CA2616844C - Creatine-fatty acids - Google Patents
Creatine-fatty acids Download PDFInfo
- Publication number
- CA2616844C CA2616844C CA002616844A CA2616844A CA2616844C CA 2616844 C CA2616844 C CA 2616844C CA 002616844 A CA002616844 A CA 002616844A CA 2616844 A CA2616844 A CA 2616844A CA 2616844 C CA2616844 C CA 2616844C
- Authority
- CA
- Canada
- Prior art keywords
- creatine
- acid
- fatty acid
- methylguanidino
- anhydride
- 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.)
- Expired - Fee Related
Links
- 239000000194 fatty acid Substances 0.000 title claims abstract description 38
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 claims abstract description 168
- 229960003624 creatine Drugs 0.000 claims abstract description 78
- 239000006046 creatine Substances 0.000 claims abstract description 77
- 235000014113 dietary fatty acids Nutrition 0.000 claims abstract description 30
- 229930195729 fatty acid Natural products 0.000 claims abstract description 30
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 26
- -1 thionyl halide Chemical class 0.000 claims abstract description 23
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- 238000004821 distillation Methods 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- 150000001266 acyl halides Chemical class 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 4
- 150000001336 alkenes Chemical group 0.000 claims description 4
- 239000000908 ammonium hydroxide Substances 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 17
- 150000001875 compounds Chemical class 0.000 abstract description 14
- 150000008064 anhydrides Chemical class 0.000 abstract description 9
- 230000000153 supplemental effect Effects 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 24
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 14
- 230000009469 supplementation Effects 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 12
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 11
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 10
- DRBBFCLWYRJSJZ-UHFFFAOYSA-N N-phosphocreatine Chemical compound OC(=O)CN(C)C(=N)NP(O)(O)=O DRBBFCLWYRJSJZ-UHFFFAOYSA-N 0.000 description 10
- POULHZVOKOAJMA-UHFFFAOYSA-N methyl undecanoic acid Natural products CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 10
- UKMSUNONTOPOIO-UHFFFAOYSA-N Behenic acid Natural products CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- VKOBVWXKNCXXDE-UHFFFAOYSA-N ethyl stearic acid Natural products CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 description 8
- IPCSVZSSVZVIGE-UHFFFAOYSA-N n-hexadecanoic acid Natural products CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 8
- 229940109239 creatinine Drugs 0.000 description 7
- 210000003205 muscle Anatomy 0.000 description 7
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 7
- 150000004671 saturated fatty acids Chemical class 0.000 description 7
- 210000002027 skeletal muscle Anatomy 0.000 description 7
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 6
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 6
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- MEJYXFHCRXAUIL-UHFFFAOYSA-N 2-[carbamimidoyl(methyl)amino]acetic acid;hydrate Chemical compound O.NC(=N)N(C)CC(O)=O MEJYXFHCRXAUIL-UHFFFAOYSA-N 0.000 description 5
- 235000021355 Stearic acid Nutrition 0.000 description 5
- 229960004826 creatine monohydrate Drugs 0.000 description 5
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 5
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 5
- 229950007002 phosphocreatine Drugs 0.000 description 5
- 210000001057 smooth muscle myoblast Anatomy 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 235000021357 Behenic acid Nutrition 0.000 description 4
- 235000021314 Palmitic acid Nutrition 0.000 description 4
- 150000001263 acyl chlorides Chemical class 0.000 description 4
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 4
- ZOQQZTXQYQQHIQ-UHFFFAOYSA-N azanium;2-[carbamimidoyl(methyl)amino]acetate Chemical compound [NH4+].NC(=N)N(C)CC([O-])=O ZOQQZTXQYQQHIQ-UHFFFAOYSA-N 0.000 description 4
- 229940116226 behenic acid Drugs 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- AOHAPDDBNAPPIN-UHFFFAOYSA-N myristicinic acid Natural products COC1=CC(C(O)=O)=CC2=C1OCO2 AOHAPDDBNAPPIN-UHFFFAOYSA-N 0.000 description 4
- 229960002446 octanoic acid Drugs 0.000 description 4
- SECPZKHBENQXJG-FPLPWBNLSA-N palmitoleic acid Chemical compound CCCCCC\C=C/CCCCCCCC(O)=O SECPZKHBENQXJG-FPLPWBNLSA-N 0.000 description 4
- MXGJGSQXRDQNJG-UHFFFAOYSA-M sodium;2-[carbamimidoyl(methyl)amino]acetate Chemical compound [Na+].NC(=N)N(C)CC([O-])=O MXGJGSQXRDQNJG-UHFFFAOYSA-M 0.000 description 4
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 3
- YUUVURNOUHULKZ-UHFFFAOYSA-N [2-[carbamimidoyl(methyl)amino]acetyl] butanoate Chemical compound CCCC(=O)OC(=O)CN(C)C(N)=N YUUVURNOUHULKZ-UHFFFAOYSA-N 0.000 description 3
- KDVNKHNRCGBMGK-UHFFFAOYSA-N [2-[carbamimidoyl(methyl)amino]acetyl] hexanoate Chemical compound CCCCCC(=O)OC(=O)CN(C)C(N)=N KDVNKHNRCGBMGK-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 3
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 description 3
- 235000004626 essential fatty acids Nutrition 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- NIPYIXMXODGEES-UHFFFAOYSA-N hexanoyl bromide Chemical compound CCCCCC(Br)=O NIPYIXMXODGEES-UHFFFAOYSA-N 0.000 description 3
- WTBAHSZERDXKKZ-UHFFFAOYSA-N octadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCCCC(Cl)=O WTBAHSZERDXKKZ-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 235000003441 saturated fatty acids Nutrition 0.000 description 3
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 3
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 3
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 2
- FBWMYSQUTZRHAT-HZJYTTRNSA-N (9z,12z)-octadeca-9,12-dienoyl chloride Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(Cl)=O FBWMYSQUTZRHAT-HZJYTTRNSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 241000251468 Actinopterygii Species 0.000 description 2
- DPUOLQHDNGRHBS-UHFFFAOYSA-N Brassidinsaeure Natural products CCCCCCCCC=CCCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-UHFFFAOYSA-N 0.000 description 2
- 101100180402 Caenorhabditis elegans jun-1 gene Proteins 0.000 description 2
- URXZXNYJPAJJOQ-UHFFFAOYSA-N Erucic acid Natural products CCCCCCC=CCCCCCCCCCCCC(O)=O URXZXNYJPAJJOQ-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 206010020880 Hypertrophy Diseases 0.000 description 2
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 235000021319 Palmitoleic acid Nutrition 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- BQWNJVAQVIPCFZ-UHFFFAOYSA-N [2-[carbamimidoyl(methyl)amino]acetyl] dodecanoate Chemical compound CCCCCCCCCCCC(=O)OC(=O)CN(C)C(N)=N BQWNJVAQVIPCFZ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 239000003929 acidic solution Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 description 2
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 2
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 2
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 235000021342 arachidonic acid Nutrition 0.000 description 2
- 229940114079 arachidonic acid Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- SECPZKHBENQXJG-UHFFFAOYSA-N cis-palmitoleic acid Natural products CCCCCCC=CCCCCCCCC(O)=O SECPZKHBENQXJG-UHFFFAOYSA-N 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 2
- 229940090949 docosahexaenoic acid Drugs 0.000 description 2
- KFEVDPWXEVUUMW-UHFFFAOYSA-N docosanoic acid Natural products CCCCCCCCCCCCCCCCCCCCCC(=O)OCCC1=CC=C(O)C=C1 KFEVDPWXEVUUMW-UHFFFAOYSA-N 0.000 description 2
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 2
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 2
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 2
- DPUOLQHDNGRHBS-KTKRTIGZSA-N erucic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-KTKRTIGZSA-N 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- RBLWMQWAHONKNC-UHFFFAOYSA-N hydroxyazanium Chemical compound O[NH3+] RBLWMQWAHONKNC-UHFFFAOYSA-N 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 235000020778 linoleic acid Nutrition 0.000 description 2
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 2
- 229960004488 linolenic acid Drugs 0.000 description 2
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000037257 muscle growth Effects 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 210000001087 myotubule Anatomy 0.000 description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 229960002969 oleic acid Drugs 0.000 description 2
- 235000021313 oleic acid Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- JRIVBVODFZKVND-UHFFFAOYSA-M potassium;2-[carbamimidoyl(methyl)amino]acetate Chemical compound [K+].NC(=N)N(C)CC([O-])=O JRIVBVODFZKVND-UHFFFAOYSA-M 0.000 description 2
- 125000005471 saturated fatty acid group Chemical group 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 2
- DLNGCCQFGNSBOP-UHFFFAOYSA-N 2-[carbamimidoyl(methyl)amino]acetic acid;2-oxopropanoic acid Chemical class CC(=O)C(O)=O.NC(=N)N(C)CC(O)=O DLNGCCQFGNSBOP-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- NJJBCUBZPPZCIF-UHFFFAOYSA-N C(CCCC=CCC=C/CC=C/CC=C/CC=C/CC=C/CC)(=O)OC(CCCC=CCC=C/CC=C/CC=C/CC=C/CC=C/CC)=O Chemical compound C(CCCC=CCC=C/CC=C/CC=C/CC=C/CC=C/CC)(=O)OC(CCCC=CCC=C/CC=C/CC=C/CC=C/CC=C/CC)=O NJJBCUBZPPZCIF-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028311 Muscle hypertrophy Diseases 0.000 description 1
- 229910003202 NH4 Inorganic materials 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 208000026214 Skeletal muscle atrophy Diseases 0.000 description 1
- XEJSGMSEEYIETD-JEBPEJKESA-N [2-[carbamimidoyl(methyl)amino]acetyl] (5z,8z,11z,14z,17z)-icosa-5,8,11,14,17-pentaenoate Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)OC(=O)CN(C)C(N)=N XEJSGMSEEYIETD-JEBPEJKESA-N 0.000 description 1
- XRIUIRFRWHDWIA-JPFHKJGASA-N [2-[carbamimidoyl(methyl)amino]acetyl] (6Z,9Z,12Z)-octadeca-6,9,12-trienoate Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCC(=O)OC(=O)CN(C)C(N)=N XRIUIRFRWHDWIA-JPFHKJGASA-N 0.000 description 1
- OXJOUWBMKJJMPU-NQLNTKRDSA-N [2-[carbamimidoyl(methyl)amino]acetyl] (9z,12z)-octadeca-9,12-dienoate Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC(=O)CN(C)C(N)=N OXJOUWBMKJJMPU-NQLNTKRDSA-N 0.000 description 1
- SBAJPMBZFUFCCE-KHPPLWFESA-N [2-[carbamimidoyl(methyl)amino]acetyl] (Z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC(=O)CN(C)C(N)=N SBAJPMBZFUFCCE-KHPPLWFESA-N 0.000 description 1
- RQPRTCUEMPRFCT-KHPPLWFESA-N [2-[carbamimidoyl(methyl)amino]acetyl] (z)-docos-13-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCC(=O)OC(=O)CN(C)C(N)=N RQPRTCUEMPRFCT-KHPPLWFESA-N 0.000 description 1
- CPSJVLQKBSWQFF-HJWRWDBZSA-N [2-[carbamimidoyl(methyl)amino]acetyl] (z)-hexadec-9-enoate Chemical compound CCCCCC\C=C/CCCCCCCC(=O)OC(=O)CN(C)C(N)=N CPSJVLQKBSWQFF-HJWRWDBZSA-N 0.000 description 1
- WUMFTWPFOUMDHT-UHFFFAOYSA-N [2-[carbamimidoyl(methyl)amino]acetyl] decanoate Chemical compound CCCCCCCCCC(=O)OC(=O)CN(C)C(N)=N WUMFTWPFOUMDHT-UHFFFAOYSA-N 0.000 description 1
- OXBHSYSCUWFTNL-UHFFFAOYSA-N [2-[carbamimidoyl(methyl)amino]acetyl] docosanoate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OC(=O)CN(C)C(N)=N OXBHSYSCUWFTNL-UHFFFAOYSA-N 0.000 description 1
- ZBOPCNPAPBFHHW-UHFFFAOYSA-N [2-[carbamimidoyl(methyl)amino]acetyl] hexadecanoate Chemical compound CCCCCCCCCCCCCCCC(=O)OC(=O)CN(C)C(N)=N ZBOPCNPAPBFHHW-UHFFFAOYSA-N 0.000 description 1
- OFPBJSMGRXVKFA-UHFFFAOYSA-N [2-[carbamimidoyl(methyl)amino]acetyl] icosanoate Chemical compound CCCCCCCCCCCCCCCCCCCC(=O)OC(=O)CN(C)C(N)=N OFPBJSMGRXVKFA-UHFFFAOYSA-N 0.000 description 1
- UASXCLZMGAOZFD-UHFFFAOYSA-N [2-[carbamimidoyl(methyl)amino]acetyl] octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(=O)CN(C)C(N)=N UASXCLZMGAOZFD-UHFFFAOYSA-N 0.000 description 1
- ZBVOYXAIGBESMT-UHFFFAOYSA-N [2-[carbamimidoyl(methyl)amino]acetyl] octanoate Chemical compound CCCCCCCC(=O)OC(=O)CN(C)C(N)=N ZBVOYXAIGBESMT-UHFFFAOYSA-N 0.000 description 1
- MUBDQHWJMMSGDG-UHFFFAOYSA-N [2-[carbamimidoyl(methyl)amino]acetyl] tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OC(=O)CN(C)C(N)=N MUBDQHWJMMSGDG-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001262 acyl bromides Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 150000001345 alkine derivatives Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- UFIVEPVSAGBUSI-UHFFFAOYSA-N dihydroorotic acid Chemical class OC(=O)C1CC(=O)NC(=O)N1 UFIVEPVSAGBUSI-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 230000002270 ergogenic effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 230000012042 muscle hypertrophy Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- BDTYMGCNULYACO-UHFFFAOYSA-N octadeca-9,12-dienoyl octadeca-9,12-dienoate Chemical compound CCCCCC=CCC=CCCCCCCCC(=O)OC(=O)CCCCCCCC=CCC=CCCCCC BDTYMGCNULYACO-UHFFFAOYSA-N 0.000 description 1
- 229960005010 orotic acid Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940076788 pyruvate Drugs 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000025185 skeletal muscle atrophy Effects 0.000 description 1
- 230000025175 skeletal muscle hypertrophy Effects 0.000 description 1
- 210000000419 skeletal muscle satellite cell Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 125000005314 unsaturated fatty acid group Chemical group 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- DTOSIQBPPRVQHS-UHFFFAOYSA-N α-Linolenic acid Chemical compound CCC=CCC=CCC=CCCCCCCCC(O)=O DTOSIQBPPRVQHS-UHFFFAOYSA-N 0.000 description 1
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
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/175—Amino acids
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Mycology (AREA)
- Health & Medical Sciences (AREA)
- Nutrition Science (AREA)
- Engineering & Computer Science (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention describes compounds produced from a creatine molecule and a fatty acid molecule. The compounds being in the form of creatine-fatty acid compounds being bound by an anhydride linkage, or mixtures thereof made by reacting creatine or derivatives thereof with an appropriate fatty acid previously reacted with a thionyl halide. The administration of such molecules provides supplemental creatine with enhanced bioavailability and the additional benefits conferred by the specific fatty acid.
Description
._. __ _~......,~..~ _ ,,: ....W b..~.,~~.
Creatine-Fatty Acids Field of the Invention The present invention relates to structures and synthesis of creatine-fatty acid compounds bound via an anhydride linkage. Another aspect of the present invention relates to a compound comprising a creatine molecule bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid and bound to the creatine via an anhydride linkage.
Background of the Invention Creatine is a naturally occurring amino acid derived from the amino acids glycine, arginine, and methionine. Although it is found in meat and fish, it is also synthesized by humans. Creatine is predominantly used as a fuel source in muscle. About 65% of creatine is stored in the musculature of mammals as phosphocreatine (creatine bound to a phosphate molecule).
Muscular contractions are fueled by the dephosphorylation of adenosine triphosphate (ATP) to produce adenosine diphosphate (ADP). In the absence of a mechanism to replenish ATP stores, the supply of ATP would be totally consumed in 1-2 seconds. Phosphocreatine serves as a major source of phosphate from which ADP is regenerated to ATP. Within six seconds following the commencement of exercise, muscular concentrations of phosphocreatine drop by almost 50%. Creatine supplementation has been shown to increase the concentration of creatine in the muscle (Harris RC, Soderlund K, Hultman E.
Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond). 1992 Sep;83(3):367-74) and further, 8303917.1 the supplementation enables an increase in the resynthesis of phosphocreatine (Greenhaff PL, Bodin K, Soderlund K, Hultman E. Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am J Physiol.
1994 May;266(5 Pt 1):E725-30) leading to a rapid replenishment of ATP within the first two minutes following the commencement of exercise. Through this mechanism, creatine is able to improve strength and reduce fatigue (Greenhaff PL, Casey A, Short AH, Harris R, Soderlund K, Hultman E. Influence of oral creatine supplementation of muscle torque during repeated bouts of maximal voluntary exercise in man. Clin Sci (Lond). 1993 May;84(5):565-71).
The beneficial effects of creatine supplementation with regard to skeletal muscle are apparently not restricted to the role of creatine in energy metabolism.
It has been shown that creatine supplementation in combination with strength training results in specific, measurable physiological changes in skeletal muscle compared to strength training alone. For example, creatine supplementation amplifies the strength training-induced increase of human skeletal satellite cells as well as the number of myonuclei in human skeletal muscle fibres (Olsen S, Aagaard P, Kadi F, Tufekovic G, Verney J, Olesen JL, Suetta C, Kjaer M.
Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training. J Physiol. 2006 Jun 1;573(Pt 2):525-34). Satellite cells are the stem cells of adult muscle.
They are normally maintained in a quiescent state and become activated to fulfill roles of routine maintenance, repair and hypertrophy (Zammit PS, Partridge TA, Yablonka-Reuveni Z. The Skeletal Muscle Satellite Cell: The Stem Cell That
Creatine-Fatty Acids Field of the Invention The present invention relates to structures and synthesis of creatine-fatty acid compounds bound via an anhydride linkage. Another aspect of the present invention relates to a compound comprising a creatine molecule bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid and bound to the creatine via an anhydride linkage.
Background of the Invention Creatine is a naturally occurring amino acid derived from the amino acids glycine, arginine, and methionine. Although it is found in meat and fish, it is also synthesized by humans. Creatine is predominantly used as a fuel source in muscle. About 65% of creatine is stored in the musculature of mammals as phosphocreatine (creatine bound to a phosphate molecule).
Muscular contractions are fueled by the dephosphorylation of adenosine triphosphate (ATP) to produce adenosine diphosphate (ADP). In the absence of a mechanism to replenish ATP stores, the supply of ATP would be totally consumed in 1-2 seconds. Phosphocreatine serves as a major source of phosphate from which ADP is regenerated to ATP. Within six seconds following the commencement of exercise, muscular concentrations of phosphocreatine drop by almost 50%. Creatine supplementation has been shown to increase the concentration of creatine in the muscle (Harris RC, Soderlund K, Hultman E.
Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci (Lond). 1992 Sep;83(3):367-74) and further, 8303917.1 the supplementation enables an increase in the resynthesis of phosphocreatine (Greenhaff PL, Bodin K, Soderlund K, Hultman E. Effect of oral creatine supplementation on skeletal muscle phosphocreatine resynthesis. Am J Physiol.
1994 May;266(5 Pt 1):E725-30) leading to a rapid replenishment of ATP within the first two minutes following the commencement of exercise. Through this mechanism, creatine is able to improve strength and reduce fatigue (Greenhaff PL, Casey A, Short AH, Harris R, Soderlund K, Hultman E. Influence of oral creatine supplementation of muscle torque during repeated bouts of maximal voluntary exercise in man. Clin Sci (Lond). 1993 May;84(5):565-71).
The beneficial effects of creatine supplementation with regard to skeletal muscle are apparently not restricted to the role of creatine in energy metabolism.
It has been shown that creatine supplementation in combination with strength training results in specific, measurable physiological changes in skeletal muscle compared to strength training alone. For example, creatine supplementation amplifies the strength training-induced increase of human skeletal satellite cells as well as the number of myonuclei in human skeletal muscle fibres (Olsen S, Aagaard P, Kadi F, Tufekovic G, Verney J, Olesen JL, Suetta C, Kjaer M.
Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training. J Physiol. 2006 Jun 1;573(Pt 2):525-34). Satellite cells are the stem cells of adult muscle.
They are normally maintained in a quiescent state and become activated to fulfill roles of routine maintenance, repair and hypertrophy (Zammit PS, Partridge TA, Yablonka-Reuveni Z. The Skeletal Muscle Satellite Cell: The Stem Cell That
2 8303917.1 Came In From the Cold. J Histochem Cytochem. 2006 Aug 9). 'True' muscle hypertrophy can be defined as "as an increase in fiber diameter without an apparent increase in the number of muscle fibers, accompanied by enhanced protein synthesis and augmented contractile force" (Sartorelli V, Fulco M.
Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy.
Sci STKE. 2004 Jul 27;2004(244):re11). Postnatal muscle growth involves both myofiber hypertrophy and increased numbers of myonuclei - the source of which are satellite cells (Oisen S, Aagaard P, Kadi F, Tufekovic G, Verney J, Olesen JL, Suetta C, Kjaer M. Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training. J Physiol. 2006 Jun 1;573(Pt 2):525-34).
Although creatine is used predominantly in muscle cells and most of the total creatine pool is found in muscle, creatine is actually synthesized in the liver and pancreas. Thus, the musculature's creatine concentration is maintained by the uptake of creatine from the blood stream regardless of whether the source of creatine is endogenous, i.e. synthesized by the liver or pancreas, or dietary, i.e.
natural food sources or supplemental sources. The creatine content of an average 70 kg male is approximately 120 g with about 2 g being excreted as creatinine per day (Williams MH, Branch JD. Creatine supplementation and exercise performance: an update. J Am Coll Nutr. 1998 Jun;17(3):216-34). A
typical omnivorous diet supplies approximately I g of creatine daily, while diets higher in meat and fish will supply more creatine. As a point of reference, a g uncooked steak contains about 2 g of creatine which equates to more than two
Molecular and cellular determinants of skeletal muscle atrophy and hypertrophy.
Sci STKE. 2004 Jul 27;2004(244):re11). Postnatal muscle growth involves both myofiber hypertrophy and increased numbers of myonuclei - the source of which are satellite cells (Oisen S, Aagaard P, Kadi F, Tufekovic G, Verney J, Olesen JL, Suetta C, Kjaer M. Creatine supplementation augments the increase in satellite cell and myonuclei number in human skeletal muscle induced by strength training. J Physiol. 2006 Jun 1;573(Pt 2):525-34).
Although creatine is used predominantly in muscle cells and most of the total creatine pool is found in muscle, creatine is actually synthesized in the liver and pancreas. Thus, the musculature's creatine concentration is maintained by the uptake of creatine from the blood stream regardless of whether the source of creatine is endogenous, i.e. synthesized by the liver or pancreas, or dietary, i.e.
natural food sources or supplemental sources. The creatine content of an average 70 kg male is approximately 120 g with about 2 g being excreted as creatinine per day (Williams MH, Branch JD. Creatine supplementation and exercise performance: an update. J Am Coll Nutr. 1998 Jun;17(3):216-34). A
typical omnivorous diet supplies approximately I g of creatine daily, while diets higher in meat and fish will supply more creatine. As a point of reference, a g uncooked steak contains about 2 g of creatine which equates to more than two
3 8303917.1 8 oz. steaks per day. Since most studies examining creatine supplementation employ dosages ranging from 2-20 g per day it is unrealistic to significantly increase muscle creatine stores through merely food sources alone. Therefore, supplemental sources of creatine are an integral component of increasing, and subsequently maintaining supraphysiological, muscular creatine levels.
Creatine supplementation, thus results in positive physiological effects on skeletal muscle, such as: performance improvements during brief high-intensity anaerobic exercise, increased strength and enhanced muscle growth.
Creatine monohydrate is a commonly used supplement. Creatine monohydrate is soluble in water at a rate of 75 ml of water per gram of creatine.
Ingestion of creatine monohydrate, therefore, requires large amounts of water to be co-ingested. Additionally, in aqueous solutions creatine is known to convert to creatinine via an irreversible, pH-dependent, non-enzymatic reaction. Aqueous and alkaline solutions contain an equilibrium mixture of creatine and creatinine.
In acidic solutions, on the other hand, the formation of creatinine is complete.
Creatinine is devoid of the ergogenic beneficial effects of creatine. It is therefore desirable to provide, for use in individuals, e.g. animals and humans, forms and derivatives of creatine with improved characteristics such as stability and solubility. Furthermore, it would be advantageous to do so in a manner that provides additional functionality as compared to creatine monohydrate alone.
The manufacture of hydrosoluble creatine salts with various organic acids have been described. U.S. Pat. No. 5,886,040, purports to describe a creatine pyruvate salt with enhanced palatability which is resistant to acid hydrolysis.
Creatine supplementation, thus results in positive physiological effects on skeletal muscle, such as: performance improvements during brief high-intensity anaerobic exercise, increased strength and enhanced muscle growth.
Creatine monohydrate is a commonly used supplement. Creatine monohydrate is soluble in water at a rate of 75 ml of water per gram of creatine.
Ingestion of creatine monohydrate, therefore, requires large amounts of water to be co-ingested. Additionally, in aqueous solutions creatine is known to convert to creatinine via an irreversible, pH-dependent, non-enzymatic reaction. Aqueous and alkaline solutions contain an equilibrium mixture of creatine and creatinine.
In acidic solutions, on the other hand, the formation of creatinine is complete.
Creatinine is devoid of the ergogenic beneficial effects of creatine. It is therefore desirable to provide, for use in individuals, e.g. animals and humans, forms and derivatives of creatine with improved characteristics such as stability and solubility. Furthermore, it would be advantageous to do so in a manner that provides additional functionality as compared to creatine monohydrate alone.
The manufacture of hydrosoluble creatine salts with various organic acids have been described. U.S. Pat. No. 5,886,040, purports to describe a creatine pyruvate salt with enhanced palatability which is resistant to acid hydrolysis.
4 8303917.1 U.S. Patent No. 5,973,199, purports to describe hydrosoluble organic salts of creatine as single combination of one mole of creatine monohydrate with one mole of the following organic acids: citrate, malate, fumarate and tartarate individually. The resultant salts described therein are claimed to be from 3 to 15 times more soluble, in aqueous solution, than creatine itself.
U.S. Pat. No. 6,166,249, purports to describe a creatine pyruvic acid salt that is highly stable and soluble. It is further purported that the pyruvate included in the salt may be useful to treat obesity, prevent the formation of free radicals and enhance long-term performance.
U.S. Pat. No. 6,211,407 purports to describe dicreatine and tricreatine citrates and a method of making the same. These dicreatine and tricreatine salts are claimed to be stable in acidic solutions, thus hampering the undesirable conversion of creatine to creatinine.
U.S. Pat. No. 6,838,562, purports to describe a process for the synthesis of mono, di, or tricreatine orotic acid, thioorotic acid, and dihydroorotic acid salts which are claimed to have increased oral absorption and bioavailability due to an inherent stability in aqueous solution. It is further claimed that the heterocyclic acid portion of the salt acts synergistically with creatine.
U.S. Pat. No. 7,109,373 purports to describe creatine salts of dicarboxytic acids with enhanced aqueous solubility.
The above disclosed patents recite creatine salts, methods of synthesis of the salts, and uses thereof. However, nothing in any of the disclosed patents teaches, suggests or discloses a compound comprising a creatine molecule bound to a fatty acid.
In addition to salts, creatine esters have also been described. U.S. Pat.
No. 6,897,334 describes method for producing creatine esters with lower alcohols i.e. one to four carbon atoms, using acid catalysts. It is stated that creatine esters are more soluble than creatine. It is further stated that the protection of the carboxylic acid moiety of the creatine molecule by ester-formation stabilizes the compound by preventing its conversion to creatinine.
The creatine esters are said to be converted into creatine by esterases i.e.
enzymes that cleave ester bonds, found in a variety of cells and biological fluids.
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 essential fatty acids being 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, 8303917.1 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 salts and the formation of esters. The majority of the above referenced patents are creatine salts. These salts, esterification via carboxylate reactivity, may essentially be formed, as disclosed in U.S. Pat. No.
7,109,373, through a relatively simple reaction by mixing a molar excess of creatine or derivative thereof with an aqueous dicarboxylic acid and heating from room temperature to about 50 C.
Alternatively, a creatine-fatty acid may be synthesized through ester formation. 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.
8303917.1 While the above referenced creatine compounds have attempted to address issues such as stability and solubility in addition to, and in some cases, to add increased functionality as compared to creatine alone, no description has yet been made of any creatine-fatty acid compound, particularly that comprising a saturated fatty acid.
Summary of the Invention In the present invention, compounds are disclosed, where the compounds comprise a molecule of creatine bound to a fatty acid, via an anhydride linkage, and having a structure of Formula 1:
Formula 1 O O
II II
H2C' C" O'.~ C~R
I
HN~C'-N~CH3 I
where:
R is an alkyl group, preferably saturated, and containing from about 3 to a maximum of 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.
8303917.1 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 creatine-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 creatine 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 not less then four carbon atoms. Furthermore, essential fatty acids are herein understood to be included by the term 'fatty acid'.
As used herein, "creatine" refers to the chemical N-methyl-N-guanyl Glycine, (CAS Registry No. 57-00-1), also known as, (alpha-methyl guanido) acetic acid, N-(aminoiminomethyl)-N-glycine, Methylglycocyamine, Methylguanidoacetic Acid, or N-Methyl-N-guanylglycine. Additionally, as used herein, "creatine" also includes derivatives of creatine such as esters, and 8303917.1 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 a creatine molecule bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid. Furthermore, the creatine and fatty acid being bound by an anhydride 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 0 0 Step 1 0 _ C
C + S 35 C 5- 0C
R~ ~OH X~ " X 0.5 - 2 h R~ ~X
II II
MOICI~ CHz Step 2 HOCl~ CH
Step 3 1)Na0 HH 20 I Z
where: H3CC%NH 2)evap. H20 H3C'N",c:~,,NH
R = alkane or alkene (C = 3 to 21) NH2 NH2 X=C1,Br,F,orI 6 5 M= Na, K, Li, or NH4 0 0 II II
H2C' C, O"C" R
I
HN~C'-Nll CH3 I
With reference to Scheme 1, in Step 1 an acyl halide (4) is produced via reaction of a fatty acid (2) with a thionyl halide (3).
In various embodiments of the present invention, the fatty acid of (2) is selected from the saturated fatty acid group comprising butyric or butanoic acid, caproic or hexanoic acid, caprylic or octanoic acid, capric or decanoic acid, lauric 8303917.1 or dodecanoic acid, myristic or tetradecanoic acid, palmitic or hexadecanoic acid, stearic or octadecanoic acid, arachidic or eicosanoic acid, and behenic or docosanoic acid.
In alternative embodiments, of the present invention, the fatty acid of (2) is selected from the unsaturated fatty acid group comprising oleic acid, linoleic acid, linolenic acid, arachidonic acid, palmitoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and erucic acid.
Furthermore, the thionyl halide of (3) is selected from the group consisting of fluorine, chlorine, bromine, and iodine, the preferred method using chlorine or bromine.
The above reaction proceeds under conditions of heat ranging between from about 35 C to about 50 C and stirring over a period from about 0.5 hours to about 2 hours during which time the gases sulfur dioxide and acidic gas, wherein the acidic gas species is dependent on the species of thionyl halide employed, are evolved. Preferably, the reaction proceeds at 45 C for 1.5 hours.
Step 2 of Scheme 1 entails the neutralization of the carboxylic acid of the creatine 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, 8303917.1 potassium hydroxide, when used as the inorganic base, results in the production of the potassium creatine salt.
Step 3 of Scheme 1 involves the drop wise addition of the prepared acyl halide (4) to the creatine 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 a creatine fatty acid compound of the present invention.
In various embodiments, according to aforementioned, using the saturated fatty acids, the following compounds are produced produced: butyric 2-(1-methylguanidino)acetic anhydride, hexanoic 2-(1-methylguanidino)acetic anhydride, 2-(1-methylguanidino)acetic octanoic anhydride, decanoic 2-(1-methylguanidino)acetic anhydride, 2-(1-methylguanidino)acetic tetradecanoic anhydride, 2-(1-methylguanidino)acetic palmitic anhydride, icosanoic 2-(1-methylguanidino)acetic anhydride, and docosanoic 2-(1-methylguanidino)acetic anhydride.
In additional embodiments, according to aforementioned, using the unsaturated fatty acids, the following compounds are produced produced: (Z)-hexadec-9-enoic 2-(1-methylguanidino)acetic anhydride, 2-(1-methylguanidino)acetic oleic anhydride, (Z)-docos-13-enoic 2(1-methylguanidino)acetic anhydride, 2-(1-methylguanidino)acetic (9Z, 1 2Z)-octadeca-9,12-dienoic anhydride, 2-(1-methylguanidino)acetic (9Z,12Z,15Z)-octadeca-9,12,15-trienoic anhydride, 2-(1-methylguanidino)acetic (6Z,9Z,12Z)-octadeca-6,9,12-trienoic anhydride, (5Z,8Z,11 Z,14Z)-icosa-5,8,11,14-tetraenoic 8303917.1 2(1-methylguanidino)acetic anhydride, (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoic 2(1-methylguanidino)acetic anhydride, 2(1-methylguanidino)acetic (8Z,11Z,14Z,17Z,20Z)-tricosa-5,8,11,14,17,20-hexaenoic anhydride.
The following examples illustrate specific creatine-fatty acids 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
Butyric 2-(1-methylguanidino)acetic anhydride H2C' C" 0 "1 C1-1 C"C'CH
HN C~N'CH3 I
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 8.75ml (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, 6.56g (50mmol) of creatine is dissolved in 500m1 of water.
To 8303917.1 this is added 55ml of 1 M sodium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, sodium 2-(1-methylguanidino)acetate, shown below.
NaO' C1-1 CH2 ' N~ C ~NH
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 12.08g (66mmol) of sodium 2-(1-methylguanidino)acetate. 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 butyric 2-(1-methylguanidino)acetic anhydride.
Example 2 Hexanoic 2-(1-methylguanidino)acetic anhydride H2C'C C~C~CH3 HNCCH
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 6.97ml (90mmol) of thionyl 8303917.1 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 creatine is dissolved in 500m1 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-(1-methylguanidino)acetate, shown below.
O
I I
NaO' C"I CH2 H C' N~C~NH
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 13.18g (72mmol) of sodium 2-(1-methylguanidino)acetate. 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 8303917.1 receiving flask. This crude distillate is then further fractionally distilled to yield hexanoic 2-(1-methylguanidino)acetic anhydride.
Example 3 Dodecanoic 2-(1-methylguanidino)acetic anhydride H C' C~0~C CH3 HN~C'_Nl~ CH3 I
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 5.85m1 (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, 7.87g (60mmol) of creatine is dissolved in 600ml 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-(1-methylguanidino)acetate, shown below.
8303917.1 O
ii H4NO' C" CH2 H C' N~C~NH
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 15.31g (70mmol) of the prepared dodecanoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 12.44g (84mmol) of ammonium 2-(1-methylguanidino)acetate. 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 dodecanoic 2-(1-methylguanidino)acetic anhydride.
Example 4 2-(1-methylguanidino)acetic stearic anhydride H2C' C " O~C(C,C CH
I H2 g 3 HN C'-N~CH
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 8303917.1 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 creatine is dissolved in 600ml 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-(1-methylguanidino)acetate, shown below.
I I
' N~ C ~NH
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 23.40g (77mmol) of potassium 2-(1-methylguanidino)acetate. 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-(1-methylguanidino)acetic stearic anhydride.
Example 5 2-(1-methylguanidino)acetic (9Z,12Z)-octadeca-9,12-dienoic anhydride 8303917.1 H2C' C" O~C~C"C~C"C=C" C"C=C" C"- C-" C~C-" CH3 HN~C~N,, CH3 I
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 24.90ml (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, 7.87g (60mmol) of creatine is dissolved in 600m1 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-(1-methylguanidino)acetate, shown below.
O
H4NO' C~CH2 H C' N~C ~NH
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 17.93g (60mmol) of the prepared (9Z,12Z)-octadeca-9,12-8303917.1 dienoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 10.66g (72mmol) of ammonium 2-(1-methylguanidino)acetate. 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-(1-methylguanidino)acetic(9Z,12Z)-octadeca-9,12-dienoic anhydride.
Thus while not wishing to be bound by theory, it is understood that reacting a creatine or derivative thereof with a fatty acid or derivative thereof to form an anhydride can be used enhance the bioavailability of the creatine or derivative thereof by improving stability of the creatine moiety in terms of resistance to hydrolysis in the stomach and blood 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 creatine 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.
8303917.1
U.S. Pat. No. 6,166,249, purports to describe a creatine pyruvic acid salt that is highly stable and soluble. It is further purported that the pyruvate included in the salt may be useful to treat obesity, prevent the formation of free radicals and enhance long-term performance.
U.S. Pat. No. 6,211,407 purports to describe dicreatine and tricreatine citrates and a method of making the same. These dicreatine and tricreatine salts are claimed to be stable in acidic solutions, thus hampering the undesirable conversion of creatine to creatinine.
U.S. Pat. No. 6,838,562, purports to describe a process for the synthesis of mono, di, or tricreatine orotic acid, thioorotic acid, and dihydroorotic acid salts which are claimed to have increased oral absorption and bioavailability due to an inherent stability in aqueous solution. It is further claimed that the heterocyclic acid portion of the salt acts synergistically with creatine.
U.S. Pat. No. 7,109,373 purports to describe creatine salts of dicarboxytic acids with enhanced aqueous solubility.
The above disclosed patents recite creatine salts, methods of synthesis of the salts, and uses thereof. However, nothing in any of the disclosed patents teaches, suggests or discloses a compound comprising a creatine molecule bound to a fatty acid.
In addition to salts, creatine esters have also been described. U.S. Pat.
No. 6,897,334 describes method for producing creatine esters with lower alcohols i.e. one to four carbon atoms, using acid catalysts. It is stated that creatine esters are more soluble than creatine. It is further stated that the protection of the carboxylic acid moiety of the creatine molecule by ester-formation stabilizes the compound by preventing its conversion to creatinine.
The creatine esters are said to be converted into creatine by esterases i.e.
enzymes that cleave ester bonds, found in a variety of cells and biological fluids.
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 essential fatty acids being 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, 8303917.1 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 salts and the formation of esters. The majority of the above referenced patents are creatine salts. These salts, esterification via carboxylate reactivity, may essentially be formed, as disclosed in U.S. Pat. No.
7,109,373, through a relatively simple reaction by mixing a molar excess of creatine or derivative thereof with an aqueous dicarboxylic acid and heating from room temperature to about 50 C.
Alternatively, a creatine-fatty acid may be synthesized through ester formation. 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.
8303917.1 While the above referenced creatine compounds have attempted to address issues such as stability and solubility in addition to, and in some cases, to add increased functionality as compared to creatine alone, no description has yet been made of any creatine-fatty acid compound, particularly that comprising a saturated fatty acid.
Summary of the Invention In the present invention, compounds are disclosed, where the compounds comprise a molecule of creatine bound to a fatty acid, via an anhydride linkage, and having a structure of Formula 1:
Formula 1 O O
II II
H2C' C" O'.~ C~R
I
HN~C'-N~CH3 I
where:
R is an alkyl group, preferably saturated, and containing from about 3 to a maximum of 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.
8303917.1 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 creatine-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 creatine 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 not less then four carbon atoms. Furthermore, essential fatty acids are herein understood to be included by the term 'fatty acid'.
As used herein, "creatine" refers to the chemical N-methyl-N-guanyl Glycine, (CAS Registry No. 57-00-1), also known as, (alpha-methyl guanido) acetic acid, N-(aminoiminomethyl)-N-glycine, Methylglycocyamine, Methylguanidoacetic Acid, or N-Methyl-N-guanylglycine. Additionally, as used herein, "creatine" also includes derivatives of creatine such as esters, and 8303917.1 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 a creatine molecule bound to a fatty acid, wherein the fatty acid is preferably a saturated fatty acid. Furthermore, the creatine and fatty acid being bound by an anhydride 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 0 0 Step 1 0 _ C
C + S 35 C 5- 0C
R~ ~OH X~ " X 0.5 - 2 h R~ ~X
II II
MOICI~ CHz Step 2 HOCl~ CH
Step 3 1)Na0 HH 20 I Z
where: H3CC%NH 2)evap. H20 H3C'N",c:~,,NH
R = alkane or alkene (C = 3 to 21) NH2 NH2 X=C1,Br,F,orI 6 5 M= Na, K, Li, or NH4 0 0 II II
H2C' C, O"C" R
I
HN~C'-Nll CH3 I
With reference to Scheme 1, in Step 1 an acyl halide (4) is produced via reaction of a fatty acid (2) with a thionyl halide (3).
In various embodiments of the present invention, the fatty acid of (2) is selected from the saturated fatty acid group comprising butyric or butanoic acid, caproic or hexanoic acid, caprylic or octanoic acid, capric or decanoic acid, lauric 8303917.1 or dodecanoic acid, myristic or tetradecanoic acid, palmitic or hexadecanoic acid, stearic or octadecanoic acid, arachidic or eicosanoic acid, and behenic or docosanoic acid.
In alternative embodiments, of the present invention, the fatty acid of (2) is selected from the unsaturated fatty acid group comprising oleic acid, linoleic acid, linolenic acid, arachidonic acid, palmitoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and erucic acid.
Furthermore, the thionyl halide of (3) is selected from the group consisting of fluorine, chlorine, bromine, and iodine, the preferred method using chlorine or bromine.
The above reaction proceeds under conditions of heat ranging between from about 35 C to about 50 C and stirring over a period from about 0.5 hours to about 2 hours during which time the gases sulfur dioxide and acidic gas, wherein the acidic gas species is dependent on the species of thionyl halide employed, are evolved. Preferably, the reaction proceeds at 45 C for 1.5 hours.
Step 2 of Scheme 1 entails the neutralization of the carboxylic acid of the creatine 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, 8303917.1 potassium hydroxide, when used as the inorganic base, results in the production of the potassium creatine salt.
Step 3 of Scheme 1 involves the drop wise addition of the prepared acyl halide (4) to the creatine 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 a creatine fatty acid compound of the present invention.
In various embodiments, according to aforementioned, using the saturated fatty acids, the following compounds are produced produced: butyric 2-(1-methylguanidino)acetic anhydride, hexanoic 2-(1-methylguanidino)acetic anhydride, 2-(1-methylguanidino)acetic octanoic anhydride, decanoic 2-(1-methylguanidino)acetic anhydride, 2-(1-methylguanidino)acetic tetradecanoic anhydride, 2-(1-methylguanidino)acetic palmitic anhydride, icosanoic 2-(1-methylguanidino)acetic anhydride, and docosanoic 2-(1-methylguanidino)acetic anhydride.
In additional embodiments, according to aforementioned, using the unsaturated fatty acids, the following compounds are produced produced: (Z)-hexadec-9-enoic 2-(1-methylguanidino)acetic anhydride, 2-(1-methylguanidino)acetic oleic anhydride, (Z)-docos-13-enoic 2(1-methylguanidino)acetic anhydride, 2-(1-methylguanidino)acetic (9Z, 1 2Z)-octadeca-9,12-dienoic anhydride, 2-(1-methylguanidino)acetic (9Z,12Z,15Z)-octadeca-9,12,15-trienoic anhydride, 2-(1-methylguanidino)acetic (6Z,9Z,12Z)-octadeca-6,9,12-trienoic anhydride, (5Z,8Z,11 Z,14Z)-icosa-5,8,11,14-tetraenoic 8303917.1 2(1-methylguanidino)acetic anhydride, (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoic 2(1-methylguanidino)acetic anhydride, 2(1-methylguanidino)acetic (8Z,11Z,14Z,17Z,20Z)-tricosa-5,8,11,14,17,20-hexaenoic anhydride.
The following examples illustrate specific creatine-fatty acids 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
Butyric 2-(1-methylguanidino)acetic anhydride H2C' C" 0 "1 C1-1 C"C'CH
HN C~N'CH3 I
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 8.75ml (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, 6.56g (50mmol) of creatine is dissolved in 500m1 of water.
To 8303917.1 this is added 55ml of 1 M sodium hydroxide with vigorous stirring, until heat production ceases. At this point the water is removed by evaporation to yield the carboxylate salt, sodium 2-(1-methylguanidino)acetate, shown below.
NaO' C1-1 CH2 ' N~ C ~NH
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 12.08g (66mmol) of sodium 2-(1-methylguanidino)acetate. 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 butyric 2-(1-methylguanidino)acetic anhydride.
Example 2 Hexanoic 2-(1-methylguanidino)acetic anhydride H2C'C C~C~CH3 HNCCH
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 6.97ml (90mmol) of thionyl 8303917.1 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 creatine is dissolved in 500m1 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-(1-methylguanidino)acetate, shown below.
O
I I
NaO' C"I CH2 H C' N~C~NH
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 13.18g (72mmol) of sodium 2-(1-methylguanidino)acetate. 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 8303917.1 receiving flask. This crude distillate is then further fractionally distilled to yield hexanoic 2-(1-methylguanidino)acetic anhydride.
Example 3 Dodecanoic 2-(1-methylguanidino)acetic anhydride H C' C~0~C CH3 HN~C'_Nl~ CH3 I
In a dry 2-necked, round bottomed flask, equipped with a magnetic stirrer and fixed with a separatory funnel, containing 5.85m1 (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, 7.87g (60mmol) of creatine is dissolved in 600ml 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-(1-methylguanidino)acetate, shown below.
8303917.1 O
ii H4NO' C" CH2 H C' N~C~NH
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 15.31g (70mmol) of the prepared dodecanoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 12.44g (84mmol) of ammonium 2-(1-methylguanidino)acetate. 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 dodecanoic 2-(1-methylguanidino)acetic anhydride.
Example 4 2-(1-methylguanidino)acetic stearic anhydride H2C' C " O~C(C,C CH
I H2 g 3 HN C'-N~CH
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 8303917.1 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 creatine is dissolved in 600ml 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-(1-methylguanidino)acetate, shown below.
I I
' N~ C ~NH
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 23.40g (77mmol) of potassium 2-(1-methylguanidino)acetate. 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-(1-methylguanidino)acetic stearic anhydride.
Example 5 2-(1-methylguanidino)acetic (9Z,12Z)-octadeca-9,12-dienoic anhydride 8303917.1 H2C' C" O~C~C"C~C"C=C" C"C=C" C"- C-" C~C-" CH3 HN~C~N,, CH3 I
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 24.90ml (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, 7.87g (60mmol) of creatine is dissolved in 600m1 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-(1-methylguanidino)acetate, shown below.
O
H4NO' C~CH2 H C' N~C ~NH
Finally, in a dry 2-necked, round bottomed flask, fixed with a separatory funnel, containing 17.93g (60mmol) of the prepared (9Z,12Z)-octadeca-9,12-8303917.1 dienoyl chloride, and side arm water condenser fixed with a dry receiving flask, is placed 10.66g (72mmol) of ammonium 2-(1-methylguanidino)acetate. 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-(1-methylguanidino)acetic(9Z,12Z)-octadeca-9,12-dienoic anhydride.
Thus while not wishing to be bound by theory, it is understood that reacting a creatine or derivative thereof with a fatty acid or derivative thereof to form an anhydride can be used enhance the bioavailability of the creatine or derivative thereof by improving stability of the creatine moiety in terms of resistance to hydrolysis in the stomach and blood 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 creatine 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.
8303917.1
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method for producing creatine 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 a creatine with an inorganic base to form a creatine salt;
reacting said acyl halide with the creatine salt; and isolating the resulting creatine fatty acid.
mixing an excess of a thionyl halide with a fatty acid to form an acyl halide;
neutralizing the carboxylic acid of a creatine with an inorganic base to form a creatine salt;
reacting said acyl halide with the creatine salt; and isolating the resulting creatine fatty acid.
2. The method of claim 1 wherein the halide of the thionyl halide is fluorine, chlorine, bromine, or iodine.
3. The method of claim 1 or 2 wherein the fatty acid comprises from 4 to 22 carbons.
4. The method of according to any one of claims 1 to 3 wherein the acyl halide is produced at temperatures from between about 35°C to about 50°C.
5. The method of according to any one of claims 1 to 4 wherein the inorganic base is sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, or sodium carbonate.
6. The method of according to any one of claims 1 to 5 wherein the creatine fatty acid is isolated by distillation.
7. The method of according to any one of claims 1 to 6 wherein the creatine fatty acid has the general structure of:
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.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002577439A CA2577439C (en) | 2007-02-20 | 2007-02-20 | Creatine-fatty acids |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002577439A Division CA2577439C (en) | 2007-02-20 | 2007-02-20 | Creatine-fatty acids |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2616844A1 CA2616844A1 (en) | 2007-05-07 |
CA2616844C true CA2616844C (en) | 2009-10-27 |
Family
ID=38024518
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002616844A Expired - Fee Related CA2616844C (en) | 2007-02-20 | 2007-02-20 | Creatine-fatty acids |
CA002577439A Expired - Fee Related CA2577439C (en) | 2007-02-20 | 2007-02-20 | Creatine-fatty acids |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002577439A Expired - Fee Related CA2577439C (en) | 2007-02-20 | 2007-02-20 | Creatine-fatty acids |
Country Status (1)
Country | Link |
---|---|
CA (2) | CA2616844C (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7314945B1 (en) | 2007-02-20 | 2008-01-01 | Multi Formulations Ltd. | Creatine-fatty acids |
US7319157B1 (en) | 2007-02-20 | 2008-01-15 | Multi Formulations Ltd. | Creatine-fatty acids |
US7511162B2 (en) | 2007-02-20 | 2009-03-31 | Multi Formulations Ltd. | Preparation of amino acid-fatty acid anhydrides |
WO2008138090A1 (en) * | 2007-05-10 | 2008-11-20 | Multi Formulations Ltd. | Preparation of amino acid-fatty acid anhydrides |
WO2009076741A1 (en) * | 2007-12-18 | 2009-06-25 | Multi Formulations Ltd. | Creatinol-fatty acid esters |
-
2007
- 2007-02-20 CA CA002616844A patent/CA2616844C/en not_active Expired - Fee Related
- 2007-02-20 CA CA002577439A patent/CA2577439C/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CA2577439A1 (en) | 2007-05-07 |
CA2577439C (en) | 2008-04-08 |
CA2616844A1 (en) | 2007-05-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US7511163B2 (en) | Creatine-fatty acids | |
WO2008101310A1 (en) | Creatine-fatty acids | |
CA2616844C (en) | Creatine-fatty acids | |
US5973005A (en) | Aqueous creatine solution and process of producing a stable, bioavailable aqueous creatine solution | |
US20090253797A1 (en) | Creatine oral supplementation using creatine hydrochloride salt | |
JP3131655B2 (en) | Method for producing N-acetylneuraminic acid | |
US20080200704A1 (en) | Preparation of amino acid-fatty acid amides | |
WO2008101309A1 (en) | Creatine-fatty acids | |
US7314945B1 (en) | Creatine-fatty acids | |
US20080254198A1 (en) | Method of Preparing Creatine Ester Salts and Uses Thereof | |
CA2408528C (en) | Creatine salt having enhanced nutritional and therapeutic efficacy and compositions containing same | |
ES2288990T3 (en) | COMPONENTS AND PRONUTRIENT FORMULATIONS OF CREATININE ESTER. | |
CA2577437C (en) | Creatine-fatty acids | |
AU2001290939A1 (en) | Creatine ester pronutrient compounds and formulations | |
CA2622478A1 (en) | Creatine-fatty acids | |
AU733272B2 (en) | Solid compositions suitable for oral administration comprising non hygroscopic salts of L-carnitine and alkanoyl-L-carnitine with 2-aminoethanesulfonic acid | |
US7714154B2 (en) | Preparation of amino acid-fatty acid anhydrides | |
US7511162B2 (en) | Preparation of amino acid-fatty acid anhydrides | |
BRPI0115019B1 (en) | solid compositions suitable for oral administration containing non-hygroscopic salts of l-carnitine and l-carnitines and alkanoyl with taurine chloride and glycine chloride | |
CA2621925A1 (en) | Preparation of amino acid-fatty acid anhydrides | |
RU2720985C1 (en) | Method of producing gamma-butirobethaine and hydrochloride thereof | |
US20070093677A1 (en) | Creatine salts and method of making same | |
JPS61501776A (en) | Aminocarnitines | |
WO2008138090A1 (en) | Preparation of amino acid-fatty acid anhydrides | |
JPWO2007058278A1 (en) | Stable salt of 3'-phosphoadenosine-5'-phosphosulfate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
EEER | Examination request | ||
MKLA | Lapsed |
Effective date: 20220221 |
|
MKLA | Lapsed |
Effective date: 20220221 |