CN1436166A - 肉碱和氨基酸的富马酸复盐以及含有该盐的食品添加剂、饮食添加剂和药物 - Google Patents
肉碱和氨基酸的富马酸复盐以及含有该盐的食品添加剂、饮食添加剂和药物 Download PDFInfo
- Publication number
- CN1436166A CN1436166A CN01811109A CN01811109A CN1436166A CN 1436166 A CN1436166 A CN 1436166A CN 01811109 A CN01811109 A CN 01811109A CN 01811109 A CN01811109 A CN 01811109A CN 1436166 A CN1436166 A CN 1436166A
- Authority
- CN
- China
- Prior art keywords
- carnitine
- fumarate
- creatine
- fumaric acid
- composition
- 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.)
- Granted
Links
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical compound C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 title claims abstract description 38
- 150000001413 amino acids Chemical class 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 title claims abstract description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims description 105
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims description 73
- 229940079593 drug Drugs 0.000 title abstract description 3
- 235000015872 dietary supplement Nutrition 0.000 title abstract 4
- 239000001530 fumaric acid Substances 0.000 title description 32
- 150000003839 salts Chemical class 0.000 title description 29
- 229960004203 carnitine Drugs 0.000 title description 7
- 235000005550 amino acid supplement Nutrition 0.000 title 1
- IGQBPDJNUXPEMT-SNVBAGLBSA-N isovaleryl-L-carnitine Chemical compound CC(C)CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C IGQBPDJNUXPEMT-SNVBAGLBSA-N 0.000 claims abstract description 5
- 239000004480 active ingredient Substances 0.000 claims abstract 2
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 claims description 58
- 229960003624 creatine Drugs 0.000 claims description 28
- 239000006046 creatine Substances 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 17
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 15
- 229930182817 methionine Natural products 0.000 claims description 14
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims description 13
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 12
- 229960003104 ornithine Drugs 0.000 claims description 12
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 9
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 7
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 239000003826 tablet Substances 0.000 claims description 6
- 239000002778 food additive Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 230000003078 antioxidant effect Effects 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000005515 coenzyme Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- -1 isovaleryl Chemical group 0.000 claims description 2
- 239000007937 lozenge Substances 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 239000002552 dosage form Substances 0.000 claims 1
- 235000013373 food additive Nutrition 0.000 claims 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 abstract 1
- 229940024606 amino acid Drugs 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 14
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 12
- DRBBFCLWYRJSJZ-UHFFFAOYSA-N N-phosphocreatine Chemical compound OC(=O)CN(C)C(=N)NP(O)(O)=O DRBBFCLWYRJSJZ-UHFFFAOYSA-N 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 5
- 235000016709 nutrition Nutrition 0.000 description 5
- 230000035764 nutrition Effects 0.000 description 5
- 229950007002 phosphocreatine Drugs 0.000 description 5
- 229940095064 tartrate Drugs 0.000 description 5
- 239000004475 Arginine Substances 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 210000002027 skeletal muscle Anatomy 0.000 description 4
- 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 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 3
- 101100001794 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) aps-2 gene Proteins 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 230000003570 biosynthesizing effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229960004826 creatine monohydrate Drugs 0.000 description 3
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical group CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 3
- QEVHRUUCFGRFIF-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C(C5=CC=C(OC)C=C5N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 QEVHRUUCFGRFIF-MDEJGZGSSA-N 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 239000002250 absorbent Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 235000013376 functional food Nutrition 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- CFPWPNDPUSLDPF-UHFFFAOYSA-N 2-[carbamimidoyl(methyl)amino]-2-phosphonoacetic acid Chemical group NC(=N)N(C)C(C(O)=O)P(O)(O)=O CFPWPNDPUSLDPF-UHFFFAOYSA-N 0.000 description 1
- 230000002407 ATP formation Effects 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 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
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 description 1
- UFAHZIUFPNSHSL-MRVPVSSYSA-N O-propanoyl-L-carnitine Chemical compound CCC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C UFAHZIUFPNSHSL-MRVPVSSYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- HNSUOMBUJRUZHJ-UEMBJLSASA-N [(2r)-3-carboxy-2-hydroxypropyl]-trimethylazanium;(e)-4-hydroxy-4-oxobut-2-enoate Chemical compound OC(=O)\C=C\C(O)=O.C[N+](C)(C)C[C@H](O)CC([O-])=O HNSUOMBUJRUZHJ-UEMBJLSASA-N 0.000 description 1
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- VNWKTOKETHGBQD-OUBTZVSYSA-N carbane Chemical compound [13CH4] VNWKTOKETHGBQD-OUBTZVSYSA-N 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 230000004098 cellular respiration Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000000663 muscle cell Anatomy 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 230000010016 myocardial function Effects 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 210000001087 myotubule Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000002220 organoid Anatomy 0.000 description 1
- 230000010627 oxidative phosphorylation Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- 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
- A23L27/00—Spices; Flavouring agents or condiments; Artificial sweetening agents; Table salts; Dietetic salt substitutes; Preparation or treatment thereof
- A23L27/30—Artificial sweetening agents
-
- 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
- A23L33/13—Nucleic acids or derivatives thereof
-
- 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
- A23L33/15—Vitamins
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
- C07H3/02—Monosaccharides
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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Abstract
研究揭示L－肉碱和异戊酰L－肉碱与氨基酸的富马酸复盐可用作食品添加剂、饮食添加剂和药物的活性成分。
Description
本发明涉及一个稳定的不吸潮的“肉碱”和氨基酸的富马酸复盐(在下文称做“富马酸复盐”)，其中的“肉碱”指L-肉碱或异戊酰L-肉碱。本发明也涉及含有该富马酸复盐的食品添加剂，饮食添加剂，营养制品和药物。
富马酸[(E)-2-丁烯二酸]在营养和医疗两个方面都显示出令人感兴趣的应用。
富马酸可以在饮料和发酵粉的制备中用作酒石酸(由于具有轻泻的作用，酒石酸会带来令人不快的肠胃副作用)的替代品，也可以用作果汁饮料中柠檬酸的替代品。
富马酸保护心脏的作用已经在灌注的大鼠心脏(La Plante等人，“灌注的大鼠心脏中富马酸盐的作用及代谢：一项13C同位素研究(Effects and Metabolism of fumarate in the perfused rat heart：A 13C mass isotopomer study)”，Am.J.Physiol.272：E74-E82，1997)及不成熟的心肌中(Pearl等人，“富含富马酸盐的血液性心脏麻痹导致了不成熟的心肌功能的完全恢复(Fumarate enrichedblood cardioplegia results in complete functional recovery ofimmature myocardium)”，Ann.Thorac.Surg.57：1636-41，1993)进行了估定。
此外，富马酸是一种“药理学上可接受的酸”：事实上其盐类是在“FDA批准的商业上上市的盐类”的列表中的，该列表发表在如药物科学杂志(Journal of Pharmaceutical Sciences，Vol.66，No.1，(1977)pages 1-19)上。
将药物转化为各自药理学可接受的盐形式是一种广为采用的手段，以优化药物的施用形式或某些性质，如稳定性、吸水性、流动性等。
L-肉碱和异戊酰L-肉碱的富马酸酸性盐均为已知化合物。(富马酸是一种二羧酸：在前述的富马酸酸性盐中只有其中的一个羧基基团参与了盐的生成。)
在美国第4,602,039号专利中已经揭示了L-肉碱富马酸酸性盐的制备及理化性质，该盐的开发是为了解决因L-肉碱内盐的吸潮性而带来的贮存及加工的复杂问题。事实上，L-肉碱的富马酸酸性盐非常稳定，不引起肠胃的副作用，并且显示了甚至超过L-肉碱的酒石酸盐的抗吸潮性，后者也是一种开发来克服L-肉碱吸水性的更不容易潮解的盐。
然而，酒石酸盐具有一有利条件，即它的两个羧基都与L-肉碱形成了盐，因而含有高百分比的L-肉碱(68％对58％)。
异戊酰L-肉碱的富马酸酸性盐也是一种对潮湿具有相当大抗性的稳定化合物，其制备如美国第5,227,518号专利所述。
到目前为止，使其中富马酸酸性盐的另一个羧基与L-肉碱或异戊酰L-肉碱形成了盐的富马酸酸性盐的自由羧基也形成盐的每一次努力都失败了。例如，制备L-肉碱的富马酸盐(即一种具有高百分比L-肉碱有利条件的中性盐，与酒石酸盐相比约73.5％对68％，与富马酸酸性盐相比约为73.5％对58％)的尝试结果得到了一种很可能由L-肉碱的富马酸酸性盐和L-肉碱内盐混和组成的高吸水性物质。就是后一种盐使得终产物整体具有了高的吸水性。
使富马酸酸性盐的自由羧基基团与烷酰基L-肉碱，如乙酰L-肉碱和丙酰L-肉碱形成盐的尝试也失败了。
本发明的一个目的是提供一种稳定而不潮解的富马酸复盐，其中富马酸的一个羧基基团与L-肉碱或异戊酰L-肉碱形成盐，而另一个羧基也与一种化合物形成盐，该化合物具有有用的营养、饮食及医疗性质。
因此，很明显本发明中盐的效用不仅在于其不潮解和高稳定性的方面，还在于其两个阳离子部分一起对盐营养的、能量的、和/或医疗的功效有贡献。因而，这些新盐类前述的功效就不只归功于盐中“肉碱”的部分。
通过L-肉碱或异戊酰L-肉碱和氨基酸形成的富马酸复盐实现了前述的目的，该复盐分子式为(I)：
其中：R是氢或异戊酰；[A+]是从肌酸、鸟氨酸、赖氨酸、精氨酸和组氨酸(hystidine)中选择出来的一种带正电的氨基酸。
应该认为本发明明确地包括具有分子式(I)的如下化合物：
-L-肉碱和肌酸的富马酸盐；
-异戊酰L-肉碱和肌酸的富马酸盐；
-L-肉碱和鸟氨酸的富马酸盐；
-异戊酰L-肉碱和鸟氨酸的富马酸盐；
-L-肉碱和赖氨酸的富马酸盐；
-异戊酰L-肉碱和赖氨酸的富马酸盐；
-L-肉碱和精氨酸的富马酸盐；
-异戊酰L-肉碱和精氨酸的富马酸盐；
-L-肉碱和组氨酸的富马酸盐；
-异戊酰L-肉碱和组氨酸的富马酸盐；
赖氨酸、精氨酸和组氨酸是在蛋白质中出现的氨基酸，即它们是可以通过有控制地水解天然蛋白质而得到的二十种氨基酸中的三种(例如，见J.Dayid Rawn，
《生物化学》(Biochemistry)，第3章“氨基酸及蛋白质的一级结构”(Amino acids and the primarystructure of proteins)；McGraw-Hill，1990)。
尽管要大体上阐明氨基酸的营养和医疗功效要参考到目前为止在这方面发表的极大量的文献(例如，见F.Fidanza和G.Liguori，Nutrizione umana，Chapter 3：“Le proteine”，Casa EditriceLibraria Idelson，1995；以及I.Goldberg(Ed.)，《功能性食物》(
Functional Foods)，第12章，“氨基酸、肽和蛋白质(Amino acids，peptides and proteins)”Chapman & Hall Inc.1994)，考虑到肌酸和鸟氨酸特殊的生理功能，相信简单地讨论一下两者是很有用的。
肌酸是在脊椎动物的骨骼肌组织中相当大量存在的一种氨基酸，其中约2/3以磷酸肌酸形式存在。
肌酸主要在肝脏和肾脏中自三种氨基酸生物合成：即甘氨酸提供碳骨架，精氨酸释放脒基，以及甲硫氨酸释放甲基。肌酸与尿以肌酸酐形式分泌。由于主要存在于肉类中，因而从食物中可以得到肌酸。然而，为了每天获取10克肌酸，应该食用2.5千克肉。外源的供应和内源的生物合成应该补偿每天由肌酸转化为肌酸酐的损失，这个量对于一个70千克的男性估计约为2克。
肌酸的生理功能非常重要：它通过可逆地吸收ATP的磷酸基团，主要在骨骼肌里，但也在脑、肝脏和肾脏里，充当高能磷酸基团的贮藏所。这一反应极其重要，这是因为在超过一个非常有限的阈值之后ATP就不能在组织中贮存。就是磷酸肌酸提供了磷酸基团，它在组织中的量为ATP的5倍。在一次中度疲倦的体育运动之后，骨骼肌中磷酸肌酸比ATP降低相应更多的量，这显示当ATP脱磷酸化时，磷酸肌酸使得ADP重新磷酸化。
当ATP代谢合成的速率超过ATP使用速率时，将导致磷酸肌酸的形成。因此，磷酸肌酸是即时可用能量的贮藏所，适合于在代谢磷酸化过程中使超过ATP合成速率的能量需求平衡。
由于肌酸仅当其摄入伴随持久的体育锻炼时才可以增加骨骼肌肉***，因此获得肌酸的主要为运动员和运动家。肌酸的摄入导致脂肪的减少，但它可以使骨骼肌加强。最近研究表明同时摄入肌酸和糖类能促进肌酸的效果，这是因为单糖刺激的胰岛素的产生在使肌酸转运至肌肉细胞中起作用。
鸟氨酸是一种非蛋白源氨基酸，是赖氨酸的一种低级同系物，它是尿素生物合成循环的一个重要中间物，其中它由精氨酸转胍基作用而生成。鸟氨酸也可以转化为谷氨酸。
具有分子式(I)的富马酸盐完全实现了本发明的目的，其原因在于它们不仅是稳定且不潮解的化合物，这使得它们很容易制成在营养制品、营养及饮食添加剂中优选的固体形式，还在于它们在单个盐分子中组合了“肉碱”和前述的氨基酸的互补的生理活性。
例如，那些在单个化合物中协同性组合了肌酸和“肉碱”的富马酸盐一方面刺激肌细胞中能量的产生，尤其是在I型肌纤维中，从而使得重要的能量载体(脂肪酸)进入线粒体；另一方面，它还可以刺激通过细胞呼吸(氧化磷酸化)形成的ATP离开同样的细胞器。该ATP为肌肉收缩提供了需要的机械能。
下列非限制性实施例阐明了本发明中一些化合物的制备及理化性质。
实施例1
L-肉碱和肌酸的富马酸盐(BS/231)
C15H27N4O9 分子量407.35
14.9g(0.1摩尔)肌酸一水合物与16.1g(0.1摩尔)L-肉碱内盐溶于500mL水中。
在所得的溶液里不断搅动加入11.6g(0.1摩尔)富马酸。待完全溶解后加入异丁醇，然后混合物于40℃在真空中蒸馏。所得残余物用丙酮吸收，将混合物搅拌数小时。
然后将混合物在真空中过滤，将所得的固体在一个恒温烤箱中30℃干燥过夜。得到了40.5g的L-肉碱和肌酸的富马酸盐，该盐为一种已证明是不潮解的和味道舒适的白色结晶固体。
产率96％。
m.p. ＝134℃(dec.)
K.F. ＝0.7％
[α]20 D ＝-10.7(c＝1％ H2O)
pH ＝5.5(c＝1％ H2O)
比例：
L-肉碱 40％
肌酸 32％
富马酸 28％
元素分析 C％ H％ N％
计算值 44.22 6.67 13.75
测量值 44.01 6.59 13.68
NMR：D2Oδ＝6.6(2H，s，
)；4.6-4.4(1H，m，
)；
3.9(2H，s，N-CH2-COOH)；3.4-3.3(2H，d，N-CH2-CH)；
3.2(9H，s，CH3)3-N)；2.9(3H，s，N-CH3)；2.5-2.4(2H，d，CH2-COOH)
HPLC：
柱： Hypersil APS-2(5μm)200×4.6
温度： ＝30℃
流动相： CH3CN/H2O+0.05M KH2PO4/CH3CN(65-35v/v)
pH： 4.7，用磷酸
流动速度：0.7mL/min
Rt＝ 富马酸12.5；肌酸7.4；L-肉碱10.8。
实施例2
异戊酰L-肉碱和肌酸的富马酸盐(BS/232) 
C20H35N4O10 分子量491
14.9g(0.1摩尔)肌酸一水合物与24.5g(0.1摩尔)异戊酰L-肉碱内盐溶于500mL水中。
在所得的溶液里不断搅动加入11.6g(0.1摩尔)富马酸。待完全溶解后加入异丁醇，然后混合物于40℃在真空中蒸馏。所得残余物用丙酮吸收，将混合物搅拌数小时。
然后将混合物在真空中过滤，将所得的固体在一个恒温烤箱中30℃干燥过夜。得到了47.2g的异戊酰L-肉碱和肌酸的富马酸盐，该盐为一种已证明是不潮解且可在95％乙醇中结晶的白色结晶固体。
产率： 97％
m.p. ＝125-127℃(dec.)
K.F. ＝0.5％
[α]20 D＝-8(c＝1％H2O)
pH ＝5.3(c＝1％H2O)
元素分析 C％ H％ N％
计算值 48.9 7.13 11.4
测量值 48.7 7.11 10.98
NMR：D2Oδ＝6.6(2H，s，
)；4.6-4.4(1H，m，
)；
3.9(2H，s，N-CH2-COOH)；3.4-3.3(2H，d，N-CH2-CH)；
3.2(9H，s，(CH3)3-N)；2.9(3H，s，N-CH3)；
2.5-2.4(2H，d，CH2-COOH)；2.4-2.2(2H，d，CH2-
)；
2.2-1.9(1H，m，
)；1-0.8(6H，d，
)
HPLC：
柱： Hypersil APS-2(5μm)200×4.6
温度： ＝30℃
流动相： CH3CN/H2O+0.05M KH2PO4/CH3CN(65-35v/v)
pH： 4.7，用磷酸
流动速度：0.7mL/min
λ： 205nm
Rt＝ 富马酸12.5；肌酸7.4；异戊酰L-肉碱6.3。
比例：
异戊酰L-肉碱 50％
肌酸 27％
富马酸 23％。
实施例3
L-肉碱和L-鸟氨酸的富马酸盐(BS/238)
分子量409
8g(0.05摩尔)L-肉碱内盐，5.8g(0.05摩尔)富马酸和6.6gL-鸟氨酸在60℃溶于7.5L水中，将所得的透明粘稠物质在剧烈的机械搅动中缓缓倒入丙酮溶液中(800mL)。将沉淀的固体过滤出来并干燥。得到了17g白色不潮解的标题中所述的化合物固体。
产率： 92％
m.p. ＝185-187℃(dec.)
K.F. ＝0.9％
[α]20 D ＝-7.5(c＝1％ H2O)
pH ＝4.7(c＝1％ H2O)
NMR：D2O＝6.6(2H，s，CH＝CH)；4.6-4.4(1H，m，-CH-)；
3.8-3.6(1H，t，-CH-NH2)；3.4-3.3(2H，d，N-CH2)；3.2(9H，s，(CH3)3)；
3-2.9(2H，t，CH2-NH2)；2.6-2.5(2H，d，-CH2-COOH)；
2-1.8(2H，m，CH2-CH2-NH2)；1.8-1.6(2H，q，CH2-CH2-CH).
HPLC：
柱： Hypersil APS-2(5nm)200×4.6
温度： ＝30℃
流动相： CH3CN/H2O+0.05M KH2PO4/CH3CN(65-35v/v)
pH： 4.7，用磷酸
流动速度：0.7mL/min
Rt＝ 富马酸12.5；L-肉碱10.8；L-鸟氨酸9。
比例：
富马酸 28.3％
L-肉碱 39.4％
L-鸟氨酸 32.3％
实施例4
赖氨酸和L-肉碱的富马酸盐/赖氨酸和异戊酰L-肉碱的富马酸盐
(BS/239，BS/240)
遵循实施例1和实施例2的程序，用0.1摩尔赖氨酸替代0.1摩尔肌酸一水合物，分别得到了白色不潮解的化合物L-肉碱和赖氨酸的富马酸盐及异戊酰L-肉碱和赖氨酸的富马酸盐。
在下表1中，通过与L-肉碱内盐和异戊酰L-肉碱内盐及无水肌酸对比，将本发明中的一些化合物在一个25％时相对湿度为60.5±5％的环境中暴露24小时，显示了它们重量的增加(％)及外观。
参考文献：Pharmaeuropa，1996年11月。
表1化合物 重量的增加(％) 外观L-肉碱内盐 19 潮解异戊酰L-肉碱内盐 20 潮解无水肌酸 3 易流动的实施例1的化合物(BS/231) 0.18 无变化实施例2的化合物(BS/232) 0.19 无变化实施例3的化合物(BS/238) 0.16 无变化
含有至少一种分子式为(I)的富马酸复盐的组合物的制备对药物技术或药剂学的任何专家而言都是显而易见的。
该组合物可进一步含有其他成分如抗氧化剂、辅酶及矿物质，并且可以以片剂、可咀嚼的片剂、药丸、药片、锭剂、胶囊、颗粒或粉末等形式存在。
在单位剂量中，这些组合物可含有一定量的分子式为(I)的富马酸盐，能提供50-2000mg，优选100-1000mg的L-肉碱内盐或异戊酰L-肉碱内盐。
Claims (8)
1.一种分子式为(I)的富马酸盐：
其中：R是氢或异戊酰；[A+]是从肌酸、鸟氨酸、赖氨酸、精氨
酸和组氨酸中选择出来的一种带正电的氨基酸。
2.权利要求1中的富马酸盐，选自：
-L-肉碱和肌酸的富马酸盐；
-异戊酰L-肉碱和肌酸的富马酸盐；
-L-肉碱和鸟氨酸的富马酸盐；
-异戊酰L-肉碱和鸟氨酸的富马酸盐；
-L-肉碱和赖氨酸的富马酸盐；
-异戊酰L-肉碱和赖氨酸的富马酸盐；
-L-肉碱和精氨酸的富马酸盐；
-异戊酰L-肉碱和精氨酸的富马酸盐；
-L-肉碱和组氨酸的富马酸盐；
-异戊酰L-肉碱和组氨酸的富马酸盐。
3.一种包含如权利要求1-2所述的化学通式为(I)的富马酸盐作为主要活性成分及一种药学上可接受的赋形剂的组合物。
4.权利要求3中的组合物，进一步含有从抗氧化剂、辅酶及矿物质中选择得来的一种或多种其他成分。
5.权利要求3或4中的组合物，以片剂、可咀嚼的片剂、药丸、药片、锭剂、胶囊、颗粒或粉末等形式存在。
6.权利要求3-5中以单位剂量形式存在的组合物，包含一种分子式为(I)的富马酸盐作为活性成分，包含50-2000mg，优选100-1000mg的L-肉碱内盐或异戊酰L-肉碱内盐。
7.权利要求3-6中的组合物，供人类用做食物添加剂、饮食添加剂或药物。
8.权利要求3-5中的组合物，供兽医用做饲料添加剂。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2000RM000322A IT1317042B1 (it) | 2000-06-14 | 2000-06-14 | Fumarati doppi di una carnitina e creatina, e integratori alimentari,dietetici e farmaci che li contengono. |
| ITRM2000A000322 | 2000-06-14 | ||
| PCT/IT2001/000199 WO2001096281A1 (en) | 2000-06-14 | 2001-04-24 | Double salts of fumaric acid with a carnitine and an amino acid and food supplements, dietary supplements and drugs containing same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1436166A true CN1436166A (zh) | 2003-08-13 |
| CN1326832C CN1326832C (zh) | 2007-07-18 |
Family
ID=11454785
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB018111092A Expired - Lifetime CN1326832C (zh) | 2000-06-14 | 2001-04-24 | 肉碱和氨基酸的富马酸复盐以及含有该盐的食品添加剂、饮食添加剂和药物 |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US6730693B2 (zh) |
| EP (1) | EP1289931B1 (zh) |
| JP (1) | JP4430301B2 (zh) |
| KR (1) | KR100596732B1 (zh) |
| CN (1) | CN1326832C (zh) |
| AT (1) | ATE286016T1 (zh) |
| AU (1) | AU783291B2 (zh) |
| BR (1) | BR0111579A (zh) |
| CA (1) | CA2412055C (zh) |
| CZ (1) | CZ302371B6 (zh) |
| DE (1) | DE60108122T2 (zh) |
| DK (1) | DK1289931T3 (zh) |
| ES (1) | ES2233635T3 (zh) |
| HK (1) | HK1056549A1 (zh) |
| HU (1) | HU228837B1 (zh) |
| IT (1) | IT1317042B1 (zh) |
| MX (1) | MXPA02012265A (zh) |
| PL (1) | PL203876B1 (zh) |
| PT (1) | PT1289931E (zh) |
| WO (1) | WO2001096281A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008080287A1 (en) * | 2006-12-29 | 2008-07-10 | Shenyang Koncepnutra Corporation, Limited | L-carnitine calcium fumarate, preparation method and application for the same |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT2801354T (pt) * | 2004-10-08 | 2017-06-05 | Forward Pharma As | Composições farmacêuticas de libertação controlada compreendendo um éster de ácido fumárico |
| EP1915334A2 (en) * | 2005-07-07 | 2008-04-30 | Aditech Pharma AB | Novel salts of fumaric acid monoalkylesters and their pharmaceutical use |
| UA112975C2 (uk) | 2009-01-09 | 2016-11-25 | Форвард Фарма А/С | Фармацевтичний склад, що містить в матриці, яка піддається ерозії, один або більше ефірів фумарової кислоти |
| US8669281B1 (en) | 2013-03-14 | 2014-03-11 | Alkermes Pharma Ireland Limited | Prodrugs of fumarates and their use in treating various diseases |
| SG10201707543PA (en) | 2013-03-14 | 2017-11-29 | Alkermes Pharma Ireland Ltd | Prodrugs of fumarates and their use in treating various deseases |
| CA2940845C (en) | 2014-02-24 | 2019-09-24 | Alkermes Pharma Ireland Limited | Sulfonamide and sulfinamide prodrugs of fumarates and their use in treating various diseases |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0150688B1 (en) * | 1983-12-28 | 1987-04-22 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Salts of l-carnitine and alkanoyl l-carnitines and process for preparing same |
| FR2635264B1 (fr) | 1988-08-12 | 1992-02-28 | Bellon Labor Sa Roger | Compositions pharmaceutiques et/ou dietetiques contenant de la l-carnitine et de la l-lysine |
| IT1245699B (it) * | 1991-05-29 | 1994-10-14 | Sigma Tau Ind Farmaceuti | Derivati della l-carnitina quali agenti terapeutici per il trattamento delle miopatie, della degenarazione neuronale e per inibire la proteolisi |
| US5994581A (en) * | 1998-03-09 | 1999-11-30 | Amt Labs, Inc. | Carnitine creatinate |
-
2000
- 2000-06-14 IT IT2000RM000322A patent/IT1317042B1/it active
-
2001
- 2001-04-24 US US10/297,843 patent/US6730693B2/en not_active Expired - Lifetime
- 2001-04-24 JP JP2002510425A patent/JP4430301B2/ja not_active Expired - Lifetime
- 2001-04-24 AU AU60603/01A patent/AU783291B2/en not_active Expired
- 2001-04-24 EP EP01934310A patent/EP1289931B1/en not_active Expired - Lifetime
- 2001-04-24 CN CNB018111092A patent/CN1326832C/zh not_active Expired - Lifetime
- 2001-04-24 AT AT01934310T patent/ATE286016T1/de active
- 2001-04-24 CA CA002412055A patent/CA2412055C/en not_active Expired - Lifetime
- 2001-04-24 WO PCT/IT2001/000199 patent/WO2001096281A1/en active IP Right Grant
- 2001-04-24 ES ES01934310T patent/ES2233635T3/es not_active Expired - Lifetime
- 2001-04-24 MX MXPA02012265A patent/MXPA02012265A/es active IP Right Grant
- 2001-04-24 KR KR1020027016899A patent/KR100596732B1/ko active IP Right Grant
- 2001-04-24 PL PL363511A patent/PL203876B1/pl unknown
- 2001-04-24 PT PT01934310T patent/PT1289931E/pt unknown
- 2001-04-24 HU HU0301568A patent/HU228837B1/hu unknown
- 2001-04-24 DK DK01934310T patent/DK1289931T3/da active
- 2001-04-24 DE DE60108122T patent/DE60108122T2/de not_active Expired - Lifetime
- 2001-04-24 BR BR0111579-0A patent/BR0111579A/pt not_active Application Discontinuation
- 2001-04-24 CZ CZ20023949A patent/CZ302371B6/cs not_active IP Right Cessation
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008080287A1 (en) * | 2006-12-29 | 2008-07-10 | Shenyang Koncepnutra Corporation, Limited | L-carnitine calcium fumarate, preparation method and application for the same |
| CN101209975B (zh) * | 2006-12-29 | 2010-12-01 | 沈阳科硕营养科技有限公司 | 左旋肉碱富马酸钙及其制备方法与用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2001096281A1 (en) | 2001-12-20 |
| ITRM20000322A1 (it) | 2001-12-14 |
| AU6060301A (en) | 2001-12-24 |
| KR20030017536A (ko) | 2003-03-03 |
| US20030171417A1 (en) | 2003-09-11 |
| HUP0301568A3 (en) | 2004-12-28 |
| DE60108122D1 (de) | 2005-02-03 |
| DE60108122T2 (de) | 2005-12-29 |
| EP1289931A1 (en) | 2003-03-12 |
| PL363511A1 (en) | 2004-11-29 |
| PT1289931E (pt) | 2005-03-31 |
| JP4430301B2 (ja) | 2010-03-10 |
| KR100596732B1 (ko) | 2006-07-04 |
| AU783291B2 (en) | 2005-10-13 |
| EP1289931B1 (en) | 2004-12-29 |
| CZ20023949A3 (cs) | 2003-04-16 |
| ITRM20000322A0 (it) | 2000-06-14 |
| CN1326832C (zh) | 2007-07-18 |
| CA2412055C (en) | 2009-02-03 |
| ATE286016T1 (de) | 2005-01-15 |
| JP2004503521A (ja) | 2004-02-05 |
| PL203876B1 (pl) | 2009-11-30 |
| ES2233635T3 (es) | 2005-06-16 |
| HK1056549A1 (en) | 2004-02-20 |
| CZ302371B6 (cs) | 2011-04-13 |
| US6730693B2 (en) | 2004-05-04 |
| IT1317042B1 (it) | 2003-05-26 |
| HU228837B1 (en) | 2013-06-28 |
| HUP0301568A2 (hu) | 2003-08-28 |
| MXPA02012265A (es) | 2004-02-27 |
| BR0111579A (pt) | 2003-03-18 |
| CA2412055A1 (en) | 2001-12-20 |
| DK1289931T3 (da) | 2005-04-25 |
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