Indian Patents. 229419:PYRROLOIMIDAZOLE DERIVATIVES, THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITION CONTAINING THEM

Title of Invention	PYRROLOIMIDAZOLE DERIVATIVES, THEIR PREPARATION, AND PHARMACEUTICAL COMPOSITION CONTAINING THEM
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.

Full Text	The present Invention relates to new compounds of formula (I) appearing hereinafter, their process of preparation, the pharmaceutical compositions containing them, and their use as nootropic, neuroprotective, analgesic and anti-hyperalgesic agents. State of the art Compounds that possess nootropic activity are already known in the literature. In particular, the derivatives substituted in position 4 of 2-oxo-1- pyrroiidineacetamide 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, 447,1982byltiletal. Amongst the most widely known molecules belonging to the class mentioned above there may be cited: 2-oxo-1-pyrrolidineacetamide (piracetam), 4-hydroxy- 2-oxo-1-pyrroIidineacetamide (oxiracetam), 2-(2-oxopyrrolidin-1-yl) butyramide (levetiracetam) and W-(2,5-dimethylphenyl)-2-oxo-1-pyrrolidineacetamide (nefiracetam). Another chemical class that possesses nootropic activity is represented by Imidazolic condensed derivatives, in particular 2,5-dIoxohexahydro-1H- pyn-olo[1,2-a]imida2ole (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 demonstrated that nefiracetam could be a good therapeutic agent in the treatment of neuropathic pain. The anti-hyperalgesic action induced by nefiracetam appears to be of non-oploid nature and is probably due to the stimulation of the nicotinic cholinergic system at a spinal and supersplnal level (Rashid Harunor M.D. J. Pharmacol. Exp. Ther, 303, 226, 2002). EP 0174136 discloses compounds of the formula below. As evident, the imidazole ring has a completely different pattern of substituition, lacking inter alia the A substituent in position 1, typical of the present invention. EP 0335483, Mario pinza et. al. J. of Medicinal chemistry vol. 36 No.6, 1993 pages 4214 to 4220 and WO 9309120 disclose compounds of the formula below, wherein none of the meanings of Rl (= hydrogen, unsubstituted alkyl, alkylaminocarbonylalkyl, alkoxycarbonylalkyl) anticipates the substituent "A", typical of the present invention. 2~ Summary of the invention The present applicant has now found new N-substituted bicyclic imidazolones of formula (I), appearing hereinafter, that have demonstrated improved psychotropic properties and more marked analgesic and antihyperalgesic effects In numerous models of neuropathic pain, with respect to the already known rusotropic agents. The present compounds of formula (I) are consequently useful in the treatment of many disorders of the central nervous system (CNS), for example in the deterioration of learning, dysfunctions of the cognitive sphere and of the memory, Afehelmer's disease, dementias, including senile dementia of the Alzheimer type, post stroke vascular type dementia, epilepsy, cerebral ischaemla, mood disorders, indudfng depression, chronic, inflammatory, neuropathic and visceral pain, and emesis. Consequently, representative of the subject of the present Invention are compounds of the general formula (t) in which: A is chosen among carbocyclic aromatic groups, heterocyclic aromatic groups and arylC1alkyl; Ri is chosen among: - hydrogen, - arylC1.yalkyi, optionally substituted on the aryi moiety with one or more groups chosen among hydroxy, C1alkoxy, halogen, haloC1alkyl; - heterocyclylC1.7alkyl, optionally substituted on the heterocyclyl moiety with one or more groups chosen among C1-4(alkyl and hydroxy, - C1.7 alkyl, optionally Interrupted by an oxygen or sulphur atom or optionally substituted at any position by one or more groups chosen among hydroxy, thio, amino, carboxyl, aminocarbonyi, guanidinyt. Rz is chosen among hydrogen, C1alkyl, arylC1alkyl and phenyl; or else Ri and R2, laken together, form a saturated carbocyclic ring containing from 3 to 8 carbon atoms; R3 is chosen among hydrogen, C1alkyl, arylC1alkyl, CONH2 and COOR5 in which Rs is chosen between hydrogen and C1-4alkyI; R4 is chosen among hydrogen, C1-,alkyl, aryl, arylC1alkyl and heterocyciyl; and 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 of preparation of the compounds of formula (i) appearing above, the pharmaceutical compositions containing them and their use for the preparation of medicaments with nootropic and neuroprotective action, with analgesic and/or anti-hyperalgesic action, and anti-emetic action, constitute a further subject of the invention. Characteristics and advantages of the present compounds of formula (I) will be illustrated in detail in the following description. Description of the figures Figures la, 1b: non limiting examples of aminoacids of formula (IV), useful in the synthesis of the compounds of formula (i). The encircled portion indicates thesubstituentRi. Detailed description of the Invention In the frameworiocyclic aromatic group" means single or fused aromatic rings with 6 to 12 ring members, optionally substituted. The terms "heterocyclic aromatic group" and "heterocyciyl" mean single or fused aromatic rings, each ring having 5 to 12 members and comprising up to four hetero atoms, chosen among oxygen, sulphur and nitrogen, optionally substituted. Whenever not othenvise specified, the term "aryl" means single or fused unsaturated rings, each ring having from 5 to 8 members, and preferably 5 or 6 members, optionally substituted; by the term "arylCiw«alkyr is Indicated a group having an aryl group, as defined above, and a CM alkyl moiety connecting the aryl group to the point of substitution. All the aforesaid C1 alkyl groups, including those being part of the arylC1alkyl group, may i^e indifferently linear or branched or cyclic (i.e cyclopropyl, cydopropylmetyl or methylcydopropyl). Preferred C1-C4 alkyl groups are Me, Et, i-Pr, i-Bu, and cyclopropylmethyl. All the aforesaid C1.7 alkyl groups, including those being part of C1.7 alkyl- containing groups, can either be linear, branched or cyclic, and may include double or triple bonds. The term "Ci-r alkyl groups interrupted by oxygen or sulphur" means, respectively, any ether and thioether groups containing from 1 to 7 carbon atoms. By the term "heterocyciyiCi-ralkyl" is indicated a group having an heterocyclyl group, as defined above, and a C^.^ alkyl moiety connecting the aryl group to the point of substitution. By the term "aryiCi-7alkyi" is indicated a group having an aryl group, as defined above, and a C1.7 alkyl moiety connecting \he aryl group to the point of substitution. By "halogen" is meant an atom chosen among fluorine, chlorine, bromine or iodine; by "haloC1alkyl" is meant a C1 aikyi group substituted at any position by one or more halogen atoms, e.g. trlfluoromethyl. Unless differently specified, "optionally substituted" groups are groups optionally substituted with 1 to 3 substituents, chosen preferably among Me, Et, i-Pr, OH, COOEt, COOH, CH2OH, SO2NH2. SO2MB, OMe, CI. F, CN and CF3, and more preferably among Me, Et, i-Pr, OH, CN, CI and CF3; the subsftuents may be in any position of the group to be sutistituted. Preferred compounds according to the invention are the compounds of formula (I), In which A Is a optionally substituted phenyl, optionally substituted benzyl, or else a optionally substituted heterocyclic aromatic group with 5 or 6 members and comprising up to two hetero atoms chosen between oxygen, sulphur and nitrogen, Ri, R2, R3 and R4 are chosen among hydrogen, C1.4 alkyl or benzyl, and n is equal to 2 or 3. Preferably, A is phenyl, thlenyl, pyridyl, pyrimidinyl group, optionally substituted, benzyl or 4-methylbenzyl; Ri is hydrogen. CM alkyl (for example methyl, isopropy! or isobutyl). benzyl, -CH2OH, -CH2CH2CONH2. -CH2COOH, lndol(3- yl)methyl, Rj is hydrogen, C1 alkyl or benzyl, R3 and R* are hydrogen or methyl, and n !s 2. More preferably, A is a phenyl, opt'onaily substituted, Ri, R2, R3 and R4 are hydrogen, and n is equal to 2. When Ri and R2, taken together, form a saturated carbocyclic ring containing from 3 to 8 carbon atoms, the resulting compound of formula (I) is a spirocyclic compound. Preferred compounds of formula (I) according to the invention are chosen in the group consisting of: 1-Phenyl-tetrBhydro-1 H-pyrrolo[1,2-a]!mldazoIe-2,5-dione; 1-o-tolyl-tetrahydro-1 H-pyrrolo[1,2-a]lmida2ole-2,5-dione; 1 -(2,6-Dimethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]lmidazole-2,5-dione; 1 -Thiophen-2-yl-tetrahydro-pyrrolo[1,2'a]imidazole-2,5-dione; 1-m-Tolyl-tetrahydro-pyrrolo[1,2-a] imidazole-2,5-dione; 1 -p-Tolyl-tetrahydro-pyrrolo[1,2-a] imidazole-2,5-dione; 1-(5-Fluoro-2-methyl-phenyl)-tetrahydro-pynrolo[1,2-a]imidazole-2,5-dione; 1-(3-Fluoro-2-methyl-phenyl)-te^hydra-pyn'olo[1,2-a]imidazole-2,5-dione; 1-(2-Trifluoromethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazoIe-2,5-dione; 1-(4-Chloro-2-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1 -(3-Chloro-phenyl)-tetrahydro-pyn"olo[1,2-a]imldazole-2,5-dione; 1 -(3-Methoxy-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1 -(3-Cyano-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1 -(4-Chloro-phenyl)-tetraihydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1 -(3-Hydroxy-phenyI>-t6trahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1-(3-Trlfluoromethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imldazole-2,5-dione; 1-(4-Trifluoromethyl-phenyl)-tetrahydro-pynrolo[1,2-a]imidazole-2,5-dione; 1-(4-Methoxy-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazol©-2,5-dione; 1-(3,5-Dimethyl-phenyl)-tetrahydro-pyrolo[1,2-a]imidazole-2,5-dione; 1-(3,4-Dimethyl-phenyl)-tatrahydro-pynrolo[1,2-a]imidazole-2,5-dione; 1 -Naphthalen-2-yl-tetrahydro-pyrroloI1,2-a]imidazole-2,5-dione; 1-(3-lsopropyl-pinenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1-(4-Chloro-3-methyl-phenyl)-tetrahydra-pyrrolo[1,2-a]imlda20le-2,5-dione; 3-Ben2yI-1 -phenyl-t8trahydro-pyrrolo[1,2-a]imldazole-2,5-dlone; 3-Methyl-1-phenyl-tetrahydro-pyrroIo[1,2-a]imida2ol0-2,5-dione; 3-lsobutyl-1 -phenyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1-(3-Fluoro-5-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1-(3-Fl uo ro-4-nnethyl-phenyl)-tetrahydro-pyiTOlo[1,2-a]i midazolB-2,5-dione; 7a-Methyl-1 -phenyl-tetrahydrcvpyrrolojl ,2-a]imidazole-2,5-dione,- (S)-1 -o-Tol>^-tetrahydro-pyrrolo[1,2-alimidazote-2,5-dione; (R)-1 -o-Tolyl-tetrahydro-pyrrolo[1,2-a]ifnidazole-2,5-dione; 1 -(4-Ethyl-phBnyl)-tetrahydropyrTolo[1,2-a]imida2ole-2,5-dione; 1-(4-lsopropyl-phGnyl)-tetrahydro-pyrroIo[1,2-a]imfdazole-2,5-dione; 1 -(4-Hydroxymethyl-phenyl)-tetrahydro-pynrolo[1,2-a]lmidazole-2,5-dione; 4-(2,5-Dioxo-hexahydro-pyrrolo[1,2-a]lmidazol-1-yl)-benzoic acid; 4-(2,5-Dioxo-hexahydro-pyrrolo[1,2-a]imidazol-1-yl)-benzoic acid etliyi ester; 1-(4-MQthanesulfonyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1 -(4-Fluoro-plienyl)-tetraliydro-pyiTolo[1,2-a]innidazole-2,5-dione; 1 -(4-Cyano-phenyI)-tetrahydra-pyrrola[1,2-a]imidazoIe-2,5-dione; 1 -Pyridin-2-yl-tetrahydro-pyiToloI1,2-a]innldazole-2,5-dFone; 1 -Pyridin-3-yl-tetraliydro-pyiTClo[1,2-a]imidazole-2,5-dione; 1-(5-lV1ethylpyridin-2-yl)-tetrahydropyrrolo[1,2-a}imidazole-2,5-dione; 1 -(2-Cyano-plienyl)-letraliydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1-(3-Fluoro-phenyl)-tetrahydrD-pyrToio[1,2-a]imidazole-2,5-dione; 1 -Benzyl-tetrahydro-pyrrolo[1,2-alimidazole-2,5-dione; 1 -(4-metliylbenzyl)-tetrahydro-pyrrolG[1,2-a]imidazole-2,5-dione. It will be noted that some compounds of formula (I) can contain one or more stereogenic centres. The present invention extends to all Vne optical isomers of tliese compounds in their forms entirely or partially resolved and in the form of racemic mixtures. A further subject of the invention is a process for the preparation of the compounds of formula (I), or one of their salts, and/or one of their solvates, comprising the reaction of a compound of formula (11) with a compound of formula (ill) A-X (111) in which A, R1, R2, R3. R4 and n are defined as above for the compounds of formula (I), and X is a halogen atom, chosen preferably between bromine and iodine. When A is a aromatic carbocydic group or a heterocyclic aromatic group as above defined, the reaction between the compounds of fomrjula (II) and the compound of formula (III) can be conducted according to the appropriate conditions of the Goldberg reaction {Angew. Chem. Int. E., 39, 4492, 2000). In particular, the compounds of formula (II) are dissolved in a suitable solvent, such as A/-methylpyrrolldone, together with the compounds of 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 yield an adequate percentage of fonmation of the product required, suitably at a high temperature, such as a temperature of between 60'C and 140C, for example at 120'C. The reaction mixture is heated using a system of conventional heating or a microwave reactor of adequate power, for example comprised between 25 and 250 W {Tetrahedron Letters, 43,1101,2002). When A is arylC1alkyl, the reaction can be carried out in a suitable solvent such as acetonitrile, methylene chloride, acetone, in the presence of a suitable base such as triethyiamine, potassium carbonate, 2-ferf-Butyllmino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (also known as BEMP), N,N-OiisopropylethylamJne (also known as Hunig base), at a suitable temperature such as reflux temperature (60-140°C, preferably 100°C). The aforesaid compounds of formula (II) and the methods for their preparation are described in the European patent application EP-A-335483 and in the International patent application No. WO-A-93/09120 and in J.Med.Chem., 36, 4214,1993, by PInza et al. The compounds of formula (ill) are commercially available or can be prepared from i^nown compounds by known methods. Altematively, the compounds of formula (I) can be prepared with a process comprising the following stages: i) reaction of an aminoacid of formula (IV) or of one of its activated derivatives In which Ri, Rj and A are as defined above for the compound of formula (I), and P is H or a suitable protective group. The activation of aminoacids is a well-known synthetic procedure; examples of activated derivatives of the aminoacids are mixed anhydrides, acyl chlorides and activated esters, ii) reaction of the compound of formula (VI) obtained at stage i) with a compound of formula (VII) (VIII) in which A, Ri, R2, R3, R4 and n are as defined above for the compound of formula (I), P Is defined as above, and R' is an alkyl group; lit) possible removal of the protective group P by means of hydrogenolysis of the compound of formula (VIII), obtained in stage ii), to obtain the corresponding compound (VIII), in which P is H; and iv) cyciization of the compound of formula (VIII), in which P is H coming from stage Ii) or from stage ill), to obtain the desired compound of formula (I). According to a prefenred embodiment of the invention, the all(yl residue R' is chosen between methyl and tert-bulyl, and P Is chosen between hydrogen, a benzyl or a benzyloxycarbonyf group. The reaction in stage i) between the compound of formula (IV) and the compound of formula (V) can be performed: (a) by preparing, In the first place, an acidic chloride of the compound of formula (IV) and uniting to said acidic chloride the compound of formula (V) in th9 presence of an inorganic or organic base In an adequate aprotic solvent, such 10 as dimethylformamlde (DMF) at a temperature of between -70°C and 50°C, and preferably between -10'C and 20°C; or else: (b) by reacting together the connpound of formula (IV) with the compound of formula (V) in the presence of a suitable condensating agent, such as N.N'-carbonyl diimidazole (CD!) or a carbodiimmide such as dicyclohexylcarbodiimmlde (DCC) or W-dlmethylamlnopropyl-A/-ethylcarbodilmmide, preferably in the presence of A/-hydroxybenzotriazole (HOBT) to maximize the yield and prevent the processes of racemization (cf. Synthesis, 453, 1972), or 0-benzotriazol-1-yl-N,A/,W,A/-tetramethyluronium hexafluorophosphate (HBTU), in an aprotic solvent, such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for example, a mixture with volumetric ratio comprised between 1:9 and 7:3 (MeCNiTHF), at any temperature capable of yielding an adequate percentage of formation of the product required, such as a temperature of between -70°C and 50°C, and preferably between -10°C and 25°C. At stage ii) of the present process, the compounds of formula (VI) and (VII) are preferably refiux-heated 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 formula (VI) is used in the fomn of one of its salts obtained by addition of acid, for an adequate period of time, preferably comprised between 2 and 24 hours. Removal of the protective group P by means of hydrogenolysis at stage iii) is preferably conducted using ammonium fomntate as a source of hydrogen in a suitable protic solvent, such as methanol or a methanoi-water mixture. The cyclizatlon reaction in stage iv) is carried out directly on the compound of formula (VIII) coming from stage II) if P is H, or else, if in said compound (Vlli) P is a protective group, the first step is to remove It, as described above in stage iii). The cyclizatlon reaction is conducted in drastic conditions by conventionally heating the compound of formula (VIII) without solvent at 120'C and in vacuum conditions, or else by means of reflux-heating in xylene for a suitable period of time, for example between 4 hours and 3 days, or by microwave irradiation. 11 The compounds of formula (IV), (V) and (Vil) are commercially available compounds or can be prepared from known compounds using known methods. In particular, the compounds of formula (iV) can be conveniently selected from any naturally occurring aminoacids or derivatives thereof. Examples of aminoacids useful in the present Invention are shown in figure 1, where the part encircled corresponds to the substituent R1 of formula (IV): accordingly, all these meanings for R1 are also preferred in formula (I), being the object of the present invention. The present compounds of fomriula (I) are useful as therapeutic agents and in particular possess a nootropic and neuroprotective activity, i.e., they contribute to restoring the learning and memory functions deteriorated in the process of ageing or on account of ischaemic traumas, and are effective in various pathologies of the CNS, amongst which learning dysfunctions, dysfunctions of the cognitive sphere and of the memory, Alzheimer's disease, dementias, including senile dementia of the Alzheimer type, post stroke vascular type dementia, epilepsy, cerebral ischaemla, and mood disorders, including depression. The present compounds of formula (I) moreover possess analgesic and/or anti-hyperalgesic activity, i.e., they contribute to combat the sensations of pain, in particular those caused by conditions of neuropathic pain, chronic inflammatory pain and visceral pain, and have proven their efficacy also in the treatment of emesis. The subject of the present Invention is lience also the use of the present compounds of fomnula (I) or of their pharmaceutically acceptable salts and/or solvates for the preparation of medicaments for recovery of difficulties of learning and memory and for treatment of dementias, Alzheimer's disease, post stroke vascular type dementia, epilepsy, cerebral ischaemla, and mood disorders, including depression. Also provided is a method to treat the aforesaid diseases and disorders characterised by administering a pharmaceutically active anrKSunt of a compound of formula (I) to a patient in need thereof. It is widely known that cognitive disorders that occur in said pathologies are correlated to the deficit of the cerebral cholinergic system, as emerges from morphological findings (B.E. Tomilnson in "Biochemistry of Dementias"; P.J. Roberts Ed.; John Wiley & Sons, New Yori The activity of the compounds of formula (I) can be determined in rats in regard to the amnesia-provolry and learning can be evaluated in rats using the passive-avoidance test, as described by Essman, Pharmacol. Res. Commun. 5, 295, 1973. The subject of the present invention is, nwreover, the use of the present compounds of 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 to treat the aforesaid diseases characterised by administering a pharmaceutically active amount of a compound of formula (I) to a patient in need thereof. It is hypothesized that the process of learning and memory is Implicated 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 (Amstein P.M., J. Neurosci Nurs. 29, 179, 1997; Kumazava T., Neurosci. Res., 32, 9, 1998). Cognitive dysfunction has been described in various neuropathic conditions (Kuhajda M.C., Ann. Behav. Med., 20, 31. 1998), and it has recently been observed that nefiracetam, a nootropic agent, alleviates neuropathic pain thanks to its specific effects on neuropathies (Rashid HanjnorM.D. J. Pharmacol. Exp. Ther., 303, 226, 2002). It has been shown that the analgesic and/or antl-hyperaigesic effect of nefiracetam expresses itself through stimulation of the nicotinic cholinergic receptors at the spinal and supraspinal level, in so far as said effect is inhibited In a dose-dependent way by mecamylamine, a known antagonist of the nicotinic acetylC1line receptor. The activity of the compounds of formula (1) can be determined in mice by means of tl^ thermal-hyperalgesia test (paw-withdrawal test) and the mechanical-hyperaigesia test (paw-pressure test) induced by partial ligation of the sciatic nerve or by treatment with streptozotocine, following the protocols described in J. Pharmacol. Exp. Ther., 303, 226, 2002 and in the bibliography cited therein. When used in the therapeutic treatment of humans and animals, the compounds of formula (I) are nomnaily formulated, in compliance with standard pharmaceutical practice, as a pharmaceutical composition, l-lence, a further subject of the invention is represented by a pharmaceutical composition comprising, as active principle, a compound of formula (i) or one of its pharmaceutically acceptable salts or solvates, together with vectors, diluents and pharmaceutically acceptable excipients suitable for the chosen form of administration. The compounds of formula (I) can be administered in a standard way in the treatment of the disorders Indicated above, for example via oral, parenteral, rectal, transdermal route or by administration through the mucosa (for example, the sublingual, buccal, or nasal mucosa). The compounds of formula (I) which are administered orally or via sublingual route or via buccal administration, can be formulated as syrups, tablets, capsules, and lozenges. A formulation In the form of syrup consists generally of a suspension or solution of the compound or of one of its salts in a liquid vector, for example ethanol, glycerine or water with a flavouring or colouring agent. When the composition is in the fomrt of tablets. It is possible to use any pharmaceutical vector used conventionally in the preparation of solid foonulations. Examples of said vectors comprise magnesium stereate, starch, lactose and sucrose. When the composition is in the form of capsules, any conventional method of encapsulation is suitable, for example using the vectors mentioned above in a capsule of hard gelatine. When the composition is in the form of capsules made of soft gelatine, it is possible to use any pharmaceutical vector used conventionally in the preparation of dispersions or suspensions, for example aqueous gums, cellulose, silicates or oils, to be incorporated into a shell made of soft gelatine. Typical parenteral compositions consist of a solution or suspension of the compound of fomnula (i) In a aqueous or non-aqueous sterile vector, possibly containing an oil acceptable for the parenteral route, for example polyethyiene-giycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil. The typical formulation in suppositories comprises a compound of formula (t), which is active if administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatine, cocoa butter, or other low-melting waxes or vegetable fats. Typical transdermal formulations comprise a conventional aqueous or non¬aqueous vector, for example cream, ointment; lotion or paste, or can be in the form of medicated plasters, patches or membranes. Preferably, the composition Is in a unit-dose forni, for example tablete or capsules, so that the patient can take a single dose. Oxyracetam Is a compound used in ^e treatment of senile dementia and of pathological conditions correlated thereto. The compounds of formula (I) can be administered with regimes similar to the ones established for oxyracetam with any appropriate adjustment of the levels of dosage or of the frequency of dosage in relation to the greater activity and to the better pharmacological profile of the compounds of formula (I). Each dosage unit for oral administration may expediently contain from 0.05 mg/kg to 50mg/kg, nwre expediently from 0.1 mg/kg to 25mg/kg of a compound of formula (I). The active ingredient can be administered from 1 to 6 times a day. The compounds of formula (I) can be co-administered with other pharmaceutlcaily active compounds, for example in association, concurrently or sequentially, in particular together with other compounds used in the treatment of elderly patients, such as tranquilizers, diuretics, anti-hypertensive drugs, vasodilator drugs, and inotropic agents. Examples of the present invention are provided in what follows, purely for illustrative and non-limiting purposes. EXPERIMENTAL PART Description 1.3-lsobutyl-tetrahydrO'pyrrolo[1,2'a]imldazole-2,5-dione. To a solution of DL-leucinamide hydrochloride (1.5 g, 9 mmoi) in water (40 ml), adjusted to pH 9.5 with 10% sodium hydroxide, ethyl-4-oxobutanoate (1 g, 7.5 mmoi) was added. The mixture was placed In a microwave oven and refluxed for 1 hour. Water was then evaporated under vacuum and the residue was chromatographated over silica gel (CH2CI2/ MeOH / NH4OH 98/2/0.1) to afford 1.1 g of the title compound. ^H-NMR (CDCIs) 5: 6.48 (broad s, 1H); 5.30 (t, 1H); 4.23 (dd, 1H); 2.71-2.39 (m, 3H); 2.20-1.93 (m, 1H); 1.86-1.73 (m, 1H); 1.70-1.42 (m, 2H), 1.05 (d, 3H); 0.96 (d, 3H). MS: El TSQ 700; source 180 C; 70 V; 200 uA: 196 (M+), 97. Example 1.1-Phenyl-tetrahydro-1H-pyrrolo[1,2-aJimldazole-2,S-dIone. To a solution of tetrahydro-pyrrolo[1,2-a]lmidazo!e-2,5-dion6 (1 g, 7.14 mmoi; prepared as described in J. Med. Chem. 36, 4214-4220, 1994.) in N-methyipyrroiidone {NMP, 12 cc), Cul (0.2 g, 1.05 mmoi), K2CO3 (1 g, 7.14 mmoi) and iodobenzene (5 g, 24.5 mmoi) were added under stiring. The suspension was heated In a microwave apparatus (250 Watt) for 45 min. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Ci2. The organic phases were gathered and dried over Na2S04, 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= IBS-ISB^C. ^H-NMR (CDCI3) 8: 7.46-7.37 (m, 4H); 7.28-7.21 (m, 1H); 5.84 (m, 1H); 4.48 (d, 1H); 3.74 (d, 1H); 2.78-2.60 (m, 2H); 2.51-2.38 (m, 1H); 2.08-1.96 (m, 1H). MS: El TSQ 700; source 180 C; 70 V; 200 uA: 216 (M+). 160, 97. Example 2.1-o-tolyl-tetrahydro-1H-pyirolo[1,2-a]imidazole-2,6-dionQ, To a solution of tetrahydro-pyrrolo[1,2-a]imldazole-2,5-dione (1.3 g, 9.28 mmoi, prepared as described in J. Med. Chem. 36,4214,1994) in N-methylpyrroIidone (NMP, 12 cc), Cul (0.5 g, 2.62 mmoi), K2CO3 (1.3 g, 9.28 mmoi) and 2-bromotoluene (6 g, 35 mmoi) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 1 h. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2CI2- The organic phases were gathered and dried over Na2S04, filtered and concentratea to dryness. The residue was triturated with EtaO. 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. ^H-NMR (CDCia) 8: 7.35-7.23 (m, 4H): 7.13-7.06 (m, 1H); 5.69 (m br, 1H); 4.45 (d, 1H); 3.78 (d. 1H); 2.68 (ddd, 1H); 2.48 (ddd, 1H); 2.40-2.29 (m, 1H); 2.24 (s. 3H);1.93(mbr, 1H). IVIS: El TSQ 700; source 180 C; 70 V; 200 uA: 230(M+), 143,118, 97. Example 3-44 (Table 1). General procedure for arylation of tetrahydro-pyrrolo[1,2-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), in 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 under stirring. The suspension was heated in a microwave apparatus (25 Watt) for 20 min. Ethyl acetate (50 nnl) and water (5 ml) were added to the suspension and the mixture was stirred 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 Na2S04, filtered and concentrated to dryness. The residue was tritunated with EtzO to give the desired compound. Yields vary from 30% to 60%. Example 45.1'Ben2yl-tBtrahydro-pyrrolo[1,2-a]lmi'dazole-2,5-dione. A solution of tetrahydro-pyrtiolo[1,2-a]imidazole-2,5-dione (0.5 g, 3.5 mmol, prepared as described in J. Med. Chem. 36,4214,1994), BEMP (2 mi, 7 mmol) and benzylbromide (0.6ml, 5 mmol) In CH3CN (20 ml) was refluxed for 1hour. The reaction mixture was concentrated to dryness; the residue was then re-dissolved in ethyl acetate and washed with a saturated solution of NaCI, dried over Na2S04, filtered and evaporated under vacuum. The residue was purified by flash chromatography over silica gel (CH2CI2/ MeOH / NH4OH 95 / 5 / 0.5) to afford 0.7 g of the title compound as yellow oil. Yield: 87% ^H-NIVIR (CDCI3) 5: 7.39-7,10 (m, 5H); 5.03 (dd, 1H); 4.71 (d, 1H); 4.29 (d, 1H); 4.28 (d, 1H); 3.59 (d, 1H); 2,57 (ddd. 1H); 2.39-2.125 (m, 2H); 1.92-1.77 (m, 1H). 17 91.03. Example 46. 1-(4-methybenzyl) -tetrahydrt)-pyirolo[1,2-aJimidazol0-2,5^ione. A solution of tetrahydro-pyrroIo[1,2-a]imida2oIe-2,5-dione (0.5 g, 3.5 mmol, prepared as described in J. Med. Chem. 36, 4214,1994), BEIVIP (2 ml, 7 mmol) and 4-methylben2ylbromide (0.95 ml, 5 mmol) in CH3CN (20 ml) was refljxed for 1hour. The reaction mixture was concentrated to dryness; the residue was tlien re-dissolved In ethyl acetate and washed with a saturated solution of NaCI, dried over NazSOA, filtered and evaporated under vacuum. The residue was purified by flash chromatography over silica gel (CHaCIa/ MeOH / NH4OH 95 / 5 / 0.5) to afford 0.8 g of the title compound as yellow oil. Yield: 93% ^H-NMR (CDCI3) & 7.29-7.11 (m, 4H); 5.01 (m, 1H); 4.69 (d, 1H); 4.29 (d, 1H); 4.23 (d, 1H); 3.58 (d, 1H); 2.65-2.50 (m, 1H); 2.40-2.24 (m. 2H); 2.33 (s, 3H); 1.93-1.78 (m.lH). MS: El TSQ 700; source 180 C; 70 V; 200 uA: 244.13 (M+), 161.05,105.02 Pharmacological Methods Chronic constriction Injury model A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve according to the method described by Bennett & Xie (Pain 1988, 33, 87-107). Rats were anesthetized with chloral hydrate. The common sciatic nerve was exposed at the level of the middle of the thigh by blunt dissection through biceps femoris. Proxlnnal to sciatica's trifurcation, about 1 cm of the nerve was freed of adhering tissue and four ligatures (3/0 silk tread) were tied loosely around it with about 1 mm spacing. The length of the nerve thus affected was 1 cm long. Great care was taken to tie the ligatures such that the diameter of the nerve was seen to be just barely constricted when viewed with 40 x magnification. The left paw was untouched. Paw pressure test The nociceptive threshold in the rat was determined with an analgesimeter (Ugo Basile, Varese, Italy), according to the method described by Leighton ef at. {Br. J. Pharmacol. 1988, 93, 553-560). Rats scoring below 40 g or over 75 g during the test before drug administration (25%) were rejected. An arbitrary cut-off value of 250 g was adopted. All experiment were perfonmed on rats submitted to paw-pressure test 14 days after the operation since at this time a significantly reduction of the pain threshold of the injured paw (dx) was observed. Gabapentin (30µg i.c.v.), levetiracetam (300 µg i.c.v.), dimiracetam (100)µg i.c.v.), Example 1 (10 µg i.c.v.). Example 2 (10 µg I.e.v.), Example 5 (3 µg i.c.v.), Example 6 (3 µg i.c.v.), Example 13 (30 µg i.c.v.) and Example 22 (30 µ.g i.cv.) of the present invention showed an antihyperalgic effect when compared with saline or vehicle treated group. All componds did not modify pain threshold in controlateral, non operated, paw. It should be noted that all compounds elicited their antihyperalgic effect without changing animals' gross behavior and spontaneous motility in comparison with saline/vehicle treated rats. Furthermore no modification of motor coordination was revealed by the rat rota-rod test (Vaught J. et al. Neuropharmacology 188S, 24,211-216). WE CLAIM: 1 • A compounds of the general formula (I) in which: A is chosen among carbocyclic aromatic groups, heterocyclic aromatic groups, and arylC1-4alky!; R1 is chosen among: - hydrogen, - arylC1-7alkyl, optionally substituted on the aryl moiety with one or more groups chosen among hydroxy, C1-4alkoxy, halogen, haloC1-4alkyl; - heterocyclylC1.7alkyl, optionally substituted on the heterocydy! moiety with one or more groups chosen among C1.4alkyl and hydroxy; - C1.7 alkyl, optionally interrupted by an oxygen or sulphur atom or optionally substituted at any position by one or more groups chosen among hydroxy, thio, amino, carboxyl, aminocarbonyl, guanidinyl. R2 is chosen among hydrogen, C1.4alkyl, arylC1.4alkyl and phenyl; or else R1 and Rg, taken together, form a saturated carbocyclic R1ng containing from 3 to 8 carbon atoms; R3 is chosen among hydrogen, C1.4alkyl, arylC1.4alkyl, CONH2 and GOOR5 in which R5 is chosen between hydrogen and C1.4alkyl; R4 is chosen among hydrogen, C1.4alkyl, 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 pharmaceuticaliy acceptable salts or solvates thereof. 2. The compounds according to claim 1, in which: A is phenyl, thienyl, pyR1dyl, pyR1midinyl group, optionally substituted, benzyl or 4-methylbenzyl; R1 is hydrogen. C1-4 alkyl, benzyl, -CHaOH, -CH2CH2CONH2, -CHaCOOH, indol(3-yl)methy!; Ra is hydrogen. CM alkyl or benzyl; R3 and R4 are hydrogen or methyl, and n is 2. 3. The compounds according to claim 2, in whicli: A is ptienyl optionally substituted; R1, R2, R3 and R4 are liydrogen; and n is 2. 4. The compounds according to claims 1-3, in wliiC1i A Is substituted witin 1 to 3 substituents chosen among Me, Et, i-Pr, OH, COOEt, COOH, CH2OH, SO2NH2. SO2Me, OMe, C1, F, CN and CF3. 5. The compounds according to claim 4, in wliiC1i A is substituted with 1 to 3 substituents cliosen among Me, Et, i-Pr, OH, CN, C1 and CF3, 6. Tine compounds according to claim 1 or 2, in whicli said C1^ail 7. The compounds according to clainn 1, chosen in the group consisting of: 1 -Phenyl-tetraliydro-1 H-pyrrolo[1,2-a]imidazole-2,5-dione; 1 -o-tolyl-tetrahydro-1 H-pyrrolo[1,2-a]imidazole-2,5-dione; 1-(2,6-Dimethy!-phenyl)-tetrahydro-pyrrolo[1,2-a]iniidazol6-2,5-dione; 1 -Thiophen-2-yl-tetrahydro-pyrrolo[1,2-a]imidazoie-2,5-dione; 1 -m-Toiyl-tetrahydro-pyrrolo[1,2-a] imidazole-2,5-dione; 1-p-Tolyl-tetrahydro-pyrrolo[1,2-a] imidazole-2,5-dione; 1-(5-Fluoro-2-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1-(3-Fluoro-2-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dlone; 1-{2-TR1fluoromethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazol6-2,5-dione; 1'(4-Chloro-2rmethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imldazole-2,5-dione; 1 -{3-Chloro-phenyl)-tetrahydro-pyn-olo[1,2-a]imidazole-2,5-dione; 1-(3-Methoxy-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dlone; 1-(3-Cyano-phenyl}-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; l-(4-Chloro-phenyl)-tetrahydro-pyn-olo[1,2-a]imidazole-2,5-dione; 1-(3-Hydroxy-phBnyI}-tetrahydro-pyrroio[1,2-a]imidazole-2,5-dione; 1-(3-TR1fluoromethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imida2olB-2,5-dione; 1-(4-TR1fluoromethyi-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1-(4-MBthoxy-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazoie-2,5-dlone; 1-(3,5-Dimethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1-{3,4-Dimethyl-phBnyl)-tetrahydro-pyrroloIl,2-a]imidazole-2,5-dione; 1-Naphthalen-2-yl-tetrahydro-pyrroio[1,2-a]imidazole-2,5-dione; 1-(3-lsopropyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imldazole-2,5-dione; 1-(4-Chloro-3-methyl-ph6nyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 3-Benzy!-1-phenyl-tetrahydro-pyrrolo[1,2-a]imidazol6-2,5-dione; 3-Methyl-1.-phenyI-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 3-lsobutyl-1-phenyl-tetrahydro-pyrrolo[1,2-a]imida2ole-2,5-dione; 1-(3-Fluoro-5-methyl-ph9nyl)-tetrahydro-pyrrolo[1,2-a]imida2ole-2,5-dione; 1-(3-Fluoro-4-methyl-phenyl)-t6trahydro-pyrrolo[1,2-a]innidazole-2,5-dione; 7a-Methyl-1 -phenyl-tetrahydro-pyrrolo[1,2-a]imida2ole-2,5-dione; (S)-1 -o-Tolyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; (R}-1 -oToly!-tetrahydro-pyrroio[1,2-a]irnidazoie-2,6-dione; 1-(4-Ethyl-phenyI)-tetrahydro-pyrroloi;i,2-a]imida2ole-2,5-dione; 1'(4-lsopropyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1-(4-Hydroxymethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imida2ole-2,5-dione; 4-(2,5-Dioxo-hexahydro-pyrro!o[1,2-a]imida2ol-1 -yl)-ben2oic aC1d; 4-(2,5-Dioxo-hexahydro-pyrrolo[1,2-a]imida2ol-1-yI)-benzoic aC1d atliyl ester; 1-(4-Metlianesulfonyl-pliBnyi)-tetraliydro-pyrrolo[1,2-a]imldazo)e-2,5-dione; 1-(4-Fluoro-plienyl)-tetrahydro-pyiTolo[1,2-a]imidazole-2,5-dione; 1-(4-Cyano-piienyl)-tetraliydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1-PyR1din-2-yl-tetraliydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1 -PyR1din-3-yl-tetraliydro-pyrroio[1,2-a]imidazoie-2,5-dlone; 1-(5-MethylpyR1din-2-yl)-tetraliydropyrroio[1,2-a]imidazDle-2,5-dione; 1-(2-Cyano-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazol6-2,5-dione; 1-(3-Fluoro-phenyl)-tetralnydro-pyrrolo[1,2-a]imidazole-2,5-dione; 1 -Benzyl-tetraliydro-pyrrolo[1,2-a]imidazole-2,5-dione. 1-(4-metliy!ben2yl)-tetraliydro-pyrrolo[1,2-a]imidazole-2,5-dione. 8. A process for ttie preparation of the compounds of formula (I) as descR1bed in c laim 1, compR1sing the reaction of a compound of formula (II) (H) with a compound of formula (111) A-X (III) in which A, R1, R2, R3, R4 and n are defined as in Claim 1, and X is a halogen atom, to obtain the desired compounds of formula (I). 9. The process according to claim 8, in which in the compound of formula (111) X is chosen between bromine and iodine. 10. The process according to claims 8-9, for the preparation of the compounds of formula (1) wherein A is a carbocyclic aromatic group or a heterocyclic aromatic group, optionally substituted, in which the compound of formula (II) is dissolved in an appropR1ate solvent together with the compound of formula (111) in the presence of a base and of a catalytic amount of a copper salt, at a temperature of between 60oC and 140°C. 11. The process according to claim 10, in which said solvent is N- methylpyrrolidone, said base is potassium carbonate, said copper salt is copper iodide, and the reaction is conducted at a temperature of 120o'C. 12. The process according to claims 8-9, for the preparation of the compounds of formula (1) wherein A is arylC1.4alky!, in which the compound of formula (II) is dissolved in an appropR1ate solvent together with the compound of formula- (III), in the presence of a suitable base at a temperature between 60 °C and 140*^. 13.The process according to claim 12, in which said solvent is chosen among acetonitR1le, methylene chloR1de, acetone, said base Is chosen among tR1ethylamine, potassium carbonate, 2-te/t-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphoR1ne, N,N-Diiso-propylethylamlne, at a temperature of 100 °C. 14, The process for the preparation of compounds of formula (I) as descR1bed in claim 1, compR1sing the following stages: i) reaction of an amtnoaC1d of formula (IV) or of one of its activated deR1vatives (IV) with a compound of formula (V) A-NH2 (V) to obtain a compound of formula (VI): in which R1, R2 and A are as defined above in Claim 1, and P Is H or a suitable. protective group; ii) reaction of tHe compound of fomula (VI) obtained in stage i) with a compound of formula (VII) (Vli) to obtain a compound of formula (VIII) in which A, R1, R2, R3, R4 and n are as defined in Claim 1, P is defined a above, and R' is an alkyl group; iii) possible removal of the protective group P by means of hydrogenolysis of the compound of formula (Vlll) obtained from stage fi), to obtain the correspondin compound (VIII), In which P is H; and iv) cyclization of the compound of formula (Vlll), In which P is H coming from stage ii) or from stage iii), to obtain the desired compound of formula (1). 15. The process according to claim 14, in which R' is chosen between methyl and terf-butyl, and P is chosen between H, benzyl-and benzyloxycarbonyl. 16. The process according to claim 14, in which, in said stage iv), the cyclization reaction is canied out by heating the compound (Vlfl) in the. absence of solvent at 120°C and in vacuum conditions, or else by reflux-heating the compound (VIII) in xylene for a time compR1sed between 4 hours.and 3 days. 17. The process according to claim 14, in which said stage ii) is conducted by reflux-heating the compounds of fomnula (VI) and (VII) in a protic solvent for a time compR1sed between 2 and 24 hours, possibly in the presence of a base. . 18. The process according to claim 14, in which the reaction descR1bed in stage i) is conducted between the aC1dic chloR1de of the compound (IV) and the compound (V) in the presence of an Inorganic or organic base in a suitable aprotic solvent at a temperature of between -70oC and 50oC. 19. The process according to claim 14, in which the reaction of stage i) is conducted by reacting together the compound (IV) and the compound (V) in the . presence of a suitable condensating agent, in an aprotic solvent at a temperature of between -TCC and 5p°C. 20. The process according to claims 18 or 19, in which said temperature is compR1sed between -10oC and 20oC. 21. A pharmaceutical composition compR1sing as active piinoiple one or more compounds of fomnula (I) as descR1bed in claim 1, or pharmaceutically acceptable salts or solvates thereof. 22. The pharmaceutical composition according to claim 21, wherein it compR1ses vectors, diluents and/or pharmaceutically. acceptable exC1pients suitable for forms of administration chosen between oral, parenteral, rectal, transdermal, and transmucosal. 23. The pharmaceutical composition according to claims 21 and 22, in the form of solutions, suspensions, soluble powders, granules, microcapsules, capsules, lozenges, tablets, coated tablets, suppositoR1es, creams, ointments, lotions, pastes, medicated plasters, membranes or gels.

Full Text

The present Invention relates to new compounds of formula (I) appearing
hereinafter, their process of preparation, the pharmaceutical compositions
containing them, and their use as nootropic, neuroprotective, analgesic and
anti-hyperalgesic agents.
State of the art
Compounds that possess nootropic activity are already known in the literature.
In particular, the derivatives substituted in position 4 of 2-oxo-1-
pyrroiidineacetamide 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,
447,1982byltiletal.
Amongst the most widely known molecules belonging to the class mentioned
above there may be cited: 2-oxo-1-pyrrolidineacetamide (piracetam), 4-hydroxy-
2-oxo-1-pyrroIidineacetamide (oxiracetam), 2-(2-oxopyrrolidin-1-yl) butyramide
(levetiracetam) and W-(2,5-dimethylphenyl)-2-oxo-1-pyrrolidineacetamide
(nefiracetam).
Another chemical class that possesses nootropic activity is represented by
Imidazolic condensed derivatives, in particular 2,5-dIoxohexahydro-1H-
pyn-olo[1,2-a]imida2ole (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 demonstrated that nefiracetam could be a good
therapeutic agent in the treatment of neuropathic pain. The anti-hyperalgesic
action induced by nefiracetam appears to be of non-oploid nature and is
probably due to the stimulation of the nicotinic cholinergic system at a spinal
and supersplnal level (Rashid Harunor M.D. J. Pharmacol. Exp. Ther, 303, 226,
2002).
EP 0174136 discloses compounds of the formula below.

As evident, the imidazole ring has a completely different pattern of substituition, lacking inter alia the A substituent in position 1, typical of the present invention.
EP 0335483, Mario pinza et. al. J. of Medicinal chemistry vol. 36 No.6, 1993 pages 4214 to 4220 and WO 9309120 disclose compounds of the formula below,

wherein none of the meanings of Rl (= hydrogen, unsubstituted alkyl, alkylaminocarbonylalkyl, alkoxycarbonylalkyl) anticipates the substituent "A", typical of the present invention.
2~

Summary of the invention
The present applicant has now found new N-substituted bicyclic imidazolones of formula (I), appearing hereinafter, that have demonstrated improved psychotropic properties and more marked analgesic and antihyperalgesic effects In numerous models of neuropathic pain, with respect to the already known rusotropic agents.
The present compounds of formula (I) are consequently useful in the treatment of many disorders of the central nervous system (CNS), for example in the deterioration of learning, dysfunctions of the cognitive sphere and of the memory, Afehelmer's disease, dementias, including senile dementia of the Alzheimer type, post stroke vascular type dementia, epilepsy, cerebral ischaemla, mood disorders, indudfng depression, chronic, inflammatory, neuropathic and visceral pain, and emesis.
Consequently, representative of the subject of the present Invention are compounds of the general formula (t)

in which:
A is chosen among carbocyclic aromatic groups, heterocyclic aromatic groups
and arylC1alkyl;
Ri is chosen among:
- hydrogen,
- arylC1.yalkyi, optionally substituted on the aryi moiety with one or more groups chosen among hydroxy, C1alkoxy, halogen, haloC1alkyl;
- heterocyclylC1.7alkyl, optionally substituted on the heterocyclyl moiety with one or more groups chosen among C1-4(alkyl and hydroxy,
- C1.7 alkyl, optionally Interrupted by an oxygen or sulphur atom or optionally substituted at any position by one or more groups chosen among hydroxy, thio, amino, carboxyl, aminocarbonyi, guanidinyt.

Rz is chosen among hydrogen, C1alkyl, arylC1alkyl and phenyl;
or else Ri and R2, laken together, form a saturated carbocyclic ring containing
from 3 to 8 carbon atoms;
R3 is chosen among hydrogen, C1alkyl, arylC1alkyl, CONH2 and COOR5 in
which Rs is chosen between hydrogen and C1-4alkyI;
R4 is chosen among hydrogen, C1-,alkyl, aryl, arylC1alkyl and heterocyciyl;
and
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 of preparation of the compounds of formula (i) appearing above,
the pharmaceutical compositions containing them and their use for the
preparation of medicaments with nootropic and neuroprotective action, with
analgesic and/or anti-hyperalgesic action, and anti-emetic action, constitute a
further subject of the invention.
Characteristics and advantages of the present compounds of formula (I) will be
illustrated in detail in the following description.
Description of the figures
Figures la, 1b: non limiting examples of aminoacids of formula (IV), useful in
the synthesis of the compounds of formula (i). The encircled portion indicates
thesubstituentRi.
Detailed description of the Invention
In the frameworiocyclic aromatic group"
means single or fused aromatic rings with 6 to 12 ring members, optionally
substituted.
The terms "heterocyclic aromatic group" and "heterocyciyl" mean single or
fused aromatic rings, each ring having 5 to 12 members and comprising up to
four hetero atoms, chosen among oxygen, sulphur and nitrogen, optionally
substituted.
Whenever not othenvise specified, the term "aryl" means single or fused
unsaturated rings, each ring having from 5 to 8 members, and preferably 5 or 6
members, optionally substituted; by the term "arylCiw«alkyr is Indicated a group

having an aryl group, as defined above, and a CM alkyl moiety connecting the
aryl group to the point of substitution.
All the aforesaid C1 alkyl groups, including those being part of the arylC1alkyl
group, may i^e indifferently linear or branched or cyclic (i.e cyclopropyl,
cydopropylmetyl or methylcydopropyl). Preferred C1-C4 alkyl groups are Me,
Et, i-Pr, i-Bu, and cyclopropylmethyl.
All the aforesaid C1.7 alkyl groups, including those being part of C1.7 alkyl-
containing groups, can either be linear, branched or cyclic, and may include
double or triple bonds. The term "Ci-r alkyl groups interrupted by oxygen or
sulphur" means, respectively, any ether and thioether groups containing from 1
to 7 carbon atoms.
By the term "heterocyciyiCi-ralkyl" is indicated a group having an heterocyclyl
group, as defined above, and a C^.^ alkyl moiety connecting the aryl group to
the point of substitution.
By the term "aryiCi-7alkyi" is indicated a group having an aryl group, as defined
above, and a C1.7 alkyl moiety connecting \he aryl group to the point of
substitution.
By "halogen" is meant an atom chosen among fluorine, chlorine, bromine or
iodine; by "haloC1alkyl" is meant a C1 aikyi group substituted at any position
by one or more halogen atoms, e.g. trlfluoromethyl.
Unless differently specified, "optionally substituted" groups are groups optionally
substituted with 1 to 3 substituents, chosen preferably among Me, Et, i-Pr, OH,
COOEt, COOH, CH2OH, SO2NH2. SO2MB, OMe, CI. F, CN and CF3, and more
preferably among Me, Et, i-Pr, OH, CN, CI and CF3; the subsftuents may be in
any position of the group to be sutistituted.
Preferred compounds according to the invention are the compounds of formula
(I), In which A Is a optionally substituted phenyl, optionally substituted benzyl, or
else a optionally substituted heterocyclic aromatic group with 5 or 6 members
and comprising up to two hetero atoms chosen between oxygen, sulphur and
nitrogen, Ri, R2, R3 and R4 are chosen among hydrogen, C1.4 alkyl or benzyl,
and n is equal to 2 or 3.
Preferably, A is phenyl, thlenyl, pyridyl, pyrimidinyl group, optionally substituted,
benzyl or 4-methylbenzyl; Ri is hydrogen. CM alkyl (for example methyl,

isopropy! or isobutyl). benzyl, -CH2OH, -CH2CH2CONH2. -CH2COOH, lndol(3-
yl)methyl, Rj is hydrogen, C1 alkyl or benzyl, R3 and R* are hydrogen or
methyl, and n !s 2.
More preferably, A is a phenyl, opt'onaily substituted, Ri, R2, R3 and R4 are
hydrogen, and n is equal to 2.
When Ri and R2, taken together, form a saturated carbocyclic ring containing
from 3 to 8 carbon atoms, the resulting compound of formula (I) is a spirocyclic
compound.
Preferred compounds of formula (I) according to the invention are chosen in the
group consisting of:
1-Phenyl-tetrBhydro-1 H-pyrrolo[1,2-a]!mldazoIe-2,5-dione;
1-o-tolyl-tetrahydro-1 H-pyrrolo[1,2-a]lmida2ole-2,5-dione;
1 -(2,6-Dimethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]lmidazole-2,5-dione;
1 -Thiophen-2-yl-tetrahydro-pyrrolo[1,2'a]imidazole-2,5-dione;
1-m-Tolyl-tetrahydro-pyrrolo[1,2-a] imidazole-2,5-dione;
1 -p-Tolyl-tetrahydro-pyrrolo[1,2-a] imidazole-2,5-dione;
1-(5-Fluoro-2-methyl-phenyl)-tetrahydro-pynrolo[1,2-a]imidazole-2,5-dione;
1-(3-Fluoro-2-methyl-phenyl)-te^hydra-pyn'olo[1,2-a]imidazole-2,5-dione;
1-(2-Trifluoromethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazoIe-2,5-dione;
1-(4-Chloro-2-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1 -(3-Chloro-phenyl)-tetrahydro-pyn"olo[1,2-a]imldazole-2,5-dione;
1 -(3-Methoxy-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1 -(3-Cyano-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1 -(4-Chloro-phenyl)-tetraihydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1 -(3-Hydroxy-phenyI>-t6trahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1-(3-Trlfluoromethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imldazole-2,5-dione;
1-(4-Trifluoromethyl-phenyl)-tetrahydro-pynrolo[1,2-a]imidazole-2,5-dione;
1-(4-Methoxy-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazol©-2,5-dione;
1-(3,5-Dimethyl-phenyl)-tetrahydro-pyrolo[1,2-a]imidazole-2,5-dione;
1-(3,4-Dimethyl-phenyl)-tatrahydro-pynrolo[1,2-a]imidazole-2,5-dione;
1 -Naphthalen-2-yl-tetrahydro-pyrroloI1,2-a]imidazole-2,5-dione;
1-(3-lsopropyl-pinenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;

1-(4-Chloro-3-methyl-phenyl)-tetrahydra-pyrrolo[1,2-a]imlda20le-2,5-dione;
3-Ben2yI-1 -phenyl-t8trahydro-pyrrolo[1,2-a]imldazole-2,5-dlone;
3-Methyl-1-phenyl-tetrahydro-pyrroIo[1,2-a]imida2ol0-2,5-dione;
3-lsobutyl-1 -phenyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1-(3-Fluoro-5-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1-(3-Fl uo ro-4-nnethyl-phenyl)-tetrahydro-pyiTOlo[1,2-a]i midazolB-2,5-dione;
7a-Methyl-1 -phenyl-tetrahydrcvpyrrolojl ,2-a]imidazole-2,5-dione,-
(S)-1 -o-Tol>^-tetrahydro-pyrrolo[1,2-alimidazote-2,5-dione;
(R)-1 -o-Tolyl-tetrahydro-pyrrolo[1,2-a]ifnidazole-2,5-dione;
1 -(4-Ethyl-phBnyl)-tetrahydropyrTolo[1,2-a]imida2ole-2,5-dione;
1-(4-lsopropyl-phGnyl)-tetrahydro-pyrroIo[1,2-a]imfdazole-2,5-dione;
1 -(4-Hydroxymethyl-phenyl)-tetrahydro-pynrolo[1,2-a]lmidazole-2,5-dione;
4-(2,5-Dioxo-hexahydro-pyrrolo[1,2-a]lmidazol-1-yl)-benzoic acid;
4-(2,5-Dioxo-hexahydro-pyrrolo[1,2-a]imidazol-1-yl)-benzoic acid etliyi ester;
1-(4-MQthanesulfonyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1 -(4-Fluoro-plienyl)-tetraliydro-pyiTolo[1,2-a]innidazole-2,5-dione;
1 -(4-Cyano-phenyI)-tetrahydra-pyrrola[1,2-a]imidazoIe-2,5-dione;
1 -Pyridin-2-yl-tetrahydro-pyiToloI1,2-a]innldazole-2,5-dFone;
1 -Pyridin-3-yl-tetraliydro-pyiTClo[1,2-a]imidazole-2,5-dione;
1-(5-lV1ethylpyridin-2-yl)-tetrahydropyrrolo[1,2-a}imidazole-2,5-dione;
1 -(2-Cyano-plienyl)-letraliydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1-(3-Fluoro-phenyl)-tetrahydrD-pyrToio[1,2-a]imidazole-2,5-dione;
1 -Benzyl-tetrahydro-pyrrolo[1,2-alimidazole-2,5-dione;
1 -(4-metliylbenzyl)-tetrahydro-pyrrolG[1,2-a]imidazole-2,5-dione.
It will be noted that some compounds of formula (I) can contain one or more
stereogenic centres. The present invention extends to all Vne optical isomers of
tliese compounds in their forms entirely or partially resolved and in the form of
racemic mixtures.
A further subject of the invention is a process for the preparation of the
compounds of formula (I), or one of their salts, and/or one of their solvates,
comprising the reaction of a compound of formula (11)

with a compound of formula (ill) A-X
(111) in which A, R1, R2, R3. R4 and n are defined as above for the compounds of formula (I), and X is a halogen atom, chosen preferably between bromine and iodine.
When A is a aromatic carbocydic group or a heterocyclic aromatic group as above defined, the reaction between the compounds of fomrjula (II) and the compound of formula (III) can be conducted according to the appropriate conditions of the Goldberg reaction {Angew. Chem. Int. E., 39, 4492, 2000). In particular, the compounds of formula (II) are dissolved in a suitable solvent, such as A/-methylpyrrolldone, together with the compounds of 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 yield an adequate percentage of fonmation of the product required, suitably at a high temperature, such as a temperature of between 60'C and 140C, for example at 120'C. The reaction mixture is heated using a system of conventional heating or a microwave reactor of adequate power, for example comprised between 25 and 250 W {Tetrahedron Letters, 43,1101,2002).
When A is arylC1alkyl, the reaction can be carried out in a suitable solvent such as acetonitrile, methylene chloride, acetone, in the presence of a suitable base such as triethyiamine, potassium carbonate, 2-ferf-Butyllmino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine (also known as BEMP), N,N-OiisopropylethylamJne (also known as Hunig base), at a suitable temperature such as reflux temperature (60-140°C, preferably 100°C).

The aforesaid compounds of formula (II) and the methods for their preparation are described in the European patent application EP-A-335483 and in the International patent application No. WO-A-93/09120 and in J.Med.Chem., 36, 4214,1993, by PInza et al.
The compounds of formula (ill) are commercially available or can be prepared from i^nown compounds by known methods.
Altematively, the compounds of formula (I) can be prepared with a process comprising the following stages: i) reaction of an aminoacid of formula (IV) or of one of its activated derivatives

In which Ri, Rj and A are as defined above for the compound of formula (I), and P is H or a suitable protective group. The activation of aminoacids is a well-known synthetic procedure; examples of activated derivatives of the aminoacids are mixed anhydrides, acyl chlorides and activated esters, ii) reaction of the compound of formula (VI) obtained at stage i) with a compound of formula (VII)

(VIII) in which A, Ri, R2, R3, R4 and n are as defined above for the compound of formula (I), P Is defined as above, and R' is an alkyl group; lit) possible removal of the protective group P by means of hydrogenolysis of the compound of formula (VIII), obtained in stage ii), to obtain the corresponding compound (VIII), in which P is H; and
iv) cyciization of the compound of formula (VIII), in which P is H coming from stage Ii) or from stage ill), to obtain the desired compound of formula (I). According to a prefenred embodiment of the invention, the all(yl residue R' is chosen between methyl and tert-bulyl, and P Is chosen between hydrogen, a benzyl or a benzyloxycarbonyf group.
The reaction in stage i) between the compound of formula (IV) and the compound of formula (V) can be performed:
(a) by preparing, In the first place, an acidic chloride of the compound of formula (IV) and uniting to said acidic chloride the compound of formula (V) in th9 presence of an inorganic or organic base In an adequate aprotic solvent, such
10

as dimethylformamlde (DMF) at a temperature of between -70°C and 50°C, and preferably between -10'C and 20°C; or else:
(b) by reacting together the connpound of formula (IV) with the compound of formula (V) in the presence of a suitable condensating agent, such as N.N'-carbonyl diimidazole (CD!) or a carbodiimmide such as dicyclohexylcarbodiimmlde (DCC) or W-dlmethylamlnopropyl-A/-ethylcarbodilmmide, preferably in the presence of A/-hydroxybenzotriazole (HOBT) to maximize the yield and prevent the processes of racemization (cf. Synthesis, 453, 1972), or 0-benzotriazol-1-yl-N,A/,W,A/-tetramethyluronium hexafluorophosphate (HBTU), in an aprotic solvent, such as a mixture of acetonitrile (MeCN) and tetrahydrofuran (THF), for example, a mixture with volumetric ratio comprised between 1:9 and 7:3 (MeCNiTHF), at any temperature capable of yielding an adequate percentage of formation of the product required, such as a temperature of between -70°C and 50°C, and preferably between -10°C and 25°C.
At stage ii) of the present process, the compounds of formula (VI) and (VII) are preferably refiux-heated 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 formula (VI) is used in the fomn of one of its salts obtained by addition of acid, for an adequate period of time, preferably comprised between 2 and 24 hours.
Removal of the protective group P by means of hydrogenolysis at stage iii) is preferably conducted using ammonium fomntate as a source of hydrogen in a suitable protic solvent, such as methanol or a methanoi-water mixture. The cyclizatlon reaction in stage iv) is carried out directly on the compound of formula (VIII) coming from stage II) if P is H, or else, if in said compound (Vlli) P is a protective group, the first step is to remove It, as described above in stage iii).
The cyclizatlon reaction is conducted in drastic conditions by conventionally heating the compound of formula (VIII) without solvent at 120'C and in vacuum conditions, or else by means of reflux-heating in xylene for a suitable period of time, for example between 4 hours and 3 days, or by microwave irradiation.
11

The compounds of formula (IV), (V) and (Vil) are commercially available compounds or can be prepared from known compounds using known methods. In particular, the compounds of formula (iV) can be conveniently selected from any naturally occurring aminoacids or derivatives thereof. Examples of aminoacids useful in the present Invention are shown in figure 1, where the part encircled corresponds to the substituent R1 of formula (IV): accordingly, all these meanings for R1 are also preferred in formula (I), being the object of the present invention.
The present compounds of fomriula (I) are useful as therapeutic agents and in particular possess a nootropic and neuroprotective activity, i.e., they contribute to restoring the learning and memory functions deteriorated in the process of ageing or on account of ischaemic traumas, and are effective in various pathologies of the CNS, amongst which learning dysfunctions, dysfunctions of the cognitive sphere and of the memory, Alzheimer's disease, dementias, including senile dementia of the Alzheimer type, post stroke vascular type dementia, epilepsy, cerebral ischaemla, and mood disorders, including depression.
The present compounds of formula (I) moreover possess analgesic and/or anti-hyperalgesic activity, i.e., they contribute to combat the sensations of pain, in particular those caused by conditions of neuropathic pain, chronic inflammatory pain and visceral pain, and have proven their efficacy also in the treatment of emesis.
The subject of the present Invention is lience also the use of the present compounds of fomnula (I) or of their pharmaceutically acceptable salts and/or solvates for the preparation of medicaments for recovery of difficulties of learning and memory and for treatment of dementias, Alzheimer's disease, post stroke vascular type dementia, epilepsy, cerebral ischaemla, and mood disorders, including depression.
Also provided is a method to treat the aforesaid diseases and disorders characterised by administering a pharmaceutically active anrKSunt of a compound of formula (I) to a patient in need thereof.
It is widely known that cognitive disorders that occur in said pathologies are correlated to the deficit of the cerebral cholinergic system, as emerges from

morphological findings (B.E. Tomilnson in "Biochemistry of Dementias"; P.J. Roberts Ed.; John Wiley & Sons, New Yori The activity of the compounds of formula (I) can be determined in rats in regard to the amnesia-provolry and learning can be evaluated in rats using the passive-avoidance test, as described by Essman, Pharmacol. Res. Commun. 5, 295, 1973.
The subject of the present invention is, nwreover, the use of the present compounds of 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 to treat the aforesaid diseases characterised by administering a pharmaceutically active amount of a compound of formula (I) to a patient in need thereof.
It is hypothesized that the process of learning and memory is Implicated 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 (Amstein P.M., J. Neurosci Nurs. 29, 179, 1997; Kumazava T., Neurosci. Res., 32, 9, 1998). Cognitive dysfunction has been described in various neuropathic conditions (Kuhajda M.C., Ann. Behav. Med., 20, 31. 1998), and it has recently been observed that nefiracetam, a nootropic agent, alleviates neuropathic pain thanks to its specific effects on neuropathies (Rashid HanjnorM.D. J. Pharmacol. Exp. Ther., 303, 226, 2002). It has been shown that the analgesic and/or antl-hyperaigesic effect of nefiracetam expresses itself through stimulation of the nicotinic cholinergic receptors at the spinal and supraspinal level, in so far as said effect is inhibited

In a dose-dependent way by mecamylamine, a known antagonist of the nicotinic acetylC1line receptor.
The activity of the compounds of formula (1) can be determined in mice by means of tl^ thermal-hyperalgesia test (paw-withdrawal test) and the mechanical-hyperaigesia test (paw-pressure test) induced by partial ligation of the sciatic nerve or by treatment with streptozotocine, following the protocols described in J. Pharmacol. Exp. Ther., 303, 226, 2002 and in the bibliography cited therein.
When used in the therapeutic treatment of humans and animals, the compounds of formula (I) are nomnaily formulated, in compliance with standard pharmaceutical practice, as a pharmaceutical composition, l-lence, a further subject of the invention is represented by a pharmaceutical composition comprising, as active principle, a compound of formula (i) or one of its pharmaceutically acceptable salts or solvates, together with vectors, diluents and pharmaceutically acceptable excipients suitable for the chosen form of administration.
The compounds of formula (I) can be administered in a standard way in the treatment of the disorders Indicated above, for example via oral, parenteral, rectal, transdermal route or by administration through the mucosa (for example, the sublingual, buccal, or nasal mucosa).
The compounds of formula (I) which are administered orally or via sublingual route or via buccal administration, can be formulated as syrups, tablets, capsules, and lozenges. A formulation In the form of syrup consists generally of a suspension or solution of the compound or of one of its salts in a liquid vector, for example ethanol, glycerine or water with a flavouring or colouring agent. When the composition is in the fomrt of tablets. It is possible to use any pharmaceutical vector used conventionally in the preparation of solid foonulations. Examples of said vectors comprise magnesium stereate, starch, lactose and sucrose. When the composition is in the form of capsules, any conventional method of encapsulation is suitable, for example using the vectors mentioned above in a capsule of hard gelatine. When the composition is in the form of capsules made of soft gelatine, it is possible to use any pharmaceutical vector used conventionally in the preparation of dispersions or suspensions, for

example aqueous gums, cellulose, silicates or oils, to be incorporated into a shell made of soft gelatine.
Typical parenteral compositions consist of a solution or suspension of the compound of fomnula (i) In a aqueous or non-aqueous sterile vector, possibly containing an oil acceptable for the parenteral route, for example polyethyiene-giycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil. The typical formulation in suppositories comprises a compound of formula (t), which is active if administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatine, cocoa butter, or other low-melting waxes or vegetable fats.
Typical transdermal formulations comprise a conventional aqueous or non¬aqueous vector, for example cream, ointment; lotion or paste, or can be in the form of medicated plasters, patches or membranes.
Preferably, the composition Is in a unit-dose forni, for example tablete or capsules, so that the patient can take a single dose.
Oxyracetam Is a compound used in ^e treatment of senile dementia and of pathological conditions correlated thereto. The compounds of formula (I) can be administered with regimes similar to the ones established for oxyracetam with any appropriate adjustment of the levels of dosage or of the frequency of dosage in relation to the greater activity and to the better pharmacological profile of the compounds of formula (I).
Each dosage unit for oral administration may expediently contain from 0.05 mg/kg to 50mg/kg, nwre expediently from 0.1 mg/kg to 25mg/kg of a compound of formula (I). The active ingredient can be administered from 1 to 6 times a day. The compounds of formula (I) can be co-administered with other pharmaceutlcaily active compounds, for example in association, concurrently or sequentially, in particular together with other compounds used in the treatment of elderly patients, such as tranquilizers, diuretics, anti-hypertensive drugs, vasodilator drugs, and inotropic agents.
Examples of the present invention are provided in what follows, purely for illustrative and non-limiting purposes. EXPERIMENTAL PART Description 1.3-lsobutyl-tetrahydrO'pyrrolo[1,2'a]imldazole-2,5-dione.

To a solution of DL-leucinamide hydrochloride (1.5 g, 9 mmoi) in water (40 ml), adjusted to pH 9.5 with 10% sodium hydroxide, ethyl-4-oxobutanoate (1 g, 7.5 mmoi) was added. The mixture was placed In a microwave oven and refluxed for 1 hour. Water was then evaporated under vacuum and the residue was chromatographated over silica gel (CH2CI2/ MeOH / NH4OH 98/2/0.1) to afford 1.1 g of the title compound.
^H-NMR (CDCIs) 5: 6.48 (broad s, 1H); 5.30 (t, 1H); 4.23 (dd, 1H); 2.71-2.39 (m, 3H); 2.20-1.93 (m, 1H); 1.86-1.73 (m, 1H); 1.70-1.42 (m, 2H), 1.05 (d, 3H); 0.96 (d, 3H).
MS: El TSQ 700; source 180 C; 70 V; 200 uA: 196 (M+), 97. Example 1.1-Phenyl-tetrahydro-1H-pyrrolo[1,2-aJimldazole-2,S-dIone. To a solution of tetrahydro-pyrrolo[1,2-a]lmidazo!e-2,5-dion6 (1 g, 7.14 mmoi; prepared as described in J. Med. Chem. 36, 4214-4220, 1994.) in N-methyipyrroiidone {NMP, 12 cc), Cul (0.2 g, 1.05 mmoi), K2CO3 (1 g, 7.14 mmoi) and iodobenzene (5 g, 24.5 mmoi) were added under stiring. The suspension was heated In a microwave apparatus (250 Watt) for 45 min. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2Ci2. The organic phases were gathered and dried over Na2S04, 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= IBS-ISB^C.
^H-NMR (CDCI3) 8: 7.46-7.37 (m, 4H); 7.28-7.21 (m, 1H); 5.84 (m, 1H); 4.48 (d, 1H); 3.74 (d, 1H); 2.78-2.60 (m, 2H); 2.51-2.38 (m, 1H); 2.08-1.96 (m, 1H). MS: El TSQ 700; source 180 C; 70 V; 200 uA: 216 (M+). 160, 97. Example 2.1-o-tolyl-tetrahydro-1H-pyirolo[1,2-a]imidazole-2,6-dionQ, To a solution of tetrahydro-pyrrolo[1,2-a]imldazole-2,5-dione (1.3 g, 9.28 mmoi, prepared as described in J. Med. Chem. 36,4214,1994) in N-methylpyrroIidone (NMP, 12 cc), Cul (0.5 g, 2.62 mmoi), K2CO3 (1.3 g, 9.28 mmoi) and 2-bromotoluene (6 g, 35 mmoi) were added under stirring. The suspension was heated in a microwave apparatus (250 Watt) for 1 h. Ethyl acetate was added to the suspension and the solid was filtered. The organic phase was washed with water and the aqueous phase was re-extracted with CH2CI2- The organic

phases were gathered and dried over Na2S04, filtered and concentratea to dryness. The residue was triturated with EtaO. 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.
^H-NMR (CDCia) 8: 7.35-7.23 (m, 4H): 7.13-7.06 (m, 1H); 5.69 (m br, 1H); 4.45 (d, 1H); 3.78 (d. 1H); 2.68 (ddd, 1H); 2.48 (ddd, 1H); 2.40-2.29 (m, 1H); 2.24 (s. 3H);1.93(mbr, 1H).
IVIS: El TSQ 700; source 180 C; 70 V; 200 uA: 230(M+), 143,118, 97. Example 3-44 (Table 1). General procedure for arylation of tetrahydro-pyrrolo[1,2-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), in 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 under stirring. The suspension was heated in a microwave apparatus (25 Watt) for 20 min. Ethyl acetate (50 nnl) and water (5 ml) were added to the suspension and the mixture was stirred 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 Na2S04, filtered and concentrated to dryness. The residue was tritunated with EtzO to give the desired compound. Yields vary from 30% to 60%. Example 45.1'Ben2yl-tBtrahydro-pyrrolo[1,2-a]lmi'dazole-2,5-dione. A solution of tetrahydro-pyrtiolo[1,2-a]imidazole-2,5-dione (0.5 g, 3.5 mmol, prepared as described in J. Med. Chem. 36,4214,1994), BEMP (2 mi, 7 mmol) and benzylbromide (0.6ml, 5 mmol) In CH3CN (20 ml) was refluxed for 1hour. The reaction mixture was concentrated to dryness; the residue was then re-dissolved in ethyl acetate and washed with a saturated solution of NaCI, dried over Na2S04, filtered and evaporated under vacuum. The residue was purified by flash chromatography over silica gel (CH2CI2/ MeOH / NH4OH 95 / 5 / 0.5) to afford 0.7 g of the title compound as yellow oil. Yield: 87%
^H-NIVIR (CDCI3) 5: 7.39-7,10 (m, 5H); 5.03 (dd, 1H); 4.71 (d, 1H); 4.29 (d, 1H); 4.28 (d, 1H); 3.59 (d, 1H); 2,57 (ddd. 1H); 2.39-2.125 (m, 2H); 1.92-1.77 (m, 1H).
17

91.03.
Example 46. 1-(4-methybenzyl) -tetrahydrt)-pyirolo[1,2-aJimidazol0-2,5^ione.
A solution of tetrahydro-pyrroIo[1,2-a]imida2oIe-2,5-dione (0.5 g, 3.5 mmol,
prepared as described in J. Med. Chem. 36, 4214,1994), BEIVIP (2 ml, 7 mmol)
and 4-methylben2ylbromide (0.95 ml, 5 mmol) in CH3CN (20 ml) was refljxed
for 1hour. The reaction mixture was concentrated to dryness; the residue was
tlien re-dissolved In ethyl acetate and washed with a saturated solution of NaCI,
dried over NazSOA, filtered and evaporated under vacuum. The residue was
purified by flash chromatography over silica gel (CHaCIa/ MeOH / NH4OH 95 / 5
/ 0.5) to afford 0.8 g of the title compound as yellow oil.
Yield: 93%
^H-NMR (CDCI3) & 7.29-7.11 (m, 4H); 5.01 (m, 1H); 4.69 (d, 1H); 4.29 (d, 1H);
4.23 (d, 1H); 3.58 (d, 1H); 2.65-2.50 (m, 1H); 2.40-2.24 (m. 2H); 2.33 (s, 3H);
1.93-1.78 (m.lH).
MS: El TSQ 700; source 180 C; 70 V; 200 uA: 244.13 (M+), 161.05,105.02

Pharmacological Methods
Chronic constriction Injury model
A peripheral mononeuropathy was produced in adult rats by placing loosely constrictive ligatures around the common sciatic nerve according to the method described by Bennett & Xie (Pain 1988, 33, 87-107).
Rats were anesthetized with chloral hydrate. The common sciatic nerve was exposed at the level of the middle of the thigh by blunt dissection through biceps femoris. Proxlnnal to sciatica's trifurcation, about 1 cm of the nerve was freed of adhering tissue and four ligatures (3/0 silk tread) were tied loosely around it with about 1 mm spacing. The length of the nerve thus affected was 1 cm long. Great care was taken to tie the ligatures such that the diameter of the nerve was seen to be just barely constricted when viewed with 40 x magnification. The left paw was untouched.
Paw pressure test
The nociceptive threshold in the rat was determined with an analgesimeter (Ugo Basile, Varese, Italy), according to the method described by Leighton ef at. {Br. J. Pharmacol. 1988, 93, 553-560). Rats scoring below 40 g or over 75 g during the test before drug administration (25%) were rejected. An arbitrary cut-off value of 250 g was adopted.
All experiment were perfonmed on rats submitted to paw-pressure test 14 days after the operation since at this time a significantly reduction of the pain threshold of the injured paw (dx) was observed.
Gabapentin (30µg i.c.v.), levetiracetam (300 µg i.c.v.), dimiracetam (100)µg i.c.v.), Example 1 (10 µg i.c.v.). Example 2 (10 µg I.e.v.), Example 5 (3 µg i.c.v.), Example 6 (3 µg i.c.v.), Example 13 (30 µg i.c.v.) and Example 22 (30 µ.g i.cv.) of the present invention showed an antihyperalgic effect when compared with saline or vehicle treated group. All componds did not modify pain threshold in controlateral, non operated, paw. It should be noted that all compounds elicited their antihyperalgic effect without changing animals' gross behavior and spontaneous

motility in comparison with saline/vehicle treated rats. Furthermore no modification of motor coordination was revealed by the rat rota-rod test (Vaught J. et al. Neuropharmacology 188S, 24,211-216).

WE CLAIM:
1 • A compounds of the general formula (I)

in which:
A is chosen among carbocyclic aromatic groups, heterocyclic aromatic groups,
and arylC1-4alky!;
R1 is chosen among:
- hydrogen,
- arylC1-7alkyl, optionally substituted on the aryl moiety with one or more groups chosen among hydroxy, C1-4alkoxy, halogen, haloC1-4alkyl;
- heterocyclylC1.7alkyl, optionally substituted on the heterocydy! moiety with one or more groups chosen among C1.4alkyl and hydroxy;
- C1.7 alkyl, optionally interrupted by an oxygen or sulphur atom or optionally substituted at any position by one or more groups chosen among hydroxy, thio, amino, carboxyl, aminocarbonyl, guanidinyl.
R2 is chosen among hydrogen, C1.4alkyl, arylC1.4alkyl and phenyl;
or else R1 and Rg, taken together, form a saturated carbocyclic R1ng containing
from 3 to 8 carbon atoms;
R3 is chosen among hydrogen, C1.4alkyl, arylC1.4alkyl, CONH2 and GOOR5 in
which R5 is chosen between hydrogen and C1.4alkyl;
R4 is chosen among hydrogen, C1.4alkyl, 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
pharmaceuticaliy acceptable salts or solvates thereof.
2. The compounds according to claim 1, in which: A is phenyl, thienyl, pyR1dyl, pyR1midinyl group, optionally substituted, benzyl or 4-methylbenzyl; R1 is hydrogen. C1-4 alkyl, benzyl, -CHaOH, -CH2CH2CONH2, -CHaCOOH, indol(3-yl)methy!; Ra is hydrogen. CM alkyl or benzyl; R3 and R4 are hydrogen or methyl, and n is 2.

3. The compounds according to claim 2, in whicli: A is ptienyl optionally
substituted; R1, R2, R3 and R4 are liydrogen; and n is 2.
4. The compounds according to claims 1-3, in wliiC1i A Is substituted witin 1 to 3 substituents chosen among Me, Et, i-Pr, OH, COOEt, COOH, CH2OH, SO2NH2. SO2Me, OMe, C1, F, CN and CF3.
5. The compounds according to claim 4, in wliiC1i A is substituted with 1 to 3 substituents cliosen among Me, Et, i-Pr, OH, CN, C1 and CF3,
6. Tine compounds according to claim 1 or 2, in whicli said C1^ail 7. The compounds according to clainn 1, chosen in the group consisting of:
1 -Phenyl-tetraliydro-1 H-pyrrolo[1,2-a]imidazole-2,5-dione;
1 -o-tolyl-tetrahydro-1 H-pyrrolo[1,2-a]imidazole-2,5-dione;
1-(2,6-Dimethy!-phenyl)-tetrahydro-pyrrolo[1,2-a]iniidazol6-2,5-dione;
1 -Thiophen-2-yl-tetrahydro-pyrrolo[1,2-a]imidazoie-2,5-dione;
1 -m-Toiyl-tetrahydro-pyrrolo[1,2-a] imidazole-2,5-dione;
1-p-Tolyl-tetrahydro-pyrrolo[1,2-a] imidazole-2,5-dione;
1-(5-Fluoro-2-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1-(3-Fluoro-2-methyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dlone;
1-{2-TR1fluoromethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazol6-2,5-dione;
1'(4-Chloro-2rmethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imldazole-2,5-dione;
1 -{3-Chloro-phenyl)-tetrahydro-pyn-olo[1,2-a]imidazole-2,5-dione;
1-(3-Methoxy-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dlone;
1-(3-Cyano-phenyl}-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
l-(4-Chloro-phenyl)-tetrahydro-pyn-olo[1,2-a]imidazole-2,5-dione;
1-(3-Hydroxy-phBnyI}-tetrahydro-pyrroio[1,2-a]imidazole-2,5-dione;
1-(3-TR1fluoromethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imida2olB-2,5-dione;
1-(4-TR1fluoromethyi-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1-(4-MBthoxy-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazoie-2,5-dlone;
1-(3,5-Dimethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1-{3,4-Dimethyl-phBnyl)-tetrahydro-pyrroloIl,2-a]imidazole-2,5-dione;

1-Naphthalen-2-yl-tetrahydro-pyrroio[1,2-a]imidazole-2,5-dione;
1-(3-lsopropyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imldazole-2,5-dione;
1-(4-Chloro-3-methyl-ph6nyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
3-Benzy!-1-phenyl-tetrahydro-pyrrolo[1,2-a]imidazol6-2,5-dione;
3-Methyl-1.-phenyI-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
3-lsobutyl-1-phenyl-tetrahydro-pyrrolo[1,2-a]imida2ole-2,5-dione;
1-(3-Fluoro-5-methyl-ph9nyl)-tetrahydro-pyrrolo[1,2-a]imida2ole-2,5-dione;
1-(3-Fluoro-4-methyl-phenyl)-t6trahydro-pyrrolo[1,2-a]innidazole-2,5-dione;
7a-Methyl-1 -phenyl-tetrahydro-pyrrolo[1,2-a]imida2ole-2,5-dione;
(S)-1 -o-Tolyl-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
(R}-1 -oToly!-tetrahydro-pyrroio[1,2-a]irnidazoie-2,6-dione;
1-(4-Ethyl-phenyI)-tetrahydro-pyrroloi;i,2-a]imida2ole-2,5-dione;
1'(4-lsopropyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1-(4-Hydroxymethyl-phenyl)-tetrahydro-pyrrolo[1,2-a]imida2ole-2,5-dione;
4-(2,5-Dioxo-hexahydro-pyrro!o[1,2-a]imida2ol-1 -yl)-ben2oic aC1d;
4-(2,5-Dioxo-hexahydro-pyrrolo[1,2-a]imida2ol-1-yI)-benzoic aC1d atliyl ester;
1-(4-Metlianesulfonyl-pliBnyi)-tetraliydro-pyrrolo[1,2-a]imldazo)e-2,5-dione;
1-(4-Fluoro-plienyl)-tetrahydro-pyiTolo[1,2-a]imidazole-2,5-dione;
1-(4-Cyano-piienyl)-tetraliydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1-PyR1din-2-yl-tetraliydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1 -PyR1din-3-yl-tetraliydro-pyrroio[1,2-a]imidazoie-2,5-dlone;
1-(5-MethylpyR1din-2-yl)-tetraliydropyrroio[1,2-a]imidazDle-2,5-dione;
1-(2-Cyano-phenyl)-tetrahydro-pyrrolo[1,2-a]imidazol6-2,5-dione;
1-(3-Fluoro-phenyl)-tetralnydro-pyrrolo[1,2-a]imidazole-2,5-dione;
1 -Benzyl-tetraliydro-pyrrolo[1,2-a]imidazole-2,5-dione.
1-(4-metliy!ben2yl)-tetraliydro-pyrrolo[1,2-a]imidazole-2,5-dione.
8. A process for ttie preparation of the compounds of formula (I) as descR1bed in c laim 1, compR1sing the reaction of a compound of formula (II)
(H)

with a compound of formula (111)
A-X
(III) in which A, R1, R2, R3, R4 and n are defined as in Claim 1, and X is a halogen atom, to obtain the desired compounds of formula (I).
9. The process according to claim 8, in which in the compound of formula (111) X
is chosen between bromine and iodine.
10. The process according to claims 8-9, for the preparation of the compounds
of formula (1) wherein A is a carbocyclic aromatic group or a heterocyclic
aromatic group, optionally substituted, in which the compound of formula (II) is
dissolved in an appropR1ate solvent together with the compound of formula (111)
in the presence of a base and of a catalytic amount of a copper salt, at a
temperature of between 60oC and 140°C.
11. The process according to claim 10, in which said solvent is N-
methylpyrrolidone, said base is potassium carbonate, said copper salt is copper
iodide, and the reaction is conducted at a temperature of 120o'C.
12. The process according to claims 8-9, for the preparation of the compounds
of formula (1) wherein A is arylC1.4alky!, in which the compound of formula (II) is
dissolved in an appropR1ate solvent together with the compound of formula- (III),
in the presence of a suitable base at a temperature between 60 °C and 140*^.
13.The process according to claim 12, in which said solvent is chosen among acetonitR1le, methylene chloR1de, acetone, said base Is chosen among tR1ethylamine, potassium carbonate, 2-te/t-Butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphoR1ne, N,N-Diiso-propylethylamlne, at a temperature of 100 °C.
14, The process for the preparation of compounds of formula (I) as descR1bed in claim 1, compR1sing the following stages:

i) reaction of an amtnoaC1d of formula (IV) or of one of its activated deR1vatives

(IV)
with a compound of formula (V)
A-NH2
(V)
to obtain a compound of formula (VI):

in which R1, R2 and A are as defined above in Claim 1, and P Is H or a suitable. protective group;
ii) reaction of tHe compound of fomula (VI) obtained in stage i) with a compound of formula (VII)

(Vli) to obtain a compound of formula (VIII)

in which A, R1, R2, R3, R4 and n are as defined in Claim 1, P is defined a
above, and R' is an alkyl group;
iii) possible removal of the protective group P by means of hydrogenolysis of the
compound of formula (Vlll) obtained from stage fi), to obtain the correspondin
compound (VIII), In which P is H; and
iv) cyclization of the compound of formula (Vlll), In which P is H coming from
stage ii) or from stage iii), to obtain the desired compound of formula (1).
15. The process according to claim 14, in which R' is chosen between methyl
and terf-butyl, and P is chosen between H, benzyl-and benzyloxycarbonyl.
16. The process according to claim 14, in which, in said stage iv), the
cyclization reaction is canied out by heating the compound (Vlfl) in the. absence
of solvent at 120°C and in vacuum conditions, or else by reflux-heating the
compound (VIII) in xylene for a time compR1sed between 4 hours.and 3 days.
17. The process according to claim 14, in which said stage ii) is conducted by reflux-heating the compounds of fomnula (VI) and (VII) in a protic solvent for a time compR1sed between 2 and 24 hours, possibly in the presence of a base. .
18. The process according to claim 14, in which the reaction descR1bed in stage i) is conducted between the aC1dic chloR1de of the compound (IV) and the compound (V) in the presence of an Inorganic or organic base in a suitable aprotic solvent at a temperature of between -70oC and 50oC.
19. The process according to claim 14, in which the reaction of stage i) is conducted by reacting together the compound (IV) and the compound (V) in the . presence of a suitable condensating agent, in an aprotic solvent at a temperature of between -TCC and 5p°C.
20. The process according to claims 18 or 19, in which said temperature is
compR1sed between -10oC and 20oC.

21. A pharmaceutical composition compR1sing as active piinoiple one or more
compounds of fomnula (I) as descR1bed in claim 1, or pharmaceutically
acceptable salts or solvates thereof.
22. The pharmaceutical composition according to claim 21, wherein it compR1ses
vectors, diluents and/or pharmaceutically. acceptable exC1pients suitable for
forms of administration chosen between oral, parenteral, rectal, transdermal, and transmucosal.
23. The pharmaceutical composition according to claims 21 and 22, in the form
of solutions, suspensions, soluble powders, granules, microcapsules, capsules,
lozenges, tablets, coated tablets, suppositoR1es, creams, ointments, lotions,
pastes, medicated plasters, membranes or gels.

Documents:

2757-chenp-2005 abstract.pdf

2757-chenp-2005 claims.pdf

2757-chenp-2005 correspondence-others.pdf

2757-chenp-2005 correspondence-po.pdf

2757-chenp-2005 description(complete).pdf

2757-chenp-2005 drawings.pdf

2757-chenp-2005 form-1.pdf

2757-chenp-2005 form-18.pdf

2757-chenp-2005 form-26.pdf

2757-chenp-2005 form-3.pdf

2757-chenp-2005 form-5.pdf

2757-chenp-2005 pct search report.pdf

2757-chenp-2005 pct.pdf

2757-chenp-2005 petition.pdf

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Patent Number

229419

Indian Patent Application Number

2757/CHENP/2005

PG Journal Number

12/2009

Publication Date

20-Mar-2009

Grant Date

17-Feb-2009

Date of Filing

24-Oct-2005

Name of Patentee

NIKEM RESEARCH S.R.L

Applicant Address

VIA ZAMBELETTI 25, I-20021 BARANZATE DI BOLLATE,

Inventors:

#	Inventor's Name	Inventor's Address
1	FARINA, Carlo	c/o NIKEM RESEARCH S.R.L., VIA ZAMBELETTI 25, I-20021 BARANZATE DI BOLLATE,
2	GAGLIARDI, Stefania	c/o NIKEM RESEARCH S.R.L., VIA ZAMBELETTI 25, I-20021 BARANZATE DI BOLLATE,
3	PARINI, Carlo	c/o NIKEM RESEARCH S.R.L., VIA ZAMBELETTI 25, I-20021 BARANZATE DI BOLLATE,
4	MARTINELLI, Marisa	c/o NIKEM RESEARCH S.R.L., VIA ZAMBELETTI 25, I-20021 BARANZATE DI BOLLATE,
5	GHELARDINI, Carla	c/o Dipartimento di Farmacologia Preclinica, e Clinica "M. Aiazzi Mancini" Università di, Firenze, Viale G. Pieraccini 6, I-50139 FIRENZE,

PCT International Classification Number

C07D487/00

PCT International Application Number

PCT/EP04/50339

PCT International Filing date

2004-03-22

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	MI2003A000573	2003-03-24	Italy