IMIDAZO[1,2-a]QUINOXALIN-4-AMINES ACTIVE AS ADENOSINE ANTAGONISTS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THEREOF

Abstract: There are described imidazo[1,2-a]quinoxalin-4-amines derivatives of formula (I) and salt thereof active as adenosine antagonists and a process for their preparation and pharmaceutical compositions containing them as therapeutically active compounds for psychiatric and neurological disorders of the central nervous system.

Description: IMIDAZO[1,2-a]QUINOXALIN- -AMINES ACTIVE AS ADENOSINE ANTAGONISTS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THEREOF. DESCRIPTION The present invention relates to the lmidazo [1, 2- a] quιnoxalιn-4-ammes and their salts, that are active as antagonists cf the adenosine receptors; a process for their preparation as well as the pharmaceutical compositions containing them as active ingredients that are useful m the theraphy for the treatment of various psychiatric and neurological disorders of the central nervous system. It is known that theophyllme U,3- dimethylxanthme) and caffeine (1, 3, 7-trιmethylxantnιne > are capable of antagonizing the effects of adenosine through interaction with its receptors, and that it is mainly to such a property that their central nervous system stimulant effects are to be ascrioeα. However the presence of pharmacologically relevant effects also at the heart, kidney and smooth muscle level has determined a serious limitation tc the therapeutical use of these substances as agents for effectively treating the central nervous system diseases characterized by abnormalities in the neuronal transmission processes, such as, for example, depression and senile dementia. Moreover, their low affinity to the adenosine receptors implies that the therapeutically effective dosages are too close tc those causing serious side effects at the central level too. A series of compounds having various non-xanthme structures have exhibited, at different levels, affinity to the adenosine receptors (see for example documents EP 515,107 A2 and J. Med. Chem . 1991, 34, 1202), but none of them has the structure of lmidazo[1, 2-a]qumoxalin- 4-amιnes. Several derivatives of imidazo f1, 2-a] qumoxalme derivatives have been described in the literature: for example m U.S. Patent N. 5,182,38o lmidazoquinoxalinones are disclosed that interact with the central GABA receptors, whilst in WO 94/22865 analogous compounds (especially derivatives of 4, 5-dιhydro-4-oxoιmιdazo [1, 2-a] qumoxalme-2-carboxylιc acid) are described as antagonists of excitatory ammo acids. In no case, however, an affmit of such substances to the adenosine receptors has been pointed out. With the present invention, it has surprisingly been discovered that a group of imidazo [1, 2-a] qumoxalin- 4-amines are potent antagonists of the adenosine receptors that are active i n VJ VC on the central nervous system at much lower dosages as compared with the compounds that are presently m general use m theraphy. The compounds of the invention might therefore exhibit a lower incidence of side effects, especially at the peripheral level. The present invention relates therefore to a compound of the formula (I) : wherein: Ri is hydrogen or methyl; R_ is hydrogen, straight- or branched- chain (Cj-C,-) alkyi; R, is hydrogen, straight- or branched- chain (Cι-C&) alkyl that is possibly substituted with OH, (C 3 ~C 8 ) cycloalkyl; or R_ and R-, together form (CH,)m wherein Z is a direct bond, or 0, NR , R, being a straight- or branched- chain (C X -CJ alkyl; m and n, same or different, are 1, 2 or 3; R H and R- can be the same or different and are hydrogen or halogen chosen from CI, F, Br; and its pharmacologically acceptable salts; In the present invention, there are preferred the compounds of formula (Ij in which R 2 is hydrogen or methyl, R_ is hydrogen, R-, is hydrogen, straight- or branched- chain (C ^ -C alkyl that is possibly substituted with OH, (C--C t ) cycloalkyl, R 4 and R can be the same or different and are hydrogen, chlorine or fluorine. Especially preferred is the compound of formula (I) in which x is methyl, R t is hydrogen, R ; , is cyclopentyl, Rj and R» are both hydrogen, that is the compound 4- cyclopentylamino-1-methylimidazo [1, 2-a] qumoxaline. The salts of the compounds of formula (I) comprise the acid addition salts that can be prepared m si t u during the final isolation and the purification or by means of a separate reaction of the free base with the suitable organic or inorganic acid chosen, for example, from hydrochloric, hydrobromic, phosphoric, metha- phosphoric, nitric, sulphuric, tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and p-toluene sulfonic acids. An object of the present invention is also a process for the preparation of the compounds of the general formula (I) . Said process comprises reacting the 2, 3-dιchloroqumoxalme of the formula (II) wherein R4 and R5 are as defined for the compound of formula (I), with amino acetaldehyde dimethyl acetal or with propargyl amine, thereby to obtain, respectively, the compounds of the formulae (III) and (IV) that are subsequently submitted to a cyclization reaction m an acidic medium, preferably at a temperature comprised between 50 and 120°C, to obtain the imidazo [1, 2-a] qumoxalm-4 (5H) -ones of formula (V) m which R is hydrogen or methyl depending on whether the starting compound was compound (III) or compound (IV), respectively, Ri and R being as defined above. The transformation of the compounds of formula (V) into the inventive compounds having the formula (It can be carried out following two different synthetic sequences: m the first one, the chloride of the formula (VI) (VI in which all the substituents are as already defined, said chloride being obtained by treatment of compound of formula (V) with POC1 or another chlorinating agent, is reacted with the suitable amine HNR ^ R , m which R is hydrogen, straight- or branched- chain (C -C ) alkyl; R is hydrogen, straight or branched chain (d-Cβ) alkyl, possibly substituted with hydroxy, \ ^-X ) cycloalkyl; or R t and R together form ;CH 2 )m \ / (CH 2 )n wherein Z is a direct bond, or 0, NR , R, being a straight- or branched- chain (Cι.-C«) alkyl; m_ and n, same or different, are 1, 2 or 3. As an alternative, the compound of formula (V) can be directly converted into the compounds of formula (I), by reacting it with a silylatmg agent, such as hexamethyl disila ane and the suitable amine HNR R in which R_ and R are as defined m formula (I), at a temperature between 80 and 180°C, possibly m the presence of a catalyst, such as ammonium sulphate. The preparation of the compounds of formula (I) m which R_ and R are both hydrogen, can also be carried out by reacting the chloride of formula (VI) with hydrazine to obtain a compound of formula (VII) m which all the suDstituents are as defined above, followed by hydrogenation of this compound by conventional methods, such as, for example, hydrogen and palladium-on-carbon, or Raney nickel. The preferred compound of the present invention can be prepared according to the general process described above through the formation of the compound of formula (V) . Said compound is then converted to the preferred compounds of formula (I) by means of either synthetic sequence shown above. For example, the especially preferred compound of formula (I) of the present invention can be prepared by treating 2,3- dichloroqumoxalme (compound of formula (II) m which R., and R r are both hydrogen) with propargylamme to obtain the 2-propargylammo-3-chloroquιnoxaiιne ycompound of formula (IV) m which both R and R are hydrogen), followed by reacting this latter compound m an acidic medium, for example with concentrated sulphuric acid, at a temperature of between 50 and 120°C, to give 1- methylimidazo[1, 2-a] quιnoxalιn- (5H) -one (compound of formula (V) in which R x is methyl and R ^ and R. are both hydrogen) . This compound can finally be converted to 4- cyclopentylammo-1-methylimidazo [1, 2-a]qu oxalme through the formation of the intermediate 4-chloro-l- methylimidazo [1, 2-a] qumoxalme (compound of formula (VI) in which R x is methyl and R and R are both hydrogen) by chlor ation with one of known chlorinating agents at a temperature of between 50 and 150°C, followed b\ the reaction of the latter compound with cyclopentylam e, or SUBSTITUTESHEET(R UtE ^ alternatively, by reaction of 1-methylimidazo [1, 2- a] qumoxalm-4 (5H) -one with cyclopentylamme hexamethyl disilazane or other silylat g agent at a temperature of between 80 and 180°C, possibly in the presence of a catalyst, such as ammonium sulphate. The preparation of the compounds of formula (II), when they are not commercially available, can be carried out with methods such as the one shown below. Specifically, phenylenediamine (VIII) is reacted with dialkyl oxalate to give the 2, 3-dιhydroxyqumoxalme (IX), wich is then subjected to a chlorinating reaction with one of the usual chlorinating agents, such as for example POCl ^ , thereby obtaining the compounds (II) (VIII ' :ιx; As shown hereinafter in Examples 28 to 30, the compounds of formula (I) of the present invention are antagonists of the adenosine receptors, are active on the central nervous system and can therefore be advantageously used as active ingredients for the preparation of medicaments that are useful therapy for the treatment of various psychiatric disorders of the central nervous system, such as the depressive syndromes of various etiology and symptomatology and mood disorders general, bulimia nervosa, sleep disorders, obsessive- compulsive disorders, phobias, panic attacks. Further indications are neurological diseases, such as pre-senile and senile dementia, the Alzheimer's disease, the multimfarctual dementias, the encephalopathies of toxic or traumatic origin, the Parkinson disease, the post-neurological deficits, the respiratory depression, the neonatal cerebral damage. Besides being employed as drugs acting on the central nervous system, the compounds of the present invention and their salts could be used for the treatment of diseases of the renal system, such as acute renal failure, or of diseases of the cardiovascular system. For all the above-mentioned therapeutical uses, the compounds of the present invention can be administered by oral, transdermal or transmucosal route, parenteraliy or rectally in formulations containing them as the active ingredients at a therapeutically effective dosage with conventional, non-toxic pharmaceutical excipients. The term parenteral as used herein comprises subcutaneous, intravenous, mtra uscolar and mtracerebroventricular injections. If the compounds of the present invention are the form of a pharmaceutical composition, as in a preferred embodiment of the invention, the precise formulation employed will opviously depend on the administration route chosen. The pharmaceutical compositions that are suitable for the oral administration can be for example tablets, aqueous or oily suspensions, dispersible powders or granules, hard or soft capsules, syrups or elixirs. The compositions for the oral administration can contain one or more sweetening agents, colorants, flavouring and preserving agents that are suitable to make the pharmaceutical composition elegant and palatable. The formulations for oral administration comprise tablets in which the active ingredient is admixed with non-toxic, pharmaceutically acceptable excipients. Said excipients can be inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating or disgregatmg agents, such as wheat starch or alginic acid; binding agents, such as starch or gelatines; lubricant agents, such as magnesium stearate, stearic acid or talc. The tablets can be non-coated or coated w ^ th conventional techniques known to a person skilled the art order to delay disintegration and absorption in the gastrointestinal tract, order tc achieve a sustained release action. The aqueous suspensions generally contain the active ingredients admixed with the suitable excipients. The excipients can be suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxyprop^l methyl cellulose, sodium algmate, polyv ylpyrrolidone; dispersants and wetting agents. They can also contain one or more preservatives, such as ethyl and n-propyl p- hydroxybenzoate; one or more flavouring agent; one or more sweetening agents. The oily suspensions can be formulated by suspending the active ingredient in a vegetable or mineral oil; they can contain sweetening agents and flavouring agents m order to make the preparation palatable. The dispersible powders and granules that are suitable to the preparation of an aqueous suspension by adding water contain the active ingredient m admixture with the dispersing or wetting agent, a suspending agent and one or more preserving agents. The pharmaceutical compositions of the present invention can also be the form of a water/oil emulsion. The oily phase can consist of a vegetable or mineral oil. The emulsifying agents can be natural gums, such as acacia, or natural phosphatides, such as lecithins, or natural or synthetic fatty acid esters. The syrups and the elixirs can be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. The pharmaceutical compositions can be the form of aqueous or oily, sterile injectable suspensions. The suspensions can be formulated with the known techniques by using dispersing or wetting agents and suspending agents that are known in the art. The sterile injectable preparations can be sterile injectable solutions or suspensions m a non-toxic solvent or diluent that is suitable for the parenteral use. The compounds of the present invention can also be administered by the rectal route in the form of suppositories. These compositions can be prepared by mixing the active ingredient with a suitable, non irritating excipient that is solid at room temperature but liquid at the rectal temperature, thereby melting in rectum to release the drug. The polyethylene glycols and the cocoa butter are suitable compounds for this purpose. The therapeutically or prophylactically effective amounts of a compound of the present invention will depend on a number of factors including, for example, the age and weight of the patient, the severity of the specific disease requiring the treatment, the administration route. However, an effective amount of the compound of the present invention for the treatment of depressive syndromes and of senile dementia will generally be comprised in the range of 0.005-20 mg/kg of body weight per day, more frequently in the range of 0.05-2 mg/kg per day. In order to better illustrate the present invention, the following examples are reported, that are in no way to be considered as limiting. Example 1 (a) A mixture of 5.0 g of 2, 3-dιchloroquιnoxalιne and 5.5 ml of ammoacetaldehyde dimethyl acetal 7 5 ml of ethanol is refiuxed for 4 h. After concentrating under vacuum, the resulting mixture is added with water and extracted with ethyl acetate. The organic extracts are then washed with saturated NaCl, dried and evaporated. The residue is finally chromatographed on SiO (eluent: CH.CI , thereby obtaining 5.0 g of 2-chloro-3- (2, 2- dimethoxyethylamino) qumoxalme (IR (KBr) : 3347, 2936, 1580, 1523, 1129 cιτf J ) . 4.5 g of this product are then treated with 20 ml of 48% HBr and the mixture is refiuxed for 4 h. After cooling down, the mixture is neutralized with aqueous NaOH and the resulting precipitate is filtered under vacuum and dried to obtain 3.2 g of imidazo [1, 2-a] quιnoxalιn-4 (5H) -one (m.p. >300°C) (b) A mixture of 0.47 g of imidazo [1,2- a]qu oxalm-4 (5H)-one and 0.42 ml of N,N-dimethylaniline in 5.6 ml of phosphorus oxychloride is refiuxed for 2 h. After evaporating under vacuum the resulting mixture, the residue is taken up in chloroform and repeatedly washed with water, then with saturated NaCl, then it is dried and evaporated thereby obtaining, after recrystallization from n-hexane / chloroform, 0.29 g of 4-chloroιmιdazo- [1, 2-a] qumoxalme (IR (KBr) : 1456, 755 cm "1 ) . (c) A mixture of 0.25 g of 4-chloromιdazo [1, 2- α] qumoxalme and 0.5 ml of hydrazine hydrate m 1.5 ml of ethanol is refiuxed for 2 h. After cooling the mixture, the resulting precipitate is filtered under vacuum, washed and dried, thereby obtaining 0.22 g of 4- hydrazmoιmιdazo[l, 2-a] qumoxalme (IR (KBr) : 3308, 3237, 1570 cm "1 ) . (d) A mixture of 0.17 g of 4-hydrazmoιmιdazo [1, 2- a] qumoxalme and 3.4 ml of Raney nickel m 20 ml of water is refiuxed for 1.5 h. After cooling down, the mixture is filtered on Celite, followed by washing with methanolic chloroform. The filtrate is concentrated under vacuum and extracted with ethyl acetate. The organic extracts are then washed with saturated NaCl, dried and evaporated, thereby obtaining 0.17 g of imidazo [1,2- a]qumoxalm-4-amme. M.p. (DSC) = 205.3°C (onset); IR (KBr) : 3301, 3143, 1653, 1525 cm "1 ; ÷H-NMR (CDC1 3 ) : & 8.0 (lH,s), 7.8-7.45 (3H,m) , 7.45÷7.2 (2H,m), 5.8 (2H,sb) ; UV (EtOH) : ^ max = 229, 295, 331 nm. Elementary analysis for Cι 0 H 8 N 4 ( .w. 184.20) : calcd. C 65.21, H 4.38, N 30.42%; found C 65.48, H 4.71, N 30.10%. Example 2 (a) A mixture of 10 g of 2, 3-dichloroquinoxalme, 4.5 ml of propargyla ine, 10.5 ml of triethylamine in 50 ml of ethanol is refiuxed for 4 h. After evaporating under vacuum the resulting mixture, the residue is chromatographed on Si0 (eluent: CH 2 C1 2 ) thereby obtaining 7.0 g of 2-chloro-3- (propargyla ino) qumoxalme (IR (KBr) : 3441, 3282, 1518 cm "1 ) . This product is then added with 10 ml of concentrated sulphuric acid and the resulting mixture is stirred at 90°C for 1 h. After cooling down and cautiously neutralizing with aqueous NaOH, the resulting precipitate is filtered under vacuum, washed, dried, decolorized and recrystallized from dimethylformamide, thereby obtaining 2.4 g of 1- ethylimidazo [1, 2-a] quinoxaline- (5H) -one (m.p. >300°C) . (b) The chlorination of 1-methylιmidazo [1, 2- a] qumoxalm-4 (5H) -one with P0C1 3 is carried out according to a closely analogous procedure to that reported m example 1 (b) , thereby obtaining 4-chloro-l- methylimidazo [1, 2-a] qumoxalme (IR (KBr) : 1486, 754 cm " ' ) . (c) The reaction of 4-chloro-l-methylιmidazo [1, 2- a]qumoxalme with hydrazine hydrate is carried out according to a strictly analogous procedure to that followed in example 1 (c) , thereby obtaining 4-hydrazmo- 1-methylimidazo [1, 2-a] qumoxalme (IR (KBr) : 3298, 3250, 1564 cm "1 ) . (d) The hydrogenation of 4-hydraz o-l- methylimidazo [1, 2-a]qumoxalme with Raney nickel is carried out according to a strictly analogous procedure to that followed m example 1 (d) , thereby obtaining 1- methylimidazo[1, 2-a] qumoxalin-4-amme. m.p. (DSC) = 184.8°C (onset); IR (KBr) : 3379, 3295, 1640, 1516 cm "1 ; -H-NMR (CDC1 : <$ " 8.05 (lH,dd), 7.9-7.2 (3H,m), 7.2 (IH, s), 5,7 (2H, sb) , 2.85 (3H, s) ; UV (EtOH) : λ a = 225, 270, 304, 329 nm. Elementary analysis for C l H- l0 N, ( .w. 198.23) : calcd. C 66.65, H 5.08, N 28.26?; found C 66.79, H 5.30, N 28.03s. Example 3 A mixture of 2,8 g of 4-chloroιmidazo [1, 2- a] qumoxalme (example 1) and 9.8 ml of diethylamme m 40 ml of ethanol is refiuxed for 4 h. After evaporating the solvent, the residue is taken up m chloroform and washed with water and saturated NaCl, then dried and evaporated, thereby obtaining 2.2 g of raw product that is subsequently chromatographed on SiO (eluent: CH_C1_) : after recrystallization from n-hexane there are obtained 1.3 g of 4- diethylammoimidazo [1, 2-a] qumoxalme. m.p. (DSC) = 91.7°C (onset); IR (KBr) : 2976, 1518, 1425, cπr 1 ; J H-NMR (CDC1 3 ) : 0^ 7.9 (lH,s) , 7.7-7.4 (3H,m), 7.35-7.05 (2H,m), 4.15 (4H,q), 1.3 (6H,t); UV (EtOH) : α = 231, 250, 293, 305, 332, 348 nm. Elementary analysis for C^H^ ,] (m.w. 240.31) : calcd. C 69.97, H 6.71, N 23.31%; found C 69.99, H 6.80, N 23.13?,. Example 4 By reaction of 4-chloroimιdazo[1, 2-a] qumoxalme (example 1) with isopropylamine according to a procedure that is similar to that followed in example 3 there is obtained 4-isopropylaminoimιdazo [1, 2-a] qumoxalme. m.p. (DSC) = 102.7°C (onset); IR (KBr) : 3230, 2966, 1559 cm "1 ; -H-NMR (DMSO-d 6 ) : & 8.55 (lH,s), 8.2÷7.95 (lH,m), 7.6 ^ 7.4 (2H,m), 7.4÷7.2 (3H,m), 4.5 (lH,m), 1.25 (6H,d) ; UV (EtOH) : , α. = 227, 244, 285, 297, 318, 332 nm. Elementary analysis for C^H^N ( .w. 226.28) : calcd. C 69.00, H 6.23, N 24.76?; found C 69.17, H 6.70, N 25.05 E o. Example 5 By reaction of 4-chloro-l-methylimidazo[1, 2- a] qumoxalme (example 2) with 1-ethylpropylamme, according to a procedure that is similar to that followed example 3, there is obtained 4- (1-ethylpropylamino) -1- methylimidazo [1, 2-a] quinoxaline. m.p. (DSC) = 75.9°C (onset); IR (KBr) : 3231, 2965, 1546 cm "" ; Η-NMR (CDC1,) : & 8.0 (lH,dd), 7.7 (lH,dd), 7.4-7.1 (3H,m) , 5.9 (lH,d), 4.2 (lH,m), 2.85 (3H,s), 1.65 (4H,m) , 0.95 (6H,t) ; UV (EtOH) : \ ra = 221, 241, 268, 298, 313 nm. Elementary analysis for Cι,H 0 N, (m.w. 268.36) : calcd. C 71.61, H 7.51, N 20.83Ϊ; found C 71.12, H 7.53, N 20.79%. Example 6 By reaction of 4-chloromιdazo [1, 2-a] qumoxalme (example 1) with ethanolamme according to a procedure that is similar to that followed example 3 there is obtained 4- (2-hydroxyethylammo) imidazo [1, 2-a] qumoxa ¬ lme. m.p. (DSC) = 150.8°C (onset); IR (KBr) : 3312, 1598, 1564 cm l ; H-NMR (CDCl j /CD j OD) : S 8.2 (lH,s), 8.1-7.55 (2H,m), 7.55 (1H,S), 7.4-7.2 (2H,m), 3.8 (4H,s) ; UV (EtOH) : ^ π ci = 227, 285, 297, 317, 330 nm. Elementary analysis for C ι2 H 12 4 (m.w. 228.25) : calcd. C 63.14, H 5.30, N 24.55%; found C 63.16, H 5.40, N 24.99%. Example 7 By reaction of 4-chloro-l-methylιmιdazo [1, 2- a] qumoxalme (example 2) with ethanolamme, according to a procedure that is similar to that followed in example 3 there is obtained 4- (2-hydroxyethylammo) -1-methyl imidazo [1, 2-a]qumoxalme. m.p. (DSC) = 173. °C (onset); IR (KBr) : 3415, 3217, 1558 cm " '; H-NMR (CDC1 3 ) : 6 8.0 (lH,dd), 7.7-7.2 (3H,m), 7.2 (lH,s), 6.b (lH,m), 5.3 (IH, sb), 3.85 (4H,m) , 2.8 (3H,s) ; UV (EtOH) : aλ = 225, 242, 271, 301, 314, 327 nm. Elementary analysis for C H 14 N 4 (m.w. 242.28) : calcd. C 64.45, H 5.82, N 23.12%; found C 64.29, H 5.91, N 23.13%. Example 8 By reaction of 4-chloromιdazo [1, 2-a] qumoxalme (example 1) with cyclopentylamme according to a procedure that is similar to that followed example 3 there is obtained 4-cyclopentylammoιmιdazo[1, 2-a] qumoxalme. m.p. (DSC) = 114.3°C (onset); IR (KBr) : 3419, 2962, 1543 cm " ; H-NMR (CDC1 ) : C .9 (lH,s), 7.8- 7.0 (5H,m), 6.2 (lH,d), 4.7 (lH,m), 2.3τ2.05 (4H,m) , 2.0- 1.3 (4H,m); UV (EtOH) : " λ raa = 228, 244, 285, 297, 319, 333 nm. Elementary analysis for (m.w. 252.32) : calcd. C 71.40, H 6.39, N 22.20%; found C 71.13, H 7.30, N 22.29%. Example 9 A mixture of 3.5 g of 1-methylimidazo[1, 2-a] qumoxalm-4 (5H) -one ιexample 2), 13 ml of hexamethyl disilazane, 0.5 g of ammonium sulphate and 8. 1 ml di cyclopentylamme is stirred at 120°C m a Dean-Starl apparatus for 24 h. After concentrating the resulting mixture under vacuum, the residue is added with water and extracted with ethyl acetate. The organic extracts are then washed with water and saturated NaCl, dried and evaporated, thereby obtaining 1.5 g of a raw product that is subsequently chromatographed on SiO (eluent: CH 2 Cl 2 /AcOEt 97:3) . By recrystallizing from ethyl acetate, there is obtained 4-cyclopentylammo-l-methyi imidazo [1, 2-a] qumoxalme. m.p. (DSC) = 167.3°C (onset); IR (KBr) : 3294, 2948, 1544 cm " ; H-NMR (CDC1 ) : <5 " 8.0 (lH,dd), 7.7 (lH,dd), 7.4-7.05 (3H,m), 6.0 (lH,d), 4.6 (lH,m), 2.8 (3H,s), 2.3-2.05 (4H,m), 2.0-1.4 (4H,m); UV (EtOH) : ' X = 225, 243, 272, 301 , 316, 329 nm . Elementary analysis for C]fH 16 N,, (m.w. 266.35) : calcd. C 72.15, H 6.81, N 21.03%; found C 71.86, H 6.81, N 20.79%. Example 10 By reaction of 4-chloroimidazo[1, 2-a] quinoxaline (example 1) with cylohexylamine, according to a procedure that is similar to that followed in example 3, there is obtained 4-cyclohexylaminoimidazo [1, 2-a]quinoxaline. m.p. (DSC)= 94.0°C (onset) ; IR (KBr) : 3227, 2924, 1560 crrr 1 ; ÷H-NMR (CDC1- : 0^ 7.85 (lH,d, J=2Hz), 7.8-7.4 (3H,m), 7.4÷7.1 (2H,m), 6.0 (lH,d), 4.2 (lH,m), 2.3÷1.95 (4H,m), 1.95÷0.9 (6H,m) ; UV (EtOH) : 1 ιnd = 225, 242, 283, 294, 316, 330 nm. Elementary analysis for C,H :β N. (m.w.266.35) : calcd. C 72.15, H 6.81, N 21.03%; found C 72.25, H 7.04, N 21.19%. Example 11 By reaction of 1-methylimidazo[1, 2-a] quinoxalin- 4(5H)-one (example 2) with cyclohexylamine, according to a procedure that is similar to that followed in example 9, there is obtained 4-cyclohexylamino-l-methyl imidazo [1, 2-a] quinoxaline. m.p. (DSC)=126.5°C (onset); IR (KBr) : 3345, 2938, 1546 cm "1 ; X H-NMR (CDC1 : T8.0 (lH,dd), 7.7 (lH,dd), 7.5÷7.1 (3H,m), 6.0 (lH,d), 4.2 (lH,m) , 2.85 (3H,s), 2.3÷1.95 (4H,m), 1.95÷0.9 (6H,m); UV (EtOH) : = 225, 243, 272, 301, 316, 329 nm. Elementary analysis for CnHinN.j (m.w. 280.37) : calcd. C 72.83, H 7.19, N 19.98fe; found C 72.21, H 7.54, N 20.14%. Example 12 By reaction of 4-chloroimidazo [1, 2-a] quinoxaline (example 1) with pipeπdine, according to a procedure that is similar to that followed in example 3, there is obtained 4- (1-piperidinyl) imidazo [1,2-a]quinoxaline. m.p. (DSC)=108.2°C(onset) ; IR(KBr) : 3107, 2935, 1517 cirT ; Η- NMR (CDCl j ) : <57.9 (lH,d, J=2Hz) , 7.75-÷7.4 (3H,m), 7.4-7.1 (2H,m), 4.3 (4H,t), 1.9÷1.6 (6H,m); UV (EtOH) : _. a = 231, 249, 293, 305, 333 nm. Elementary analysis for Cι.,H ι ,-.N„ (m.w. 252.32) : calcd. C 71.40, H 6.39, N 22.20%; found C 71.38, H 6.63, N 22.61%. Example 13 By reaction of 4-chloro-l-methylimidazo [1, 2- a] quinoxaline (example 2) with piperidine, according to a procedure that is similar to that followed in example 3, there is obtained l-methyl-4-pipeπdinylimidazo [1, 2- a]quinoxaline. m.p. (DSC) = 78.9°C (onset); IR (KBr) : 3018, 2927, 1502 c -; ÷H-NMR (CDCl : 6 * 8.05 (lH,dd), 7.65 (lH,dd) , 7.5-7.0 (3H,m), 4.25 (4H,t), 2.85 (3H,s), 1.9÷ 1.6 (6H,m) ; UV (EtOH) : X ma = 249, 281, 297, 310, 329 nm. Elementary analysis for C K HIΛN, (m.w. 266.35) : calcd. C 72.15, H 6.81, N 21.03*; found C 71.84, H 7.09, N 20.70%. Example 14 By reaction of 4-chloroimidazo [1, 2-a] quinoxaline (example 1) with morpholine, according to a procedure that is similar to that followed m example 3, there is obtained 4- (4-morpholmyl) imidazo [1, 2-a] qumoxalme. m.p. (DSC)= 142.8°C (onset) ; IR (KBr) : 3016, 2962, 1517 cm "1 ; ! H-NMR (CDC1 3 ) : £ " 8.0 (lH,s), 7.8-7.5 (3H,m), 7.5-7.2 (2H,m), 4.4 (4H,t), 3.9 (4H,t) ; UV (EtOH) : ^ md = 230, 248, 292, 304, 330 nm. Elementary analysis for CπH^N^O(m.w. 254.29) : calcd. C 66.13, H 5.55, N 22.03%; found C 65.43, H 5.47, N 22.25%. Example 15 By reaction of 4-chloroιmidazo [1, 2-a] qumoxalme (example 1) with N-methylpiperazme, according to a procedure that is similar to that followed m example 3, there is obtained 4- (N 1 -methylpiperazmyl) imidazo [1, 2-a] quinoxaline, that is subsequently converted to the dihydrochloπde by treatment with ethanolic HCl. m.p. (DSC)- 305.6°c (onset); IR (KBr) : 2697, 1560, 1508 cm- 1 ; X H-NMR (DMSO-d t /CD,OD) : <58.7 (lH,sb), 8.3-8.0 (lH,m), 7.8- 7.35 (4H,m), 5.5 (4H,t), 3.7-3.3 (4H,m), 2.8 (3H,s) ; UV (EtOH) : ma = 230, 291, 304, 320 nm. Elementary analysis for C 15 H 17 N^.2HC1 (m.w. 340.25) : calcd. C 52.95, H 5.63, N 20.58%; found C 52.81, H 5.78, N 20.13%. Example 16 By reaction of 4-chloro-l-methylιmιdazo [1, 2- a]qumoxalme (example 2) with N-methylpiperazme, according to a procedure that is similar to that followed m example 3, there is obtained l-methyl-4- (N' -methyl¬ piperazmyl) imidazo [1, 2-a] quinoxaline. m.p. (DSC)= 108.0°C (onset) ; IP (KBr) : 2928, 1535, 1S1U crtr ; !H-NMR (CDC1 3 ) : S Q . 1 (lH,dd) , 7.7 (iH,dd), 7.4-7.0 (3H,m), 4.35 (4H,t), 2.85 (3H,s), 2.6 (4H,t), 2.3 (3H,s> ; UV (EtOH) : ^ mdΛ - 228, 248, 279, 309, 325 nm. Elementary analysis for C -H^ ., (m.w. 281.36) : calcd. C 68.30, H 6.81, N 24.89%; found C 68.37, H 7.15, N 25.05%. Example 17 By reaction of 2, 3, 6-trichloroqumoxaline with aminoacetaldehyde dimethyl acetal, according tc a procedure that is similar to that described in example 1, there is obtained 8-chloroimidazo [1, 2-a] quιnoxalin-4 \5Hι - one (m.p. >300°C) . By reacting this product with 1-ethyl propylamine according to the method described m example 9, there is obtained 8-chloro-4- (1-ethylpropyl- amino) imidazo [1, 2-a] quinoxaline. m.p. (DSC)= 125.1°C (onset); IR (KBr) : 3406, 3105, 2964, 1532 cm " -; -H-NMR (CDC1./CD,OD) : S 8. (lH,s), 8.0b !H,d, J=2Hz), 7.8-7.4 (3H,m), 3.85 (lH,m), 1.65 (4H,mj, .95 (6H,t); UV (EtOH) : \ ma .= 230, 245, 289, 301, 326 nm. Elementary analysis for (m.w. 288.78) : calcd. C 62.39, H 5.93, N 19.40%; found C 62.17, H 6.02, N 19.46%. Example 18 By reacting 8-chloroιmιdazo [1, 2-a] quinoxalιn-4 v 5H; - one (example 17) with P0C1 3 , following a procedure that is similar to that described in example 1, there is obtained , 8-dichloroimidazo [1, 2-a] quinoxaline that is subsequently reacted with cyclopentylamine according to the method described m example 3, thereby obtaining 4- cyclopentylammo-8-chloroιmιdazo [1, 2-a] qu oxalme. m.p. (DSC) = 140.1°C (onset) ; IR (KBr) : 3401, 2955, 1554 cm- ; % iH-NMR (CDC1 : (5 * 7.8 (lH,d, J=2Hz), 7.7-7.2 (4H,m), 6.15 (lH,d) 4.6 (lH,m), 2.3-2.05 (4H,m), 2.05-1.3 (4H,m) ; UV (EtOH) : m ^= 229, 245, 289, 301, 326, 34n n . Elementary analysis for d H C1N (m.w. 286.76) : calcd. C 62.83, H 5.27, N 19.54%; 0 found C 63.04, H 5.36, N 19.64?. Example 19 By reacting 4, 8-dιchloroιmιdazo[1, 2-a] qu oxalme (example 18) with cyclohexylamine, following a procedure that is similar to that described m example 3, there is 5 obtained 4-cyclohexylamιno-8-chloroιmιdazo [1, 2-a] quinoxa¬ line. m.p. (DSC)=126.7°C (onset) ; IR (KBr) : 3413, 2926, 1555 cm-; H-NMR (CDCl : <&7.85 (lH,s), 7.7-7.2 (4H,m), 6.1 (lH,d), 4.2 (lH,m), 2.3-2.0 (4H,m), 2.0-1.2 (6H,m); UV (EtOH) : 0 d = 229, 245, 289, 301, 326, 340 nm. Elementary analysis for Cj.H, C1N 4 (m.w. 300.79) : calcd. C 63.89, H 5.70, N 18.63o found C 64.07, H 5.79, N 18.80i Example 20 5 By reacting 2, 3, 6-trιchloroqumoxalιne with propargylamme, following a procedure that is similar to that described m example 2, there is obtained 8-chloro- 1-methylιmιdazo [1, 2-a] qumoxalm-4 (5H) -one (m.p. >300°C) and, subsequently, 4, 8-dιchloro-l-methylιmιdazo [1, 2-a] qumoxalme. By reacting this product with cyclo ¬ pentylam e according to the method described m example 3, there is obtained 4-cyclopentylamιno-8-chloro-l- methylimidazo [1, 2-a] qu oxalme. m.p. 5 (DSC)= 130.5°C (onset) ; IR (KBr) : 3421, 2954, 1555 cm ' ; -NMR (CDCl,) : σ 7.95 (lH,d, J=2Hz), 7.t (lH,d, J=9Hz), 7.35-7.15 (2H,m), 6.1 (lH,d), 4.5 (lH,s), 2.8 (3H,s,, 2.4-2.05 (4H,m), 2.0-1.3 (4H,m) ; UV (EtOH) : λ = 22 ~ , 251, 276, 305, 323, 336 nm. Id Elementary analysis for C lt H^ClN,, (m.w. 300.79) : calcd. C 63.89, H 5.70, N 18.63' found C 63.79, H 5.79, N 18.58 Example 21 By reacting 4, 8-dιchloro-l-methylιmιdazo [ 1, 2-a] 15 qumoxalme (example 20) with cyclohexylamine, followmα a procedure that is similar to that described in example 3, there is obtained 4-cyclohexylammo-8-chloro-l- ethylimidazo [1, 2-a] qumoxal e. m.p. (DSC) = 130. °C (onset) ; IR (KBr) : 3410, 2927, 1551 cm ; 20 H-NMR (CDC1 : c 7.95 (lH,d, J=2Hz), 7.t (lH,d, J=9Hz) , 7.4-7.2 (2H,m), 6.1 (lH,d), 4.2 (lH,m), 2.8 (3H,2) , l . X 1.1 (10H,m) ; UV (EtOH) : " λ md = 227, 250, 276, 305, 323, 336 nm. Elementary analysis for C -HnCIN,, (m.w. 314.82) : 25 calcd. C 64.86, H 6.08, N 17.80? found C 64.86, H 6.21, N 17.91% Example 22 By reacting 2, 3, 6, 7-tetrachloroqumoxalme with aminoacetaldehyde dimethyl acetal, followmq a procedure that is similar to that described in example 1, there is obtained 7, 8-dichloroimidazo [1, 2-a] quinoxalin- (5H ) -one (m.p.>300°C) and, subsequently, , 7, 8-trichloroimidazo [1, 2-a] quinoxaline. By reacting this product with cyclopentylamine according to the method described in example 3, there is obtained 4-cyclopentylamino-7, 8- dichloroimidazo [1, 2-a] quinoxaline. m.p. (DSC) = 139.4°C (onset) ; IR (KBr) : 3247, 2961, 1589, 1556 cm-' ; l H-NMR (CDCl,) : 7.8 (2H,m) , 7.7 (lH,s) , 7.55 (lH,s), 6.2 (lH,d), 4.6 (lH,m), 2.4-1.3 (8H,m) ; UV (EtOH) : \ M = 235, 274, 292, 304, 330, 345 nm. Elementary analysis for C-, r ,Hι.ιCl 2 N 4 (m.w. 321.21) : calcd. C 56.09, H 4.39, N 17.44%; found C 56.13, H 4.41, N 17.52%. Example 23 By reacting 4, 7, 8-trichloroimidazo [1, 2- a] quinoxaline (example 22) with cyclohexylamine, following a procedure that is similar to that described in example 3, there is obtained 4-cyclohexyiamino-7, 8- dichloroimidazo [1, 2-a] quinoxaline. m.p. (DSC) = 162.3°C (onset) ; IR (KBr) : 3332, 2929, 1587, 1550 cπr ' '; ! H- R (CDCl- : cS7.8 (2H,m), 7.7 (lH,s), 7.55 (lH,d, J=2Hz), 6.2 (lH,d) , 4.4 (lH,m), 2.3÷1.2 (10H,m) ; UV (EtOH) : ,1X = 234, 274, 292, 304, 330, 345 nm. Elementary analysis for C lh H lD Cl_N„ . l/2H^O (m.w. 344.25) : calcd. C 55.82, H 4.98, N 16.28V found C 55.83, H 5.00, N 16.31% Example 24 By reacting 2, 3, 6, -tetrachloroquinoxaline with propargylamine, following a procedure that is similar to that described in example 2 there is obtained 7,8- dichloro-1-methylimidazo[1, 2-a] quinoxalin-4 (5H) -one (m.p.>300°C) and, subsequently, l-methyl-4, 7, 8-trιchloro- imidazo [1, 2-a] quinoxaline. By reacting this product with cyclopentylamine according to the method described in example 3, there is obtained 4-cyclopentylammo-7, 8- dichloro-1-methylimidazo [1, 2-a] quinoxaline. m.p. (DSC) = 213.5°C (onset); IR (KBr) : 3411, 2960, 1548 cm " ; 'H-NMR (CDC1,) : <=T 8. U (lH,s), 7.75 (lH,s), 7.25 (1H,S), 6.2 (lH,d), 4.6 (lH,m), 2.8 (3H,s) , 2.3÷1.3 (8H,m) ; UV (EtOH) : m^ = 233, 279, 308, 327, 341 nm. Elementary analysis for C ι „H ,Cl 2 N., (m.w. 335.23) : calcd. C 57.33, H 4.81, N 16.71%; found C 57.41, H 4.82, N 16.68%. Example 25 By reacting 2, 3-dichloro-6-fluoroqumoxal e with aminoacetaldehyde dimethyl acetal, following a procedure that is similar to that described in example 1, there is obtained 8-fluoroimidazo [1, 2-a]quinoxalin- (5H) -one (m.p. >300°C) and, subsequently, 4-chloro-8-fluoroimidazo [1, 2- a]quinoxaline. By reacting this product with cyclopentyl amine according to the method described m example 3, there is obtained 4-cyclopentylamino-8-fluoroimidazo [1, 2- a] quinoxaline. m.p. (DSC) = 85.7°C (onset); IR (KBr) : 3255, 2964, 1551 cm "1 ; ! H-NMR (CDCl,) : <5 7.8 (lH,s), 7.7-7.35 (lH,dd, J 1 =16Hz), 7.5 {IH, , J=2Hz), 7.6÷7.25 (lH,dd, J M; =16Hz) , 7.05 (lH,dd), 6.0 (lH,d), 4.55 (lH,m), 2.35τl.3 (3H,m); UV (EtOH) : ιτa = 226, 268, 285, 296, 323, 336 nm. Elementary analysis for (m.w. 270.31) : calcd. C 66.65, H 5.59, N 20.73;; found C 66.36, H 5.66, N 20.86- 1 ,. Example 26 By reacting 4-chloro-8-fluoroimidazo [1, 2-a] quinoxaline (example 25) with cyclohexylamine, following a procedure that is similar to that described in example 3, there is obtained 4-cyclohexylamino-8-fluoro- imidazo [1, 2-a] quinoxaline. m.p. (DSC) = 157.6°C (onset) ; IR (KBr) : 3415, 2927, 1556 cm--; -H-NMR (CDC1 5 ) : C 7.8 (lH,dd, J=2Hz), 7.7-7.35 (lH,dd, J .L =16Hz), 7.55 (lH,d, J=2Hz), 7.55-7.25 (lH,dd, J n _=16Hz), 7.05 (lH,dd), 6.0 (lH,d), 4.25 (lH,m), 2.35τ 1.2 ( 10H,m ) ; UV ( EtOH ) : ,„ = 226 ' 239 ' 285 ' 297 ' 323 ' 337 nm. Elementary analysis for CH./FN, (m.w. 284.33) : calcd. C 67.59, H 6.03, N 19.71ι found C 67.31, H 6.04, N 19.70- Example 27 By reacting 2, 3-dichloro-6, 7-difluoroqu oxaline with aminoacetaldehyde dimethyl acetal, following a procedure that is similar to that described in example 1, there is obtained 7, 8-difluoroimidazo [1, 2-a] quinoxalin- 4(5H)-one (m.p. >300°C) and, subsequently, 4-chloro-7, 8- difluoroimidazo [1, 2-a] quinoxaline. By reacting this product with cyclopentylamine according to the method described in example 3, there is obtained 4-cyclo- pentylamino-7, 8-difluoroimidazo [1, 2-a] quinoxaline. m. . (DSC) = 146.0°C (onset); IR (KBr) : 3263, 2955, 1554 crrr ; H-NMR (CDCl j ) : 5 " 7. " ' (lH,s), 7.65-7.15 (3H,m), 6.1 (lH,d), 4.6 (lH,m, , 2.3-1.3 (8H,m) ; UV (EtOH) : λ 1 = 225, 241, 270, 295, 323, 337 nm. Elementary analysis for C H^F ^ N, (m.w. 288.30) : calcd. C 62.49, H 4.89, N 19.43 0 ; found C 62.46, H 5.03, N 19.65i. Example 28 Binding on the adenosine receptors. The binding on A receptors has been carried out according to the method described m Naunyn-Schmied. Arch. Pharmacol. 1987, 336, 204 on preparations of synaptosomial membranes from rat brain by incubating 200 μg of memPrane proteins for 1 h at 25°C with the substance to be tested and 0.3 nM [ H]-DPCPX m 400 μl of 50 mM Tπs.HCl ph = . . The non-specific binding ha been determined with 5 nM R-PIA. The binding on A receptors has been carried out according to the method described FASEB J. 1989, 3, A1047 on preparations of rat stπatal membranes by incubating 200 μg of membrane proteins for 1 h at 25°C with the substance to be tested, 5 nM [ H]-CGS21680 and 50 nM CPA. The non-specific binding has been determined The incubations were blocked by filtration by means of a cell-harvester and, after completion of the separation of the bound from the free, the radioactivity contents were evaluated by liquid scintillation. The concentration-inhibition curves were obtained by assaying the receptor displacement at at least ten different concentrations of the test substance ^all the assays were carried out in triplicate) . The tested substances were dissolved m dimethyl sulphoxide and diluted in 50 mM Tris.HCl buffer pH = 7.4. The IC values have been determined by non-linear regression curves and transformed into Ki values according to the Cheng-Prusoff equation. Table I shows the results obtained with the compounds of examples 5, 9, 13, 18, 22 and 25 of the invention. TABLE I : Adenosine receptors affinities Example 29 Forced swim test The test described by R.D.Porsolt et al . in Arch. Int.Pharmacocyn.Ther. 1977, 229, 327, has been carried out which is widely used as an animal model for the study of the antidepressant activity of new drugs. Male albino CD 1 mice weighing 25-35 g were used. One hour before immersion in water, the test compound is mtrapeπtoneally (l.p.) administered to the animal; the vehicle is administered to the control animals. The duration of permanence in water is 6' : from the 2 " to the 6 minute the time is measured during which the animal remains motionless. Table II shows the results obtained with the compounds of examples 9, 13, 16, 18 and 21 of the invention, expressed as the percent variation of the immobility time of the treated animals versus the control group. As the reference substance the tricyclic antidepressant drug desipramme was used. TABLE II: Forced swim test (***) p<0.001; (**) p<0.01; (*) p<0.05 Example 30 Tail suspension test The test described by L.Steru, et al . in Psychopharmacology 1985, 85, 367, also widely used as an animal model for the screening of antidepressant activity- has been carried out. Male albino CD 1 mice weighing 25-35 g were used. Half an hour before the test, the animal is administered the test compound by the ι.ρ. route; the control animals are administered the vehicle. The mouse is suspended from a horizontal bar at about 40 cm from the support plane by means of an adhesive tape applied at the end of the tail and secured to a hook. The immobility time period is registered during 6' . Table III shows the results obtained with the compound of example 9 of the invention, as the percent change of the immobility time period ol the treated animals versus the control group. As the reference substance the tπcyclic antidepressant drug desipramme was used. TABLE III: Tail suspension test (***) p<0.001; p<0.01, ) p<0.05

Claims: CLAIMS 1 . A compound o f the formula ( I ) : wherein: R) is hydrogen or methyl; R is hydrogen, straight- or branched- chain (C.-C. ) alkyl; R, is hydrogen, straight- or branched- chain (C ; -C t .) alkyl that is possibly substituted with OH, (C.-C M ) cycloalkyl; or R-. and R ( together form Z / (CH 2 )n wherein Z is a direct bond, or 0, NR. , R, being a straight- or branched- chain (Cι-C b ) alkyl; m and n, same or different, are 1, 2 or 3; R 4 and R. can be the same or different and are hydrogen or halogen chosen from CI, F, Br; and its pharmacologically acceptable salts 2. A compound according to claim 1 characterized in that Pi is hydrogen or methyl, R ^ is hydrogen, R is hydrogen, straight- or branched- chain (C . -C * .) alkyl that is possibly substituted with OH, (C ,-C ) cycloalkyl, R and R_ can be the same or different and are hydrogen, chlorine or fluorine. 3. A compound according to claims 1 and 2 characterized in that R t is methyl, R is hydrogen, P is cyclopentyl, R 4 and R=, are both hydrogen. 4. A process for the preparation of the compounds of the formula (I) according to claims 1 to 3, characterized in that a compound of formula (II) (ID m which R,| and X, are as defined in claim 1, is reacted with amino acetaldehyde dimethyl acetal or with propargyl amine, thereby to obtain, respectively, the compounds of the formulae (III) and (IV) in which R and R., are as de f ined in cl aim 1 , said compounds being subsequentl y cvcl i zed in an acidi c mi l ieu to give the compound of formula (V) (V) in which R is hydrogen or methyl, Ri and R are as defined claim 1; compound (V) is then reacted with a chlorinating agent such as POCl, to provide the compound of formula (VI) m which all the substituents are as defined above, which is subsequently reacted with the am e HNR R , which P and R. are as defined m claim 1; or compound (V) , prepared as described above, is reacted with a silylat g agent, such as hexamethyl disilazane, and amme HNR_R,, m which R and R are as defined m claim 1, at a temperature of between 80 and 180°C; or for the preparation of the compounds of formula (I 1 in which R and P are both hydrogen, the compound (VI; , prepared as described above is reacted with hydrazine to give the compound of the formula (VII) (VII in which R : , R<, and R- are as defined claim 1, which is subsequently hydrogenated according to conventional methods. 5. Pharmaceutical compositions characterized in that they contain at least a compound according to claim 1 as an active ingredient at an effective dosage together with one or more conventional, non-toxic excipient. 6. Use of the compounds of claim 1 as adenosine antagonists . 7. Use of compounds according to claim 1 for the preparation of a medicament for the treatment of psychiatric disorders. 8. Use of compounds according to claim 1 for the preparation of a medicament for the treatment of neurological diseases of the central nervous system.

Inventors: ALTOBELLI MARIA, CECCARELLI STEFANO, D ALESSANDRO ALESSANDRA, ZANARELLA SERGIO, ALTOBELLI, MARIA, CECCARELLI, STEFANO, D'ALESSANDRO, ALESSANDRA, ZANARELLA, SERGIO
Applicants: ALESSANDRO ALESSANDRA D, ALTOBELLI MARIA, CECCARELLI STEFANO, FOSCAMA BIOMED CHIM FARMA, ZANARELLA SERGIO, ALTOBELLI, MARIA, BIOMEDICA FOSCAMA INDUSTRIA CHIMICO-FARMACEUTICA S, CECCARELLI, STEFANO, D'ALESSANDRO, ALESSANDRA, ZANARELLA, SERGIO
Application year: 1996
Main classification: C07D487
IPC codes: C07D487