WO2008003511A1

WO2008003511A1 - Use of aminothiazole derivative compounds, pharmaceutical compositions thereof, in the treatment of diseases characterized by abnormal repression of gene transcription, particularly huntington's disease

Info

Publication number: WO2008003511A1
Application number: PCT/EP2007/006007
Authority: WO
Inventors: Elena Cattaneo; Dorotea Rigamonti; Aleksey Kazantsev
Original assignee: Dialectica S.R.L.
Priority date: 2006-07-05
Filing date: 2007-07-03
Publication date: 2008-01-10
Also published as: ITVA20060041A1

Abstract

The present invention relates to the use of aminothiazole compounds and pharmaceutical compositions thereof in the medical practice. More specifically, the instant invention relates to the use of aminothiazole derivatives and pharmaceutical compositions thereof in the treatment and/or prophylaxis and/or prevention of diseases and/or pathological conditions characterized by the abnormal repression of gene transcription and/or by neurodegeneration, particularly the Huntington's disease.

Description

"USE OF AMINOTHIAZOLE DERIVATIVE COMPOUNDS, PHARMACEUTICAL COMPOSITIONS THEREOF, IN THE TREATMENT OF DISEASES CHARACTERIZED BY ABNORMAL REPRESSION OF GENE TRANSCRIPTION, PARTICULARLY HUNTINGTON' S DISEASE"

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

The present invention relates to the use of aminothiazole derivatives as modulators of gene transcription repressor factors. The invention relates also to pharmaceutical compositions containing these compounds. Compounds and pharmaceutical compositions of the present invention are particularly suitable for the modulation of gene transcription repressor factors and, accordingly, they can be advantageously used as agents against diseases characterized by the abnormal repression of gene transcription, including neurodegenerative pathologies or conditions, e.g. Huntington's Chorea, and tumours. In particular, the present invention is based on previous findings regarding a molecular mechanism characterizing Huntington's Chorea.

Huntington's Disease is an inherited dominant genetic disorder starting in midlife. The neurological damage comprises the loss of the striatal neurons in the basal ganglia, a cerebral region which is central of involuntary movements. Huntington's Disease progression is slow and inexorable during which patients lose motor and cognitive ability and acquire psychiatric disturbance (Hayden MR Huntington's chorea, Springer-Verlag : London, Berlin Heidelberg, 1981) . Usually, the disease onset is in fertile age (35 years of age) with an estimate prevalence of 1 out of 10.000 individuals in the Caucasian population and an average duration of about 17 years until death. Frequently, Huntington patients become aware of their situation and future even before any manifested behavioural alteration and thus progressively isolate themselves from society, quit their job or social activity. In addition to the consequences for the patients and their families, the- long clinical course of the disease results in high economic cost for the society.

The genetic defect responsible for the pathology was identified in 1993 and it is based on a mutation within the gene encoding a protein called huntingtin, then demonstrated to play a neuroprotective role (Huntington' s Disease Collaborative Research Group, Cell, 1993, vol 72, pp. 971-983). The mutation of the gene consists in an aberrant expansion of a CAG triplet nucleotides located at the beginning of the gene which produces, in the encoded protein, the aminoacid glutamine. In the disease state, the amino-terminal portion of mutant huntingtin contains a polyglutamine sequence which led to a newly acquired toxic funtion(gain of function mechanism). In addition to that, the mutation also causes the loss of the neuronal protective function of the wild-type protein (loss of function mechanism) (Cattaneo, Nat Rev Neurosci, 2005, vol.12, pp. 919-930). The loss of wild- type huntingtin function together with the new toxic activity acquired by the mutant protein cause the progressive degeneration of brain striatal neurons which control the involuntary movements, leading to choreic manifestations.

At the moment there are no specific therapies available which can cure patients affected with Huntington's Disease (Merck Manual, Ed. Merck Res. Laboratories, 17th ed. , 1999,1464). It is therefore clear the interest in the development of pharmacological appraoches able to delay the disease onset, to reduce the severity of the pathology and/or to slow its progression.

It has been found that, in physiological conditions, normal huntingtin is able to stimulate the production of a neurotrophin called BDNF (Brain-Derived Neurotrophic Factor, part of the NGF, Nerve Growth Factor, family of neuronal growth factor) (Zuccato, Science 2001, vol. 293, pp. 493-8) which is a pro- survival factor for the neurons in the central nervous system, and in particular for the striatal neurons which are the most affected in the pathology. It has been previously demonstrated that physiologically huntingtin presents in the organism, here referred to as normal huntingtin, stimulates the production of BDNF by- increasing the transcription of the gene encoding for this protein. This function is lost with the mutation.

The structure of the gene responsible for BDNF production is known (Timmusk, Neuron 1993, 10 pp 475-489).

It has been reported (Zuccato, Nat Genetic 2003, vol. 35, pp. 76-83) that on BDNF promoter II is present a minimal DNA sequence necessary for wild-type huntingtin activity on BDNF gene transcription. This sequence is a known palindromic sequence of 53 base pairs, named REl/NRSE (Restrictive Element l/Neuron Restrictive Silencer Element) (Mori, Neuron 1990, vol. 4, p. 583- 94; Mori, Neuron 1992, vol. 9, pp. 45-54; Maue, Neuron 1990 vol. 4, pp. 223-31) present on the promoter of more than 1000 human genome loci (Bruce, Proc Natl Acad Sci USA 2004, vol. 101, pp. 10458-10463) (5¹-

TCCATTCAGCACCTTGGACAGAGCCAGCGGATTTGTCCGAGGTGGTAGACTT-S ' ) . REl/NRSE controlled genes play a key role in the maturation and neuronal phenotype maintenance (Bruce, 2003 op.cit.; Schoenherr, Science 1995, vol. 267, pp. 1360-1363). It has been also reported (Zuccato, 2003 op. cit . ) that this sequence functions as a molecular target for normal huntingtin, regulating its neurotrophic and neuroprotective function. More specifically, the NRSE sequence has a silencer role on the BDNF gene: normal huntingtin, indirectly acting on this sequence, blocks its silencing activity, thus stimulating transcriptional activity of REl/NRSE controlled genes. More specifically, this block is due to the sequestering into the cytoplasm of the principal factor involved in the activation of the REl/NRSE sequence. This factor is named REST/NRSF (REl silencing transcription factor/neuron- restrictive silencer factor) and is a protein that, due to the presence of 9 structural motives specific for DNA binding, is able to bind to REl/NRSE sequence preventing the expression of REl/NRSE regulated genes (Schoenherr, 1995 op. cit . ; Lietz, Eur. J. Neurosci. 2001 vol. 14, pp. 1303-12. ).

Moreover, in literature is reported an increase in REST/NRSF mRNA levels after global ischemia (Calderone et al . , J.Neurosci. 2003, vol. 23, pp. 2112-2121). This is suggestive of the fact that drugs aimed to counteract REST/NRSF activity should be of interest also in ischemic condition.

A correlation between the neurotrophin receptor TrkC levels and favourable outcome in medulloblastoma has been observed, too (Segal et al . , Proc .Natl .Acad. Sci .USA 1994, vol. 91, pp .12867-71) . TrkC is one of the REl/NRSE regulated genes (Nakatani, Brain Res MoI Brain Res, 2005, vol. 135, pp. 249-59). The exposure of nude mice to REST-VP16, a recombinant transcription factor that can compete with REST/NRSF and activate REST/NRSF target genes instead of repressing them, was able to block the growth of estabilished tumors (Fuller et al., MoI. Cancer Ther. 2005, vol. 4, pp. 343-9). A decrease in expression levels of REl/NRSE regulated genes has been demosntrated also in the Down condition (Bahn, Lancet 2002, vol. 359, pp. 310-315).

From these results derive the interest in compounds able to block the silencer activity of the REl/NRSE sequence, thus mimicking the transcriptional effects phisiologically observed in the presence of normal huntingtin, but lost with the mutation. These compounds might reveal of interest in Huntington's Disease and in the above listed pathologies, but also in other pathologies in which neurodegeneration is present, given their capability to promote the transcription of genes able to support neuronal phenotype maintenance .

Accordingly, there is a need for compounds which effectively modulate transcriptional repressor factors, for example by acting as the native huntingtin in inhibiting the silencing activity of the REl/NRSE sequence, for use as agents to prevent and to treat Huntington's disease and other pathological conditions characterized by the abnormal repression of gene transcription and/or by neurodegeneration.

The development of specific inhibitors of the REl/NRSE sequence-mediated silencing activity is found useful in the treatment of Huntington's disease and other pathological conditions characterized by a diminished transcription of REl/NRSE-controlled genes DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to the use of aminothiazole derived compounds, and of pharmaceutically acceptable salts thereof, which resulted surprisingly useful as modulators of transcriptional repressor factors. The object compounds may be used individually or in combination with other therapeutic or prophylactic agents, such as compounds favouring cellular energetic metabolism, compounds capable to modulate positively or negatively the formation and/or the accumulation of intracellular or intranuclear aggregates and/or inclusions, antidepressants, antiproliferatives (intercalators, antimitotics) , and they meet a need for the treatment or prophylaxis of diseases characterized by abnormal repression of gene transcription.

According to a preferred embodiment, the compounds of the present invention mimic the action of the native huntingtin by impairing the activation of the silencing element REl/NRSE.

Therefore, it is a first aspect of the present invention the use as modulators of transcriptional repressor factors of compounds represented by the following formula (I) :

wherein:

E is hydrogen; a group -OR, wherein R is hydrogen, C(I- 6)alkyl; -NR¹R², wherein R¹, R², which may be the same or different, is each independently hydrogen, C (1-6) alkyl;

G is a fused, aromatic, heterobicyclic ring system selected from:

im iidazo[l,2«i]pyridin-3-yl imidazo[l,2-a]piyimidin-3-yl imidazo[l,2-c]pyrimidin-3-yl

imidazo[l,2-b][l,2,4]triazin-7-yl imidazo[l,2-α]pyrazin-3-yl imidazo[l,2-b]pyridazin-3-yl

imidazo[l,2-αl[l,3,5]triazin-6-yl imidazo[2,l-/|[l,2,4]triazin-7-yl

wherein R^a, R^b, R^c and R^d, which may be the same or different, is each independently hydrogen, C (1-6) alkyl, -F, -Cl, -Br, -I, - OR, -NO₂, -NR¹R², CF₃, -OCF₃, -CN, wherein R¹, R² are as previously defined;

R^e is hydrogen, C (1-6) alkyl ; and pharmaceutically acceptable salts thereof.

Another aspect of the present invention is directed to the use of a compound of formula (I) as previously defined, or of a pharmaceutically acceptable salt thereof, in the modulation of factors repressor of gene transcription in vitro and/or in vivo, the said use comprising contacting said factors repressor of gene transcription with an effective amount of a compound of formula (I), or of a pharmaceutically acceptable salt thereof.

Another aspect of the present invention is directed to the use of a compound of formula (I) as previously defined, or of a pharmaceutically acceptable salt thereof, in the inhibition of the silencing activity of the RE1/NRSE sequence in vitro and/or in vivo, the said use comprising contacting said REl/NRSE sequence with an effective amount of a compound of formula (I) , or of a pharmaceutically acceptable salt thereof.

Another aspect of the present invention is directed to the use of a compound of formula (I) as previously defined, or of a pharmaceutically acceptable salt thereof, in the treatment or prevention of a condition or disease characterized by the abnormal repression of gene transcription, the said use comprising administering to an animal in need of such treatment or prevention, an effective amount of a compound of formula (I) , or of a pharmaceutically acceptable salt thereof.

Another aspect of the present invention is directed to the use of a compound of formula (I) as previously defined, or of a pharmaceutically acceptable salt thereof, in the manufacture of a parmaceutical composition to treat or prevent a condition or disease characterized by the abnormal repression of gene transcription.

Yet another aspect of the present invention is providing a pharmaceutical composition useful in the treatment or prevention of a condition or disease characterized by the abnormal repression of gene transcription, the said composition containing an effective amount of a compound of formula (I) in admixture with one or more pharmaceutically acceptable carriers or diluents.

The compounds of formula (I) are either commercially available known compounds or they are obtained by the use of standard chemical synthetic methods known to an ordinary skilled practitioner in the art .

According to a preferred embodiment, in the compounds of formula (I) , E is

-OCH₃, -OCH₂CH₃, -N(CH₃)₂; and G is a fused, aromatic heterobicyclic ring system chosen from: imidazo [1 , 2 - a] pyridin-3 -yl , imidazo [1 , 2 -a] pyrimidin-3 -yl , imidazo [1, 2- c] pyrimidin-3-yl, imidazo [1, 2-b] pyridazin-3-yl, imidazo [1, 2 -jb] [1,2,4] triazin-7-yl, imidazo [1,2-a] [1,3,5] triazin-6-yl, wherein, for each occurence of G, the substituents R^a, R^b, R^c, R^d and R^e are as previously defined.

According to another more preferred embodiment, in the compounds of formula (I) , E is -OCH₃, -OCH₂CH₃, -N(CH₃) ₂,^• and G is a fused, aromatic heterobicyclic ring system chosen from: imidazo [1 ,2-a] pyridin-3-yl, imidazo [1, 2 -a] pyrimidin-3-yl, imidazo [1, 2-c] pyrimidin-3-yl, imidazo [1 , 2-b] pyridazin-3-yl, imidazo [1,2-a] [1,3,5] triazin-6-yl, wherein, for each occurence of G, the substituents R^b and R^e, the same or different, are each independently hydrogen, C (1-6) alkyl, particularly methyl, ethyl; and R^a, R^c, and R^d are hydrogen.

Yet according to another more preferred embodiment, more preferred compounds of formula (I), are:

Yet according to another most preferred embodiment, most preferred compounds of formula (I), are:

(4-Methoxyphenyl) - [4- (2 -methylimidazo [1,2-a] pyridin-3 -yl) thiazol- 2-yl] amine (Compound 1) ;

(4-Methoxyphenyl) - [4- (2, 7-dimethylimidazo [1,2 -a] pyridin-3-yl) thiazol-2-yl] amine (Compound 2) ;

(4-Methoxyphenyl) - [4- (2-methylimidazo [1, 2-a]pyrimidin-3- yl) thiazol-2-yl] amine (Compound 3) ;

(4-Methoxyphenyl) - [4- (2, 7-dimethylimidazo [1,2 -a] pyrimidin-3-yl) thiazol-2-yl] amine (Compound 4) ; (4-Methoxyphenyl) - [4- (2, 7-dimethylimidazo [1,2-a] [1, 3 , 5] triazin -6-yl) tiazol-2-yl] amine (Compound 6);

(4-Methoxyphenyl) - [4- (2 , 7-dimethylimidazo [1, 2-c] pyrimidin-3- yl) thiazol-2-yl] amine (Compound 8);

(4-Ethoxyphenyl) - [4- (2, 7-dimethylimidazo [1, 2 -a] pyridin-3- yl) thiazol-2-yl] amine (Compound 10);

N, N-Dimethyl-W - [4- (2, 7-dimethylimidazo [1, 2 -a] pyridin-3- yl) thiazol-2-yl] benzene-1 , 4 -diamine (Compound 18); and N, N-Dimethyl-N' - [4- (2 -methylimidazo [1,2-a] pyrimidin-3-yl) thiazol- 2-yl] benzene-1, 4 -diamine (Compound 19).

Pharmaceutically acceptable salts of the present invention comprise, for instance, salts derived from pharmaceutically acceptable inorganic and organic acids. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, p-toluenesulphonic, tartaric, acetic, citric, methansulphonic, formic, benzoic, tnalonic, naphthalen-2-sulphonic and benzenesulphonic acids.

The present invention encompasses also the "quaternization" of any group containing a basic nitrogen of the compounds of formula (I) . The basic nitrogen may be quaternized by any agent known to an expert in the art, comprising, for instance, lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulphates including dimethyl, diethyl, dibutyl and amyl sulphate; long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide, and aralkyl halides including benzyl and phenetyl bromide. Products which are soluble or dispersible in water may be obtained from such quaternization.

In one embodiment, the compounds of formula (I) are to be used to treat or prevent neurodegenerative conditions or diseases. In particular, the compounds may be used to treat conditions or diseases such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, brain ischemia, and Rett's syndrome.

In another embodiment, the compounds of formula (I) are to be used to treat or prevent conditions and diseases in which morphological aberrations are observed during the development to differentiated neurons. In particular, the compounds may be used to treat conditions or diseases such as Down's syndrome.

In another embodiment, the compounds of formula (I) are to be used to treat or prevent tumoural conditions and diseases in which there is an aberrant modulation of RE1/NRSE controlled genes. In particular, the compounds may be used to treat conditions or diseases such as medulloblastoma.

The present invention is also directed to pharmaceutical compositions of the compounds of formula (I) , and to methods to obtain such compositions:

The present invention provides the use of the compounds of formula (I) as defined by the appended claims for the manufacture of a suitable medicament to treat neurodegenerative diseases, and other conditions characterized by an abnormal repression of gene transcription, in particular Huntington's Disease, where the mutation responsible for the pathology leads to the loss of the physiological role of huntingtin protein to selectively inhibit the silencing activity of the REl/NRSE element, said use comprising the administration to an animal in need of such a treatment a therapeutically effective amount of one or more compounds selected in the class of compounds represented by the formula (I) . The compounds of formula (I) may be administered in association with one or more non-toxic, pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.

The compounds of formula (I) of the present invention can be used to treat inflammatory conditions and diseases including, but not limited to, Alzheimer's disesase, Parkinson's disease, Huntington's chorea, brain ischemia, Rett's syndrome, Down's syndrome, medulloblastoma.

In particular, the present compounds may be used to treat Huntington's disease. It is known that normal huntingtin sequester into the cytoplasm the transcription factor REST/NRSF. This binding prevents the entering of REST/NRSF into the nucleus and the formation of the transcriptional complex that leads to the activation of REl/NRSE mediated silencing. In the presence of the mutation, huntingtin lost the capability to bind REST/NRSF. REST/NRSF is thus free to enter into the nucleus, where it activates the REl/NRSE element. Following this, there is an excessive silencing of RE1/NRSE controlled genes, among these the BDNF and other genes crucial for survival and neuronal phenotypic mainteinance . The compounds in the present invention, being able to mimick the effect of native huntingtin, prevent the activation of the silencer element REl/NRSE.

The compounds of the present invention may be administered in an effective amount within the dosage range of from about 0.1 μg/kg to about 300 mg/kg, preferably between 1.0 μg/kg and 10 mg/kg body weight. The compounds of the present invention may be administered in a single daily dose, or the total daily dosage may^¬ be administered in divided doses of 2, 3 or 4 times daily.

The pharmaceutical compositions of the present invention can be administered to any animal that can experience the beneficial effects of the compounds of the invention. Foremost among such animals are humans, although the invention is not intended to be so limited.

The pharmaceutical compositions of the present invention can be administered by any means that achieve their intended purpose. For example, administration can be by parenteral, subcutaneous, intravenous, intraarticular, intrathecal, intramuscular, intraperitoneal, or intradermal injections, or by transdermal, buccal, oromucosal, ocular routes or via inhalation. Alternatively, or concurrently, administration can be by the oral route. Particularly preferred is oral administration. The dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

In addition to the pharmacologically active compounds, the pharmaceutical preparations of the compounds can contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. The pharmaceutical preparations of the present invention are manufactured in a manner that is, itself, known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores .

Suitable excipients are, in particular, fillers such as saccharides, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example, tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as starch paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone. If desired, disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.

Auxiliaries are, above all, flow-regulating agents and lubricants, for example silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol Dragee cores are provided with suitable coatings, that, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate, are used. Slow-release and prolonged-release formulations may be used with particular excipients such as methacrylic acid-ethylacrylate copolymers, methacrylic acid-ethyl acrylate copolymers, methacrylic acid- methyl methacrylate copolymers and methacrylic acid-methyl methylacrylate copolymers. Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.

Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form, for example water soluble salts and alkaline solutions. Especially preferred salts are maleate, fumarate, succinate, (S, S) - tartrate, (R, R) -tartrate. In addition, suspensions of the active compounds as appropriate oily injection suspensions can be administered.

Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides or polyethylene glycol-400. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, for example sodium carboxymethyl cellulose, sorbitol, and/or dextran. Optionally, the suspension may also contain stabilizers.

The following examples are illustrative, but not limiting, of the present invention.

EXEMPLES

Example 1: In vitro inhibition, activity on the promoter REl/NRSE BDNF300bp.

"Promoter REl/NRSE BDNF 300bp" = 300 base pairs on the murine BDNF exon 2 containing the REl/NRSE sequence. 300 base pairs have been cloned into the pGL3 Luciferase vector (Promega Corp.) . Neural derived cells have been engineered using the reporter vector. Following antibiotic selection, stable subclones have been isolated. Among these, a subclone, named REl/NRSE BDNF 300 base pairs LUC-8, able to express luciferase in basal conditions and to mantain the expression levels during normal growth conditions up to 50 in vitro passages. Responsiveness of this cellular subclones to stimuli specifically mediated by the REST/NRSF REl/NRSE transcriptional complex has been evaluated by infecting the subclone using a gene codifying for REST/NRSF Dominant Negative. The expression of the Dominant Negative is able to induce, as expected, an increase in luciferase activity (the Dominant Negative competes with the transcription factor REST/NRSF endogeneously present into the cells, thus preventing the activity of the RE1/NRSF silencer) .

REl/NRSE BDNF 300 base pairs LUC-8 cells have been exposed to the compounds of the invention and after 72 hours has been evaluated:

(a) luciferase activity, expressed as EC₅₀, i.e. Compound concentration in the assay able to give rise to 50% increase in the maximal answer of the compound itself.

(b) cell viability, through MTT assay, expressed as EC₅₀. i.e. Compound concentration in the assay able to give rise to cell death in 50% of the cellualr population.

In Table 1 there are reported results a) and b) . Example 2 : In vitro inhibition, activity on endogenous BDNF gene

Neural derived cells have been exposed to compounds 2, 18 and 19 and after 73 hours RNA have been isolated. To evaluate RNA amount and to exclude DNA contamination. After purification the RNA has been runned on agarose gel. After retrotranscritpion, cDNA has been exposed to PCR analysis using specific primer for total BDNF (BDNF-F 5'-GAT GAG GAC CAG AAG GTT CG-3'; BDNF-R 5'-GAT TGG GTA GTT CGG CAT TG-3'; The amplification cycles consisted of an initial 10-minute denaturing cycle at 95°C, followed by 40 cycles of 10 sec at 95°C, 10 sec at 56⁰C, and 20 sec at 72⁰C. Using a reference gene (beta-actin) gene induction has been evaluated with respect to untreated sample. In Table 2 are reported the results obtained after three independent experiments, each one performed in triplicate. They indicate the ability of the compounds of the inventions to increase mRNA levels codifying for endogenous BDNF. Values are referred to mRNA levels for BDNF observed after the indicated treatments, with respect to basal expression levels (white column). ** p<0,01%, ANOVA test. Example 3 : In vitro inhibition, activity on BDNF protein

Neural derived cells have been exposed to compounds 2, 18 e 19 and after 72 hours proteins have been collected. Proteins have been quantified and BDNF levels evaluated via ELISA assay using a specific antibody (Promega Corp.). In Table 3 are reported results obtained from three independent experiments, which indicates the ability of the compounds of the invention to increase endogenous BDNF protein levels. Values are referred to BDNF protein levels observed after the indicated treatments, with respect to basal expression levels (white column). ** p<0,01%, ANOVA test. Example 4: In vitro inhibition, activity on BDNF protein in a cellular context presenting the genie mutation responsible for Huntington's Disease.

Striatal cells obtained from striatum of mice kin for the mutation have been used (in these mice has been introduced the mutation responsible for Huntington's Disease on the gene codifying for huntingtin) (Trettel, Hum MoI Genetics 2000, vol. 9, pp. 2799-809), named 109/109^hdh . These cells have been demonstrated able to express lower levels of BDNF with respect to cells in which the mutation is not present (Zuccato, 2001 op. cit.). These cells have been exposed to compounds 2 and 18 and after 72 hours proteins have been isolated. Proteins have been quantified and BDNF levels evaluated via ELISA assay using a specifici antibody (Promega Corp.). In Table 4 are reported the results obtained from three independent experiments, that indicate the ability of compounds 2 and 18 to increase endogenous BDNF protein levels, also in the presence of mutant huntingtin. ** p<0,01%, *p<0,05%, ANOVA test. Example 5: In vitro rescue of cell viability

109/109^hdh cells (Trettel, 2000 op. cit.) have been exposed to a stress stimulus (37⁰C, in Serum Deprived Medium) in the presence or absence of compound 18, and cell viability was assessed by MTT assay 48 hours after treatment. Cell viability was increased by 17-1-6.6% in the presence of 50 nM of compound 18, and an increase was observed at a dose of 25nM as reported in Table 5. ** p<0,01%, ANOVA test. The increase in cell number in the compound treated group was not due to increased cell proliferation as the percentage of BrdU-positive cells was not increased by the presence of the compound.

Table 1

Claims

1. Use of a compound of formula (I)

wherein:

E is hydrogen; a group -OR, wherein R is hydrogen, C(I-

6)alkyl; -NR¹R², wherein R¹, R², which may be the same or different, is each independently hydrogen, C (1-6) alkyl;

G is a fused, aromatic, heterobicyclic ring system selected from:

imidazo[l,2-α]pyridin-3-yl imidazo[l,2-a]piyimidin-3-yl imidazo[l,2-c]pyrimidin-3-yl

imidazo[l,2-fc][l,2,4]triazin-7-yl imidazo[l,2-α]pyrazin-3-yl imidazo[l,2-b]pyridazin-3-yl

imidazo[l,2-α][l,3,5]triazin-6-yl imidazo[2,l-/|[l₎2,4]triazin-7-yl

wherein R^a, R , R^c and R , which may be the same or different, is each independently hydrogen, C(l-6)alkyl, -F, -Cl, -Br, -

I, -OR, -NO₂,

-NR¹R², CF₃, -OCF₃, -CN, wherein R¹, R² are as previously defined;

R^e is hydrogen, C(l-6)alkyl; to modulate gene transcription repressor factors, comprising in contacting gene transcription repressor factors with an effective amount of a compound of formula (I) , or of a pharmaceutically acceptable salt thereof.

2. Use according to Claim 1, where said contact is in vitro.

3. Use according to Claim 1, where said contact is in vivo.

4. Use according to Claim 1, where said factor repressor of gene transcription is the silencer element RE1/NRSE.

5. Use of a compound of formula (I)

wherein:

E is hydrogen; a group -OR, wherein R is hydrogen, C(I- 6)alkyl; -NR¹R², wherein R¹, R², which may be the same or different, is each independently hydrogen, C (1-6) alkyl ;

G is a fused, aromatic, heterobicyclic ring system selected from :

imidazo[ 1 ,2-α]pyridin-3-yl imidazo[l ,2-a]piyimidin-3-yl imidazof 1 ,2-c]pyrimidin-3-yl

imidazo[ 12-b][ 1 ,2,4]triazin-7-yl imidazo[l,2-α]pyrazin-3-yl imidazo[l,2-b]pyridazin-3-yl

imidazo[l ,2-α] [ 1 ,3,5]triazin-6-yl imidazo[2,l -f\[ 1 ,2,4]triazin-7-yl

wherein R^a, R^b, R^c and R^d, which may be the same or different, is each independently hydrogen, C (1-6) alkyl, -F, -Cl, -Br, -

I, -OR, -NO₂,

-NR¹R², CF₃, -OCF₃, -CN, wherein R¹, R² are as previously defined;

R^e is hydrogen, C(l-6)alkyl,- or of a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical composition to treat or prevent a condition or disease characterized by the abnormal repression of the gene transcription.

6. Use according to Claim 5, wherein, in the compound of formula

(I) , E is

-OCH₃, -OCH₂CH₃, -N (CH₃) ₂,^• and

G is a fused, aromatic heterobicyclic ring system chosen from: imidazo [1 , 2 -a] pyridin-3 -yl , imidazo [1 , 2 -a] pyrimidin-3-yl, imidazo [1 , 2 - c] pyrimidin-3-yl , imidazo [1, 2-b] pyridazin-3-yl , imidazo [1,2-a] [1,3,5] triazin-6-yl , wherein, for each occurence of G, the substituents R^b and R^e, the same or different, are each independently hydrogen, C(I- 6) alkyl, particularly methyl, ethyl; and R^a, R^c, and R^d are hydrogen.

7. Use according to Claim 5, wherein said condition or disease characterized by the abnormal repression of gene transcription is a neurodegenerative condition or disease.

8. Use according to Claim 7, wherein said neurodegenerative condition or disease is selected from the group comprising Alzheimer's disease, Parkinson's disease, Huntington's chorea, brain ischemia, Rett's syndrome.

9. Use according to Claim 5, wherein said condition or disease characterized by the abnormal repression of gene transcription is a condition or disease wherein morphological aberration are observed during the development to differentiated neurons.

10. Use according to Claim 9, wherein said condition or disease where morphological aberration are observed during the development to differentiated neurons, is Down's syndrome.

11. Use according to Claim 5, wherein said condition or disease characterized by the abnormal repression of gene transcription is a tumoural condition or disease wherein there is an aberrant modulation of RE1/NRSE controlled genes.

12. Use according to Claim 11, wherein said tumoural condition or disease wherein there is an aberrant modulation of RE1/NRSE controlled genes is medulloblastoma.

13. Use according to Claim 5, wherein the compound of formula (I) is selected from:

(4-Methoxyphenyl) - [4- (2-methylimidazo [1, 2 -a] pyridin-3- yl) thiazol-2-yl] amine;

(4-Methoxyphenyl) - [4- (2, 7-dimethylimidazo [1, 2 -a] pyridin-3-yl) thiazol-2-yl] amine;

(4-Methoxyphenyl) - [4- (2 -methylimidazo [1 ,2-a] pyrimidin-3- yl) thiazol-2-yl] amine;

(4-Methoxyphenyl) - [4- (2, 7-dimethylimidazo [1, 2 -a] pyrimidin-3- yl) thiazol-2-yl] amine;

(4-Methoxyphenyl) - [4- (2, 7-dimethylimidazo [1,2a] [1 , 3 , 5] triazin -6-yl) tiazol-2-yl] amine ;

(4-Methoxyphenyl) - [4- (2 , 7-dimethylimidazo [1, 2-c] pyrimidin-3- yl) thiazol-2-yl] amine;

(4-Ethoxyphenyl) - [4- (2, 7 -dimethylimidazo [1 , 2 -a] pyridin-3- yl) thiazol-2-yl] amine;

N, N-Dimethyl-W - [4- (2 , 7-dimethylimidazo [1,2-a] pyridin-3- yl) thiazol-2-yl] benzene-1, 4 -diamine; and N, N-Dimethyl-W - [4- (2 -methylimidazo [1, 2 -a] pyrimidin-3 - yl) thiazol-2-yl] benzene-1, 4 -diamine and pharmaceutically acceptable salts tereof .

14. Pharmaceutical composition comprising a compound of formula

(I)

wherein:

E is hydrogen; a group -OR, wherein R is hydrogen, C(I-

G is a fused, aromatic, heterobicyclic ring system selected from:

imidazofl 2-b][ 1 ,2,4]triazin-7-yl imidazofl ,2-α] pyrazin-3-yl imidazo[ 1 ,2-b]pyridazin-3-yl

imidazo[l ,2-α] [ 1 ,3,5]triazin-6-yl imidazo[2,l -f\[ 1 ,2,4]triazin-7-yl

wherein R^a, R^b, R^c and R^d, which may be the same or different, is each independently hydrogen, C(l-6)alkyl, -F, -Cl, -Br, -

I, -OR, -NO₂,

-NR¹R², CF₃, -OCF₃, -CN, wherein R¹, R² are as previously defined;

R^e is hydrogen, C(l-6)alkyl; or of a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, excipient.