US3711607A - N,n -dihalomethyl phenobarbital for the treatment of convulsions - Google Patents
N,n -dihalomethyl phenobarbital for the treatment of convulsions Download PDFInfo
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- US3711607A US3711607A US00125429A US3711607DA US3711607A US 3711607 A US3711607 A US 3711607A US 00125429 A US00125429 A US 00125429A US 3711607D A US3711607D A US 3711607DA US 3711607 A US3711607 A US 3711607A
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
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 a 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'-dimethoxymethyl 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 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 percent 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 percent of the animals treated (LD was greater than 500 mg. per kilogram of body weight.
- 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 did exhibit hypnotic activity using the foregoing criterion.
- EXAMPLE 1 In a 1,000 ml. flask equipped with a stirrer and condenser, 136.4 g. (0.536 mole) of phenobarbital sodium powder was suspended in 500 ml. of dimethylforma-' mide. 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 1 hour. The resulting suspension was stirred at room temperature for 20 hours, then poured into 2,000 mi. of a mixture of ice and water and the resulting suspension was stirred for 2 hours. The crude product was removed by filtration, and washed three times with 100 ml. of distilled water, then dissolved in about 500 ml.
- the effective dose (ED the minimum dose effective in 50 percent of the animals) was 28 mg./kg., determined graphically, the 95 percent limits being 19.9-39.5.
- the time of peak activity was determined to be approximately 2 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 1 hour of stirring, the mixture became a homogeneous solution, and after about 65 hours a solid material began to precipitate. After stirring had been continued for a total of 72 hours, ml. of absolute ethanol was added to the mixture and stirring was continued for another 25 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 percent 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 10 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 70 hours, a solid material began to precipitate. When the stirring had continued for a total of 110 hours, the reaction mixture was poured into 3 kg. of a mixture of ice and water and stirring was continued for another 4 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 chloroform 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.
- the compound exhibited anticonvulsant activity against Metrazol, having a time of peak activity approximately 1 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 20 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: 3,060 (phenyl), 1,776 (lactam), 1,718 (lactam), 1,701 (lactam), 1,597 (phenyl), 1,170 (1,3,5,5-tetra-substituted barbiturate), 1,000 (C F), 764 (phenyl), 702 (phenyl) cm.
- the product exhibited the same pharmacological properties as the compounds of the preceding examples.
- the time of peak anticonvulsant activity against Metrazol was 2 hours and the effective dose (ED was about 100 mg./kg.
- a therapeutic composition for treatment of convulsions in warm blooded animals comprising a physiologically acceptable carrier and an anticonvulsant effective amount of a compound, N,N'- bishalomethyl phenobarbital.
- composition as claimed in claim 1 wherein said compound is N,N'-bischloromethylphenobarbital.
- composition as claimed in claim 1 wherein said compound is N,N'-bisbromomethylphenobarbital.
Abstract
N,N''-dihalomethyl phenobarbital compounds, including N,N''dichloromethyl phenobarbital, N,N''-dibromomethyl phenobarbital, and N,N''-difluoromethyl phenobarbital are described as well as therapeutic compositions containing the same and their use as anticonvulsant agents.
Description
I United States Patent m1 [111 3,711,607 Vida et al. 51 Jan. 16, 1973 541 N,N -DIHALOMETHYL IE1" ilefer'iicfiiil'eii PHENOBARBITAL FOR THE TE AT P NTS TREATMENT OF CONVULSIONS UNI DST ES ATE H51 Julius Vida. Boston: William 5'83??? 3413;? 335?;11111311111121:11111111322313? Wilher, Newton, both of Mass. [73] Assignee: The Kendall Company, Boston, Examiner-Jerome Goldberg Mass AttorneyR. W. Furlong 22 Filed: March 17, 1971 [57] ABSTRACT [211 App]' 125,429 N,N'-dihalomethyl phenobarbital compounds, includ- R I d U A ing N,N'-dichloromethyl phenobarbital, N,N'- e a e S pphcatmn Data dibromomethyl phenobarbital, and N,N [62] Division of Ser. No. 804,292, March 4, 1969, Pat. difluoromethyl phenobarbital are described as well as No. 3,635,980. therapeutic compositions containing the same and their use as anticonvulsant agents. [52] U.S.Cl ..424/254 [51 Int. Cl. ..A6lk 27/00 8 Claims, N0 Drawings [58] Field of Search ..424/254 N,N -DlI-IALOMETIIYL PI-IENOBARBITAL FOR THE TREATMENT OF CONVULSIONS This application is a division of application Ser. No. 804,292, filed Mar. 4, 1969 now US. Pat. No. 3,635,980 issued Jan. 18, 1972.
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 a 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'-dimethoxymethyl 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 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 percent 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 percent 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 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 1,000 ml. flask equipped with a stirrer and condenser, 136.4 g. (0.536 mole) of phenobarbital sodium powder was suspended in 500 ml. of dimethylforma-' mide. 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 1 hour. The resulting suspension was stirred at room temperature for 20 hours, then poured into 2,000 mi. of a mixture of ice and water and the resulting suspension was stirred for 2 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 product was N,N-bismethoxymethyl phenobarbital, having a melting point of l 151 17 C.
There was suspended 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 60 hours of stirring, precipitation of a solid material commenced. After hours of stirring, the reaction mixture was poured into 500 g. of a mixture of ice and water and stirred for an additional 6 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 percent of the theoretical yield) of N,N'-bischloromethyl phenobarbital, melting point 154-l 56 C. The values calculated for elemental analysis of C,,,l-I,.,N 0 -,C1 are: carbon 51.08 percent; hydrogen, 4.29 percent; nitrogen, 8.51 percent; chlorine 21.54 percent. Actual analysis of the crystalline product showed: carbon, 51.26 percent; hydrogen, 4.27 percent; nitrogen, 8.64 percent; chlorine, 21.44 percent. The infrared spectrum of the product exhibited the following peaks, inter alia: 3,065 (phenyl), 1,770 (lactam), 1,724 (lactam), 1,695 (lactam), 1,600 (phenyl), 1,170 (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 percent of the animals) was 28 mg./kg., determined graphically, the 95 percent limits being 19.9-39.5. The time of peak activity was determined to be approximately 2 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 1 hour of stirring, the mixture became a homogeneous solution, and after about 65 hours a solid material began to precipitate. After stirring had been continued for a total of 72 hours, ml. of absolute ethanol was added to the mixture and stirring was continued for another 25 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 percent 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 10 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 70 hours, a solid material began to precipitate. When the stirring had continued for a total of 110 hours, the reaction mixture was poured into 3 kg. of a mixture of ice and water and stirring was continued for another 4 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 chloroform 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 160161.5 C., amounting to 86 percent of the theoretical yield. The values calculated for elemental analysis of C H N O Br are: carbon, 40.22 percent; hydrogen, 3.37 percent; nitrogen, 6.70 percent; bromine, 38.23 percent. Actual analysis of the crystalline product showed: car
bon, 39.99 percent; hydrogen,'3.23 percent; nitrogen,
6.80 percent; bromine, 38.51 percent. The infrared spectrum of the product exhibited the following peaks, inter alia: 3,085 (phenyl), 1,770 (lactam), 1,718 (lactam), 1,695 (lactam), 1,600 (phenyl), 1,176 (l,3,5,5- tetrasubstituted barbiturate), 764 (phenyl), 702 (phenyl), 619 (C Br) cm.
The compound exhibited anticonvulsant activity against Metrazol, having a time of peak activity approximately 1 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 20 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 percent of the theoretical yield) of N,N'bisfluoromethyl 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 percent; hydrogen, 4.76 percent; nitrogen, 9.45 percent; fluorine, 12.83 percent. Actual analysis of the crystalline product showed: carbon, 56.61 percent; hydrogen, 4.85 percent; nitrogen, 9.57 percent; fluorine, 12.88 percent. The infrared spectrum of the product exhibited the following peaks, inter alia: 3,060 (phenyl), 1,776 (lactam), 1,718 (lactam), 1,701 (lactam), 1,597 (phenyl), 1,170 (1,3,5,5-tetra-substituted barbiturate), 1,000 (C F), 764 (phenyl), 702 (phenyl) cm.
The product exhibited the same pharmacological properties as the compounds of the preceding examples. The time of peak anticonvulsant activity against Metrazol was 2 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:
l. A therapeutic composition for treatment of convulsions in warm blooded animals comprising a physiologically acceptable carrier and an anticonvulsant effective amount of a compound, N,N'- bishalomethyl phenobarbital.
2. A composition as claimed in claim 1 wherein said compound is N,N'-bischloromethylphenobarbital.
3. A composition as claimed in claim 1 wherein said compound is N,N'-bisbromomethylphenobarbital.
compound is N,N-bischloromethyl phenobarbital.
7. The method as claimed in claim 5 wherein said compound is N,N-bisbromomethyl phenobarbital.
8. The method as claimed in claim 5 wherein said compound is N,N-bisfluoromethyl phenobarbital.
r?- Home Patent No. 3, 1 115 607 Dated January 16, 1973 n fl Juiius A0 Viola and minam moraine? It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:
In the beadnote the first invenbor s name should be "Julius A. Vida;
In the Absnzzi ae'zb line 1 "dibelomebbyl" should be ---bisbe.iomethyl--=;
In the Abstract, line 2, "diehloromebhyl" should be --=-bisehloromebhyl--;
In the Abstreet line 3 "dibromon'zethyl" should be --bisbromoznethyl-;
In the Absbaeacb line '4, "difluoromebhyl" should be --bisfluorometbyl--;
Column 1 line 11 "a" should be --e.n--;
Column 1 line 25, "difiuoromethyl should be --bisfluoromethyl--;
Column 1 line 2? "dimebhoxymebhyl" should be ---bismetheigvmetbyl--a Signed and sealed this 29th day of May 1973 Attest;
EDWARD MFLETCHERJR. ROBERT GOTTSCHALK Arresting Officer Commissioner of Patents FORM Podoso (10-69) USCOMM-DC 60376-P69 fi us, GOVERNMENT PRINTING OFFICE I969 O-366-33A
Claims (7)
- 2. A composition as claimed in claim 1 wherein said compound is N,N''-bischloromethyl phenobarbital.
- 3. A composition as claimed in claim 1 wherein said compound is N,N''-bisbromomethyl phenobarbital.
- 4. A composition as claimed in claim 1 wherein said compound is N,N''-bisfluoromethyl phenobarbital.
- 5. The method of treating convulsions in warm blooded animals which comprises administering to said animals an anticonvulsant effective amount of a compound, N,N''-bishalomethyl phenobarbital.
- 6. The method as claimed in claim 5 wherein said compound is N, N''-bischloromethyl phenobarbital.
- 7. The method as claimed in claim 5 wherein said compound is N, N''-bisbromomethyl phenobarbital.
- 8. The method as claimed in claim 5 wherein said compound is N, N''-bisfluoromethyl phenobarbital.
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| Application Number | Priority Date | Filing Date | Title |
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| US12542971A | 1971-03-17 | 1971-03-17 |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2521634A1 (en) * | 1974-05-17 | 1975-11-27 | Kendall & Co | METHOD FOR PREPARING 1,3-BIS (HALOGENMETHYL) -PHENOBARBITALS |
| EP1485101A1 (en) * | 2002-01-30 | 2004-12-15 | Taro Pharmaceutical Industries Limited | Non-sedating barbituric acid derivatives |
| US20060035915A1 (en) * | 2000-07-26 | 2006-02-16 | Taro Pharmaceutical Industries, Ltd. | Non-sedating barbituric acid derivatives |
| US20060122208A1 (en) * | 2000-07-26 | 2006-06-08 | Daniella Gutman | Composition and method for improved bioavailability and enhanced brain delivery of 5,5-diphenyl barbituric acid |
| US20060205747A1 (en) * | 2000-07-26 | 2006-09-14 | Moros Daniel A | Non-sedating barbiturate compounds as neuroprotective agents |
| US20070072886A1 (en) * | 2002-12-11 | 2007-03-29 | Daniel Moros | Method of treating movement disorders using barbituric acid derivatives |
| US20070167624A1 (en) * | 2004-07-02 | 2007-07-19 | Taro Pharmaceutical Industries Ltd. | Process for preparing 1-methoxymethyl 5,5-diphenybarbituric acid |
| US20080132529A1 (en) * | 2006-11-14 | 2008-06-05 | Avraham Yacobi | Method of improving bioavailability for non-sedating barbiturates |
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| US2013717A (en) * | 1935-09-10 | Cahs coxnh | ||
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Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2521634A1 (en) * | 1974-05-17 | 1975-11-27 | Kendall & Co | METHOD FOR PREPARING 1,3-BIS (HALOGENMETHYL) -PHENOBARBITALS |
| US20100144769A1 (en) * | 2000-07-26 | 2010-06-10 | Taro Pharmaceutical Industries Limited | Composition and method for improved bioavailability and enhanced brain delivery of 5 5-diphenyl barbituric acid |
| US20060035915A1 (en) * | 2000-07-26 | 2006-02-16 | Taro Pharmaceutical Industries, Ltd. | Non-sedating barbituric acid derivatives |
| US20060122208A1 (en) * | 2000-07-26 | 2006-06-08 | Daniella Gutman | Composition and method for improved bioavailability and enhanced brain delivery of 5,5-diphenyl barbituric acid |
| US20060205747A1 (en) * | 2000-07-26 | 2006-09-14 | Moros Daniel A | Non-sedating barbiturate compounds as neuroprotective agents |
| US8158639B2 (en) | 2000-07-26 | 2012-04-17 | Taro Pharmaceutical Industries Ltd. | Non-sedating barbiturate compounds as neuroprotective agents |
| US8076346B2 (en) | 2000-07-26 | 2011-12-13 | Taro Pharamaceutical Industries Ltd. | Composition and method for improved bioavailability and enhanced brain delivery of 5,5-diphenyl barbituric acid |
| US7683071B2 (en) | 2000-07-26 | 2010-03-23 | Taro Pharmaceuticals Industries Ltd. | Composition and method for improved bioavailability and enhanced brain delivery of 5,5-diphenyl barbituric acid |
| US7723346B2 (en) | 2000-07-26 | 2010-05-25 | Taro Pharmaceutical Industries Ltd. | Non-sedating barbiturate compounds as neuroprotective agents |
| EP1485101A1 (en) * | 2002-01-30 | 2004-12-15 | Taro Pharmaceutical Industries Limited | Non-sedating barbituric acid derivatives |
| EP1485101A4 (en) * | 2002-01-30 | 2006-04-12 | Taro Pharma Ind | Non-sedating barbituric acid derivatives |
| US7776871B2 (en) | 2002-12-11 | 2010-08-17 | Taro Pharmaceutical Industries Ltd. | Method of treating movement disorders using barbituric acid derivatives |
| US20070072886A1 (en) * | 2002-12-11 | 2007-03-29 | Daniel Moros | Method of treating movement disorders using barbituric acid derivatives |
| US8314115B2 (en) | 2002-12-11 | 2012-11-20 | Taro Pharmaceutical Industries Limited | Method of treating movement disorders using barbituric acid derivatives |
| US20070167624A1 (en) * | 2004-07-02 | 2007-07-19 | Taro Pharmaceutical Industries Ltd. | Process for preparing 1-methoxymethyl 5,5-diphenybarbituric acid |
| US20080132529A1 (en) * | 2006-11-14 | 2008-06-05 | Avraham Yacobi | Method of improving bioavailability for non-sedating barbiturates |
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