NEW N-((2-OXO-1-PYRROLIDINYL)ACETYL)PIPERAZINES, THE METHODS OF PRODUCING SUCH NEW COMPOUNDS AND THEIR SALTS AS WELL AS PHARMACEUTICAL PREPARATIONS FOR THERAPEUTIC USE CONTAINING THESE COMPOUNDS OR SALTS

Abstract: The present invention concerns new N-[(2-oxo-1-­ pyrrolidinyl)acetyl] piperazines of the following formula: wherein R represents hydrogen or an alkyl group which contains 1 to 3 carbon atoms which can be arranged as straight or branched chain and R′ represents an allyl, cinnamyl or p-methoxybenzyl group, as well as their pharmaceutically acceptable acid addition salts. These piperazine derivatives are useful as drugs, espe­ cially in the treatment of cerebrovascular disturbances in the elderly.

Description: Title New W-[(2-oxo-1-pyrrolidinyl)acetyl]piperazines, the methods of producing such new compounds and their salts as well as pharmaceutical preparations gor therapeutic use.containing these compounds or salts. This invention relates to N- ( (2-oxo-1-pyrrolidinyl)acetyl] - piperazines which are of use as medicines and as intermediates for the productions of medicines. This invention also relates to methods of producing these novel compounds. More specifically, this invention relates to piperazines of the formula I EMI1.1 wherein R represents hydrogen or an alkyl group which contains 1 to 3 carbon atoms which can be arranged as straight or branched chain and R represents an ally. cinn-amyl or p-methoxybenzyl group. The following are included as biologically acceptable :salts: acetates, citrates, succinates, maleates, ascorbates-, hydro- chlorides, sulfates, etc. These salts may be prepared by known salification methods. Preferred compounds in this invention are: N-[(2-oxo-pyrrolidinyl)acetyl]-N'-allylpiperazine N- [(2-oxo-l-pyrrolidinyl)acetyl] -N-cinnamylpiperazine and N-[(2-oxo-pyrrolidinyl)acetyl]-N'-(p-methoxybenzyl)piperazine The N- [ (2-oxo-1-pyrrolidinyl)acetyl3 piperazines of the present. invention may be produced by means of the following methods: I. By ammirzolysis of an ester1 illustrated as follows: EMI3.1 wherein R and R'have the same meanings as above and R represents an alkyl radical which contains 1 or 2 carbon atoms or an aryl radical with or without substitution. The method s characteristic is in the use of a stoichiometric quantity, or an excess (1 to 5 mol) of formula II ester in relation to amine III. The formula IV alcohol formed is gradually eliminated by distillation at normal or reduced pressure. In this last case a .14 mm vacuum is enough. The reaction's temperature depends on the type of ester used; in the case R represents a substituted or non-substituted phenyl radical, the working temperature should be room temperature or slightly higher, for example 800 C. In the case R' represents alkyl radicals the working temperature should be between 100 and 1900 C. Reaction times should be of 6 to 14 hours. Formulas compounds are isolated as free bases by distillation or crystallization. In the case when excess formula II-ester is used, it is -desirable to eliminate this ester by previous distillation in a vacuum. Formula II esters may be recycled in a different operation. 11. By alkylation of a salt of pyrrolidinone (preferentially the sodium or the potassium salt) with a haloacetamide of formula V illustrated as follows: EMI5.1 wherein R and RI have the same meanings as above and Hal represents an halogen atom, preferentially chlorine or bromine. The solvents employed are aromatic hydrocarbons, for instance benzene, toluene or xylenes. The reaction's temperature may oscillate between 75 and 1300C. Formula V haloacetamides are prepared by reacting substituted piperazines of formula III EMI6.1 wherein R'has the same meaning as above with the acid chloride of a haloacetic acid of formula VI EMI6.2 illustrated as follows: EMI7.1 Inert solvents such as ether, benzene, toluene or xylene may be used as solvents. Most suitable working temperature is room temperature in presence of one mol of base, in order to neutralize' the acid formed. Inorganic salts may be used as. bases, for instancd thoroughly grinded carbonates,or organic bases for instance triethylamine; preferentially an excess of the substituted piperazine should be used. The compound N-chloroacctyl-N'-cinnamyl piperazine is described by S. Zikolova et al.: Tr. Nauchnoizsled. Khim.-Farm. Inst. 10, 47 (CA 94 30707 u). III. By acyclation of the substituted piperazines of the formulaII7 with the acid chloride of an haloacetic acid of the formula VII illustrated as follows: EMI8.1 EMI8.2 EMI8.3 The radicals R and R' have the same meaning as above. The acid chlorides of. formula VII are prepared from the 2-(2-oxo-l-pyrrolidinyl)acetic acids and SOCl2. Benzene or toluene may be used as solvents. It is also possible to work with an excess SOC12 as solvent. Working temperature should be room temperature. Appropriate time of reaction is between 2 and 3 hours. After elimination of solvent or excess SOCl2, the acid chlorides of formula. VII are used in crude state The reactions of compounds of formula VII with the substituted .piperazines of formula III are performed by known methods in inert solvents such as ether, benzene or aliphatic hydrocarbons. Appropriate temperatures are between -10 C and + 25 C. They may be performed in presence of.an inorganic base , for instance carbonates, or of organic bases, for instance triethylamine, in order to neutralize the hydrochloric acid formed. It Zs also possible to use the substituted pipera7ines of formula lEl as base, thus working in the 1/2VII/III molar proportion¯ It is -also possible to work in the l/lII/IiI molar proportion. In this last case, more polar solvents should be used, such as CHC13 or CH3CN and the compounds of formula -I are obtained in their hydrochloride form. The N[(2-oxo-1-pyrrolidinyl)acethyl]piperezines, according to this invention are compounds which show pharmacological actions useful in therapeutical purposes. The following results were obtained in experimental studies: - ELECTROMAGNETIC BLOOD FLOW MEASUREMENT As can be seen in Meth and Find. Exptl. Clin. Pharmacol. 3 (6) 397-401-(1981)- J. Boca, M. Grau and J.Balasch., the measurement of cerebral blood flow was performed by attaching an electromagnetic blood flow transducer to the vertebral -artery of the anesthetized dogs. After orotraqueal intubation, artificial respiration with normal air was instituted using a Manley Pulmovent respirator. The correct ventilation of the dogs was checked after all the surgical procedures by determining the pO2, PC02 a-nd pli in arterial blood samples, as well as several times during the experiment by means of an Astrup apparatus. Blood pressure (4) was measured in left saphenous artery by means of a Bell & Howell pressure transducer, and the heart rate by means of a Beckman ECC device. Recordings were made on an ink-writing Beckman. polygraph. Left saphenous vein and right saphenous artery were canulated with polyethylene catheters for drug administration and blood collection respectively. Vertebral blood flow was measured by a non-cannulating electromagnetic flowmeter (Carolina Medical Electronics) placed in the- vertebral artery. The Carolina digital flowmeter was connected to an Omniscribe Houston Instruments plotter. Piracetam and nicotine acid were used as control drugs. The results are shown in the following table: TABLE I CONTROL AND SYNTHETIZED DRUGS EFFECT DOSE (2-oxo-l-pyrrolidinyl) No acetamide No effect Nicotinic acid No effect N-[(2-oxo-1-pyrrolidinyl)acethyl]-N' -(p-methoxybenzyl)piperazine Actlve 1 mg/kg N- [(2-oxo-1-pyrrolidinyl)acethyl] -N'- Active cinnamylpiperazine Active 2,5 mg/kg N-[(2-oxo-1-pyrrolidinyl)acethyl]-N'- Active 2,5 mg/hg allylpiperazine INESPECIFIC PROTECTION AGAINST LETALITY BY "MOOTROPIC" DRUGS It is known that the nootropic drugs, as Piracetam, as well as the phenobarbital or hydantoine have a protection on the survival time of animals. When the subjects are submitted to several types of hypoxia, the letality is significantly diminished by the protection given by the nootropic drug. In the intention to increase the accuracy, we have a three trials panel in order to study the effect of tote new synthetized drugs. We have chosen the hypoxia-hypobara :-the decompression kills. the animals, because of the lack of 02. The survival time is clearly increased by the active drugs. The second trial is the quick decapitation of mouse. The head has a typical mandibular movement, known as gasping, as searching the breathing air. The gasping time is well prolonged by the active-drugs. The third trial is by CNK. Obviously CNK kills the animals. Again the protected animals live a good number of seconds more than the controls. The summary of results is found in Table II. TABLE II CONTROL AND SYNTHETIZED DRUGS DOSE HYPOXIA GASPING ANOXIA BY CNK Pentobarbital 40mg/kg Active Active Active Diphenylhydantoine 100/kg Active Very Active Active (2-oxo-1-pyrrolidinyl)- lOOOmg/kg No effect No effect No effect acetamide N-[(2-oxo-1-pyrrolidinyl)acetyl]- 250mg/kg Active Active No effect -N'-(p-methoxybenzyl)piperazine N-[(2-oxo-1-pyrrolidinyl]- 300mh/kg Active Active Active -N'-cinnamylpiperazine N- C(Z-oxo-l-pyrrolidinyl)acetylj - 500mg/kg Active Active -N'-allylpiperazine 500mg/kg Active Active Active LD of the three representative compounds are included in 50 Table III: TABLE III COMPOUND LD : :50 N-[(2-oxo-1-pyrrolidinyl)acetyl]-N'- 1,112 mg/kg -(p-methoxybenzyl)piperazine N-[(2-oxo-1-pyrrolidinyl)acetyl]-N'- 1400 mg/kg -cinnamylpiperazine 1,400 mg/kg N-[(2-oxo-1-pyrrolidinyl)acetyl]-N'- 1400 mg/kg -allylpiperazine a In view of the above pharmacological and toxicological results, it appears that the compounds of formula (I) may be used as drugs in therapeutics, especially in the treatment of cerebrovascular disturbances in the elderly. The present invention extends therefore to pharmaceutical compositions containing (a) as active ingreaient at least.one of the compounds. of formula (I) and (b) a pharmaceutically acceptable carrier, these compositions being preferably formulated with a view to their oral administration. Thus they may be administrated orally for example in the form of pills, capsules or tablets, in an amount of 10 to 100 mg of active ingredient (twice a day). The following examples will further illustrate the invention without, however, limiting it thereto. Example I According to method 1, 33,4 g (165 mmoles) of N-cimnamylpiperazine are mixed with 56,5 g(330 mmoles) of ethyl 2-(2-oxo-1-pyrrlidinyl -acetate. In a 14 mm vacuum this mixture is heated to 180 C during 7 hours. After this heating period, the excess ester is distilled in a vacuum. 25 ml ethyl acetate are added and the crystals formed filtered. By crystallization of the same of 70 ml ethyl acetate 51,2 g (156 mmoles; 95%) of N- [(2-oxo-1-pyrrolidinyl)-acetyl] -N'-cinnamylpiperazine are obtained in the form of white crystals having a melting point of 1130 - 50C. Calc. (C19H25N3O2): 69,70%C 7,70%H 12,83%N Found: : 69,85% C 7,81% H 12,70% N Rr = 0,45 (CHCl3/MeOH = 100/15) The IR spectrum (XBr) shows, among others, the following bands: 3820, 2770, 1680, 1660, 1600, 1585, 995, 965, 790, 740 and 690 cm Example 2 According to method I 68,87 g (550 mmoles) of N-allyl-piperazine are mixed with 190,09 g (1,11 moles) of ethyl 2-(2-oxo-1 -pyrrolidinyl)acetate. The mixture is heated to 175-180 C during 7 hours. After this period of time, the temperature is incresed to 190 C and the mixture kept at this temperature for two more hours; At the same time, the ethanol formed by distillation at normal pressure is eliminated and 12,6 g are collected. Once the heating period over, the mixture is distilled in a vacuum and 105,69 g (420 mmoles;76%) of N-[(2-oxo-1-pyrrolidinyl)acetyl]-N lallylpiperazine collected in the form of a heavy oil with a boiling point of 200-202 C/0,5mm Calc. [C13H21N3O2): 62,12% C 8,42% H 16,72% N Found : 62,30%C 8,57%H 16,60%N The IR spectrum (CHCl3) shows among others the following bands: 1680, 1655, 1465, 1290 and 100 cm-1 From 14,176 g (56,5 mmoles) of N- [ (2-oxo-l-pyrrolidinyl)acetyl3 -N1-allypiperazine and 6,547 g (56,5 mmoles) of maleic acid, dissolved in MeOH, 17,245 g(46,93 mmoles; 83%) of the piperazine maleate mentioned at the beginning are obtained, with a melting point of 163-5 C (EtOH). Calc. (C17H25N306) 6 55,57%C 6,86% H 11,43% N Found : 55,69% C 6,97% H 11,27% N = 0,35 (MeOH) Example 3 According to method I the following products are mixed: 53,59 g (260 mmoles) of N-(p-methoxybenzyl)piperazine with 88,8 g (519 mmoles) of ethyl 2-(2-oxo-1-pyrrolidinyl)acetate. In a 14mm vacuum the mixture is heated to 175-80 C during 7 hours Once the hcating period over, the excess ester is distilled in a vacuum. The remaining product is grinded with a mixture of 25 ml ethyl acetate and 150 ml ether. By filtration the following is obtained: 72,69 g (219 mmoles; 85%) of N- [(2-oxo-1-pyrrolidinyl) acetyl]-N'-(p-methoxybenzyl)piperazine in the form of white crystals with a melting point of 87-9 C. Calc. (C18H25N3O3) ) : 65,23 % C 7,60% H 12,68% N Found : 65,10% C 7,75% H 12,82% N Rf = 0,51 (CHCl3/MeOH = 80/20 The IS spectrum (KBr) shows, between others the following bands: 2800, .2780s 1680, 1660, 1610, 1585, 1290, 1280, 1240, 1030, -1 800 and 750 cm Example 4 According to method I, th following products are mixed: 199,25g (1 mol) of ethyl 2-(2-oxo-1-pyrrolidinyl)butyrate (previously prepared by alkylation of the sodium salt of pyrrolidinone with ethyl 2-bromobutyrate). In a 14mm vacuum the mixture is heated to 175-80 C during 12 hours. Once the heating time over, the excess ester is distilled. The remaining product is grinded with ligroin (boiling point 80-100 C) and by filtration 158,69 g (446mmoles; 89%) of N-[2-(2-oxo-1-pyrrolidinyl)butyroyl]-N'cinnamyl-piperazine is obtained in the form of white crystals. Calc. (C21H29N3O2) : 70,95% C 8,22%H 11,82%N Found: 71,11% C 8,34% H 11,70% N Example 5 According to method I, 199,25 g (1 mol) of ethyl 2-(2-oxo-1 -pyrrolidinyl)butyrate arc mixed with 103,146 g (500 mmoles) of N-(p-methoxybenzyl)piperazine and heated as described in Example 4. The excess ester is then eliminated by distillation in a vacuum. The remaining product is distributed between HC1 1N and ether. The aequous phase is extracted repeatedly with ether, NaOH is then added to the aequous phase until an alkaline pH is obtained, and evaporated. to dryness. The remaining product is grinded with ether By evaporating the ether 133,00 g (370mmoles ; 74%) of N- g2-(2-oxc-l-pyrrolidinyl) butyroyl 3 -N' (p-methoxybenzyl)-piperazine are obtained in the form of-a heavy oil. Calc. (C20H29N3O3) : 66,82% C 8,13% H 11,69% N Found: 66,95% C 8,26% H 11,54% N Example 6 According to method II, dissolve 28,7 g (141,8 mmoles) of N -cinnamyl-piperazine in 250 ml anhidrous toluene; the solution is then cooled to O C. A solutiion of 13,149 g (70,9 mmoles) of 2- bromobutyroyl-chloride (O.S. 30, 62,1950) in 80 ml of toluene is then added drop by drop. Once all the amount -of solution added, the mixture is stirred during 2 hours at room temperature. 16,3 g of the hydrochloride of N-cinnamylpiperazine is then obtained by filtration. The-filtrate is evaporated to dryness, then dissoved in EtOH and acidified with EtOH/HCl. By precipitation with ether 22,5-g (58,0 mmoles-; 82%) of the hydrochloride of N-cinnamyl-N'-(2-bromcbutyroyl)iperazin are obtained in the forir. of white crystals with a melting point of 184 - 60c (dec.). Calc. (C17H24BrClN2O) : 52,65% C 6,23% H 7,22% N Found: 52,57% C 6,10% H 7,30% N The free base consists in a heavy oil. Its IR (CC14) shows, among others, the following bands: 2940, 2820, 2780, 1665, 1460, 1350, 1235, 1190,-1145, 1130, 1000, 970 and 690 cm-1. Example 7 The sodium salt of pyrrolidinone is prepared with 3,8805 g (45,6 mmoles) of pyrrolidinone, 0,9614 g (41,8 mmoles) of Na and 100 ml toluene. At a temperature of 97 C we gradually add a solution of N-cinnamyl-N'-(2-bromobutyroyl)-piperazine previously prepared by neutralization with NaOH and toluene extraction of 14,737 g (38 mmoles) of the hydrochloride. Once all the solution added, the mixture is reflux boiled during 6,5 hours. The mixture is filtered, and the filtered product evaporated to dryness. By crystallization of petroleum ether (boiling point 60-90 C) we obtain N-[2-(2-oxo-1-pyrrolidinyl)butyroyl] N cinnamylpiperazine. The IS spectrum shows absorptions at 1690 and 1650 cm Example 8 According to method III, 100 ml SOC12recently distilled are poured on 17,12 g (100 mmoles) of 2-(2-oxo-l-pyrrolidinyl) -buty.ric acid (CA 89 P 59834 r) and stirred at room temperature during 2 hours. The excess SOCl2 is then distilled by vacuum distillation. The residual oil obtained is dissolved in 100 ml toluene and a solution of 40,46 g (200 mmoles) of N-cinnamylpiperazine in 150 ml toluene is then added, drop by drop. The mixture is filtered, and the filtered product evaporated to dryness, thus obtaining 32,35 g (91 mmoles; 91%) of N- L 2-ethyl-2-(2-oxo-1-pyrrolidinyl)acetyl] 3 -N1-cinnamyl piperazine. Examples of preparations ready for administration When the new compounds of this invention are intended for use in the treatment of cerebrovascular disturbances in the elderly, typus of suitable preparations can be examplified as follows: 1. Tablet (1) N- [(2-oxo-1-pyrrolidinyl)acetyl]-N'-cinnamyl- 50 g (2) Lactose piperazine 50 (3) Corn starch 29 g (4) Magnesium sterate 1 g 1000 tablets 130 g Components (1) and (2) and 17 g of the corn-starch (3) were granulated together with a paste prepared from 7 g of the corn-starch. To thesse granules were added the remaining 5 g of the corn-starch and component (4). The mixture was then compressed Sy.a tabletting machine to prepare 1000 tablets of 7 mm. diameter, -each containi-ng 50-mg of (1). 2. Capsule (1) N-[(2-oxo-1-pyrrolidinyl)acetyl]-N'-allypiperazine 50 g (2) Lactose 100 g (3) Cellulose fine powder 45 g (4) Magnezium sterate 5 g 1000 capsules 200 g All the materials were mixed and filled into 1000 capsules of gelatin; each capsule contains 50 mg of (1).

Claims: CLAIMS 1) N- [(2-oxo-1-pyrrolidinyl)acetyl] piperazinesof the following formula: EMI24.1 wherein R represents hydrogen or an alkyl group which contains to 3 carbon atoms which can be arranged as straight or branched chain and R represents an allyl, cinnamyl or p-methoxybenzyl group, as well as their pharmaceutically acceptable acid addition salts. 2) N-[(2-oxo-1-pyrrolidinyl)acetyl]-N'-allypiperazine 3) N-[(2-oxo-1-pyrrolidinyl)acetyl]-N'-cinnamylpiperazine 4) N-[(2-oxo-1-pyrrolidinyl)acetyl]-N'-(p-methoxybenzyl) piperazine. 5) A pharmaceutical composition which comprises; a) as an active ingredie-nt an effective amount of the Diperazine compound as defined in cla-im 1) and b) a pharmaceutically acceptable carrier or diluent therefore. 6) A method for producing a piperazine compound as defined in claim 1) consisting in subjecting a compound of the formula EMI25.1 wherein R is as defined in claim 1 and-R represents an alkyl radical which contains 1 or 2 carbon atoms or an aryl radical with or without substitutionf to amminolysis with a piperazine of the formula EMI25.2 wherein R is as defined in claim 1. 7) Process for producing a piperazine compound as defined in claim 1, consisting in the alkylation of a salt of pyrrolidinone wìth¯a. haloacetamide illustrated in the following sheet : EMI26.1 wherei R and R are as defined in claim 1. 8) Process according to claim 7, wherein the salt of pyrrolidinone is the sodium or the potassium salt. 9) Process for producing a piperazine compound as defined in claim 1, consisting in acyclating the substituted piperazines with an 2-(2-oxo-1-pyrrolidinyl)acetyl chloride illustrated in the following sheet: EMI27.1 EMI27.2 EMI27.3 wherein R and R' are as defined in claim 1.

Inventors: VEIT, DAGMAR MARIA VEDRILLA
Applicants: PRODES S.A.
Application year: 1983
Main classification: C07D207
IPC codes: C07D207