WO2008101309A1 - Creatine-fatty acids - Google Patents
Creatine-fatty acids Download PDFInfo
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- 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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- 0 CCC(C)*NC(C)(C)[Mn] Chemical compound CCC(C)*NC(C)(C)[Mn] 0.000 description 1
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- 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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Abstract
The present invention describes compounds produced from a creatine molecule and a fatty acid molecule. The compounds being in the form of creatine-fatty acid compounds being bound by an anhydride linkage, or mixtures thereof made by reacting creatine or derivatives thereof with an appropriate fatty acid previously reacted with a thionyl halide. The administration of such molecules provides supplemental creatine with enhanced bioavailability and the additional benefits conferred by the specific fatty acid. Formula (I).
Description
CREATINE-FATTY ACIDS Field of the Invention
[001] The present invention relates to structures and synthesis of creatine-fatty acid compounds bound via an anhydπde 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.
Background of the Invention
[002] Creatine is a naturally occurring ammo acid deπved 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)
[003] Muscular contractions are fueled by the dephosphorylation of adenosine triphosphate (ATP) to produce adenosine diphosphate (ADP). In the absence of a mechanism to replenish ATP stores, the supply of ATP would be totally consumed in 1-2 seconds. Phosphocreatine serves as a major source of phosphate from which ADP is regenerated to ATP. Within six seconds following the commencement of exercise, 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). 1992 Sep;83(3):367-74) and further, the supplementation enables an increase in the resynthesis of phosphocreatine (Greenhaff PL, Bodm K, Soderlund K, Hultman E. Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis Am J Physiol. 1994 May;266(5 Pt l)Ε725-30) leading to a rapid replenishment of ATP withm the first two minutes following the commencement of exercise. Through this mechanism, creatine is able to improve strength and reduce fatigue (Greenhaff PL, Casey A, Short AH, Harris R, Soderlund K, Hultman E. Influence of oral creatine supplementation of muscle torque duπng repeated bouts of maximal voluntary exercise in man. Clin Sci (Lond). 1993 May;84(5):565-71).
[004] The beneficial effects of creatine supplementation with regard to skeletal muscle are 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. 2006 Jun 1 ;573(Pt 2):525-34). 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. 2004 JuI 27;2004(244):rel 1). Postnatal muscle growth involves both myofiber 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).
[005] Although 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. Thus, 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. As a point of reference, 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.
[006] Creatine supplementation, thus results in positive physiological effects on skeletal muscle, such as: performance improvements duπng brief high-intensity anaerobic exercise, increased strength and enhanced muscle growth.
[007] 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 characteπstics 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.
[008] The manufacture of hydrosoluble creatine salts with various organic acids have been described. U.S. Pat. No. 5,886,040, purports to describe a creatine pyruvate salt with enhanced palatability which is resistant to acid hydrolysis.
[009] 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 acids1 citrate, malate, fumarate and tartarate individually. The resultant salts descπbed therein are claimed to be from 3 to 15 times more soluble, in aqueous solution, than creatine itself. [0010] 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.
[0011] U.S. Pat. No. 6,211,407 purports to descπbe dicreatine and tricreatme citrates and a method of making the same. These dicreatine and tπcreatine salts are claimed to be stable in acidic solutions, thus hampering the undesirable conversion of creatine to creatinine.
[0012] 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. [0013] U.S. Pat. No. 7,109,373, incorporated herein in its entirety by reference, purports to descπbe creatine salts of dicarboxyhc acids with enhanced aqueous solubility.
[0014] The above disclosed patents recite creatine salts, methods of synthesis of the salts, and uses thereof However, nothing in any of the disclosed patents teaches, suggests or discloses a compound comprising a creatine molecule bound to a fatty acid. [0015] In addition to salts, creatine esters have also been descπbed. U.S. Pat. No. 6,897,334 describes method for producing creatine esters with lower alcohols i.e. one to four carbon atoms, using acid catalysts. It is stated that creatine esters are more soluble than creatine It is further stated that the protection of the carboxylic acid moiety of the creatine molecule by ester-formation stabilizes the compound by preventing its conversion to creatinine. The creatine esters are said to be converted into creatine by esterases i.e. enzymes that cleave ester bonds, found in a variety of cells and biological fluids.
[0016] 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
[0017] 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 α-lmolenic acid.
[0018] Examples of saturated fatty acids include, but are not limited to myπstic or tetradecanoic acid, palmitic or hexadecanoic acid, steaπc 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.
[0019] 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 [0020] 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, esteπfication 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 500C.
[0021] Alternatively, a creatine-fatty acid may be synthesized through ester formation. The formation of creatine esters has been described (Dox AW, Yoder L. Esteπfication 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 500C as disclosed in U.S. Pat. No. 6,897,334. [0022] While the above referenced 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 descπption has yet been made of any creatine-fatty acid compound, particularly that comprising a saturated fatty acid.
Summary of the Invention [0023] In the present invention, compounds are disclosed, where the compounds compnse a molecule of creatine bound to a fatty acid, via an anhydride linkage, and having a structure of [0024] Formula 1 -
Formula 1
O O
Il Il
H2C O R
^C CH3
NH2
[0025] where:
[0026] R is an alkyl group, preferably saturated, and containing from about 3 to a maximum of 21 carbons.
[0027] Another aspect of the invention comprises the use of a saturated fatty acid in the production of compounds disclosed herein.
[0028] 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
[0029] In the following descπption, for the purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding of the present invention. It will be apparent, however, to one skilled in the art that the present invention may be practiced without these specific details. [0030] The present invention relates to structures and synthesis of creatine-fatty acid compounds bound via an anhydπde linkage.. In addition, specific benefits are conferred by the particular fatty acid used to form the compounds in addition to, and separate from, the creatine substituent. [0031] As used herein, 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. Furthermore, essential fatty acids are herein understood to be included by the term 'fatty acid'.
[0032] As used herein, "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, 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 deπvatives having pharmacoproperties upon metabolism to an active form.
[0033] According to the present invention, 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
O O Step 1 O
C + S 350C - 5O0C c R-" "OH x" "x 0.5 - 2 h R^-χ
whe
M = Na, K, Li, or NH4
O O
I l I l r Γ H2C "θ R
HN^ /N^ ^C" "CH3
NH2
1
[0035] With reference to Scheme 1, in Step 1 an acyl hahde (4) is produced via reaction of a fatty acid (2) with a thionyl hahde (3).
[0036] In various embodiments of the present invention, 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, capπc or decanoic acid, lauric or dodecanoic acid, myπstic or tetradecanoic acid,
palmitic or hexadecanoic acid, steaπc or octadecanoic acid, arachidic or eicosanoic acid, and behenic or docosanoic acid.
[0037] In alternative embodiments, of the present invention, 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.
[0038] Furthermore, the thionyl hahde of (3) is selected from the group consisting of fluorine, chlorine, bromine, and iodine, the preferred method using chlorine or bromine. [0039] The above reaction proceeds under conditions of heat ranging between from about 35°C to about 500C 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 0C for 1.5 hours. [0040] 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.
[0041] Neutralization, as descπbed above, is followed by the evaporation of water, resulting in the isolation of the corresponding salt. For example, potassium hydroxide, when used as the inorganic base, results m the production of the potassium creatine salt. [0042] 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 anhydπde compound being a creatine fatty acid compound of the present invention. [0043] In various embodiments, according to aforementioned, using the saturated fatty acids, 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 anhydπde, 2-(l-methylguanidino)acetic tetradecanoic anhydπde, 2-(l-
methylguamdmo)acetic palmitic anhydπde, icosanoic 2 -(I -methyl guanidmo)acetic anhydride, and docosanoic 2-(l-methylguamdino)acetic anhydπde.
[0044] In additional embodiments, according to aforementioned, using the unsaturated fatty acids, the following compounds are produced: (Z)-hexadec-9-enoic 2-(l-methylguanidmo)acetic anhydride, 2-(l -methyl guamdino)acetic oleic anhydride, (Z)-docos-13-enoic 2(1 -methyl guanidino)acetic anhydride, 2-(l-methylguanidino)acetic (9Z,12Z)-octadeca-9,12-dienoic anhydπde, 2-(l- methylguanidmo)acetic (9Z,12Z,15Z)-octadeca-9,12,15-tπenoic anhydπde, 2-(l- methylguanidino)acetic (6Z,9Z,12Z)-octadeca-6,9,12-tπenoic anhydπde, (5Z,8Z,l lZ,14Z)-icosa- 5, 8,11,14-tetraenoic 2(l-methylguamdino)acetic anhydride, (5Z,8Z,l lZ,14Z,17Z)-icosa-5,8, 11, 14,17- pentaenoic 2(l-methylguanidmo)acetic anhydride, 2(l-methylguanidino)acetic (8Z,1 lZ,14Z,17Z,20Z)-tπcosa-5,8,l 1,14,17,20-hexaenoic anhydride.
[0045] The following examples illustrate specific creatine-fatty acids and routes of synthesis thereof. One of skill in the art may envision vaπous other combinations within the scope of the present invention, considering examples with reference to the specification herein provided. Example 1
Butyric 2-(l -methyl guamdino)acetic anhydπde
[0046] In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 8.75ml (120mmol) of thionyl chloπde, and a water condenser, is placed 9 05ml (lOOmmol) of butanoic acid. Addition of the thionyl chloπde is completed with heating to about 40°C over the course of about 30 minutes. When addition of the thionyl chloride is complete the mixture is heated and stirred for an additional 30 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloπde, butyryl chloride.
[0047] Separately, in a smgle-necked, round bottomed flask, equipped with a magnetic stirrer, 6 56g (50mmol) of creatine is dissolved in 500ml of water. To this is added 55ml of IM sodium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, sodium 2-(l-methylguamdmo)acetate, shown below.
O I l
/C^ NaO CH2
H3C" "C ^ NH2
[0048] Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 6.39g (60mmol) of the prepared butyryl chloπde, and side arm water condenser fixed with a dry receiving flask, is placed 12.08g (66mmol) of sodium 2-(l -methyl guanidmo)acetate The round bottomed flask is placed in an ice bath and the butyryl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield butyric 2-(l-methylguanidino)acetic anhydride. Example 2
Hexanoic 2-(l-methylguanidmo)acetic anhydride
[0049] In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 6.97ml (90mmol) of thionyl bromide, and a water condenser, is placed 5.68ml (45mmol) of hexanoic acid. Addition of the thionyl bromide is completed with heating to about 50°C over the course of about 50 minutes. When addition of the thionyl bromide is complete the mixture is heated and stirred for an additional hour. The water condenser is then replaced with a
distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl bromide, hexanoyl bromide. [0050] Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 6 56g (50mmol) of creatine is dissolved in 500ml of water. To this is added 55ml of IM sodium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, sodium 2-(l-methylguanidino)acetate, shown below.
[0051] Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 10.81g (όOmmol) of the prepared hexanoyl bromide, and side arm water condenser fixed with a dry receiving flask, is placed 13.18g (72mmol) of sodium 2-(l-methylguanidmo)acetate The round bottomed flask is placed in an ice bath and the hexanoyl bromide is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield hexanoic 2-(l-methylguanidino)acetic anhydπde. Example 3
Dodecanoic 2 -(I -methyl guanidmo)aceϋc anhydπde
[0052] In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 5.85ml (80mmol) of thionyl chloride, and a water condenser, is placed 10 02g (50mmol) of dodecanoic acid. Addition of the thionyl chloπde is completed with heating to about 450C over the course of about 40 minutes. When addition of the thionyl chloride is complete
the mixture is heated and stirred for an additional 50 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloπde, dodecanoyl chloride. [0053] Separately, in a smgle-necked, round bottomed flask, equipped with a magnetic stirrer, 7.87g (όOmmol) of creatine is dissolved in 600ml of water. To this is added 78ml of IM ammonium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, ammonium 2-(l-methylguanidino)acetate, shown below
O
/C^ H4NO CH2
I
/N^ ^NH H3C ^C X
NH2
[0054] Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 15.31 g (70mmol) of the prepared dodecanoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 12.44g (84mmol) of ammonium 2-(l -methyl guamdino)acetate. The round bottomed flask is placed in an ice bath and the dodecanoyl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield dodecanoic 2-(l-methylguanidmo)acetic anhydride. Example 4
2-(l-methylguanidmo)acetic steaπc anhydπde
[0055] In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 4.81ml (66mmol) of thionyl chloride, and a water condenser, is placed 15.65g (55mmol) of steaπc acid. Addition of the thionyl chloπde is completed with heating to about
45 "C over the course of about 40 rmnutes. When addition of the thionyl chloπde is complete the mixture is heated and stirred for an additional 45 minutes. The water condenser is then replaced with a distillation side arm condenser and the crude mixture is distilled. The crude distillate in the receiving flask is then fractionally distilled to obtain the acyl chloπde, stearoyl chloπde. [0056] Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 7 87g (60mmol) of creatine is dissolved in 600ml of water. To this is added 72ml of IM potassium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, potassium 2-(l-methylguanidino)acetate, shown below.
O I l
/Cx KO CH2
H3C ^C X NH2 [0057] Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 21.27g (70mmol) of the prepared stearoyl chlonde, and side arm water condenser fixed with a dry receiving flask, is placed 23.4Og (77mmol) of potassium 2-(l-methylguanidino)acetate. The round bottomed flask is placed in an ice bath and the stearoyl chloπde is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2-(l-methylguanidmo)acetic stearic anhydπde. Example 5
2-( 1 -methylguamdmo)acetic (9Z, 12Z)-octadeca-9, 12-dienoic anhydride
[0059] Separately, in a smgle-necked, round bottomed flask, equipped with a magnetic stirrer, 7 87g (60mmol) of creatine is dissolved in 600ml of water. To this is added 78ml of IM ammonium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, ammonium 2-(l-methylguamdino)acetate, shown below
O
/Cx
H4NO CH2
^Nx ^NH H3C C ^
NH2
[0060] Finally, in a dry 2-necked, round bottomed flask, fixed with a separately funnel, containing 17.93g (60mmol) of the prepared (9Z,12Z)-octadeca-9,12-dienoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 10.66g (72mmol) of ammonium 2-(l- methylguanidmo)acetate. The round bottomed flask is placed in an ice bath and the (9Z,12Z)- octadeca-9,12-dienoyl chloride is added drop wise. After addition is completed the mixture is shaken and the ice bath is replaced by a heating mantle. The flask is then heated until no more solution is dropping into the receiving flask. This crude distillate is then further fractionally distilled to yield 2- ( 1 -methylguanidino)acetic(9Z, 12Z)-octadeca-9, 12-dienoic anhydπde. [0061] Thus while not wishing to be bound by theory, it is understood that reacting a creatine or derivative thereof with a fatty acid or derivative thereof to form an anhydπde can be used enhance the bioavailability of the creatine or deπvative thereof by improving stability of the creatine moiety in terms of resistance to hydrolysis in the stomach and blood and by increasing solubility and absorption Furthermore, it is understood that, dependent upon the specific fatty acid, for example, saturated fatty
acids form straight chains allowing mammals to store chemical energy densely, or derivative thereof employed in the foregoing synthesis, additional fatty acid-specific benefits, separate from the creatine substituent, will be conferred.
Extensions and Alternatives
[0062] In the foregoing specification, the invention has been described with a specific embodiment thereof; however, it will be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention.
Claims
What is claimed:
1 A compound having the general structure:
O O
Il Il
H2C O R
^C" ^CH3
NH2
wherein R is selected from the group consisting of alkanes and alkenes.
2. The compound according to claim 1 wherein R is an alkane having 3 to 5 carbons.
3. The compound of claim 2 having a molecular weight of between about 201 and about 229.
4. The compound according to claim 1 wherein R is an alkane having 7 to 9 carbons
5. The compound of claim 4 having a molecular weight of between about 257 and about 285.
6. The compound according to claim 1 wherein R is an alkane having 11 to 13 carbons.
7. The compound of claim 6 having a molecular weight of between about 313 and about 342.
8 The compound according to claim 1 wherein R is an alkane having 15 to 17 carbons.
9. The compound of claim 8 having a molecular weight of between about 369 and about 398.
10. The compound according to claim 1 wherein R is an alkane having 19 to 21 carbons.
11. The compound of claim 10 having a molecular weight of between about 425 and about 454
12 The compound according to claim 1 wherein R is an alkene having at least one carbon-carbon double bond, compπsing 3 to 5 carbons.
13. The compound of claim 12 having a molecular weight of between about 199 and about 227
14 The compound according to claim 1 wherein R is an alkene having at least one carbon-carbon double bond, comprising 7 to 9 carbons
15. The compound of claim 14 having a molecular weight of between about 251 and about 283
16 The compound according to claim 1 wherein R is an alkene having at least one carbon-carbon double bond, comprising 11 to 13 carbons.
17. The compound of claim 16 having a molecular weight of between about 303 and about 340
18. The compound according to claim 1 wherein R is an alkene having at least one carbon-carbon double bond, compπsing 15 to 17 carbons.
19. The compound of claim 18 having a molecular weight of between about 355 and about 396.
20. The compound according to claim 1 wherein R is an alkene having at least one carbon-carbon double bond, comprising 17 to 21 carbons.
21. The compound of claim 20 having a molecular weight of between about 407 and about 452.
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| PCT/CA2007/000257 WO2008101309A1 (en) | 2007-02-20 | 2007-02-20 | Creatine-fatty acids |
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| US20120277305A1 (en) * | 2011-04-29 | 2012-11-01 | Catabasis Pharmaceuticals, Inc. | Fatty acid guanidine and salicylate guanidine derivatives and their uses |
| EP2692719A1 (en) | 2012-07-30 | 2014-02-05 | Commissariat à l'Énergie Atomique et aux Énergies Alternatives | Method for preparing creatine fatty esters, creatine fatty esters thus prepared and uses thereof |
| WO2014203198A3 (en) * | 2013-06-22 | 2015-04-02 | Mahesh Kandula | Compositions and methods for the treatment of neurological diseases and renal complications |
| US11332438B2 (en) | 2017-12-01 | 2022-05-17 | Ultragenyx Pharmaceutical Inc. | Creatine prodrugs, compositions and methods of use thereof |
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| US5994581A (en) * | 1998-03-09 | 1999-11-30 | Amt Labs, Inc. | Carnitine creatinate |
| WO2003099806A1 (en) * | 2002-05-27 | 2003-12-04 | Licrea S.R.L. | Creatine salt having enhanced nutritional, antioxidant and therapeutic efficacy and compositions containing same |
| WO2003101402A2 (en) * | 2002-06-04 | 2003-12-11 | Avicena Group, Inc. | Methods of treating cognitive dysfunction by modulating brain energy metabolism |
| WO2006081682A1 (en) * | 2005-02-07 | 2006-08-10 | New Cell Formulations Ltd. | Creatine hydroxycitric acids salts and methods for their production and use in individuals |
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| US5994581A (en) * | 1998-03-09 | 1999-11-30 | Amt Labs, Inc. | Carnitine creatinate |
| WO2003099806A1 (en) * | 2002-05-27 | 2003-12-04 | Licrea S.R.L. | Creatine salt having enhanced nutritional, antioxidant and therapeutic efficacy and compositions containing same |
| WO2003101402A2 (en) * | 2002-06-04 | 2003-12-11 | Avicena Group, Inc. | Methods of treating cognitive dysfunction by modulating brain energy metabolism |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 (en) | 2012-07-30 | 2014-02-05 | Commissariat à l'Énergie Atomique et aux Énergies Alternatives | Method for preparing creatine fatty esters, creatine fatty esters thus prepared and uses thereof |
| WO2014019855A1 (en) | 2012-07-30 | 2014-02-06 | Commissariat à l'énergie atomique et aux énergies alternatives | Method for preparing creatine fatty esters, creatine fatty esters thus prepared and uses thereof |
| 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 (en) * | 2013-06-22 | 2015-04-02 | Mahesh Kandula | Compositions and methods for the treatment of neurological diseases and renal complications |
| 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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