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WO2008101310A1 - Créatine-acides gras - Google Patents

Créatine-acides gras Download PDF

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Publication number
WO2008101310A1
WO2008101310A1 PCT/CA2007/000258 CA2007000258W WO2008101310A1 WO 2008101310 A1 WO2008101310 A1 WO 2008101310A1 CA 2007000258 W CA2007000258 W CA 2007000258W WO 2008101310 A1 WO2008101310 A1 WO 2008101310A1
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WO
WIPO (PCT)
Prior art keywords
creatine
acid
fatty acid
compound
acetic acid
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/CA2007/000258
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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/CA2007/000258 priority Critical patent/WO2008101310A1/fr
Publication of WO2008101310A1 publication Critical patent/WO2008101310A1/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
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
    • 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 amide 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 amide linkage.
  • Creatine is a naturally occurring ammo acid de ⁇ ved from the ammo acids glycine, argimne, 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 m the musculature of mammals as phosphocreatme (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
  • Phosphocreatme serves as a major source of phosphate from which ADP is regenerated to ATP.
  • 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. Clin 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 in 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 Ihe number of myonuclei in 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 contracve force" (Sartorelh V, Fulco M. Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy. Sci STKE.
  • Postnatal muscle growth involves both myo fiber hypertrophy and increased numbers of myonuclei - the source of which are satellite cells (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. 2006 Jun l;573(Pt 2):525-34).
  • satellite cells 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. 2006 Jun l;573(Pt 2):525-34).
  • 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 in 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 characteristics such as stability and solubility. Furthermore, it would be advantageous to do so m 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: citrate, malate, fumarate and tartarate individually.
  • the resultant salts described 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 t ⁇ creatine 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 purports to describe creatine salts of dicarboxylic 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 linoleic acid and ⁇ -hnolenic acid.
  • saturated fatty acids include, but are not limited to myristic 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, linoleic 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 in 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 maj o ⁇ ty of the above referenced patents are creatine salts.
  • salts 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 5O 0 C.
  • a creatme-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, 6' 7 , 671-673). These are typically formed by reacting creatine with an alcohol in the presence of an acid catalyst at temperatures from 35 0 C to 50 0 C as disclosed in U.S. Pat. No.
  • 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.
  • the present invention relates to routes of synthesis of creatme-fatty acid compounds bound via an amide 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 carboxylic 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 refers to the chemical N-methyl-N-guanyl Glycine, (CAS Registry No. 57-00-1), also known as, (alpha-methyl guanido) acetic acid, N-(aminoiminomethyl)-N-glycine, Methylglycocyamine, Methylguanidoacetic Acid, or N-Methyl-N-guanylglycme.
  • 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.
  • the creatine and fatty acid being bound by an amide 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 :
  • 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, linoleic acid, linolenic acid, arachidonic acid, palmitoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and erucic acid
  • thionyl hahde of (3) is selected from the group consisting of fluo ⁇ ne, chlorine, bromine, and iodme, the preferred method using chlorine or bromine.
  • Step 2 describes the addition of the prepared acyl halide (3) to a suspension of creatine (5) in dichloromethane (DCM), in the presence of catalytic pyridine (pyr), to form the desired creatine-fatty acid amide (1).
  • DCM dichloromethane
  • pyr catalytic pyridine
  • acyl halide takes place at temperatures between about -15°C and about 0°C and with vigorous stirring. Following complete addition of the acyl halide the reaction continues to stir and is allowed to warm to room temperature before the target amide compound is isolated, the amide compound being a creatine fatty acid compound.
  • acyl chloride dodecanoyl chlo ⁇ de.
  • This acyl chloride 7.65g (35mmol) is put into a dry separatory funnel and combined with 50ml of dry dichloromethane for use in the next step of the reaction.
  • acyl bromide palmitoyl bromide.
  • This acyl bromide 16 02g (50mmol) is put into a dry separatory funnel and combined with 75ml of dry dichloromethane for use in the next step of the reaction.
  • acyl chlo ⁇ de docosanoyl chlo ⁇ de.
  • This acyl chloride 21.6Og ( ⁇ Ommol) is put into a dry separatory funnel and combined with 100ml of dry dichloromethane for use in the next step of the reaction.
  • acyl chlo ⁇ de (Z)-hexadec-9-enoyl chloride.
  • This acyl chlo ⁇ de, 10.95g (40mmol) is put into a dry separately funnel and combined with 75ml of dry dichloromethane for use in the next step of the reaction.

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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

Composés obtenus à partir d'une molécule de créatine et d'une molécules d'acides gras. Ces composés se présentent sous la forme de composés de créatine-acides gras liés par une liaison amide, ou bien de mélanges de ces composés ou de dérivés de ces derniers obtenus par réaction de la créatine ou de ses dérivés avec un acide gras approprié en présence de dichlorométhane et d'un catalyseur de pyridine, ayant précédemment réagi avec un halogénure de thionyle. L'administration de telles molécules fournit un supplément de créatine à biodisponibilité accrue et offre un surcroît d'avantages conférés par l'acide gras spécifique. Formule (I).
PCT/CA2007/000258 2007-02-20 2007-02-20 Créatine-acides gras Ceased WO2008101310A1 (fr)

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Application Number Priority Date Filing Date Title
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Application Number Priority Date Filing Date Title
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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
JP2013028562A (ja) * 2011-07-28 2013-02-07 Mitsubishi Paper Mills Ltd ナノファイバー形成化合物、ナノファイバーの形成方法およびナノファイバー集合体の形成方法
WO2014203198A3 (fr) * 2013-06-22 2015-04-02 Mahesh Kandula Compositions et procédés de traitement de maladies neurologiques et de complications rénales
JP2016536372A (ja) * 2013-11-05 2016-11-24 ウルトラジェニクス ファーマシューティカル インク．Ｕｌｔｒａｇｅｎｙｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｉｎｃ． クレアチン類似体及びその使用
JP2018502911A (ja) * 2014-12-22 2018-02-01 ファーミントン ファーマ ディベロップメントＦａｒｍｉｎｇｔｏｎ Ｐｈａｒｍａ Ｄｅｖｅｌｏｐｍｅｎｔ クレアチンプロドラッグ、その組成物、及びその使用方法
CN108840808A (zh) * 2018-06-13 2018-11-20 北京合力众盈医药科技有限责任公司 一种益母草碱衍生物、制备方法及其用途
US11021501B2 (en) 2015-03-30 2021-06-01 Farmington Pharma Development Creatine phosphate analog prodrugs, compositions and methods of use thereof
US11332438B2 (en) 2017-12-01 2022-05-17 Ultragenyx Pharmaceutical Inc. Creatine prodrugs, compositions and methods of use thereof

Citations (7)

* 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
WO2000040217A1 (fr) * 1999-01-08 2000-07-13 Yugenic Limited Partnership Composition topique comprenant des aldosamines de n-acetyle ou des acides amines de n-acetyle
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
US20040029969A1 (en) * 2000-07-06 2004-02-12 Beiersdorf Ag Use of creatine or creatine derivatives in cosmetic or dematological preparations
US20040120983A1 (en) * 2002-12-23 2004-06-24 Philip Connolly Nutritional supplement
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
US20060269535A1 (en) * 2005-05-31 2006-11-30 Naidu A S Metallo-lactoferrin-coenzyme compositions for trigger and release of bioenergy

Patent Citations (7)

* 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
WO2000040217A1 (fr) * 1999-01-08 2000-07-13 Yugenic Limited Partnership Composition topique comprenant des aldosamines de n-acetyle ou des acides amines de n-acetyle
US20040029969A1 (en) * 2000-07-06 2004-02-12 Beiersdorf Ag Use of creatine or creatine derivatives in cosmetic or dematological preparations
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
US20040120983A1 (en) * 2002-12-23 2004-06-24 Philip Connolly Nutritional supplement
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
US20060269535A1 (en) * 2005-05-31 2006-11-30 Naidu A S Metallo-lactoferrin-coenzyme compositions for trigger and release of bioenergy

Cited By (17)

* 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
JP2013028562A (ja) * 2011-07-28 2013-02-07 Mitsubishi Paper Mills Ltd ナノファイバー形成化合物、ナノファイバーの形成方法およびナノファイバー集合体の形成方法
WO2014203198A3 (fr) * 2013-06-22 2015-04-02 Mahesh Kandula Compositions et procédés de traitement de maladies neurologiques et de complications rénales
JP2016536372A (ja) * 2013-11-05 2016-11-24 ウルトラジェニクス ファーマシューティカル インク．Ｕｌｔｒａｇｅｎｙｘ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｉｎｃ． クレアチン類似体及びその使用
JP2025118733A (ja) * 2014-12-22 2025-08-13 ファーミントン ファーマ ディベロップメント クレアチンプロドラッグ、その組成物、及びその使用方法
US11407722B2 (en) 2014-12-22 2022-08-09 Farmington Pharma Development Creatine prodrugs, compositions and methods of use thereof
JP2020128379A (ja) * 2014-12-22 2020-08-27 ファーミントン ファーマ ディベロップメントＦａｒｍｉｎｇｔｏｎ Ｐｈａｒｍａ Ｄｅｖｅｌｏｐｍｅｎｔ クレアチンプロドラッグ、その組成物、及びその使用方法
TWI832450B (zh) * 2014-12-22 2024-02-11 美商法明頓製藥發展公司 肌酸前藥、組合物及其使用方法
EP3771709A1 (fr) * 2014-12-22 2021-02-03 Farmington Pharma Development Promédicaments de la créatine, compositions en contenant et leurs procédés d'utilisation
JP7037597B2 (ja) 2014-12-22 2022-03-16 ファーミントン ファーマ ディベロップメント クレアチンプロドラッグ、その組成物、及びその使用方法
JP2018502911A (ja) * 2014-12-22 2018-02-01 ファーミントン ファーマ ディベロップメントＦａｒｍｉｎｇｔｏｎ Ｐｈａｒｍａ Ｄｅｖｅｌｏｐｍｅｎｔ クレアチンプロドラッグ、その組成物、及びその使用方法
US11021501B2 (en) 2015-03-30 2021-06-01 Farmington Pharma Development Creatine phosphate analog prodrugs, compositions and methods of use thereof
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
CN108840808B (zh) * 2018-06-13 2020-12-11 北京合力众盈医药科技有限责任公司 一种益母草碱衍生物、制备方法及其用途
CN108840808A (zh) * 2018-06-13 2018-11-20 北京合力众盈医药科技有限责任公司 一种益母草碱衍生物、制备方法及其用途

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