DE1939787B2 - ANTIEPILEPTICS (OR ANTICONVULSIVE) - Google Patents

Description

It has long been known that phenobarbital and diphenylhydantoin are used as antispasmodic agents Warm-blooded animals are useful. For example, they have been used in the treatment of epilepsy. However Phenobarbital not only has antispasmodic activity but also has the disadvantage that it shows a hypnotic activity. Diphenylhydantoin is not hypnotic, but has the disadvantage that it is results in a number of undesirable side effects, such as: B. hypertropic gingivitis, megaloblastic Anemia, toxic psychosis and hirsutism. It has now been found that certain N-lower alkoxymethyl, Benzyloxymethyl and acyloxymethylphenobarbital compounds, barbital compounds and diphenylhydantoin compounds effective anticonvulsant agents are those from the pharmacological point of view have unexpected properties compared to the corresponding parent compounds.

Admittedly, in Doran, Medicinal Chemistry, New York, 1959, Volume IV, John Wiley & Sons, Inc., page 187 (War Department Army Medical Library, Microfilm No. 1720, I. G. Farbenindustrie Plant, Elberfeld, Germany), reports that a material given for its structural formula Ν, Ν'-dimethoxymethylphenobarbital was tested as a hypnotic but found to be ineffective. But there are none there Information about any useful therapeutic effect. There was also no information about the Manufacture and made about the properties.

The invention now provides antiepileptic drugs or anticonvulsants which are in the Opposite to the well-known Ti compounds diphenylhydantoin and Phenobarbiial are free from hypnotic effects.

ZN

C-N

O Y

part

is where Z is —CO— or part of a single bond between the adjacent carbon and nitrogen atoms; X and X 'both represent phenyl radicals when Z represents part of a direct bond, or X and X' both represent ethyl radicals or X represents an ethyl radical and X 'represents a phenyl radical when Z represents —CO—; and Y and Y ' both represent alkoxymethyl radicals having 1 to 12 carbon atoms in the alkoxy moiety, benzyloxymethyl radicals or acetoxymethyl radicals or propionoxymethyl radicals, where Y' can also represent hydrogen when Z forms part of a single bond.

The means are characterized by the fact that they have a very good long-term effect and that they are practical have no side effects.

Examples of compounds contained in the agents are: Ν, Ν'-dibenzyloxymethylphenobarbital and Ν, Ν'-dialkoxymethyldiphenylhydantoin, in which the alkoxy groups contain 1 to 12 carbon atoms, such as. B. methoxy, ethoxy, propoxy and Lauryloxy. The compounds in which the alkoxy groups are methoxy or ethoxy are preferred Ν, Ν'-dimethoxymethylphenobarbital and 3-methoxymethyldiphenylhydantoin are particularly preferred.

Further examples of compounds contained in the agents are N.N'-diacetoxymethylphenobarbital, N.N'-diacyloxymethylbarbital, 3-acetoxy methyldiphenylhydantoin and Ν, Ν'-diacyloxymethyldi phenylhydantoin. Further examples are: the corresponding propionoxy compounds. The connection with acetoxy groups are preferred; Ν, Ν'-diacetoxymethylphenobarbital and 3-acetoxymethyldiphe nylhydantoin are particularly preferred.

The compounds in which at least Y 'is alkoxy methyl or benzyloxymethyl can durcl Alkoxymethylation or benzyloxymethylation before phenobarbital or of diphenylhydantoin or dei corresponding alkali metal salts, in particular the sodium salts, are prepared. Alkoxymethylation or benzyloxymethylation can be carried out by reaction with aqueous formaldehyde under basic conditions gene and subsequent reaction with the corre sponding alkanol or benzyl alcohol under acid Conditions are executed. But it can also be done by simultaneous implementation with both formals hyd (or paraformaldehyde) as well as the corresponding alkanol or benzyl alcohol under acidic conditions gen are executed. Finally, it can also be achieved by reaction with a halomethyl alkyl -benzyl ether. for example a chloromethyl alkyl or benzyl ether in a suitable dilution medium, such as B. dimethylformamide, where a temperature within a large tempe ratiirbereich is applied, in expedient

ßiger way from below 0 ⁰ C to the boiling point of the diluent.

The compounds in which at least Y 'is acyloxy methyl. can by hydroxymethylation or Alkoxymethylation or benzyloxymethylation of Barbitai or Phenobarbiita! or diphenylhydantoin or the corresponding alkali metal salts, especially the sodium salts, and subsequent reaction with the corresponding carboxylic anhydride, preferably in the presence of a base or a Catalyst, such as tin (IV) chloride will. The hydroxymethylation can be achieved by reacting with formaldehyde (or paraformaldehyde) acidic conditions or with aqueous formaldehyde under basic conditions. the Alkoxymethylation or benzyloxymethylation can be carried out as above.

The compounds can be mixed with the conventional physiologically acceptable carriers in order to Manufacture syrups, isutonic solutions, tablets or other forms of administration. The toxicity and the potencies of the compounds are such that each administration unit contains 10 to 500 mg of active material may contain.

The procedures for testing the effectiveness of the in The compounds mentioned in the following examples were as follows:

All experiments, except where indicated otherwise, were carried out in adult male white mice (Charleis River strain). Administration was by oral route in a 10% aqueous acacia gum in which the active agent was suspended, unless otherwise specified.

The acute oral toxicity and the acute intraperitoneal toxicity were determined in the usual manner. The results were expressed as LD50. This is the dose required to kill 50% of the animals. The determination was made graphically. The 95% limit values are given in brackets.

The doses that produced neurological failures were determined by the method of S wi η yard et al.,]. Pharmacol. Exptl. Therap. 106, 319 (1952), but using an additional test. The ability of the animals to remain on a "rotostab", ie a horizontal rod that rotated at 6 rpm, for at least 1 minute was also examined. The results were expressed as TDm, which is the dose required to produce neurological damage. The determination was made graphically. The 95% limit values are also attached.

The time of maximum anticonvulsant effect was determined by taking doses of different Sizes were administered to a group of animals and then the animals at certain time intervals A maximal electric shock was given by passing a current of 60 mA through a corneal electrode 0.2 seconds was applied. Protection was given when the animal did not receive the tonic extensor component of the maximum electroshock image in unprotected animals. The time of the maximum The effect thus determined was used for subsequent tests for anticonvulsant activity of the same active agent used.

The anticonvulsant effect of each agent was assessed against the maximum electric shock administered as described above, against a convulsive dose of pentetrazole (106.25 mg / kg) injected subcutaneously, and against a lethal dose of strychnine sulfate (1.5 mg / kg) kg), which was injected subcutaneously, determined In the case of the maximum electric shock, was the criterion for effectiveness there? Absence of the tonic extensor component of the seizure picture. In the case of pentetrazole, the criterion for effectiveness was the absence of a clonic seizure. In the case of strychnine sulfate, the criteria for effectiveness was if the animals did not die even though seizures did occur.

Hypnotic activity or central nervous system depression resulting from loss of the Righting reflex (beginning of sleep) has been displayed, did not become any of the compounds at any dosage genes caused at less than a lethal dose.

Phenobarbital itself, on the other hand, was hypnotic Activity if the above criterion is used

became.

Below is the making of each Active ingredients explained in more detail.

a) Manufacture of \ Ν, Ν'-dimethoxymethylphenobarbital

In a 1000 ml flask fitted with a

With a stirrer and a condenser, 136.4 g (0.536 mol) of phenobarbital sodium powder were added to 500 ml of dimethylformamide suspended. The flask was placed in an ice bath. For cold suspension were 100 g (1.25 mol) of chloromethyl methyl ether added over a period of one hour. The suspension obtained was at 20 hours Stirred at room temperature and then poured into 2000 ml of ice water. The suspension obtained was a further 2 Stirred for hours. The crude product was used for filtration separated, three times with 100 ml of distilled water washed and then dissolved in about 500 ml of hot ethanol. 1 g was added to the boiling solution Activated charcoal was added and the boiling solution was filtered through a Buchner funnel having a 1 cm thick pressed layer of a finely divided diatomaceous acid. The cake was poured three times in 25 ml Ethanol and the hot solution was allowed to cool to room temperature along with the washes. The resulting crystals

were filtered, washed with ethanol and dried in a vacuum desiccator. That way were 58 g of N.N'-dimethoxymethylphenobarbiUil with a Melting point of 115 to 117 ° C obtained.

Pharmacological testing of this compound gave the following results:

acute toxicity

Dosage mg / kg

LD50 (oral)
LD50 (intraperitoneal)

Neurological deficit

TD50

Antispasmodic effect

Maximum electric shock,
ED50

Penetetrazole, EDw

Strychnine, ED50

Time of the maximum

effect

470 (376-588) 490 (408-588)

47 (33-66)

13.5 (8-23)
47 (29-75)
200 (125-320)

2 hours after
administration

Repeated daily administration to the same animals for four days showed none

noticeable change in the EDw value during protection against maximum electric shock. The duration of the anticonvulsant effect against maximum electric shock was compared with that of phenobarbital sodium at a dose of 0.1 millimoles / kg each. The compound gave protection only after two hours, but the protection remained on for more than 8 hours about the same height. Phenobarbital gave protection in less than 0.5 hours, but protection started after 4 hours to sink and was practically over in 8 hours.

The antispasmodic properties of the compound against maximum electric shock was also measured in the rat (Sprague-Dawley-Stamrn). The EDso value was found to be 6.6 (4.2-10.4).

b) Production of 3-methoxymethyl-5 ^ -diphenylhydantoin

27.5 g (0.1 mole) of 5,5-diphenylhydantoin sodium became suspended in 250 ml of dimethylformamide. To the suspension 8.8 g (8.25 ml) of chloromethyl methyl ether were added over a period of 30 minutes. The suspension obtained was stirred at room temperature overnight and then poured into 1 l of ice water poured. A solid material precipitated out. The suspension was stirred for 1 hour and then the solid became separated by filtration and washed three times on the filter with 100 ml of water. The wet cake was dissolved in 125 ml of ethanol. 1 g of activated charcoal was added to the boiling solution jo, and the boiling Solution was filtered through a Buchner funnel, which was a 1 cm thick pressed layer of finely divided Contained diatomaceous silica. The cake was washed three times with 15 ml of ethanol and the hot Ethanol solution was diluted together with the washing liquids with 100 ml of hot water and then on Allowed to cool to room temperature. The crystals that appeared were filtered and spotted on the filter three times Washed 25 ml of 50% aqueous ethanol and then dried in a vacuum desiccator. In this way 20 g of 3-methoxymethyl-5,5-diphenylhydantoin with a melting point of 127 were obtained at 128 ° C. (yield 67%). Pharmacological testing of this compound showed that it had an LDw of approximately 500 mg / kg. It showed an antispasmodic effect (maximum electric shock) within a few than 0.5 hours after the administration. The effect lasted more than 2 hours. The EDw value was smaller than 25 mg / kg.

c) Production of N.N'-dibenzyloxymethylphenobarbital

25 g of powdered phenobarbital sodium was suspended in 250 ml of dimethylformamide. Under violent While stirring, 15.0 g of chloromethyl benzyl ether were added at room temperature / ur suspension. That Reaction mixture was left overnight at room temperature touched. The suspension was then poured into 500 g of fco poured ice-cold water, which became (lemisch I hour stirred and the solid was separated by filtration. The crude product was in about 1 Sf) ml dissolved in boiling ethanol. 0.5 g of activated charcoal were added to the boiling solution, and the boiling solution was added. Solution was filtered through a Buchner 11 'thter, the one compacted layer; ius leinteilijer diatoms contained silica. The cake wtii'l ■ · dreirrui! nut Washed 10 ml of ethanol, and the hot solution was brought to room temperature together with the washing liquids let cool down. The crystals obtained were filtered off and from 100 ml of ethanol in the recrystallized in the same way as described for the first crystallization. In this way, J. 5.27 g of N.N'-dibenzyloxymethylphenobarbital with one Mp. From 74 to 75 ° C obtained.

d) Manufacture of
N.N'-di-n-butoxymethylphenol barbital

25 g of powdered phenobarbital sodium were suspended in 350 ml of dimethylformamide. With vigorous stirring, 15 g of chloromethyl-n-butyl ether were added to the suspension at room temperature. The suspension was stirred at room temperature overnight. The reaction mixture was then poured into 1 kg of ice-cold water, the mixture was stirred for 1 hour and the solid was separated off by filtration. The crude product was dissolved in 100 ml of hot ethanol, 1 g of activated charcoal was added, and the boiling solution was filtered through a Buchner funnel containing a compacted layer of finely divided diatomaceous silica. The cake was washed three times with 10 ml of ethanol and the hot solution was allowed to cool to room temperature along with the washes. The crystals obtained were filtered off and recrystallized twice more from 100 ml of ethanol in the same manner as is described for the first crystallization. In this way, 12.3 g of N.N'-di-n-butoxymethylphenobarbital with a melting point of 71 at 72 ° C. were obtained. If the compound was tested as above, then it exhibited anticonvulsant activity against maximal electroshock, the ED less than 100 mg / kg was ₅ o-value and the LD _W value (oral) was more than 500 mg / kg.

e) Manufacture of
N.N'-diethoxymethylphenobarbital

25 g of phenobarbital sodium were dissolved in 250 ml of dimethylformamide at 120 ° C. The solution was cooled to 60 ° C., and at this temperature 25 g of chloromethyl ethyl ether were added with thorough stirring. The reaction mixture was allowed to cool to room temperature and stirred for 20 hours, then poured into 500 g of ice water, stirred for 1 hour, after which the product was separated by filtration. The solid material was dissolved in 150 ml of boiling ethanol. One gram of activated charcoal was added and the boiling solution was filtered through a Buchner funnel containing a compacted layer of finely divided diatomaceous acid. The cake was washed three times with 10 ml of ethanol. To the hot solution and washes 50 ml of hot water was added and the solution was allowed to cool to room temperature. The crystals obtained were filtered off and recrystallized twice more in the same manner as described for the first crystallization. In this way, to g of N.N'-Diäihoxjüiethylphenoharbital with a melting point of 65 C were obtained. When the compound was rinsed as above, it showed antispasmodic activity against maximal Kleklrosi.hock, with the portion of maximal activity I ¹ /. Lasted hours and d-.T LD, ..- value less than 25 mc / ki; betnm.

f) Manufacture of
3-n-butoxymethyl-5,5-diphenylhydantoin

27.5 g of 5,5-diphenylhydantoin sodium were ^{suspended at 100 °} C. in 250 ml of dimethylformamide. The suspension was cooled to 50 ° C. with thorough stirring. At this temperature 16 g of chloromethyl n-butyl ether were added and the suspension was stirred for 3 hours, during which the temperature was allowed to fall to 20 ° C. The reaction mixture was then poured into 1 l of ice-cold water and stirred for one hour. The solid product obtained was separated by filtration and dissolved in 150 ml of hot ethanol. 1 g of activated charcoal was added and the boiling solution was filtered through a Buchner funnel containing a compacted layer of finely divided diatomaceous silica. The cake was washed three times with 10 ml of ethanol and the hot solution was allowed to cool to room temperature along with the washes. The crystals obtained were filtered off and recrystallized two more times in the same manner as described for the first crystallization. In this way 8.9 g of 3-n-butoxymethyl-5,5-diphenylhydantoin with a melting point of 108 to HO ⁰ C were obtained. When tested as described above, the compound showed an anticonvulsant effect against maximal electric shock, the ED 50 value being less than 25 mg / kg. The LD ₅₀ (oral) was also determined and found to be greater than 500 mg / kg.

g) Manufacture of
3-benzyloxymethyl-5,5-diphenyl-hydantoin

27.5 g of 5,5-diphenylhydantoin sodium were suspended in 250 ml of dimethylformamide. 15 ml of chloromethylbenzyl ether were added to the suspension with thorough stirring, and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into 1 liter of ice-cold water and stirred for 1 hour. The solid product was separated by filtration and dissolved in 150 ml of hot ethanol. 1 g of activated charcoal was added to the boiling solution, and the hot solution was filtered through a Buchner funnel which contained a compacted layer of finely divided diatomaceous silica. The cake was washed three times with 10 ml of ethanol and the hot solution, along with the washes, was allowed to cool to room temperature. The crystals obtained were filtered off and recrystallized two more times in the same way as described for the first crystallization. In this way, 13.1 g of 3-benzyloxymethyl-5,5-diphenylhydantoin with a melting point of 151 to 152 ° C. were obtained obtain.

h) Manufacture of Ν, Ν'-DüauryloxymethylphenobarbitaI

25.4 g of powdered phenobarbital sodium was suspended in 250 ml of dimalylformamide at room temperature, and 22.1 g of C-woromethyldodecanyl ether was added to the suspension. The reaction mixture was stirred overnight and poured into H ice water. The mixture was then stirred for 3 hours and the waxy solid was separated by filtration. The wet solid was dissolved in 150 ml of boiling ethanol. 1 g of activated charcoal was added to the hot solution and the boiling solution was filtered through a Buchner funnel which contained a compacted layer of finely divided diatomaceous silica. The filter cake was washed three times with 15 ml of ethanol and the hot solution

ίο was allowed to cool overnight along with the washing liquids. The crystals obtained were filtered off and recrystallized once more in the same manner as described for the first crystallization. In this way, N'-Dilauryloxymethylphenobarbital were obtained with a mp. Of 48 to 5O ⁰ C N 13 g. When tested as above, the compound showed anticonvulsant activity against maximal electric shock, with maximal activity lasting 2 hours and the ED10 value being approximately 50 mg / kg. The LD ₅ o value (oral) was determined to be more than 500 mg / kg.

i) Manufacture of
N.N'-diacetoxymethylphenobarbital

Into a 500 ml flask equipped with a stirrer and a condenser were 11.5 g (0.05 mol) of phenobarbital in a mixture of 20 ml of dioxane and 100 ml of 37% strength aqueous Formaldehyde solution dissolved. 1 ml of a 38% strength hydrochloric acid was added to this solution, and the Solution was refluxed for 16 hours. The solution was cooled to room temperature and the Product was extracted into ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and then evaporated to dryness. Were oily residue 12.5 ml of acetic anhydride and 12.5 ml of pyridine are added, and the solution was left to stand at room temperature overnight. The solution was cold in 500 ml Poured water containing 12.5 ml of 38% hydrochloric acid, and stirred for 3 hours. The crude product which in Form of a solid precipitate was obtained, was filtered off and washed with water and then through Heat dissolved in 100 ml of ethanol. 1 g of activated charcoal was added to the hot solution, the boiling one Solution was filtered through a Buchner funnel,

One of them is a 1 cm thick layer of finely divided diatomaceous silica contained. The cake was washed three times with 15 ml of ethanol and then the hot The solution was allowed to cool to room temperature along with the washes. The received

The crystals were filtered off, washed three times with 20 ml of ethanol and dried in a vacuum desiccator. They then weighed 10.1 g. The m.p. was 136-137 ° C., yield 53%. Further purification was achieved by dissolving this material in 100 ml of ethyl acetate, washing the solution four times with a cold saturated potassium carbonate solution, drying the solution over sodium sulfate and evaporating the ethyl acetate. The solid obtained was crystallized from 100 ml of ethanol, 8 g of N, N'-diacet oxymethylphenobarbital (47% overall yield) with a melting point of 146 ° to 148 ° C. being obtained.

The results of pharmacological tests on this compound were as follows

609 530/447

Acute toxicity

LD ₅₀ (oral)

LD5o (intraperitoneal)

Neurological deficit

Antispasmodic effect

Maximum electric shock,

Metrazol, EDw

Strychnine, ED ₅ O

Time of maximum

activity

Dosage / mg / kg

640 (474-864)
350 (437-673)

140 (110-178)

28 (22- 35)
104 (80-135)
120 (90-160)

1.5 hours

The connection is also in the following way
available:

In a 500 ml flask fitted with a A stirrer and a condenser were fitted, 11.5 g (0.05 mol) of phenobarbital were added to a mixture of Dissolved 20 ml of dioxane and 100 ml of a 37% strength aqueous formaldehyde solution. To this solution were 20 mg of sodium carbonate was added and the remainder of the procedure was followed in exactly the same way carried out by heating to reflux, etc. There were 6.5 g of the same product (34% yield) with a Mp. From 146 to 148 ° C obtained.

30th

k) Manufacture of
3-acetoxymethyl-5.5diphenylhydantoin

6 g of 3-methoxymethyl-5,5-diphenylhydantoin, which had been obtained according to Example 2, were suspended in 20 ml of acetic anhydride. Four drops of tin (IV) chloride were added to the suspension. The suspension was stirred at room temperature overnight. Then it was poured into 600 ml of ice water, whereby a solid material precipitated. The suspension was stirred for 3 hours in order to decompose the excess acetic anhydride. Then the solid product was separated by filtration and washed three times on the Filter ^r with 50 ml of water. The wet product was dissolved in 50 ml of hot ethanol. To the boiling solution was added 1 g of activated charcoal and the solution was filtered through a Buchner funnel containing a 1 cm thick pressed layer of diatomaceous silica. The cake was washed three times with 15 ml of hot ethanol. The hot ethanol solution was then diluted with 50 ml of hot water and allowed to cool to room temperature. The crystals obtained were separated by filtration. 6 g of the product were obtained. The crude product was recrystallized from 60 ml of 80% strength aqueous ethanol, 4.7 g of a slightly impure product with a melting point of 157 ° to 158 ° C. being obtained. This impure product was further purified by recrystallization from ethanol, with 2j6 g of pure 3-A-oxymethyl-5,5-diphenyIhydantoin with a melting point of 162 to 163 ° C.

The pharmacological test showed that the compound had an LD50 of slightly less than 500 mg / kg. It showed no anticonvulsant effect against metrazol, but against maximal electroshock it showed maximal activity of about 1 Hour after administration; the EDw value was less than 1.5 mg / kg.

I) manufacture of
N.N'-diacetoxymethyldiphenyl hydantoin

25.2 g (0.1 mol) of 5,5-diphenylhydantoin were dissolved in a mixture of 25 ml of dioxane and 100 ml of water. 44 ml of a 37% strength aqueous formaldehyde solution and 5 ml of triethanolamine were added to the solution, and the solution was refluxed for 7 hours. The hot solution was cooled to room temperature and then acidified to pH 1 with dilute hydrochloric acid. The solution was repeatedly extracted with ether, and the combined ether solutions were washed with aqueous sodium chloride solution and dried over sodium sulfate. The ether was evaporated under reduced pressure to give an oil consisting of 1,3-dihydroxymethyl-5,5-diphenylhydantoin. The oil was acetylated using 25 ml of acetic anhydride and 25 ml of pyridine, with which it was left to stand at room temperature overnight, and then poured into ice water containing 25 ml of concentrated hydrochloric acid. A solid material precipitated out. The suspension was stirred for 4 hours to decompose any unreacted acetic anhydride, after which the solid product was separated by filtration and then washed several times with water on the filter. The wet cake was dissolved in methanol (ca. 500 ml) with heating. To the boiling solution was added 1 g of activated charcoal and the boiling solution was filtered through a Buchner funnel containing a 1 cm thick pressed layer of diatomaceous acid. The cake was washed three times with 25 ml of hot ethanol and the hot solution was allowed to cool to room temperature. The resulting crystals were filtered off, washed three times with 25 ml of methanol and dried in a vacuum desiccator. 21.2 g of N ₁ N'-diacetoxymethyldiphenylhydantoin with a melting point of 150 to 15 ° C. were obtained (yield 53.5%).

Pharmacological testing of this compound showed the following results:

acute toxicity

Dosage, mg / kg

LD ₅₀ (oral)

Neurological deficit

Antispasmodic effect

Maximum electric shock,

Time of maximum

effect

570 (259-1254) 76 (41-140)

16.5 (12-22)
3 hours

m) Production of Ν, Ν'-Dipropionoxymethylphenobarbital

3 g of phenobarbital were dissolved in 20 ml of dioxane. 100 ml of a 37% strength were added to the solution aqueous formaldehyde solution and 1 ml of concentrated hydrochloric acid were added, and the reaction mixture was heated to reflux over a period of 20 hours. The mixture was brought to room temperature cooled, and the product was several May with Ethyl acetate extracted The ethyl acetate solutions mrden combined and washed with water, over

3

19 39 7ö /

Dried sodium sulfate and evaporated to dryness. 16 ml of propionic anhydride were added to the oily residue and 16 ml of pyridine were added, and the solution was left to stand at room temperature overnight. The solution was then poured into 500 g of ice containing 16 ml of 5 contained concentrated hydrochloric acid. The mixture was stirred for 4 hours after which the oily product passed through Filtration was separated and dissolved in 100 ml of hot ethanol. 1 g was added to the boiling solution Activated charcoal was added and the hot solution was filtered through a Buchner funnel, which compressed a Containing layer of finely divided diatomaceous acid.

The cake was washed three times with 10 ml of ethanol and the hot solution, along with the washes, was allowed to cool to room temperature. The crystals obtained were filtered off and recrystallized in the same manner as described for the first crystallization. In this way, 4 g Ν, Ν'-Dipropionoxymethyiphenobarbital were obtained with a mp. 93.5 to 94.5 C ^0. When tested as described above, this compound exhibited an ED 50 against maximal electric shock of less than 25 mg / kg and an LD _W (oral) of approximately 500 mg / kg. ; 5

n) Manufacture of
Ν, Ν'-diacetoxymethylbarbital

18.4 g of 5,5-diethylbarbituric acid (barbital) were in Dissolved 20 ml of dioxane. 100 ml of a 37% strength aqueous formaldehyde solution and 1 ml were added to the solution a 38% hydrochloric acid was added, and the solution was heated to reflux for 16 hours. The solution was cooled to room temperature and the product was extracted several times with ethyl acetate. the Ethyl acetate solutions were combined and washed with water, dried over sodium sulfate and then used for Evaporated to dryness. 20 ml of acetic anhydride and 20 ml of pyridine were added to the oily residue, and the solution was allowed to stand at room temperature overnight. The solution was then cold in 500 ml Poured water containing 20 ml of 38% hydrochloric acid and the mixture was stirred for 3 hours, whereupon the oily product was extracted several times with methylene chloride. The methylene chloride solutions were combined and washed with water, dried over sodium sulfate and then to separate off the methylene chloride evaporated. The product was obtained from the oily residue by column chromatography isolated using silica gel (grade 950). Elution with a benzene-ethyl acetate mixture (Volume ratio 9: 1) gave a semi-crystalline product, which was first as hexane and then as pentane was crystallized. In this way became pure Ν, Ν'-diacetoxymethylbarbital with a melting point from 64 to 65 ° C. When tested as above, the connection showed an EDso-Wcrt against maximum electric shock of less than 25 mg / kg, with maximum activity approximately 2 hours occurred after administration. The hypnotic activity was very weak; the ED ^ o value was 260 up to 300 mg / kg.

o) Production of N, N'-dimethoxymethyl-5,5-diethylbarbituric acid

By the general procedure of Example 1 but using sodium 5,5-diethyl barbiturate

ίο (sodium barbital) as starting material instead of Phenobarbital sodium gave an oily product which was purified by chromatography. That Product was identified as N, N'-dimethoxymethyl-5,5-diethylbarbituric acid. Their analysis was as follows:

is calculated values for C ₁₂ H ₂₀ N ₂ O ₅ : carbon 52.93%, hydrogen 7.40%, nitrogen 103%. Values found: carbon 53.07%, hydrogen 7.51%, nitrogen 10.35%. Pharmacological testing of the compound showed that it had antispasmodic activity against metrazol, the ED ₅₀ being 7 mg / kg. The time of maximum effect occurs approximately 1 hour after the administration.

Comparison of pharmacological properties

Diphenyl phenobarbital Examples hydantoin 12 4 5 6 Acute toxicity LD »(per oral) 225 325 470 500> 500> 500 Antispasmodic activity 8.4 12th 13.5 <25 <100 <25 <25 EDm (per oral) MES Therapeutic index (LDso / EDso) -26.8 27 - 34.8 20 duration after about 4 h. ~ 8 2 Activity decrease to 0 after 8h Time of peak activity 2 h 0.5 1.5 Neurological failures (TDx) (r * o.) 22nd 47 Hypnotic activity available absent, with the exception of the lethal dose Mans (pjo. & Ip .) rat available absent, with the exception of the lethal dose dog available absent at 200 & 400 mg / kg monkey available absent at dosages up to 3200 mg / kg Hexobarbital sleep time extended not extended with the exception of 5x de

EDso versus MES

Comparison of pharmacological properties (continued)

Examples
8th

Acute toxicity LD50 (per oral)> 500
Antispasmodic activity -50

EDso (orally) MES
Therapeutic index (LDm / EDw)
duration

Peak activity time 2 hours

Neurological failures (TDw) (p.o.)

640
28

-22.8

1.5
140

<500
<12.5

-40
1.0

CS 14

13th

570
16.5

-34.5

3.0

76

Hypnotic activity

Mouse (po & ip)
rat
dog
monkey
ücxcbarbital sleep time

absent, with the exception of the lethal dose

absent, with the exception of the lethal dose absent at 200 & 400 mg / kg absent at doses up to 3200 mg / kg not extended with the exception of 5x the

15th

Ib

500

<25 <25

(Pcntetrazole)

2.0

1.0

against FMD

example 1
(Tablets)

Hydrous lactose (8.25 kg), potato starch j _S (1775.0 g) and pregelatinized corn starch (900.0 g) were sieved through a sieve with a mesh size of 0.250 mm into the ball of a mixer. Then, N, N'-bis (methoxymethyl) -phenobarbital (6.0 kg) through a sieve with a mesh size of 0.84 mm ^ ₀ te in the ball are sieved, and the resulting mixture was mixed for 10 minutes . Sufficient distilled water was added to wet the mixture and mixing was continued for 20 to 30 minutes. The mixture was then granulated in a grinding machine using a 1.90 cm sieve. Hitrauf was dried in a fluid bed dryer until the moisture content of the grains was between 1 and 2. The dry grains were sieved through a sieve with a mesh size of 0.84 mm. Magnesium stearate (50.0 g) and stearic acid (125.0 g) were sieved through a sieve with a mesh size of 0.250 mm and then mixed with about 5 kg of the dried, sieved grains. All of the ingredients were then placed in a blender and mixed for 10 minutes. The granules were tabletted on a conventional machine using a 9.5 mm punch. Each tablet weighed approximately 342.0 mg and contained 120.0 mg of N, N'-bis (methoxymethyl) phenobarbital.

Example 2
(30 mg capsules) ^M.

Hydrous lactose (2310.0 g) and magnesium stearate (30.0 g) were sieved through a sieve with a mesh size of 0.250 mm. N, N'-bis (methoxymethyl) phenolbarbital (180.0 g) was passed through a sieve sieved with a mesh size of 0.84 mm. The above ingredients were mixed for about 30 minutes in an I ^ -Oter-Kugeimfihle, then sieved through a sieve with a mesh size of 0.250 and filled into No. 1 gelatmkapseln, including one hand operated *; Kapsefüllmaschme was used. Each capsule contained 30 mg of NJ>i'-bis (methoxy methylj-phenobarbital, 385.0 mg of hydrous lactose and 5.0 mg of magnesium stearate.

Example 3
(60 mg capsules)

The procedure of Example 2 was repeated with the exception that N, N'-bis (methoxymethyl) phenobarbital as components (360.0 g). hydrous lactose (2010.0 g) and magnesium stearate (30.0 g) are used became. Each capsule contained 60.0 mg of N, N'-bis (methoxymethyl) -phcnobarbital. 335.0 mg hydrous lactose and 5.0 mg magnesium stearate.

Example 4
(120 mg capsules)

Following the procedure of Example 2, capsules containing 120.0 mg of N, N'-bis (methoxymethyl) phenobarbital, 275.0 mg of hydrous lactose and 5.0 mg of magnesium stearate are produced, however was worked with the exception that an approach was used, the 720.0 g of the barhita compound, Contained 1650.0 g of hydrous lactose and 30.0 g of magnesium stearate.

Example 5
(Intravenous solution)

100 mg of N, N'-bis (methoxymethyl) phenobarbita were dissolved in 10 ml of polyethylene glycol with heating at 40 ° C. The solution was at room temperature allowed to cool and then sterilized to give a solution suitable for intravenous Administration was appropriate.

Example 6

10 kg of a 10 percent aqueous gum acacia solution were introduced into the ball of a mixer. Then 1.0 kg of N, N'-dimethoxymethylphenobarbital was sieved into the ball through a sieve with a mesh size of 0.84 mm. The mixture was mixed for 10 minutes whereby a suspension suitable for oral administration was obtained; was suitable. 1 ml of this suspension is a suitable dosage, although larger or smaller doses can be used.

L1571

Claims (1)

Patent claims: 1. Antiepileptic drugs (or anticonvulsants), characterized in that they are a compound of the general formula X Z-N C C = O X 'C-N Ii i
O Y ' contain, wherein Z represents —CO— or part of a single bond between the adjacent carbon and nitrogen atoms; X and X ' both represent phenyl radicals when Z represents part of a direct bond, or X and X' both represent ethyl radicals or X represents an ethyl radical and X 'represents a phenyl radical when Z represents —CO—; and Y and Y 'both represent alkoxymethyl radicals with 1 to 12 carbon atoms in the alkoxy moiety, benzyloxymethyl radicals or acetoxymethyl radicals or propinoxymethyl radicals, where Y' can also represent hydrogen when Z forms part of a single bond. The invention therefore relates to antiepileptic drugs (or anticonvulsants), which are characterized by that they are a compound of the general formula