of two or more rings, by a bridging atom, e.g. oxygen, sulfur, nitrogen or by a bridging group, e.g. alkandiyl or alkenediyl. A heterocycle may be substituted by one or more substituents selected from the group consisting of oxo (=0), halogen, nitro, cyano, alkyl, alkandiyl, alkenediyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, halogenalkyl, aryl, aryloxy and arylalkyl. Examples of heterocyclic moieties include pyrrole, pyrroline, pyrrolidine, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine, triazole, triazoline, triazolidine, tetrazole, furane, dihydrofurane, tetrahydrofurane, furazane (oxadiazole), dioxolane, thiophene, dihydrothiophene, tetrahydrothiophene, oxazole, oxazoline, oxazolidine, isoxazole, isoxazoline, isoxazolidine, thiazole, thiazoline, thiazlolidine, isothiazole, istothiazoline, isothiazolidine, thiadiazole, thiadiazoline, thiadiazolidine, pyridine, piperidine, pyridazine, pyrazine, piperazine, triazine, pyrane, tetrahydropyrane, thiopyrane, tetrahydrothiopyrane, oxazine, thiazine, dioxine, morpholine, purine, pterine, and the corresponding benz- annelated heterocycles, e.g. indole, isoindole, cumarine, cumaronecinoline, isochinoline, cinnoline and the like.

"Hetero atoms" are atoms other than carbon and hydrogen, preferably nitrogen (N), oxygen (O) or sulfur (S). "Halogen" represents fluoro, chloro, bromo or iodo, preferably represents fluoro, chloro or bromo and particularly preferably represents chloro.

Various compounds having rmGluR, in particular mGluRδ, modulating activity are described herein. Where the specification refers to compounds, agents or active ingredients of the invention, this is generally taken to mean a compound having mGluR modulating activity unless specified otherwise. In embodiments of the invention, the mGluR modulators are mGluRδ antagonists. When the specification refers to mGluR antagonists, this is generally taken to include compounds that are capable of interacting with an mGluR to inhibit the effect of a natural ligand for the mGluR e.g. such that a response pathway of a mGluR expressing cell is not stimulated.

In one embodiment, the mGluR modulator is an mGluRδ antagonist.

Compounds of the invention may exist in free or acid addition salt form. In this specification, unless otherwise indicated, reference to "compounds of the invention" is to be understood as embracing the compounds in any form, for example free base or acid addition salt form. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds of the invention, such as picrates or perchlorates, are also included. For therapeutic use, only pharmaceutically acceptable salts or free compounds are employed (where applicable in the form of pharmaceutical preparations), and are therefore preferred.

It will be understood that any discussion of methods or references to the active ingredients also includes pharmaceutically acceptable salts. If these active ingredients have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The active ingredients having an acid group (for example COOH) can also form salts with bases. The active ingredient or a pharmaceutically acceptable salt thereof may also be used in the form of a hydrate or may include other solvents used for crystallization. Examples of mGluRδ modulators, e.g. antagonists, and their manufacture are known, e.g. from WO 03/047681 and WO 2006/1 14262, both of which are incorporated herein by reference. On account of the asymmetrical carbon atom(s) that may be present in the compounds of the invention and their salts, the compounds may exist in optically active form or in form of mixtures of optical isomers, e.g. in form of racemic mixtures or diastereomeric mixtures. All optical isomers and their mixtures, including racemic mixtures, are part of the present invention.

In one embodiment, the mGluR modulator is a compound of the formula (I)

wherein

R¹ represents optionally substituted alkyl or optionally substituted benzyl; and

R² represents hydrogen (H), optionally substituted alkyl or optionally substituted benzyl; or

R¹ and R² form together with the nitrogen atom to which they are attached an optionally substituted heterocycle with less than 14 ring atoms;

R³ represents halogen, alkyl, alkoxy, alkylamino or dialkylamino;

R⁴ represents hydroxy (OH), halogen, alkyl or alkoxy;

Q represents CH, CR⁴ or N;

V represents CH, CR⁴ or N; W represents CH, CR⁴ or N; X represents CH or N;

Y represents CH, CR³ or N;

Z represents CH₂, NH or O; and provided that Q, V and W are not N at the same time; in free base or acid addition salt form.

In another embodiment, the mGluR modulator is a compound of the formula (II), wherein a compound of the formula (II) is a compound of formula (I) in which at least one of Q, V and W is N; in free base or acid addition salt form. In yet a further embodiment, the mGluR modulator is a compound of the formula (III), wwhheerreeiinn aa ccoommppoouunndd ooff tthhee ffoorrmmuullaa (III) is a compound of formula (II) in which Y is CR³; in free base or acid addition salt form.

Preferred substituents, preferred ranges of numerical values or preferred ranges of the radicals present in the formula (I), (II) and (III) and the corresponding intermediate compounds are defined below.

X preferably represents CH.

Y preferably represents CH or CR³, wherein R³ preferably represents halogen, particular preferably chloro.

Z preferably represents NH.

R³ preferably represents fluoro, chloro, C_1-4 alkyl, e.g. methyl.

R³ particularly preferably represents chloro.

R¹ and R² preferably form together with the nitrogen atom to which they are attached an unsubstituted or substituted heterocycle having 3 - 11 ring atoms and 1 - 4 hetero atoms; the hetero atoms being selected from the group consisting of N, O, S, the substituents being selected from the group consisting of oxo (=0), hydroxy, halogen, amino, nitro, cyano, C_1-4 alkyl, C_1-4 alkoxy, C_1-4 alkoxyalkyl, C_1-4 alkoxycarbonyl, C_1-4 alkoxycarbonylalkyl, C_1-4 halogenalkyl, C_6-io aryl, halogen- C_6-io aryl, C_6-io aryloxy and C₆.io-aryl-C_1-4 alkyl.

R¹ and R² form together with the nitrogen atom to which they are attached form an unsubstituted, a single or twofold substituted heterocycle having 5 - 9 ring atoms and 1 - 3 hetero atoms; the hetero atoms being selected from the group consisting of N and O; the substituents being selected from the group consisting of halogen and C_1-4 alkyl. R¹ and R² preferably form together with the nitrogen atom to which they are attached an unsubstituted, a single or twofold substituted heterocycle selected from the group consisting of

and the substituents being selected from the group consisting of fluoro, chloro, methyl, ethyl, propyl, butyl, trifluoromethyl, fluoropropyl and difluoropropyl.

R¹ and R² preferably represent, independently from each other, Ci-C₄ alkyl or benzyl, optionally substituted by C₁-C₄ BIkOXy or halogen.

The above mentioned general or preferred radical definitions apply both to the end products of the formulae (I), (II) and (III) and also, correspondingly, to the starting materials or intermediates required in each case for the preparation. These radical definitions can be combined with one another at will, i.e. including combinations between the given preferred ranges. Further, individual definitions may not apply.

Preference according to the invention is given to compounds of the formulae (I), (II) and (III) which contain a combination of the meanings mentioned above as being preferred. Particular preference according to the invention is given to compounds of the formulae (I), (II) and (III) which contain a combination of the meanings listed above as being particularly preferred.

Very particular preference according to the invention is given to the compounds of the formula (I) which contain a combination of the meanings listed above as being very particularly preferred.

Preferred are those compounds of formulae (I), (II) and (III) wherein R² represents an unsubstituted or substituted heterocycle.

Particular preferred are compounds of formulae (Ma to Me) as shown below:

wherein the substituents have the meaning given in this specification;

wherein the substituents have the meaning given in this specification;

wherein the substituents have the meaning given in this specification;

(Hd) wherein R⁴ represents Ci-C₄ alkyl, preferably methyl, and the other substituents have the meaning given in this specification;

wherein R⁴ represents halogen, preferably chloro, and the other substituents have the meaning given in this specification.

Further preferred compounds of the present invention have the formulae (IMa to IMe) as shown below:

wherein all of the substituents have the meaning given in this specification;

wherein the substituents have the meaning given in this specification;

wherein the substituents have the meaning given in this specification;

(MId) wherein R⁴ represents C₁-C₄ alkyl, preferably methyl, and the other substituents have the meaning given in this specification;

Particular compounds of the formulae (I), (II) and (III) include those described in the Examples given herein.

In another embodiment, the mGluR modulator is a compound of the formula (IV):

wherein m is 0 or 1 , n is 0 or 1 and A is hydroxy X is hydrogen and Y is hydrogen, or

A forms a single bond with X or with Y;

R₀ is hydrogen, (C_1-4)alkyl, (C_1-4)alkoxy, trifluoromethyl, halogen, cyano, nitro, -COOR₁ wherein R₁ is (C_1-4)alkyl or -COR₂ wherein R₂ is hydrogen or (C_1-4)alkyl, and R is -COR₃, -COOR₃, -CONR₄R₅ Or -SO₂R₆, wherein R₃ is (C_1-4)alkyl, (C_3-7)cycloalkyl or optionally substituted phenyl, 2-pyridyl or 2-thienyl; R₄ and R₅, independently, are hydrogen or (C_1-4)alkyl; and R₆ is (C_1-4)alkyl, (C_3-7)cycloalkyl or optionally substituted phenyl, R' is hydrogen or (C^alkyl and R" is hydrogen or (C_1-4)alkyl, or R' and R" together form a group -CH₂-(CH₂)_m- wherein m is 0, 1 or 2, in which case one of n and m is different from 0, with the proviso that R₀ is different from hydrogen, trifluoromethyl and methoxy when n is 0, A is hydroxy, X and Y are both hydrogen, R is COOEt and R' and R" together form a group - ' (CHz)₂-, in free base or acid addition salt form.

Exemplary compounds of formula (IV) include:

(-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (-)-(3aR,4S,7aR)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid ethyl ester

(-)-(3aR,4S,7aR)-Furan-2-yl-(4-hydroxy-4-m-tolylethynyl-octahydro-indol-1-yl)-methanone

(±)- (3aRS,4SR,7aRS)-4-(3-Chlorophenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylic acid ethyl ester

(±)-(3aRS,4SR,7aRS)-4-(3-Fluoro-phenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylic acid ethyl ester

(SaRS^SRJaRS^-Hydroxy^-phenylethynyl-octahydro-indole-i-carboxylic acid(S)(tetrahydrofuran-3-yl)ester

(SaRS^SRJaRS^-Hydroxy^-phenylethynyl-octahydro-indole-i-carboxylic acid(R)(tetrahydrofuran-3-yl)ester

(3aRS,4SR,7aRS)-4-Hydroxy-4-(3-chlorophenylethynyl)-octahydro-indol-1-carboxylic acid- (S)(tetrahydrofuran-3yl)ester

(±)-(3aRS,4SR,7aRS)-4-Hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid ethyl ester

(±)-(3aRS,4SR,7aRS)-4-(4-Fluoro-phenylethynyl)-4-hydroxy-octahydro-indole-1-carboxylic acid ethyl ester

(±)-(3aRS,4SR,7aRS)-4-(3-chlorophenylethynyl)-4-hydroxy-1-methanesulfonyl-octahydro- indole

(±)-(3aRS,7aRS)-4-Phenylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester and (±)-(RS)-4-phenylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester (±J-CSRSJaRSJ^^^-Trifluoro-i-C^phenylethynyl^.S.Sa.ej.ya-hexahydro-indol-i-yl)- ethanone

(±)-(RS)-4-m-Tolylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester (±)-(3RS,7aRS)-4-m-Tolylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1 -carboxylic acid ethyl ester

(±)-(3RS, 7aRS)-4-(4-Chloro-phenylethynyl)-2,3,3a, 6, 7,7a-hexahydro-indole-1 -carboxylic acid ethyl ester

(±)-(3RS, 7aRS)-4-(2-Fluoro-phenylethynyl)-2, 3,3a, 6, 7, 7a-hexahydro-indole-1 -carboxylic acid ethyl ester

(±)-(3RS,7aRS)-4-(3-Fluoro-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester

(±)-(RS)-4-(3-Fluoro-phenylethynyl)-2,3,5,6,7,7a-hexahydro-indole-1 -carboxylic acid ethyl ester

(±)-(3RS,7aRS)- 4-(3-Methoxy-phenylethynyl)-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester

(±)-(RS)-4-(3-Methoxy-phenylethynyl)-2, 3,5,6, 7, 7a-hexahydro-indole-1 -carboxylic acid ethyl ester

(±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-phenylethynyl-octahydro-isoindole-2-carboxylic acid ethyl ester

(±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic acid ethyl ester

(±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-p-tolylethynyl-octahydro-isoindole-2-carboxylic acid ethyl ester

(±)-(3aRS,4RS,7aSR)-4-(3-Cyano-phenylethynyl)-4-hydroxy-octahydro-isoindole-2- carboxylic acid ethyl ester

(±HSaRS^RSJaSRM-Hydroxy^S-methoxy-phenylethynyO-octahydro-isoindole^- carboxylic acid ethyl ester

(±HSaRS^RSJaSRM-CS-Fluoro-phenylethynyl^-hydroxy-octahydro-isoindole^- carboxylic acid ethyl ester

(±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-phenylethynyl-octahydro-isoindole-2-carboxylic acid tert- butyl ester

(±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic acid tert- butyl ester (±)-(3aRS,4RS,7aSR)-4-Hydroxy-4-m-tolylethynyl-octahydro-isoindole-2-carboxylic acid methyl ester

(±)-(3aRS,4RS,7aSR)-Furan-2-yl-(4-hydroxy-4-m-tolylethynyl-octahydro-isoindol-2-yl)- methanone (±J^SaRS^RS.yaSRJ-Cyclopropyl^-hydroxy^-m-tolylethynyl-octahydro-isoindol^-yl)- methanone (±)-(3aRS,4RS,7aSR)- (4-Hydroxy-4-m-tolylethynyl-octahydro-isoindol-2-yl)-pyridin-3-yl- methanone

(±)-((1SR,3SR)-3-Hydroxy-3-/r7-tolylethynyl-cyclohexyl)-methyl-carbamic acid methyl ester and (±)-((1 RS,3SR)-3-hydroxy-3-/n-tolylethynyl-cyclohexyl)-methyl-carbamic acid methyl ester

(±)-(1 RS,3SR)-((3-Hydroxy-3-/n-tolylethynyl-cyclohexyl)-(4-methoxy-benzyl)-carbamic acid ethyl ester

(±)-(1 RS,3RS)-((3-Hydroxy-3-/r7-tolylethynyl-cyclohexyl)-(4-methoxy-benzyl)-carbamic acid ethyl ester

(±)-[(1 RS,3SR)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-5,5-dimethyl-cyclohexyl]-methyl- carbamic acid methyl ester

(±)-(1 RS,3SR)-(3-Hydroxy-5,5-dimethyl-3-/r7-tolylethynyl-cyclohexyl)-methyl-carbamic acid methyl ester

(±)-[(1 RS,3SR)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-5,5-dimethyl-cyclohexyl]-methyl- carbamic acid methyl ester

(±)-[(1 RS,3RS)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester

(±)-[(1 RS,3SR)-3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester

(±)-[(1 RS,3RS)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-methyl-carbamic acid methyl ester

(±)-[(1 RS,3SR)-3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-methyl-carbamic acid methyl ester

(±)-[(1 RS,3RS)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester

(±)-[(1 RS,3SR)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-methyl-carbamic acid methyl ester (±)-(1 RS,3RS)-N-(3-hydroxy-3-m-tolylethynyl-cyclohexyl)-acetamide

(±)-(1 RS,3SR)-N-(3-hydroxy-3-m-tolylethynyl-cyclohexyl)-acetamide

(±)-(1 RS,3RS)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acid ethyl ester

(±)-(1 RS,3SR)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acid ethyl ester

(±)-(1 RS,3RS)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid ethyl ester

(±)-(1 RS,3SR)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid ethyl ester

(±)-(1 RS,3RS)-[3-(3-Methoxy-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid ethyl ester

(±)-(1 RS,3RS)-N-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-acetamide. (±)-(1 RS,3SR)-N-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-acetamide (±)-(1 RS,3SR)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbamic acid ethyl ester

(±)-(1 RS,3RS)-N-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-acetamide (±)-(1 RS,3SR)-N-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-acetamide. (±)-(1 RS,3RS)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbamic acid terf-butyl ester (±)-(1 RS,3SR)-[3-Hydroxy-3-(3-methoxy-phenylethynyl)-cyclohexyl]-carbamic acid terf-butyl ester

(±)-(1 RS,3RS)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acid tert-butyl ester (±)-(1 RS,3SR)-(3-Hydroxy-3-m-tolylethynyl-cyclohexyl)-carbamic acid tert-butyl ester (±)-(1 RS,3RS)-(3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid tert-butyl ester (±)-(1 RS,3SR)-(3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid tert-butyl ester

(±)-(1 RS,3RS)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid methyl ester (±)-(1 RS,3SR)-[3-(3-Fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-carbamic acid methyl ester (±)-(3-Phenylethynyl-cyclohex-2-enyl)-carbamic acid ethyl ester and (±)-3-phenylethynyl- cyclohex-3-enyl)-carbamic acid ethyl ester

(±)-Methyl-(3-phenylethynyl-cyclohex-3-enyl)-carbamic acid ethyl ester (±)-(4aRS,5RS,8aSR)-5-Hydroxy-5-phenylethynyl-octahydro-quinoline-1-carboxylic acid ethyl ester (±)-[(4aRS,5SR,8aSR)- 5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-furan-

2-yl-methanone (±)-[(4aRS,5RS,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-furan- 2-yl-methanone

(±)-(4aRS,5RS,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1- carboxylic acid tert-butyl ester

(±)-[(4aRS,5SR,8aSR)-5-(3-Chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]- morpholin-4-yl-methanone

(±)-[(4aRS,5SR,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinolin-1-yl]-(4- methyl-piperazin-1-yl)-methanone

(±)-(4aRS,5RS,8aSR)-5-(3-chloro-phenylethynyl)-5-hydroxy-octahydro-quinoline-1- carboxylic acid ethyl ester and (±)-(4aRS,5SR,8aSR)- 5-(3-chloro-phenylethynyl)-5-hydroxy- octahydro-quinoline-1 -carboxylic acid ethyl ester

(±)-(4aRS,5SR,8aSR)- 5-Hydroxy-5-m-tolylethynyl-octahydro-quinoline-1 -carboxylic acid ethyl ester

(±)-(4aRS,5RS,8aSR)- 5-Hydroxy-5-m-tolylethynyl-octahydro-quinoline-1 -carboxylic acid ethyl ester.

In a further embodiment, the mGluR modulator is a compound of the formula (V):

wherein

R¹ represents hydrogen or alkyl;

R² represents an unsubstituted or substituted heterocycle or R² represents an unsubstituted or substituted aryl; R³ represents alkyl or halogen;

X represents a single bond or an alkandiyl-group, optionally interrupted by one or more oxygen atoms or carbonyl groups or carbonyloxy groups in free base or acid addition salt form.

Exemplary compounds of formula (V) include:

Furan-3-carboxylic acid [(1S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide Furan-2-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide Furan-2-carboxylic acid [(1S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide 3H-lmidazole-4-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- amide

3H-lmidazole-4-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- amide

4H-[1 ,2,4]Triazole-3-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

4H-[1 ,2,4]Triazole-3-carboxylic acid [(1S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

2-Methyl-furan-3-carboxylic acid [(±)-(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

N-[(±)-(1 R,3R)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-3,4-difluoro-benzamide Benzo[1 ,3]dioxole-2-carboxylic acid [(±)-(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

5-Methyl-pyrazine-2-carboxylic acid [(±)-(1R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

Quinoxaline-2-carboxylic acid [(±)-(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- amide

Benzofuran-2-carboxylic acid [(±)- (1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- amide

Benzooxazole-2-carboxylic acid [(±)- (1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

2,5-Dimethyl-furan-3-carboxylic acid [(±)- (1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

(R,S)-Tetrahydro-furan-3-carboxylic acid [(±)-(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

Furan-3-carboxylic acid ((1 R.SRJ-S-hydroxy-S-m-tolylethynyl-cyclohexyO-amide Furan-3-carboxylic acid ((1S,3S)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-amide Furan-3-carboxylic acid ((±)-(1 R.SRJ-S-hydroxy-S-m-tolylethynyl-cyclohexyO-amide

Furan-2-carboxylic acid ((1 R,3R)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-amide

Furan-2-carboxylic acid ((1 S,3S)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-amide

Furan-2-carboxylic acid ((±)-(1 R,3R)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-amide lsoxazole-5-carboxylic acid ((1 R,3R)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-amide lsoxazole-5-carboxylic acid ((1 S,3S)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-amide lsoxazole-5-carboxylic acid ((±)-(1 R,3R)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-amide

5-Methyl-pyrazine-2-carboxylic acid ((±) -(1 R,3R)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)- amide

4H-[1 ,2,4]Triazole-3-carboxylic acid ((±)-(1 R,3R)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)- amide

3H-lmidazole-4-carboxylic acid ((±)- (1 R,3R)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)-amide

Tetrahydro-pyran-4-carboxylic acid ((±)-(1 R,3R)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)- amide

1-Methyl-1 H-imidazole-4-carboxylic acid ((±)-(1 R,3R)-3-hydroxy-3-m-tolylethynyl-cyclohexyl)- amide

(R,S)-Tetrahydro-furan-2-carboxylic acid ((±)-(1 R,3R)-3-hydroxy-3-m-tolylethynyl- cyclohexyl)-amide

(R,S)-Tetrahydro-furan-3-carboxylic acid ((±)-(1 R,3R)-3-hydroxy-3-m-tolylethynyl- cyclohexyl)-amide

Furan-3-carboxylic acid [(1 R,3R)-3-(3-fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide Furan-3-carboxylic acid [(1 S,3S)-3-(3-fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide Furan-2-carboxylic acid [(1 R,3R)-3-(3-fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide Furan-2-carboxylic acid [(1 S,3S)-3-(3-fluoro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide 3H-lmidazole-4-carboxylic acid [(±)-(1 R,3R)-3-(3-fluoro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

N-[(1 S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-3,4-difluoro-benzamide N-[(1 R,3R)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-3,4-difluoro-benzamide Pyridine-2-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide Pyridine-2-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-nicotinamide N-[(1 R,3R)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-nicotinamide Benzo[1 ,3]dioxole-2-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

5-Methyl-pyrazine-2-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

2-Methyl-furan-3-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- amide

(R)-Tetrahydro-furan-2-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

(S)-Tetrahydro-furan-2-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide lsoxazole-5-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide 5-Methyl-pyrazine-2-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

2-Methyl-furan-3-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- amide lsoxazole-5-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide 5-Chloro-furan-2-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- amide

5-Chloro-furan-2-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- amide

(S)-Tetrahydro-furan-3-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

(R)-Tetrahydro-furan-3-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

N-[(1 S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-isonicotinamide N-[(1 R,3R)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-isonicotinamide 3,5-Difluoro-pyridine-2-carboxylicacid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

3,5-Difluoro-pyridine-2-carboxylicacid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

6-Methyl-pyridine-2-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide 6-Methyl-pyridine-2-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

S-Chloro-pyridine^-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide δ-Chloro-pyiϊdine^-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide δ-Chloro-pyridine^-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

6-Chloro-pyridine-2-carboxylic acid [(1S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

5-Chloro-1-methyl-1 H-pyrrole-2-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3- hydroxy-cyclohexyl]-amide

5-Chloro-1 -methyl-1 H-pyrrole-2-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3- hydroxy-cyclohexyl]-amide

5-Chloro-1 H-pyrrole-2-carboxylic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

5-Chloro-1 H-pyrrole-2-carboxylic acid [(1S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

N-[(1 S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-4-dimethyl amino- benzamide

1 H-Pyrrole-3-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hyd roxy-cyclohexyl]-amide

N-[(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-4-methyl-benzamide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-4-methyl-benzamide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-3-fluoro-benzamide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-2-ethyl-butyramide

N-[(1 S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-4-(2,5-dimethoxy-phenyl)-4- oxo-butyramide

2-(2-Benzyloxy-ethoxy)-N-[(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- acetamide

N-[(1 S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-2-phenyl-acetamide

N-[(1 S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-3-(1 H-indol-4-yl)-propionamide 2-Benzo[1 ,3]dioxol-5-yl-N-[(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- acetamide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-2-phenoxy-propionamide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-2-(2-fluoro-phenyl)-acetamide

5-Hydroxy-1 H-indole-2-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

1 -Methyl-1 H-pyrrole-2-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

N-[(1 S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-terephthalamic acid methyl ester

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-2-(2-trifluoromethoxy-phenyl)- acetamide

5-Chloro-N-[(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-2-hydroxy-benzamide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-4-hydroxy-benzamide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-2-hydroxy-benzamide

4-Amino-N-[(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-benzamide

4-Amino-5-chloro-N-[(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-

3-Amino-4-chloro-N-[(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-benzamide

3-Amino-N-[(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-4-methyl-benzamide

2-Amino-N-[(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-nicotinamide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-4-hydroxy-3-methoxy- benzamide

N-[(1 S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-2-fluoro-benzamide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-4-methanesulfonyl-benzamide

Pyridine-2-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide

3-Amino-pyrazine-2-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

6-Amino-N-[(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-nicotinamide

4-(4-Amino-benzoylamino)-benzoic acid [(1 R,3R)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

2,6-Dioxo-1 ,2,3,6-tetrahydro-pyrimidine-4-carboxylic acid [(1 S,3S)-3-(3-chloro- phenylethynyl)-3-hydroxy-cyclohexyl]-amide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-isonicotinamide 3-Chloro-N-[(1S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-benzamide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-2,3-dimethoxy-benzamide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-4-oxo-4-phenyl-butyramide

2-Chloro-N-[(1S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-nicotinamide

5-Bromo-N-[(1S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-nicotinamide lsoquinoline-1 -carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- amide

Pyrazine-2-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide

3-Benzoyl-pyridine-2-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-2-methyl-nicotinamide

Quinoxaline-2-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- amide

Pyridazine-4-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- amide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-2-methylsulfanyl-nicotinamide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-4-trifluoromethyl-nicotinamide

2-Chloro-N-[(1S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-isonicotinamide

2-Chloro-N-[(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-6-methyl-nicotinamide

6-Chloro-N-[(1S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-nicotinamide

2-Chloro-N-[(1S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-6-methyl- isonicotinamide

N-[(1 S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-2-(4,5-dimethoxy-3-oxo-1 ,3- dihydro-isobenzofuran-1-yl)-acetamide

1 ^.δ.β-Tetrahydro-cyclopentapyrazole-S-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-

3-hydroxy-cyclohexyl]-amide

N-[(1 S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-3-(1 H-indol-2-yl)-propionamide

6-[(1 S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexylcarbamoyl]-pyridine-2-carboxylic acid isopropyl ester

Quinoline-6-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-amide

5-Methyl-isoxazole-4-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy- cyclohexyl]-amide Benzofuran-3-carboxylic acid [(1 S,3S)-3-(3-chloro-phenylethynyl)-3-hydroxy-cyclohexyl]- amide

N-[(1S,3S)-3-(3-Chloro-phenylethynyl)-3-hydroxy-cyclohexyl]-2-(2-methoxy-phenoxy)- acetamide.

In a further embodiment, the mGluR modulator is a compound of the formula (VI)

wherein

R¹ represents hydrogen or alkyl;

RR²² rreepprreesseennttss aann uunnssuubbssttiittuutteedd oor substituted heterocycle or

R² represents an unsubstituted or substituted aryl;

R³ represents alkyl or halogen; in free base or acid addition salt form.

Further examples of mGluR, in particular mGluR5, modulators include compounds of the formula (I) as defined in WO 2004/014881 and compounds of the formula (I) as defined in WO 2007/021575; the contents of these publications are incorporated herein by reference.

Compounds of the invention and their pharmaceutically acceptable acid addition salts, hereinafter referred to as agents of the invention, exhibit valuable pharmacological properties and are therefore useful as pharmaceuticals.

Compounds of the invention may exhibit a marked and selective modulating, especially antagonistic, action at human mGluRs, in particular mGluRδs. This can be determined in vitro for example at recombinant human metabotropic glutamate receptors, especially PLC- coupled subtypes thereof such as mGluR5, using different procedures like, for example, measurement of the inhibition of the agonist induced elevation of intracellular Ca²⁺ concentration in accordance with L. P. Daggett et al., Neuropharm. Vol. 34, pages 871-886 (1995), P. J. Flor et al., J. Neurochem. Vol. 67, pages 58-63 (1996) or by determination to what extent the agonist induced elevation of the inositol phosphate turnover is inhibited as described by T. Knoepfel et al., Eur. J. Pharmacol. Vol. 288, pages 389-392 (1994), L. P. Daggett et al., Neuropharm. Vol. 67, pages 58-63 (1996) and references cited therein. Isolation and expression of human mGluR subtypes are described in US-Patent No. 5,521 ,297. Selected agents of the invention show IC50 values for the inhibition of the agonist (e.g. glutamate or quisqualate) induced elevation of intracellular Ca2+ concentration or the agonist (e.g. glutamate or quisqualate) induced inositol phosphate turnover, measured in recombinant cells expressing hmGluR5a of about 1 nM to about 50 μM.

Compounds of the invention are useful in the treatment, prevention or delay of progression of a pervasive developmental disorder (PDD), for example, a disorder associated with the fragile X mental retardation I gene (FMR1 gene). Disorders associated with the FMR1 gene include for example Fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS).

The patient population is, in one embodiment, an adult population.

In one embodiment, the invention is for the treatment of Fragile X syndrome. Fragile X syndrome is one of the most common inherited causes of mental impairment and is almost exclusively caused by an expansion of a CGG repeat in the 5' untranslated region of the FMR1 gene, which is carried on the X chromosome. Fragile X patients typically have more than 200 CGG units that are usually hypermethylated and the methylation extends to the adjacent promoter region of the FMR1 gene. The result of this expansion is the lack of expression of the FMR1 protein, which typically leads to mental retardation in the subject. Patients suffering from Fragile X syndrome typically exhibit neurological deficits, including moderate to severe mental retardation (IQ=30-70), seizures during childhood, visual spatial defects, learning difficulties and characteristics of autism e.g. repetitive, obsessive- compulsive-like behaviours. Compounds of the invention may be useful to treat, prevent or delay the progression of one or more of the characteristics of Fragile X syndrome. In one embodiment, the invention relates to the treatment of symptoms of fragile X- associated tremor/ataxia syndrome (FXTAS). FXTAS is an adult onset neurodegenerative disorder that affects carriers, principally males, of permutation alleles (55-200 CGG repeats) of the FMR1 gene. Characteristics of FXTAS include cerebellar ataxia, intention tremor, short term memory loss, cognitive decline, executive function deficits, parkinsonism, peripheral neuropathy, lower limb proximal muscle weakness and autonomic dysfunction. Compounds of the invention may be useful to treat, prevent or delay the progression of one or more of the characteristics of FXTAS.

In one aspect of the invention, the invention relates to the treatment, prevention or delay of progression of Fragile X syndrome when not associated with mutation of the FMR1 gene, using compounds as described herein.

One class of "pervasive developmental disorders" (PDD) is a group of disorders which are characterized by qualitative impairments in social interaction and verbal and nonverbal communication as well as repetitive and stereotyped patterns of interests and behavior. Such disorders include for example autism, Asperger's Syndrome, Childhood Disintegrative Disorder, and Rett's Syndrome. The disorders included in the term "pervasive developmental disorders" may also be referred to as autism spectrum disorders (ASD).

Treatment may comprise cognitive enhancement of PDD patients e.g. Fragile X and/or FXTAS patients. The term "cognitive enhancement" includes, but is not limited to, cognition enhancement, vigilance, counteracting effects of fatigue, enhancing alertness, attention, memory (working, episodic), learning ability, reaction time, cognitive performance enhancement, excess daytime somnolence, reversal of information processing deficits, improvement of disorganization, i.e. improving organizational skills/level of organizational ability.

For the above-mentioned indications (the conditions and disorders) the appropriate dosage will vary depending upon, for example, the compound employed, the host, the mode of administration and the nature and severity of the condition being treated. However, in general, satisfactory results in animals are indicated to be obtained at a daily dosage of from about 0.01 to about 100 mg/kg body weight, preferably from about 0.1 to about 10 mg/kg body weight, e.g. 1 mg/kg. In larger mammals, for example humans, an indicated daily dosage is in the range from about 0.1 to about 1000 mg, preferably from about 1 to about 400 mg, most preferably from about 10 to about 100 mg of an mGluR, e.g. mGluR5, antagonist or other modulator conveniently administered, for example, in divided doses up to four times a day.

For use according to the invention, an mGluR modulator (e.g. an mGluR5 modulator, in particular an mGluR5 antagonist) may be administered as single active agent or in combination with other active agents, in any usual manner, e.g. orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injection solutions or suspensions.

Moreover, the present invention provides a pharmaceutical composition comprising an mGluR modulator (e.g. an mGluR5 modulator, in particular an mGluR5 antagonist) in association with at least one pharmaceutical carrier or diluent for use in the treatment of a pervasive developmental disorder e.g. disorder associated with the FMR1 gene, e.g. Fragile X syndrome. In one embodiment, the composition is for the treatment, prevention or delay of progression of Fragile X syndrome. In one embodiment, the composition is for the treatment, prevention or delay of progression of FXTAS. Such compositions may be manufactured in conventional manner. Unit dosage forms may contain, for example, from about 2.5 to about 25 mg of one or more mGluR modulator, e.g. mGluR5 antagonist or other modulator.

The usefulness of the compounds of the invention in the treatment of the above-mentioned disorders can be confirmed in a range of standard tests including those indicated below:

The pharmaceutical compositions according to the invention are compositions for enteral, such as nasal, rectal or oral, or parenteral, such as intramuscular or intravenous, administration to warm-blooded animals (human beings and animals) that comprise an effective dose of the pharmacological active ingredient alone or together with a significant amount of a pharmaceutically acceptable carrier. The dose of the active ingredient depends on the species of warm-blooded animal, body weight, age and individual condition, individual pharmacokinetic data, the disease to be treated and the mode of administration

The pharmaceutical compositions comprise from approximately 1% to approximately 95%, preferably from approximately 20% to approximately 90%, active ingredient. Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.

The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional dissolving, lyophilizing, mixing, granulating or confectioning processes. Such processes are exemplified in WO 2005/079802, WO 2003/047581 , WO 2004/000316, WO 2005/044265, WO 2005/044266, WO 2005/044267, WO 2006/114262 and WO 2007/071358

Diagnosis

During the 1970's and 1980's the test available for diagnosing fragile X syndrome was the chromosomal or cytogenetic test While it was helpful, it was not always accurate In the 1990's, two molecular DNA tests became available These are

The Southern Blot analysis -this determines if the gene has a full mutation and its approximate size, if the gene has been methylated and if there is mosaicism (a mixture of different cell types)

The polymerase chain reaction (PCR) analysis can determine the actual number of repeats in individuals with a normal size gene or with a premutation It is not the test of choice to diagnose a full mutation, but is quite accurate in determining premutation and normal gene repeat numbers

Methods for diagnosing Fragile X are known, e.g in US Patent number 6,107,025.

Fragile X can be diagnosed using the person's blood for the analysis of the FMR1 gene This DNA test, available since the gene was first identified in 1991 can detect Fragile X in normal carriers and in those affected, but it cannot tell from that analysis if the child is or will be intellectually impaired or the severity of many of the symptoms

Clinical Testing The action of mGluR modulatos, e.g. mGluR anatagonists on PDD, e.g. Fragile X, as described herein, may be conducted in the following way.

Firstly, it has been found through imaging techniques that the compounds of the present invention are able to penetrate the brain and bind to mGluR receptors, in particular mGluR5 receptors. Secondly, it has been observed that patients taking a compound, such as an mGluR modulators as described herein have shown an increase in cognition or the like.

Clinical testing of the compounds as mentioned herein may be conducted, for example, in one of the following study designs. The skilled physician may look at a number of aspects of a patients behavious and abilities. For example, to assess any effect the skilled person may look at social behaviour such as aggression or docility and social interactiveness, for example, or may look at level of eye contact of degree of face-scanning. The skilled person will of course realise that such studies are considered as guidelines and the certain aspects of the studies may be modified and redefined depending on the circumstance and environment, for example.

Clinical Design: Improvement Trials

Characteristics of Fragile X, e.g. deficits, in people include an average IQ of about 50, deficits in certain types of short-term memory, autistic behavior, sleep problems, hyperactivity, attention deficits, and susceptibility to seizures. The improvement of such deficits can be measured in clinical tests.

Trial A: Normal Patient Population

A patient population, with a normal control is dosed once a day for a week or longer and cognition is tested. The test is designed to allow for improvement, I.e. that there is a measurable parameter increase. The patients are tested at the beginning and at the end of the dosage period and the results are compared and analysed.

Trial B: Deficit population

A patient population with a deficit associated with Fragile X is dosed once a day for a week or longer and cognition is tested. The test is designed to allow for improvement, I.e. that there is a measurable parameter increase. The patients are tested at the beginning and at the end of the dosage period and the results are compared and analysed.

Exemplary parameters to test could include restored memory-dependent function, increased attention times and fewer or absence of seizures. Also measurable could be visualization of the reversal of some of the neuronal structural defects (by imaging).

Considerations for designing a trial

• When designing a trial, the skilled person will appreciate the need to protect both against floor and ceiling effects. In other words, the study designing should allow cognition to the measurably raised or lowered.

• Conditions that artificially impair a function, e.g. cognition, are one way to test enhancement of that function. Such conditions are, for example, sleep deprivation and pharmacological challenges.

• Placebo control is required for all trials.

• In assessing the data, evaluation of the likelihood of learning and practice effects from repeat assessments must be made. The likelihood of such effects contaminating the data to produce false positives should be taken in to account when designing the test, e.g. the tests should not be identical (e.g. commit the same list of words to memory) but designed to study the same mechanism. Other countermeasures may include single testing at the end of a trial only.

Claims

1 . The use of an mGluR modulator for the treatment, prevention or delay of progression of a Pervasive Developmental Disorder (PDD).

2. Use of claim 1 , wherein the PDD is a disorder associated with Fragile X mental / retardation I gene (FMR1).

3. Use according to claim 1 or claim 2, wherein the modulator is an mGluR5 modulator.

4. Use according to any preceding claim, wherein the modulator is an mGluR antagonist.

5. Use according to claim 3 or claim 4, wherein the modulator is an mGluR5 antagonist.

6. Use according to any preceding claim, wherein the modulator is a compound of the formula (I)

wherein

R³ represents halogen, alkyl, alkoxy, alkylamino or dialkylamino;

R⁴ represents hydroxy (OH), halogen, alkyl or alkoxy;

Q represents CH, CR⁴ or N;

V represents CH, CR⁴ or N; W represents CH, CR⁴ or N; X represents CH or N;

Y represents CH, CR³ or N; Z represents CH₂, NH or O; and provided that Q, V and W are not N at the same time; in free base or acid addition salt form.

7. Use according to any of claims 1 to 5, wherein the modulator is a compound of the formula (II), wherein a compound of the formula (II) is a compound of formula (I) in which at least one of Q, V and W is N, in free base or acid addition salt form.

8. Use according to any of claims 1 to 5, wherein the modulator is a compound of the formula (IV) or the formula (V):

wherein m is 0 or 1 , n is 0 or 1 and

A is hydroxy

X is hydrogen and

Y is hydrogen, or

A forms a single bond with X or with Y;

R₀ is hydrogen, (C_1-4)alkyl, (C_1-4)alkoxy, trifluoromethyl, halogen, cyano, nitro, -COOR₁ wherein R₁ is (C_1-4)alkyl or -COR₂ wherein R₂ is hydrogen or (C_1-4)alkyl, and

R is -COR₃, -COOR₃, -CONR₄R₅ Or -SO₂R₆, wherein R₃ is (C_1-4)alkyl, (C₃.₇)cycloalkyl or optionally substituted phenyl, 2-pyridyl or 2-thienyl; R₄ and R₅, independently, are hydrogen or (C_1-4)alkyl; and R₆ is (C_1-4)alkyl, (C₃.₇)cycloalkyl or optionally substituted phenyl,

R' is hydrogen or (C_1-4)alkyl and

R" is hydrogen or (C_1-4)alkyl, or

R' and R" together form a group -CH₂-(CH₂)_m- wherein m is 0, 1 or 2, in which case one of n and m is different from 0, with the proviso that Ro is different from hydrogen, trifluoromethyl and methoxy when n is 0,

A is hydroxy, X and Y are both hydrogen, R is COOEt and R' and R" together form a group

(CH₂J₂-,

OR

wherein

R¹ represents hydrogen or alkyl; represents an unsubstituted or substituted heterocycle or

R^ represents an unsubstituted or substituted aryl; R³ represents alkyl or halogen; X represents a single bond or an alkandiyl-group, optionally interrupted by one or more oxygen atoms or carbonyl groups or carbonyloxy groups; in free base or acid addition salt form.

9. Use according to any preceding claim, wherein the disorder is selected from Fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS)

10. Use according to any preceding claim, wherein the disorder is Fragile X syndrome.

1 1 . A method for the treatment, prevention or delay of progression of a Pervasive Developmental Disorder (PDD) in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of an mGluR modulator.

12. A method according to claim 11 , wherein the disorder is a disorder associated with Fragile X mental retardation I gene (FMR1)

13. . A method according to claim 11 or claim 12, wherein the mGluR modulator is as defined in any of claims 3 to 8.

14. A method according to any of claims 11 to 13, wherein the mGluR modulator is an mGluR5 modulator.

15. A method according to claim 14, wherein the mGluR modulator is an mGluR5 antagonist.

16. A method according to any of claims 11 to 15, wherein the disorder is as defined in claim 9 or claim 10.

17. A pharmaceutical composition comprising an mGluR modulator, for the treatment, prevention or delay of progression of a Pervasive Developmental Disorder.

18. A composition according to claim 17, wherein the disorder is a disorder associated with Fragile X mental retardation I gene (FMR1). .

19. A composition according to claim 17 or claim 18, wherein the mGluR modulator is as defined in any of claims 3 to 8.

20. A composition according to any of claims 17 to 19, wherein the mGluR modulator is an mGluR5 modulator.

21. A composition according to claim 19 or claim 20, wherein the mGluR modulator is an mGluR5 antagonist.

22. A composition according to any of claims 19 to 21 , wherein the disorder is selected from Fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS).

23 A kit comprising an mGluR modulator and instructions for using the modulator in the treatment, prevention or delay of progression of a Pervasive Developmental Disorder.

24. A kit according to claim 23, wherein the disorder is a disorder associated with Fragile X mental retardation I gene (FMR1). .

/

25. A kit according to claim 23 or claim 24, wherein the mGluR modulator is as defined in any of claims 3 to 8 and the disorder is as defined in claim 9 or claim 10.