WO2009076741A1 - Esters de créatinol-acide gras - Google Patents

Esters de créatinol-acide gras Download PDF

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Publication number
WO2009076741A1
WO2009076741A1 PCT/CA2007/002307 CA2007002307W WO2009076741A1 WO 2009076741 A1 WO2009076741 A1 WO 2009076741A1 CA 2007002307 W CA2007002307 W CA 2007002307W WO 2009076741 A1 WO2009076741 A1 WO 2009076741A1
Authority
WO
WIPO (PCT)
Prior art keywords
creatinol
acid
fatty acid
ethyl
methylguanidino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CA2007/002307
Other languages
English (en)
Inventor
Marvin A. Heuer
Ken Clement
Shan Chaudhuri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Multi Formulations Ltd
Original Assignee
Multi Formulations Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Multi Formulations Ltd filed Critical Multi Formulations Ltd
Priority to PCT/CA2007/002307 priority Critical patent/WO2009076741A1/fr
Priority to AU2007362563A priority patent/AU2007362563A1/en
Priority to EP07855589A priority patent/EP2234965A4/fr
Publication of WO2009076741A1 publication Critical patent/WO2009076741A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—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

Definitions

  • 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 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.
  • 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 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 phosphocreatine.
  • Creatine esters have 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 5O 0 C as disclosed in U.S. Pat. No. 6,897,334. 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.
  • 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 :
  • R is an alkyl group, preferably saturated, and containing from about 3 to a maximum of about 21 carbons.
  • Another aspect of the invention comprises the use of a saturated fatty acid in the production of compounds disclosed herein.
  • a further aspect of the present invention comprises the use of an unsaturated fatty in the production of compounds disclosed herein.
  • the present invention relates to structures and methods for the production of Creatinol-fatty acid compounds bound via an ester linkage.
  • 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.
  • fatty acid includes both saturated, i.e. an alkane chain as known in the art, having no double bonds between carbons of the chain and having the maximum number of hydrogen atoms, and unsaturated, i.e. an alkene or alkyne chain, having at least one double or alternatively triple bond between carbons of the chain, respectively, and further terminating the chain in a carboxylic acid as is commonly known in the art, wherein the hydrocarbon chain is not less then four carbon atoms.
  • essential fatty acids are herein understood to be included by the term "fatty acid”.
  • 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 ⁇ -linolenic acid.
  • 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.
  • 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.
  • Creatinol refers to the chemical l-(2-hydroxyethyl)-l-methylguanidine.
  • the compounds disclosed herein comprise a Creatinol molecule bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid.
  • 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 : Scheme 1
  • Step 1 an acidic solution comprising the by product 2-(l- methylguanidino)ethyl acetate (4) an acid (5), corresponding to the halide of the acetyl halide (3), and Creatinol (2) is produced by slowly adding the acetyl halide (3) to Creatinol (2) dissolved in dry Dichloromethane (DCM) at reduced temperatures.
  • DCM dry Dichloromethane
  • 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 0 0 C to about 4°C with stirring over a period of about 25 minutes.
  • the reactions proceed at about O 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 with vigorous stirring.
  • the reaction is slowly heated to a temperature between about 5O 0 C to about 75°C, preferably about 6O 0 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.
  • 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.
  • 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.
  • 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 (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.
  • the following compounds are produced: 2-(l -methyl guanidino)ethyl butyrate, 2-(l- methylguanidino)ethyl hexanoate, 2-( 1 -methylguanidino)ethyl octanoate, 2-( 1 - methylguanidino)ethyl decanoate, 2-(l-methylguanidino)ethyl dodecanoate, 2-(l- methylguanidino)ethyl tetradecanoate, 2-(l-methylguanidino)ethyl palmitate, 2-(l- methylguanidino)ethyl stearate, 2-(l-methylguanidino)ethyl icosanoate, and 2-(l- methylguanidino)ethyl docosanoate.
  • the following compounds are produced: 2-(l-methylguanidino)ethyl oleate, (9Z,12Z)-2-(l- methylguanidino)ethyl octadeca-9,12-dienoate, (5Z,8Z,1 lZ,14Z)-2-(l-methylguanidino)ethyl icosa-5,8,11,14-tetraenoate, (Z)-2-(l-methylguanidino)ethyl hexadec-9-enoate, (5Z,8Z,1 lZ,14Z,17Z)-2-(l-methylguanidino)ethyl icosa-5,8,11,14,17-pentaenoate, (4Z,7Z, 1 OZ, 13Z, 16Z, 19Z)-2-(l -methylguanidino)ethyl docosa-4,7,
  • 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 35.14 g (300 mmol) of Creatinol and 150 mL of dry DCM, and cooled with an ice-water bath to about 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.
  • 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 bromide and 25 niL of dry DCM.
  • the flask is charged with 35.14 g (300 mmol) of Creatinol and 150 niL 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.
  • 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 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.
  • 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 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 O 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.
  • 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 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.

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

Abstract

L'invention concerne des composés élaborés à partir d'une molécule de créatinol et d'une molécule d'acide gras. Elle concerne des composés de forme créatinol-acide gras reliés par une liaison ester, ou des mélanges correspondants élaborés par la réaction de créatinol ou de dérivés de créatinol et d'acide gras approprié en présence de dichlorométhane et de catalyseur acide. L'administration de telles molécules apporte un supplément de créatinol à biodisponibilité renforcée et offre des avantages additionnels conférés par l'acide gras spécifique.
PCT/CA2007/002307 2007-12-18 2007-12-18 Esters de créatinol-acide gras Ceased WO2009076741A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PCT/CA2007/002307 WO2009076741A1 (fr) 2007-12-18 2007-12-18 Esters de créatinol-acide gras
AU2007362563A AU2007362563A1 (en) 2007-12-18 2007-12-18 Creatinol-fatty acid esters
EP07855589A EP2234965A4 (fr) 2007-12-18 2007-12-18 Esters de créatinol-acide gras

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CA2007/002307 WO2009076741A1 (fr) 2007-12-18 2007-12-18 Esters de créatinol-acide gras

Publications (1)

Publication Number Publication Date
WO2009076741A1 true WO2009076741A1 (fr) 2009-06-25

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PCT/CA2007/002307 Ceased WO2009076741A1 (fr) 2007-12-18 2007-12-18 Esters de créatinol-acide gras

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EP (1) EP2234965A4 (fr)
AU (1) AU2007362563A1 (fr)
WO (1) WO2009076741A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120277305A1 (en) * 2011-04-29 2012-11-01 Catabasis Pharmaceuticals, Inc. Fatty acid guanidine and salicylate guanidine derivatives and their uses

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2595907A1 (fr) * 2005-02-07 2006-08-10 New Cell Formulations Ltd. Sel d'acides creatine-hydroxycitriques et procedes pour les produire et les utiliser chez l'etre humain
CA2577439A1 (fr) * 2007-02-20 2007-05-07 Multi Formulations Ltd. Composes a base de creatine et d'acides gras
CA2577437A1 (fr) * 2007-02-20 2007-05-21 Multi Formulations Ltd. Acides gras a creatine

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102004009962A1 (de) * 2004-03-01 2005-09-22 Degussa Ag Verwendung von Guanidin-Verbindungen als physiologisches Stärkungsmittel in Form von Nahrungsergänzungsmitteln, Futtermittelzusätzen, in kosmetischen Zubereitungen und als Pflanzenstärkungsmittel

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2595907A1 (fr) * 2005-02-07 2006-08-10 New Cell Formulations Ltd. Sel d'acides creatine-hydroxycitriques et procedes pour les produire et les utiliser chez l'etre humain
CA2577439A1 (fr) * 2007-02-20 2007-05-07 Multi Formulations Ltd. Composes a base de creatine et d'acides gras
CA2577437A1 (fr) * 2007-02-20 2007-05-21 Multi Formulations Ltd. Acides gras a creatine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2234965A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120277305A1 (en) * 2011-04-29 2012-11-01 Catabasis Pharmaceuticals, Inc. Fatty acid guanidine and salicylate guanidine derivatives and their uses
US9150504B2 (en) * 2011-04-29 2015-10-06 Catabasis Pharmaceuticals, Inc. Fatty acid guanidine and salicylate guanidine derivatives and their uses

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Publication number Publication date
AU2007362563A1 (en) 2009-06-25
EP2234965A1 (fr) 2010-10-06
EP2234965A4 (fr) 2011-01-19

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