DE1645994A1 - Process for the preparation of 5,5-disubstituted barbituric acid derivatives - Google Patents

Description

Aspro-Nicholas Limited

Process for the preparation of 5,5-disubstituted barbituric acid derivatives.

Addition to patent ....., (patent application Ur. A50 01T IVd / 12p)

The present invention relates to the production of barbituric acid derivatives more precisely, a process for the preparation of certain 5,5-disubstituted barbituric acid compounds, namely those of the following general formula:

^ NH

O*

as well as pharmaceutically acceptable salts thereof, In this formula:

X is an oxygen atom or an imino group}

009883/2180

R _{1 is} a group of the general formula Ha or, if -X stands for oxygen, also of the following general formula .1Ib:

wherein R 1 represents a hydrogen atom or a lower one Alkyl group (preferably liethyl group) and Rp means:

(A) a phenyl group which may be substituted by, one or more halogen atoms, hydroxy, lower alkyl · (preferably methyl) or lower alkoxy (preferably Methoxy) substituents;

(B) a glycoalkyl group containing 5 to 7 carbon atoms, for example cyclohexyl;

(G) a phenyl lower alkyl group, for example Benzyl; or ,

(D) containing a straight or branched chain alkyl group 3 to 7 (preferably 4 or 5) carbon atoms, for example a propyl, butyl, amyl, hexyl or Heptyl group, preferably n ~ 3utyl- or sec-amyl.

The terms "lower alkyl" and "lower alkoxy" mean For the purposes of the present invention, alkyl or alkoxy groups containing T up to 4 carbon atoms *

A preferred group of compounds of the formula I is that in the R ^ for a 2-, 3- or 4-pyridy! methyl or

-:. - 3 .- ■■■■

009883/2180 bad'OWQlKAL-

;} -, · - or 4 piperidinyl methyl substituents and Sp for a .uenyl-, cyclohexyl-, benzyl-, sec -amyl or n-butyl-Jul: st; l t'ionten. stand"

iJie iarbi *: ^urs: acid derivatives of formula T in which X is an oxygen atom and R ₂ is B, C or D has, are wipe products useful because of their pharmaceutical properties or as an "in this connection to British Patent Specification Ur. 976551 referenced.

The "arbituric acid derivatives of formula I, in which X is an oxygen atom and R _{2 is} A, are useful as intermediates for the preparation of certain other barbituric acid compounds which have valuable pharmacological properties in that they are active in suppressing tremors in induced spasms in mice which eats a recognized screening test for compounds useful in the treatment of Parkinson's disease · In this regard, reference is made to British patents Kr. 977,321 and 1,015,029 ·

The barbituric acid derivatives of the formula I in which X represents a Iffiittogruppe are useful as intermediates because they _f can be converted to the corresponding Verbindurigen in which X is an oxygen atom, if the latter can not be produced directly in a convenient manner or in an economical manner *. In this regard, reference is made to British Patent Specification No. 1.073 »299,

009883/2180, - 4 -

'' * ■ "" "'" "■■" ■ * "■" ■ BAD ORIGINAL

The present invention is based on the task a new improved method for. Production of 5,5-disubstituted To develop barbituric acid compounds of the formula I. Subject of the patent. . . . (the patent application A 50017 IVd / 12p) is a process for the production of 5,5-disubstituted barbituric acids of the general formula:

R.

r;

O ^ N

and of pharmaceutically acceptable salts of these compounds, where X is an oxygen atom or the imino group, R- is a group of the following general formula

II

wherein R, represents a hydrogen atom or a lower alkyl group, and

Rg for one optionally by one or more = Halogens, hydroxyl groups, lower alkyl or lower alkoxy groups, substituted phenyl groups, a cycloalkyl group with 5-7 carbon atoms, an aralkyl group, or a straight or branched alkyl group with 3- * T Carbon atoms, which is characterized in that an aminoalkylating agent of the general formula

-R ₁ Y III ..-

.or-an acid addition salt of this compound,

009883/2180

- ■■ · '■■' ^L "- 5 -

where R _{1 has} the same meaning as above and Y stands for chlorine, bromine, iodine or an alkyl or aryl sulfonate radical,

with an adsorbate of a 5-monosubstituted barbittir acid derivative the general formula

0
H

IV

where X and R "have the above meaning, or an acid addition salt of this compound reacted on a strongly basic anion exchange resin, optionally the product obtained, if X stands for an imino group, by treatment with a hydrolyzing agent into the corresponding barbituric acid compound and / or the obtained Base into a salt of a pharmaceutically acceptable Acid is transferred.

It has now surprisingly been found that the aforementioned reaction between an amino-alkylating agent of formula III and a 5-monosubstituted barbituric acid derivative of the formula IV without the last-mentioned compound absorbed on a strongly basic anion exchange material can be carried out when in the presence a quaternary ammonium compound is carried out. This new method has the advantage that it can be carried out more quickly and can be carried out on a larger scale

^can 009883/2180

- * ■ - ■■

The present invention accordingly relates to a method for the preparation of 5 »5-disubstituted barbituric acids of the formula I and salts thereof according to x'atent. . (Patent application A 50017 IVd / i2p), which is characterized is that a compound of formula III with one: 5-monosubstituted barbituric acid derivative of the formula IV in Presence of an aqueous solution of a quaternary ammonium compound reacted and then, if desired, the reaction product obtained by processes known per se converted into a desired salt.

The alkylation reaction at ITormaldruck and at a temperature of about 40 ⁰ C is advantageous, preferably between 80 and 100 ° C. The reaction is carried out until the alkylation has ended or the alkylation agent has been consumed. This period of time can last from 1 to 24 hours, depending in particular on the reaction conditions used. If, for example, the reaction is carried out under reflux temperatures, the reaction will be more common. "Welse will be complete after 2 to 6 hours. The reaction components are preferably used in stoichiometric proportions -monosubstituted barbituric acid or the alkylating agent can be used.

That used in accordance with the method of the present invention Quaternary ammonium compound is preferably a quaternary one Alkyl, cycloalkyl or aralkyl ammonium hydroxide or -Alkoxide, for example a methoxide, ethoxide or butoxide.

- ". '■■■■ '"'-T-

009883/2180

If an aralfcyl radical is used, the aryl moiety can this radical one or more oxygen ,. Nitrogen or Contain sulfur atoms. Some examples of quaternary Ammonium compounds, which according to the method of the present In accordance with the invention, the following are i

Benzyltrimethylammonium hydroxide Benzyl triethylaramonium ethoxide Dibenzyldibutylammonium ethoxide

Tetraethylammonium hydroxide *

Tetramethylammonium Tetrabutylammoniumbutoxid cyclohexyl trimethylamnoniiäinhydroxid Phenäthyldimethylpropylanunoniumäthoxid Cycloheptyltriäthylammoniumniethoxid CyclopentyliaethyldiäthylammoniiUBhydröxid 2-Pyridylmetb.yitrimethylanimoniufliliydroxiä 4-Pyridylmethyldiäthylpropylai! UBoalumhydroxid S-methyl-i-thiazolylmethyltrimethylammoniummethoxid furfuryl triäthylammoniiamäthoxid Purfuryldiäthylpropylamnioniumhydroxid TetVahydrofurfuryltrimethylanunoniumhydroxid *! • urfuryläthyldibutylammoniumhydroxid Dibenzyldimethylammoniumhydroxid 2-Naphtylmethyltriäthylammoniummethoxid Thenyltributylammoniumhydroxid Methyläthyldibutylammoniumhydroxid

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After completion of the alkylation reaction, the precipitated one becomes Solid preferably removed from the reaction medium, for example by filtration before the 5,5-disubstituted compound is dissolved therefrom. This dissolution can take place according to methods known per se, for example by removing the Solids with the required amount of a solution a strong mineral acid, for example hydrochloric acid. The 5> 5-disubstituted compound can then be obtained from the solution, for example by neutralization, the desired compound being precipitated, filtered off and can be dried or converted to the salt form, for example in an acid addition salt, if so desired.

5,5-disubstituted imino-barbituric acid compounds, which according to obtained by the process described above can be converted into the corresponding oxo compound by hydrolysis using a hydrolyzing agent such as an aqueous solution of a strong acid such as hydrochloric acid will. -

The 5-Fyridyimethyl-5-R2- substituted oxo-bearbituric acid compounds, which can be obtained by one of the methods described above, can then be reduced using, for example, hydrogen and a hydrogenation catalyst such as Adam's platinum oxide to obtain a · ' 5-PiperidiBylmethyl- * > -R ₂ to produce substituted barbituric acid compound. When the basic nitrogen atom of the saturated

009883/2180

.164599A

heterocyclic group is unsubstituted, the free barbituric acids are unstable and cyclize quickly, "so that these compounds should be prepared as salts and handled in the form of their salts, or, if desired, by N-lower alkylation into a 5- (lmriedefalkyl · - piperidinylmethyl) -5-R ₂ -substituted ^{Barbi 'tlirsäure} connection should be performed. If an R-methyl compound is desired, this can conveniently be prepared by heating an acid addition salt of an N-unsuhstituierten compound with formic acid and formaldehyde in aqueous solution, preferably in the presence of a soluble format, for example an alkali metal format such as sodium format Since the N-alkylated compounds are stable, their salts can be converted into the free N-alkylated barbituric acid derivatives.

The 5> 5-disubstituted barbituric acids obtained after the above reactions can be converted into salts such as metal salts, acid addition salts and salts with an ion exchange resin by processes known per se. For example , acid addition salts can be prepared by reaction, preferably in solution in a solvent or a solvent mixture, with the corresponding acid or a solution thereof, or with an anion exchanger preparation and the desired salt can be isolated, which may be obtained in the form of a hydrate or crystal May contain solvents ».

Acid addition salts are, in particular, pharmaceutically acceptable addition salts with suitable acids such as with

009883/2180 _ ' _Q ^:

inorganic acids, for example hydrochloric acid, 'Tiromwasser- chemical acid, nitric acid, sulfuric or phosphoric acids, or with organic acids such as organic carboxylic acids, for example acetic acid,! glycolic acid, maleic acid, Y / one acid, Citric acid, jD-acetyloxybenzoic acid, nicotinic acid or isonicotinic acid, or with organic sulfonic acids, for example methanesulphone, ethanesulphone, 2-hydroxyethanesulphone, p-Toluenesulphonic or: vaphthalene-2-sulphonic acid. In addition to pharmaceutically acceptable acid addition salts to "- the present invention also encompasses the preparation of other acid addition salts. They can be used as intermediates in the purification of the compounds or in the preparation of other, for example pharmaceutically acceptable, acid addition salts serve, or they are useful for identification, Characterization or purification of the free acids.

An acid addition salt obtained can be converted into the free compound by methods known per se, for example by, JBehandlmg_jde.r_Jfer_bjjidujag_jb3Jljelnsr., JBase, like a Metal hydroxide, for example an alkali metal or alkaline earth metal hydroxide, for example lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide; a metal carbonate such as an alkali metal or an alkaline earth metal carbonate or hydrogen carbonate, for example sodium, Potassium or potassium carbonate or hydrjögenjsar "bonati ammonia, -; -, with a hydroxyl ion exchange preparation; or with any

- 11 -

009883/2180

another suitable reagent "

The acid addition salt obtained in this way can also be converted into a different acid addition salt. For example, a salt with an inorganic silic acid can be mixed with a metal salt, such as a sodium, 3arium or silver salt. ^; -ure in one _; eeigneten diluent .behandelt in ä <?.. "a rtenilaetes inorganic salt is insoluble and 'can be removed from the reaction medium else''on ilcüe ¹ Cin ii ^ ureadditionssal-z can au.ch another Säureadditionssals by 3ehandlun _{ ^; r rait an anion exchanger preparation over _; * be carried out.

The 5, ^ - disubstituted barbituric acids can also be used in "etallsalne converted by per se known" method are, for example, by reactions, preferably in solution in a solvent or a solvent mixture, with the appropriate base or a solution . of it, or with a cationic exchanger preparation and by isolating the desired salt that is in the form of a hydrate or may contain crystal solvents.

The metal salts prepared according to the invention are preferably the pharmaceutically acceptable, non-toxic salts with suitable bases such as those with, for example, one Alkali metal or alkaline earth metal hydroxide alkoxide, hydroxide

* - 12 -

0Q9883 / 2T80 . / _Λ

BADQRtGlNAL

V ¹² "16 k 5994

or carbonate, for example Lithiumhyäroxiä, lithium alkoxide, Sodium hydride, potassium hydride, potassium carbonate or hydrogen carbonate, sodium carbonate or hydrogen carbonate, Sodium alkoxide or sodium hydroxide; or with a hydroyl ion exchange preparation, or with any another suitable reagent.

A obtained metal salt can be converted into the free acid by methods known per se, for example by treatment with an acid, ie an inorganic acid, for example hydrochloric acid, hydrogen bromide ^; ! ure, nitric acid, sulfuric or phosphoric acid. A basic jelly obtained can also be converted into another basic jelly according to well-known processes, for example a silver salt can be treated with a sodium or barium salt in a suitable diluent in which the silver salt thus obtained is insoluble and in this way is removed from the reaction medium.

Err ecun'len, "conneri obtained v, ^r grounded by contacting a strong Ka ^ resin Salae 5, S-disucstituierten barbituric acids, - - that is, substances in which the barbituric" -.ure ionically bonded to an ion Austauschematerial ". Ior.tn— or anior.enexauschermaterialrr.with a solution ... ^ of an arbituric acid in an inert, preferably colar lot number, until the respective degree of saturation is reached , in which brick an essentially complete saturation of the exchanger with the arbituric acid has taken place

009883 / 2ia0 " ¹⁵ / ■

~ BATH ORIGINAL

Cation exchange resins for this purpose are those listed under * the trade names Zeocarb 225 H, Dowex 50 W-X 8, Amberlite IR 120 (H), Zeocarb 226 H and Amberlite IRG 50 (H) known Products. Suitable anion exchange resins are, for example, those under the trade name Deacidite FF, Amberlite IRA-400, Dowex 1 and Dowex 2 well-known products. The words "Deaeidite", "Amberlite" and "Dowex" are registered Trademark in Great Britain.

The following examples illustrate the invention: Example 1:

(a) 2-pyridylmethyl chloride (12.7-5 g »0.1 mol) slowly became a stirred mixture of 5-phenylbarbituric acid over half an hour (20.4 gj 0.1 mol) and benzyltrimethylammonium hydroxide (42 g of a 4% aqueous solution; 0.1 mol) in water (250 ml) given at 90 ° C. After the exothermic addition was complete, the mixture was stirred and refluxed for 3 hours. After cooling, the precipitated solid was filtered off, washed with 5N hydrochloric acid and the pH of the acidic filtrate was increased by adding

adjusted to 6 by aqueous ammonia, whereupon crystals of 5- (2 ^r -pyridylmethyl) -5-phenylbarbituric acid, mp 318-320 ° C., precipitated (11 g).

(b) Si ^ '- PyridylmethylJ-S-phenylbarbituric acid (25 g) ,,, 0098S3 / 2180 - H - ·'

"Was warned in a mixture of glacial acetic acid (30 ml; dissolved, and concentrated hydrochloric acid (10 ml) was added. The desired product was obtained by adding precipitated from acetone, filtered off, washed with acetone and dried, leaving 21 g of 5- (2'-pyridylmethyl) -5-phenylbarbituric acid hydrochloride were obtained.

(c) A solution of 5- (2'-pyridy! methyl) -5-phenylbarbituric acid hydrochloride (21 g) in anhydrous!.! Ethanol (220 ml) was at room temperature (25 ° C) and below Formal pressure hydrogenated using Adams platinum oxide (0.5 g). When the "barrel" he would stop taking on (after adding 5.55 liters), the solution was filtered and the '-! ethanol was evaporated. The residue (20.2 g) was dissolved in warm water (55 ml). Concentrated Hydrochloric acid was added and the!,! Ishing was cooled. The crystals that fell out became filtered off, 18.3 g of 5- (2'Piperidiny! methyl) -5-phenylbarbituric acid hydrochloride as hydrate, F.p. 197-199 ° G were obtained. ·

(d) A mixture of 5- (2'-piperidiny! methyl) -5-phenylbarbituric acid hydrochloride (4.8 g), 'tasser (7.5 ml), Formic acid (1.3 ml), sodium format (1.6 g) and Formalin (1.9 ml; 37 - 41 ^ weight / volume! Formaldehyde) was refluxed for 6 hours. The pH / ert of the cooled solution was increased by adding of dilute sodium hydroxide set to 9, and

009883/2180

the mixture was extracted with chloroform. Treatment of the dried chloroform extract with ethereal hydrochloric acid led to the precipitation of ^ - (N-methyl-2 ¹ -piperidinyl-methyl) -5-phenylbarbituric acid hydrochloride hydrate, melting point 195-200 ° C. after recrystallization from chloroform ether.

Example 2 ;

-_ (2'-Pyridylmethyl) -5-phenylbarbituric acid was like described in Example 1 produced with the modification that tetramethylammonium hydroxide (36.4 g of a 25 ^ -igen aqueous solution) was used in place of benzyltrimethylammonium hydroxide. The yield obtained was 10.6 g.

example 3 '

5- (2 ^l -Pyridylmethyl) -5-phenylbarbituric acid was prepared as in Example T, with the modification that tetraethylammonium hydroxide (58.8 g of a 25% aqueous solution) was used instead of the benzyltrimethylammonium hydroxide. A yield of 9.6 g was obtained.

Example 4:

(a) 2-Pyridylmethylchloride (0.2 mol) was during a Slowly stirred for 45 minutes

Ä Q09 & 83/2180

Mixture of 5-ph.enyl-2-iminobarbituric acid (0.2 mol) and iretramethylammonium hydroxide (72.8 g of a 25 $ igeri aqueous solution; 0.2 mol) in water (450 ml) at 90 ° C given. The further work-up and treatment took place as described in Example 1, with 5- (2'-pyridylmethyl) - ^ - phenyl - ^ - iminobarbituric acid, F.p. 300 ° C (decomposition) was obtained.

(b) 5- (2 ^L -Pyridylmethyl) -5-phenyl-2-iminobarbitate acid (5g) was refluxed in 20% hydrochloric acid (50 ml) for 8 hours. To the resulting solution, 0.88 ammonium hydroxide was added dropwise until the pH of the solution reached 4. The product which precipitated was filtered off, washed and dried, 3.5 g of 5- (2 ^f -pyridylmethyl) -5-phenylbarbituric acid, mp 328 321 ° C. being obtained.

example 5 '

By reacting 4-pyridylmethylbenzenesulphonate and 5-sec. Amylbarbituric acid in the manner described in Example 1 (a) gave 5 "-sec.amyl-5- (4 ^l -pyridylmethyl) barbituric acid Pp 238-24o ° C.

Example 6 ;

Following the procedure of Example 5, using of 2-pyridylmethyl chloride 5-sec.amyl-5- (2'-pyridy! methyl) barbituric acid F, ρ. 206 - 208 ° C

keep,-' ....,-.:

0öS88: 3 / 218.0. . '■. ~ ^r? ~ ^: "■ BAD ORIGINAL

example

The compound obtained according to Example 5 was reduced according to the method described in Example 1 (c), 5-sec-amyl-5- (4 ^l -piperidinylmethyl) barbituric acid hydrochloride mp 272-274 ° C. being obtained,

Example 8 ; - ■ - - ■ · ' ^{: L} * ^i]; v -'- '*' ^:

The compound obtained according to Example 6 was after the procedure described in example 1 (c) reduced, wherein 5-sec.'Amyl-5- (2'-piperidinylmethyl) barbituric acid hydrochloride F.p. 192-193 ° C was obtained.

example 9 :

Using the procedures described below, a number of 5,5-disubstituted Barbituric acid compounds or pharmaceutically acceptable ones Salts prepared therefrom, being any of the following Compounds of the formula III: »'■

2-pyridylmethyl chloride
2-pyridylmethyl bromide
2-Pyridylmethylbenzenesulphonate 2-Pyridylmethyltoludllbulphonat 3-Pyridylmethylchloride
4-pyridylmethylbenzene sulphonate 6-methyl-2-pyridylmethyl chloride "5-ethyl-2-pyridylmethyl bromide

4-n.Bufcyl-2-pyridylmethyl chloride.

009883/2180

- 10 -

Ί6Λ5 99Λ

^ -Methyl ^ -pyridylmethyl chloride 6-methyl-3-pyridylmethylbenzenesulphonate '4-isopropyl-3-pyridylmethyl bromide 5-ethyl-3-pyridylmethyl chloride 5-methyl-4-pyridylmethyl chloride e-jt.Butyl - ^ - pyridylmethyl chloride " 2-methyl-4-pyridylmethyltoluene sulphonate, 2-ethyl-4-pyridylmethyrbromide 3-methyl-4-pyridylmethyl iodide ö -ethyl - ^ - pyridylmethyl chloride 4-pyridylmethyl chloride 3-pyridylmethyl toluene sulfionate 3-I ^ ridylmetliyll) romid

with any of the following compounds of Formula IV was implemented: '

5-phenylbarbituric acid 5-phenyl-2-iminobarbituric acid 5- (o-Cb.lorphenyl) ~ barbituric acid 5 - (^ - bromophenyl) -barbituric acid 5- (m-chlorophenyl) -barbituric acid 5- (2 '; 4 ^r -dicilophenyl) -barbituric acid • 5- (£ -GhlQrphenyl) -2-iminobarbituric acid 5- (p_-Metb.ylplienyl) -2-iminobarbituric acid 5- (£ * -i »butyl phenyl) -barbituric acid 5- (3 ' : 5 ' - MäthylphenylJ-barbituric acid 5- (in-isopropylphenyl) ~ 2-iminobarbituric acid 5- (jo-methoxyplienyl) -barbi door acid

009883/2180 " ¹⁹ ~

5 ~ (£ -Methoxyphenyl) -2-iminobarbituric acid 5_ (o-ethoxyphenyl) -barbituric acid 5- (p_-n.Butoxyphenyl) -2-iminobarbituric acid 5- (2: 4 ^l -dimethoxyphenyl) -2-iminobarbituric acid 5_ (3 «-Chloro-? ¹ -methoxyphenyl) barbituric acid 5-cyclopentylbarbituric acid. ? -Cyclopenty1-2-iminobarbituric acid b-cyclohexylbarbituric acid 5-cyclohexyl-2-iminobarbituric acid 5-cycloheptylbarbituric acid 5-benzylbarbituric acid 5-benzyl-2-iminobarbituric acid 5-phenäthy1-2-iminobarbituric acid 2-isopropyl-phenoburic acid 5-isopropyl-isopropyl-isopropyl-isopropylbarbituric acid ,; 5-n-propylbarbituric acid 5-n-butylbarbituric acid 5-n. Butyl-2-iminobarbituric acid-. 5-1 ^. Butylbarbituric acid 5-isobutyl-2-iminobarbituric acid 5-n-amyl-2-iminobarbituric acid 5-n-amyibarbituric acid 5- sec 5-n-heptylbarbituric acid

Patent claims ;

Claims (8)

16A5994 Patent claims : Process for the preparation of 5,5-disubstituted Barbituric acid formula ¹ ^ C-0 -HH R ₂ I ■ I wherein X is oxygen or an imino group: R | a group of the formula Ha or, if X is Oxygen is a group of the formula Hb \ ^ ^CH 2 - Ha H ^iCH 2 Hb wherein R, hydrogen or a lower alkyl is ^ and Rp ^e i ⁿ phenyl, which may be substituted by one or more halogen atoms, hydroxy, lower alkyl or lower alkoxy groups; Cycloalkyl of 5 to 7 carbon atoms; Phenyl lower alkyl; or a straight chain or branched alkyl group with 3 to 7 carbon atoms, and salts thereof, according to patent. . «. (Patent application A 5OOT7 I? D / 12p), thus g e k e η η - 009 883/21 80 - 21 - BADORlQlISiAt. ζ e i c h η e t that a compound of the formula III where R- is a group of the formula XIa, Y represents chlorine, bromine, iodine or an alkyl or aryl sulfonate,
with a 5-monosubstituted barbituric acid of the formula G O B. C. R ₂ , O. ο- ■■ * ■■■ F. H- IH IV ■ "" X where X and Rp have the above meaning, is reacted in the presence of an aqueous solution of a quaternary ammonium compound, the desired Compound of formula I is obtained in which X and Rp have the above meaning and R ^ is a group of the formula Ha is, and then, if desired, the 2-iminobarbituric acid obtained hydrolyzed into the corresponding 2-oxobarbituric acid will, and then, if a compound of formula I, in the R.J is a group of formula Hb, if desired, the corresponding Compound in which R * is a group of the formula Ha is, is reduced; and then, if a compound of the formula I in which R _{1 is} a group of the formula Hb in which the nitrogen atom is substituted by lower alkyl is desired, the \ - ^, - K · ■■ ' JD 0 9 8 8 3/21 80 - 22 - corresponding compound in which the nitrogen atom is unsubstituted is, is N-lower alkylated, and the compounds obtained are isolated either as such or as salts. 2. The method according to claim 1, characterized in that in the above compounds the symbol R ₁ for a 2-, 3- or 4-pyridy! Methyl or piperidinylmethyl group and ILj for a phenyl, cyclohexyl, benzyl, sec. Amy1 or n-butyl group. 3. The method according to claims 1 to 2, characterized in that that the reaction between the compound of formula III and the compound of formula IV in Normal pressure and at a temperature above 40 ° C is carried out. 4. The method according to claims 1 to 3, characterized in that the reaction for a period of 1 to 24 hours. 5. Process according to Claims 1 to 4, characterized in that the quaternary ammonium compound is a C [uarternary alkyl. _} Is cycloalkyl or aralkyl ammonium hydroxide or alkoxide. 6. Process according to Claims 1 to 5, characterized in that that the quaternary ammonium compound - 23 009883/2180 Benzyltrimethylammonium hydroxide, tetramethylammonium hydroxide or is tetraethylammonium hydroxide * 7 * Process according to claims 1 to 6, - characterized in that that the 2-IminobarMturic acid obtained for corresponding 2-oxobarbituric acid using an aqueous solution of a strong acid is hydrolyzed * 8.- Procedure according to. Claims 1 to 7, characterized in that a compound of the formula I in which E _{1 is} a group of the formula Hb, by reducing the corresponding compound of the formula I »in which H ₁ 'is a group of the formula Ha, using Hydrogen is produced in the presence of a hydrogenation catalyst. Process according to claims 1 to 8, characterized in that a compound of the formula I in which S _{1 is} an N-methyl'-piperidinylmethyl group by reaction of the corresponding compound of the formula I in which R ^ is a piperidinylmethyl group , is made with formic acid and formaldehyde in aqueous solution * € 3372 180