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AU2007362563A1 - Creatinol-fatty acid esters - Google Patents

Creatinol-fatty acid esters Download PDF

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Publication number
AU2007362563A1
AU2007362563A1 AU2007362563A AU2007362563A AU2007362563A1 AU 2007362563 A1 AU2007362563 A1 AU 2007362563A1 AU 2007362563 A AU2007362563 A AU 2007362563A AU 2007362563 A AU2007362563 A AU 2007362563A AU 2007362563 A1 AU2007362563 A1 AU 2007362563A1
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AU
Australia
Prior art keywords
acid
creatinol
fatty acid
methylguanidino
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
AU2007362563A
Inventor
Shan Chaudhuri
Ken Clement
Marvin A. Heuer
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Northern Innovations and Formulations Corp
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Northern Innovations and Formulations Corp
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Filing date
Publication date
Application filed by Northern Innovations and Formulations Corp filed Critical Northern Innovations and Formulations Corp
Publication of AU2007362563A1 publication Critical patent/AU2007362563A1/en
Abandoned legal-status Critical Current

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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
    • C07C279/08—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 singly-bound oxygen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

WO 2009/076741 PCT/CA2007/002307 Creatinol-Fatty Acid Esters Field of the Invention The present invention relates to structures and methods for the production of Creatinol-fatty acid esters. Another aspect of the present invention relates to a compound comprising a Creatinol 5 molecule bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid and is bound to the Creatinol via an ester linkage. Background of the Invention Creatinol is closely akin to Creatine, since both molecules contain a guanidino group. It is this guanidine group that binds to the phosphate group in the formation of phosphocreatine. The 10 major difference between Creatinol and Creatine is that the former lacks a carboxylic acid functional group and instead contains a hydroxyl functional group. Where Creatine has a tendency to undergo cyclization to form Creatinine, the Creatinol lacks the carboxylic group that is necessary for the cyclization reaction to take place. Therefore, Creatinol is unable to form the inactive Creatinine, making Creatinol readily available for phophorylation to form an energetic species like 15 phosphocreatine. The formation of Creatine esters has been described (Dox AW, Yoder L. Esterification of Creatine. J. Biol. Chem. 1922, 67, 671-673). These are typically formed by reacting Creatine with an alcohol in the presence of an acid catalyst at temperatures from 35'C to 50'C as disclosed in U.S. Pat. No. 6,897,334. 20 Although Creatine esters act to protect Creatine from cyclizing into its inactive form, Creatinine, removal of the ester by esterases, present throughout the body, will again make the Creatine susceptible to inactivation by cyclization. Therefore, a need exists for a Creatine-like molecule that is not as susceptible to conversion into an inactive form and can be easily absorbed by the intestine. 1 WO 2009/076741 PCT/CA2007/002307 Summary of the Invention In the present invention, compounds are disclosed, where the compounds comprise a molecule of Creatinol bound to a fatty acid, via an ester linkage, and having a structure of Formula 1: 5 Formula 1 NH
H
2 N N O R 0 where: R is an alkyl group, preferably saturated, and containing from about 3 to a maximum of about 21 carbons. 10 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 15 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 methods for the production of Creatinol-fatty 20 acid compounds bound via an ester linkage. In addition, specific benefits are conferred by the particular fatty acid used to form the compounds in addition to, and separate from, those conferred by the Creatinol 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 2 WO 2009/076741 PCT/CA2007/002307 of hydrogen atoms, and unsaturated, i.e. an alkene or alkyne chain, having at least one double or alternatively triple bond between carbons of the chain, respectively, and further terminating the chain in a carboxylic acid as is commonly known in the art, wherein the hydrocarbon chain is not less then four carbon atoms. Furthermore, essential fatty acids are herein understood to be included 5 by the term "fatty acid". The human body can produce all but two of the fatty acids it requires, thus, essential fatty acids are fatty acids that must be obtained from food sources due to an inability of the body to synthesize them, yet are required for normal biological function. The essential fatty acids being linoleic acid and a-linolenic acid. 10 Examples of saturated fatty acids include, but are not limited to 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, wherein the aforementioned comprise from at least 4 carbons to 22 carbons in the chain. 15 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. As used herein, "Creatinol" refers to the chemical 1-(2-hydroxyethyl)- 1 -methylguanidine. 20 According to the present invention, the compounds disclosed herein comprise a Creatinol molecule bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid. Furthermore, the Creatinol and fatty acid are bound by an ester linkage and having a structure according to Formula 1. The aforementioned compound being prepared according to the reaction as set forth for the purposes of the description in Scheme 1: 3 WO 2009/076741 PCT/CA2007/002307 Scheme 1 NH 0NH
H
2 N N xOH + Se 1 *H 2 N N O + 2 + HX OOC-40C O 2 3 25 min 4 5 Step 2 0 DCM 50 0 C - 75 0 C HO R 2 - 12 h 6 where: R = alkane or alkene (C = 3 to 21) X = CI, Br, F, or I NH
H
2 N N O R +2+4+ 5 0 With reference to Scheme 1, in Step 1 an acidic solution comprising the by product 2-( 1 methylguanidino)ethyl acetate (4) an acid (5), corresponding to the halide of the acetyl halide (3), 5 and Creatinol (2) is produced by slowly adding the acetyl halide (3) to Creatinol (2) dissolved in dry Dichloromethane (DCM) at reduced temperatures. The halide (X) of the acetyl halide (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 a nitrogen atmosphere at temperatures between about 10 0 0 C to about 4'C with stirring over a period of about 25 minutes. Preferably, the reactions proceed at about 0 0 C for about 25 minutes. Step 2, all of which takes place under a nitrogen atmosphere, describes the addition of a fatty acid (6) to the resultant acidic solution of Step 1, to form the desired Creatinol-fatty acid ester (1). The addition of the fatty acid (6) takes place at temperatures between about 0 0 C to about 4'C 15 with vigorous stirring. Following complete addition of the fatty acid, the reaction is slowly heated to a temperature between about 50'C to about 75'C, preferably about 60'C, for between about 2 hours to about 12 hours, before the target ester (1) is isolated and purified, by either fractional distillation of flash chromatography, the preferred purification method being flash chromatography. 4 WO 2009/076741 PCT/CA2007/002307 The heating of the reaction in Step 2 is maintained, prior to isolation of the target ester, for between about 2 hours to about 6 hours, preferably about 4 hours, if the fatty acid has from about 4 to about 12 carbon atoms, and for between 6 hours and about 12 hours, preferably about 8 hours, if the fatty acid has from about 14 to about 22 carbon atoms. 5 In various embodiments of the present invention, the fatty acid of (6) 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. 10 In additional or alternative embodiments of the present invention, the fatty acid of (6) 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. In various embodiments, according to aforementioned, using the saturated fatty acids, the following compounds are produced: 2-(1-methylguanidino)ethyl butyrate, 2-(1 15 methylguanidino)ethyl hexanoate, 2-(1-methylguanidino)ethyl octanoate, 2-(1 methylguanidino)ethyl decanoate, 2-(1-methylguanidino)ethyl dodecanoate, 2-(1 methylguanidino)ethyl tetradecanoate, 2-(1-methylguanidino)ethyl palmitate, 2-(1 methylguanidino)ethyl stearate, 2-(1-methylguanidino)ethyl icosanoate, and 2-(1 methylguanidino)ethyl docosanoate. 20 In additional embodiments, according to aforementioned, using the unsaturated fatty acids, the following compounds are produced: 2-(1-methylguanidino)ethyl oleate, (9Z,12Z)-2-(1 methylguanidino)ethyl octadeca-9,12-dienoate, (5Z,8Z, I1Z, 14Z)-2-(1 -methylguanidino)ethyl icosa-5,8,11,14-tetraenoate, (Z)-2-(1-methylguanidino)ethyl hexadec-9-enoate, (5Z, 8Z, 1IZ, 1 4Z, 1 7Z)-2-(1 -methylguanidino)ethyl icosa-5,8,11,14,17-pentaenoate, 25 (4Z,7Z,10Z,13Z,16Z,19Z)-2-(1-methylguanidino)ethyl docosa-4,7,10,13,16,19-hexaenoate, (Z)-2 (1-methylguanidino)ethyl docos-13-enoate.
WO 2009/076741 PCT/CA2007/002307 The following examples illustrate specific Creatinol-fatty acid esters 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 5 2-(1-methylguanidino)ethyl octanoate NH
H
2 N N In a dry 3-necked round bottomed flask, containing a magnetic stirrer, equipped with a dropping funnel, a reflux condenser protected from moisture by a calcium chloride filled drying tube and a rubber septum. The dropping funnel is filled with 10.66 mL (150 mmol) of acetyl 10 chloride and 25 mL of dry DCM. The flask is charged with 35.14 g (300 mmol) of Creatinol and 150 mL of dry DCM, and cooled with an ice-water bath to about 0 0 C, under a nitrogen atmosphere. The acetyl chloride solution is then added slowly with stirring, over a period of 15 minutes, to the Creatinol solution. The solution is stirred for another 10 minutes, after which 13.36 mL (50 mmol) of Octanoic acid is added in one portion and the reaction is slowly heated to about 60'C for about 4 15 hours. Then the solution is allowed to cool to room temperature, after which the solvent is removed under reduced pressure to yield the crude ester. The crude ester is then purified by flash chromatography (ethyl acetate/hexanes; 1/3) to yield pure 2-(1 -methylguanidino)ethyl octanoate. Example 2 2-(1-methylguanidino)ethyl decanoate NH
H
2 N N 20 1 In a dry 3-necked round bottomed flask, containing a magnetic stirrer, equipped with a dropping funnel, a reflux condenser protected from moisture by a calcium chloride filled drying tube and a rubber septum. The dropping funnel is filled with 10.60 mL (125 mmol) of acetyl 6 WO 2009/076741 PCT/CA2007/002307 bromide and 25 mL of dry DCM. The flask is charged with 35.14 g (300 mmol) of Creatinol and 150 mL of dry DCM, and cooled with an ice-water bath to about 0 0 C, under a nitrogen atmosphere. The acetyl bromide solution is then added slowly with stirring, over a period of 10 minutes, to the Creatinol solution. The solution is stirred for another 15 minutes, after which 9.64 mL (50 mmol) 5 of Decanoic acid is added in one portion and the reaction is slowly heated to about 65'C for about 6 hours. Then the solution is allowed to cool to room temperature, after which the solvent is removed under reduced pressure to yield the crude ester. The crude ester is then purified by flash chromatography (ethyl acetate/hexanes; 1/5) to yield pure 2-(1-methylguanidino)ethyl decanoate. Example 3 10 2-(1 -methylguanidino)ethyl palmitate NH
H
2 N N 1 0 In a dry 3-necked round bottomed flask, containing a magnetic stirrer, equipped with a dropping funnel, a reflux condenser protected from moisture by a calcium chloride filled drying tube and a rubber septum. The dropping funnel is filled with 12.44 mL (175 mmol) of acetyl 15 chloride and 35 mL of dry DCM. The flask is charged with 41.00 g (350 mmol) of Creatinol and 175 mL of dry DCM, and cooled with an ice-water bath to about 0 0 C, under a nitrogen atmosphere. The acetyl chloride solution is then added slowly with stirring, over a period of 15 minutes, to the Creatinol solution. The solution is stirred for another 10 minutes, after which 15.38 g (60 mmol) of Palmitic acid is added in one portion and the reaction is slowly heated to about 65'C for about 10 20 hours. Then the solution is allowed to cool to room temperature, after which the solvent is removed under reduced pressure to yield the crude ester. The crude ester is then purified by flash chromatography (ethyl acetate/hexanes; 2/5) to yield pure 2-(1-methylguanidino)ethyl palmitate. Example 4 2-(1-methylguanidino)ethyl docosanoate 7 WO 2009/076741 PCT/CA2007/002307 NH
H
2 N N In a dry 3-necked round bottomed flask, containing a magnetic stirrer, equipped with a dropping funnel, a reflux condenser protected from moisture by a calcium chloride filled drying tube and a rubber septum. The dropping funnel is filled with 12.73 mL (150 mmol) of acetyl 5 bromide and 35 mL of dry DCM. The flask is charged with 35.14 g (300 mmol) of Creatinol and 150 mL of dry DCM, and cooled with an ice-water bath to about 0 0 C, under a nitrogen atmosphere. The acetyl bromide solution is then added slowly with stirring, over a period of 10 minutes, to the Creatinol solution. The solution is stirred for another 15 minutes, after which 23.84 g (70 mmol) of Docosanoic acid is added in one portion and the reaction is slowly heated to about 65'C for about 10 12 hours. Then the solution is allowed to cool to room temperature, after which the solvent is removed under reduced pressure to yield the crude ester. The crude ester is then purified by flash chromatography (ethyl acetate/hexanes; 1/3) to yield pure 2-(1 -methylguanidino)ethyl docosanoate. Example 5 (Z)-2-(1 -methylguanidino)ethyl hexadec-9-enoate NH
H
2 N N 15 0 In a dry 3-necked round bottomed flask, containing a magnetic stirrer, equipped with a dropping funnel, a reflux condenser protected from moisture by a calcium chloride filled drying tube and a rubber septum. The dropping funnel is filled with 10.66 mL (150 mmol) of acetyl chloride and 25 mL of dry DCM. The flask is charged with 38.07 g (325 mmol) of Creatinol and 20 150 mL of dry DCM, and cooled with an ice-water bath to about 0 0 C, under a nitrogen atmosphere. The acetyl chloride solution is then added slowly with stirring, over a period of 15 minutes, to the Creatinol solution. The solution is stirred for another 10 minutes, after which 14.21 mL (50 mmol) of Palmitoleic acid is added in one portion and the reaction is slowly heated to about 55'C for about 8 WO 2009/076741 PCT/CA2007/002307 9 hours. Then the solution is allowed to cool to room temperature, after which the solvent is removed under reduced pressure to yield the crude ester. The crude ester is then purified by flash chromatography (ethyl acetate/hexanes; 1/6) to yield pure (Z)-2-(1-methylguanidino)ethyl hexadec 9-enoate. 5 Thus while not wishing to be bound by theory, it is understood that reacting a Creatinol or derivative of Creatinol with a fatty acid or derivative thereof to form an ester can be used enhance the bioavailability of the Creatinol or derivative Creatinol by improving intestinal absorption, via improved lipophilicity. 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 10 densely, or derivative thereof employed in the foregoing synthesis, additional fatty acid-specific benefits, separate from the Creatinol 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 15 without departing from the broader spirit and scope of the invention. 9

Claims (11)

1. A compound having the general structure: NH H 2 N N OyR 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. 10
AU2007362563A 2007-12-18 2007-12-18 Creatinol-fatty acid esters Abandoned AU2007362563A1 (en)

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PCT/CA2007/002307 WO2009076741A1 (en) 2007-12-18 2007-12-18 Creatinol-fatty acid esters

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AU (1) AU2007362563A1 (en)
WO (1) WO2009076741A1 (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9150504B2 (en) * 2011-04-29 2015-10-06 Catabasis Pharmaceuticals, Inc. Fatty acid guanidine and salicylate guanidine derivatives and their uses

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004009962A1 (en) * 2004-03-01 2005-09-22 Degussa Ag Use of guanidine compounds as physiological restorative in the form of nutritional supplements, feed additives, in cosmetic preparations and as plant strengthening agents
CN101115714A (en) * 2005-02-07 2008-01-30 新细胞制剂有限公司 Creatine hydroxycitric acid salts, methods of making, and uses in individuals
CA2577439C (en) * 2007-02-20 2008-04-08 Multi Formulations Ltd. Creatine-fatty acids
CA2577437C (en) * 2007-02-20 2008-02-12 Multi Formulations Ltd. Creatine-fatty acids

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WO2009076741A1 (en) 2009-06-25
EP2234965A1 (en) 2010-10-06

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