WO2008138090A1 - Preparation of amino acid-fatty acid anhydrides - Google Patents
Preparation of amino acid-fatty acid anhydrides Download PDFInfo
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- WO2008138090A1 WO2008138090A1 PCT/CA2007/000810 CA2007000810W WO2008138090A1 WO 2008138090 A1 WO2008138090 A1 WO 2008138090A1 CA 2007000810 W CA2007000810 W CA 2007000810W WO 2008138090 A1 WO2008138090 A1 WO 2008138090A1
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
Definitions
- the present invention relates to structures and synthesis of amino acid-fatty acid compounds bound via an anhydride linkage. Specifically, the present invention relates to a compound comprising an amino acid bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid and bound to the amino acid via an anhydride linkage.
- Participation in sports at any level either professional or amateur requires an athlete to strive to bring their bodies to a physical state which is considered optimum for the sport of interest.
- One of the factors that correlate positively with successful participation in a sport is a high degree of development of the aerobic capacity and/or strength of skeletal muscle. Consequently, it is important that nutrients and other requirements of muscles be readily available and that they be transported to areas where they are needed without obstructions.
- Strength and aerobic capacity are both functions of training and of muscle mass. As such, an athlete who can train harder and longer is often considered to be the most effective at participation in the sport of interest. Strenuous exercise is an effective stimulus for protein synthesis. However, muscle requires a large array of nutrients, including amino acids, in order to facilitate this increased level of protein synthesis.
- a negative nitrogen balance is a state in which the body requires more nitrogen, to facilitate repair and growth of muscle, than is being ingested.
- This state causes the body to catabolize muscle in order to obtain the nitrogen required, and thus results in a decrease in muscle mass and/or attenuation of exercise-induced muscle growth. Therefore, it is important that athletes ingest adequate amounts of amino acids in order to minimize the catabolism of muscle in order to obtain the results desired from training.
- amino acids Although supplementation with amino acids are quite common, the uptake of amino acids by cells is limited or slow since amino acid residues are not soluble or only slightly soluble in nonpolar organic solution, such as the lipid bilayer of cells. As a result amino acids must be transported into cells via transport mechanisms which are specific to the charges that the amino acid bears. It is therefore desirable to provide, for use in individuals, e.g. animals and humans, forms and derivatives of amino acids with improved characteristics that result in increased stability and increased uptake by cells. Furthermore, it would be advantageous to do so in a manner that provides additional functionality as compared to amino acids alone.
- 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 carboxylic 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 fatty acids which are essential to humans are linoleic acid and ⁇ - linolenic acid.
- saturated fatty acids include, but are not limited to myristic or tetradecanoic acid, palmitic or hexadecanoic acid, stearic 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.
- 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 carboxylic acids. Of particular relevance to the present invention are the formation of anhydrides and the formation of esters.
- Ri is an alkyl group, preferably saturated, and containing from about 3 to a maximum of 21 carbons.
- R 2 is hydrogen, methyl, isopropyl, isobutyl, sec butyl, acetylamide, propylamide, butyl-1 -amine, or 1-butylguanidine.
- 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 amino acid-fatty acid compounds bound via an anhydride linkage.
- specific benefits are conferred by the particular fatty acid used to form the compounds in addition to, and separate from, the amino acid 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 greater than four carbon atoms.
- essential fatty acids are herein understood to be included by the term 'fatty acid'.
- amino acid refers a compound consisting of a carbon atom to which are attached a primary amino group, a carboxylic acid group, a side chain, and a hydrogen atom.
- amino acid includes, but is not limited to, Glycine, Alanine, Valine, Leucine, Isoleucine, Asparagine, Glutamine, Lysine and Arginine.
- amino acid also includes derivatives of amino acids such as esters, and amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form.
- the compounds disclosed herein comprise an amino acid bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid. Furthermore, the amino acid and fatty acid are bound via an anhydride linkage and having a structure according to that of Formula 1.
- the aforementioned compound being prepared according to the reaction as set forth for the purposes of the description in Scheme 1 :
- R 2 hydrogen, methyl, isopropyl, isobutyl, ⁇ 5 sec butyl, acetylamide, propylamide, butyl-1-amine, and 1 -butylguamdine O O
- Step 1 an acyl halide (4) is produced via reaction of a fatty acid (2) with a thionyl halide (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, capric or decanoic acid, lauric or dodecanoic acid, myristic or tetradecanoic acid, palmitic or hexadecanoic acid, stearic 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, capric or decanoic acid, lauric or dodecanoic acid, myristic or tetradecanoic acid, palmitic or hexadecanoic acid, stearic or octadecanoic acid, arachidic or
- 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.
- the thionyl halide 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 ° 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 halide employed, are evolved.
- the reaction proceeds at 45 ° C for 1.5 hours.
- Step 2 of Scheme 1 entails the neutralization of the carboxylic acid of the amino acid 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. Neutralization, as described above, is followed by the evaporation of water, resulting in the isolation of the corresponding salt. For example, using the amino acid, Arginine and the inorganic base potassium hydroxide, results in the production of the potassium Arginine salt.
- Step 3 of Scheme 1 involves the drop wise addition of the prepared acyl halide (4) to the amino acid salt (6) in a cooled flask and subsequent purification by two rounds of distillation to yield the desired anhydride compound (1), the anhydride compound being an amino acid-fatty acid compound of the present invention.
- a number of compounds are produced; examples include, but are not limited to: 2-amino-3-methylbutanoic butyric anhydride, 2-amino-3- methylpentanoic hexanoic anhydride, 2,4-diamino-4-oxobutanoic octanoic anhydride, 2,4-diamino-4-oxobutanoic decanoic anhydride, 2-amino-5- guanidinopentanoic dodecanoic anhydride, 2,6-diaminohexanoic tetradecanoic anhydride, 2-amino-5-guanidinopentanoic palmitic anhydride, 2-amino-4- methylpentanoic stearic anhydride, 2-aminopropanoic icosanoic anhydride, and 2- aminoacetic docosanoic anhydride.
- a number of compounds are produced; examples include, but are not limited to: 2-aminopropanoic (7Z,10Z)-hexadeca-7,10-dienoic anhydride, 2,5-diamino-5-oxopentanoic oleic anhydride, 2,4-diamino-4-oxobutanoic (9Z,12Z,15Z)-octadeca-9,12,15-trienoic anhydride, 2-aminoacetic (5Z,8Z,11Z,14Z)- icosa-5,8,11 ,14-tetraenoic anhydride, 2-amino-5-guanidinopentanoic (Z)-hexadex- 9-enoic anhydride, 2-amino-3-methylpentanoic (5Z,8Z,11Z,14Z,17Z)-icosa- 5,8,11 , 14, 17-
- the flask is then heated until no more solution is dropping into the receiving flask.
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Abstract
The present invention describes compounds produced from an ammo acid molecule and a fatty acid molecule The compounds being in the form of ammo acid-fatty acid compounds of Formula I being bound by an anhydride linkage, or mixtures thereof made by reacting ammo acids or derivatives with an appropriate fatty acid previously reacted with a thionyl halide. Wherein R1 is selected from alkanes or alkenes and R2 is selected from hydrogen, methyl, isopropyl, isobutyl, sec butyl, acetylamide, propylamide, butyl- 1 -amine and 1 -propyl guamdme The administration of such molecules provides supplemental ammo acids with enhanced bioavailability and the additional benfits conferred by the specific fatty acid
Description
Preparation of Amino Acid-Fatty Acid Anhydrides
Cross-Reference To Related Application
The present application is a Continuation-in-Part of U.S. Patent Application Serial No. 11/676,623 entitled "Creatine-Fatty Acids," filed February 20, 2007, and claims benefit of priority thereto; the disclosure of which is hereby fully incorporated by reference.
Field of the Invention
The present invention relates to structures and synthesis of amino acid-fatty acid compounds bound via an anhydride linkage. Specifically, the present invention relates to a compound comprising an amino acid bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid and bound to the amino acid via an anhydride linkage.
Background of the Invention
Participation in sports at any level either professional or amateur requires an athlete to strive to bring their bodies to a physical state which is considered optimum for the sport of interest. One of the factors that correlate positively with successful participation in a sport is a high degree of development of the aerobic capacity and/or strength of skeletal muscle. Consequently, it is important that nutrients and other requirements of muscles be readily available and that they be transported to areas where they are needed without obstructions.
Strength and aerobic capacity are both functions of training and of muscle mass. As such, an athlete who can train harder and longer is often considered to be the most effective at participation in the sport of interest. Strenuous exercise is an effective stimulus for protein synthesis. However, muscle requires a large array
of nutrients, including amino acids, in order to facilitate this increased level of protein synthesis.
Following periods of strenuous exercise, muscle tissue enters a stage of rapid nitrogen absorption in the form of amino acids and small peptides. This state of increased nitrogen absorption is a result of the body repairing exercise-induced muscle fiber damage as well as the growth and formation of new muscle fibers. It is important that muscles have sufficient levels of nitrogen, in the form of amino acids and small peptides, during this period of repair and growth. When an athlete is participating in a strenuous exercise regime and fails to ingest enough nitrogen, e.g. amino acids, the body often enters a state of negative nitrogen balance. A negative nitrogen balance is a state in which the body requires more nitrogen, to facilitate repair and growth of muscle, than is being ingested. This state causes the body to catabolize muscle in order to obtain the nitrogen required, and thus results in a decrease in muscle mass and/or attenuation of exercise-induced muscle growth. Therefore, it is important that athletes ingest adequate amounts of amino acids in order to minimize the catabolism of muscle in order to obtain the results desired from training.
Although supplementation with amino acids are quite common, the uptake of amino acids by cells is limited or slow since amino acid residues are not soluble or only slightly soluble in nonpolar organic solution, such as the lipid bilayer of cells. As a result amino acids must be transported into cells via transport mechanisms which are specific to the charges that the amino acid bears. It is therefore desirable to provide, for use in individuals, e.g. animals and humans, forms and derivatives of amino acids with improved characteristics that result in increased stability and
increased uptake by cells. Furthermore, it would be advantageous to do so in a manner that provides additional functionality as compared to amino acids alone.
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 carboxylic 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 fatty acids which are essential to humans are linoleic acid and α- linolenic acid.
Examples of saturated fatty acids include, but are not limited to myristic or tetradecanoic acid, palmitic or hexadecanoic acid, stearic 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 carboxylic acids. Of particular relevance to the present invention are the formation of anhydrides and the formation of esters.
Summary of the Invention In the present invention, compounds are disclosed, where the compounds comprise an amino acid bound to a fatty acid, via an anhydride linkage, and having a structure of Formula 1 :
Formula 1
O O
I l I l
H2Nx X^ ^CN CH O R1
R2 where:
Ri is an alkyl group, preferably saturated, and containing from about 3 to a maximum of 21 carbons.
R2 is hydrogen, methyl, isopropyl, isobutyl, sec butyl, acetylamide, propylamide, butyl-1 -amine, or 1-butylguanidine.
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
In the following description, 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.
The present invention relates to structures and synthesis of amino acid-fatty acid compounds bound via an anhydride linkage. In addition, specific benefits are conferred by the particular fatty acid used to form the compounds in addition to, and separate from, the amino acid substituent.
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 carboxylic acid as is commonly known in the art, wherein the hydrocarbon chain is greater than four carbon atoms. Furthermore, essential fatty acids are herein understood to be included by the term 'fatty acid'. As used herein, "amino acid" refers a compound consisting of a carbon atom to which are attached a primary amino group, a carboxylic acid group, a side chain, and a hydrogen atom. For example, the term "amino acid" includes, but is not limited to, Glycine, Alanine, Valine, Leucine, Isoleucine, Asparagine, Glutamine, Lysine and Arginine. Additionally, as used herein, "amino acid" also includes derivatives of amino acids such as esters, and amides, and salts, as well as other derivatives, including derivatives having pharmacoproperties upon metabolism to an active form.
According to the present invention, the compounds disclosed herein comprise an amino acid bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid. Furthermore, the amino acid and fatty acid are bound via an
anhydride linkage and having a structure according to that of Formula 1. The aforementioned compound being prepared according to the reaction as set forth for the purposes of the description in Scheme 1 :
Scheme 1
2 3 4
O O
C NH-, . SteP 2 /C. .NH2
Step 3 where: MO^ CH I)MOH5 H2O H0 C,H
' 2)evap. H2O R2
R1 = alkane or alkene (C = 3 to 21)
R2 = hydrogen, methyl, isopropyl, isobutyl, β 5 sec butyl, acetylamide, propylamide, butyl-1-amine, and 1 -butylguamdine O O
X = Cl, Br, F, or I N N
M = Na, K, Li, or NH4 2 CH ^ ^R1
R2 i
With reference to Scheme 1 , in Step 1 an acyl halide (4) is produced via reaction of a fatty acid (2) with a thionyl halide (3).
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, capric or decanoic acid, lauric or dodecanoic acid, myristic or tetradecanoic acid, palmitic or hexadecanoic acid, stearic or octadecanoic acid, arachidic or eicosanoic acid, and behenic or docosanoic acid.
In alternative embodiments, of the present invention, 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.
Furthermore, the thionyl halide 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°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 halide employed, are evolved.
Preferably, the reaction proceeds at 45 °C for 1.5 hours.
Step 2 of Scheme 1 entails the neutralization of the carboxylic acid of the amino acid 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. Neutralization, as described above, is followed by the evaporation of water, resulting in the isolation of the corresponding salt. For example, using the amino acid, Arginine and the inorganic base potassium hydroxide, results in the production of the potassium Arginine salt.
Step 3 of Scheme 1 involves the drop wise addition of the prepared acyl halide (4) to the amino acid salt (6) in a cooled flask and subsequent purification by two rounds of distillation to yield the desired anhydride compound (1), the anhydride compound being an amino acid-fatty acid compound of the present invention.
In various embodiments, according to the aforementioned, using the saturated fatty acids, a number of compounds are produced; examples include, but are not limited to: 2-amino-3-methylbutanoic butyric anhydride, 2-amino-3-
methylpentanoic hexanoic anhydride, 2,4-diamino-4-oxobutanoic octanoic anhydride, 2,4-diamino-4-oxobutanoic decanoic anhydride, 2-amino-5- guanidinopentanoic dodecanoic anhydride, 2,6-diaminohexanoic tetradecanoic anhydride, 2-amino-5-guanidinopentanoic palmitic anhydride, 2-amino-4- methylpentanoic stearic anhydride, 2-aminopropanoic icosanoic anhydride, and 2- aminoacetic docosanoic anhydride.
In additional embodiments, according to the aforementioned, using the unsaturated fatty acids, a number of compounds are produced; examples include, but are not limited to: 2-aminopropanoic (7Z,10Z)-hexadeca-7,10-dienoic anhydride, 2,5-diamino-5-oxopentanoic oleic anhydride, 2,4-diamino-4-oxobutanoic (9Z,12Z,15Z)-octadeca-9,12,15-trienoic anhydride, 2-aminoacetic (5Z,8Z,11Z,14Z)- icosa-5,8,11 ,14-tetraenoic anhydride, 2-amino-5-guanidinopentanoic (Z)-hexadex- 9-enoic anhydride, 2-amino-3-methylpentanoic (5Z,8Z,11Z,14Z,17Z)-icosa- 5,8,11 , 14, 17-pentaenoic anhydride, 2-amino-4-methylpentanoic (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7, 10,13, 16,19-hexenoic anhydride, and 2- amino-3-methylbutanoic (Z)-docos-13-enoic anhydride.
The following examples illustrate specific amino acid-fatty acid anhydrides and routes of synthesis thereof. One of skill in the art may envision various other combinations within the scope of the present invention, considering examples with reference to the specification herein provided. Example 1
2-amino-3-methylbutanoic butyric anhydride
10 Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 5.86g (δOmrnol) of Valine is dissolved in 200ml of water. To this is added 55ml of 1M 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-amino-3-methylbutanoate, shown below.
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 6.39g (60mmol) of the prepared butyryl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 9.18g (66mmol) of sodium 2-amino-3-methylbutanoate. The round bottomed flask is placed in an ice 20 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 2-amino-3-methylbutanoic butyric anhydride. Example 2
2-amino-3-methylpentanoic hexanoic anhydride
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. Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 6.56g (50mmol) of lsoleucine is dissolved in 200ml of water. To this is added 55ml of 1 M 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-amino-3-methylpentanoate, shown below.
O
/C^ .NH2 NaO CH
I
.CH H3C "CH2
CH3
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 10.81g (ΘOmmol) of the prepared hexanoyl bromide, and side arm water condenser fixed with a dry receiving flask, is placed 11.03g (72mmol) of sodium 2-amino-3-methylpentanoate. 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 2-amino-3-methylpentanoic hexanoic anhydride.
Example 3
2-amino-5-guanidinopentanoic dodecanoic anhydride
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 chloride is completed with heating to about 45°C 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 chloride, dodecanoyl chloride.
Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 10.45g (ΘOmmol) of Arginine is dissolved in 300ml of water. To this is added 78ml of 1 M 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-amino-5-guanidinopentanoate, shown below.
O
-NH 2
H4NO CH
H 2c.
TΉ2
H;
' N I H
HN^ NH2
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 15.31g (70mmol) of the prepared dodecanoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 16.06g (84mmol) of ammonium 2-amino-5-guanidinopentanoate. 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 2-amino-5- guanidinopentanoic dodecanoic anhydride.
Example 4
2-amino-4-methylpentanoic stearic anhydride
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 4.81 ml (66mmol) of thionyl chloride, and a water condenser, is placed 15.65g (55mmol) of stearic acid. Addition of the thionyl chloride is completed with heating to about 45°C over the course of about 40 minutes. When addition of the thionyl chloride 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 chloride, stearoyl chloride.
Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 7.87g (ΘOmmol) of Leucine is dissolved in 300ml of water. To this is added 72ml of 1 M 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-amino-4-methylpentanoate, shown below.
2-aminopropanoic (7Z,10Z)-hexadeca-7,10-dienoic anhydride
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 9.35ml (128mmol) of thionyl chloride, and a water condenser, is placed 24.90ml (δOmrnol) of linoleic acid. Addition of the thionyl chloride is completed with heating to about 40°C 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 chloride, (9Z, 12Z)-octadeca-9, 12-dienoyl chloride.
Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 5.34g (60mmol) of Alanine is dissolved in 200ml of water. To this
is added 78ml of 1 M 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-aminopropanoate, shown below.
Thus while not wishing to be bound by theory, it is understood that reacting an amino acid or derivative thereof with a fatty acid or derivative thereof to form an anhydride can be used enhance the bioavailability of the amino acid or derivative thereof by improving stability of the amino acid 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 amino acid substituent, will be conferred.
Extensions and Alternatives
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
1. A compound having the general structure:
O O
I l I !
H2N. X^ /C^ CH O R
I H2C^
CH2
H2C^
NH
I
^C v HN 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 244 and about 273.
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 300 and about 329.
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 356 and about 385.
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 412 and about 441.
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 468 and about 497.
12. The compound according to claim 1 wherein R is an alkene having at least one carbon-carbon double bond, comprising 3 to 5 carbons.
13. The compound of claim 12 having a molecular weight of between about 242 and about 271.
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 294 and about 327.
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 346 and about 383.
18. The compound according to claim 1 wherein R is an alkene having at least one carbon-carbon double bond, comprising 15 to 17 carbons.
19. The compound of claim 18 having a molecular weight of between about 398 and about 439.
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 450 and about 495.
22. A compound having the general structure: O O
I l I l
H2N. .C^ /C^ CH O R1
R2
wherein Ri is selected from the group consisting of alkanes and alkenes; wherein R2 is selected from the group consisiting of hydrogen, methyl, isopropyl, isobutyl, sec butyl, acetylamide, propylamide, and butyl-1 -amine.
23. The compound according to claim 22 wherein R-i is an alkane having 3 to 5 carbons.
24. The compound of claim 23 having a molecular weight of between about 145 and about 231.
25. The compound according to claim 22 wherein Ri is an alkane having 7 to 9 carbons.
26. The compound of claim 25 having a molecular weight of between about 201 and about 287.
27. The compound according to claim 22 wherein Ri is an alkane having 11 to 13 carbons.
28. The compound of claim 27having a molecular weight of between about 257 and about 343.
29. The compound according to claim 22 wherein Ri is an alkane having 15 to
17 carbons.
30. The compound of claim 29 having a molecular weight of between about 313 and about 399.
31. The compound according to claim 22 wherein Ri is an alkane having 19 to 21 carbons.
32. The compound of claim 31 having a molecular weight of between about 341 and about 455.
33. The compound according to claim 22 wherein Ri is an alkene having at least one carbon-carbon double bond, comprising 3 to 5 carbons.
34. The compound of claim 33 having a molecular weight of between about 143 and about 229.
35. The compound according to claim 22 wherein Ri is an alkene having at least one carbon-carbon double bond, comprising 7 to 9 carbons.
36. The compound of claim 35 having a molecular weight of between about 195 and about 285.
37. The compound according to claim 22 wherein Ri is an alkene having at least one carbon-carbon double bond, comprising 11 to 13 carbons.
38. The compound of claim 37 having a molecular weight of between about 247 and about 341.
39. The compound according to claim 22 wherein Ri is an alkene having at least one carbon-carbon double bond, comprising 15 to 17 carbons.
40. The compound of claim 39 having a molecular weight of between about 299 and about 397.
41.The compound according to claim 22 wherein Ri is an alkene having at least one carbon-carbon double bond, comprising 17 to 21 carbons.
42. The compound of claim 41 having a molecular weight of between about 351 and about 453.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CA2007/000810 WO2008138090A1 (en) | 2007-05-10 | 2007-05-10 | Preparation of amino acid-fatty acid anhydrides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CA2007/000810 WO2008138090A1 (en) | 2007-05-10 | 2007-05-10 | Preparation of amino acid-fatty acid anhydrides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2008138090A1 true WO2008138090A1 (en) | 2008-11-20 |
Family
ID=40001613
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CA2007/000810 WO2008138090A1 (en) | 2007-05-10 | 2007-05-10 | Preparation of amino acid-fatty acid anhydrides |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2008138090A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3024272A (en) * | 1958-04-22 | 1962-03-06 | Du Pont | Organic acid salts of basic amino acids and their use |
| US20040023889A1 (en) * | 2000-02-01 | 2004-02-05 | Paul Gardiner | Alpha lipoic acid based food supplement for increasing lean muscle mass and strength |
| CA2577439A1 (en) * | 2007-02-20 | 2007-05-07 | Multi Formulations Ltd. | Creatine-fatty acids |
-
2007
- 2007-05-10 WO PCT/CA2007/000810 patent/WO2008138090A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3024272A (en) * | 1958-04-22 | 1962-03-06 | Du Pont | Organic acid salts of basic amino acids and their use |
| US20040023889A1 (en) * | 2000-02-01 | 2004-02-05 | Paul Gardiner | Alpha lipoic acid based food supplement for increasing lean muscle mass and strength |
| CA2577439A1 (en) * | 2007-02-20 | 2007-05-07 | Multi Formulations Ltd. | Creatine-fatty acids |
Non-Patent Citations (2)
| Title |
|---|
| KRETSCHMAYER R. AND JESSERER, H. BIOCHEMISCHE ZEITSCHRIFT, vol. 292, no. 403-418, 1937, pages 419 - 423 * |
| TAZAWA Y., ACTA PHYTOCHIM. (JAPAN), vol. 8, 1935, pages 331 - 336 * |
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