WO1996001806A1 - Derives de glycinamide, compositions pharmaceutiques les contenant et procede dans lesquels ils sont utilises - Google Patents

Derives de glycinamide, compositions pharmaceutiques les contenant et procede dans lesquels ils sont utilises Download PDF

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Publication number
WO1996001806A1
WO1996001806A1 PCT/US1995/009413 US9509413W WO9601806A1 WO 1996001806 A1 WO1996001806 A1 WO 1996001806A1 US 9509413 W US9509413 W US 9509413W WO 9601806 A1 WO9601806 A1 WO 9601806A1
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WIPO (PCT)
Prior art keywords
subject
amount
effective
compound
comprises administering
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PCT/US1995/009413
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English (en)
Inventor
Meir Bialer
Saleem Hadad
Original Assignee
Yissum Research Development Company Of The Hebrew University Of Jerusalem
Lemon Company
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Publication date
Application filed by Yissum Research Development Company Of The Hebrew University Of Jerusalem, Lemon Company filed Critical Yissum Research Development Company Of The Hebrew University Of Jerusalem
Priority to AU31475/95A priority Critical patent/AU3147595A/en
Publication of WO1996001806A1 publication Critical patent/WO1996001806A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated

Definitions

  • the present invention relates to new glycinamide derivatives. More particularly the present invention relates to novel glycinamide derivatives to pharmaceutical compositions containing the same and to methods of treatment utilizing the same, especially in the treatment of epileptic seizures, convulsions and other central nervous system dysfunctions.
  • Valproic acid (2-propylpentanoic acid, hereinafter VPA) and its alkali salts are major drugs in the arsenal of drugs for the treatment of epileptic seizures and convulsions.
  • VPA is a major drug in the arsenal of drugs for the treatment of epileptic seizures and convulsions.
  • approximately 25% of epileptic patients do not respond to current treatment.
  • VPA itself has considerable adverse effects, including hepatotoxicity and teratogenicity.
  • VPA and 2-ene-VPA-related glycine amides have been disclosed by Granneman, et al., Xenobiotica. 14. 375 (1984), to be minor metabolites of VPA.
  • an examination of the mass spectral date therein shows that those compounds are in fact VPA and 2-ene-VPA glycine and cannot be glycinamide conjugates, wherein the glycine nitgrogen moiety is attached to the VPA or 2-ene-VPA carbonyl.
  • R is a 7-carbon branched aliphatic group and pharmaceutically-acceptable salts thereof with the proviso that R is not 1-propylbutyl.
  • R is a C_-branched alkyl group or an alkadienyl group and the compounds of the present invention are selected from the group consisting of N-(2-ethyl-3- methy1 pentanoy1)glycinamide, N-[di-2-propy1)acety1] glycinamide, N[dimetrylbutyl-acetyl)glycinamide, N[ (2-ethyl- 2-isobutyl) acety1/glycinamide, and N-[diallyl-acetyl) glycinamide.
  • the compounds according to the present invention are selected from the group consisting of N-(2-ethyl-3- methyl pentanoyl) glycinamide and N-[di-2-propyl)acetyl] glycinamide
  • the invention further provides a pharmaceutical composition which comprises a compound of general formula I or a pharmaceutically acceptable salt thereof in a therapeutically effective amount and in combination with a pharmaceutically acceptable carrier.
  • the invention encompasses a pharmaceutical composition as hereinabove described wherein the carrier is a solid and the composition is a tablet.
  • the invention also encompasses a pharmaceutical composition as hereinabove described wherein the carrier is a gel and the composition is a suppository.
  • the invention further encompasses a pharmaceutical composition as hereinabove described wherein the carrier is a liguid and the composition is a solution.
  • the invention provides a method of treating a subject afflicted with epilepsy which comprises administering to the subject an amount of a compound according to the invention effective to treat epilepsy in the subject.
  • the invention also provides a method of treating a subject afflicted with affective illness which comprises administering to the subject an amount of a compound according to the invention effective to treat the affective illness in the subject.
  • the invention additionally provides a method of treating a subject afflicted with cognitive disorders which comprises administering to the subject an amount of compound according to the invention effective to treat cognitive disorders in the subject.
  • the invention further provides a method of treating a subject afflicted with neurodegenerative disease which comprises administering to the subject an amount of compound according to the invention effective to treat neurodegenerative disease in the subject.
  • the invention also provides a method of treating a subject afflicted with dyskinesiae which comprises administering to the subject an amount of compound according to the invention effective to treat dyskinesiae in the subject.
  • the invention still further provides a method of treating a subject afflicted with neurotoxic injury which comprises administering to the subject an amount of compound according to the invention effective to treat neurotoxic injury in the subject.
  • the invention provides a method of alleviating convulsions in a subject afflicted with epilepsy which comprises administering to the subject an amount of compound according to the invention effective to alleviate convulsions in the subject.
  • the invention also provides a method of treating a subject afflicted with stroke which comprises administering to the subject an amount of compound according to the invention effective to treat stroke in the subject.
  • the invention additionally provides a method of treating a subject afflicted with brain ischemia which comprises administering to the subject an amount of compound according to the invention effective to treat brain ischemia in the subject.
  • the invention still further provides a method of treating a subject afflicted with head trauma injury which comprises administering to the subject an amount of compound according to the invention effective to treat head trauma injury in the subject.
  • the compounds of the present invention are potent anti-convulsant agents in conventional models of human epilepsy.
  • Several of the compounds have a surprisingly better therapeutic profile than milacemide, VPA, VPA amide analogs or N-valproyl glycine.
  • the compounds of the invention are highly effective in the MES (maximal electroshock) and scMet (subcutaneous pentylenetetrazol) tests.
  • the median effective doses (ED ) of the agents claimed herein are considerably lower than those required to produce neurological impairment.
  • results in animal models distinguish the compounds of the present invention from other anti-epileptic agents and indicate that some of the disclosed compounds are effective against generalized and partial seizures, in addition to other forms of epilepsy, including absence seizures.
  • Some of the compounds of this invention possess chiral centers. It is a further embodiment of this invention that these compounds may comprise substantially pure D or L enantiomers or racemic mixtures.
  • the compounds of general formula I are diamides of carboxylic acids and may be prepared via conventional amidation processes, e.g. by reacting an activated form of the aforementioned acid either with glycinamide or a glycine ester with subsequent conversion to the amide of formula I.
  • the preferred method of the preparation of compounds of formula I consists of combining an aqueous solution of glycinamide or a suitable salt, preferably hydrochloride with the appropriate carboxylic acid chloride in a suitable water immiscible organic solvent e.g. dichloromethane or toluene in the presence of a suitable organic or inorganic base, preferrably triethylamine at a temperature ranging between 0 and 50 C, preferably at 0-10 C, for a period of 1 to 24 hours, preferably 1-5 hours.
  • the base must be present in a quantity sufficident to neutralize the hydrohalic acid formed during the reaction.
  • the amount of the compound incorporated in the pharmaceutical composition may vary widely.
  • a pharmaceutical composition in unit dose form for treatment of the disorders listed hereinabove comprises 10 to 500 mg of the active ingredient.
  • the compounds of the present invention are administered in a pharmaceutical composition which comprises the compound and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier encompasses any of the standard pharmaceutically accepted carriers, such as a phosphate-buffered saline solution, water, emulsions such as an oil/water emulsion or a triglyceride emulsion, various types of wetting agents, tablets, coated tablets, and capsules.
  • An example of an acceptable triglyceride emulsion useful in the intravenous and intraperitoneal administration of the compounds is the triglyceride emulsion commerciallyl known as Intralipid.
  • such carriers typically contain excipients such a starch, milk, sugar, certain types of clay, gelatin, stensic acid, talc, vegetable fats or oils, gums, glycols, or other known excipients.
  • excipients such as starch, milk, sugar, certain types of clay, gelatin, stensic acid, talc, vegetable fats or oils, gums, glycols, or other known excipients.
  • Such carriers may also include flavor and color additives or other ingredients.
  • the administration of the pharmaceutical composition may be effected by any of the well-known methods, including, but not limited to, oral, intravenous, intraperitoneal, intramuscular or subcutaneous or topical administration.
  • Topical administration can be effected by any method commonly known to those skilled in the art and includes, but is not limited to, incorporation of the pharmaceutical composition into creams, ointments, or transdermal patches.
  • the reaction mixture is then stirred for 2 hours, after which the organic layer is evaporated under reduced pressure.
  • the precipitate is then extracted with two portions of 60 ml chloroform.
  • the chloroform is then washed twice with 50 ml of water, 50 ml of 5% NaHCO. solution and 50 ml of saturated NaCl solution, after which it is evaporated to dryness.
  • the solid precipitate is dissolved with 15 ml of chloroform and heated in a water bath while hexane is added until turbidity appeared.
  • the mixture is then left at room temperature until smooth crystals are obtained.
  • the crystals are then filtered and dried in a vacuum to give 12.5 g (»62%) of valnoctyl glycinamide.
  • a 50 ml solution of butyl lithium 10 M in hexane is placed under a stream of nitrogen at room temperature.
  • 75 ml of dry chisopropyla ine and 250 ml of dry tetrahydrofuran are then added.
  • the suspension is cooled to -80°C by a bath containing MeOH and liquid N_ .
  • 75 ml (0.5 mole) of ethylisovalerate is added rapidly and stirred and cooled to -78°C for 40 minutes.
  • a mixture of 65 ml (0.65 mole) of 2-Iodopropane and 25 ml (0.12 ml) of hexamethylphosphoramide (HMPA) is then added while cooling is kept to -78°C for 40 minutes. After heating to room temperature, the reaction mixture is stirred for 12 hours. The reaction mixture is then washed twice with 150 ml of cool water and saturated sodium chloride solution, after which the upper organic layer is separated, and the product 2-isopropyl ethyl isovalerate is distilled under reduced pressure (150°C/5mm/Hg) . The product is then transferred to a 500 ml flask, and a solution of 100 ml of 50% KOH and 150 ml of MeOH is added.
  • HMPA hexamethylphosphoramide
  • the reaction mixture is stirred for 2 hours after which the organic layer is evaporated under reduced pressure.
  • the precipitate is extracted with two portions of 60 ml chloroform.
  • the chloroform is washed twice with 50 ml of water, 5% NaHCO. solution, and 50 ml of saturated NaCl solution.
  • the organic layer is then evaporated to dryness.
  • the solid precipitate is dissolved with 15 ml chloroform and heated in a water bath while hexane is added until turbidity appears.
  • the mixture is then left at room temperature until smooth crystals are obtained, at which time it is filtered and dried in a vacuum to give 13.4 g (or 67%) of diisopropylacetylglycinamide (DIGD) .
  • DIGD diisopropylacetylglycinamide
  • EXAMPLE 3 BIOLOGICAL ACTIVITY o
  • the compound provided herein were screened for their ability to protect against chemically and electrically induced convulsions, in at least two different models of epilepsy.
  • the first model the subcutaneous pentylenetetyrazol (s.c. Met) seizure threshold test, is a standard screening procedure to show efficacy for agents against absence seizures.
  • the second model the maximal electroshock (MES) test, is used to show efficacy for anti- epileptic agents against generalized seizures.
  • MES maximal electroshock
  • convulsions were inhibited or prevented in mice after intraperitoneal (i.p.) administraiton and/or in rats after oral (p.o) administration of the compounds.
  • mice i.p. administration
  • rats p.o. aministration
  • positional sense test and gait and stance test See E.A. Swinyard, et al., in "Anti-Epileptic Drugs," ed. by R.H. Levy, et al.. Raven Press, New York, at 85-100 (1989).

Abstract

L'invention concerne d'une part des dérivés de glycinamide de formule générale (I) où R représente un groupe aliphatique ramifié à 7 atomes de de carbone, et d'autre part des sels pharmaceutiquement acceptables de ces derniers, à condition que R ne représente pas 1-propylbutyle.
PCT/US1995/009413 1994-07-12 1995-07-11 Derives de glycinamide, compositions pharmaceutiques les contenant et procede dans lesquels ils sont utilises WO1996001806A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU31475/95A AU3147595A (en) 1994-07-12 1995-07-11 Glycinamide derivatives, pharmaceutical compositions containing the same and methods utilizing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US27419494A 1994-07-12 1994-07-12
US274,194 1994-07-12

Publications (1)

Publication Number Publication Date
WO1996001806A1 true WO1996001806A1 (fr) 1996-01-25

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PCT/US1995/009413 WO1996001806A1 (fr) 1994-07-12 1995-07-11 Derives de glycinamide, compositions pharmaceutiques les contenant et procede dans lesquels ils sont utilises

Country Status (4)

Country Link
AU (1) AU3147595A (fr)
IL (1) IL114483A0 (fr)
WO (1) WO1996001806A1 (fr)
ZA (1) ZA955800B (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0046707A1 (fr) * 1980-08-27 1982-03-03 Sanofi S.A. Dérivés de l'acide amino-4 butyrique et les médicaments, actifs notamment sur le système nerveux central, en contenant
WO1990014429A1 (fr) * 1989-05-25 1990-11-29 Novo Nordisk A/S Procede pour la preparation d'amino-acides n-acyle et des amides d'amino-acides n-acyle

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0046707A1 (fr) * 1980-08-27 1982-03-03 Sanofi S.A. Dérivés de l'acide amino-4 butyrique et les médicaments, actifs notamment sur le système nerveux central, en contenant
WO1990014429A1 (fr) * 1989-05-25 1990-11-29 Novo Nordisk A/S Procede pour la preparation d'amino-acides n-acyle et des amides d'amino-acides n-acyle

Also Published As

Publication number Publication date
ZA955800B (en) 1996-02-22
IL114483A0 (en) 1995-11-27
AU3147595A (en) 1996-02-09

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