NEW 2-OXO-1-PYRROLIDINEACETIC ACID ESTERS, THEIR METHODS OF PRODUCTION AND THERAPEUTIC COMPOSITIONS CONTAINING THE SAME

Abstract: The invention concerns new 3,3,5-trimethylcyclohexyl 2-oxo-1-pyrrolidineacetates of the formula: wherein R₁ and R₂ are hydrogen, methyl or ethyl, these compounds being in the forms cis, trans or cis/trans. These compounds of formula (I) are useful as drugs, especially in the treatment of the Raynaud's disease, the arteriosclerosis obliterans, he thromboangiitis obliterans and the senility diseases.

Description: Title New 2-oxo-l-pyrròlidineacetic acid esters, their methods of production and therapeutic compositionscontaining the same. This invention relates to 2-oxo-pyrrolidineacetic acid esters which are of use as medicines. The invention also relates to methods of producing these novel esters. More particularly, this invention relates to esters of the formula: EMI1.1 wherein R1 and R2 are hydrogen, methyl or ethyl. The esters of the present invention may be produced: I. By reacting an alkyl 2-oxo-l-pyrrolidineacetate of formula EMI2.1 (wherein R1 and R2 have the same meaning as in the general formula I, and R3 may be methyl, ethyl, l-propyl or isopropyl) with 3,3,5-trimethylcyclo hexanol III, in the presence of an alkoxide (usually alkaline) of III at 100-1800C (ueually 120-1600C) for a period of 6 to 15 hours. The alkoxide of 3,3,5-trimethylcyclohexanol III may be prepared "in situ" by previous reaction of the alcohol with the metal or the corresponding hydride in anhydrous conditions. II. By reacting 2-oxo-pyrrolidine with an alkaline metal or metal hydride (usually sodium) and the resulting alkaline metal derivative is treated with a 3,3,5-trimethylcyclohexyl 2-haloacetate of general formula EMI2.2 in which Rl 1 and R 2 have the same meanings as above, and X represents an halogen group (usually chloro or bromo). Compounds of formula I may be as isomers cis/trans;by using the appropriate 3,3,5-trimethylcyclohexanol (method I) or 3,3,5-trimethylcyclohexyl haloacetate (method II) the desired isomer will be obtained. These new 2-oxo-l-pyrrolidineacetic acid esters according to this invention are compounds that show pharmacological actions useful for therapeutical purpcses. 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. Roca, M. Grau and J. Balasch., the measurement of cerebral blood flow was performed by attaching an electro-magnetic 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 p02, pC02, and pH in arterial blood samples, as well as several times during the experiment by means of an Astrup apparatus. Blood pressure was measured in left saphenous artery by means of a Bell & Howell pressure transducer, and the heart rate by means of a Beckman ECG device. Recordings were made on an ink-writing Beckman polygraph. Left saphenous vein and right saphenous artery were cannulated with polyethylene catheters for drug administration and blood collection respectively. Vertebral blood flow was measured by a non-cannulating electro-magnetic flowmeter (Carolina Medical Electronics) placed in the vertebral artery. The Carolina digital flowmeter was connected to an Omniscribe Houston Instruments plotter. Piracetam and nicotinic acid were used as control drugs. The results are shown in the following table TABLE I CONTROL AND SYNTHETIZED DRUGS EFFECT DOSE Piracetam No effect Papaverine Active 0.5 mg/kg Nicotinic acid No effect cis/trans-3,3,5-trimethylcyclohexyl Active 1 mg/kg 2-oxo-l-pyrrolidineacetate cis-3,3,5-trimethylcyclohexyl 2-(2-oxo- Active 0,5- mg/kg -1-pyrrolidinyl )butyrbate * 2-oxo-l-pyrrolidineacetamide INESPECIFIC PROTECTION AGAINSTLETALITY BY "NOOTROPIC" 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 the 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. Obsviously 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 DOSE HYPOXIA ANOXIA BY DRUGS DOSE HYPOBARA GASPING CNK Pentobarbital 40mg/kg Active Active Active Difenilhydantoine 100mg/kg Active Very active Active Piracetam * 1000mg/kg No effect No effect No effect cis/trans-3,3,5-trimethylcyclohexyl-2-oxo-l-pyrrolidine- 500mg/kg Active Very active Very acetate active cis 3, 3,5-trimethylcyclohexyl 2(2-oxo-l-pyrrolidinyl)butyrate 50Omg/kg Active Very active Very . . * 2-oxo-Spyrrolidineacetamide LD50 of representative compounds included in Table III. Table III COMPOUND LD50 cis/trans-3,3,5-trimethylcyclohexyl 2- 3,168 mg/kg oxo- 1-pyrrolidineacetate cis-3,3-5-trimethylcyclohexyl 2-(2-oxol-pyrrolidinyl)butyrate 2,850 mg/kg 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 the Raynaud's disease, the arteriosclerosis obliterans, the thromboangiitis obliterans and the senility diseases. The present invention extends therefore to pharmaceutical compositions containi(a) as active ingredient 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 50 to 300 mg of active ingredient (1 to 4 times a day). The following example will further illustrate the invention without, however, limiting it thereto: Example 1 cis/trans 3,3,5-trimethylcyclohexyl 2-oxo-l-pyrrolidineacetate 0,080 gr (0,003 mol) of sodium hydride is added to 4,120 gr (0,029 mol) of cis/trans 3,3,5-trimethylcyclohexanol and the mixture is hated at 70 C until gas evolution ceases. Then Sgr (0,029 mol) of ethyl 2-oxo-l-pyrrolidineacetate is added and the temperature is raised to 1600C and kept for 12 hours, while distilling ethanol simultaneously. After reaction, the mixture is fractionally distilled to yield 4,520 gr (57%) of cis/trans 3,3,5-trimethylcyclohexyl 2-oxo-l pyrrolidineacetate .b.p. 150-2"0/0,4 mm. R f = 0,33, TLC on silicagel Merck-60 (0,25 mm) eluted with ethyl acetate. Detected with Iodine (esters) and the mixture vainilline 0,5 gr/acetic 30 ml/H2S04 (c) 1 ml, at 1200C (cyclohexyl derivatives). IR: (CCl4)max 2950, 1745, 1700, 1490, 1460, 1430, 1420, 1400, 1385, 1360, 1320, 1285, 1200, 1150, 1070, 985, 960 and 940 cm 1. Example 2 cis 3, 3, 5-trimethylcyclohexyl 2-( 2-oxo-l-pyrrolidinyl ) butyrate 0,240 gr (0,005 mol) of sodium hydride (50 % in mineral oil) is added to 7,100 gr (0,050 mol) of cis 3,3,5-trimethylcyclohexanol and the mixture is heated at 700C until gas evolution ceases. Then 10 gr (0,050 mol) of 2-(2-oxo-l-pyrrolidinyl)butyrate is added and the temperature is raised to 1600C and kept for 12 hours, while distilling ethanol. After reaction, the mixture is fractionally distilled to yield 9,740 gr (66%) of cis-3,3,5trimethylcyclohexyl 2-(2-oxo-l-pyrrolidinyl)butyrate. b.p. 153-4 C/0,6 mm. Rf = 0,41 (TLC under the same conditions as example 1) IR : (CC14) 2 max 2960, 1740, 1700, 1460, 1420, 1385, -1 1360, 1280 (d), 1190, 1075 and 975 cm Example 3 cis - 3, 3, 5-trimethylcyclohexyl 2-( 2-oxo-l-pyrrolidinyl ) butyrate 0,240 gr (0,005 mol) of sodium hydride (50 % in mineral oil) is added to 7,100 gr (0,050 mol) of cis 3,3,5-trimethylcyclohexanol and the mixture is heated at 700C until gas evolution ceases. Then 10 gr (0,050 mol) of ethyl 2-(2-oxo-l-pyrrolidinyl)butyrate is added and the temperature is raised to 1300 and kept for 6 hours under 20 mm pressure. After reaction, the mixture is fractionally distilled to yield 11,658 gr (79%) of cis-3,3,5-trimethylcyclohexyl 2-(2-oxo-l-pyrrolidinyl)butyrate. Exemple Ii cis/trans - 3, 3, 5-trimethylcyclohexyl 2-oxo-l-pyrrolidineacetate A mixture containing 6,210 gr (0,272 mol) of sodium and 275 ml of dry toluene is heated to 970 C while stirring. When sodium is melted, 23,800 gr (0,280 mol) of 2-oxopyrrolidine is added in 45 min., the temperature raises to 1070C while forming the white sodium derivative suspension. After addition, the mixture is externally heated at 100C for 2,5 hours until sodium is completely dissolved. Then it is cooled to 700C and 59,570 gr (0,272 mol) of cis/trans 3,3,5-trimethylcyclohexyl chloroacetate is added in 45 min., and kept for 4 hours. The sodium chloride is filtered and the toluene is removed under reduced pressure. The residual oil is dissolved in chloroform, washed three times with water and dried over anhydrous sodium sulfate. Finally the solution is concentrated and the residue fractionally distilled to yield 59,028 gr (81%) of cis/trans - 3,3,5-trimethylcyclohexyl 2-oxo-lpyrrolidineacetate ; b.p. 177/80C/2 mm. Example 5 cis 3, 3, 5-trimethylcyclohexyl 2- ( 2-oxo-l-pyrrolidinyl ) butyrate A mixture containing 5,400 gr (0,234 mol) of sodium and 250 ml of dry toluene is heated to 970C while stirring. When sodium is melted, 20,485 gr (0,240 mol) of 2-oxopyrrolidine is added dropwise in 20 minutes, the temperature raises to 1070C while forming the white sodium derivative suspension. After addition, the mixture is externally heated at 1000C for 2,5 hours. Then 57,681 gr (0,234 mol) of cis-3,3-5-trimethylcyclohexyl 2-chlorobutyrate is added and heated at 1000C for 7 hours. After reaction 250 mol of toluene is added, and the solution is washed twice with 150 ml of water and dried over anhydrous sodium sulfate. Finally the toluene is removed under reduced pressure and the residue is fractionally distilled to yield 53,272 gr (77%) of cis-3,3,5-trimethylcyclohexyl 2-(2oxo-l-pyrrolidinyl)butyrate. Example 6 When compound of this invention is intended for therepeutic use, types of suitable preparations can be examplified as follows 1. Tablet (1) cis/trans 3, 3,5-trimethylcyclohexyl 2 oxo- 1-pyrrolidineacetate 5g (2) Lactose 75 g (3) Corn starch 49 g (4) Magnesium stearate ig 1000 tablets 130 g Components (1) and (2) and 29 g of the corn-starch (3) were granulated together with a paste prepared from 11 g of the corn-starch. To these granules were added the remaining 9 g. of the corn-starch and component (4). The mixture was then compressed by a tabletting machine to prepare 1000 tablets of 7mm diameter, each containing 5 mg. of (1). 2. Capsule (1) cis 3, 3, 5-trimethylcyclohexyl 2-(2-oxo l-pyrrolidinyl)butyrate 10 g (2) Lactose 140 g (3) Cellulose fine powder 45 g (LI) Magnesium stearate 5g 1000 capsules 200 g All the materials were mixed and filled into 1000 capsules to prepare capsules each containing 10 mg of (1).

Claims: CLAIMS 1.- 3,3,5-trimethylcyclohexyl 2-oxo-l-pyrrolidineacetates of the formula EMI13.1 wherein R1 and R2 are hydrogen, methyl or ethyl, these compounds being in the forms cis, trans or cis/trans. 2.- 3;3,5-trimethylcyclohexyl 2-oxo-l-pyrrolidineacetate 3.- 3, 3, 5-trimethylcyclohexyl 2- ( 2-oxo-l-pyrrolidinyl ) propionate 4.- 3,3,5-trimethylcyclohexyl 2-( 2-oxo-l-pyrrolidinyl ) butyrate 5.- 3, 3, 5-trimethylcyclohexyl 2-methyl-2-( 2-oxo-l-pyrrolidinyl )propionate .6.- 3, 3, 5-trimethylcyclohexyl 2-methyl-2-( 2-oxo- 1-pyrrolidinyl ) butyrate 7.- 3, 3, 5-trimethylcyclohexyl 2-ethyl-2-( 2-oxo-l-pyrrolidinyl )butyrate 8.- A pharmaceutical composition which comprises a) as an active ingredient, an effective amount of the 2-oxo-l-pyrrolidineacetates as defined in claim 1.- and b) a pharmaceutically acceptable carrier therefore. 9.- A method for the production of the 3,3,5-trimethylcyclohexyl 2-oxo 1-pyrrolidineacetates according to claim 1.-, which comprises reacting a 2-oxo-l-pyrrolidineacetate of formula EMI13.2 wherein R1 and R2 have the same meaning as in the general formula I, and R3 is methyl, ethyl, 1-propyl or isopropyl, with 3,3,5-trimethylcyc)ohexanol (III) in the presence of its alkoxide (usually alkaline) as catalyst. 10.- b process for the productionof the 3,3,5-trimethylcyclohexyl 2-oxo-l-pyrrolici'ine- acetates according to claim 1, which comprises reacting 2-oxopyrrolidine wfth an alkali metal or metal hydride and the resulting alkali metal derivative is treated with a 3,3,5-trimethylcyclohexyl 2-haloacetate of the general formula: EMI14.1 in which R1 and R2 have the same meanings as above, and X represents and halogen atom.

Inventors: SALLENT, JUAN PI
Applicants: PRODES S.A.
Application year: 1983
Main classification: C07D207
IPC codes: C07D207