CS244144B2 - Aminomethylpyrrolidinones production method - Google Patents

Abstract

bound in position 4 or 5, and their admixed 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 radical, optionally substituted with one or two substituents selected from the group consisting of ethoxy, fluorine and chlorine atoms, trifluoromethyl and methyl, or represents a pyridyl radical and R 1a, they are either the same or different and the 3 ' represents an alkyl group having from 1 to 3 carbon atoms or both R1 and R4 together with the nitrogen atom form a pyrrolidine, piperidino, morpholino, H-methylpiperazin or imidazole ring, the aminomethyl group being Yippee

Description

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of novel aainoaathylpyrrolldinones and their acid addition salts.

These novel compounds counteract short-term memory limitations after administration of musculine cholesterol antagonists and, in addition, show significant efficacy against hypoxil.

Structurally related nootropics include 1-carbaaoylaathylpyrrolidin-2-one (Piracetam), 1- (p-methoxybenzoyl) pyrrolidin-2-one (Aniracetam) and tukarbaaoylaathyl-4-hydroxypyrrolidin-2-one (Oxiraeetaa) - see BJR Nco. , 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 aminoastyl group into the pyrrolldlnone molecule has greatly improved the efficacy of such compounds over the known compounds.

The present invention provides a process for the preparation of the novel aalnomethylpyrrolidinones of general formula I

in which

R 1 represents a hydrogen atom or a methyl group,

R 8 represents a phenyl radical optionally substituted by one or two substituents selected from the group consisting of methoxy, fluorine and chlorine atoms, trifluoroethyl and an aryl group, or represents a pyrldyl radical and

R @ 1 and R @ 2 are either the same or different and represent a C1 -C3 alkyl group or both R @ 1 and R @ 2 together and the nitrogen atom form a pyrrolidine. a piperdino, morpholine, N-ethylpiperazine or iaidazole ring, wherein the amino group is attached at the 4 or 5 position, and their editorial aols and acids.

The pyridyl ring in the meaning of syabol% a can be attached to the methylene bridge by position 2 or 4.

The resulting products of formula (I) may be converted, if appropriate, by conventional methods, and physiologically acceptable acid addition salts and acids.

Suitable acids for this purpose are both inorganic acids, such as hydrohalic acids, sulfuric acid, phosphoric acid and aalnosulfonic acid, as well as organic acids. such as formic acid, acetic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, aaleic acid, fuaaric acid, succinic acid, tartaric acid, benzoic acid, salicylic acid, citric acid, aacorbic acid, p-tolusnaulfonic acid or acid hydroxyothansulfone.

Preferred are those compounds of formula (I), in which atoa is hydrogen, a phenyl radical optionally substituted in the o- or p-polose fluoroea chlorea, an aryl or aethoxy group, and B 1 is a methyl group.

In accordance with the invention and the compounds of formula (1) above, the hydroxymethylpyrrolidiaone of formula (II) is prepared.

in which

B, e, Bg are as defined above, by reaction and converting thioayl halide, phosphorus halide or tosyl or meheyl halide to a compound of formula III

(III) wherein

B, and Bg are as defined above and

X is halogen, toeyloxy or mesyloxy, and the compound is then reacted with a primary or secondary amine of formula IV

in which

B 1 and B 2 are as defined above.

According to this procedure, the compound of formula II is either converted by reaction with thionyl halide or phosphorus halide to the corresponding 4-halomethyl derivative, or by reaction with tosyl or mesyl halide n is converted to the corresponding 4-tosyl- or mesylated halide. 4-mesyl ester. The slurry is preferably carried out using an inert organic solvent, for example chloroform, methylea 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-halomethyl 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 corresponding primary or secondary amines yields the corresponding end products of formula I. This reaction can be carried out in tetrahydrofuran, dloxane, acetonitrile or preferably dimethylformamide, at a temperature between about 50 and 150 ° C, the reaction conditions employed. depends on the basicity and boiling point of the amine. The reaction can be carried out without solvent - in excess of the amine. If low-boiling amines are used, the autoclave reaction may need to be conducted as appropriate.

244144 4

The novel compounds of the formula I contain an asymmetric center and therefore occur as racemates. These racemates can be converted into the corresponding diastereomers in a conventional manner, for example by salt formation with optically active acids, from which the optically active final can then be obtained; products.

If desired, the alcohols of formula (II) can be converted to the corresponding diastereomeric mixture by formation of esters with optically active acids, which can then be separated into the corresponding diaethereomers in a conventional manner, for example by column chromatography or crystallisation. After saponification of these esters, the enantiomeric alcohols are mixed with which the corresponding amines are prepared as described above.

From the pure enantiomeric nor-compounds, reductive alkylation, for example by the action of acetaldehyde in the presence of hydrogen gas and a catalyst, can be prepared by the corresponding optically pure diethyl derivatives or by the action of formaldehyde and formic acid corresponding to the optically flying dimethylderivatives.

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-pyrrolediaocarboxylic acids, which are esterified, alkylated on nitrogen with optionally substituted beasyl halides, and then subjected to a further reaction as described above.

By the process according to the invention it is possible, for example, to prepare the following end products, optionally in acid addition 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) -ethylpyrrolidin-2-one t-benzyl-4-aidaaol-1-ylaethylpyrrolldin-2-one

1-Benzyl-4-methylaainomethyl-pyrrolidin-2-one

1- (p-Fluorobenzyl) -4-palethylaminoethyl ethyl pyrrolidia-2-one;

1-benayl-4-diethylaainoaethylpyrrolidin-2-one

1- (o-Chloro-benzayl) -4-diethylaninone-ethylpyrrolidin-2-one

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

1-benzyl-5-diaethyleainoaethylpyrrolidin-2-one 1-beaayl-S-dlethylaalnomethylpyrrolidin-2-o and t-benzyl-5-aorfolinoaethylpyrrolidin-2-one

1-Bemyl-5- (4-ethyl-piperazino) -ethylpyrrolidin-2-one

1-Benzyl-5-pyrrolidinone-ethylpyrrolidia-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-diethylaninomethylpyrrolidin-2-one - (3,4-dichlorobenzyl) -5-dimethylaminomethylpyrrolidin-2-one - (3> 4 (dichlorobenzyl) -5-diethylamino-methylpyrrolidin-2-one

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

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

Pyrrolidinone derivatives have been tested in animals for their ability to completely inhibit or reduce various forms of limited cerebral performance.

Said compounds show no acute toxicity when administered orally at a single dose of up to 2 g / kg in a screening test in mice (observation period of 14 days). In animal tests, these substances have excellent effects on spontaneous cognitive performance, such as experimentally limited learning and memory skills. In attempts and limitations of short-term memory, optionally with inhibition of short-term memory contents transients, by administration of muscarinic cholinergic receptor antagonists [scopolamin at an intraperitoneal dose of 0.6 mg / kg] see also Psychopharmacology 78, 104-11, (1982) 3. able to counteract or prevent this pharmacologically induced cerebral insufficiency.

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

In animal closed cell survival tests (hypoxia tolerance test) introducing a gas mixture consisting of 96.5% nitrogen with 3.5% oxygen, animals pre-treated with new substances exhibit a statistically highly significant survival rate over control animals and optionally animals pre-treated with Piracetamea. In addition, the protective effect of the test substances on the brain, already tested orally at 50 mg / kg, is clearly demonstrated by this method.

The novel pyrrolidinone derivatives have been compared with other structurally related pyrrolidinones which are already being used as medicaments (Piracetam), or are being clinically tested (Aniracetam) in the treatment of cerebellar insufficiency or organic brain paychodrome, post-traumatic and alcoholic foot damage etc.

The novel compounds are significantly superior to the above-mentioned known compounds both in terms of effective dose level and in terms of the improvement in brain performance found in animal experiments.

The following overview shows the specific results of the potency assays for representative compounds of the invention as compared to a standard comparator (Piracetaa).

In this case, there is an activity inhibiting the manifestations of dementia induced by acopolamine stimulation.

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

Cage rats are used as test animals, the bottom of which is formed by a wire net. Rats are taught to avoid the electrical discharges they receive on the wire floor of the cage by escaping to the Isolated Platform. Over a period of time, 80% of the animals learn that they are from this plateau

244144 6 protected from electric discharges.

When these animals are injected intravenously with scopolamine at a dose of 0.6 mg / kg, a retrograde effect on short-term steam can be observed in 80 rats, i.e., animals are forgotten that they are safe on the isolated midfielder.

a substance acting against cerebral insufficiency can ease this blockade. After administration of scopolamine, the test substance is administered to the test animals and shows how many animals (v *) are able to remember and learned the actions despite scopolamine administration. The dosages of the compounds of the invention and the comparator are approximately 50% dementia due to acopolamine was inhibited in animals.

Active substance

Dose in mg / kg (rat, per os)

1- (4-fluorobenzyl) -4-β-methylpiperazinyl · - methylpyrrolidin-2-one 1-Benzyl-4-diethylaainomethyl- 30 pyrrolidin-2-one 1- (3,4-dichlorobenzyl) -5-diethylamino 30 methylpyrrolidin-2-one 50 Piracetaa 100 ALIGN!

The novel compounds of the present invention may be used alone or in combination with other active ingredients of the present invention, optionally in combination and other pharacologically active compounds, for example, and other cerebroactivators. Suitable dosage forms are, for example, tablets, capsules, suppositories, solutions, syrups, emulsions or dispersible powders. The tablets may be obtained, for example, by mixing the active ingredient (s) with known excipients, such as inert diluents such as calcium carbonate, calcium phosphate or sugar, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, glidants such as magnesium stearate or talc and / or a depot effecting agent such as carboxypolyaathylan, carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate. Tablets may also be multi-layered.

Correspondingly, dragees can be prepared by coating dragee cores prepared in an analogous manner to tablets with conventional agents commonly used as coatings in the manufacture of dragees such as, for example, colldone or belak, gum arabic, talc, titanium dioxide or sugar. In order to obtain a depot effect or to avoid incompatibility, the cores of the dragee can also be composed of several layers, in which case the excipients mentioned above can be used in the manufacture of tablets.

The syrups containing the active ingredient according to the invention or the active ingredient combination may further comprise a sweetening agent, such as saccharin, cyclamate, glycerin or sugar, as well as agents improving the organoleptic properties, for example flavoring agents such as vanillin or orange extract. These syrups may further contain auxiliary suspending or suspending agents, such as sodium carboxymethyl cellulose, and wetting agents, such as the condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxyheasoates.

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

Capsules containing one or more active compounds or combinations of active compounds can be prepared, for example, by dispersing the active compounds from inert carriers such as milk sugar or aorbit, and filling the mixture with a gelatin capsule.

Suitable arrows may be prepared, for example, by mixing the corresponding carriers, such as neutral fats or polyethylene glycol, or derivatives thereof, with the active ingredient or substances.

The invention is illustrated by the following non-limiting examples.

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 was added 4.8 ml of formalin solution and the mixture was stirred overnight with heating in an oil bath at 00 ° C. The excess acid was distilled off in vacuo, the residue was taken up in water, basified with concentrated caustic soda and shaken three times with methylene chloride. The combined methylene chloride phase was washed with water, dried over sodium sulfate, the solvent was evaporated in vacuo and the residue was filtered through a silica gel column eluting with methylene chloride / methanol (97: 3). The uniform fractions were evaporated in vacuo.

Yield: 3.5 g.

D -7.6 ° (c 1.0, methanol)

D -16.8 ° (c · 1.0; water)

In analogy to Example 1, 6.1 g of (+) -, - benzyl-4-aminoaethylpyrrolidin-2-one, 7.9 g of 85% formic acid and 7 ml of formalin solution are obtained from 5.8 g (0.028 mol). (+) -, - benzyl-4-dimethylaainoaethylpyrrolidin-2-one with optical rotation and _D + + 7.9 ° (c 1.0, methanol).

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 (+) - are dissolved in another 200 ml of hot methanol. tartaric acid. The two solutions are mixed and allowed to cool while stirring, the corresponding salt crystallizing out. The crystals are sucked off cold and washed with cold methanol.

16.0 g of 4-aminoethyl-.beta.-benzylpyrrolidin-2-one tartrate are obtained, melting after methanol crystallization at 204 DEG-206 DEG.

[Α] D = 6.3 ° (1,0 1.0; water).

b) To convert the n * free base, the cold tartrate is dissolved in 20 ml of water and 0 ml of concentrated sodium hydroxide solution, extracted three times with methylene chloride, the combined methylene chloride phases are dried over magnesium sulphate and the solvent is evaporated off under vacuum.

There was obtained (-) - 4-aainoaethyl-1-benzyl-pyrrolidin-2-one with an optical rotation of _β -8.4 ° (c 1.0; water).

c) The mother liquors remaining after processing of the reaction product in a) are evaporated in vacuo. 38.0 g of tartrate are obtained, which is dissolved in 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 off under vacuum.

19.3% of base is obtained, which is reacted with D (-) tartaric acid according to the procedure described in a) to the corresponding tartrate. Product yield 19.0 g, mp 204-205 ° C.

(d) The conversion of this tartrate to the free base shall be carried out as described in paragraph (b).

5.7 g of (+) - 4-aminomethyl-1-benzylpyrrolidin-2-one are obtained with an optical rotation of _.alpha . At + 8.4 DEG (c * 1.0; water).

Example 2

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

10 g (61% of theory) of the desired product are obtained with a boiling point of 155-158 DEG C./7 mm Hg.

Example 3 (-) - 1-Benzyl-4-diethylaminomethyl-pyrrolidin-2-one

A mixture of 11.5 g (0.056 mol) of (-) - 1-behzyl-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 The mixture was hydrogenated at 25 ° C at 0.5 VPa for 5 1/4 hours. 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 was basified and also extracted with methylene chloride.

11.2 g (76.4% of theory) of the title compound were obtained by distillation in a flask and the optical rotation was - 9.4 ° (c 1.0, methanol).

Using an anologic procedure as in Example 3, hydrogenation of a mixture of 8.4 g (0.041 mol) of (+) - 1-benzyl-4-aminomethylpyrrolidin-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 and charcoal gave (+) - 1-benzyl-4-diethylaminomethylpyrrolidin-2-one with an optical rotation of » _D and * 9.4 ° (c 1.0, methanol).

Example 4

1- (4-Fluoro-benzyl) -4-N-methyl-piperazinylmethyl-pyrrolidin-2-one

24 g (0.11 mol) of 1- (4-fluorbanayl) -4-hydroxymethylpyrrolidin-2-one are refluxed in 200 ml of methylea chloride and 10 ml (0.14 mol) of thionyl chloride for 10 hours and after the addition of further 10 ml of thionyl chloride and refluxed for 6 hours. The reaction mixture is neutralized with ammonia with ice-cooling, the organic phase is separated off and evaporated after evaporation. 23 g (92% of theory) of a reddish-brown oily product are obtained as residue ae which are used without further purification.

b) 5 g (0.002 aol) of the above oil and 4.4 g (0.04 mol) of 1-methylpiperazine in 30 ml of dimethylformamide are heated to reflux for 1-2 hours. Dimethylformamide is distilled off in vacuo, the residue is taken up in 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). The main fraction was evaporated, the residue (5 g) was dissolved in 30 ml of ethanol and 2.8 g of fumaric acid was added. 5.2 g (48% of theory) of the title compound precipitated as a crystalline product as a fumarate, m.p. 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-oau, 100 ml of absolute methylene chloride and 4.8 g of pyridine is added 6.9 g (0.06 mol) of methanesulfonic acid chloride. The reaction mixture was heated at reflux for 2.5 hours, then cooled and shaken with dilute ammonia and water. The organic phase was dried and evaporated.

11 g (93% of theory) of the crude ester of melting point 84-86 DEG C. are obtained.

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

The yield of colorless crystals, m.p. 175 DEG-176 DEG C., is 7 g (57% of theory).

The following end products are also obtained in an analogous manner to the previous examples:

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 n-N-CH ₃ v / ³ H -O 190 to 192 (fumarate) 8 / = N -IN] H 230 / 6.7 (base) 9 -HN-CH ₃ H O 180 / 6.7 (base) 10 ' ^N C 1 ^C 2 ^H 5 H 156 / 6.7 (base) 1 ^C 2 ^H 5

244144 10 Example number WITH «1 ¾ Melting point (° C) Boiling point (° C / Pa) 1, HH-CH _{(CH3) 2} H 175 / 6.7 (base) , 2 ^^ c ₂ H ₅ -H ^^ ^{C2 H5} H - ^^ - CH ₃ 175 / 6.7 (base)

Example, 3'-Benzyl-5-dimethylaminomethyl-pyrrolidin-2-one

a) To a solution, 0.26 g (0.05 mol) of 1-benzyl-5-hydroxymethylpyrrolidin-2-one (m.p. 76-77 ° C) and 5.6 g (0.055 mol) of triethylamine in 80 ml of methylene chloride and e. 6.3 g (0.055 mol) of methanesulfonic acid chloride in 20 ml of methylene chloride are added. The reaction mixture is refluxed for an hour, then cooled and shaken with water; The organic phase is dried over anhydrous sodium sulphate and evaporated on a rotary evaporator. This gave 4 g of the crude ester of 1-benzyl-5-hydroxymethylpyrrolidin-2-one and methanesulfonic acid (yellow oil) which was used without further purification in the next step.

(b) 8.5 g (0.03 mol) of the mesylate obtained in (a), together with a solution of 0 g of dimethylamine in 60 ml of dioxane, are heated in an autoclave for 3 hours at a temperature of 50 ° C. The cooled reaction mixture was evaporated to dryness in vacuo, the residue was dissolved in 2N hydrochloric acid and the solution was dissolved. extract with ether. The acidic aqueous phase is basified with concentrated ammonia and shaken with methylene chloride. The methylene chloride solution was evaporated and evaporated, and the 6.5 g residue was converted to the hydrogen fumarate of the title compound using an equivalent amount of fumaric acid. The product, m.p. 37 DEG-138 DEG C., yielded 6.4 g (6.0%). The following compounds were prepared in an analogous manner to Example 3.

Example number R ^R , «2 Melting point (° C) 14 H -Ό , 63 to 64 (hydrochloride) 15 Dec -O H -Ό 167 to 169 (oxalate) , 6 / -Λ V / ^N_CH3 H -O 258 (dihydroehlorid) Ř 17 -and H -O 188 to 90 (hydrochloride) , 8 H _{(CH3) 2} H “^ O ~ ^CH3 , 63 to 64 (furmate) , 9 H -O ' ^CH 3 52 to 153 (hydrochloride)

Example number TO «1 «2 Melting point (° C) 20 May -N (CH ₃ ) ₂ H O- ^ci 157 to 158 (fumarate) 2, -h (c ₂ h ₅ ) ₂ H -O- ^or Cl 149 to 151 (hydrochloride) 22nd - »(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 are examples of compositions and preparations of pharmaceutical compositions.

A. Tablets

Folder on 1 tablet

active substance 100 mg powdered milk sugar 140 mg cornstarch 240 mg polyvinylpyrrolidone 15 mg magnesium etearét 5 mg

500 mg

The finely divided active ingredient is mixed with milk sugar and part of the maize starch.

The mixture is sieved, moistened with an aqueous solution of polyvinylpyrrolidone, sagged, the wet mass is granulated and dried. The granulate, corn starch residue and magnesium stearate are sieved, emitted and compressed into tablets of suitable form and size.

B. Tablets

Component on 1 tablet active substance 80 mg cornstarch , 90 mg milk sugar 55 mg microcryatal cellulose 35 mg polyvinylpyrrolidone 15 Dec mg sodium carboxymethyl starch 23 mg magnesium stearate 2 mg

400 mg

The finely milled active ingredient is blackened with corn starch, milk sugar, microcrystalline cellulose and polyvinylpyrrolidone, the mixture is sieved, with the aid of the corn starch and water, processed to a granulate which is sieved and sieved. The dry granulate is

sodium carboxymethyl starch and magnesium stearate, tablets of appropriate size. β. Ampoule The mixture is mixed and pressed Component amount active substance 57.0 mg sodium chloride 10.0 mg redistilled water to 1.0 ml The active ingredient and sodium chloride are dissolved in redeetilized water and the ampoules are filled under sterile conditions. 0. Drops and Component amount active substance 5.0 g p-hydroxybenzoic acid methyl ester 0.1 g propyl ether of p-hydroxybeazoic acid 0.1 g demineralised water to 100.0 ml The active substance and preservatives are dissolved in demineralized conductor, solution ee it filters and fills vials in 100 ml portions.

p SevenWeight Climbs

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, " Bj " 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.