IL32744A - Phenobarbitals,barbitals and hydantoins,their preparation and pharmaceutical compositions containing them - Google Patents

Description

.ontR o* *9sn mnpn »"i»c»fn ciiisn Hovel j¾cmo†>!¾r¾ital0, xfcist s and yaaatol¾s, hei preparation and p¾a aa8c¾ ica3, eomposltions eoR atntcg; them <3 U.S. 7-4.9.972-3 This 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 activity 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 alkoxymeth l, 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 l87 (War Department Army Medical Library, Microfilm No. 1720, I. Gc Parbenindustrie Plant, Elber-feld, Germany) that a material identified by the struc- 32744/2 tural formula of Ν,Ν' -dimethoxymethy1 phenobarbital has been tested as a hypnotic and found to be without effeot, there has been no indication that it has any useful fchera-peutio effect and no suggestion as to" how to make it or what its properties are. i.

The compounds according to the invention may be designated by the formula) I in which Z is > CO or part of a single bond between the ! neighboring carbon and nitrogen atoms; X and X' are both phenyl ! radicals when 2 is part of the direct bond,' or X and X' are both ethyl radicals or X is an ethyl radical and X' is a phenyl radical when is >C0; and Y and Y.' are both alkoxymethyl of from 1-12 *' carbon atoms in the alkoxy p ortion, benzyloxymethyl, or carboxylic acyloxymethyl, or Y can also be hydrogen and Y' cart be alkoxymethyl, j benzyloxymethyl, or carboxylic acyloxymethyl when Z is part of the j single bond#with the proviso that Y and Υ· are not both methoxymothyl | when Z is >C0, X is an ethyl radical and X' is a phenyl group.

The compounds of the present invention include Ν,Ν'- dialkoxymethyl phenobarbital, Ν,Ν'-dibenzyloxymethyl phenobarbital» J 3-alkoxymethyl diphenylhydantoin, and Ν,Ν'-dialkoxymethyl di- phenylhydantoin in which the alkoxy groups contain from 1 to 12 j carbonatoms, such as methoxy, ethoxy, propoxy, butoxy, and lauryloxy* I The compounds in which the alkoxy groups are methoxy or ethoxy are j 32744/2 3-methoxymethyl diphenylhydantoin are particularly pre- ferred.

The compounds of the invention also include Ν,Ν'-di(carboxylic acyloxy)methyl phenobarbital, N,N'-di(carboxylic acyloxy")methyl barbital, 3-(carboxylic acyloxy)methyl diphenylhydantoin, and N,N'-di( carboxylic acyloxy)methyl diphenylhydantoin. The above carboxyliq acyloxy groups include acetoxyf- aeryloyloxy, methac yloyioxy, propionoxy, and benzoyloxy. The compounds in which the carboxylic acyloxy groups are acetoxy are preferred; Ν,Ν'-di-acetoxymethyl phenobarbital, and 3-acetoxymethyl diphenylhydantoin are particularly preferred.

The compounds wherein at least Y' is alkoxymethyl | methyl or benzyloxy/may be made b alkoxymethylation or benzyloxymethylation of phenobarbital or of diphenylhy- ! i ; " ' idantoin or of their respective alkali metal salts, par- i : · 1 ticularly the sodium salts. The alkoxymethylation or i benzyloxymethylation may be oarried out by reaoting ! with aqueous formaldehyde under basic conditions followed ' i by reaotion with the appropriate alkanol or benzyl al- ' \ oohol under aoidic conditions; or it may be oarried out by reacting simultaneously with both formaldehyde (or paraformaldehyde) and the appropriate alkanol or benzyl alcohol under acidio conditions; or it may be oarried out by reaoting with a halomethyl-alkyl or -benzyl ether, e.g. a ohloromethyl alkyl or benzyl ether, in a suitable diluent, e.g. dimethyl formamide, over a wide range of temperatures, conveniently from below 0°0. up to the boiling point of the diluent.

The oompounds wherein at least Y* is carboxylic aqyloxy may be made by hydroxy-methylation or alkoxymethylation or benzyloxymethylation of barbital or phenobarbi tal 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 alkoxymethyl-ation 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 effective ness of the compounds are such that each dosage unit may contain from 10 to 00 mg. of active materialo 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 the dose required to produce death in $0% of the animals treated, determined graphically, with the 9$% limits shown in paren- theses „ The dosage required to produce a neurological deficit was determined by the method of Swinyard et al., J. Pharmacolo Exptl. Therapo 106, 319 (1952) 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 ^D^, the dose required to produce the effect, determined graphically, with 9 limits.

The time of peak anticonvulsant activity was determined by administering dosages of various sizes to a group of animals and administering a maximal electro-shock to the animals at intervals thereafter by supplying 60 mae current through a corneal electrode for 0.2 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 active agent.

Anticonvulsant effectiveness of each agent was determined against maximal electoshock administered as described above, against a convulsive dose of etrazol (106.25 mg/kg. ) injected subcutaneously, and against a 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- ure 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, I36.I. o (0„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. (1.25 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 resulting 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 go 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 2$ ml of ethanol and the hot solution together with the washings was allowed to cool to room temperature. The resulting crystals were Example 2 , -Diphenylhydantoin sodium ( *5 g., 0.1 mole) was suspended in 250 ml of dimethyIformamide „ To. the suspension was added over a period of 30 minutes 808 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 precipitatedo 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 12 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 2 ml of 0$ aqueous ethanol, then dried in a vacuum desiccator. There was obtained 20 go of 3-methoxymethyl-5»5-diphenylhydantoin » m»p. 127-128° (yield 67%). Pharmacological testing of this compound showed it to have of approximately 5Q0 mg/kg0 It exhibited anticonvulsant activity (maximal electro-shock) within less than 0.5 hour after ingestion, and the. activity lasted for more than 2 hours; the ED^Q was less than 25 mg/kg.

Example 3 Powdered phenobarbital sodium (25 g) was suspended in 250 ml of dimethyIformamide. With vigorous 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 removed by filtration. The crude product was dissolved in about l£0 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 recrys tallized from 100 ml of ethanol in the same manner as described for the first crystallization. There was obtained 5· 27 g of N, N1 -dibenzyloxymethyl phenobarbital, m.p. 7ΐ|.-750 · Example h.

Powdered phenobarbital sodium (25g ) was suspended in 350 ml of dimethylformamide . With vigorous 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 removed 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 Ν,Ν' -di- (n )-butoxymethyl pheno-barbital, 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/kgo 0 and an (oral) greater than 00 mg/kg.

Example 5 Phenobarbital sodium (25 g) was dissolved in 250 ml of dimethyIformamide at 120°C. The solution was cooled to 60° and at this temperature 25 g of chloro-methylethylether 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 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 solution together with the washings there was added 0 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 obtained 605 g of Ν,Ν' -diethoxymethy 1 phenobarbital, m.p0 65-65° · When tested as described above, the compound exhibited anticonvulsant activity against maximal electro-shock, the time of peak activity being 1 1/2 hours and the being less than 25 mg/kg.

Example 6 , 5-Diphenylhydantoin sodium (27.5 g) was suspended in 250 ml of dimethylformamide at 100°C. The suspension was cooled to 50oCo 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°C. 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 Buch-ner 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 809 g of 3 - (n )-butoxy-methyl-5, 5-diphenylhydantoin, m.p. 108 -110° . Upon testing as described above, the compound exhibited anticonvulsant activity against maximal elec-troshock, (oral) was also determined to be greater than 500 mg/kg.

Example 7 , 5-Diphenylhydantoin sodium (27.5 g) was 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 recrys tallized two more times in the same manner as described for the first crystallization. There was obtained 13.1 g of 3-benzyloxymethyl-5» 5-diphenyl-hydantoin, m0po l5l-l 2° o Example 8 Powdered phenobarbital sodium (25.1+ g) was suspended at room temperature in 2 0 ml of dimethylformamide and 22.1 g of chloromethyldodecanyl ether was edded 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 1 ml of ethanol and the hot solution together with the washings was allowed to cool overnight. The resulting crystals were filtered and recrystallized in the same manner as described for the first crystallization,, There was obtained 13 g of N,N ' -dilauryloxyme hyl phenobarbital, m0p0 L|.8 -50O .

When tested as described above the compound exhibited anticonvulsant activity against maximal electroshock, the peak activity occurring at 2 hours and the ED^^ being about 0 mg/kgo The (oral) was determined to be greater than 500 mg/kg.

Example 9 In a 500 ml flask equipped with a stirrer and condenser, 11 , 5 g« ( 0. 05 mole) of phenobarbital was dissolved in a mixture of 20 ml dioxane and 1 00. ml of 37 aqueous formaldehyde solution. To the solution 1 ml 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 evapor ated to drynesso To the oily residue 12 . 5 nil of acetic anhydride and 12 . 5 nil of pyridine were added and the solu tion was allowed to stand at room temperature overnight. The solution was poured into 500 ml cold water containing 12 . 5 ml of 38 $ hydrochloric acid and was stirred for three hours. The crude product in the form of a soli 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 containing a 1 cm layer of finely divided diatomaceous sili- ca. The cake was washed three times with 15 ml of ethanol 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 . 1 g iS2>% yield) m„p. 136-137° . 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 acetates The resulting solid was crystallized from 100 ml of ethanol to give 8 „ 9 g ih-7 overall yield) of Ν,Ν'-diacetoxymethyl phenobarbital, m.p0 II4.6-I.4.80 0 The results of pharmacological testing of this compound were as follows : Acute Toxicity Dosage, mg/kg.

LD . (oral) 61+0 (1.7..-861+ ) 0 LD^0 (intraperitoneal) . 550 (-4-37-673 ) Neurological Deficit TD^o 11+0 (II -I78 ) Anticonvulsant Activity Maximal electroshock, ED^Q 28 (22 -35 ) Metrazol, ED^Q 101+ (80-135 ) Strychnine, ED 120 ( 90-160 ) 50 Time of peak activity 1.5 hours Example 10 In a 500 ml flask equipped with a stirrer and condenser 11 „ 5 g ( 0o 05 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 (3k% yield) of the same product, m„p. 1-4.6-114.8° Co Example 11 N,N ' -Dimethoxymethylphenobarbital (2,0 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 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 pro-duct as in Examples and/2.

Example 12 3-Methoxymethyl-5,5-diphenylhydantoin (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 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 times with $0 ml of water. The wet product was dissolved in 0 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 was washed three times with 1 nil of hot ethanol j the hot ethanol solution was then diluted with 50 ml of hot water and allowed to cool to room temperature. The resulting crystals were removed by filtration, yielding 6 g of product. This crude product was recrystallized from 60 ml of Q0% aqueous ethanol to yield l .07 g of slightly impure product, m.p. 1 7-158° · This impure product was further purified by recrystallization from ethanol to yield 2.6 g of pure 3-acetoxymethyl-5» 5-diphenyl-hydantoin; m.p. 162-163° o 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 lesa than 12.5 mg/kg.

Example 13 , 5-Dipnenylhydantoin (25.2 g, 0.1 mole) was dissolved in a mixture of 25 ml dioxane and 100 ml of water. To the solution JL.I. ml of 37$ aqueous formaldehyde solution and 5 ml of triethanolamine was added and the solution was heated at reflux for 7 hours 0 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-d.iphenylhydantoin. The oil was acetylated using 25 ml of acetic anhydride and 25 ml of pyridine with which it was allowed to stand 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. 500 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 o 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 5 ml of methanol and dried in a vacuum desiccator. Obtained 21.2 g of N, 1 -diacetoxymethyl diphenylhydantoin; m.p. 1 0-151° (yield 53.5#).

Pharmacological testing of this compound showed the following results : Acute Toxicity Dose, mg/kg.

LD (oral) 570 (259-1251*.) Neurological Deficit TD^ 76 (1+1-11+0) 50 Anticonvulsant Activity Maximal electroshock, ED^Q 16.5 (12-22) Time of peak activity 3 hours Example llj Phenobarbital (11.5 g) was dissolved in 20 ml of dioxane. To the solution 100 ml of 37$ aqueous formaldehyde solution and 1 ml of concentrated hydrochloric - 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 00 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 0 The resulting crystals were filtered and recrystallized in ^ e same manner as described for the first crystallization. There was obtained a 1+ g of Ν,Ν' -dipropionoxymethyl phenobarbi-tal, rn.p. 93.5-914..50 · When tested as described above, this compound exhibited an against maximal electro-shock less than 25 mg/kg. and an"LD^0 (oral) of about 00 mg/kg.

Example 15 , 5-Diethylbarbituric acid (barbital) (18,1+ 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 3>Q% 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 „ Prom 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) provided a semi -crystal line product which was crystallized first from hexane, then from pentane. There was obtained pure Ν,Ν'-di-acetoxymethyl barbital having a melting point of 6I.-65°C. When tested as described above, the compound exhibited an against maximal electroshock less than 2 mg/kg., peak activity occurring approximately two hours after dosage. Hypnotic activity was very weak, the ED being 250-300 mg/kg. 50 Example 16 By following the general procedure of Example 1, but using sodium 5#5-cliethyl-barbiturate (sodium bar was purified by chromatography. The product was identified as Ν,Ν' -dimethoxymethyl-5,5-diethylbarbituric acid, having the analysis: Calc for CAR~ bon 52.93 , hydrogen 7.1+0%$ nitrogen 10.29$; found, car bon 3.07$, hydrogen 7. 1$, nitrogen 10.35$. Pharmacological testing of the compound showed it to have anticonvulsant activity against Metrazol, the being 7 mg/kg. The peak time of activity was approximately one hour after dosage. 32744/5

Claims (1)

1. CLAIMS Compounds of the general formula in which Z is CO or part of a single bond between the neighboring carbon and nitrogen X and are both phenyl radicals when Z is part of the direct or X and are both ethyl radicals or X is an ethyl and is phenyl radical when Z is and Y and are both alkoxymethyl of from carbon atoms in the alkoxy or carbox or Y can also be hydrogen and can be or carboxylic ayloxymethyl when is part of the single with the proviso that Y and are not both methoxymethyl when Z is X is an ethyl radical and is a phenyl diphenylhydantoin or diphenylhydantoin in which eaeh alkoxy group contains 1 to 12 carbon o oxymethylphenobarbltal in which eaoh alkoxy contains from two to twelve carbon or A compound to Claim 1 or in which each carboxylio aoyloxy group is propionoxy or A process for preparing a compound of formula according to claim including that in which when Y and are is X is ethyl and is which comprises corresponding or diphenylhydantion or an alkali salt thereof to provide a compound wherein at least is or it is desired to prepare at least carboxylic the compound obtained or the hydantion an alkali metal sal thereof and aeylating the compound the agent carboxylic acid Λ preparing compound of formula I according to claim substantially as herein described to Example A compound obtained by the process according to A according to Claim in which a pound to claim 2 or 5 for a to claim 2 or substantially as herein deacribed with reference to Examples to A produced by process according to claia 15 or therapeutic composition for treatment of acceptable carrier and an effeotlve amount of a compound according to any one of Claims 11 and and including that in which when Y and are both Z is X is ethyl and is A composition for treatment of sions in warm blooded animals comprising a physiologically acceptable carrier and an effective amoung of a according any one of Claims 2 to 10 and A compound having the fozmula I according to Claim 1 or a therapeutic composition comprising same as herein A compound according to Claim 2 or or a peutic composition comprising same as A method of treating convulsions in warm blooded animals excluding human which comprises administering to said animals an effective amount of a compound or sition according to any one of Claims 2 to 10 and 18 and 21 and including the use of a compound of fo mula I in Claim 1 in which when Y and are both Z X is ethyl and is A method of treating convulsions in warm blooded animals excluding which comprises administering to aid animals an amount of a compound or sition according to any one of Claims and For the Applicants insufficientOCRQuality