US3325361A - Anticonvulsant agents - Google Patents

Anticonvulsant agents Download PDF

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US3325361A
US3325361A US331103A US33110363A US3325361A US 3325361 A US3325361 A US 3325361A US 331103 A US331103 A US 331103A US 33110363 A US33110363 A US 33110363A US 3325361 A US3325361 A US 3325361A
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sodium
seizures
mice
convulsions
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Meunier Henry Eugene Jea Marie
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Chemetron Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/126—Acids containing more than four carbon atoms
    • C07C53/128—Acids containing more than four carbon atoms the carboxylic group being bound to a carbon atom bound to at least two other carbon atoms, e.g. neo-acids
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/80—Two oxygen atoms, e.g. hydantoin with hetero atoms or acyl radicals directly attached to ring nitrogen atoms

Definitions

  • This invention relates to a method of treating convulsions and seizures in warm-blooded animals. More particularly, the invention is concerned with treating epilepsy with dialkyl-substituted acetic acid and derivatives thereof.
  • the compounds of this invention which have been found to be effective in treating epilepsy in Warm-blooded animals are characterized by the formula wherein Alk is a lower alkyl containing 2-7 carbon atoms inclusive and Alk is a lower alkyl containing 3-7 carbon atoms inclusive; wherein Y is an OM group in which M is hydrogen or an alkali metal of Group IA of the Periodic Table of Elements including sodium and potassium; Y also is an OR radical where R is a lower alkyl either straight or branched chained containing 1-5 carbon atoms inclusive; Y further designates a NHZ group in which Z is hydrogen or carbamyl; and Y is still further a 5,5-diphenylhydantoinyl group.
  • Alk represents straight or branched chained lower alkyl such as ethyl; iso and npropyl; as well as the normal, iso, secondary and tertiary isomers of the butyl, pentyl, hexyl and heptyl alkyls.
  • Alkg likewise represents the same alkyls described for Alk except that the lowest alkyl is propyl.
  • the compounds of this invention can be suitably formulated in physiologically acceptable solutions and carriers to make tablets, syrups, isotonic solutions, injections, suppositories and other dosage forms.
  • the total daily dose of the active compound should be in the range of about 200 to 1000 mg. per day with single dosages ranging from about 50 mg. to about 1000 mg.
  • the dosage can, of course, be adjusted by the attending physician with respect to age, weight and sex of the recipient.
  • Metrazole penentylenetetrazol
  • the preventive product is'administered either rectally, intraperitoneally or intravenously from 15 minutes to six hours before the animal is injected with Metrazole. Protection is considered total if no seizure sets in or if the seizure is very considerably reduced in its duration and its intensity in one or the other of the two phases (tonic or clonic). Partial protection is evidenced by the absence of one of the two phases.
  • the first type is similar to that performed in rabbits except that the dosage of Metrazole must produce death in 95-100% of the animals. This dosage has been found to be 64 mg./kg. given intravenously by the tail vein. This test is described by R. Charonnat et al., Therapie (1958) XIII, 1-16. I
  • the second type is a group of tests to determine efficacy against standard maximum electroshock seizures and low frequency electroshock seizures as well as against the usual Metrazole seizure. Since these tests are well recognized in the literature only a brief description will be given.
  • the electrically induced convulsions measure the ability of the drug to prevent the hindleg tonic-extensor component of maximal electroshock seizures (MES test) evoked by supermaximal current employing 50 ma. alternating current, 0.2 second stimulus duration and corneal elec trodes.
  • the low frequency electroshock seizures (LP. EST test) is the ability of the drug to elevate two-fold the threshold of the electroshock seizure induced in mice by electrical Current delivered at an intensity twice threshold using 0.2 millisecond pulses, three second stimulus duration at six pulses per second.
  • a Grass stimulator (model 8413) was used for the LP.
  • Di-n-propylacetic acid is a colorless liquid and very slightly soluble in water. Its synthesis is described in the literature by E. Oberreit in Berichte, vol. 29, 19982001 (1896). Twelve mice were rectally administered 200 mg./ kg. of di-n-propylacetic acid in the form of suppositories by mixing the designated dosage in liquefied cocoa butter. After a period of 45 minutes, each mouse was intravenously administered the 64 mg./kg. of Metrazole as described in test No. 1 for mice. Complete protection against death was obtained for 40% of the mice.
  • Di-n-propylacetic acid was also rectally administered in the described cocoa butter mixture to 12 rabbits in a dosage ranging from 200 mg./kg. to 400 mg./kg.
  • the time interval between administration of the drug and the Metrazole injection is described in Table I along with the results of the test.
  • Sdium-di-n-pr0pylacetate is a white powder and is readily soluble in water.
  • the sodium salt is preferably formed from di-n-propylacetic acid by the interaction of sodium hydroxide in an aqueous solution. This procedure is more explicitly set forth in Example XI.
  • the sodium salt was given intra-peritoneally in an aqueous solution to 21 rabbits in dosages ranging from 168 mg./kg.420 mg./kg.
  • the time after injection when Metrazole was administered varied from minutes to six hours.
  • Substantially complete protection was obtained at a dosage of 200 mg./kg. at a 40 minute period before the injection of Metrazole.
  • Similar experiments were performed using the intravenous route and the same aqueous solution.
  • the threshold of protection and comparable degrees of protection have been found for the following number of rabbits at the described dosages: three rabbits at 25 mg. kg.; three rabbits at 50 mg./kg.; and two rabbits at 100 mg./kg.
  • mice Thirty mice were also injected with sodium di-n-propylacetate by the intraperitoneal route, employing a suitable aqueous solution, in the following manner: ten animals received 50 mg./kg.; six were given 100 mg./kg.; 14 were administered 200 mg./kg They were tested according to procedure No. 1 for mice with a minute time interval between the administration of sodium di-npropylacctate and Metrazole. The results were as follows: survived with the mg./kg. dosage; 50% survived with 100 mg./kg. and 57% survived at the 200 mg./kg. dosage level.
  • the efficacy of the sodium salt is further indicated by the protection given to rats when the are subjected to the standard maximal electroshock test. Thirty minutes prior to the shock treatment seven rats were orally administered in aqueous solution 400 mg./kg. of sodium di-n-propylacetate and seven others received orally 800 mg./kg. Those receiving the larger dosage evidenced complete protection in all seven of the animals while three of the seven administered the smaller dose were protected.
  • Convulsions and seizures were also controlled when sodium di-n-propylacetate was administered to humans 4 in conjunction with standard anti-epileptic drugs of which phenobarbital, belladenal, diphenylhydantoin or primidone are representative.
  • a typical daily dosage was 50 mg. of phenobarbital, 10 mg. of belladenal and sodium di-n-propylacetate corresponding to 600' mg. of di-n-propylacetic acid.
  • EXAMPLE III Comparative anticonvulsalnl activity
  • Tables II and III are presented for the purpose of illustrating certain comparative tests for sodium di-n propylacetate and four well-known anticonvulsant agents, namely phenobarbital, diphenylhydantoin, trimethadoine and phenacemide.
  • the recipient mice were male albinos. They were allowed access to water and received the same diet; they were kept under the same conditions prior to administration.
  • Sodium di-n-propylacetate (DPA Sodium) was administered orally, subcutaneously and intraperitoneally in aqueous solutions.
  • Comparative drugs were given orally in aqueous solutions or as suspensions in 6% acacia. The concentration of the drug solution or suspension employed was such that the dose administered per 100 grams body weight was always contained in 1 ml.
  • Table II compares the time for peak effect, as well as the LD and TD of the sodium salt and the well-known anticonvulsant agents.
  • a suitable number of mice were subjected to the standard MES test to determine the ED which is a dose which protects 50% of the animals against seizures. Additional mice were then subjected to the MES test at various intervals to determine the time during which the drug manifests its peak effect.
  • DPA Sodium 56 animals were employed in the test and for the remaining drugs, 24 were used for each compound.
  • the LD is the single dose of each compound which was fatal to 50% of the tested animals within 24 hours.
  • DPA Sodium 42 mice were employed in this test, while for the other compounds 24 mice were used for each drug.
  • the TD is the single dose producing evidence of minimum neurotoxi-city in 50% of the mice at the time of peak drug action. The method of its determination will be explained later.
  • the end point of minimum neurotoxicity was motor incoordination, based on the inability of the animal to maintain equilibrium for one minute on a horizontal rod rotating at six revolutions per minute and evidenced by the presence of other overt signs of toxicity such as loss of placing response, decreased skeletal tone, ataxia, etc.
  • DPA Sodium has the fastest peak effect of the drugs tested. It is also one of the least toxic of the group. It has a TD about 16.5 times that for phenobarbital and 14 times that for diphenylhydantoin. With respect to the LD50, DPA Sodium, when compared to phenobarbital, has an average LD better than eight times greater, and with respect to diphenylhydantoin, better than three times greater.
  • the comparative anticonvulsant activity is illustrated in Table III for the compounds under consideration.
  • This table compares the protective index of the compounds which is a potency index arrived at by dividing the TD by the ED.
  • the ED as well as the TD is calculated on a statistical basis employing a significant number of mice which were given various doses of the drugs and tested at a predetermined time of peak action until at least three points were established in the range between and 100% seizure protection in the instance of the ED or minimum neurotoxicity with respect to the TD
  • the results were then plotted on a logarithmic probability paper and a regression line was fitted to the plotted points. From this plot the respective TD ED and 95% fiducial limits for protection indexes were calculated by the method of Lichfield and Wilcoxon as described in the Journal of Pharmacology and Experimental Therapeutics, 96:99, 1949.
  • mice were also administered the same dosage of Metrazole. In the control group, nine out of ten mice died, while in the group receiving the ethyl ester of di-n-propylacetic acid, five out of ten survived.
  • EXAMPLE IV Ethyl di-n-propylacetate is an oily liquid which has been prepared by Burton, American Chemical Journal, 3, 390 18-81).
  • the ethyl ester was rectally administered in the herein described cocoa butter mixture to five rabbits in a dosage of 240 mg./kg. One hour thereafter the rabbits were administered the designated dosage of Metrazole. One of the animals was completely protected; two were partially protected; and one was not protected.
  • the subject compound was also rectally administered in a dosage of 200 mg./ kg. in the described cocoa butter mixture to ten mice. They were subjected to the Metrazole test outlined at B(1) for mice, one hour after administration of the ethyl ester. One half of the mice were found to be fully protected from death.
  • mice Ten additional mice were rectally given 119 mg./ kg. in
  • mice were intraperitoneally administered 180 mg./kg. of the amide compound in an aqueous solution and after a period of one hour were given the Metrazole injection according to Mice Test No. B(1). This resulted in survival of the ten mice. A 50% survival was found when 12 mice were intraperitoneally given 45 mg./ kg. in the previously described solution and subjected to the same test.
  • the amide derivative was rectally administered in the described cocoa butter mixture to ten mice in a dosage of 200 mg./ kg. Ten additional mice served as a control group. All 20 were subjected after administration to the Metrazole Test No. 13(1). All the mice in the control group died while there were no deaths among the mice receiving the amide compound. Among the group receiving the compound, only three had clonic movements of the head with no tonic seizures.
  • Table V represents the results of previously described rectal administration of various doses of the urea compound administered to 14 rabbits. The number of animals receiving the specified dosages is indicated in Table V along with the time between administration and injection of Metrazole.
  • the urea compound was also found eflective in 50% of 12 mice when administered rectally in a dosage of 100 mg./kg. according to .the procedure outlined in the previous examples and tested according to Test No. B(l) with a one hour interval between administration of the urea derivative and the Metrazole.
  • mice Ten mice rectally received 126 mg./kg. of the urea compound as previously described and ten others served as controls. One hour after administration of the compound, ten mice were given the Metrazole test described in Test No. B-(1). In the group not receiving the urea derivative, nine out of ten mice died whereas in the group receiving the urea compound eight out of ten survived.
  • EXAMPLE VII Sodium Z-isopropylvalerate 2-isopropylvaleric acid can be prepared by the method of E. Fischer, Holzapfel and Gwinner, Berichte d. Dentschen Chemisehen Deutschen, vol. 45, p. 256.
  • the sodium salt can be conveniently made according to the procedure described in Example XI.
  • a dose of the sodium salt equivalent to 200 mg./kg. of the valeric acid was administered intraperitoneally in an aqueous solution .to ten mice.
  • Ten additional mice served as controls. In the group not receiving the sodium salt, all died while all survived in the group receiving the valeric acid salt.
  • EXAMPLE VIII Sodium di-n-butylacetate Di-n-butylacetic acid can be prepared by the method of Levene and Cretcher as described in the Journal of Biological Chemistry, vol. 33, p. 508. The sodium salt is I prepared according to the procedure described in Example' X.
  • mice When ten mice were intraperitoneally injected with an aqueous solution of sodium di-n-butylacetate at a dosage of 100 mg./kg. according to the procedure for testing mice as outlined in the previous example, 100% were protected. All the ten mice which served as controls, died.
  • the upper organic layer was washed with water and the solvent was removed subsequently by vacuum distillation at 60 C.
  • the methanolic layer was separated, heated to boiling and enough water added to cause a slight turbidity.
  • the product 1(di-n-propy1acetyl)-5,5-phenylhydantoin crystallized in the form of needles. It was collected on.a filter and crystallized from aqueous methanol.
  • the di-n-propylacetyl-S,S-diphenylhydantoin is characterized by its melting point of l50.5-l52.5 C.
  • the acylated hydantoin was administered in a dosage of 200 and 300 mg./kg. by the intraperitoneal route in an olive oil suspension. Eight rabbits were employed and tested according to the herein described procedure for testing rabbits with a 40 minute interval being employed between the administration of .the subject compound and the Metrazole.
  • Examples X to XIII illustrate dosage formulations for administering sodium di-n-propylacetate as well as di-npropylacetic acid, di-n-propylacetamide and di-n-propyl acetyl urea.
  • the formulation of the sodium derivative is described as being made from di-n-propylacetic acid.
  • the di-n-propylacetic acid is neutralized with sodium hydroxide and the water is subsequently added to this mixture to form a cloudy solution.
  • the pH is adjusted to 7.5 with the dropwise addition of the sodium hydroxide solution. After adjustment of the pH, the solution subsequently becomes clear. Twenty drops of the formulated solution contain 20 mg. of the acid.
  • EXAMPLE XI Di-n-propylacetic acid suppositories Ingredient: Amount Dl-n-propylacetic acid -mg 200 Glycocoll -mg 200 Cocoa butter, q.s g 2 The butter is melted and the di-n-propylacetic acid is admixed therewith. Previously, the glyc'ocoll is finely ground, and added to the agitated mixture. The mass is poured into a suitable mold and rapidly cooled.
  • EXAMPLE XII Di-n-propylacemmide and di-n-propylacetyl urea suppositories Ingredient: Amount Di-n-propylactamide mg 200 Cocoa butter, q.s g 2 The butter is melted and the di-n-propylaceta mide is dissolved therein. The mixture is cooled slowly while being agitated and is then poured into a suitable mold and cooled rapidly.
  • EXAMPLE XIII Sodium di-n-propylacetaze tablets
  • tablets each containing 100 mg. of active material were prepared by mixing together 100 grams of sodium di-n-propylacetate, three grams of corn starch and cc. of ethylether. The granulation is forced through a screen and dried. To the dried material is added five grams of talc and two grams of magnesium stearate as lubricants; and twelve grams of additional corn starch as a disintegrator. The material thus prepared is compressed into 1000 tablets each containing 100 mg. of active material. The tablets can be scored if and Adams, JACS, vol. 52, p. 1290.
  • alkali metal salts of the acids specifically or generally described herein, and whether disclosed in the salt or ester form, can be employed according to the teachings of this invention.
  • Such alkali metal salts include sodium, potassium and lithium.
  • the group of lower alkyl esters formed from the disclosed acids and alcohols containing a total of 1-5 carbon atoms can also be employed; this group includes the methyl, ethyl, propyl and isopropyl esters a well as the esters of the isomeric butyl and pentyl alcohols.
  • the urea and the amide derivatives of the herein described acids can also be utilized.
  • esters can be prepared by known procedures from the acids falling within the scope of the general formula and from the corresponding alcohols.
  • the urea and the amides can likewise be prepared, for example, by known methods from the acid by converting them to the acid chloride and further reacting with urea and ammonia, respectively.
  • the chlorides of the acids falling within the scope of this invention can also be utilized to form acid derivatives of 5,5-diphenylhydantoin pursuant to the procedure outlined in Example IX.
  • a method of controlling convulsions and seizures in warm-blooded animals in need of such therapy comprising administering to said animals in an amount sufficient to control convulsions and seizures, a compound of the formula Alki (I C H C Y Alkg wherein Alk is lower alkyl containing 2-7 carbon atoms inclusive and Alk is lower alkyl containing 3-7 carbon atoms both forming straight and branched chained alkyl groups;
  • Y is selected from the group consisting of OM, OR, NHZ and 5,5-diphenylhydantoinyl groups, M is selected from the group consisting of hydrogen, sodium, potassium and lithium, R is lower alkyl containing l-S carbon atoms inclusive, and Z is selected from the group consisting of hydrogen and carbamyl.
  • a method of controlling convulsions and seizures in warm-blooded animals in need of such therapy comprising administering to said animals an antiepileptic drug and a compound of the formula Alk; (l'l) CH-C-Y inclusive and Alk is lower alkyl containing 3-7 carbon atoms inclusive both forming straight and branched chained alkyl groups; Y is selected from the group consisting of OM, OR, NHZ and 5,5-diphenylhydantoinyl groups, M is selected from the group consisting of hydrogen, sodium, potassium and lithium, R is lower alkyl containing 1-5 carbon atoms inclusive, and Z is selected from the group consisting of hydrogen and carbamyl.
  • a method of controlling convulsions and seizures in warm blooded animals in need of such therapy comprising administering to said animals an anti-epileptic drug and a compound of the formula Alk (I) CHCY A kg
  • Alk is lower alkyl containing 2-7 carbon atoms inclusive and Alk is lower alkyl containing 3-7 carbon atoms inclusive both forming straight and branched chained alkyl groups and Y is selected from the group consisting of amino and ureido.
  • a method of controlling convulsions and seizures in warm-blooded animals in need of such therapy comprising administering to said animals in an amount suflicient to control said convulsions and seizures, a compound of the formula wherein R is lower alkyl containing 1-5 carbon atoms inclusive.
  • a method of controlling convulsions and seizures in warm-blooded animals in need of such therapy which comprises administering di-n-propylacetic acid to said animals in an amount sufficient to control said convulsions and seizures.
  • a method of controlling convulsions and seizures in Warm-blooded animals in need of such therapy which comprises administering sodium di-n-propylacetate to said animals in an amount sufficient to control said convulsions and seizures.
  • a method of controlling convulsions and seizures in warm-blooded animals in need of such therapy which comprises administering ethyl di-n-propylacetate to said animals in an amount suflicient to control said convulsions and seizures.
  • a method of controlling convulsions and seizures in Warm-blooded animals in need of such therapy which comprises administering di-n-propylacetamide to said animals in an amount sufficient to control said convulsions and seizures.
  • a method of controlling convulsions and seizures in warm-blooded animals in need of such therapy which comprises administering di-n-propylacetyl urea to said animals in an amount sufficient to control said convulsions and seizures.
  • a method of controlling convulsions and seizures in warm-blooded animals in need of such therapy which comprises administering sodium Z-isopropylvalerate to said animals in an amount sufficient to control said convulsions and seizures.
  • a method of controlling convulsions and seizures in warm-blooded animals in need of such therapy which comprises administering sodium di-n-butylacetate to said animals in an amount sufficient to control said convulsions and seizures.
  • a method of controlling convulsions and seizures in warm-blooded animals in need of such therapy which comprises administering 1-(di-n-propylacetyl)-5,5 diphenylhydantoin to said animals in an amount sufficient to control said convulsions and seizures.
  • a therapeutic composition useful in the control of convulsions and seizures comprising an effective amount of a compound of the formula CHa-CHz-CH: (H)
  • R represents straight or branched chained lower alkyl containing 1-5 carbon atoms inclusive and a physiologically acceptable solid or fluid carrier where in the instance said fluid carrier is water, the resulting composition is sterile.
  • a therapeutic composition useful in the control of convulsions and seizures comprising an effective amount of di-n-propylacetic acid and a physiologically acceptable solid or fluid carrier where in the instance said fluid is water the resulting composition is sterile.
  • a therapeutic composition useful in the control of convulsions and seizures comprising an effective amount of sodium di-n-propylacetate and a physiologically acceptable solid or fluid carrier where in the instance said fluid is water the resulting composition is sterile.
  • a therapeutic composition useful in the control of convulsions and seizures comprising ethyl di-n-propylacetate present in the range of about 50 mg. to about 1000 mg, and a solid physiologically acceptable carrier in a unit dosage form.
  • a therapeutic composition useful in the control of convulsions and seizures comprising di-n-propylacetyl urea present in the range of about 50 mg. to about 1000 mg, and a solid physiologically acceptable carrier in a unit dosage form.
  • a therapeutic composition useful in the control of convulsions and seizures comprising sodium 2-isopropylvalerate present in a range of about 50 mg. to about 1000 mg., and a solid physiologically acceptable carrier in a unit dosage form.
  • a therapeutic composition useful in the control of convulsions and seizures comprising l-(di-n-propylacetyl)-5,5-diphenylhydantoin present in the range of about about 50 mg. to about mg, and a solid physiologically acceptable carrier in a unit dosage form.
  • a therapeutic composition useful in the control of convulsions and seizures comprising sodium di-n-butylacetate present in a range of about 50 mg. to about 100 mg., and a solid physiologically acceptable carrier in a unit dosage form.

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Description

United States Patent 3,325,361 ANTICONVULSANT AGENTS Henry Eugene Jean Marie Meunier, Grenoble, Isere, France, assignor to Chemetrou Corporation, Chicago, Ill., a corporation of Delaware No Drawing. Filed Dec. 17, 1963, Ser. No. 331,103 Claims priority, application France, Oct. 17, 1962.,
23 Claims. (Cl. 167-65) This application is a continuation-in-part of my application, Ser. No. 265,371, filed Mar. 15, 1963, and now abandoned.
This invention relates to a method of treating convulsions and seizures in warm-blooded animals. More particularly, the invention is concerned with treating epilepsy with dialkyl-substituted acetic acid and derivatives thereof.
The compounds of this invention which have been found to be effective in treating epilepsy in Warm-blooded animals are characterized by the formula wherein Alk is a lower alkyl containing 2-7 carbon atoms inclusive and Alk is a lower alkyl containing 3-7 carbon atoms inclusive; wherein Y is an OM group in which M is hydrogen or an alkali metal of Group IA of the Periodic Table of Elements including sodium and potassium; Y also is an OR radical where R is a lower alkyl either straight or branched chained containing 1-5 carbon atoms inclusive; Y further designates a NHZ group in which Z is hydrogen or carbamyl; and Y is still further a 5,5-diphenylhydantoinyl group. In the above formula, Alk represents straight or branched chained lower alkyl such as ethyl; iso and npropyl; as well as the normal, iso, secondary and tertiary isomers of the butyl, pentyl, hexyl and heptyl alkyls. Alkg likewise represents the same alkyls described for Alk except that the lowest alkyl is propyl.
There is a constant search for drugs effective for treating convulsions and for the control of the various types of epileptic conditions. While there are available many types of compounds useful as anticonvulsants, many of these compounds are highly toxic and cause serious side effects. Further, some of the well-known anticonvulsant agents are toxic at relatively low dosage levels. Others are useful for treating only one type of epilepsy.
It is therefore an object of this invention to provide novel anticonvulsant agents of low toxicity for treating convulsions and for the control of various types of epileptic seizures having a highly favorable therapeutic index; and having a chemical configuration entirely different from any of the well-known antiepileptics.
The compounds of this invention, as depicted in the general formula, can be suitably formulated in physiologically acceptable solutions and carriers to make tablets, syrups, isotonic solutions, injections, suppositories and other dosage forms. Irrespective of the dosage form, the total daily dose of the active compound should be in the range of about 200 to 1000 mg. per day with single dosages ranging from about 50 mg. to about 1000 mg. The dosage can, of course, be adjusted by the attending physician with respect to age, weight and sex of the recipient.
All of the compounds useful in the present invention A.-Rabbits The minimum dosage of Metrazole (pentylenetetrazol) which provokes 100% seizures in all the animals is injected .in the marginal vein of the car. This dosage was found to be 30 mg./kg. The preventive product is'administered either rectally, intraperitoneally or intravenously from 15 minutes to six hours before the animal is injected with Metrazole. Protection is considered total if no seizure sets in or if the seizure is very considerably reduced in its duration and its intensity in one or the other of the two phases (tonic or clonic). Partial protection is evidenced by the absence of one of the two phases.
The experiments conducted are classified as follows:
(1) The first type is similar to that performed in rabbits except that the dosage of Metrazole must produce death in 95-100% of the animals. This dosage has been found to be 64 mg./kg. given intravenously by the tail vein. This test is described by R. Charonnat et al., Therapie (1958) XIII, 1-16. I
(2) The second type is a group of tests to determine efficacy against standard maximum electroshock seizures and low frequency electroshock seizures as well as against the usual Metrazole seizure. Since these tests are well recognized in the literature only a brief description will be given.
The electrically induced convulsions measure the ability of the drug to prevent the hindleg tonic-extensor component of maximal electroshock seizures (MES test) evoked by supermaximal current employing 50 ma. alternating current, 0.2 second stimulus duration and corneal elec trodes. The low frequency electroshock seizures (LP. EST test) is the ability of the drug to elevate two-fold the threshold of the electroshock seizure induced in mice by electrical Current delivered at an intensity twice threshold using 0.2 millisecond pulses, three second stimulus duration at six pulses per second. A Grass stimulator (model 8413) was used for the LP. test; otherwise, the details of the various procedures, the end points employed in mice, and the characteristics of the electroshock apparatus are described in detail in such references as Swinyard, E. A., Brown, W. C. and Goodman, L. S., in I. Pharmacology and Experimental Therapeutics, vol. 10 6; 319, 1952. The Metrazole test was carried out by the usual subcutaneous injection of the Metrazole at mg./kg. as described in the preceding literature reference.
These animals were subjected to some of the same standard tests as described in 13(2) for mice as will be evident later in the disclosure.
EXAMPLE I Di-n-propylacetic acid Di-n-propylacetic acid is a colorless liquid and very slightly soluble in water. Its synthesis is described in the literature by E. Oberreit in Berichte, vol. 29, 19982001 (1896). Twelve mice were rectally administered 200 mg./ kg. of di-n-propylacetic acid in the form of suppositories by mixing the designated dosage in liquefied cocoa butter. After a period of 45 minutes, each mouse was intravenously administered the 64 mg./kg. of Metrazole as described in test No. 1 for mice. Complete protection against death was obtained for 40% of the mice.
Di-n-propylacetic acid was also rectally administered in the described cocoa butter mixture to 12 rabbits in a dosage ranging from 200 mg./kg. to 400 mg./kg. The time interval between administration of the drug and the Metrazole injection is described in Table I along with the results of the test.
Sdium-di-n-pr0pylacetate Sodium di-n-propylacetate is a white powder and is readily soluble in water. The sodium salt is preferably formed from di-n-propylacetic acid by the interaction of sodium hydroxide in an aqueous solution. This procedure is more explicitly set forth in Example XI.
The sodium salt was given intra-peritoneally in an aqueous solution to 21 rabbits in dosages ranging from 168 mg./kg.420 mg./kg. The time after injection when Metrazole was administered varied from minutes to six hours. Substantially complete protection was obtained at a dosage of 200 mg./kg. at a 40 minute period before the injection of Metrazole. Similar experiments were performed using the intravenous route and the same aqueous solution. The threshold of protection and comparable degrees of protection have been found for the following number of rabbits at the described dosages: three rabbits at 25 mg. kg.; three rabbits at 50 mg./kg.; and two rabbits at 100 mg./kg.
Thirty mice were also injected with sodium di-n-propylacetate by the intraperitoneal route, employing a suitable aqueous solution, in the following manner: ten animals received 50 mg./kg.; six were given 100 mg./kg.; 14 were administered 200 mg./kg They were tested according to procedure No. 1 for mice with a minute time interval between the administration of sodium di-npropylacctate and Metrazole. The results were as follows: survived with the mg./kg. dosage; 50% survived with 100 mg./kg. and 57% survived at the 200 mg./kg. dosage level.
The efficacy of the sodium salt is further indicated by the protection given to rats when the are subjected to the standard maximal electroshock test. Thirty minutes prior to the shock treatment seven rats were orally administered in aqueous solution 400 mg./kg. of sodium di-n-propylacetate and seven others received orally 800 mg./kg. Those receiving the larger dosage evidenced complete protection in all seven of the animals while three of the seven administered the smaller dose were protected.
Convulsions and seizures were also controlled when sodium di-n-propylacetate was administered to humans 4 in conjunction with standard anti-epileptic drugs of which phenobarbital, belladenal, diphenylhydantoin or primidone are representative. A typical daily dosage was 50 mg. of phenobarbital, 10 mg. of belladenal and sodium di-n-propylacetate corresponding to 600' mg. of di-n-propylacetic acid.
EXAMPLE III Comparative anticonvulsalnl activity The following Tables II and III are presented for the purpose of illustrating certain comparative tests for sodium di-n propylacetate and four well-known anticonvulsant agents, namely phenobarbital, diphenylhydantoin, trimethadoine and phenacemide. In the instance of each compound administered, the recipient mice were male albinos. They were allowed access to water and received the same diet; they were kept under the same conditions prior to administration. Sodium di-n-propylacetate (DPA Sodium) was administered orally, subcutaneously and intraperitoneally in aqueous solutions. Comparative drugs were given orally in aqueous solutions or as suspensions in 6% acacia. The concentration of the drug solution or suspension employed was such that the dose administered per 100 grams body weight was always contained in 1 ml.
Table II compares the time for peak effect, as well as the LD and TD of the sodium salt and the well-known anticonvulsant agents. To determine the time of peak effect, a suitable number of mice were subjected to the standard MES test to determine the ED which is a dose which protects 50% of the animals against seizures. Additional mice were then subjected to the MES test at various intervals to determine the time during which the drug manifests its peak effect. In the instance of DPA Sodium, 56 animals were employed in the test and for the remaining drugs, 24 were used for each compound.
The LD is the single dose of each compound which was fatal to 50% of the tested animals within 24 hours. In the instance of DPA Sodium, 42 mice were employed in this test, while for the other compounds 24 mice were used for each drug.
The TD is the single dose producing evidence of minimum neurotoxi-city in 50% of the mice at the time of peak drug action. The method of its determination will be explained later. The end point of minimum neurotoxicity was motor incoordination, based on the inability of the animal to maintain equilibrium for one minute on a horizontal rod rotating at six revolutions per minute and evidenced by the presence of other overt signs of toxicity such as loss of placing response, decreased skeletal tone, ataxia, etc.
It will be noted in both Tables II and III that certain numerical ranges appear beneath an average number. These values represent fiducial limits for the various dosages.
From Table II it is evident that DPA Sodium has the fastest peak effect of the drugs tested. It is also one of the least toxic of the group. It has a TD about 16.5 times that for phenobarbital and 14 times that for diphenylhydantoin. With respect to the LD50, DPA Sodium, when compared to phenobarbital, has an average LD better than eight times greater, and with respect to diphenylhydantoin, better than three times greater.
The comparative anticonvulsant activity is illustrated in Table III for the compounds under consideration. This table compares the protective index of the compounds which is a potency index arrived at by dividing the TD by the ED The ED as well as the TD is calculated on a statistical basis employing a significant number of mice which were given various doses of the drugs and tested at a predetermined time of peak action until at least three points were established in the range between and 100% seizure protection in the instance of the ED or minimum neurotoxicity with respect to the TD The results were then plotted on a logarithmic probability paper and a regression line was fitted to the plotted points. From this plot the respective TD ED and 95% fiducial limits for protection indexes were calculated by the method of Lichfield and Wilcoxon as described in the Journal of Pharmacology and Experimental Therapeutics, 96:99, 1949.
the described cocoa butter mixture one hour before Metrazole injection as described in the preceding paragraph. Ten control mice were also administered the same dosage of Metrazole. In the control group, nine out of ten mice died, while in the group receiving the ethyl ester of di-n-propylacetic acid, five out of ten survived.
TABLE III Compound MES, PI. L.F. EST, PI. S.C. Met, Pl.
mg./kg. rug/kg. mgJkg.
DPA Sodium 605 330 265 (484-756) 1. 0 (226-482) 3. (151-466) 4. 4 Phenobarbital 30.0 2 18. 5
(23.6-38.1) 2.3 (13. 3-30. 0) 3.5 (12. 7-26. 8) 3.8 Diphenylhydantoin 14. 4 25. 0 Ineffective (12. 0-17. 3) 5.8 (16.7-37.5) 3.4 Trimethadione 1, 190 430 410 (1, 063-1, 333) 1. 0 (307-602) 2. 7 (273-615) 2. 6 Phenacemide 82 94 In the foregoing table a total of aproximately 95 mice TABLE IV were employed to determlne the ED for sodlum di-npropylacetate. From these and from the TD values the Dose fDi Number or Time MES, L.F. EST and S.C. Met tests, the protechve lndexes p y t- Animals Iut erval Results were computed. For the other anti-convulsant agents 72 m e (11') mice were used for each drug for the same purpose. 70 3 l 2 Seizures 1 mm m An evaluation of the protective indexes in Table III tection, p p indicates the DPA sodium has very favorable indexes. g armpm Comparison of the P.I.s as derived from the various tests tectionj p indicates that DPA sodium ranks second by the L.F. EST 2 2 1 1 partial P test, second by the S.C. Met test and fourth by the MES test. Thus, DPA sodium has a satisfactory margin of safety. It is also effective in all three standard anticonvulsant tests.
EXAMPLE IV Ethyl di-n-propylacetate Ethyl di-n-propylacetate is an oily liquid which has been prepared by Burton, American Chemical Journal, 3, 390 18-81).
The ethyl ester was rectally administered in the herein described cocoa butter mixture to five rabbits in a dosage of 240 mg./kg. One hour thereafter the rabbits were administered the designated dosage of Metrazole. One of the animals was completely protected; two were partially protected; and one was not protected.
The subject compound was also rectally administered in a dosage of 200 mg./ kg. in the described cocoa butter mixture to ten mice. They were subjected to the Metrazole test outlined at B(1) for mice, one hour after administration of the ethyl ester. One half of the mice were found to be fully protected from death.
Ten additional mice were rectally given 119 mg./ kg. in
Ten mice were intraperitoneally administered 180 mg./kg. of the amide compound in an aqueous solution and after a period of one hour were given the Metrazole injection according to Mice Test No. B(1). This resulted in survival of the ten mice. A 50% survival was found when 12 mice were intraperitoneally given 45 mg./ kg. in the previously described solution and subjected to the same test.
The amide derivative was rectally administered in the described cocoa butter mixture to ten mice in a dosage of 200 mg./ kg. Ten additional mice served as a control group. All 20 were subjected after administration to the Metrazole Test No. 13(1). All the mice in the control group died while there were no deaths among the mice receiving the amide compound. Among the group receiving the compound, only three had clonic movements of the head with no tonic seizures.
EXAMPLE VI Di-n-propylacetyl urea Di-n-propylacetyl urea in a colorless crystalline material. Its preparation is described by Fischer and Dilthey in Annalen der Chemie, 335, 367 (1904).
Table V represents the results of previously described rectal administration of various doses of the urea compound administered to 14 rabbits. The number of animals receiving the specified dosages is indicated in Table V along with the time between administration and injection of Metrazole.
protection.
The urea compound was also found eflective in 50% of 12 mice when administered rectally in a dosage of 100 mg./kg. according to .the procedure outlined in the previous examples and tested according to Test No. B(l) with a one hour interval between administration of the urea derivative and the Metrazole.
Additional tests were conducted on 20 mice. Ten mice rectally received 126 mg./kg. of the urea compound as previously described and ten others served as controls. One hour after administration of the compound, ten mice were given the Metrazole test described in Test No. B-(1). In the group not receiving the urea derivative, nine out of ten mice died whereas in the group receiving the urea compound eight out of ten survived.
EXAMPLE VII Sodium Z-isopropylvalerate 2-isopropylvaleric acid can be prepared by the method of E. Fischer, Holzapfel and Gwinner, Berichte d. Dentschen Chemisehen Gesellschaft, vol. 45, p. 256. The sodium salt can be conveniently made according to the procedure described in Example XI.
A dose of the sodium salt equivalent to 200 mg./kg. of the valeric acid was administered intraperitoneally in an aqueous solution .to ten mice. The mice were tested against Metrazole according to the procedure outlined for mice at B=(l). Ten additional mice served as controls. In the group not receiving the sodium salt, all died while all survived in the group receiving the valeric acid salt.
Eleven rabbits each weighing 2 /2 kilos were also given intraperitoneally dosages of the sodium salt of the valeric acid compound in an aqueous solution. They were tested according to the procedure outlined under A-Rabbits The results are shown in Table VI with the time interval between administration of Metrazole and the valeric acid salt being 40 minutes.
EXAMPLE VIII Sodium di-n-butylacetate Di-n-butylacetic acid can be prepared by the method of Levene and Cretcher as described in the Journal of Biological Chemistry, vol. 33, p. 508. The sodium salt is I prepared according to the procedure described in Example' X.
8 A total of 15 rabbits were administered the sodium salt of di-n-butylacetic acid. The same method for administering and testing the dibutylacetic acid salt in the rabbits was employed as described in the previous example. The results are described in Table VII.
TABLE VII Dose of Sodium Number of Di-n-butyl- Rabbits Results acetate, mg/kg.
225 3 2 partial protection, 1
seizure. 337.5 7 4 total protection, 3 partial protection. 450 5 4 total protection, 1 partial protection.
It should be noted that with the animals receiving the 337.5 and 450 mg./kg. dosages a hypnotic effect was also observed.
When ten mice were intraperitoneally injected with an aqueous solution of sodium di-n-butylacetate at a dosage of 100 mg./kg. according to the procedure for testing mice as outlined in the previous example, 100% were protected. All the ten mice which served as controls, died.
EXAMPLE IX 1-(di-n-propylacetyl)-5,5-diphenylhydantoin HN C=O To a boiling solution of 30.2 g. of 5,5-diphenylhydantoin in 35 ml. of pyridine, 19.5 g. of di-n-propylacetylchloride were added. The resulting mixture was refluxed for ten hours then cooled and diluted with 25 ml. of benzene. The diluted solution was extracted with ml. of a 6 N hydrochloric acid solution. A slight amount of unreacted diphenylhydantoin crystallized and was removed by filtration. The filtrate was transferred into a separatory funnel. The upper organic layer was washed with water and the solvent was removed subsequently by vacuum distillation at 60 C. To the concentrated reaction mixture was added ml. of 90% methanol and 20 ml. of heptane with the desired residue being partitioned between the methanol and the heptane. The methanolic layer was separated, heated to boiling and enough water added to cause a slight turbidity. On cooling the methanolic solution, the product, 1(di-n-propy1acetyl)-5,5-phenylhydantoin crystallized in the form of needles. It was collected on.a filter and crystallized from aqueous methanol. The di-n-propylacetyl-S,S-diphenylhydantoin is characterized by its melting point of l50.5-l52.5 C.
The acylated hydantoin was administered in a dosage of 200 and 300 mg./kg. by the intraperitoneal route in an olive oil suspension. Eight rabbits were employed and tested according to the herein described procedure for testing rabbits with a 40 minute interval being employed between the administration of .the subject compound and the Metrazole.
The results as shown in Table VIII.
TABLE VIII Dose of l-(di-n- Number of p ropyl-acetyl)-5,5- Rabbits Results dlphonylhydautoin 200 4 1 total protection. 2 partial protection, 1 seizure. 300 4 2 total protection, 2 partial protection.
Examples X to XIII illustrate dosage formulations for administering sodium di-n-propylacetate as well as di-npropylacetic acid, di-n-propylacetamide and di-n-propyl acetyl urea. In the instance of Example XI, the formulation of the sodium derivative is described as being made from di-n-propylacetic acid.
EXAMPLE X Oral solution of 20% sodium di-n-propylacetate Ingredient: Amount, grams Di-n-propylacetic acid 20 Sodium hydroxide 30% 17 Water, q.s. 100
The di-n-propylacetic acid is neutralized with sodium hydroxide and the water is subsequently added to this mixture to form a cloudy solution. The pH is adjusted to 7.5 with the dropwise addition of the sodium hydroxide solution. After adjustment of the pH, the solution subsequently becomes clear. Twenty drops of the formulated solution contain 20 mg. of the acid.
EXAMPLE XI Di-n-propylacetic acid suppositories Ingredient: Amount Dl-n-propylacetic acid -mg 200 Glycocoll -mg 200 Cocoa butter, q.s g 2 The butter is melted and the di-n-propylacetic acid is admixed therewith. Previously, the glyc'ocoll is finely ground, and added to the agitated mixture. The mass is poured into a suitable mold and rapidly cooled.
EXAMPLE XII Di-n-propylacemmide and di-n-propylacetyl urea suppositories Ingredient: Amount Di-n-propylactamide mg 200 Cocoa butter, q.s g 2 The butter is melted and the di-n-propylaceta mide is dissolved therein. The mixture is cooled slowly while being agitated and is then poured into a suitable mold and cooled rapidly.
The same procedure is employed for formulating 200 mg. suppositories of di-n-propylacetyl urea.
EXAMPLE XIII Sodium di-n-propylacetaze tablets In illustration of a tablet dosage 1000 tablets each containing 100 mg. of active material were prepared by mixing together 100 grams of sodium di-n-propylacetate, three grams of corn starch and cc. of ethylether. The granulation is forced through a screen and dried. To the dried material is added five grams of talc and two grams of magnesium stearate as lubricants; and twelve grams of additional corn starch as a disintegrator. The material thus prepared is compressed into 1000 tablets each containing 100 mg. of active material. The tablets can be scored if and Adams, JACS, vol. 52, p. 1290. It should be under stood that the alkali metal salts of the acids specifically or generally described herein, and whether disclosed in the salt or ester form, can be employed according to the teachings of this invention. Such alkali metal salts include sodium, potassium and lithium. The group of lower alkyl esters formed from the disclosed acids and alcohols containing a total of 1-5 carbon atoms can also be employed; this group includes the methyl, ethyl, propyl and isopropyl esters a well as the esters of the isomeric butyl and pentyl alcohols. In addition, to the salts and the esters previously described, the urea and the amide derivatives of the herein described acids can also be utilized.
Certain literature references have been given with respect to specific compounds. By obvious adaptations of these methods, all of the compounds described herein can be prepared. The esters can be prepared by known procedures from the acids falling within the scope of the general formula and from the corresponding alcohols. The urea and the amides can likewise be prepared, for example, by known methods from the acid by converting them to the acid chloride and further reacting with urea and ammonia, respectively. The chlorides of the acids falling within the scope of this invention can also be utilized to form acid derivatives of 5,5-diphenylhydantoin pursuant to the procedure outlined in Example IX.
It will thus be seen from the foregoing description of the present invention that there are now provided novel anticonvulsant agents which are highly effective yet are low in toxicity. The present anticonvulsant compounds are additionally valuable because they can be administered by several routes without loss of effectiveness. Further, the dialkyl-substitt1ted acetic acids and derivatives thereof provide fast protection and are useful in protection against the various types of seizures in which epilepsy manifests itself.
Others may readily adapt the invention for use under various conditions of service by employing one or more of the novel features disclosed or equivalents thereof. All such which do not depart from the spirit of this disclosure are intended to be within its scope, which at present advised is best defined in the appended claims.
I claim:
1. A method of controlling convulsions and seizures in warm-blooded animals in need of such therapy comprising administering to said animals in an amount sufficient to control convulsions and seizures, a compound of the formula Alki (I C H C Y Alkg wherein Alk is lower alkyl containing 2-7 carbon atoms inclusive and Alk is lower alkyl containing 3-7 carbon atoms both forming straight and branched chained alkyl groups; Y is selected from the group consisting of OM, OR, NHZ and 5,5-diphenylhydantoinyl groups, M is selected from the group consisting of hydrogen, sodium, potassium and lithium, R is lower alkyl containing l-S carbon atoms inclusive, and Z is selected from the group consisting of hydrogen and carbamyl.
2. A method of controlling convulsions and seizures in warm-blooded animals in need of such therapy comprising administering to said animals an antiepileptic drug and a compound of the formula Alk; (l'l) CH-C-Y inclusive and Alk is lower alkyl containing 3-7 carbon atoms inclusive both forming straight and branched chained alkyl groups; Y is selected from the group consisting of OM, OR, NHZ and 5,5-diphenylhydantoinyl groups, M is selected from the group consisting of hydrogen, sodium, potassium and lithium, R is lower alkyl containing 1-5 carbon atoms inclusive, and Z is selected from the group consisting of hydrogen and carbamyl.
3. A method of controlling convulsions and seizures in warm blooded animals in need of such therapy comprising administering to said animals an anti-epileptic drug and a compound of the formula Alk (I) CHCY A kg
wherein Alk is lower alkyl containing 2-7 carbon atoms inclusive and Alk is lower alkyl containing 3-7 carbon atoms inclusive both forming straight and branched chained alkyl groups and Y is selected from the group consisting of amino and ureido.
4. A method of controlling convulsions and seizures in warm-blooded animals in need of such therapy comprising administering to said animals in an amount suflicient to control said convulsions and seizures, a compound of the formula wherein R is lower alkyl containing 1-5 carbon atoms inclusive.
5. A method of controlling convulsions and seizures in warm-blooded animals in need of such therapy which comprises administering di-n-propylacetic acid to said animals in an amount sufficient to control said convulsions and seizures.
6. A method of controlling convulsions and seizures in Warm-blooded animals in need of such therapy which comprises administering sodium di-n-propylacetate to said animals in an amount sufficient to control said convulsions and seizures.
7. A method of controlling convulsions and seizures in warm-blooded animals in need of such therapy which comprises administering ethyl di-n-propylacetate to said animals in an amount suflicient to control said convulsions and seizures.
8. A method of controlling convulsions and seizures in Warm-blooded animals in need of such therapy which comprises administering di-n-propylacetamide to said animals in an amount sufficient to control said convulsions and seizures.
9. A method of controlling convulsions and seizures in warm-blooded animals in need of such therapy which comprises administering di-n-propylacetyl urea to said animals in an amount sufficient to control said convulsions and seizures.
10. A method of controlling convulsions and seizures in warm-blooded animals in need of such therapy which comprises administering sodium Z-isopropylvalerate to said animals in an amount sufficient to control said convulsions and seizures.
11. A method of controlling convulsions and seizures in warm-blooded animals in need of such therapy which comprises administering sodium di-n-butylacetate to said animals in an amount sufficient to control said convulsions and seizures.
12. A method of controlling convulsions and seizures in warm-blooded animals in need of such therapy which comprises administering 1-(di-n-propylacetyl)-5,5 diphenylhydantoin to said animals in an amount sufficient to control said convulsions and seizures.
Alk O I CH-C-Y Alkg wherein Alk is lower alkyl containing 2-7 carbon atoms inclusive and Alk is lower alkyl containing 37 carbon atoms inclusive both forming straight and branched chained alkyl groups; Y is selected from the group consisting of OM, OR, ureido and 5,5-di-phenylhydantoinyl groups; M is selected form the group consisting of hydrogen, sodium, potassium and lithium, R is lower alkyl containing 1-5 carbon atoms inclusive and a physiologically acceptable solid or fluid carrier for said compound where in the instance said fluid is water the resulting composition is sterile.
15. A therapeutic composition useful in the control of convulsions and seizures comprising an effective amount of a compound of the formula CHa-CHz-CH: (H)
CH-CO R wherein R represents straight or branched chained lower alkyl containing 1-5 carbon atoms inclusive and a physiologically acceptable solid or fluid carrier where in the instance said fluid carrier is water, the resulting composition is sterile.
16. A therapeutic composition useful in the control of convulsions and seizures comprising an effective amount of di-n-propylacetic acid and a physiologically acceptable solid or fluid carrier where in the instance said fluid is water the resulting composition is sterile.
17. A therapeutic composition useful in the control of convulsions and seizures comprising an effective amount of sodium di-n-propylacetate and a physiologically acceptable solid or fluid carrier where in the instance said fluid is water the resulting composition is sterile.
18. A therapeutic composition useful in the control of convulsions and seizures comprising ethyl di-n-propylacetate present in the range of about 50 mg. to about 1000 mg, and a solid physiologically acceptable carrier in a unit dosage form.
19. A therapeutic composition useful in the control of convulsions and seizures comprising di-n-propylacetyl urea present in the range of about 50 mg. to about 1000 mg, and a solid physiologically acceptable carrier in a unit dosage form.
20. A therapeutic composition useful in the control of convulsions and seizures comprising sodium 2-isopropylvalerate present in a range of about 50 mg. to about 1000 mg., and a solid physiologically acceptable carrier in a unit dosage form.
21. A therapeutic composition useful in the control of convulsions and seizures comprising l-(di-n-propylacetyl)-5,5-diphenylhydantoin present in the range of about about 50 mg. to about mg, and a solid physiologically acceptable carrier in a unit dosage form.
22. A therapeutic composition useful in the control of convulsions and seizures comprising sodium di-n-butylacetate present in a range of about 50 mg. to about 100 mg., and a solid physiologically acceptable carrier in a unit dosage form.
23. 1- di-n-propylacetyl -5 ,5 -diphenylhydantoin.
(References on following page) 13 14 References Cited Fischer & Dilthey, Berichte d. Deutschen Chemischen Gesellschaft, 35, 853 (1902). FOREIGN PATENTS Fischer & 'Dilthey, Annalen der Chemie, 335-367 672,475 5/1952 Great Britain. (1904)- 5 Levene 8: Cretcher, I. of Biol. Chemistry, v61. 33, p. OTHER REFERENCES 508.
Cherhical Decennial Index, vol. 31-40, 1937-46 P-Z, ALBERT MEYERS primary Examine p. 9627;;Valeramide.
E. Fischer et a1., Berichte d. Deutschen Chemischen SAM ROSEN Exammer' Gesellsh aft, vol. 4 5, p. 256. 10 STANLEY FRIEDMAN, MARTIN J. COHEN,
E. Oberrelt, Benchte, v01. 29, 19982001 (1896). Assistant Examiners.

Claims (1)

1. A METHOD OF CONTROLLING CONVULSIONS AND SEIZURES IN WARM-BLOODED ANIMALS IN NEED OF SUCH THERAPY COMPRISING ADMINISTERING TO SAID ANIMALS IN AN AMOUNT SUFFICIENT TO CONTROL CONVULSIONS AND SIEZURES, A COMPOUND OF THE FORMULA ALK1-CH(-ALK2)-CO-Y WHEREIN ALK1 IS LOWER ALKYL CONTAINING 2-7 CARBON ATOMS INCLUSIVE AND ALK2 IS LOWER ALKYL CONTAINING 3-7 CARBON ATOMS BOTH FORMING STRAIGHT AND BRANCHED CHAINED ALKYL GROUPS; Y IS SELECTED FROM THE GROUP CONSISTING OF OM, OR, NHZ AND 5,5-DIPHENYLHYDANTIONYL GROUPS, M IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, SODIUM, POTASSIUM AND LITHIUM, R IS LOWER ALKYL CONTAINING 1-5 CARBON ATOMS INCLUSIVE, AND Z IS SELECTED FROM THE GROUP CONSISTING OF HYDROGEN AND CARBAMYL. 23. 1-(DI-N-PROPYLACETYL)-K,5-DIPHENYLHYDANTOIN.
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US20050276850A1 (en) * 2004-06-15 2005-12-15 Nilobon Podhipleux Controlled release sodium valproate formulation
US20050276848A1 (en) * 2004-06-15 2005-12-15 Nilobon Podhipleux Sustained release neutralized divalproex sodium
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FR2470758A1 (en) 1979-12-07 1981-06-12 Sanofi Sa METHOD FOR FIXING ALKYL GROUPS ON A CARBONIC CHAIN CARRYING A FUNCTIONAL GROUP
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DE3709230A1 (en) * 1987-03-20 1988-10-06 Desitin Arzneimittel Gmbh NEW VALPROINIC ACID CALCIUM
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US4238389A (en) * 1979-02-12 1980-12-09 Syva Company Valproate conjugation using dicarbonyls
US4442124A (en) * 1979-06-08 1984-04-10 Texcontor-Anstalt Valproic acid ester with antiepileptic and anticonvulsant activity and pharmaceutical compositions therefrom
US4301176A (en) * 1980-08-18 1981-11-17 Warner-Lambert Company Method of administering calcium valproate
EP0078785A1 (en) * 1981-11-04 1983-05-11 "PHARLYSE", Société Anonyme Salts of valproic acid, their preparation and their use
US4595695A (en) * 1983-01-05 1986-06-17 Teva Pharmaceutical Industries Ltd. 1'-ethoxycarbonyloxyethyl ester of valproic acid, its preparation and pharmaceutical compositions containing it
JPS6041610A (en) * 1983-07-20 1985-03-05 サノフイ Novel pharmaceutical composition based on valproic acid and its manufacturing method
EP0133110B1 (en) * 1983-07-20 1988-02-17 Sanofi Pharmaceutical composition on the basis of valproic acid, and its manufacturing process
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JPH0696524B2 (en) 1983-07-20 1994-11-30 サノフイ Novel pharmaceutical composition based on valproic acid and process for producing the same
WO1994006743A1 (en) * 1992-09-12 1994-03-31 Heinz Nau Analogues of vpa used as anti-epileptica
JP2887419B2 (en) 1992-09-12 1999-04-26 ナウ、ハインツ Antiepileptic drugs similar to valproic acid
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AU683425B2 (en) * 1992-09-12 1997-11-13 Heinz Nau Analogues of vpa used as anti-epileptica
US5786380A (en) * 1992-09-12 1998-07-28 Nau; Heinz VPA-analogous antiepileptics
US7569609B2 (en) 1993-06-01 2009-08-04 Ono Pharmaceutical Co., Ltd. Pentanoic acid derivatives
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EP0632008A1 (en) * 1993-06-01 1995-01-04 Ono Pharmaceutical Co., Ltd. Pentanoic acid derivatives
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US5672746A (en) * 1994-08-30 1997-09-30 American Biogenetic Sciences, Inc. Antiproliferative and neurotrophic molecules
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US6458840B2 (en) 1998-06-22 2002-10-01 American Biogenetic Sciences, Inc. Use of valproic acid analog for the treatment and prevention of migraine and affective illness
US6268396B1 (en) 1998-06-22 2001-07-31 American Biogenetic Sciences, Inc. Use of valproic acid analog for the treatment and prevention of migraine and affective illness
US6610326B2 (en) 2001-02-16 2003-08-26 Andrx Corporation Divalproex sodium tablets
US20030211148A1 (en) * 2001-02-16 2003-11-13 Chih-Ming Chen Divalproex sodium tablets
US20040105886A1 (en) * 2001-02-16 2004-06-03 Chih-Ming Chen Divalproex sodium tablets
US20050276848A1 (en) * 2004-06-15 2005-12-15 Nilobon Podhipleux Sustained release neutralized divalproex sodium
US20050276850A1 (en) * 2004-06-15 2005-12-15 Nilobon Podhipleux Controlled release sodium valproate formulation
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US3301754A (en) 1967-01-31
GB980279A (en) 1965-01-13

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