US20090012157A1 - Sesamol Derivatives as Novel Inhibitors of Arachidonic Acid Formation - Google Patents
Sesamol Derivatives as Novel Inhibitors of Arachidonic Acid Formation Download PDFInfo
- Publication number
- US20090012157A1 US20090012157A1 US12/278,226 US27822607A US2009012157A1 US 20090012157 A1 US20090012157 A1 US 20090012157A1 US 27822607 A US27822607 A US 27822607A US 2009012157 A1 US2009012157 A1 US 2009012157A1
- Authority
- US
- United States
- Prior art keywords
- acid
- sesamol
- derivative
- composition
- fatty acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical class N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 title claims abstract description 44
- 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 title claims abstract description 21
- 235000021342 arachidonic acid Nutrition 0.000 title claims abstract description 11
- 229940114079 arachidonic acid Drugs 0.000 title claims abstract description 10
- 230000015572 biosynthetic process Effects 0.000 title claims description 7
- 239000003112 inhibitor Substances 0.000 title abstract description 6
- LUSZGTFNYDARNI-UHFFFAOYSA-N Sesamol Natural products OC1=CC=C2OCOC2=C1 LUSZGTFNYDARNI-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000000203 mixture Substances 0.000 claims description 25
- 150000004665 fatty acids Chemical class 0.000 claims description 22
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 21
- 229930195729 fatty acid Natural products 0.000 claims description 21
- 239000000194 fatty acid Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 19
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 17
- 231100000252 nontoxic Toxicity 0.000 claims description 13
- 230000003000 nontoxic effect Effects 0.000 claims description 13
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 11
- 241000124008 Mammalia Species 0.000 claims description 9
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 8
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 4
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000005642 Oleic acid Substances 0.000 claims description 4
- 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 claims description 4
- 235000013361 beverage Nutrition 0.000 claims description 4
- 235000015872 dietary supplement Nutrition 0.000 claims description 4
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 claims description 4
- VKOBVWXKNCXXDE-UHFFFAOYSA-N icosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCC(O)=O VKOBVWXKNCXXDE-UHFFFAOYSA-N 0.000 claims description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 4
- 229940049964 oleate Drugs 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- SBHCLVQMTBWHCD-METXMMQOSA-N (2e,4e,6e,8e,10e)-icosa-2,4,6,8,10-pentaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C(O)=O SBHCLVQMTBWHCD-METXMMQOSA-N 0.000 claims description 2
- 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 claims description 2
- 235000021314 Palmitic acid Nutrition 0.000 claims description 2
- HXWJFEZDFPRLBG-UHFFFAOYSA-N Timnodonic acid Natural products CCCC=CC=CCC=CCC=CCC=CCCCC(O)=O HXWJFEZDFPRLBG-UHFFFAOYSA-N 0.000 claims description 2
- 235000020661 alpha-linolenic acid Nutrition 0.000 claims description 2
- MBMBGCFOFBJSGT-SFGLVEFQSA-N 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-SFGLVEFQSA-N 0.000 claims description 2
- MBMBGCFOFBJSGT-KUBAVDMBSA-N docosahexaenoic acid Natural products 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 claims description 2
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims description 2
- LQJBNNIYVWPHFW-QXMHVHEDSA-N gadoleic acid Chemical compound CCCCCCCCCC\C=C/CCCCCCCC(O)=O LQJBNNIYVWPHFW-QXMHVHEDSA-N 0.000 claims description 2
- 230000028709 inflammatory response Effects 0.000 claims description 2
- 229960004488 linolenic acid Drugs 0.000 claims description 2
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 2
- 235000021313 oleic acid Nutrition 0.000 claims description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 4
- 230000001988 toxicity Effects 0.000 abstract description 4
- 230000002209 hydrophobic effect Effects 0.000 abstract description 3
- 230000004968 inflammatory condition Effects 0.000 abstract description 2
- 102100034542 Acyl-CoA (8-3)-desaturase Human genes 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 206010061218 Inflammation Diseases 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 150000002066 eicosanoids Chemical class 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- 239000003440 toxic substance Substances 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 235000013305 food Nutrition 0.000 description 5
- 230000000770 proinflammatory effect Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 108010073542 Delta-5 Fatty Acid Desaturase Proteins 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 229940053200 antiepileptics fatty acid derivative Drugs 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- -1 sesamol compound Chemical class 0.000 description 3
- HOBAELRKJCKHQD-UHFFFAOYSA-N (8Z,11Z,14Z)-8,11,14-eicosatrienoic acid Natural products CCCCCC=CCC=CCC=CCCCCCCC(O)=O HOBAELRKJCKHQD-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 235000021298 Dihomo-γ-linolenic acid Nutrition 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 241000207961 Sesamum Species 0.000 description 2
- 235000003434 Sesamum indicum Nutrition 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 125000002843 carboxylic acid group Chemical group 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- HOBAELRKJCKHQD-QNEBEIHSSA-N dihomo-γ-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCCCC(O)=O HOBAELRKJCKHQD-QNEBEIHSSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000021323 fish oil Nutrition 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 229930013686 lignan Natural products 0.000 description 2
- 150000005692 lignans Chemical class 0.000 description 2
- 235000009408 lignans Nutrition 0.000 description 2
- 235000012054 meals Nutrition 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 231100000683 possible toxicity Toxicity 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 235000013410 fast food Nutrition 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229920013746 hydrophilic polyethylene oxide Polymers 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 150000002889 oleic acids Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
Images
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
-
- 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
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
-
- 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
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/745—Polymers of hydrocarbons
- A61K31/75—Polymers of hydrocarbons of ethene
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
- A61K31/77—Polymers containing oxygen of oxiranes
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- 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
Definitions
- the invention relates to compositions and methods for treating, moderating, and preventing inflammation. Specifically, the invention relates to compositions useful for inhibiting the formation of arachidonic acids, which are precursors of pro-inflammatory eicosanoids. The invention also relates to methods of preparing and administering such compositions.
- sesamol As a specific inhibitor of D5D.
- sesamol is believed to be potentially toxic.
- natural compounds such as sesame lignans and curcumin have been demonstrated to exhibit inhibitory activity on D5D, their complex structures make them difficult to synthesize.
- sesame lignans also have potential toxicity.
- compositions comprising a carboxylic derivative of sesamol that are useful as anti-inflammatory agents.
- the derivative is non-toxic, or has a low toxicity that can be tolerated by mammals including humans.
- the carboxylic derivative may comprise at least one fatty acid.
- the carboxylic derivative may comprise a carboxylic acid derivative of polyethylene oxide, i.e., a polyethylene oxide with at least one carboxylic acid terminal group. Both types of derivatives allow sesamol to be released slowly in its active form, thus reducing any potential toxicity of the composition. Such controlled release of sesamol also helps to modulate the activity of D5D in a more consistent fashion.
- compositions of the invention may be administered to human patients that require treatment for conditions associated with inflammation.
- inflammation-associated conditions include, but are not limited to, obesity, type 2 diabetes, cardiovascular disease, cancer, neurological disorders, as well as any inflammatory conditions that cause pain.
- the compositions of the invention also may be administered to non-human mammals for veterinary purposes.
- the invention provides methods for inhibiting the formation of arachidonic acid in a mammal by administering to the mammal a composition comprising a non-toxic chemical derivative of sesamol.
- the non-toxic chemical derivative may comprise a carboxylic derivative of sesamol.
- the sesamol may be derivatized with at least one fatty acid.
- the at least one fatty acid may have a carbon chain comprising 2 to 22 carbon atoms. Additionally, the at least one fatty acid may have a degree of unsaturation in the range of 0 to 6 per fatty acid molecule.
- the non-toxic chemical derivative is sesamol oleate.
- the non-toxic chemical derivative may comprise a carboxylic acid derivative of polyethylene oxide.
- the polyethylene oxide may comprise 2 to 400 repeating units.
- compositions comprising a non-toxic chemical derivative of sesamol.
- the non-toxic chemical derivative may include the embodiments described above.
- the composition may be administered via an enteral or parenteral route, and may comprise other biologically acceptable carriers, excipients, or diluents. Supplementary active ingredients also may be incorporated into the composition.
- the composition may be administered as a nutritional supplement, and may be prepared in various forms including, but not limited to, a capsule, a bar, a tablet, a powder, or a beverage package.
- FIG. 1 illustrates the metabolic pathways leading to the production of pro-inflammatory eicosanoids.
- FIG. 2 shows the chemical structures of two embodiments of the invention.
- the enzyme ⁇ -5-desaturase is required for converting dihomo gamma linolenic acid (DGLA) into arachidonic acid (AA).
- DGLA dihomo gamma linolenic acid
- AA arachidonic acid
- Sesamol is a chemical compound that has been shown to inhibit D5D activity. However, sesamol is believed to be potentially toxic. The applicant has discovered that the toxicity of sesamol can be significantly reduced by acylating the free hydroxyl group of sesamol with a suitable carboxylic acid moiety, including fatty acids and carboxylic derivatives of polyethylene oxide.
- FIG. 2 shows the chemical structures of two sesamol compounds derivatized with a generic fatty acid (compound Ia) and a carboxylic acid derivative of methoxy polyethylene oxide (compound Ib), respectively.
- the variables m and n may be an integer in the range of 1 to 11, and 2 to 400, respectively.
- Such derivatization also helps to enhance the stability and bioavailability of the sesamol compound by attaching it to a biologically inert hydrophilic (i.e., polyethylene oxide) or hydrophobic (i.e., fatty acid) moiety.
- a biologically inert hydrophilic i.e., polyethylene oxide
- hydrophobic i.e., fatty acid
- Fatty acid derivatives of sesamol may be prepared from various fatty acids. Natural fatty acids, either isolated from natural sources or made synthetically, are preferred. Both saturated fatty acids and fatty acids with various degrees of unsaturation may be used, depending on the physical properties that one desires to impart to the invention. For instance, the fatty acid may have a degree of unsaturation in the range of 0 to 6 per fatty acid molecule. The fatty acid may be of various lengths and may have 2 to 22 carbon atoms per molecule. Fatty acid derivatives are hydrophobic in nature, and thus can be incorporated into circulating lipoproteins or cell membranes as a long-lived drug depot for sesamol.
- Suitable fatty acids include, but are not limited to, palmitic acid, oleic acid, linoleic acid, alpha-linolenic acid, arachidic acid, gadoleic acid, 5,8,11,14,17-eicosapentaenoic acid, and 4,7,10,13,16,19-docosahexaenoic acid.
- Fatty acid derivatives of sesamol may be synthesized using standard organic chemistry via the activation of the carboxylic group with an acid chloride, an acid anhydride, or other activating agents such as 1,1 carbonyl diimidazole (CDI).
- a hydrophilic derivative of sesamol may be prepared by attaching a carboxylic acid derivative of polyethylene oxide to the sesamol molecule.
- a carboxylic acid derivative of polyethylene oxide refers to a polymer of ethylene oxide with 2 to 400 repeating units having at least one of the two hydroxyl terminal groups converted into a carboxylic acid group.
- the other hydroxyl terminal group may remain underivatized or may be modified. For instance, the other terminal group may be methoxylated or converted into a second carboxylic acid group.
- the process of attaching one or more chains of polyethylene oxide to a compound is often referred to as “pegylation.”
- the attachment of the hydrophilic polyethylene oxide moiety helps to increase the lifetime of the sesamol compound in the plasma compartment, which after the derivatization acts as a circulating depot.
- sesamol is being slowly released into the system, which helps to reduce its toxicity.
- the sesamol derivative may be delivered through traditional methods of administration such as via the enteral or various parenteral routes.
- a composition comprising the sesamol derivative may be formulated into a pill, a soft gelatin capsule, or other methods known to those skilled in the art with or without other carriers, excipients, or diluents.
- Supplementary active ingredients also may be incorporated into the composition.
- the composition comprising the sesamol derivative may be formulated into a soft gelatin capsule with an appropriate oil (e.g., fish oil).
- Parenteral administration may be through intravenous or subcutaneous injections.
- the composition may be prepared as an aqueous solution, whereas if a fatty acid is used to derivatize the sesamol compound, the composition may be prepared as an emulsion, a liposome, or a micellar formation.
- the sesamol derivative may be delivered neat or may be combined with other pharmaceuticals or natural products (e.g., fish oil) that also have anti-inflammatory benefits.
- the composition of the invention may be consumed as a food product, for example, as a nutritional supplement.
- the food product comprises between about 1 gram and about 60 grams of carbohydrate and between about 1 gram and about 40 grams of protein. More preferably, both protein and carbohydrate are present in the food product at a ratio of between about 0.5 and about 1.0 of protein to carbohydrate, inclusive. This ratio helps to lower secretion of insulin, thus reducing the activating impact that insulin has on D5D activity.
- Food products of the invention may be prepared in various forms including, but not limited to, a food bar, a confection product (e.g., an ice cream), a beverage (e.g., a ready-to-drink mix), a convenience food (e.g., a frozen meal), and a stabilized meal.
- a food bar e.g., a confection product (e.g., an ice cream), a beverage (e.g., a ready-to-drink mix), a convenience food (e.g., a frozen meal), and a stabilized meal.
- Fatty acid is activated using a 1:1 molar amount of 1,1 carbonyl diimidazole in a dry benzene solution. The solution is taken to dryness at the completion of the activation. To the dried compound is added an equimolar amount of sesamol. The combined reactants are heated under vacuum at a low temperature for 1-2 hours. The completeness of the reaction is determined by thin layer chromatography. The acylated sesamol is then isolated by column chromatography to yield the isolated invention. The physical state of the invention depends on the chain length of the fatty acid and its degree of unsaturation.
- Methoxy polyethylene oxide molecules of various chain lengths are oxidized by KMnO4 to yield a carboxylic acid derivative.
- the carboxylic acid derivative of methoxy polyethylene oxide is activated using a 1:1 molar amount of 1,1 carbonyl diimidazole in a dry benzene solution. The solution is taken to dryness at the completion of the activation.
- To the dried compound is added an equimolar amount of sesamol.
- the combined reactants are heated under vacuum at a low temperature for 1-2 hours. The completeness of the reaction is determined by thin layer chromatography.
- the acylated sesamol is then isolated by column chromatography to yield the isolated invention.
- the physical state of the invention depends on the chain length of the methoxy polyethylene oxide molecule.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Polymers & Plastics (AREA)
- Food Science & Technology (AREA)
- Nutrition Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Hematology (AREA)
- Mycology (AREA)
- Obesity (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Child & Adolescent Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a novel class of inhibitor of arachidonic acid useful for treating inflammatory conditions. Specifically, the invention relates to hydrophobic and hydrophilic derivatives of sesamol that confer lower toxicity and increased circulatory lifetimes than pure sesamol.
Description
- The invention relates to compositions and methods for treating, moderating, and preventing inflammation. Specifically, the invention relates to compositions useful for inhibiting the formation of arachidonic acids, which are precursors of pro-inflammatory eicosanoids. The invention also relates to methods of preparing and administering such compositions.
- It is becoming increasingly recognized that increased inflammation is strongly associated with, if not the underlying cause of, many disease conditions including obesity,
type 2 diabetes, cancer, heart disease, and neurological conditions such as multiple sclerosis and Alzheimer's disease. - It has been shown that the regulation of certain eicosanoids, a class of biologically active metabolites, can help control inflammation. While many anti-inflammatory drugs directly target the production of pro-inflammatory eicosanoids, e.g., by inhibiting the enzyme required in their production, an alternative and more sophisticated approach would be to reduce the amount of substrate upstream in the pathway, i.e., by regulating the formation of the precursors of pro-inflammatory eicosanoids, namely arachidonic acid (AA). Since AA is produced by the enzyme Δ-5-desaturase (D5D), the synthesis and/or identification of specific inhibitors of D5D can help to treat, moderate, and prevent inflammation. U.S. Pat. No. 6,172,106, the entire disclosure of which is incorporated by reference herein, has identified sesamol as a specific inhibitor of D5D. Unfortunately, sesamol is believed to be potentially toxic. Additionally, although natural compounds such as sesame lignans and curcumin have been demonstrated to exhibit inhibitory activity on D5D, their complex structures make them difficult to synthesize. Furthermore, sesame lignans also have potential toxicity. Hence, there is a need to develop non-toxic inhibitors of D5D that are easy to synthesize and can be produced on an industrial scale.
- It has been discovered that the toxicity of sesamol can be reduced or completely eliminated by preparing a carboxylic derivative of sesamol without compromising its inhibitory effect on Δ-5-desaturase (D5D).
- The invention thus provides compositions comprising a carboxylic derivative of sesamol that are useful as anti-inflammatory agents. Specifically, the derivative is non-toxic, or has a low toxicity that can be tolerated by mammals including humans.
- In some embodiments, the carboxylic derivative may comprise at least one fatty acid. In other embodiments, the carboxylic derivative may comprise a carboxylic acid derivative of polyethylene oxide, i.e., a polyethylene oxide with at least one carboxylic acid terminal group. Both types of derivatives allow sesamol to be released slowly in its active form, thus reducing any potential toxicity of the composition. Such controlled release of sesamol also helps to modulate the activity of D5D in a more consistent fashion.
- The compositions of the invention may be administered to human patients that require treatment for conditions associated with inflammation. Exemplary inflammation-associated conditions include, but are not limited to, obesity,
type 2 diabetes, cardiovascular disease, cancer, neurological disorders, as well as any inflammatory conditions that cause pain. The compositions of the invention also may be administered to non-human mammals for veterinary purposes. - In another aspect, the invention provides methods for inhibiting the formation of arachidonic acid in a mammal by administering to the mammal a composition comprising a non-toxic chemical derivative of sesamol. The non-toxic chemical derivative may comprise a carboxylic derivative of sesamol. In some embodiments, the sesamol may be derivatized with at least one fatty acid. The at least one fatty acid may have a carbon chain comprising 2 to 22 carbon atoms. Additionally, the at least one fatty acid may have a degree of unsaturation in the range of 0 to 6 per fatty acid molecule. In one embodiment, the non-toxic chemical derivative is sesamol oleate. In other embodiments, the non-toxic chemical derivative may comprise a carboxylic acid derivative of polyethylene oxide. The polyethylene oxide may comprise 2 to 400 repeating units.
- Yet another aspect of the invention provides methods for moderating an inflammatory response in a mammal by administering to the mammal a composition comprising a non-toxic chemical derivative of sesamol. The non-toxic chemical derivative may include the embodiments described above. The composition may be administered via an enteral or parenteral route, and may comprise other biologically acceptable carriers, excipients, or diluents. Supplementary active ingredients also may be incorporated into the composition. The composition may be administered as a nutritional supplement, and may be prepared in various forms including, but not limited to, a capsule, a bar, a tablet, a powder, or a beverage package.
-
FIG. 1 illustrates the metabolic pathways leading to the production of pro-inflammatory eicosanoids. -
FIG. 2 shows the chemical structures of two embodiments of the invention. - As shown in
FIG. 1 , the enzyme Δ-5-desaturase (D5D) is required for converting dihomo gamma linolenic acid (DGLA) into arachidonic acid (AA). Thus, being able to control the activity of D5D via a suitable inhibitor can significantly reduce the production of AA, which in turn reduces the supply of the substrate required to generate pro-inflammatory eicosanoids. - Sesamol is a chemical compound that has been shown to inhibit D5D activity. However, sesamol is believed to be potentially toxic. The applicant has discovered that the toxicity of sesamol can be significantly reduced by acylating the free hydroxyl group of sesamol with a suitable carboxylic acid moiety, including fatty acids and carboxylic derivatives of polyethylene oxide.
FIG. 2 shows the chemical structures of two sesamol compounds derivatized with a generic fatty acid (compound Ia) and a carboxylic acid derivative of methoxy polyethylene oxide (compound Ib), respectively. The variables m and n may be an integer in the range of 1 to 11, and 2 to 400, respectively. Such derivatization also helps to enhance the stability and bioavailability of the sesamol compound by attaching it to a biologically inert hydrophilic (i.e., polyethylene oxide) or hydrophobic (i.e., fatty acid) moiety. - Fatty acid derivatives of sesamol may be prepared from various fatty acids. Natural fatty acids, either isolated from natural sources or made synthetically, are preferred. Both saturated fatty acids and fatty acids with various degrees of unsaturation may be used, depending on the physical properties that one desires to impart to the invention. For instance, the fatty acid may have a degree of unsaturation in the range of 0 to 6 per fatty acid molecule. The fatty acid may be of various lengths and may have 2 to 22 carbon atoms per molecule. Fatty acid derivatives are hydrophobic in nature, and thus can be incorporated into circulating lipoproteins or cell membranes as a long-lived drug depot for sesamol. Examples of suitable fatty acids include, but are not limited to, palmitic acid, oleic acid, linoleic acid, alpha-linolenic acid, arachidic acid, gadoleic acid, 5,8,11,14,17-eicosapentaenoic acid, and 4,7,10,13,16,19-docosahexaenoic acid. Fatty acid derivatives of sesamol may be synthesized using standard organic chemistry via the activation of the carboxylic group with an acid chloride, an acid anhydride, or other activating agents such as 1,1 carbonyl diimidazole (CDI).
- In alternative embodiments, a hydrophilic derivative of sesamol may be prepared by attaching a carboxylic acid derivative of polyethylene oxide to the sesamol molecule. As used herein, “a carboxylic acid derivative of polyethylene oxide” refers to a polymer of ethylene oxide with 2 to 400 repeating units having at least one of the two hydroxyl terminal groups converted into a carboxylic acid group. The other hydroxyl terminal group may remain underivatized or may be modified. For instance, the other terminal group may be methoxylated or converted into a second carboxylic acid group. The process of attaching one or more chains of polyethylene oxide to a compound is often referred to as “pegylation.” In this case, the attachment of the hydrophilic polyethylene oxide moiety helps to increase the lifetime of the sesamol compound in the plasma compartment, which after the derivatization acts as a circulating depot. As the pegylated sesamol circulates in the plasma, sesamol is being slowly released into the system, which helps to reduce its toxicity.
- The sesamol derivative may be delivered through traditional methods of administration such as via the enteral or various parenteral routes. For enteral administration, a composition comprising the sesamol derivative may be formulated into a pill, a soft gelatin capsule, or other methods known to those skilled in the art with or without other carriers, excipients, or diluents. Supplementary active ingredients also may be incorporated into the composition. In preferred embodiments, the composition comprising the sesamol derivative may be formulated into a soft gelatin capsule with an appropriate oil (e.g., fish oil). Parenteral administration may be through intravenous or subcutaneous injections. For a sesamol derivative comprising polyethylene oxide, the composition may be prepared as an aqueous solution, whereas if a fatty acid is used to derivatize the sesamol compound, the composition may be prepared as an emulsion, a liposome, or a micellar formation. The sesamol derivative may be delivered neat or may be combined with other pharmaceuticals or natural products (e.g., fish oil) that also have anti-inflammatory benefits.
- In other embodiments, the composition of the invention may be consumed as a food product, for example, as a nutritional supplement. Preferably, the food product comprises between about 1 gram and about 60 grams of carbohydrate and between about 1 gram and about 40 grams of protein. More preferably, both protein and carbohydrate are present in the food product at a ratio of between about 0.5 and about 1.0 of protein to carbohydrate, inclusive. This ratio helps to lower secretion of insulin, thus reducing the activating impact that insulin has on D5D activity. Food products of the invention may be prepared in various forms including, but not limited to, a food bar, a confection product (e.g., an ice cream), a beverage (e.g., a ready-to-drink mix), a convenience food (e.g., a frozen meal), and a stabilized meal.
- The following examples are provided to illustrate further and to facilitate the understanding of the invention and are not intended to limit the invention.
- Fatty acid is activated using a 1:1 molar amount of 1,1 carbonyl diimidazole in a dry benzene solution. The solution is taken to dryness at the completion of the activation. To the dried compound is added an equimolar amount of sesamol. The combined reactants are heated under vacuum at a low temperature for 1-2 hours. The completeness of the reaction is determined by thin layer chromatography. The acylated sesamol is then isolated by column chromatography to yield the isolated invention. The physical state of the invention depends on the chain length of the fatty acid and its degree of unsaturation.
- 17.7 mmoles of oleic acid was dissolved in 40 ml of dry benzene. To the mixture was added 17.7 mmoles of 1,1 carbonyldiimidazole. The reaction to activate the oleic acid was continued at room temperature until vigorous evolution of carbon monoxide has ceased. The reaction was then driven to completion by driving off the excess benzene under vacuum at 60° C. To the neat activated oleic acid was added 21 mmoles of sesamol. The mixture was heated at 60° C. for 2 hours under vacuum with constant rotation. The crude reaction mixture was purified using 50 grams of silica gel 60 in 2×44 cm column eluting with hexane and increasing percentages of acetone. The fractions containing the active compound were collected and evaporated to dryness giving 10 mmoles of the sesamol oleate for a 56% yield. HPLC chromatography using a 98:2 cyclohexanone/isopropyl eluting solvent give a single component with greater than 90% purity.
- Methoxy polyethylene oxide molecules of various chain lengths are oxidized by KMnO4 to yield a carboxylic acid derivative. The carboxylic acid derivative of methoxy polyethylene oxide is activated using a 1:1 molar amount of 1,1 carbonyl diimidazole in a dry benzene solution. The solution is taken to dryness at the completion of the activation. To the dried compound is added an equimolar amount of sesamol. The combined reactants are heated under vacuum at a low temperature for 1-2 hours. The completeness of the reaction is determined by thin layer chromatography. The acylated sesamol is then isolated by column chromatography to yield the isolated invention. The physical state of the invention depends on the chain length of the methoxy polyethylene oxide molecule.
- Variations, modifications, and other implementations of what is described herein will be occur to those of ordinary skill in the art without departing from the spirit and the essential characteristics of the invention. Accordingly, the scope of the invention is to be defined not by the preceding illustrative description but instead by the following claims, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.
Claims (12)
1. A method for inhibiting the formation of arachidonic acid in a mammal comprising administering to a mammal a composition comprising a non-toxic derivative of sesamol.
2. The method of claim 1 wherein the non-toxic derivative comprises at least one fatty acid.
3. The method of claim 2 wherein the at least one fatty acid comprises 2 to 22 carbon atoms.
4. The method of claim 2 wherein the degree of unsaturation of the at least one fatty acid ranges from 0 to 6.
5. The method of claim 2 wherein the at least one fatty acid is selected from the group consisting of palmitic acid, oleic acid, linoleic acid, alpha-linolenic acid, arachidic acid, gadoleic acid, 5,8,11,14,17-eicosapentaenoic acid, and 4,7,10,13,16,19-docosahexaenoic acid.
6. The method of claim 2 wherein the non-toxic derivative comprises sesamol oleate.
7. The method of claim 1 wherein the non-toxic derivative comprises a carboxylic acid derivative of polyethylene oxide.
8. The method of claim 7 wherein the carboxylic acid derivative of polyethylene oxide comprises 2 to 400 repeating units.
9. The method of claim 1 wherein the composition is prepared as a nutritional supplement in a form selected from the group consisting of a capsule, a bar, a tablet, a powder, and a beverage package.
10. A method for moderating an inflammatory response in a mammal comprising administering to a mammal a composition comprising a non-toxic derivative of sesamol.
11. The method of claim 10 wherein the administering step is carried out enternally or parenternally.
12. The method of claim 10 wherein the composition is prepared as a nutritional supplement in a form selected from the group consisting of a capsule, a bar, a tablet, a powder, and a beverage package.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/278,226 US20090012157A1 (en) | 2006-02-06 | 2007-02-06 | Sesamol Derivatives as Novel Inhibitors of Arachidonic Acid Formation |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US76555906P | 2006-02-06 | 2006-02-06 | |
US12/278,226 US20090012157A1 (en) | 2006-02-06 | 2007-02-06 | Sesamol Derivatives as Novel Inhibitors of Arachidonic Acid Formation |
PCT/US2007/003032 WO2007092379A2 (en) | 2006-02-06 | 2007-02-06 | Sesamol derivatives as novel inhibitors of arachidonic acid formation |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2007/003032 A-371-Of-International WO2007092379A2 (en) | 2006-02-06 | 2007-02-06 | Sesamol derivatives as novel inhibitors of arachidonic acid formation |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/619,904 Continuation US20100068292A1 (en) | 2006-02-06 | 2009-11-17 | Novel Inhibitors of Arachidonic Acid Formation |
Publications (1)
Publication Number | Publication Date |
---|---|
US20090012157A1 true US20090012157A1 (en) | 2009-01-08 |
Family
ID=38197986
Family Applications (5)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/278,226 Abandoned US20090012157A1 (en) | 2006-02-06 | 2007-02-06 | Sesamol Derivatives as Novel Inhibitors of Arachidonic Acid Formation |
US12/619,904 Abandoned US20100068292A1 (en) | 2006-02-06 | 2009-11-17 | Novel Inhibitors of Arachidonic Acid Formation |
US13/315,359 Abandoned US20120251624A1 (en) | 2006-02-06 | 2011-12-09 | Novel inhibitors of arachidonic acid formation |
US13/893,803 Expired - Fee Related US8987325B2 (en) | 2006-02-06 | 2013-05-14 | Inhibitors of arachidonic acid formation |
US14/620,664 Abandoned US20150190368A1 (en) | 2006-02-06 | 2015-02-12 | Novel Inhibitors of Arachidonic Acid Formation |
Family Applications After (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/619,904 Abandoned US20100068292A1 (en) | 2006-02-06 | 2009-11-17 | Novel Inhibitors of Arachidonic Acid Formation |
US13/315,359 Abandoned US20120251624A1 (en) | 2006-02-06 | 2011-12-09 | Novel inhibitors of arachidonic acid formation |
US13/893,803 Expired - Fee Related US8987325B2 (en) | 2006-02-06 | 2013-05-14 | Inhibitors of arachidonic acid formation |
US14/620,664 Abandoned US20150190368A1 (en) | 2006-02-06 | 2015-02-12 | Novel Inhibitors of Arachidonic Acid Formation |
Country Status (2)
Country | Link |
---|---|
US (5) | US20090012157A1 (en) |
WO (1) | WO2007092379A2 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090099873A1 (en) * | 2007-10-10 | 2009-04-16 | Karl Vincent Kurple | Method and Apparatus for Monitoring Calorie, Nutritent, and Expense of Food Consumption and Effect on Long Term and Short Term State |
US10639313B2 (en) | 2017-09-01 | 2020-05-05 | Ndsu Research Foundation | Compound for inhibition of delta-5-desaturase (D5D) and treatment of cancer and inflammation |
US10668038B2 (en) | 2009-10-16 | 2020-06-02 | Mochida Pharmaceutical Co., Ltd. | Emulsion and emulsion preconcentrate compositions comprising omega-3 fatty acids and uses thereof are disclosed |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101921186B (en) * | 2010-08-12 | 2013-01-09 | 天津科技大学 | Method for extracting linoleic acid from safflower seed oil by silvered silica-gel column chromatography |
WO2015138224A1 (en) * | 2014-03-13 | 2015-09-17 | Sears Barry D | Compositions and methods for reducing chronic low-level inflammation |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5762935A (en) * | 1994-02-25 | 1998-06-09 | Beth Israel Deaconess Medical Center, Inc. | Anti-inflammatory and infection protective effects of sesamin-based lignans |
US6172106B1 (en) * | 1998-02-09 | 2001-01-09 | R. Armour Forse | Sesamol inhibition of Δ-5-desaturase activity and uses therefor |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0418430A1 (en) * | 1989-09-22 | 1991-03-27 | Duphar International Research B.V | Phenylalkyl amine derivatives having anti-ischaemic activity |
JPH06279432A (en) * | 1993-03-26 | 1994-10-04 | Tsumura & Co | New compound and anticancer agent containing the compound as active component |
US5977117A (en) * | 1996-01-05 | 1999-11-02 | Texas Biotechnology Corporation | Substituted phenyl compounds and derivatives thereof that modulate the activity of endothelin |
ES2239442T3 (en) * | 1998-05-11 | 2005-09-16 | Pharma Mar, S.A. | METABOLITES OF ECTEINASCIDINE 743. |
US20040208939A1 (en) * | 2003-04-18 | 2004-10-21 | Barry Sears | Novel dietary compositions to reduce inflammation |
DE10334663A1 (en) * | 2003-07-30 | 2005-03-10 | Merck Patent Gmbh | urea derivatives |
-
2007
- 2007-02-06 US US12/278,226 patent/US20090012157A1/en not_active Abandoned
- 2007-02-06 WO PCT/US2007/003032 patent/WO2007092379A2/en active Application Filing
-
2009
- 2009-11-17 US US12/619,904 patent/US20100068292A1/en not_active Abandoned
-
2011
- 2011-12-09 US US13/315,359 patent/US20120251624A1/en not_active Abandoned
-
2013
- 2013-05-14 US US13/893,803 patent/US8987325B2/en not_active Expired - Fee Related
-
2015
- 2015-02-12 US US14/620,664 patent/US20150190368A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5762935A (en) * | 1994-02-25 | 1998-06-09 | Beth Israel Deaconess Medical Center, Inc. | Anti-inflammatory and infection protective effects of sesamin-based lignans |
US6172106B1 (en) * | 1998-02-09 | 2001-01-09 | R. Armour Forse | Sesamol inhibition of Δ-5-desaturase activity and uses therefor |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090099873A1 (en) * | 2007-10-10 | 2009-04-16 | Karl Vincent Kurple | Method and Apparatus for Monitoring Calorie, Nutritent, and Expense of Food Consumption and Effect on Long Term and Short Term State |
US10668038B2 (en) | 2009-10-16 | 2020-06-02 | Mochida Pharmaceutical Co., Ltd. | Emulsion and emulsion preconcentrate compositions comprising omega-3 fatty acids and uses thereof are disclosed |
US10639313B2 (en) | 2017-09-01 | 2020-05-05 | Ndsu Research Foundation | Compound for inhibition of delta-5-desaturase (D5D) and treatment of cancer and inflammation |
Also Published As
Publication number | Publication date |
---|---|
WO2007092379A2 (en) | 2007-08-16 |
US20120251624A1 (en) | 2012-10-04 |
US20100068292A1 (en) | 2010-03-18 |
WO2007092379A3 (en) | 2007-11-01 |
US8987325B2 (en) | 2015-03-24 |
US20140056988A1 (en) | 2014-02-27 |
US20150190368A1 (en) | 2015-07-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20150190368A1 (en) | Novel Inhibitors of Arachidonic Acid Formation | |
KR20200011972A (en) | Multibiotics and how to use them | |
EP0609001A2 (en) | Triglycerides | |
JP2002521330A (en) | Nutritional and therapeutic use of 3-hydroxyalkanoic acid oligomers | |
JPH07509247A (en) | Rapamycin derivative | |
EP2181706A2 (en) | Florfenicol esters for treating bacterial infections | |
US5420335A (en) | Parenteral nutrients based on watersoluble glycerol bisacetoacetates | |
WO1994010125A1 (en) | Glycerin derivatives and uses thereof | |
WO2019213333A1 (en) | Combination therapies with edaravone and prodrugs of edaravone that are orally bioavailable and have altered pharmacokinetic properties | |
WO2019213335A1 (en) | Orally bioavailable prodrugs of edaravone with altered pharmacokinetic properties and methods of use thereof | |
JP2009084266A (en) | Carcinostatic agent utilizing acyl derivative of epigallocatechin gallate | |
US5519161A (en) | Nutritive glycerol esters of β-acyloxy butyrates | |
US5023239A (en) | Sialosyl cholesterol, process for producing the same, and neuropathy remedy comprising the same | |
JPH08283163A (en) | Enantiomer reinforced nutrition energy substrate | |
WO1991007421A1 (en) | Novel soluble and non-toxic derivatives of basic polyenic macrolides and their preparation and use | |
US3916008A (en) | Biologically active substances | |
US20170014432A1 (en) | Compositions and methods for reducing chronic low-level inflammation | |
JPS61176598A (en) | Acyl derivative of cytidine-diphosphate-choline, its production and its medical use | |
CN110124049B (en) | Pegylated fenretinide prodrug and application thereof | |
WO2004080455A1 (en) | Antibacterial agent and anticancer agent | |
JP2002535251A (en) | Novel compounds for cancer treatment | |
WO1994029327A1 (en) | Anticancer compounds | |
EP1230252A1 (en) | Beta-d-5-thioxylose derivatives, preparation method and therapeutic use | |
WO2013085346A1 (en) | Novel phytosphingosine derivatives, and composition comprising same for preventing and treating inflammatory skin diseases, autoimmune diseases, and hyperkeratosis diseases | |
US4758591A (en) | Dialkanoyloxybenzylidene dialkanoate |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |