HK1138271A - 3-cyano-4-(4-phenyl-piperidin-1-yl)-pyridin-2-one derivatives - Google Patents

Description

3-cyano-4- (4-phenyl-piperidin-1-yl) -pyridin-2-one derivatives

Technical Field

The present invention relates to novel pyridin-2-one derivatives which are positive allosteric modulators of the metabotropic glutamate receptor subtype 2 ("mGluR 2") and which are useful for the treatment or prevention of glutamate dysfunction and disease-related neurological and psychiatric disorders associated with the mGluR2 subtype of metabotropic receptors. The invention is also directed to pharmaceutical compositions comprising these compounds, to processes to prepare these compounds and these compositions, and to the use of these compounds for the prevention or treatment of mGluR 2-related neurological and psychiatric disorders.

Background

Glutamate is the major amino acid neurotransmitter in the mammalian central nervous system. Glutamate plays an important role in many physiological functions, such as learning and memory, as well as in the development of sensory perception, synaptic plasticity, motor control, respiration, and cardiovascular and cerebrovascular function regulation. In addition, glutamate is key to a number of different neurological and psychiatric disorders in which there is an imbalance in glutamatergic neurotransmission.

Glutamate mediates synaptic neurotransmission through ionotropic glutamate receptor channels (iglurs) and activation of NMDA, AMPA and kainate receptors responsible for fast excitatory transmission.

In addition, glutamate activates metabotropic glutamate receptors (mGluR), which have greater modulatory effects that facilitate fine-tuning of synaptic efficacy.

Glutamate enables activation of mglurs by binding to the large extracellular amino-terminal domain of the receptor, referred to herein as the orthosteric binding site. This binding induces conformational changes in the receptor that result in the activation of G-proteins and intracellular signaling pathways.

The mGluR2 subtype binds inversely to adenylate cyclase through activation of G α i-protein, and its activation leads to inhibition of glutamate release in the synapse. In the Central Nervous System (CNS), mGluR2 receptors are mainly concentrated in the cortex, thalamic regions, accessory olfactory bulb, hippocampus, amygdala, caudate putamen and nucleus accumbens.

Activation of mGluR2 has been shown in clinical trials to be effective in the treatment of anxiety disorders. In addition, activation of mGluR2 has been shown to be effective in a variety of animal models, thus representing a potential new therapeutic approach for the treatment of schizophrenia, epilepsy, addiction/drug dependence, parkinson's disease, pain, sleep disorders and huntington's disease.

To date, the most effective pharmacological approaches to mGluR are ortho ligands, which, because they are structural analogues of glutamate, are capable of activating multiple members of the family.

A new approach for the development of selective compounds acting at mglurs is to identify compounds acting through an allosteric mechanism that modulate the receptor by binding to a site different from the well-recognized orthosteric binding site.

Recently, positive allosteric modulators of mglurs have emerged as new alternative pharmacological entities offering this attraction. As a positive allosteric modulator of mGluR2, a variety of compounds have been described.

WO2004/092135(NPS & Astra Zeneca), WO2004/018386, WO2006/014918 and WO2006/015158(Merck), WO2001/56990(Eli Lilly) and WO2006/030032(Addex & Janssen Pharmaceutica) describe the use of phenylsulfonamide, acetophenone, indanone, pyridylmethyl sulfonamide and pyridone derivatives, respectively, as mGluR2 positive allosteric modulators. None of the specifically disclosed compounds are structurally related to the compounds of the present invention.

WO2007/104783 describes 1, 4-disubstituted 3-cyano-pyridone derivatives which are positive allosteric modulators of the metabotropic receptor subtype 2 ("mGluR 2").

These compounds have been shown to be unable to activate the receptor themselves. Rather, they are capable of maximizing the response of the receptor to glutamate concentration by producing minimal responses by themselves. Mutational analysis has clearly shown that binding of the positive allosteric modulators of mGluR2 does not occur at the orthosteric site, but rather at an allosteric site located in the seven transmembrane domain of the receptor.

Both animal data indicate that positive allosteric modulators of mGluR2 have effects on anxiety and mental models, similar to those obtained with orthosteric agonists. Allosteric modulators of mGluR2 have been shown to be effective in fear-enhanced startle and stress-induced hyperthermia models of anxiety (anxiety). Furthermore, these compounds show an effect on the reversal of ketamine-induced or amphetamine-induced rapid locomotor activity and on the amphetamine-induced reversal of schizophrenia by prepulse inhibition of the acoustic startle effect model (J.Pharmacol. Exp. Ther.2006, 318, 173-doped 185; Psychotopharmacol 2005, 179, 271-doped 283) of schizophrenia.

Recent animal studies further suggest that selective positive modulators of the metabotropic glutamate receptor subtype 2 diphenyl indanone (BINA) prevent the hallucinogenic drug model of psychosis, supporting the hypothesis that mGluR2 receptors are useful for the treatment of glutamate dysfunction in schizophrenia (moi. pharmacol.2007, 72, 477-.

Positive allosteric modulators result in enhanced glutamate responses, but they have also been shown to enhance responses to orthotopic mGluR2 agonists such as LY379268 or DCG-IV. These data provide evidence for yet another novel therapeutic approach to treat the above mentioned neurological and psychiatric disorders associated with mGluR2, which would use a combination of a positive allosteric modulator of mGluR2 together with an orthosteric agonist of mGluR 2.

The compounds of the present invention are characterized by a central pyridin-2-one moiety substituted at the 3-position with cyano and at the 4-position with piperidin-1-yl, wherein the piperidin-1-yl group is itself substituted at the 4-position with phenyl. The compounds of the present invention are potent positive allosteric mGluR2 modulators.

Disclosure of Invention

The present invention relates to compounds having metabotropic glutamate receptor 2 modulator activity. The present invention provides a compound represented by the general formula (I),

including any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein R₁Is C_4～6Alkyl or C_3～7Cycloalkyl-substituted C_1～3An alkyl group;

R₂is hydrogen; fluorine; hydroxy-substituted C_1～4An alkyl group; fluorine substituted C_1～4An alkyl group; or fluorine substituted C_1～4An alkoxy group.

The invention also relates to the use of a compound of formula (I) or any subgroup thereof for the manufacture of a medicament for the treatment or prevention, in particular treatment of a disease in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, in particular positive allosteric modulators thereof.

One embodiment of the invention is a compound of formula (I),

including any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein

R₁Is C_4～6Alkyl, or C_3～7Cycloalkyl-substituted C_1～3An alkyl group;

R₂is hydrogen; fluorine; hydroxy-substituted C_1～4An alkyl group; fluorine substituted C_1～4An alkyl group; or fluorine substituted C_1～4An alkoxy group.

As long as the compound is not

And

one embodiment of the present invention are compounds of formula (I) wherein R₁Is C_4～6Alkyl, especially C_4～5Alkyl groups such as 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl; in particular 1-butyl.

One embodiment of the present invention are compounds of formula (I) wherein R₁Is C_3～7Cycloalkyl-substituted C_1～3Alkyl, in particular cyclopropylmethyl or 2- (cyclopropyl) -1-ethyl.

An embodiment of the invention is a compound of formula (I) or any subgroup thereof previously mentioned as embodiments, wherein R₂Is hydrogen.

An embodiment of the invention is a compound of general formula (I) or, whenever possible, any subgroup thereof preceding as embodiment wherein R₂Is fluorine; hydroxy-substituted C_1～4An alkyl group; fluorine substituted C_1～4An alkyl group; or fluorine substituted C_1～4An alkoxy group.

An embodiment of the invention is a compound of general formula (I) or, whenever possible, any subgroup thereof preceding as embodiment wherein R₂Is hydrogen; fluorine; or fluorine substituted C_1～4An alkoxy group; in particular R₂Is fluorine or fluorine substituted C_1～4An alkoxy group.

An embodiment of the present invention is a compound of formula (I), or any subgroup thereof previously mentioned as embodiments, wherein R₂Is fluorine.

An embodiment of the invention is a compound of general formula (I) or, whenever possible, any subgroup thereof preceding as embodiment wherein R₂Is hydroxy-substituted C_1～4Alkyl, especially wherein R₂Is a hydroxy-substituted methyl group.

An embodiment of the invention is a compound of general formula (I) or, whenever possible, any subgroup thereof preceding as embodiment wherein R₂Is fluorine substituted C_1～4Alkyl, especially wherein R₂Is a fluoro-substituted methyl group.

An embodiment of the invention is a compound of general formula (I) or, whenever possible, any subgroup thereof preceding as embodiment wherein R₂Is fluorine substituted C_1～4Alkoxy, especially wherein R₂Is a fluorine substituted ethoxy group.

One embodiment of the present invention is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is₁Is C_4～6Alkyl, in particular 1-butyl or 3-methyl-1-butyl; or is C_{3～ 7}Cycloalkyl-substituted C_1～3Alkyl, especially cyclopropylmethyl; r₂Is hydrogen; fluorine; hydroxy-substituted C_{1～ 4}Alkyl, especially hydroxy-substituted methyl; fluorine substituted C_1～4Alkyl, especially fluoro-substituted methyl; or fluorine substituted C_1～4Alkoxy, in particular fluorine-substituted ethoxy.

One embodiment of the present invention is a compound of formula (I) selected from the group consisting of,

or a pharmaceutically acceptable salt or solvate thereof.

One embodiment of the present invention is a compound of formula (I) selected from the group consisting of,

or a pharmaceutically acceptable salt or solvate thereof.

Expression C as used in the context_1～3The alkyl group as a group or a partial group defines a saturated straight-chain or branched-chain hydrocarbon group having 1 to 3 carbon atoms, such as methyl, ethyl, 1-propyl and 1-methyl-1-ethyl.

Expression C as used in the context_1～4The alkyl group defines, as a radical or as a partial radical, a saturated, linear or branched hydrocarbon radical having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methyl-1-ethyl, 1-butyl, 2-methyl-1-propyl. Preferably, C_1～4Alkyl represents methyl.

Expression C as used in the context_4～6The alkyl group defines a saturated straight-chain or branched-chain hydrocarbon group having 4 to 6 carbon atoms as a group or a partial group, and examples thereof include 1-butyl group, 2-methyl-1-propyl group, 1-pentyl group, 2-methyl-1-butyl group, 3-methyl-1-butyl group, and 1-hexyl group.

Expression C as used in the context_4～5Alkyl defines as a radical or part of a radical a saturated straight-chain or branched hydrocarbon radical having 4 or 5 carbon atoms, such as 1-butyl, 2-methyl-1-propyl, 1-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, etc.

Expression C as used in the context_3～7Cycloalkyl as a radical or part of a radical defines a saturated cyclic hydrocarbon radical having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferably, C_3～7Cycloalkyl represents cyclopropyl.

For therapeutic use, salts of the compounds of formula (I) are those in which the counterion is pharmaceutically acceptable. However, also find use in salts of acids and bases which are not pharmaceutically acceptable, for example in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the invention.

Pharmaceutically acceptable salts are defined to include the therapeutically active non-toxic acid addition salt forms which the compounds according to formula (I) may form. The salts are obtainable by treating the base form of the compounds according to formula (I) with a suitable acid, for example an inorganic acid, such as hydrohalic acids, in particular hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids such as acetic acid, glycolic acid, propionic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, and pamoic acid.

Instead, the acid salt form can be converted to the free base form by treatment with a suitable base.

Compounds according to formula (I) comprising an acid proton may also be converted into their therapeutically active non-toxic base salt forms by treatment with suitable organic and inorganic bases. Suitable base salt forms include, for example, ammonium, alkali metal and alkaline earth metal salts, particularly lithium, sodium, potassium, magnesium and calcium salts; salts with organic bases, such as benzathine, N-methyl-D-glucamine, hydroxyalkylamine (hybramine) salts; and salts with amino acids, such as arginine and lysine.

Instead, the base salt form can be converted to the free acid form by treatment with a suitable acid.

Pharmaceutically acceptable acid addition salt forms of the compounds of the general formula (I) are the preferred pharmaceutically acceptable salt forms of the compounds of the general formula (I).

The term solvate includes the addition forms of the solvent which the compound of formula (I) is able to form and the pharmaceutically acceptable salt forms thereof. Examples of such solvent addition forms are, for example, hydrates, alcoholates and the like.

It will be appreciated that some compounds of formula (I) and salts and solvates thereof may contain one or more chiral centers and exist as stereochemically isomeric forms.

The term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric forms which the compounds of general formula (I) may possess. Unless otherwise specified or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. The invention also covers each individual isomeric form of formula (I) and salts or solvates thereof, substantially free of other isomers, i.e. with less than 10%, preferably less than 5%, particularly less than 2%, and most preferably less than 1% of other isomers. Thus, for example, when a compound of formula (I) is defined as (R), this means that the compound is substantially free of the (S) isomer.

Specifically, the stereogenic center may contain the R-or S-configuration; the substituents on the divalent cyclic (partially) saturated radicals may have cis-or trans-configuration.

According to CAS nomenclature rules, when two stereogenic centers of known absolute configuration are present in a compound, the R or S label (based on Cahn-Ingold-Prelog sequence rules) is on the least numbered chiral center, the reference center. The configuration of the second three-dimensional Gene center is marked with a relative marker [ R ]^*，R^*]Or [ R ]^*，S^*]Is represented by the formula (I) in which R^*Always designated as the reference center, and [ R^*，R^*]Represents a center of the same chirality, [ R ]^*，S^*]Representing centers of different chirality. For example, if the least numbered chiral center in a compound has the S configuration and the second center is R, the stereogenic label should be designated S- [ R ]^*，S^*]. If "α" and "β" are used: the position of the most preferred substituent on the asymmetric carbon atom having the smallest ring number in the ring system is always variably located at the "α" position of the average plane defined by the ring system. The position of the most preferred substituent on the other asymmetric carbon atom in the ring system (hydrogen atom in the compound according to formula (I)) relative to the position of the most preferred substituent of the reference atom is marked "α" if it is located on the same side of the average plane defined by the ring system; or "β" if it is located on the other side of the plane defined by the ring system.

Whenever used hereinafter, the term "compounds of general formula (I)" or any subgroup thereof is meant to also include their stereochemically isomeric forms, their pharmaceutically acceptable salts and solvates thereof. Those compounds of the general formula (I) which are stereochemically pure are of particular interest.

In the structures of the present application, an element, particularly when described in relation to a compound according to formula (I), includes all isotopes and isotopic mixtures of that element, whether naturally occurring or synthetically produced, whether in natural abundance or in isotopically enriched form. In particular, when hydrogen is mentioned, it is understood to mean¹H、²H、³H or mixtures thereof; when carbon is mentioned, it is understood to mean¹¹C、¹²C、¹³C、¹⁴C or mixtures thereof; when nitrogen is mentioned, it is understood to mean¹³N、¹⁴N、¹⁵N or mixtures thereof; when referring to oxygen, it is understood to mean¹⁴O、¹⁵O、¹⁶O、¹⁷O、¹⁸O or mixtures thereof; when fluorine is mentioned, this is understood to mean¹⁸F、¹⁹F or mixtures thereof. Thus, the compounds according to the invention also include compounds having one or more isotopes of one or more elements and mixtures thereof, including radioactive compounds, also known as radiolabelled compounds, in which one or more non-radioactive atoms is substituted by one of its radioisotopes. In particular, the radioactive atom is selected from the group of hydrogen, carbon, nitrogen, sulfur, oxygen and halogen. Preferably, the radioactive atom is selected from the group of hydrogen, carbon and halogen. In particular, the radioactive isotope is selected from³H、¹¹C、¹⁸F、¹²²I、¹²³I、¹³¹I、⁷⁵Br、⁷⁶Br、⁷⁷Br and⁸²group of Br. Preferably the radioisotope is selected from³H、¹¹C and¹⁸group F.

Whenever used in context, substituents may each be independently selected from a series of definitions, encompassing all possible combinations that are chemically possible.

In general, the compounds of formula (I) can be prepared according to the following experimental procedures 1 to 4.

Experimental procedure 1

According to reaction scheme (1), the compounds of formula (I) can be prepared by reacting an intermediate of formula (II) wherein Y represents a suitable leaving group, e.g. F, with an intermediate of formula (III)₃C-S(＝O)₂O-or halogen, such as bromine, etc. The reaction can be carried out under the following conditions: in a suitable reaction-inert solvent, such as dimethoxyethane or acetonitrile; in the presence of a suitable base, e.g. Cs₂CO₃Or N, N-diisopropylA phenylethylamine; the reaction mixture is heated under thermal conditions, for example microwave radiation at 150 ℃ for 15 minutes.

The reaction described in reaction scheme (1) can also be carried out under the following conditions: in a suitable reaction-inert solvent, such as 1, 4-dioxane; in the presence of a suitable base, e.g. K₃PO₄An aqueous solution; suitable catalysts, e.g. Pd complex catalysts, e.g.The reaction mixture is heated under thermal conditions, for example at 80 ℃ for 12 hours.

In the reaction scheme (1), all variables are as defined in the general formula (I).

Reaction scheme (1)

Experimental Process 2

A compound of the general formula (I) (wherein R₂Represents fluorine substituted C_1～4Alkyl radical, said C_1～4The alkyl group is represented by L and the compound is represented by the general formula (I-a) can be represented by a compound of the general formula (I) (wherein R is₂Represents hydroxy-substituted C_1～4Alkyl group, represented by the general formula (I-b) with a compound such as (diethylamino) sulfur trifluoride [ CAS: 38078-09-0]And the like, by reaction with a suitable fluorinating agent. The reaction can be carried out under the following conditions: in a suitable reaction-inert solvent, such as dichloromethane; at moderately low temperatures, for example, in the temperature range of-78 ℃ to 30 ℃; for example, the reaction is carried out for 0.5 to 12 hours.

In the reaction scheme (2), all variables are as defined in the general formula (I).

Reaction scheme (2)

Experimental procedure 3

The compounds of formula (I) can be prepared by reacting an intermediate of formula (IV) wherein R is R with a suitable fluorinating agent such as (diethylamino) sulfur trifluoride₂Represents fluorine, said compound being represented by general formula (I-c). The reaction can be carried out under the following conditions: in a suitable reaction-inert solvent, such as dichloromethane; at moderately low temperatures, for example, in the temperature range of-78 ℃ to 30 ℃; for example, the reaction is carried out for 0.5 to 12 hours.

In the reaction scheme (3), all variables are as defined in the general formula (I).

Reaction scheme (3)

Experimental procedure 4

According to reaction scheme (4), the compounds of general formula (I) can be prepared by hydrogenating intermediates of general formula (XIV) wherein R is₂Represents fluorine substituted C_1～4Alkoxy radical, the said R₂From R'₂The compound is represented by the general formula (I-d). The reaction can be carried out under the following conditions: in a suitable solvent such as an alcohol, e.g. methanol; in the presence of a suitable catalyst, such as palladium on activated carbon; and a suitable base such as triethylamine. In the reaction scheme (4), all variables are as defined in the general formula (I).

Reaction scheme (4)

The compounds of formula (I) and some of the intermediates of the present invention may contain asymmetric carbon atoms. Pure stereochemically isomeric forms of said compounds and of said intermediates may be prepared by methods known in the art. For example, diastereomers may be separated by physical methods such as selective crystallization or chromatographic techniques, e.g., counter-current distribution, chiral liquid chromatography, and the like. Enantiomers can be prepared from racemic mixtures by first converting the racemic mixture into a mixture of diastereomeric salts or compounds with a suitable resolving agent, for example a chiral acid; the mixture of diastereomeric salts or compounds is then physically separated by methods such as selective crystallization or chromatographic techniques, e.g., liquid chromatography; and finally converting said separated non-corresponding isomeric salt or compound into the corresponding enantiomer. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intermediate reactions occur stereospecifically.

Alternative methods of separating the enantiomeric forms of the compounds of formula (I) and intermediates include liquid chromatography or SCF (supercritical fluid) chromatography, particularly using a chiral stationary phase.

Some intermediates and starting materials are known compounds and are commercially available or can be prepared according to methods known in the art.

These intermediates can also be prepared according to the following experimental procedures 5-13.

Experimental procedure 5

According to reaction scheme (5), intermediates of formula (II) can be prepared by reacting intermediates of formula (V) with compounds such as P (═ O) Br₃And the like, in formula (II), Y represents halogen, and the intermediate is represented by formula (II-a). The reaction can be carried out inThe following conditions were used: in a suitable reaction-inert solvent, such as DMF; at moderately elevated temperatures, for example 110 ℃. In the reaction scheme (5), all variables are as defined in the general formula (I).

Reaction scheme (5)

Experimental procedure 6

According to reaction scheme (6), intermediates of general formula (II) can be prepared by reacting an intermediate of general formula (V) wherein Y represents F with trifluoromethanesulfonic anhydride (also known as trifluoromethanesulfonic anhydride)₃C-S(＝O)₂-O-, said intermediate being represented by the general formula (II-b). The reaction can be carried out under the following conditions: in a suitable reaction-inert solvent, such as dichloromethane; in the presence of a suitable base, such as pyridine; at low temperatures, for example-78 ℃. In the reaction scheme (6), all variables are as defined in the general formula (I).

Reaction scheme (6)

Experimental procedure 7

According to reaction scheme (7), intermediates of formula (V) can be prepared by reacting intermediates of formula (VI) with a reagent for the cleavage of dimethyl ether, such as NaOH, using methods known in the art. The reaction can be carried out under the following conditions: in a suitable solvent, such as water; at moderately elevated temperatures, for example 100 ℃. In the reaction scheme (7), all variables are as defined in the general formula (I).

Reaction ofSchematic diagram (7)

Experimental procedure 8

According to reaction scheme (8), intermediates of general formula (VI) can be prepared by reacting commercially available 4-methoxy-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile with an alkylating agent of general formula (VII) wherein Z represents a suitable leaving group such as halogen, e.g. bromine, etc., using methods known in the art. An example of an alkylating agent of general formula (VII) is for example cyclopropylmethyl bromide. The reaction can be carried out under the following conditions: in an inert solvent, such as acetonitrile; with a suitable base, e.g. K₂CO₃Or K₂CO₃And iodonium salts, such as KI; at moderately elevated temperatures, for example 120 ℃. In the reaction scheme (8), all variables are as defined in the general formula (I).

Reaction scheme (8)

Experimental procedure 9

According to scheme (9), intermediates of formula (III) can be prepared by deprotecting the piperidine nitrogen of the intermediates by methods known in the art, in formula (VIII) X represents a suitable protecting group for the piperidine derivative nitrogen atom, such as tert-butoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzyl and methyl. For example, when X represents benzyl, then the deprotection reaction can be carried out under the following conditions: in a suitable solvent such as alcohols, e.g. methanol and 1, 4-cyclohexadiene; in the presence of a suitable catalyst, such as palladium on charcoal; at moderately elevated temperatures, for example 100 ℃. For example, when X represents an ester, the deprotection reaction may be carried out by reaction with a suitable acid such as hydrochloric acid in a suitable solvent such as dioxane. In the reaction scheme (9), all variables are as defined in the general formula (I).

Reaction scheme (9)

Experimental process (10)

According to reaction scheme (10), step (a), intermediates of formula (III) can be prepared by contacting an intermediate of formula (IX) with a compound such as (diethylamino) sulfur trifluoride [ CAS: 38078-09-0]Prepared by reaction of a suitable fluorinating agent to give an intermediate of the general formula (X) in which R is₂Represents fluorine or fluorine substituted C_1～4Alkyl radical, said R₂from-L₁-F represents wherein L₁Represents C_{1～ 4}An alkyl group or a covalent bond, and the intermediate is represented by the general formula (III-a); in formula (IX), X is a suitable protecting group for the nitrogen atom of the piperidine moiety, for example tert-butyloxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzyl and methyl. The reaction can be carried out under the following conditions: in a suitable reaction-inert solvent, such as dichloromethane; at moderately low temperatures, for example, in the temperature range of-78 ℃ to 30 ℃; for example, the reaction is carried out for 0.5 to 12 hours. The intermediates of general formula (X) obtained according to step (b) of reaction scheme (10) can be converted into intermediates of general formula (III-a) by deprotecting the piperidine nitrogen in the intermediates using methods known in the art, such as the method described above in Experimental procedure 9. In the reaction scheme (10), all variables are as defined in the general formula (I).

Reaction scheme (10)

Experimental process (11)

According to reaction scheme (11), step (a), intermediates of formula (III) can be prepared by reacting a hydroxy-substituted intermediate of formula (XI) with a compound such as (diethylamino) sulfur trifluoride [ CAS: 38078-09-0]Prepared by reaction with a suitable fluorinating agent to give an intermediate of the general formula (XII) in which R is₂Represents fluorine substituted C_1～4Alkoxy radical, said C_1～4Alkoxy is represented by the general formula Q, R₂Represented by-Q-F and said intermediates represented by the general formula (III-b), in the general formula (XI) X represents a suitable protecting group for the nitrogen atom of the piperidine moiety, for example tert-butoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzyl and methyl. The reaction can be carried out under the following conditions: in a suitable reaction-inert solvent, such as dichloromethane; at moderately low temperatures, for example, in the temperature range of-78 ℃ to 30 ℃; for example, the reaction is carried out for 0.5 to 12 hours. The intermediates of formula (XII) obtained according to step (b) of reaction scheme (11) may be converted to intermediates of formula (III-b) by deprotection of the piperidine nitrogen using methods known in the art, such as the method described above in Experimental procedure 9. In the reaction scheme (11), all variables are as defined in the general formula (I).

Reaction scheme (11)

Experimental procedure 12

According to reaction scheme (12), intermediates of formula (IX) wherein L is prepared by reacting intermediates of formula (XIII) with a suitable reducing agent such as lithium aluminium hydride₁Represents CH₂In said, inThe intermediate is represented by the general formula (IX-a); in formula (XIII), X represents a suitable protecting group for the nitrogen atom of the piperidine moiety, for example tert-butyloxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl, benzyl and methyl. The reaction can be carried out under the following conditions: in a suitable solvent, such as tetrahydrofuran; at moderately low temperatures, for example-20 ℃.

In the reaction scheme (12), all variables are as defined in the general formula (I).

Reaction scheme (12)

Experimental procedure 13

According to scheme (13), intermediates of formula (XIV) can be reacted with fluoro C via intermediates of formula (XV)_1～4Alkyl-4-tosylate. The reaction may be carried out in the presence of NaH in a suitable solvent such as DME.

In reaction scheme (13), all variables are as defined in formula (I) and R'₂As defined above.

Reaction scheme (13)

Intermediates of formula (IV) and formula (XV) also exhibit activity as positive allosteric mGluR2 modulators. The invention therefore also relates to a compound of the general formula (I').

Including any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein

R₁Is C_4～6Alkyl, especially 1-butyl; or C_3～7Cycloalkyl-substituted C_1～3Alkyl, especially cyclopropylmethyl;

R₃is hydrogen or halogen; in particular hydrogen, fluorine or chlorine.

One embodiment of the present invention are compounds of formula (I') wherein R₁Is C_4～6Alkyl, especially C_4～5Alkyl groups such as 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl; in particular 1-butyl.

One embodiment of the present invention are compounds of formula (I') wherein R₁Is C_3～7Cycloalkyl-substituted C_1～3Alkyl, in particular cyclopropylmethyl or 2- (cyclopropyl) -1-ethyl.

An interesting embodiment of the compounds of formula (I') is that wherein R is₃A compound which is hydrogen.

An interesting embodiment of the compounds of formula (I') is that wherein R is₃Are halogen, in particular chlorine or fluorine.

An interesting embodiment of the compounds of formula (I') is that wherein R is₁Is 1-butyl or cyclopropylmethyl and R₂Is a compound of hydrogen, fluorine or chlorine.

The compound of the general formula (I') is, for example, the following compound or a pharmaceutically acceptable salt or solvate thereof.

The compounds of formula (I') may be prepared as hereinbefore described to prepare intermediates of formula (IV) or formula (XV). Reference is also made to example a13 below.

The invention also relates to the use of a compound of formula (I') or any subgroup thereof in the manufacture of a medicament for the treatment or prevention, in particular treatment of a disease in a mammal, including a human, which treatment or prevention is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, in particular positive allosteric modulators.

Since the compounds of formula (I) and formula (I ') are both positive allosteric mGluR2 modulators, the invention also relates to compounds of formula (I'),

including any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein

R₁Is C_4～6Alkyl, or C_3～7Cycloalkyl-substituted C_1～3An alkyl group;

R₂is hydrogen; a hydroxyl group; fluorine; hydroxy-substituted C_1～4An alkyl group; fluorine substituted C_1～4An alkyl group; fluorine substituted C_1～4An alkyl group; or fluorine substituted C_1～4An alkoxy group;

R₃is hydrogen or halogen;

if R is₃Is halogen, then R₂Is a hydroxyl group.

One embodiment of the present invention are compounds of the general formula (I'), wherein R₁Is C_4～6Alkyl, especially C_4～5Alkyl groups such as 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl; in particular 1-butyl.

One embodiment of the present invention are compounds of the general formula (I'), wherein R₁Is C_3～7Cycloalkyl-substituted C_1～3Alkyl, in particular cyclopropylmethyl or 2- (cyclopropyl) -1-ethyl.

An embodiment of the present invention is a compound of formula (I'), or any subgroup thereof previously mentioned as embodiments, wherein R₂Is hydrogen.

An embodiment of the present invention is a compound of the general formula (I'), or any subgroup thereof as embodiments hereinbefore described, where R is R, where possible₂Is fluorine; hydroxy-substituted C_1～4An alkyl group; fluorine substituted C_1～4An alkyl group; or fluorine substituted C_1～4An alkoxy group.

An embodiment of the present invention is a compound of the general formula (I'), or any subgroup thereof as embodiments hereinbefore described, where R is R, where possible₂Is hydrogen; fluorine; or fluorine substituted C_1～4An alkoxy group; in particular R₂Is fluorine or fluorine substituted C_1～4An alkoxy group.

An embodiment of the present invention is a compound of formula (I'), or any subgroup thereof previously mentioned as embodiments, wherein R₂Is fluorine.

An embodiment of the present invention is a compound of the general formula (I'), or any subgroup thereof as embodiments hereinbefore described, where R is R, where possible₂Is hydroxy-substituted C_1～4Alkyl, especially wherein R₂Is a hydroxy-substituted methyl group.

An embodiment of the present invention is a compound of the general formula (I'), or any subgroup thereof as embodiments hereinbefore described, where R is R, where possible₂Is fluorine substituted C_1～4Alkyl, especially wherein R₂Is a fluoro-substituted methyl group.

An embodiment of the present invention is a compound of the general formula (I'), or any subgroup thereof as embodiments hereinbefore described, where R is R, where possible₂Is fluorine substituted C_1～4Alkoxy radicals, especiallyIn which R is₂Is a fluorine substituted ethoxy group.

An embodiment of the present invention is a compound of the general formula (I'), or any subgroup thereof as embodiments hereinbefore described, where R is R, where possible₂Is a hydroxyl group.

The invention also relates to the use of a compound of formula (I ") or any subgroup thereof in the manufacture of a medicament for the treatment or prevention, in particular treatment of a disease in a mammal, including a human, which treatment or prevention is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, in particular positive allosteric modulators.

Pharmacology of

The compounds provided by the present invention are positive allosteric modulators of metabotropic glutamate receptors, in particular they are positive allosteric modulators of mGluR 2. The compounds of the invention appear not to bind to the glutamate recognition site, the vicinal ligand site, but to an allosteric site in the heptatransmembrane domain of the receptor. The compounds of the invention enhance mGluR2 responses in the presence of glutamate or agonists of mGluR 2. The compounds provided by the present invention should have an effect on mGluR2 by virtue of their ability to enhance the response of these receptors to glutamate or mGluR2 agonists, thereby enhancing receptor response. The present invention therefore relates to the use of a compound according to the invention as a pharmaceutical product and to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment or prevention, in particular for the treatment of a disease in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, in particular positive allosteric modulators. The invention also relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment or prevention, especially the treatment of a disease in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, especially positive allosteric modulators. The invention also relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment or prevention, especially the treatment of a disease in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, especially positive allosteric modulators.

Furthermore, the present invention relates to the use of a compound according to the present invention or a pharmaceutical composition according to the present invention for the manufacture of a medicament for the treatment, prevention, amelioration, control or reduction of risk of various neurological and psychiatric disorders in mammals, including humans, associated with glutamate dysfunction, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of positive allosteric modulators of mGluR 2.

Where the invention is said to relate to the use of a compound or composition according to the invention for the manufacture of a medicament for the treatment of, for example, a mammal, it is to be understood that such use is to be interpreted in certain jurisdictions as a method of treatment of, for example, a mammal, including, for example, where such treatment is desired, administering to the mammal an effective amount of a compound or composition according to the invention.

In particular, neurological and psychiatric disorders associated with glutamate dysfunction include one or more of the following conditions or diseases: acute neurological and psychiatric disorders such as cardiac bypass surgery and transplantation, stroke, cerebral ischemia, spinal cord injury, brain injury, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal injury, dementia (including aids-induced dementia), alzheimer's disease, huntington's chorea, amyotrophic lateral sclerosis, vision impairment, retinopathy, cognitive disorders, congenital and drug-induced parkinson's disease, muscle spasms and disorders associated with muscle spasticity including tremors, epilepsy, convulsions, migraine (including migraine), urinary incontinence, substance tolerance, substance withdrawal (including substances such as opiates, nicotine, smoking products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder, and obsessive compulsive disorder), mood disorders (including depression, anxiety, depression, spasticity, and obsessive compulsive disorder), and the like, Mania, bipolar disorder), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, cerebral edema, pain (including acute and chronic states, severe pain, intractable pain, neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleep disorders (including narcolepsy), attention/hyperactivity disorders, and brain deficits following conduct disorder.

In particular, the present invention relates to the use of a compound of general formula (I) for the manufacture of a medicament for the treatment or prophylaxis, in particular for the treatment of central nervous system disorders, wherein the central nervous system disorder is selected from the group of anxiety disorders, psychotic disorders, personality disorders, substance-related disorders, eating disorders, mood disorders, migraine, epilepsy or convulsive disorders, childhood disorders, cognitive disorders, neurodegeneration, neurotoxicity and ischemia. Preferably, the central nervous system disorder is an anxiety disorder selected from the group of agoraphobia, Generalized Anxiety Disorder (GAD), Obsessive Compulsive Disorder (OCD), panic disorder, Post Traumatic Stress Disorder (PTSD), social phobia and other phobias.

Preferably, the central nervous system disorder is a psychotic disorder selected from the group of schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder and substance-induced psychotic disorder.

Preferably the central nervous system disorder is a personality disorder selected from the group of obsessive-compulsive personality disorder and schizoid personality, schizotypal personality disorder.

Preferably the central nervous system disorder is a substance-related disorder selected from the group of alcohol abuse, alcohol dependence, alcohol withdrawal delirium, alcohol-induced psychotic disorder, amphetamine dependence, amphetamine withdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence, nicotine withdrawal, opioid dependence and opioid withdrawal.

Preferably, the central nervous system disorder is an eating disorder selected from the group of anorexia nervosa and bulimia nervosa.

Preferably the central nervous system disorder is a mood disorder selected from the group of bipolar disorders (I & II), cyclothymic disorder, depression, dysthymic disorder, major depression and substance-induced mood disorder.

Preferably, the central nervous system disorder is epilepsy or a convulsive disorder selected from the group of generalized non-convulsive epilepsy, generalized convulsive epilepsy, petit mal epilepsy, grand mal epilepsy, conscious or unconscious lesional epilepsy, infantile spasms, epilepsy partialis continua and other forms of epilepsy.

Preferably the central nervous system disorder is attention deficit/hyperactivity disorder.

Preferably the central nervous system disorder is a cognitive disorder selected from the group of delirium, substance-induced persisting delirium, dementia due to HIV disease, dementia due to huntington disease, dementia due to parkinson disease, dementia of the alzheimer type, substance-induced persisting dementia and mild cognitive disorder.

Of the above diseases, the treatment of anxiety, schizophrenia, migraine, depression and epilepsy are of particular value.

Currently, the fourth edition of the American psychiatric Association of the Diagnostic & Statistical Manual of mental Disorders (DSM-IV) provides a Diagnostic tool for the definitive diagnosis of the disease described herein. It will be appreciated by those skilled in the art that there are alternative names, disease taxonomies and classification systems for neurological and psychiatric disorders described herein, and that these will evolve with medical and scientific advances.

Since positive allosteric modulators of mGluR2, including compounds of formula (I), enhance the response of mGluR2 to glutamate, an advantage is that the method uses endogenous glutamate.

Because positive allosteric modulators of mGluR2 comprising a compound of formula (I) enhance the response of mGluR2 to agonists, it will be appreciated that the invention extends to the treatment of neurological and psychiatric disorders associated with glutamate dysfunction by the administration of an effective amount of a positive allosteric modulator of mGluR2 comprising a compound of formula (I) in combination with an mGluR2 agonist.

The compounds of the present invention may be used in combination with one or more other pharmaceutical agents in the treatment, prevention, control, amelioration, or reduction of the risk of a disease or condition for which the compound of formula (I) or the other pharmaceutical agent is effective, provided that the combination of the pharmaceutical agents is safer or more effective than the pharmaceutical agent itself.

Pharmaceutical composition

The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, a therapeutically effective dose of a compound according to the invention, in particular a compound according to formula (I), including stereochemically isomeric forms thereof, or a pharmaceutically acceptable salt or solvate thereof.

The compounds according to the invention, in particular the compounds according to general formula (I), including stereochemically isomeric forms thereof, or a pharmaceutically acceptable salt or solvate thereof, or any subgroup or combination thereof, may be formulated for administration in a variety of pharmaceutical forms. Suitable compositions include all compositions which are customarily used for systemic administration.

To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier or diluent, which carrier or diluent may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are ideally in single dose form and are particularly suitable for oral, rectal or transdermal administration by injection of injectable drugs or by inhalation. For example, in preparing the compositions in oral dosage form, conventional pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions, and solutions; or in the case of powders, pills, capsules and tablets, solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like may be employed. Oral administration is preferred for ease of administration, and tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For injectable pharmaceutical compositions, the carrier will usually comprise at least a major proportion of sterile water, although other components may be included, for example to aid solubility. For example, injectable solutions may be prepared in which the carrier comprises saline, dextrose solution, or a mixture of saline and dextrose solution. Injectable solutions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. In formulations suitable for transdermal administration, the carrier optionally includes a penetration enhancer and/or a suitable wetting agent, optionally in combination with any minor constituent additives that do not have a significant deleterious effect on the skin. The additives may aid in application to the skin and/or may aid in the preparation of the desired formulation. These formulations can be administered in a variety of ways, such as transdermal patch application, topical application, ointment application.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powdered product pouches, wafers, suppositories, injectable solutions or suspensions, and the like, as well as multiples thereof.

The exact dosage and frequency of administration will depend upon the particular compound of formula (I) used, the particular disease to be treated, the severity of the disease to be treated, the age, weight, sex, degree of disorder and the general physical condition of the particular patient and other medications, respectively, which are well known to those skilled in the art. Furthermore, it is apparent that the effective daily amount may be reduced or increased depending on the response of the subject and/or depending on the evaluation of the compounds of the invention as ordered by the physician.

According to the mode of administration, the pharmaceutical composition will comprise 0.05 to 99 wt%, preferably 0.1 to 70 wt%, more preferably 0.1 to 50 wt% of the active ingredient, and 1 to 99.95 wt%, preferably 30 to 99.9 wt%, more preferably 50 to 99.9 wt% of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.

As already indicated, the present invention also relates to a pharmaceutical composition comprising a compound according to the invention and one or more pharmaceutical products for the treatment, prevention, control, amelioration or reduction of the risk of a disease or condition for which a compound of formula (I) or other pharmaceutical product may have applicability, and to the use of such a composition for the manufacture of a medicament. The invention also relates to a combination of a compound according to the invention and an mGluR2 orthoagonist. The invention also relates to the use of such a combination as a medicament. The invention also relates to a product containing (a) a compound according to the invention and pharmaceutically acceptable salts or solvates thereof, and (b) an mGluR2 ortho agonist, as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of a disorder in a mammal, including a human, whose treatment or prevention is affected or facilitated by the neuromodulatory effect of mGluR2 allosteric modulators, particularly positive mGluR2 allosteric modulators. The various products of such combinations or products may be combined in a single formulation with a pharmaceutically acceptable carrier or diluent, or they may each be included in a single formulation with a pharmaceutically acceptable carrier or diluent.

The following examples are intended to illustrate, but not limit the scope of the invention.

Experimental part

Several methods for preparing the compounds of the present invention are illustrated in the following examples. Unless otherwise indicated, all starting materials were obtained by the manufacturer and used without further purification. In particular, the following abbreviations may be used in the examples and in the present description and claims:

EtOAc (ethyl acetate)	M (mole)
		LCMS (liquid chromatography mass spectrometry)	MeOH (methanol)
DCM (dichloromethane)	g (gram)
		ml (milliliter)	min (minutes)
mmol (millimole)	DMF (dimethylformamide)
		P(＝O)Br3(Tribromooxyphosphorus)	THF (tetrahydrofuran)
Et2O (diethyl ether)	HPLC (high pressure liquid chromatography)
		DME (dimethoxyethane)

All references to saline refer to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. All reactions were not carried out at room temperature under an inert atmosphere unless otherwise specified.

The microwave-assisted reaction is carried out in a single-mode reactor or a multi-mode reactor, wherein the single-mode reactor is Emrys^TMAn optizer microwave reactor (Personal Chemistry a.b., currently Biotage), which is MicroSYNTH laboratory (Milestone).

A. Preparation of intermediates

Example A.1

1-Cyclopropylmethyl-4-methoxy-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile (intermediate 1)

To a solution of 4-methoxy-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile (12.2g, 81.48mmol) in acetonitrile (250ml) were added bromomethyl-cyclopropane (11g, 81.48mmol) and potassium carbonate (22.48g, 162.9mmol), and the mixture was heated at 110 ℃ for 24 h. The mixture was cooled to room temperature and the solid was filtered off. The filtrate was evaporated until dryness, then the resulting crude residue was triturated with diethyl ether to yield pure intermediate 1 as a white solid (15.72g, 94%).

Example A.2

1-butyl-4-methoxy-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile (intermediate 2)

To a solution of 4-methoxy-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile (20g, 133mmol) in acetonitrile (800ml) were added 1-bromobutane (15.8ml, 146mmol) and potassium carbonate (36.7g, 266mmol) and the mixture was heated at 110 ℃ for 24 h. The mixture was cooled to room temperature and the solid was filtered off. The filtrate was evaporated until dryness, then the resulting crude residue was triturated with diethyl ether to afford pure intermediate 2(27.39g, > 99%) as a white solid.

Example A.3

1-Cyclopropylmethyl-4-hydroxy-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile (intermediate 3)

Intermediate 1(15.7g, 76.8mmol) was added to a 1N aqueous solution of sodium hydroxide (300ml) and THF (50ml) at room temperature. The reaction mixture was heated at 140 ℃ (oil bath temperature) for 16 hours. The mixture was cooled to room temperature and THF was substantially evaporated in vacuo. The aqueous layer was cooled to 0 ℃ and acidified by addition of aqueous 2N HCl, adjusting the pH to about 3, at which point a white solid precipitated. The solid was filtered off and Et₂O wash and dry in vacuo to afford intermediate 3(10.44g, 71%) as a white solid which was used without further purification.

Example A.4

1-butyl-4-hydroxy-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile (intermediate 4)

Intermediate 2(27.39g, 133mmol) was added to a 1N aqueous solution of sodium hydroxide (500ml) and THF (100ml) at room temperature. The reaction mixture was heated at 110 ℃ (oil bath temperature) for 24 hours. The mixture was cooled to room temperature and the solvent was evaporated in vacuo until the volume was reduced to about 250 ml.The aqueous layer was then cooled to 0 ℃ and acidified by addition of aqueous 2N HCl, adjusting the pH to about 3, at which point a white solid precipitated. The solid was filtered off and Et₂O washed and dried in vacuo to afford intermediate 4(25g, 98%) as a white solid which was used without further purification.

Example A.5

4-bromo-1-cyclopropylmethyl-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile (intermediate 5)

To a solution of intermediate 3(10.4g, 54.67mmol) in DMF (250ml) was added P (═ O) Br₃(31.3g, 109.3mmol) and the mixture was heated at 110 ℃ for 1.5 h. After cooling in an ice bath, the solution was partitioned between water and EtOAc. After three extractions with EtOAc, the combined organic fractions were washed with brine, MgSO₄Dried and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 5(8.83g, 64%).

Example A.6

4-bromo-1-butyl-2-oxo-1, 2-dihydro-pyridine-3-carbonitrile (intermediate 6)

To a solution of intermediate 4(39g, 203mmol) in DMF (600ml) was added P (═ O) Br₃(116g, 406mmol) and the mixture was heated at 110 ℃ for 1.5 h. After cooling in an ice bath, the solution was partitioned between water and EtOAc. After three extractions with EtOAc, the combined organic fractions were washed with brine, Na₂SO₄Dried and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel, DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 6(36.7g, 72%).

Example A.7

4-hydroxy-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester (intermediate 7)

To a solution of 4-hydroxy-4-phenylpiperidine (2g, 11.28mmol) in dichloromethane (50ml) was added di-tert-butyl dicarbonate (2.95g, 13.53mmol) at room temperature. The resulting mixture was stirred at room temperature for 5 hours. The volatiles were evaporated in vacuo to afford crude intermediate 7(3.12g, 100%) which was used without further purification.

Example A.8

4-fluoro-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester (intermediate 8)

The reaction was carried out in a nitrogen atmosphere. To a solution of (diethylamino) sulfur trifluoride (0.74ml, 5.67mmol) in dichloromethane (30ml) was added dropwise a solution of intermediate 7(1.5g, 5.4mmol) in dichloromethane (30ml) before cooling to-78 ℃. The resulting mixture was then stirred at-78 ℃ for 1 hour, after which the reaction mixture was allowed to warm to room temperature and stirred for a further 30 minutes. Adding NaHCO₃(saturated aqueous solution, 90ml) and the mixture was stirred for 15 minutes. The organic layer was separated and treated with 3-chloroperoxybenzoic acid (0.2g, 1.18mmol) and stirred for 30 minutes. NaHCO for ligation₃The reaction mixture was washed with water (saturated aqueous solution). With Na₂SO₄DryingThe organic layer was evaporated in vacuo to afford crude intermediate 8(1.5g, 100%) which was used without further purification.

Example A.9

4-fluoro-4-phenyl-piperidine hydrochloride (intermediate 9)

Intermediate 8(1.5g, 5.37mmol) was dissolved in hydrochloric acid (4N in 1, 4-dioxane, 20ml) and the resulting solution was stirred at room temperature for 2 hours. The volatiles were evaporated in vacuo to yield solid intermediate 9(1.15g, 100%; HCl).

Example A.10

1-benzyl-4-phenyl-piperidine-4-carboxylic acid benzyl ester (intermediate 10)

4-phenyl-4-piperidinecarboxylic acid 4-toluenesulfonate (CAS83949-32-0) (2g, 5.3mmol), benzyl bromide (0.76ml, 6.36mmol) and potassium carbonate (2.92g, 21.2mmol) were suspended in acetonitrile (6ml) and heated by microwave irradiation at 130 ℃ for 15 minutes. The cooled reaction mixture was filtered through a pad of celite. The celite pad was washed with acetonitrile, EtOAc and dichloromethane. The combined organic filtrates were evaporated in vacuo to yield crude intermediate 10(2.04g, 100%) which was used without further purification.

Example A.11

(1-benzyl-4-phenyl-piperidin-4-yl) -methanol (intermediate 11)

The reaction was carried out in a nitrogen atmosphere. Intermediate 10(2.04g, 5.3mmol) was suspended in dry tetrahydrofuran (25ml) and the mixture was cooled to-78 ℃. Lithium aluminum hydride (1M in tetrahydrofuran, 7.95ml, 7.95mmol) was added dropwise. The resulting reaction mixture was gradually warmed to room temperature and further stirred for 2 hours. Addition of NH₄Cl (saturated aqueous solution) and the reaction mixture was extracted first with EtOAc and then with 1-hydroxybutane. With Na₂SO₄The combined organic extracts were dried and evaporated in vacuo to afford crude intermediate 11(0.65g, 43%) which was used without further purification.

Example A.12

(4-phenyl-piperidin-4-yl) -methanol (intermediate 12)

The reaction was carried out in a nitrogen atmosphere. Intermediate 11(0.65g, 2.31mmol) was suspended in methanol (10 ml). 1, 4-cyclohexadiene (2.17ml, 23.1mmol) and 10% palladium activated on charcoal (0.65g) were then added. The resulting mixture was heated at 100 ℃ for 24 hours in a sealed tube. The cooled reaction mixture was filtered through a pad of celite. The celite pad was washed successively with methanol and 7N ammonia saturated methanol solution. The combined organic extracts were evaporated in vacuo to afford crude intermediate 12(0.47g, 100%) which was used without further purification.

Example A.13

1 '-butyl-4-hydroxy-2' -oxo-4- (4-chlorophenyl) -3, 4, 5, 6, 1 ', 2' -hexahydro-2H- [1, 4 '] bipyridinyl-3' -carbonitrile (intermediate 13)

A mixture of intermediate 6(0.255g, 1.39mmol), 4- (4-chlorophenyl) -4-hydroxypiperidine (C.A.S.39512-49-7) (0.265g, 1.25mmol) and N, N-diisopropylethylamine (0.348ml, 2mmol) in acetonitrile (2.5ml) was heated with a microwave at 150 ℃ for 10 minutes. With NaHCO₃The reaction mixture was diluted (saturated aqueous solution) and extracted with DCM. With Na₂SO₄The organic layer was dried and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (silica gel, DCM to DCM/EtOAc 9: 1 to 1: 9). The desired fractions were collected and evaporated in vacuo to yield intermediate 13(0.357g, 93%).

1 '-butyl-4-hydroxy-2' -oxo-4- (3-chlorophenyl) -3, 4, 5, 6, 1 ', 2' -hexahydro-2H- [1, 4 '] bipyridinyl-3' -carbonitrile (intermediate 13a)

Intermediate 13a was prepared according to the protocol for intermediate 13, except that 4- (3-chlorophenyl) -4-hydroxypiperidine was used initially.

Example A.14

1 '-butyl-4-fluoroethoxy-2' -oxo-4- (4-chlorophenyl) -3, 4, 5, 6, 1 ', 2' -hexahydro-2H- [1, 4 '] bipyridinyl-3' -carbonitrile (intermediate 14)

To NaH (0.020g, 0.5mmol, 60% in mineral oil) at 0 ℃ was added dropwise fluoroethyl-4-tosylate (C.A. S.383-50-3) (0.063g, 0.029mmol) in DME (2 ml). The mixture was stirred at room temperature for 15 minutes. Then adding DME (1)ml) of intermediate 13(0.1g, 0.26mmol) and microwave heating the reaction mixture at 150 ℃ for 10 min. Then NH is added₄Cl (saturated aqueous solution). The resulting mixture was extracted with AcOEt. With Na₂SO₄The organic layer was dried and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (silica gel, DCM to DCM/EtOAc 9: 1). The desired fractions were collected and evaporated in vacuo to yield intermediate 14(0.038g, 34%).

To prepare 1 '-butyl-4-fluoroethoxy-2' -oxo-4- (3-chlorophenyl) -3, 4, 5, 6, 1 ', 2' -hexahydro-2H- [1, 4 '] bipyridinyl-3' -carbonitrile (intermediate 14a), intermediate 13a was reacted according to the scheme used for the preparation of intermediate 14.

B. Preparation of the Final Compounds

Example B.1

1 '-Cyclopropylmethyl-4-fluoro-2' -oxo-4-phenyl-3, 4, 5, 6, 1 ', 2' -hexahydro-2H- [1, 4 '] bipyridinyl-3' -carbonitrile (Compound 1)

A mixture of intermediate 5(1.0g, 4.84mmol), intermediate 9(1.15g, 5.33mmol) and N, N-diisopropylethylamine (3.3ml, 19.36mmol) in acetonitrile (3ml) was heated with a microwave at 150 ℃ for 15 minutes. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. The crude reaction mixture was chromatographed on a column (silica gel, DCM with DCM/MeOH (NH)₃) A mixed solution having a ratio of at most 5% as an eluent). The desired fractions were collected and evaporated in vacuo to yield compound 1(0.874g, 51%) as a pale yellow solid.

Example B.2

1 '-butyl-4-fluoro-2' -oxo-4-phenyl-3, 4, 5, 6, 1 ', 2' -hexahydro-2H- [1, 4 '] bipyridinyl-3' -carbonitrile (Compound 2)

A mixture of intermediate 6(0.354g, 1.39mmol), intermediate 9(0.3g, 1.39mmol) and N, N-diisopropylethylamine (0.72ml, 4.17mmol) in acetonitrile (3ml) was heated with a microwave at 150 ℃ for 15 minutes. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. The crude reaction mixture was chromatographed on a column (silica gel, DCM with DCM/MeOH (NH)₃) A mixed solution having a ratio of at most 10% as an eluent). The desired fractions were collected and evaporated in vacuo to yield compound 2 as a pale pink solid (0.104g, 21%).

Example B.3

1 '-Cyclopropylmethyl-4-hydroxymethyl-2' -oxo-4-phenyl-3, 4, 5, 6, 1 ', 2' -hexahydro-2H- [1, 4 '] bipyridinyl-3' -carbonitrile (Compound 3)

A mixture of intermediate 5(0.32g, 1.3mmol), intermediate 12(0.25g, 1.3mmol) and N, N-diisopropylethylamine (0.45ml, 2.6mmol) in acetonitrile (3ml) was heated with a microwave at 150 ℃ for 15 minutes. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. The crude reaction mixture was chromatographed on a column (silica gel, DCM with DCM/MeOH (NH)₃) A mixed solution having a ratio of at most 10% as an eluent). The desired fractions were collected and evaporated in vacuo to yield compound 3(0.385g, 81%) as an oil.

Example B.4

1 '-butyl-4-hydroxymethyl-2' -oxo-4-phenyl-3, 4, 5, 6, 1 ', 2' -hexahydro-2H- [1, 4 '] bipyridinyl-3' -carbonitrile (Compound 4)

A mixture of intermediate 6(0.267g, 1.04mmol), intermediate 12(0.2g, 1.04mmol) and N, N-diisopropylethylamine (0.54ml, 3.12mmol) in acetonitrile (2ml) was heated with a microwave at 150 ℃ for 15 minutes. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. The crude reaction mixture was chromatographed on a column (silica gel, DCM with DCM/MeOH (NH)₃) A mixed solution having a ratio of at most 10% as an eluent). The desired fractions were collected and evaporated in vacuo to yield compound 2(0.100g, 26%) as a pale brown solid.

Example B.5

1 '-Cyclopropylmethyl-4-fluoromethyl-2' -oxo-4-phenyl-3, 4, 5, 6, 1 ', 2' -hexahydro-2H- [1, 4 '] bipyridinyl-3' -carbonitrile (Compound 5)

The reaction was carried out in a nitrogen atmosphere. To a solution of (diethylamino) sulfur trifluoride (0.145ml, 1.11mmol) in methylene chloride (30ml) was added dropwise a solution of compound 3(0.385g, 1.06mmol) in methylene chloride (30ml) before cooling to-78 ℃. The resulting mixture was then stirred at-78 ℃ for 1 hour, after which the reaction mixture was allowed to warm to room temperature and stirred for a further 30 minutes. Adding NaHCO₃(saturated aqueous solution, 90ml) and the mixture was stirred for 15 minutes. The organic layer was separated and treated with 3-chloroperoxybenzoic acid (0.047g, 0.27mmol) and stirred for 30 minutes. NaHCO for ligation₃The reaction mixture was washed with water (saturated aqueous solution). With Na₂SO₄The organic layer was dried and evaporated in vacuo. The crude product was purified by reverse phase preparative HPLC to afford compound 5(0.112g, 29%).

Example B.6

1 '-butyl-4-fluoromethyl-2' -oxo-4-phenyl-3, 4, 5, 6, 1 ', 2' -hexahydro-2H- [1, 4 '] bipyridinyl-3' -carbonitrile (Compound 6)

The reaction was carried out in a nitrogen atmosphere. To a solution of (diethylamino) sulfur trifluoride (0.075ml, 0.57mmol) in dichloromethane (15ml) was added dropwise a solution of compound 4(0.20g, 0.54mmol) in dichloromethane (15ml) before cooling to-78 ℃. The resulting mixture was then stirred at-78 ℃ for 1 hour, after which the reaction mixture was allowed to warm to room temperature and stirred for a further 30 minutes. Adding NaHCO₃(saturated aqueous solution, 90ml) and the mixture was stirred for 15 minutes. The organic layer was separated and treated with 3-chloroperoxybenzoic acid (0.024g, 0.14mmol) and stirred for 30 minutes. NaHCO for ligation₃The reaction mixture was washed with water (saturated aqueous solution). With Na₂SO₄The organic layer was dried and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (silica gel, mixture of DCM and DCM/EtOAc up to 20% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 6(0.035g, 17%) as a white solid.

Example B.7

1 '-butyl-4-fluoroethoxy-2' -oxo-4-phenyl-3, 4, 5, 6, 1 ', 2' -hexahydro-2H- [1, 4 '] bipyridinyl-3' -carbonitrile (Compound 7)

A solution of intermediate 14(0.038g, 0.09mmol) in methanol (2ml) and triethylamine (0.025g, 0.18mmol) were hydrogenated in the presence of palladium 10% (0.005g) on activated carbon at room temperature for 2 hours. The solid was filtered off and the filtrate was evaporated until dryness. The crude reaction mixture was purified by column chromatography (silica gel, DCM to DCM/MeOH ratio up to 1% mixed as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 7(0.019g, 53%).

An alternative method of preparing compound 7 is to react intermediate 14a according to the above scheme.

Example B.8

3-cyano-1-cyclopropylmethyl-4- (4-phenyl-piperidin-1-yl) -pyridin-2 (1H) -one (Compound 8)

A mixture of intermediate 5(0.3g, 1.18mmol), 4-phenylpiperidine (0.286g, 1.77mmol) and diisopropylethylamine (0.615ml, 3.54mmol) in acetonitrile (5ml) was heated with a microwave at 150 ℃ for 15 minutes. The mixture was cooled to room temperature and the solvent was evaporated in vacuo. Subjecting the residue thus obtained to flash chromatography (SiO)₂，DCM/MeOH(NH₃) Mixture) to obtain the desired compound. The compound was then recrystallized from ether to give compound 8(0.29g, 73%).

Compound 9 was prepared according to the protocol described for compound 8.

Table 1 lists compounds of general formula (I) prepared according to one of the above examples (example number).

TABLE 1

C. Analysis section

For LCMS characterization of the inventive compositions, the following method was used.

LCMS-general procedure

The HPLC assay was performed using an agilent technology HP1100, the HP1100 comprising a pump (quaternary or binary) equipped with a degasser, an autosampler, a column oven, a Diode Array Detector (DAD) and a column as specified in the respective methods below. The fluid from the column was diverted to the MS detector. The MS detector was configured with an electrospray ion source. Nitrogen was used as the atomizer gas. The source temperature was maintained at 140 ℃. Data acquisition was performed using MassLynx-Openlynx software.

Method 1

In addition to the general procedure: reverse phase HPLC was carried out on an Agilent XDB-C18 column (1.8 μm, 2.1X 30mm) at a flow rate of 1ml/min at 60 ℃. The gradient conditions used were: 90% A (0.5g/l ammonium acetate solution), 5% B (acetonitrile) and 5% C (methanol) reached 50% B and 50% C in 6.5 minutes, 100% B at 7 minutes, and equilibrium was the initial condition up to 9.0 minutes at 7.5 minutes. The injection volume was 2. mu.l. High resolution mass spectrometry (time of flight, TOF) is only obtained in a positive ionization mode with a 0.1 second dwell time scanning 100-750 times in 0.5 seconds. The capillary needle voltage is 2.5kV, and the taper hole voltage is 20V. Leucine-Enkephaline is a reference for lock-in mass calibration.

Method 2

In addition to the general procedure: reverse phase HPLC was carried out on a Phenomenex LUNA-C18 column (2.5 μm, 2.1X 30mm) at a flow rate of 1.0ml/min at 60 ℃. The gradient conditions used were: 90% A (0.5g/l ammonium acetate solution), 5% B (acetonitrile) and 5% C (methanol) reached 50% B and 50% C in 6.5 minutes, 100% B at 7 minutes, and equilibrium was the initial condition up to 9.0 minutes at 7.5 minutes. The injection volume was 5. mu.l. High resolution mass spectra (time of flight, TOF) were only obtained in positive ionization mode with a 0.1 second dwell time scanning 100-750 times in 0.5 seconds. The capillary needle voltage in positive ionization mode was 2.5kV and the cone voltage was 20V. Leucine-Enkephaline is a reference for lock-in mass calibration.

Method 3

In addition to the general procedure: reverse phase HPLC was performed on an ACE-C18 column (3.0 μm, 4.6X 30mm) from Advanced Chromatography Technologies at a flow rate of 1.5ml/min at 40 ℃. The gradient conditions used were: 80% A (0.5g/l ammonium acetate solution), 10% B (acetonitrile) and 10% C (methanol) reached 50% B and 50% C in 6.5 minutes, 100% B at 7 minutes, and equilibrium was the initial condition up to 9.0 minutes at 7.5 minutes. The injection volume was 5. mu.l. High resolution mass spectra (time of flight, TOF) were only obtained in positive ionization mode with a 0.1 second dwell time scanning 100-750 times in 0.5 seconds. The capillary needle voltage in positive ionization mode was 2.5kV and the cone voltage was 20V. Leucine-Enkephaline is a reference for lock-in mass calibration.

Melting point determination

Melting point measurements were performed using a Mettler FP62 instrument.

TABLE 2: analytical data (R)_tIndicates the retention time in minutes; (MH)⁺Represents the protonation mass of the compound (free base)

Compound numbering	Melting Point (. degree.C.)	(MH)+	Rt(minutes)	Method of producing a composite material
					Compound 1	189.2	352	3.98	1
Compound 2	n.d.	354	4.27	1
					Compound 3	n.d.	364	3.29	1
Compound 4	103.2	366	3.58	1
					Compound 5	Decomposition of	366	4.19	1
Compound 6	n.d.	368	4.45	1
					Compound 7	n.d.	398	4.45	2
Compound 8	128	334	4.05	1
					Compound 9	Decomposition of	350	4.76	3

n.d. means not determined

D. Pharmacological examples

The compounds provided by the present invention are positive allosteric modulators of mGluR 2. These compounds appear to potentiate glutamate response by binding to allosteric sites rather than to glutamate binding sites. When a compound of the formula (I) is presentAt this time, mGluR2 responds increasingly to glutamate concentrations. The compounds of formula (I) should be substantially effective at mGluR2 due to their ability to enhance receptor function. The behavior of the positive allosteric modulator is described below³⁵S]GTP γ S binding assays, and are suitable for identifying these compounds, more specifically, compounds according to general formula (I) are shown in table 3.

[ ³⁵ S]GTPγS binding assay

[³⁵S]The GTP γ S binding assay is a functional membrane assay for studying the function of a G-protein coupled receptor (GPCR), whereby non-hydrolyzed form of GTP, [ 2 ]³⁵S]GTP γ S (guanosine 5' -triphosphate, gamma-irradiated³⁵S label). In the GPCR agonized form³⁵S]G-proteins under GTP γ S-activated conditionsγThe subunits catalyze the exchange of Guanosine Triphosphate (GTP) with guanosine 5' -diphosphate (GDP), which becomes integral and does not insist on continuing the exchange cycle (Harper (1998) Current Protocols in Pharmacology 2.6.1-10, John Wiley&Sons, Inc.). Radioactivity [ alpha ]³⁵S]GTP γ S addition is a direct measure of G-protein activity and therefore agonist activity can be determined. mGluR2 receptors were shown to preferentially couple to Ggai-proteins for preferential coupling in this method and are therefore widely used for studying mGluR2 receptor activation in recombinant cell lines and tissues (Schaffhauser et al 2003, Pinkerton et al, 2004, Mutel et al (1998) Journal of neurochemistry.71: 2558-64; Schaffhauser et al (1998) molecular Pharmacology 53: 228-33). Here we describe the use of a membrane transfected with the mGluR2 receptor from the human body and used by Schaffhauser et al ((2003) molecular Pharmacology 4: 798-³⁵S]Application of GTP gamma S binding assays for detecting the Positive Allosteric Modulation (PAM) performance of the compounds of the invention.

Membrane preparation

Prior to washing in PBS, CHO cells were cultured to pre-confluence and stimulated with 5mM butyric acid for 24 hours, and then harvested by scraping in homogenization buffer (50mM Tris-HCl buffer, pH7.4, 4 ℃). The cell lysate was briefly homogenized with an ultra-turrax homogenizer (15 s). The resulting homogenate product was centrifuged at 23500Xg for 10 minutes and the supernatant discarded. The resulting pellet was resuspended in 5mM Tris-HClpH7.4 and centrifuged again (30000Xg, 20min, 4 ℃). The final pellet was resuspended in 50mM HEPES, pH7.4 and stored in the appropriate aliquot at-80 ℃ prior to use. Protein concentration was determined by the Bradford method (Bio-Rad, USA) using bovine serum albumin as a standard.

[³⁵S]GTP gamma S binding experimental method

Determination of the mGluR2 positive allosteric modulatory activity of test compounds in a membrane containing human mGluR2 was performed using frozen membranes that were thawed and simply homogenized prior to pre-incubation, then placed in 96-well microwell plates in test buffer (50mM HEPES pH7.4, 100mM NaCl, 3mM MgCl. RTM.)₂50 μ M GDP, 10 μ g/ml saponin) with gradually increasing positive allosteric modulator concentration (from 0.3nM to 50 μ M) with minimal or no addition of glutamate (PAM assay) at the predetermined concentration. For PAM identification, films were tested with glutamate in EC₂₅Concentration pre-incubation, i.e., glutamate concentration that gives a maximal response of 25%, and is consistent with published data (Pin et al (1999) Eur. JPharmacol.375: 277-. In addition³⁵S]After GTP γ S (0.1nM, f.c.) to reach a total reaction volume of 200. mu.l, the microplate was briefly shaken and further incubated so that³⁵S]GTP γ S binds under activation (30 min, 30 ℃). The reaction was filtered by rapid vacuum through a glass fiber filter plate (Unifilter 96-well GF/B filter plates, Perkin-Elmer, USA) of a 96-well plate cell harvester (Filtermate, Perkin-Elmer, Downers Grove, USA) microplate, followed by washing with 300. mu.l of ice-cold wash buffer (Na. sub.l)₂PO₄.2H₂O 10mM，NaH₂PO₄-H₂O10 mM, pH 7.4) was stopped by three washes. The filters were then air dried and 40. mu.l of liquid scintillator (Microscint-O) was added to each well,the membrane-bound [ alpha ], [ beta ] -olefin polymer, and [ beta ] -olefin polymer, were measured in a 96-well scintillation plate reader (Top-Count, Perkin-Elmer, USA)³⁵S]GTP γ S. Non-specific [ 2 ]³⁵S]GTP γ S binding was determined in the presence of cold 10 μ M GTP. Each curve was run at least once with duplicate samples at 11 concentrations per data point.

Data analysis

The compounds represented by the invention are added with EC₂₅Concentration-response curves for the determination of Positive Allosteric Modulation (PAM) in the presence of the mGluR2 agonist glutamate were obtained using Prism GraphPad software (GraphPad Inc, San Diego, USA). These curves are fitted to a four-parameter logistic equation (Y ═ min + (max-min)/(1 + 10)^Λ((LogEC₅₀-X) slope) to determine EC₅₀The value is obtained. EC (EC)₅₀Is the concentration of compound that results in half the maximal enhancement of glutamate response. It is calculated by subtracting the maximum response of glutamate in the presence of a full saturating concentration of positive allosteric modulator from the response of glutamate in the absence of positive allosteric modulator. The concentration EC which produces half of the maximum effect is then calculated₅₀。

Table 3.Pharmaceutical data of the compounds according to the invention.

At mGluR2 agonist, predetermined EC₂₅Compounds were assayed in the presence of glutamate at concentrations to determine positive allosteric modulation (GTP γ S-PAM). The data represent the average of the 11 replicate concentration response curves from at least one experiment. All tested compounds showed pEC greater than 5.0₅₀(-logEC₅₀) The value is obtained. pEC of Individual experiment₅₀The value test deviation was estimated to be about 0.3log units.

Compound numbering	GTPgS-hR2PAM pEC50
		1	6.58
2	6.76
		3	nm
4	5.69
		5	5.92
6	6.35
		7	6.73
8	6.5
		9	7.2

nm: not tested

E. Composition examples

The "active ingredient" used in these examples relates to the final compound of general formula (I), its pharmaceutically acceptable salts, solvates and stereochemically isomeric forms.

Conventional examples of formulation of dosage forms of the present invention are as follows:

1. tablet formulation

5-50 mg of active ingredient

Dicalcium phosphate 20mg

Lactose 30mg

10mg of slide

Magnesium stearate 5mg

Potato starch to 200mg

In this example, the active ingredient may be replaced by an equal amount of any compound according to the invention, in particular an equal amount of any of the exemplified compounds.

2. Suspension liquid

Aqueous suspensions for oral administration are prepared containing 1-5 mg of one active compound per 1ml, 50mg sodium carboxymethylcellulose, 1mg sodium benzoate, 500mg sorbitol and up to 1ml water.

3. Injection solution

The pharmaceutical composition for injection is prepared by stirring 1.5 wt% of the active ingredient of the present invention in 10 vol% propylene glycol aqueous solution.

4. Ointment

5-1000 mg of active ingredient

Stearyl alcohol 3g

Lanolin 5g

White Petroleum 15g

Make up to 100g of water

In this example, the active ingredient may be replaced by an equal amount of any compound according to the invention, in particular an equal amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from the scope of the invention. It is therefore obvious for a person skilled in the art that the invention described can be varied in a number of ways.

Claims (46)

1. A compound of the general formula (I'),

including any stereochemically isomeric form of said compound, or a pharmaceutically acceptable salt or solvate of said compound, wherein,

R₁is C_4～6Alkyl or C_3～7Cycloalkyl-substituted C_1～3An alkyl group;

R₂is hydrogen; a hydroxyl group; fluorine; hydroxy-substituted C_1～4An alkyl group; fluorine substituted C_1～4An alkyl group; or fluorine substituted C_1～4An alkoxy group;

R₃is hydrogen or halogen;

when R is₃When it is halogen, R₂Is a hydroxyl group.

2. The compound of claim 1, wherein the compound has the general formula:

including any stereochemically isomeric form of said compound, or a pharmaceutically acceptable salt or solvate of said compound, wherein,

R₁is C_4～6Alkyl or C_3～7Cycloalkyl-substituted C_1～3An alkyl group;

R₂is hydrogen; fluorine; hydroxy-substituted C_1～4An alkyl group; fluorine substituted C_1～4An alkyl group; or fluorine substituted C_1～4An alkoxy group.

3. The compound of claim 2, wherein the compound is not:

4. a compound of claim 2 or 3, wherein R₂Is fluorine; hydroxy-substituted C_1～4An alkyl group; fluorine substituted C_1～4An alkyl group; or fluorine substituted C_1～4An alkoxy group.

5. A compound according to any one of claims 1 to 4, wherein R₁Is C_4～6An alkyl group.

6. The compound of claim 5, wherein R₁Is a 1-butyl group.

7. A compound according to any one of claims 1 to 4, wherein R₁Is C_3～7Cycloalkyl-substituted C_1～3An alkyl group.

8. The compound of claim 7, wherein R₁Is cyclopropylmethyl.

9. A compound according to any one of claims 1 to 8, wherein R₂Is fluorine.

10. A compound according to any one of claims 1 to 8, wherein R₂Is hydroxy-substituted C_1～4An alkyl group.

11. The compound of claim 10, wherein R₂Is a hydroxy-substituted methyl group.

12. A compound according to any one of claims 1 to 8, wherein R₂Is fluorine substituted C_1～4An alkyl group.

13. The compound of claim 12, wherein R₂Is a fluoro-substituted methyl group.

14. A compound according to any one of claims 1 to 8, wherein R₂Is fluorine substituted C_1～4An alkoxy group.

15. The compound of claim 14, wherein R₂Is a fluorine substituted ethoxy group.

16. The compound of any one of claims 1, 2, 3, 5-7, wherein R₂Is hydrogen; fluorine; or fluorine substituted C_1～4An alkoxy group.

17. The compound of claim 16, wherein R₂Is fluorine; or fluorine substituted C_1～4An alkoxy group.

18. The compound of claim 1, wherein the compound has the general formula:

including any stereochemically isomeric form of said compound, or a pharmaceutically acceptable salt or solvate of said compound, wherein,

R₁is C_4～5Alkyl or C_3～7Cycloalkyl-substituted C_1～3An alkyl group;

R₃is hydrogen or halogen.

19. The compound of claim 18, wherein R₃Is halogen.

20. The compound of claim 18, wherein R₃Is chlorine.

21. The compound of claim 20, wherein the compound is, or is a pharmaceutically acceptable salt or solvate of:

22. the compound of claim 1, wherein R₁Is 1-butyl, 3-methyl-1-butyl or cyclopropylmethyl; r₂Is hydrogen; fluorine; hydroxy-substituted methyl; fluoro-substituted methyl; a fluorine substituted ethoxy group.

23. The compound of claim 1, wherein R₁Is 1-butyl or cyclopropylmethyl; r₂Is fluorine; hydroxy-substituted methyl; fluoro-substituted methyl; a fluorine substituted ethoxy group.

24. The compound of claim 18, wherein R₁Is 1-butyl or cyclopropylmethyl; r₂Is hydrogen; fluorine or chlorine.

25. The compound of claim 1, wherein the compound is selected from, or is a pharmaceutically acceptable salt or solvate of:

26. the compound of claim 1, wherein the compound is selected from the group consisting of, or is a pharmaceutically acceptable salt or solvate of,

27. a compound as claimed in any one of claims 1 to 26 for use as a medicament.

28. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 26 and a pharmaceutically acceptable carrier or diluent.

29. A compound according to any one of claims 1 to 26 or a pharmaceutical composition according to claim 28 for use in the treatment or prevention of a disease in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of positive allosteric modulators of mGluR 2.

30. The use of a compound according to any one of claims 1 to 26 or a pharmaceutical composition according to claim 28 in the manufacture of a medicament for the treatment or prevention of a disease in a mammal, including a human, which treatment or prevention is affected or facilitated by the neuromodulatory effect of positive allosteric modulators of mGluR 2.

31. Use of a compound according to any one of claims 1 to 26 or a pharmaceutical composition according to claim 28 for the manufacture of a medicament for the treatment or prevention of a central nervous system disorder selected from the group of anxiety disorders, psychotic disorders, personality disorders, substance-related disorders, eating disorders, mood disorders, migraine, epilepsy or convulsive disorders, childhood disorders, cognitive disorders, neurodegeneration, neurotoxicity and ischemia.

32. Use according to claim 31, wherein the central nervous system disorder is an anxiety disorder selected from the group of agoraphobia, Generalized Anxiety Disorder (GAD), Obsessive Compulsive Disorder (OCD), panic disorder, Post Traumatic Stress Disorder (PTSD), social phobia and other phobias.

33. Use according to claim 31, wherein the central nervous system disorder is a psychotic disorder selected from the group of schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder and substance-induced psychotic disorder.

34. The use according to claim 31, wherein the central nervous system disorder is a personality disorder selected from the group of obsessive-compulsive personality disorder and schizotypal, schizotypal personality disorder.

35. Use according to claim 31, wherein the central nervous system disorder is a substance-related disorder selected from the group of alcohol abuse, alcohol dependence, alcohol withdrawal delirium, alcohol-induced psychotic disorder, amphetamine dependence, amphetamine withdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence, nicotine withdrawal, opioid dependence and opioid withdrawal.

36. The use according to claim 31, wherein the central nervous system disorder is an eating disorder selected from the group of anorexia nervosa and bulimia nervosa.

37. Use according to claim 31, wherein the central nervous system disorder is a mood disorder selected from the group of bipolar disorder (I & II), cyclothymic disorder, depression, dysthymic disorder, major depression and substance-induced mood disorder.

38. The use according to claim 31 wherein the central nervous system disorder is migraine.

39. Use according to claim 31, wherein the central nervous system disorder is epilepsy or a convulsive disorder selected from the group of generalized non-convulsive epilepsy, generalized convulsive epilepsy, petit mal epilepsy, grand mal epilepsy, epilepsy locales with or without conscious impairment, infantile spasms, epilepsy partialis continua and other forms of epilepsy.

40. The use of claim 31, wherein the central nervous system disorder is a childhood disorder.

41. The use of claim 40, wherein the childhood disorder is attention deficit/hyperactivity disorder.

42. Use according to claim 31, wherein the central nervous system disorder is a cognitive disorder selected from the group of delirium, substance-induced persisting delirium, dementia due to HIV disease, dementia due to huntington disease, dementia due to parkinson disease, dementia of the alzheimer type, substance-induced persisting dementia and mild cognitive impairment.

43. Use according to claim 31, wherein the central nervous system disorder is selected from the group of anxiety, schizophrenia, migraine, depression and epilepsy.

44. Use of a compound as claimed in any one of claims 1 to 26 in combination with an ortho agonist of mGluR2 in the manufacture of a medicament for the treatment or prevention of a disorder as claimed in any one of claims 30 to 43, in a mammal, including a human.

45. The use of a compound as claimed in any one of claims 1 to 26 for the treatment of a disease or disorder as claimed in any one of claims 30 to 43.

46. A process for the preparation of a compound according to claim 1,

a) reacting an intermediate of formula (II) wherein Y represents a suitable leaving group with an intermediate of formula (III) in the presence of a suitable base in a suitable reaction inert solvent with heating; or reacting an intermediate of formula (II) with an intermediate of formula (III) in the presence of a suitable base and a suitable catalyst under heating in a suitable reaction-inert solvent,

R₁and R₂As defined in claim 1;

b) reacting a compound of formula (I-b) with a suitable fluorinating agent in a suitable reaction-inert solvent at moderately low temperature,

l represents C_1～4Alkyl, and R₁As defined in claim 1;

c) reacting the intermediate of formula (IV) with a suitable fluorinating agent in a suitable reaction-inert solvent at moderately low temperature,

R₁as defined in claim 1;

d) hydrogenating the intermediate of formula (XIV) in a suitable solvent in the presence of a suitable catalyst and a suitable base,

R₁as defined in claim 1, and R'₂Represents fluorine substituted C_1～4An alkoxy group;

or, if desired, further converting the compound of formula (I) into a mutual variant known in the art; or if desired, further converting the compound of formula (I) into a therapeutically active non-toxic acid addition salt by treatment with an acid; or conversely, treating with a base to convert the acid addition salt form to the free base; or, if desired, preparing stereochemically isomeric forms of said compounds of formula (I).