8-ALKYLAMINOIMIDAZO[1,2-A]PYRAZINES AND DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION IN THERAPY

Abstract: Novel 8-alkylamino-imidazo(1,2-a)pyrazines of formula (I) show advantageous pharmacological activities. They can be used for medical products in human and veterinary therapy in the field of applications of antispasmodics, uterine relaxants, bronchodilators, cardiac analeptics and neurosedatives.

Description: 8-Alkylaminoimidazo [1 , 2-a]pyrazines and derivatives , their preparation and their application in therapy The present invention relates to 8-a I kyI am i no- imidazo[1,2-a]pyraziπes and their derivatives, their pre¬ paration and their therapeutic application in human or veterinary medicine in the field of antispasmodics, uterine relaxaπts, broπchodi I ators, cardiac analeptics and πeuro- sedat i ves . Im i dazoC 1 ,2-aHpyraz i πes possessing advantageous pharmacological activities have already been described in the literature, for example in U.S. patents Nos. 4,507,294, 4,483,858, 4,376,772 and 4,242,344, in British patent No. 2,132,203, in European patents Nos. 0,013,914, 0,113,236 and 0,154,494 and in various publications such as those produced by ABIGNENTE, E. et al. Eur. J. Med. Che istry, 1985, p. 79-85, 2_0 and SABLAY OLLES C. et al. J. Med. Chem., 1984 p. 206-212, 21_ . The present invention encompasses the compounds corresponding to the formula: as well as the corresponding salts which are compatible with pharmaceut cal application. In this formu la ( I ) : . Y and Z independently denote: a) a hydrogen atom, b) a halogen atom such as F, Cl, Br or I, c) C0 2 H^ d) CN, e) a linear or branched C1-C5 alkyl radical, f) a C - j —C5 alkoxy radical, g) CF3 h) - \ with R3 and R4 as defined belo ; . R - ] and R , when they are independent, denote, a) a hydrogen atom, b) a halogen atom such as F, Cl, Br or I, c) a Linear or branched C -j—C5 alkyl radical, d) a radical -CCH 2 ) π -C0 2 R5, with R5 denoting a C-1-C5 alkyl radical and π being between 0 and , e) a pheπyl radical, optionally substituted, f > C0 - N \ B 7 with and R7 independently denoting a hydrogen atom, a Linear or branched C ^—C5 alkyl radical or an aryl radical, g) CN, ) CH 2 - \ R 7 i) NH , j) CH 2 Cl, k) CH 2 0H, L) CF3, / c ) S0 2 - R_ n) -N0 2 , o) -NO, p) a C3-C6 cycloalkyL radical, q) an acyl radical, r) a linear or branched C-1-C5 alkylthio radical; . R- ] and R 2 , when they are linked to one another, denote -CH 2 -CH 2 -CH 2 -CH 2 -, . R3 and R4 independently denote: a ) a hydrogen atorn b) a linear or branched C1-C5 alkyl radical, capable of bearing one or more hydrogen atoms or a hydroxy, N( C - j -C4 alkyl) 2 , carbamoyl or C —C4 alkoxy rad cal, either a C3-Cg cycloalkyL rad cal or a phenyl radical, c) a C -j —C5 acyl radical, d) a furfuryl radical, . R3 and R4, linked to one another denote -CH 2 -CH - CH 2 -CH -CH 2 or -CH -CH 2 -X-CH 2 -CH 2 - in which X denotes 0 or S. The preferred compounds of the invention are those in which R3 is a hydrogen atom, R4 a hydrogen atom or a methyl or ethyl radical, R < | a hydrogen atom or an ethyl carboxylate group, Y and Z denote either a hydrogen atom or a bromine atom and R denotes either a bromine atom or a hydrogen atom. Among these compounds, there may be mention¬ ed more espe ially the compound in which R3=H, R4=CH3, Y=H, Z=H, Y=Br, Z=H, R =H, R-] =H and the compound in which R3=H, R =H, Y=Br, Z=H, R 2 =Br and R-|=H. The salts that are compatible with pharmaceutical appl ication are the salts resulting from the neutral ization of the basic compounds corresponding to the formula (I) with an acid. The acids employed are either inorganic or organic acids. As examples of such inorganic acids, halogen hydracids, such as hydrochloric acid, hydrobro ic acid and hydriodic acid, phosphoric acid, sulfuric acid, and the l ike should be mentioned. As examples of organic acids, carboxylic acids such as acetic acid, aleic acid, succiπic ac id, citric acid, 'tartaric acid, oxalic acid, mal ic acid, pi-val ic acid, heptaπoic acid, Laurie acid, sal icyl ic acid, beπzoic acid, gluta ic acid, lactic acid, and the L ike and non-carboxylic acids such as sethioπic acid and methaπe- sulfoπic acid, should be mentioned. The salts of halogen hydracids, especially the hydrochlorides, the salts of maleic acid, especially the acid maleates, and the salts of methanes u I fon i c acid are preferred. According to the invention, the compounds (I) may be prepared according to the reaction schemes 1 and 2 below, which employ known processes and which use known starting substances. The particular methods and the reaction sequences are derived from the specific nature of the substituents and their position. One of the processes for producing the compounds (I) (scheme 1) consists in condensing a 2,3-diamino- or 3- aLkylamiπo-2-aminopyraziπe CII) containing the substi uents Y and Z with an alpha-ha locarbonyl compound (III). Scheme 1 Another process (scheme 2 ) for producing the compounds (I) consists in carrying out a substitution reaction starting with an imidazoL " 1,2-a]pyraziπe derivati e, according to a traditional method, for example by the action of ammonia, alkylamiπes or a nitrogenous heterocycle on a halogenated derivative. The halogeπated derivative used can be either a de ivati e halogenated at the 8-posit ion (compound IV), or a derivative halogenated at the 5-position (compound V), the substitution . reaction in this case being accompanied by a change in the position of substitution (telesubstitution). In the compounds of the formulae (IV) and (V), X denotes a chlorine or bromine atorn. Scheme 2 The halogenated derivatives (IV) possessing a halogen at the 8-position may in turn be obtained (scheme 3) from a substituted 2-amino-3-halopyraziπe (VI) which is condensed with an alpha-halocarboπyl derivative (III) . Scheme 3 Another method for obtaiπing-a compound of general formula (IV) possessing a chlorine atom at the 8-positioπ consists in treating an imidazoC1,2-a]pyraziπe with suL- furyl chloride. There is thus obtained, for example, from • ethyl imidazoC1,2-a]pyraziπe-2-carboxylate (VII), a mixture of ethyl trichloro- and 5,6,7,8 tetrachloroimidazo-l.1,2- a 3py r az i πe-2-c a rboxy I a te (VIII) (scheme 4), in which the chlorine at the 8-position is the atom which may be most readily substituted by an amiπe of type: / R 3 H-N \ R The halogeπated derivatives possessing a halogen atom at the 5-position (compound V) may be obtained according to the above process (scheme 3), replacing the compound (VI) by the compound (VI ' ) ( v r ) in which the halogen is, for example, a bromine atom, but also by direct halogenatiσπ ( scheme 5 ) of a substituted inτidazoC1,2-a]pyraziπe possessing a hydrogen atom at the 5- position, using the-usual reagents, for example brom ne in ethaπol or acetic acid, N-bromosucciπimide, and the like. Scheme 5 The 2-a no pyrazines (VI) and (VI 1 ), the alpha- halocarboπyl compounds (III) and the imidazo 1,2-aϋp i— azines (VII) and (X) employed in the production methods described above are commercial products or products prepared from common starting substances by traditional methods known to those versed in the art. The groups R- ] , R , Y and Z of the general formula (I) of the compounds of the invention are provided by the starting compounds (VI), (VI 1 ), (II) and (III) or are obtained after condensation to the corresponding substitu¬ ted i idazoC 1 ,2-alpyraz i πe . For example, πucleophilic substitution reactions are carried out starting out with derivatives halogeπated at the 3-, 5- and 6-positioπs, using traditional πucleophilic reagents (CN , X , HNR3R ., R0 , RS , and the l ke); an ester group is converted to amide by the action of ammonia in concentrated aqueous solution, and then either to an am πe by the action of sodium hypobromite or to a πitrile by dehydra ion u ing phosphorus αxytri bromide. A chloromethyl group leads via the action of ammonia to an amiπomethyl group, or via the action of an N-alkylamiπe to an N-a I ky I am i πome thy I group. In the same manner, different derivative ' s may be prepared from an i idazoC1,2-a]pyrazine by an electrophilic substitution reaction on the uπsubstituted 3-position. A trifluoroalkylthio group is thereby obtained via the action of t r i f luorome anesu I foπy I ch lor i de and the sulfona ide derivative via the action of chlorosulfonic acid followed by thionyl chloride and an amine, such as methylamiπe, for example. Similarly, reaction of N-b ro osuc i n i i de or N- c h I o rosuc c i n i m i de yields, respectively, the derivatives brominated or chlorinated at the 3-positioπ. Perchloryl fluoride yields the derivative fluoriπated at the 3- pos ition. The action of nitrous acid prepared at the time of use or butyl nitrite gives the πi roso deriva ive. The ni'tro derivative results from the action of nitric acid in sulfuric medium. The examples which follow are given by way of illustration and in no way imply l imitation of the in ention. The analyses and the IR, NMR and MS spectra confirm the structure of the compounds. Examp I e 1 3-Bromo-8-methylamiπoi idazoC1,2-a]pyrazine. Stage. A: preparation of i idazoC1,2-a]pyrazine A mixture of 34 g (0.2 ol) of b romoa c e ta I dehyde dimethyl acetal, 6,6 ml of concentrated aqueous HBr solu¬ tion and 28 ml of distilled water is brought to reflux for one hour. After reaction, the mixture is alkal inized and extracted with ether. This organic phase is added to a solution of 19 g (0.2 mol) of am i nopyra z i πe in 50 ml of d i me t h I fo rma i de (DMF) . The ether is removed by disti lla¬ tion and the mixture is maintained with stirring and under a stream of nitrogen for 12 hours. After reaction, the DMF is distilled off; the reaction medium is dissolved in 150 ml of anhydrous ethaπol, and then brought to reflux for one hour. The alcohol is then removed by distillation; the residue is dissolved in water, alkaliπized with Na C03 and extracted using d i c loro ethane. After chro atography on a neutral alumina column (eluaπt = anhydrous ether), 10.7 g (Yld = 45%) of imidazoL ~ 1,2-a]pyraziπe ( m.p. 84°C). are obtained. Stage B: preparation of 3,5-d ibromo i idazoL " 1,Z-a3- pyraz iπe. A solution of 12 ml of bromine n 10 ml of acetic acid is added dropwise to a solution of 6 g (50.5 mmol) of imτdazoC1,2-alpyraz ine in 70 ml of acetic acid. The sol¬ ution brought to reflux for one and a half hours is then evaporated under vacuum. The residue is then dissolved in water, alkaliπ zed ith Na C03 and extracted with dichloro- methaπe. After chromatography on a neutral alumina column (eluaπt = anhydrous ether), 8,38 g (Yld = 60%) of 3,5- . dibromo i idazoC1,2-a pyraziπe (m.p. J.50°C) are obtained. Stage C: preparation of 3-bromα-8-methyIam iπo- im dazoL ~ 1, r 2-a3pyraziπe. A mixture of 1 g (3,6 mmol) of.3,5-dibromoimidazo- L " 1,2-a]pyraziπe in 9 ml of a 40% strength aqueous methyl¬ amiπe solution is maintained with stirring for 12 hours. After evaporation under reduced pressure and chromatography on a silica column eluted with ether, 0.33 g (Yld = 40%) of 3-bromo-8-methyI am iπo i m idazoCI ,2-a3pyraz i ne (m.p. 139°C) is obtained. By replacing, in Example 1 above, stage C, methyl- a ine b : ammoπiacal alcohol, 8-am iπo-3-bromo im i dazoC 1 ,2-a 3- pyrazine (m.p. 239 C) is obtained; ethyla iπe, 3-bromo-4-ethylaminoimidazoC1,2-a3- pyraziπei ((mm..pp. 8 822'°C) is obtained, Example Z 8-MorpholiπoimidazoC1,Z-a3pyraziπe. Stage A: preparation of 6,8-d bromo i idazoC 1 ,2-a3- pyrazine. This derivative is obta ned according to a tech ¬ nique iden ical to that of Example 1, stage A, by replacing 2-a nopyraz πe by Z-am iπo-3,5-d bromopyraziπe. 10 g (39.5 mmol ) of this compound yield 5.47 g (Yld = 50%) of 6,8-dibromoimidazoC1,2-a3pyraziπe (m.p. 165°C ) . Stage B: preparation of 6-b romσ-8-morpho I i πo- imidazoC1,2-a3pyraziπe. A solution of 1 g (3,6 mmol) of 6,8-dibromo- i idazoC1,2-a3pyraziπe and 1 g (11.2 mmol) of morpholine in 15 ml of anhydrous ethaπol is brought to reflux for 12 hours. After evaporation of the solvaπt and chromatography on an alumina column (eluant = CH 2 Cl ), 0.88 g (Yld = 85%) of 6-bromo 8-morpholinoimidazoC1,2-a3pyraziπe (m.p. 191 °C ) is obta i ned . Stage C: preparation of 8-mo rpho I i no i m i dazo [ 1 ,2-a 3- p raziπe. 200 mg of palladium on charcoal (10% palladium) are added to a solution containing 0.5 g ( 1.77 mmol) of 6- b romo-8-morpho I i no i m i dazoC 1 ,2-a p raz i ne for 120 ml of anhydrous methaπol and 2 g of potassium hydro ide. The mixture is hydrogenated at atmospheric pressure for 12 hours. The solution is filtered, concentrated and taken up with water; after extraction with dichloromethane and evaporation of the solvent, 0.34 g (9Z%) of 8-mo rpho I i πo- i m i dazoC 1 ,2-a3p raz i ne (m.p. 127°C) is obtained. By replacing, in Example 2 above, stage B, morphol ine by the different amines referred to in Table I below, the corresponding substituted 6-bromoimidazoC1,2-a3- pyraziπes, recorded in the same table, are obtained. Treat¬ ment of the products thereby obtained according to the pro¬ cess described in Example 2, stage C, yields the substituted imidazoC1,2-a3pyraziπes referred to in Table I. Table I Amiπes Results of stage B Result of Stage C Ammoniaca I 8-amino-6—brαmoi idazo- 8-amiπoimidazoC1,2-a3- alcohol C 1,2-a3pyraz iπe pyrar ne (m.p. 22Q°C) (m.p. 210°C) Methyl amine 6-bromo-8-methylamiπo- 8-methylamiπoimidazo- τmidazαC1,Z-a3pyraziπe C1,2-a3p raz iπe (m.p. 16Z°C) (m.p. 96°C) Ethyla ne 6-bromo-8-ethylamiπo- 8-ethylaminoimida∑o- imidazoC1,2-a3pyraziπe L " 1,Z-a3pyraziπe (m.p. 99°C) (m.p. 98°C) Furfuryl- 6-bromo-8-furfurlamiπo- 8-furfurylamiπoimidazo- a ine imidazoC1,Z-a3pyraziπe C1,2-a3pyraziπe (m.p. 164°C) (m.p. = pasty) Example 3 Ethyl 6-bromo-8-methylamiπoim dazoC1,2-a pyraziπe-2- acetate . Sta'ge A: preparation of 2-amino-5-bromo-3-methy l- amiπopyraz iπe . 1.55 g ( 50 mmol) of 40% strength aqueous methylamiπe solution is added to a solution of Z.53 g (10 mmol) of 3,5- dibromo-Z-am πopyrazi πe in ethaπol. The mixture is stirred in an autoclave at 13Q°C for 17 hours. After evaporation of the solvent under reduced pressure, the product is purified by chromatography on a silica column (eluaπt = CH^C1 2 , to which 3% of CH3OH has been added). 0.8 g (Yld = 40%) of Z-amiπo-5- bromo-3-methyl a inopyrazine (m.p. 1Z1°C) is obtained. Stage B: preparation of ethyl 6-bromo-8-methyIami no- im dazoC1,Z-a3pyraziπe-Z-acetate. Z.Q3 g ( 10 mmol) of Z-am iπo-5-b omo-3-methyla πo- pyraziπe are dissolved in 5 ml of dimethylforma ide (DMF). A solution of 1.645 g(10 mmol) of ethyl (chloroacetyl)acetate in 5 ml of DMF is added drop ise with stirring. The mixture is maintained with stirring and under gentle reflux for 3 hours. The DMF is then evaporated off under reduced pressure and the residue, dissolved i.n 50 ml of anhydrous ethaπol, is brought to refl x for one hour. After remo al of t e solvent, the residue is taken up with water, alkal inized and extracted with d i c h I o ro e t h aπe . After dehydration over anhydrous calcium chloride, the solvent is evaporated off under reduced pressure. The crude product is purified by chromatography on a sil ica column (eluant = dichloromethaπe to which 5% of ethanol has been added) . 0.4 g (Yld = 30%) of ethyl 6-b romo-8-me thy I am i no i m i dazoC 1 ,2-a 3pyra z i ne-2- acetate (m.p. 104°C) is obtained. By replacing, in the Example 3 above, stage B, 2- amiπo-5-bromo-3-methyla inopyraziπe by an equi molar amount of substituted 2-aminopyrazines and ethyl (chloroacetyl)acetate by ethyl bromopyruvate, the 8-amiπoi idazoC1,2-a3pyraziπe derivatives appearing in Table II below are obtained. For the final derivative l isted in this Table II, only the replacement of 2-am i no-5-b romo-3-methy I am i nopy ra z i πe by the substituted 2-amiπopyraziπe is. necessary. Table II Substituted 2-aminopyrazines: 8-AmiπoimidazoC1,2-a3- pyrazine derivatives: 2,3-diaminopyrazine ethyl 8-amiπoimidazoC1,2-a3- pyrazine-2-carbox late (m.p. 230°C). 2,3-diamino-5-bromopyrazine ethyl 8-amiπo-6-bromoimid- azoC1,2-a3pyraziπe-2-car- boxylate (m.p. 245°C) . 2-amino-3-methylaminopyrazine ethyl 8-methylaminoimid- azo[1,2-a3pyrazine-2-car- boxylate (m.p. 184°C) . 2-amiπo-5-bromo-3-methyl- ethyl 6-bromo-8-methylamino- am i nopy raz i πe i i dazo C 1 ,2-a 3py raz i πe-2- carboxylate (m.p. 234°C) . 2-a i πo-5-b romo-3-e thy I - ethyl 6-b romo-8-e t hy I am i πo- aminopyrazine imidazoC1,2-a3pyraziπe-2- carboxylate (m.p. 180°C) . 2-amino-3-propylaminopyraziπe ethyl 8-propylaminoimidazo- [1,2-a3pyrazine-2-carboxy- late (m.p. 145°C) . 2-a i πo-5-b romo-3-p ropy I - ethyl 6-b romo-8-p ropy I am i no- aminooyrazine imidazoC1,2-a3pyrazine-2- carboxylate (m.p. 190°C). 2-amiπo-5-bromo-3-butyI- ethyl 6-bromo-8-but la iπo- amiπopyraz πe i idazoC1,Z-a3pyraziπe-Z- carboxylate ( m.p. 176°C ) . 5 Z-amiπo-5-bromo-3-sec- ethyl 6-bromo-8-sec-butyl- butylamiπopyraziπe amiπoimidazoC1,Z-a3pyra- ∑ ine-2-carboxyIate (m.p. 187°C). 2-ami πo-3-p iper idylpyraz iπe ethyl 8-p ipe ridyL i i dazo- 10 C1,Z-a3pyraz iπe-Z-carboxy- late (m.p. 1H°C). Z-am ino-5-bromo-3-p ipe rid l- ethyl 6-bromo-8-p iper i dyl- pyraziπe i dazoC1,Z-a]pyraziπe-Z- carboxylate (m.p. 134°C). 15 Z-amiπo-3-morphoI iπylp raz iπe ethyl 8-morphol inyI i id- azoC-l,Z-a3pyrazine-Z-car- boxylate (m.p. 155°C). Z-am ino-5-bromo-3-morpho- ethyl 6-bromo-8-morphoI i nyI- linylpyraz ne imidazoC1,2-a3pyrazine-2- 20. _ carboxylate (m.p. 140°C). 2-am ino-5-bromo-3-(2-hy- ethyl 6-bromα-8-(2-hydroxy- droxyethyLamiπo)pyraziπe ethylaminα)imidaroL ~ 1,2-a3- pyra∑iπe-2-carbox late (m.p. 208°C). 25 Z,3-di a πo-5-bro op raziπe ethyl 8-amiπo-6-bromo im i- dazoC1,Z-aJpyraziπe-Z- acetate (m.p 181°C) Example 4 5-Chloro-8-ethylaminoimidazoL1,Z-a3pyraziπe. 0 Stage A: preparation of 5,8-di chloro imidazo- C 1 ,Z-a3pyraziπe . This derivative is obtained according to a tech¬ nique identical to that of Example 1, stage A, by replac¬ ing Z-a πop raz iπe by Z-am iπo-3,6-d i ch Ioropyraz ine . 35 Z.4 grams (18.6 mmol) of this compound yield 1 g (Yld = 37%) of 5,8-d i ch loro im idazoC 1,2-a3pyraz iπe (m.p. 102°C). Stage B: preparat on of 8-ethylamino-5-chloro- imidazoC1,Z-a3pyrazine. A solution of 1.5 g (9.8 mmol) of 5,8-d ch lo ro- imidazoC1,2-a3pyraziπe in 25 ml of a 40% strength aqueous ethylamiπe solution is maintained with stirring for 12 hours. After concentration under reduced pressure and chromatography. on a silica column (eluant = ether), 5- ch Ioro-8-ethy Ia ino im idazoC 1 ,2-a3p raz ine (m.p. 94°C), is obtained. Examp I e 5 8-Amino-3,6-dibromoimidazoC1,2-a3pyraziπe. Stage A: preparation of 3,6,8-tribromoimidazo- C 1,2-a 3pyraz iπe . A solution of 0.8 g (2.9 mmol) of 6,8-dibromo- imidazoC1,2-a3pyrazine and 1.2 g of N-bromosuccinimide in 40 ml of chloroform is brought to reflux for two hours. After being cooled, the organic solution is treated with aqueous a 2 03 solution. The chloroform phase is collected and then evaporated. 1 g (Yld = 97%) of 3,6,8- tπ ' bromoimidazo[1,2-a3pyraziπe (m.p. 161°C) is obtained. Stage B: preparation of 8-a i no-3,6-d i b romo- imidazoC1,2-a3pyraziπe. A solution of 1 g (2.8 mmol) of 3,6,8-tribromo- im idazoC 1 ,2-a3pyraz ine in 50 ml of am oniacal alcohol heated to 120°C for 5 hours in a 250-ml autoclave. After reaction and evaporation of the solvent, 0.8 g (Yld = 98%) of 8-amiπo-3,6-dibromoimidazoC1,2-a3pyraziπe (m.p. = 24ό°C ) is obta ined. By replacing, in Example 5 above, stage B, am¬ moniacal alcohol by: ■methyla ine, 3,6-dibromo-8-methylaminoimidazo- C1,2-a3pyraziπe (m.p. 229°C) is obtained ' ; or ethylamiπe,_ 3,6-dibromo-8-ethylaminoimidazo- C 1 ,2-a3p raz i πe (m.p. 131°C) is obtained; or morpholine, 3,6-dibromo-8-morpholiπoi idazo- C1,2-a3pyrazine (m.p. 141°C) is obtained; or furfurylamiπe, 3,6-dibromo-8-furfurylaminoimidazo- C 1 ,2-a 3py az i πe (m.p. 143°C) is obtained; or piperidine, 3,6-dibromo-8-piperidylimidazo- C 1 ,2-a3py rraazz iinnee ((im.p. 72°C) is obtained, Example 6 6-8romo-8-methylaminoimidazoC1,2-a3pyraziπe-2- carboxa ide. A suspension of 0.470 g ( 1.57 mmol) of ethyl 6-bromo-8-methylamiπoimidazoC1,Z-a3pyrazine-Z-carboxylate, obtained according to the process described in Example 3, 5 in 50 ml of concentrated aqueous ammonia solution, is brought to reflux for 4 hours. After the mixture is cooled, the precipitate is drained, washed and dried. 0.160 g (Yld = 40%) of 6-bromo-8-meth Iam ino imidazo- 1,Z-a3pyraz iπe-2-carboxam de (m.p. 312°C) is obtained. 10 Example 7 3,5,6-Trichloro-8-methylamiπo-N-methylim dazo- C1,2-a3pyrazine-2-carboxamide. Stage A: preparation of ethyl im i dazoCI ,2-a 3- p raz iπe-2-carboxylate . 15 This derivative is obtained according to the tech¬ nique described in Example 3, stage B-, by reacting 2- a inop raz πe and ethyl bro opyruvate . Ethyl imidazo- C1,Z-a3pyrazine-2-carboxylate (m.p. 179°C, Yld = 25%) is obtained. 20 Stage B: preparation of ethyl 3,5,6,8-tetrac loro- im dazoLT1,2-a]pyraziπe-2-carboxylate. 4 ml of sulfuryl chlo ide are added with stirring to a suspension of 0.720 g (3.77 mmol) of ethyl imidazo- C1 ,2-a3pyrazi πe-2-carboxyl ate in 10 ml of anhydrous beπ- Z5 zeπe, and the mixture is then brought to reflux for one hour. The solvent is then evaporated off under reduced pressure. The res due is poured onto ice, and then ex¬ tracted after al kal iπi za tion. A mixture of 0.750 g (70%) of ethyl trichloroim dazoC1,Z-alpyrazine-Z-carboxylate, 30 m.p. 13Z°C, and 0.350 g (30%) of ethyl 3,5, 6,8-tetrach loro- im i dazoC 1 ,Z-a3pyraziπe-Z-carboxylate (m.p. 171°C) is there¬ by obtained, and these are separated by chromatography on a silica column (eluaπt = dichloromethane to which Z% of methaπol has been added). 35 Stage C: preparation of 8-methyIa iπo-3,5,6-tr - chloro-N-methylimidazoC1,Z-a3pyraziπe-Z-carboxamide. 0.330 g (0.1 mmol) of ethyl 3,5,6,8-tetrach loro- imidazoC ,Z-a p raziπe-Z-carboxylate, obtained according to the above method, is dissol ed at room temperature and with stirring in 20 ml of a concentrated aqueous methyl¬ a ine solution. After extraction with dichloromethaπe, 0.Z96 g (96%) of 8-methyI am i πo-3, 5, 6- t r i c h loro-N-me t hy I - im idazoC 1,2-a3py raz iπe-2- arboxa ide, m.p.262°C. and 0.02 g of ethyl 8-met y I am i no-3,5,6-1 r i c h I oro i m i dazo- C 1 ,2-a3pyraz iπe-2-carboxy la te are isolated. Examp le 8 6-Bromo-8-methylamiπoimidazoC1,2-a3pyrazin-2- a i ne . 0.42 g of bromine (8 mmol) is added to a solution, cooled with a mixture of ice and salt, of 1.9 g of NaOH (47.5 mmol) in 10 ml of water. After the addition of 1.62 g (6 mmol) of 6-b romo-8-me thy I a i no i i dazoC 1 ,2-a 3py r a z i ne- 2-carboxamide (obtained according to Example 6), ' the mixture is brought to reflux for half an hour. After the mixture is cooled, the precipitate f-ormed is collected and the mother liquors are evaporated to dryness. These two fractions are treated with 10% strength HCl until the evolution of gas has ceased. The acid solution is then alkal inized. Extraction with dichlor-omethane gives 6- bromo-8-methylamiπoimidazoC1,2-a3pyrazin-2-amiπe. Examp I e 9 6-Bromo-8-methylamino-2-phenyl imidazoC1,2-a3- pyraziπe. Stage A: preparation of 6, 8-d i bromo-2-pheπy I - imidazoC1,2-a3pyraziπe. This derivative is obtained according to a tech¬ nique identical to that of Example 2, stage A, by replac¬ ing bromoaceta Idehyde dimethyl acetal by 1-bromoace o- phenone. 10 g (39.5 mmol) of 3, 5-d i b romo-2-ami nopy r a- ziπe yield 8.3 g (Yld = 60%) of 6,8-d i bromo-2-pheny l- i m i dazoC 1 ,2-a3py raz i ne (m.p. 254°C) . Stage B: preparation of 6-bromo-8-methylamiπo- 2-pheπyl imidazoC1,2-a3pyrazine. This derivative is obtained according to a tech¬ nique identical to that of Example 2, stage B, by replac¬ ing morphol ine by concentrated aqueous methylamiπe solution. 6-Bromo-8-methylamino-2-phenyl imidazoC1,Z-a3pyraziπe is obtained. E xamp l e 1 0 6-Bromo-Z-chloromethyl-8-d imethyl ami no i idazo- 1 ,Z-aJpyraz iπe . Stage A: preparation of 2-amino-5-bromo-3-d i- 5 meth lam πop raz ine. This derivative is obtained according to a tech¬ nique identical to that of Example 3, stage A, by replacing methylamine by a 40% aqueous dimethyl amine solution. 5 g (19.8 mmol) of Z-amiπo-3,5-d ibromop raz i πe give 3.18 g 10 (Yld = 74%) of Z-am iπo-5-bromo-3-d imethyla i πopyraziπe Cm.p.U5°C ) . Stage B: preparation of 6-bromo-Z-chloromethyl- 8-dimethylamiπσimidazoC1,Z-a3pyraz ne. 1.17 g (9.Z mmol) of 1,3-di c loroacetone is ad- 15 ded dropwise to a solution of Z g ( 9.Z mmol) of Z-a iπo- 5-bromo-3-dimethyl am iπopyrazi ne . Afjrer 3 hours under re¬ flux, the alcohol is evaporated off under reduced pressure and the res due taken up with water, alkaliπized and ex¬ tracted with d chloro ethane. After purification by Z0 chromatography, 6-bromo-Z-ch loromethyl-8-d imethylam i πo- imidazoC1,Z-a3pyrazιπe is obtained. - Example 11 ό-Bromo-S-morphol ino im idazoC 1,Z-aJpyraz πe-Z- carbonitrile Z5 Stage A: preparation of 6,8-dibromoimidazo- 1 ,Z-a pyraziπe-Z-carboxa ide . This derivative is obtained according to a tech¬ nique identical to that described in Example 6, by re¬ placing ethyl 6-bromo-8-methylami no im idazoC 1 ,Z-a3pyraz ine- 30 2-carboxylate by ethyl 6,8-dibromoim dazoC1,Z-a3pyraziπe- 2-carboxyIate . Starting with 3.5 g (10 mmol) of ester, 2.56 g of amide (Yld = 80%) (m.p. 26Q°C) are obtained. Stage B: preparation of 6,8-d ibromo im idazo- 35 C1,2-a3pyraziπe-2-carboπitrile. A suspension of 1 g (3.1 mmol) of amide obtained in stage A above in 9 ml of phosphorus oxytribromide is brought to reflux for one hour. After dissolution, the excess P0Br3 is driven off by distillation. The residue is carefully poured onto ice. After a I k a I i π i z a t ion , ex¬ traction yields 0.6 g (63%) of 6,8-dibromoimidazoC1,Z,-a3- pyraz iπe-2-carboπ i tri le (m.p. 208°C). Stage C: preparation of 6-bromo-8-morpholino- i idazoC 1,2-a3pyraz iπe-2-carbon i t r i le . 0.2 g (0.66 mmol) of πitrile is dissolved at room temperature and with stirring (one hour) in 3 ml of mor¬ pholine. After evaporation of the excess morpholine under reduced pressure, the residue is taken up with dichloro- methane. The evaporated filtered solution yields 0.2 g (Yld = 98%) of 6-bromo-8-morpholinoimidazoC1,2-a3-pyrazine- 2-ca rbon i t r i le (m.p. 265 C) . The compounds which form the subject of the in¬ vention, as well as their phar aceutically usable salts, possess pharmacological properties justifying their ap¬ plication in human or veterinary therapy. In particular, some derivatives proved to be endowed with greater aπti- spas odic, uterine relaxant, broπchodilatory and cardiac aπaleptic (iπotropic arid positive chronotropic function) activities than those of theophyll iπe (Theo), chosen as reference constituent. It will be noted, in addition, that the compounds which form the subject of the present inven¬ tion do not possess the neuros t i mu I a tory s ide effects of Theo and that, on the contrary, they prove to be endowed with neurosedat i ve properties. The demonstration of the pharmacological activi ties of some of the compounds of the present invention was car¬ ried out according to the tests described below. The test compounds are identified by a number corresponding to the structures specified in Table III below. 1. Aπtispas odic activity Fragments of duodenum are removed from male rats (200 g), fasted for 24 hours and killed by decapita ion, and are mounted, after being washed, in a the rmos ta t ted (37°C) isolated organ cell and maintained in survi al in Tyrode's solution according to Magnus 's classical technique. The spasmogenic agent used is barium chloride (10~ 4 M). In the first instance, the spasmogeπic agent is added to the nutrient bath and, as soon as the contraction of the organ reaches its maximum, the relaxant agent is added to the medium. Working in relation to a fixed con¬ centration of barium chloride with var able concentrations of relaxant, the ED50 of the latter, capable of reducing the induced contraction by 50%, is determined. The results expressed in Table IV below show the ratio ED50 Theo/ED5Q product, established on the basis of the mean of the results of 5 to 6 determinat ons per product (ED5Qtheophylliπe = 8 x 10 -4 M) Table III Compound No. Y Z R 2 R 3 R 4 M. C 1 H H H H H H 2 H H H H H CH 3 3 H H H H H C 2 H 5 4 H H H H -(CH 2 ) 2 -0 -(CH 2 ) 2 - 5 H H H Br H H 6 H H H Br H CH 3 7 H H H Br H C 2 H 5 8 Br H H H H H 9 Br H H H H CH 3 10 Br H H H H C 2 H 5 11 Br H H H -(CH 2 ) 2 -0 -(CH 2 ) 2 - 1 12 H Cl H H. H C 2 H 5 13 Br H H Br H H 2 14 Br H H Br H CH 3 2 15 Br H H Br H C 2 H 5 1 16 Br H H Br -(CH 2 J 2 -0 -(CH 2 ) 2 - 1 17 H H C0 2 Et H H H 2 18 H H C0 2 Et H H CH 3 1 19 H H C0 2 Et H H C 3 H 7 1 20 H H C0 2 Et H -(CH 2 ) 5 " 1 21 H H C0 2 Et H -(CH 2 ) 2 -0- (CH 2 ) 2 - 1 22 Br H C0 2 Et H H H 2 23 Br H C0 2 Et H H CH 3 2 24 Br H C0 2 Et H H 1 C 2 H 5 25 Br H C0 2 Et H H C 3 H ? 1 26 Br H C0 2 Et H H- n-C 4 H 9 1 27 Br H C0 2 Et H H s- 4 H 9 1 28 Br H C0 2 Et H -(CH 2 ) 5 " 1 29 8r H C0 2 Et H -(CH 2 ) 2 -0- (CH 2 ) 2 - 14 30 Br H C0 2 Et H H -(CH 2 ) 2 0H 20 31 Br H C0NH 2 H H -CH 3 31 32 βr H CH 2 C0 2 Et H H H 18 33 Br H CH 2 C0 2 t H H CH 3 10 Table III (cont nued). 34 ■ Cl Cl CO HCH, Cl H CH 3 262' Table IV " - Ant i spasmodic act vity _ - P roduct Theo/ED ED 50 p roduct 6 32 8 32 9 20 10 40 12 27 17 „ 13 • • - - Z. Uterine relaxant activity Female rats (150 - 180 g) are killed by decapi ¬ tation Z4 hours after the intraper toπea I administration of stilbestrol (0.1 mg/kg). The uterine horns are removed and fragments mounted in a thermostatted ( 37 C ) isolated organ cell and maintained in survival in oxygenated De Jalon's solution of composition ( M ) : NaCl ( 153.8 ) ; KCt (5.6); CaCl 2 (Z.16); NaHC03 (1.8); dextrose ( 5.5 ) . One end of the uterine fragment is maintained fixed, while the other is attached to a recording myograph under a tension of the order of 0.5 g. The spontaneous uterine contractions are recorded on a kymograph. The organ is left at rest for 30 m nutes and washed three times. The test products are introduced directly into the bath after being dissolved in De Jalon's solution, and the activity measured ED5Q) corresponds to the dose capable of reducing the magnitude of the spontaneous contractions by 50%. The results expressed in Table V below show the r 3 tio ED5Q Theo/ED5 Q product, established on the basis of the mean of the results of 5 to 10 determinations per product. (ED50 theophylline = 0.9 x 10 M) . Table V - Uterine relaxant activity Compound ED5Q Theo/ED5Q product 6 9 8 3 9 5.6 10 7.2 17 2.6 3. Ant i b roπc hospas t i c activity 3.1. Broπchospasm induced in guinea pigs Guinea pigs of both sexes weighing between 400 and 600 g are anesthetized ith ethyl carbamate (1.20/kg i .p. ) . After tracheotomy, the animal is placed under artificial respiration at a constant flowrate (Palmer pump 1 m1/100 g x 60/miπ). A take-off at the tracheal caππula enables the volume of air to be gaged at each inhalation by meaπs ' of a Marey drum. Bronchospasm is induced by iπtraveneous (jugular) administration of hista ine. For each animal, the dose of histamine (8 to 12 μg/kg) inducing an increase in the recording trace equal to double its initial value is determined. The dose adopted should provide three identical responses at intervals of 10 minutes. The test product is ad inistered iπtraveneously and then, 30 seconds later, histamine is administered again. The measured ED50 represents the dose which reduces the histamiπe-induced broπchocoπstrictioπ by 50%. Table VI below shows the ratio ED5Q Theo/ED5g product, establ ished on the basis of the mean of the results of 5 to 8 deter ¬ minations per product (ED50 Theo = 4.3 x 10 M/kg) . Product ι ED 5Q Theo/ED 5Q p roduct P roduct ED Theo/BD ' product ' 5 ' 2 23 I 6 2 24 I 0 • ] ' 25 < 1 9 5.4 26 ! < l 10 2 27 | < 1 I I 1 28 ! < r 13 3.5 29 | I 16 1.9 30 ! < 1 15 1.6 31 I 1 16 • 1 32 ! 1-6 17 1.1 33 i 1 18 1 34 ! 1.2 19 < 1 35_ i < ι 20 i 1 36 ! < i 21 ! < ι 37 1 1.4 22. ! 1.5 38 i L1 3.2. Isolated guinea pig trachea Guinea pigs of both sexes weighing on average 400 to 600 g are sacrificed, and the tracheas are removed and placed at 37°C in an oxygenated environment (95% 0 2 - 5% C0 2 ) in rebs fluid of the following composition (mM): NaCl (116), MgS0 (1.2), Cl (3.7), CaCl 2 (2.6), KH 2 P0 4 (Z.Z), aHCθ3 (Z4.9), glucose (10). The tracheal segments are then mounted horizontally between two hooks, one of which is fixed to the base of the isolated organ cell and the other is attached to a myograph under a tension of 0.5 g. The organ is left at rest for one hour and is subjected to four washes. The contraction- i nduc iπg reagent (carbachol) is added at a concentration (10 ) greater than the concentration giving the maximum effect. After stabili ation of the contractioπal effect, gradually increasing accumulative amounts of the test products are added to the cell. The broπchodilatory effect is measured as the percentage inhibition of the max al contraction and ECςg represents the concentra ion inhibiting this concentra ¬ tion by 50% . Table VII below shows the ratio EC5Q theophyl- l iπe/EC5Q product, establ ished on the basis of the mean of the results of 5 to 6 deter inations by. product EC5Q Theo = 10~ 3 M). Table VII - Aπti-contractional activity (trachea) P roduc t EC50 Theo/EC5Q product Product EC50 Theo/EC5Q product] 1 1.5 7 5 2 <1 8 11.3 3 1 9 8.3 4 <1 10 5 5 11 11 <1 6 12.5 39 <1 4. Cardiac activity (inotropic and chroπotropic function) Guinea pigs of both sexes weighing between 300 and 500 g are killed by decapitation. The hearts are rapidly removed and placed in an oxygenated environment (95% 0 2 - 5% C0 2 ) in Chenoweth-Koelle's solu ion of the following composition (mM) : NaCl (120), KCl (5.63), CaCl 2 (2.0), dextrose (9.7), MgCl 2 (2.0), NaHC0 3 (26.0) . The right and left atria are then separated from the heart and mounted in an isolated organ cell . The right atrium beats spontaneously and the left atrium is electrically stimulated. The organs under a tension of 1 g are left at rest for two hours and washed every fifteen minutes. The products are added directly to the nutrient bath. The right atrium is used for measuring the modifications of rate (chronotropic function) whereas the left atrium indic¬ ates the modifi ations brought about in the contractile force ( inotropic function) . For the inotropic function, the concentration capable of producing an increase in magnitude of 0.5 g wi th respect to the basi contraction is measured. For the chroπotropic function, the concentration capable of producing a 20% increase in the basic value of the rate is determined. Table VIII below shows the ratio of activity between theophylliπe and Product for these two parameters ED Theo/ED Product. ED Theo inotropic function = 8 1Q~ 4 M chroπotropic function = 4 x 10 -4 Table VIII - Cardiac activity 10 15 Motor a tiv ty Z0 The measurement of the neurosedat ve effect is based on the test of activity measurements in mice. Male mice weighing on average Z5 to 30 g receive 55 and 166 μ.mol/kg of the test products iπtrapεr toneally, and the control animals receive the corresponding doses of the vehicle. Five minutes Z5 after the administration, the animals are placed in acti ity- measuring cages, wh ch record their movements digitally by means of the interrup ion of beams of light. The results a r e recorded in Table IX and expressed as the percentage varia¬ tion (increase T or decrease ) in activi y compared with the 30 controls during a period of 50 minutes following the adminis¬ tration. Tab le IX - spontaneous activity - % variation compared with the controls. 35 PRODUCT 55 umol /kg 166 μ ol/kg 6 25 57 8 53 V 83 9 74 83 10 13 73 17 28 V 17 23 43 56 'Theophylliπe T 130 t 170 Naturally, the results of the trials presented above have been given only by way of illustration of the pharmaco¬ logical properties which may be possessed by the compounds of the invention. The latter may hence be combined with any suitable excipient customarily used -in human or veterinary therapy for the purpose of preparing and presenting pharma¬ ceutical compositions which may be administered in the field ■ of application of -ant i spas od i cs, uterine relaxants, broncho- dilators, cardiac analeptics and neuro-sedat i ves . Thus, these compositions may take conventional p armaceutical or modified- release forms, intended for oral or parenteral administration or admin stration via the mucosal and cutaneous linings, and containing the desired dose of active agent. Naturally, the dosage and the methods of admin¬ istration will, for each case., be left to the judgment and decision of the treating practitione . It is self-evident that the present invention has been described only in purely explanatory fashion and without any implied limitation, and that any expedient modification may be applied thereto without departing from the scope thereof.

Claims: CLAIMS 1. 8-Amiπo- and 8-a IkylamiπoimidazoC 1,2-a]pyraz iπe compounds, as well as their derivatives corresponding to the formula (I) below and their salts that are compatible with pharmaceutical application, which correspond to the formula: in which formula: . Y and Z independently denote: a) a hydrogen atom, b) a halogen atom such as F, Cl, Br or I, c) C0 H d) CN, e) a I'iπear or branched C -j - C 5 alkyl radical, f) a C -j — C 5 alkoxy radical, g) CF3 h ) with R3 and R as defined below; . R- ] and R , when they are independent, denote, a) a hydrogen atom, b) a halogen atom such as F, Cl, Br or I, c) a linear or branched C1-C5 alkyl radical, d) a radical -( CH 2 ) n - 0 2 R5, with R5 denoting a C1—C5 alkyl radical and n being between 0 and 4, e) a pheπyl radical, optionally substituted, Λ /' o f) CO-N with R 0 and R7 independentl denoting a hydrogen atom, a linear or branched C-1-C5 alkyl radical or an aryl radical, g) CN, h ) CH^ R 7 i) NH 2 , j) CH 2 Cl, k) CH 2 0H, I) CF 3 , m ) Ξ0 2 - ^ R_ π) -N0 2 , o) -NO, p) a C3-C cycloalkyl radical, q) an acy I radical, r) a linear or branched C 1—C5. alkylthio radical; . R - j and R 2 , when they are linked to one another, denote -CH 2 -CH 2 -CH 2 -CH -, . R3 and R independently denote: a) a hydrogen atom b) a linear or branched C- j -C j alkyl radical, capable of bearing one or more hydrogen atoms or a hydroxy, N(C- ] -C4 alkyl) 2 , carbamoyl or C - | —C alkoxy radical, either a 3-C6 cycloalkyl radical or a pheπyl radical, c) a C - j —C5 acyl radical, d) a furfuryl radical, . R3 and R4, linked to one another denote -CH 2 -CH 2 - CH -CH -CH 2 or -CH 2 -CH -X-CH -CH 2 - in which X denotes 0 or S. 2. The compounds as clai ed in claim 1, which correspond to the formula (I) in which R3 = H, R4 = H or a methyl or ethyl radical, R 1 = H o r an ethyl carboxylate group, Y and Z denote either H or Br and R 2 denotes Br or H. 3. The compounds as claimed in claim 1 or 2, which correspond to the formula (I) in which R3 = H, R4 = CH3 or C 2 H 5' Y = H, Z = H, R 2 = Br and R < | = H, namely, respect¬ ively the compounds of formulae: - Z3 - C 2 H 5 , Y = H, Z = H, R 2 = Br and R 1 = H, namely, respect- ively the compounds of formulae: 10 having, respectively, a melt ng point of 143°C and 8Z°C. 4. A compound as claimed in clai 1 or Z, wh ch corresponds to the formula (I ) n which Y denotes a bromine atom and R-], R 2 , R3, R4 and Z denote hydrogen atoms, namely 15 the compound of formula having a melting point of 210 C. 5. The compounds as claimed in claim 1 or Z, which correspond to the formula (I) in which R3 = H, R4 = CH3 or Z5 C H5, Y = Br, Z = H, R = H, and R- | = H, namely, respect¬ ively, the compounds of formulae: 35 ha ing, respectively, a melting point of 16Z°C and 99°C. 6. A compound as claimed in cla m 1 or Z, which corresponds to the formula (I) in which R3 = H, R4 = H, Y = Br, Z = H, R 2 = Br and R-j = H, namely the compound of formula : t r having a melting point of 246 C. 7. A compound as claimed in claim 1 or 2, which corresponds to the formula (I) in which Y, Z, R <| , R , R3 and R4 denote hydrogen atoms, namely the compound of formula: having a melting point of 220 C. 8. The compounds as claimed in claim 1 or 2, which correspond to the formula (I) in which Y, Z, R-j, R and R3 denote hydrogen atoms and R4 denotes a methyl or ethyl radical, namely, the compounds of formulae: having, respectively, a melting point of 96°C and 98°C. 9. A compound as claimed in claim 1 , which corresponds to the formula ( I) in which Y, Z, R^ and R 2 denote hydrogen atoms and R3 and R4 are linked to one another to denote a -( CH ) 2 -0- ( CH 2 ) 2 - radical, namely the compound of formula: having a melting point of 127 C. 10. A compound as claimed in claim 1 or 2, which corresponds to the formula (I) in which Y, Z, R- j , R and R4 denote hydrogen atoms and R denotes a bromine atom, namely the compound of formula: having a melting point of Z39 C. 11. A compound as claimed in claim 1, which corresponds to the formula (I) in w i"ch Y denotes a bromine atom, Z, R- j and R 2 denote hydrogen atoms and R3 and R4 are linked to one another to denote a - ( CH ) 2 -0- ( CH 2 ) 2 - radical, namely the compound of formula: having a melting point of 191 C. 12. A compound as claimed in claim 1, which corresponds to the formula (I) in which Y, R- j , R and R3 denote hydrogen atoms, Z denotes a chlorine atom and R4 denotes a C 2 H5 radical, namely the compound of formula: having a melting point of 94 U C. 13. The compounds as clai ed in claim 1 or 2, which correspond to the formula (I) in which Y and R 2 denote bromine atoms, Z, R-| and R3 denote hydrogen atoms and R4 denotes a methyl or ethyl radical, namely the compounds of formulae: having, respectively, a melting point of 229°C and 131°C. 14. A compound as claimed in claim 1, which corresponds to the formula (I) in which Y and R denote bromine atoms, Z and R -j denote hydrogen atoms and R3 and R4 are l inked to one another to denote a - ( C H 2 ) 2 -0- ( CH 2 ) - radical, namely the compound of formula: β having a melting point of 151 C. 15. The compounds as claimed in Claim 1 or 2, which correspond to the formula ( I) in which Y, Z, R and R3 denote hydrogen atoms and R4 hydrogen or' a -CH3 radical or a -C3H7 radical, and R -] denotes a -C0 C 2 H5 group, namely t compounds, respectively of formulae: having, respect vely, a melting point of Z30°C, 184°C and 145°C. 16. The compounds as claimed * in claim 1, which cor¬ respond to the formula (I) in which Y, Z and R denote hydrogen atoms, R1 denotes a -C0 2 C H5 and R3 and R4 are linked to one another to denote either a -(CH )5~ radical or a -(CH 2 );?-0-( CH ) 2 - radical, namely the compounds, respectively, of formulae: / s Cs, i having, respect vely, a melting point of 114°C and 155°C 17. The compounds as claimed in claim 1, which cor¬ respond to the formula (I), in which Y denotes a bromine atom, Z, R3 and R 2 denote hydrogen atoms, R<| denotes a -C0 2 C 2 H5 and R4 denotes either a hydrogen atom or one of the radicals -CH3, -C 2 H5, -C3H7, n - C H 9 , S-C4H9, namely the compounds, respectively, of formulae: B H K fcHik C H:/' ^ .^ B having, respecti ely, a melting point of Z45 C, Z34°C, 180°C, 190°C, 176°C and 187°C. 18. The compounds as claimed in claim 1, which cor¬ respond to the formula (I) in which Y denotes a bromine atom, Z and R denote hydrogen atoms, R- ] denotes a -C0 C 2 H5 group and R3 and R4 are linked to one another to denote either a -(CH 2 >5- radical, or a - ( CH ) 2 -0-(CH 2 ) 2 - radical, namely the compounds, respecti ely, of formulae: having, respect vely, a melting point of 134°C and 140°C. 19. A compound as claimed in claim 1, which corresponds Z5 to the formula (I) in which Y denotes a bromine atom, Z, R and R3 denote hydrogen atoms, R4 denotes a -(CH 2 ) 2 0H radical and R^ denotes a -C0 2 C H5 group, namely the compound of formula: 35 having a melting point of Z08 C. ZO. A compound as claimed in clai 1, which corresponds to the formula ( I ) in which Y denotes a bromine atom, Z, R and R3 denote hydrogen atoms, R4 denotes a -CH3 radical and R - ] denotes a -C0NH group, namely the compound of formula: having a melting point of 312 C. 21. The compounds as claimed in claim 1, which correspond to the formula (I) in which Y denotes a bromine atom, Z, R 2 and R3 denote hydrogen atoms, R -| denotes a -CH 2 C0 2 C 2 H5 and R4 denotes either hydrogen or a methyl radical, namely the compounds, respectively, of formulae: Mr ^\ having, respectively, a melting point of 181 C and 104 C. 22. A compound as claimed in clai 1, which corresponds to the formula (I) in which Y, Z and R 2 denote chlorine atoms, R3 denotes hydrogen, R4 denotes a -CH3 radical and Ri denotes a CONHCH3 group, namely the compound of formula: having a melting point of 262 C. 23. A compound as claimed in claim 1, which corresponds to the formula (I) in which Y denotes a bromine atom, Z and R denote hydrogen atoms, R-j denotes a -CN radical and R3 and R& are linked to one another to denote a -(CH 2 ) 2 -0- (CH ) 2 - radical, namely the compound of formula having a melting point of 265 C. Z4. The compounds as claimed in claim 1, which cor¬ respond to the formula (I) in which Y denotes a bromine 10 atom, Z, and R3 denote hydrogen atoms, R denotes either a hydrogen atom or a bromine atom and R4 denotes a -CH 4! / group, namely the compounds, respecti ely, of fαrmulae : M fV- .W. _ιπτ? having, respecti ely, a melting point of 164°C and 143°C. 30 Z5. A compound as claimed in claim 1, which corresponds to the formula (I) in which Y and R denote bromine atoms, Z and R- ] denote hydrogen atoms and R3 and R4 are linked to one another to denote a -(CH 2 )5, namely the compound of formula : 35 having a melting point of 72 C. 26. A compound as claimed in claim 1, in which Y, Z, R-|, R 2 and R3 denote hydrogen atoms and 4 denotes a -CH 2 TΪJ group, namely the compound of formula: This compound is pasty. 27. The compounds as claimed in any one of claims 1 to 26, which are the salts thereof resulting from the neutralization of the basic compounds corresponding to the formula (I) with an acid chosen from inorganic acids of the halogen hydracid type (such as hydrochloric acid, hydro- bro ic acid and hydriodic ac id), phosphoric acid, sulfur i c acid and the like, and chosen from organic acids of the carboxyl ic acid type, such as acetic acid, maleic acid, succinic acid, citric acid, tartaric acid, oxalic acid, mal ic acid, pival ic acid, heptaπoic acid, Laurie acid, salicylic acid, benzoic acid, gluta ic acid. Lactic acid and the Like as well as from non-ca rboxyI i c acids such as i seth ionic acid and methanesulfoπic acid, and more especi¬ ally the salts of halogen hydracids such as the hydrochlo- rides, the salts of maleic acid, in particular the acid maleates, and the salts of ethaπesulfoπic acid. 28. A process for preparing compounds as claimed in any one of claims 1 to 27, wherein the halogeπated derivatives represented by the general formulae (IV) and (V) in which X is a halogen such as chlorine or bromine, the other radicals R-], R 2 , Y and Z having the meanings given in these claims, are converted to amines. 29. The compounds as claimed in any one of claims 1 to Z7, as medicinal products used in human and veterinary therapy in the field of application δ " f antispasmodics, uterine relaxaπts, broπchodilators, cardiac analeptics and πeurosedatives . 30. A pharmaceutical compos itioπ, .wh i ch contains at. least one compound as claimed in any one of claims 1 to Z7 in combination or otherwise with any excipieπt, the said composition having an application in human or veterinary therapy in the field of application of antispasmodics, uterine relaxaπts, broπchod lators, cardiac analeptics and πeurosedatives.

Inventors: BONNET PIERRE-ANTOINE, BOUCARD MAURICE, CHAPAT JEAN-PIERRE, CROS GERARD, SABLAYROLLES CLAIRE, BONNET, PIERRE-ANTOINE, BOUCARD, MAURICE, CHAPAT, JEAN-PIERRE, CROS, GERARD, SABLAYROLLES, CLAIRE
Applicants: BYK GULDEN LOMBERG CHEM FAB, BYK GULDEN LOMBERG CHEMISCHE FABRIK GMBH
Application year: 1987
Main classification: C07D487
IPC codes: A61K31, A61P9, A61P11, A61P13, A61P15, A61P25, C07D487