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WO2010005465A1 - Phytates de l-carnitine et d’alcanoyle l-carnitine, et leur procédé de préparation - Google Patents

Phytates de l-carnitine et d’alcanoyle l-carnitine, et leur procédé de préparation Download PDF

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WO2010005465A1
WO2010005465A1 PCT/US2009/003522 US2009003522W WO2010005465A1 WO 2010005465 A1 WO2010005465 A1 WO 2010005465A1 US 2009003522 W US2009003522 W US 2009003522W WO 2010005465 A1 WO2010005465 A1 WO 2010005465A1
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carnitine
mole ratio
phytate
phytic acid
alkanoyl
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Jian Chen
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SCIAN LABORATORIES LLC
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SCIAN LABORATORIES LLC
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Priority to CA2727918A priority Critical patent/CA2727918A1/fr
Priority to JP2011514588A priority patent/JP2011524415A/ja
Priority to EP09788797A priority patent/EP2299994A1/fr
Priority to CN200980000526.7A priority patent/CN101903020B/zh
Priority to US12/584,769 priority patent/US8067468B2/en
Publication of WO2010005465A1 publication Critical patent/WO2010005465A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/08—Esters of oxyacids of phosphorus
    • C07F9/09—Esters of phosphoric acids
    • C07F9/117—Esters of phosphoric acids with cycloaliphatic alcohols
    • 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
    • C07C229/22—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 the carbon skeleton being further substituted by oxygen atoms

Definitions

  • the present invention relates to novel salt form clusters of L-carnitine and alkanoyl L-carnitine, i.e., L-carnitine phytate and alkanoyl L-carnitine phytates, and the process for preparing the same.
  • L-carnitine and its alkanoyl derivatives lend themselves to various therapeutical and nutritional uses.
  • L-carnitine and its alkanoyl derivatives inner salts are represented by formula:
  • L-Carnitine or Alkanoyl L-Carnitine wherein R represents either a hydrogen atom or an alkanoyl group.
  • L-Carnitine is a cofactor required for transformation of free long- chain fatty acids into acylcarnitines, and for their subsequent transport into the mitochondrial matrix, where they undergo bate-oxidation for cellular energy production. Mitochondrial fatty oxidation is the primary fuel source in heart and skeletal muscles, pointing to the relative importance of the nutrient for proper function in tissue.
  • L-Carnitine and its alkanoyl derivatives also have important antioxidant effects, as demonstrated by their protective effect against lipoperoxidation of phospholipid cell membranes caused by oxidative stress induced at the myocardial and endothelial cell level.
  • Conditions which appear to benefit from L-camitine and its alkanoyl derivatives include anorexia, chronic fatigue, coronary vascular disease, diphtheria, hypoglycemia, male infertility, muscular myopathies, Rett Syndrome, Alzheimer's disease, mood enhancement, cognitive improvement, and sports performance. See, e.g., Gregory S. Kelly, "L-Carnitine: Therapeutic Applications of a Conditionally- Essential Amino Acid", Alternative Medicine Review, 3 (5): 345-360 (1998).
  • Phytic acid also known as inositol hexaphosphate, myo-inositol hexaphosphate, and IP6, is a 6-phosphate ester of inositol as represented by the molecular formula:
  • Phytic acid is naturally occurring in substantial amounts in whole grain, cereals, legumes, nuts, and seeds, and is the primary energy source for germinating plants. Phytic acid and its lower phosphorylated forms are also found in most mammalian cells, where they assist in regulating a variety of important cellular functions. Phytic acid functions as an antioxidant by chelating divalent cations such as copper and iron, preventing the generation of reactive oxygen species responsible for cell injury and carcinogenesis. Both in vivo and in vitro studies utilizing IP6 have revealed a significant anticancer activity with a variety of tumor types, possibly via inhibition of tumor cell growth and differentiation.
  • IP6 IP6's anticancer properties.
  • Other properties of IP6 include an anti-platelet aggregating and lipid-lowering effect, suggesting a potential health benefit for the cardiovascular system; inhibition of HIV-1 virus replication; modulation of insulin secretion in pancreatic beta cells; and inhibition of urinary calcium oxalate crystallization, thereby preventing renal stone development. See e.g. Monograph, "Inositol Hexaphosphate", Alternative Medicine Review, 7 (3): 244-248 (2002).
  • phytic acid Other notable functions include the deodorant effect of body odor, bad breath or uraroma; the prevention of acute alcoholism; and the enrichment of the taste of meat and fish. These properties of phytic acid provide its pharmaceutical and/or nutritional added value. [0015] The biochemistry and pharmacokinetics of phytic acid have also been studied. Inositol phosphates are synthesized from the parent molecule inositol and daily dietary consumption of inositol is estimated to be one gram.
  • inositol Once inositol reaches the cells of the intestinal tract it is phosphorylated to create inositol hexaphosphate (IP6), and then subsequently dephosphorylated to its lower forms, such as inositol pentaphosphate (IP5), inositol tetraphosphate (P4), inositol triphosphate (IP3), inositol monophosphate (IP1), which play important roles in signal transduction.
  • IP6 Independent of the route of administration, IP6 has been discovered to be absorbed almost instantly, transported intracellular ⁇ and dephosphorylted into lower inositol phosphates. IP6 can reach targeted tumor tissue as early as one hour post-administration. When incubated with a human mammary cancer cell line, low levels of IP6 were detected as early as one minute post-incubation.
  • phytic acid is a novel acid to react with L-carnitine and alkanoyl L-carnitine inner salts to produce L-carnitine phytate and alkanoyl L-carnitine phytates. It is apparently an innovation in the evolution of salt forms of L-carnitine and salt forms of alkanoyl L-carnitine.
  • An object of the present invention is to provide a novel generation of L-carnitine and alkanoyl L-carnitine salt form derivatives derived from their corresponding inner salts and phytic acid, i.e., L-carnitine phytate and alkanoyl L-carnitine phytates.
  • These salts are represented by General Formula (I):
  • Ri is the phytate anion
  • R is hydrogen, or straight or branched- chain alkanoyl group having 2-12 carbon atoms; preferably, the alkanoyl group is a lower alkanoyl group having 2-5 carbon atoms; and more preferably, the alkanoyl group is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl and isovaleryl groups.
  • Another object of the invention is to supply a process for the preparations of the salts represented by the formula shown in General Formula
  • a further object of the invention is to provide the use of L-carnitine phytate and alkanoyl L-carnitine phytates.
  • phytic acid is a 6- phosphate ester of inositol with each phosphate group possessing 2 proton dissociation sites. There are total of 12 proton dissociation sites in one phytic acid molecule; six of which are strongly acidic with an approximate pKa value of 1.5; three sites are weakly acidic with pKa values 5.7, 6.8 and 7.6; and the remaining three sites are very weakly acidic, with pKa values greater than 10. See Costello, AJ.
  • the six strongly acidic protons are the first dissociation protons of each of the six phosphate groups in the phytic acid molecule.
  • This dissociation ability is similar to the proton dissociations of phosphoric acid, i.e., PKa 1 (2.12) ⁇ pKa 2 (7.21) ⁇ pKa 3 (12.67).
  • Dissociation of the protons of phytic acid leaves the molecule with several negative charges, which can attract positively charged molecules to generate phytate.
  • each negatively charged phosphate group will preferably incorporate one inner salt at its quaternary ammonium cation and the corresponding phosphate dissociated proton incorporates the carboxyl anion of the inner salt. While there are 12 dissociation sites in one phytic acid molecule, theoretically, only up to 6 molecules of L-carnitine inner salt or its alkanoyl derivative inner salt can be incorporated. Because as described above, there are 6 phosphate groups in one phytic acid molecule, only the first dissociation site of each phosphate group is acidic enough (pKa 1.5) to incorporate with a inner salt to generate a corresponding salt.
  • the other dissociation sites are too weakly acidic (with pKa values of 5.7, 6.8, 7.6, and in some instances greater than 10) to form stable ionic bonds with the quaternary ammonium cation of L- carnitine or its alkanoyl derivatives' inner salt, because the pKa value of L- carnitine's inner salt is 3.8. See, Cogt C, et al, "Enantiomeric Separation of D/L-Carnitine Using HPLC and CZE after Derivatization", Chromatographia, Vol. 40 (5/6): 287-295, (1995).
  • each phosphate group of phytic acid can only incorporate 1 inner salt, and a total of 6 phosphate groups of phytic acid can incorporate a total of 6 inner salts of L-carnitine or its alkanoyl derivatives.
  • One phytic acid molecule can preferably incorporate 1 to 6 molecules of L-carnitine or its alkanoyl derivatives' inner salts depending on the mole ratio of added inner salts.
  • the salt product when equal molar ratio of inner salt and phytic acid are added together, then the salt product will be L-carnitine phytate (in a 1:1 ratio), or alkanoyl L-carnitine phytate (in a 1:1 ratio); and similarly, when 2, 3, 4, 5 times the number of moles of inner salt are added, individually, the phytate product will be 2:1, 3:1, 4:1, and 5:1 respectively. But practically, since there are 6 same strong acidic dissociation sites in one phytic acid molecule, when an equal mole number of inner salt and phytic acid moles are added together, the phytate product is a mixture of 1:1 to 6:1 mole ratio more or less randomly created, and there is unreacted phytic acid leftover.
  • the mole ratios between L-carnitine cation moiety or its alkanoyl derivatives cation moiety and the phytic acid anion moiety of L-carnitine phytate or alkanoyl L-carnitine phytate can be 1:1 , 2:1, 3:1, 4:1 , 5:1, and 6:1, corresponding salts as represented by General Formula (I).
  • the mole ratio is 6:1 with the salts being L- carnitine phytate (6:1) and alkanoyl L-carnitine phytates (6:1) as represented by General Formula (II):
  • R is either hydrogen, or a straight or branched-chain alkanoyl group having 2-12 carbon atoms.
  • the alkanoyl group is a lower alkanoyl group having 2-5 carbon atoms.
  • the alkanoyl group is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl and isovaleryl groups.
  • L-carnitine and alkanoyl L-carnitine phytates possess many desirable characteristics:
  • [0028] 2 They contain 6 L-carnitine or alkanoyl L-carnitine molecules clustered around one phytic acid anion in one salt form of phytate (in a 6:1 mole ratio) molecule. In comparison with all the other L-carnitine or alkanoyl L- carnitine salt forms, a 6:1 mole ratio is the biggest mole ratio achieved, so far.
  • L-carnitine phytate in a 6:1 mole ratio (C48H108N6O42P6, molecular weight 1627.24) is a six-directional dendrimer as shown by Formula (1):
  • acetyl L-carnitine phytate (in a 6:1 mole ratio) (C6oHi2oN6 ⁇ 48P6, molecular weight 1879.44) is a six-directional dendrimer as shown by Formula (2):
  • propionyl L-carnitine phytate in a 6:1 mole ratio (C66H132N6O48P6, molecular weight 1963.61) is a six-directional dendrimer as shown by Formula (3):
  • butyryl L-carnitine phytate (in a 6:1 mole ratio) (C72H144N6O48P6, molecular weight 2046.76) is a six-directional dendrimer as shown by Formula (4):
  • isobutyryl L-carnitine phytate (in a 6:1 mole ratio) (C72H144N6O48P6, molecular weight 2046.76) is a six- directional dendrimer as shown by Formula (5):
  • valeryl L-carnitine phytate in a 6:1 mole ratio
  • CT ⁇ His ⁇ N ⁇ O-wP ⁇ molecular weight 2129.76
  • Formula (6) is a six-directional dendrimer as shown by Formula (6):
  • isovaleryl L-carnitine phytate (in a 6:1 mole ratio) (C7 ⁇ Hi 56NeCMePe, molecular weight 2129.76) is a six- directional dendrimer as shown by Formula (7):
  • Both cation moiety i.e., L-carnitine or alkanoyl L-carnitines
  • anion moiety i.e., phytate
  • these biologically beneficial properties can reasonably be expected to be due to the synergistic efficacy of their salt form complex.
  • Phytic acid is a liquid substance (syrup), strongly acidic and not convenient for storage, processing, and consuming. However, when it is composed with L-carnitine or its alkanoyl derivatives inner salt, the salt form phytates are weakly acidic, and according to one embodiment, L-carnitine phytate (in a 6:1 mole ratio) and lower alkanoyl L-carnitine phytate (in a 6:1 mole ration), such as acetyl L-carnitine phytate (in a 6:1 mole ratio) and propionyl L-carnitine phytate (in a 6:1 mole ratio), are solid, and, thus easy to handle and use. [0039] 6.
  • L-carnitine and its alkanoyl derivative inner salts are strongly hygroscopic, but according to one embodiment, their phytates (in a 6:1 mole ratio) are less hygroscopic, which is acceptable for processing and storage. [0040] 7. L-carnitine and its alkanoyl derivative hydrochlorides have unpleasant and irritating hydrochloric smells, which according to one embodiment, their phytates (in a 6: 1 mole ratio) do not have. [0041] 8.
  • L-carnitine and alkanoyl L- camitine phytates are stable and almost odorless, without the unpleasant fishy smell given off by the inner salts (which is the emission of traces of amine that is usually generated by the decomposition of inner salts).
  • both L-carnitine or its alkanoyl derivatives and phytic acid as well as their salt form complexes are non-toxic and safe to consume.
  • L-carnitine phytates are produced by a reaction between an L-carnitine inner salt, or an alkanoyl L-carnitine inner salt, and phytic acid as shown by reaction Scheme (I):
  • the alkanoyl group is a lower alkanoyl group having 2 - 5 carbon atoms.
  • the alkanoyl group is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl and isovaleryl groups.
  • L-carnitine or alkanoyl L-carnitine inner salt is added to an aqueous solution of phytic acid while stirring.
  • the mole ratio between the combined L-carnitine or alkanoyl L-carnitine inner salt and phytic acid may range from a 1 :1 mole ratio to a 6:1 mole ratio with the ratio depending on the desired purpose.
  • L-carnitine or alkanoyl L-carnitine inner salt is added to an aqueous solution of phytic acid and stirred about 15 minutes a clear solution is obtained which is further stirred for another 20 minutes at the same conditions and then was dried in a vacuum to obtain the resulting product.
  • L-carnitine or alkanoyl L-carnitine phytate (in a 6:1 mole ratio) is prepared as shown by reaction Scheme (II):
  • R represents either a hydrogen or an alkanoyl group (either a straight or branched-chain alkanoyl group) having 2 -12 carbon atoms.
  • the alkanoyl group is a lower alkanoyl group having 2 - 5
  • the alkanoyl group is selected from acetyl, propionyl, butyryl, isobutyryl, valeryl and isovaleryl groups.
  • a 6 times mole ratio of L-carnitine or alkanoyl L-carnitine inner salt is added to a 1 time mole ratio of 50% aqueous solution of phytic acid (having a pH value lower than 1) and stirred at 10-50 degrees Celsius.
  • a 6 times mole ratio of L- carnitine or alkanoyl L-carnitine inner salt is added to a 1 time mole ratio of 50% aqueous solution of phytic acid (having a pH value lower than 1) and stirred at 10-50 degrees Celsius for about 15 minutes until a clear solution (having a pH value of 3-4) is obtained.
  • the clear solution (having a pH value of 3-4) is stirred for an additional 20 minutes and then concentrated under a vacuum at 40-70 degrees Celsius.
  • the residue is repeatedly taken up with anhydrous ethanol.
  • the final residue is dried in a vacuum oven at 40- 70 degrees Celsius to obtain the resultant product.
  • L-carnitine and alkanoyl L-carnitine phytate can be used for pharmaceutical, nutriceutical, and cosmetic purposes, including but not limited to antioxidants, improvement for immunity, anticancer, a treatment and/or cure of disease (for example, for cardiovascular disease, strokes, Alzheimer's disease, Down's syndrome, and various neuropathies), boosting brain functions, improving learning and memory capacities (including age associated memory impairment), an anti-aging supplement, athletic performance, weight loss, and an animal feed additive.
  • antioxidants for antioxidants, improvement for immunity, anticancer, a treatment and/or cure of disease (for example, for cardiovascular disease, strokes, Alzheimer's disease, Down's syndrome, and various neuropathies), boosting brain functions, improving learning and memory capacities (including age associated memory impairment), an anti-aging supplement, athletic performance, weight loss, and an animal feed additive.
  • improvement for immunity for example, for cardiovascular disease, strokes, Alzheimer's disease, Down's syndrome, and various neuropathies
  • boosting brain functions for example, improving learning and memory capacities (including
  • IP6 phytic acid
  • IP1 inositol monophosphate
  • IP2 inositol diphosphate
  • IP3 inoistol triphosphate
  • IP4 inositol tetraphosphate
  • IP5 inositol pentaphosphate
  • L-carnitine and alkanoyl L-carnitine inositol monphosphates L-carnitine and alkanoyl L-carnitine inositol diphosphates
  • L-carnitine and alkanoyl L-carnitine inositol triphosphates L- carnitine and alkanoyl L-carnitine inositol tetraphosphates
  • L-carnitine and alkanoyl L-carnitine inositol pentaphosphates are within the scope of certain particular embodiments of the present invention.
  • the mole ratio between L- camitine (or alkanoyl L-carnitine) and phytic acid is selected from within a range of a mole ratio of 1:1 to 6:1, for L-carnitine phytate salt and alkanoyl L-carnitine phytate salt, since there are 12 dissociation sites in one phytic acid molecule, a mole ratio larger than 6:1 (for example, 7:1 to 12:1) is also included in the scope of an embodiment.
  • L-Carnitine Phytate (in a mole ratio of 1 :1 - 6:1 )
  • L-Carnitine Phytate (in a mole ratio of 1:1-6:1) is represented by Formula (8):
  • 32.2 grams (0.2 mole) of L-carnitine inner salt (C7H15NO3, molecular weight 161.20) are added to a 50% aqueous solution (pH value ⁇ 1) of 66.0 gram (0.1 mole) phytic acid and stirred at room temperature resulting in an exothermic reaction.
  • 32.2 grams (0.2 mole) of L-carnitine inner salt (C7H15NO3, molecular weight 161.20) are added to a 50% aqueous solution (pH value ⁇ 1) of 66.0 gram (0.1 mole) phytic acid and after stirred at room temperature for about 15 minutes creates a solution.
  • the solution (having a pH value ⁇ 1) was further stirred 20 minutes.
  • the solution is concentrated on an evaporator under a vacuum at 50 0 C.
  • the residue is repeatedly (3 times) taken up using anhydrous ethanol under a vacuum to dry the solution as much as possible.
  • the residue is further dried in a vacuum oven at 50 0 C to obtain 106.1 grams of residue from the mixture of L-carnitine phytate (1:1-6:1) and phytic acid, which appears clear, thick and sticky.
  • L-Carnitine Phytate (in a 6:1 mole ratio)
  • C48H108N6O42P6, molecular weight 1627.24 is represented by the formula shown by Formula (1).
  • 96.7 grams (0.6 mole) of L-carnitine inner salt (C7H15NO3, molecular weight 161.20) was added to a 50% aqueous solution (having a pH value ⁇ 1) of 66.0 grams (0.1 mole) phytic acid and stirred at room temperature resulting in an exothermic reaction.
  • L-carnitine inner salt (C7H15NO3, molecular weight 161.20) was added to a 50% aqueous solution (having a pH value ⁇ 1) of 66.0 grams (0.1 mole) phytic acid and was stirred at room temperature for about 15 minutes to create a solution.
  • the solution (having a pH value of about 4) was further stirred 20
  • the solution was concentrated on an evaporator under a vacuum at 50 0 C.
  • the residue was repeatedly (3 times) taken up using anhydrous ethanol under a vacuum to dry the solution as much as possible.
  • the residue is further dried in a vacuum oven at 50 0 C to obtain 166.2 grams of white solid powder with an almost quantitative yield (i.e., the white solid powder contains 2% H2O).
  • Acetyl L-Carnitine Phytate (in a 6:1 mole ratio)
  • Acetyl L-Carnitine Phytate (in a 6:1 mole ratio) (C6oHi2oN6 ⁇ 4 ⁇ P6, molecular weight 1879.44) is represented by Formula (2).
  • 122.09 grams (0.6 mole) of acetyl L- carnitine inner salt (C9H17NO4, molecular weight 203.24) was added to a 50% aqueous solution (having a pH value ⁇ 1) of 66.0 grams (0.1 mole) phytic acid and stirred at room temperature resulting in an exothermic reaction.
  • acetyl L-carnitine inner salt (C9H17NO4, molecular weight 203.24) was added to a 50% aqueous solution (having a pH value ⁇ 1) of 66.0 grams (0.1 mole) phytic acid and was stirred at room temperature for about 15 minutes to create a solution.
  • the solution (having a pH value of about 4) was further stirred 20 minutes.
  • the solution is concentrated on an evaporator under a vacuum at 50 0 C.
  • Vl residue was repeatedly (3 times) taken up with anhydrous ethanol in a vacuum to dry the residue as much as possible.
  • the residue is further dried in a vacuum oven at 50 0 C to obtain 192.7 grams of white solid powder with an almost quantitative yield (i.e., the white solid powder contains 2% H2O).
  • 130.4 grams (0.6 mole) of propinoyl L-carnitine inner salt (C10H19NO4, molecular weight 217.26) was added to a 50% aqueous solution (having a pH value ⁇ 1) of 66.0 grams (0.1 mole) phytic acid and was stirred at room temperature for about 15 minutes to create a solution.
  • the solution (having a pH value of about 3.5) was further stirred 20 minutes.
  • the solution is concentrated on an evaporator under a vacuum at 50 0 C.
  • the residue was repeatedly (3 times) taken up with anhydrous ethanol in a vacuum to dry the residue as much as possible.
  • C10H19NO4 propinoyl L-carnitine inner salt
  • the residue is further dried in a vacuum oven at 50 0 C to obtain 201.3 grams of white solid powder with an almost quantitative yield (i.e., the white solid powder contains 2% H2O).
  • Butyryl L-Carnitine Phytate (in a 6:1 mole ratio)
  • Butyryl L-Carnitine Phytate (in a 6:1 mole ratio) (C72H144N6O48P6, molecular weight 2046.76) is represented by Formula (4).
  • 138.8 grams (0.6 mole) of butyryl L- carnitine inner salt (C11H21NO4, molecular weight 231.26) was added to a 50% aqueous solution (having a pH value ⁇ 1) of 66.0 grams (0.1 mole) phytic acid and stirred at room temperature resulting in an exothermic reaction.
  • 138.8 grams (0.6 mole) of butyryl L-carnitine inner salt (C11H21NO4, molecular weight 231.26) was added to a 50% aqueous solution (having a pH value ⁇ 1) of 66.0 grams (0.1 mole) phytic acid and was stirred at room temperature for about 15 minutes to create a solution.
  • the solution (having a pH value of about 3.8) was further stirred 20 minutes.
  • the solution is concentrated on an evaporator under a vacuum at 50 0 C.
  • the residue was repeatedly (3 times) taken up with anhydrous ethanol in a vacuum to dry the residue as much as possible.
  • the residue is further dried in a vacuum oven at 50 0 C to obtain 209.5 grams of
  • lsobutyryl L-Camitine Phytate (in a 6:1 mole ratio)
  • lsobutyryl L-Carnitine Phytate (in a 6:1 mole ratio) (C72H144N6O48P6, molecular weight 2046.76) is represented by Formula (5).
  • 34.7 grams (0.15 mole) of isobutyryl L-carnitine inner salt (C11H21NO4, molecular weight 231.26) was added to a 50% aqueous solution (having a pH value ⁇ 1) of 16.5 grams (0.025 mole) phytic acid and stirred at room temperature resulting in an exothermic reaction.
  • 34.7 grams (0.15 mole) of isobutyryl L-carnitine inner salt (C11H21NO4, molecular weight 231.26) was added to a 50% aqueous solution (having a pH value ⁇ 1) of 16.5 grams (0.025 mole) phytic acid and was stirred at room temperature for about 15 minutes to create a solution.
  • the solution (having a pH value of about 3.7) was further stirred 20 minutes.
  • the solution is concentrated on an evaporator under a vacuum at 50 0 C.
  • the residue was repeatedly (3 times) taken up with anhydrous ethanol in a vacuum to dry the residue as much as possible.
  • the residue is further dried in a vacuum oven at 50 0 C to obtain 52.8 grams of transparent gel-like product with an almost quantitative yield (i.e., the transparent gel-like product contains 3% H2O).
  • Valeryl L-Carnitine Phytate (in a 6:1 mole ratio) (C7 ⁇ Hi56N6 ⁇ 4 ⁇ P6, molecular weight 2129.76) is represented by Formula (6).
  • 24.5 grams (0.1 mole) of valeryl L- carnitine inner salt (Ci2H23NO4, molecular weight 245.32) was added to a 50% aqueous solution (having a pH value ⁇ 1) of 11.0 grams (0.0166 mole) phytic acid and stirred at room temperature resulting in an exothermic reaction.
  • valeryl L-carnitine inner salt C12H23NO4, molecular weight 245.32
  • a 50% aqueous solution having a pH value ⁇ 1
  • 11.0 grams (0.0166 mole) phytic acid was stirred at room temperature for about 15 minutes to create a solution.
  • the solution having a pH value of about 3.5
  • the solution is concentrated on an evaporator under a vacuum at 50 0 C.
  • the residue was repeatedly (3 times) taken up with anhydrous ethanol in a vacuum to dry the residue as much as possible.
  • the residue is further dried in a vacuum oven at 50 0 C to obtain 36.56 grams of transparent gel-like product with an almost quantitative yield (i.e., the transparent gel-like product contains 2.9% H2O).
  • Isovaleryl L-Carnitine Phytate (in a 6:1 mole ratio)
  • Isovaleryl L-Carnitine Phytate (in a 6:1 mole ratio) (Cy ⁇ HiseNeCu ⁇ Pe, molecular weight 2129.76) is represented by Formula (7).
  • 12.25 grams (0.05 mole) of isovaleryl L-carnitine inner salt (Ci2H23NO4, molecular weight 245.32) was added to a 50% aqueous solution (having a pH value ⁇ 1) of 5.5 grams (0.0083 mole) phytic acid and stirred at room temperature resulting in an exothermic reaction.
  • the residue is further dried in a vacuum oven at 50 0 C to obtain 18.3 grams of transparent gel-like product with an almost quantitative yield (i.e., the transparent gel-like product contains 3.0% H2O).
  • mice The single dose oral acute toxicity of L-carnitine phytate (in a 6:1 mole ratio) was evaluated in mice.
  • Five dosages 25, 20, 15, 10, and 5 g/Kg were orally administrated to five groups of mice in which each group had five male and five female mice. After dosing, the five groups of mice were observed and daily records (for 14 days) were made of their general conditions, toxic response, and deaths. All of the dead mice were necropsied, in which each of the body's thorace and abdomen were opened, and each heart, liver, spleen, lung, kidney, and intestine were examined and recorded.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Cosmetics (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention concerne des sels de L-carnitine et des alcanoyle L-carnitines avec acide phytique de formule générale (I), et leur procédé de préparation, le rapport molaire entre la L-carnitine ou son cation dérivés alcanoyle et anion acide phytique étant compris dans la gamme de 1:1 à 6:1, n valant de 1 à 6; R1 étant l’anion phytate; R étant de l’hydrogène, un groupe alcanoyle linéaire ayant de 2 à 12 atomes de carbone ou un groupe alcanoyle à chaîne ramifiée ayant de 2 à 12 atomes de carbone.
PCT/US2009/003522 2008-06-16 2009-06-10 Phytates de l-carnitine et d’alcanoyle l-carnitine, et leur procédé de préparation Ceased WO2010005465A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA2727918A CA2727918A1 (fr) 2008-06-16 2009-06-10 Phytates de l-carnitine et d'alcanoyle l-carnitine, et leur procede de preparation
JP2011514588A JP2011524415A (ja) 2008-06-16 2009-06-10 Ｌ−カルニチンフィチン酸塩及びアルカノイル−ｌ−カルニチンフィチン酸塩と、その製造方法
EP09788797A EP2299994A1 (fr) 2008-06-16 2009-06-10 Phytates de l-carnitine et d`alcanoyle l-carnitine, et leur procédé de préparation
CN200980000526.7A CN101903020B (zh) 2008-06-16 2009-06-10 L-肉碱植酸盐和烷酰基l-肉碱植酸盐及其制备
US12/584,769 US8067468B2 (en) 2009-06-10 2009-09-12 L-carnitine and alkanoyl L-carnitine phytates and process for preparing the same

Applications Claiming Priority (2)

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US6195608P 2008-06-16 2008-06-16
US61/061,956 2008-06-16

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WO2010005465A1 true WO2010005465A1 (fr) 2010-01-14

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WO (1) WO2010005465A1 (fr)

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CN103204874A (zh) * 2012-01-12 2013-07-17 辽宁科硕营养科技有限公司 植酸盐及其制备方法与用途
JP6473352B2 (ja) * 2015-03-10 2019-02-20 利幸 糸井 虚血性疾患治療薬

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0349143A2 (fr) * 1988-07-01 1990-01-03 Sanwa Kagaku Kenkyusho Co., Ltd. Utilisation de l'acide phytique ou leurs sels pour la prévention ou le traitement des maladies hépatiques
WO1998044918A1 (fr) * 1997-04-08 1998-10-15 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Compositions solides adaptees a l'administration par voie orale, contenant un citrate de magnesium d'alcanoyle-l-carnitine
WO2000073258A1 (fr) * 1999-05-28 2000-12-07 Biosalts S.R.L. Derives de principes actifs ameliores d'un point de vue therapeutique et/ou nutritionnel, et compositions administrees par voie orale contenant ces derives
WO2003010131A1 (fr) * 2001-07-25 2003-02-06 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Alpha-cetoglutarates d'ingredients actifs et compositions les contenant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0349143A2 (fr) * 1988-07-01 1990-01-03 Sanwa Kagaku Kenkyusho Co., Ltd. Utilisation de l'acide phytique ou leurs sels pour la prévention ou le traitement des maladies hépatiques
WO1998044918A1 (fr) * 1997-04-08 1998-10-15 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Compositions solides adaptees a l'administration par voie orale, contenant un citrate de magnesium d'alcanoyle-l-carnitine
WO2000073258A1 (fr) * 1999-05-28 2000-12-07 Biosalts S.R.L. Derives de principes actifs ameliores d'un point de vue therapeutique et/ou nutritionnel, et compositions administrees par voie orale contenant ces derives
WO2003010131A1 (fr) * 2001-07-25 2003-02-06 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Alpha-cetoglutarates d'ingredients actifs et compositions les contenant

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CN101903020B (zh) 2013-04-10
EP2299994A1 (fr) 2011-03-30
CA2727918A1 (fr) 2010-01-14
CN101903020A (zh) 2010-12-01
JP2011524415A (ja) 2011-09-01

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