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WO2008101309A1 - Composés créatine-acides gras - Google Patents

Composés créatine-acides gras Download PDF

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Publication number
WO2008101309A1
WO2008101309A1 PCT/CA2007/000257 CA2007000257W WO2008101309A1 WO 2008101309 A1 WO2008101309 A1 WO 2008101309A1 CA 2007000257 W CA2007000257 W CA 2007000257W WO 2008101309 A1 WO2008101309 A1 WO 2008101309A1
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WO
WIPO (PCT)
Prior art keywords
creatine
acid
fatty acid
compound
carbons
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/CA2007/000257
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English (en)
Inventor
Shan Chaudhuri
Joseph Macdougall
Jason Peters
James Ramsbottom
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.)
Multi Formulations Ltd
Original Assignee
Multi Formulations Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Multi Formulations Ltd filed Critical Multi Formulations Ltd
Priority to PCT/CA2007/000257 priority Critical patent/WO2008101309A1/fr
Publication of WO2008101309A1 publication Critical patent/WO2008101309A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups

Definitions

  • the present invention relates to structures and synthesis of creatine-fatty acid compounds bound via an anhyd ⁇ de linkage.
  • Another aspect of the present invention relates to a compound comprising a creatine molecule bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid and bound to the creatine via an anhydride linkage.
  • Creatine is a naturally occurring ammo acid de ⁇ ved from the amino acids glycine, arginine, 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 the musculature of mammals as phosphocreatine (creatine bound to a phosphate molecule)
  • Muscular contractions are fueled by the dephosphorylation of adenosine triphosphate (ATP) to produce adenosine diphosphate (ADP).
  • 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% Creatine supplementation has been shown to increase the concentration of creatine in the muscle (Harris RC, Soderlund K, Hultman E. Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. CIm Sci (Lond).
  • creatine supplementation with regard to skeletal muscle is apparently not restricted to the role of creatine in energy metabolism. It has been shown that creatine supplementation in combination with strength training results m specific, measurable physiological changes in skeletal muscle compared to strength training alone. For example, creatine supplementation amplifies the strength training-induced increase of human skeletal satellite cells as well as the number of myonuclei m human skeletal muscle fibres (Olsen S, Aagaard P, Kadi F, Tufekovic G, Verney J, Olesen JL, Suetta C, Kjaer M. Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training J Physiol.
  • Satellite cells are the stem cells of adult muscle. They are normally maintained in a quiescent state and become activated to fulfill roles of routine maintenance, repair and hypertrophy (Zammit PS, Partridge TA, Yablonka-Reuveni Z. The Skeletal Muscle Satellite Cell: The Stem Cell That Came In From the Cold J Histochem Cytochem 2006 Aug 9) 'True' muscle hypertrophy can be defined as "as an increase in fiber diameter without an apparent increase in the number of muscle fibers, accompanied by enhanced protein synthesis and augmented contractile force" (Sartorelli V, Fulco M. Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy. Sci STKE.
  • creatine is used predominantly in muscle cells and most of the total creatine pool is found in muscle, creatine is actually synthesized in the liver and pancreas.
  • the musculature's creatine concentration is maintained by the uptake of creatine from the blood stream regardless of whether the source of creatine is endogenous, i.e. synthesized by the liver or pancreas, or dietary, i e natural food sources or supplemental sources.
  • the creatine content of an average 70 kg male is approximately 12O g with about 2 g being excreted as creatinine per day (Williams MH, Branch JD. Creatine supplementation and exercise performance: an update. J Am Coll Nutr. 1998 Jun, 17(3) 216- 34).
  • a typical omnivorous diet supplies approximately 1 g of creatine daily, while diets higher m meat and fish will supply more creatine.
  • a 500 g uncooked steak contains about 2 g of creatine which equates to more than two 8 oz. steaks per day. Since most studies examining creatine supplementation employ dosages ranging from 2-20 g per day it is unrealistic to significantly increase muscle creatine stores through merely food sources alone. Therefore, supplemental sources of creatine are an integral component of increasing, and subsequently maintaining supraphysiological, muscular creatine levels.
  • Creatine supplementation thus results in positive physiological effects on skeletal muscle, such as: performance improvements du ⁇ ng brief high-intensity anaerobic exercise, increased strength and enhanced muscle growth.
  • 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, therefore, requires large amounts of water to be co-ingested. Additionally, in aqueous solutions creatine is known to convert 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. It is therefore desirable to provide, for use in individuals, e g. animals and humans, forms and derivatives of creatine with improved characte ⁇ stics such as stability and solubility. Furthermore, it would be advantageous to do so in a manner that provides additional functionality as compared to creatine monohydrate alone.
  • U.S. Patent No. 5,973,199 purports to describe hydrosoluble organic salts of creatine as single combination of one mole of creatine monohydrate with one mole of the following organic acids 1 citrate, malate, fumarate and tartarate individually.
  • the resultant salts desc ⁇ bed therein are claimed to be from 3 to 15 times more soluble, in aqueous solution, than creatine itself.
  • U S. Pat. No. 6,166,249 purports to describe a creatine pyruvic acid salt that is highly stable and soluble. It is further purported that the pyruvate included in the salt may be useful to treat obesity, prevent the formation of free radicals and enhance long-term performance.
  • U.S. Pat. No. 6,838,562 purports to describe a process for the synthesis of mono, di, or tricreatme orotic acid, thioorotic acid, and dihydroorotic acid salts which are claimed to have increased oral absorption and bioavailability due to an inherent stability in aqueous solution It is further claimed that the heterocyclic acid portion of the salt acts synergistically with creatine.
  • U.S. Pat. No. 7,109,373, incorporated herein in its entirety by reference purports to desc ⁇ be creatine salts of dicarboxyhc acids with enhanced aqueous solubility.
  • Fatty acids are carboxylic acids, often containing a long, unbranched chain of carbon atoms and are either saturated or unsaturated. Saturated fatty acids do not contain double bonds or other functional groups, but contain the maximum number of hydrogen atoms, with the exception of the carboxyhc acid group. In contrast, unsaturated fatty acids contain one or more double bonds between adjacent carbon atoms, of the chains, in cis or trans configuration
  • the human body can produce all but two of the fatty acids it requires, thus, essential fatty acids are fatty acids that must be obtained from food sources due to an inability of the body to synthesize them, yet are required for normal biological function.
  • the essential fatty acids being lmoleic acid and ⁇ -lmolenic acid.
  • saturated fatty acids include, but are not limited to my ⁇ stic or tetradecanoic acid, palmitic or hexadecanoic acid, stea ⁇ c or octadecanoic acid, arachidic or eicosanoic acid, behenic or docosanoic acid, butyric or butanoic acid, caproic or hexanoic acid, caprylic or octanoic acid, capric or decanoic acid, and lauric or dodecanoic acid, wherein the aforementioned comprise from at least 4 carbons to 22 carbons in the chain.
  • Examples of unsaturated fatty acids include, but are not limited to oleic acid, lmoleic acid, linolenic acid, arachidonic acid, palmitoleic acid, eicosapentaenoic acid, docosahexaenoic acid and erucic acid, wherein the aforementioned comprise from at least 4 carbons to 22 carbons m the chain
  • Fatty acids are capable of undergoing chemical reactions common to carboxyhc acids. Of particular relevance to the present invention are the formation of salts and the formation of esters.
  • the majority of the above referenced patents are creatine salts. These salts, este ⁇ fication via carboxylate reactivity, may essentially be formed, as disclosed in U.S. Pat. No. 7,109,373, through a relatively simple reaction by mixing a molar excess of creatine or derivative thereof with an aqueous dicarboxylic acid and heating from room temperature to about 50 0 C.
  • a creatine-fatty acid may be synthesized through ester formation.
  • the formation of creatine esters has been described (Dox AW, Yoder L. Este ⁇ fication of Creatine. J. Biol. Chem. 1922, 67, 671-673). These are typically formed by reacting creatine with an alcohol in the presence of an acid catalyst at temperatures from 35°C to 50 0 C as disclosed in U.S. Pat. No. 6,897,334.
  • creatine compounds have attempted to address issues such as stability and solubility in addition to, and in some cases, to add increased functionality as compared to creatine alone, no desc ⁇ ption has yet been made of any creatine-fatty acid compound, particularly that comprising a saturated fatty acid.
  • R is an alkyl group, preferably saturated, and containing from about 3 to a maximum of 21 carbons.
  • Another aspect of the invention comprises the use of a saturated fatty acid in the production of compounds disclosed herein.
  • a further aspect of the present invention comprises the use of an unsaturated fatty in the production of compounds disclosed herein. Detailed Description of the Invention
  • the present invention relates to structures and synthesis of creatine-fatty acid compounds bound via an anhyd ⁇ de linkage.
  • specific benefits are conferred by the particular fatty acid used to form the compounds in addition to, and separate from, the creatine substituent.
  • the term 'fatty acid' includes both saturated, i.e.
  • an alkane chain as known in the art, having no double bonds between carbons of the chain and having the maximum number of hydrogen atoms, and unsaturated, i.e. an alkene or alkyne chain, having at least one double or alternatively triple bond between carbons of the chain, respectively, and further terminating the chain in a carboxyhc acid as is commonly known in the art, wherein the hydrocarbon chain is not less then four carbon atoms.
  • essential fatty acids are herein understood to be included by the term 'fatty acid'.
  • creatine also includes derivatives of creatine such as esters, and amides, and salts, as well as other derivatives, including de ⁇ vatives having pharmacoproperties upon metabolism to an active form.
  • the compounds disclosed herein comprise a creatine molecule bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid. Furthermore, the creatine and fatty acid being bound by an anhydride linkage and 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 : [0034] Scheme 1
  • Step 1 an acyl hahde (4) is produced via reaction of a fatty acid (2) with a thionyl hahde (3).
  • the fatty acid of (2) is selected from the saturated fatty acid group comprising butyric or butanoic acid, caproic or hexanoic acid, caprylic or octanoic acid, cap ⁇ c or decanoic acid, lauric or dodecanoic acid, my ⁇ stic or tetradecanoic acid, palmitic or hexadecanoic acid, stea ⁇ c or octadecanoic acid, arachidic or eicosanoic acid, and behenic or docosanoic acid.
  • the saturated fatty acid group comprising butyric or butanoic acid, caproic or hexanoic acid, caprylic or octanoic acid, cap ⁇ c or decanoic acid, lauric or dodecanoic acid, my ⁇ stic or tetradecanoic acid, palmitic or hexadecanoic acid, stea ⁇ c or octadecanoic acid
  • the fatty acid of (2) is selected from the unsaturated fatty acid group comprising oleic acid, lmoleic acid, lmolenic acid, arachidonic acid, palmitoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and erucic acid.
  • the thionyl hahde of (3) is selected from the group consisting of fluorine, chlorine, bromine, and iodine, the preferred method using chlorine or bromine.
  • the above reaction proceeds under conditions of heat ranging between from about 35°C to about 50 0 C and stirring over a period from about 0.5 hours to about 2 hours during which time the gases sulfur dioxide and acidic gas, wherein the acidic gas species is dependent on the species of thionyl hahde employed, are evolved. Preferably, the reaction proceeds at 45 0 C for 1.5 hours.
  • Step 2 of Scheme 1 entails the neutralization of the carboxyhc acid of the creatine portion through the addition of an inorganic base.
  • the inorganic base is selected from the group comprising sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, sodium carbonate
  • Preferred inorganic bases for the purposes of the present invention are sodium hydroxide and potassium hydroxide.
  • Step 3 of Scheme 1 involves the drop wise addition of the prepared acyl hahde (4) to the creatine salt (6) in a cooled flask and subsequent purification by two rounds of distillation to yield the desired anhydride compound (1), the anhyd ⁇ de compound being a creatine fatty acid compound of the present invention.
  • the following compounds are produced: butyric 2 -(I -methyl guanidino)acetic anhydride, hexanoic 2-(l- methylguanidino)acetic anhydride, 2 -(I -methyl guanidino)acetic octanoic anhydnde, decanoic 2-(l- methylguanidmo)acetic anhyd ⁇ de, 2-(l-methylguanidino)acetic tetradecanoic anhyd ⁇ de, 2-(l- methylguamdmo)acetic palmitic anhyd ⁇ de, icosanoic 2 -(I -methyl guanidmo)acetic anhydride, and docosanoic 2-(l-methylguamdino)acetic anhyd ⁇ de.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention porte sur des composés obtenus à partir d'une molécule de créatine et d'une molécule d'acide gras. Ces composés se présentent sous la forme de composés créatine-acide gras liés par une liaison anhydride, ou de mélanges de ceux-ci, obtenus par réaction de créatine ou de dérivés de celle-ci avec un acide gras approprié ayant préalablement réagi avec un halogénure de thionyle. L'administration de telles molécules fournit une créatine supplémentaire à biodisponibilité accrue et avantages supplémentaires conférés par l'acide gras spécifique. Formula (I).
PCT/CA2007/000257 2007-02-20 2007-02-20 Composés créatine-acides gras Ceased WO2008101309A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120277305A1 (en) * 2011-04-29 2012-11-01 Catabasis Pharmaceuticals, Inc. Fatty acid guanidine and salicylate guanidine derivatives and their uses
EP2692719A1 (fr) 2012-07-30 2014-02-05 Commissariat à l'Énergie Atomique et aux Énergies Alternatives Procédé de préparation d'esters gras de créatine, esters gras de créatine ainsi préparés et leurs utilisations
WO2014203198A3 (fr) * 2013-06-22 2015-04-02 Mahesh Kandula Compositions et procédés de traitement de maladies neurologiques et de complications rénales
US11332438B2 (en) 2017-12-01 2022-05-17 Ultragenyx Pharmaceutical Inc. Creatine prodrugs, compositions and methods of use thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5994581A (en) * 1998-03-09 1999-11-30 Amt Labs, Inc. Carnitine creatinate
WO2003099806A1 (fr) * 2002-05-27 2003-12-04 Licrea S.R.L. Sel de creatine a efficacite nutritive, antioxydante et therapeutique amelioree et preparations le contenant
WO2003101402A2 (fr) * 2002-06-04 2003-12-11 Avicena Group, Inc. Methodes de traitement de dysfonctionnements cognitifs par modulation du metabolisme energetique du cerveau
WO2006081682A1 (fr) * 2005-02-07 2006-08-10 New Cell Formulations Ltd. Sels d’acides creatine-hydroxycitriques et procedes pour les produire et les utiliser chez l'etre humain

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5994581A (en) * 1998-03-09 1999-11-30 Amt Labs, Inc. Carnitine creatinate
WO2003099806A1 (fr) * 2002-05-27 2003-12-04 Licrea S.R.L. Sel de creatine a efficacite nutritive, antioxydante et therapeutique amelioree et preparations le contenant
WO2003101402A2 (fr) * 2002-06-04 2003-12-11 Avicena Group, Inc. Methodes de traitement de dysfonctionnements cognitifs par modulation du metabolisme energetique du cerveau
WO2006081682A1 (fr) * 2005-02-07 2006-08-10 New Cell Formulations Ltd. Sels d’acides creatine-hydroxycitriques et procedes pour les produire et les utiliser chez l'etre humain

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120277305A1 (en) * 2011-04-29 2012-11-01 Catabasis Pharmaceuticals, Inc. Fatty acid guanidine and salicylate guanidine derivatives and their uses
US9150504B2 (en) * 2011-04-29 2015-10-06 Catabasis Pharmaceuticals, Inc. Fatty acid guanidine and salicylate guanidine derivatives and their uses
EP2692719A1 (fr) 2012-07-30 2014-02-05 Commissariat à l'Énergie Atomique et aux Énergies Alternatives Procédé de préparation d'esters gras de créatine, esters gras de créatine ainsi préparés et leurs utilisations
WO2014019855A1 (fr) 2012-07-30 2014-02-06 Commissariat à l'énergie atomique et aux énergies alternatives Procédé de préparation d'esters gras de créatine, esters gras de créatine ainsi préparés et leurs utilisations
US10144705B2 (en) 2012-07-30 2018-12-04 Commissariat A L'energie Atomique Et Aux Energies Alternatives Method for preparing creatine fatty esters, creatine fatty esters thus prepared and uses thereof
WO2014203198A3 (fr) * 2013-06-22 2015-04-02 Mahesh Kandula Compositions et procédés de traitement de maladies neurologiques et de complications rénales
US11332438B2 (en) 2017-12-01 2022-05-17 Ultragenyx Pharmaceutical Inc. Creatine prodrugs, compositions and methods of use thereof
US11753369B2 (en) 2017-12-01 2023-09-12 Ultragenyx Pharmaceutical Inc. Creatine prodrugs, compositions and methods of use thereof

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