Novel phenobarbitals,barbitals and hydantoins,their preparation and pharmaceutical compositions containing them

The invention relates to a process for the preparation of new barbital and hydantoin compounds, which are suitable as anticonvulsants for the treatment of convulsions and epileptic seizures in Warmblü factors.

Phenobarbital and diphenylhydantoin have long been known to be useful as anticonvulsants in 5 warm-blooded animals. For example, they have been used in the treatment of epilepsy. However, phenobarbital not only has an anticonvulsant activity but also has the disadvantage of exhibiting hypnotic activity. Although not hypnotic, dipheiylhydantoin has the disadvantage that it gives rise to a number of undesirable side effects, such as Hypertrophic gingivitis, megaloblastic anemia, toxic psychosis and hirsutism. It has now been found that certain N-lower alkoxymexyl, benzyloxymetbyl and acyloxymethyl phenobarbital compounds. barbaric compounds and diphenyl diantoin compounds are effective anticonvulsant agents which, from the pharmacological point of view, have unexpected properties over the corresponding parent compounds.

It has been reported in Doran, Medicinal Chemisty, New York, Vol. IV [1959], John Wiley & Sons, Inc., p. 187 (War Department Army Medical Library, Microfilm No. 1720,1.G. Farbenindustrie Plant, Elberfeld, Germany ) 15 states that a material whose structural formula was N, N'-dimethoxymethylphenobarbital was tested as a hypnotic but found to be ineffective. There are no indications of any useful therapeutic effect. Also, no information was given about the manufacture and properties.

The compounds which can be prepared according to the invention have the general formula

Y

ZN

<img file="AT303755B_D0001.tif" />

GN

OY * wherein Z&gt; CO or a part of a simple bond between the adjacent carbon and nitrogen atoms; X and X 'are both phenyl radicals when Z is part of a direct bond, or X and X' are both ethyl radicals or X is an ethyl radical and X is¹ represents a phenyl radical when Z&gt; CO; and X and X 'are both alkoxymettyl radicals having from 1 to 12 carbon atoms in the alkoxy 25 part, benzyloxymethyl radicals or carboxylic acid acyloxymethyl radicals, where Y is also hydrogen and X¹ may represent an alkoxy methyl, benzyloxymethyl or carboxylic acyloxymethyl radical when Z forms part of a simple bond.

Examples of compounds which can be prepared according to the invention are: N, N'-dialkoxymethylphenobarbital, N, N'-dibenzyloxymethylphenobarbital 3-alkoxymethyldiphenyuanantoin and N, Ν'-dialkoxymethyldiphenylamine where 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;

N, Ν'-dimethoxymethylphenobarbital and 3-methoxymethyldiphenylhydantoin are particularly preferred.

Further examples of compounds which can be prepared according to the invention are N, N'-diacyloxymethylphenobarbital, N, N'-diacyloxymethylbarbital, 3-acyloxymethyldiphenylhydantoin and N, N'-diacyloxymethyldiphenyl-35-hydantoin. Examples of the above acyloxy groups are acetoxy, acryloyloxy, methacryloyloxy, propionoxy and benzoyloxy. The compounds in which the acyloxy groups are acetoxy groups are preferred;

N, N'-diacetoxymethylphenobarbital and 3-acetoxymethyldiphenylhydantoin are particularly preferred.

The compounds of the formula (I) in which at least Y 'is alkoxymethyl or benzyloxymethyl are prepared according to the invention by alkoxymethylation or benzyloxymethylation of phenobarbital or of diphenylhydantoin or the corresponding alkali metal salts, in particular the sodium salts, wherein the alkoxy methylation or benzyloxymethylation is then carried out by reaction with aqueous formaldehyde under basic conditions followed by reaction with the corresponding alkanol or benzyl alcohol under acidic conditions or by co-reaction with formaldehyde (or paraformaldehyde) and the corresponding alkanol or benzyl alcohol under acidic conditions.

The compounds in which at least Y 'is acyloxy methyl can be prepared by hydroxy methylation or

Alkoxymethylation or Benzyloxymethylierung of barbital or phenobarbital 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

No. 303755

- 3, for example, tin (IV) chloride, are produced. The hydroxymethylation can be carried out by reaction with formaldehyde (or paraformaldehyde) under acidic conditions or with aqueous formaldehyde under basic conditions. The alkoxymethylation or benzyloxymethylation can be carried out as above.

The compounds of this invention can be mixed with the conventional physiologically acceptable carriers to produce syrups, isotonic solutions, tablets or other forms of administration. The toxicity and effectiveness of the compounds are such that each administration unit can contain from 10 to 500 mg of active material.

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

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

Acute oral toxicity and acute intraperitoneal toxicity are determined in the usual way. The results were called LD₅₀ expressed. That's the dose required to kill 50% of the animals. The determination was made graphically. The 95% allowances are given in parenthesis.

The doses required to produce a neurological deficit were determined by the method of Swinyard et al., J. Pharmacol. Exptl. Therap. 106 [1952], p.319, but an additional test was used. The ability of the animals to remain on a rotostab for at least 1 min, a horizontal bar rotating at 6 rpm, was also examined. The results were called TD_g0expressed, that is the dose required to achieve the effect. The determination was made graphically.

The 95% limits are also included.

The time of maximum anticonvulsant activity was determined by administering doses of various goblets to a group of animals and then subjecting the animals to a maximum of electroshock at certain intervals by supplying a current of 60 mA through a corneal electrode for 0.2 sec , Protection was provided if the animal did not show the tonic extensor component of the maximum electrosurgical seizure scheme in unprotected animals. The maximum effect time thus determined was used for all subsequent tests for anticonvulsant activity of the same active agent.

The anticonvulsant activity of each agent was challenged against the maximum electroshock administered as described above, against a convulsant dose of metrazol (106.25 mg / kg) injected subcutaneously, and against a lethal dose of strychnine sulfate (1.5 mg / kg). which was injected subcutaneously. In the case of maximum electric shock, the criterion for effectiveness was the absence of the tonic component of the seizure scheme. In the case of metrazol, the criterion for efficacy was the absence of a clonic seizure. In the case of strychnine sulfate, the criterion for efficacy was if the

Animals did not die, although seizures occurred.

Hypnotic activity or depression of the central nervous system, as indicated by loss of the righting reflex (onset of sleep), was not elicited with any dosage of any of the compounds of the invention at less than a lethal dose. Phenobarbital itself, on the other hand, showed hypnotic activity when the above criterion was used.

The invention will be explained in more detail with reference to the following examples.

Example 1: 23 g of phenobarbital were dissolved in a mixture of 20 ml of dioxane and 100 ml of 33% aqueous formaldehyde. The solution was treated with 5 g of triethylamine and then heated at reflux for 16 h. The mixture was cooled, treated with 200 ml of water and extracted with ethyl acetate. The ethyl acetate solution was dried and the ethyl acetate was evaporated under reduced pressure. The residual oil was added with 20 ml of methanol, 200 ml of benzene and 2 ml of concentrated hydrochloric acid; the mixture was refluxed with vigorous stirring for 20 hours. Thereafter, the formed reaction water was removed by azeotropic distillation. To complete the reaction, methanol (50 ml) 50 was added slowly to the reaction mixture. The azeotropic distillation was continued for 20 h. At the end of this period, a crystalline solid separated which was filtered off and recrystallized to give N, N-dimethoxymethylphenobarbital, m.p., 119-120 ° C.

A pharmacological test of this compound eigab the following results.

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<td>acute toxicity</td><td>Dosage mg / kg</td>

<td>LD₅0 C^orally)</td><td>470 (376 - 588)</td>

<td>LD_S"(Intraperitoneally)</td><td>490 (408 - 588)</td>

<td>Neurological deficit td₅₀</td><td>47 (33 - 66)</td>

<td>Spasmolytic effect</td><td>13.5 (8 - 23)</td>

<td>Maximum electroshock, ED₅₀</td><td></td>

<td>Metrazole, ED₅"</td><td>47 (29 - 75)</td>

<td>Strychnine, ED₅"</td><td>200 (125 - 320)</td>

<td>Time of maximum effect</td><td>2h</td>

<td>A repeated daily administration</td><td>to the same animals during 4 days showed no noticeable</td>

Change of the ED₅Value for protection against maximum electric shock. The duration of anticonvulsant activity against maximal electroshock was compared to that of phenobarbital sodium at a dose of 0.1 mmol / kg each. The compound according to the invention gave a protection only after 15 2 h, but the protection remained more than 8 h at about the same height. Phenobarbital gave protection in less than 0.5 hours, but protection began to decline after 4 hours and was practically over after 8 hours. The anticonvulsant activity of the compound against maximal electroshock was also measured in the rat (Sprague Dawley strain). The ED₅₀Value was found to be 6.6 (4.2 to 10.4).

Example 2s 23 g of phenobarbital and 9 g of paraformaldehyde (trioxymethylene) were dissolved in a mixture of 22 g of benzyl alcohol, 1 g of p-toluenesulfonic acid and 200 ml of toluene. The reaction mixture was refluxed with vigorous stirring for 24 hours, using a Dean-Stark distillation column to remove the water formed during the course of the reaction. At the end of this period, a solid had precipitated which upon recrystallization from ethanol gave N, N'-dibenzyloxymethylphenobarbital, m.p.74-75 ° C.

Example 3: 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% aqueous formaldehyde solution. To this solution was added 1 ml of 38% hydrochloric acid and the solution was heated at reflux 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, over

Dried sodium sulfate and then evaporated to dryness. To the oily residue was added 12.5 ml of acetic anhydride and 12.5 ml of pyridine, and the solution was allowed to stand at room temperature overnight. The solution was poured into 500 ml of cold 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, was filtered off and washed with water and then dissolved by heating in 100 ml of ethanol. To the hot solution was added 1 g of activated carbon, and the boiling solution was filtered through a Buchner funnel containing a 1 cm thick layer of finely divided diatomaceous silica. The cake was washed three times with 15 ml of ethanol and then the hot solution was allowed to cool to room temperature along with the washings. The resulting 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 mp was 136 to 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 resulting solid was crystallized from 100 ml of ethanol to give 8.9 g of N, N'-diacetoxymethylphenobarbital (47% overall yield) of m.p. was obtained from 146 to 148 ° C.

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

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<td>acute toxicity</td><td>Dosage mg / kg</td>

<td>LD_S0 (orally)</td><td>640 (474 ​​- 864)</td>

<td>LD_S0 (Intraperitoneal)</td><td>550 (437-673)</td>

<td>Neurological deficit</td><td></td>

<td>5 TD₅₀</td><td>140 (110 - 178)</td>

<td>Spasmolytic effect</td><td></td>

<td>Maximum electroshock, ED_5fl</td><td>28 (22 - 35)</td>

<td>Metrazole, ED₅₀</td><td>104 (80-135)</td>

<td>Strychnine, ED₅₀</td><td>120 (90 - 160)</td>

<td>10 time of maximum activity</td><td>1.5 h.</td>

Example 4: In a 500 ml flask equipped with stirrer and condenser, 11.5 g (0.05 mol) of phenobarbital were dissolved in a mixture of 20 ml of dioxane and 100 ml of 37% aqueous formaldehyde solution. To this solution was added 20 mg of sodium carbonate and the remainder of the process was carried out in exactly the same manner by heating to reflux and so on. There were obtained 6.5 g of the same product as in Example 3 (34% yield) with a mp of 146 to 148 ° C.

Example 5: 2, 0 g of N, N'-dimethoxymethylphenobarbital.das obtained according to Example 1 were suspended in 5 ml of acetic anhydride. Two drops of tin (TV) chloride were added to this suspension. The suspension was stirred for 20 h and then poured into 20 ml of cold water. The mixture was stirred for 3 h and the solid was separated by filtration. The solid was crystallized from ethanol. There were obtained 2, 0 g (85% yield) of the same product as in Example 3 and 4.

Example 6: 6 g of 3-methoxy-methyl-1-5,5-diphenyhydrate obtained by the process according to the invention were suspended in 20 ml of acetic anhydride. Four drops of stannic 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 to decompose the excess acetic anhydride. Then, the solid product was separated by filtration and washed three times on the filter 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 obtained crystals were separated by filtration. There were obtained 6 g of product. The crude product was recrystallized from 60 ml of 80% aqueous ethanol to give 4.7 g of a slightly impure product having a mp of 157-158 ° C. This impure product was further purified by recrystallization from ethanol to give 2.6 g of pure 3-acetoxymethyl-5,5-diphenylhydrogen of melting point 162.degree.-163.degree.

The pharmacological test showed that the compound has a LDg ,, value of slightly less than

500 mg / kg. It did not give an anticonvulsant effect against metrazol, but against maximum electroshock it showed maximum activity about 1 h after administration; the ED_SoValue was less than 12.5 mg / kg.

Example 7: 25.2 g (0.1 mol) of 5,5-diphenylhydantoin were dissolved in a mixture of 25 ml of dioxane and 40 ml of water. To the solution was added 44 ml of a 37% aqueous formaldehyde solution, 5 ml of triethanolamine, and the solution was heated at reflux 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 to allow it to stand overnight at room temperature and then poured into ice-water containing 25 ml of concentrated hydrochloric acid. It fell out a solid material. 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 (about 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 silica. 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. There were obtained 21.2 g of N, Ν'-diacetoxymethyldiphenylhydantoin having a melting point of 150 to 151 cerium (yield 53.5%).

A pharmacological examination of this compound showed the following results:

acute toxicity

LD_S0 (orally)

Neurological deficit td₅₀

Antispasmodic effect Maximum electroshock, ED₅₀Time of maximum effect

Dosage, mg / kg 570 (259 - 1254) (41 - 140)

16.5 (12 - 22) h

Example 8: 11.5 g of phenobarbital were dissolved in 20 ml of dioxane. To the solution, 100 ml of a 37% aqueous solution of formaldehyde and 1 ml of concentrated hydrochloric acid were added, and the reaction mixture was refluxed for a period of 20 hours. The mixture 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 evaporated to dryness. To the oily residue was added 16 ml of propionic anhydride and 16 ml of pyridine, and the solution was allowed to stand at room temperature overnight. The solution was then poured into 500 g of ice containing 16 ml of concentrated hydrochloric acid. The mixture was stirred for 4 hours, after which the oily product was separated by filtration and dissolved in 100 ml of hot ethanol. To the boiling solution was added 1 g of activated charcoal and the hot solution was filtered through a Buchner funnel containing a densified layer of finely divided diatomic 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 washings. The resulting crystals were filtered off and recrystallized in the same manner as described for the first crystallization. In this way, 4 g of N, N'-dipropionoxymethylphenobarbital having a melting point of 93.5 to 94.5 ° C were obtained. When tested as described above, this compound showed an ED_5oValue against maximum electroshock of less than 25 mg / kg and one LD_S0 Value (orally) of about 500 mg / kg.

Example 9: 18.4 g of 5,5-diethyl barbituric acid (barbital) were dissolved in 20 ml of dioxane. To the solution was added 100 ml of a 37% aqueous formaldehyde solution and 1 ml of 38% hydrochloric acid, 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. The ethyl acetate solutions were combined and washed with water, dried over sodium sulfate and then evaporated to dryness. To the oily residue was added 20 ml of acetic anhydride and 20 ml of pyridine, and the solution was allowed to stand at room temperature overnight. The solution was then poured into 500 ml of cold water containing 20 ml of 38% hydrochloric acid, 35, and the mixture was stirred for 3 hours, after which 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 evaporated to remove the methylene chloride. From the oily residue, the product was isolated by column chromatography using silica gel (grade 950). Elution with a benzene / ethyl acetate mixture (9: 1 by volume) gave a semi-crystalline product which was crystallized first as hexane 40 and then as pentane. In this way, pure N, N'-diacetoxy methyl barbital having a melting point of 64 to 65 ° C was obtained. When tested as above, the compound showed an EDI value against maximum electroshock of less than 25 mg / kg, with maximum activity occurring approximately 2 hours after administration. The hypnotic activity was very weak; the ED_{5 ()}Value was 260 to

300 mg / kg.