DE1939787C3 - AntiepHeptics (or anticonvulsants) - Google Patents

Description

X Ζ — Ν .ο

C C = O

X 'C-N

Il I <s

O Y '

contain, wherein Z —CO— or part of a simple bond between the neighboring Represents carbon and nitrogen atom; X and X 'both represent Phenyireste when Z is part of a means direct bond or X and X 'represent both ethyl radicals or X is an ethyl radical and X' represents a phenyl radical when Z denotes —CO—; and Y and Y 'are both alkoxymethyl radicals having 1 to 12 Carbon atoms in the alkoxy part, benzyloxymethyl radicals or acetoxymethyl radicals or propionoxymethyl radicals represent, where Y 'can also represent hydrogen, if Z is part of a easy bond

Ζ — Ν

X '

C = O

C-N

Il I

O Y '

Phenobarbital and diphenylhydantoin have long been known to act as antispasmodics Warm-blooded animals are useful. For example, ties have been used in the treatment of epilepsy, however Phenobarbital not only has antispasmodic activity but also has the disadvantage that it shows hypnotic activity Diphenylhydantoin is not hypnotic, but has the disadvantage that it is There are 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 which are pharmacological to the corresponding parent compounds have unexpected properties.

In Doran, Medicinal Chemistry, New York, 1959, Volume IV, John Wiley & Sons, Ine, 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 im Contrasted with the well-known compounds diphenylhydantoin and phenobarbital of hypnotic effects, where Z —CO— or part of a simple bond between the adjacent carbon and represents nitrogen atom; X and X 'both represent Phenyireste when Z is part of a direct Bond denotes or X and X 'both represent ethyl radicals or X is an ethyl radical and X' is one Is phenyl when Z denotes —CO—; and Y and Y 'are both alkoxymethyl radicals having 1 to 12 Carbon atoms in the alkoxy part, benzyloxymethyl radicals or acetoxymethyl radicals or propionoxymethyl radicals represent, 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: N, N'-dibenzyloxymethylphenobarbital and Ν, Ν'-dialkoxymethyldiphenylhydantoin, in which the alkoxy groups contain 1 to 12 carbon atoms, such as 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 Ν, Ν'-diacetoxymethylphenobarbital, NJ ^ '- Diacyloxymethylbarbital, 3-acetoxymethyldiphenylhydantoin and Ν, Ν'-diacyloxymethyldiphenylhydantoin. Further examples are: the corresponding Propionoxy compounds. The compounds with acetoxy groups are preferred; N, N'-diacetoxymethylphenobarbital and 3-acetoxymethyldiphenylhydantoin are particularly preferred

The compounds in which at least Y 'is alkoxymethyl or benzyloxymethyl can be obtained by alkoxymethylation or benzyloxymethylation of Phenobarbital or diphenylhydantoin or the corresponding alkali metal salts, especially the Sodium salts. Alkoxymethylation or benzyloxymethylation can be carried out by reaction with aqueous formaldehyde under basic conditions and subsequent reaction with the appropriate Alkanol or benzyl alcohol can be run under acidic conditions. But it can also by simultaneous reaction with both formaldehyde (or paraformaldehyde) and the corresponding one Alkanol or benzyl alcohol can be run under acidic conditions. After all, she can get through Reaction with a halomethyl alkyl or benzyl ether, for example a chloromethyl alkyl or benzyl ether in a suitable diluent, such as. B. dimethylformamide, are carried out, a temperature within a wide temperature range 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 acyloxymethyl is can by hydroxymethylation or alkoxymethylation or benzyloxymethylation of Barbital or phenobarbital or diphenylhydantoin or the corresponding alkali metal salts, in particular the sodium salts, and subsequent reaction with the corresponding carboxylic acid anhydride, preferably in the presence of a base or a catalyst such as tin (rV} 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, isotonic solutions, tablets or other forms of administration. The toxicity and the effectiveness of the compounds are such that each Administration unit 10 to 500 mg active material \ may contain.

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

MIe attempts, except when something else indicated were performed on adult male white mice (Charles River strain) Administration took place in a 10% aqueous acacia gum in which the active agent is suspended was, by the oral route, unless otherwise specified

The acute oral toxicity and the acute intraperitoneal Toxicity was determined in the usual manner. The results were expressed as LD50. That is 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 w i η y a r d et al, J. PharmacoL ExptL Therap. 106, 319 (1952), determined however, an additional test was used. The ability of the animals to be at least 1 minute a "Rotostab", i.e. a horizontal rod that spinning at 6 rpm, remaining was also examined. The results were expressed as TD50, that is the dose that is required to be neurological Damage to be generated a The determination was carried out graphically. The 95% limit values are also attached

The time of maximum anticonvulsant effect was determined by administering doses of various sizes to a group of animals and then giving the animals a maximum electric shock at regular intervals by applying a current of 60 mA through a corneal electrode for 0.2 seconds . Protection was given if the animal did not exhibit the tonic extensor component of the maximal electroshock image in unprotected animals. The time of maximum effect so determined was used for all subsequent tests for anticonvulsant activity of the same active agent. ⁶ p

The anticonvulsant effect of each agent was administered against that as described above maximal electric shock, against a convulsive dose of pentetrazole (106.25 mg / kg) administered subcutaneously and against a lethal dose of strychnine sulfate (1.5 mg / kg) injected subcutaneously, In the case of maximum electric shock, the criterion for effectiveness was the lack of tonic Extensor component of the seizure picture. In the case of pentetrazole, the criterion for effectiveness was that Absence of clonic seizure. In the case of strychnine sulfate, the criterion was for effectiveness 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 (onset of sleep) was indicated with no dosage of any of the compounds caused at less than a lethal dose. Phenobarbital itself, on the other hand, was hypnotic Activity if the above criterion was used.

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

a) Manufacture of
N, N'-dimethoxymethylphenobarbital

In a 1000 ml flask fitted with a With a stirrer and a condenser, 136.4 g (0.530 mol) of phenobarbital sodium powder were added to 500 ml of dimethylformamide suspended. The flask was placed in an ice bath for the 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. For filtration, the crude product was separated off 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 washed and the hot solution was brought to room temperature along with the washing liquids let cool down. The resulting crystals were filtered, washed with ethanol and im Vacuum desiccator dried In this way, 58 g Ν, Ν'-Dimethoximethylphenobarbital with a Melting point of 115 to 117 ° C obtained.

Pharmacological testing of this compound gave the following results:

acute toxicity Dosage mg / kg

LD ₅₀ (oral)

LD50 (intraperitoneal)

Neurological deficit

Antispasmodic effect

Maximum electric shock,

Penetetrazole, ED50

Strychnine, ED »

Time of 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 only gave protection 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 craniofiotic activity of the compound against maximal electric shock was also measured in the rat (Sprague-Dawley strain). The EDso-Werl was to 6.6 (4.2 to 10.4) found. '

b) production of v <jn
3-methoxymethyl 5,5-diphenylhydantoin

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

c) Manufacture of
N.N'-Dibeni.yloxymethylphenobarbital

25 g of powdered phenobarbital sodium was suspended in 250 ml of dimethylformamide. Under violent 15.6 g of chloromethyl benzyl ether were added to the suspension at room temperature while stirring. The The reaction mixture was stirred at room temperature overnight. The suspension was then in 500 g Poured ice-cold water, the mixture was stirred for 1 hour, and the solid was collected by filtration severed. The crude product was dissolved in approximately 150 ml of boiling ethanol. To the boiling solution 0.5 g of activated charcoal was added and the boiling solution was filtered through a Buchner funnel, one compacted layer of one-part diatomaceous silica contained. The cake was washed three times with 10 ml of ethanol and the hot solution became allowed to cool to room temperature together with the washing liquids. The obtained crystals were filtered off and extracted from 100 ml of ethanol in the same way as it was for the first crystallization is described, recrystallized In this way, 5.27 g of Ν, Ν'-Dibenzyloxymethjiphenobarbital with a 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 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 acid. The cake was washed three times with 10 ml of ethanol and the hot solution became allowed to cool to room temperature together with the washing liquids. The crystals obtained were filtered off and recrystallized two more times 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 obtained from 72 ° C. When the compound was tested as above, it showed an anticonvulsant effect against maximal electric shock, the ED 50 value being less than 100 mg / kg and the LD ₅₀ value (oral) being more than 500 mg / kg.

e) Manufacture of
N, N'-diethoxymethylphenobarbital

25 g of phenobarbital were dissolved at 120 ⁰ C in 250 ml of dimethylformamide, the solution was cooled to 6O ⁰ C and at this temperature, 25 g of chloromethyl ethyl ether was added with good 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, 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 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 obtained crystals were filtered off, and twice more in the same manner as described for the first crystallization, recrystallized In this manner, b, 5 g of N, N'-Diäthoxymethylphenobarbital with a mp. Obtained from 65 ⁰ C. If the compound was tested as above, then it exhibited anticonvulsant activity against maximal electroshock, wherein the time of the maximum activity I ¹ / lasted 2 hours and the ED 25 mg / ₅₀ value less than kg.

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. Was left, the suspension was cooled with good stirring at 50 ° C. At this temperature 16 g were Chloromethyl-n-butyl ether was added, and the suspension was stirred for 3 hours, the temperature while at 20 ⁰ C fall. 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 acid. 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 washing liquids . The obtained crystals were filtered off, and twice more in the same manner as described for the first crystallization, recrystallized In this way, 8.9 g of Sn-butoxymethyl-S ^ -diphenylhydantoin with a mp. Of 108 to 110 ⁰ C were obtained . When tested as described above, the compound demonstrated anticonvulsant activity against maximal electric shock, the ED »value being less than 25 mg / kg. The LD »value (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 in 250 ml of dimethylformamide suspended. 15 ml of chloromethylbenzyl ether were added to the suspension under good pressure Stirring was added and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into 1 l of ice-cold water and stirred for 1 hour. The solid product was through Separated by filtration and dissolved in 150 ml of hot ethanol. 1 g of activated charcoal was added to the boiling solution was added, and the hot solution was filtered through a Buchner funnel which was a compacted layer from finely divided diatomaceous acid contained The cake was washed three times with 10 ml of ethanol, and the hot solution along with the washes were allowed to cool to room temperature gelassea The obtained crystals were filtered off and further twice in the same manner as it was for the The first crystallization described is recrystallized. In this way, 13.1 g of 3-benzyloxymethyl-5,5-diphenylhydantoin were obtained with a melting point of 151 to 152 ° C get »,. _. .

h) Manufacture of
NJsl'-dilauryloxymethylphenobarbital

25.4 g of powdered sodium phenobarbital were dissolved in 250 ml of dimethylformamide at room temperature suspended, and 22.1 g of chloromethyldodecanyl ether were added to the suspension. The reaction mixture was stirred overnight and poured into 1 liter of ice water poured. The mixture was then stirred for 3 hours and the waxy solid passed through Filtration separated. The wet solid was dissolved in 150 ml of boiling ethanol. To the hot solution 1 g of activated charcoal was added and the boiling solution was filtered through a Buchner funnel, which contained a compacted layer of finely divided diatomaceous silica. The filter cake was three times washed 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'-Dilauryloxymethylphcnobarbital 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 ED ₅₀ value being approximately 50 mg / kg. The LDw 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 Dissolved 20 ml of dioxane and 100 ml of a 37% strength aqueous formaldehyde solution. This solution became 1 ml of 38% hydrochloric acid was added 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 dried Evaporated to dryness To the oily residue, 12.5 ml of acetic anhydride and 12.5 ml of pyridine were 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 was obtained in the form of a solid precipitate became filtered off and washed with water and then dissolved by heating in 100 ml of ethanol. To the hot 1 g of activated charcoal was added to the solution and the boiling solution was filtered through a Buchner funnel which contained a 1 cm thick layer of finely divided diatomaceous silica. The cake was served three times Washed 15 ml of ethanol, and then the hot solution was up together with the washing liquids Allowed to cool to room temperature. The crystals obtained were removed, three times with 20 ml of ethanol washed and dried in a vacuum desiccator. They then weighed 10.1 g. The m.p. was 136-137 ° C

■ jy sj ^ yr.ite 53%. ^; Ng more jlpg & gijgg ^ y dasrgl ^ achieved that this Maicris! in 100 ttj! Aihyiacctat dissolved, the solution was washed four times with a cold saturated potassium carbonate solution, the solution was dried over sodium sulfate and the ethyl acetate was evaporated. The solid obtained was crystallized from 100 ml of ethanol, S3 g of Ν, Ν'-diacetoxymethylphenobarbital (47% overall yield) with a melting point of 146 ° to 148 ° C. being obtained.

The results of the pharmacological tests this connection were as follows:

709 609'99

acute toxicity

Dosage / mg / kg

LD ₅₀ (oral)

LD »(intraperitoneal)

Neurological deficit

Antispasmodic effect

Maximum electric shock,

Metrazol, ED ₅₀

Strychnine, ED ₅ O

Time of maximum

activity

640 (474-864)
550 (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 equipped with a stirrer and a condenser, 11.5 g (0.05 mol) of phenobarbital was dissolved in a mixture of 20 ml of dioxane and 100 ml of a 37% strength aqueous formaldehyde solution. To this solution was added 20 mg of sodium carbonate and the remainder of the procedure was carried out in exactly the same manner by refluxing, etc. 6.5 g of the same product (34% yield), mp 146-148, were obtained ⁰ C.

k) Manufacture of
3-acetoxymethyl-5,5-diphenylhydantoin

6 g of 3-methoxymethyl-5,5-diphenylhydantoin, which had been obtained according to Example 2, were in 20 ml Acetic anhydride suspended Four drops of tin (IV) chloride were added to the suspension. the Suspension was stirred overnight at room temperature. Then it was poured into 600 ml of ice water, whereby a solid material precipitated. The suspension was stirred for 3 hours to remove the excess acetic anhydride to decompose. Then the solid product was separated by filtration and three times on the filter washed with 50 ml of water. The wet product was dissolved in 50 ml of hot ethanol to the boiling point Solution was added 1 g of activated charcoal and the solution was filtered through a Buchner funnel, which contained a 1 cm thick pressed layer of diatomaceous acid. The cake was cooked three times with 15 ml hot ethanol washed a The hot ethanol solution was then diluted with 50 ml of hot water and allowed to cool to room temperature. the obtained crystals were separated by filtration. 6 g of the product were obtained. The raw one Product was recrystallized from 60 ml of 80% strength aqueous ethanol, 4Jg being slightly impure Product with a melting point of 157 to 158 ° C -were obtained .. This immature Prodskt wardsjojriier d «« & .. " UmkristsIIkaiicn sas Athssci cleaned, leaving 2.6 g pure 3-acetoxymeth ^ -5 ^ -diphenylhydantoin with mp 162-163 ° C.

Pharmacological testing showed that the compound had an LD 50 value slightly less than 500 mg / kg. It showed no anticonvulsant effect against metrazole, but against maximum hectrostock it showed maximum activity about 1 hour after administration; was the ED »value less than 124 mg / kg.

1) Manufacture of
Ν, Ν'-diacetoxymethyldiphenylhydantoin

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 diluted with; Hydrochloric acid to pH 1. The solution wurdi repeatedly extracted with ether, and the combined "ether solutions were washed with aqueous solution Natriumchloridlö over sodium sulfate getrocknel The ether was evaporated under reduced pressure, whereby an oil was obtained, which au ¹ 1,3- Dihydroxymethyl-5,5-diphenylhydantoin consisted of the oil was made using 25 ml of acetic acid

anhydride and 25 ml of pyridine, with which it be Left to stand at room temperature overnight, was acetylated and then poured into ice water, which: 25 ml of concentrated hydrochloric acid contained a solid: material precipitated out. The suspension was stirred for 4 hours

to decompose any unreacted acetic anhydride, whereupon the solid product is filtered through separated and then washed several times with water on the filter. The wet cake was ir Methanol (approx. 500 ml) dissolved with heating Zui

1 g of activated charcoal was added to the boiling solution, and the boiling solution was filtered through a Buchner funnel, which formed a 1 cm thick pressed layer; 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 vacuum dried irr were 2UgN ₁ N 'Diacetoxymethyldiphenylhydantoin with a mp. 151 ⁰ C before bis obtain 150 (yield 53.5%).

Pharmacological testing of this compound showed the following results:

Acute toxicity dosage, mg / kg

LDso (oral)

Neurological deficit

TD _5n

Antispasmodic effect

Maximum electric shock,

ED ₅₀

Time of maximum

effect

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

16.5 (12-22)
3 hours

m) Manufacture of
i

11.5 g of phenobarbital were in 20 ml of dioxar dissolved 100 ml of a 37% aqueous formaldehyde solution and 1 ml of concentrated solution were added Hydrochloric acid was added and the reaction mixture was refluxed over a period of 20 hours The mixture was cooled to room temperature and the product was heated several times Ethylacetate extracted The ethylacetate solutions were combined and washed with water, over

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 concentrated hydrochloric acid Stirred for hours, after which the oily product was separated off by filtration and dissolved in 100 ml of hot ethanol was dissolved. 1 g of activated charcoal was added to the boiling solution, and the hot solution was ι ο filtered through a Büchner funnel, which is a compacted layer of finely divided diatomaceous acid contained

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 obtained crystals were filtered off and in the same manner as described for the first crystallization, recrystallized In this way, 4 g of Ν, Ν'-Dipropionoxymethylphenobarbital obtained with a mp. Of 933 to 94.5 ⁰ C. When tested as described above, this compound exhibited an ED 50 against maximal electric shock of less than 25 mg / kg and an LD »(oral) of approximately 500 mg / kg. ,

n) Manufacture of
Ν, Ν'-diacetoxymethylbarbital

18.4 g of 5,5-diethylbarbituric acid (barbital) were in 20 ml of dioxane dissolved. 100 ml of a 37% strength aqueous formaldehyde solution and 1 ml were added to the solution 38% hydrochloric acid was added, and the solution was refluxed for 16 hours. The solution was cooled to room temperature and the product was extracted several times with ethyl acetate 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 left 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 from the oily residue, the product was obtained by column chromatography isolated using silica gel (grade 950). The Eiuiion 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. Thus became pure N, N'-diacetoxymethylbarbital with a melting point from 64 to 65 ° C. When tested as above, the compound showed an ED 50 versus maximum electric shock of less than 25 mg / kg, with maximum activity approximately 2 hours after the administration occurred. The hypnotic activity was very weak; the ED 50 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 (Sodium barbital) as the starting material instead of Phenobarbital sodium gave an oily product which was purified by chromatography. The Product was named N.N'-dimethoxymethyl-S.S-diethylbarbituric acid identified your analysis was as follows:

Calculated values for Ci _{2 HmN 2} O ₅ : carbon 52.93%, hydrogen 7.40%, nitrogen 103%. Values found: carbon 53.07%, hydrogen 7.51%, nitrogen 1035%. Pharmacological testing of the compound showed that it had anticonvulsant activity against metrazole, the ED »value being 7 mg / kg. The time of maximum effect is approximately 1 hour after administration.

Comparison of pharmacological properties

Acute toxicity LDso (per oral)
Antispasmodic activity

ED »(orally} MES

Therapeutic index (LDso / EDso) -263
length of time

Time of peak activity
Neurological failures fTD ») (pa)
Hypnotic activity

Mouse (puo. & Lp.)
rat
dog
monkey
Hexobarbhal sleep time

Diphenyl phenobarbital Examples 2 4th 5 6th hydantoin 1 500 > 500 > 500 225 325 470 <25 <100 <25 <25 8.4 12th 133 20th -263 27 -34.8 2 after about 4 hJüi. ~ 8 Activity decline - -sahiue sm £ 0 after δη 03 13th 13th 2h 22nd 47 Exception for the lethal dose present missing with

present absent, with the exception of the lethal dose

present absent at 200 & 400 mg / kg

present absent at dosages up to 3200 mg / kg

extended not extended with the exception of 5x d

EDsd versus MES

Comparison of pharmacological properties (continued)

Examples 9 12 13th 14th 15th 2.0 16 8th 640 <500 570 500 Acute toxicity LDso (per oral) > 500 28 <12.5 16.5 <25 <25 Antispasmodic activity -50 (Pentetrazole) EDso (orally) MES -22.8 -40 -34.5 Therapeutic index (LD50 / ED50) length of time 1.5 1.0 3.0 1.0 Time of peak activity 2h 140 76 MES Neurological failures (TDso) (p.o.) Except for the lethal dose Hypnotic activity missing, with Mouse (p.o. & i.p.) Except for the lethal dose rat missing, with 200 & 400 mg / kg dog is absent from Dosages up to 3200 mg / kg monkey is absent from with the exception of 5x the ED50 eesen Hexobarbital sleep time not ver

example 1
(Tablets)

Hydrous lactose (8.25 kg), potato starch (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) was sifted into the ball through a sieve of 0.84 mm mesh 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 grinder using a 1.90 cm sieve. This was followed by drying in a fluid bed dryer until the moisture content of the granules was between 1 and 2. The dry grains were sieved through a sieve with a mesh size of 0.84 µm. 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 ingredients were then placed in a mixer 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)

Hydrous lactose (2310.0 g) and magnesia sulfite (30.0 g) was checked through a sight with a clear Mesh size of 0.250 mm sieved "njn" -BiMmethoxymethyl) -phenolbarbital (180.0 g) was passed through a sieve with a mesh size of 034 mm sifted The above ingredients were mixed for about 30 minutes in a 1.9 liter ball mill, Now sieved through a sieve with a mesh size of 0.250 and filled into No. 1 gelatin capsules, for which a hand-operated capsule filling machine was used. Each capsule contained 30 mg of N, N'-bis (inethoxymethyl) phenobarbital, 385.0 mg orphan lactose and 5.0 mg magnesium stearate.

Example 3
(60 mg capsules)

The procedure of Example 2 was repeated with the exception that N, N'-bis (methoxymethyl) phenobarbital (360.0 g), water-containing lactose (2010.0 g) and magnesium stearate (30, 0 g) were used. Each capsule contained 60.0 mg of N, N'-bis (methoxymethyl) phenobarbital, 335.0 mg of hydrous lactose and 5.0 mg of magnesium stearate.

B e i s ρ i e I 4

(120 mg capsules)

Following the procedure of Example 2, capsules containing 120.0 mg of N, N'-bis (methoxyme-

thyl) phenobarbital, 275.0 mg of hydrous lactose and 5.0 mg of magnesium stearate , with the exception that an approach was used that contained 720.0 g of the barbital compound, 1650.0 g of hydrous lactose and 30, Contained 0 g of magnesium stearate

Example 5
(Intravenous solution)

100 mg N, N'-bis {methoxymethyl) -phenobarbital were dissolved in 10 ml Polyäthyienglycol with heating at 40 ⁰ C. The solution was allowed to cool to room temperature and then sterilized to give a solution was obtained that intravenous for Administration was appropriate.

Example 6

10 kg of a 10 percent aqueous gum acacia solution was put into the ball of a mixer. Then 1.0 kg of NJJ'-dimethoxymethylphenobarbital was sieved into the ball through a sieve with a mesh size of 034 mm. whereby a suspension suitable for oral administration was obtained. 1 ml of this suspension is a suitable dosage, although larger or smaller doses can be used.

60

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Claims (1)

Patent address: The invention therefore relates to antiepileptics (or anticonvulsants), which are characterized in that they are a compound of the general formula 1. Antiepileptic drugs (or anticonvulsants), characterized in that they are a compound the general formula