JP2017061579A - 非アルファトコトリエノールの存在下でのアルファトコトリエノールの選択的酸化のための方法 - Google Patents
非アルファトコトリエノールの存在下でのアルファトコトリエノールの選択的酸化のための方法 Download PDFInfo
- Publication number
- JP2017061579A JP2017061579A JP2017005308A JP2017005308A JP2017061579A JP 2017061579 A JP2017061579 A JP 2017061579A JP 2017005308 A JP2017005308 A JP 2017005308A JP 2017005308 A JP2017005308 A JP 2017005308A JP 2017061579 A JP2017061579 A JP 2017061579A
- Authority
- JP
- Japan
- Prior art keywords
- tocotrienol
- alpha
- metal salt
- quinone
- 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
- RZFHLOLGZPDCHJ-DLQZEEBKSA-N alpha-Tocotrienol Natural products Oc1c(C)c(C)c2O[C@@](CC/C=C(/CC/C=C(\CC/C=C(\C)/C)/C)\C)(C)CCc2c1C RZFHLOLGZPDCHJ-DLQZEEBKSA-N 0.000 title abstract description 133
- 235000019145 α-tocotrienol Nutrition 0.000 title abstract description 97
- 229940064063 alpha tocotrienol Drugs 0.000 title abstract description 96
- 239000011730 α-tocotrienol Substances 0.000 title abstract description 96
- RZFHLOLGZPDCHJ-XZXLULOTSA-N α-Tocotrienol Chemical compound OC1=C(C)C(C)=C2O[C@@](CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1C RZFHLOLGZPDCHJ-XZXLULOTSA-N 0.000 title abstract description 91
- 238000000034 method Methods 0.000 title abstract description 70
- 238000007254 oxidation reaction Methods 0.000 title abstract description 43
- 230000003647 oxidation Effects 0.000 title abstract description 28
- 150000003773 α-tocotrienols Chemical class 0.000 title 1
- 229910052751 metal Inorganic materials 0.000 abstract description 86
- 239000002184 metal Substances 0.000 abstract description 86
- 150000003839 salts Chemical class 0.000 abstract description 72
- 239000007800 oxidant agent Substances 0.000 abstract description 70
- LNOVHERIIMJMDG-KTWAZNHYSA-N 2-[(6e,10e)-3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl]-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CCC(C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O LNOVHERIIMJMDG-KTWAZNHYSA-N 0.000 abstract description 37
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 abstract description 12
- 230000008569 process Effects 0.000 abstract description 11
- 238000007792 addition Methods 0.000 abstract description 10
- 230000001590 oxidative effect Effects 0.000 abstract description 8
- 239000000463 material Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 description 105
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 80
- 150000001875 compounds Chemical class 0.000 description 69
- OTXNTMVVOOBZCV-UHFFFAOYSA-N 2R-gamma-tocotrienol Natural products OC1=C(C)C(C)=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 OTXNTMVVOOBZCV-UHFFFAOYSA-N 0.000 description 55
- -1 alpha-tocopherol quinones Chemical class 0.000 description 40
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 40
- OTXNTMVVOOBZCV-YMCDKREISA-N gamma-Tocotrienol Natural products Oc1c(C)c(C)c2O[C@@](CC/C=C(\CC/C=C(\CC/C=C(\C)/C)/C)/C)(C)CCc2c1 OTXNTMVVOOBZCV-YMCDKREISA-N 0.000 description 37
- 239000011722 γ-tocotrienol Substances 0.000 description 37
- 235000019150 γ-tocotrienol Nutrition 0.000 description 37
- OTXNTMVVOOBZCV-WAZJVIJMSA-N γ-tocotrienol Chemical compound OC1=C(C)C(C)=C2O[C@@](CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1 OTXNTMVVOOBZCV-WAZJVIJMSA-N 0.000 description 37
- FGYKUFVNYVMTAM-UHFFFAOYSA-N (R)-2,5,8-trimethyl-2-(4,8,12-trimethyl-trideca-3t,7t,11-trienyl)-chroman-6-ol Natural products OC1=CC(C)=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1C FGYKUFVNYVMTAM-UHFFFAOYSA-N 0.000 description 36
- FGYKUFVNYVMTAM-YMCDKREISA-N beta-Tocotrienol Natural products Oc1c(C)c2c(c(C)c1)O[C@@](CC/C=C(\CC/C=C(\CC/C=C(\C)/C)/C)/C)(C)CC2 FGYKUFVNYVMTAM-YMCDKREISA-N 0.000 description 36
- FGYKUFVNYVMTAM-MUUNZHRXSA-N epsilon-Tocopherol Natural products OC1=CC(C)=C2O[C@@](CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1C FGYKUFVNYVMTAM-MUUNZHRXSA-N 0.000 description 36
- 239000011723 β-tocotrienol Substances 0.000 description 36
- 235000019151 β-tocotrienol Nutrition 0.000 description 36
- FGYKUFVNYVMTAM-WAZJVIJMSA-N β-tocotrienol Chemical compound OC1=CC(C)=C2O[C@@](CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1C FGYKUFVNYVMTAM-WAZJVIJMSA-N 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 201000010099 disease Diseases 0.000 description 33
- 229930003802 tocotrienol Natural products 0.000 description 24
- 239000011731 tocotrienol Substances 0.000 description 24
- 235000019148 tocotrienols Nutrition 0.000 description 24
- 239000000090 biomarker Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- GJJVAFUKOBZPCB-UHFFFAOYSA-N 2-methyl-2-(4,8,12-trimethyltrideca-3,7,11-trienyl)-3,4-dihydrochromen-6-ol Chemical compound OC1=CC=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-UHFFFAOYSA-N 0.000 description 20
- 239000006227 byproduct Substances 0.000 description 20
- SFVAYPRWECRHTF-QRCIITMISA-N 2-[(6e,10e)-3-hydroxy-3,7,11,15-tetramethylhexadeca-6,10,14-trienyl]-6-methylcyclohexa-2,5-diene-1,4-dione Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CCC(C)(O)CCC1=CC(=O)C=C(C)C1=O SFVAYPRWECRHTF-QRCIITMISA-N 0.000 description 19
- 230000037396 body weight Effects 0.000 description 19
- ODADKLYLWWCHNB-UHFFFAOYSA-N 2R-delta-tocotrienol Natural products OC1=CC(C)=C2OC(CCC=C(C)CCC=C(C)CCC=C(C)C)(C)CCC2=C1 ODADKLYLWWCHNB-UHFFFAOYSA-N 0.000 description 18
- BTNBMQIHCRIGOU-UHFFFAOYSA-N delta-tocotrienol Natural products CC(=CCCC(=CCCC(=CCCOC1(C)CCc2cc(O)cc(C)c2O1)C)C)C BTNBMQIHCRIGOU-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000011729 δ-tocotrienol Substances 0.000 description 18
- 235000019144 δ-tocotrienol Nutrition 0.000 description 18
- ODADKLYLWWCHNB-LDYBVBFYSA-N δ-tocotrienol Chemical compound OC1=CC(C)=C2O[C@@](CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1 ODADKLYLWWCHNB-LDYBVBFYSA-N 0.000 description 18
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 17
- 230000015572 biosynthetic process Effects 0.000 description 16
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 16
- 208000024891 symptom Diseases 0.000 description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 208000012268 mitochondrial disease Diseases 0.000 description 11
- 239000012071 phase Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 229940087168 alpha tocopherol Drugs 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 229960000984 tocofersolan Drugs 0.000 description 9
- 239000002076 α-tocopherol Substances 0.000 description 9
- 235000004835 α-tocopherol Nutrition 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 230000009286 beneficial effect Effects 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 208000024412 Friedreich ataxia Diseases 0.000 description 5
- 235000019482 Palm oil Nutrition 0.000 description 5
- 230000002411 adverse Effects 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 239000002540 palm oil Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000001993 wax Substances 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 102000018832 Cytochromes Human genes 0.000 description 4
- 108010052832 Cytochromes Proteins 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 239000003240 coconut oil Substances 0.000 description 4
- 235000019864 coconut oil Nutrition 0.000 description 4
- 235000017471 coenzyme Q10 Nutrition 0.000 description 4
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- VCJMYUPGQJHHFU-UHFFFAOYSA-N iron(3+);trinitrate Chemical compound [Fe+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O VCJMYUPGQJHHFU-UHFFFAOYSA-N 0.000 description 4
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 4
- 239000006186 oral dosage form Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical group [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 208000032087 Hereditary Leber Optic Atrophy Diseases 0.000 description 3
- 201000000639 Leber hereditary optic neuropathy Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000010936 aqueous wash Methods 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 3
- 230000001684 chronic 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
- 230000000694 effects Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 230000000887 hydrating effect Effects 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012454 non-polar solvent Substances 0.000 description 3
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 230000002861 ventricular Effects 0.000 description 3
- VKZRWSNIWNFCIQ-WDSKDSINSA-N (2s)-2-[2-[[(1s)-1,2-dicarboxyethyl]amino]ethylamino]butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NCCN[C@H](C(O)=O)CC(O)=O VKZRWSNIWNFCIQ-WDSKDSINSA-N 0.000 description 2
- GJJVAFUKOBZPCB-ZGRPYONQSA-N (r)-3,4-dihydro-2-methyl-2-(4,8,12-trimethyl-3,7,11-tridecatrienyl)-2h-1-benzopyran-6-ol Chemical class OC1=CC=C2OC(CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-ZGRPYONQSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- LTVDFSLWFKLJDQ-IEOSBIPESA-N 2-[(3r,7r,11r)-3-hydroxy-3,7,11,15-tetramethylhexadecyl]-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@](C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O LTVDFSLWFKLJDQ-IEOSBIPESA-N 0.000 description 2
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 2
- HCAJQHYUCKICQH-VPENINKCSA-N 8-Oxo-7,8-dihydro-2'-deoxyguanosine Chemical compound C1=2NC(N)=NC(=O)C=2NC(=O)N1[C@H]1C[C@H](O)[C@@H](CO)O1 HCAJQHYUCKICQH-VPENINKCSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 240000005979 Hordeum vulgare Species 0.000 description 2
- 235000007340 Hordeum vulgare Nutrition 0.000 description 2
- 208000035172 MERRF Diseases 0.000 description 2
- HPEUJPJOZXNMSJ-UHFFFAOYSA-N Methyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC HPEUJPJOZXNMSJ-UHFFFAOYSA-N 0.000 description 2
- 206010058799 Mitochondrial encephalomyopathy Diseases 0.000 description 2
- 208000036572 Myoclonic epilepsy Diseases 0.000 description 2
- DRBBFCLWYRJSJZ-UHFFFAOYSA-N N-phosphocreatine Chemical compound OC(=O)CN(C)C(=N)NP(O)(O)=O DRBBFCLWYRJSJZ-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 201000009028 early myoclonic encephalopathy Diseases 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 230000009969 flowable effect Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- WBJZTOZJJYAKHQ-UHFFFAOYSA-K iron(3+) phosphate Chemical compound [Fe+3].[O-]P([O-])([O-])=O WBJZTOZJJYAKHQ-UHFFFAOYSA-K 0.000 description 2
- PVFSDGKDKFSOTB-UHFFFAOYSA-K iron(3+);triacetate Chemical compound [Fe+3].CC([O-])=O.CC([O-])=O.CC([O-])=O PVFSDGKDKFSOTB-UHFFFAOYSA-K 0.000 description 2
- NPFOYSMITVOQOS-UHFFFAOYSA-K iron(III) citrate Chemical compound [Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NPFOYSMITVOQOS-UHFFFAOYSA-K 0.000 description 2
- 229910000399 iron(III) phosphate Inorganic materials 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 208000006443 lactic acidosis Diseases 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000199 molecular distillation Methods 0.000 description 2
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 239000006201 parenteral dosage form Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 239000004848 polyfunctional curative Substances 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- 229940068778 tocotrienols Drugs 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- PIEPQKCYPFFYMG-UHFFFAOYSA-N tris acetate Chemical compound CC(O)=O.OCC(N)(CO)CO PIEPQKCYPFFYMG-UHFFFAOYSA-N 0.000 description 2
- JLEXUIVKURIPFI-UHFFFAOYSA-N tris phosphate Chemical compound OP(O)(O)=O.OCC(N)(CO)CO JLEXUIVKURIPFI-UHFFFAOYSA-N 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- DIWZKTYQKVKILN-VKHMYHEASA-N (2s)-2-(dicarboxymethylamino)pentanedioic acid Chemical compound OC(=O)CC[C@@H](C(O)=O)NC(C(O)=O)C(O)=O DIWZKTYQKVKILN-VKHMYHEASA-N 0.000 description 1
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SFOKDWPZOYRZFF-UHFFFAOYSA-H 2,3-dihydroxybutanedioate;iron(3+) Chemical compound [Fe+3].[Fe+3].[O-]C(=O)C(O)C(O)C([O-])=O.[O-]C(=O)C(O)C(O)C([O-])=O.[O-]C(=O)C(O)C(O)C([O-])=O SFOKDWPZOYRZFF-UHFFFAOYSA-H 0.000 description 1
- KBPZVLXARDTGGD-UHFFFAOYSA-N 2,3-dihydroxybutanedioic acid;iron Chemical compound [Fe].OC(=O)C(O)C(O)C(O)=O KBPZVLXARDTGGD-UHFFFAOYSA-N 0.000 description 1
- FKOKUHFZNIUSLW-UHFFFAOYSA-N 2-Hydroxypropyl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(C)O FKOKUHFZNIUSLW-UHFFFAOYSA-N 0.000 description 1
- VLEIUWBSEKKKFX-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid Chemical compound OCC(N)(CO)CO.OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O VLEIUWBSEKKKFX-UHFFFAOYSA-N 0.000 description 1
- AXAVXPMQTGXXJZ-UHFFFAOYSA-N 2-aminoacetic acid;2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound NCC(O)=O.OCC(N)(CO)CO AXAVXPMQTGXXJZ-UHFFFAOYSA-N 0.000 description 1
- HWKRAUXFMLQKLS-UHFFFAOYSA-N 2-oxidanylidenepropanoic acid Chemical compound CC(=O)C(O)=O.CC(=O)C(O)=O HWKRAUXFMLQKLS-UHFFFAOYSA-N 0.000 description 1
- KVZLHPXEUGJPAH-UHFFFAOYSA-N 2-oxidanylpropanoic acid Chemical compound CC(O)C(O)=O.CC(O)C(O)=O KVZLHPXEUGJPAH-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 101150113809 COQ10 gene Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 244000194101 Ginkgo biloba Species 0.000 description 1
- 208000028782 Hereditary disease Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000006136 Leigh Disease Diseases 0.000 description 1
- 208000017507 Leigh syndrome Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 201000009035 MERRF syndrome Diseases 0.000 description 1
- 208000024556 Mendelian disease Diseases 0.000 description 1
- 201000002169 Mitochondrial myopathy Diseases 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 208000026072 Motor neurone disease Diseases 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- 201000009623 Myopathy Diseases 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 239000004264 Petrolatum Substances 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 235000019484 Rapeseed oil Nutrition 0.000 description 1
- 241000220010 Rhode Species 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 235000009754 Vitis X bourquina Nutrition 0.000 description 1
- 235000012333 Vitis X labruscana Nutrition 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- OBYRLAGSPYKPGO-UHFFFAOYSA-N [2,5,8-trimethyl-2-(4,8,12-trimethyltridecyl)-3,4-dihydrochromen-6-yl] acetate Chemical compound CC(=O)OC1=CC(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C OBYRLAGSPYKPGO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000003915 air pollution Methods 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- ZOJBYZNEUISWFT-UHFFFAOYSA-N allyl isothiocyanate Chemical compound C=CCN=C=S ZOJBYZNEUISWFT-UHFFFAOYSA-N 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- LTVDFSLWFKLJDQ-DKGMKSHISA-N alpha-Tocopherolquinone Natural products CC(C)CCC[C@H](C)CCC[C@@H](C)CCC[C@@](C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O LTVDFSLWFKLJDQ-DKGMKSHISA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- MGZZPZRFHXCQGY-UHFFFAOYSA-N alpha-tocopheryl quinone Natural products CC(C)CCCC(C)CCCC(C)CCCC1(C)CCc2c(C)c(OC3=CC(=O)C=CC3=O)c(C)c(C)c2O1 MGZZPZRFHXCQGY-UHFFFAOYSA-N 0.000 description 1
- LTVDFSLWFKLJDQ-UHFFFAOYSA-N alpha-tocopheryl-para-quinone Natural products CC(C)CCCC(C)CCCC(C)CCCC(C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O LTVDFSLWFKLJDQ-UHFFFAOYSA-N 0.000 description 1
- 229940020439 alpha-tocopherylquinone Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 239000012179 bayberry wax Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052793 cadmium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000004204 candelilla wax Substances 0.000 description 1
- 235000013868 candelilla wax Nutrition 0.000 description 1
- 229940073532 candelilla wax Drugs 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 235000021466 carotenoid Nutrition 0.000 description 1
- 150000001747 carotenoids Chemical class 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 229940110767 coenzyme Q10 Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- CAMHHLOGFDZBBG-UHFFFAOYSA-N epoxidized methyl oleate Natural products CCCCCCCCC1OC1CCCCCCCC(=O)OC CAMHHLOGFDZBBG-UHFFFAOYSA-N 0.000 description 1
- HCTNDDRMUNVGSU-UHFFFAOYSA-N ethanol;2-methoxy-2-methylpropane Chemical compound CCO.COC(C)(C)C HCTNDDRMUNVGSU-UHFFFAOYSA-N 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- YAGKRVSRTSUGEY-UHFFFAOYSA-N ferricyanide Chemical compound [Fe+3].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] YAGKRVSRTSUGEY-UHFFFAOYSA-N 0.000 description 1
- 229960002089 ferrous chloride Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- FOYKKGHVWRFIBD-UHFFFAOYSA-N gamma-tocopherol acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 FOYKKGHVWRFIBD-UHFFFAOYSA-N 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000010448 genetic screening Methods 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- IUJAMGNYPWYUPM-UHFFFAOYSA-N hentriacontane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC IUJAMGNYPWYUPM-UHFFFAOYSA-N 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000010929 in-process HPLC Method Methods 0.000 description 1
- 208000023692 inborn mitochondrial myopathy Diseases 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 239000006204 intramuscular dosage form Substances 0.000 description 1
- 239000006206 intraperitoneal dosage form Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- FBAFATDZDUQKNH-UHFFFAOYSA-M iron chloride Chemical group [Cl-].[Fe] FBAFATDZDUQKNH-UHFFFAOYSA-M 0.000 description 1
- NMCUIPGRVMDVDB-UHFFFAOYSA-L iron dichloride Chemical compound Cl[Fe]Cl NMCUIPGRVMDVDB-UHFFFAOYSA-L 0.000 description 1
- NQXWGWZJXJUMQB-UHFFFAOYSA-K iron trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].Cl[Fe+]Cl NQXWGWZJXJUMQB-UHFFFAOYSA-K 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 229940119170 jojoba wax Drugs 0.000 description 1
- 150000003893 lactate salts Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000944 linseed oil Substances 0.000 description 1
- 235000021388 linseed oil Nutrition 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 230000004898 mitochondrial function Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 239000008164 mustard oil Substances 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000010466 nut oil Substances 0.000 description 1
- 235000019488 nut oil Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 239000003346 palm kernel oil Substances 0.000 description 1
- 235000019865 palm kernel oil Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000007981 phosphate-citrate buffer Substances 0.000 description 1
- 229950007002 phosphocreatine Drugs 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940093625 propylene glycol monostearate Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940076788 pyruvate Drugs 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000004170 rice bran wax Substances 0.000 description 1
- 235000019384 rice bran wax Nutrition 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 208000012201 sexual and gender identity disease Diseases 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000003351 stiffener Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000020238 sunflower seed Nutrition 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940080258 tetrasodium iminodisuccinate Drugs 0.000 description 1
- GYBINGQBXROMRS-UHFFFAOYSA-J tetrasodium;2-(1,2-dicarboxylatoethylamino)butanedioate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CC(C([O-])=O)NC(C([O-])=O)CC([O-])=O GYBINGQBXROMRS-UHFFFAOYSA-J 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 150000003612 tocotrienol derivatives Chemical class 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 229910000314 transition metal oxide Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical group OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
- 125000000255 β-tocotrienol group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C46/00—Preparation of quinones
- C07C46/02—Preparation of quinones by oxidation giving rise to quinoid structures
- C07C46/06—Preparation of quinones by oxidation giving rise to quinoid structures of at least one hydroxy group on a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
- C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
- C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Ophthalmology & Optometry (AREA)
- Neurology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
【解決手段】アルファ−トコトリエノールキノンまたはその立体異性体を生成する方法であって、本方法は金属塩酸化剤を用いてアルファ−トコトリエノールを酸化させることにより非アルファ−トコトリエノールクロマンの存在下においてアルファ−トコトリエノールクロマンをアルファ−トコトリエノールキノンへと選択的に開環させることを含み、金属塩酸化剤/アルファ−トコトリエノールの化学量論比が少なくとも4:1であり、出発アルファ−トコトリエノールクロマン材料に存在している可能性のある任意の量の非アルファ−トコトリエノールクロマンの酸化を減少させるために上記の金属酸化剤を遂次添加で添加する。このプロセスは非アルファ−トコトリエノールクロマンと比較してアルファ−トコトリエノールクロマンの酸化速度に好都合な条件を使用する。
【選択図】なし
Description
本特許出願は、2011年7月19日に出願した米国仮特許出願第61/572,645号の優先権の利益を主張する。この特許出願の内容全体は、本明細書中に参考として援用される。
本発明は、式I:
の化合物を合成する方法に関し、上記の方法は、金属塩酸化剤を用いて、非アルファ−トコトリエノールの存在下において、アルファ−トコトリエノールを選択的に酸化させ、式Iのアルファ−トコトリエノールを形成することを含み、ここで、金属塩酸化剤/アルファ−トコトリエノールの化学量論の総比率を少なくとも4:1の当量の範囲内で選択し、上記の金属酸化剤を、逐次添加で添加する。本発明のプロセスは、このアルファ異性体について優先的な酸化条件を使用し、出発アルファ−トコトリエノール材料に存在していた可能性のある非アルファ−トコトリエノールクロマンの存在下において、アルファ−トコトリエノールクロマンをアルファ−トコトリエノールキノンへと選択的に開環させるための方法である。
アルファ−トコトリエノールキノンは、ミトコンドリア病に関連する症状の処置用に開発が進められている。アルファ−トコトリエノールキノンを用いたインビトロ実験では、ミトコンドリア機能の向上において、COQ10よりはるかに強力であることを示している(Shrader,W.D.ら;Bioorganic Medicinal Chemistry Letters,2011;21(12):3693−3698)。予備研究では、フリードライヒ運動失調症、リー症候群、およびレーバー遺伝性視神経萎縮症などのミトコンドリア病に苦しむ患者においてある程度の効力を有することが示されている(例えば、それぞれ、特許文献1(米国出願公開第2010/0222436号)、特許文献2(米国出願公開第2011/0172312号)、および特許文献3(米国出願公開第2010/0273894号)として公開された、同一出願人に譲渡された出願である米国出願第12/777,179号、米国出願第12/982,716号、米国出願第12/768,565号を参照のこと)。
中に生じ得るいくつかの副生成物について記載している(Skinner,W.A.,Ph.D.Thesis,University of Texas at Austin(1952))。Robesonらは、アルファ−トコフェロールと塩化第二鉄とを二相溶媒反応媒体中で反応させることにより、好ましくない量の他のアルファ−トコフェロール酸化生成物を含有しないアルファ−トコフェリルキノンを生成する、改良された反応条件下における手法について記載し、主張した(特許文献4(米国特許第2,856,414号))。
本発明は、式I
の化合物(アルファ−トコトリエノールキノン)またはその立体異性体を生成する方法に
関し、本方法は、金属塩酸化剤を用いてアルファ−トコトリエノールを酸化させることにより、非アルファ−トコトリエノールクロマンの存在下において、アルファ−トコトリエノールクロマンを式Iのアルファ−トコトリエノールキノンへと選択的に開環させることを含み、ここで、金属塩酸化剤/アルファ−トコトリエノールの化学量論比は、少なくとも4:1または約4:1であり、上記の金属酸化剤は、逐次添加で添加される。
の化合物、すなわち、2−[(3R,6E,10E)−3−ヒドロキシ−3,7,11,15−テトラメチル−6,10,14−ヘキサデカトリエニル]−3,5,6−トリメチル−2,5−シクロヘキサジエン−1,4−ジオンである。
、本組成物は、ベータ−トコトリエノール、ベータ−トコトリエノールキノン、ガンマ−トコトリエノール、ガンマ−トコトリエノールキノン、デルタ−トコトリエノール、デルタ−トコトリエノールキノン、またはそれらの組み合わせから選択される、2.5%(wt/wt)未満または約2.5%未満の非アルファ−トコトリエノールキノン化合物を有する。いくつかの実施形態において、本組成物は、ベータ−トコトリエノール、ベータ−トコトリエノールキノン、ガンマ−トコトリエノール、ガンマ−トコトリエノールキノン、デルタ−トコトリエノール、デルタ−トコトリエノールキノン、またはそれらの組み合わせから選択される、1%(wt/wt)未満または約1%未満の非アルファ−トコトリエノールキノン化合物を有する。いくつかの実施形態において、本組成物は、ベータ−トコトリエノール、ベータ−トコトリエノールキノン、ガンマ−トコトリエノール、ガンマ−トコトリエノールキノン、デルタ−トコトリエノール、デルタ−トコトリエノールキノン、またはそれらの組み合わせから選択される、0.5%(wt/wt)未満または約0.5%未満の非アルファ−トコトリエノールキノン化合物を有する。いくつかの実施形態において、本組成物は、アルファ−トコトリエノール、ベータ−トコトリエノール、ベータ−トコトリエノールキノン、ガンマ−トコトリエノール、ガンマ−トコトリエノールキノン、デルタ−トコトリエノール、デルタ−トコトリエノールキノン、またはそれらの組み合わせから選択される、0.2%(wt/wt)未満または約0.2%未満の非アルファ−トコトリエノールキノン化合物を有する。
本発明は、金属塩酸化剤の化学量論比を制御することにより、非アルファ−トコトリエノールキノンの形成を制限する方法に関する。本発明は、非アルファ−トコトリエノールのいずれの反応速度より速い、アルファ−トコトリエノールと金属塩酸化剤との反応速度を使用して、いくつかの非アルファ−トコトリエノールを含むアルファ−トコトリエノールを選択的に酸化させてアルファ−トコトリエノールキノンにすること、および反応の完了に不可欠な、金属塩酸化剤と出発材料との化学量論比を使用することに関する。
0)14,1995 1998;S.Uranoら、Chem.Pharm.Bull.(1983)31,4341 4345,Pearceら、J.Med Chem.(1992),35,3595 3606およびPearceら、J.Med.Chem.(1994).37,526 541を参照のこと。これらの報告されたプロセスはどれも、トコトリエノールの天然形態を生じず、むしろラセミ混合物を生成する。天然d体のトコトリエノールの合成が公開されている。例えば、J.Scottら、Helv.Chim.Acta(1976)59,290 306,Satoら(日本国特許第63063674号);Satoら(日本国特許第01233278号)およびCouladourosら(米国特許第7,038,067号)を参照のこと。
する。いくつかの実施形態において、金属塩酸化剤を、75%、85%、87%、90%、92%、95%、97%、98%、99%、99,5%または99.9%を式Iの化合物に酸化させるのに十分な量で添加する。
、例えば、ベータ−トコトリエノールキノン、ガンマ−トコトリエノールキノン、デルタ−トコトリエノールキノンおよびそれらの組み合わせを含むことができるがそれらに限定されない。
いくつかの実施形態において、本発明は、式I:
の化合物またはその立体異性体を合成する方法に関し、ここで、本合成は、式Iの化合物に対して2%未満、1.5%未満、1.0%未満、0.8%未満、0.6%未満、0.4%未満、または0.2%未満(mol/mol)の非アルファ−トコトリエノールキノンを有する組成物を生じる。
により記載される二重結合が全てのトランスのR立体配座の状態、すなわち、2−[(3R,6E,10E)−3−ヒドロキシ−3,7,11,15−テトラメチル−6,10,14−ヘキサデカトリエニル]−3,5,6−トリメチル−2,5−シクロヘキサジエン−1,4−ジオンであり得る。
いくつかの実施形態において、本発明の方法により生成される式Iの化合物を使用し、被験体における1つ以上の状態を処置することができる。本組成物は、式Iの化合物に加えて他の材料および化合物を含むことができる。
化剤、またはそれらの組み合わせであり得るが、それらに限定されない。
wax)、米ぬか蝋、およびそれらの組み合わせを含むがそれらに限定されない。
da)およびNeusilin(登録商標)(メタケイ酸アルミン酸マグネシウム、Fuji Chemical Co.,Japan)を含むことができる。経口投与のための全ての組成物は、このような投与に適した投与量であるべきである。
ず、被験体が1日基準で本発明の方法により生成される化合物の合計300mgを受けることを意味する。式Iの化合物を投与する従来の手段は、単回用量、1日2回投与、1日3回投与、または1日4回投与としてであってよい。用語「1日1回」または「1日の(毎日;daily)」は、24時間の時間内に1回の本発明の組成物の投与を指す。
後に起こるが、抑制は、疾患の有害な症状が被験体に現れる前に起こることである。抑制は、部分的、実質的に全体、または全体であり得る。ミトコンドリア障害の多くが遺伝性であるため、遺伝的スクリーニングを使用し、この疾患の危険のある患者を同定することができる。次いで、本発明の化合物および方法を、いずれかの有害な症状の出現を抑制するために、この疾患の臨床症状を発症する危険のある無症状の患者に投与することができる。「被験体」は、ヒトおよび非ヒト動物、例えば、飼育動物および家畜動物、および動物園、競技用および愛玩動物、例えば、家庭用ペットならびに他の飼育動物、例えば、ウシ、ヒツジ、フェレット、ブタ、ウマ、ウサギ、ヤギ、イヌ、ネコなどを含むがそれらに限定されないものを指す。いくつかの実施形態において、愛玩動物は、イヌおよびネコである。
(項1)
式I:
(項2)
二相溶液中において、金属塩酸化剤を用いてアルファ−トコトリエノールを酸化させることを含み、ここで、該アルファ−トコトリエノールは非極性溶媒中に溶解され、前記金属塩酸化剤は極性溶媒中に溶解され、そして個別の溶液が混合されて該酸化を可能にする、上記項1に記載の方法。
(項3)
前記金属塩酸化剤が、ハロゲン化鉄(III)、酢酸鉄(III)、クエン酸鉄(III)、硝酸鉄(III)、酒石酸鉄(III)またはリン酸鉄(III)から選択される鉄(III)塩である、上記項1または2に記載の方法。
(項4)
前記金属塩酸化剤が塩化鉄(Fe(III)Cl 3 )である、上記項1または2に記載の方法。
(項5)
前記金属酸化剤が、前記アルファ−トコトリエノールクロマンのうちの少なくとも約98%を前記アルファ−トコトリエノールキノンへと酸化させるのに十分である、上記項4に記載の方法。
(項6)
前記酸化から得られる組成物が、アルファ−トコトリエノール、ベータ−トコトリエノール、ベータ−トコトリエノールキノン、ガンマ−トコトリエノール、ガンマ−トコトリエノールキノン、デルタ−トコトリエノール、デルタ−トコトリエノールキノンまたはそれらの組み合わせから選択される、約1%未満の1つ以上の非アルファ−トコトリエノールキノン化合物を有する、上記項5に記載の方法。
(項7)
前記酸化から得られる組成物が、アルファ−トコトリエノール、ベータ−トコトリエノール、ベータ−トコトリエノールキノン、ガンマ−トコトリエノール、ガンマ−トコトリエノールキノン、デルタ−トコトリエノール、デルタ−トコトリエノールキノンおよびそれらの組み合わせから選択される、約0.7%未満の1つ以上の非アルファ−トコトリエノールキノン化合物を有する、上記項5に記載の方法。
(項8)
前記酸化から得られる組成物が、アルファ−トコトリエノール、ベータ−トコトリエノール、ベータ−トコトリエノールキノン、ガンマ−トコトリエノール、ガンマ−トコトリエノールキノン、デルタ−トコトリエノール、デルタ−トコトリエノールキノンおよびそれらの組み合わせから選択される、約0.2%未満の1つ以上の非アルファ−トコトリエノールキノン化合物を有する、上記項5に記載の方法。
(項9)
前記酸化が、アルコールおよび/またはエーテルの混合物に溶解させたアルファ−トコトリエノール、および水または水とアルコールの混合物に溶解させた金属塩酸化剤の二相溶液において行われる、上記項2に記載の方法。
(項10)
前記酸化が、エタノールとメチルtert−ブチルエーテル(MTBE)とのおよそ1:2混合物に溶解させたアルファ−トコトリエノール、および水とエタノールとのおよそ2:1混合物に溶解させた塩化鉄(III)の二相溶液において行われる、上記項4に記載の方法。
(項11)
前記酸化金属塩を複数部分に分けて順次添加することができ、ここで、第1の部分の金属塩を添加して前記アルファ−トコトリエノールと反応させた後、該第1の部分の極性相を除去し、そしてその後の部分の金属塩溶液を添加する、上記項9に記載の方法。
(項12)
前記塩化鉄(III)塩を、3〜5つの部分に分けて順次添加し、第1の部分の塩化鉄(III)を添加した後、該第1の部分の極性相を除去し、そしてその後の部分の塩化鉄(III)溶液を添加する、上記項10に記載の方法。
(項13)
前記酸化反応を、望ましくない副生成物のうちの1つ以上の形成を測定しながら進行させ、該望ましくない副生成物のうちの1つ以上が検出されたときに中断させる、上記項11に記載の方法。
(項14)
前記酸化反応を、望ましくない副生成物のうちの1つ以上の形成を測定しながら進行させ、該酸化を、1つの副生成物のレベルが約1%であるときに中断させる、上記項13に記載の方法。
(項15)
前記酸化反応を、望ましくない副生成物のうちの1つ以上の形成を測定しながら進行させ、該酸化を、1つの副生成物のレベルが約0.5%であるときに中断させる、上記項13に記載の方法。
Claims (1)
- 明細書に記載の発明。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161572645P | 2011-07-19 | 2011-07-19 | |
US61/572,645 | 2011-07-19 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014521798A Division JP2014520894A (ja) | 2011-07-19 | 2012-07-19 | 非アルファトコトリエノールの存在下でのアルファトコトリエノールの選択的酸化のための方法 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018071493A Division JP2018104471A (ja) | 2011-07-19 | 2018-04-03 | 非アルファトコトリエノールの存在下でのアルファトコトリエノールの選択的酸化のための方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2017061579A true JP2017061579A (ja) | 2017-03-30 |
JP6568880B2 JP6568880B2 (ja) | 2019-08-28 |
Family
ID=47558483
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014521798A Withdrawn JP2014520894A (ja) | 2011-07-19 | 2012-07-19 | 非アルファトコトリエノールの存在下でのアルファトコトリエノールの選択的酸化のための方法 |
JP2017005308A Active JP6568880B2 (ja) | 2011-07-19 | 2017-01-16 | 非アルファトコトリエノールの存在下でのアルファトコトリエノールの酸化のための方法 |
JP2018071493A Withdrawn JP2018104471A (ja) | 2011-07-19 | 2018-04-03 | 非アルファトコトリエノールの存在下でのアルファトコトリエノールの選択的酸化のための方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2014521798A Withdrawn JP2014520894A (ja) | 2011-07-19 | 2012-07-19 | 非アルファトコトリエノールの存在下でのアルファトコトリエノールの選択的酸化のための方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018071493A Withdrawn JP2018104471A (ja) | 2011-07-19 | 2018-04-03 | 非アルファトコトリエノールの存在下でのアルファトコトリエノールの選択的酸化のための方法 |
Country Status (5)
Country | Link |
---|---|
US (4) | US9162957B2 (ja) |
EP (1) | EP2734512B1 (ja) |
JP (3) | JP2014520894A (ja) |
CA (1) | CA2842486C (ja) |
WO (1) | WO2013013078A1 (ja) |
Families Citing this family (28)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005032544A1 (en) | 2003-09-19 | 2005-04-14 | Galileo Pharmaceuticals, Inc. | Treatment of mitochondrial diseases |
EP2471530B1 (en) | 2005-06-01 | 2017-01-11 | Edison Pharmaceuticals, Inc. | Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers |
CA2635280C (en) | 2006-02-22 | 2017-12-12 | Edison Pharmaceuticals, Inc. | Side chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers |
WO2009061744A2 (en) | 2007-11-06 | 2009-05-14 | Edison Pharmaceuticals, Inc. | 4- (p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases |
EA023618B1 (ru) | 2008-01-08 | 2016-06-30 | Эдисон Фармасьютикалз, Инк. | Производные (гет)арил-п-хинона для лечения митохондриальных болезней |
EP2262508B1 (en) | 2008-03-05 | 2018-10-03 | BioElectron Technology Corporation | SUBSTITUTED-p-QUINONE DERIVATIVES FOR TREATMENT OF OXIDATIVE STRESS DISEASES |
US8716486B2 (en) | 2008-06-25 | 2014-05-06 | Edison Pharmaceuticals, Inc. | 2-heterocyclylaminoalkyl-(p-quinone) derivatives for treatment of oxidative stress diseases |
WO2010030607A1 (en) | 2008-09-10 | 2010-03-18 | Edison Pharmaceuticals, Inc. | Treatment of pervasive developmental disorders with redox-active therapeutics |
US10039722B2 (en) | 2008-10-14 | 2018-08-07 | Bioelectron Technology Corporation | Treatment of oxidative stress disorders including contrast nephropathy, radiation damage and disruptions in the function of red cells |
SI2963006T1 (sl) | 2008-10-28 | 2019-01-31 | Bioelectron Technology Corporation | Sestavek vsebujoč alfa-tokotrienol kinon in njegove vmesne povezave |
DK2424495T3 (en) | 2009-04-28 | 2018-04-30 | Bioelectron Tech Corp | TREATMENT OF LEVERS HEREDIC OPTICAL NEUROPATHY AND DOMINANT OPTICAL ATROPHY WITH TOCOTRIENOL QUINONES |
KR101578318B1 (ko) * | 2010-09-30 | 2015-12-16 | 미쓰비시덴키 가부시키가이샤 | 화상 복호 장치, 화상 복호 방법, 화상 부호화 장치 및 화상 부호화 방법 |
EP2720689A4 (en) | 2011-06-14 | 2014-11-26 | Edison Pharmaceuticals Inc | CATÉCHOL DERIVATIVES FOR THE TREATMENT OF OXIDATIVE STRESS DISEASES |
JP2014520894A (ja) | 2011-07-19 | 2014-08-25 | エジソン ファーマシューティカルズ, インコーポレイテッド | 非アルファトコトリエノールの存在下でのアルファトコトリエノールの選択的酸化のための方法 |
WO2014039862A1 (en) | 2012-09-07 | 2014-03-13 | Edison Pharmaceuticals, Inc. | Quinone derivatives for use in the modulation of redox status of individuals |
US9670170B2 (en) | 2013-03-15 | 2017-06-06 | Bioelectron Technology Corporation | Resorufin derivatives for treatment of oxidative stress disorders |
US9296712B2 (en) | 2013-03-15 | 2016-03-29 | Edison Pharmaceuticals, Inc. | Resorufin derivatives for treatment of oxidative stress disorders |
JP2016515526A (ja) | 2013-03-15 | 2016-05-30 | エジソン ファーマシューティカルズ, インコーポレイテッド | 酸化ストレス障害の処置のためのアルキル−ヘテロアリール置換されたキノン誘導体 |
US9868711B2 (en) | 2013-03-15 | 2018-01-16 | Bioelectron Technology Corporation | Phenazine-3-one and phenothiazine-3-one derivatives for treatment of oxidative stress disorders |
KR102626895B1 (ko) | 2014-12-16 | 2024-01-18 | 피티씨 테라퓨틱스, 인크. | (r)-2-하이드록시-2-메틸-4-(2,4,5-트리메틸-3,6-디옥소사이클로헥사-1,4-디에닐)부탄아미드의 다형성 및 무정형 형태 |
US11267777B2 (en) | 2015-11-19 | 2022-03-08 | Concert Pharmaceuticals, Inc. | Deuterated EPI-743 |
WO2017106786A1 (en) | 2015-12-16 | 2017-06-22 | Bioelectron Technology Corporation | Improved methods for enriching alpha-tocotrienol from mixed tocol compositions |
WO2017106803A1 (en) | 2015-12-17 | 2017-06-22 | Bioelectron Technology Corporation | Flouroalkyl, flouroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders |
JP2018083799A (ja) | 2016-11-15 | 2018-05-31 | バイオエレクトロン テクノロジー コーポレイション | 2−置換アミノ−ナフト[1,2−d]イミダゾール−5−オン化合物またはその製薬学上許容される塩 |
WO2018191732A1 (en) | 2017-04-14 | 2018-10-18 | Bioelectron Technology Corporation | Methods and compositions for treatment of inflammation and oxidative stress |
CN113365616A (zh) | 2018-10-17 | 2021-09-07 | Ptc医疗公司 | 用于抑制和治疗α-突触核蛋白病、tau蛋白病及其他疾病的2,3,5-三甲基-6-壬基环己-2,5-二烯-1,4-二酮 |
AU2022306868A1 (en) | 2021-07-08 | 2024-02-22 | Ptc Therapeutics, Inc. | Pharmaceutical compositions comprising 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione |
WO2023009610A1 (en) * | 2021-07-29 | 2023-02-02 | Ptc Therapeutics, Inc. | Methods for synthesis of racemic, scalemic, and chiral alpha-tocotrienol quinone |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2856414A (en) * | 1958-10-14 | Oxidation of alpha-tocopherol | ||
JP2004504313A (ja) * | 2000-07-14 | 2004-02-12 | ビーエーエスエフ アクチェンゲゼルシャフト | 抗高コレステロール作用を有するトコトリエノールキノン環化生成物 |
US20100105930A1 (en) * | 2008-10-28 | 2010-04-29 | Wesson Kieron E | Process for the production of alpha-tocotrienol and derivatives |
Family Cites Families (73)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3406188A (en) | 1964-03-27 | 1968-10-15 | Sun Oil Co | Preparation of alpha-tocopherylquinone |
US4603142A (en) | 1984-06-01 | 1986-07-29 | Wisconsin Alumni Research Foundation | Cholesterol lowering method of use |
JPS636186A (ja) | 1986-06-23 | 1988-01-12 | タツタ電線株式会社 | 点滴監視装置 |
JP2685785B2 (ja) | 1988-03-11 | 1997-12-03 | エーザイ株式会社 | 光学活性α−トコトリエノールの製造方法 |
AU618791B2 (en) | 1988-03-16 | 1992-01-09 | Bioindustry Development Centre | Production of high concentration tocopherols and tocotrienols from palm oil by-product |
US5157132A (en) | 1990-05-18 | 1992-10-20 | Carotech Associates | Integrated process for recovery of carotenoids and tocotrienols from oil |
EP0543417A1 (en) | 1991-11-22 | 1993-05-26 | Lipogenics, Incorporated | Tocotrienols and tocotrienol-like compounds and methods for their use |
US6232060B1 (en) | 1996-01-19 | 2001-05-15 | Galileo Laboratories, Inc. | Assay system for anti-stress agents |
US5801159A (en) | 1996-02-23 | 1998-09-01 | Galileo Laboratories, Inc. | Method and composition for inhibiting cellular irreversible changes due to stress |
US6224717B1 (en) | 1998-01-29 | 2001-05-01 | Eastman Chemical Company | Methods for separating a tocotrienol from a tocol-containing mixture and compositions thereof |
US6395915B1 (en) | 1999-09-10 | 2002-05-28 | Technikrom, Inc. | Method for producing purified tocotrienols and tocopherols using liquid chromatography |
MY127451A (en) | 1999-11-04 | 2006-12-29 | Malaysian Palm Oil Board | A method of chromatographic isolation for vitamin e isomers |
US7034054B2 (en) | 2000-12-15 | 2006-04-25 | Galileo Pharmaceuticals, Inc. | Methods for the prevention and treatment of cerebral ischemia using non-alpha tocopherols |
US6838104B2 (en) | 2000-12-20 | 2005-01-04 | Archer Daniels Midland Company | Process for the production of tocotrienols |
US6608196B2 (en) | 2001-05-03 | 2003-08-19 | Galileo Pharmaceuticals, Inc. | Process for solid supported synthesis of pyruvate-derived compounds |
JP4842455B2 (ja) | 2001-06-13 | 2011-12-21 | コマツNtc株式会社 | 半導体単結晶引上げ装置及びそのライン構成 |
JP2003171376A (ja) | 2001-09-27 | 2003-06-20 | Lion Corp | トコフェロール類及びトコトリエノール類濃縮物、その製造方法 |
US6667330B2 (en) | 2002-01-31 | 2003-12-23 | Galileo Pharmaceuticals, Inc. | Furanone derivatives |
US6653346B1 (en) | 2002-02-07 | 2003-11-25 | Galileo Pharmaceuticals, Inc. | Cytoprotective benzofuran derivatives |
EP1558922B1 (en) | 2002-10-30 | 2013-02-27 | Ampere Life Sciences, Inc. | Identifying therapeutic compounds based on their physical-chemical properties |
WO2005032544A1 (en) | 2003-09-19 | 2005-04-14 | Galileo Pharmaceuticals, Inc. | Treatment of mitochondrial diseases |
WO2005035491A2 (en) | 2003-10-10 | 2005-04-21 | Yasoo Health, Inc. | PROCESS FOR SYNTHESIZING d-TOCOTRIENOLS FROM 2- VINYLCHROMANE COMPOUND |
US7393662B2 (en) | 2004-09-03 | 2008-07-01 | Centocor, Inc. | Human EPO mimetic hinge core mimetibodies, compositions, methods and uses |
EP2471530B1 (en) | 2005-06-01 | 2017-01-11 | Edison Pharmaceuticals, Inc. | Redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers |
PT1933821T (pt) | 2005-09-15 | 2020-10-15 | Ptc Therapeutics Inc | Variantes de cauda de terapêuticos redox-ativos para tratamento de doenças mitocondriais e outras condições e modulação de biomarcadores energéticos |
CA2635280C (en) | 2006-02-22 | 2017-12-12 | Edison Pharmaceuticals, Inc. | Side chain variants of redox-active therapeutics for treatment of mitochondrial diseases and other conditions and modulation of energy biomarkers |
EP2101808A4 (en) | 2007-01-10 | 2011-11-30 | Edison Pharmaceuticals Inc | TREATMENT OF BREATHLY TROUBLES USING COMPOUNDS OF ERYTHROPOIETIN OR THROMBOPOIETIN ACTIVITY |
WO2009061744A2 (en) | 2007-11-06 | 2009-05-14 | Edison Pharmaceuticals, Inc. | 4- (p-quinonyl)-2-hydroxybutanamide derivatives for treatment of mitochondrial diseases |
US20100266591A1 (en) | 2008-01-07 | 2010-10-21 | Peter Bugelski | Method of treating erythropoietin hyporesponsive anemias |
EA023618B1 (ru) | 2008-01-08 | 2016-06-30 | Эдисон Фармасьютикалз, Инк. | Производные (гет)арил-п-хинона для лечения митохондриальных болезней |
EP2262508B1 (en) | 2008-03-05 | 2018-10-03 | BioElectron Technology Corporation | SUBSTITUTED-p-QUINONE DERIVATIVES FOR TREATMENT OF OXIDATIVE STRESS DISEASES |
WO2009111543A2 (en) | 2008-03-05 | 2009-09-11 | Edison Pharmaceuticals, Inc. | Treatment of hearing and balance impairments with redox-active therapeutics |
US20110142834A1 (en) | 2008-05-15 | 2011-06-16 | Edison Pharmaceuticals, Inc. | Treatment of hearing and balance impairments using compounds having erythropoietin activity |
US20090291092A1 (en) | 2008-05-22 | 2009-11-26 | Miller Guy M | Treatment of mitochondrial diseases with an erythropoietin mimetic |
US8716486B2 (en) | 2008-06-25 | 2014-05-06 | Edison Pharmaceuticals, Inc. | 2-heterocyclylaminoalkyl-(p-quinone) derivatives for treatment of oxidative stress diseases |
US20100010100A1 (en) | 2008-07-09 | 2010-01-14 | Hinman Andrew W | Dermatological compositions with anti-aging and skin even-toning properties |
US20100029706A1 (en) | 2008-07-30 | 2010-02-04 | Edison Parmaceuticals, Inc. a Delaware Corporation | HYDROGENATED PYRIDO[4,3-b]INDOLES FOR THE TREATMENT OF OXIDATIVE STRESS |
US20100029784A1 (en) | 2008-07-30 | 2010-02-04 | Hinman Andrew W | Naphthoquinone compositions with anti-aging, anti-inflammatory and skin even-toning properties |
WO2010030607A1 (en) | 2008-09-10 | 2010-03-18 | Edison Pharmaceuticals, Inc. | Treatment of pervasive developmental disorders with redox-active therapeutics |
US10039722B2 (en) | 2008-10-14 | 2018-08-07 | Bioelectron Technology Corporation | Treatment of oxidative stress disorders including contrast nephropathy, radiation damage and disruptions in the function of red cells |
DK2424495T3 (en) | 2009-04-28 | 2018-04-30 | Bioelectron Tech Corp | TREATMENT OF LEVERS HEREDIC OPTICAL NEUROPATHY AND DOMINANT OPTICAL ATROPHY WITH TOCOTRIENOL QUINONES |
JP2012525397A (ja) | 2009-04-28 | 2012-10-22 | エジソン ファーマシューティカルズ, インコーポレイテッド | 眼科疾患を治療するためのトコトリエノールキノンの製剤 |
WO2010151348A1 (en) | 2009-06-25 | 2010-12-29 | Edison Pharmaceuticals, Inc. | Treatment of pervasive developmental disorders with tocotrienols or tocotrienol enriched extracts |
CN102647981B (zh) | 2009-08-26 | 2016-09-28 | 爱迪生制药有限公司 | 预防和治疗脑缺血的方法 |
EA201200977A1 (ru) | 2009-12-31 | 2013-01-30 | Эдисон Фармасьютикалз, Инк. | Лечение синдрома ли и ли-подобного синдрома токотриенолхинонами |
MX2012010337A (es) | 2010-03-09 | 2012-11-16 | Edison Pharmaceuticals Inc | Sintesis de derivados de alfa-tocoferolquinona y metodos para usar los mismos. |
WO2011113018A1 (en) | 2010-03-12 | 2011-09-15 | Ampere Life Sciences, Inc. | Measurement and control of biological time |
WO2011126998A1 (en) | 2010-04-06 | 2011-10-13 | Edison Pharmaceuticals, Inc. | Treatment of ataxia telangiectasia |
CN105147651A (zh) | 2010-04-27 | 2015-12-16 | 爱迪生药物公司 | 治疗眼科疾病的醌类的制剂 |
US20120101169A1 (en) | 2010-07-14 | 2012-04-26 | Penwest Pharmaceuticals Co. | Methods of providing anticoagulation effects in subjects |
EP2600857A4 (en) | 2010-08-06 | 2014-06-11 | Edison Pharmaceuticals Inc | TREATMENT OF OCHONDRIAL DISEASES WITH NAPHTHOCHINONES |
US20120295985A1 (en) | 2010-11-19 | 2012-11-22 | Miller Guy M | Methods for improving blood glucose control |
WO2012154613A1 (en) | 2011-05-06 | 2012-11-15 | Edison Pharmaceuticals, Inc. | Improved process for the preparation of d-alpha-tocotrienol from natural extracts |
WO2012170773A1 (en) | 2011-06-08 | 2012-12-13 | Edison Pharmaceuticals, Inc. | Adjunctive therapy for the treatment of mitochondrial disorders with quinones and naphthoquinones |
EP2720689A4 (en) | 2011-06-14 | 2014-11-26 | Edison Pharmaceuticals Inc | CATÉCHOL DERIVATIVES FOR THE TREATMENT OF OXIDATIVE STRESS DISEASES |
WO2013006736A1 (en) | 2011-07-06 | 2013-01-10 | Edison Pharmaceuticals, Inc | Treatment of leigh syndrome and leigh-like syndrome, including complications of sucla2 mutations, with tocotrienol quinones |
ES2795798T3 (es) | 2011-07-06 | 2020-11-24 | Ptc Therapeutics Inc | Tratamiento de aciduria metilmalónica, aciduria isovalérica, y otras acidurias orgánicas con tocotrienol quinonas |
JP2014520894A (ja) | 2011-07-19 | 2014-08-25 | エジソン ファーマシューティカルズ, インコーポレイテッド | 非アルファトコトリエノールの存在下でのアルファトコトリエノールの選択的酸化のための方法 |
WO2014039862A1 (en) | 2012-09-07 | 2014-03-13 | Edison Pharmaceuticals, Inc. | Quinone derivatives for use in the modulation of redox status of individuals |
US20140275045A1 (en) | 2013-03-15 | 2014-09-18 | Edison Pharmaceuticals, Inc. | Phenazine-3-one and phenothiazine-3-one derivatives for treatment of oxidative stress disorders |
US9670170B2 (en) | 2013-03-15 | 2017-06-06 | Bioelectron Technology Corporation | Resorufin derivatives for treatment of oxidative stress disorders |
JP2016515526A (ja) | 2013-03-15 | 2016-05-30 | エジソン ファーマシューティカルズ, インコーポレイテッド | 酸化ストレス障害の処置のためのアルキル−ヘテロアリール置換されたキノン誘導体 |
US9868711B2 (en) | 2013-03-15 | 2018-01-16 | Bioelectron Technology Corporation | Phenazine-3-one and phenothiazine-3-one derivatives for treatment of oxidative stress disorders |
US9296712B2 (en) | 2013-03-15 | 2016-03-29 | Edison Pharmaceuticals, Inc. | Resorufin derivatives for treatment of oxidative stress disorders |
MX2015016014A (es) | 2013-05-31 | 2016-04-04 | Edison Pharmaceuticals Inc | Derivados de acido carboxilico para el tratamiento de trastornos por agresion oxidativa. |
US20180002247A1 (en) | 2014-12-16 | 2018-01-04 | Bioelectron Technology Corporation | Methods for chiral resolution of trolox |
KR102626895B1 (ko) | 2014-12-16 | 2024-01-18 | 피티씨 테라퓨틱스, 인크. | (r)-2-하이드록시-2-메틸-4-(2,4,5-트리메틸-3,6-디옥소사이클로헥사-1,4-디에닐)부탄아미드의 다형성 및 무정형 형태 |
JP2018502127A (ja) | 2015-01-12 | 2018-01-25 | バイオエレクトロン テクノロジー コーポレイション | 放射線被曝に対する防護のためのキノン |
WO2017106803A1 (en) | 2015-12-17 | 2017-06-22 | Bioelectron Technology Corporation | Flouroalkyl, flouroalkoxy, phenoxy, heteroaryloxy, alkoxy, and amine 1,4-benzoquinone derivatives for treatment of oxidative stress disorders |
WO2017123823A1 (en) | 2016-01-12 | 2017-07-20 | Bioelectron Technology Corporation | Alkyl-, acyl-, urea-, and aza-uracil sulfide:quinone oxidoreductase inhibitors |
WO2018081644A1 (en) | 2016-10-28 | 2018-05-03 | Bioelectron Technology Corporation | Methods of analyzing p-hydroquinone levels and ratios |
WO2018093957A1 (en) | 2016-11-15 | 2018-05-24 | Bioelectron Technology Corporation | 2-substituted amino-naphth[1,2-d]imidazol-5-one compounds or pharmaceutically acceptable salts thereof cross reference to related applications |
WO2018129411A1 (en) | 2017-01-06 | 2018-07-12 | Bioelectron Technology Corporation | Aryl- and heteroaryl-resorufin derivatives for treatment of oxidative stress disorders and liver and kidney disorders |
-
2012
- 2012-07-19 JP JP2014521798A patent/JP2014520894A/ja not_active Withdrawn
- 2012-07-19 US US14/233,734 patent/US9162957B2/en active Active
- 2012-07-19 WO PCT/US2012/047455 patent/WO2013013078A1/en active Application Filing
- 2012-07-19 CA CA2842486A patent/CA2842486C/en active Active
- 2012-07-19 EP EP12814970.5A patent/EP2734512B1/en active Active
-
2015
- 2015-09-10 US US14/850,855 patent/US9567279B2/en active Active
-
2017
- 2017-01-16 JP JP2017005308A patent/JP6568880B2/ja active Active
- 2017-01-20 US US15/411,861 patent/US10029971B2/en active Active
-
2018
- 2018-04-03 JP JP2018071493A patent/JP2018104471A/ja not_active Withdrawn
- 2018-07-19 US US16/040,281 patent/US10202325B2/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2856414A (en) * | 1958-10-14 | Oxidation of alpha-tocopherol | ||
JP2004504313A (ja) * | 2000-07-14 | 2004-02-12 | ビーエーエスエフ アクチェンゲゼルシャフト | 抗高コレステロール作用を有するトコトリエノールキノン環化生成物 |
US20100105930A1 (en) * | 2008-10-28 | 2010-04-29 | Wesson Kieron E | Process for the production of alpha-tocotrienol and derivatives |
Also Published As
Publication number | Publication date |
---|---|
US9162957B2 (en) | 2015-10-20 |
EP2734512B1 (en) | 2019-11-20 |
EP2734512A4 (en) | 2015-04-08 |
CA2842486A1 (en) | 2013-01-24 |
US10202325B2 (en) | 2019-02-12 |
US20170297991A1 (en) | 2017-10-19 |
WO2013013078A8 (en) | 2016-05-06 |
US20180319730A1 (en) | 2018-11-08 |
US10029971B2 (en) | 2018-07-24 |
US9567279B2 (en) | 2017-02-14 |
JP2018104471A (ja) | 2018-07-05 |
WO2013013078A1 (en) | 2013-01-24 |
US20160002138A1 (en) | 2016-01-07 |
JP6568880B2 (ja) | 2019-08-28 |
US20140249332A1 (en) | 2014-09-04 |
EP2734512A1 (en) | 2014-05-28 |
JP2014520894A (ja) | 2014-08-25 |
CA2842486C (en) | 2022-09-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6568880B2 (ja) | 非アルファトコトリエノールの存在下でのアルファトコトリエノールの酸化のための方法 | |
US20110263720A1 (en) | Synthesis of alpha-tocopherolquinone derivatives, and methods of using the same | |
JP2018516281A (ja) | 安定なカンナビノイド製剤 | |
BG108071A (bg) | Есенциални мастни n-3-киселини в лечението на сърдечна недостатъчност и сърдечна слабост | |
US20190175542A1 (en) | Methods of treating age related disorders | |
US10744102B2 (en) | Methods and compositions for preventing or treating tissue calcification | |
US10987320B2 (en) | Methods and compositions for preventing or treating calciphylaxis | |
US10052305B2 (en) | Lipoic acid and derivatives thereof for the treatment of cystinuria | |
US20180042886A1 (en) | Methods of treating age related disorders | |
JPS6011422A (ja) | 抗筋ジストロフイ−症剤 | |
JPH0759505B2 (ja) | シクロペンテノン類を活性成分とする骨形成促進剤 | |
JPH09227376A (ja) | 白血病治療剤 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20170116 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20171003 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20171221 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20180215 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180403 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20180710 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20181005 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20181206 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190121 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190418 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20190704 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20190805 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6568880 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
S111 | Request for change of ownership or part of ownership |
Free format text: JAPANESE INTERMEDIATE CODE: R313113 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
S531 | Written request for registration of change of domicile |
Free format text: JAPANESE INTERMEDIATE CODE: R313531 |
|
R350 | Written notification of registration of transfer |
Free format text: JAPANESE INTERMEDIATE CODE: R350 |