MX2008008202A

MX2008008202A - New compounds

Info

Publication number: MX2008008202A
Application number: MXMX/A/2008/008202A
Authority: MX
Inventors: Nogradi Katalin; Wagner Gabor; Keseru Gyorgy; Bielik Attila; Gati Tamas; Hada Viktor; Koti Janos; Gal Krisztina; Vastag Monika; Agnes Bobok Amrita
Original assignee: Bielik Attila; Agnes Bobok Amrita; Gal Krisztina; Gati Tamas; Hada Viktor; Keserue Gyoergy; Koti Janos; Nogradi Katalin; Richter Gedeon Vegyeszeti Gyar Rt; Vastag Monika; Wagner Gabor
Priority date: 2005-12-20
Filing date: 2008-06-20
Publication date: 2008-09-26

Abstract

The present invention relates to new mGluRl and mGluR5 receptor subtype preferring ligands of formula (I) wherein X represents a group selected from SO, SO2;Y represents a group selected from (CH2)n, NH, NHCH2;n is an integer of 0 to 1;Z is H or monosubstituted by alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxyl, alkylsulfonylamino;R1is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl;R2is an optionally substituted phenyl, heterocyclyl, or NR3R4group wherein R3and R4are independently selected from the group of hydrogen and an optionally substituted alkyl, or R3and R4together with the N atom to which they are attached form an optionally substituted C5-7heterocyclyl group, containing one or more heteroatom(s), or NH-CO-NR5R6group, wherein R5and R6are independently selected from the group of hydrogen and an optionally substituted alkyl, or R5and R6together with the N atom to which they are attached form an optionally substituted C5-7heterocyclyl group, containing one or more heteroatom(s);and/or hydrates and/or solvates and/or pharmaceutically acceptable salts thereof formed with acids or bases, to the processes for producing the same, to pharmaceutical compositions containing the same and to their use in therapy and/or prevention of pathological conditions which require the modulation of mGluRl and mGluR5 receptors such as neurological disorders, psychiatric disorders, acute and chronic pain, neuromuscular dysfunctions of the lower urinary tract and gastrointestinal disorders.

Description

NEW COMPOUNDS Field of the Invention The present invention relates to new preferred ligands of the subtype of the mGluR I and mGluR5 receptors of formula (I) and / or to the salts and / or hydrates and / or solvates thereof, to processes for their preparation, to pharmaceutical compositions containing these compounds and their use in the therapy and / or prevention of conditions requiring the modulation of mGluR I and mGl uR5 receptors.

Background of the Invention A major excitatory neurotransmitter in the central nervous system (CNS) in mammals is the gluthamate molecule, which binds to neurons thereby activating the surface cell receptors. These receptors can be divided into two main classes, the ionotropic and metabotropic glutamate receptors, according to the structural characteristics of the receptor proteins, means by which the receptors transduce the signals within the cell and the pharmacological profiles. Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that activate various intracellular second messenger systems after glutamate binding. The activation of mGluRs in intact neurons of mammals causes one or more of the following responses: activation of phospholipase C; increased hydrolysis of phosphoinositide (Pl); intracellular calcium release; activation of phospholipase D; activation or inhibition of adenyl cyclase; increase or decrease in the formation of cyclic adenosine monophosphate (cAM P); activation of guanylyl cyclase; increase in the formation of cyclic guanosine monophosphate (cGM P); activation of phospholipase A2; increased release of arachidonic acid; and increase or decrease in the activity of the ligand- and voltage-dependent ion channels (Trends Pharmacol, Sci., 1993, 14:13, Neurochem, Int. 1994, 24: 439, Neuropharmacology, 1995, 34: 1, Prog. Neurobiol., 1999, 59:55, Berl, Psychopharmacology, 2005, 179, 4). Eight different mGluR subtypes, named mGluRI to mGluRß, have been identified by molecular cloning (Neuron, 1994, 13: 1031; Neuropharmacology, 1995, 34: 1; J. Med. Chem., 1995, 38: 1417). Various other receptors are revealed via the expression of alternative splice forms of certain mGluR subtypes (PNAS, 1992, 89: 10331, BBRC, 1994, 199: 1136, J. Neurosci., 1995, 15: 3970). The subtypes of metabotropic glutamate receptors can be subdivided into three groups, the mGluRs of Group I, Group I I and Group I I, depending on the homology of amino acid sequences, the second message systems used by the receptors and according to their pharmacological characteristics. The mGluRs of Group I they comprise mGluRI, mGluR5 and their alternative splice variants. Attempts to clarify the physiological role of Group I mGluRs suggest that activation of these receptors causes neuronal excitation. Evidence indicates that this excitation is due to the direct activation of postsynaptic mGluRs, but it has also been suggested that activation of the presynaptic mGluRs occurs, resulting in a greater release of neurotransmitters (Trends Pharmacol.Sci., 1992 , 15, 92; Neurochem, Int., 1994, 24, 439; Neuropharmacology, 1995, 34, 1; Trends Pharmacol, Sci., 1994, 15, 33). The metabotropic glutamate receptors are involved in several common processes in the mammalian CNS. It has been shown that it was necessary to activate mGluRs to induce long-term hippocampal potentiation and long-term cerebellar depression. { Nature, 1993, 363: 347; Nature, 1994, 368: 740; Cell, 1994, 79: 365; Cell, 1994, 79: 377). The role of the activation of mGluRs in nociception and analgesia has also been demonstrated (Neuroreport, 1993, 4: 879, Brain Res., 1999, 871: 223). It has been suggested that metabotropic glutamate receptors in Group I, and mGluR5 in particular, have a role in various disorders and pathophysiological processes that affect the CNS. These include stroke, head trauma, anoxic and ischemic lesions, hypoglycemia, epilepsy, neurodegenerative disorders such as Alzheimer's disease, acute and chronic pain, substance use and abstinence, obesity and gastroesophageal reflux disease (GERD) (Schoepp et al., Trends Pharmacol.Sci. 1993, 14: 13; Cunningham et al., Life Sci. 1994, 54: 135; Hollman et al., Ann. Rev. Neurosci., 1994, 17:31; Pin et al., Neuropharmacology 1995, 34: 1; Knopfel et al., J. Med. Chem. 1995; 38: 1417; Spooren et al., Trends Pharmacol, Sci. 2001, 22: 331; Gasparini et al., Curr Opin, Pharmacol. 2002, 2:43; Neugebauer Pain 2002, 98: 1, Slassi et al., Curr Top Med Chem. 2005; 5 (9): 897-911). Selective mGluRd compounds such as 2-methyl-6- (phenylethynyl) pyridine ("M PEP") are effective in animal models of mood disorders, including anxiety and depression (Spooren et al., J. Pharmacol. Exp. Ther 2000, 295: 1267; Tatarczynska et al., Br. J. Pharmacol., 2001, 132: 1423; KIodzynska et al., Pol. J. Pharmacol., 2001, 132: 1423). It is thought that much of the pathology under these conditions is due to excessive excitation of the CNS neurons induced by glutamate. As it seems that Group I mGluRs increase neuronal excitation mediated by glutamate through postsynaptic mechanisms and increase the release of presynaptic glutamate, its activation probably contributes to the pathology. Therefore, selective antagonists of the mGluR receptors of Group I could be therapeutically beneficial, especially as neuroprotective, analgesic or anticonvulsant agents.

It is thought that much of the pathology under these conditions is due to excessive excitation induced by the glutamate of S NC neurons. As it appears that Group I mGluRs (mGluRI and mGl uR5) increase neuronal excitation mediated by glutamate through postsynaptic mechanisms and increased release of presynaptic glutamate, their activation probably contributes to the pathology. Accordingly, selective antagonists of the mGl uR receptors of Group I could be therapeutically beneficial, in particular as neuroprotective, analgesic or anticonvulsant agents. The International Patent Application WO 09739000 discloses new thienopyridine sulfonamide derivatives useful for inhibiting the binding of an endothelin peptide to ETA or ETP and its use in the treatment of hypertension, cardiovascular diseases, asthma, eye diseases, renal failure, wound healing, endotoxic shock, immediate type hypersensitivity and hemorrhagic shock. Japanese Patent JP 07076586 describes furopyridines and thienopyridines as inhibitors of bone absorption for the treatment of osteoporosis. The thienopyridine derivatives are useful as hematinics, antitumor agents and immunostimulants, as described in the patent application JP 07053562. According to E. Zeinab et al. (Arch. Pharm. 1992, 325 (5), 301), thienopyridine and thienopyrimine derivatives were synthesized and evaluated their mycotoxin inhibitory activities. Some of the compounds inhibit mycotoxin production and fungal growth. International patent application WO 02/087584 describes thienopyridine sulfone derivatives as inhibitors of aldose reductase in a formulation also containing 2-cyclooxygenase inhibitors. Of the compounds mentioned in the above publications, an activity on mGluR receptors is not known or even suggested.

Summary of the Invention The present invention relates to new preferred ligands of the subtype of mGluRI and mGluR5 receptors of formula (I): (I) where X represents a selected group of SO, SO2; Y represents a group selected from (CH2) ", NH, NHCH2; n is an integer from 0 to 1; Z is H or is monosubstituted by an alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxyl, alkylsulfonylamino; Ri is an alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl, optionally substituted; R2 is an optionally substituted phenyl, heterocyclyl, or group NR3R where R3 and R4 are independently selected from the group consisting of hydrogen and an optionally substituted alkyl, or R3 and R, together with the N atom to which they are attached, form a heterocyclyl group C5- optionally substituted containing one or more heteroatom (s); or group NH-CO-NR5R6 where R5 and R6 are independently selected from the group consisting of hydrogen and an optionally substituted alkyl, or R5 and R6, together with the N atom to which they are attached, form an optionally substituted Cs-7 heterocyclyl group containing one or more heteroatom (s) and / or hydrates and / or solvates and / or pharmaceutically acceptable salts thereof formed with acids or bases. Another aspect of the present invention provides processes for the synthesis of the compounds of formula (I). A further aspect of the present invention relates to the intermediates of the preparation process. A further aspect of the present invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of formula (I) and / or enantiomers and / or racemates and / or diastereomers and / or salts and / or hydrates or solvates thereof, as active ingredient, and diluents, excipients and / or pharmaceutically acceptable inert carriers. A further aspect of the present invention provides the use of a compound of formula (I) for the prevention and / or treatment of disorders mediated by the mGluRd receptor, in particular neurological disorders, psychiatric disorders, acute and chronic pain and neuromuscular dysfunctions of the lower urinary tract and gastrointestinal disorders. A further aspect of the present invention provides the use of a compound of formula (I) for the manufacture of a medicament for the prevention and / or treatment of disorders mediated by the mGluR5 receptor, in particular of neurological disorders, psychiatric disorders , acute and chronic pain and neuromuscular dysfunctions of the lower urinary tract and gastrointestinal disorders.

Detailed Description of the Invention The present invention relates to new preferred ligands of the mGluRI and mGluR5 receptor subtype of formula (a): (I) where X represents a selected group of SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is H or is monosubstituted by an alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxyl, alkylsulfonylamino; Ri is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is an optionally substituted phenyl, heterocyclyl, or group NR3R where R3 and R4 are independently selected from the group consisting of hydrogen and an optionally substituted alkyl, or R3 and R4, together with the N atom to which they are attached, form a heterocyclic group C5- optionally substituted containing one or more heteroatom (s); or group NH-CO-NR5R6 where R5 and R6 are independently selected from the group consisting of hydrogen and an optionally substituted alkyl, or R5 and R6 together with the N atom to which they are attached, form a C5-7 heterocyclyl group optionally substituted containing one or more heteroatom (s) and / or hydrates and / or solvates and / or salt is pharmaceutically acceptable thereof formed with acids or bases. A more preferred embodiment of the invention is a compound of formula (I) (I) where X represents a selected group of SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is H or is monosubstituted by an alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxyl, alkylsulfonylamino; Ri is a C3-? 0 alkyl or cycloalkyl group, optionally substituted with one or more substituent (s) selected from alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen; or phenyl or biphenyl optionally substituted with one or more substituent (s) selected from alkyl, methoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, alkylsulfonyl, alkylsulfonylamino, cyano, halogen; or monocyclic or bicyclic, saturated or unsaturated heterocyclyl, containing 1 -4 heteroatom (s) selected from O, N or S, such as pyridyl, quinolinyl, thiazolyl, piperidi nyl, morpholyl, tetrahydroquinolinyl, oxazolyl, isoxazolyl, furylthiophenyl, triazolyl, pyrrolidinyl, optionally substituted with one or more hydroxyl, hydroxyalkyl, alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen or oxo groups; R2 is phenyl optionally substituted with one or more substituent (s) selected from alkyl, methoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, alkylsulfonyl, alkylsulfonylamino, cyano, halogen; or C5-7 monocyclic or bicyclic, saturated or unsaturated heterocyclyl group containing 1 -4 heteroatom (s) selected from O, N or S, such as a pi-ridyl, quinolinyl, thiazolyl, piperidinyl, morpholyl, tetrahydroquinolinyl, oxazolyl ring, isoxazolyl, furylthiophenyl, triazolyl, pyrrolidinyl, optionally substituted with one or more hydroxyl, hydroxyalkyl, alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen or oxo groups; or NR3R4 group where R3 and R4 are independently selected from the group consisting of hydrogen and alkyl group optionally substituted with one or more substituent (s) selected from alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, amyomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen, or R3 and R4, together with the N atom to which they are attached, form a C5-7 heterocyclyl group containing one or more heteroatom (s) selected from O, N or S, optionally substituted with one or more hydroxyl groups , hydroxyalkyl, alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen or oxo; or NH-CO-NR5R6 group, wherein R5 and R6 are independently selected from the group consisting of hydrogen and alkyl group optionally substituted with one or more substituent (s) selected from alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl , acylamino, cyano, halogen, or R5 and R6, together with the N atom to which they are attached, form a heterocyclyl group Cs-7 containing one or more heteroatom (s) selected from O, N or S, optionally substituted with one or more hydroxyl, hydroxyalkyl, alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen or oxo groups and / or hydrates and / or solvates and / or pharmaceutically acceptable salts thereof formed with acids or bases.

With respect to Z and the substituents of R1 (R2, R3, R4, R5 and R6, the term alkyl means an alkyl group containing 1 to 4 straight or branched chain carbon atoms, except when Ri represents cycloalkyl, the cycloalkyl part then having 3 to 10 carbon atoms. When Ri and / or R3 and / or R4 and / or R5 and / or R6, the alkyl group may be optionally substituted with one or more substituent (s) selected from alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl , dialkylaminomethyl, acylamino, cyano, fluorine, chlorine, bromine. When R-representa represents cycloalkyl, the cycloalkyl part contains from 3 to 10 carbon atoms and may be a mono-, bi-, or tri-cyclic group, such as cyclohexyl or adamantyl, and the cycloalkyl group may be optionally substituted with one or more substituent (s) selected from alkyl, methoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, fluoro, chloro, bromo. When Ri and / or R2 represents phenyl or Ri represents biphenyl, the phenyl or biphenyl group may be optionally substituted with one or more substituent (s) selected from alkyl, methoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, alkylsulfonyl, alkylsulfonylamino, cyano, fluorine, chlorine, bromine. When R and / or R 2 represents a C 5 heterocyclyl, the heterocyclic ring may be a monocyclic or bicyclic, saturated ring or unsaturated, containing 1 -4 heteroatom (s) selected from O, N or S, such as a pyridyl, quinolinyl, thiazolyl, piperidinyl, morpholyl, tetrahydroquinolinyl, oxazolyl, isoxazolyl, furylthiophenyl, triazolyl, pyrrolidinyl ring. When the hetero atom containing the ring in R2 has no aromatic character it must contain at least one basic nitrogen atom by which the heterocyclic group is connected to the thienopyridine part. The heterocyclyl group may be optionally substituted with one or more hydroxyl, hydroxyalkyl, alkyl, methoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, fluoro, chloro, bromo or oxo groups. The compounds of formula (I) can form salts with acids. The invention also relates to the salts of the compounds of formula (I) formed with acids, especially the salts formed with pharmaceutically acceptable acids. The meaning of compound of formula (I) is either the free base or the salt, even if express reference is not made separately. For the formation of the acid addition salts, both organic and inorganic acids can be used. Suitable inorganic acids can be, for example, hydrochloric, sulfuric, nitric and phosphoric acids. Representatives of monovalent organic acids can be, for example, formic, acetic, propionic acids, and various butyric acids, valeric acids and capric acids. Representatives of divalent organic acids can be, for example, oxalic, malonic acids, malefic, fumaric and succinic. Other organic acids, such as hydroxy acids, for example citric acid, tartaric acid, or aromatic carboxylic acids, for example benzoic acid or salicylic acid, as well as aliphatic and aromatic sulphonic acids, for example methanesulfonic acid, naphthalenesulfonic acid, can be used. and p-toluenesulfonic acid. A particularly valuable group is that of acid addition sawhere the acid component itself is physiologically acceptable and has no therapeutic effect on the applied dose or does not have an unfavorable influence on the effects of the active ingredient. These acid addition saare pharmaceutically acceptable acid addition sa The reason why the addition acid sa which do not belong to the pharmaceutically acceptable acid addition sa belong to the present invention is that, in certain cases, it can be advantageous for the purification and isolation of the product. the desired compounds. The solvates and / or hydrates of the compounds of formula (I) are also included within the scope of the invention. Especially important compounds of formula (I) of the present invention are the following: 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2, 3-t »] pyridine, 2- (4-chlorobenzenesulfinyl) -3- (4-chlorophenyl) thieno [2, 3- / 5] pi ri di na, 3- (4-cl orofenyl) -2- (4-fl uoro benzenes ulf onyl) thieno [2, 3-a > ] pyridine, 3- (4-chlorophenyl) -2- (toluene-4-sulfonyl) thieno [2, 3- £ > ] pyridine, 4- [3- (4-chlorofenyl) thieno [2,3-b] pyridin-2-sulfonyl] benzonitrile, 2-benzenesulfonyl-3- (4-chlorophenyl) t-ene [2,3-b] ] pyridine, 3- [3- (4-chlorofenyl) thieno [2,3-D] pyridin n-2-sulfonyl I] benzonitrile, 3- (4-chlorophenyl) -2- (pyridin-3-) sulfonyl) thieno [2,3-D] pyridine, 2- (butane-1-sulfonyl) -3- (4-chlorophenyl) thieno [2,3-b] pyridine, 3- (4-chlorophenyl) -2- ( 2,4-dimethylthiazole-5-sulfonyl) thieno [2,3-b] pyridine, 3- (4-chlorophenyl) -2- (thiophene-2-sulfonyl) thieno [2,3-b] pyridine, (4- chlorophenyl) 3- (4-chlorophenyl) thieno [2,3-b] pyridine-2-sulphonic acid amide, 3- (4-chlorofinyl) -2-phenylmethanesulfonyl thiol- [2,3-b] ] pyridine, 2- (3-chlorobenzenesulfonyl) -3- (4-chlorophen-yl) thieno [2,3-b] pyridine, 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -6-chloro- thieno [2,3-b] pyridine, 2- (3-fluorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-bjpyridine, 2- (3-cyanobenzenesulfonyl) -3- (3-f luorofenil) ) thieno [2,3-bjpyridine, 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -6-fluorothieno [2,3-jpyridine, 2- (4-cyanobenzenesulfonyl)] -3- (3-chlorophenyl) thieno [2,3-bipyridine, 2- (3-cyanobenzenesulfonyl) -3- (3-methylpiperidinyl) thieno [2,3-pyridine, 2- (3-cyanobenzenesulfonyl) -3- ( 4-methylpiperidinyl) thieno [2,3- bjpyridine, 2- (3-cyanobenzenesulfonyl) -3- (4-tol i I) thieno [2,3-b] pyridine, 2- (3-cyanobenzenesulfonyl) -3- (3-methoxyphenyl) thieno [2,3- bjpyridine, 2- (3-methoxybenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-bjpyridine, 2- (3-cyano-5-fluorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3- bjpyridine, 2- (3-fluoro-4-methylbenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-bjpyridine, 2- (3,4-dimethylbenzenesulfonyl) -3- (4-fluorophenyl) thieno [2, 3-bjpyridine, 2- (3-cyanobenzenesulfonyl) -3- (4-f luorofenyl) -6-chloro-thieno [2, 3-bjpyridine, 2- (3-cyano-5-fluorobenzenesulfonyl) -3- ( 4-fluorophenyl) tyeno [2,3-bjpyridine, 2- (3-cyanobenzenesulfonyl) -3- (4-f luorofenyl) -6-f Iorothieno [2, 3-bjpyridine, 2- (4-bromobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-bjpyridine, 5-amino-2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-bjpyridine, 2- (3,4- dichlorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-bjpyridine, 2- (3-f-U-4-methyl benzenesulphonyl) -3- (4-f luorof in I) ti eno [2 , 3- bjpyridine, 2- (3-cyanobenzenesulfonyl) -3- (2-chlorophenyl) thieno [2,3-bjpyridine, 2- (3-cyano-5-fluorobenzenesulfonyl) -3- (4-chlorophenyl) -6-chloro-thieno [2,3-b] pyridine, 2- (3-f I uor-4-m-ethoxy benzenes ulf onyl) -3- (4-chlorofenyl) ti in o [2, 3-bjpyridine, 2- (4- chlorobenzenesulfonyl) -3- (4-methylpiperidinyl) thieno [2,3-bjpyridine, 2- (3-cyano-5-fluorobenzenesulfonyl) -3- (4-methylpiperidinyl) thieno [2, 3-b] pyridine, 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -5-fluorothieno [2,3-bjpyridine, 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -5-chloro-thieno [2,3-bjpyridine, 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -4-chloro-thieno [2,3-jpyridine, 2- (4-chlorobenzenesulfonyl) -3 - (4-chlorophenyl) -4-fluorothieno [2,3-bipyridine, 5-amino-2- (4-chlorobenzenesulfonyl) -3- (4-methylpiperidinyl) thieno [2,3-b] pyridine, 2- (3 -cyano-5-fluorobenzenesulfonyl) -3- (3-fluorophenyl) thieno [2,3-bjpyridine, 5-amino-2- (4-chlorobenzenesulfonyl) -3- (3-fluorophenyl) thieno [2,3-b] pyridine, 2- (4-Cl-orobenzenesulfonyl) -3- (4-m ethyl pi-peny ni I) -6-chloro-thieno [2,3-b] pyridine, 2- (3-fluoro-4-methoxybenzenesulfonyl) -3 - (4-fluorophenyl) thieno [2, 3-bjpyridine, 2- (3-fluor-4-methoxybenzenesulfonyl) -3- (3-fluorophenyl) thieno [2,3-bjpyridine, 2- (3-cyano-5- fluorobenzenesulfonyl) -3- (2-fluorophenyl) thieno [2,3-bjpyridine, 2- (3-cyano-5-fluorobenzenesulfonyl) -3- (3-chlorophenyl) thieno [2,3-b] pyridine.

Pharmaceutical Formulations The invention also relates to pharmaceutical compositions containing the compounds of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates thereof, as an active ingredient, and one or more physiological vehicles. ologically acceptable. The compounds of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates thereof can be administered by any suitable method, for example by oral, parenteral administration (including subcutaneous, intramuscular administration). and intravenous), buccal, subliangual, nasal, rectal or transdermal and the pharmaceutical compositions adapted accordingly. The compounds of formula (I) and / or physiological salts acceptable and / or hydrates and / or solvates thereof which are active when administered orally can be formulated as liquids or solids, for example, syrups, suspensions or emulsions, tablets, capsules and dragees. A liquid formulation of the compounds of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates thereof generally consists of a suspension or solution of the compound of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates thereof, in a suitable liquid carrier (s), for example an aqueous solvent such as water and ethanol or glycerin, or in a non-aqueous solvent, such as polyethylene glycol or an oil . The formulation may also contain suspending agents, preservatives, flavors or colorants.

A composition in solid form of a tablet can be prepared using any suitable pharmaceutical carrier (s) of those normally used to prepare solid formulations. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, etc. Optionally, the tablets may be coated by standard aqueous or non-aqueous techniques. A composition in solid form of a capsule can be prepared by normal encapsulation procedures. For example, the granules containing the active ingredient can be prepared with the standard vehicles and then they fill a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared with any suitable pharmaceutical carrier (s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled in a soft gelatin capsule. Typical parenteral compositions are composed of a solution or suspension of the compound of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates thereof in a sterile aqueous carrier or in a parenterally acceptable oil, for example polyethylene glycol. , polyvinyl pyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration. The compositions of the present invention for nasal administration containing a compound of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates thereof can be conveniently formulated as aerosols, drops, gels and powders. The aerosol formulations of the present invention typically comprise a solution or fine suspension of the compound of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates, in a physiologically acceptable aqueous or non-aqueous solvent and are generally presented in single-dose or multi-dose quantities, in sterile form, in a sealed container, which can take the form of a cartridge or spare part for use with an atomizing device. Alternatively, the sealed container may be a unit dosage device, such as a single-dose nasal inhaler or an aerosol dispenser provided with a dosing valve for the purpose of disposing of it once the contents of the container have been exhausted. If the dosage form comprises an aerosol dispenser, it will contain a propellant, which may be a compressed gas, such as compressed air, or an organic propellant, such as a fluorochlorohydrocarbon. The dosage form of the aerosol can also take the form of a pump spray. The compositions of the present invention containing a compound of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates are suitable for buccal or sublingual administration, including tablets, dragees and lozenges where the active ingredient is formulated with a vehicle such as sugar and acacia, tragacanth, or gelatin, glycerin, etc. The compositions of the present invention containing a compound of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates thereof for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, as cocoa butter, and the rest of the materials commonly used in the art. The suppositories can be suitably formed first by mixing the composition with the softened vehicle (s) or melted (s), followed by cooling and forming into molds. The compositions of the present invention containing a compound of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates thereof for transdermal administration include ointments, gels and patches. The compositions of the present invention containing a compound of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates thereof are preferably in unit dosage form, such as tablet, capsule or ampoule. Each dosage unit of the present invention for oral administration preferably contains from 0.1 to 500 mg of a compound of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates thereof, calculated as a base free. Each dosage unit of the present invention for parenteral administration preferably contains from 0.1 to 500 mg of a compound of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates thereof, calculated as a base free. The compounds of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates thereof may be administered normally in a daily dosage regimen.

In the treatment of disorders mediated by mGluR I and mGluR5, for example schizophrenia, anxiety, depression, panic, disorders bipolar, and circadian disorders or chronic and acute pain disorders, dosage levels of about 0.01 mg / kg to about 140 mg / kg per body weight per day or, alternatively, about 0.5 mg to about 7 g are useful. per patient per day. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary according to the patient to be treated and the particular route of administration. For example, a formulation directed to oral administration in humans may suitably contain from about 0.5 mg to about 5 g of active agent, composed of an appropriate and convenient amount of carrier material which may vary from about 5 to about 95. percent of the total composition. The unit dosage forms will generally contain between about 1 mg and about 1,000 mg of active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 250-300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1,000 mg. It is understood, however, that the specific dose level for any particular patient will depend on various factors, including age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, combination of medications and the severity of the particular disease to be treated.

Medical Use It has been found that the compounds of formula (I) and / or physiologically acceptable salts and / or hydrates and / or solvates of the present invention exhibit biological activity on the mGluRI and mGluR5 receptors and are expected to be useful in the treatment of disorders mediated by mGluRI and mGluRd. It has been found that the compounds according to the present invention or their salts have a high degree of potency and selectivity for the individual subtypes of the metabotropic glutamate receptors (mGluR). In particular, there are compounds according to the present invention that are potent and selective for the mGluRI and mGluR5 receptors. Accordingly, it is envisioned that the compounds of the present invention will be useful in the prevention and / or treatment of conditions associated with the excitatory activation of mGluRI and mGluR5 receptors and to inhibit neuronal damage caused by the excitatory activation of mGluRI receptors. and mGluR5. The compounds can be used to produce an inhibitory effect of mGluRI and mGluR5 in mammals, including humans. Thus, it is expected that the compounds of the invention are suitable for the prevention and / or treatment of disorders mediated by the mGluRI and mGluRd receptors, such as acute and chronic psychiatric and neurological disorders, chronic and acute pain disorders and neuromuscular dysfunctions of the lower urinary tract and disorders gastrointestinal The dose necessary for the therapeutic or preventive treatment of a particular disorder will necessarily vary according to the patient treated and the route of administration. The invention relates to the compounds of formula (I) as defined hereinabove, for use in therapy. The invention relates to the compounds of formula (I) as defined hereinabove, for use in the prevention and / or treatment of disorders mediated by the mGluRI and mGluRd receptors. The invention relates to the compounds of formula (I) as defined hereinabove, for use in the prevention and / or treatment of neurological disorders. The invention relates to the compounds of formula (I) as defined above, for use in the prevention and / or treatment of psychiatric disorders. The invention relates to the compounds of formula (I) as defined above, for use in the prevention and / or treatment of chronic and acute pain disorders. The invention relates to the compounds of formula (I) as defined hereinabove, for use in the prevention and / or treatment of neuromuscular dysfunctions of the lower urinary tract and of gastrointestinal disorders.

The invention relates to the compounds of formula (I) as defined above, for use in the prevention and / or treatment of pain associated with migraine, inflammatory pain, neuropathic pain disorders such as diabetic neuropathies. , arthritis and rheumatoid diseases, pain in the lower back, postoperative pain and pain associated with various conditions, including angina, renal or biliary colic, menstruation, migraine and gout. The invention relates to the compounds of formula (I) as defined hereinabove, for use in the prevention and / or treatment of Alzheimer's disease, senile dementia, dementia induced by SI DA, Parkinson's disease, Amyotrophic lateral sclerosis, Huntington's disease, migraine, epilepsy, schizophrenia, depression, anxiety, acute anxiety, obesity, obsessive-compulsive disorders, ophthalmological disorders such as retinopathies, diabetic retinopathies, glaucoma, neuropathic auditory disorders such as tinnitus, neuropathies induced by chemotherapy, postherpetic neuralgia and trigeminal neuralgia, tolerance, dependence, Fragile X, autism, mental retardation, schizophrenia and Down Syndrome. The invention relates to the compounds of formula (I) as defined hereinabove, for use in the prevention and / or treatment of strokes, cranial trauma, anoxic and ischemic lesions, hypoglycaemia, cardiovascular diseases and epilepsy. .

The compounds are also suitable for the treatment of neuromuscular dysfunctions of the lower urinary tract, such as urinary urgency, overactive bladder, increased urinary frequency, reduced urinary continence, cystitis, incontinence, enuresis and dysuria. In addition, the compounds are also suitable for the treatment of gastrointestinal disorders such as transient lower esophageal sphincter relaxation (TLESR), gastrointestinal reflux disease and irritable bowel syndrome. The present invention also relates to the use of a compound of formula (I) as defined hereinabove, in the manufacture of a medicament for the prevention and / or treatment of disorders mediated by mGluRI and mGluRd receptors and any disorder cited above. The invention also provides a method for the treatment and / or prevention of disorders mediated by the mGluRI and mGluRd receptors and of any disorder mentioned above, in a patient suffering from or in danger of suffering from said condition, a method comprising administration to the patient. of an effective amount of a compound of formula (I) as defined hereinabove. In the context of the present specification, the term "therapy" includes treatment as well as prevention, unless expressly specified otherwise. The terms "Therapeutic" and "therapeutically" must be interpreted accordingly. In this specification, unless otherwise stated, the term "antagonist" means a compound that partially or completely blocks, by any means, the transduction pathways, which leads to a response by the ligand. The term "disorder", unless stated otherwise, means any condition and disease associated with the activity of metabotropic glutamate receptors. Preparation Methods Abbreviations The abbreviations used here have the following agreed meaning. The following non-agreed abbreviations have the usual meaning, unless specifically stated otherwise. DMF? /,? / - dimethylformamide TEA triethylamine THF tetrahydrofuran DMSO dimethyl sulfoxide According to the present invention, a process for the preparation of a compound of formula (la): (la) where X represents a selected group of SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is H or is monosubstituted by an alkyl or nitro group; Ri is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is phenyl optionally substituted with alkyl or halogen; it consists of reacting a compound of formula (I I I): (I I I) where A is a substituent as defined for R2 in formula (la) and Z is H or is monosubstituted by an alkyl or nitro group with a compound of formula (Vi l): HlgCH2SOYR? (V i l) where Hlg is chlorine or bromine, Y and R1 are as they have been described above for formula (la), or with a compound of formula (VI I I): HlgCH2SO2YR? (VI II) where Hlg is chloro or bromo, Y and R ^ are as previously described for formula (la), in the presence of sodium methoxide in dimethylformamide as solvent, to obtain a compound of formula (Ia) , and optionally subsequently forming the salts and / or hydrates and / or solvates of the compounds of formula (la) (Scheme 1). Scheme 1 gives) to. SOCI2, Ph-A (compound of formula (VI) wherein A is a substituent as defined for R2 in formula (la)), catalytic amount of DM F, 80-1 30 ° C, 2-3 hours. b. AICI3, 80-130 ° C, 5-8 hours. c. Thiourea, water / ethanol, reflux, 20-24 hours; d. HlgCH2SOYR1 or HlgCHzSO? YRT (respectively compounds of formulas (Vil) and (VIII) where Hlg is chlorine or bromine), NaOCH3, DMF, 70-1dO ° C, 2-6 hours. An acid chloride was prepared from the appropriate 2-chloronicotinic acid or d-nitro-2-chloronicotinic acid by reaction of thionyl chloride with the appropriate 4-monosubstituted benzene derivative, in the presence of AICI3. The reaction can be carried out by well-known methods suitable for the Friedel-Crafts reactions using the appropriate benzene derivative as the solvent. The product (II) was purified by crystallization and subjected to reaction with thiourea in a mixture of water and ethanol under reflux according to the method of J. Katrizky (see: J. Chem. Soc. 1958, 3610). The resulting compounds of formula (III) are in crystalline form. S-alkylation and ring closure were carried out by the method of F. Guerrera (Drug Ed. Sci., 1976, 31, 21). The compounds of formula (III) were reacted with various halomethyl sulfoxide, halomethylsulfone or halomethylsulfonamide derivatives in the presence of a base (for example NaOMe, Cs2CO3 or KOH). The halomethylsulfoxide derivatives can be prepared from the appropriate halomethisulfides with m-acid. chloroperbenzoic according to the method of G. Letts et al. , (J. Med. Chem., 2003, 465). The halomethyl sulfone derivatives are crcial or can be synthesized by known methods, for example Y. Yinfa et al. (Synth, Cn., 2004, 34, 13, 2443). The halomethylsulfonamido derivatives can be prepared, for example, by the method of K. Wojciechowski et al. , (Tetrahedron, 2001, 57, d009). According to the present invention, a process for the preparation of a compound of formula (I b): (I b) where X represents SO, SO2; Y represents a group selected from (CH2) n, NH, N HCH2; n is an integer from 0 to 1; Z is H or alkyl group; Ri is optionally substituted alkyl, cycloalkyl, phenyl, biphenyl or heterocyclyl; R2 is phenyl, or aromatic heterocyclyl, optionally substituted with one or more substituent (s) selected from alkyl, alkoxy. trifluoromethyl, amino, alkylamino, dyalkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, fluoro, chloro, bromo, hydroxyl, methylsulfonyl; on reacting a compound of formula (XI): (XI) with a compound of formula (Vi l): HlgCH2SOYR? (VII) where Hlg is chloro or bromo, Y and Ri are as described above for the formula (I b), or with a compound of the formula (VI I I): HlgCH2SO2YR? (VII I) where Hlg is chloro or bromo, Y and R, are as described above for the formula (I b) in the presence of sodium methoxide in dimethylformamide as the solvent and and on reacting the obtained compound of the formula (IV) ): where R ^ is as described above for formula (I b) with copper bromide (11) and rerf-butyl nitrite in acetonitrile; and on reacting the compound obtained of formula (V): (V) where R ^ is as described above for the formula (Ib) with a compound of the formula (IX): R2-B (OH) 2 (IX) where R2 is as defined above for the formula (I b), in the presence of base and catalyst, in a solvent, to obtain a compound of formula (Ib), and then optionally forming the salts and / or hydrates and / or solvates of the compounds of formula (Ib) (Scheme 2). Scheme 2 (Ib) to. HlgCH2SOYR? or HlgCHzSO? YR, (respectively compounds of formulas (Vil) and (VI I I) where Hlg is chlorine or bromine), DM F or butanol, 70-150 ° C, 1 -3 hours; b. CuBr2) ferf-butyl nitrite, CH3CN, 60-80 ° C, 1-3 hours; c. R2-B (OH) 2 (compound of formula (IX) where R 2 is as defined above for formula (I b)), Na 2 CO 3, ethanol-toluene or dimethoxyethane, Pd (PPh 3) 4, 1 -5 hours, -1 10 ° C. The compounds of formula (IV) were prepared from 2-mercaptonicotinonitrile and the corresponding halomethisulfone compound of formula (VI I I) by the method of F. Guerrera (Drug Ed. Sci., 1976, 31, 21). The aminothienopyridine derivatives of formula (IV) obtained were converted to the corresponding bromo derivatives of formula (V) by means of analogous methods described in the literature, H.C. Wals (for example, Tetrahedron, 1988, 44, 5921). The reaction was carried out in acetonitrile using t-butyl nitrite or i-amyl nitrite and Cu (II) salt (for example CuBr2) at a temperature between 60 and 80 ° C. The compounds of formula (Ib) were synthesized by the well-known methods of the coupling reactions of Suzuki, using boric acid or a suitable borate, a base and a palladium catalyst, as described, for example, by A. Suzuki & H.C. Brown: Organic Syntheses via Boranes, Vol. 1 -3.

According to the present invention, a process for the preparation of a compound of formula (le): (le) where X represents SO2; Y represents a group selected from (CH2) ", NH, NHCH2; n is an integer from 0 to 1; Z is H or alkyl group; R-i is an alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl, optionally substituted; R2 is NR3R, where R3 and R4 are independently selected from the group consisting of hydrogen, an optionally substituted alkyl group, or R3 and R4, together with the N atom to which they are attached, form an optionally substituted C5- heterocyclyl group containing one or more heteroatom (s), by reacting a compound of formula (V): (V) where Ri is as described above for the formula (le), with a compound of formula (XVI): HNR3R4 (XVI) wherein R3 and R4 are as described above for formula (le) to obtain the compound of formula (le), and then optionally forming the salts and / or hydrates and / or solvates of the compounds of formula (le) (Scheme 3). Scheme 3 (V) (Ic) to. HNR3R4, 70-200 ° C, 1-5 hours, acetonitrile or DMF or assisted reaction with microwaves. The reaction described above was carried out according to a simple Kirsch method. G. (Tetrahedron 55, 21, 1999, 6511). The corresponding bromine compound (V) was heated with an appropriate amine (HNR3R4) in a suitable solvent (acetonitrile, DMF or water), advantageously at a temperature between 70 ° C and 200 ° C. In special cases, a sealed tube was used for the preparation or the reaction was aided with microwaves or also by raising the temperature. According to the present invention a process for the Preparation of a compound of formula (Id): (I d) where X represents SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is H or alkyl group; R ^ is an alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl, optionally substituted; R2 is NH-CO-NR3R group, where R and R6 are independently selected from the group consisting of hydrogen or optionally substituted alkyl group, or R3 and R, together with the N atom to which they are attached, form a C5 heterocyclyl group - optionally substituted one containing one or more heteroatom (s), upon reacting a compound of formula (IV): (I V) where R1 is as previously described for the formula (Id), with a compound of formula (XI II): HN R3R4 (XI II) wherein R3 and R are as described above for the formula (Id), in the presence of phosgene or triphosgene and a base for obtaining a compound of formula (Id), and then optionally forming the salts and / or hydrates and / or solvates of the compounds of formula (Id) (Scheme 4). Scheme 4 (IV) (Id) b. phosgene or triphosgene, NHR3R4 (compounds of formula (XIII), base, -5 ° C. The process for preparing the compounds of formula (Id) in situ transforms an amine of formula (IV) into its isocyanate derivative and makes the latter with an amine of formula (XIII) .The above reaction can be carried out by known methods.The transformation of the amine (IV) into its isocyanate derivative was carried out in situ in an aprotic solvent (for example tetrahydrofuran, hydrocarbons chlorinated) using an appropriate derivative of carbonic acid (eg phosgene or triphosgene) in the presence of a base (for example triethylamine), advantageously at a temperature between -d ° C and room temperature. According to the present invention a process for the preparation of a compound of formula (le): (l e) where X represents a selected group of SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is amino, alkylsulfonylamino, halogen; Ri is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R is phenyl optionally substituted with alkyl or halogen; when reacting a compound of formula (la): (l a) where X represents a selected group of SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is nitro; R is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is phenyl optionally substituted with alkyl or halogen; with a suitable reducing agent, to obtain the compound of formula (le): (le) where Z is amino; X, Y, n, R ^ and R are as described above for the formula (le) and then optionally forming the salts and / or hydrates and / or solvates of the obtained amino derivatives, or a. by optionally reacting the amino derivatives obtained from formula (le), wherein Z is amino, X, Y, n, Ri and R2 are as described above for formula (le), with sodium nitrite in the presence of acid hydrochloric and copper iodide (l) or copper chloride (l) or copper bromide (l) or sodium tetrafluoroborate, to obtain a compound of formula (le), where Z is halogen, X, Y, n, R ^ and R2 are as they have been described above for formula (le), and then optionally forming the salts and / or hydrates and / or solvates of the halo derivatives obtained from formula (le), or b. optionally reacting the amino derivatives obtained from formula (le), where Z is amino, X, Y, n, R and R2 are as described above for formula (le), with alkylsulfonyl chloride derivatives, for obtaining the compounds of formula (le) wherein Z is alkylsulfonylamino, X, Y, n, Ri and R2 are as described above for formula (le), and then optionally forming the salts and / or hydrates and / or solvates of the alkylsulfonylamino derivatives obtained from formula (le) (Scheme 5). Scheme 5 (the) (him) (him) to. SnCl2 or Fe / HCl powder b. NaNO2, HCl conc. , Cu (l) l or Cu (l) CI or Cu (l) Br or NaBF4; c. alkylSO2CI, base, 0-80 ° C. The compounds of formula (la) (wherein Z is nitro; X, Y, n, R ^ and R2 are as described above for the formula (le)) were used as starting material for the preparation of the corresponding 5-substituted thienopyridines of formula (le). The appropriate nitro compounds, as shown in Scheme 5, were selectively reduced, for example with tin chloride in ethyl acetate, under heating, using the method of FD Bellamy (Tetrahedron Lett., 25, 83, 1984) or with iron in combination with HCl according to the Org method. . Synth Coll., 5, 346, 1973. This reaction yielded the compound of formula (le) (where Z is amino; X, Y, n, Ri and R2 are as described above for formula (le)), which it was optionally diazotized according to well-known techniques of Sandmeyer chemistry after Ito, S. et al. (Bull. Chem. Soc. Jpn., 49, 1920, 1976). The reaction was carried out with sodium nitrite in concentrated hydrochloric acid in the presence of copper iodide (I) or copper chloride (I) or copper bromide (I), advantageously at a temperature between (-) d- ( +) d ° C. In the case of the preparation of the corresponding fluorine compound, sodium tetrafluoroborate was used at the same temperature to obtain the aryldiazonium salt, which was decomposed by heating at 160-200 ° C. The halo derivatives of formula (le) (where Z is halogen, X, Y, n, RT and R2 are as described above for formula (Ie)) were obtained by this preparation process. Alternatively, the compound of formula (le) (where Z is amino, X, Y, n, R-i and R2 are as described above for formula (le)), were converted to sulfonamide derivatives. The reaction was carried out using the corresponding sulfonyl chlorides in the presence of an appropriate base ( example pyridine or triethylamine), at a temperature between 0 and 80 ° C.

According to the present invention a process for the preparation of a compound of formula (If): (lf) where X represents SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is amino, alkylsulfonylamino, halogen; Ri is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is a phenyl, heterocyclyl group, optionally substituted, or NR3R4 where R3 and R are independently selected from the group consisting of hydrogen or optionally substituted alkyl group, or R3 and R, together with the N atom to which they are attached, form an optionally substituted C5-7 heterocyclic group containing one or more heteroatom (s), upon reacting a compound of formula (V): (V) where Rt and Y are as previously described for the formula (If), with an appropriate oxidizing agent and reacting the obtained N-oxide derivative of formula (X): (X) where Ri and Y are as previously described for the formula (If), with aqueous nitric acid in acetic acid, the reaction then being subjected to the nitro derivative of formula (XI): (XI) where Rf and Y are as previously described for the formula (If), with a suitable reducing agent, and subjecting reaction the amino derivative obtained of formula (Xl l): (Xl l) where R T and Y are as previously described for the formula (If), a. with a compound of formula (IX): R2-B (OH) 2 (IX) wherein R2 is optionally substituted phenyl, heterocyclyl, in the presence of base and catalyst, in a solvent, to obtain a compound of formula (If) where Z is amino, R2 is optionally substituted phenyl, heterocyclyl, Y and RT are as described above for the formula (If), and then optionally forming the salts and / or hydrates and / or solvates of the amino derivatives obtained from the formula (If), and (i) optionally reacting the non-obtained amine derivatives of the formula (If), where Z is amino, R2 is optionally substituted phenyl, heterocyclyl, Y and RT are as described above for the formula ( If), with sodium nitrite in the presence of hydrochloric acid and copper iodide (l) or copper chloride (l) or copper bromide (l) or tetrafluroborate of sodium, to obtain a compound of formula (If) where Z is halogen, R2 is optionally substituted phenyl, heterocyclyl, Y and RT are as described above for the formula (If), and then optionally forming the salts and / or hydrates and / or solvates of the halo derivatives obtained from the formula (If), or (ii) optionally reacting the obtained amine of the formula (If), where Z is amino; R2 is optionally substituted phenyl, heterocyclyl, Y and RT are as described above for the formula (If), with alkylsulfonyl chloride derivatives, to obtain a compound of the formula (If), and then optionally forming the salts and / or hydrates and / or solvates of the alkylsulfonylamino derivatives obtained from the formula (If), or b. with a compound of formula (XI II): NHR3R4 (XII I) wherein R3 and R4 are as described above for the formula (If), at 70-200 ° C, to obtain a compound of formula (If) where Z is amino, Y, RT and R2, which form the group NR3R4, are as previously described for the formula (If), and then optionally forming the salts and / or hydrates and / or solvates of the amino derivatives obtained from formula (If), or (i) optionally reacting the amino derivatives obtained from the formula (If), where Z is amine; And, RT and R2, which form the group NR3R4, are as described above for the formula (If), with sodium nitrite in the presence of hydrochloric acid and copper iodide (1) or copper chloride (1) or copper bromide (1) or sodium tetrafluoroborate, to obtain a compound of formula (If) where Z is halogen, Y, RT and R2, which form the group NR3R4, are as described above for the formula (If), and then optionally forming the salts and / or hydrates and / or solvates of the halo derivatives obtained from formula (If), or (ii) optionally reacting the amino derivatives obtained, wherein Z is amino, Y, RT and R2, which form the group NR3R4, are as described above for the formula ( If), with alkylsulfonyl chloride derivatives, to obtain a compound of formula (If) where Z is alkylsulfonylamino, Y, RT and R2, which form the group NR3R4, are as described above for the formula (If), and then optionally forming the salts and / or hydrates and / or solvates of the d Alkylsulphonylamino obtained from formula (If) (Scheme 6).

Scheme 6 (V) (X) pa > 0c) (fc) (xm to. 3-chloroperoxybenzoic acid, 0 ° C - T. amb. , CHCI3, 1 -3 days, b. aqueous HNO3-acetic acid, 100-130 ° C, 2-10 hours, c. SnCl2 or Fe powder, ethyl acetate or conc. HCl. , d. R2-B (OH) 2 (compounds of formula (IX), wherein R2 is optionally substituted phenyl, heterocyclyl); Na2CO3, ethanol, toluene or dimethoxyethane, Pd (PPh3) 4) 1 -5 hours, 20-1 10 ° C, e. NHR3R4 (compounds of formula (XI II) wherein R3 and R4 are as described above for formula (lf)), 70-200 ° C, 1-5 hours, acetonitrile or DM F, f. NaNO2, HCl conc. , Cu (l) l or Cu (l) CI or Cu (l) Br or NaBF4, g. AlkylSO2CI, base, 0-80 ° C. From the compound of formula (V) the molecule of formula (X) was synthesized according to the method described in Patent P0501 166. The corresponding bromo derivative was transformed with m-chloroperoxybenzoic acid in the N-oxide of formula (X), in an aprotic solvent (for example chlorinated hydrocarbons) advantageously at low temperature, between 0 ° C and room temperature. The compounds of formula (XI) were prepared from the corresponding N-oxide of formula (X) by a selective nitration reaction using aqueous nitric acid. The reaction was carried out in a temperature range of 100-130 ° C, in acetic acid, according to the method of Klemm, L. H. (J. Heterocycl, Chem., 7, 1970, 81). The conversion is approximately 20% and the untransformed starting material can be recovered. The processes for the following reaction steps (c, d, e, f and g) were carried out as described above (see Schemes 2, 3 and 5). In accordance with the present invention a process for the preparation of a compound of formula (Ig): (ig) where X represents SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is amino, bromo, chloro, iodo, methoxy, mono- or dialkylamino; RT is an alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl, optionally substituted; R2 is an optionally substituted phenyl, heterocyclyl, or group NR3R4, wherein R3 and R are independently selected from the group consisting of hydrogen or optionally substituted alkyl, or R3 and R4, together with the N atom to which they are attached, form a heterocyclyl group C5-7 optionally substituted containing one or more heteroatom (s), upon reaction of a compound of formula (X): (X) where RT and Y are as described above for the formula (lg), with a compound of the formula (IX): R2-B (OH) 2 (IX) wherein R2 is optionally substituted phenyl, heterocyclyl, the presence of base and catalyst, in a solvent, to obtain the compounds of formula (XIV): (XIV) wherein R2 is an optionally substituted phenyl, heterocyclyl, Rn and Y are as described above for the compounds of formula (Ig), or with a compound of formula (XI II): NH R3R4 (XI II) where R3 and R are as described above for the formula (Ig) to obtain the compounds of formula (XIV) wherein R2 is a group NR3R4, wherein R3 and R are independently selected from the group consisting of hydrogen or an optionally substituted alkyl, or R3 and R4, together with the N atom to which they are attached, form an optionally substituted C5-7 heterocyclyl group containing one or more heteroatom (s); and reacting the compounds of formula (XIV), wherein R1 f R2 and Y are as described above for the formula (Ig), with trifluoroacetic anhydride in a solvent to obtain the compounds of formula (XV): (XV) wherein RT, R2 and Y are as previously described for the formula (Ig), and by reacting the compounds of formula (XV) (wherein RT, R2 and Y are as described above for the formula (lg)) a. with phosphorus oxybromide (III), to obtain the compounds of formula (Ig) wherein Z is bromine, X, Y, n, RT and R2 are as described above for the formula (Ig), and then optionally forming the salts and / or hydrates and / or solvates of the bromine derivatives obtained from formula (Ig); or (i) reacting the bromine derivatives of formula (Ig), wherein Z is bromine; X, Y, n, R and R2 are as described above for the formula (Ig), with potassium fluoride in DMSO, to obtain the compounds of formula (Ig) where Z is fluoro, X, Y, n, RT and R2 are as described above for the formula (Ig), and then optionally forming the salts and / or hydrates and / or solvates of the fluorine derivatives obtained from formula (Ig); or b. with phosphorus oxychloride (III), to obtain the compounds of formula (Ig) wherein Z is chloro, X, Y, n, R and R2 are as described above for the formula (Ig), and then optionally forming the salts and / or hydrates and / or solvates of the chloro derivatives obtained from formula (Ig); or (i) by reacting the chloro derivatives of formula (I g) wherein Z is chloro, X, Y, n, RT and R2 are as described above for the formula (Ig), with potassium fluoride in DMSO, to obtain the compounds of formula (Ig) wherein Z is fluorine, X, Y, n, RT and R2 are as described above for the formula (Ig), and then optionally forming the salts and / or hydrates and / or solvates of the fluorine derivatives obtained from formula (Ig); or c. with iodomethane in the presence of silver carbonate in a solvent, to obtain the compounds of formula (Ig) wherein Z is methoxy, X, Y, n, RT and R2 are as described above for the formula (Ig), and then optionally forming the salts and / or hydrates and / or solvates of the obtained methoxy derivatives of formula (Ig); or d. with trifluoromethanesulfonic anhydride in a solvent and then with ammonia or mono- and di-alkylamines, to obtain the compounds of formula (Ig) wherein Z is, respectively, amino or monoalkylamino or diakylamino, X, Y, n, RT and R2 are such as described above for the formula (Ig), and then optionally forming the salts and / or hydrates and / or solvates of the obtained methoxy derivatives of formula (Ig) (Scheme 7).

Scheme 7 (X) psv) (XV) 0 to. R2-B (OH) 2 (compounds of formula (IX) wherein R2 is optionally substituted phenyl, heterocyclyl); Na2CO3, ethanol, toluene or dimethoxyethane, Pd (PPh3) 4, 1-5 hours, 20-110 ° C; b. NHR3R4 (compounds of formula (XIII) wherein R3 and R4 are as described above for the formula (If), 70-200 ° C, 1-5 hpras, acetonitrile or DMF; c. Polonovsky type reaction (CF3CO) 2O, DMF, 0 ° C- T.amb .; d.POBr3> DMF, 80-130 ° C and then optionally KF, DMSO, 100-1d0 ° C; and. POCI3, DMF, 80-130 ° C and then optionally KF, DMSO, 100-150 ° C; F. Yodomethane, AgCO3, dichloromethane-DMF, 0 ° C -T.amb .; g. i. (CF3SO2) 2O, dichloromethane, pyridine, 0-5 ° C, ii. NH3 or mono- or di-alkylamine, 0 ° C-T.amb. The compounds of formula (Ig) which contain the substituents Z (amino, dialkylamino, methoxy and halogen) are usually synthesized by conversion of a cyclic amide group of formula (XV). The synthesis of the compounds of formulas (XIV) and (XV) is described in Hungarian Patent Application number HU / PO501 166. From an N-oxide of formula (X), which was synthesized by the method shown above, the compounds of formula (Ig) were obtained by treatment of the compounds of formula (XIV) with acetic anhydride or trifluoroacetic anhydride, in dimethylformamide, at 0-2d ° C of temperature according to a Polonovsky type reaction following the method of Hartling, R (J. Het Chem. 13, 1976, 1 197). The compounds of formula (Ig) wherein Z is chloro or bromo can be prepared from the corresponding pyridones of formula (XV). In this field, various methods are known, which involve the transformation of this reaction. A reaction is carried out using phosphorus oxychloride or oxybromide in a suitable solvent, advantageously DM F, at 80-130 ° C temperature, by the method of Dennis W. (J. Org. Chem., 60, 12, 1995 , 37d0). The compounds of formula (Ig) where Z is fluorine can be synthesized from the corresponding chlorine or bromine compound of formula (Ig) using the simplified method of Dolle F.

(Bioorg. &Med., Chem., 11, 2003, 5333). The reaction is carried out at a temperature between 100 and 150 ° C with potassium fluoride in DMSO. In the one where Z is a methoxy group of formula (I g), the corresponding compound of formula (XV) was subjected to reaction with iodomethane in a halogenated solvent, for example dichloromethane or chloroform (10 F DM was sometimes used. 20% to improve the solubility), in the presence of silver carbonate, at room temperature, according to the Ned A process (J. Org. Chem. 26, 2004, 921 5). The 6-amino or 6-amino-substituted compounds of formula (Ig) where Z is a non-amino group, or mono- or di-alkylami were not prepared from the compounds of formula (XV) following a two-step process using the Hisayo I method. and col. (Bioorg, Med. Chem. Lett., 13, 5, 2003, 913). First the amide function was converted to triflate using trifluoromethanesulfonic anhydride in a dry halogenated solvent, for example dichloromethane or chloroform, in the presence of pyridine, at a temperature between 0 and 5 ° C. The crude product was reacted with ammonia in methanol or DMSO or mono- or di-alkylene amine in DMSO at a temperature between 0 and 2d ° C. According to the present invention a process for the preparation of a compound of formula (Ih): (Ih) where X represents SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is amino, hydroxyl, bromo, chloro, fluoro, methoxy, mono- or dialkylamino; RT is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is optionally substituted phenyl, heterocyclyl, or NR3R group, where R3 and R4 are independently selected from the group consisting of hydrogen or optionally substituted alkyl, or R3 and R4, together with the N atom to which they are attached, form a C5 heterocyclyl group -7 optionally substituted containing one or more heteroatom (s), by reacting a compound of formula (XIV): (XIV) where RT, R2 and Y are as previously described for the formula (I h), a. with phosphorus oxychloride (III) or phosphorous pentachloride, to obtain the compounds of formula (I h) wherein Z is chloro, X, Y, n, RT and R2 are as described above for the formula (I h), or b. with phosphorus oxybromide (III), to obtain the compounds of formula (I h) wherein Z is chloro, X, Y, n, RT and R2 are as described above for formula (Ih), and then optionally The salts and / or hydrates and / or solvates of the chloro or bromo derivatives obtained from formula (I h) wherein Z is chloro or bromo, X, Y, n, RT and R2 are as described above for the formula (I h); or (i) by reacting the chloro or bromo derivatives of the formula (Ih) wherein Z is chloro or bromo, X, Y, n, R and R2 are as described above for the formula (Ih), with fluoride of potassium in DMSO, to obtain the compounds of formula (Ih) wherein Z is fluoro, X, Y, n, RT and R2 are as described above for the formula (Ih), and then optionally forming the salts and / or hydrates and / or solvates of the fluorine derivatives obtained from formula (Ih); or (ii) by reacting the chloro or bromo derivatives of the formula (Ih) wherein Z is chloro or bromo, X, Y, n, RT and R2 are as described above for the formula (Ih), with methylate sodium in methanol, to obtain the compounds of formula (I h) wherein Z is methoxy, X, Y, n, RT and R2 are as described above for the formula (I h), and then optionally forming the salts and / or hydrates and / or solvates of the methoxy derivatives obtained from formula (I h); or (ii) by reacting the chloro or bromo derivatives of the formula (Ih) wherein Z is chloro or bromo, X, Y, n, RT and R2 are as described above for the formula (I h), with sodium acetate in acetic acid, to obtain the compounds of formula (Ih) wherein Z is hydroxyl, X, Y, n, RT and R2 are as described above for the formula (I h), and then optionally forming the salts and / or hydrates and / or solvates of the hydroxy derivatives obtained from formula (I ri); or (iv) by reacting the chloro or bromo derivatives of the formula (Ih) wherein Z is chloro or bromo, X, Y, n, RT and R2 are as described above for the formula (I h), with anhydride trifluoromethanesulfonic acid in a solvent and then with ammonia or mono- and di-alkylamines, to obtain the compounds of formula (Ih) wherein Z is, respectively, amino or monoalkylamino or dialkylamino, X, Y, n, RT and R2 are as have previously described for the formula (I h), and then optionally forming the salts and / or hydrates and / or solvates of the obtained methoxy derivatives of the formula (Ih) wherein Z is, respectively, amino or monoalkylamino or dialkylamino; or (v) reacting the chloro or bromo derivatives of formula (Ih) where Z is chloro or bromo, X, Y, n, RT and R2 they are as described above for the formula (Ih), with sodium azide in DMF and water, to obtain the compounds of the formula (Ih) wherein Z is azide, X, Y, n, R and R2 are as described above for the formula (Ih), and then reacting the obtained azide derivatives with sodium borohydride in a solvent, to obtain the compounds of the formula (Ih) wherein Z is amino, X, Y, n, RT and R2 they are as described above for the formula (Ih), and then optionally forming the salts and / or hydrates and / or solvates of the amino derivatives obtained from the formula (Ih) (Scheme 8). Scheme 8 pav) flg) Pe) to. POCI3, POBr3, PCI5, 50-150 ° C, pure or in DMF; b. KF, DMSO or DMF, 100-150 ° C c. NaOCH3, methanol, 0-60 ° C d. CH3COONa, CH3COOH, 80-100 ° C e. NH3 or mono- or di-alkylamine or DMF, 100-150 ° C, sealed tube or microwave assisted reaction f. i. NaN3, DMF-water, 80-100 ° C, ii. NaBH4, methanol 0-30 ° C The compounds of formula (Ih) wherein Z is chlorine or bromine were prepared from an N-oxide derivative of formula (XIV) according to the method of Sakamoto et al. (Chem. Pharm. Bull. 36, 1988, 2244). The reaction was carried out with a suitable phosphorous reagent containing a pure halogen or in an appropriate solvent, for example DM F, at a temperature between 50 and 150 ° C. The process resulted in two halogen isomers at positions 4 and 6 of the thienopyridine ring, which can be separated by crystallization or chromatography. The substituted 4-halogen (chloro or bromo) compounds of formula (Ih) can be transformed into 4-hydroxy derivatives by applying the procedure of Fujimoto et al. , (Pharm. Bull., 2, 1954, 131) using acetic acid and sodium acetate, at a temperature between 80 and 100 ° C. The compounds with the 4-amino function of formula (Ih) were prepared following a two-step process: first, the compounds of formula (Ih) where Z is chlorine or bromine were reacted with sodium azide, which produced derivatives azide of the compounds of formula (I h) wherein Z is an azide group, which are reduced to the corresponding amino derivatives with an appropriate borohydride, for example with sodium borohydride, in methanol or ethanol. An alternative method for the preparation of the compound wherein Z is amino or monoalkyl or substituted dyalkylamino of formula (I h) consists of treating the 4-halogen derivatives of the compounds of formula (Ih) with ammonia, with a mono- or di-substituted amine or with dimethylformamide according to the method of Gawley R.E. et al., (Tetrahedron Lett., 45, 4, 2004, 757) and Prem. M.S. (Synth, Comm. 34, 16, 2004, 292d). In some cases the procedure was carried out in a sealed tube or by microwave assisted reaction at a temperature between 100 and 150 ° C. The compounds of formula (Ih) wherein Z is a methoxy group can be prepared by the well-known method described by Neumann K. (Chem. Ber, 48, 1915, 961). The compound of formula (Ih) wherein Z is chlorine or bromine is reacted with sodium methoxide in methanol, at a temperature between 0 and 60 ° C. The fluorination reaction starting from the corresponding chlorine or bromine compound of formula (Ih) can be carried out with potassium fluoride in a suitable solvent, for example DMF or DMSO, at a temperature between 100 and 150 ° C, applying the simplified method of Hochberg RB (J. Med. Chem., 4d, 2002, d397), which leads to the 4-fluor compounds of formula (Ih). All the treatment of the reaction mixture can be carried out by various well-known methods of synthetic chemistry processes. The products can be purified by crystallization or by column or flash chromatography. Biological Assay Methods mGluRI receptor binding assay The mGluRI receptor binding assays were carried out according to the method of Lavreysen et al. modified (Mol.Pharm., 2003, 63, 1082). Based on the high homology between the human and rat mGluRI receptors, a rat brain membrane preparation was used to determine the binding characteristics of the reference compounds and the new compounds to rat mGluR I. Radioligand [3H] R214127 (3 nM) was used and the non-specific binding was determined in the presence of 1 μM of R214127. The IC-50 values were determined from the displacement curves by non-linear regression analysis and converted to Ki values with the Cheng and Prusoff equation (Biochem Pharmacol., 1973, 22, 3099). MGluRd receptor binding assays mGluRd receptor binding was determined according to Gasparini et al., (Bioorg, Med. Chem. Lett, 2000, 12: 407-409) with modifications. The preparation of a rat brain-cortical membrane was used to determine the binding characteristics of the reference compounds and the new compounds to the rat mGluRd. The A18 cell line expressing hmGluRda (provided by Euroscreen) was used to determine the binding characteristics of the chemical compounds to the human mGluRda receptor. As radioligrant, [3 H] -M-M PEP (2 nM) was used. The non-specific binding was determined in the presence of 10 μM of M-MPEP.

Evaluation of functional activity Cell cultures for the mGluRI and mGluRd native receptors The functional potency of rat mGluRd and mGluRI native receptors was estimated in primary cultures of neocortical cells from 17-day-old Charles River rat embryos and primary cultures of brain cells from 4-day-old Wistar rats respectively (for details on the preparation of neural cell cultures, see Johnson, MI, Bunge, RP (1992): Primary cell cultures of central neurons and glia, in : Protocols for Neural Cell Culture, eds .: Fedoroff, S., Richardson A., The Human Press Inc., d1-77). After isolation, the cells were cultured on 96-well standard microplates and the cultures were maintained in a medium 9d% air-d% CO2 at 37 ° C. For the calcium measurements, neocortical and cerebral cultures were used after d-7 and 3-4 days in vitro, respectively. Cell cultures for recombinant human mGluR5 receptors Chinese hamster (CHO) ovarian cells stably expressing recombinant human mGluRda receptors (CHO-mGluR5a, provided by Euroscreen) were cultured in an F12 medium containing 10% FCS, 1% antibiotic antifungal solution , 400 μg / ml G418, 250 μg / ml zeosin, 5 μg / ml puromycin. The cells were maintained at 37 ° C in an incubator humidified in a medium d% C02-9d% air and were subjected to three passes per week. 2, d-3, d × 10 4 cells / well were cultured in standard 96-well plates, receptor expression was induced by the addition of 600 ng / ml doxycycline the next day. Calcium measurements were carried out 16-24 hours after the addition of the inducing agent. Fluorometric measurement of cytosolic calcium concentration Measures of cytosolic calcium concentration ([Ca2 +] ¡) were carried out in neocortical and cerebral primary cultures and in CHO-mGluRda cells stably expressing human mGluRd receptors. Cells were cultured in 96-well standard microplates and, prior to measurement, they were loaded with a fluorescent dye sensitive to Ca2 +, fluo-4 / AM (2 μM): the neural cultures were loaded into their growth medium, loaded the CHO-mGluRda cells in an assay buffer (14 d mM NaCl, d mM KCl, 2 mM MgCl 2, 2 mM CaCl 2, 10 mM HEPES, 20 mM D-glucose, 2 mM probenecid, pH = 7.4) supplemented with 2 mM Na-pyruvate and 30 μg / ml glutamate-pyruvate transaminase (in the case of CHO-mGluRda cells, these supplements were also present in the measurements of [Ca2 +] ¡). The loading was performed by incubating the cells with 100 μl / well of a coloring solution, at 37 ° C, in a humidified incubator, in a d% CO2- 9d% air medium, for 40-120 minutes. To interrupt the dye loading, the cells were washed twice with the assay buffer. After washing, it added several concentrations of the compounds to be tested (diluted in the assay buffer from a stock solution (stock solution) of DMSO or dimethylformamide (DM F), the final concentration DMSO / DM F was <0.1% ) or a buffer to each well according to the experimental system. In the case of neocortical cultures, the assay buffer also contained TTX (0.5 μM) to suppress the spontaneous oscillations of [Ca2 +] ¡, in the case of brain cultures the probenecid was replaced by sulfinpyrazone (0.25 mM) ). After incubation at 37 ° C for 10-20 minutes, the baseline and the changes provoked by the [Ca 2+] agonist were measured, column by column, with a plate reader fluorometer (FlexStation I I, Molecular Devices). The excitation and emission detection was carried out from the bottom of the plate. The entire measurement process was performed at 37 ° C and was controlled by a solftware to that effect. The inhibitory potency of the test compounds was measured by measuring the decrease in the [Ca2 +] elevation caused by the agonist in the presence of different concentrations of the compounds. It was used as a DHPG agonist for the three columns, the concentration was 20 and 100 μM respectively for neocortical and cerebral cultures. In the case of CHO-mGl uRda cells, the DHPG was applied at an EC80 concentration, EC80 values came from dose-response curves determined daily. Fluorescence data were expressed as? F / F (normalized fluorescence change to the baseline). All treatments of a single plate were measured in multiple wells. The data from all the wells with the same treatment were averaged and the mean values for the analysis were used. The inhibitory potency of a compound at a single concentration point was expressed as percentage inhibition of the response of the control agonist. The sigmoidal concentration-inhibition curves were fitted to the data (from at least three independent experiments) and the IC50 values were determined as the concentration that produces one half of the maximum inhibition caused by the compound. The raw data on fluorescence was analyzed in a Soft Max Pro (Molecular Devices), the adjustment of the curves was performed with GraphPad Prism. Results The compounds of formula (I) of the present invention showed affinity for both rat and human receptors mGluRI and mGluRd and proved to be functional antagonists that inhibited the functional responses elicited by the stimulation of mGluRd receptors.

Table ** dOOn < K < LdOOnM *** K¡ > LdOOnM The 1 H-NMR spectra were obtained on a Varian Unity Inova 300 spectrometer, Varian Unity Inova dOO or on a V-400 Var. Chemical shifts are recorded in parts per million with respect to TMS as an internal standard. The invention is further illustrated by the following non-limiting examples. Examples Example 1: (4-chlorophenyl) - (2-chloropyridin-3-yl) methanone; Intermediate (II) Thionyl chloride (15 ml, 0.2 mol) and DMF (0.5 ml) were added dropwise to a suspension of 2-chlorocyclic acid (31.5 g, 0.2 mol) in chlorobenzene. (100 mL) and the reaction mixture was stirred at 120 ° C for 4 hours. Aluminum chloride (33 g, 0.25 mol) was added at 0 ° C to the reaction mixture and boiled for 6 hours. The reaction mixture was poured onto ice (100 ml) and ethyl acetate (100 ml) was added. The mixture was stirred for half an hour at room temperature. The pH was adjusted to 8 with a solution Aqueous sodium hydroxide (40%). The emulsion was filtered, the filtrate was separated and extracted with ethyl acetate (2 x dO ml). The organic phase was washed with water (100 ml), dried over Na 2 SO 4 and concentrated in vacuo. The crude product was crystallized from iopropanol (20 mL) to yield 19.5 g (34%) of the title compound. The reaction is the same when we start with 2-chloro-5-nitronicotinic acid (Klunder, J. M. et al., J. Med. Chem. 1992, 3d, 1887). Example 2: (4-chlorophenyl) -2-mercaptopyridin-3-yl) methanone. hydrochloride salt A solution of thiourea (1 d, 6 g, 0.200 mmol) in water (d0 ml) and ethanol (2 d ml) was added dropwise to the suspension of (4-chlorophenyl) - (2-chloropyridin-3-yl) methanone (7.6d g, 30 mmol) in ethanol (20 ml). The reaction mixture was heated for 24 hours, then cooled and stirred at 0 ° C for 2-3 hours. The precipitate was filtered off, washed with water and purified by stirring in a NaOH solution (2.5 g of NaOH in 60 ml of water) at room temperature for one hour. The mixture was filtered and the filtrate was adjusted to pH 1 with 6N aqueous hydrochloric acid. The product was filtered off, washed with water, to give 6.48 g (76%) of the title compound. Example 3: 2- (4-chloro-benzenesulfonyl) -3- (4-chlorophenol) thienor-2,3-blpiri ina General method for the preparation of the compound of the formula To a solution of (4-chlorophenyl) - (2-mercaptopyridin-1-yl) methanone hydrochloride (0.7 g, 2.4 mmol) in DM F (15 mL) was added (4-chlorophenyl) chloromethyl sulfone. (0.7 g, 3.0 mmol) and NaOMe (0.28 g, 5.0 mmol). The reaction mixture was maintained at a temperature between 120 and 130 ° C for 2 hours, followed by evaporation in vacuo. Water (15 ml) was added to the residue and extracted with chloroform (3 x 20 ml). The organic phase was dried over Na2SO, it was filtered and concentrated in vacuo. The crude product was purified by crystallization from ether containing 10% dichloromethane and yielded 0.71 g of the title compound. The compounds of No. 1 -14, 16, 17, 18, 19, 22, 23, 24, 26-31, 33-35, 37, 39-41, 44, 45, 48, 54 were prepared by the same reaction. -56, 59, 61-63, 68, 70, 72, 78, 80, 82, 87, 88 and 91. The reactive chloromethylene sulfone salts were either commercial or obtained by the method of Y. Yinfa et al. . (Synth, Communication, 2004, 34, 13, 2443). Example 4: 3- (4-chlorophenyl) thienor-2,3-b-pyridine-2-sulfonic acid (4-chlorophenyl) amide (Compound 15) A mixture of N- (4-chlorophenyl) chloromethanesulfonamide (0.265 g, 1.1 mmol) (Intermediate A), (4-chlorophenyl) - (2-mercaptopyridin-3-yl) methanone hydrochloride (0.29 g, 1 mmol) (Example 2) and NaOCH3 (0.12 g, 2.2 mmol) in DM F (5 ml) at 130 ° C for 2 hours. Then the solvent was removed vacuum, water (1 d ml) was added to the residue, and the mixture was extracted three times with chloroform (1 d-15 ml). The organic phase was dried and concentrated. The residue was triturated with n-hexane (10 mL) and, after decanting the n-hexane, the oily product was purified by column chromatography (Kieselgel 60, eluent: chloroform: methanol = 98: 2) to yield 0.225 g ( 52%) of the title compound. N- (4-chlorophenyl) chloromethanesulfonamide (Intermediate A) To a stirred solution of 4-chloroaniline (0.65 g, 5.0 mmol) in dichloromethane (10 mL) was added TEA (1.4 mL, 10 mmol). The solution was cooled to 5 ° C and a solution of chloromethanesulfonyl chloride (0.9 ml, 10 mmol) in dichloromethane (d ml) was added dropwise, maintaining the temperature at d ° C. After the addition, the reaction mixture was stirred for 30 minutes at 10 ° C, and then at room temperature for 20 hours. The reaction mixture was evaporated to dryness and 2N aqueous NaOH (25 mL, 50 mmol) was added, and the mixture was stirred for 2 hours. Then the solution was neutralized with aqueous HCl to pH = 7 and extracted three times with ethyl acetate (30-30 ml). The organic phase was dried and concentrated. The crude product was purified by column chromatography (Kieselgel 60, eluent: n-hexane: ethyl acetate = 2: 1) to yield 0.7 g (58%) of the title compound as a crystalline substance. Melting point: 102-104 ° C.

Example 5: 4-chlorobenzylamine of 3- (4-chlorophenyl) thienof2.3-blpyridine-2-sulfonic acid (Compound 21) The title compound was prepared from N- (4-chlorobenzyl) chloromethanesulfonamide (Intermediate A) and (4-chlorophenyl) - (2-mercaptopyridin-1-yl) methanone hydrochloride (Example 2) according to the method described in Example 4. The crude product was purified by column chromatography (Kieselgel 60, eluent: n -hexane: ethyl acetate = 2: 1) to yield 0.2 g (45%) of the title compound. N- (4-c-lorobenzyl) phenestephine (Intermediate A) The title compound was prepared from 4-chlorobenzylamine and chloromethanesulfonyl chloride according to the method described in Example 4 for Intermediate A. The compound was purified by column chromatography to give a crystalline product (54%). Melting point: 91 -92 ° C. Example 6: 3- (4-C lorof en yl) -2- (4-methylpiperidin-1-sulfonyl) thienor 2,3-blpyridine (Compound 20) The title compound was prepared from 1-chloromethanesulfonyl-4- methylpiperidine (Intermediate A) and (4-chlorophenyl) - (2-mercaptopyridin-1-yl) methanone hydrochloride (Example 2) of according to the method described in Example 3. The pure product was purified by column chromatography (Kieselgel 60, eluent: n-hexane: ethyl acetate = 1: 1) to yield 0.23 g (56%) of the Title. 1-Chlorinated N-methyl-piperidine (Intermediate A) To a stirred solution of 4-methylpiperidine (0.6 mL, 10 mmol) in dichloromethane (10 mL), TEA (1.4 mL; mmol). The solution was cooled to d ° C and a solution of chloromethanesulfonyl chloride (0.4 ml, 4.4 mmol) in dichloromethane (d ml) was added dropwise maintaining the temperature at d ° C. After the addition, the reaction mixture was stirred for 30 minutes at 10 ° C, and then at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane (10 ml) and washed twice with 0, dN aqueous hydrochloric acid (10-10 ml), then with water. The organic phase was dried and concentrated. The crude product was solidified with n-hexane (d mi), and then crystallized from a n-hexane: ethyl acetate (3: 1) mixture (4 ml) to yield 0.4d g (48%) of the compound of the title as a crystalline substance. Melting point: 90-92 ° C. Example 7: 2- (4-chlorobenzenesulfonyl) thienor2,3-b1pyridin-3-yl General method for the preparation of intermediate (IV) A solution of 3-cyanopyridin-2 was stirred at 120 ° C for 2 hours. thiol (6.8 g, 50 mmol), chloromethyl- (4-chlorophenyl) - sulfone (12.3 g; dd mmol) and sodium methoxide (3.0 g; dd mmol) in anhydrous N, N-dimethylformamide (1 d0 ml). The reaction mixture was cooled to room temperature and poured into water (1 d0 ml). The solid was filtered, washed (H2O) and dried, to yield 13.7 g (84%) of the title compound. Example 8: 3-brom o-2- (4-c-loro-benzene) ulf oni l) ti in of 2, 3-b] pyridine General method for the preparation of intermediate (V) To a mixture of copper bromide ( 11) anhydrous (1.1 g, 50 mmol) and tert-butyl nitrite (9.0 mL, 75 mmol) in anhydrous acetonitrile (100 mL), under argon, was added 2- (4-chlorobenzenesulfonyl) thieno [2,3-b] pyridin-3-ylamine (10.7 g, 34 mmol), intermediate (IV), little by little, while maintaining the temperature below 70 ° C. The reaction mixture was maintained at 65 ° C for 1.5 hour, then cooled to room temperature. The crystalline product was filtered and washed with acetonitrile to give the pure product (7.7 g, d8.3%). Example 9: 2- (3-cyano-5-fluorobenzenesulfonyl) -3- (3-fluorophenyl) thienor-2,3-blpyridine (Compound 10) General procedure for the preparation of the compounds of formula (Ib); 3-Bromo-2- (3-cyano-5-fluorobenzenesulfonyl) thieno [2,3-b] pyridine (Example 8) was dissolved (0.2 g, 0.5 mmol) in toluene (4 ml) and ethanol (4.5 ml), under an argon atmosphere. To the solution was added Pd (PPh3) 4 (28 mg, 0.025 mmol), 3-fluorophenylboronic acid (85 mg, 0.6 mmol) and a 2M Na2CO3 solution (2.3 mL). The reaction mixture was refluxed for 1.5-2 hours, then the organic solvent was evaporated in vacuo. Water (10 ml) was added to the residue and the obtained suspension was extracted three times with chloroform (3 x 10 ml). The organic phase was washed with water (5.0 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Kieselgel 60, chloroform: methanol = 5: 0, Od) to yield 0.1 g (2d%) of the title compound. The compounds 38, 42, 52, 53, 60, 66, 67, 69, 71, 73, 83, 84, 108-110, 113, 114, 126-128, 130, 132, 136 and 137 were prepared in accordance with the procedure described above. Example 10: 2- (3-Cyanobenzenesulfonyl) -3- (4-methylpiperidinyl) thienof2.3-blpyridine (Compound 36) General procedure for the synthesis of some compounds of formula (le) (Scheme 3a) 3-bromo- was dissolved 2- (3-cyanobenzenesulfonyl) thieno [2, 3-bipyridine (prepared according to Example 8) (2.18 g, 5.75 mmol) and 4-methylpiperidine (2.0 ml; 17 mmol) in DM F (9.0); mi) and heated to a temperature of 100 ° C for one hour under argon. The reaction mixture was cooled and water (60 ml) was added and extracted with chloroform (3 x 20 ml). The organic layer was washed with water (2 x 20 mL), dried and evaporated in vacuo. The crude product was purified by chromatography (Kieselgel 60, hexane: ethyl acetate = 2: 1) giving 1.64 g (72.4%). The compounds prepared analogously were 32, 36, 46, 92-96, 98-100, 106, 116-118, 129, 1 33, 134, 140 and 141. Example 11: N-r2- (4-methoxybenzenesulfonyl) thienor2.3-blpyridin-3-yl1-4-methylpiperidine-1-carboxamide (Compound 120) General procedure for the synthesis of some compounds of formula (le) (Scheme 3b) 2- (4-methoxybenzenesulfonyl) thieno [2,3-b] pyridin-3-ylamine (IV) (prepared as in Example 7) (0.48 g; 1.5 mmol) in dry tetrahydrofuran was suspended, triethylamine (0.3 ml, 2 mmol) was added and it was poured into triphosgene (0.18 g, 0.6 mmol) dissolved in tetrahydrofuran. After stirring for one hour at room temperature, 4-methylpiperidine (0.36 ml, 3 mmol) was added and the stirring continued for a further 20 hours. The mixture was evaporated in vacuo, the residue was dissolved in chloroform, washed with water, dried and evaporated in vacuo. Purification with flash chromatography afforded the title compound (0.43 g, 65%). Applying the above procedure, the following compounds were prepared: 111, 112, 120-122. Example 12: 2- (4-Chlorobenzenesulfonyl) -3- (4-chlorophenyl) thienor-2,3-b1-pyridin-5-ylamine (Compound 79) To a solution of 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -5 -nitrothieno [2,3-b] pyridine (Example 3, compound 72) (0.90 g; 1.93 mmol) in ethyl acetate (12 mL), SnCl2-2H2O (2, 19) was added in one portion. g, 9.71 mmol). The reaction mixture was stirred at 70 ° C for 1 hour. The mixture was poured into an ice-filled flask and neutralized with a solution of NaHCO3 (10%), then dichloromethane (60 ml) was added and the organic layer was separated. The aqueous phase was extracted with dichloromethane (2 x 30 mL). The organic phases were collected, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was subjected to column chromatography (SiO2, cyclohexane: acetone = 7: 3), giving 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-b] pyridin-5-ylamine (0.46 g, yield: 55%). Example 13: N-r2- (4-Chlorobenzenesulfonyl-p-3- (4-chlorophenyl) thienor-2,3-blpyridin-5-yl] methanesulfonamide (Compound 85) To a solution in pyridine (2 ml) of 2- ( 4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-b] pyridin-d-ylamine (0.09 g, 0.22 mmol) (Example 12) methanesulfonyl chloride (0.02 g) was added 022 mmol) at once The reaction mixture was refluxed for 3 hours.

Evaporated the solvent in vacuo, suspended the residue in methanol (5 mL) and filtered. Water (10 ml) was added to the filtrate and the formed mixture was extracted with dichloromethane (2 x 10 ml). The organic phases were collected, dried, filtered and concentrated in vacuo. The crystals were collected, washed with cold methanol and removed by filtration, to give the title compound (73 mg; yield: 65%). Example 14: 5-chloro-2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thienor-2,3-blpyridine (Compound 97) A suspension of 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-b] pyridin-d-ylamine (Example 12) (0.69 g; 1, d8 mmol), concentrated HCl (6 mL) and water (4 mL) was cooled to 0 ° C and a ice-cold aqueous NaNO2 solution (3 ml, 0.1 g, 1.58 mmol). The mixture was stirred for half an hour at 0 ° C. A solution in concentrated HCl (4 mL) of Cu (1) CI (0.188 g, 1.9 mmol) was then added in one portion. The mixture was allowed to warm to room temperature and then immersed in an oil bath at 60 ° C for one hour. The mixture was cooled by pouring it into ice (10 g), neutralized with a solution of NaHCO3 (10%) and extracted with dichloromethane (3 x 50 ml). The organic phases were collected, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, cyclohexane: acetone = 7: 3) giving the title compound (0.27 g, 38%). Example 15: 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -5-fluorothienor2.3-blpyridine (Compound 123) A suspension of 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [ 2, 3-b] pyridin-d-ylamine (0, d0 g; 1.14 mmol) (Example 12), concentrated HCl (8 mL) and water (4 mL) was cooled to 0 ° C and a solution was added. NaNO2 cooled aqueous phase (dm; 0.084 g; 1.21 mmol). The mixture was stirred for half an hour at 0 ° C. Then a cooled aqueous NaBF4 solution (0.177 g, 1.59 mmol) was added at once. The mixture was stirred at 0 ° C for half an hour and filtered. The solid obtained was washed with cold water and methanol and dried overnight. The compound was melted at 179-182 ° C and stirred for 10 minutes. The mixture was then cooled to room temperature and subjected to column chromatography (SiO2, cyclohexane: acetone = 9: 1) to give the compound 5-fluor (0.126 g, 25%). Example 16: 3-brom o-2- (3-c to a non-5-f luoro benzenes ulf onil) thienor2.3-blpyridine N-oxide General method for the preparation of Intermediate XA a solution of 3-bromo-2 - (3-cyano-d-fluorobenzenesulfonyl) thieno [2, 3-b] pyridine (3, d1 g; 8, 8 mmol) in chloroform (130 ml) was added m-chloroperoxybenzoic acid (6.08) g; 35 mmol; 77%) and the reaction mixture was stirred at room temperature overnight. The solution was washed with NaHCO3 (10%, 3 x 50 mL), then twice with water (25 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by treatment with ether to yield 3.06 g (84%) of the title compound. Example 17: 3-brom o-2- (4-C I orobenzenesulfonyl) -5-nitrotien of2,3-b1 pyridine-N-oxide General method for the preparation of Intermediate XI Boiled 3-bromo- 2- (4-chlorobenzenesulfonyl) thieno [2,3-bjpyridine N-oxide (prepared as described in Example 16) (4.95 g; 12.2 mmol) at 120 ° C with 70% nitric acid ( 0.75 ml; 12 mmol) in acetic acid for 4 hours. The reaction mixture was evaporated and the residue was purified by chromatography (Kieselgel 60, chloroform: methanol = 5: 0.1) to yield a yellow solid compound (0.8 g, 15%) and the starting material (2, 4 g, 49%). Example 18: 5-amino-3-bromo-2- (4-chlorobenzenesulfonyl) thienor 2,3-blpyridine General method for the preparation of Intermediate Xll 3-Bromo-2- (4-chlorobenzenesulfonyl) -5-nitrothien [2 , 3-b] pyridine N-oxide (Example 17) (0.8 g, 1.78 mmol) in acetic acid (12 mL) and Fe powder (0.61 g, 10 mmol) was added. The reaction mixture was stirred at 70 ° C for 30 minutes, followed of evaporation in vacuo, and the residue was purified by chromatography (Kieselgel 60, chloroform: methanol = 5: 0.1) to yield the title compound (0.51 g, 71%). Example 19: 5-amino-2- (4-chlorobenzenesulfonyl) -3- (3-f luorofenyl) thienor2, 3-blpyridine (Compound 115) 5-amino-3-bromo-2- ( 4-chlorobenzenesulfonyl) thieno [2,3-b] pyridine with 3-fluorophenylboronic acid as described in Example 9. The yield is 20%. The compound 131 was prepared according to the same method. Example 20: 5-amino-2- (4-chlorobenzenesulfonyl) -3- (4-methylpiperidine) thienor 2,3-blpyridine (Compound 104) 5-Amino-3-bromo-2- (4-chlorobenzenesulfonyl) was reacted thieno [2,3-b] pyridine with 4-methylpiperidine as described in Example 10. Example 21: 2- (4-chlorobenzenesulfonyl) -3- (3-f luorofenyl) -5-fluorothienor 2, 3 -blpyridine (Compound 137) 5-amino-2- (4-chlorobenzenesulfonyl) -3- (3- fluorophenol) thieno [2,3-b] pipdin (Example 19) as described in Example 1 d to produce the d-fluor compound. Example 22: 2- (3-cyano-5-fluorobenzenesulfonyl) -3- (4-chlorophenyl) thienof2.3-blpyridine N-oxide General method for the preparation of Intermediate XIV (R2 is phenyl or aromatic heterocycle) Reacted 3-bromo-2- (3-cyano-5-fluorobenzenesulfonyl) thieno [2,3-b] pyridine N-oxide (Example 16) with 4-chlorophenylboronic acid using the same procedure as described in Example 9 to produce the composed of the title (yield: 63%). Example 23: 2- (4-chlorobenzenesulfonyl) -3- (4-methylpiperidinyl) thienor2.3-blpyridine N-oxide General method for the preparation of Intermediate XIV (R2 is a substituted amino group) 3-bromo- 2- (4-Chlorobenzenesulfonyl) thieno [2,3-b] pyridine N-oxide (prepared according to Example 16) with 4-methylpiperidine according to the process of Example 10 at a temperature of 80 ° C, giving the title compound. Example 24: 2- (3-cyano-5-f luoro be ncenosulf onyl) -3- (4-chlorophenyl) -7H-thieno [2,3-b] pyridin-6-one General Method for the Preparation of Intermediate XV 2- (3-Cyano-5-fluorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-b] pyridine N-oxide (1, 3d g; 3.0) mmol) in a suspension of DM F (11 mL) with trifluoroacetic anhydride (8.6 mL, 61 mmol) at room temperature for 1.5 hours. At the end of the reaction, a solution was obtained which was concentrated to half its volume in vacuo. Water (8.6 ml) was added, the crystalline product was filtered off and washed with water. The reaction gave 0.93 g (68.9%) of the title compound. Example 25: 2- (4-Chlorobenzenesulfonyl) -3- (4-methylpiperidinyl) -5-hydroxy-2,3-pyridine hydrochloride From 2- (4-chlorobenzenesulfonyl) -3- (4-methylpiperidinyl) thieno [2, 3-b] pyridine N-oxide (Example 23), the reaction was prepared by the same procedure as that described in Example 24 and as a by-product the title product was isolated (yield 10%). The yield of corresponding 2- (4-chlorobenzenesulfonyl) -3- (4-methylpiperidinyl) -7-thieno [2,3-b] pyridin-6-one was 60% (Intermediate XV). Example 26: 2- (3-cyano-5-fluorobenzenesulfonyl) -3- (4-chlorofenyl) -6-chlorothienof2,3-b1 pyridine (Compound 86) M General method for the preparation of the 6-chloro compounds of formula (I), for example compounds 43, 5, 51, 74, 76, 81, 119 and 138. 2- (3-Cyano-5-fluorobenzenesulfonyl) -3- (4-chlorophenyl) -7 - / - thieno [2,3-b] pyridin-6-one (0.92 g) was dissolved. 2.1 mmol) in DM F (14 mL) and phosphorus oxychloride (2.0 mL, 21 mmol) was added, and the reaction mixture was heated at 90-100 ° C for 2.5 hours. It was then cooled, cooled rapidly with ice (10 g) and made alkaline with ammonium hydroxide (25%, 2.5 ml). The solid product was filtered, washed with water and methanol. It was recrystallized from hot dioxane to give 0.73 g (7d%) of the title compound. Example 27: 2- (3-cyano-5-fluoro-benzenesulfonyl) -3- (4-c-orofenyl) -6-fluorothi in of 2,3-b] pyridine (Compound 90) General method for the preparation of the 6-fluorine compounds of formula (I), for example compounds 58, 65, 75, 77, 89 and 139. 2- (3-cyano-5-fluorobenzenesulfonyl) -3- (4-chlorophenyl) -6 was dissolved Chlorothieno [2,3-b] pyridine (0.83 g; 1.8 mmol) in DMSO (10 mL) and potassium fluoride (0.3 g; d, 0 mmol) was added. The reaction mixture was heated at 140 ° C for 1.5 hours. After cooling, water (10 ml) was added and the crystalline product was not filtered, washed with water. It was recrystallized from hot methanol to yield 0.65 g (62.5%) of compound No. 90. Example 28: 2- (3-cyanobenzenesulfonyl) -3- (4-chlorophenyl) -6-methoxy enor2,3- blpyridine (Compound 64) 2- (3-Cyanobenzenesulfonyl) -3- (4-chlorophenyl) -7 / - / - thieno [2, 3-b] pyridin-6-one (0.1 g; 2d mmol) (Example 24), silver carbonate (1) (95 mg, 0.35 mmol) and iodomethane (0.1 d mi, 2.4 mmol) in dichloromethane (d mi) and DM F (0, d). my). The reaction mixture was stirred at room temperature for 24 hours. It was filtered, washed with dichloromethane (2 x 10 mL), the filtrate was washed with a solution of Na2CO3 (10%, 10 mL) and water (10 mL). The organic solvent was dried, evaporated in vacuo and the residue was purified by chromatography (Kieselgel 60, ethyl acetate: hexane = 1: 1) to yield the title product (47 mg, 43%). Example 29: 6-amino-2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thienof2.3-blpyridine (Compound 49) 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -7 was dissolved - / - thieno [2,3-b] pyridin-6-one (0.30 g; 0.69 mmol) (Example 24) in DM F abs. (10 ml), cooled to 0 ° C and abs. Pyridine was added. (0.06 mL, 0.74 mmol) and trifluoromethanesulfonic anhydride (0.026 mL, 0.77 mmol). The reaction mixture was kept at 0 ° C for 1 hour, then dimethyl chloride (10 ml) and 1 N NaHCO 3 (10 ml) were added. After separation, the organic phase was washed with water (10 ml), dried and evaporated in vacuo. The crude triflate was treated with methanol saturated with NH3 (3 mL) at 0-5 ° C for 2 hours. HE Evaporate the reaction mixture in vacuo and purify the residue by chromatography (Kieselgel 60, chloroform: methanol = 5: 0.2) to yield the title compound (120 mg, 40%). Example 30: 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -6-di methylammonium phenylidine (Compound 47) 2- (4-chlorobenzenesulfonyl) -3- was reacted (4-chlorophenyl) -7 / -thieno [2,3-b] pyridin-6-one (0.19 mmol) (Example 24) using the same procedure as for Example 29, but using dimethylamine hydrochloride as Amine source (0.49 mmol) in DMSO (2.0 ml) in the presence of TEA (0.49 mmol), at room temperature, for 2 hours. The yield was 73.7%. Example 31: 4-chloro-2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thienor-2,3-blpyridine (Compound 57) ß-chloro-2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) tienor2,3-blpiridine (Compound 43) A mixture of 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-b] pyridine N-oxide (prepared according to the procedure described in Example 16) (6.4 g, 14.7 mmol) and phosphorus oxychloride (III) (10.2 mL, 109.4 mmol) was stirred and heated to a 60 ° C for 3 hours. The obtained solution was poured onto ice and basified with a 5M sodium hydroxide solution. After cooling, the precipitate was filtered and washed with water. The crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: dichloromethane) to obtain the compound 4-chloro (3.31 g) and 6-chloro-2- (4-chlorobenzenesulfonyl) -3- ( 4-chlorophenyl) thieno [2,3-b] pyridine (3.03 g) (Compound 43). Example 32: 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -4-di methylamino no2of2,3-b1 pyridine (Compound 135) 4-chloro-2- (4-chlorobenzenesulfonyl) was irradiated with microwaves ) -3- (4-chlorophenyl) thieno [2,3-b] pyridine (100 mg, 0.22 mmol) in DM F (5 ml) in a 300 W reactor at 210 ° C for 10 minutes. The solvent was evaporated in vacuo. The crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroform: methanol = 98: 2) to obtain the title compound (36 mg). Example 33: 4-Fluoro-2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl-2,3-bipyridine (Compound 102) A mixture of 4-chloro-2- (4-chlorobenzenesulfonyl) -3- (4 chlorophenyl) thieno [2, 3-b] pyridine (454 mg, 1 mmol) and potassium fluoride (173 mg, 3 mmol) in DM F (5 mL) was stirred and heated to 140 ° C for 48 hours. The solvent was evaporated in vacuo. The crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: n-hexane: ethyl acetate = 2: 1) to obtain the title compound (101 mg). Example 34: 2- (4-Chlorobenzenesulfonyl) -3- (4-chlorofenyl) -4-methoxytienor2.3-blpyridine (Compound 101) A mixture of 4-chloro-2- (4-chlorobenzenesulfonii) -3- ( 4-chlorophenyl) thieno [2,3-b] pyridine (150 mg, 0.33 mmol) and sodium methoxide (1.5 g, 27.8 mmol) in methanol (150 ml) was stirred and heated to reflux for 4 hours. The solvent was evaporated in vacuo. Water (100 mL) was added and the mixture obtained was extracted with chloroform (3 x 20 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated in vacuo. The crude residue was purified by crystallization from diethyl ether to obtain the title compound (105 mg). Example 35: 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -4-hydroxytienor2,3-blpyridine (Compound 103) A mixture of 4-chloro-2- (4-chlorobenzenesulfonyl) -3- (4- chlorophenyl) thieno [2, 3-b] pyridine (150 mg, 0.33 mmol) and sodium acetate (280 mg, 3.4 mmol) in acetic acid (7 mL) and water (0.1 mL) was stirred and heated at 100 ° C for 48 hours. The solution was diluted with water (2d mi). The precipitate was filtered, washed with water (3 x 10 ml) and dried. The crude product was purified by crystallization from chloroform to obtain the title compound (dd mg). Example 36: 4-amino-2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thienof2,3-blpyridine (Compound 125) A mixture of 4-chloro-2- (4-chlorobenzenesulfonyl) -3- (4 -chlorophenyl) thieno [2,3-b] pyridine (400 mg; 0.88 mmol) and sodium azide (360 mg; 5, d4 mmol) in DMF (11 mL) and water (4 mL) was stirred and heated at 10 ° C for d hours. The solution was diluted with water (1 d mi). The precipitate was filtered, washed with water (d x 10 mL) and dried. The crude 4-azido-2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-b] pyridine obtained (400 mg, 0.87 mmol) was dissolved in methanol (20 ml). To the solution was added sodium borohydride (400 mg, 10.6 mmol) and the mixture was stirred at room temperature for 24 hours. Water (30 ml) was added and the mixture obtained was extracted with chloroform (3 x 60 ml). The combined organic layer was dried over sodium sulfate, filtered and evaporated in vacuo. The crude residue was purified by crystallization from diethyl ether to obtain the title compound (193 mg). Example 37: 3- (4-chlorophenyl) -4-dimethylamino-2- (4-dimethylaminobenzenesulfonyl) thienof2.3-b] pyridine (Compound 124) Microwave 4-chloro-2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-b] pyridine (100 mg, 0.22 mmol) in DM F (5 ml) was irradiated in a 300 W reactor at 2d0 ° C for 10 minutes. The solvent was evaporated in vacuo. The crude product was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroform: methanol = 98: 2) to obtain the title compound (26 mg). All compounds were analyzed by HPLC-MS or MS and 1 H-NMR. The purity of the compounds of formula (I) was measured by HPLC methods and all compounds have a purity > 95% Example 38: Preparation of the pharmaceutical compositions a) Tablets 0.01 - 50% of active ingredient of formula (I) were mixed, -d0% lactose, 1 d-d0% potato starch, d-1 d% polyvinyl pyrrolidone, 1-d% talc, 0.01 -3% magnesium stearate, 1 -3% dioxide colloidal silicon and 2-7% of ultraamilopectin, then granulated by wet granulation and compressed into tablets. b) Dragees, film-coated tablets The tablets prepared according to the method described above were coated with a layer composed of an entire film- or gastro-solvent, or sugar and talc. The dragees were polished with a mixture of beeswax and wax carnuba c) Capsules 0.01 -50% of the active ingredient of formula (I), 1-5% of lauryl-sodium sulfate, 15-d% starch, 15-d% lactose, 1 -3 were mixed well. % of colloidal silicon dioxide and 0.01 -3% magnesium stearate, the mixture passed through a sieve and filled with hard gelatin capsules. d) Suspensions Ingredients: 0.01 -1 d% active ingredient of formula (I), 0.1 -2% sodium hydroxide, 0.1-3% citric acid, 0.0d-0.2% of nipagine (methyl sodium 4-hydroxybenzoate), 0.006-0, 02% nipasol, 0.01 -0.5% carbopol (polyacrylic acid), 0.1-5% 96% ethanol, 0, 1 -1% flavoring agent, 20-70% sorbitol (70% aqueous solution) and 30-50% distilled water. To the solution of nipagine and citric acid in 20 ml of distilled water the carbopol was added in small portions under strong agitation, and the solution was allowed to stand for 10-12 hours. Then the sodium hydroxide was added in 1 ml of distilled water, the aqueous solution of sorbitol and finally the ethanolic raspberry flavor by stirring. To this vehicle the active ingredient was added little by little and suspended in an immersion homogenizer. Finally, the suspension was completed to the desired final volume with distilled water and the syrup in suspension was passed through a colloidal milling equipment. e) Suppositories For each suppository, a 0.01 -15% active ingredient of formula (I) and a 1-20% lactose were mixed well, then 50-9d% of adeps were melted for suppositories (eg Witepsol 4), it was cooled to 3d ° C and the active ingredient together with the lactose were mixed therein in a homogenizer. The obtained mixture was molded into cooled forms. f) Compositions for lyophilized powder ampoules A 5% solution of mannitol or lactose was made with bidistilled water for use in injections and the solution was filtered to obtain a sterile solution. A solution of 0.01 -d% active ingredient of formula (I) was also made with bidistilled water for use in injections, and this solution was filtered to obtain a sterile solution, both solutions were mixed under aseptic conditions, filled with it ampoules of 1 ml, the contents of the ampoules were lyophilized and the ampoules were sealed under nitrogen. The contents of the ampoules were dissolved in sterile water or in a sterile aqueous solution of sodium chloride (physiological) at 0.9% before its administration.

Claims

CLAIMS 1. Compound of formula (I): (l) where X represents a selected group of SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is H or is monosubstituted by alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxyl, alkylsulfonylamino; R-i is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is optionally substituted phenyl, heterocyclyl, or group NR3R4 where R3 and R4 are independently selected from the group consisting of hydrogen and an optionally substituted alkyl, or R3 and R4, together with the N atom to which they are attached, form a C5 heterocyclyl group - optionally substituted containing one or more heteroatom (s), or NH-CO-NRsRβ group wherein R5 and R6 are independently selected from the group consisting of hydrogen and an optionally substituted alkyl, or R5 and R6, together with the N atom to which they are attached, form an optionally substituted Cs- heterocyclyl group containing one or more heteroatom (s); and / or hydrates and / or solvates and / or pharmaceutically acceptable salts thereof formed with acids or bases. 2. Compound of formula (I): (I) where X represents a selected group of SO, SO2; And represents a group selected from (CH2) ", NH, NHCH2; n is an integer from 0 to 1; Z is H or is monosubstituted by alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxyl, alkylsulfonylamino; R1 is an alkyl or C3-cycloalkyl group or, optionally substituted with one or more substituent (s) selected from alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen, or phenyl or biphenyl optionally substituted by one or more substituent (s) selected from alkyl, methoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, alkylsulfonyl, alkylsulfonylamino, cyano, halogen, or monocyclic or bicyclic, saturated or unsaturated heterocyclyl, containing 1 -4 heteroatom (s) selected from O, N or S, such as a pyridyl, quinolinyl, thiazolyl, piperidinyl, morpholyl, tetrahydroquinolinyl, oxazolyl, isoxazolyl ring , furylthiophenyl, triazolyl, pyrrolidinyl, optionally substituted with one or more hydroxyl, hydroxyalkyl, alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen or oxo groups; R2 is phenyl optionally substituted with one or more substituent (s) selected from alkyl, methoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, alkylsulfonyl, alkylsulfonylamino, cyano, halogen, or monocyclic C5-7 heterocyclyl group or bicyclic, saturated or unsaturated, containing 1-4 heteroatom (s) selected from O, N or S, such as a pyridyl, quinolinyl, thiazolyl, piperidinyl, morpholyl, tetrahydroquinolinyl, oxazolyl, isoxazolyl, furylthiophenyl, triazolyl, pyrrolidinyl ring, optionally substituted with one or more hydroxyl, hydroxyalkyl, alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen or oxo groups, or group NR3R4 where R3 and R4 are independently selected from the group consisting of hydrogen and alkyl group optionally substituted with one or more substituent (s) selected from alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen, or R3 and R, together with the N atom to which they are attached , form a C5-7 heterocyclic group containing one or more heteroatom (s) selected from O, N or S, optionally substituted with one or more hydroxyl, hydroxyalkyl, alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen or oxo group, or NH-CO-NR5R6 group wherein R5 and R6 are independently selected from the group consisting of hydrogen and alkyl group optionally substituted with one or more substituent (s) selected from alkoxy, trifluoromethyl, amino, alkylamine, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen, or R5 and Re, together with the N atom to which they are attached, form a Cs-7 heterocyclyl group containing one or more heteroatom (s) selected from O, N or S, optionally substituted with one or more hydroxyl, hydroxyalkyl groups, alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, halogen or oxo and / or hydrates and / or solvates and / or pharmaceutically acceptable salts thereof formed with acids or bases. 3. Compound selected from: 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-b] pyridine, 2- (4-chlorobenzenesulfinyl) -3- (4-chlorophenyl) thieno [2, 3-o] pyridine, 3- (4-cl orofenyl) -2- (4-f luoro benzenes ulf onyl) thieno [2, 3-bjpyridine, 3- (4-cl orof eni I) -2- (toluene -4-sulf oni I) thieno [2,3-b] pyridine, 4- [3- (4-cl orofeni l) thieno [2,3-?] Piri di n-2-sulf onyl] benzonitrile , 2-benzenes ulf oni l-3- (4-chloropheni I) thieno [2,3-b] pyridine, 3- [3- (4-chlorophenyl) thieno [2,3-D] pyridine-2-sulfonyl] benzonitrile, 3- (4-cl orof eni I) -2- (pi ri di n-3-sulfonyl I) thieno [2,3-b] pyridine, 2- (butane-

1-sulfonyl) -3- ( 4-chlorophenyl) thieno [2,3-t)] pyridine, 3- (4-chlorophenyl) -2- (2,4-dimethylthiazole-5-sulfonyl) thieno [2,3-b] pyridine, 3- (4 -cl orof eni I) -2- (ti ofeno-2-s ulf oni I) ti in o [2, 3-b] pyridine, 3- (4-chlorophenyl) thieno [4-chlorophenyl] amide [2] , 3-b] pyridine-2-sulfonic acid, 3- (4-chlorofenyl) -2-f eni -methanesulfonyl-ene- [2, 3-b] pyridine, 2- (3-chlorobenzenesulfonyl) -3 - (4-chlorophenyl) thieno [2,3- J] pyridine, 2- (4-Chlorobenzenesulfonyl) -3- (4-chlorophenyl) -6-chloro-thieno [2,3-jpyridine, 2- (3-fluorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3- bjpyridine, 2- (3-cyanobenzenesulfonyl) -3- (3-fluorophenyl) thieno [2,3-bjpyridine, 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -6-fluorothieno [2,3-b] ] pyridine, 2- (4-cyanobenzenesulfonyl) -3- (3-chlorophenyl) thieno [2,3-bjpyridine, 2- (3-cyanobenzenesulfonyl) -3- (3-methylpiperidinyl) thieno [2,3-b] pyridine , 2- (3-cyanobenzenesulfonyl) -3- (4-methylpiperidinyl) thieno [2,3-bjpyridine, 2- (3-cyanobenzenesulfonyl) -3- (4-toli I) thieno [2,3-b] pyridine , 2- (3-cyanobenzenesulfonyl) -3- (3-methoxyphenyl) thieno [2,3-bjpyridine, 2- (3-m-ethoxy benzenesulphonyl) -3- (4-cl orofenyl) thieno [2, 3 -bjpyridine, 2- (3-cyano-5-fluorobenzenesulfonyl) -3- (4-chlorophenyl) thieno [2,3-bjpyridine, 2- (3-f Io-4-m ethyl benzenesulphonyl) -3- (4-cl orof eni I) ti eno [2, 3-bjpyridine, 2- (3,4-dimethylbenzenesulfonyl) -3- (4-fluorophenyl) thieno [2,3-bjpyridine, 2- (3-ci to noben folds ulf onyl) -3- (4-f luorofenyl) -6-chloro-thieno [2, 3-bjpyridine, 2- (3-cyano-5-fluorobenzenesulfonyl) -3- (4-fluorophenyl) thieno [2, 3- bjpyridine, 2- (3-cyanobenzenesulfonyl) -3- (4-fluorophenyl) -6-fluorothieno [2,3-bjpyridine, 2- (4-bromobenzenesulfonyl) -3- (4-cl orofenyl) thieno [2, 3-bjpyridine, 5-amino-2- (4-chlorobenzenesulfonyl) -3- (4-cl orofenyl) thieno [2, 3-bjpyridine, 2- (3,4-dichlorobenzenesulfonyl) -3- (4- cl orofenyl) thieno [2, 3-bjpyridine, 2- (3-f Io-4-methylbenzenesulfonyl) -3- (4-f luorofenyl) thieno [2,3-bpyridine, 2- (3-cyanobenzenesulfonyl ) -3- (2-chlorophenyl) thieno [2,3-bjpyridine, 2- (3-cyano-5-f-Iorobenzenesulfonyl) -3- (4-cl orofenyl) -6-chloro-thieno [2, 3-b] pyridine, 2- (3-f-U-4-m-ethoxy benzenesulphonyl) -3- (4-cl orofenyl) thieno [2,3-bpyridine, 2- (4-chlorobenzenesulfonyl) -3 - (4-methylpiperidinyl) thieno [2,3-bjpyridine, 2- (3-cyanoan-df Ioorobenzenesulfonyl) -3- (4-methylpiperidinyl) thieno [2,3-b] pyridine, 2- ( 4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -d-fluorothieno [2,3-bjpyridine, 2- (4-chlorobenzenesulfonyl) -3- (4-cl orofenyl) -d-chloro-thieno [2, 3- jpiridine,

2- (4-Chlorobenzenesulfonyl) -

3- (

4-chloro-enyl) -4-chloro-thieno [2,3-b-pyridine, 2- (4-chlorobenzenesulfonyl) -3- (4-chlorophenyl) -4-fluorothien [2,3-bjpyridine,

5-amino-2- (4-chlorobenzenesulfonyl) -3- (4-methylpiperidinyl) thieno [2,3-b] pyridine, 2- (3-cyano-d-fl uorobenzenesulfonyl) - 3- (3-f luorof eni I) ti eno [2, 3-bjpyridine, d-amino-2- (4-chlorobenzenesulfonyl) -3- (3-fluorophenyl) thieno [2,3-bjpyridine, 2- (4 -chlorobenzenesulfonyl) -3- (4-methylpiperidinyl) -

6-chloro-thieno [2, 3-b] pyridine, 2- (3-f Io-4-methoxy benzenes ulf onyl) -3- (4-f luorof en i I) ene ene [2, 3-bjpiridine, 2- (3-f I uor-4-m ethoxy benzenes ulf onyl) -3- (3-f luorofenyl) thieno [2, 3-b] pyridine, 2 - (3-cyano-5-fl uorobenzenesulfonyl) -3- (2-f luorofeni l) thieno [2, 3-bjpyridine, 2- (3-cyano-df I uorobenzenesulfonyl) -3- (3-cl) orofenyl) thieno [2, 3-bjpyridine. 4. Process for preparing a compound of formula (Ia): (l a) where X represents a selected group of SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is H or is monosubstituted by an alkyl or nitro group; Ri is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is phenyl optionally substituted with alkyl or halogen; on reacting a compound of formula (I I I): (I II) wherein A is a substituent such as that defined as R 2 in the formula (la) and Z is H or is monosubstituted by an alkyl or nitro group with a compound of the formula (Vi l): HlgCHzSOYRT (Vil) where Hlg is chloro or bromo, Y and Ri are as described above for formula (la), or with a compound of formula (VIII): HlgCH2SO2YR? (VIII) where Hlg is chloro or bromo, Y and RT are as described above for formula (la) in the presence of sodium methoxide, in dimethylformamide as solvent, to obtain a compound of formula (la), and optionally forming the salts and / or hydrates and / or solvates of the compounds of formula (la). 5. Process for preparing a compound of formula (Ib): (Ib) where X represents SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is H or alkyl group; Ri is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R 2 is phenyl, or aromatic heterocyclyl, optionally substituted with one or more substituent (s) selected from alkyl, alkoxy, trifluoromethyl, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, acylamino, cyano, fluorine, chlorine, bromine, hydroxyl, methylsulfonyl; on reacting a compound of formula (XI): (XI) with a compound of formula (Vi l): HlgCHzSOYR! (Vi l) where Hlg is chloro or bromo, Y and R, are as described above for the formula (I b), or with a compound of the formula (VI I I): HlgCHzSOzYR! (VI II) where Hlg is chloro or bromo, Y and RT are as described above for formula (I b) in the presence of sodium methoxide, in dimethylformamide as solvent, and subjecting the obtained compound of formula (IV) ): (IV) wherein Ri is as described above for the formula (Ib) with copper bromide (11) and ferf-butyl nitrite in acetonitrile; and subjecting the compound obtained of formula (V): (V) where Ri is as described above for the formula (Ib) with a compound of the formula (IX): R2-B (OH) 2 (IX) where R2 is as defined above for the formula (Ib) in the presence of base and catalyst, in a solvent, to obtain a compound of formula (I b), and then optionally forming the salts and / or hydrates and / or solvates of the compounds of formula (Ib). 6. Process for preparing a compound of formula (I): (l e) where X represents SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is H or alkyl group; R T is an alkyl, cycloalkyl, phenyl, biphenium, heterocyclyl, optionally substituted; R2 is NR3R wherein R3 and R4 are independently selected from the group consisting of hydrogen or an optionally substituted alkyl group, or R3 and R, together with the N atom to which they are attached, form an optionally substituted C5-7 heterocyclyl group containing one or more heteroatom (s), upon reacting a compound of formula (V): (V) where R T is as described above for the formula (le), with a compound of formula (XVI): HN R3R4 (XVI) wherein R3 and R4 are as described above for formula (le) to obtain the compound of formula (le), and then optionally forming the salts and / or hydrates and / or solvates of the compounds of formula (le). 7. Process for preparing a compound of formula (Id): (Id) where X represents SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is H or alkyl group; RT is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is NH-CO-NR3R4 l group where R5 and R6 are independently selected from the group consisting of hydrogen or group optionally substituted alkyl, or R3 and R4, together with the N atom to which they are attached, form an optionally substituted C5-7 heterocyclyl group containing one or more heteroatom (s), by reacting a compound of formula (IV): (IV) where RT is as described above for the formula (Id), with a compound of the formula (XI II): HNR3R4 (XI II) where R3 and R4 are as described above for the formula (Id. ), in the presence of phosgene or triphosgene and a base, to obtain a compound of formula (Id), and then optionally forming the salts and / or hydrates and / or solvates of the compounds of formula (Id). 8. Process for preparing a compound of formula (le): (l e) where X represents a selected group of SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is amino, alkylsulfonylamino, halogen; Ri is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is phenyl optionally substituted with alkyl or halogen; when reacting a compound of formula (la): (la) where X represents a selected group of SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is nitro; RT is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is phenyl optionally substituted with alkyl or halogen; with a suitable reducing agent, to obtain the compound of formula (le): (le) where Z is amino, X, Y, n, RT and R2 are as described above for the formula (le) and then optionally forming the salts and / or hydrates and / or solvates of the derivatives obtained, or a. by optionally reacting the amino derivatives obtained from formula (le) wherein Z is amino, X, Y, n, RT and R2 are as described above for formula (le), with sodium nitrite in the presence of acid hydrochloric and copper iodide (l) or copper chloride (l) or copper bromide (l) or sodium tetrafluoroborate, to obtain a compound of formula (le) where Z is halogen, X, Y, n, RT and R2 they are as described above for the formula (le), and then optionally forming the salts and / or hydrates and / or solvates of the halo derivatives obtained from formula (le), or b. optionally reacting the amino derivatives obtained from formula (le) where Z is amino, X, Y, n, RT and R2 are as described above for formula (le), with alkylsulfonyl chloride derivatives, to obtain the compounds of formula (le) wherein Z is alkylsulfonylamino, X, Y, n, RT and R2 are as described above for the formula (le), and then optionally forming the salts and / or hydrates and / or solvates of the alkyl sulfonylamino derivatives obtained from formula (le). 9. Process for preparing a compound of formula (If): (if) where X represents SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is amino, alkylsulfonylamino, halogen; RT is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is a phenyl, heterocyclyl, optionally substituted, or NR3R4 group, wherein R3 and R4 are independently selected from the group consisting of hydrogen or optionally substituted alkyl, or R3 and R4, together with the N atom to which they are attached, form a group optionally substituted C5-7 heterocyclyl which contains one or more heteroatom (s), on reacting a compound of formula (V): (V) where RT and Y are as previously described for the formula (If), with an appropriate oxidizing agent and by reacting the obtained N-oxide derivative of formula (X): (X) where RT and Y are as previously described for the formula (If), with aqueous nitric acid in acetic acid, the nitro derivative obtained of formula (XI) then being subjected to reaction: where RT and Y are as previously described for formula (I), with a suitable reducing agent, and by reacting the amine derivative not obtained of formula (XII): (Xl l) where R and Y are as previously described for the formula (lf), a. with a compound of formula (IX): R2-B (OH) 2 (IX) wherein R2 is optionally substituted phenyl, heterocyclyl, in the presence of base and catalyst, in a solvent, to obtain a compound of formula (If) where Z is amino, R2 is optionally substituted phenyl, heterocyclyl, Y and RT are as described above for the formula (If) and then optionally forming the salts and / or hydrates and / or solvates of the amino derivatives obtained from formula ( If), and (i) optionally reacting the obtained amino derivatives of formula (If) where Z is amino, R2 is optionally substituted phenyl, heterocyclyl, Y and RT are as described above for the formula (If), with nitrite sodium in the presence of hydrochloric acid and copper iodide (1) or copper chloride (1) or copper bromide (1) or tetrafluorobamate of sodium or, to obtain a compound of formula (If) where Z is halogen, optionally substituted phenyl, heterocyclyl, Y, and RT are as described above for formula (I), and then optionally forming the salts and / or hydrates and / or solvates of the halo derivatives obtained from the formula (If), or (ii) optionally reacting the amino obtained from formula (If) where Z is amino, R2 is optionally substituted phenyl, heterocyclyl, Y and R are as described above for the formula (If), with derivatives alkylsulfonyl chloride, to obtain a compound of the formula (If), and then optionally forming the salts and / or hydrates and / or solvates of the alkylsulfonylamino derivatives obtained from the formula (If), or b. with a compound of formula (XI II): NHR3R4 (XI II) wherein R3 and R4 are as described above for the formula (If), at 70-200 ° C, to obtain a compound of formula (If) where Z is amine, Y, RT and R2, which form the group NR3R, are as described above for the formula (If) and then optionally forming the salts and / or hydrates and / or solvates of the derivatives amino acids obtained from the formula (If), or (i) optionally reacting the amino derivatives obtained from formula (If) where Z is amino, Y, R and R2, which form the group NR3R, are as described above for the formula (If), with sodium nitrite in the presence of hydrochloric acid and copper iodide (l) or copper chloride (l) or copper bromide (l) or sodium tetrafluoroborate, to obtain a compound of formula (If) where Z is halogen, Y, RT and R2, which form the group NR3R4 , are as previously described for the formula (If) and then optionally forming the salts and / or hydrates and / or solvates of the halo derivatives obtained from the formula (If), or (ii) optionally reacting the amino derivatives obtained from formula (If) where Z is amino, Y, RT and R2 which form the group NR3R, are as described above for the formula (If), with alkylsulfonyl chloride derivatives, to obtain a compound of formula (If) where Z is alkylsulfonylamino, Y, RT and R2, which form the group NR3R4, are such as described above for the formula (If), and then optionally forming the salts and / or hydrates and / or solvates of the alkylsulfonylamino derivatives obtained from the formula (If). 10. Process for preparing a compound of formula (Ig): (i g) where X represents SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is amine, bromine, chlorine, iodine, methoxy, mono- or di-alkylamino; RT is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R is an optionally substituted phenyl, heterocyclyl, or group NR3R4 where R3 and R are independently selected from the group consisting of hydrogen or an optionally substituted alkyl, or R3 and R, together with the N atom to which they are attached, form a heterocyclyl group C5-7 optionally substituted containing one or more heteroatom (s), upon reaction of a compound of formula (X): (X) where RT and Y are as described above for the formula (Ig), with a compound of formula (IX): R2-B (OH) 2 (IX) wherein R2 is optionally substituted phenyl, heterocyclyl, the presence of base and catalyst in a solvent, to obtain the compounds of formula (XIV): (XIV) wherein R2 is an optionally substituted phenyl, heterocyclyl, RT and Y are as described above for the compounds of formula (Ig), or with a compound of (XI I I): (XIII) where R3 and R4 are as described above for the formula (Ig) to obtain the compounds of formula (XIV), wherein R 2 is a group NR 3 R 4 l independently selected R 3 and R from hydrogen or an optionally substituted alkyl, or R 3 and R, together with the N atom to which they are joined, form an optionally substituted C5-7 heterocyclyl group containing one or more heteroatom (s); and reacting the compounds of formula (XIV), wherein RT, R2 and Y are as described above for the formula (Ig), with trifluoroacetic anhydride in a solvent, to obtain the compounds of formula (XV): (XV) where RT, R2 and Y are as previously described for the formula (Ig); and reacting the compounds of formula (XV) (wherein RT, R2 and Y are as described above for the formula (Ig): a.with phosphorus oxybromide (III), to obtain the compounds of formula (Ig) wherein Z is bromine, X, Y, n, RT and R2 are as described above for the formula (Ig), and then optionally forming the salts and / or hydrates and / or solvates of the bromine derivatives obtained from the formula (I g); (i) by reacting the bromine derivatives of formula (Ig) wherein Z is bromine, X, Y, n, RT and R2 are as described above for the formula (Ig), with potassium fluoride in DMSO, for obtaining the compounds of formula (Ig) wherein Z is fluorine, X, Y, n, RT and R2 are as described above for the formula (Ig), and then optionally forming the salts and / or hydrates and / or solvates of the fluorine derivatives obtained from formula (Ig); or b. with phosphorus oxychloride (ll l), to obtain the compounds of formula (Ig) where Z is chloro, X, Y, n, RT and R2 are as described above for the formula (Ig), and then optionally forming salts and / or hydrates and / or solvates of the chloro derivatives obtained from formula (Ig); or (i) by reacting the chloro derivatives of formula (Ig) wherein Z is chloro, X, Y, n, RT and R2 are as described above for the formula (Ig), with potassium fluoride in DMSO, to obtain the compounds of formula (Ig) wherein Z is fluorine, X, Y, n, RT and R2 are as described above for the formula (Ig), and then optionally forming the salts and / or hydrates and / or solvates of the fluorine derivatives obtained from formula (Ig); or c. with iodomethane in the presence of silver carbonate, in a solvent, to obtain the compounds of formula (Ig) wherein Z is methoxy, X, Y, n, RT and R2 are as described above for the formula (Ig) , and then forming optionally the salts and / or hydrates and / or solvates of the obtained methoxy derivatives of formula (Ig); or d. with trifluoromethanesulfonic anhydride in a solvent and then with ammonia or mono- and di-alkylamines to obtain the compounds of formula (Ig) wherein Z is, respectively, amino or monoalkylamino or dialkylamino, X, Y, n, R and R2 are as have been described above for the formula (Ig), and then optionally forming the salts and / or hydrates and / or solvates of the obtained methoxy derivatives of formula (Ig). 11. Process for preparing a compound of formula (Ih): (lh) where X represents SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is amino, hydroxy, bromo, chloro, fluoro, methoxy, mono- or di-alkylamino; RT is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is optionally substituted phenyl, heterocyclyl, or NR3R4 group, wherein R3 and R4 are independently selected from the group consisting of hydrogen or optionally substituted alkyl, or R3 and R4, together with the N atom to which they are attached, form an optionally substituted C5-7 heterocyclyl group containing one or more heteroatom (s), by reacting a compound of formula (XIV): (XIV) where RT, R2 and Y are as previously described for formula (Ih), a. with phosphorus oxychloride (III) or phosphorous pentachloride, to obtain the compounds of formula (Ih) wherein Z is chloro, X, Y, n, R and R2 are as described above for formula (Ih), or . with phosphorus oxybromide (III), to obtain the compounds of formula (Ih), wherein Z is chloro, X, Y, n, RT and R2 are as described above for formula (Ih), and then optionally forming the salts and / or hydrates and / or solvates of the obtained chloro or bromo derivatives of formula (Ih) wherein Z is chloro or bromo, X, Y, n, R and R2 are as described above for the formula (Ih ); or (i) by reacting the chloro or bromo derivatives of formula (Ih) wherein Z is chloro or bromo, X, Y, n, RT and R2 are as described above for formula (Ih), with potassium fluoride in DMSO, to obtain the compounds of formula (Ih) wherein Z is fluorine, X, Y, n, R and R2 are as described above for the formula (Ih), and then optionally forming the salts and / or hydrates and / or solvates of the fluorine derivatives obtained from formula (Ih); or (ii) by reacting the chloro or bromo derivatives of formula (Ih) wherein Z is chloro or bromo, X, Y, n, RT and R2 are as described above for formula (Ih), with methylate sodium in methanol, to obtain the compounds of formula (Ih) wherein Z is methoxy, X, Y, n, RT and R2 are as described above for the formula (Ih), and then optionally forming the salts and / or hydrates and / or solvates of the methoxy derivatives obtained from formula (Ih); or (iii) by reacting the chloro or bromo derivatives of the formula (Ih) wherein Z is chloro or bromo, X, Y, n, RT and R2 are as described above for the formula (Ih), with sodium in acetic acid, to obtain the compounds of formula (Ih) wherein Z is hydroxyl, X, Y, n, RT and R2 are as described above for the formula (Ih), and then optionally forming the salts and / or hydrates and / or solvates of the hydroxyl derivatives obtained from formula (Ih); or (iv) reacting the chloro derivatives or bromine of formula (Ih) wherein Z is chlorine or bromine, X, Y, n, RT and R2 are as described above for formula (Ih), with trifluoromethanesulfonic anhydride in a solvent and then with ammonia or mono- and di-alkylamines, to obtain the compounds of formula (Ih) wherein Z is, respectively, amino or monoalkylamino or dialkylamino, X, Y, n, RT and R2 are as described above for formula (Ih), and then optionally forming the salts and / or hydrates and / or solvates of the obtained methoxy derivatives of formula (Ih) wherein Z is respectively amino or monoalkylamino or dialkylamino; or (v) by reacting the chloro or bromo derivatives of the formula (Ih) wherein Z is chloro or bromo, X, Y, n, RT and R2 are as described above for the formula (Ih), with azide of sodium in DM F and water, to obtain the compounds of formula (Ih) wherein Z is azide, X, Y, n, RT and R2 are as described above for the formula (Ih), and then reacting the azide derivatives obtained with sodium borohydride in a solvent, to obtain the compounds of formula (Ih) wherein Z is amino, X, Y, n, RT and R2 are as described above for the formula (I h), and then optionally forming the salts and / or hydrates and / or solvates of the amino derivatives obtained from formula (I h). 12. Pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I): (I) where X represents a selected group of SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is H or is monosubstituted by alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxyl, alkylsulfonylamino; R is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R is an optionally substituted phenyl, heterocyclyl, or group NR3R4 where R3 and R4 are independently selected from the group consisting of hydrogen and an optionally substituted alkyl, or R3 and R, together with the N atom to which they are attached, form a heterocyclyl group C5-7 optionally substituted containing one or more heteroatom (s), or NH-CO-NRsRe group, wherein R5 and R6 are independently selected from the group consisting of hydrogen and an alkyl optionally substituted, or R5 and R6, together with the N atom to which they are attached, form an optionally substituted C5-7 heterocyclyl group containing one or more heteroatom (s); and / or hydrates and / or solvates and / or pharmaceutically acceptable salts thereof formed with acids or bases, in association with one or more inert physiologically acceptable diluents, excipients and / or carriers. 13. The pharmaceutical composition according to claim 12, for use in the prevention and / or treatment of disorders mediated by the mGluRI and mGluRd receptors. 14. Use of a compound of formula (I): (I) where X represents a selected group of SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is H or is monosubstituted by alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxyl, alkylsulfonylamino; R T is an alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl, optionally substituted; R2 is an optionally substituted phenyl, heterocyclyl or, or group NR3R4 where R3 and R4 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, or R3 and R4, together with the N atom to which they are attached, form an optionally substituted C5-7 heterocyclyl group containing one or more heteroatom (s), or NH-CO-NR5R6 group, wherein R5 and R6 are independently selected from the group consisting of hydrogen and an optionally substituted alkyl, or R5 and R6, together with the N atom to which they are attached, form a Cs-optionally substituted heterocyclyl group containing one or more heteroatom (s); and / or hydrates and / or solvates and / or pharmaceutically acceptable salts thereof formed with acids or bases for the manufacture of a medicament for the treatment and / or prevention of disorders mediated by the mGluRI and mGl uRd receptors. 1 d. Use of a compound according to claim 14, characterized in that said disorders mediated by the mGluR I and mGluRd receptors are psychiatric disorders. 16. Use of a compound according to claim 14, characterized in that said disorders mediated by the mGl uR I and mGluRd receptors are neurological disorders. 17. Use of a compound according to claim 14, characterized in that said disorders mediated by the mGluRI and mGluRd receptors are chronic and acute pain. 18. Use of a compound according to claim 14, characterized in that said disorders mediated by the mGluRI and mGluRd receptors are neuromuscular dysfunctions of the lower urinary tract and gastrointestinal disorders. 19. Method for the prevention and / or treatment of disorders mediated by mGluRI and mGluRd receptors, comprising administration to a mammal in need of such prevention and / or treatment of a therapeutically effective amount of a compound of formula (I) ): (l) where X represents a selected group of SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is H or is monosubstituted by alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylamomethyl, dialkylaminomethyl, hydroxyl, alkylsulfonylamino; RT is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is an optionally substituted phenyl, heterocyclyl, or group NR3R4 where R3 and R4 are independently selected from the group consisting of hydrogen and an optionally substituted alkyl, or R3 and R4, together with the N atom to which they are attached, form a heterocyclyl group Optionally substituted C5.7 containing one or more heteroatom (s), or NH-CO-NRsRβ group, wherein R5 and Re are independently selected from the group consisting of hydrogen and an optionally substituted alkyl, or R5 and R6, together with the atom of N to which they are attached form an optionally substituted C5-7 heterocyclyl group containing one or more heteroatom (s); and / or hydrates and / or solvates and / or pharmaceutically acceptable salts thereof formed with acids or bases. 20. Method according to claim 19, characterized in that said mammal is a human. The method according to claim 19, characterized in that said disorders mediated by the mGluRI and mGluR5 receptors are psychiatric disorders. 22. Method according to claim 19, characterized in that said disorders mediated by the mGluRI and mGluRd receptors are neurological disorders. 23. Method according to claim 19, characterized because such disorders mediated by the mGluRI and mGluRd receptors are chronic or acute pain disorders. 24. Method according to claim 19, characterized in that said disorders mediated by the mGluRI and mGluRd receptors are neuromuscular dysfunctions of the lower urinary tract and gastrointestinal disorders. SUMMARY The present invention relates to new preferred ligands of the subtype of mGluR I and mGluRd receptors of formula (I) wherein X represents a group selected from SO, SO2; Y represents a group selected from (CH2) n, NH, NHCH2; n is an integer from 0 to 1; Z is H or is monosubstituted by alkyl, nitro, halogen, alkoxy, trifluoromethyl, cyano, amino, alkylamino, dialkylamino, aminomethyl, alkylaminomethyl, dialkylaminomethyl, hydroxyl, alkylsulfonylamino; RT is an optionally substituted alkyl, cycloalkyl, phenyl, biphenyl, heterocyclyl; R2 is an optionally substituted phenyl, heterocyclyl, or group NR3R where R3 and R4 are independently selected from the group consisting of hydrogen and optionally substituted alkyl, or R3 and R, together with the N atom to which they are attached, form a group optionally substituted Cs-7 heterocyclyl which contains one or more heteroatom (s); or NH-CO-NR5R6 group where R5 and R6 are independently selected from the group consisting of hydrogen and an optionally substituted alkyl, or R5 and Re, together with the N atom to which they are attached, form an optionally substituted C5-7 heterocyclic group containing one or more heteroatom (s) and / or the hydrates and / or solvates and / or pharmaceutically acceptable salts thereof formed with acids or bases, processes for producing them, pharmaceutical compositions containing them and their use in the therapy and / or prevention of pathological conditions that require the modulation of mGluRI and mGluRd receptors such as neurological disorders, psychiatric disorders, acute and chronic pain, neuromuscular dysfunctions of the lower urinary tract and gastrointestinal disorders.