Phenobarbitals,barbitals and hydantoins,their preparation and pharmaceutical compositions containing them

Thia invention relates to new chemical compounds and to the use of these compounds as anticonvulsant agents for treating convulsions and seizures in warm blooded animals.

Phenobarbital and diphenylhydantoin have both long been known to be useful as anticonvulsant agents in warm blooded animals, having been employed in the treatment of epilepsy; however, phenobarbital suffers from the disadvantage that it exhibits hypnotic activlty as well as anticonvulsant activity, while diphenylhydantoin has the disadvantage that although not hypnotic, it does have a multiplicity of undesirable side effects, for example, hypertrophic gingivitis, megaloblastic anemia, toxic psychoses, and hirsutism. It has now been found that certain N-lower alkoxymethyl, benzyloxymethyl, and acyloxymethyl-phenobarbital, barbital, and diphenylhydantoin compounds are effective anticonvulsants which possess unexpected advantages from the pharmacological standpoint over their respective parent compounds.

Although it has been reported 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, Elberfold, Germany) that a material identified by the struc-2-

' ’ י 32744/2

/ . י tural formula of N,Ν’-dimethoxymethyl phenobarbital has been tested as a hypnotic and found to be without effect, there has been no indication that it has any useful there♦ peutio effect and no suggestion as to'how to make it or what its properties are, 1

The compounds according to the invention may * be designated by the formula; . .

<img file="IL32744A_D0001.tif" />

Y' k in which Z is> CO or part of a single bond between the . ' !

neighboring carbon and nitrogen atoms; X apd X' are both phenyl radicals when Z is part of the direct bond,¹ or X and X' are both ethyl radicals or X is an ethyl radical and X'. is a phenyl radical when Z is χ► CO; and Y and Y.' are both alkoxymethyl of from 1-12 ‘ carbon atoms in the alkoxy portion, benzyloxymethyl, or carboxylic acyloxymethyl, or Y can also be hydrogen and Y’ cart be alkoxymethyl, benz^loxymethyl, or carboxylic acyloxymethyl when Z is part of the single bond,with the proviso that Y and Y’ are not both methoxymethyl when Z is >C0, X is an ethyl radical and X' is a phenyl group.

The compounds of the present invention include N,N'dialkoxymethyl phenobarbital, N,N'-dibenzyloxymethyl phenobarbital,

3-alkoxymethyl diphenylhydantoin, and N,Ν'-dialkoxymethyl diphenylhydantoin in which the alkoxy groups contain from 1 to 12 carbonatoms, such as methoxy, ethoxy, propoxy, butoxy, and lauryloxy* The compounds in which the alkoxy groups are methoxy or ethoxy are preferred; N,Ν'-dimethoxymethyl phenobarbital(when produced by the process of the invention), and

3-methoxymethyl diphenylhydantoin are particularly preferred. . '

The compounds of the invention also include N,N׳'I ' di(carboxylic acyloxy)methyl phenobarbital, N,N'-di(oarboxylic acyloxy)methyl barbital, ?-(carboxylic acyloxy)methyl diphenylhydantoin, and N,Ν'-di(carboxylic acyloxy)methyl diphenylhydantoin. . The above carboxylic acyloxy groups include acetoxy, acryloyloxy, methacryloyloxy, propionoxy, and benzoyloxy. The compounds in which the carboxylic acyloxy groups are acetoxy are preferred; N,N'-di- ',. acetoxymethyl phenobarbital, and ?-acetoxymethyl diphenylhydantoin ' are particularly preferred.

The compounds wherein at least Y’ is alkoxymethyl ' methyl .' I or benzyloxy/may be made by alkoxy-methylation or benzyloxymethylation of phenobarbital or of diphenylhy-!

ί . .j dantoln or of their respective alkali metal salts, par-ף tioularly the sodium salts. The alkoxy^nethylatlon or} benzyloxymethylation may be carried out by reacting| with aqueous formaldehyde under basic conditions followed ! by reaction with the appropriate alkanol or benzyl al- ' •1 oohol under acidic conditions; or it may.be carried out by reacting simultaneously with both formaldehyde (or ן paraformaldehyde) and the appropriate alkanol or benzyl . | alcohol under acidic conditions; or it may be carried!

out by reacting with a halomethyl-alkyl or -benzyl ether, e.g. a chloromethyl alkyl or benzyl ether, inן a suitable diluent, e.g. dimethyl formamide, over a| wide range of temperatures, conveniently from below 0°0&lt;1 up to the boiling point of the diluent.ן

The compounds wherein at least Y' is carboxylic aqyloxy may be made by hydroxy-methylation or alkoxymethylationI or benzyloxymethylation of barbital or phenobarbital or diphenylhydantoin or their respective alkali metal salts, particularly the sodium salts, followed by reaction with the appropriate carboxylic acid anhydride, preferably in the presence of a base or of a catalyst, e.g. stannic chloride. The hydroxymethylation may be carried out by reacting with formaldehyde (or paraformaldehyde) under acidic conditions or with aqueous formaldehyde under basic conditions. The alkoxymethylation or benzyloxy-methylation may be carried out as above.

The compounds of the invention may be formulated with conventional physiologically acceptable vehicles and carriers to make syrups, isotonic solutions, tablets, and other dosage forms. Toxicity and effectiveness of the compounds are such that each dosage unit may contain from 10 to £00 mg. of active material.

The procedures employed for demonstrating efficacy of the compounds as set forth in the following examples were as follows.

All tests, with the exceptions noted, were conducted on adult albino male mice (Charles River strain); the dosage consisted of the active agent suspended in 10% aqueous acacia and was administered orally unless otherwise indicated.

Acute oral toxicity and acute intraperitoneal toxicity were determined in the conventional manner. The results were expressed as LD^q, the dose required to produce death in 50% of the animals treated, determined graphically, with the 95% limits shown in paren-

־5־ theses

The dosage required to produce a neurological deficit was determined by the method of Swinyard et al., J. Pharmacol» Exptl» Therap1952) 319 ,106 ־) except that one additional test was employed: the ability of the animal to remain for at least one minute on a roto rod, a horizontal rod rotated at 6 r.p.m. The results were expressed as the dose required to produce the effect, determined graphically, with 95% limits.

The time of peak anticonvulsant activity was determined by administering dosages of various sizes to a group of animals and administering a maximal electroshock to the animals at intervals thereafter by supplying 60 ma» current through a corneal electrode for 0»2 15 second» Protection was indicated if the animal failed to show the tonic extensor component of the maximal electroshock seizure pattern in unprotected animals. The time of peak effect thus determined was used for all subsequent tests of anticonvulsant activity on the same ac20 tive agent.

Anticonvulsant effectiveness of each agent was determined against maximal electoshock administered as described above, against a convulsive dose of Metrazol (106.25 mg/kg.) injected subcutaneously, and against a 25 lethal dose of strychnine sulfate (1»5 mg/kg.) injected subcutaneously» In the case of maximal electroshock the criterion for effectiveness was failure to show the tonic extensor component of the seizure pattern; in the case of Metrazol, the failure to show clonic convulsive seizures; and in the case of strychnine sulfate the fail-6ure to die, even though seizures appeared.

Hypnotic activity or depression of the central nervous system as Indicated by loss of the righting reflex (onset of sleep) was not produced by any dosage of any of the compounds of the present invention less than a lethal dose. Phenobarbital itself, on the other hand, did exhibit hypnotic activity using the foregoing criterion.

The following specific examples are intended to illustrate more fully the nature of the present invention without acting as a limitation on its scope.

Example 1

In a 1000 ml flask equipped with a stirrer and condenser, 136.4 g0.536) ־ mole) of phenobarbital sodium powder was suspended in 500 ml of dimethylformamide. The flask was placed in an ice bath. To the cold suspension was added 100 g. (125־ mole) of chloromethyl methyl ether over a period of one hour. The resulting suspension was stirred at room temperature for twenty hours, then poured into 2000 ml of ice water pnd the resuiting suspension was stirred for two hours. The crude product was removed by filtration, and washed three times with 100 ml of distilled water, then dissolved in about 500 ml of hot ethanol. To the boiling solution 1 g״ of activated carbon was added and the boiling solution was filtered through a Buchner funnel which contained a 1 cm־ pressed layer of finely divided diatomaceous silica. The cake was washed three times with 25 ml of ethanbl and the hot solution together with the washings was allowed to cool to room temperature. The resulting crystals were filtered, washed with ethanol, and dried in a vacuum

<img file="IL32744A_D0002.tif" />

desiccator. There was obtained 58 g. of N,N'-dimethoxymethy1 phenobarbital, melting point 115°-117°C. The lattet compound is novel. However, the method,־ of preparation was not disclosed In ,4 .

Doran publication mentioned hereinbefore. ., ׳ '’ . Pharmacological testing of! a. therapeutic composition comprising this compound gave the following results.

<img file="IL32744A_D0003.tif" />

not the ״״“_Aout0 Dosage, mg/kg.

. ld. (oral) ' 470 (376-580) , 5 *־θ ל י ׳ ^! ED. (intraperitoneal) 490 (408-588) ; ׳ .

Neurological Deficit : . ' _TD 47 (33-66)

- i ⁵⁰ * 10 Anticonvulsant Activity

Maximal electroshock, Εϋ^θ 13.5 (θ-23) ׳’ Metrazol, Εϋ^θ ; 47 (29-75) • Strychnine, ED^_Q j ²°0 (125-320)

Time of peak activity 2 hours . !5 Repeated daily dosage of the same animals for

׳ ' . . .1 . .

four days showed no significant change in the EDtjQ to . protect against maximal electroshock. The duration of the anticonvulsant effect against maximal electroshock was compared with that of phenobarbital sodiuA at 8

7 . ׳ 1 ,. ׳ dosage, level of 0.1 millimole/kg. ;of each, The oompound of this example protected only after two hours, . ׳ but protection continued at about.the same level for . more than eight hours. Phenobarbital provided proteo/ tion in less than 0.5 hour, but protection began to de25 crease after four hours and was nearly gone by eight houra.p-—־..-..--.-ך---—.״’.—----------— ---!-—-.-—

I .1ιιιι.!.ΛΙΜ .I .(״“׳

Anticonvulsant activity of the abae therapeutic composition against maximal electroshock was also measured in the rat (Sprague Dawley Strain)., the ΕΪ^θ was found to be 646 ' (4.2-10.4). / ' ’ 'י י ' j ^!. ' - 8 - ;

. ¹. ' . . ־' •

Example 2 5,5־Diphenylhydantoin sodium (27.5 g., 0.1 mole) was suspended in 250 ml of dimethylformamide. To the suspension was added over a period of 30 minutes 88־ g. (8.25 ml) of chloromethyl methyl ether. The resulting suspension was stirred at room temperature overnight, then poured into 1 liter of ice water. A solid material precipitated. The suspension was stirred for one hour and the solid was removed by filtration, washed on the filter three times with 100 ml of water, and the wet cake was dissolved in 125 ml of ethanol with heating. To the boiling solution of 1 g. of activated carbon was added and the boiling solution was filtered through a Buchner funnel containing a 1 cm pressed layer of finely divided diatomaceous silica. The cake was washed three times with 15 ml of ethanol and the hot ethanol solution together with the washings was diluted with 100 ml of hot water, then allowed to cool to room temperature. The crystals which appeared were filtered and washed three times on the filter with 25 ml of 5θ$ aqueous ethanol, then dried in a vacuum desiccator. There was obtained g־ of 3-methoxymethyl5,5־-^dipbenylhydantoin; m.p.

127-128° (yield 67$). Pharmacological testing of this compound showed it to have LD^q of approximately 5θθ mg/kg־

It exhibited anticonvulsant activity (maximal electroshock) within less than 0.5 hour after ingestion, and the activity lasted for more than 2 hours; the ED ^was less than 25 mg/kg.

Example 3

Powdered phenobarbital sodium (25 g) was suspended in 250 ml of dimethylformamide. With vigorous stirring 156־ g of chloromethyl benzyl-ether was added

9- ^; to the suspension at room temperature. The reaction mixture was stirred overnight at room temperature. The suspension was then poured into £00 g of ice cold water, the mixture was stirred for one hour and the solid re5 moved by filtration־ The crude product was dissolved in about 150 ml boiling ethanol; to the boiling solution 0.5 gram of activated carbon was added, and the boiling 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 together with the washings was allowed to cool to room temperature. The resulting crystals were filtered and recrystallized from 100 ml of ethanol in the same manner as described for the first crystallization. There was obtained 527־ g of N, Ν’-dibenzyloxymethyl phenobarbital, m.p. 7l|.75⁰־.

Example U

Powdered phenobarbital sodium (25g) was suspended in 350 ml of dimethylformamide. With vigorous 20 stirring 15 g of chloromethyl-(n)-butyl-ether was 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 one hour, and the. solid re25 moved by filtration. The crude product was dissolved in hot ethanol (100 ml), 1 g of activated carbon was added and the boiling 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 together with the washings was allowed to cool to room temperature.

The resulting crystals were filtered and recrystallized two more times from 100 ml of ethanol in the same manner as described for the first crystallization. There was obtained 12.3 g of N,Ν'-di-(n)-butoxymethyl phenobarbital, m.p. 71-72°C. When tested as described above the compound exhibited anticonvulsant activity against maximal electroshock, the ED being less than 100 mg/kg.;

and an “50 (oral) greater than 5θθ mg/kg.

Example 5

Phenobarbital sodium (25 g) was dissolved in

250 ml of dimethylformamide at 120°C. The solution was cooled to 60° and at this temperature 25 g of chloro methylethylether was added with good stirring. The re action mixture was allowed to cool to room temperature and stirred for 20 hours, then poured into 5θ0 g of ice water, stirred for one hour, and the solid product was removed by filtration. The solid material was dissolved in 150 ml of boiling ethanol, 1 g of activated carbon was added and the boiling 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 to the hot solu tion together with the washings there was added 50 ml of hot water and the solution was allowed to cool to room temperature. The resulting crystals were filtered and recrystallized two more times in the same manner as described for the first crystallization. There was obtalned 605 g of N,Ν’-diethoxymethyl phenobarbital, m.p. 65-65°. When tested as described above, the compound exhibited anticonvulsant activity against maximal electroshock, the time of peak activity being 1 1/2 hours and the Εϋ^θ being less than 2£ mg/kg.

Example 6

5»5-DiPhenylhydantoin sodium (27.5 g) ״as ^3u3־ pended in 2£0 ml of dimethylformamide at 100°C. The suspension was cooled to 50°C_o with good stirring. At this temperature 16 g of chloromethyl־ (n )-butylether was added and the suspension was stirred for three hours while allowing the temperature to drop to 20°0. The reaction mixture was then poured into 1 liter of ice cold water and stirred for one hour. The resulting solid product was removed by filtration and dissolved in 150 ml of hot ethanol,. 1 g of activated carbon was added and the boiling 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 together with the washings was allowed to cool to room temperature. The resulting crystals were filtered and recrystallized two more times in the same manner as described for the first crystallization. There was obtained 8.9 g of 3-(מ)-butoxy-methyl-5,5”d.ipbonylhydantoln, m.p. 108-110°. Upon testing as described above, the compound exhibited anticonvulsant activity against maximal electroshock, the׳ ED^q being less than 25 mg/kg. The LD^q (oral) was also determined to be greater than 500 mg/kg.

Example 7 '

5,5-Diphenylhydantoin sodium (27.5 β) ״as suspended in 250 ml of dimethylformamide. To the suspension was added 15 ml of chloromethylbenzylether with good 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 one hour» The solid product was removed by filtration and dissolved in 150 ml of hot ethanol. To the boiling solution 1 g of activated carbon was added 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 together with the washings was allowed to cool to room temperature. The resulting crystals were filtered and recrystallized two more times in the same manner as described for the first crystallization. There was obtained 131־ g of 3-benzyloxymethyl-5»5־diphenylhydantoin, m»p» 151-152°»

Example 8

Powdered phenobarbital sodium (254־ g) 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 1 liter of ice-water; the mixture was then stirred .for 3 hours and the waxy solid removed by filtration. The wet solid was dissolved in 150 ml of boiling ethanol, to the hot solution 1 g of activated carbon 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 washed three times with 15 ml of ethanol and the hot solution together with the washings was allowed to cool overnight. The resulting crystals wore filtered, and recrystallized in the same manner as described for the first crystallization. There was obtained 13 g of N,N’-dilauryloxymethyl phenobarbital, m.p. 4θ5־θ⁰. 5 When tested as described above the compound exhibited anticonvulsant activity against maximal electroshock, the peak activity occurring at 2 hours and the being about £0 mg/kg. The ΕΏ^θ (oral) was determined to be greater than 500 mg/kg.

Example 9

In a 500 ml flask equipped with a stirrer and condenser, 115־ g. (0.θ5 mole) of phenobarbital was dissolved in a mixture of 20 ml dioxane and 100 ml of 37% aqueous formaldehyde solution. To the solution 1 ml 15 of 38% hydrochloric acid was added and the solution was heated at a reflux for 16 hours. The solution was cooled to room temperature and the product was extracted into ethylacetate. The combined organic layer was washed with water, dried over sodium sulfate, then evapor20 ated to dryness. To the oily residue 125־ ml of acetic anhydride and 125־ ml of pyridine were added and the solution was allowed to stand at room temperature overnight. The solution was poured into 500 ml cold water containing 12.5 ml of 380 hydrochloric acid and was stirred 25 for three hours. The crude product in the form of a solid precipitate was filtered and washed with water, then dissolved by heating in 100 ml of ethanol. To the hot solution 1 g of activated carbon was added and the boiling solution was filtered through a Buchner funnel con30 taining a 1 cm layer of finely divided diatomaceous sili

-Uca״ The cake was washed three times with 15 ml of ethan01 and the hot solution together with the washings was allowed to cool to room temperature. The resulting crystals after filtering, washing three times with 20 ml of ethanol, and drying in a vacuum desiccator, weighed

10,1 g (53% yield) m״p136-137° ״. Further purification was achieved by dissolving this material in 100 ml of ethylacetate, washing the solution four times with a cold, saturated solution of potassium carbonate, drying the solution over sodium sulfate, and evaporating the ethyl acetate״ The resulting solid was crystallized from 100 ml of ethanol to give 89־ g (47% overall yield) of N,N.diacetoxymethyl phenobarbital, m.p146 ״-I48⁰־

The results of pharmacological testing of this

<td colspan="3"> compound were as follows :</td>

<td> Acute Toxicity</td><td colspan="2"> Dosage, mg/kg.</td>

<td>^LD5q (oral)</td><td> 640</td><td> (864־474)</td>

<td> LD^₀ (intraperitoneal)</td><td> . 550</td><td> (437-673)</td>

<td> Neurological Deficit</td><td colspan="2"></td>

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

<td> Anticonvulsant Activity</td><td colspan="2"></td>

<td> Maximal electroshock, Εϋ^θ</td><td> 28</td><td> (22-35)</td>

<td> Metrazol, Εϋ^θ</td><td> 104</td><td> (80-135)</td>

<td> Strychnine, ED. 50</td><td> 120</td><td> (90-160)</td>

<td> Time of peak activity</td><td> 5־1</td><td> hours</td>

Example 10

In a 500 ml flask equipped with a stirrer and condenser 115״ g (005״ mole) of phenobarbital was dissolved in a mixture of 20 ml dioxane and 100 ml of 37% aqueous formaldehyde solution. To this solution 20 mg of sodium carbonate was added and the remainder of the procedure was carried out exactly the same way as described in Example 9 by refluxing, etc., obtaining 6.5 g (34% yield) of the' same product, m.p. 114.6-148° C.

Example 11

N,N^,-Dimethoxymethylphenobarbital (20־ g) obtained according to Example 1 was. suspended in 5 ml of acetic anhydride. To the suspension was added 2 drops of stannic chloride. The. suspension was stirred for 10 twenty hours, then poured into 20 ml of cold water. The mixture was stirred for three hours and the solid removed by filtration. The solid was crystallized from ethanol. Obtained 2.0 g (85% yield) of the same pro9 10 duct as in Examples and/Z.

Example 12

3-Methoxymethyl־5,5־dlphenylhydantoin (6 g) obtained according to Example 2 was suspended in 20 ml of acetic anhydride. To the suspension was added four drops of stannic chloride. The suspension was stirred 20 at room temperature overnight, then poured into 600 ml of ice water, whereupon a solid material precipitated. The suspension was stirred for three hours to decompose the excess of acetic anhydride, then the solid product was removed by filtration and washed on the filter three 25 times with 5θ 11״ of water. The wet product was dissolved in 5θ ml of hot ethanol, and to the boiling solution 1 g of activated carbon was added and the solution was filtered through a Buchner funnel which contained a 1 cm pressed layer of diatomaceous silica. The cake 30 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 resuiting crystals were removed by filtration, yielding 6 g of product־ This crude product was recrystallized from 60 ml of 80$ aqueous ethanol to yield 47־ g of slightly impure product, m.p. 15715־־θ°. This impure product was further purified by recrystallization from ethanol to yield 2.6 g of pure 3־acetoxymethyl-5»5־Hiphenylhydantoin; m.p. 162-163°־

Pharmacological testing showed the compound to have LD somewhat less than £00 mg/kg. It provided 50 no anticonvulsant activity against Metrazol, but against maximal electroshock it exhibited peak activity approximately one hour after dosage, exhibiting an less than 12.5 mg/kg.

Example 13

5,5-Diphenylhydantoin (25.2 g, 0.1 mole) was dissolved in a mixture of 25 ml dioxane and 100 ml of water. To the solution 44 ml of 37% aqueous formaldehyde solution and 5 ml of triethanolamine was added and the solution was heated at reflux for 7 hours־ The hot solution was cooled to room temperature, then acidified with dilute hydrochloric acid to pH 1. The solution was repeatedly extracted with ether and the combined ether solution washed with aqueous sodium chloride solution and dried over sodium sulfate; the ether was evaporated under reduced pressure to yield an oil consisting of l,3-dihydroxymethyl-5,5־^diphenylhydantoin. The oil was acetylated using 25 ml of acetic anhydride and 25 ml of pyridine with which it was allowed to stand at room temperature overnight, then poured into ice water containing 25 ml of concentrated hydrochloric acid. A solid material precipitated. The suspension was stirred for four hours to decompose any unreacted acetic anhydride, after which the solid product was removed by filtration, then washed on the filter several times with water. The wet cake was dissolved in methanol (ca. $00 ml) with heating. To the boiling solution 1 g of activated carbon was added and the boiling solution was filtered through a Buchner funnel which contained a 1 cm 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, washed three times with 25 ml of methanol and dried in a vacuum desiccator. Obtained 21.2 g of N,Ν’-diacetoxymethyl diphenylhydantoin; m.p. 150-151° (yield 535%־).

Pharmacological testing of this compound showed the following results:

Acute Toxicity Dose, mg/kg.

LD^ (oral) 570 (259-125^)

Neurological Deficit

TD_ 76 (λμΙ-114.0)

Anticonvulsant Activity

Maximal electroshock, Εϋ^θ 16.5 (12-22)

Time of peak activity 3 hours

Example 114.

Phenobarbital (11.5 g) was dissolved in 20 ml of dioxane. To the solution 100 ml of 37% aqueous for30 maldehyde solution and 1 ml of concentrated hydrochloric acid was added and the reaction mixture was heated at re flux 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 16 ml of propionic anhydride and 16 ml of pyridine were added and the solution was allowed to stand at room temperatures overnight. The solution was then poured into 500 g ice containing 16 ml of concentrated hydrochloric acid and the mixture was stirred for four hours, after which the oily product was removed by filtration and dissolved in 100 ml of hot ethanol. To the boiling solution 1 g of activated carbon was added 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 together with the washings was allowed to cool to room temperature« The resulting crystals were filtered and recrystallized in ¹־he same manner as described for the first crystallization. There was obtained a 4 g of N,N’-dipropionoxymethyl phenobarbitai, m.p. 93.55⁰.94־. When tested as described above, this compound exhibited an Εϋ^θ against maximal electroshock less than 25 mg/kg. and an LD^q (oral) of about JOO mg/kg.

Example 15

5,5“Diethy!barbituric acid (barbital) (184־ g.) was dissolved in 20 ml of dioxane. To the solution 100 ml of 37% aqueous formaldehyde solution and 1 ml of 38% hydrochloric acid was added, and the solution was heated at reflux for 16 hours» The solution was cooled to room temperature and the product extracted several times with ethyl acetate□־ The ethyl acetate solutions were combined and washed with water, dried over sodium sulfate, then evaporated to dryness. To the oily residue 20 ml of acetic anhydride and 20 ml of pyridine were added and the solution was allowed to stand at room temperature overnight. The solution was then poured into £00 ml of cold water containing 20 ml of 38% hydrochloric acid and the mixture was stirred for three 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, then evaporated to remove the methylene chloride« From the oily residue the product was isolated by column chromatography using sillca gel (grade 950). Elution with a benzene-ethyl acetate mixture (9:1 by volume) provided a semi-crystalline product which was crystallized first from hexane, then from pentane. There was obtained pure Ν,Ν'-diacetoxymethyl barbital having a melting point of 61!.65 C. When tested as described above, the compound exhibited an Εϋ^θ against maximal electroshock less than 25 mg/kg., peak activity occurring approximately two hours after dosage. Hypnotic activity was very weak, the ED^ being 2^0-300 mg/kg.

Example 16

By following the general procedure of Example 1, but using sodium 5,5־diethyl-barbiturate (sodium barbital) as the starting material instead of phenobarbitai sodium, there was obtained an oily product which was purified by chromatography. The product was identified as N,Ν’-dimethoxymethyl-5,5-diethy!barbituric acid, having the analysis: Calc, for ^2^20^2°5>! ^carbon £2.93%, hydrogen 7.4θ%* nitrogen 10.29%; found, car5 bon 53.07%, hydrogen 751%־, nitrogen 10.35%. Pharmacological testing of the compound showed it to have anticonvulsant activity against Metrazol, the Εϋ^θ being 7 mg/kg. The peak time of activity was approximately one hour after dosage.