The subject invention concerns novel compounds that are useful as ultrashort acting hypnotic barbiturates. Specifically exemplified are derivatives of barbituric and thiobarbituric acids. They are rapidly metabolized by blood and tissue enzymes to form polar metabolites with no hypnotic activity and which are rapidly eliminated.
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3. A compound selected from the group consisting of:
4,6-dioxo-5-allyl-5-isopentylhexahydropyrimidine-3-aceticacid, Ethyl Ester ethyl 2-(5-allyl-5-isopentyl-4,6-dioxo-2-thioxotetrahydropyrimidin-1(2H)-yl)acetate
##STR00026##
3-ethoxycarbonyl-4,6-dioxo-5-allyl-5-isopentylhexahydropyrimidine ethyl 5-allyl-5-isopentyl-4,6-dioxo-2-thioxotetrahydropyrimidine-1(2H)-carboxylate
##STR00027##
and pharmaceutically acceptable salts thereof.
2. A compound selected from the group consisting of:
3-methyl-4,6-dioxo-5-phenylhexahydropyrimidine-5-acetic Acid, Neopentyl Ester neopentyl 2-(1-methyl-4,6-dioxo-5-phenyl-2-thioxohexahydropyrimidin-5-yl)acetate
##STR00022##
3-methyl-4,6-dioxo-5-phenylhexahydropyrimidine-5-acetic Acid Isobutyl Ester isobutyl 2-(1-methyl-4,6-dioxo-5-phenyl-2-thioxohexahydropyrimidin-5-yl)acetate
##STR00023##
3-methyl-4,6-dioxo-5-δ2-cyclopentylhexahydropyrimidine-5-acetic Acid Neopentyl Ester neopentyl 2-(5-(cyclopent-2-enyl)-1-methyl-4,6-dioxo-2-thioxohexahydropyrimidin-5-yl)acetate
##STR00024##
3-methyl-4,6-dioxo-5-δ2-cyclopentylhexahydropyrimidine-5-acetic Acid Isobutyl Ester isobutyl 2-(5-(cyclopent-2-enyl)-1-methyl-4,6-dioxo-2-thioxohexahydropyrimidin-5-yl)acetate
##STR00025##
and pharmaceutically acceptable salts thereof.
1. A compound selected from the group consisting of:
3-methyl-4,6-dioxo-5-phenylhexahydropyrimidine-5-acetic Acid, Adamantanemethyl Ester adamantan-1-ylmethyl(1-methyl-4,6-dioxo-5-phenyl-2-thioxohexahydropyrimidin-5-yl)acetate
##STR00018##
3-methyl-4,6-dioxo-5-phenylhexahydropyrimidine-5-acetic Acid, Cyclohexyl Ester cyclohexyl 2-(1-methyl-4,6-dioxo-5-phenyl-2-thioxohexahydropyrimidin-5-yl)acetate
##STR00019##
3-methyl-4,6-dioxo-5-δ2-cyclopentylhexahydropyrimidine-5-acetic Acid Adamantanemethyl Ester adamantan-1-ylmethyl(5-cyclopent-2-en-1-yl-1-methyl-4,6-dioxo-2-thioxohexahydropyrimidin-5-yl)acetate
##STR00020##
3-methyl-4,6-dioxo-5-δ2-cyclopentylhexahydropyrimidine-5-acetic Acid Cyclohexyl Ester cyclohexyl 2-(5-(cyclopent-2-enyl)-1-methyl-4,6-dioxo-2-thioxohexahydropyrimidin-5-yl)acetate
##STR00021##
and pharmaceutically acceptable salts thereof.
4. A composition comprising the compound according to
5. A composition comprising the compound according to
6. A composition comprising the compound according to
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3-methyl-4,6-dioxo-5-phenylhexahydropyrimidine-5-acetic Acid, Adamantanemethyl Ester: 13 adamantan-1-ylmethyl (1-methyl-4,6-dioxo-5-phenyl-2-thioxohexahydropyrimidin-5-yl)acetate: 13
##STR00006##
To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole of the ester 5 followed by 0.1 mole of dry N-methylthiourea in hot absolute ethanol. After refluxing for 8 hours, hot water (500 ml) is added, followed by enough HCl to make the solution acidic. The solution is then filtered and cooled in an ice-bath overnight. The white product is collected by filtration and dried in vacuo.
##STR00007##
To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole of the ester 6 followed by 0.1 mole of dry N-methylthiourea in hot absolute ethanol. After refluxing for 8 hours, hot water (500 ml) is added, followed by enough HCl to make the solution acidic. The solution is then filtered and cooled in an ice-bath overnight. The white product is collected by filtration and dried in vacuo.
##STR00008##
To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole of the ester 7 followed by 0.1 mole of dry N-methylthiourea in hot absolute ethanol. After refluxing for 8 hours, hot water (500 ml) is added, followed by enough HCl to make the solution acidic. The solution is then filtered and cooled in an ice-bath overnight. The white product is collected by filtration and dried in vacuo.
##STR00009##
To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole of the ester 8 followed by 0.1 mole of dry N-methylthiourea in hot absolute ethanol. After refluxing for 8 hours, hot water (500 ml) is added, followed by enough HCl to make the solution acidic. The solution is then filtered and cooled in an ice-bath overnight. The white product is collected by filtration and dried in vacuo.
##STR00010##
To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole of the ester 9 followed by 0.1 mole of dry N-methylthiourea in hot absolute ethanol. After refluxing for 8 hours, hot water (500 ml) is added, followed by enough HCl to make the solution acidic. The solution is then filtered and cooled in an ice-bath overnight. The white product is collected by filtration and dried in vacuo.
##STR00011##
To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole of the ester 10 followed by 0.1 mole of dry N-methylthiourea in hot absolute ethanol. After refluxing for 8 hours, hot water (500 ml) is added, followed by enough HCl to make the solution acidic. The solution is then filtered and cooled in an ice-bath overnight. The white product is collected by filtration and dried in vacuo.
##STR00012##
To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole of the ester 11 followed by 0.1 mole of dry N-methylthiourea in hot absolute ethanol. After refluxing for 8 hours, hot water (500 ml) is added, followed by enough HCl to make the solution acidic. The solution is then filtered and cooled in an ice-bath overnight. The white product is collected by filtration and dried in vacuo.
##STR00013##
To 0.1 mole of sodium ethoxide in absolute ethanol is added 0.1 mole of the ester 12 followed by 0.1 mole of dry N-methylthiourea in hot absolute ethanol. After refluxing for 8 hours, hot water (500 ml) is added, followed by enough HCl to make the solution acidic. The solution is then filtered and cooled in an ice-bath overnight. The white product is collected by filtration and dried in vacuo.
##STR00014##
To 0.1 mole of ethyl isothiocyanatoacetate in ethanol (50 ml) is added 50 ml of a 2M ethanolic solution of ammonia. After 2 hours at room temperature, the precipitated product is collected by filtration and used in the next step.
##STR00015##
To 0.1 mole of ethoxycarbonyl isothiocyanate in ethanol (50 ml) is added 50 ml of a 2M ethanolic solution of ammonia. After 2 hours at room temperature, the precipitated product is collected by filtration and used in the next step.
##STR00016##
Compound 21 (10 mmoles) is dissolved in ethanol containing 10 mmoles of sodium ethoxide. To this is added 10 mmoles of diethyl (allylisopentyl)malonate and the mixture is refluxed for 8 hours. The product crystallized upon cooling.
##STR00017##
Compound 22 (10 mmoles) is dissolved in ethanol containing 10 mmoles of sodium ethoxide. To this is added 10 mmoles of diethyl (allylisopentyl)malonate and the mixture is refluxed for 8 hours. The product crystallized upon cooling.
When compounds 13 to 20, 23, and 24 are administered to rats intraperitoneally at a dose of 50 mg/kg, they induce sleep within 10 minutes after administration. The hypnosis is of short duration (less than one hour), consistent with the scope of this invention.
9.89 g of Glycine methyl ester, hydrochloride salt, and 6.9 g of potassium thiocyanate are heated at 150° C. in an oil bath with occasional stirring for 15 minutes or until a brownish melt is obtained. The reaction is cooled down and 100 ml of ethanol is added. Stir at room temperature for 4 hours. Filter off the precipitate and wash it with ethanol. The filtrate is evaporated and the residue is crystallized from acetone and methyl ter-butyl ether.
5.8 g of 2-Thiohydantoin and 15 g of barium hydroxide hydrate are refluxed in 200 ml of water for 1 hour. The mixture is cooled in an ice bath and acidified to pH 2.0 with 10% sulfuric acid. Filter through celite. The filtrate is then continuously extracted for 2 days with ethyl ether. The extract is evaporated and the residual water is removed by co-distillation with methanol/ethyl acetate. The product is then crystallized from methanol/ethyl acetate.
The γ-aminoalkylcarboxylate ester and 1.1 equivalent amount of thiophosgene are added to a stirring mixture of methylene chloride (100 ml) and saturated sodium bicarbonate solution (100 ml). After stirring for 2 hours, the organic phase is washed with 100 ml water, dried over magnesium sulfate, and evaporated. The yield of product is nearly quantitative. The following compounds were prepared from this method:
The isothiocyanatoalkyl carboxylate esters and amides described in example 3 are dissolved in THF and one equivalent amount of ammonia in methanol/water is added dropwise at 0° C. The solvent is evaporated and the residue is purified by flash chromatography through a short plug of silica. An example is given for the preparation of 1-Carbethoxymethylthiourea, where 2.3 ml of 28-30% Aqueous ammonia solution in 10 ml of methanol is added dropwise to an ice-cooled solution of 5 g ethyl isothiocyanato-2-acetate in 50 ml of THF. The mixture is stirred at room temperature for another 2 hours and is evaporated. The residual water is removed by co-distillation with ethyl acetate and is filtered through a short plug of silica, eluting with methanol/methylene chloride 03:97. The product (4.83 g) is an orange solid.
Equivalent amounts of 2,2-disubstituted malonyl chloride and 1-substituted thiourea are mixed and stirred at 80° C. overnight. The mixture is then diluted with water and extracted with an organic solvent. The crude product is either distilled or is precipitated by acidification of its sodium salt. The following are examples of compounds made after this procedure:
1-Carbethoxymethyl-5,5-diethylthiobarbituric acid: 39 g of Diethylmalonyl chloride is mixed with 64 g of 2-thiohydantoic acid ethyl ester. Heat at 80° C. for 18 hours. Cool down to room temperature and then dilute with 200 ml of water. Extract with dichloromethane and then evaporate the solvent. The oily residue is dissolved in 1N NaOH and is then precipitated out by slow addition of 1N HCl. The product is purified by solubilizing again in 1N NaOH and then precipitating it with 1N HCl.
1-carbethoxymethyl-5-ethyl-5-isoamylthiobarbituric acid: 35 g of 2-Ethyl-2-isoamylmalonyl chloride, prepared from 2-ethyl-2-isoamylmalonic acid (52 g) and phosphorus pentachloride (148 g), and thiohydantoic acid ethyl ester are mixed and heated at 80° C. for 18 hours. Cool to room temperature and then pour into 200 ml of cold water. Extract with dichloromethane. Evaporate the solvent and then distill the oily residue at 1 mm Hg.
1-Carbethoxymethyl-5,5-dibutylthiobarbituric acid: 44 g of Dibutylmalonyl chloride is mixed with 64 g of 2-thiohydantoic acid ethyl ester and is stirred at 80 C. for 18 hours. Cool down to room temperature and then dilute with 200 ml of water. Extract with dichloromethane and then evaporate the solvent. The oily residue is dissolved in 1N NaOH and is then precipitated out by slow addition of 1N HCl. The product is purified by solubilizing again in 1N NaOH and then precipitating it with 1N HCl. The following compounds were also made after the same procedure:
The thiobarbiturate is dissolved in an equivalent amount of 0.8N ethanolic sodium hydroxide solution. Most of the solvent is then evaporated and the salt is precipitated with hexane. Filter and wash with more hexane. Dry in vacuo.
It should be understood that the examples, reaction schemes, and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims.
Milner, Peter G., Druzgala, Pascal
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