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WO2008031184A1 - Sels d'acide créatine-pyroglutamique; méthodes d'obtention et d'utilisation chez un individu - Google Patents

Sels d'acide créatine-pyroglutamique; méthodes d'obtention et d'utilisation chez un individu Download PDF

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Publication number
WO2008031184A1
WO2008031184A1 PCT/CA2006/001491 CA2006001491W WO2008031184A1 WO 2008031184 A1 WO2008031184 A1 WO 2008031184A1 CA 2006001491 W CA2006001491 W CA 2006001491W WO 2008031184 A1 WO2008031184 A1 WO 2008031184A1
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WO
WIPO (PCT)
Prior art keywords
creatine
administration
salt
structure according
wherem
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CA2006/001491
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English (en)
Inventor
Michele Molino
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
New Cell Formulations Ltd
Original Assignee
New Cell Formulations Ltd
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Filing date
Publication date
Application filed by New Cell Formulations Ltd filed Critical New Cell Formulations Ltd
Priority to PCT/CA2006/001491 priority Critical patent/WO2008031184A1/fr
Publication of WO2008031184A1 publication Critical patent/WO2008031184A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to hydrosoluble stable organic salts of creatine and pyroglutamic acid.
  • the present invention discloses a composition and a method for production of the composition. Additionally, the invention relates to administration of the compositional to a mammal as a method to improve athletic and cognitive functions.
  • Creatine monohydrate is a commonly used supplement. Creatine monohydrate is soluble in water at a rate of 75 ml of water per gram of creatine. Ingestion of creatine monohydrate thereof requires large amounts of water to also be ingested. Additionally, in aqueous solutions, creatine converts to creatinine via an irreversible, pH-dependent, non-enzymatic reaction. Aqueous and alkaline solutions contain an equilibrium mixture of creatine and creatinine In acidic solutions, on the other hand, the formation of creatinine is complete. Creatinine is devoid of the ergogenic beneficial effects of creatine and is typically excreted in the u ⁇ ne. It is therefore desirable to provide, for use in individuals, e.g. animals and humans, forms and derivatives of creatine with improved characteristics such as stability and solubility. Furthermore, it would be advantageous to do so in a manner that provides additional functionality compared to creatine monohydrate alone.
  • Hydrosoluble creatine monohydrate salts are obtainable and have been described elsewhere.
  • U.S. Patent No. 5,973,199 incorporated herein in its entirety by reference, purports to desc ⁇ be hydrosoluble organic salts of creatine as single combination of one mole of creatine monohydrate with one mole of the following organic acids: citrate, malate, fumarate, tartarate, and malate.
  • dicreatme and tricreatme citrate are claimed to be stable in acidic solution, in a guise to prevent or impede the formulation of creatine to creatinine.
  • the present invention discloses a hydrosoluble stable organic salt of creatine and D,L- pyroglutamic acid, i e., creatine pyroglutamate, characterized by high water solubility, i e., from 2 to 25 times higher than that of creatine itself and having a melting point about 160 to about 168°C with a molecular weight range of about 242 to about 262.
  • the present invention describes processes for the preparation of the salt and methods for administering the salt to a mammal, such as a human.
  • the present invention also discloses methods of using effective amounts of creatine pyroglutamate for the regulation of athletic and cognitive functions in mammals, and for affording preventative neuroprotection and preservation of cognitive activity in aging, neurodegenerative disease, reperfusion msult, ischemic brain infarction and cerebral ischemia
  • the present invention relates to the production and use of hydrosoluble stable organic salts of creatine and pyroglutamic acid
  • the organic salts may be useful as a compositional ingredient for regulating athletic and cognitive functions in addition to post-msult recovery.
  • athletic functions refers to the sum of physical attributes which can be dependent to any degree on skeletal muscle contraction.
  • athletic functions include, but are not limited to, maximal muscular strength, muscular endurance, running speed and endurance, swimming speed and endurance, throwing power, lifting and pulling power.
  • cognitive functions refers to any mental component of brain function.
  • cognitive functions include, but are not limited to, attention, concentration, memory and focus.
  • Creatine refers to the chemical N-methyl-N-guanyl Glycine, (CAS Registry No. 57-00-1), also known as, (alpha-methyl guanido) acetic acid, N-(aminoirnmomethyl)- N-glycine, Methylglycocyamme, Methylguanidoacetic Acid, or N-Methyl-N-guanylglycine Additionally, as used herein, “Creatine” also includes derivatives of Creatine such as esters, and amides, and salts, as well as other derivatives, including de ⁇ vatives that become active upon metabolism. Furthermore, Creatinol (CAS Registry No.
  • Creatinol-O- Phosphate N-methyl-N-(beta-hydroxyethyl)guamdine O-Phosphate, or 2-(carbamimidoyl-methyl- amino)ethoxyphosphomc acid, is henceforth m this disclosure considered to be a Creatine derivative. Creatine
  • Creatine is a naturally occurring ammo acid de ⁇ ved from the amino acids glycine, argmme, and methionine. Although it is found in meat and fish, it is also synthesized by humans Creatine is predominantly used as a fuel source in muscle. About 65% of Creatine is stored in muscle as Phosphocreatine (Creatine bound to a Phosphate molecule). Muscular contractions are fueled by the dephosphorylation of adenosine triphosphate (ATP) to produce adenosine diphosphate (ADP) and without a mechanism to replenish ATP stores, the supply of ATP would be totally consumed in 1-2 seconds.
  • ATP adenosine triphosphate
  • ADP adenosine diphosphate
  • Phosphocreatine serves as a major source of Phosphate from which ADP is regenerated to ATP.
  • muscular concentrations of Phosphocreatine drop by almost 50% and Creatine supplementation has been shown to increase the concentration of Creatine m the muscle (Hams RC, Soderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation Clin Sci (Lond). 1992 Sep;83(3):367-74) and further said supplementation enables an increase m the resynthesis of Phosphocreatine (Greenhaff PL, Bodin K, Soderlund K, Hultman E.
  • Creatine may have antioxidant properties that may additionally aid post-exercise muscle recovery and recovery from neuronal insults (Sestili P, Martinelli C, Bravi G, Piccoli G, Curci R, Battistelli M, Falcie ⁇ E, Agostmi D, Gioacchini AM, Stocchi V. Creatine supplementation affords cytoprotection in oxidatively injured cultured mammalian cells via direct antioxidant activity. Free Radic Biol Med. 2006 Mar l;40(5):837-49). Thus, creatine supplementation may result in positive physiologic effects on skeletal muscle, such as: performance improvements du ⁇ ng b ⁇ ef high-intensity anaerobic exercise, increased strength and ameliorated body composition in physically active subjects.
  • Creatine also mediates remarkable neuroprotection in experimental models of amyotrophic lateral sclerosis, Huntmgton's disease, Parkinson's disease, and traumatic bram injury. Also, oral creatine administration to expe ⁇ mental animals has been shown to result in a remarkable reduction in ischemic brain infarction and neuroprotection after cerebral ischemia (Zhu S, Li M, Figueroa BE, Lm A, Stavrovskaya IG, Pasinelh P, Beal MF, Brown RH Jr, K ⁇ stal BS, Ferrante RJ, F ⁇ edlander RM. Prophylactic creatine administration mediates neuroprotection in cerebral ischemia m mice. J Neurosci. 2004 Jun 30;24(26):5909-12). Pyroglutamic Acid
  • Pyroglutamic acid (CAS 98-79-3) is naturally occurring amino acid derived from L- glutamic acid and involved m glutathione metabolism. Pyroglutamic acid crosses the blood-bram barrier and is found in high levels in the bram where it is thought to act in improving cognitive function Pyroglutamate is generally available as argimne pyroglutamate wherein, the primary claim made for this argmine salt of pyroglutamic acid relates to its cognitive enhancement capacity. It is asserted by some that this substance can help overcome memory defects induced by alcohol abuse and in those with some forms of dementia.
  • Pyroglutamic acid has been shown to improve specific aspects of cognitive function in rats (Drago F, Vale ⁇ o C, D'Agata V, Astuto C, Spadaro F, Continella G, Scapagnini U Pyroglutamic acid improves learning and memory capacities in old rats. Funct Neurol. 1988 Apr- Jun;3(2): 137-43). In humans pyroglutamic acid improves age-associated memory impairment (Gnoh S, Lomeo C, Quattropani MC, Spignoh G, Villardita C. Pyroglutamic acid improves the age associated memory impairment. Fundam CIm Pharmacol. 1990;4(2): 169-73). Creatine Pyroglutamate
  • Creatine Pyroglutamate combines the muscle-enhancing and neuroprotective effects of creatine with the cognition-enhancing activity afforded by pyroglutamic acid.
  • the novel organic compound can be used in sports nutrition as an ergogenic aid to increase strength, muscle volume and size, while affording improved capacity of concentration and mental focus during physical exertion
  • this creatine salt can find employment in metabolic nutrition by defending against ischemic brain infarction and affording neuroprotection after cerebral ischemia
  • the salt is prepared by reacting eqmmolar amounts of creatine and D,L-pyroglutamic acid in aqueous or hydroalcoholic concentrated solution or in a water-immiscible solvent (or mixture of solvents), at temperatures ranging from room temperature to 50 ° C Additionally, the reaction may be induced to proceed through the melting of pyroglutamic acid, forming a liquid reaction medium and adding creatine, followed by a subsequent extraction of the salt from the reaction mixture with cyclohexane.
  • the aforementioned salt can be prepared by reacting creatine with an equimolar amount of D,L-pyroglutamic acid in ethyl acetate (or m a mixture of equal parts ethyl acetate and ethanol) until complete formation of the salt.
  • the solution can be optionally concentrated and, upon cooling, the crystallized salts are filtered and washed with ethyl acetate (or a mixture of ethyl acetate and ethanol).
  • the procedure can be carried on by reacting excess D,L-pyroglutamic acid with creatine in ethyl acetate (or a mixture of ethyl acetate and ethanol).
  • creatine pyroglutamate can be used as a composition, either alone or as part of a larger composition containing any number of additional ingredients. It will be apparent to those skilled in the art as to which specific ingredients may be included in such compositions
  • creatine pyroglutamate as a compositional ingredient may be administered m any form common m the art.
  • the compositional ingredient may be administered in the form of a powder to be mixed in liquid or m a solid dosage form such as a tablet, capsule or caplet.
  • creatine pyroglutamate may be suspended or dissolved in any pharmaceutically acceptable earner or vehicle medium for injection. As such, it may be combined with any number of commonly accepted excipients, as is regular practice in the art.
  • the meltmg range of the crystalline product from Experiment 2 was determined to be within 162- 168 ° C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un sel conjugué de créatine et d'acide pyroglutamique. Le sel est soluble et stable dans l'eau et peut être utilisé pour la régulation des fonctions athlétiques et cognitives d'un mammifère. L'invention concerne également un procédé de production dudit sel par réaction de la créatine avec une quantité équimolaire d'acide pyroglutamique dans un solvant organique. Le sel ainsi obtenu est de 2 à 25 fois plus soluble que la créatine.
PCT/CA2006/001491 2006-09-11 2006-09-11 Sels d'acide créatine-pyroglutamique; méthodes d'obtention et d'utilisation chez un individu Ceased WO2008031184A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CA2006/001491 WO2008031184A1 (fr) 2006-09-11 2006-09-11 Sels d'acide créatine-pyroglutamique; méthodes d'obtention et d'utilisation chez un individu

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CA2006/001491 WO2008031184A1 (fr) 2006-09-11 2006-09-11 Sels d'acide créatine-pyroglutamique; méthodes d'obtention et d'utilisation chez un individu

Publications (1)

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WO2008031184A1 true WO2008031184A1 (fr) 2008-03-20

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5973199A (en) * 1994-08-04 1999-10-26 Flamma S.P.A. Hydrosoluble organic salts of creatine
US6166249A (en) * 1996-12-20 2000-12-26 Skw Trostberg Aktiengesellschaft Creatine pyruvates
US6211407B1 (en) * 2000-05-03 2001-04-03 Pfanstiehl Laboratories, Inc. Dicreatine citrate and tricreatine citrate and method of making same
US6838562B2 (en) * 2003-04-01 2005-01-04 Sal Abraham Process for preparing a creatine heterocyclic acid salt and method of use
US6861544B1 (en) * 2000-06-22 2005-03-01 University Of Pittsburgh Fluorous tin compounds an methods of using fluorous tin compounds

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5973199A (en) * 1994-08-04 1999-10-26 Flamma S.P.A. Hydrosoluble organic salts of creatine
US6166249A (en) * 1996-12-20 2000-12-26 Skw Trostberg Aktiengesellschaft Creatine pyruvates
US6211407B1 (en) * 2000-05-03 2001-04-03 Pfanstiehl Laboratories, Inc. Dicreatine citrate and tricreatine citrate and method of making same
US6861544B1 (en) * 2000-06-22 2005-03-01 University Of Pittsburgh Fluorous tin compounds an methods of using fluorous tin compounds
US6838562B2 (en) * 2003-04-01 2005-01-04 Sal Abraham Process for preparing a creatine heterocyclic acid salt and method of use

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