CS244144B2 - Process for producing aminomethylpyrrolidinones - Google Patents

Abstract

bound in position 4 or 5, and their adiSnlch salts and acids. The compounds produced are, according to animal tests, capable of reducing, or completely inhibiting various forms of limited cerebral performance. in which R. represents a hydrogen atom or a methyl group R. represents a phenyl residue, optionally substituted by one or two substituents selected from the group comprising an ethoxy group, fluorine and chlorine atoms, a trifluoromethyl group and a methyl group, or represents a pyridyl residue and R. * and are either the same or different and 3 * each represent an alkyl group with 1 to 3 carbon atoms or both symbols R-1 and R^ together with the nitrogen atom form a pyrrolidine, piperidine, morpholine, H-methylpiperazine or imidazole ring, wherein the aminomethyl group is

Description

The invention relates to a process for the production of novel aminoethylpyrroldinones and their acid addition salts.

These new compounds counteract the short-term memory impairment following the administration of muscarinic cholinergic antagonists and, in addition, show significant efficacy against hypoxia.

Structurally related nootropics include 1-carbamoylethylpyrrolidin-2-one (Piracetam), 1-(p-methoxybenzoyl)pyrrolidin-2-one (Aniracetam) and tukamboylethyl-4-hydroxypyrrolidin-2-one (Oxiracetam) - see B. J. R. Nlcolaua, Brug Development Ree. £,

464 (1982), P.L. Paytasch, J. Amer. Chea. Soc. ]2, 1415 (1950).

It has now been found that the introduction of an aminoacetyl group into the pyrrolidone molecule significantly improves the effectiveness of such substances compared to known substances.

The subject of the invention is a process for the production of new alkylmethylpyrrolidinones of the general formula I

in which

R, represents a hydrogen atom or a methyl group,

Rg represents a phenyl radical optionally substituted with one or two substituents selected from the group consisting of methoxy, fluorine and chlorine atoms, trifluoroethyl and ethyl, or represents a pyridyl radical and

R^ and R^ are either the same or different and represent an alkyl group of 1 to 3 carbon atoms or both symbols R^ and R^ together with the nitrogen atom form a pyrrolidine, piperidine, morpholine, N-ethylpiperazine or imidazole ring, the aminoethyl group being attached in position 4 or 5, and their derivatives and acids.

The pyridyl ring in the meaning of the word % can be attached to the methylene moiety at position 2 or 4.

The resulting products of the general formula I can optionally be converted into physiologically acceptable addition salts and acids in a conventional manner.

Suitable acids for this purpose are both inorganic acids, such as hydrohalic acids, sulfuric acid, phosphoric acid and ethanesulfonic acid, and organic acids, such as formic acid, acetic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, oleic acid, fumaric acid, succinic acid, tartaric acid, benzoic acid, salicylic acid, citric acid, ascorbic acid, p-toluenesulfonic acid or hydroxyethanesulfonic acid.

Preferred are those compounds of general formula I, in which R represents a hydrogen atom, R represents a phenyl radical optionally substituted in the o- or p-position by a fluorine, chlorine, ethyl or ethoxyl group, and B1 and B2 each represent a methyl group.

In accordance with the invention, the compounds of the above general formula 1 are prepared by reacting hydroxymethylpyrrolidinone of the general formula II

in which

B, e Bg have the meaning given above, by reaction with a thioyl halide, a phosphorus halide or a tosyl or meyl halide, it is converted into a compound of the general formula III

(III) in which

B, and Bg have the meanings given above and

X represents a halogen atom, a toeyloxy group or a mesyloxy group, and this compound is then subjected to reaction with a primary or secondary amine of the general formula IV

in which

Bj and B^ have the meanings given above.

In accordance with this procedure, the compound of the general formula II is converted into the corresponding 4-halogenomethyl derivative either by reaction with a thionyl halide or a phosphorus halide, or by reaction with a tosyl or mesyl halide into the corresponding 4-tosyl or 4-mesyl ester. The reaction is preferably carried out using an inert organic solvent, for example chloroform, methyl chloride, tetrahydrofuran or dimethylformamide, at a temperature between room temperature and the boiling point of the solvent used. In the case of esterification, a tertiary organic base, for example triethylamine or pyridine, is expediently added to the reaction mixture. The 4-halogenomethyl derivatives or 4-tosyl or 4-mesyl esters formed as intermediates can be isolated, but they can also be further processed in situ. The reaction of these intermediates with the appropriate primary or secondary amines gives the corresponding final products of the general formula I. This reaction can be carried out in tetrahydrofuran, diloxane, acetonitrile or preferably in dimethylformamide, at a temperature of approximately between 50 and 150 °C, the reaction conditions used depending on the basicity and boiling point of the amine. The reaction can also be carried out without a solvent - in an excess of amine. In the case of using low-boiling amines, the reaction must be carried out in an autoclave, depending on the circumstances.

244144 4

The compounds of the general formula I contain a center of asymmetry and therefore occur as racemates. These racemates can be converted into the corresponding diastereomers by conventional means, for example by the formation of salts with optically active acids, from which the optically active final products can then be obtained.

If necessary, the alcohols of the general formula II can be converted into the corresponding dietheromers by ester formation with optically active acids, which can then be separated into the corresponding dietheromers in the usual manner, for example by column chromatography or fractional crystallography. After separation of these esters, the enantiomeric alcohols are obtained, with which the corresponding amines can be prepared by the procedure described above.

From pure enantiomeric nor-compounds, it is possible to prepare the corresponding optically pure diethyl derivatives by reductive alkylation, for example by treatment with acetaldehyde in the presence of hydrogen gas and a catalyst, or the corresponding optically pure dimethyl derivatives by treatment with formaldehyde and formic acid.

The starting materials for the processes described above are either known or can be obtained by known methods.

In the case of 5-aminoethyl derivatives, it is possible to start from commercially available 5-pyrrolediocarboxylic acids, which are esterified, alkylated on nitrogen with optionally substituted beacyl halides and then subjected to a further reaction as described above.

By the method according to the invention, it is possible to prepare, for example, the following final products, optionally in the form of acid salts and optionally in the form of pure enantiomers:

1-Benzyl-4-plperldinomethylpyrrolidin-2-one

1-(4-fluorobenzyl)-4-morpholinomethylpyrrolidin-2-oa

1-beasyl-4-(>-ethylpiperaslao)aethylpyrrolidln-2-one t-benzyl-4-iaidaaol-1-ylaethylpyrroldin-2-one

1-Benzyl-4-ethylaminomethylpyrroldlin-2-one

1-(p-Fluorobenzyl)-4-dlaethyleaioaethylpyrrolidia-2-one k

1-benayl-4-diethylaminoaethylpyrrolidin-2-one

1-(o-ohlorbenayl)-4-dlethylaninoneethylpyrrolidin-2-one t-beasyl-4-lsopropylaaioaethylpyrrolidin-2-one

1-(p-ethylbenzyl)-4-diethylaminomethylpyrrolidin-2-one

1-Benzyl-5-diethylainoaethylpyrrolidin-2-one 1-beaayl-S-dlethylalnomethylpyrrolidin-2-oa t-benzyl-5-aorfolinoaethylpyrrolidin-2-one

1-Bemzyl-5-(4-ethylplperazino)ethylpyrrolidin-2-one

1-Benzyl-5-pyrrolidinoneethylpyrrolidin-2-one

1-(4-methylbenzyl)-5-dimethylaminomethylpyrrolidin-2-one

1-(4-Methylbenzyl)-5-diethylsminomethylpyrrolidin-2-one

- (p-chlorobenzyl)-5-dimethylaminomethylpyrrolidin-2-one ) - (p-chlorobenzyl)-5-dlethylaninomethylpyrrolidin-2-one — (3,4-dichlorobenzyl)-5-dimethylaminomethylpyrrolidin-2-one — (3 > 4-dichlorobenzyl)-5-dlethylainomethylpyrrolidin-2-one

1-(p-Methoxybenzyl)-5-dimethylaminomethylpyrrolidin-2-one

1-(p-Methoxybenzyl)-5-diethylaminomethylpyrrolidin-2-one.

’.ονά pyrrolidinone derivatives have been tested in animal tests for their ability to completely inhibit, or possibly reduce, various forms of limited cerebral performance.

The compounds mentioned in the orientation tests of tolerability in mice show no acute toxicity after a single oral application in a dose of up to 2 g/kg (observation period of 14 days). In animal tests, these substances show excellent effects on spontaneous cognitive performance, such as experimentally limited learning and memory abilities. In experiments and limitations of short-term memory, or with inhibition of transitions of short-term memory content to long-term memory by administration of muscarinic cholinergic receptor antagonists [scopolamine in an intraperitoneally applied dose of 0.6 mg/kg] see also Psychopharmacology 78. 104 to 11, (1982)3, these compounds are able to counteract this pharmacologically induced cerebral insufficiency, or to completely prevent it.

It will also improve the ability of rats to learn to avoid objects or objects associated with unpleasant stimuli during active habituation, as well as their spontaneous habituation, or their exploratory orientation activity in a new environment.

In tests of the ability of animals to survive in a closed chamber (hypoxia tolerance test), into which a gas mixture consisting of 96.5% nitrogen and 3.5% oxygen is introduced, animals premedicated with the new substances show a statistically highly significant higher survival ability than control animals or animals premedicated with Piracetam. In addition, the protective effect of the tested substances on the brain tested by this method is significantly manifested even at an orally administered dose of 50 mg/kg.

The new pyrrolidinone derivatives were compared in terms of efficacy with other structurally related pyrrolidinones that are already used as drugs (Piracetam) or are being clinically tested (Aniracetam) in the treatment of cerebral insufficiency, organic cerebral pachydrome, post-traumatic and alcoholic leg injuries, etc.

The new compounds are significantly superior to the above-mentioned known substances, both in terms of effective dose levels and in terms of improvements in brain performance observed in animal experiments.

The following overview presents specific efficacy test results for representative compounds of the invention, compared to a standard comparator (Piracetam).

In this case, one of the effects of inhibiting the manifestations of dementia caused by acopolamine is attributed.

The test is performed according to data published in Psychopharmacology, 78. 104-11, (1982).

The experimental animals used are rats kept in cages with a wire mesh bottom. The rats are taught to avoid the electric shocks they receive on the wire bottom of the cage by running to an insulated platform. Over time, 80% of the animals learn to avoid this platform.

244144 6 protected against electric shock.

If scopolamine is administered intravenously to these animals at a dose of 0.6 mg/kg, a retrograde effect on short-term memory can be observed in 80% of rats, i.e., the animals forget that they are safe on the isolated platform.

A substance acting against cerebral insufficiency can inhibit this blockade. After administration of scopolamine, the test substance is administered to the experimental animals and it is determined how many animals (in *) are able to remember the learned behaviors despite the administration of scopolamine. The following table shows the doses of the compounds according to the invention and the comparative substances, when administered, dementia caused by scopolamine is inhibited in approximately 50% of the animals.

Active ingredient

Dose in mg/kg (rat, per os)

1-(4-Fluorobenzyl)-4-B-methylpiperazinyl·- methylpyrrolidln-2-one 1 -benzyl-4-diethylaminomethyl- 30 pyrrolidin-2-one 1-(3,4-dichlorobenzyl)-5-diethylamino- 30 methylpyrrolidin-2-one 50 Piraceta 100

The compounds according to the invention can be used alone or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active compounds, for example with other cerebroactivators. Suitable application forms are, for example, tablets, capsules, suppositories, solutions, syrups, emulsions or dispersible powders. Tablets can be obtained, for example, by mixing the active substance or active substances with known excipients, such as inert diluents, such as calcium carbonate, calcium phosphate or lactose, tablet disintegrating agents, such as corn starch or alginic acid, binders, such as starch or gelatin, lubricants, such as magnesium stearate or talc and/or agents for achieving a depot effect, such as carboxypolyethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets can also consist of several layers.

Dragees can be produced in a corresponding manner by coating dragee cores prepared in a similar manner as tablets with conventional agents usually used as coatings in the production of dragees, such as collodion or belak, gum arabic, talc, titanium dioxide or sugar. To achieve a depot effect or to avoid incompatibility, dragee cores can also consist of several layers, and in their production it is possible to use the excipients mentioned above for the production of tablets.

Syrups containing the active ingredient according to the invention, or a combination of active ingredients, may further contain a sweetener, such as saccharin, cyclamate, glycerin or sugar, as well as agents improving organoleptic properties, for example aromatic additives, such as vanillin or orange extract. These syrups may further contain auxiliary suspending agents or gelling agents, such as sodium carboxymethyl cellulose, emulsifiers, such as condensation products of fatty alcohols with ethylene oxide or preservatives, such as p-hydroxyhexanoates.

Injection solutions are prepared in the usual manner, for example with the addition of preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, and filled into injection vials or ampoules.

Capsules containing one or more active substances, or a combination of active substances, can be prepared, for example, by dissolving the active substance in an inert carrier, such as lactose or aorbitol, and filling the mixture into a gelatin capsule.

Suitable darts can be prepared, for example, by mixing appropriate carriers, such as neutral fats or polyethylene glycol, or their derivatives, with the active substance or substances.

The invention is illustrated by the following examples of embodiments, which, however, do not limit the scope of the invention in any way.

Example 1 (-)-,-benzyl-4-dimethylaminomethylpyrrolidin-2-one

To a mixture of 4.0 g (0.02 mol) of (-)-,-benzyl-4-aminomethylpyrrolidin-2-one and 5.4 g of 35% formic acid, 4.8 ml of formalin solution were added and the mixture was stirred overnight while heating on an oil bath at a temperature of ,00 °C. The excess acid was distilled off in vacuo, the residue was taken up with water, made alkaline with concentrated sodium hydroxide solution and shaken three times with methylene chloride. The combined methylene chloride phases were washed with water, dried with sodium sulfate, the solvent was evaporated in vacuo and the residue was filtered through a silica gel column using a mixture of methylene chloride and methanol (97:3) as eluent. Uniform fractions were evaporated in vacuo.

The title compound is obtained in the form of an oil in a yield of 3.5 g.

D -7.6° (c 1.0; methanol)

D -16.8° (c 1.0; water)

By a procedure analogous to that in Example 1, 6.1 g of (+)-,-benzyl-4-dimethylaminoethylpyrrolidin-2-one with an optical rotation of +7.9° (c » 1.0; _methanol ) was obtained from 5.8 g (0.028 mol) of (+)-,-benzyl-4-aminoethylpyrrolidin-2-one, 7.9 g of 85% formic acid and 7 ml of formalin solution.

The starting materials are prepared as follows:

I resolution of racemic 1-benzyl-4-aminomethylpyrrolidin-2-one

a) 24.0 g (0.117 mol) of 1-benzyl-4-aminomethylpyrrolidin-2-one are dissolved in 200 ml of hot methanol and 17.6 g (0.117 mol) of L(+)-tartaric acid are dissolved in another 200 ml of hot methanol. The two solutions are mixed and allowed to cool with stirring, during which the corresponding salt crystallizes. The crystals are filtered off with suction in the cold and, after washing with cold methanol, dried.

16.0 g of 4-aminoethyl-,-benzylpyrrolidin-2-one tartrate melting after crystallization from methanol at 204-206°C is obtained.

«D * *6.3° (o 1.0; water).

b) To convert to the free base, the tartrate is dissolved cold in 20 ml of water and 0.0 ml of concentrated sodium hydroxide solution, the mixture is extracted three times with methylene chloride, the combined methylene chloride phases are dried over magnesium sulfate and the solvent is evaporated off in vacuo.

This gives (-)-4-aminoethyl-1-benzyl-pyrrolidin-2-one with an optical rotation of _β -8.4° (c 1.0; water).

c) The mother liquors remaining after the treatment of the reaction product in paragraph a) are evaporated in vacuo. 38.0 g of tartrate are obtained, which are dissolved in the cold in 40 ml of water and 50 ml of concentrated sodium hydroxide solution. The mixture is shaken three times with methylene chloride, the combined methylene chloride phases are dried over magnesium sulfate and the solvent is evaporated in vacuo.

19.3 g of base are obtained, which is converted by the reaction with D(-)-tartaric acid into the corresponding tartrate by the procedure described in paragraph a). Yield of product 19.0 g, melting point 204-205 °C.

d) Conversion of this tartrate to the free base is carried out by the procedure described in paragraph b).

5.7 g of (+)-4-aminomethyl-1-benzylpyrrolidin-2-one are obtained with an optical rotation α _β » +8.4° (c * 1.0; water).

Example 2

1-Benzyl-4-diethylaminomethylpyrrolidin-2-one. Dry 14 g (0.06 mol) of crude 1-benzyl-4-chloromethylpyrrolidin-2-one, prepared according to Example 1a), 10 g of diethylamine and 50 ml of dimethylformamide are stirred or shaken in an autoclave for 2 hours at 150 °C. The reaction mixture is evaporated to dryness in vacuo, the residue is taken up with methylene chloride, the solution is first washed with water and then the title compound is extracted from it twice with 25 ml of 2N hydrochloric acid each time. The aqueous phases are separated, made alkaline with sodium hydroxide solution and the organic phases are shaken with methylene chloride. The methylene chloride solution is evaporated and the residue is subjected to vacuum distillation.

10 g (61% of theory) of the desired product with a boiling point of 155-158°C/6.7 Pa are obtained.

Example 3 (-)-1-Benzyl-4-diethylaminomethylpyrrolidin-2-one

A mixture of 11.5 g (0.056 mol) of (-)-1-benzyl-4-aminomethylpyrrolidin-2-one, 130 ml of water, 13 g of acetaldehyde, 5.8 ml of concentrated hydrochloric acid and 6.5 g of 20% palladium on carbon is hydrogenated for 5 1/4 hours at 25 °C under a pressure of 0.5 VPa. After evaporation, the residue is taken up in 30 ml of water and the solution is shaken with methylene chloride. The aqueous solution containing hydrochloric acid is made alkaline and also extracted with methylene chloride.

Distillation in a neck flask gives 11.2 g (76.4% of theory) of the title compound, with an optical rotation of α -*9.4° (c 1.0; methanol).

By a similar procedure as in Example 3, hydrogenation of a mixture of 8.4 g (0.041 mol) of (+)-1-benzyl-4-diethylaminomethylpyrrolidin-2-one, 95 ml of water, 9.5 g of acetaldehyde, 4.2 ml of concentrated hydrochloric acid and 4.7 g of 20% palladium on carbon gives (+)-1-benzyl-4-diethylaminomethylpyrrolidin-2-one with an optical rotation of <» _D and *9.4° (c 1.0; methanol).

Example 4

1-(4-fluorobenzyl)-4-N-methylpiperazinylmethylpyrrolidln-2-one

·) 24 g (0.11 mol) of 1-(4-fluorobanayl)-4-hydroxymethylpyrrolidin-2-one are refluxed for 10 hours in 200 ml of methyl chloride and 10 ml (0.14 mol) of thionyl chloride and refluxed for another 6 hours after adding a further 10 ml of thionyl chloride. The reaction mixture is neutralised with ammonia while cooling in ice, the organic phase is separated and, after concentration, evaporated. As a residue, 23 g (92% of theory) of a reddish-brown oily product are obtained, which is used without further purification.

b) 5 g (0.002 mol) of the oil prepared above and 4.4 g (0.04 mol) of 1-methylpiperazine in 30 ml of dimethylformamide are heated to reflux for 1 to 2 hours. The dimethylformamide is distilled off in vacuo, the residue is taken up with methylene chloride, the solution is washed with water, the organic phase is dried and evaporated. The residue is chromatographed on silica gel using a mixture

2441 44 methylene chloride and methanol (95:5) as eluent. The main fraction is evaporated, the residue (5 g) is dissolved in 30 ml of ethanol and 2.8 g of fumaric acid is added to the solution. 5.2 g (48% of theory) of the title compound precipitates as a crystalline product, in the form of the fumarate, melting at 179-180 °C.

Example 5. 1-(4-Fluorobenzyl)-4-morpholinomethylpyrrolidin-2-one

a) To a mixture of 8.9 g (0.04 mol) of 1-(4-fluorobenzyl)-4-hydroxymethylpyrrolidin-2-ol, 100 ml of absolute methylene chloride and 4.8 g of pyridine are added 6.9 g (0.06 mol) of methanesulfonic acid chloride. The reaction mixture is heated to reflux for 2.5 hours, then cooled and extracted with dilute ammonia and water. The organic phase is dried and evaporated.

11 g (93% of theory) of crude ester with a melting point of 84-86°C are obtained.

b) 6.7 g (0.023 mol) of this ester and 2.6 g (0.02 mol) of morpholine are heated to reflux in 20 ml of dioxane for 2 hours. The solvent is evaporated off in vacuo, the residue is taken up in methylene chloride and the solution is extracted with 50 ml of 2N hydrochloric acid. The acidic aqueous extracts are made alkaline with ammonia and the oily base is shaken out with methylene chloride. The methylene chloride phase is dried and evaporated off, the residue weighing 4.2 g is taken up in 30 ml of methanol and 1.2 g of fumaric acid is added to the solution while hot. After cooling, the crystalline fumarate of the title compound precipitates.

The yield of colorless crystals with a melting point of 175-176°C is 7 g (57% of theory).

In an analogous manner to the previous examples, the following final products are also obtained:

HC-R ¹

Example number B ^R i «2 Melting point (°C) Boiling point (°C/Pa) 6 -O H -o 58 to 60 180/6.7 (base) ' 7 r~\ —N N-CH ₃ v_/ ³ H -o 190 to 192 (fumarate) 8 /=N -V] H 230/6.7 (base) 9 -HN-CH ₃ H About 180/6.7 (base) 10 ' ^N C ^{^ C2H5} H 156/6.7 (base) ^{^ C2H5}

244144 10 Example number With «1 ¾ Melting point (°C) Boiling point (°C/Pa) 1, -HH-CH(CH ₃ ) ₂ H 175/6.7 (base) ,2 ^^c ₂ h ₅ -H ^^ ^C 2 ^H 5 H —^^-CH ₃ 175/6.7 (base)

Example, 3,-benzyl-5-dimethylaminomethylpyrrolidin-2-one

a) To a solution of 0.26 g (0.05 mol) of 1-benzyl-5-hydroxymethylpyrrolidin-2-one (melting point 76-77 °C) and 5.6 g (0.055 mol) of triethylamine in 80 ml of methylene chloride, 6.3 g (0.055 mol) of methanesulfonic acid chloride in 20 ml of methylene chloride are added. The reaction mixture is heated to reflux for one hour, then cooled and shaken with water; The organic phase is dried over anhydrous sodium sulfate and evaporated on a rotary evaporator. 4.4 g of crude 1-benzyl-5-hydroxymethylpyrrolidin-2-one methanesulfonic acid ester (yellow oily product) are obtained, which is used in the next reaction step without further purification.

b) 8.5 g (0.03 mol) of the mesylate obtained in paragraph a) are heated in an autoclave for 3 hours at .50 °C together with a solution of .0 g of dimethylamine in 60 ml of dioxane. The cooled reaction mixture is evaporated to dryness in vacuo, the residue is dissolved in 2L hydrochloric acid and the solution is extracted with ether. The acidic aqueous phase is made alkaline with concentrated ammonia and shaken with methylene chloride. The methylene chloride solution is used up and evaporated, and the residue weighing 6.5 g is converted into the hydrogen fumarate of the title compound using an equivalent amount of fumaric acid. The product with a melting point of .37 to 138 °C results in a yield of 6.4 g (6. * theory). The following compounds are prepared by an analogous procedure to that in example .3.

Example number R ^R , «2 Melting point (°C) 14 H -Ό .63 to .64 (hydrochloride) 15 -o H -Ό 167 to 169 (oxalate) ,6 /-Λ V/ ^N_CH3 H -O 258 (dihydrochloride) ř 17 -a H -o 188 to .90 (hydrochloride) ,8 -H(CH ₃ ) ₂ H “^O~ ^CH 3 .63 to .64 (formate) ,9 H -O" ^CH 3 .52 to 153 (hydrochloride)

Example number To «1 «2 Melting point (°C) 20 -N(CH ₃ ) ₂ H ^Father 157 to 158 (fumarate) 2, -h(c ₂ h ₅ ) ₂ H -O~ ^ci Cl 149 to 151 (hydrochloride) 22 -»{CH ₃ ) ₂ H Cl .67 to 168 (fumarate) 23 -n(c ₂ h ₅ ) ₂ H .59 to 16, (hydrochloride) 24 -n(ch ₃ ) ₂ H -θ— ^Oh 3 oil (base) 25 -n(c ₂ h ₅ ) ₂ H -0~ ^OCH 3 oil (base)

The following section provides examples of the composition and preparation of pharmaceutical compositions.

A. Tablets

Ingredients per 1 tablet

active substance 100mg powdered milk sugar 140 mg Corn Starch 240 mg polyvinylpyrrolidone 15 mg magnesium etherate 5mg

500 mg

The finely ground active ingredient is mixed with milk sugar and part of corn starch.

The mixture is sieved, moistened with an aqueous solution of polyvinylpyrrolidone, kneaded, the moist mass is granulated and dried. The granulate, the rest of the corn starch and magnesium stearate are sieved, extruded and tablets of suitable shape and size are pressed from the mixture.

B. Tablets

Folder to 1 tablet active substance 80 mg Corn Starch .90 mg milk sugar 55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium carboxymethyl starch 23 mg magnesium stearate 2 mg

400 mg

The finely ground active ingredient is mixed with a portion of corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone, the mixture is sieved, and with the help of the rest of the corn starch and water it is processed into a granulate, which is then dried and sieved. The dry granulate is

add sodium carboxymethyl starch and magnesium stearate, tablets 0 suitable size. β. Ampoules the dough is mixed and pressed out of it Folder quantity active substance 57.0 mg sodium chloride 10.0 mg redistilled water into 1.0ml The active substance and sodium chloride are dissolved in redistilled water and the solution is filled into ampoules under sterile conditions. 0. Drops i Folder quantity active substance 5.0g p-hydroxybenzoic acid methyl ester 0.1g p-hydroxybeazoic acid propyl ether 0.1g demineralized water to 100.0 ml The active ingredient and preservatives are dissolved in demineralized lead, solution ee filters · fills and bottles with it in 100 ml doses.

p Seventy in the mountains

Claims (2)

A process for the preparation of aminomethylpyrrolidinones of the general formula I in which R 1 represents a hydrogen atom or a methyl group, R 1 represents a phenyl radical optionally substituted by one or two substituents selected from the group consisting of methoxy, fluorine and chlorine atoms, trifluoroethyl and methyl, or represents a pyridyl radical i 83 * 84 are either the same or different and represent either a C 1 -C 3 alkyl group or both R 7 and R 6 together with the nitrogen atom form a pyrrolidine, piperidine, morpholine, K-methylpiperazine or imidazole ring, the aminomethyl group being attached, in position 4 or 5 'and their editorial aols and acids, characterized in that the hydroxymethylpyrrolidinone of formula II' Z '»3 in which (II) R @ 1 and R @ 2 are as defined above, by reaction with thlonyl halide, phosphorus halide or toeyl-8i asesyl halide to give the compound of formula III 1-0¾ (III) HC-R, R in which 8, &quot; Bj &quot; X represents a halogen atom, a tosyloxy group or a mesyloxy group, and this compound is then reacted with a primary or secondary amine of formula IV (IV) in which: R1 and R1 are as defined above, and the resulting product of formula (I) is optionally converted into a physiologically acceptable acid addition hall. 2. A process according to claim 1, wherein the corresponding starting materials are used to give compounds of formula (I) wherein R @ 1, R @ 8, R @ 3 and R @ 4 are as defined in point 1 and the aminomethyl group is attached at the 4-position. , and their acid addition salts.