MXPA05009903A - Pyrroloimidazole derivatives, their preparation, pharmaceutical composition containing them, and their use as nootropic agents - Google Patents

Abstract

Described herein are new bicyclic arylimidazolones having nootropic action (i.e., protecting and stimulating cerebral functions), analgesic action and anti hyperalgesic action;also described is the process for their preparation and pharmaceutical compositions comprising them, useful for the treatment of cognitive deficits, and of various types of pain.

Description

DERIVATIVES OF PIRRO OIMID AZOLE, ITS PREPARATION, PHARMACEUTICAL COMPOSITION CONTAINING THEM AND ITS UTILIZATION AS NOOTROPIC AGENTS Field of the Invention The present invention relates to new compounds of the formula (I) appearing hereafter, the process for their preparation, the pharmaceutical compositions containing it, and their use as nootropic, neuroprotective, analgesic and anti-hyperalgesic agents.

State of the Art State-of-the-art compounds that possess nootropic activity are already known in the literature. In particular, the substituted 4-position derivatives of 2-oxo-1-pyrrolidineacetamide are valid psychotropic agents that re-establish damaged cognitive functions. These compounds are described, for example, in Pharm. Res. Commun. 16, 67, 1984 by Banfi, et al. and in Drug Development Res. 2, 447, 1982 by Útil et al.

Among the most widely known molecules belonging to the aforementioned class are: 2-oxo-l-pyrrolidineacetamide (piracetam), 4-hydroxy-2-oxo-l-pyrrolidineacetamide (oxiracetam), 2- (2-oxopyrrolidin-l-yl) butyramide (levetiracetam) and N- (2,5-dimemethylphenyl) -2-oxo-l -pyrrolidineacetamide (nefiracetam).

Another chemical class possessing nootropic activity is represented by condensed imidazole derivatives, in particular 2,5-dioxohexahydro-lH-pyrrolo [1,2-a] imidazole (dimiracetam), described in EP 335483 and in WO-9309120, and in J. Med. Chem., 36, 4214, 1993 by Pinza M. et al.

Recently, it has been shown that nefiracetam could be a good therapeutic agent in the treatment of neuropathic pain. The anti-hyperalgesic action induced by nefiracetam appears to be non-opioid in nature and is probably due to the stimulation of the cholinergic nicotinic system at the spinal and super spinal level (Rashid Harunor M.J. J Pharmacol.Exp.Ther, 303.226, 2002).

Brief Description of the Invention The current applicant has now found new iV-substituted bicyclic imidazolones of the formula (I), which will appear immediately, which have shown improved psychotropic properties and more marked anti-hyperalgesic and analgesic effects in several models of neuropathic pain, compared to the agents known nootropics.

Consequently, the present compounds of the formula (I) are useful in the treatment of many disorders of the central nervous system (CNS), for example in the deterioration of learning, dysfunction of the cognitive and memory sphere, Alzheimer's disease, dementias, including senile dementia of the Alzheimer's type, post-stroke vascular dementia, epilepsy, cerebral ischemia, mood disorders, including depression, chronic, inflammatory, neuropathic and visceral pain, and emesis.

Accordingly, compounds of the general formula (I) are representative of the subject of the current invention (I) in which: A is selected from carbocyclic aromatic groups, heterocyclic aromatic groups and arylC? -alkyl; Ri is chosen from: - hydrogen; C1-alkyl aryl, optionally substituted in the alkyl moiety with one or more groups selected from hydroxy, C1- to oxy, halogen, haloC1-alkyl; heterocyclylC1-7alkyl, optionally substituted in the heterocyclyl moiety with one or more groups selected from C1-alkyl and hydroxy; C1-7alkyl, optionally interrupted by an oxygen or azxtrher atom or optionally substituted at any position by one or more groups selected from hydroxy, thio, amino, carboxyl, amino-carboxyl, guanidinyl.

R2 is chosen from: hydrogen, and phenyl; or Ri and R2 are taken together, of a saturated carbocyclic ring containing between 3 and 8 carbon atoms; R3 is chosen from hydrogen, C1-alkyl, arylC1-alkyl, CONH2 and COOR5 wherein R5 is chosen from hydrogen and C ^ alkyl; R4 is selected from hydrogen, C1-alkyl, aryl, arylC1-4alkyl and heterocyclyl; n is 2, 3 or 4; in the form of a racemic mixture or in the form of enantiomers, and pharmaceutically acceptable salts or solvates thereof.

The process for the preparation of the compounds of the formula (I) appearing above, the pharmaceutical compounds containing it and their use in the preparation of drugs with nootropic and neuroprotective action, with analgesic and / or anti-hyperalgesic action, and anti-inflammatory action. -emética, constitute another matter of the invention.

The features and advantages of the present compounds of the formula (1) will be illustrated in detail in the following description.

Description of the Figures Figures la, lb are non-limiting examples of amino acids of the formula (IV), useful in the synthesis of the compounds of the formula (I). The portion inside the circle indicates the R substituent Detailed description of the invention Within the scope of the present invention, the term "carbocyclic aromatic group" means simple or fused aromatic rings with 6 to 12 ring elements, optionally substituted.

The terms "heterocyclic aromatic group" and "heterocyclyl" mean single or fused non-saturated rings, each ring with between 5 and 12 elements consisting of up to four hetero atoms, chosen from oxygen, sulfur and nitrogen, optionally substituted.

When not specified, the term "aryl" means single or fused unsaturated rings, each ring having between 5 and 8 elements, and preferably 5 or 6 elements, optionally substituted; by the term "aryl C 1 -alkyl" is meant a group having an aryl group, as defined above, and a C 1 - alkyl moiety that connects the aryl group to the substitution point.

All of the above mentioned groups including those that are part of the group can be indistinctly linear or branched or cyclic (for example, cyclopropyl, cyclopropylmethyl or methylcyclopropyl). Preferred C1-C4 alkyl groups are Me, Et, i-Pr, i-Bu, and cyclopropylmethyl All of the above-mentioned C1-alkyl groups, including those which form part of the groups containing C? -7alkyl, can be indistinctly linear, branched or cyclic, and can include double or triple bonds. The term "C1-7alkyl groups interrupted by oxygen or sulfur" means, respectively, any ether and thio ether group containing between 1 and 7 carbon atoms.

The term "heterocyclylC? -7alkyl" denotes a group having a heterocyclyl group, as defined above, and a C 1-7 alkyl moiety that connects the aryl group with the substitution point.

The term "arylC1-7alkyl" denotes a group having an aryl group, as defined above, and a Ci-7 alkyl moiety that connects the aryl group to the substitution point.

"Halogen" means an atom chosen from fluorine, chlorine, bromine and iodine; "haloCA 4alkyl" means an alkylC ^ group substituted at any position by one or more halogen atoms, for example trifluoromethyl.

Unless otherwise indicated, "optionally substituted" groups are optionally substituted with 1 to 3 substituents selected, preferably from Me, Et, i-Pr, OH, COOEt, COOH, CH20H, S02NH2, SO2Me, OMe, Cl, F, CN and CF3, and more preferably Me, Et, i-Pr, OH, CN, Cl and CF3; the substituents may be in any position in the group to be substituted.

Preferred compounds according to the invention are compounds of the formula (I), in which A is an optionally substituted phenyl, an optionally substituted benzyl or a heterocyclic aromatic group optionally substituted with 5 or 6 elements, and consisting of up to two hetero atoms chosen from oxygen, sulfur or nitrogen, Ri, R2, R3 and R4 are chosen from hydrogen, or benzyl, and n is equal to 2 or 3.

Preferably, A is phenyl, thienyl, pyridyl, pyrimidinyl group, optionally substituted, benzyl or 4-methylbenzyl; R] is hydrogen, (for example methyl, isopropyl or isobutyl), benzyl, -CH2OH, -CH2CH2CONH2, -CH2COOH, indole (3-yl) methyl, R2 is hydrogen, C1-alkyl or benzyl, R3 and R4 are hydrogen or methyl, and n is 2.

More preferably, A is an optionally substituted phenyl, Rls R2, R3 and R are hydrogen, and n is equal to 2.

When Rt and R2, taken together, form a saturated carbocyclic ring containing between 3 and 8 carbon atoms, the compound resulting from the formula (I) is a spirocyclic compound.

Preferred compounds of the formula (I) according to the invention are chosen from a group consisting of: 1-Phenyl-tetrahydro-1 H -pyrrolo [1,2-a] imidazole-2,5-dione; l-o-tolyl-tefra-MAHro-lH-pyrrolo [l, 2-a] imidazole-2,5-dione; 1- (2,6-Dimethyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; l-Thiophene-2-yl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; l-m-Tolyl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; l-p-Tolyl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (5-Fluoro-2-methyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (3-Fluoro-2-methyl-phenyl) -tetrahydro-pyrrolo [1, 2-a] imidazole-2,5-dione; 1- (2-Trifluoromethyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Chloro-2-methyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; l- (3-Chloro-phenyl) -tetrahydyO-phenyl [1, 2-a] imidazole-2,5-dione; 1- (3-Methoxy-phenyl) -tetrahydyO-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (3-Cyano-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Chloro-femyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (3-Hydroxy-phenyl) -tetrahydro-pi? tolo [1, 2-a] imidazole-2,5-dione; 1- (3-Trifluoromethyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Trifluoromethyl-phenyl) -tetrahydro-pinolo [1,2- a] imidazole-2,5-dione; 1- (4-Methoxy-phenyl) -tetrahydro-pyrrolo [1,2- a] imidazole-2,5-dione; 1- (3,5-Dimethyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (3,4-Dimethyl-phenyl) -tetra-pyrrolo [1,2,2-a] imidazole-2,5-dione; l-Nafialen-2-yl-tefrahia-ro-pyrrolo [l, 2-a] imidazole-2,5-dione; 1- (3-Isopropyl-phenyl) -tetrahydro-pinolo [1,2- a] imidazole-2,5-dione; l- (4-Chloro-3-methyl-phenyl) te1raH? io-pyrrolo [l, 2-a] imidazole-2,5-dione; 3-Benzyl-1-phenyl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 3-Methyl-1-phenyl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 3-isobutyl-1-phenyl-tetrahydro-pyrrolo [1, 2-a] imidazole-2,5-dione; l- (3-Fluoro-5-methyl-femlo) -tetra a ^ o-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (3-Fluoro-4-methyl-phenyl) -tetrahydro-pyrrolo [1,2-a] imidazole-2,5-dione; 7a-Methyl-l-phenyl-tetrahydiO-pyrrolo [1,2,2-a] imidazole-2,5-dione; (S) -1-O-Tolyl-tetrahydro-pyrrolo [1, 2-a] imidazole-2,5-dione; (R) -l-o-Tolyl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Ethyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Isopropyl-phenyl) -tetrahi O-pyrrolo [1,2,2-ajimidazole-2,5-dione; 1- (4-Hydroxymethyl-ferdyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 4- (2,5-Dioxo-hexahydro-pyrrolo [1,2- a] imidazole-1-yl) -benzoic acid; 4- (2,5-Dioxo-hexahydro-pyrrolo [1, 2-a] imidazole-1-yl) -benzoic acid ethyl ester; 1- (4-methanesulfonyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Fluoro-ferrino) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Cyano-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1-Pyridine-2-yl-tetrahydro-pyrrolo [1,2-a] imidazole-2,5-dione; l-Pyridine-3-yl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (5-Methylpyridin-2-yl) -tetrahydropyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (2-Cyano-phenyl) -tetrahydro-pi? tolo [1, 2-a] imidazole-2,5-dione; 1- (3-Fluoro-phenyl) -tetrahydro-pyrrolo [1, 2-a] imidazole-2,5-dione; 1-Benzyl-tephrahydro-pyrrolo [1,2- a] imidazole-2,5-dione; 1- (4-methylbenzyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione.

It should be noted that some of the compounds of the formula (I) may contain one or more stereogenic centers. The present invention extends to all optical isomers of the compounds in their fully or partially resolved forms and in the form of racemic mixtures.

Another subject of the invention is the process for the preparation of the compounds of the formula (I), or one of their salts, and / or one of their solvates, which consists of the reaction of a compound of the formula (II) with a compound of the formula (III) A-X (ip) wherein A, Ri, R2, R3 and R and n are defined as an anba for the compounds of the formula (I), and X is a halogen atom, chosen preferably from bromine and iodine.

When A is a carbocyclic aromatic group or a heterocyclic aromatic group as defined above, the reaction between the compounds of the formula (II) and the compound of the formula (III) can be carried out according to the appropriate conditions of the Goldberg reaction ( Angew, Chem. Int. E., 39, 4492, 2000). In particular, the compounds of the formula (II) are dissolved in a suitable solvent, such as N-methylpyrrolidone, together with the compounds of the formula (III) in the presence of a catalytic amount of copper salt such as copper iodide. , and a base such as potassium carbonate, at any temperature that will produce an adequate percentage of product formation that is required, suitably at a high temperature, for example at a temperature of between 60 ° C and 140 ° C, for example at 120 ° C. The reaction mixture is heated using a conventional heating system or a microwave reactor of suitable power, for example, consisting of between 25 and 250 (Tetrahedron Letters, 43.1101, 2002).

When A is arylC1-4alkyl, the reaction can be carried out in a suitable solvent such as acetonitrile, dichloromethane, acetone, in the presence of a suitable base such as triethylamine, potassium carbonate, 2-tert-Butylimino-2-diethylamino- 1,3-dimethylperhydro-1,2,3-diasaphosphorine (also known as BEMP), N, N-Diisopropylethylamine (also known as Hunig base), at a suitable temperature such as reflux temperature (60-140 ° C, preferably 100 ° C).

The aforementioned compounds of the formula (II) and the methods for their preparation are described in the European patent application EP-A-335483 and in the application for International patent No. WO-A-93/09120 and in J Med. Chem. ., 36, 4214, 1993, by Pinza et al.

The compounds for the formula (III) are commercially available or can be prepared from known compounds by known methods.

Alternatively, the compounds of the formula (I) can be prepared with the process consisting of the following steps: i) reaction of an amino acid of the formula (IV) or one of its activated derivatives (IV) with a compound of the formula (V) NK (V) to obtain a compound of the formula (VI) (SAW) in which R1; R2 and A are as defined above for the compound of the formula (I), and P is H or a suitable protecting group. Activation of amino acids is a well-known synthetic procedure; examples of activated amino acid derivatives are mixed with anhydrides, acyl chlorides and activated esters; ii) reaction of the compound of the formula (VI) obtained in step i) with the compound of the formula (VII) (VII) to obtain a compound of the formula (HIV) (HIV) where A, R1} R2, R3 and R4 and n are as defined above for the compound of the formula (I), P is defined as above, and R 'is an alkyl group; iii) possible removal of the protective group P by means of hydrogenolysis of the compounds of the formula (VIII), obtained in step ii), to obtain the corresponding compound (VIII), in which P is H; Y iv) cyclization of the compound of the formula (VIII), in which P is H coming from step ii) or step iii), to obtain the desired compound of the formula (I).

According to a preferred embodiment of the invention, the alkyl residue R 'is chosen from methyl and tert-butyl, and P is chosen from hydrogen, a benzyl or benzyl-oxycarbonyl group.

The reaction in step i) between the compound of the formuela (IV) and the compound of the formula (V) can be carried out: (a) by preparing, first, an acidic chloride in the compound of the formula ( IV) and by binding said acidic chloride to the compound of the formula (V) in the presence of an inorganic or organic base in a suitable aprotic solvent, such as dimethylformamide (DMF) at a temperature between -70 ° C and 50 ° C, and preferably between -10 ° C and 20 ° C; or: (b) by reacting together the compound of the formula (TV) with the compound of the formula (V) in the presence of a suitable condenser-agent, for example N, N '-carbonyl diimidazole (CDl) or a carbodiimide such as dicyclohexylcarbodiimide (DCC) or V-dimethylaminopropyl-iV7-ethylcarbodiimide, preferably of iV-hydroxybenzotriazole (HOBT) to maximize the yield and prevent the racemisation processes ( see Synthesis, 453, 1972) or O-benzotriazol-l-il-iVi-? "yiV" -tetramethyluronium hexafluorophosphate (HBTU), in an aprotic solvent, for example a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for example, a mixture with the volumetric ratio between 1: 9 and 7: 3 ( MeCN: THF), at any temperature capable of yielding an adequate percentage of formation of the required product, for example a temperature between -70 ° C and 50 ° C, and preferably between -10 ° C and 25 ° C.

In step ii) of the current process, the compounds of formulas (VI) and (VII) are heated, preferably with reflux heat, in a protic solvent, such as water or methanol, and possibly in the presence of a base, such as NaOH, in the case where the compound of the formula (VI) is used to form one of its salts that is obtained through the incorporation of an acid, for a suitable period of time, preferably between 2 and 24 hours.

Removal of the protective group P is carried out by hydrogenolysis in step iii) using ammonium formate as the source of hydrogen in a suitable protic solvent, for example methanol or a mixture of water and methanol.

The cyclization reaction is carried out in step iv) directly in the compound of the formula (VIII) coming from step ii) if P is H, or if said compound (VIII) P is a protective group, the first step is to remove it, as described above in step iii).

The cyclization reaction is carried out under drastic conditions through conventional heating of the compound of formula (VIII) without solvent at 120 ° C and under vacuum conditions, or by heating reflux in xylene for a suitable period of time, for example during between 4 hours and 3 days, or through irradiation with microwaves.

The compounds of formulas (IV), (V) and (VII) are commercially available, or can be prepared from known compounds by known methods.

In particular, the compounds of the formula (IV) can be chosen from any naturally occurring amino acid or derivatives thereof. In Figure 1 are shown examples of amino acids which are useful in the present invention, wherein the part within the circle corresponds to the substituent Ri of the formula (IV); and therefore all these meanings of R] are preferred in the formula (I), the object of the present invention being.

The present compounds of the formula (I) are useful as therapeutic agents and, in particular, they possess nootropic and neuroprotective activity, for example, they contribute to the restoration of learning and memory functions that have deteriorated with age or due to traumas of ischemia, and are effective in several pathologies of the CNS, including learning dysfunctions, cognitive and memory dysfunctions, Alzheimer's disease, dementias, including senile dementia of the Alzheimer type, post-stroke dementia, epilepsy, ischemia brain and mood disorders, including depression.

In addition, the present compounds of the formula (I) have analgesic and / or anti-hyperalgesic activity, for example, they contribute to combating pain sensations, in particular those caused by conditions of neuropathic pain, chronic inflammatory pain and visceral pain, and They have also proven effective in the treatment of emesis.

The subject of the present invention is also, therefore, the use of the present compounds of the formula (I) or their pharmaceutically acceptable salts and / or solvates in the preparation of medicaments for the recovery of learning and memory disorders and for the treatment of dementias, Alzheimer's disease, post-apoplexy vascular dementia, epilepsy, cerebral ischemia and mood disorders, including depression.

It also provides a method for the treatment of the above-mentioned conditions and diseases, characterized by the administration of a pharmaceutically active amount of a compound of the formula (I) to a patient in need thereof.

It is well known that the cognitive disorders that occur in these pathologies are correlated with the deficit of the cerebral cholinergic system, as it is discovered through morphological results (BETomlinson in "Biochemistry of Dementias", PJ.Roberts Ed., John Wiley & Sons, New York, NY pp. 15-22, 1980) and neurochemical discoveries (RT Bartus et al., Science, 217, 408, 1982). It is also well known that significant impairments of cognitive functions are the most obvious and debilitating signs observed in patients suffering from Alzheimer's disease, senile dementia of the Alzheimer type, and dementia due to multiple infarcts.

The activity of the compounds of the formula (I) in rats can be determined in relation to the action causing scopolamine amnesia (DA Drachman, Archs Neurol., Chicago, 30,113, 1974; DA Eckerman, Pharmacol. Biochem. Behav. 12,595, 1980) in the mnemonic route and in the reduction of acetylcholine levels in the hippocampus. The effect on memory and learning can be evaluated in rats using the passive avoidance test, as described in Essman, Pharmacol Res. Commun. 5, 295, 1973.

The subject of the present invention is, furthermore, the use of the present compounds of the formula (I) or their pharmaceutically acceptable salts or solvates in the treatment of conditions of neuropathic pain, chronic inflammatory pain and visceral pain. Also provided is a method for the treatment of such diseases characterized by the administration of a pharmaceutically active amount of a compound of the formula (I) to a patient in need thereof.

It is hypothesized that the learning and memory process is involved in the mechanisms of chronic pain (Flor H., Prog. Brain Res., 129, 313, 2000), and recent evidence supports the hypothesis that chronic inflammatory pain is an acquired maladaptive phenomenon (Arnstein PM, J Neurosci, Nurs 29, 179, 1997, Kumazava T., Neurosci Res, 32, 9, 1998). Cognitive dysfunction has been described in several neuropathic conditions. (Kuhajda M. C, Ann. Behav. Med, 20, 31, 1998), and recently it has been observed that nephiracetam, a nootropic agent, relieves neuropathic pain thanks to its effects on neuropathies (Rashid Harunor MDJ Pharmacol. Exp. Ther., 303,226, 2002). It has been shown that the analgesic and / or anti-hyperalgesic effect of nefiracetam is expressed through the stimulation of nicotinic cholinergic receptors at the spinal and supraspinal levels, as this effect is inhibited in a dose-dependent manner by mecamylamine, a known antagonist. of the nicotinic cholinergic receptor.

The activity of the compounds of the formula (I) can be determined in mice through the hyperalgesia-thermal test (leg retraction test) and the hyperalgesia-mechanical test (pressure test in the leg) induced by the partial ligation of the sciatic nerve or by treatment with streptozotocin, following the protocols described in J. Pharmacol. Exp. Ther., 303, 226, 2002 and in the bibliography cited therein.

When used in therapeutic treatment in humans and animals, the compounds of the formula (I) are usually formulated according to standard pharmaceutical practice, as a pharmaceutical compound.

Therefore, another subject of the invention is represented by a pharmaceutical compound which consists of, as an active principle, a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with suitable vectors, diluents and excipients for the form of administration that is chosen pharmaceutically acceptable.

The compounds of the formula (I) can be administered in a standard manner in the treatment of the above mentioned diseases, for example oral, parenteral, rectal, transdermal route or by the administration through the mucosa (for example, the sublingual, buccal or nasal mucosa).

The compounds of formula (I) that are administered orally or sublingually or via the buccal can be formulated as syrups, tablets, capsules and tablets. A formulation in the form of syrup generally consists of a suspension or solution of the compound or a salt thereof in a liquid vector, for example ethanol, glycerin or water with a flavoring or coloring agent.

When the compound is in the tablet form, it is possible to use any pharmaceutical vector that is conventionally used in the preparation of solid formulations. Examples of such vectors consist of magnesium stearate, starch, lactose and sucrose. When the compound is in the form of capsules, any conventional method of encapsulation is suitable, for example, the use of the aforementioned vectors in a hardened gelatin capsule. When the compound is in the form of capsules made of soft gelatin, it is possible to use any pharmaceutical vector which is conventionally used in the preparation of dispersions or suspensions, for example aqueous gums, cellulose, silicates or oils, which will be incorporated in the shell made of soft gelatin.

Typical parenteral compounds consist of a solution or suspension of the compound of the formula (I) in a sterile aqueous or non-aqueous vector, possibly containing an oil acceptable for the parenteral route, for example, polyethylene glycol, polyvinyl pyrrolidone, lecithin. , peanut oil or sesame oil.

The typical suppository formulation consists of a compound of formula (I), which is activated if administered in this manner, with a binding agent and / or lubricant, for example polymeric glycols, gelatin, cocoa butter, or other waxes of low melting point or vegetable oils.

Typical transdermal formulations consist of a conventional aqueous or non-aqueous vector, for example cream, ointment, lotion or paste, or may be in the form of medicated plaques, patches or membranes.

Preferably, the compound is in the unit dosage form, for example tablets or capsules, so that the patient can take a single dose.

Oxiracetam is a compound that is used in the treatment of senile dementia and the pathological conditions related to it. The compounds of the formula (I) can be administered with regimens similar to those established for oxiracetam, with any appropriate adjustment of the dose or dose frequency levels in relation to the increased activity and the improved pharmaceutical profile of the compounds of the formula (I).

Each dose unit for oral administration may conveniently contain from 0.05 mg / kg to 50 mg / kg, more conveniently from 0.1 mg / kg to 25 mg / kg of a compound of the formula (I). The active ingredient can be administered 1 to 6 times per day. The compounds of the formula (I) can be co-administered with other pharmaceutically active compounds, for example in association, concurrence or sequence with, in particular together with, other compounds used in the treatment of elderly patients, such as tranquilizers, diuretics, anti-drugs. -hypersensitive, vasodilator drugs, and inotropic agents.

Examples of the present invention are provided in the following, for strictly illustrative and non-limiting purposes.

EXPERIMENTAL PART Description 1. 3-Isobutyl-tetrahydro-pyrrolo [1,2- a] imidazole-2,5-dione.

To a solution of DL-hydrochloride leucinamide (1.5 g, 9 mmol) in water (40 ml), adjusted to a pH of 9.5 with 10% sodium hydroxide, was added ethyl-4-oxobutanoate (1 g, 7.5 mmol) . The mixture was introduced in a microwave oven and kept in a reflux condition for 1 hour. The water was then evaporated in vacuo and the residue chromatographed on silica gel. (CH2C12 / MeOH / NH40H 98/2 / 0.1) to yield 1.1 g of the title compound. 1 H-NMR (CDCl 3) d: 6.48 (broad s, ÍH); 5.30 (t, ÍH); 4.23 (dd, ÍH); 2. 71-2.39 (m, 3H); 2.20-1.93 (m, ÍH); 1.86-1.73 (m, ÍH); 1.70-1.42 (m, 2H), 1.05 (d, 3H); 0.96 (d, 3H).

MS: The TSQ 700; 180 C source; 70 V; 200 uA: 196 (M +), 97.

Example 1. l-Phenyl-tetrahydro-lH-pyrrolo [l, 2-a] imidazole-2, 5-dione To a solution of tetrahydro-pyrrolo [l, 2-a] imidazole-2,5-dione (1 g, 7. 14 mmol; prepared as described in J Med. Chem. 36, 4214-4220, 1994,) in N-methylpyrrolidone (NMP, 12 ce), Cul (0.2 g, 1.05 mmol), K2CO (1 g, 7.14 mmol) and iodobenzene ( 5 g, 24.5 mmol) were added while stirring constantly. The suspension was heated in a microwave oven (250 Watts) for 45 min. Ethyl acetate was added to the suspension and the solid filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were collected and dried over Na2SO, filtered and concentrated to dryness. The residue was triturated with isopropyl ether. The solid was filtered, triturated with water and filtered to yield 0.18 g of the title compound, mp = 185-188 ° C. 1 H-NMR (CDCl 3) d: 7.46-7.37 (m, 4H); 7.28-7.21 (m, ÍH); 5.84 (m, ÍH); 4.48 (d, ÍH); 3.74 (d, ÍH); 2.78-2.60 (m, 2H); 2.51-2.38 (m, ÍH); 2.08-1.96 (m, ÍH).

MS: The TSQ 700; 180 C source; 70 V; 200 uA: 216 (M +), 160.97.

Example 2. l-O-Tolyl-tetrahydro-lH-pyrrolo [1,2- a] imidazole-2,5-dione.

To a solution of tetrahydro-pyrrolo [1,2-a] imidazole-2,5-dione (1.3 g, 9.28 mmol, prepared as described in J. Med. Chem. 36, 4214, 1994) in N-methylpyrrolidone ( NMP, 12 ce), Cul (0.5 g, 2.62 mmol), K2CO3 (1.3 g, 9.28 mmol) and 2-bromotoluene (6 g, 35 mmol) was added while moving. The suspension was heated in a microwave apparatus (250 Watts) for 1 h. Ethyl acetate was added to the suspension and the solid filtered. The organic phase was washed in water and the aqueous phase was re-extracted with CH2Cl2. The organic phases were collected and dried over a2SO4, filtered and concentrated to dryness. The residue was triturated with Et2 ?. The solid was filtered and crystallized the first time with iPrOH and then with AcOEt to yield 0.33 g of the title compound, mp = 138-139 ° C. 1 H-NMR (CDCl 3) d: 7.35-7.23 (m, 4H); 7.13-7.06 (m, ÍH): 5.69 (m br, ÍH); 4.45 (d, ÍH); 3.78 (d, ÍH); 2.68 (ddd, ÍH); 2.48 (ddd, ÍH); 2.40-2.29 (m, ÍH); 2.24 (s, 3H); 1.93 (m br, ÍH).

MS: The TSQ 700; 180 C source; 70 V; 200 uA: 230 (M +), 143, 118, 97.

Example 3-44 (Table 1). General procedure for the arylation of tetrahydro-pyrrolo [l, 2-a] imidazole-2,5-diones with aryl halides.

To a solution of tetrahydro-pyrrolo [1,2-a] imidazole-2,5-dione (3.5 mmol, prepared as described in J Med. Chem. 36, 4214-4220, 1994 or in WO-9309120), N-methylpyrrolidone (NMP 1 ml), Cul (0.19 g, 1 mmol), K2CO3 (0.5 g, 3.5 mmol) and the appropriate aryl halide (7 mmol) were added constantly stirring. The suspension was heated in a microwave apparatus (25 Watt) for 20 min. Ethyl acetate (50 ml) and water (5 ml) were added to the suspension and the mixture was mixed for 30 'in the presence of celite. The reaction was filtered and the ethyl acetate was washed with a saturated solution of NaCl, dried over Na 2 SO 4, filtered and concentrated to dryness. The residue was triturated with Et2? to yield the desired compound. The yield varies between 30% and 60%.

Example 45. l-Benzyl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione.

A solution of tetraWdro-pi? Tolo [l, 2-a] imidazole-2,5-dione (0.5 g, 3.5 mmol, as described in J Med. Chem. 36, 4214, 1994), BEMP (2 ml, 7 mmol) and benzylbromide (0.6 ml, 5 mmol) in CH3CN (20 ml) was kept under reflux conditions for 1 hour.

The reaction was concentrated to dryness; The residue was then redissolved in ethyl acetate and washed with a saturated solution of NaCl, dried over Na 2 SO 4, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel. (CH2Cl2 / MeOH / NH40H 95/5 / 0.5) to yield 0.7 g of the title compound as a yellow oil.

Performance: 87% ? -NMR (CDCI3) d: 7.39-7.10 (, 5H); 5.03 (dd, ÍH); 4.71 (d, ÍH); 4.29 (d, ÍH); 4.28 (d, ÍH); 3.59 (d, ÍH); 2.57 (ddd, ÍH); 2.39-2.125 (m, 2H); 1.92-1.77 (m, ÍH).

MS: The TSQ 700; 180 C source; 70 V; 200 uA: 230.13 (M +), 174.09, 139.04, 91. 03.

Example 46. 1- (4-methylbenzyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione.

A solution of tetrahydro-pyrrolo [1,2-a] imidazole-2,5-dione (0.5 g, 3.5 mmol, as described in J Med. Chem. 36, 4212, 1994), BEMP (2 ml, 7 mmol) and 4-methylbenzylbromide (0.95 ml, 5 mmol) in CH 3 CN (20 ml) and kept under reflux conditions for 1 hour. The reaction was concentrated to dryness; then the residue mixture was redissolved in ethyl acetate and washed with a saturated solution of NaCl, dried over Na 2 SO, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel. (CH2C12 / MeOH / NH40H 95 / S / 0.5) to yield 0.8 g of the title compound as a yellow oil.

Performance: 93% 1 H-NMR (CDCl 3) d: 7.29-7.11 (m, 4H); 5.01 (m, ÍH); 4.69 (d, ÍH); 4.29 (d, ÍH); 4.23 (d, ÍH); 3.58 (d, 1H); 2.65-2.50 (m, ÍH); 2.40-2.24 (m, 2H); 2.33 (s, 3H); 1.93-1.78 (m, lH).

MS: The TSQ 700; 180 C source; 70 V; 200 uA: 244.13 (M +), 161.05, 105.02 TABLE 1 Structure, chemical name (generated by Beilstein's Autonom), data of! H NMR, MS and melting point for compounds prepared according to the general procedure described above. 13 21 az 23 2T Zr 2. 3 2. 3"" ÍIS'MR "(cbc d: 7.SS (ttdd, 1H); 7.Í3 (do'J, 1H; 7.15 (ddd, 1HK O.B5 (dtfdd, 1Hfe S.81 (, 1H.). , 4 9 (d, 1H.); 375 (d, 1H); 2.B5-2.G5 G ^ A ^ -A, 1-p-Muoro-feffll) -tefrahydro-ptaolol,] 2- (ro, 2ri); 2.53-248 m, 1H); 2.13-1.3? (ffi, lH), a] imide ol-2,5-diupa MS: ADA ESI Pos, 3 £ XV; patent 3QV; pracba253 * C: 235.1 (MH *). mpr 14B-149"C, Pharmacological methods Chronic constriction wound model A peripheral mono-neuropathy was produced in adult rats by surrounding the common sciatic nerve with constrictive ligatures loosely according to the method described by Bennett & Xie (Pain 1988, 33, 87-107).

The rats were anesthetized with chloral hydrate. The common sciatic nerve at the level of the middle thigh was exposed through blunt dissection by the biceps femoris. Tissue was released approximately 1 cm from the nerve proximal to sciatica trifurcation and four ligatures (3/0 silk thread) were tied loosely around with approximately 1 mm spacing. The length of the nerve that was affected was 1 cm. Careful measures were taken to tie the ligatures to ensure that the nerve diameter was barely restrained when viewed with an amplification of 40 x. It was left without affecting the left leg.

Test depression in the leg The nociceptive threshold of the rat was determined with an analgesimeter (Ugo Basile, Várese, Italy); according to the method described by Leighton et al. (Br. J.

Pharmacol. 1988, 93, 553-560). Rats with scores below 40 g or above 75 g (25%) were rejected during the test, before the administration of the drug. An arbitrary limit value of 250 g was adopted.

All experiments were carried out on rats subjected to the pressure test on the paw 14 days after the operation because at that time a significant reduction in the pain threshold of the injured paw (dx) was observed.

Gabapentin (30μg icv), levetiracetam (300μg icv), dimiracetam (100μg icv), Example 1 (10μg icv), Example 2 (10μg icv), Example 5 (3μg icv), Example 6 (3μg icv), Example 13 (30μg) icv) and Example 22 (30μg icv) of the current invention showed an antihyperglastic effect when compared to the group treated with saline or a vehicle. None of the compounds modified the pain threshold in the non-operated contro-lateral paw. It should be noted that all the compounds caused their anti-hyperalgic effect without changing the general behavior of the animals or their individual motility in comparison with vehicle-treated / saline rats. In addition, no change in motor coordination was revealed as measured by the rota-rod test for rats (Vaught J. et al., Neuropharnacology 1285, 24, 211-216).

EFFECT OF THE COMPOUNDS OF THE INVENTION AND REFERENCE COMPOUNDS (Lev.) IN A MODEL OF MONO-NEUROPATHY RATS dx EVALUATED IN THE PATA PRESSURE TEST Rat pressure in rats (g) BEFORE AFTER THE TREATMENT (Í.C.V.) PATA TREATMENT TREATMENT SALINA dx 24.3 ± 2.9 23.7 ± 2.5 VEHICLE dx 26.5 ± 3.5 22.9 ± 3.6 GABAPENTIN 30 μg dx 24.5 ± 4.7 46.3 ± 4.2 * LEVETIRACETAM 300 μg dx 24.0 ± 3.9 37.3 ± 4.6? DDV? RACETAM 100 μg dx 25.1 ± 2.4 42.8 ± 2.5 * EXAMPLE 1 10 μg dx 26.0 ± 2.2 36.3 ± 5.1? EXAMPLE 2 10 μg dx 23.5 + 4.0 42.2 + 3.9 * EXAMPLE 5 3μg dx 27.7 ± 2.8 39.3 ± 4.5? EXAMPLE 6 3μg dx 26.7 ± 3.6 46.1 ± 5.0? EXAMPLE 13 30 μg dx 28.5 ± 2.9 55.4 ± 4.7 * EXAMPLE 22 30 μg dx 25.4 ± 2.7 48.5 ± 4.6 * Each value represents the average of at least 8 rats (in two separate experiments). All compounds were administered 30-45 min. Before the test. ? P < 0.05; * PO.01

Claims (26)

1. CLAIMS Compounds of the general formula (I) in which: A is chosen from carbocyclic aromatic groups, heterocyclic aromatic groups, and arylC ^ alkyl; Ri is chosen from: hydrogen, aryl optionally substituted in an aryl moiety with one or more of the groups selected from hydroxy, C ^ to oxy, halogen, heterocyclylC1-alkyl, optionally substituted in the heterocyclic moiety with one or more groups chosen from Ci ^ alkyl and hydroxy; Ci-yalkyl, optionally interrupted by an oxygen or sulfur atom or optionally substituted at any position by one or more groups selected from hydroxy, thio, amino, carboxyl, aminocarbonyl, guanidinyl. R2 is chosen from hydrogen, C1-alkyl, aryl C1-alkyl and phenyl; or R! and R2 which together form a carbocyclic ring containing between 3 and 8 carbon atoms; R3 is chosen from hydrogen, C? -alkyl, arylC? -alkyl, CON? 2 and COOR5 wherein R5 is chosen from hydrogen and C] -alkyl; R 4 is selected from hydrogen, C 1 alkyl, aryl, aryl C 1 -alkyl and heterocyclyl; n is 2, 3 or 4; in the form of a racemic mixture or in the form of enantiomers, and pharmaceutically acceptable salts or solvates thereof.
2. 2. The compounds according to Claim 1, wherein: A is phenyl, thienyl, pyridyl, pyrimidinyl group, optionally substituted, benzyl or 4-methylbenzyl; Ri is hydrogen, ^ alkyl, benzyl, -CH2OH, -CH2CH2CONH2, -CH2COOH, indole (3-yl) methyl; R2 is hydrogen, they are hydrogen or methyl, and n is 23.
3. The compounds according to Claim 2, wherein: A is optionally substituted phenyl; Rls R2, R3 and R are hydrogen; and n is 2.
4. 4. The compounds according to Claims 1-3, in which: A is substituted with 1 to 3 substituents chosen from ME, Et, i-Pr, OH, COOEt, COOH, CH2OH, SO2NH2, SO2Me, OMe, Cl, F, CN and CF3.
5. 5. The compounds according to Claim 4, wherein: A is substituted with 1 to 3 substituents selected from Me, Et, i-Pr, OH, CN, Cl and CF3.
6. 6. The compounds according to Claim 1 or 2, wherein: said alkyl C group is chosen from Me, Et, i-Pr, i-Bu and cyclopropylmethyl.
7. 7. The compounds according to Claim 1, chosen in the group consisting of: 1 - . 1-Phenyl-tetrahydro-1 H -pyrrolo [1,2- a] imidazole-2,5-dione; l-o-tolyl-tetrahydro-lH-phtolo [l, 2-a] imidazole-2,5-dione; 1- (2,6-Dimethyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1-Thiophene-2-yl-tetrahydro-pyrrolo [1, 2-a] imidazole-2,5-dione; 1-7"-Tolyl-tetrahydro-pyrrolo [1, 2-a] irnidazole-2,5-dione; 1-I-Tolyl-tetrahydro-pyrrolo [1, 2-a] imidazole-2,5-dione; l- (5-Fluoro-2-methyl-femlo) -tetraMdro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (3-Fluoro-2-methyl-phenyl) -tetrahydyO-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (2-Trifluoromethyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Chloro-2-methyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (3-Chloro-phenyl) -tetrahydro-pyrrolo [1, 2-a] imidazole-2,5-dione; 1- (3-Methoxy-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (3-Cyano-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Chloro-fern o) -tetra-Mdro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (3-Hydroxy-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (3-Trifluoromethyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Trifluoromethyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Methoxy-phenyl) -tetrahydro-pyrrolo [1,2- a] imidazole-2,5-dione; 1- (3,5-Dimethyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (3,4-Dimethyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; l-Naphialen-2-yl-tetrahydro-pyrrolo [l, 2-a] imidazole-2,5-dione; 1- (3-Isopropyl-phenyl) -tetrahydro-pyrrolo [1, 2-a] imidazole-2,5-dione; 1- (4-Chloro-3-methyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 3-Benzyl-1-phenyl-tetrahydro-pyrrolo [1, 2-a] imidazole-2,5-dione; 3-methyl-1-phenyl-tetrahydro-pyrrolo [1,2-a] imidazole-2,5-dione; 3-Isobutyl-1-phenyl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (3-Fluoro-5-methyl-phenyl) -tetrahydro-pyrrolo [1, 2-a] imidazole-2,5-dione; 1- (3-Fluoro-4-methyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 7a-Methyl-1-phenyl-tetrahydro-pyrrolo [1,2-a] imidazole-2,5-dione; (S) -l-o-Tolyl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; (R) -l-o-Tolyl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Ethyl-phenyl) -tetrahydro-pyrrolo [1,2- a] imidazole-2,5-dione; 1- (4-Isopropyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Hydroxymethyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 4- (2,5-Dioxo-hexahydro-pyrrolo [1, 2-a] imidazole-1-yl) -benzoic acid; 4- (2,5-Dioxo-hexahydro-pyrrolo [1, 2-a] imidazole-1-yl) -benzoic acid ethyl ester; 1- (4-Methanesulfonyl-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Fluoro-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-Cyano-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; l-Pyridine-2-yl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1-Pyridine-3-yl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (5-Methylpyridin-2-yl) -tetrahydropyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (2-Cyano-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (3-Fluoro-phenyl) -tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; l-Benzyl-tetrahydro-pyrrolo [1,2,2-a] imidazole-2,5-dione; 1- (4-methylbenzyl) -tetrahydro-pyrrolo [1,2- a] imidazole-2,5-dione.
8. 8. A process for the preparation of the compounds of the formula (I) as described in Claim 1, which consists in the reaction of a compound of the formula (II) With a compound of the formula (III) A-X (III) In which Als R1; R2, R3, R and n are defined as in Claim 1, and X is a halogen atom, to obtain the desired compounds of the formula (I).
9. 9. The process according to Claim 8, wherein X is chosen from bromine and iodine in the compound of the formula (III).
10. 10. The process according to Claims 8-9, for the preparation of the compounds of the formula (I) in which: A is a carbocyclic aromatic group or an optionally substituted heterocyclic aromatic group, in which the compound of the formula (II) is it dissolves in a suitable solvent together with the compounds of the formula (III) in the presence of a base and a catalytic amount of a copper salt, at a temperature of between 60 ° C and 140 ° C.
11. 11. The process according to Claim 10, wherein said solvent is N-methylpyrrolidone, said base is potassium carbonate, said copper salt is copper iodide, and the reaction is carried out at a temperature of 120 ° C.
12. 12. The process according to Claims 8-9, for the preparation of the compounds of the formula (I) in which: A is arylC 1 -alkyl, wherein: the compound of the formula (II) is dissolved in an appropriate solvent together with the compound of the formula (III), in the presence of a suitable base at a temperature between 60 ° C and 140 ° C.
13. 13. The process according to Claim 12, in which: said solvent is chosen from acetonitrile, dichloromethane, acetone, and said base is chosen from triethylamine, potassium carbonate, 2-butyl-2-diethylamino-l, 3-dimethylperhydro- 1, 3,2-diazaphosphorine, N, N-Diiso-propylethylamine, at a temperature of 100 ° C.
14. 14. The process for the preparation of compounds of the formula (I) as described in Claim 1, which consists of the following steps: i) the reaction of an amino acid of the formula (IV) or one of its activated derivatives with a compound of the formula (V) (V) To obtain a compound of the formula (VI): (VI) Where Ri, R2 and A are as defined above in Claim 1, and P is H or a suitable protecting group; ii) the reaction of the compound of the formula (VI) obtained in step i) with a compound of the formula (VII) (Vile) to obtain a compound the formula (VIII) (VH £) in which: A, Rl5 R2, R3, R and n are as defined in Claim 1, P is defined as above, and R 'is an alkyl group; iii) the possible removal of the protective group P through hydrogenolysis of the compound of the formula (VIII) obtained from step ii), to obtain the corresponding compound (VIII), in which: P is H; and iv) cyclization of the compound of the formula (VIII), wherein: P is H coming from step iii), to obtain the desired compound of the formula (I).
15. 15. The process according to Claim 14, wherein: R 'is chosen from methyl and tert-butyl, and P is chosen from H, benzyl and benzyloxycarbonyl.
16. 16. The process according to claim 14, wherein in said step iv), the cyclization reaction is carried out by heating the compound (VIII) in the absence of a solvent at 120 ° C and under vacuum conditions, or through reflux heating of compound (VIII) in xylene for a time consisting of between 4 hours and 3 days.
17. 17. The process according to claim 14, wherein said step ii) is carried out by reflux heating the compounds of the formula (VI) and (VII) in a protic solvent for a time consisting of between 2 and 24 hours, possibly in the presence of a base.
18. 18. The process according to Claim 14, wherein the reaction described in step i) is carried out between the acidic chloride of the compound (TV) and the compound (V) in the presence of an inorganic or organic base in a solvent Suitable protic at a temperature between -70 ° C and 50 ° C.
19. 19. The process according to Claim 14, in which the reaction of step i) is carried out through the reaction of the compound (IV) together with the compound (V) in the presence of a suitable condensing agent, in an aprotic solvent a temperature between -70 ° C and 50 ° C.
20. 20. The process according to Claims 18 or 19, wherein said temperature consists of between -10 ° C and 20 ° C.
21. 21. The pharmaceutical composition consisting of an active ingredient, one or more compounds of the formula (I) as described in claim 1, or pharmaceutically acceptable salts or solvates thereof.
22. 22. The pharmaceutical composition according to Claim 21, further comprising suitable pharmaceutically acceptable vectors, diluents and / or excipients for administration forms chosen from oral, parenteral, rectal, transdermal, and mucosal.
23. 23. The pharmaceutical composition according to Claims 21 and 22, in the form of solutions, suspensions, soluble powders, granules, microcapsules, capsules, tablets, tablets, coated tablets, suppositories, creams, ointments, lotions, pastes, medicated plastics, membranes or gels .
24. 24. The use of a compound of the formula (I) as described in claim 1 or one of the pharmaceutically acceptable salts or solvates for the preparation of a medicament having nootropic and / or neuroprotective, analgesic and / or anti-hyperalgesic action , and anti-emetic.
25. 25. The use according to Claim 24, for the treatment of learning deficit and memory, Alzheimer's disease, dementia, senile dementia, vascular dementia of the post-stroke type, epilepsy, cerebral ischemia, alterations in mood, depression, for the treatment of conditions of chronic pain, inflammatory pain, neuropathic pain, visceral pain, and for the treatment of emesis.
26. 26. The use according to Claim 24, wherein said compound of the formula (I) is administered in association, concurrently or sequentially, with one or more other active ingredients.