CA2621925A1 - Preparation of amino acid-fatty acid anhydrides - Google Patents
Preparation of amino acid-fatty acid anhydrides Download PDFInfo
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Abstract
The present invention describes compounds produced from an amino acid molecule and a fatty acid molecule. The compounds being in the form of amino--fatty acid compounds being bound by an anhydride linkage, or mixtures thereof made by reacting amino acids or derivatives thereof with an appropriate fatty acid previously reacted with a thionyl halide. The administration of such molecules provides supplemental amino acids with enhanced bioavailability and the additional benefits conferred by the specific fatty acid.
Description
Preparation of Amino Acid-Fatty Acid Anhydrides 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.
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 a-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.
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 II II
H2N CH'C" O"C~R
I ' Rz, where:
R, 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-l-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 11 + 0 Step 1~ 0 R~" OH X~ " x 0.5 - 2 h Ri "-~X
0 o Step 2 0 11 Step 3 MO,,C CH NHZ i)MOH, H20 HO,C CH NHz where: 2)evap. H20 R2 Rl = alkane or alkene (C = 3 to 21) Rz R2 = hydrogen, methyl, isopropyl, isobutyl, 6 5 sec butyl, acetylamide, propylamide, butyl- l -amine, and 1-butylguanidine 0 0 X=C1,Br,F,orI
H2N~ ,C~ "C' M Na, K, Li, or NH4 CH O Ri RZ
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, paimitoleic 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 paimitic 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, 11 Z,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 I
2-amino-3-methylbutanoic butyric anhydride H2N'CH C'O'CH C'CH3 H3CCH*CH3 In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 8.75m1 (120mmol) of thionyl chloride, and a water condenser, is placed 9.05m1 (100mmol) of butanoic acid.
Addition of the thionyl chloride 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 chloride, butyryl chloride.
Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 5.86g (50mmol) of Valine is dissolved in 200m1 of water. To this is added 55m1 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-methylbutanoate, shown below.
C.
"NH2 NaO CH
H3C,CH.CH3 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 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 H2N~ ' C~ ~C "C
H3C,.CH2 In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 6.97m1 (90mmol) of thionyl bromide, and a water condenser, is placed 5.68m1 (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 Isoleucine is dissolved in 200m1 of water.
To this is added 55mi 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.
"C' e NH2 NaO CH
H3C,CH.CH2 Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 10.81g (60mmol) 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 HZN, .C' "C "C
I H CICHZ (H2 5 i HN'CH2 I
HZN'C~NH
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 (60mmol) of Arginine is dissolved in 300m1 of water.
To this is added 78m1 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
il H2C'CH2 HZC1, NH
I
HNNHZ
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 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 H
H
2N CH C'-Di C"C~CH3 H3C"CH~CH2 H2 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 (60mmol) of Leucine is dissolved in 300m1 of water. To this is added 72m1 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.
I I
KO CH
H2C CH.CH3 I
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 21.27g (70mmol) of the prepared stearoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 13.03g (77mmol) of potassium 2-amino-4-methylpentanoate. The round bottomed flask is placed in an ice bath and the stearoyl 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-4-methylpentanoic stearic anhydride.
Example 5 2-aminopropanoic (7Z,10Z)-hexadeca-7,10-dienoic anhydride HzN CH'C'OiC~CaC~C _C~C.C_C~C'C~C'C'CH3 In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 9.35m1 (128mmol) of thionyl chloride, and a water condenser, is placed 24.90m1 (80mmol) 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 78m1 of 1M 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.
"C ' .NH2 Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory 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 7.64g (72mmol) of ammonium 2-aminopropanoate. 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-aminopropanoic (7Z,10Z)-hexadeca-7,10-dienoic anhydride.
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.
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 II II
H2N CH'C" O"C~R
I ' Rz, where:
R, 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-l-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 11 + 0 Step 1~ 0 R~" OH X~ " x 0.5 - 2 h Ri "-~X
0 o Step 2 0 11 Step 3 MO,,C CH NHZ i)MOH, H20 HO,C CH NHz where: 2)evap. H20 R2 Rl = alkane or alkene (C = 3 to 21) Rz R2 = hydrogen, methyl, isopropyl, isobutyl, 6 5 sec butyl, acetylamide, propylamide, butyl- l -amine, and 1-butylguanidine 0 0 X=C1,Br,F,orI
H2N~ ,C~ "C' M Na, K, Li, or NH4 CH O Ri RZ
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, paimitoleic 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 paimitic 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, 11 Z,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 I
2-amino-3-methylbutanoic butyric anhydride H2N'CH C'O'CH C'CH3 H3CCH*CH3 In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 8.75m1 (120mmol) of thionyl chloride, and a water condenser, is placed 9.05m1 (100mmol) of butanoic acid.
Addition of the thionyl chloride 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 chloride, butyryl chloride.
Separately, in a single-necked, round bottomed flask, equipped with a magnetic stirrer, 5.86g (50mmol) of Valine is dissolved in 200m1 of water. To this is added 55m1 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-methylbutanoate, shown below.
C.
"NH2 NaO CH
H3C,CH.CH3 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 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 H2N~ ' C~ ~C "C
H3C,.CH2 In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 6.97m1 (90mmol) of thionyl bromide, and a water condenser, is placed 5.68m1 (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 Isoleucine is dissolved in 200m1 of water.
To this is added 55mi 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.
"C' e NH2 NaO CH
H3C,CH.CH2 Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 10.81g (60mmol) 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 HZN, .C' "C "C
I H CICHZ (H2 5 i HN'CH2 I
HZN'C~NH
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 (60mmol) of Arginine is dissolved in 300m1 of water.
To this is added 78m1 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
il H2C'CH2 HZC1, NH
I
HNNHZ
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 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 H
H
2N CH C'-Di C"C~CH3 H3C"CH~CH2 H2 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 (60mmol) of Leucine is dissolved in 300m1 of water. To this is added 72m1 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.
I I
KO CH
H2C CH.CH3 I
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 21.27g (70mmol) of the prepared stearoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 13.03g (77mmol) of potassium 2-amino-4-methylpentanoate. The round bottomed flask is placed in an ice bath and the stearoyl 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-4-methylpentanoic stearic anhydride.
Example 5 2-aminopropanoic (7Z,10Z)-hexadeca-7,10-dienoic anhydride HzN CH'C'OiC~CaC~C _C~C.C_C~C'C~C'C'CH3 In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 9.35m1 (128mmol) of thionyl chloride, and a water condenser, is placed 24.90m1 (80mmol) 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 78m1 of 1M 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.
"C ' .NH2 Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory 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 7.64g (72mmol) of ammonium 2-aminopropanoate. 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-aminopropanoic (7Z,10Z)-hexadeca-7,10-dienoic anhydride.
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 (30)
1. A compound having the general structure:
wherein R is selected from the group consisting of alkanes and alkenes;
said alkanes and alkenes having from 3 to 21 carbons.
wherein R is selected from the group consisting of alkanes and alkenes;
said alkanes and alkenes having from 3 to 21 carbons.
2. The compound according to claim 1 wherein R is an alkane having 3 to 5 carbons.
3. The compound according to claim 1 wherein R is an alkane having 7 to 9 carbons.
4. The compound according to claim 1 wherein R is an alkane having 11 to 13 carbons.
5. The compound according to claim 1 wherein R is an alkane having 15 to 17 carbons.
6. The compound according to claim 1 wherein R is an alkane having 19 to 21 carbons.
7. The compound according to claim 1 wherein R is an alkene having at least one carbon-carbon double bond, comprising 3 to 5 carbons.
8. The compound according to claim 1 wherein R is an alkene having at least one carbon-carbon double bond, comprising 7 to 9 carbons.
9. The compound according to claim 1 wherein R is an alkene having at least one carbon-carbon double bond, comprising 11 to 13 carbons.
10. The compound according to claim 1 wherein R is an alkene having at least one carbon-carbon double bond, comprising 15 to 17 carbons.
11. The compound according to claim 1 wherein R is an alkene having at least one carbon-carbon double bond, comprising 19 to 21 carbons.
12.A compound having the general structure:
wherein R1 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;
said alkanes and alkenes having from 3 to 21 carbons.
wherein R1 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;
said alkanes and alkenes having from 3 to 21 carbons.
13. The compound according to claim 12 wherein R1 is an alkane having 3 to carbons.
14. The compound according to claim 12 wherein R1 is an alkane having 7 to 9 carbons.
15.The compound according to claim 12 wherein R1 is an alkane having 11 to 13 carbons.
16.The compound according to claim 12 wherein R1 is an alkane having 15 to
17 carbons.
17.The compound according to claim 12 wherein R1 is an alkane having 19 to 21 carbons.
17.The compound according to claim 12 wherein R1 is an alkane having 19 to 21 carbons.
18.The compound according to claim 12 wherein R1 is an alkene having at least one carbon-carbon double bond, comprising 3 to 5 carbons.
19.The compound according to claim 12 wherein R1 is an alkene having at least one carbon-carbon double bond, comprising 7 to 9 carbons.
20.The compound according to claim 12 wherein R1 is an alkene having at least one carbon-carbon double bond, comprising 11 to 13 carbons.
21.The compound according to claim 12 wherein R1 is an alkene having at least one carbon-carbon double bond, comprising 15 to 17 carbons.
22. The compound according to claim 12 wherein R1 is an alkene having at least one carbon-carbon double bond, comprising 19 to 21 carbons.
23.A method for producing amino acid fatty acids comprising at least the steps of:
mixing an excess of a thionyl halide with a fatty acid to form an acyl halide;
neutralizing the carboxylic acid of an amino acid with an inorganic base to form an amino acid salt;
said acyl halide then being reacted with the amino acid salt; and isolating the resulting amino acid fatty acid.
mixing an excess of a thionyl halide with a fatty acid to form an acyl halide;
neutralizing the carboxylic acid of an amino acid with an inorganic base to form an amino acid salt;
said acyl halide then being reacted with the amino acid salt; and isolating the resulting amino acid fatty acid.
24. The method of claim 23 wherein the halide of the thionyl halide is selected from the group consisting of fluorine, chlorine, bromine, and iodine.
25. The method of claim 23 or 24 wherein the fatty acid comprises between 4 and 22 carbons.
26.The method of any one of claims 23 to 25 wherein the acyl halide is produced at temperatures from between about 35°C to about 50°C.
27.The method of any one of claims 23 to 26 wherein the inorganic base is selected group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, sodium carbonate.
28.The method of any one of claims 23 to 27 wherein the amino acid is selected from the group consisting of Glycine, Alanine, Valine, Leucine, Isoleucine, Asparagine, Glutamine, Lysine and Arginine
29.The method of any one of claims 23 to 28 wherein the amino acid fatty acid is isolated by distillation.
30.The method of any one of claims 23 to 29 wherein the amino acid fatty acid has the general structure of:
wherein R is selected from the group consisting of alkanes and alkenes;
said alkanes and alkenes having between 3 and 21 carbons;
wherein R2 is selected from the group consisiting of hydrogen, methyl, isopropyl, isobutyl, sec butyl, acetylamide, propylamide, butyl-1-amine, and 1-butylguanidine.
wherein R is selected from the group consisting of alkanes and alkenes;
said alkanes and alkenes having between 3 and 21 carbons;
wherein R2 is selected from the group consisiting of hydrogen, methyl, isopropyl, isobutyl, sec butyl, acetylamide, propylamide, butyl-1-amine, and 1-butylguanidine.
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| CA002577439A CA2577439C (en) | 2007-02-20 | 2007-02-20 | Creatine-fatty acids |
| US11/747,203 US7511162B2 (en) | 2007-02-20 | 2007-05-10 | Preparation of amino acid-fatty acid anhydrides |
| US11/747,203 | 2007-05-10 | ||
| CA 2621925 CA2621925A1 (en) | 2007-02-20 | 2008-02-20 | Preparation of amino acid-fatty acid anhydrides |
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