ES2362249T3 - DERIVATIVES OF 3-CIANO-4- (4-TETRAHYDROPIRAN-PHENYL) -PIRIDIN-2-ONA. - Google Patents

Abstract

A compound of the formula: ** Formula ** (I) including any of its stereochemically isomeric forms, in which: R1 is C4-6 alkyl or C1-3 alkyl substituted with C3-7 cycloalkyl; - R2 is hydrogen, halogen or trifluoromethyl; - R3 is hydrogen or C1-4 alkyl substituted with hydroxyl; - X is O or NH; - n is an integer with a value of 1 or 2; or one of its pharmaceutically acceptable salts or solvates, said compound being different from: ** Formula **

Description

Field of the Invention

The present invention relates to novel derivatives of pyridin-2-one that are positive allosteric modulators of the subbotot 2 metabotropic glutamate receptor ("mGluR2") that are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. The invention also relates to pharmaceutical compositions containing said compounds, to methods for preparing said compounds and said compositions and to the use of said compounds for the prevention or treatment of neurological and psychiatric disorders and diseases in which mGluR2 is involved.

Background of the invention

Glutamate is the main neurotransmitter amino acid in the central nervous system of mammals. Glutamate plays a leading role in numerous physiological functions, such as learning and memory, but also in sensory perception, the development of synaptic plasticity, motor control, respiration and the regulation of cardiovascular function. In addition, glutamate is the center of several neurological and psychiatric diseases in which there is an imbalance in glutamatergic neurotransmission.

Glutamate mediates synaptic neurotransmission by activating the ionotropic glutamate receptor channels (iGluRs) and receptors for NMDA, AMPA and kainate that are responsible for rapid excitatory transmission.

In addition, glutamate activates metabotropic glutamate receptors (mGluRs) that have a more modulating role that contributes to the fine tuning of synaptic efficacy.

Glutamate activates mGLuRs by binding to the large amino-terminal extracellular domain of the receptor, referred to herein as an orthostatic binding site. This link induces a change of conformation in the receptor which causes the activation of the G protein and in the intracellular signaling pathways.

The mGluR2 subtype is negatively coupled with adenylate cyclase by activating the G� protein and its activation leads to inhibition of glutamate release at the synapse. In the central nervous system (usually abbreviated as CNS by its initials in English: central nervous system), mGluR2 receptors are abundant, mainly in the cortex, thalamic regions, the accessory olfactory bulb, the hippocampus, the amygdala, the caudate. putamen and nucleus accumbens.

It has been shown in clinical trials that mGluR2 activation is effective in treating anxiety disorders. In addition, the activation of mGluR2 in several animal models proved effective, thus representing a potential new therapeutic approach, for the treatment of schizophrenia, epilepsy, drug addition / dependence, Parkinson's disease, pain, Sleep disorders and Huntington's disease.

To date, most of the available pharmacological tools that target mGluRs are orthostatic ligands that activate several family members since they are structural analogs of glutamate.

A new way to develop selective compounds that act as mGluRs is the identification of compounds that act through allosteric mechanisms, modulating the receptor by binding to a different site from the highly conserved orthostatic binding site.

Positive allosteric modulators of mGluRs have recently emerged as new pharmacological entities that offer this attractive alternative. Several compounds have been described as positive allosteric modulators of mGluR2.

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

WO2007 / 104783 describes 1,4-disubstituted 3-cyano-pyridone derivatives that are positive allosteric modulators of metabotropic receptors of subtype 2 ("mGluR2"). Derivatives of 3-cyano-pyridin2-one and its use as antagonists of mGluR2 are also described in WO2006 / 030032 and WO2007 / 104783.

It has been shown that said compounds do not activate the receptor themselves. Rather, they allow the receptor to produce a maximum response to a glutamate concentration that by itself induces a minimal response. Mutational analysis has unequivocally demonstrated that the binding of positive allosteric modulators of the

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mGluR2 does not occur at the orthostatic site but at an allosteric site located between the transmembrane region seven of the receptor.

Animal data suggest that mGluR2 positive allosteric modulators have effects in anxiety and psychosis models similar to those obtained with orthostatic agonists. It has been shown that mGluR2 allosteric modulators are active in fear-driven shock and stress-induced hyperthermia in anxiety models. In addition, these compounds have been shown to be active in the reversal of amphetamine-induced disorder of prepulse inhibition of the effect of acoustic shock in schizophrenia models (J. Pharmacol. Exp. Ther. 2006, 318, 173-185; Psychopharmacology 2005, 179, 271-283).

Recent animal studies have also revealed that the selective positive allosteric modulator of the biphenyl-indanone subtype 2 metabotropic glutamate receptor (BINA) blocks a hallucinogenic psychosis drug model, supporting the targeting strategy in mGluR2 receptors to treat dysfunction glutamatergic in schizophrenia (Mol. Pharmacol. 2007, 72, 447-484).

Positive allosteric modulators allow the potentiation of the glutamate response, but it has also been shown to enhance the response to orthostatic agonists of mGluR2, such as LY379268 or DCG-IV. These data provide evidence for yet another new therapeutic approach to treat the neurological and psychiatric diseases mentioned above that involve mGluR2, which would use a combination of a positive allosteric modulator of mGluR2 together with an orthosteric agonist of mGluR2.

The present compounds are characterized by a central moiety of pyridine-2-one substituted in the 3-position with cyano and in the 4-position optionally substituted with a phenyl which in turn is substituted, in the 4-position, by a linking group with optionally substituted tetrahydropyran. The compounds present are potent positive allosteric modulators of mGluR2.

Description of the invention

The invention relates to compounds that have modulating activity of metabotropic glutamate receptor 2. The present invention provides a compound according to formula (I):

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Including any of its sterochemically isomeric forms, in which: -R1 is a C4-6 alkyl or C1-3 alkyl substituted with C3-7 cycloalkyl; -R2 is hydrogen, halogen or trifluoromethyl; -R3 is hydrogen or C1-4 alkyl substituted with hydroxyl; -ZesOoNH; -n is an integer of value 1 or 2;

or one of its pharmaceutically acceptable salts or solvates; with the proviso that the compound is different from: The present invention also relates to a compound of formula (I) or any of its subgroups for use in the treatment or prevention, in particular for the treatment, of a condition in a mammal, including a human, whose treatment or prevention is affected or facilitated by the neuromodulatory effect of an allosteric modulator of mGluR2, in particular a positive allosteric modulator.

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An embodiment of the present invention are those compounds of formula (I) in which R1 is a C4-6 alkyl, in particular C4-5 alkyl, such as for example 1-butyl, 2-methyl-1-propyl or 3-methyl-1-butyl; in particular 1-butyl

or 3-methyl-1-butyl.

An embodiment of the present invention are those compounds of formula (I) in which R 1 is a C 1-3 alkyl substituted with C 3-7 cycloalkyl, in particular cyclopropylmethyl or 2- (cyclopropyl) -1-ethyl, more particularly cyclopropylmethyl .

An embodiment of the present invention are those compounds of formula (I) or any of its subgroups as mentioned hereinbefore as an embodiment, wherein R2 is hydrogen.

An embodiment of the present invention are those compounds of formula (I) or, whenever possible, any of its subgroups as mentioned hereinbefore as an embodiment, in which R2 is a halogen, in particular fluorine or chlorine

An embodiment of the present invention are those compounds of formula (I) or, whenever possible, any of its subgroups as mentioned hereinbefore as an embodiment, wherein R2 is a trifluoromethyl.

An embodiment of the present invention are those compounds of formula (I) or, whenever possible, any of its subgroups as mentioned hereinbefore as an embodiment, in which R3 is hydrogen.

An embodiment of the present invention are those compounds of formula (I) or, whenever possible, any of its subgroups as mentioned hereinbefore as an embodiment, in which R3 is a C1-4 alkyl substituted with hydroxyl; in particular where R3 is CH2OH.

An embodiment of the present invention are those compounds of formula (I) or, whenever possible, any of its subgroups as mentioned hereinbefore as an embodiment, in which X is O.

An embodiment of the present invention are those compounds of formula (I) or, whenever possible, any of its subgroups as mentioned hereinbefore as an embodiment, in which X is NH.

An embodiment of the present invention are those compounds of formula (I) or, whenever possible, any of its subgroups as mentioned hereinbefore as an embodiment, in which n is 1.

An embodiment of the present invention are those compounds of formula (I) or, whenever possible, any of its subgroups as mentioned hereinbefore as an embodiment, in which n is 2.

An embodiment of the present invention are those compounds of formula (I) or, whenever possible, any of its subgroups as mentioned hereinbefore as an embodiment, in which n is 1 and R2 is different of hydrogen and said R2 is located in meta-position with respect to the rest of pyridinone.

An embodiment of the present invention are those compounds of formula (I) or, whenever possible, any of its subgroups as mentioned hereinbefore as an embodiment, in which n is 1 and R2 is other than hydrogen and said R2 is positioned ortho-with respect to the rest of pyridinone.

An embodiment of the present invention are those compounds of formula (I) in which R1 is C4-6 alkyl,

10 in particular 1-butyl or 3-methyl-1-butyl; or C1-3 alkyl substituted with C3-7 cycloalkyl, in particular cyclopropylmethyl or 2- (cyclopropyl) -1-ethyl;

-R2 is hydrogen, fluorine, chlorine or trifluoromethyl;

-R3 is hydrogen;

-nes1.

An embodiment of the present invention are those compounds of formula (I) chosen from,

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or one of its pharmaceutically acceptable salts or one of its solvates.

As used in the front or in the back of the present specification, the C1-3 alkyl notation as a

A group or a part of a group defines a saturated, linear or branched hydrocarbon radical having 1 to 3 carbon atoms, such as methyl, ethyl, 1-propyl and 1-methyl-1-ethyl. Preferably C1-3 alkyl represents methyl.

As used in the previous part or in the later part of the present specification, the C1-4 alkyl notation as a group or a part of a group defines a saturated, linear or branched hydrocarbon radical having 1 to 4 atoms of carbon, such as methyl, ethyl, 1-propyl, 1-methyl-1-ethyl, 1-butyl, 2-methyl-1-propyl. Preferably C1-4 alkyl represents methyl.

As used in the front or back of the present specification, the C4-6 alkyl notation as a group or a part of a group defines a saturated, linear or branched hydrocarbon radical, having 4 to 6 atoms of carbon, such as 1-butyl, 2-methyl-1-propyl, 1-pentyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 1-hexyl and the like. Preferably C4-6 alkyl represents 1-butyl.

As used in the front or back of the present specification, the C4-5 alkyl notation as a group or a part of a group defines a saturated, linear 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 and the like.

As used in the front or back of the present specification, the C3-7 cycloalkyl notation defines a saturated cyclic hydrocarbon radical having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl . Preferably the C3-7 cycloalkyl represents cyclopropyl.

As used in the front or the back of the present specification, the halo (or halogen) notation is generic for fluorine, chlorine, bromine and iodine.

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

Pharmaceutically acceptable salts are defined to comprise the saline forms of addition of non-toxic active acids that the compounds according to formula (I) are capable of forming. Said salts can be obtained by treating the base form of the compounds according to the formula () with appropriate acids, for example inorganic acids, for example hydrazic acids, in particular hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; organic acids, for example acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, masonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, ptoluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid and pammic acid.

Conversely, said acidic salt forms can be converted into the free base form by treatment with the appropriate base.

The compounds according to formula (I) which contain acidic protons can also be converted into their basic non-toxic basic salt forms therapeutically active by treatment with organic and inorganic bases. Suitable basic salt forms comprise, for example, ammonium salts, alkali metal and alkaline earth metal salts, in particular lithium, sodium, potassium, magnesium and calcium salts, salts with organic bases, for example benzathine salts, N -methyl-D-glucamine and hibramiana and salts with amino acids, for example arginine and lysine.

Conversely, said basic salt forms can be converted into their free acid forms by treatment with an appropriate acid.

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

The term solvate comprises the solvent addition forms as well as their pharmaceutically acceptable salts that the compounds of formula (I) are capable of forming. Examples of such solvent addition forms are, for example, hydrates, alcoholates and the like.

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

The term "stereochemically isomeric forms" as used hereinbefore defines all possible isomeric forms that the compounds of formula (I) may possess. Unless otherwise indicated or indicated, the chemical designation of the compounds indicates the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the base molecular structure. But the invention also includes each of the individual isomeric forms of the formula (I) and their essentially free salts or solvates, that is to say associated with less than 10%, preferably less than 5%, in particular less than 2% and more preferably less than 1% of the other isomers. Therefore, when a compound of formula (I) is specified for example as (R), this means that the compound is essentially free of the isomer (S).

In particular, stereogenic centers may have the R-or S- configuration; the substituents on the (partially) saturated bivalent cyclic radicals may have either the cis- or trans- configuration.

According to the conventions of the CAS nomenclature, when two stereogenic centers of known absolute configuration are present in a compound, an R or S descriptor (based on the Cahn-Ingold-Prelog sequence rule) is assigned for the chiral center with the lowest numbering , the reference center. The configuration of the second stereogenic center is indicated using the relative descriptors [R *, R *], where R * is always specified as the reference center and [R *, R *] indicates the centers with the same chirality and [R * , S *] indicate centers with different chirality. For example, if the chiral center with the lowest numbering in the compound has an S configuration and the second center is R, the stereo descriptor would be specified as S- [R *, S *]. If “�” and “�” are used: the position of the highest priority substituent in the asymmetric carbon atom in the ring system that has the smallest number in the ring, is always arbitrarily in the “�” position of the middle plane determined by the ring system. The position of the highest priority substituent on the other asymmetric carbon atoms in the ring system (hydrogen atom in the compounds according to formula (I)) with respect to the position of the highest priority substituent on the reference atom is called "�", if it is on the same side of the middle plane determined by the ring system, or "�" if it is on the other side of the middle plane determined by the ring system.

Whenever the term "compounds of formula (I)" or any of its subgroups is used in the following part of the present specification, it is also considered to include its stereochemically isomeric forms, pharmaceutically acceptable salts and solvates. Of special interest are those compounds of formula (I) that are sterochemically pure.

Within the framework of this application, an element, in particular when mentioned in relation to a compound according to formula (I), comprises all isotopes and isotopic mixtures of this element, either naturally present or synthetically processed, or with natural abundance or in an isotopically enriched form. In particular when hydrogen is mentioned, it is understood that it refers to 1H, 2H, 3H or mixtures thereof; when carbon is mentioned, it is understood that it refers to 11C, 12C, 13C, 14C or mixtures thereof; when nitrogen is mentioned, it is understood that it refers to 13N, 14N, 15N or mixtures thereof; when oxygen is mentioned, it is understood that it refers to 14O, 15O, 16O, 17O, 18O or mixtures thereof; and when fluorine is mentioned it is understood that it refers to 18F, 19F or mixtures thereof. The compounds according to the invention also therefore comprise compounds with one or more isotopes of one or more elements, and mixtures thereof, including radioactive compounds, also called radiolabeled compounds, in which one or more non-radioactive atoms have been replaced by one of its radioactive isotopes. In particular, the radioactive atom is chosen from the group of hydrogen, carbon, nitrogen, sulfur, oxygen and halogen. Preferably, the radioactive atom is chosen from the group of hydrogen, carbon and halogen. In particular, the radioactive isotope is chosen from the group of 3H, 11C, 18F, 122I, 123I, 125I, 131I, 75Br, 76Br, 77Br and 82Br. Preferably the radioactive isotope is chosen from the group of 3H, 11C and 18F.

Whenever it is used in the previous part or in the following part of the present specification that the substituents can each be chosen independently from a list of definitions, it is understood that all possible combinations are chemically possible.

The lines drawn on the substituents in the ring systems indicate that the bond can be attached to any of the suitable ring atoms.

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

Experimental Procedure 1

The compounds of the formula (I) can be prepared by reacting an intermediate of formula (II) in which Y represents a group suitable for coupling mediated by Pd with boronic acids or boronic esters, such as, for example, a halogen or triflate, with an intermediate of formula (III) in which R4 and R5 represent hydrogen

or C1-4 alkyl, or in which R4 and R5 can be taken together to form, for example, the bivalent radical of the formula -CH2CH2-, -CH2CH2CH2-or -C (CH3) 2-C (CH3) 2-, according to reaction scheme (1). The reaction can be carried out in a suitable inert solvent with respect to the reaction, such as, for example, 1,4-dioxane, or mixtures of inert solvents, such as, for example, 1,4-dioxane / DMF, in the presence of a suitable base, such as, for example, aqueous NaHCO3 or Na2CO3, a suitable catalyst, such as for example a catalyst with Pd complex such as, for example, Pd (PPh3) 4, under thermal conditions such as, for example , heat the reaction mixture at 150 ° C with microwave irradiation, for example 10 minutes. In the Reaction Scheme (1), all variables are defined as in formula (I) or as defined above.

Reaction Scheme (1)

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The compounds of formula (I) and some of the intermediates in the present invention may contain an asymmetric carbon atom. The stereochemically pure isomeric forms of said compounds and said intermediates can be obtained by applying procedures known in the art. For example, diastereoisomers can be separated by physical methods, such as selective recrystallization or chromatographic techniques, for example counter current distribution, chiral liquid chromatography and similar methods. The enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolution agents, such as, for example, chiral acids, into mixtures of salts or diasteromeric compounds; then separating said mixtures of salts or diasteromeric compounds by, for example, selective crystallization or chromatographic techniques, for example liquid chromatography and similar methods; and finally, converting said salts or separated diasteromeric compounds into the corresponding enantiomers. Sterochemically pure isomeric forms can also be obtained from stereochemically pure isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions proceed stereospecifically.

An alternative way of separating the enantiomeric forms of the compounds of formula (I) and intermediates involves liquid chromatography or SCF chromatography (supercritical fluids, for its initials in English: supercritical fluid), in particular using a stationary chiral phase.

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

Intermediates can also be prepared by the following experimental procedures 2 to 11.

Experimental Procedure 2

The intermediates of formula (II) in which Y represents halogen, said intermediates being represented by formula (II-a), can be prepared by reacting an intermediate of formula (IV) with a suitable halogenating agent, such as, for example , P (= 0) Br3. The reaction can be carried out in a suitable inert solvent for the reaction, such as, for example, DMF, at a moderately elevated temperature, such as, for example, 110 ° C. In the Reaction Scheme (3) all variables are defined as in formula (I).

Reaction Scheme (2)

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Experimental Procedure 3

The intermediates of formula (II) in which Y represents triflate, said intermediates being represented by formula (II-b), can be prepared by reacting an intermediate of formula (IV) with triflic anhydride (also called trifluoromethanesulfonic anhydride) according to the reaction scheme (4). The reaction can be carried out in a suitable inert solvent for the reaction, such as, for example, dichloromethane, in the presence of a suitable base, such as, for example, pyridine, at a low temperature, such as, for example, -78 ° C . In the reaction scheme (2) all variables are as defined in formula (I).

Reaction Scheme (3)

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Experimental procedure 4

The intermediates of the formula (IV) can be prepared by procedures known in the art by reacting an intermediate of the formula (V) with a reagent suitable for the cleavage of the methyl ether, such as, for example, NaOH, in a suitable solvent, such as, for example, water, at a moderately high temperature, such as, for example, 100 ° C. In the reaction scheme (4), all variables are defined as in formula (I).

Reaction Scheme (4)

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Experimental procedure 5

The intermediates of formula (V) can be prepared by methods known in the art by reacting the commercially available 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile with an alkylating agent of formula (VI), such as, for example, cyclopropylmethyl bromide, according to the reaction scheme (5). The reaction can be carried out in an inert solvent, such as, for example, acetonitrile, using a suitable base, such as, for example, K2CO3, and, optionally, an iodide salt, such as, for example KI, at a temperature moderately high, such as, for example, 120 ° C. In the reaction scheme (5), all variables are as defined in formula (I) and Z is a suitable leaving group, such as, for example, halogen, for example, bromine.

Reaction Scheme (5)

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Experimental procedure 6

The intermediates of the formula (III) can be prepared by procedures known in the art by reacting an intermediate of the formula (VII) in which halo represents chlorine, bromine or iodine, with a suitable boron source, such as, for example, bis (pinacolato) diboro, in the presence of a suitable catalyst, such as a palladium catalyst, such as, for example, 1,1'-bis (diphenylphosphino) ferrocenopaladium (II) dichloride, according to reaction scheme (6) . The reaction can be carried out in an inert solvent, such as, for example, dichloromethane, in the presence of a suitable salt, such as, for example, potassium acetate, at a moderately elevated temperature, such as, for example, 110 ° C, during for example 16 hours.

Alternatively, intermediates of formula (III) can also be prepared by methods known in the art of metal-halogen exchange and subsequent reaction with a suitable boron source from intermediates of formula (VII) with an organolytic compound, such such as, for example, n-butyllithium, at a moderately low temperature, such as, for example, -40 ° C, in an inert solvent, such as, for example, THF, followed by subsequent reaction with a suitable boron source, such as, for example, trimethoxyborane.

In the reaction scheme (6), all variables are defined as in formula (I), and R4 and R5 are as defined hereinbefore.

Reaction Scheme (6)

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Experimental procedure 7

The intermediates of formula (VII) in which X represents NH and R3 represents hydrogen, being represented

5 said intermediates by the formula (VII-a), can be prepared by procedures known in the art by reacting an aniline intermediate of formula (VIII-a) with tetrahydro-4h-pyran-4-one according to the reaction scheme ( 7). The reaction can be carried out in the presence of a suitable reducing agent, such as, for example, sodium hydride, in an inert solvent, such as, for example, 1,2-dichloroethane, at a moderately low temperature, such as, for example 25 ° C for example 3 days. In the reaction scheme (7) all variables are defined

10 as in formula (I) and halo can be chlorine, bromine or iodine.

Reaction Scheme (7)

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Experimental procedure 8

The intermediates of formula (VII) in which X represents O and R3 represents hydrogen, being represented

Said intermediates by the formula (VII-b), can be prepared by methods known in the art by reacting a phenol intermediate of formula (VIII-b) with tetrahydro-4-pyranol according to the reaction scheme (8). The reaction can be carried out in the presence of a phosphine, such as for example triphenylphosphine, and a coupling agent suitable for Mitsunobu type couplings, such as, for example, di-tertbutyl azodicarboxylate, in an inert solvent, such as, for example , dichloromethane, at moderately low temperature, such as,

20 for example 25 ° C for example 2 hours. In the reaction scheme (8) all variables are defined as in formula (I) and halo can be chlorine, bromine or iodine.

Reaction Scheme (8)

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Experimental procedure 9

The intermediates of formula (VII) can also be prepared by methods known in the art from an intermediate similar to the aniline of formula (IX) by a Sandmeyer type reaction according to the reaction scheme (9). In the reaction scheme (9) all variables are defined as in formula (I) and halo can be chlorine, bromine or iodine.

Reaction Scheme (9)

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Experimental procedure 10

The intermediates of formula (IX) can be prepared by procedures known in the art from a nitro intermediate of formula (X) by reduction of the nitro group to the amine function by procedures known in the art, such as catalytic hydrogenation or use of zinc (II) chloride dihydrate as a reducing agent, according to the reaction scheme (10). In the reaction scheme (10) all variables are as defined in formula (I) and halo can be chlorine, bromine or iodine.

Reaction Scheme (10)

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Experimental procedure (11)

The intermediates of formula (X) can be prepared by methods known in the art by reacting an intermediate of formula (XI) with a suitable tetrahydropyranyl intermediate of formula (XII), such as, for example, tetrahydro-4-pyranol, according to the reaction scheme (11). The reaction can be carried out in the presence of a suitable base, such as, for example, cesium carbonate, in an inert solvent, such as, for example, tetrahydrofuran, at a moderately elevated temperature, such as, for example, 140 ° C, for example 16 hours. In the reaction scheme (11) all variables are defined as in formula (I) and halo can be chlorine, bromine or iodine.

Reaction Scheme (11)

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Pharmacology

The compounds provided by this invention are positive allosteric modulators of metabotropic glutamate receptors, in particular they are positive allosteric modulators of mGluR2. The compounds of the present invention do not appear to bind to the glutamate recognition site, the orthostatic ligand site, but to an allosteric site in the transmembrane region seven of the receptor. In the presence of glutamate or an mGluR2 antagonist, the compounds of this invention increase the response of mGluR2. The compounds provided in this invention are expected to have their effect on mGluR2 by virtue of their ability to increase the response of said receptors to glutamate or mGluR2 agonists, increasing the response of the receptor. Therefore, the present invention relates to a compound according to the present invention for use as a medicine, as well as to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the preparation of a medicament for the treatment or treatment. prevention, in particular the treatment, of a state in a mammal, including a human, whose treatment or prevention which is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, in particular its positive allosteric modulators. The present invention also relates to a compound according to the present invention or a pharmaceutical composition according to the invention for use in the preparation of a medicament for the treatment or prevention, in particular in the treatment, of a condition in a mammal, including a human, whose treatment or prevention is affected or facilitated by the neuromodulatory effect of mGluR2 modulators, in particular their positive allosteric modulators. The present invention also relates to a compound according to the present invention or a pharmaceutical composition according to the invention for the treatment or prevention, in particular the treatment, of a condition in a mammal, including a human, whose treatment or prevention is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, in particular their positive allosteric modulators.

Furthermore, the present invention relates to the use of a compound according to the invention or a pharmaceutical composition according to the invention for the preparation of a medicament for the treatment, prevention, improvement, control or reduction of the risk of various neurological disorders and psychiatric associated with glutamate dysfunction in a mammal, including a human, whose treatment or prevention is affected or facilitated by the neuromodulatory effect of mGluR2 positive allosteric modulators.

When it is said that the invention relates to the use of a compound or composition according to the invention for the preparation of a medicament, for example for the treatment of a mammal, it is understood that said use should be interpreted in some jurisdictions as a method for, for example, the treatment of a mammal which comprises administering to a mammal in need of said treatment an amount of a compound or a 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, for example, brain deficits subsequent to graft and coronary artery bypass grafting, attack, ischemia cerebral, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia (including AIDS-induced dementia), Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, eye damage, retinopathy, cognitive disorders, Idiopathic and drug-induced Parkinson's disease, muscle spasms and disorders associated with muscle spasticity, including tremor, epilepsy, seizures, migraine (including migraine headache), urinary incontinence, substance tolerance, substance abandonment (including substances such as, by axis mplo, opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety (including generalized anxiety disorder, panic disorder and obsessive-compulsive disorder), state disorders mood (including depression, mania, bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, pulmonary edema, pain (including acute and chronic states, severe panic, intractable panic, neuropathic panic and post-panic traumatic), tardive dyskinesia, sleep disorders (including narcolepsy), attention deficit / hyperactivity disorder and behavioral disorders.

In particular, the present invention relates to the use of a compound of formula (I) for the preparation of a medicament for the treatment or prevention, in particular for the treatment, of a disorder of the central nervous system chosen from the group of anxiety disorders, psychotic disorders, personality disorders, substance-related disorders, eating disorders, mood disorders, migraine, epilepsy or seizure disorders, childhood disorders, cognitive disorders, neurodegeneration, neurotoxicity and ischemia.

Preferably, the central nervous system disorder is an anxiety disorder chosen from the agoraphobia group, generalized anxiety disorder (usually abbreviated as GAD by its initials in English: generalized anxiety disorder), obsessive-compulsive disorder (usually abbreviated as OCD for its initials in English: obsessive-compulsive disorder), panic disorder, post-traumatic stress disorder (usually abbreviated as PTSD for its initials in English: posttraumatic stress disorder), social phobia and other phobias.

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

Preferably, the central nervous system disorder is a disorder related to a substance chosen from the group of alcohol abuse, alcohol dependence, alcohol withdrawal, 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 chosen from the group of anorexia nervosa and bulimia nervosa.

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

Preferably, the central nervous system disorder is migraine.

Preferably, the disorder of the central nervous system is epilepsy or a seizure disorder chosen from the group of generalized nonconvulsive epilepsy, generalized seizure epilepsy, poor small epileptic state, large bad epileptic state, partial epilepsy with or without alterations of consciousness, spasms children, continuous partial epilepsy and other forms of epilepsy.

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

Preferably, the central nervous system disorder is a cognitive disorder chosen from the group of delirium, persistent delirium induced by a substance, dementia, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's dementia due to Alzheimer's disease, persistent substance-induced dementia and mild cognitive deficiency.

Of the disorders mentioned above, the treatment of anxiety, schizophrenia, migraine, depression and epilepsy are of particular importance.

To this day, the fourth edition of the Diagnostic & Statistical Manual of Mental Disorders (DSM-IV) document of the American Psychiatric Association provides a diagnostic tool for the identification of the disorders described herein. Those skilled in the art will recognize that there are alternative nomenclatures, nosologies and classification systems for the disorders described herein and that these evolve with medical and scientific progress.

Because such positive allosteric modulators of mGluR2, including the compounds of formula (I), increase the response of mGluR2 to glutamate, it is an advantage that the methods herein use endogenous glutamate.

Because such positive allosteric mGluR2 modulators, including the compounds of formula (I), increase the response of mGluR2 to agonists, it is understood that the present invention extends to the treatment of neurological and psychiatric disorders associated with glutamate dysfunction by administration of an effective amount of a positive allosteric modulator of mGluR2, including the compounds of formula (I), in combination with an agonist of mGluR2.

The compounds of the present invention can be used in combination with one or more other drugs in the treatment, prevention, control, improvement or reduction of the risk of diseases or conditions for which the compounds of formula (I) or Other drugs may be useful, when the combination of drugs together is safer or more effective than each drug alone.

Pharmaceutical compositions

The invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, an effective amount of a compound according to the invention, in particular a compound according to formula (I), including one of its stereochemically forms isomeric, or one of its pharmaceutically acceptable salts or one of its solvates.

The compounds according to the invention, in particular the compounds according to formula (I), including one of its stereochemically isomeric forms, or one of its pharmaceutically acceptable salts or one of its solvates, or any of its subgroups or combinations, can be formulated in various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions commonly employed for the systematic administration of drugs.

To prepare the pharmaceutical compositions of the present invention, an effective amount of a particular compound, optionally in the form of salt, as an active ingredient is combined intimately mixed with a pharmaceutically acceptable carrier or diluent, whose carrier or diluent can take a wide variety of forms. depending on the form of preparation desired for administration. These pharmaceutical compositions are suitable in unit dosage forms, in particular for oral, rectal, percutaneous, parenteral injection or inhalation administration. For example, in the preparation of compositions in oral dosage form, any usual pharmaceutical medium such as, for example, water, glycols, oils, alcohols and the like can be used in the case of oral liquid preparations such as, for example, suspensions , syrups, elixirs, emulsions and solutions; or solid vehicles such as, for example, starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, tablets, capsules and tablets. Due to the ease of administration, oral administration is preferred, and the tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier will generally comprise sterile water, at least to a large extent, although other ingredients may be included, for example to aid in solubility. Injectable solutions can be prepared, for example, in which the vehicle comprises saline solution, glucose solution or a mixture of saline solution and glucose. Injectable suspensions can also be prepared in which case appropriate liquid vehicles, suspending agents and the like can be used.

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Also included are preparations in solid form that are intended to convert them, immediately before use, into preparations in liquid form. In compositions suitable for percutaneous administration, the vehicle optionally a penetration enhancing agent and / or a suitable moisturizing agent, optionally combined with suitable additives of any nature in minor proportions, whose additives do not introduce a significant detrimental effect on the skin. Such additives may facilitate administration to the skin and / or may be useful for preparing the desired compositions. These compositions can be administered in various ways, for example as transdermal patches, as a spot-on pipette or as an ointment.

It is especially advantageous to formulate the pharmaceutical compositions mentioned above in a unit dosage form for ease of administration and dosage uniformity. The unit dosage form, as used herein, refers to physically discrete units suitable for unit dosage, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical vehicle. . Examples of such unit dosage forms are tablets (including grooved or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and their multiple segregates.

The exact dose and frequency of administration depends on the compound of particular formula (I) used, the particular condition being treated, the severity of the condition being treated, age, weight, sex, extent of the disorder and the general physical condition of the particular patient as well as other medication that the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be decreased or increased depending on the response of the treated subject and / or depending on the evaluation of the prescribing physician of the compounds of the present invention.

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

As already mentioned, the invention also relates to a pharmaceutical composition comprising the compounds according to the invention and other or other drugs in the treatment, prevention, control, improvement or reduction of the risk of diseases or conditions for the that the compounds of the formula (I) or the other drugs may have utility, as well as the use of said composition in the manufacture of a medicament. The present invention also relates to a combination of a compound according to the present invention and an orthostatic agonist of mGluR2. The present invention also relates to a product comprising (a) a compound according to the present invention, one of its pharmaceutically acceptable salts or one of its solvates, and (b) an orthostatic agonist of mGluR2, as a combined preparation for use. Simultaneous, separate or sequential in the treatment or prevention of a condition in a mammal, including a human, whose treatment or prevention is affected or facilitated by the neuromodulatory effect of allosteric modulators of mGluR2, in particular mGluR2 positive allosteric modulators. Drugs other than said combination or product may be combined in a single preparation together with pharmaceutically acceptable carriers or diluents, or they may each be present in a separate preparation together with pharmaceutically acceptable carriers or diluents.

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

Experimental part

Several methods for preparing the compounds of this invention are illustrated in the following examples. Unless otherwise indicated, all initial materials are obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and through the specification.

DMC

dichloromethane

DMF

dimethylformamide

Et2O

diethyl ether

EtOAc

ethyl acetate

g

grams

HPLC

High Resolution Liquid Chromatography

LCMS

Liquid Chromatography-Mass Spectrometry

MeOH

methanol

MHz

megahertz

ml

milliliters

min

minutes

mmol

millimoles

Pd (PPh3) 4

tetrakis (triphenylphosphine) palladium (0)

THF

tetrahydrofuran

All references to brine refer to a saturated aqueous solution of NaCl. Unless otherwise indicated, all temperatures are expressed in ° C (degrees Celsius). All reactions were performed in an inert atmosphere at room temperature, unless otherwise indicated.

Microwave assisted reactions were performed in a single-mode reactor: EmrysTM Optimizer microwave reactor (Personal Chemistry A. B., currently Biotage) or in a multimode reactor: MicroSYNTH Labstation (Milestone, Inc.).

A.-Preparation of intermediates

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To a solution of 2-cyclopropyl-ethanol (15.1 g, 175.3 mmol) and triethylamine (48.6 ml, 350.6 mmol) in dichloromethane (300 ml) at 0 ° C, methanesulfonyl chloride (20 , 35 ml, 262.9 mmol) dropwise and the mixture was then stirred at room temperature for 2 hours. Water was added and the phases were separated. The organic phase was dried (Na2SO4) and evaporated in vacuo to give the crude intermediate 1 (100%) used without

15 additional purification.

Example A.2

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

image2

To a solution of 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (12.2 g, 81.48 mmol) in acetonitrile (250 ml)

20 Bromomethyl-cyclopropane (11 g, 81.48 mmol) and potassium carbonate (22.48 g, 162.9 mmol) were added and the mixture was heated at 110 ° C for 24 hours. The mixture was cooled to room temperature and the solid was filtered. The filtrate was evaporated to dryness and the resulting crude residue was then triturated with diethyl ether to give pure intermediate 2 (15.72 g, 94%) as a white solid.

Example A.3

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

image2

To a solution of 4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (19.81 g, 131.98 mmol) in acetonitrile (520 ml) was added intermediate 1 (34.36 g, 171.57 mmol) and potassium carbonate (56.73 g, 410.3 mmol) and the mixture was heated at 105 ° C for 12 hours. The mixture was cooled to room temperature and the solid was filtered. He

The filtrate was evaporated to dryness. The crude product was purified by column chromatography (silica gel; DCM to DCM / EtOAc up to 20% as eluent). The desired fractions were collected and evaporated in vacuo to give pure intermediate 3 (13.18 g, 46%).

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Example A.4 1-Butyl-4-methoxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (intermediate 4)

image2

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

Example A.5

1-Cyclopropylmethyl-4-hydroxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (intermediate 5)

image2

Intermediate 2 (15.7 g, 76.8 mmol) was added at room temperature to a 1N aqueous solution of sodium hydroxide (300 ml) and THF (50 ml). The reaction mixture was heated at 140 ° C (oil bath temperature) for 16 hours. The mixture was cooled to room temperature and the THF was evaporated almost completely in vacuo. The aqueous phase was cooled to 0 ° C and acidified by the addition of 2N HCl, adjusting the pH to approximately 3, at which time a white solid precipitated. The solid was filtered, washed with Et2O and dried in vacuo to give intermediate 5 as a white solid (10.44 g, 71%) that was used without further purification.

Example A.6

1- (2-Cyclopropyl-ethyl) -4-hydroxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (intermediate 6)

image2

Intermediate 3 (13.18 g, 60.4 mmol) was added at room temperature to a 0.5N aqueous solution of sodium hydroxide (221 ml). The reaction mixture was heated at 110 ° C (oil bath temperature) for 12 hours. The mixture was cooled to 0 ° C and acidified by the addition of 2N HCl, adjusting the pH to approximately 3, at which time a white solid precipitated. The solid was filtered, washed with Et2O and dried in vacuo to give intermediate 6 as a white solid (11.24 g, 91%) that was used without further purification.

Example A.7

1-Butyl-4-hydroxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (intermediate 7)

image2

Intermediate 4 (27.39 g, 133 mmol) was added at room temperature to a 1N aqueous solution of sodium hydroxide (500 ml) and THF (50 ml). The reaction mixture was heated at 110 ° C (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 phase was then cooled to 0 ° C and acidified by the addition of 2N HCl, adjusting the pH to approximately 3, at which time a white solid precipitated. The solid was filtered, washed with Et2O and dried in vacuo to give intermediate 7 as a white solid (25 g, 98%) that was used without further purification.

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Example A.8 4-Bromo-1-cyclopropylmethyl-2-oxo-1,2-dihydro-pyridine-carbonitrile (intermediate 8)

image2

To a solution of intermediate 5 (10.4 g, 54.67 mmol) in DMF (250 ml) was added phosphorus oxybromide (III) (31.3 g, 109.3 mmol) and the mixture was heated to 110 ° C for 1.5 hours 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, dried over MgSO4 and the solvent was 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 give intermediate 8 (8.83 g, 64%).

Example A.9

4-Bromo-1- (2-cyclopropyl-ethyl) -2-oxo-1,2-dihydro-pyridine-3-carbonitrile (intermediate 9)

image2

To a solution of intermediate 6 (6.0 g, 29.37 mmol) in DMF (150 ml) was added phosphorus oxybromide (III) (16.84 g, 58.75 mmol) and the mixture was heated to 110 ° C during 3 hours. 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, dried over Na2SO4 and the solvent was 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 give intermediate 9 (7.0 g, 89%).

Example A.10

4-Bromo-1-butyl-2-oxo-1,2-dihydro-pyridine-3-carbonitrile (intermediate 10)

image2

To a solution of intermediate 7 (39 g, 203 mmol) in DMF (600 ml) was added phosphorus oxybromide (III) (116 g, 406 mmol) and the mixture was heated at 110 ° C for 1.5 hours. 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, dried over Na2SO4 and the solvent was 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 give intermediate 10 (36.7 g, 72%).

Example A.11

(4-Bromo-2-fluoro-phenyl) - (tetrahydro-pyran-4-yl) -amine (intermediate 11)

image2

A mixture of 4-bromo-2-fluoro-phenylamine (1 g, 5.26 mmol), tetrahydro-4H-pyran-4-one (0.73 ml, 7.89 mmol) and sodium triacetoxyborohydride (1.66 g, 7.89 mmol) in 1,2-dichloroethane (50 ml) was stirred at room temperature for 72 hours. The mixture was filtered through a diatomaceous earth pad. The diatomaceous earth pad was washed with dichloromethane. The combined filtrates were washed with NaHCO3 (saturated aqueous solution), dried over Na2SO4 and evaporated to dryness. The crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM / MeOH (NH3) up to 5%). The desired fractions were collected and evaporated in vacuo to give intermediate 11 as a yellow oil (1.44 g, 100%).

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image4

A mixture of 4-bromo-2-chloro-phenylamine (4 g, 19.37 mmol), tetrahydro-4H-pyran-4-one (2.69 ml, 29.05 mmol), oven-dried 4Å molecular sieves (2 g) and sodium triacetoxyborohydride (6.12 g, 29.05 mmol) in 1,2-dichloroethane (100 ml) was stirred at room temperature for 72 hours. The mixture was filtered through a diatomaceous earth pad. The diatomaceous earth pad was washed with dichloromethane. The combined filtrates were washed with NaHCO3 (saturated aqueous solution), dried over Na2SO4 and evaporated to dryness. The crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM / MeOH (NH3) up to 5%). The desired fractions were collected and evaporated in vacuo to give intermediate 12 as a brown oil (4.83 g, 86%).

Example A.13

(4-Bromo-2-trifluoromethyl-phenyl) - (tetrahydro-pyran-4-yl) -amine (intermediate 13)

image2

A mixture of 4-bromo-2-trifluoromethyl-phenylamine (0.88 g, 3.66 mmol), tetrahydro-4H-pyran-4-one (0.5 ml, 5.49 mmol), dried 4Å molecular sieves In an oven (1 g) and sodium triacetoxyborohydride (1.15 g, 5.49 mmol) in 1,2-dichloroethane (30 ml) was stirred at room temperature for 72 hours. The mixture was filtered through a diatomaceous earth pad. The diatomaceous earth pad was washed with dichloromethane. The combined filtrates were washed with NaHCO3 (saturated aqueous solution), dried over Na2SO4 and evaporated to dryness. The crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM / MeOH (NH3) up to 5%). The desired fractions were collected and evaporated in vacuo to give intermediate 13 as a yellow oil (1.11 g, 99%).

Example A.14

4- (4-Bromo-2-chloro-phenoxy) -tetrahydro-pyran (intermediate 14).

image2

A mixture of 4-bromo-2-chloro-phenol (4 g, 19.28 mmol), tetrahydro-4-pyranol (2.20 ml, 23.13 mmol) and triphenylphosphine on polymeric support (17.29 g, 39.29 mmol, purchased at Argonaut, with a load of 2.23 mmol / g) was suspended in dichloromethane (230 ml) and then cooled to 0 ° C. Di-tert-butyl azadicarboxylate (6.65 g, 28.92 mmol) was added portionwise and the reaction mixture was heated to room temperature and stirred for 2 hours. The resin was filtered and washed with dichloromethane. The combined filtrates evaporated to dryness. The crude product thus obtained was purified by column chromatography (silica gel; DCM to DCM / MeOH (NH3) up to 2%). The desired fractions were collected and evaporated in vacuo to give intermediate 14 as a colorless oil (5.38 g, 95%).

Example A.15

[2-Fluoro-4- (4,4,5,5, -tetramethyl- [1,3,2] dioxoborolan-2-yl) -phenyl] - (tetrahydro-pyran-4-yl) amine (intermediate 15)

image2

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To a solution of intermediate 11 (0.7 g, 2.55 mmol) in 1,4-dioxane (4.5 ml) and DMF (0.5 ml) was added bis (pinacolato) diboro (0.77 g , 3.06 mmol) and potassium acetate (0.75 g, 7.65 mmol). The mixture was degassed and then [1,1'-bis (diphenylphosphino) -ferrocene] -dichloropaladium (II) complex with DCM (1: 1) (0.062 g, 0.07 mmol) was added. The reaction mixture was heated at 150 ° C for 10 minutes with microwave irradiation. After cooling to room temperature, the mixture was filtered through a pad of diatomaceous earth. The diatomaceous earth pad was washed with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated in vacuo to give intermediate boronate (100%) as a crude product that was used without further purification.

Example A.16

[2-Chloro-4- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolan-2-yl) -phenyl] - (tetrahydropyran-4-yl) -amine (intermediate 16)

image2

To a solution of intermediate 12 (2 g, 6.88 mmol) in 1,4-dioxane (10.8 ml) and DMF (1.2 ml) was added bis (pinacolato) diboro (2.09 g, 8 , 25 mmol) and potassium acetate (2.02 g, 20.64 mmol). The mixture was degassed and then [1,1'-bis (diphenylphosphino) -ferrocene] -dichloropaladium (II) complex with DCM (1: 1) (0.16 g, 0.2 mmol) was added. The reaction mixture was heated at 150 ° C for 10 minutes with microwave irradiation. After cooling to room temperature, the mixture was filtered through a pad of diatomaceous earth. The diatomaceous earth pad was washed with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated in vacuo to give intermediate 16 boronate (100%) as a crude product that was used without further purification.

Example A.17

(Tetrahydropyran-4-yl) - [4- (4,4,5,5-tetramethyl- [1,3,2] dioxoborolan-2-yl) -2-trifluoromethyl-phenyl] -amine (intermediate 17)

image2

To a solution of intermediate 13 (1.11 g, 3.42 mmol) in 1,4-dioxane (4.5 ml) and DMF (0.5 ml) was added bis (pinacolato) diboro (1.04 g , 4.1 mmol) and potassium acetate (1.00 g, 10.26 mmol). The mixture was degassed and then [1,1'-bis (diphenylphosphino) -ferrocene] -dichloropaladium (II) complex with DCM (1: 1) (0.083 g, 0.1 mmol) was added. The reaction mixture was heated at 150 ° C for 10 minutes with microwave irradiation. After cooling to room temperature, the mixture was filtered through a pad of diatomaceous earth. The diatomaceous earth pad was washed with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated in vacuo to give intermediate 17 boronate (100%) as a crude product that was used without further purification.

Example A.18

4- [2-Chloro-4- (4,4,5,5-tetramethyl- [1,3,2] dioxoborolan-2-yl) phenoxy] -tetrahydro-pyran (intermediate 18)

image2

To a solution of intermediate 14 (2 g, 6.85 mmol) in 1,4-dioxane (10.8 ml) and DMF (1.2 ml) was added bis (pinacolato) diboro (2.01 g, 8 , 23 mmol) and potassium acetate (2.01 g, 20.55 mmol). The mixture was degassed and then [1,1’-bis (diphenylphosphino) -ferrocene] -dichloropaladium (II) complex with DCM (1: 1) (0.16 g, 0.2

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mmoles). The reaction mixture was heated at 150 ° C for 10 minutes with microwave irradiation. After cooling to room temperature, the mixture was filtered through a pad of diatomaceous earth. The diatomaceous earth pad was washed with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 and the solvent was evaporated in vacuo to give intermediate 18 boronate (100%) as a crude product that was used without further purification.

B.-Preparation of the final compounds.

Example B.1

1-Cyclopropylmethyl-4- [3-fluoro-4- (tetrahydro-pyran-4-ylamino) -phenyl] -2-oxo-1,2-dihydro-pyridine-3-carbonitirlo (compound 1)

image2

To a solution of intermediate 15 (0.8 g, 2.55 mmol) in 1,4-dioxane (3 ml) and a saturated solution of Na2CO3 (3 ml) was added intermediate 8 (0.58 g, 2 , 31 mmol). The resulting solution was degassed using a stream of nitrogen and Pd (PPh3) 4 (0.26 mg, 0.23 mmol) was added thereto. The reaction mixture was then irradiated with microwaves in a sealed tube at 150 ° C for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a diatomaceous earth pad. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM / EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to give compound 1 (0.241 g, 30%).

Example B.2

1-Cyclopropylmethyl-4- [3-chloro-4- (tetrahydro-pyran-4-ylamino) -phenyl] -2-oxo-1,2-dihydro-pyridine-3-carbonitrile (compound 2)

image2

To a solution of intermediate 16 (0.57 g, 1.7 mmol) in 1,4-dioxane (2 ml) and a saturated solution of Na2CO3 (2 ml) was added intermediate 8 (0.43 g, 1 , 7 mmol). The resulting solution was degassed using a stream of nitrogen and Pd (PPh3) 4 (0.19 mg, 0.17 mmol) was added thereto. The reaction mixture was then irradiated with microwaves in a sealed tube at 150 ° C for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a diatomaceous earth pad. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM / EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to give compound 2 (0.103 g, 16%).

Example B.3

1-Cyclopropylmethyl-2-oxo-4- [4- (tetrahydro-pyran-4-ylamino) -3-trifluoromethyl-phenyl] -1,2-dihydro-pyridine-3carbonitrile (compound 3)

image2

To a solution of intermediate 17 (0.63 g, 1.69 mmol) in 1,4-dioxane (3 ml) and a saturated solution of Na2CO3 (3 ml) was added intermediate 8 (0.42 g, 1 , 69 mmol). The resulting solution was degassed using a stream of nitrogen and Pd (PPh3) 4 (0.19 mg, 0.17 mmol) was added thereto. The reaction mixture was then irradiated with microwaves in a sealed tube at 150 ° C for 10 minutes. The resulting reaction mixture

5 cooled was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM / EtOAc up to 30% as eluent). The desired fractions were collected and evaporated in vacuo to give compound 3 (0.59 g, 9%).

Example B.4

10 4- [3-Chloro-4- (tetrahydro-pyran-4-yloxy) -phenyl] -1- (2-cyclopropyl-ethyl) -2-oxo-1,2-dihydro-pyridine-3-carbonitrile (compound 4)

image2

To a solution of intermediate 18 (0.57 g, 1.7 mmol) in 1,4-dioxane (2 ml) and a saturated solution of Na2CO3 (2 ml) was added intermediate 9 (0.45 g, 1 , 7 mmol). The resulting solution was degassed using a stream of nitrogen and Pd (PPh3) 4 (0.19 mg, 0.17 mmol) was added thereto. The reaction mixture was then irradiated with microwaves in a sealed tube at 150 ° C for 10 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a diatomaceous earth pad. The filtrate was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM / EtOAc up to 30% as eluent). The

20 desired fractions were collected and evaporated in vacuo to give compound 4 (0.108 g, 17%).

Table 1 shows the compounds of formula (I) that were prepared according to one of the previous examples (example No.).

Table 1

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40

C.-Analytical part

HPLC measurements were performed using an HP 1100 from Agilent Technologies comprising a pump (quaternary or binary) with a degasser, an autosampler, a column oven, a diode network detector (DAD) and a column as specified in the respective methods below. The column flow was divided to an MS detector. The EM detector was configured with an electrospray ionization source. Nitrogen was used as a nebulizer gas. The source temperature was maintained at 140 ° C. The data was acquired with the MassLynx-Openlynx program.

Method 1

In addition to the general procedure: reverse phase HPLC analysis was performed with an XDB-C18 cartridge (1.8 µm, 2.1 x 30 mm) from Agilen, with a flow rate of 1 ml / min at 60 ° C. The gradient conditions used were: 90% A (0.5 g / l ammonium acetate solution), 5% B (acetonitrile), 5% C (methanol) at 50% B and 50% C in 6.5 minutes. The injection volume was 2 µl. High resolution mass spectra (flight time, TOF) were collected only in positive ionization mode sweeping 100 to 750 in 0.5 seconds using a retention time of 0.1 seconds. The capillary needle voltage was 2.5 kV and the cone voltage was 20 V. The standard substance for the fixed mass calibration was leucine-enkephalin.

Method 2

In addition to the general procedure: reverse phase HPLC analysis was performed with an ACE-C18 column (3.0 µm, 4.6 x 30 mm) from Advanced Chromatography Technologies, with a flow rate of 1.5 ml / min at 40 ° C . The gradient conditions used were: 80% A (0.5 g / l ammonium acetate solution), 10% B (acetonitrile), 10% C (methanol) at 50% B and 50% C in 6.5 minutes, at 100% B at 7 minutes and equilibrated to the initial conditions at 7.5 minutes up to 9.0 minutes. The injection volume was 5 µl. High resolution mass spectra (flight time, TOF) were collected only in positive ionization mode sweeping 100 to 750 in 0.5 seconds using a retention time of 0.1 seconds. The capillary needle voltage was 2.5 kV for the positive ionization mode and the cone voltage was 20 V. The standard substance for the fixed mass calibration was leucine-enkephalin.

Melting Point Determination

Melting point determinations were performed with a Mettler FP62 apparatus.

Table 2: Analytical data (Rt means the retention time in minutes; (MH) + means the protonated mass of the compound (free base).

Comp. No.

Melting point (ºC) (MH) + Rt (min) LCMS method

one

249.5 368 3.56

one

2

It decomposes 384 3.81 one

3

It decomposes 418 4.17 one

4

It decomposes 399 4.26 one

5

nd 401 4.58 one

6

> 300 398 4.20 one

7

Nd 432 4.44 one

nd = not determined

D. Pharmacological examples

The compounds provided in the present invention are positive allosteric modulators of mGluR2. These compounds appear to potentiate glutamate responses by binding to an allosteric site other than the glutamate binding site. The response of mGluR2 to a glutamate concentration increases when the compounds of the formula (I) are present. Compounds of formula (I) are expected to have their effect essentially on mGluR2 by virtue of their ability to increase receptor function. The behavior of positive allosteric modulators analyzed in mGluR2 using the GTP�S [35S] binding assay method described below and which is suitable for the identification of said compounds and more particularly the compounds according to formula (I) are shown in table 3.

[35S] GTP�S binding assay The [35S] GTP�S binding assay is a functional membrane based assay used to study the function of the G-protein coupled receptor (GPCR) by which the incorporation of a non-hydrolysable form of GTP, [35S] GTP�S (guanosine 5'-triphosphate, labeled with gamma emitter 35S). The G protein subunit catalyzes the exchange of guanosine 5'-diphosphate (GDP) for guanosine triphosphate (GTP) and by activation of GPCR by an antagonist, [35S] GTP�S, is incorporated and cannot be cleaved to continue the exchange cycle (Harper (1998) Current Protocols in Pharmacology 2.6.1-10, John Wiley & Sons, Inc.). The amount of incorporation of radioactive [35S] GTP�S is a direct measure of the activity of the G protein and, therefore, the activity of the agonist can be determined. The mGluR2 receptors are preferentially coupled to the G�i protein, a preferential coupling for this method, and therefore widely used to study the activation of the MGluR2 receptors, both in recombinant cell lines and in 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). The use of the [35S] GTP�S assay using cell membranes transfected with the human mGluR2 receptor and adapted from Schaffhauser et al. ((2003) Molecular Pharmacology 4: 798-810) for the detection of positive allosteric modulation (PAM) properties of the compounds of this invention.

Membrane Preparation

CHO cells were cultured until preconfluence and stimulated with 5mM butyrate for 24 hours before washing them in PBS and then collected by scraping in homogenization buffer (50mM Tris-HCl buffer, pH 7.4, 4 ° C). Cell lysates were homogenized briefly (15 s) using an Ultraturrax homogenizer. The homogenate was centrifuged at 23,500 xg for 10 minutes and the supernatant was removed. The precipitate was resuspended in 5mM Tris-HCl, pH 7.4 and centrifuged again (30,000 xg, 20 minutes, 4 ° C). The final precipitate was resuspended in 50mM HEPES, pH 7.4 and stored at -80 ° C in appropriate aliquots before use. The protein concentration was determined by the Bradford method (Bio-Rad, United States) with bovine serum albumin as a standard.

Link test to [35S] GTP image6 S

The measurement of the positive allosteric modulating activity of mGluR2 of the test compounds in membranes containing human mGluR2 was performed using frozen membranes that were thawed and briefly homogenized before pre-incubation in 96-well microplates (15 µg / well of test, 30 minutes, 30 ° C) in test buffer solution (50mM HEPES, pH 7.4, 100mM NaCl, 3mM MgCl2, 50µM GDP and 10 µg / ml saponin), increasing the concentrations of positive allosteric modulator (from 0.3nM to 50µM ) and with a predetermined minimum concentration of glutamate (PAM test) or without added glutamate. For the PAM test, the membranes were pre-incubated with glutamate at EC25 concentration, that is, the concentration that gives 25% of the maximum glutamate response, according to published data (Pin et al. (1999) Eur. J. Pharmacol 375: 277-294 After adding [35S] GTP�S (0.1 nM, fc) to obtain a total reaction volume of 200 µl, the microplates were shaken briefly and then incubated to allow incorporation of the [35S] GTP�S during activation (30 minutes, 30 ° C.) The reaction was stopped by rapid vacuum filtration on fiberglass filter plates (96-well Unifilter filter plates GF / B, Perkin-Elmer, Downers Grove, United States) using a 96-well plate cell culture harvester (Filtermate, Perkin-Elmer, United States), and then washing it three times with 300 µl of buffer solution (Na2PO4 · 2H2O 10mM, NaH2PO4 · H2O 10mM, pH = 7 , 4) chilled on ice, then the filters are dried They were airborne and 40 µl of cocktail was added to each well for liquid scintillation measurements (Microscint-O), and the membrane-bound [35S] GTP�S was measured in a 96-well plate scintillation reader (Top -Count, Perkin-Elmer, United States). The non-specific binding of [35S] GTP�S was determined in the presence of cold 10µM GTP. Each curve was performed at least once using a duplicate sample for each point and at 11 concentrations.

Data analysis

Concentration-response curves of representative compounds of the present invention in the presence of ECG of mGluR2 agonist glutamate to determine positive allosteric modulation (PAM) were generated using the Prism GraphPad program (Graph Pad Inc., San Diego, United States) . The curves were adjusted to a four-parameter logical equation (Y = Lower Value + (Higher Value - Lower Value) / (1 + 10 ^ ((Log EC50 - X) * Slope) that allows the determination of EC50 values. EC50 is the concentration of a compound that produces a semi-maximal potentiation of the glutamate response, which is calculated by subtracting the maximum glutamate responses in the presence of a fully saturating concentration of a positive allosteric modulator of the glutamate response in the absence of positive allosteric modulator The concentration that produces semi-maximum effects is then calculated as the EC50.

Table 3: Pharmacological data for the compounds according to the invention

The compounds were tested in the presence of mGluR2 agonist, glutamate at a predetermined EC25 concentration, to determine positive allosteric modulation (GTP�S-PAM). The values shown are the average of duplicate values of 11 response-concentration curves, for at least one experiment. All test compounds had a pEC50 value (-log EC50) of more than 5.0. It is estimated that the error in determining a pEC50 value for a single experiment is approximately 0.3 logarithmic units.

Compound No.

pEC50 (GTP image6 S-hR2 PAM)

one

About 6

2

6.17

3

5.91

4

6.55

5

6.79

6

6.66

7

6.36

E.-Composition Examples The "active ingredient" as used in these examples refers to a final compound of formula (I), its pharmaceutically acceptable salts, solvates and its stereochemically isomeric forms. Typical examples of formulations of the invention are:

1.-Tablets Active ingredient 5 to 50 mg Dicalcium phosphate 20 mg

10 Lactose 30 mg Talc 10 mg Magnesium stearate 5 mg Potato starch 200 mg

In this example, the active ingredient can be substituted by the same amount of any of the compounds of the present invention, in particular by the same amount of any of the compounds of the examples.

2.-Suspension An aqueous suspension for oral administration is prepared so that each ml contains 1 to 5 mg of one of the active compounds, 50 mg of sodium carboxymethylcellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water up to 1 ml

20 3.-Injectable

A parenteral composition is prepared by stirring 1.5% by weight of the active ingredient of the invention in 10% by volume of propylene glycol in water. 4.-Ointment

Active ingredient 5 to 1,000 mg

25 Stearyl alcohol 3 g Lanolin 5 g White oil 15 g Water up to 100 g

In this example, the active ingredient can be substituted by the same amount of any of the compounds 30 of the present invention, in particular by the same amount of any of the compounds of the examples.

Reasonable variations should not be considered as outside the scope of the invention. It is clear that the invention described herein can be varied in many ways by those skilled in the art.

Claims (13)

1.-A compound of formula: image 1 including any of its stereochemically isomeric forms, in which: 5-R1 is C4-6 alkyl or C1-3 alkyl substituted with C3-7 cycloalkyl; -R2 is hydrogen, halogen or trifluoromethyl; -R3 is hydrogen or C1-4 alkyl substituted with hydroxyl; -XesOoNH; -n is an integer with a value of 1 or 2; 10 or one of its pharmaceutically acceptable salts or solvates, said compound being different from: image2 2. A compound according to claim 1, wherein R1 is 1-butyl or 3-methyl-1-butyl; or wherein R1 is cyclopropylmethyl or 2- (cyclopropyl) -1-ethyl. 3. A compound according to any one of the preceding claims, wherein R3 is CH2OH. 4. A compound according to any one of claims 1 to 3, wherein n is 1 and R2 is different from hydrogen, and said R2 is in a meta-position relative to the pyridinone moiety. 5. A compound according to claim 1, wherein R1 is 1-butyl, 3-methyl-1-butyl, cyclopropylmethyl or 2 (cyclopropyl) -1-ethyl; R2 is hydrogen, fluorine, chlorine or trifluoromethyl; R3 is hydrogen; and n is 1. 6. A compound according to claim 1, wherein said compound is chosen from: image3 or one of its pharmaceutically acceptable salts or one of its solvates. 7. A compound according to any one of claims 1 to 6 for use as a medicine. 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or diluent. 9. A compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 8 for the treatment or prevention of a condition in a mammal, including a human, whose treatment or prevention is affected or facilitated by the Neuromodulatory effect of a positive allosteric modulator of mGluR2. 10. The use of a compound according to any one of claims 1 to 6 or a pharmaceutical composition 15 according to claim 8 for the preparation of a medicament for the treatment or prevention of a condition in a mammal, including a human, whose treatment or prevention is affected or facilitated by the neuromodulatory effect of a positive allosteric modulator of mGluR2. 11. A compound according to any one of claims 1 to 6 or a pharmaceutical composition according to claim 8 for use in the treatment or prevention of a disorder of the central nervous system chosen 20 among the group of anxiety disorders, psychotic disorders, personality disorders, substance-related disorders, eating disorders, mood disorders, migraine, epilepsy or seizure disorders, childhood disorders, cognitive disorders, neurodegeneration, neurotoxicity and ischemia. 12. A compound according to claim 11, wherein the central nervous system disorder is a disorder of 25 anxiety, chosen 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; or 5 10 fifteen twenty 25 30 35 40 in which the central nervous system disorder is a psychotic disorder chosen from the group of schizophrenia, delusional disorder, schizoaffective disorder, schizophreniform disorder and substance-induced psychotic disorder; or in which the central nervous system disorder is a personality disorder chosen from the group of obsessive-compulsive personality disorder and schizoid and schizotypal disorder; or in which the central nervous system disorder is a disorder related to a substance chosen from the group of alcohol abuse, alcohol dependence, alcohol withdrawal, alcohol withdrawal delirium, alcohol-induced psychotic disorder, amphetamine dependence , amphetamine withdrawal, cocaine dependence, cocaine withdrawal, nicotine dependence, nicotine withdrawal, opioid dependence and opioid withdrawal; or in which the central nervous system disorder is an eating disorder chosen from the group of anorexia nervosa and bulimia nervosa; or in which the central nervous system disorder is a mood disorder chosen from the group of bipolar disorders (I and II), cyclothymic disorder, depression, dysthymic disorder, major depressive disorder and substance-induced mood disorder ; or in which the disorder of the central nervous system is migraine; or in which the disorder of the central nervous system is epilepsy or a seizure disorder chosen from the group of generalized nonconvulsive epilepsy, generalized seizure epilepsy, poor small epileptic state, large bad epileptic state, partial epilepsy with or without consciousness alterations, infantile spasms, continuous partial epilepsy and other forms of epilepsy; or in which the central nervous system disorder is a childhood disorder, for example attention deficit / hyperactivity disorder; or in which the central nervous system disorder is a cognitive disorder chosen from the group of delirium, persistent delirium induced by a substance, dementia, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to the disease of Parkinson's, dementia due to Alzheimer's disease, persistent dementia induced by a substance and mild cognitive deficiency; or in which the disorder of the central nervous system is chosen from the group of anxiety, schizophrenia, migraine, depression and epilepsy. 13. A compound according to any one of claims 1 to 6, in combination with an orthostatic agonist of mGluR2 for use in the treatment or prevention of a condition according to any one of claims 10 to 12 in a mammal, including a human. 14. A process for preparing a compound according to claim 1, characterized by: a) reacting an intermediate of formula (II) in which Y represents a group suitable for coupling mediated by Pd with boronic acids or boronic esters, with an intermediate of formula (III) in which R4 and R5 represent hydrogen or alkyl C1-4, or wherein R4 and R5 can be taken together to form the bivalent radical of the formula -CH2CH2-, -CH2CH2CH2-or -C (CH3) 2-C (CH3) 2-, in a suitable solvent inert with with respect to the reaction, in the presence of a suitable base and a suitable catalyst under thermal conditions image2 R1, R2, R3, X and n being as defined in claim 1; or, if desired, further converting the compounds of formula (I) between them according to transformations known in the art; or in addition, if desired, converting the compounds of formula (I) into a therapeutically active non-toxic acid addition salt by treatment with an acid or, conversely, converting the acid addition salt form into the free base by alkali treatment ; or, if desired, prepare its stereochemically isomeric forms.