WO2013076646A1

WO2013076646A1 - A new diaza-benzofluoranthene derivative as drug

Info

Publication number: WO2013076646A1
Application number: PCT/IB2012/056561
Authority: WO
Inventors: János ÉLES; István BORZA; Károly TIHANYI; Csilla Mária HORVÁTH; Ottília BALÁZS; Mónika VASTAG; Judit Laszy; István Gyertyán; Pál KOCSIS
Original assignee: Richter Gedeon Nyrt.
Priority date: 2011-11-22
Filing date: 2012-11-20
Publication date: 2013-05-30
Also published as: HUP1100641A2; HU230482B1

Abstract

The present invention relates to a new 16-tetrazolyl-eburnamenine of formula (I) or pharmaceutically acceptable salt thereof and/or hydrates and/or solvates thereof. The invention also relates to the pharmaceutical compositions containing the compound of formula (I) or hydrates or solvates thereof as active ingredient. The invention also relates to the synthesis of compounds of formula (I), and the chemical and pharmaceutical manufacture of medicaments containing these compounds, as well as the methods of treatment of mammals - including human - with these compounds. There is still further provided methods for the treatment of neurological, neurodegenerative and psychiatric diseases or conditions as well as comprising the step of administering to human, in need of such treatment and/or prophylaxis a pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) or pharmaceutically acceptable salts thereof alone or together with at least one and a pharmaceutically acceptable carrier and/or diluent.

Description

A new diaza-benzofluoranthene derivative as drug

FIELD OF THE INVENTION

The field of this invention relates to a new diaza-benzofluoranthene derivative, a novel pharmaceutically applicable compound of formula (I), 16-tetrazolyl-eburnamenine.

The field of this invention also relates to the pharmaceutically acceptable salts, hydrates and solvates of the compound of formula (I), and the hydrates and solvates of the pharmaceutically acceptable salts of formula (I).

The field of this invention also relates to pharmaceutical compositions containing compound of formula (I), to preparation processes and new intermediate compounds thereof.

The field of this invention also relates to the use of the compound of formula (I) in relieving, treating or preventing a variety of neurological, neurodegenerative and psychiatric diseases such as Alzheimer's disease, Parkinson's disease, Attention deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age Related Memory Dysfunction, Down Syndrome, Epilepsy, Stroke, Autism, Cerebral Ischemia, Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt-Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease, Substance Induced Cognitive Impairment, Narcolepsy, and Neuropathy of various origin, including, but not limited to Diabetic Neuropathy, as well as for the treatment of Pain (in particular Neuropathic Pain and Inflammatory Pain) and painful conditions. BACKGROUND OF THE INVENTION

The eburnamine-vincamine alkaloids occur in the Apocynaceae plant family. Many eburnamine structures are pharmacologically active and exert diverse effects in the living body, the range expanding from antitumor activity through circulatory effects to cerebroprotection and on.

Vincamine Vinpocetine

Vincamine was first isolated from the leaves of Vinca minor in 1950 (Trudy nauchno- issledovatelnogo instituta lekatstvennych rajtenij. Moscow 1950;10:29-33). Studies {Compt Rend Soc Biol 1954;148: 1082-1086; Ann Pharm Fr 1955;13:328-333) demonstrated the beneficial effect of vincamine on circulation by decreasing arterial blood pressure, cardiac output, and heart rate. Subjective complaints of patients (dizziness, headache, vertigo) improved after vincamine administration and this was explained by supposing that vincamine dilated the cerebral vessels (Ther Hung 1965;13:3-6). Fischhof et al. (Neuropsychobiology 1996;34:29-35) reported on their study on the therapeutic effect of vincamine in the treatment of primary degenerative and vascular dementia.

Vincamine is readily absorbed after oral administration in man (t_max appr. 90 min) and its elimination half-life is approximately 2 hr. Vincamine undergoes largely to metabolism, only 6-7% of the parent compound is eliminated unchanged with urine. The main route of metabolism of vincamine is ester cleavage (Eur J Drug Metab Pharmacokin 1985;10:89- 103).

The most extensively studied compound with eburnamine structure is vinpocetine (ethylapovincaminate), a derivative of the Vinca minor alkaloid vincamine. Vinpocetine has been used now for decades for prevention and treatment of cerebrovascular diseases predisposing to development of dementia. Animal experiments have demonstrated a beneficial effect of vinpocetine on memory and learning deficits induced by scopolamine and hypoxia (Pharmacology, Biochemistry and Behaviour 1986;24: 1123-1128; Pharmacology, Biochemistry and Behaviour 1987;26: 183-186.). Vinpocetine has also been claimed to enhance memory function in young healthy volunteers (Drug Development and Research 1988;14:191-193)

A series of publications reveals that the effects of vinpocetine are primarily connected to the inhibition of voltage dependent Na⁺ and Ca²⁺ channels, the interaction with the glutamate receptors and the inhibition of PDE1 leading to the increase of cAMP and especially cGMP (Eur J Pharmacol 1996;314:69-73, Brain Res Bull 2000;53:245-254, Med Res Rev 2005;53:737-757).

Vinpocetine is also known of its hemodynamic effect, especially increasing cerebral blood flow in brain. Probably an improved microvascular circulation could be a favourable effect in diabetic peripheral neuropathy (DPN).

DPN is the most common complication associated with diabetes and may affect the nervous system throughout the human body. Vinpocetine can selectively improve the blood flow in ischemic peripheral nerves through multiple actions, thus ameliorating the clinical symptoms of DPN fundamentally (Chinese Journal of New Drugs, 2009;18: 1415-1418).

Vinpocetine is readily absorbed after oral administration in man, and subject of first pass metabolism. The main route of metabolism in man - similarly to vincamine - is the ester hydrolysis (Eur J Clin Pharmacol 1987;33:185-189). These results revealed that improving the pharmacokinetic profile beside keeping the pharmacodynamic profile of the above mentioned eburnamine derivatives would be advantageous, and such compounds would be needed in the art.

Therefore we prepared differently substituted eburnamenine derivatives on the C16 atom of the skeleton (phylogenetic ring numbering refers to Experientia, 1965;21:508). The prepared compounds were investigated in terms of physicochemical, ADME (Absorption Distribution Metabolism Excretion) and pharmacodynamic profile. During these trials we noticed surprisingly that the compound formed with the exchange of the metabolically liable ester group to a tetrazolyl moiety on the eburnamenine skeleton, the compound of formula (I), 16- tetrazolyl-eburnamine has some superior biological effects.

In contrast to vinpocetine and vincamine, 16-tetrazolyl-eburnamenine contains an acidic moiety (tetrazolyl ring) beside the basic nitrogen of the eburnamenine skeleton. The 16- tetrazolyl-eburnamenine was effective in a mouse cognitive impairment model and caused an increased hemodynamic response in the prefrontal cortex and the ventral hypothalamic area of the brain. 16-tetrazolyl-eburnamenine had a superior effect compared with vinpocetine in diabetic neuropathic pain model in mice.

16-Tetrazolyl-eburnamenine has high metabolic stability. This feature could lead to a stable and optimal human oral bioavailability as a therapeutic advantage.

SUMMARY OF THE INVENTION

In one aspect the present invention relates to a new 16-tetrazolyl-eburnamenine of formula (I)

(I) or pharmaceutically acceptable salt thereof and/or hydrates and/or solvates thereof.

In another aspect the invention also relates to the pharmaceutical compositions containing the compound of formula (I) or hydrates or solvates thereof as active ingredient.

In another aspect of the present invention are the synthesis of compounds of formula (I), and the chemical and pharmaceutical manufacture of medicaments containing these compounds, as well as the methods of treatment with these compounds, which means administering to a mammal to be treated - including human - effective amount/amounts of compounds of formula (I) of the present invention as such or as medicament. In another aspect the present invention also relates to the pharmaceutical compositions comprising a therapeutically effective amount of compound of formula (I) or pharmaceutically acceptable salts thereof as active ingredient. Further, there is provided a pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) or salt thereof and one or more pharmaceutically acceptable carrier and/or diluent.

In another aspect the present invention also relates to the process for manufacturing of the pharmaceutical compositions by mixing a therapeutically effective amount of a compound of formula (I) as active ingredient and a pharmaceutically acceptable carrier and/or diluent.

In another aspect there is still further provided a method for the treatment of neurological, neurodegenerative and psychiatric disease or condition as well as comprising the step of administering to human, in need of such treatment and/or prophylaxis a pharmaceutical composition comprising a therapeutically effective amount of compound of formula (I) or pharmaceutically acceptable salts thereof alone or together with at least one and a pharmaceutically acceptable carrier and/or diluent. Particularly, the said treatment and/or prophylaxis methods are used for the treatment of neurological, neurodegenerative and psychiatric disease or condition as Alzheimer's disease, Parkinson's disease, Attention deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age Related Memory Dysfunction, Down Syndrome, Epilepsy, Stroke, Autism, Cerebral Ischemia, Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt-Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease, Substance Induced Cognitive Impairment, Narcolepsy, and Neuropathy of various origin, including, but not limited to Diabetic Neuropathy, as well as for the treatment of Pain (in particular Neuropathic Pain and Inflammatory Pain) and painful conditions.

Furthermore, in another embodiment the present invention provides an industrially applicable process for the preparation of compound of formula (I). DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a new 16-tetrazolyl-eburnamenine of formula (I)

It will be understood by those skilled in the art that the compound of the present invention may also be utilized in the form of a pharmaceutically acceptable salt thereof.

Both organic and inorganic acids can be used for the formation of pharmaceutically acceptable acid addition salts of formula (I).

Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compound of this invention. Salts of the compounds of the present invention may comprise acid addition salts. In general, the salts are formed from pharmaceutically acceptable inorganic and organic acids. More specific examples of suitable acid salts include maleic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, perchloric, fumic, acetic, propionic, succinic, glycolic, formic, lactic, aleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methansulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic, hydroxynaphthoic, hydroiodic, malic, teroic, tannic, and the like.

Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to nontoxic salts of the compound of this invention. Salts of the compound of the present invention may comprise base addition salts, as well, because of the acidic character of the tetrazolyl group. Salts derived from appropriate bases include alkali metal (e.g. sodium, potassium, lithium), alkaline earth metal (e.g. magnesium) salts. Physiologically acceptable salts of a compound with a tetrazolyl group include the anion of said compound in

combination with a suitable cation such as Na⁺, K⁺, Li⁺ and Mg²⁺. Preferred salts include sodium, calcium, potassium, lithium, magnesium.

Other representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, valerate and choline salts.

Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of the compound of this invention and these should be considered to form a further aspect of the invention. These salts, such as oxalic or trifluoroacetate, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compound of the invention and their pharmaceutically acceptable salts.

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The novel compound of formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being affected. Also in the description of the synthetic methods described below, it is understood that all proposed reaction conditions, including solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be conditions standard for that reaction, which should be readily recognized by one skilled in art. One skilled in art of organic synthesis understands that the functionality present on various portions of the edict molecule must be compatible with formula (I) falling into a given class may be compatible with some of the reaction conditions required in some of the methods described.

16-Tetrazolyl-eburnamenine of formula (I) of the invention can be prepared according to the following scheme shown below.

According to the invention the compound of formula (I) may be prepared by the reaction sequence presented on Scheme 1. Briefly, amide formation from the corresponding acid (J. Med. Chem. 51, 2008, 479-486; Chinese Journal of Natural Medicines 9, 2011; 51-57), can be followed by a dehidratation with POCI₃ yielding the corresponding nitrile. Reactions of the nitrile with sodium azide can provide the desired tetrazole formula (I).

Scheme 1.

The invention further provides a pharmaceutical composition comprising a compound of formula (I) or pharmaceutically acceptable salt thereof and one or more carriers and/or diluents in the pharmaceutical arts (also referred to as excipients). The excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof (i.e., the patient).

In accordance with another aspect of the invention there is provided a process for the preparation of a pharmaceutical composition comprising mixing (or admixing) the compound of formula (I) or salt thereof with at least one excipient. 16-tetrazolyl-eburnamenine, its salts and hydrate and solvate modifications can also be processed as a cyclodextrin complex or a solid dispersion form.

Pharmaceutical compositions may be in unit dose form containing a predetermined amount of active ingredient per unit dose. Such a unit may contain a therapeutically effective dose of the compound of formula (I) or salt thereof or a fraction of a therapeutically effective dose such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical compositions may be prepared by any of the methods well-known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by any appropriate route, for example, by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such compositions may be prepared by any method known in the art of pharmacy, for example, by bringing into association the active ingredient with the excipient(s).

When adapted for oral administration, pharmaceutical compositions may be in discrete units such as tablets or capsules; powders or granules; solutions or suspensions in aqueous or nonaqueous liquids; edible foams or whips; oil-in-water liquid emulsions or water-in-oil liquid emulsions. The compound or salt thereof of the invention or the pharmaceutical composition of the invention may also be incorporated into a candy, a wafer, and/or tongue tape formulation for administration as a "quick-dissolve" medicine.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders or granules are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agents can also be present. Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin or non-gelatinous sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicine when the capsule is ingested. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.

Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, and aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt, and/or an absorption agent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compound or salt of the present invention can also be combined with a free-flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear opaque protective coating consisting of a sealing coat of shellac, a coating of sugar, or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different dosages. Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient. Syrups can be prepared by dissolving the compound or salt thereof of the invention in a suitably flavoured aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound or salt of the invention in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil, natural sweeteners, saccharin, or other artificial sweeteners, and the like, can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as, for example, by coating or embedding particulate material in polymers, wax, or the like.

In the present invention, tablets and capsules are preferred for delivery of the pharmaceutical composition. However, 16-tetrazolyl-eburnamine and salts, hydrates, solvates thereof provides excellent possibility for transdermal use, as well, e.g. in forms of gels, creams, ointments, pastes or patches.

As used herein, the term "treatment" includes prophylaxis and refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject. Prophylaxis (or prevention or delay of disease onset) is typically accomplished by administering a drug in the same or similar manner as one would do to a patient with the developed disease or condition.

The present invention provides a method of treatment of a human, suffering from a variety of neurological, neurodegenerative and psychiatric diseases such as Alzheimer's disease, Parkinson's disease, Attention deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age Related Memory Dysfunction, Down Syndrome, Epilepsy, Stroke, Autism, Cerebral Ischemia, Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt- Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease, Substance Induced Cognitive Impairment, Narcolepsy, and Neuropathy of various origin, including, but not limited to Diabetic Neuropathy, as well as for the treatment of Pain (in particular Neuropathic Pain and Inflammatory Pain) and painful conditions. Such treatment comprises the step of administering a therapeutically effective amount of the compound of formula (I) or salt thereof to a human, in need of such treatment. Treatment can also comprise the step of administering a therapeutically effective amount of a pharmaceutical composition containing the compound of formula (I) or salt thereof to a human in need of such treatment. As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.

The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of the compound of formula (I), as well as salts thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.

The precise therapeutically effective amount of the compound or salt thereof of the invention will depend on a number of factors, including, but not limited to, the age and weight of the subject (patient) being treated, the precise disorder requiring treatment and its severity, the nature of the pharmaceutical formulation/composition, and route of administration, and will ultimately be at the discretion of the attending physician or veterinarian. Typically, the compound of formula (I) or salt thereof will be given for the treatment in the range of about 0.1 to 100 mg/kg body weight of recipient (patient, mammal) per day and more usually in the range of 0.1 to 10 mg/kg body weight per day. Acceptable daily dosages may be from about 1 to about 1000 mg/day, and preferably from about 1 to about 100 mg/day. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub- doses per day such that the total daily dose is the same. An effective amount of a salt thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se. Similar dosages should be appropriate for treatment, including prophylaxis, of the other conditions referred herein for treatment. In general, determination of appropriate dosing can be readily arrived at by one skilled in medicine or the pharmacy art. ASSAY METHODS:

Mouse cognitive impairment model

Method: The two-trial place recognition test is based on the spontaneous inclination of rodents to explore a novel environment in a Y-maze {Brain Res 1992;588: 132-139).

Male NMRI mice (Toxicoop, Hungary) weighing 22-25 g were used (n=15/groups).

The learning task was carried out in a transparent plastic Y-maze (40 cm length, 12 cm width and 30 cm height). Numerous visual cues were placed around the arms and were kept constant during the experiment. The test consisted of two trials (Tl and T2) separated by intertrial intervals of 30 min. Mice were placed in the starting arm of the maze at the beginning of each trial. In Tl one of the symmetric arms of the maze were closed (it will be novel in T2) and the animals were allowed to explore the maze for 5 min (acquisition phase). In T2 mice had free access to all three arms for 2 min (retrieval phase). The time spent in each arm (novel and familiar) was measured separately by stopwatches. Following 30 min inter-trial delay mice are able to discriminate between novel and familiar arms of a Y-maze, while post-acquisition injection of scopolamine impairs the place recognition memory and the improving effect of a compound can be investigated. Immediately after Tl, 1 mg/kg dose of scopolamine was injected intraperitoneally. The protective effect of 16-tetrazolyl-eburnamine formula (I) was tested at oral doses of 10, 20 and 40 mg/kg given 60 min prior to the acquisition trial in a volume of 10 ml/kg.

Differences between exploration times spent in familiar and novel arms for each group were evaluated by paired t test. A discrimination index (DI) was calculated for each animal, expressed by the ratio DI=TN-TF /TN+TF (TN meaning the time spent in the novel and TF in the familiar arm). DI values were calculated for each group. One-way analysis of variance (ANOVA) followed by post hoc Duncan test was used for statistical comparison.

Diabetic neuropathy model

Thermal hyperalgesia is a symptom of diabetic neuropathy (DN) in humans. Although only a subpopulation in DN patients shows this symptom, it is present more frequently in DN, than in other types of neuropathy {Diabetes Care 2000;23:510-517). To model thermal hyperalgesia in animals we used diabetic mice and measured heat sensitivity by determining the temperature threshold that evokes withdrawal of the tail in an increasing temperature water bath (Eur J Pharmacol. 2007;564 (l-3):80-87). We tested if 16-tetrazolyl- eburnamenine formula (I) could reverse this thermal hyperalgesia.

Method: To induce diabetes mellitus, 200 mg/kg dose of streptozotocin was intraperitoneally injected into NMRI mice (Toxicoop, Hungary) weighing 25-3 lg. Blood glucose (BG) levels were checked 14-16 days after the STZ-challenge via AccuChek Active Glucose test stripes (Hoffmann-La Roche Ltd., Switzerland). Blood was taken from the retroorbital plexus, under halothane anaesthesia. Animals with BG level over 18 mM/liter were considered as diabetic and only these were included the experiments. Mice with BG<18 mM/liter were excluded, and also those which had mechanical tail-hurt or body weights below 20 g.

16-tetrazolyl-eburnamenine formula (I) or the vehicle (2% ascorbic acid in saline) was administered orally, by gavage with treatment volume of 10 ml/kg.

For measurement of thermal threshold (ThT) diabetic mice were held in the palm of the hand with cotton-knitted gloves. About two thirds of the tail was immersed into the increasing temperature water bath generated by a SensoStress EXP-PL-1 device (Experimetria Ltd., Hungary). The initial temperature was set as 40 °C and was increased by 24 °C/min. At the point when the tail was withdrawn, the measurement was interrupted by a foot-switch, and the withdrawal temperature was then recorded. The cut-off temperature was considered as 50 °C. fMRI study in rat

Preclinical phMRI studies have increasing importance in drug research. The best way to directly observe the effect of compounds in the brain seems to be an fMRI study. One of the fMRI methods, the BOLD (blood oxygen level dependent functional fMRI technique), uses the endogen contrast agent, deoxi-hemoglobin (Proc. Natl. Acad. Sci. USA 1990;87:9868- 9872). Several papers study the effect of various pharmacological agents on rat brain using BOLD fMRI (Nuroimage 2011;58:885-894; Psychopharmacology 2011;217:549-557). Further advantage of the method, that it gives possibility for the translation between human and animal data, the results of the animal studies with new drug candidates can compare to the results of human studies with launched drugs. Therefore our cognitive improving compounds were tested in small animal MRI system. 16- tetrazolyl-eburnamine formula (I) was also tested in a provocation model. Its effect was tested on BOLD decrease caused by frequently used cognitive disturbing agent scopolamine.

Method: Male Wistar rats weighing 240-260 g anaesthetized with isoflurane were used in the experiments. Radio frequency (RF) pulses were transmitted using a volume coil. A receive- only phased array rat brain coil was placed on the dorsal surface of the rat's head. MR images were acquired using:

Anatomical images (gems, TR=200ms, TE=3,83ms (min), flip angle=45°, averages=3, dummy scans=4, data matrix= 192x192, FOV: same like functional Fov acquired both before and after the functional EPIP sequences. The poor quality EPIP pictures are fitted to these anatomical scans to localize the activity changes.

BOLD contrast images were received with EPIP (gradient echo, TR=3000ms, TE=10,0ms, flip angle=90°, shots:3, triple reference scan, averages=l, dummy scans=4, data matrix=64x64, FOV: orientated Axial90, 35x35mm, 6 interleaved slices, thickness 1mm, gap 0,2mm).

After 10 minutes control period drugs were administered i.p. Only one experiment with a single drug administration was performed with each animal.

Provocation protocol (differences): Anatomical images (gems, TR=200ms, TE=3,83ms (min), flip angle=45°, averages=3, dummy scans=4, data matrix= 192x192, FOV: same like functional Fov acquired both before and after the functional EPIP sequences. The poor quality EPIP pictures are fitted to these anatomical scans to localize the activity changes.

Bold contrast images were received with EPIP (gradient echo, TR=3000ms, TE=10,0ms, flip angle=90°, shots:3, triple reference scan, averages=l, dummy scans=4, data matrix=64x64, FOV: orientated coronal, 35x35mm, 9 interleaved slices, thickness 1mm, gap 0,2mm).

The pretreatment time with 16-tetrazolyl-eburnamenine of formula (I) was 1 hour. Only one experiment with a double drug administration (pretreatment i.p. and provocation drug i.v.) was performed with each animal. Following 1000 sec control scanning period drugs were administered i.v. through a remote-operated pre-inserted cannula. Passive avoidance learning in scopolamine-treated rats

The aim of the experiments was to investigate the effects of acute 16-tetrazolyl-eburnamenine of formula (I) treatment on attention and memory function of adult rats in passive avoidance learning. In the applied rat model the memory function was impaired by scopolamine pre- treatment.

Method: Passive avoidance test was performed in an apparatus consisted of two compartments: one light and one dark (22 cm long, 20 cm wide and 25 cm high each) connected by a guillotine door. On the first training day rats were put into in the dark compartment. Following 3 min habituation animals were put into the light compartment and allowed to enter the dark one where they stayed another 3 min (acquisition trial 1). On the second day animals were placed in the light compartment and the guillotine door was opened (acquisition trial 2). After being allowed to stay in the dark compartment for 3 min rats were replaced to the light compartment again. Latency to entering the dark was registered (acquisition trial 3). During the 3rd trial immediately after entering the dark compartment the guillotine door was closed, and simultaneously an electrical shock (1.0 mA for 3 sec) was delivered to the animal via the metal grid floor, followed by 3 min stay in the dark. The retention trial was performed 24 h and repeated also 4 days and 10 days after the electric shock. At that time animals were put into the light compartment and the guillotine door was opened. The time taken to enter the dark compartment was recorded as step through latency (STL). A maximum latency of 300 sec was accepted.

Animals were treated on the second day, 40 minutes before the learning trial (electric shock) with scopolamine and 30 minutes before the trial with 16-tetrazolyl-eburnamenine of formula (I)-

Metabolism study

Enzyme catalyzed biotransformation (metabolism) of drugs can severely affect plasma levels and so determine drug amount available for pharmacological effect. The major place of drug metabolism in humans is the liver and in case of most drugs it is mainly mediated by cytochrome P450 enzymes. The most basic tool for determination of metabolic fate is incubation of drugs with a fraction of liver called microsomes which is rich in xenobiotic metabolizing CYPs, flavine monooxygenases (FMOs) and in several non-specific hydrolases. In microsomal systems, at low drug substrate concentrations, metabolism of drugs can be characterized by the intrinsic clearance of parent drug which reflects the rate of drug removal by biotransformation.

Method: The 16-tetrazolyl-eburnamenine formula (I) at 1 μΜ nominal concentration was incubated up to 20 minutes with human (0.5 mg/ml; Lot.No.: 1010425; pool of 50; mixed gender; XenoTech, USA), dog (0.5 mg/ml; Lot.No.: 0810143; beagle, male; pool of 11; XenoTech, USA), rat (0.5 mg/ml; Lot.No.: 1010126 pool of 200; wistar, male; XenoTech, USA) or mouse (0.5 mg/ml; Lot.No.: 1110071; pool of 1002; CD-I, male; XenoTech, USA) liver microsomes in the presence of NADPH or without it. The amount of unchanged test compound was measured by HPLC. Intrinsic clearance (Cli_nt) was calculated from the rate of compound consumption according to the following equations: Cli_nt = V_max / K_M or if [S] « K_M CL;_nt = V / [S] where V_max = maximal rate of enzyme reaction; K_M = affinity constant of a substrate; [S] = substrate concentration; V = actual rate of enzyme reaction under first order conditions.

The present invention now will be described by way of illustration, but not limitation, according to its preferred embodiments, with particular reference to the attached figures, in which:

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the time course of the anti-hyperalgesic effect of 16-tetrazolyl-eburnamenine. Shown are mean and SEM of thermal threshold data of diabetic mice treated with vehicle, 5 mg/kg and 10 mg/kg p.o. doses of 16-tetrazolyl-eburnamenine formula (I).

Figure 2 shows the dose dependent anti-hyperalgesic effect of 16-tetrazolyl-eburnamenine formula (I) compared to vinpocetine in model of diabetic neuropathy in mice;

Figure 3 shows the BOLD effect of 16-tetrazolyl-eburnamenine formula (I) in rat brain.

Figure 4 shows the effect of 16-tetrazolyl-eburnamenine formula (I) pretreatment on the scopolamine (1 mg/kg, i.v.) evoked BOLD response decrease in prefrontal cortex. EXAMPLES

The invention is further defined in the following Examples. It should be understood that the Examples are given by way of illustration only. From the above discussion and the Examples, one skilled in the art can ascertain the essential characteristics of the invention, and without departing from the spirit and scope thereof, can make various changes and modifications to adapt the invention to various uses and conditions. As a result, the invention is not limited by the illustrative examples set forth herein below, but rather defined by the claims appended hereto.

In general, the compound of formula (I) can be prepared in accordance with the general knowledge of one skilled in the art and/or using methods set forth in the Example and/or Intermediate sections that follow. Solvents, temperatures, pressures, and other reaction conditions can readily be selected by one of ordinary skill in the art. Starting materials are commercially available and/or readily prepared by one skilled in the art.

Example 1

(3aS,l lbS)-3a-Ethyl-l,2,3,3a,10,l lb-hexahydro-1 lH-5a,l la-diaza-benzorcdlfluoranthene-5- carboxylic acid

A mixture of 20 g (57.0 mmol) of (3aS,l lbS)-3a-ethyl-l,2,3,3a,10,l lb-hexahydro-11H- 5a, 1 la-diaza-benzo[cd]fluoranthene-5-carboxylic acid ethyl ester and 3.0 g (75.0 mmol) of sodium hydroxide in 120 mL of ethanol was re fluxed for 5 h. The reaction mixture was cooled, concentrated in vacuo and the residue was dissolved in 200 mL of water. The solution was acidified with 12 mL of acetic acide. The precipitated product was filtered off, washed with water and dried to yield 17.0 g (92.4 %) of the title compound. Mp: 257-259 °C. MS (EI) 323.1 (MH⁺).

Example 2

(3aS,l lbS)-3a-Ethyl-l,2,3,3a,10,l lb-hexahydro-1 lH-5a,l la-diaza-benzo[cdlfluoranthene-5- carboxylic acid amide A mixture of 12.0 g (37.2 mmol) of (3aS,l lbS)-3a-ethyl-l,2,3,3a,10,l lb-hexahydro-11H- 5a,l la-diaza-benzo[cd]fluoranthene-5-carboxylic acid, 13.1 mL (179.5 mmol) of thionyl chloride, 0.5 mL of N,N-dimethylformamide in 170 mL of chloroform was refluxed for 4 h. The reaction mixture was cooled to 20 °C, poured into a mixture of 134 mL of 25 % ammonia solution and 350 g of ice, and then stirred for 2h. The organic layer was separated and the water phase was extracted with 200 mL of chloroform. The combined organic layers were washed with water, dried over anhydrous sodium sulfate and concentrated to yield 11.9 g (99%) of the title compound. The crude product was used in the next step. MS (EI) 322.1 (MH⁺).

Example 3

(3aS,l lbS)-3a-Ethyl-l,2,3,3a,10,l lb-hexahydro-1 lH-5a,l la-diaza-benzorcd1fluoranthene-5- carbonitrile

A mixture of 11.9 g (37.0 mmol) of (3aS,l lbS)-3a-ethyl-l,2,3,3a,10,l lb-hexahydro-11H- 5a, 1 la-diaza-benzo[cd]fluoranthene-5-carboxylic acid amide, 25.0 mL (268 mmol) of phosphorus oxychloride and 200 mL of chloroform was refluxed for 8h. The reaction mixture was cooled to 20 °C, poured into 1000 g of ice and neutralised with 40 % sodium hydroxide solution. The organic layer was separated and the water phase was extracted with 500 mL of chloroform. The combined organic layers were washed with water and saturated sodium carbonate solution, dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from a 1 : 1 mixture of 2-propanol and water to yield 9.9 g (88.2 %) of the title compound. Mp.: 129-130 °C. MS (EI) 304.2 (MH⁺).

Example 4

(3aS ,1 lbS -3a-Ethyl-5-(tetrazol-5-ylVL2,3.3a,10 ,1 lb-hexahydro-1 lH-5a,l la-diaza- benzo[cdlfluoranthene

16-tetrazolyl-eburnamenine A mixture of 9.0 g (29.6 mmol) of (3aS,l lbS)-3a-ethyl-l,2,3,3a,10,l lb-hexahydro-11H- 5a,l la-diaza-benzo[cd]fluoranthene-5-carbonitrile, 9.64 g (148 mmol) of sodium azide and 7.95 g (148 mmol) of ammonium chloride in 150 mL of N,N-dimethylformamide was stirred at 110 °C for 3.5 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was submitted to flash column chromatography using Kieselgel 60 (0.015- 0.040 mm) as adsorbent (Merck) and dioxane : methanol : 25 % ammonia solution = 5 : 1 : 1 as eluent to yield after acidification with acetic acid 9.6 lg (93.40 %) of the title compound. MS (EI) 347.3 (MH⁺).

Example 5

(3 aS .11 bS -3 a-Ethyl-5 -(tetrazol-5 -vO- 1.2.3.3 a.10.11 b-hexahydro- 1 lH-5a.l la-diaza- benzorcdlfluoranthene hydrochloride

16-tetrazolyl-eburnamenine hydrochloride

2.0 g (5.8 mmol) of 16-tetrazolyl-eburnamenine (IUPAC name: (3aS,l lbS)-3a-Ethyl-5- (tetrazol-5-yl)-l,2,3,3a,10,l lb-hexahydro-1 lH-5a,l la-diaza-benzo[cd]fluoranthene) was suspended in 20 mL ethylacetate. 10 mL of 20 % HC1 in ethylacetate was added dropwise. The resulting mixture was stirred overnight. The participated product was filtered and washed with ethylacetate and then dried to yield 2.18 g (98.0 %). MS (EI) 347.3 (MH⁺)

Example 6

(3aS.l lbS -3a-Ethyl-5-(tetrazol-5-ylV1.2.3.3a.l0.1 lb-hexahydro-1 lH-5a.l la-diaza- benzorcdlfluoranthene choline salt

16-tetrazolyl-eburnamenine choline salt

To a suspension of 0.5 g (1.44 mmol) of 16-tetrazolyl-eburnamenine (IUPAC name: (3aS,l lbS)-3a-Ethyl-5-(tetrazol-5-yl)-l,2,3,3a,10,l lb-hexahydro-1 lH-5a,l la-diaza- benzo[cd]fluoranthene) and 10 mL of ethanol 1.36 ml of 46 % cholin hydroxide solution (1.46 mmol) was added. The resulting solution was concentrated in vacuo and the residue was treated with diethyl ether. The precipitated product was filtered and dried to yield 0.6 g (92.5 %) of the title compound as an amorphous solid. MS (EI) 347.3 (MH ). Example 7

(3 aS .11 bSV3 a-Ethyl-5 -(tetrazol-5 -νΠ- 1.2.3.3 a.10.11 b-hexahydro- 1 lH-5a.l la-diaza- benzorcdlfluoranthene potassium salt

16-tetrazolyl-eburnamenine potassium salt

To a suspension of 28.2299 g (81.49 mmol) of 16-tetrazolyl-eburnamenine (IUPAC name: (3aS,l lbS)-3a-Ethyl-5-(tetrazol-5-yl)-l,2,3,3a,10,l 1 b-hexahydro- 1 lH-5a,l la-diaza- benzo[cd]fluoranthene) and 640 mL of deionised water 9.144 g (81.49 mmol) of potassium tert-butoxide was added. The resulting solution was lyophilized to yield 29.87 g (95.3 %) of the title compound as an amorphous solid. MS (EI) 347.3 (MH ).

Example 8

(3aS.l lbS -3a-Ethyl-5-(tetrazol-5-ylV1.2.3.3a.l0.11 b-hexahydro- 1 lH-5a.l la-diaza- benzorcdlfluoranthene sodium salt

16-tetrazolyl-eburnamenine sodium salt

1.0 g (2.9 mmol) of 16-tetrazolyl-eburnamenine (IUPAC name: (3aS,l lbS)-3a-Ethyl-5- (tetrazol-5-yl)-l,2,3,3a,10,l 1 b-hexahydro- 1 lH-5a,l la-diaza-benzo[cd]fluoranthene) was suspended in 10 mL ethanol. 15 mL of 2.2 M NaOEt in ethanol was added dropwise. The resulting mixture was stirred for 1 hour and then it was diluted with THF : diethylether = 1 :10 (10 mL). The participated product was filtered and washed with THF : diethylether = 1 : 10 and then dried to yield 1.02 g (96.0 %). MS (EI) 347.3 (MH⁺)

Example 9

Mouse cognitive impairment model results

In the place recognition test vehicle-treated control mice could discriminate between the novel and the familiar arm in the recognition trial after an intertrial delay of 30 min, while scopolamine caused a clear discrimination deficit (Table). 16-Tetrazolyl-eburnamenine formula (I) dose-dependently and significantly improved the impairment in the place recognition, the highest dose (40 mg/kg) produced practically a complete reversal. The discrimination index values (DI) significantly differed from DI measured in the impaired group as the next table shows.

+++ p < 0.001 compared to non-impaired control,

* p < 0. 05, ** p < 0. 01 compared to impaired control (ANOVA followed by Duncan test)

Example 10

Mouse Diabetic Neuropathy model results

16-tetrazolyl-eburnamenine formula (I) at the doses of 5 and 10 mg/kg was administered in the period of 2-4 weeks after the STZ-challenge, when expressed hyperalgesia was present. Mean and S.E.M. of tail withdrawal thresholds of animals involved in the study was 45.5 °C + 0.28 before STZ administration and 43.1+ 0.18 °C before administration of test compound. On test day thermal threshold (ThT) was measured before, and 60, 120, and 180 min after administration of 16-tetrazolyl-eburnamenine formula (I).

Anti-hyperalgesic effect was characterized by calculating percentage reversal of thermal hyperalgesia from group mean values, at the time of maximum effect (Tmax) according to the following formula:

ThT Drue, Tmax " ThT Vehicle, Tmax

REVERSAL (%) = x 100

mean ThTorug and Vehicle, Tpre-STZ " ThT Vehicle, Tmax

(ThT is the mean thermal threshold value of the group in °C) Significance of differences between groups at each time point was analyzed by 2-way ANOVA followed by Tukey HSD test, comparing the ThTs for the drug-treated groups and the parallel vehicle-treated group using Statistica 5.0 software.

It can be seen in Figure 1. that 16-tetrazolyl-eburnamenine formula (I) produced a dose dependent and, at the higher dose, statistically significant reversal of thermal hyperalgesia. Maximal effects were observed 120 min post-dose as 34, and 85% reversal of hyperalgesia for the 5 and 10 mg/kg dose, respectively. It can be concluded that these results support possible utility of 16-tetrazolyl-eburnamenine formula (I) in diabetic neuropathy.

Figure 2. shows effect of 16-tetrazolyl-eburnamenine formula (I) compared to vinpocetine. The 5 and 10 mg/kg doses of 16-tetrazolyl-eburnamenine formula (I) produced 34% and 85% reversal of hyperalgesia, while the same doses of vinpocetine produced 49% and 57% reversal, respectively. When 20 mg/kg dose of vinpocetine was administered to mice, the effect was not further increased (57%). These results clearly show efficacy of 16-tetrazolyl- eburnamenine formula (I) over vinpocetine.

Example 11

fMRI study results

Administration of 16-tetrazolyl-eburnamenine formula (I) caused clear BOLD increase in the area of cortex, thalamus and hippocampus (see Figure 3.). Increased BOLD marks increased function of the parts of the brain.

Provocation model

In the study scopolamine was used as a provocation drug. The intravenously administered scopolamine decreased the BOLD responses in the prefrontal cortex, but it had no visible effect in the hippocampus. One hour pretreatment with 16-tetrazolyl-eburnamenine formula (I) prevented inhibitory effect of scopolamine in the prefrontal cortex.

Example 12 Passive avoidance

Step through latency (STL) time of experimental animals was measured 1, 4 and 11 days after receiving electric shock during the learning trial. The effect of treatments with 16-tetrazolyl- eburnamenine formula (I) resulted in significant changes in this parameter revealed.

Electric shock significantly increased the STL as compared to that found before shock in control rats. Scopolamine pre-treatment resulted in a short latency, comparable to the latency time during the last trial, which was significantly shorter compared to controls. 16-tetrazolyl- eburnamenine formula (I) induced significant elevation of STL after scopolamine pre- treatment.

Example 13

Metabolism study results

The next table shows Intrinsic clearance (Cli_nt) of 16-tetrazolyl-eburnamenine of formula (I) in a pools of human, dog, rat and mouse liver microsomes.

The 16-tetrazolyl-eburnamenine formula (I) is a low metabolic clearance compound in human, dog and rat liver microsomes; consumption of 16-tetrazolyl-eburnamenine formula (I) was not observed without NADPH; therefore extrahepatic (non CYP/FMO mediated metabolism) is not expected either. In mouse liver microsomes high metabolic clearance was obtained.

The results indicate that the human oral bioavailability of 16-tetrazolyl-eburnamenine formula (I) may not be limited by intense metabolic hepatic extraction.

Claims

1. A compound of formula (I)

(I)

or a pharmaceutically acceptable salt thereof or a hydrate or a solvate of the compound of formula (I), or a hydrate or a solvate of a pharmaceutically acceptable salt of formula (I).

A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier and/or diluent.

A process for the manufacturing pharmaceutical composition having a therapeutically effective amount of a compound according to claim 1 as active ingredient and a pharmaceutically acceptable carrier and/or diluent.

A method for treatment and/or prophylaxis of a neurological and/or neurodegenerative and/or psychiatric disease or condition comprising the step of administering a human in need of such treatment and/or prophylaxis a therapeutically-effective amount of a compound in accordance with claim 1.

A method for treatment and/or prophylaxis of a neurological and/or neurodegenerative and/or psychiatric disease or condition comprising the step of administering a human in need of such treatment and/or prophylaxis a pharmaceutical composition according to claim 2 containing a therapeutically-effective amount of a compound in accordance with claim 1.

A method for treatment according to claim 5, wherein said disease or condition is selected from Alzheimer's disease, Parkinson's disease, Attention deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age Related Memory Dysfunction, Down Syndrome, Epilepsy, Stroke, Autism, Cerebral Ischemia, Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt- Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease, Substance Induced Cognitive Impairment, Narcolepsy, and Neuropathy of various origin, including, but not limited to Diabetic Neuropathy, as well as for the treatment of Pain (in particular Neuropathic Pain and Inflammatory Pain) and painful conditions.

7. A method according to claim 6 wherein said disease or condition is Alzheimer's disease.

8. A method according to claim 6 wherein said disease or condition is Mild Cognitive Impairment.

9. A method according to claim 6 wherein said disease or condition is Attention deficit and Hyperactivity Disorder.

10. A method according to claim 6 wherein said disease or condition is Age Related Memory Dysfunction.

11. A method according to claim 6 wherein said disease or condition is Substance Induced Cognitive Impairment.

12. A method according to claim 6 wherein said disease or condition is Epilepsy.

13. A method according to claim 6 wherein said disease or condition is selected from Stroke, Cerebral Ischemia.

14. A method according to claim 6 wherein said disease or condition is selected from Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt- Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease.

15. A method according to claim 6 wherein said disease or condition is Pain.

16. The use of a compound according to claim 1 for the treatment and/or prophylaxis of a neurological and/or neurodegenerative and/or psychiatric disease or condition.

17. The use of a pharmaceutical composition according to claim 2 for the treatment and/or prophylaxis of a neurological and/or neurodegenerative and/or psychiatric disease or condition.

18. The use according to claim 16 and 17, wherein said disease or condition is selected from Alzheimer's disease, Parkinson's disease, Attention deficit and Hyperactivity Disorder, Schizophrenia, Foetal Alcohol Syndrome, Mild Cognitive Impairment, Age Related Memory Dysfunction, Down Syndrome, Epilepsy, Stroke, Autism, Cerebral Ischemia, Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt- Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease, Substance Induced Cognitive Impairment, Narcolepsy, and Neuropathy of various origin, including, but not limited to Diabetic Neuropathy, as well as for the treatment of Pain (in particular Neuropathic Pain and Inflammatory Pain) and painful conditions.

19. The use according to claim 18 wherein said disease or condition is Alzheimer's disease.

20. The use according to claim 18 wherein said disease or condition is Mild Cognitive Impairment.

21. The use according to claim 18 wherein said disease or condition is Attention deficit and Hyperactivity Disorder.

22. The use according to claim 18 wherein said disease or condition is Age Related Memory Dysfunction.

23. The use according to claim 18 wherein said disease or condition is Substance Induced Cognitive Impairment.

24. The use according to claim 18 wherein said disease or condition is Epilepsy.

25. The use according to claim 18 wherein said disease or condition is selected from Stroke, Cerebral Ischemia.

26. The use according to claim 18 wherein said disease or condition is selected from Cognitive Impairment due to HIV Disease, Cognitive Impairment due to Head Trauma, Cognitive Impairment due to Pick's Disease, Cognitive Impairment due to Creutzfeldt- Jakob Disease, Cognitive Impairment due to Parkinson's Disease, Cognitive Impairment due to Huntington Disease.

27. The use according to claim 18 wherein said disease or condition is Pain.

28. A process for the preparation of compound of formula (I) according to claim 1 comprising a) reacting the compound of formula (IV)

(IV) with thionyl chloride and ammonium hydroxide b) reacting the obtained compound of formula (III)

c) reacting the obtained compound of formula (II)

with M-N3 in the presence of additive or catalyst,

wherein the meaning of M is H, Na, Si(R)3, Sn(R)₃, A1(R)₂ and

wherein R represents Ci_₆ straight or branched alkyl group,

to yield the compound of formula (I).

29. The process according to claim 28, wherein said additive or catalyst is selected from the group consisting of the compounds of ammonium chloride, triethylammonium chloride, acetic acid, aluminium trichloride, ethoxy boron trifluoride of empirical formula BF₃*OEt, zinc bromide, cadmium chloride, trimethylaluminium, zinc sulphide- nanosphere, iron(III) chloride-silicium dioxide the compound of formula FeCl₃-Si0₂, antimony trioxide, barium wolframate, nano-zinc oxide, zinc/aluminium hydrotalcite, zinc phosphate hydrate of empirical formula Znio(P0₄)₆0H, iron(II) acetate, tetra-n- butylammonium fluoride, and dimethyl tin oxide.

30. A process for the preparation of compound of formula (I) in accordance with claim 28 comprising reacting the compound of formula (II)

(I I) with M-N₃ in the presence of additive or catalyst,

wherein the meaning of M is H, Na, Si(R)₃, Sn(R)₃, A1(R)₂

wherein R represents Ci_₄ straight or branched alkyl,

to yield the compound of formula (I).

31. The process according to claim 30, wherein said additive or catalyst is selected from the group consisting of the compounds of ammonium chloride, triethylammonium chloride, acetic acid, aluminium trichloride, ethoxy boron trifluoride of empirical formula BF₃*OEt.