Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/235—Saturated compounds containing more than one carboxyl group
  • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
  • C07C59/265—Citric acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
  • A61P21/06—Anabolic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/02—Nutrients, e.g. vitamins, minerals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
  • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
  • C07C57/13—Dicarboxylic acids
  • C07C57/15—Fumaric acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
  • C07C59/235—Saturated compounds containing more than one carboxyl group
  • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups

Definitions

• the present invention relates to a structure and method for producing stable salts of ⁇ - alanine and organic acids. More specifically, formed salts of the present invention are particularly well suited for oral administration thereby the formed salts may provide enhanced nutritional and/or therapeutical efficacy in relation to the individual components alone.
• Supplementation with other deprotonated organic acids can be used for attenuation of metabolic acidosis
• citrate lacks all of its acidic protons, yielding three carboxylate functionalities that can readily take up free protons Since all of acidic protons are removed, the citrate has three sites which are capable of taking up free protons in serum and working muscle Therefore, administration of deprotonated organic acids can inhibit the decrease in pH, which is a result of ATP hydrolysis, thereby leading to less fatigue resulting from the inhibition of enzymes that are vital for energy production and the force-producing capacity of muscles
• the compounds are salts comprising an organic acid and /3- alanine, and having a structure of Formula 1
• the present invention is directed towards the structures and synthesis of salts of /3-alanine and organic acids.
• the present invention provides for the production of stable salts, which may afford a combination of /3-alanine and an organic acid, free of physiologically unsafe additives to an individual upon administration to said individual. Furthermore, the present invention is particularly well suited for use in tablets, capsules, powders, granules, powdered beverage mixes and other forms known in the art of dietary supplements.
• /3-alanine combined with an organic acid forms a non-hygroscopic crystalline powder, which is stable in storage and can be processed without special precautions. Due to the non- hygroscopic nature of the /3-alanine salt it would be understood by one of skill in the art, that the salt is easy to process and is particularly suitable for processing with rapidly running machines, since it does not tend to stick together or become lumpy.
• ' ⁇ -alanine' refers to the chemical beta-alanine, also known as 3- aminopropionic acid. Additionally, as used herein, '/3-alanine' also includes derivatives of /3- alanine such as esters, amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form.
• 'malic acid' refers to the chemical 1 -Hydroxy- 1 ,2-ethanedicarboxylic acid, (CAS Registry No. 6915-15-17), also known as, hydroxybutanedioic acid, hydroxysuccinic acid, malate, or 2-hydroxybutanedioate. Additionally, as used herein, 'malic acid' also includes derivatives of malate such as esters, amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form.
• 'citric acid' refers to the chemical 2-hydroxy-l,2,3-propane-tricarboxylic acid, (CAS Registry No. 77-92-9), also known as, /3-hydroxytricarboxylic acid . Additionally, as used herein, 'citric acid' also includes derivatives of citrate such as esters, amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form.
• 'fumaric acid' refers to the chemical (is)-2-butenedioic acid, (CAS Registry No. 110-17-8), also known as, draws'- 1,2-ethylenedicarboxylic acid, allomaleic acid, and boletic acid. Additionally, as used herein, 'fumaric acid' also includes derivatives of fumarate such as esters, amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form.
• organic acid refers to organic compounds which contain carboxylic acids (-C(O)OH).
• Typical examples of organic acids include, but are not limited to; malic acid, fumaric acid, citric acid, orotic acid, lactic acid, pyruvic acid, and tartaric acid.
• the term 'pharmaceutically acceptable excipients' refers to substances added to produce quality tablets, chewable tablets, capsules, granulates or powders, but which do not provide nutritive value.
• excipients includes monoglycerides, magnesium stearate, modified food starch, gelatin, microcrystalline cellulose, glycerin, stearic acid, silica, yellow beeswax, lecithin, hydroxypropylcellulose, croscarmellose sodium, and crosprovidone.
• the compounds disclosed herein comprise molecules of ⁇ -alanine combined with an organic acid to form a salt having a structure according to Formula 1.
• the aforementioned compound being prepared according to the reaction as set forth for the purposes of the description in Scheme 1 :
• the /3-alanine (1) is dissolved in an excess of hot lower alcohol.
• the lower alcohol is considered to be hot, as would be known by one of ordinary skill in the art
• Preferably the lower alcohol is considered to be hot when heated to a temperature about 5°C below the boiling point of the corresponding lower alcohol.
• the lower alcohol is selected from the group consisting of methanol, ethanol, propanol, and isopropanol These lower alcohols may be used singly or in admixture containing two or more alcohols.
• the organic acid (2) is dissolved into an excess of hot lower alcohol.
• the lower alcohol is considered to be hot, as would be known by one of ordinary skill in the art
• Preferably the lower alcohol is considered to be hot when heated to a temperature about 5 0 C below the boiling point of the corresponding lower alcohol.
• Both solutions above are then mixed together and heated to about the boiling point of the corresponding lower alcohol. If there are solids still present after heating, the solution is filtered while hot to remove any unreacted starting mate ⁇ als. The solution is then allowed to cool to room temperature, covered and refrigerated or cooled until crystallization occurs, preferably for between about 24 to about 48 hours. The resultant crystals are filtered under vacuum and washed with ice cold lower alcohol, yielding a crystalline powder, the /3-alanine organic acid salt (3).
• diethyl ether can be added until the cloud point, as would be known to one of skill in the art, is reached after the mixture is cooled to room temperature, after which the solution is refrigerated or cooled to allow crystallization to complete This will facilitate greater precipitation of the product thus yielding more of the ⁇ - alanme organic acid salt (3), which would be desired in indust ⁇ al settings
• /3-alanme organic acid salts are used advantageously alone or with additional active ingredients, such as, trace elements, vitamins, mineral substances, or other ammo acids as well as, optionally, excipients usually used for the preparation of the respective forms of administration
• the forms of administration include, particularly, all varieties of tablets, both those that are swallowed without being chewed, and tablets to be chewed or dissolved in the mouth of an individual, as well as those that are dissolved in a liquid before being ingested by an individual
• the tablet forms include uncoated tablets, one-layer or multilayer or encased forms or effervescent tablets
• Further preferred forms of administration are capsules of hard and soft gelatin, the latter being particularly suitable to include a liquid core
• /3-alanme organic acid salts can be used advantageously for the preparation of solutions and suspensions and as a powder, either effervescent or granulated

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
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• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Diabetes (AREA)
• Obesity (AREA)
• Hematology (AREA)
• Nutrition Science (AREA)
• Endocrinology (AREA)
• Neurology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Physical Education & Sports Medicine (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Medicinal Preparation (AREA)

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• 2007
  • 2007-12-12 EP EP07855546A patent/EP2231588A4/de not_active Withdrawn
  • 2007-12-12 AU AU2007362357A patent/AU2007362357A1/en not_active Abandoned
  • 2007-12-12 WO PCT/CA2007/002264 patent/WO2009073947A1/en active Application Filing

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