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

The invention relates to a process for the preparation of novel barbituric and hydantoin derivatives which are useful as anticonvulsants for the treatment of convulsions and epileptic seizures in warm-blooded animals.

5-ethyl-5-phenylbarbituric acid and diphenylhydantoin have long been known to be useful as anticonvulsants in warm-blooded animals. For example, they have been used in the treatment of epilepsy. However, 5-ethyl-5-phenylbarbituric acid not only has anticonvulsant activity but also has the disadvantage of exhibiting hypnotic activity, while not hypnotic, diphenylhydantoin has the disadvantage of giving rise to a number of undesirable side effects, such as hypotension , B. Hypertrophic gingivitis, megaloblastic anemia, toxic psychoses and hirsutism It has now been found that certain N-lower alkoxymethyl, benzyloxymethyl and acyloxymethyl-5-ethyl-5-phenylbarbituric acids, 5,5-diethylbarbituric acids and diphenylhydantoin compounds are effective anticonvulsants are those that have unexpected properties from the pharmacological point of view to the corresponding parent compounds.

It was reported in Doran, Medicinal Chemistry, New York, 1959, Bd.IV., John Wiley & Sons, Inc., S, 187 (War Department, Army Medical Library, Microfilm No. 1720, IG Farbenindustrie Plant, Elberfeld, Germany). reports that a material whose structural formula was N, N'-dimethoxymethyl-5-ethyl-5-phenylbarbituric acid was tested as a hypnotic but found to be ineffective. However, there are no indications of any useful therapeutic effect there. Also, no information was given about the production and the properties.

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

Y

<img file="AT309462B_D0001.tif" />

OY »where Z&gt; CO or a direct single bond between the adjacent carbon and nitrogen atoms; X and X * are both phenyl groups when Z is a direct bond or X and X * are both ethyl groups or X is an ethyl group and X * is a phenyl group when Z is&gt; CO; and Y and Y * both represent alkoxymethyl groups of 1 to 12 carbon atoms in the alkoxy moiety, benzyloxymethyl groups or acyloxymethyl groups, or Y also represent hydrogen when Z is a direct bond.

The inventive method is characterized in that the corresponding barbituric acid or the corresponding diphenylhydantoin or their alkali metal salts alkoxymethylated by reaction with a halomethyl-alkyl ether or halomethyl-benzyl ether or benzyloxymethyliert and that, if a compound (I) is to be prepared in the Y and / or Y * represent an acyloxymethyl group which reacts the compound obtained with a carboxylic anhydride.

Examples of compounds which can be prepared according to the invention are: N, N'-dialkoxymethyl-5-ethyl-5-phenylbarbituric acid, N, N * -dibenzyloxymethyl-5-ethyl-5-phenylbarbituric acid, 3-alkoxymethyldiphenylhydantoin and N, N'-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: N, N-dimethoxymethyl-5-ethyl-5-phenylbarbituric acid and 3-methoxymethyldiphenylhydantoin are particularly preferred.

Further examples of compounds which can be prepared according to the invention are N, N * -diacyloxymethyl-5-ethyl-5-phenylbarbituric acid, N, N * -diacyloxymethyl-5,5-diethylbarbituric acid, 3-acyloxymethyldiphenylhydantoin and N, N * -diacyloxymethyldiphenylhydantoin. 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 Y and / or Y * are alkoxymethyl or benzyloxymethyl are prepared by alkoxymethylation or benzyloxymethylation of 5-ethyl-5-phenylbarbituric acid or of diphenylhydantoin or the corresponding alkali metal salts, in particular the sodium salts, by reaction with a halomethylalkyl ether or benzyl ether, for example a chloromethylalkyl or benzyl ether in a suitable diluent, such as, for example, B, Produced dimethylformamide. In this case, a temperature can be used within a wide temperature range, u. zw, from below 0 ° c to the boiling point of the diluent.

No. 309462

The compounds in which Y and / or Y * is acyloxymethyl can be prepared by alkoxymethylation or benzyloxymethylation of 5,5-diethylbarbituric acid or 5-ethyl-5-phenylbarbituric acid or diphenylhydantoin or the corresponding alkali metal salts, in particular the sodium salts, as described above, and subsequent reaction with the corresponding carboxylic anhydride, preferably in the presence of a base or a catalyst, such as, for example, tin (IV) chloride.

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 were determined in the usual way. The results were called LD₅₎₎ expressed. That's the dose required to kill 50% of the animals. The determination was made graphically, the 95% limit values ​​are given in brackets.

The doses required to produce a neurological deficit were determined by the method of Swinyard et al, J. Pharmacol. Exptl, Therap. 106, [1952] 319, but using an additional test. 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_G() expressed, that is the dose required to achieve the effect. The determination was made graphically. The 95% limits are also attached.

The time of maximum anticonvulsant activity was determined by administering doses of various sizes to a group of animals and then subjecting the animals to a maximum of electroshock at specific time intervals by applying a current of 60 mA through a comea 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 injected subcutaneously against the maximal electroshock as described above, against a convulsant dose of metrazole (106, 25 mg Ag), and against a lethal dose of strychnine sulfate (1.5 mg Ag) In the case of maximum electric shock, the criterion for effectiveness was the absence of the tonic extensor 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), has not been elicited with any dosage of any of the compounds of the present invention at less than one lethal dose. On the other hand, 5-ethyl-5-phenylbarbituric acid itself 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: hx 1000 ml flask equipped with a stirrer and condenser was suspended 136.4 g (0.356 mol) of sodium salt of 5-ethyl-5-phenylbarbituric acid in 500 ml of dimethylformamide. The flask was placed in an ice bath. To the cold suspension, 100 g (1.25 mol) of chloromethyl methyl ether were added over a period of 1 h. The resulting suspension was stirred for 20 h at room temperature and then poured into 2000 ml of ice-water. The resulting suspension was stirred for a further 2 h. The crude product was separated by filtration, washed three times with 100 ml of distilled water and then dissolved in about 500 ml of hot ethanol. 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 a finely divided diatomic silica.

The cake was washed three times in 25 ml of ethanol, and the hot solution was taken together with the

Allow washing liquids to cool to room temperature. The resulting crystals were filtered, with

Ethanol and dried in a vacuum desiccator. In this way, 58 g of N, N'-dimethoxymethyl-5-ethyl-5-phenylbarbituric acid having a melting point of 115 to 117 ° C were obtained.

A pharmacological test of this compound gave the following results:

No, 309462

acute toxicity

LD₅₀ (orally)

LD_g0 (Ihtraperitoneal) Neurological Deficit TD

Spasmolytic effect

Maximum electric shock, ED_ "00

Metrazole, ED_g0

Strychnine, ED_g0

Time of maximum effect

<td colspan="2">Dosage mgAg</td>

<td>470 490</td><td>(376 - 588) (408 - 588)</td>

<td>47</td><td>(33 - 66)</td>

<td colspan="2">13, 5 (8 - 23) 47 (29 - 75) 200 (125 - 320) 2h</td>

Repeated daily administration to the same animals for four days showed no appreciable change in ED₅₀Value for protection against maximum shock. The duration of the anticonvulsant peak effect was compared to that of the sodium salt of 5-ethyl-5-phenylbarbituric acid at a dose of 0.1 millimoles / kg each. The compound of the invention gave protection only after 2 hours, but the protection remained at about the same level for more than 8 hours, 5-ethyl-5-phenylbarbituric acid gave protection in less than 0.5 hours, but protection started after 4 hours sink 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 El ^_QValue was found to be 6, 6 (4.2 to 10.4).

Example 2: 27.5 g (0.1 mol) of 5,5-diphenylhydantoin sodium were suspended in 250 ml of dimethylformamide. To the suspension was added over a period of 30 minutes 8.8 g (8.25 ml) of chloromethyl methyl ether. The resulting suspension was stirred overnight at room temperature and then poured into 11 ice-water. It fell out a solid material. The suspension was stirred for 1 h, and the solid was then 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. 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 finely divided diatomic silica. The cake was washed three times with 15 ml of ethanol, and the hot ethanol solution was diluted with 100 ml of hot water along with the washings, then allowed to cool to room temperature. The crystals which appeared were filtered and washed on the filter three times with 25 ml of 50% aqueous ethanol and then dried in a vacuum desiccator. In this way, 20 g of 3-methoxymethyl-5, 5-diphenylhydantoin having a mp of 127 to 128 ° C were obtained (yield 67%). Pharmacological testing of this compound showed that they had an LD_goValue of approximately 500 mg / kg. She showed an antispasmodic effect (maximal electroshock) within less than 0, 5 h after the administration. The effect lasted more than 2 h. The ED_5flValue was less than 25 mgAg.

Example 3: 25 g of powdered sodium salt of 5-ethyl-5-phenylbarbituric acid were suspended in 250 ml of dimethylformamide. With vigorous stirring, 15.6 g of chloromethyl-benzyl ether were added to the suspension at room temperature. The reaction mixture was stirred at room temperature overnight. The suspension was then poured into 500 g of ice-cold water, the mixture was stirred for 1 h, and the solid was separated by filtration. The crude product was dissolved in approximately 150 ml of boiling ethanol. To the boiling solution, 0.5 g of charcoal was added and the boiling solution was filtered through a Buchner funnel containing a densified 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 washings. The resulting crystals were filtered off and recrystallized from 100 ml of ethanol in the same manner as described for the first crystallization. In this way, 5.27 g of N, N'-dibenzyloxymethyl-5-ethyl-5-phenylbarbituric acid having a mp of 74 to 75 ° C were obtained.

Example 4: 25 g of powdered sodium salt of 5-ethyl-5-phenylbarbituisäuie 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 overnight at room temperature. The reaction mixture was then poured into 1 kg of ice-cold water, the mixture was stirred for 1 h, and the solid was separated by filtration. The crude product was dissolved in 100 ml of hot ethanol, 1 g of charcoal was added, and the boiling 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 twice more from 100 ml of ethanol in the same manner as described for ice crystallization. In this way, 12.3 g of N, N'-di-n-butoxymethyl-5-ethyl-5-phenylbarbituric acid having a mp of 71 to 72 ° C was obtained. When the compound was tested as above, it showed an anticonvulsant effect against maximal electroshock, with the ED_{5 (J}Value was less than 100 mgAg and the LD_{5 ()}Value (orally) was more than 500 mg / kg.

Example 5: 25 g of sodium salt of the 5-ethyl-5-phenylbarbituric acid were added at 20 ° C in 250 ml of dimethyl 5

No. 309462 formamide dissolved. The solution was cooled to 60 ° C and at this temperature 25 g of chloromethyl ethyl ether were added with good stirring. The reaction mixture was allowed to cool to room temperature and stirred for 20 h, then poured into 500 g of ice-water, stirred for 1 h, and the product was separated by filtration. The solid material was dissolved in 150 ml of boiling ethanol, 1 g of charcoal added, and the boiling solution 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. To the hot solution and to the washings, 50 ml of hot water was added and the solution was allowed to cool to room temperature. The resulting crystals were filtered off and recrystallized a further two times in the same manner as described for the first crystallization. In this way, 6.5 g of N, N * -di10-ethoxymethyl-5-ethyl-5-phenylbarbituric acid having a melting point of 65 ° C. were obtained. When tested as above, the compound exhibited anticonvulsant activity against maximal electroshock, with maximum activity time of 11/2 h and ED₅ θ value was less than 25 mg / kg.

Example 6: 27.5 g of 5,5-diphenylhydantoine sodium were suspended at 100 ° C. in 250 ml of dimethylformamide. The suspension was cooled to 50 ° C with good stirring. At this temperature, 16 g of 15-chloromethyl-n-butyl ether were added and the suspension was stirred for 3 hours while the temperature was rising

20 ° C was dropped. The reaction mixture was then poured into ice-cold water and stirred for 1 h. The resulting solid product 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 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 a further two times in the same manner as described for the first crystallization. In this way 8.9 g of 3-n-butoxymethyl-5, 5-diphenylhydantoin were obtained with a melting point of 108 to 110 ° C. In a test as described above, the compound showed an anticonvulsant effect against maximal electroshock, with the ΕΕ ^ θ value being less than 25 mg / kg. The LD_g0Value (oral) was also determined and found to be greater than 500 mg / kg.

Example 7: 27.5 g of 5,5-diphenylhydantoin sodium were suspended in 250 ml of dimethylformamide. To the suspension was added 15 ml of chloromethylbenzyl ether with thorough stirring, and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into ice-cold water and stirred for 30 h. The solid product was separated by filtration and dissolved in 150 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 a further two times in the same manner as described for the first crystallization

13.1 g of 3-benzyloxymethyl-5,5-diphenylhydantoin having a melting point of 151 to 152 ° C.,

Example 8: 25.4 g of powdered sodium salt of 5-ethyl-5-phenylbarbituric acid was suspended at room temperature in 250 ml of dimethylformamide, and 22.1 g of chloromethyldodecanyl ether was added to the suspension. The reaction mixture was stirred overnight and poured into 11 ice-water. The mixture 40 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. To the hot solution was added 1 g of activated charcoal and the boiling solution was filtered through a Buchner funnel containing a densified layer of finely divided diatomic silica. The filter cake was washed three times with 15 ml of ethanol and the hot solution was allowed to cool together with the washings overnight. The resulting crystals were filtered off and recrystallized a second time in the same manner as described for the first crystallization. In this way, 13 g of N, N -dilauryloxymethyl-5-ethyl-5-phenylbarbituric acid having a mp of 48 to 50 ° C were obtained. When tested as above, the compound exhibited anticonvulsant activity against maximal electroshock, with maximum activity lasting 2 hours and ED_G()Value was about 50 mg / kg. The LD_gQValue (oral) was determined to be more than 500 mg / kg.

Example 9s 2.0 g of N, N-dimethoxymethyl-5-ethyl-5-phenylbarbituric acid obtained according to Example 1 were suspended in 5 ml of acetic anhydride. Two drops of stannic 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. 2.0 g (85% yield) of N, N'-diacetoxymethyl-5-ethyl-5-phenylbarbituric acid, m.p.

148 ° C, received.

Example 10: 6 g of 3-methoxymethyl-5,5-diphenylhydantoin obtained in 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, precipitating a solid material. 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

No. 309462 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-diphenylhydantoin having a melting point of 162 to 163 ° C.

The pharmacological examination showed that the compound was an LD₅₀Value of slightly less than 500 mg / kg. It did not give an anticonvulsant effect against metrazol, but against maximal electroshock it showed maximal activity about 1 h after the administration of ED_5QValue was less than 12.5 mgAg.

Example 11: By the general method of Example 1 but using sodium 5,5-diethylbarbiturate as the starting material in place of sodium 5-ethyl-5-phenylbarbituric acid, an oily product was obtained which was purified by chromatography. The product was identified as N, N-dimethoxymethyl-5,5-diethylbarbituic acid. Their analysis was as follows: calculated values ​​for carbon 52.93%, hydrogen 7.40%, nitrogen 10.29%. Values ​​found: Carbon 53, 07%, Hydrogen 7.51%, Nitrogen 10.35%. Pharmacological testing of the compound showed that it had an antispasmodic effect against metrazol, the EE value being 7 mgAg. The time of maximum effect occurred approximately 1 h after the administration.