MX2007000615A - Dimeric compounds of piperidine, piperazine or morpholine or their 7-membered analogs suitabale for the treatment of neurodegenerative disorders. - Google Patents

Abstract

Formula (I ), the N-oxide forms, the pharmaceutically acceptableaddition salts and the stereochemically isomeric forms thereof.

Description

DIMERIC COMPOUNDS OF PIPERIDINE, PIPERAZINE OR MORPHOLINE OR THEIR APPROXIMATE 7-MEMBER ANALOGS FOR THE TREATMENT OF NEURODEGENERATIVE DISORDERS DESCRIPTIVE MEMORY Neurotrophins, such as nerve growth factor (NGF), brain-derived growth factor 5 (BDNF), neurotrophic factor 3 (NT3) and neurotrophic factor 4 (NT4) mediate the survival, differentiation, growth and apoptosis of neurons . These bind to two structurally unrelated cell surface receptors, tropomyosin receptors related to kinase (Trk) and p75 neurotrophin receptor (p75NTR) (Kaplan DR and Miller FD (2000) Current Opinion in Neurobiology 10, 381-391) . By activating these two types of receptors, neurotrophins mediate both positive and negative survival signals. NGF binds with high affinity to TrkA, BDNF has a higher affinity for TrkB, NT-3 binds preferentially to TrkC. The binding of neurotrophins to Trk receptors is necessary for neurotrophic activity. P75NTR, a member of the TNF receptor superfamily was the first neurotrophin receptor to be described. This binds to all neurotrophins with similar affinity. P75NTR was initially described as a positive modulator of TrkA activity. Its co-expression led to an increase of an affinity in NGF for TrkA receptors, activation of TrkA mediated by NGF and binding specificity. P75NTR can also signal for itself and promote cell death in a variety of cell types. (Coulson E. J., Reid K., and Bartlett P. F. (1999) Molecular Neurobiology 20, 29-44).

Neurotrophins and possible therapeutic importance Neurotrophins have a well-established role in regulating the survival, differentiation and maintenance of the functions of specific neuronal populations and sometimes superimposed neuronal populations. In addition to these roles of neurotrophins during embryonic development and adulthood, there is increasing evidence that neurotrophins participate in neuronal plasticity processes. These studies suggest several potential therapeutic applications. It has been shown that neurotrophins can protect and rescue certain neuronal populations in in vitro and in vivo models of various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), stroke and peripheral neuropathies (Chao MV). (2003) Nature Reviews Neuroscience 4, 299-309; Dawbarn D. and Alien SJ (2003) Neuropathology &Applied Neurobiology 29, 211-230). In addition, in recent years cumulative evidence has shown that p75NTR plays a key role in neuronal death that occurs in some of the major disorders of the CNS such as stroke, Alzheimer's disease, ALS, epilepsy, spinal cord injury. spinal (SCI), multiple sclerosis (MS), motor neuron disease (MND) and other neurodegenerative diseases (Park et al. (2000) Journal of Neuroscience 20, 9096-9103; Oh et al. (2000) Brain Research 853 , 174-185; Lowry et al. (2001) Journal of Neuroscience Research 64, 11-17; Sedel et al. (1999) European Journal of Neuroscience 11, 3904-3912; Dowling et al. (1999) Neurology 53, 1676 -1682) and only recently, it was found that NGF plays an important role in pain, in particular in post-operative pain after surgery (Zahn et al 2004, The Journal of Pain 5 (3); 157-163 ). For these reasons, small molecules that improve the activity of neurotrophins, or that have similar effects as neurotrophins, are of great interest (Massa et al, (2002) Journal of Molecular Neuroscience 19, 107-111; Saragovi and Burgess (1999) Expert Opinion on Therapeutic Patents 9, 737-751).

Experimental evidence Peripheral neurons derived from the dorsal root ganglia of the chicken embryo (DRG) are used extensively for in vitro characterization of neurotrophic factors and other molecules with neurotrophic activities. The survival of chicken DRG neurons can be maintained by different neurotrophic factors, such as nerve growth factor (NGF) (Levi-Montalcini R. and Angeletti PU (1968) Physiological Reviews 48, 534-569) neurotrophic factor derived from the brain (Barde YA et al. (1982) EMBO Journal 1, 549 -553) and ciliary neurotrophic factor (CNTF) (Barbin G. et al. (1984) Journal of Neurochemistry 43, 1468-1478). Small molecules with neurotrophic activity, such as K-252a and CEP-1347 also maintain the survival of DRG neurons (Borasio G. D. (1990) Neuroscience Letters 108, 207-212; Borasio G. D. et al. (1998) Neuroreport 9, 1435-1439). The primary culture of DRG dissociated neurons from chicken embryo on embryonic day 8-10 has been used successfully in numerous laboratories as bioassays for neurotrophins. The assay determines the survival effect of the compounds on the DRG neurons and is based on a fluorometric measurement of Calcein-AM (HeW et al (2002) Bioorganic &Medicinal Chemistry 10, 3245-3255). This assay, which refers to the functional response of neurons as a quantitative measure of survival, may have the advantage of a few false positives. The study on HTS using a primary culture of chicken DRG neurons, resulted in the identification of compounds with neurotrophic activity (neuronal survival). The most potent compounds were identified as belonging to a series of "symmetrical compounds". This invention relates to the compounds of formula (I) the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n represents 0, 1 or 2; m represents 0, 1, 2 or 3; Z represents C, N or O, in particular Z represents CH2; -X- represents C2- alkynyl, C? _12 alkyl optionally substituted with hydroxy or X represents a divalent radical of the formula (a) (b) e where; -X represents C1-12 alkyl, phenyl or a divalent radical selected from the group consisting of -X2- represents C?-12 alkyl, C 1-4 alkyl-C 1 alkyloxy, phenyl or a divalent radical of formula -X 3 - represents phenyl or a divalent radical selected from the group consisting of C? -4 alkyl, C? -4 alkylcarbonyl, Ar1-carbonyl, Het1, Ar2, or C1- alkylcarbonyl substituted with Het2 or Ar3; or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from pyrimidinyl, indolyl, indolinyl, indazolyl, imidazolinyl, imidazolidinyl, benzoxazolyl, benzimidazolyl, quinazolinyl, quinolinyl or benzthiazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group consisting of carbonyl, Ar 5, amino, (C 1 -) -amino mono- or di-substituted, hydroxy, halo, polyhaloalkyloxy of C 1-4, or C 1 - alkyl, C 1. 4 alkyloxycarbonyl, and phenyl; R3 independently represents hydroxy or C1- alkyloxy; Het1 represents a heterocycle selected from pyridinyl, indolinyl, benzimidazolyl, benzthiazolyl, thiazolyl, pyridinyl, benzisoxazolyl, benzoxazolyl, oxadiazolyl or thiadiazolyl wherein said Het1 is optionally substituted with one or when possible two or more substituents selected from the group it consists of hydroxy, halo, Ar4, C? -4 alco alkoxycarbonyl, C alquilo alquilo alkyl, C-4-4 alquilo alkyloxy, and C - ?. alquilo alquilo alkyloxy substituted with halo; Het2 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, benzisoxazolyl, benzoxazolyl or thiadiazolyl wherein said Het2 is optionally substituted with one or when possible two or more substituents selected from the group that consists of hydroxy, halo, Het4, C? alkoxycarbonyl , C 1-4 alkyl, C 1-4 alkyloxy and C 1-6 alkyloxy substituted with halo; Het3 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl; Het4 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl wherein said Het4 is optionally substituted with one or when possible two or more substituents selected from the group consisting of hydroxy , halo, C ^ alkyl, C? -4 alkyloxy; Ar1, Ar2 and Ar3 each independently represent phenyl optionally substituted with halo, amino, Het3, C1-4 alkylcarbonyl, C4-4alkyl, C1-4alkyloxy- or C ?4alkyl substituted with one, two or three halo substituents; in particular Ar1, Ar2 and Ar3 each independently represents phenyl optionally substituted with halo, d-4 alkyl or C? -4 alkyloxy; Ar4 represents phenyl optionally substituted with halo, C-? -4 alkyl, C? - alkyloxy or C-? - alkyl substituted with one, two or three halo substituents; Ar 5 represents phenyl optionally substituted by C 3 - alkyloxy or C 3-6 cycloalkyloxy. As previously used in the present invention, the terms; - oxo or carbonyl refers to (= 0) which forms a carbonyl portion with the carbon atom to which it is attached; - halo the generic fluoro, chlorine, bromine and iodine; - C 1-4 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atom such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2, 2-dimethylethyl and the like; - C1-6alkyl is meant to include alkyl Cv and the higher homologues thereof having 6 carbon atoms such as, for example hexyl, 1, 2-dimethylbutyl, 2-methylpentyl and the like; - alkyloxy C 4 saturated hydrocarbon radicals defines straight or branched chain having 1 to 4 carbon atoms and one oxygen atom such as methoxy, ethoxy, propyloxy, butyloxy, 1-methylethyloxy, 2-methylpropyloxy and the like? . The heterocycles which are mentioned in the above-mentioned definitions and below, are intended to include all possible isomeric forms thereof, for example triazolyl also includes 1,4-triazolyl and 1,4-triazolyl; Oxadiazolyl includes 1,2-oxadiazolyl, 1,4-oxadiazolyl, 1, 2,5-oxadiazolyl and 1,4-oxadiazolyl; thiadiazolyl includes 1,2,3-thiadiazolyl, 1,4-thiadiazolyl, 1, 2,5-thiadiazolyl and 1,4-thiadiazolyl. In addition, the heterocycles as mentioned in the above-mentioned definitions and thereafter can be attached to the remaining part of the molecule of formula (I) through any carbon ring or heteroatom as appropriate. Therefore, for example, when the heterocycle is imidazolyl, it may be a 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl; when it is thiazolyl, it can be 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; when it is benzothiazolyl, it can be 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl and 7-benzothiazolyl. The pharmaceutically acceptable addition salts as mentioned above are intended to comprise the forms of non-toxic, therapeutically active, acid addition salts which are capable of forming the compounds of formula (I). The latter can be conveniently obtained by treating the basic form with said appropriate acid. Suitable acids comprise, for example, inorganic acids such as hydrohalic acids, for example hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric acids and the like; or organic acids such as, for example, acetic, propionic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (for example butanedióico acid), maleic, fumaric, malic, tartaric, critical, methanesulfonyl, ethanesulfonic, benzenesulfonic, p- Toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamico and similar acids. The pharmaceutically acceptable addition salts as mentioned above in the present invention are intended to comprise the forms of therapeutically active non-toxic basic addition salts which are capable of forming the compounds of formula (I). Examples of such forms base addition salts are, for example, sodium, potassium, calcium, and also the salts with pharmaceutically acceptable amines such as, for example, ammonia, alkylamines, benzathine, N-methyl-D- glucamine, hydrabamine, amino acids, for example arginine, lysine. Conversely said salt forms can be converted by treatment with an appropriate base or acid to the free acid or base form. The term "addition salts" as used above in the present invention also comprises the solvates which are capable of forming the compounds of formula (I), as well as the salts thereof. Said solvates are for example hydrates, alcoholates and the like. The term stereochemically isomeric forms as used above in the present invention defines the possible isomeric forms as well as conformational forms that the compounds of formula (I) may possess. Unless mentioned or which otherwise indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically and conformationally isomeric forms, said mixtures containing all diastereomers, enantiomers and / or conformers of the basic molecular structure. All stereochemically isomeric forms of the compounds of formula (I)both in pure form and in admixture with each other are intended to be considered within the scope of the present invention. The N-oxide forms of the compounds of formula (I) are intended to comprise those compounds of formula (I) wherein one or more nitrogen atoms are oxidized to the so-called N-oxide. A particular group of the compounds of the present invention consists of those compounds of formula (I) wherein one or more of the following restrictions apply; -X- represents C2.4 alkynyl, C? .12 alkyl optionally substituted with hydroxy or X represents a divalent radical of the formula (a) (b) (c) where; -X represents alkyl of C? _i2, phenyl or a divalent radical selected from the group consisting of -X2- represents C? -? 2 alkyl, C-? Alkyloxy. C? _ alkyl, phenyl or a divalent radical of formula -X3- represents phenyl or a divalent radical selected from the group consisting of n represents 1; m represents 0, 1 or 2; in particular m represents 0; R1 and R2 each independently represents hydrogen, C? .4 alkyl, Ar1-carbonyl, Het1, Ar2 or C? -4 alqu alkylcarbonyl optionally substituted with Het2 or Ar3; or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from indolyl, indolinyl, benzimidazolyl, benzthiazolyl, benzisoxazolyl or oxodiazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group consisting of hydroxy, C-? _ alkyl, C? -4 -alkyloxycarbonyl, carbonyl, Ar5 and halo; in particular R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from indolinyl, benzimidazolyl, or benzthiazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the a group consisting of hydroxy, halo, C 4 alkyl, alkyloxycarbonyl of C 4 4 and phenyl; Het1 represents a heterocycle selected from pyridinyl, indolinyl, indolyl, benzthiazolyl, benzimidazolyl, thiazolyl, thiadiazolyl or benzisoxazolyl wherein said Het1 is optionally substituted with one or when possible two or more substituents selected from the group consisting of hydroxy, halo, Ar4, C 1-4 alkyloxycarbonyl, C? - alkyl and C? -4- alkyloxy, said C? - alkyloxy being optionally substituted with halo; in particular Het1 represents a heterocycle selected from pyridinyl, indolinyl, benzimidazolyl, benzthiazolyl, thiazolyl, or thiadiazolyl wherein said Het1 is optionally substituted with one or when possible two or more substituents selected from the group consisting of hydroxy, halo , Ar 4, C 1 - alkyloxycarbonyl, C 1 - alkyl, C 1 - alkyloxy and C 4 - alkyloxy - substituted with halo; Het2 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl; Ar 1, Ar 2 and Ar 3 each independently represent phenyl optionally substituted with halo, C 1 - alkyl, C 1-4 alkyloxy, or C 1 - 4 alkyl substituted with one, two or three halo substituents; in particular Ar1, Ar2 and Ar3 each independently represents phenyl optionally substituted with halo, C-? alkyl. or C1- alkyloxy; in particular Ar 1 represents phenyl optionally substituted with halo, amino, C 1-4 alkyl or C? - alkyloxy; Ar 2 represents phenyl optionally substituted with halo, C 1 - alkyl, C 1-4 alkyloxy or Het 3 - C 1-4 alkylcarbonyl; in particular Ar2 represents phenyl substituted with halo; and Ar3 represents phenyl optionally substituted with halo, C -? - alkyl or C -? - alkyloxy; Ar 4 represents phenyl optionally substituted with halo, C 1-4 alkyl, C? - alkyloxy or C? - alkyl substituted with one, two or three halo substituents; Ar 5 represents phenyl optionally substituted by C 4 -4 alkyloxy or C 3-6 cycloalkyloxy. An interesting group of compounds are those compounds of formula (I ') the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n represents 1 or 2; m represents 0, 1, 2 or 3; -X- represents C2-4 alkynyl, CM2 alkyl optionally substituted with hydroxy or X represents a divalent radical of the formula (a) (b) (c) wherein; -Xr represents CM 2 alkyl, phenyl or a divalent radical selected from the group consisting of -X2- represents C 1. 2 alkyl, C 1-4 alkyloxyC 1-4 alkyl, phenyl or a divalent radical of formula -X3- represents phenyl or a divalent radical selected from the group consisting of R 1 and R 2 each independently represent hydrogen, C 1 - alkyl, C 1-4 alkylcarbonyl, Ar 1 -carbonyl, Het 1, Ar 2 or C 4 -4 alkylcarbonyl substituted with Het 2 or Ar 3; or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from pyrimidinyl, indolyl, indolinyl, indazolyl, imidazolinyl, imidazolidinyl, benzoxazolyl, benzimidazolyl, quinazolinyl, quinolinyl or benzthiazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group consisting of carbonyl, Ar5, amino, (C? -4) alkyl- mono- or di-substituted-, hydroxy, halo, polyhalo alkyloxy of C1 .4, C? -4 alkyl, C 1-4 alkyloxycarbonyl and phenyl; R3 independently represents hydroxy or C1- alkyloxy; Het1 represents a heterocycle selected from pyridinyl, indolinyl, benzimidazolyl, benzthiazolyl, thiazolyl, pyridinyl, benzisoxazolyl, benzoxazolyl, oxadiazoyl or thiadiazolyl wherein said Het1 is optionally substituted with one or when possible two or more substituents selected from the group that consists of hydroxy, halo, Ar4, C 1 - - alkyloxycarbonyl, C - 4 - alkyl, C - - alkyloxy and C - 4 - alkyloxy substituted with halo; Het2 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, benzisoxazolyl, benzoxazolyl or thiadiazolyl wherein said Het2 is optionally substituted with one or when possible two or more substituents selected from the group consists of hydroxy, halo, Het4, C 1 -4- alkyloxycarbonyl, C 1 - - alkyl, C 1 - alkyloxy and C 1 - alkyloxy substituted with halo; Het3 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl; Het4 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl wherein said Het4 is optionally substituted with one or when possible two or more substituents selected from the group consisting of hydroxy , halo, C? -4- alkyl and C? -4- alkyloxy; Ar 1, Ar 2 and Ar 3 each independently represent phenyl optionally substituted with halo, amino, Het 3, C 1-4 alkylcarbonyl, C 1-4 alkyl, C? -4alkyloxy or C? -4alkyl substituted with one, two or three halo substituents; in particular Ar1, Ar2 and Ar3 each independently represents phenyl optionally substituted with halo, C? - alkyl or C? -4- alkyloxy; Ar 4 represents phenyl optionally substituted with halo, C 1-4 alkyl, C 1-4 -alkyloxy or C? -alkyl substituted with one, two or three halo substituents; Ar 5 represents phenyl optionally substituted by C 3 - alkyloxy or C 3-6 cycloalkyloxy. Also of interest are those compounds of formula (I ') wherein one or more of the following restrictions apply; n represents 1; m represents 0; R1 and R2 each independently represent hydrogen, C4-4 alkyl, Ar1-carbonyl, Het1, Ar2 or C4-4 alkylcarbonyl optionally substituted with Het2 or Ar3; or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from indolyl, indolinyl, benzimidazolyl, benzthiazolyl, benzisoxazolyl or oxodiazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group consisting of hydroxy, C -? - alkyl, carbonyl, C? -? alkyloxycarbonyl, Ar5 and halo; Het1 represents a heterocycle selected from pyridinyl, indolinyl, indolyl, benzthiazolyl, benzimidazolyl, thiazolyl, thiadiazolyl or benzisoxazolyl wherein said Het1 is optionally substituted with one or when possible two or more substituents selected from the group consisting of halo, Ar4, C 1-4 alkyloxycarbonyl, C? - alkyl and C? -4 alkyloxy, said C? -alkyloxy being optionally substituted with halo; Het2 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl; Ar1, Ar2 and Ar3 each independently represent phenyl optionally substituted with halo, C? -4 alkyl, C? Alkyloxy. or C 1-4 alkyl substituted with one, two or three halo substituents; Ar4 represents phenyl optionally substituted with halo, C-? -4 alkyl, C1- alkyloxy or C? -4 alkyl substituted with one, two or three halo substituents; Ar5 represents phenyl optionally substituted with C ?4- alkyloxy or C 3-6 cycloalkyloxy-. An additional group of compounds of formula (I) consists of those compounds of formula (I) wherein one or more of the following restrictions apply; n represents 1; m represents 0; Z represents CH2; R 1 and R 2 each independently represent hydrogen, C 1 -, Ar 1 -carbonyl, Het 1, Ar 2 or C 1 - alkylcarbonyl optionally substituted with Het 2 or Ar 3; or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from indolyl, indolinyl, benzimidazolyl, benzthiazolyl, benzisoxazolyl or oxodiazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group consisting of hydroxy, C1-4 alkyl, carbonyl, C1- alkyloxycarbonyl, Ar5 and halo; Het1 represents a heterocycle selected from pyridinyl, indolinyl, indolyl, benzthiazolyl, benzimidazolyl, thiazolyl, thiadiazolyl or benzisoxazolyl wherein said Het1 is optionally substituted with one or when possible two or more substituents selected from the group consisting of halo, Ar 4, C 1-4 alkyloxycarbonyl, C 1-4 alkyl, and C 1-4 alkyloxy, said C 1-4 alkyloxy being optionally substituted with halo; Het2 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl; Ar1, Ar2 and Ar3 each independently represent phenyl optionally substituted with halo, C? -4 alkyl, C? -4 alkyloxy or C-? 4 alkyl substituted with one, two or three halo substituents; Ar 4 represents phenyl optionally substituted with halo, C 1-4 alkyl, C 1-4 alkyloxy or C-? Alkyl. substituted with one, two or three halo substituents; Ar5 represents phenyl optionally substituted with C? -4 alquilo alkyloxy or C 3-6 cycloalkyloxy. Another interesting group of compounds according to the invention are those compounds of formula (I) or of formula (I1) wherein one or more of the following restrictions apply; n represents 1; m represents 0; Z represents C, in particular CH2 for those compounds of formula (I); R1 and R2 each independently represent hydrogen, C1-4alkyl, Ar1-carbonyl-, Het1, Ar2 or C- - alkylcarbonyl substituted with Het2 or Ar3; or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from indolyl, indolinyl, or benzimidazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group which consists of carbonyl, hydroxy or halo; Het1 represents a heterocycle selected from pyridinyl, indolinyl, benzthiazolyl, thiazolyl, or thiadiazolyl, wherein said Het1 is optionally substituted with one or when possible two or more substituents selected from the group consisting of halo, Ar4, alkyloxycarbonyl of C 1 - - and C 1 - - alkyloxy - substituted with halo; Het2 represents thiophenyl; Ar 1 represents phenyl optionally substituted with halo or C 1 - alkyloxy; Ar 2 represents phenyl optionally substituted with halo or C 1-4 alkyloxy; Ar3 represents phenyl optionally substituted with halo or C? -4 alkyloxy; or Ar4 represents phenyl optionally substituted with Ci alkyl. - Also of interest are those compounds of formula (I) or (I1) wherein; m represents 0; Z represents C or N, in particular C, more in particular CH2 for those compounds of formula (I); n represents 1; -X- represents C2-4 alkynyl, C1-12 alkyl optionally substituted with hydroxy or -X- represents a divalent radical of the formula (a), (b) or (c) as defined above in the present invention in where; -Xr represents C? -12 alkyl or a divalent radical selected from (d) or (e) as defined by the compounds of formula (I) above in the present invention; -X2- represents C-M2 alkyl, C1-6 alkyl alkyloxy, phenyl or a divalent radical of formula (g) as defined by the compounds of formula (I) above in the present invention; -X3- represents phenyl or a divalent radical selected from (g), (h) and (i) as defined by the compounds of formula (I) above in the present invention; R1 and R2 each independently represent hydrogen, C? -4 alquiloalkyl or R1 and R² taken together with the nitrogen atom to which they are attached form a heterocycle selected from indolyl, indolinyl or benzimidazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group consisting of carbonyl, hydroxy or halo; Het1 represents a heterocycle selected from pyridinyl, indolinyl or benzthiazolyl wherein said Het1 is optionally substituted with halo, Ar4 or polyhaloalkyloxy of C -? - 4; Het2 represents thiophenyl; Ar 1 represents phenyl optionally substituted with halo or C 1-4 alkyloxy; Ar 2 represents phenyl optionally substituted with halo or C 1-4 alkyloxy; Ar3 represents phenyl optionally substituted with halo or C? -4 alkyl; or Ar4 represents phenyl optionally substituted with Ci alkyl. 4. Accordingly, an object of the present invention provides the compounds of formula (I ") the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein -X- represents C2.4 alkynyl, CM2 alkyl optionally substituted with hydroxy or X represents a divalent radical of the formula a) (b) (c) where; -X1 represents C? _2 alkyl, phenyl or a divalent radical selected from the group consisting of -X 2-represents C 1-12 alkyl, C 1-4 alkyloxy of C? -, phenyl or a divalent radical of formula -X 3 - represents phenyl or a divalent radical selected from the group consisting of R1 and R2 each independently represent hydrogen, C1-4alkyl, C1 - - alkyl, Ar1 - carbonyl -, Het1, Ar2 or C - 4 - alkylcarbonyl substituted with Het2 or Ar3; or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from indolinyl, benzimidazolyl, or benzthiazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group which consists of hydroxy, halo, C 4 alkyl, C 4 -4 alkyloxycarbonyl and phenyl; Het1 represents a heterocycle selected from pyridinyl, indolinyl, benzimidazolyl, benzthiazolyl, thiazolyl, pyridinyl, or thiadiazolyl wherein said Het1 is optionally substituted with one or when possible two or more substituents selected from the group consisting of hydroxy, halo , Ar 4, C 1 - alkyloxycarbonyl, C 1 - alkyl, C 4 - alkyloxy and C 1 - substituted alkyloxy with halo; Het2 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl; Ar1 represents phenyl optionally substituted with halo, C-? 4 alkyl or C? -4 alkyloxy; Ar 2 represents phenyl optionally substituted with halo, C 1-4 alkyl or C? _ Alkyloxy; in particular Ar2 represents phenyl substituted with halo; Ar 3 represents phenyl optionally substituted with halo, C 1 - alkyl or C 1 - alkyloxy; Ar 4 represents phenyl optionally substituted with halo, C 4 alkyl, or C 4 -4 alkyloxy. In a further embodiment the compounds of the present invention consist of those compounds of formula (I) wherein n represents 1, m represents 0, Z represents C, in particular CH2 and the substituent NR1R2 is in the position opposite to the N of the piperidine ring. Said substituent NR1R2 preferably consists of benzthiazolyl optionally substituted with halo or phenyl or R1 and R2 each independently represents hydrogen, Het1, Ar2, C4-4 alkyl or Ar1-carbonyl-, in particular any R1 or R2 represents hydrogen, alkyl d. 4 or methylphenylcarbonyl and R2 or R1 respectively, represents pyridinyl or benzthiazolyl. In even a further embodiment, the compounds of the present invention are selected from the compounds according to the formulas (A) - (O) below: The dimeric compounds of this invention can be prepared by any of the various standard synthetic processes commonly used by those skilled in the art of organic chemistry and are described, for example, in; "Introduction to organic chemistry" Streitweiser and Heathcock-Macmillan Publishing Co., Inc. - second edition - New York.

In general, for those compounds wherein X represents a C2.4 alkynyl or an optionally substituted C1-12 alkyl, the dimeric compounds are obtained by a nucleophilic substitution reaction between the appropriate secondary amine (i) with an alkyl halide (Scheme 1) under 5 basic reaction conditions, such as for example those described in "Introduction to Organic Chemistry" Streitweiser and Heathcock-Macmillan Publishing Co., Inc. - Second Edition - New York, page 742 - section 24.6.

SCHEME 1 wherein m, Z, X, R1, R2 and R3 are defined by the compounds of formula (I) For those compounds wherein X represents a divalent radical of formula (a) the urea derivatives of formula (lii) are prepared by reacting the appropriate secondary amine with an isocyanate of general formula (ii) under conditions known in the formula such as for example those described in "Advanced Organic Chemistry" Jerry March-John Wiley & Sons, Inc. - third edition- New York, page 802 - section 6-17.

SCHEME 2 wherein m, Z, X, R, R and R are defined by the compounds of formula (I) Those compounds wherein X represents a divalent radical of formula (b), the amide derivatives of formula (liii) are prepared by the reaction of the appropriate secondary amine with an acyl halide of general formula (iii) under conditions known in the formula such as for example those described in "Advanced Organic Chemistry" Jerry March-John Wiley & Sons, Inc. - Third Edition - New York, page 370 - section 0-54. Alternatively the amide derivatives of formula (liii) are obtained by acylation of the appropriate secondary amine with a bisanhydride of general formula (iv) under known conditions in the formula such as for example those described in "Advanced Organic Chemistry" Jerry March -John Wiley & Sons, Inc. - Third Edition - New York, page 371 - section 0-55, or by acylation of the appropriate secondary amine with an ester of the general formula (v) under conditions known in the formula such as for example those described in "Advanced Organic Chemistry" Jerry March -John Wiley & Sons, Inc. - third edition - New York, page 375 - section 0-57. wherein Xi was defined by the compounds of formula (I) and R1 represents R ", R '" N- In a further alternative the active ester intermediates of formula (v') (see scheme 3) are obtained by reaction of the appropriate secondary amine with a carboxylic acid (xviii) in the presence of reagents, for example coupling reagents such as for example N, N'-Dicyclohexylcarbodiimide (DCC), N- (3-Dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride ( EDCI), (Benzotrol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP) or O- (Benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), which in one First step converts the carboxylic acid into an activated form. This reaction is preferably carried out in the presence of a further hydroxylamine additive, such as 1-hydroxybenzotriazole (HOBt) or 7-aza-1-hydroxybenzotriazole (HOAt), to prevent dehydration of the carboxamide residues thus obtained.

SCHEME 3 + O + O O O O O II I cI_ R '(O-C) O x? O (C O) R ' halo? X "halo (iv) R'O '-OR' (v) (iii) wherein m, Z, X2, R1, R2 and R3 are defined by the compounds of formula (I), R1 represents a C? - alkyl, preferably ethyl and wherein halo represents a halogen such as for example Cl, Br and I Finally, the sulfonylamide derivative of formula (liv) wherein X represents a divalent radical of formula (c) was generally prepared by a nucleophilic substitution reaction between the appropriate secondary amine and a sulfonyl halide, preferably a sulfonyl chloride of formula (vi) under conditions known in the formula such as for example those described in "Advanced Organic Chemistry" Jerry March - John Wiley & Sons, Inc. - third edition - New York, page 445 -section 0-119.

SCHEME 4 wherein m, Z, X3, R1, R2 and R3 are defined by the compounds of formula (I) and wherein halo represents a halogen such as for example Cl, Br and I, preferably Cl The appropriate secondary amines as used above in the present invention are either commercially available or in a particular embodiment, they are prepared from 4-piperidone or 4-amino-piperidine wherein the N atom of the piperidine ring is protected by means of a protecting group such as example methyloxycarbonyl groups, benzyl or trialkylsilyl. For those compounds of formula I wherein R 1 or R 2 represents thiazolyl or benzthiazolyl the secondary amines are prepared according to the reaction scheme 5. In a first step the aminopiperidine of formula (vii) was converted to the intermediate of formula (ix) by reaction with an isothiocyanate of formula (viii) under reaction conditions known in the art (see scheme 2 mentioned above). For those intermediates where R "represents hydrogen, the compounds of formula (I) were subsequently prepared by the cyclodesulfurization reaction of the thiourea derivative of formula (ix) by the reaction of (ix) with an appropriate alkyl halide (x) in a suitable organic solvent inert to the reaction, for example, a lower alkanol such as methanol, ethanol, 2-propanol and the like For those intermediates of formula (ix) wherein R "represents optionally substituted phenyl, the cyclodesulfurization reaction it is carried out in accordance with procedures known in the art, such as for example using bromine in an aqueous solution of hydrobromic acid. Subsequently, by removing the protecting group in the intermediates thus obtained of formula (Xi) and (Xi ') respectively, appropriate secondary amines used as intermediates in the synthesis of the dimeric compounds of the present invention are provided. Removal of the protecting group P in (Xi, Xi ') can generally be carried out following the procedures known in the art such as, for example, by hydrolysis in aqueous alkaline or acidic medium.

SCHEME 5 wherein halo represents a halogen such as for example Cl, Br and I; R was defined by the compounds of formula (I); R "represents hydrogen or an optionally substituted phenyl substituent, R" 1 and R'v each independently represents hydroxy, halo, Ar4, C1- alkyloxycarbonyl, C4-4alkyl, C4-4alkyloxy or alkyloxy of C? -4- substituted with halo, wherein Ar4 was defined by the compounds of formula (I) Alternatively, the appropriate secondary amines were prepared by reductive amination from the piperidone (xii) with an amine of the general formula (xii) ) to produce the intermediate of formula (xiv). Further substitution of the secondary amine with an alkyl halide (xv) or acyl halide (xvi) under conditions known in the formula (mentioned above) provides the intermediates of formula (xvii) and (xvii ') respectively. Subsequently, by removing the protecting group in the intermediates thus obtained, the appropriate secondary amines used as intermediates in the synthesis of the dimeric compounds of the present invention are provided. Alternatively the intermediate of formula (xiv) is converted to the thiourea derivative of formula (ix) by reaction with an isothiocyanate of formula (viii) under reaction conditions known in the art (see scheme 5 above). The subsequent cyclodesulfurization (mentioned above) and deprotection (mentioned above) provides the appropriate secondary amines.

SCHEME 6 wherein halo represents a halogen such as for example Cl, Br and I; R1 and R2 are defined by the compounds of formula (I); R "represents hydrogen or an optionally substituted phenyl substituent: Rv represents hydroxy, halo, Ar4, C1- alkyloxycarbonyl, C1-4alkyl-, C1- alkyloxy- or C- alkyloxy- substituted with halo, wherein Ar4 was defined by the compounds of formula (I). Further examples for the synthesis of the compounds of formula (I) using any of the aforementioned synthesis methods are provided in the experimental part in the present invention below.

Where necessary or desirable, any one or more of the following additional steps may be carried out in any order: (i) removing any remaining protective group (s); (ii) converting a compound of formula (I) or a protected form thereof to a further compound of formula (I) or a protected form thereof; (iii) converting a compound of formula (I) or a protected form thereof to an N-oxide, a salt, a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof; (iv) converting an N-oxide, a salt, a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof to a compound of formula (I) or a protected form thereof; (v) converting an N-oxide, a salt, a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof to another N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a solvate of a compound of formula (I) or a protected form thereof; It will be appreciated by those skilled in the art that in the processes described above it may be necessary to block the functional groups of the intermediates by the protecting groups. The functional groups that it is desirable to protect include hydroxy, amino and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl groups (for example tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), benzyl and tetrahydropyranyl. Suitable protecting groups for amino include tert-butyloxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include C (? -6) alkyl or benzyl esters. The protection and deprotection of functional groups can take place before or after a reaction step. The use of protective groups is fully described in "Protective Groups in Organic Chemistry", edited by JW F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis" 2nd edition, T W Greene &; P G M Wutz, Wiley Interscience (1991). Additionally, the N atoms in the compounds of formula (I) can be methylated by methods known in the art using CH3-I in a suitable solvent such as, for example 2-propanone, tetrahydrofuran or dimethylformamide. The compounds of formula (I) can also be converted to each other following the procedures known in the art of transforming the functional group, some of whose examples were mentioned above in the present invention. The compounds of formula (I) can also be converted to the corresponding N-oxide forms following the procedures known in the art for the conversion of a trivalent nitrogen to its N-oxide form. Said N-oxidation reaction can be carried out generally by reaction of the raw material of formula (I) with 3-phenyl-2- (phenylsulfonyl) oxaziridine or an appropriate organic or inorganic peroxide. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal peroxides or ground alkaline metal peroxides, for example sodium peroxide, potassium peroxide; Suitable organic peroxides may comprise peroxyacids such as, for example, benzenecarboperoxicoic acid or halo substituted benzenecarboperoxoic acid, for example 3-chlorobenzenecarboperoxicoic acid, peroxoalkaneic acids, for example peroxoacetic acid, alkylhydroperoxides, for example t-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, for example ethanol and the like, hydrocarbons, for example toluene, ketones, for example 2-butanone, halogenated hydrocarbons, for example dichloromethane, and mixtures of said solvents. The pure stereochemically isomeric forms of the compounds of formula (I) can be obtained by the application of methods known in the art. The diastereomers can be separated by physical methods such as selective crystallization and chromatographic techniques, for example countercurrent distribution, liquid chromatography and the like. Some of the compounds of formula (I), and some of the intermediates in the present invention may contain an asymmetric carbon atom. The pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of methods known in the art. For example, the diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. countercurrent distribution, liquid chromatography and the like. The enantiomers can be obtained from racemic mixtures by the initial conversion of said racemic mixtures with agents suitable for resolution such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then said mixtures of diastereomeric salts or compounds were physically separated by, for example, selective crystallization or chromatographic techniques, for example liquid chromatography and the like; and finally converting said separated diastereomeric or compound salts to the corresponding enantiomers. The pure stereochemically isomeric forms can also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and raw materials, provided that the intermediate reactions occur stereospecifically. An alternative way to separate the enantiomeric forms of the compounds of formula (I) and intermediates includes liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Some of the intermediates and raw materials as used in the above-mentioned reaction processes in the present invention are known compounds and may be commercially available or may be prepared in accordance with procedures known in the art. The compounds of the present invention are useful because they possess pharmacological properties. Therefore these can be used as medicines, in particular to treat pain, in particular postoperative pain and pathologies associated with neuronal death, such as, stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Pick's disease, fronto-temporal dementia , progressive nuclear paralysis, corticobasal degeneration, cerebrovascular dementia, atrophy of multiple systems, dementia by argyrophilic grain, and other tauopathies. Additional conditions that include neurodegenerative processes are for example, age-related macular degeneration, narcolepsy, motor neuron diseases, prion diseases, traumatic nerve injury and repair, and multiple sclerosis. As described in the experimental part of the present invention, the neurotrophic activity of the present compounds in p75 that mediate neuronal death has been demonstrated in vitro, in an assay that determines the effect of the survival of the compounds on the neurons of the neuron. Chicken DRG using the NGF neurotrophic factor as the internal reference. This trial was based on a fluorometric measurement of Calcein-AM and refers to the functional response of neurons as a quantitative measure of survival.

Accordingly, the present invention provides the compounds of formula (I) and their pharmaceutically acceptable N-oxides, addition salts, quaternary amines and stereochemically isomeric forms for use in therapy. More particular in the treatment or prevention of disorders mediated in a neurodegenerative manner. The compounds of formula (I), and their pharmaceutically acceptable N-oxides, addition salts, quaternary amines and the stereochemically isomeric forms can be referred to in the present invention as compounds according to the invention. In view of the utility of the compounds according to the invention, a method is provided for the treatment of an animal, for example, a mammal including humans, suffering from a neurodegenerative disorder such as stroke, Alzheimer's disease, ALS, epilepsy, SCI, MS, MND and other neurodegenerative diseases as mentioned above in the present invention, which comprises administering an effective amount of a compound according to the present invention. Said method comprises the systemic or topical administration of an effective amount of a compound according to the invention, to warm-blooded animals, including humans. It is therefore an object of the present invention to provide a compound according to the present invention for use as a medicine. In particular for using the compound according to the present invention in the preparation of a medicament for the treatment of pathologies associated with neuronal death such as for example, cerebrovascular accident, Alzheimer's disease, ALS, epilepsy, SCI, MS, MND and others neurodegenerative diseases as mentioned above in the present invention. In still a further aspect, the present invention provides the use of the compounds according to the invention in the manufacture of a medicament for the treatment of any of the aforementioned neurodegenerative disorders or indications. The amount of a compound according to the present invention, also referred to in the present invention as the active ingredient, which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, age and condition of the recipient, and the particular disorder or disease to be treated. An adequate daily dose could be from 0.001 mg / kg to 500 mg / kg of body weight, in particular from 0.005 mg / kg to 100 mg / kg of body weight. A method of treatment may also include administration of the active ingredient in a regimen of between one and four intakes per day. Although it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. Accordingly, the present invention additionally provides a pharmaceutical composition comprising a compound according to the present invention, together with a pharmaceutically acceptable carrier or diluent. The vehicle or diluent must be "acceptable" in the sense that it is compatible with the other ingredients of the composition and is not deleterious to the containers thereof. The pharmaceutical compositions of this invention can be prepared by any of the methods well known in the pharmacy art, for example, using methods such as those described in Gennaro et al. Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see especially part 8: Pharmaceutical preparations and their Manufacture). A therapeutically effective amount of the particular compound, in base form or in addition salt form, since the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the form of Desired preparation for administration. These pharmaceutical compositions are desirable in unit dosage forms suitable, preferably, for systemic administration such as oral, percutaneous, or parenteral administration.; or topical administration such as via inhalation, a nasal spray, eye drops or via a cream, gel, shampoo or the like. For example, in the preparation of the compositions in oral dosage form, any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and the like can be employed in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case, solid pharmaceutical carriers are obviously employed. For parenteral compositions, the vehicle will usually comprise sterile water, at least in a large part, although other ingredients may be included, for example, to aid solubility. Injectable solutions, for example; they can be prepared in which the vehicle comprises saline solution, glucose solution or a mixture of saline solution and glucose solution. Injectable suspensions may also be prepared in which case suitable liquid carriers, suspending agents and the like may be employed. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, said additives do not cause any significant deleterious effect on the skin. Said additives may facilitate administration to the skin and / or may be useful for the preparation of the desired compositions. These compositions may be administered in various forms, for example, as a transdermal patch, as an application device or as an ointment. As the compositions suitable for topical administration, mention may be made of all the compositions usually used for the topical administration of drugs, for example creams, gels, bandages, shampoos, dyes, pastes, ointments, plasters, powders and the like. The application of said compositions can be by means of an aerosol, for example with a propellant such as nitrogen, carbon dioxide, a freon, or without a propellant such as a spray pump, drops, lotions, or a semi-solid such as a thickened composition. which can be applied with a swab. In particular, semi-solid compositions such as plasters, creams, gels, ointments and the like will be conveniently used. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. The unit dosage form as used in the specification and claims in the present invention refers to physically discrete units suitable as unit doses, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect in association with the pharmaceutical carrier. required. Examples of such unit dosage forms are tablets (including divided or coated tablets), capsules, pills, powdered packets, waters, injectable solutions or suspensions, teaspoons of tea, scoops and the like, and segregated multiple thereof. In order to improve the solubility and / or the stability of the compounds of formula (I) in pharmaceutical compositions, it may be advantageous to use -, β- or β-cyclodextrins or their derivatives. Also co-solvents such as alcohols can improve the solubility and / or stability of the compounds of formula (I) in the pharmaceutical compositions. In the preparation of the aqueous compositions, the addition salts of the present compounds are obviously more suitable due to their increased solubility in water.

Experimental part Hereinafter, in the term 'RT' means room temperature, 'MIK' means 4-methyl-2-pentanone, 'THF' means tetrahydrofuran, 'DIPE' means diisopropyl ether, 'DMSO' means dimethylsulfoxide.

A. Preparation of intermediaries EXAMPLE Al a) Preparation of the intermediary (1) A mixture of 1- (phenylmethyl) -4-piperidinone (0.1 moles), 3-pyridineamine (0.125 moles) and 4-methylbenzenesulfonic acid (catalytic amount) in toluene (150 ml) was stirred for 5 hours using a water separator. The solvent was evaporated. The residue (oil) was dissolved in DIPE, filtered and the solvent in the filtrate was evaporated, yielding 27 g of intermediate (1). b) Preparation of the intermediary (2) The intermediate (1) (0.1 mole) was stirred in ethanol (50 ml). Sodium tetrahydroborate (0.1 mole) was added and the reaction mixture was heated to 50 ° C. After the term, the solvent was evaporated. The oily residue was stirred in 1 N HCl (150 ml), then filtered. The filtrate was made alkaline with NH OH, then extracted with toluene. The separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was washed with DIPE, then dried in vacuo, yielding 14 g of intermediate (2); p.f. ± 130 ° C. c) Preparation of the intermediary (3) A mixture of intermediate (2) (0.4 moles) and N, N-diethylethanamine (1.6 moles) in benzene (2400 ml) was stirred in a 5-liter reaction funnel. A solution of 4-methoxybenzoyl chloride (0.8 mole) in benzene (1000 ml) was added dropwise (elevation of the exothermic temperature). The reaction mixture was gently heated to reflux temperature, then stirred and refluxed overnight. The mixture was cooled, filtered and the filtrate was evaporated. The residue was dissolved in MIK. This solution was washed with a dilute solution of NaOH (2 x), then with water (2 x).

The organic layer was separated, dried, filtered and the solvent partially evaporated. The concentrate (± 500 ml) was extracted three times with acidic water. The acid water layer was extracted once with CHCl3. The CHCI3 layer was extracted three times with acidic water. All layers of acidic water were combined, then washed 1 x with DIPE. The water layer was made alkaline with a dilute NaOH solution. The aqueous layers were extracted twice with CHCl3. The separated organic layer was washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from CH 3 OH, filtered and dried, yielding 22 g of the intermediate (3). d) Preparation of the intermediary (4) A mixture of intermediate (3) (0.18 mol) in methanol (500 ml) was hydrogenated with palladium on activated charcoal (10%) (10 g) as a catalyst. After taking up the hydrogen (1 equivalent), the catalyst was filtered and the filtrate was evaporated, yielding 62 g of the intermediate (4).

EXAMPLE A2 a) Preparation of the intermediary (5) Bromine (0.3 mol) was added dropwise to a mixture of 4 - [[[(4-fluorophenyl) amino] -thioxomethyl] methylamino] -1-piperidinecarboxylic acid, ethyl ester [104605-22-3] (0.3 mol) in tetrachloromethane (600 ml). The reaction mixture was stirred for one hour at room temperature, then it was heated to reflux temperature. The reaction mixture was stirred and refluxed for 3 hours (evolution of HBr gas). The mixture was cooled. The solvent (CCI4) was decanted, yielding 101 g of the intermediate (5) (quantitative yield, used in the next reaction step, without further purification). b) Preparation of the intermediary (6) A mixture of intermediate (5) (0.3 moles) in a solution of hydrobromic acid in water (48%) (800 ml) was stirred and refluxed for 6 hours, then allowed to stand over the weekend at room temperature . The solvent was evaporated. The residue was stirred in boiling 2-propanol, cooled and the resulting precipitate was filtered and dried. The solid was dissolved in water (600 ml), made basic with 50% NaOH, then extracted with dichloromethane. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent 1: CH 2 Cl 2 / CH 3 OH 98/2, then with eluent 2: CHCl 3 / CH 3 OH / NH 4 OH 85/10/5). The product fractions were collected and the solvent was evaporated, yielding 31 g (39%) of the intermediate (6).

EXAMPLE A3 a) Preparation of the intermediary (7) A mixture of 4- (methylamino) -1-piperidinecarboxylic acid, ethyl ester [73733-69-4] (0.2 moles), 2- (chloromethyl) benzothiazole [37859-43-1] (0.22 moles) and sodium carbonate (0.4 moles) in DMF (400 ml) was stirred overnight at 66 ° C, then the reaction mixture was poured into ice water and extracted with dichloromethane. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: CH 2 Cl 2 / CH 3 OH 99/1). The fractions of the product were collected and the solvent was evaporated. The obtained residue was crystallized from 2-propanol and the resulting precipitate was collected, yielding 32.5g (48.7%) of the intermediate (7); p.f. 101.9 ° C. b) Preparation of the intermediary (8) A mixture of intermediate (7) (0.05 moles) and potassium hydroxide (0.5 moles) in 2-propanol (350 ml) was stirred and refluxed for 5 hours and then the solvent was evaporated. Water was added to the residue and the resulting mixture was extracted with dichloromethane. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue obtained was dissolved in 2-propanol and acidified with HCl / 2-propanol and then the resulting hydrochloric acid salt (1: 2) was collected, yielding 6.6 g (38.4%) of the intermediate (8); p.f. 205.0 ° C.

EXAMPLE A4 a) Preparation of the intermediary (9) A mixture of 4 - [(aminothioxomethyl) amino] -1-piperidinecarboxylic acid, ethyl ester [294622-57-4] (0.1 moles) and 2-bromo-1- (3-methylphenyl) ethanone [51012-64-7] ( 0.11 moles) in ethanol (300 ml) was stirred and refluxed overnight. The solvent was evaporated. The residue was washed with DIPE, yielding 42.6 g of the intermediate (9) (quantitative yield, used in the next reaction step, without further purification). b) Preparation of the intermediary (10) A mixture of intermediate (9) (0.1 mole) in hydrobromic acid (48%) (200 ml) was stirred and refluxed for 30 minutes, then allowed to cool and crystallize while stirring. The precipitate was filtered, washed with 2-propanone / DIPE, filtered and dried, yielding 33 g of the intermediate (10); p.f. 258 ° C.

EXAMPLE A5 a) Preparation of the intermediary (11) 4- (Trifluoromethoxy) benzenamine (0.141 mol) dissolved in THF (50 ml) was added dropwise to a solution of 4-isothiocyanato-1-piperidinecarboxylic acid, ethyl ester [73733-70-7] (0.15 mol) in THF ( 200 ml) and the mixture was stirred at room temperature overnight. The precipitate was filtered and dried, yielding 51.6 g (93.5%) of the intermediate (11); p.f. 133.2 ° C. b) Preparation of the intermediary (12) Bromine (0.05 moles) was added dropwise (slowly) at 50 ° C to a mixture of intermediate (11) (0.05 moles) in a solution of hydrobromic acid in water (48%) (150 ml). The mixture was heated to reflux and stirred and refluxed for 6 hours. The mixture was cooled with stirring and crystallized. The precipitate was filtered and dried. The filtrate was evaporated, taken up in water, made alkaline with NH 4 OH and extracted with dichloromethane. The organic layer was dried, filtered and evaporated. The residue was dissolved in 2-propanone and converted to the hydrochloric acid salt (1: 2) in 2-propanol, yielding 1.8 g (9.2%) of the intermediate (12); p.f. 259 ° C.

EXAMPLE A6 a) Preparation of the intermediary (13) Hydrazine monohydrate (0.1 mol) was added dropwise to a mixture of 4-isothiocyanato-1-piperidinecarboxylester ethyl ester [73733-70-7] (0.05 mol) in THF (200 ml) and the reaction mixture was stirred for overnight at room temperature, then the mixture was stirred and refluxed for 30 minutes. After cooling, the resulting precipitate was filtered and dried, yielding 8.8 g (71.9%) of the intermediate (13). b) Preparation of the intermediary (14) A mixture of intermediate (13) (0.1 moles) and benzaldehyde (0.1 mol) in ethanol (200 ml) was stirred and refluxed overnight and then the solvent was evaporated, yielding 33.5 g (100%) of the intermediate (14). c) Preparation of the intermediary (15) A mixture of intermediate (14) (0.1 mole) and iron chloride, hydrate (1: 6) (0.36 mole) in water (300 ml) was stirred and refluxed over the weekend and the solvent was evaporated. The residue was neutralized with a 10% solution of K2CO3 and the resulting mixture was extracted with dichloromethane. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 28.6 g (86%) of the intermediate (15). d) Preparation of the intermediary (16) A mixture of intermediate (15) (0.0255 mol) in hydrobromic acid (48%) (100 ml) was stirred and refluxed for 30 minutes and the solvent was evaporated. The residue was converted to the free base with NH OH and extracted with dichloromethane. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 6 g (90.2%) of the intermediate (16).

EXAMPLE A7 a) Preparation of the intermediary (17) A solution of 1-isothiocyanato-2-methylbenzene (0.185 mol) in DIPE (100 ml) was added dropwise to a solution of 4- (methylamino) -1-piperidinecarboxylic acid, ethyl ester [73733-69-4] (0.185) moles) in DIPE (200 ml). The reaction mixture was stirred for 3 hours. The resulting precipitate was filtered and dried, yielding 53.6 g (86.5%) of the intermediate (17). b) Preparation of the intermediary (18) Bromine (0.165 moles) was added dropwise to the intermediate (17) (0.16 moles) in hydrobromic acid (48%) (272 ml), was stirred at 60 ° C. The reaction mixture was heated to reflux temperature, then stirred and refluxed overnight. The solvent was evaporated. The residue was treated with 50% NaOH and extracted with dichloromethane. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel (eluent: CHCl3 / CH3OH 95/5). The product fractions were collected and the solvent was evaporated, yielding 30 g of the product. Part (4.0 g) of the free base was dissolved in 2-propanone and converted to the hydrochloric acid salt (1: 2) with HCl / 2-propanol. The precipitate was filtered and dried, yielding 2.5 g of the intermediate (18); p.f. 295.5 ° C.

EXAMPLE A8 a) Preparation of the intermediary (19) A mixture of N- [1- (phenylmethyl) -4-piperidinyl] -3-pyridinamine [63260-34-4] (0.2 moles) and N, N-diethylethanamine (0.8 moles) in benzene (1200 ml) was stirred at room temperature. A solution of 4-methyl benzoyl chloride (0.4 moles) in benzene (500 ml) was added dropwise (slightly exothermic reaction) and the resulting reaction mixture was slowly heated to reflux temperature. The mixture was stirred and refluxed for 12 hours, then cooled, filtered and the filtrate was evaporated. The residue was dissolved in CHCl3. The organic solution was washed 3 x with one of 10% aqueous NaOH solution, twice with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was dissolved in a HCl solution? A, then stirred for a while. The acid mixture was washed once with CHCl3. The CHCI3 layer was extracted three times with acidic water. The water layers were combined, washed 1x with DIPE, then alkalinized with a 20% aqueous solution of NaOH. This mixture was extracted three times with CHCl3. The combined organic layers were washed with water, dried (MgSO4), filtered and the solvent was evaporated, yielding 61 g of the product. Part (4 g) of this product was recrystallized from 2-propanol, filtered and dried, yielding 3 g of the intermediate (19); p.f. 147.2 ° C. b) Preparation of the intermediary (20) A mixture of intermediate (19) (0.16 mol) in methanol (500 ml) was hydrogenated with palladium on activated carbon (10%) (5 g) as a catalyst. After taking up hydrogen (1 equivalent), the catalyst was filtered and the filtrate was evaporated. Part (5 g) of the residue (47 g) was crystallized from 2-propanone / DIPE 1/10, filtered and dried, yielding 4 g of the intermediate (20); p.f. 137.2 ° C.

EXAMPLE A9 a) Preparation of the intermediary (21) A mixture of 4 - [(aminothioxomethyl) amino] -1-piperidinecarboxylic acid, ethyl ester [294622-57-4] (0.1 mol) in hydrobromic acid (48%) (200 ml) was stirred and refluxed for 2 hours. The mixture was allowed to cool to room temperature and crystallization occurred. The precipitate was filtered, washed with DIPE and dried, yielding 15.1 g (47%) of the intemediate (21). b) Preparation of the intermediary (22) A suspension of the intermediate (21) (0.05 moles) in ethanol (200 ml) was heated to reflux temperature. At reflux, 3-bromo-2-oxo-propanoic acid, ethylester (0.05 mol) was added dropwise (complete dissolution resulted). The reaction mixture was stirred and refluxed overnight. The mixture was allowed to cool to room temperature while stirring. Crystallization occurred and the precipitate was filtered and dried, yielding 17.6 g (84.4%) of the intermediate (22); p.f. 236.5 ° C.

B. Preparation of the compounds EXAMPLE B1 A mixture of intermediate (4) (0.0066 moles), 1,4-dichloro-2-butine (0.0033 moles) and sodium carbonate (0.68 g) in MIK (20 ml) was stirred overnight at 100 ° C. The reaction mixture was washed with water (10 ml), and the organic solvent was evaporated. The residue was purified by HPLC on Kromasil silica gel (200 g, 100 A, 5 μm) (eluent: CH2Cl2 / (CH2Cl2 / CH3OH 90/10) / CH3OH. The pure fractions were collected and the solvent was evaporated, yielding 0.94 g of the product. This product was dried, yielding 0.492 g of compound 1.

EXAMPLE B2 A mixture of N-methyl-N-4-piperidinyl-2-benzothiazolamine (0.0005 moles) and 1,4-diisocyanatobutane (0.5 equivalents) in dichloromethane (5 ml) was stirred overnight at room temperature. The desired compound was isolated and purified by silica gel column chromatography (eluent: CH 2 Cl 2 / CH 3 OH gradient from 100/0 to 90/10). The purest fractions were collected and the solvent was evaporated, yielding 0.062 g of compound 2.

EXAMPLE B3 A mixture of 5-fluoro-N-methyl-N-4-piperidinyl-2-benzothiazolamine (0.01 mole) and N, N-diaethylethanamine (0.012 mole) in dichloromethane (50 ml) was stirred at 0 ° C. Octanedioyl dichloride (0.005 mole) was added dropwise and the mixture was allowed to warm to room temperature. The agitation was continued throughout the night. Water was added and this mixture was extracted with dichloromethane. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was stirred in DIPE, filtered and dried, yielding 1.67 g (50%) of compound 3.

EXAMPLE B4 A solution of 1,3-dihydro-1-methyl-3- (4-piperidinyl) -2H-benzimidazol-2-one (0.0005 mol) in dichloromethane (2 ml) was mixed with a solution of N, Nd-ethylethanamine ( 0.0006 moles) in dichloromethane (1 ml). This mixture was treated dropwise with a solution of 4,4'-oxybisbenzenesulfonyl chloride (0.00025 mol) in THF (1 ml) and the resulting reaction mixture was stirred overnight under atmospheric conditions. The desired compound was isolated and purified by high performance liquid chromatography over non-derivatized Kromasil Spherical silica gel (55 g, 60 A, 5 μm, eluent: CH 2 Cl 2 / (CH 2 Cl 2 / CH 3 OH 9/1) / CH 3 OH. were collected and the solvent was evaporated, yielding 0.140 g of compound 4. Table Fl lists the compounds that were prepared according to one of the aforementioned examples.

TABLE F-l Compound identification Compounds were identified by LC / MS using an elution gradient system in a reverse phase HPLC. The compounds were identified by their specific retention time and their protonated molecular MH + ion peak. The CLAR gradient was supplied by a Waters Alliance HT 2790 system with a column heater set at 40 ° C. The flow from the column was divided into a Waters 996 photodiode array detector (PDA) and a Waters-Micromass ZQ mass spectrometer with an electro-sputtering ionization source operated in positive and negative ionization mode. Reversed phase HPLC was carried out on an Xterra MS C18 column (3.5 μm, 4.6 x 100 mm) with a flow rate of 1.6 ml / minute. Three mobile phases were sent (mobile phase A 95% 25mM ammonium acetate + 5% acetonitrile; mobile phase B: acetonitrile; mobile phase C: methanol) to process a gradient condition from 100% A to 50% B and 50% C in 6.5 minutes, to 100% B in 1 minute, 100% B for 1 minute and rebalance with 100% A for 1.5 minutes An injection volume of 10 μL was used. The mass spectra were acquired by recording from 100 to 1000 in 1 s using an extension time of 0.1 seconds. The voltage of the capillary needles was 3kV and the temperature of the source was maintained at 140 ° C. Nitrogen was used as the nebulizer gas. The voltage cone was 10 V for the positive ionization mode and 20 V for the negative ionization mode. The acquisition of the data was carried out with the Waters-Micromass MassLynx-Openlynx data system.

TABLE Retention time (RT in minutes) and molecular weight as MH * C. Pharmacological examples EXAMPLE C.1 Neuronal viability test Primary culture of chicken dorsal root ganglion neurons The dorsal root ganglia were dissected from White Leghorn chicken embryos on embryonic day 10 as previously described (Skaper SD and Male S. (1986) Brain Research 389 , 39-46). The ganglia were trypsinized and dissociated by moderate trituration in a pH regulator HBSS supplemented with 0.6% glucose and 0.08% trypsin. To remove the non-neuronal cells by differential binding to the plastic for culture, the ganglion cell suspension was diluted to 2.5x105 cells / ml and seeded on plastic dishes for tissue culture at 10 ml per 100 mm dish. After 2 hours of pre-seeding, unbound neurons were harvested and resuspended in Basal Eagle medium containing 10% FCS. To remove the cell aggregates, the cell suspension was passed through a nylon mesh (50 μM pore diameter). The cell suspension enriched with neurons was seeded at 5 × 10 4 cells / ml into 96-well plates coated with poly-L-ornithine (100 μg / ml) and laminin (1 μg / ml). The compounds were dissolved in dimethyl sulfoxide and kept as a storage solution at -20 ° C. The NGF and the compounds were diluted in the culture medium and added to the cells immediately after seeding. The final concentration of dimethisulfoxide in the test medium was 0.1%. After two days of incubation, neuronal viability was evaluated with calcein-AM.

Neuronal viability assay using calcein-AM The neuronal viability assay using calcein AM was carried out as previously described (Bozyczko-Coyne D., McKenna BW, Connors TJ, and Neff NT (1993) Journal of Neuroscience Methods 50, 205 - 216). For the assay, calcein-AM in PBS was diluted to the final concentration (1 μM). For each experiment, an aliquot of calcein-AM (1 mg / ml in DMSO stored at -20 ° C) was thawed immediately before use. The medium was removed from the wells and replaced with the calcein-AM solution. The test plates were incubated for 1 hour at 37 ° C in a humidified incubator with C02. After incubation, a reading was made on a Cytofluor II or an excitation wavelength of 485 nm and an emission wavelength of 530 nm. Each plate had control wells without added neurotrophic factor (0% survival) and wells with 10 ng / ml NGF (100% survival). The drugs to be evaluated were taken from a storage solution and evaluated at a final concentration ranging from -10"5 M to 3.10" 9 M. From the dose response curves thus obtained, the plC50 value and evaluated as follows; classification 1 = value plC50 < 6, classification 2 = value plC50 in the range of 6 to 8, classification 3 = value plC50 > 8. Some of the results thus obtained are summarized in the table below.

D. Examples of the composition The following formulations exemplify typical pharmaceutical compositions suitable for systemic or topical administration to an animal and human subject in accordance with the present invention. "Active ingredient" (A. I.) as used throughout these examples refers to a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.

EXAMPLE D.1 Film coated tablets Preparation of the tablet core A mixture of AI (100 g), lactose (570 g) and starch (200 g) was mixed well and subsequently moistened with a solution of sodium dodecyl sulfate (5 g) and polyvinyl pyrrolidone (10 g) ) in approximately 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then microcrystalline cellulose (100 g) and hydrogenated vegetable oil (15 g) were added. The whole was mixed well and compressed into tablets, yielding 10,000 tablets, each comprising 10 mg of the active ingredient.

Coating To a solution of methylcellulose (10 g) in denatured ethanol (75 ml) was added a solution of ethyl cellulose (5 g) in CH 2 Cl 2 (150 ml). Then CH2Cl2 (75 ml) and 1,2,3-propanetriol (2.5 ml) were added. The polyethylene glycol (10 g) was melted and dissolved in dichloromethane (75 ml). The latter solution was added to the former and then magnesium octadecanoate (2.5 g), polyvinylpyrrolidone (5 g) and concentrated color suspension (30 ml) were added and the whole was homogenized. The tablet cores were coated with the mixture thus obtained in a coating apparatus.

Claims (12)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the formula the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n represents 1 or 2; m represents 0, 1, 2 or 3; Z represents C, N or O; -X- represents C2.4 alkynyl, C -? - 2 alkyl optionally substituted with hydroxy or X represents a divalent radical of the formula (a) (b) () where; -X represents C1-12 alkyl, phenyl or a divalent radical selected from the group consisting of -X 2 - represents C 1-12 alkyl, C 1-4 alkyl alkyloxy, phenyl or a divalent radical of formula -X3- represents phenyl or a divalent radical selected from the group consisting of R1 and R2 each independently represent hydrogen, C1.4 alkyl, C1- alkylcarbonyl, Ar1-carbonyl, Het1, Ar2, or C?-Alkylcarbonyl substituted with Het2 or Ar3; or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from pyrimidinyl, indolyl, indolinyl, indazolyl, imidazolinyl, imidazolidinyl, benzoxazolyl, benzimidazolyl, quinazolinyl, quinolinyl or benzthiazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group consisting of carbonyl, Ar5, amino, (C? -4) alkyl- mono- or di-substituted, hydroxy, halo, polyhaloalkyloxy of C 1-4 , C? -4 alkyl, C? -4 alkyloxycarbonyl, and phenyl; R3 independently represents hydroxy or C1-4 alkyloxy; Het1 represents a heterocycle selected from pyridinyl, indolinyl, benzimidazolyl, benzthiazolyl, thiazolyl, pyridinyl, benzisoxazolyl, benzoxazolyl, oxadiazolyl or thiadiazolyl wherein said Het1 is optionally substituted with one or when possible two or more substituents selected from the group consists of hydroxy, halo, Ar4, C1- alkoxycarbonyl, C? -4 alkyl, C? -4 alkyloxy, and C? -4 alquilo alkyloxy substituted with halo; Het2 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, benzisoxazolyl, benzoxazolyl or thiadiazolyl wherein said Het2 is optionally substituted with one or when possible two or more substituents selected from the group that consists of hydroxy, halo, Het 4, C 1 - alkoxycarbonyl, C 1 - alkyl -, C 1 - alkyloxy and C 4 - alkyloxy - substituted with halo; Het3 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl; Het4 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl wherein said Het4 is optionally substituted with one or when possible two or more substituents selected from the group consisting of hydroxy , halo, C 1 - alkyl, C 1-4 alkyloxy; Ar1, Ar2 and Ar3 each independently represent phenyl optionally substituted with halo, amino, Het3, C1- alkylcarbonyl, alkyl of d. , C 1-4 alkyloxy- or C 1 .4 alkyl substituted with one, two or three halo substituents; in particular Ar1, Ar2 and Ar3 each independently represents phenyl optionally substituted with halo, C? or C 1 .4 alkyloxy; Ar 4 represents phenyl optionally substituted with halo, C 4 alkyl, C 4 alkyloxy or C 4 -4 alkyl substituted with one, two or three halo substituents; Ar 5 represents phenyl optionally substituted by C 3-6 alkyloxy or C 3-6 cycloalkyloxy.

2. - The compound according to claim 1, further characterized in that; n represents 1; m represents 0, 1 or 2; in particular m represents 0; R1 and R2 each independently represent hydrogen, C? -4 -4 alkyl, Ar1-carbonyl, Het1, Ar2 or C1.4 alkylcarbonyl optionally substituted with Het2 or Ar3; or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from indolyl, indolinyl, benzimidazolyl, benzthiazolyl, benzisoxazolyl or oxodiazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group consisting of hydroxy, C 1-4 alkyl, C 1-4 alkyloxycarbonyl, carbonyl, Ar 5 and halo; Het1 represents a heterocycle selected from pyridinyl, indolinyl, indolyl, benzthiazolyl, benzimidazolyl, thiazolyl, thiadiazolyl or benzisoxazolyl wherein said Het1 is optionally substituted with one or when possible two or more substituents selected from the group consisting of halo, Ar4, C? -4 -4 alkyloxycarbonyl, C? -4 alquiloalkyl and C ^ --alkyloxy, said C-4-4 a-aicyloxy- being optionally substituted with halo; Het2 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl; Ar 1, Ar 2 and Ar 3 each independently represent phenyl optionally substituted with halo, C 1-4 alkyl, C? - alkyloxy, or C? - alkyl substituted with one, two or three halo substituents; Ar 4 represents phenyl optionally substituted with halo, C 4 alkyl, C 1 alkyloxy or C 1 alkyl substituted with one, two or three halo substituents; Ar 5 represents phenyl optionally substituted by C 1-4 alkyloxy or C 3-6 cycloalkyloxy. 3. The compound according to claim 1, further characterized in that; n represents 1 or 2; m represents 0, 1, 2 or 3; Z represents CH2; -X- represents C2-4 alkynyl, CM2 alkyl optionally substituted with hydroxy or X represents a divalent radical of the formula (a) < b > ( ) where; -Xr represents C? _2 alkyl, phenyl or a divalent radical selected from the group consisting of

-X2- represents C? .12 alkyl, C? .4 alkyloxy C1.4 alkyl, phenyl or a divalent radical of formula

-X3- represents phenyl or a divalent radical selected from the group consisting of

R1 and R2 each independently represent hydrogen, C1-4 alkyl, C1-4 alkylcarbonyl, Ar1carbonyl, Het1, Ar2, or C1- alkylcarbonyl substituted with Het2 or Ar3; or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from pyrimidinyl, indolyl, indolinyl, indazolyl, imidazolinyl, imidazolidinyl, benzoxazolyl, benzimidazolyl, quinazolinyl, quinolinyl or benzthiazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group consisting of carbonyl, Ar5, amino, (C1-) alkyl- mono- or di-substituted amino, hydroxy, halo, C1- polyhaloalkyloxy, C1-4, C 1 .4 alkyloxycarbonyl, and phenyl; R3 independently represents hydroxy or C? - alkyloxy; Het1 represents a heterocycle selected from pyridinyl, indolinyl, benzimidazolyl, benzthiazolyl, thiazolyl, pyridinyl, benzisoxazolyl, benzoxazolyl, oxadiazolyl or thiadiazolyl wherein said Het1 is optionally substituted with one or when possible two or more substituents selected from the group consists of hydroxy, halo, Ar4, C1- alkoxycarbonyl, C? -4 alkyl, C? -4 alkyloxy, and C-substituted alkyloxy with halo; Het2 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, benzisoxazolyl, benzoxazolyl or thiadiazolyl wherein said Het2 is optionally substituted with one or when possible two or more substituents selected from the group that consists of hydroxy, halo, Het4, C 1 - alkoxycarbonyl, C 1 - alkyl, C 1. 4 alkyloxy and C - 4 alkyloxy - substituted with halo; Het3 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl; Het4 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl wherein said Het4 is optionally substituted with one or when possible two or more substituents selected from the group consisting of hydroxy , halo, C-? 4 alkyl, C? - alkyloxy; Ar1, Ar2 and Ar3 each independently represent phenyl optionally substituted with halo, amino, Het3, C? Alkylcarbonyl. , C? -4 alkyl, C? -4- alkyloxy or C? -4 alkyl substituted with one, two or three halo substituents; in particular Ar 1, Ar 2 and Ar 3 each independently represents phenyl optionally substituted with halo, C 1 - alkyl or C 4 -4 alkyloxy; Ar 4 represents phenyl optionally substituted with halo, C 4 alkyl, C 1-4 alkyloxy or C 4 alkyl substituted with one, two or three halo substituents; Ar5 represents phenyl optionally substituted by C1- alkyloxy or C3.6 cycloalkyloxy. 4. The compound according to claim 1, further characterized in that; n represents 1; m represents 0; Z represents CH2; R1 and R2 each independently represent hydrogen, C-? -4 alkyl, Ar1-carbonyl, Het1, Ar2 or C? Alkylcarbonyl optionally substituted with Het2 or Ar3; or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from indolyl, indolinyl, benzimidazolyl, benzthiazolyl, benzisoxazolyl or oxodiazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group consisting of hydroxy, C1-4alkyl, C4-4alkyloxycarbonyl, carbonyl, Ar5 and halo; Het1 represents a heterocycle selected from pyridinyl, indolinyl, indolyl, benzthiazolyl, benzimidazolyl, thiazolyl, thiadiazolyl or benzisoxazolyl wherein said Het1 is optionally substituted with one or when possible two or more substituents selected from the group consisting of halo, Ar4, C 1-4 alkyloxycarbonyl, C? 4 alkyl, and C? -4- alkyloxy, said C 1-4 alkyloxy- being optionally substituted with halo; Het2 represents a heterocycle selected from thiophenyl, furanyl, pyrrolyl, pyridinyl, thiazolyl, oxazolyl, pyridinyl, or thiadiazolyl; Ar 1, Ar 2 and Ar 3 each independently represent phenyl optionally substituted with halo, d-4 alkyl, C 1-4 alkyloxy, or C 1 -α alkyl substituted with one, two or three halo substituents; Ar4 represents phenyl optionally substituted with halo, C? _4 alkyl, C? -4 alkyloxy or C? -4 alkyl substituted with one, two or three halo substituents; Ar 5 represents phenyl optionally substituted by C 1-4 alkyloxy or C 3-6 cycloalkyloxy. 5. The compound according to claim 1, further characterized in that; n represents 1; m represents 0; Z represents CH2; R1 and R2 each independently represent hydrogen, C1-6 alkyl, Ar1-carbonyl, Het1, Ar2 or C1.4 alkylcarbonyl optionally substituted with Het2 or Ar3; or R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from indolyl, indolinyl, benzimidazolyl, benzthiazolyl, benzisoxazolyl or oxodiazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group consisting of carbonyl, hydroxy or halo; Het1 represents a heterocycle selected from pyridinyl, indolinyl, benzthiazolyl, thiazolyl, or thiadiazolyl, wherein said Het1 is optionally substituted with one or when possible two or more substituents selected from the group consisting of halo, Ar4, alkyloxycarbonyl of d.4- and C 1-4 alkyloxy- substituted with halo; Het2 represents thiophenyl; Ar1 represents phenyl optionally substituted with halo or alkyloxy of d.4-; Ar 2 represents phenyl optionally substituted with halo or C 1-4 alkyloxy; Ar 3 represents phenyl optionally substituted with halo or d-4 alkyloxy; or Ar 4 represents phenyl optionally substituted with C 1-4 alkyl-.

6. The compound according to claim 1 or 2, further characterized in that; m represents 0; Z represents CH2; n represents 1; -X- represents C2- alkynyl, C? .12 alkyl optionally substituted with hydroxy or -X- represents a divalent radical of the formula (a), (b) or (c) as defined above in the present invention in where; -X represents alkyl of d.12 or a divalent radical selected from (d) or (e) as defined by the compounds of formula (I) above in the present invention; -X2- represents alkyl of C? -12, alkyloxy of d. alkyl of d.4, phenyl or a divalent radical of formula (g) as defined by the compounds of formula (I) above in the present invention; -X3-represents phenyl or a divalent radical selected from (g), (h) and (i) as defined by the compounds of formula (I) above in the present invention; R1 and R2 each independently represent hydrogen, alkyl of d-4 O R1 and R2 taken together with the nitrogen atom to which they are attached form a heterocycle selected from indolyl, indolinyl, or benzimidazolyl wherein said heterocycle is optionally substituted with one or when possible two or more substituents selected from the group consisting of carbonyl, hydroxy or halo; Het1 represents a heterocycle selected from pyridinyl, indolinyl or benzthiazolyl wherein said Het1 is optionally substituted with halo, Ar4 or polyhaloalkyloxy of C 1-4-; Het2 represents thiophenyl; Ar 1 represents phenyl optionally substituted with halo or C 1-4 alkyloxy; Ar2 represents phenyl optionally substituted with halo or C? -4 alkyloxy; Ar 3 represents phenyl optionally substituted with halo or C 1-4 alkyloxy; or Ar4 represents phenyl optionally substituted with C? - alkyl.

7. The compound according to any of claims 1 or 4, further characterized in that; Ar2 represents phenyl substituted with halo

8. The compound according to claim 1, further characterized in that the compound is selected from the compounds with the formulas (A) - (O) below:

9. - A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, an effective therapeutic amount of a compound as described in any one of claims 1 to 6.

10. A process for the preparation of a pharmaceutical composition in accordance with claim 4, further characterized in that, a pharmaceutically acceptable carrier is intimately mixed with an effective therapeutic amount of a compound as described in any one of claims 1 to 6.

11. The compound according to any of claims 1 to 6 for use as a medicine.

12. The use of a compound as defined in any of claims 1 to 6, in the preparation of a medicament for the treatment of pain, in particular post-operative pain and pathologies associated with neuronal death, such as, accident cerebrovascular disease, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Pick's disease, fronto-temporal dementia, progressive nuclear paralysis, corticobasal degeneration, cerebrovascular dementia, multiple systems atrophy, argyrophilic grain dementia, other tauopathies, and additional conditions that include neurodegenerative processes are, for example, age-related macular degeneration, narcolepsy, motor neuron diseases, prion diseases, traumatic nerve injury and repair, and multiple sclerosis.