US3635980A - N n'-bishalomethyl phenobarbital compounds - Google Patents

N n'-bishalomethyl phenobarbital compounds Download PDF

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US3635980A
US3635980A US804292A US3635980DA US3635980A US 3635980 A US3635980 A US 3635980A US 804292 A US804292 A US 804292A US 3635980D A US3635980D A US 3635980DA US 3635980 A US3635980 A US 3635980A
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phenobarbital
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bishalomethyl
hours
phenyl
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Julius A Vida
William R Wilber
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Kendall Co
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Kendall Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • C07D239/62—Barbituric acids

Definitions

  • 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 has long been known to be useful as an anticonvulsant agent in warm blooded animals, having been employed in the treatment of epilepsy; however, it suffers from the disadvantage that it exhibits hypnotic activity as well as anticonvulsant activity. It has now been found that N,N-bishalomethyl phenobarbital compounds are effective anticonvulsants which possess unexpected advantages from the pharmacological standpoint over phenobarbital itself in that they are completely devoid of hypnotic effect, among other things.
  • the N,N'-bishalomethyl phenobarbital compounds of the present invention include N,N'-bischloromethyl phenobarbital, N,N-bisbromomethyl phenobarbital, and N,N-difluoromethyl phenobarbital.
  • the compounds may be made by first preparing N,N'- bismethoxymethyl phenobarbital, then reacting it with an acyl halide such as acetyl chloride or bromide, benzoyl chloride, etc.
  • the N,N'-bisfluoromethyl phenobarbital compound may be prepared by reacting the N,N'-bisbromomethyl phenobarbital compound with silver fluoride.
  • 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 500 mg. of active material.
  • mice All tests 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.
  • Acute oral toxicity was determined in the conventional manner. In the case of each compound the dose required to produce death in 50% of the animals treated (LD' was greater than 500 mg. per kilogram of body weight.
  • Hypnotic activity or depression of the central nervous 3,035,980 Patented Jan. 18, 1972 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 did exhibit hypnotic activity using the foregoing criterion.
  • EXAMPLE 1 In a 1000 ml. flask equipped with a stirrer and condenser, 136.4 g. (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 g. (1.25 mole) of chloromethylmethyl ether over a period of one hour. The resulting suspension was stirred at room temperature for twenty hours, then poured into 2000 ml. of a mixture of ice and water and 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.
  • the effective dose (ED the minimum dose effective in 50% of the animals) was 28 mg./kg., determined graphically, the 95% limits being 19.9-39.5.
  • the time of peak activity was determined to be approximately two hours after the dosage, and the foregoing determination of effectiveness was made at that time.
  • EXAMPLE 2 There was suspended in 10.9 g. (0.078 mole) of benzoyl chloride 4.4 g. (0.0138 mole) of N,N'-bismethoxymethyl phenobarbital. To the suspension was added slowly 0.2 ml. of anhydrous stannic chloride and the reaction mixture was stirred at room temperature. After about one hour of stirring, the mixture became a homogeneous solution, and after about sixty-five hours a solid material began to precipitate. After stirring had been continued for a total of seventy-two hours, ml.
  • EXAMPLE 3 There was suspended in 365 g. (2.8 moles) of acetyl bromide 160 g. (0.5 mole) of N,N-bismethoxymethyl phenobarbital. This suspension was stirred at room temperature and there was added to it slowly over a period of ten minutes 4 g. of anhydrous stannic bromide. The suspension was heated to a temperature of 55 C. with stirring, whereupon the suspension became a homogeneous solution, and stirring was continued while maintaining the mixture at that temperature. After about seventy hours, a solid material began to precipitate. When the stirring had continued for a total of one-hundred-ten hours, the reaction mixture was poured into 3 kg.
  • the infrared spectrum of the product exhibited the following peaks, inter alia: 3085 (phenyl), 1770 (lactam), 1718 (lactam), 1695 (lactam), 1600 (phenyl), 1176 (1,3,5,5-tetrasubstituted barbiturate), 764 (phenyl), 702 (phenyl), 619 (CBr) cm.-
  • the compound exhibited anticonvulsant activity against Metrazol, having a time of peak activity approximately one hour after administration of the dose.
  • the effective dose (ED was found to be 27 mg./kg., virtually identical with that of the compound of Example 1.
  • EXAMPLE 4 There was dissolved in ml. of acetonitrile 4.2 g. (0.01 mole) of the N,N-bisbromomethyl phenobarbital produced in Example 3. To the solution was added 5.1 g. (0.04 mole) of silver fluoride, and the mixture was stirred at reflux temperature for twenty hours, after which the hot solution was filtered through a Buchner funnel containing a compacted layer of finely-divided diatomaceous silica, the filtrate being passed directly into 1 kg. of a mixture of ice and water. An oily precipitate formed which solidified when allowed to stand overnight. The solid precipitate was separated from the reaction mixture by filtration, washed with water, and dried at 40 C. at reduced pressure.
  • the infrared spectrum of the product exhibited the following peaks, inter alia: 3060 (phenyl), 1776 (lactam), 1718 (lactam), 1701 (lactam), 1597 (phenyl), 1170 (l,3,5,5-tetra-substituted barbiturate), 1000 (CtF), 764 (phenyl), 702 (phenyl cm.-
  • the product exhibited the same pharmacological properties as the compounds of the preceding examples.
  • the time of peak anti-convulsant activity against Metrazol was two hours and the effective dose ('ED was about 100 mg./kg.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

N,N''-BISHALOMETHYL PHENOBARBITAL COMPOUNDS, INCLUDING N,N''- BISCHLOROMETHYL PHENOBARBITAL, N,N''-DIBROMOMETHYL PHENOBARBITAL, AND N,N''-BISFLOUROMETHYL PHENOBARBITAL ARE DESCRIBED AS WELL AS THERAPEUTIC COMPOSITIONS CONTAINING THE SAME AND THEIR USE AS ANTI-CONVULSANT AGENTS.

Description

United States Patent ()1 hoe 3,635,980 N,N'-BISHALOMETHYL PHENOBARBITAL COMPOUNDS Julius A. Vida, Boston, and William R. Wilber, Newton, Mass., assignors to The Kendall Company, Boston,
Mass. No Drawing. Filed Mar. 4, 1969, Ser. No. 804,292 Int. Cl. C07d 51/20 US. Cl. 260-257 4 Claims ABSTRACT OF THE DISCLOSURE N,N'-bishalomethyl phenobarbital compounds, including N,N'-bischloromethyl phenobarbital, N,N'-dibromomethyl phenobarbital, and N,N'-bisfluoromethyl phenobarbital are described as well as therapeutic compositions containing the same and their use as anti-convulsant agents.
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 has long been known to be useful as an anticonvulsant agent in warm blooded animals, having been employed in the treatment of epilepsy; however, it suffers from the disadvantage that it exhibits hypnotic activity as well as anticonvulsant activity. It has now been found that N,N-bishalomethyl phenobarbital compounds are effective anticonvulsants which possess unexpected advantages from the pharmacological standpoint over phenobarbital itself in that they are completely devoid of hypnotic effect, among other things.
The N,N'-bishalomethyl phenobarbital compounds of the present invention include N,N'-bischloromethyl phenobarbital, N,N-bisbromomethyl phenobarbital, and N,N-difluoromethyl phenobarbital.
The compounds may be made by first preparing N,N'- bismethoxymethyl phenobarbital, then reacting it with an acyl halide such as acetyl chloride or bromide, benzoyl chloride, etc. The N,N'-bisfluoromethyl phenobarbital compound may be prepared by reacting the N,N'-bisbromomethyl phenobarbital compound with silver fluoride.
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 500 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 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.
Acute oral toxicity was determined in the conventional manner. In the case of each compound the dose required to produce death in 50% of the animals treated (LD' was greater than 500 mg. per kilogram of body weight.
Anticonvulsant effectiveness of each compound was determined against maximal electroshock and against a convulsive dose of Metrazol (106.25 mg./kg.) injected subcutaneously. Electroshock was produced by supplying 60 ma. current through a corneal electrode for 0.2 second. None of the compounds was effective against electroshock as determined by inhibition of the clonic extensor component of the seizure pattern in unprotected animals. In the case of Metrazol, however, the compounds are surprisingly effective, the criterion for effectiveness being suppression of clonic convulsive seizures.
Hypnotic activity or depression of the central nervous 3,035,980 Patented Jan. 18, 1972 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 g. (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 g. (1.25 mole) of chloromethylmethyl ether over a period of one hour. The resulting suspension was stirred at room temperature for twenty hours, then poured into 2000 ml. of a mixture of ice and water and 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 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 ethanol 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 desiccator. The productw as N,N-bismethoxymethyl phenobarbital, having a melting point of 117 C.
There was supended in 32.0 g. (0.4 mole) of acetyl chloride 16.0 g. (0.05 mole) of N,N-bismethoxymethyl phenobarbital prepared as described above. To the suspension was added slowly, drop by drop, 0.2 ml. of anhydrous stannic chloride. The suspension was stirred at room temperature and soon became a homogeneous solution, but after about sixty hours of stirring, precipitation of a solid material commenced. After one hundred ten hours of stirring, the reaction mixture Was poured into 500 g. of a mixture of ice and water and stirred for an additional six hours. The precipitated solid material was separated from the reaction mixture by filtration, washed with cold water, and dried at room temperature. This crude product was dissolved in 500 ml. of boiling absolute ethanol to which there was added 0.5 g. of activated carbon. 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 with hot ethanol 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 desiccator. There was obtained 13.26 g. (81% f the theoretical yield) of N,N-bischloromethyl phenobarbital, melting point 154-156" C. The values calculated for elemental analysis of C H N O Cl are: carbon, 51.08%; hydrogen, 4.29%; nitrogen, 8.51%; chlorine 21.54%. Actual analysis of the crystalline product showed: carbon, 51.26%; hydrogen, 4.27%; nitrogen, 8.64%; chlorine, 21.44%. The infrared spectrum of the product exhibited the following peaks, inter alia: 3065 (phenyl), 1770 (lactam), 1724 (lactam), 1695 (lactam), 1600 (phenyl), 1170 (l,3,5,5-tetra-substituted barbiturate), 766 (phenyl), 700 (phenyl), '687 (C-Cl) cm..
When tested for anticonvulsant activity against Metrazol, the compound exhibited extremely high potency, the effective dose (ED the minimum dose effective in 50% of the animals) was 28 mg./kg., determined graphically, the 95% limits being 19.9-39.5. The time of peak activity was determined to be approximately two hours after the dosage, and the foregoing determination of effectiveness was made at that time.
EXAMPLE 2 There was suspended in 10.9 g. (0.078 mole) of benzoyl chloride 4.4 g. (0.0138 mole) of N,N'-bismethoxymethyl phenobarbital. To the suspension was added slowly 0.2 ml. of anhydrous stannic chloride and the reaction mixture was stirred at room temperature. After about one hour of stirring, the mixture became a homogeneous solution, and after about sixty-five hours a solid material began to precipitate. After stirring had been continued for a total of seventy-two hours, ml. of absolute ethanol was added to the mixture and stirring was continued for another twenty-five hours, at which time the tan colored solid precipitate was separated from the reaction mixture by filtration, washed with cold water and dried at room temperature. This crude product was crystallized from ethanol as described in Example 1, resulting in a yield (71% of the theoretical) of the same product, N,N- bischloromethyl phenobarbital.
EXAMPLE 3 There was suspended in 365 g. (2.8 moles) of acetyl bromide 160 g. (0.5 mole) of N,N-bismethoxymethyl phenobarbital. This suspension was stirred at room temperature and there was added to it slowly over a period of ten minutes 4 g. of anhydrous stannic bromide. The suspension was heated to a temperature of 55 C. with stirring, whereupon the suspension became a homogeneous solution, and stirring was continued while maintaining the mixture at that temperature. After about seventy hours, a solid material began to precipitate. When the stirring had continued for a total of one-hundred-ten hours, the reaction mixture was poured into 3 kg. of a mixture of ice and water and stirring was continued for another four hours. The finely-divided solid precipitate was separated from the reaction mixture by filtration, washed with cold water, and dried at room temperature and reduced pressure, the resulting crude product amounting to 209 g. The material was purified by dissolving it in about 1.2 l. of boiling chlorofom to which was added 2 g. of activated carbon. The boiling solution was filtered through a Buchner funnel containing a compacted layer of finely-divided diatomaceous silica. The filter cake was washed with hot chloroform and the hot solution together with the washings was allowed to cool to room temperature. The crystals which appeared were separated by filtration, washed with chloroform and dried. There was obtained 180 g. of N,N- bisbromomethyl phenobarbital in the form of colorless needles having a melting point of 160 -161.5 0., amounting to 86% of the theoretical yield. The values calculated for elemental analysis of C H N O Br are: carbon, 40.22%; hydrogen, 3.37%; nitrogen, 6.70%; bromine, 38.23%. Actual analysis of the crystalline product showed: carbon, 39.99%; hydrogen, 3.23%; nitrogen, 6.80%; bromine, 38.51%. The infrared spectrum of the product exhibited the following peaks, inter alia: 3085 (phenyl), 1770 (lactam), 1718 (lactam), 1695 (lactam), 1600 (phenyl), 1176 (1,3,5,5-tetrasubstituted barbiturate), 764 (phenyl), 702 (phenyl), 619 (CBr) cm.-
The compound exhibited anticonvulsant activity against Metrazol, having a time of peak activity approximately one hour after administration of the dose. The effective dose (ED was found to be 27 mg./kg., virtually identical with that of the compound of Example 1.
EXAMPLE 4 There was dissolved in ml. of acetonitrile 4.2 g. (0.01 mole) of the N,N-bisbromomethyl phenobarbital produced in Example 3. To the solution was added 5.1 g. (0.04 mole) of silver fluoride, and the mixture was stirred at reflux temperature for twenty hours, after which the hot solution was filtered through a Buchner funnel containing a compacted layer of finely-divided diatomaceous silica, the filtrate being passed directly into 1 kg. of a mixture of ice and water. An oily precipitate formed which solidified when allowed to stand overnight. The solid precipitate was separated from the reaction mixture by filtration, washed with water, and dried at 40 C. at reduced pressure. The resulting crude product was purified by crystallization from 50 ml. of boiling ethanol by the same procedure as in Example 1. There was obtained 1.5 g. (50% of the theoretical yield) of N,N-bisfiuoromethyl phenobarbital in the form of colorless needles having a melting point of 148 149 C. The values calculated for elemental analysis of C H N O F are: carbon, 56.76%; hydrogen, 4.76%; nitrogen, 9.45%; fluorine, 12.83%. Actual analysis of the crystalline product showed: carbon, 56.61%; hydrogen, 4.85%; nitrogen, 9.57%; fluorine, 12.88%. The infrared spectrum of the product exhibited the following peaks, inter alia: 3060 (phenyl), 1776 (lactam), 1718 (lactam), 1701 (lactam), 1597 (phenyl), 1170 (l,3,5,5-tetra-substituted barbiturate), 1000 (CtF), 764 (phenyl), 702 (phenyl cm.-
The product exhibited the same pharmacological properties as the compounds of the preceding examples. The time of peak anti-convulsant activity against Metrazol was two hours and the effective dose ('ED was about 100 mg./kg.
Although specific embodiments of the invention have been described herein, it is not intended to limit the invention solely thereto but to include all of the variations and modifications which suggest themselves to one skilled in the art within the spirit and scope of the appended claims.
What is claimed is:
1. N,N'-bishalomethyl phenobarbital.
2. N,N'-bischloromethyl phenobarbital.
3'. N,N'-bisbromoethyl phenobarbital.
4. N,N'-bisfluoromethyl phenobarbital.
US. Cl. X.R.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3900475A (en) * 1972-06-26 1975-08-19 Kendall & Co Certain phenobarbital salts
US3947443A (en) * 1974-05-17 1976-03-30 The Kendall Company Process for preparing 1,3-bis(halomethyl)phenobarbitals
US4029662A (en) * 1976-04-30 1977-06-14 Bristol-Myers Company Method of making barbituric acid derivatives

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3900475A (en) * 1972-06-26 1975-08-19 Kendall & Co Certain phenobarbital salts
US3947443A (en) * 1974-05-17 1976-03-30 The Kendall Company Process for preparing 1,3-bis(halomethyl)phenobarbitals
US4029662A (en) * 1976-04-30 1977-06-14 Bristol-Myers Company Method of making barbituric acid derivatives

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