AP874A - Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkysilylated derivatives and alkaline iodides, and pharmacological activities thereof. - Google Patents
Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkysilylated derivatives and alkaline iodides, and pharmacological activities thereof. Download PDFInfo
- Publication number
- AP874A AP874A APAP/P/1998/001180A AP9801180A AP874A AP 874 A AP874 A AP 874A AP 9801180 A AP9801180 A AP 9801180A AP 874 A AP874 A AP 874A
- Authority
- AP
- ARIPO
- Prior art keywords
- oil
- fatty acid
- iodinated
- derivatives
- process according
- Prior art date
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- 235000014113 dietary fatty acids Nutrition 0.000 title claims abstract description 75
- 239000000194 fatty acid Substances 0.000 title claims abstract description 75
- 229930195729 fatty acid Natural products 0.000 title claims abstract description 75
- -1 fatty acid esters Chemical class 0.000 title claims abstract description 46
- 150000004665 fatty acids Chemical class 0.000 title claims abstract description 29
- 150000004694 iodide salts Chemical class 0.000 title description 2
- 230000000144 pharmacologic effect Effects 0.000 title 1
- 235000019484 Rapeseed oil Nutrition 0.000 claims abstract description 18
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims abstract description 15
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims abstract description 14
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims abstract description 11
- 235000019387 fatty acid methyl ester Nutrition 0.000 claims abstract description 8
- 229940071870 hydroiodic acid Drugs 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 206010018498 Goitre Diseases 0.000 claims abstract description 6
- 235000009518 sodium iodide Nutrition 0.000 claims abstract description 5
- 239000000446 fuel Substances 0.000 claims abstract description 4
- 239000005051 trimethylchlorosilane Substances 0.000 claims abstract description 4
- 201000003872 goiter Diseases 0.000 claims abstract description 3
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 23
- 230000008569 process Effects 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 9
- 239000011630 iodine Substances 0.000 claims description 9
- 235000019482 Palm oil Nutrition 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 8
- 239000002540 palm oil Substances 0.000 claims description 8
- 239000003921 oil Substances 0.000 claims description 6
- 235000019198 oils Nutrition 0.000 claims description 6
- 239000004006 olive oil Substances 0.000 claims description 6
- 235000008390 olive oil Nutrition 0.000 claims description 6
- 239000010491 poppyseed oil Substances 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 5
- 235000019483 Peanut oil Nutrition 0.000 claims description 5
- 235000019485 Safflower oil Nutrition 0.000 claims description 5
- 235000019486 Sunflower oil Nutrition 0.000 claims description 5
- 239000003240 coconut oil Substances 0.000 claims description 5
- 235000019864 coconut oil Nutrition 0.000 claims description 5
- 239000008169 grapeseed oil Substances 0.000 claims description 5
- 239000000944 linseed oil Substances 0.000 claims description 5
- 235000021388 linseed oil Nutrition 0.000 claims description 5
- 239000000312 peanut oil Substances 0.000 claims description 5
- 235000005713 safflower oil Nutrition 0.000 claims description 5
- 239000003813 safflower oil Substances 0.000 claims description 5
- 239000008159 sesame oil Substances 0.000 claims description 5
- 235000011803 sesame oil Nutrition 0.000 claims description 5
- 235000012424 soybean oil Nutrition 0.000 claims description 5
- 239000002600 sunflower oil Substances 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 5
- 239000008158 vegetable oil Substances 0.000 claims description 5
- 239000010497 wheat germ oil Substances 0.000 claims description 5
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 4
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-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
- 239000005642 Oleic acid Substances 0.000 claims description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 claims description 4
- 235000005687 corn oil Nutrition 0.000 claims description 4
- 239000002285 corn oil Substances 0.000 claims description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 231100000331 toxic Toxicity 0.000 claims description 3
- 230000002588 toxic effect Effects 0.000 claims description 3
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 claims description 2
- DPUOLQHDNGRHBS-UHFFFAOYSA-N Brassidinsaeure Natural products CCCCCCCCC=CCCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-UHFFFAOYSA-N 0.000 claims description 2
- URXZXNYJPAJJOQ-UHFFFAOYSA-N Erucic acid Natural products CCCCCCC=CCCCCCCCCCCCC(O)=O URXZXNYJPAJJOQ-UHFFFAOYSA-N 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 229940114079 arachidonic acid Drugs 0.000 claims description 2
- 235000021342 arachidonic acid Nutrition 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- DPUOLQHDNGRHBS-KTKRTIGZSA-N erucic acid Chemical compound CCCCCCCC\C=C/CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-KTKRTIGZSA-N 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 239000012535 impurity Substances 0.000 claims description 2
- 238000011065 in-situ storage Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 230000003449 preventive effect Effects 0.000 claims description 2
- WBHHMMIMDMUBKC-XLNAKTSKSA-N ricinelaidic acid Chemical compound CCCCCC[C@@H](O)C\C=C\CCCCCCCC(O)=O WBHHMMIMDMUBKC-XLNAKTSKSA-N 0.000 claims description 2
- 229960003656 ricinoleic acid Drugs 0.000 claims description 2
- FEUQNCSVHBHROZ-UHFFFAOYSA-N ricinoleic acid Natural products CCCCCCC(O[Si](C)(C)C)CC=CCCCCCCCC(=O)OC FEUQNCSVHBHROZ-UHFFFAOYSA-N 0.000 claims description 2
- 230000001173 tumoral effect Effects 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 230000003110 anti-inflammatory effect Effects 0.000 claims 1
- 150000002194 fatty esters Chemical class 0.000 claims 1
- 230000000699 topical effect Effects 0.000 claims 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims 1
- 230000009471 action Effects 0.000 abstract description 4
- 239000012530 fluid Substances 0.000 abstract description 2
- 238000010952 in-situ formation Methods 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- 239000000047 product Substances 0.000 description 15
- 238000001228 spectrum Methods 0.000 description 12
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 230000009469 supplementation Effects 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 206010067997 Iodine deficiency Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000004133 Sodium thiosulphate Substances 0.000 description 2
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 2
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 2
- YMEKEHSRPZAOGO-UHFFFAOYSA-N boron triiodide Chemical compound IB(I)I YMEKEHSRPZAOGO-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 230000000378 dietary effect Effects 0.000 description 2
- 229960004132 diethyl ether Drugs 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 235000006479 iodine deficiency Nutrition 0.000 description 2
- 229960004488 linolenic acid Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000010409 thin film Substances 0.000 description 2
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 2
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- VOLGAXAGEUPBDM-UHFFFAOYSA-N $l^{1}-oxidanylethane Chemical compound CC[O] VOLGAXAGEUPBDM-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- UEILPVLZADSHBO-UHFFFAOYSA-N 2-bromohexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCC(Br)C(Cl)=O UEILPVLZADSHBO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- 235000005637 Brassica campestris Nutrition 0.000 description 1
- 241001301148 Brassica rapa subsp. oleifera Species 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- 206010010510 Congenital hypothyroidism Diseases 0.000 description 1
- 208000027219 Deficiency disease Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 208000005176 Hepatitis C Diseases 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 206010039840 Secondary hypothyroidism Diseases 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 238000004061 bleaching Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- XVJFCWCVLJOKRP-UHFFFAOYSA-N boron;n-ethylethanamine Chemical compound [B].CCNCC XVJFCWCVLJOKRP-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 208000029305 central congenital hypothyroidism Diseases 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 235000020778 linoleic acid Nutrition 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- 229940093930 potassium iodate Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 230000006016 thyroid dysfunction Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Endocrinology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Fats And Perfumes (AREA)
Abstract
Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof which are stable and are of a fluid pharmaceutical quality, are obtained by iodohydrination involving, in an organic medium, alkylsilylated derivatives of the trimethylsilyl chloride or trimethylchlorosilane type reacting with an alkaline iodide of the sodium iodide type, followed by the in-situ formation of hydroiodic acid by action of water, hydroiodic acid reacting, for example, with fatty acid esters and, in particular, with the fatty acid methyl esters of rapeseed oil recommended as biological fuel for petrol engines, yielding a product with advantageous low cost price and used in therapy, in particular in treatment of iodo-deprived goitre.
Description
Description
The invention relates to iodinated fatty acid esters and iodinated fatty acids and derivatives thereof obtained by iodohydrination involving the introduction of alkylsilylated derivatives with alkaline iodides used in the treatment of endemic goitre and pharmaceutical compositions containing them. They can also be used as contrast compounds in radiology and as a vehicle for chemiemboiisation.
Endemic goitre is a deficiency disease which constitutes one of the most serious public health problems faced by the World Health Organisation (WHO). According to official WHO records, 1,000 million individuals, meaning about 20 % of the world’s population, are affected by iodine deficiency, mainly in developing countries (Hetzel B.S., Potter B.J. and Dulberg E.M. The iodine deficiency disorders : nature, pathogenesis and epidemiology. World Rev. Nutr. Diet. 62 : 59-119 (1990)). Almost all of these countries manifest variable degrees of prevalence. In the most severely affected regions, up to 80 % of subjects may suffer from thyroid dysfunction : this is documented by the appearance of unattractive glandular hypertrophy which may undergo secondary hypothyroidism with neurological problems. Adolescent girls and women of child-bearing age constitute vulnerable groups and can give birth to a high proportion of up to 10 % of newborn babies suffering from a particular form of irreversible mental disability known as endemic cretinism and considered as the most threatening medical and social complication.
It is universally accepted that iodine dietary deficiency is the primary and predominant cause of this nutritional scourge. The geological nature and the geographical environment therefore appear to be the main factors determining this situation although some dietary compounds are incriminated as aggravating secondary causes. Appropriate treatment therefore implies the supplementation of deficient populations with additional amounts of iodine to cover physiological requirements.
8110/86 /d/dV
APO00874
Theoretically, this objective is easy to achieve. However, experience over recent decades has shown that the traditional means used for iodine supplementation (drinking water, table salt, bread-flour) encounter major spreading obstacles associated with transportation, storage and consumption conditions in (sub)tropical regions. Indeed, iodine is administered in the form of sodium or potassium iodide or iodate releasing the halogen in a non-storable form in adipose tissues. It is therefore necessary to ingest this form of iodinated vehicle on a daily basis during years. The nutritional benefits are irregular and slow to obtain, and this form of supplementation does not allow to overcome the emergency problems encountered in regions of high prevalence.
There exists also an iodinated oil characterized by long-lasting effects known as Lipiodol® (Societe Guerbet) which, administered in a single yearly oral or parenteral dose, demonstrated anti-goitrous preventive and therapeutic effects. This iodinated oil, originally designed as contrast product in radiology, is expressed from the rare and relatively expensive poppyseed oil (Somnifer papaverum). Although the good tolerance and curative properties of Lipiodol® are known for a long time, this product has not compelled recognition as a tool for massive eradication owing to its relatively high cost with respect to the huge requirements of the Third World.
Our invention is intended to overcome this handicap : a new iodinated drug is proposed which is formed from iodinated fatty acid esters or iodinated fatty acids and derivatives thereof which are of pharmaceutical purity, stable, free of toxic contaminants, totally iodinated, with no double bonds, and obtained by action of an alkylsilylated reagent and an alkaline iodide on fatty acid esters or fatty acids, revealing therapeutic properties.
For example, it is possible to produce low cost iodinated fatty acid esters from iodinated fatty acid methyl esters obtained by original synthesis from rapeseed oil (Brassica campestris) used as very low cost price biological fuel in car engines, allowing to undertake mass campaigns. The new product is characterized by higher bioavailability and extended therapeutic effects because the iodine is bound to three fatty acids (oleic acid n-9, linoleic acid n-6 and α-linolenic acid n-3), of which the last two are essentia! fatty acids and which are precursors of the three main fatty acid metabolic pathways. Our iodinated product is exclusively proposed for oral administration in order to avoid the risks of blood viral contamination (hepatitis B and C, HIV).
AP/P/ 9 8/01 180
APO 0 0 8 7 4
Several methods have already been described for the transformation of unsaturated fatty acids or of unsaturated fatty acid esters into iodinated saturated derivatives. Oleic acid can be submitted to hydrobromation followed by nucleophilic substitution via potassium iodide after action of hydrobromic acid (J. F. Lane and H. W. Heine : On cyclic Intermediates in Substitution Reactions. I. The Alkaline Hydrolysis of Some Aliphatic Rromoanids. ,J. Am. Chem. Soc. 1951, 73. 1348-1350). Olive oil cooled to the region of the setting point is saturated directly with hydroiodic acid. Other fatty acids have been considered. (A. Guerbet, A. Gibaud, G. Tilly, R. Joussot, V. Loth and M. Guerbet ; Monoiodostearate d'ethyle. Preparation et caractbres analytiques. Ann. pharm. fr., 1965, 23, No. 11, 663-671). Direct iodination with hydroiodic acid is also carried out using dehydrating substances such as polyphosphoric acids, phosphorus pentoxide (W. Kuhn, H. Hartner, F. Schindler, I. Sandner and K. Hering ; German patent P 35 13 322.6/C 07 C 69/62, 1985). Hydroiodination can also be carried out with iodine in the presence of alumina generating hydroiodic acid (L. J. Stewart, D. Gray, R. M. Pagni and G. W. Kabalka; A convenient Method for the addition of HI to unsaturated hydrocarbons using l2 on AI2O3, Tetrahedron Lett, 1987, Vol. 28, No 39, 4497-4498). Hydroiodination has also been carried out using the boron-N, N-diethylamine complex involving boron triiodide. (Ch. Kishan Reddy and M. Periasamy ; A new simple procedure for the generation and addition of HI to alkenes and alkynes using BI3 : N, N-diethylaniline complex and acetic acid. Tetrahedron Lett. , 1990, Vol. 31, No 13, 1919-1920). Hydroiodination with potassium iodide in orthophosphoric acid can also be envisaged (Organic Synthesis, Vol. 9, 66).
The document JP-A 53119817 is also known, which discloses the synthesis of glyceryl tri-(2-iodohexadecanoate) in two stages. In a first stage, 2-bromopalmitoyl chloride reacts with glycerine in a water-free benzene/pyridine solvent to obtain 36 % of glyceryl tri-(2bromohexadecanoate) after purification. This product then reacts with Nal in acetone to yield 74 % of glyceryl tri-(2-iodohexadecanoate) after treatment with Na2S2O3, purification, drying, etc.
As specified, among others, in German patent No. C07 C69/62/P 3513 323.8 dated
13.4.1985 and belonging to W. Kuhn et al. , the methods for the preparation of iodinated compounds lead to products containing toxic impurities, products which are unstable in air and light during the preparation and storage thereof. Our method of preparation leads, in particular, to a product characterized by various constituents and devoid of
ΛΡ/Ρ/ 0 ft / ft 1 1 8 0
AP Ο Ο Ο 8 7 4 double bonds which are a source of instability, in particular in the presence of oxidation derivatives and free radicals.
Iodinated fatty acid esters prepared by iodohydrination involving alkysilylated derivatives and an alkaline iodide forming the substrate of the invention exhibit the form of a pharmaceutically pure, stable, light yellow, fluid, oily liquid having a relatively low cost price. The fatty acid esters used for the preparation of iodinated derivatives involving an alkylsilylated compound and an alkaline iodide can be, for example, fatty acid triglycerides originating from vegetable oils of the rapeseed oil, poppyseed oil, soya oil, safflower oil, groundnut oil, grapeseed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheatgerm oil, coconut oil and palm oil type and from oils of animal origin.
The fatty acid esters used can also be mixtures of fatty acid methyl esters or ethyl esters originating form vegetable oils of the rapeseed oil, poppyseed oil, soya oil, safflower oil, groundnut oil, grapeseed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheatgerm oil, coconut oil and palm oil type and oils of animal origin.
It is of particular interest for large-scale production to use as raw material the fatty acid methyl esters originating from rapeseed oil used as low cost price biological fuel for car engines. Fatty acids of the oleic acid, linoleic acid, α-linolenic acid, erucic acid, arachidonic acid and ricinoleic acid type can also be used as raw substrates.
The process for obtaining iodinated fatty acid esters or iodinated fatty acids implies the reaction of an alkaline iodide with an alkylsilylated halide in an organic medium yielding in situ, in the presence of water, hydroiodic acid reacting either with the fatty acid ester(s) or with the fatty acids.
To obtain iodinated fatty acid esters or iodinated fatty acids, for example, sodium iodide is reacted with trimethylsilyl chloride or trimethylchlorosilane in acetonitrile followed by the action of water and the addition either of unsaturated fatty acid esters or of unsaturated fatty acids.
The iodohydrination of fatty acid esters can be carried out according to the following reaction :
CH3CN H2O (1)
Nal + SiMe3CI-----> NaCl + SiMe3l-------> SiMe30H + HI-----> iodohydrin (1) fatty acid esters or fatty acids
AP/P/ 9 8/01180
ΑΡΰυθ874
The mode of operation, for example, for unsaturated fatty acid esters is as follows : 89.25 ml of trimethychlorosilane (or trimethylsilyl chloride) are added to a solution of 107.1 g of sodium iodide in 550 ml of acetonitrile in a nitrogen atmosphere and at 0°C. 6.65 ml of water are added dropwise after total addition of the trimethylchlorosilane. A solution of 70 g of unsaturated fatty acid methyl or ethyl esters of rapeseed oil is then added. After 24 hours of reaction with stirring, the reaction is then stopped with 700 ml of water. The mixture is extracted using ether. The organic phase is washed several times with a 10 % solution of sodium thiosulphate then several times with water. It is dried over anhydrous sodium sulphate and the ether is evaporated at a temperature of 90eC over 16 mm of Hg (2133 Pa) in order to eliminate the romaine of cilicoous ether. The residue is brown. The iodinated ratty acid esters dissolved in etner are then Pleached over coal then filtered over alumina to eliminate the peroxides. The ether is evapored and the traces of solvent are eliminated using a vane pump. The mixture of iodinated fatty acid esters obtained is golden yellow and has good fluidity. This mixture can be identified by 1H NMR and 13C NMR spectrometry. This method of synthesis of iodinated fatty acid esters was carried out over larger quantities. Other water-immiscible solvents can be used. The insolubility of sodium chloride in acetonitrile allows the total displacement of the reaction toward the formation of trimethylsilyl iodide. This reaction is exothermic and allows the generation of hydroiodic acid and hydroxylated trimethylsilyl. The secondary product βίΜθβΟΗ is c eliminated after the iodohydrination reaction by simple evaporation under reduced β pressure and washing in water. The iodohydrination reaction is visually followed by the bleaching of the solution. The sodium thiosulphate allows the elimination of the iodine c present in oxidized form. The final product is free of ethylenic bonds as shown by the ·* absence of any NMR proton signal and 13C signal. On the other hand, no degradation product appears in the NMR of the proton.
Characteristics of rapeseed oil iodinated fatty acid esters :
Nuclear magnetic resonance of the proton (NMR1H) and of the carbon 13 (NMR13C). An
NMR1H spectrum of the iodinated fatty acid esters of rapeseed oil allows to check the disappearance of the ethylene protons by comparison with the spectrum of the noniodinated fatty acid esters of rapeseed oil. Furthermore, this allows to check the absence of traces of solvent diethylether and of silica ether. Moreover, an NMR^C spectrum allows to check the disappearance of the carbons involved in the non-saturated double bounds.
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The NMR1 Η spectra obtained for several productions of iodinated fatty acid ethyl esters of rapeseed oil are identical. No spectrum reveals the presence of diethyiether or silica ether.
° NMR1H spectrum of iodinated fatty acid ethyl esters [NMR1H (CDCI3) over 200 MHz]: 0.89 ppm (3H, m, CH3), 1.20-2.00 ppm (m, CH2 of the chains and CH.sCHpQ). 2.3 ppm (2H, t. CH2-COOEt). 4.2 ppm (m, CHI, CH2-OOC).
0 NMR13C spectrum of iodinated fatty acid ethyl esters [NMR3C (CDCI3) over 200 MHz]: 14 ppm (QH3 at the chain end and CH3CH2O), 28-29 ppm (CHI) 22-24, 30-31, 34 ppm (GH2 of the chains), 39-41 ppm (CH2-CHI), 60 ppm (QH2-O), 173 ppm (COO).
The infrared absorption spectrum (NaCl) has the following characteristic bands : γ (C=O ester) at 1740 cm-1 ; γ (saturated CH) at 2850 end, γ (saturated CH) at 2950 cm'1.
0 NMR1H spectrum of iodinated fatty acid methyl esters [NMR1H (CDCI3) over 200MHz]: 0.89 ppm (3H, m, CH3), 1.25 -1.30 ppm (m, CH2 of the chains), 1,60-1.80 ppm (m, CH2I 2.3 ppm (2H, t, CH2-COO), 3.66 ppm (3H, s, CH3-OOC), 4.12 ppm (m, CHI).
e NMR13C spectrum of iodinated fatty acid methyl esters [NMR13C (CDCI3) over 200 MHz]; 14 ppm (£H3 at the chain end), 28-29 ppm (CHI), 22-24, 31-34 ppm (CH2 of the chains), 38-41 ppm (CH2-CHI), 51 ppm (ΩΗ3-Ο), 173 ppm (COO).
Stability : as most iodinated products are generally unstable substances, it is necessary to check the stability of the iodinated fatty acid esters and/or of the iodinated fatty acids. Stability is investigated by NMR1H, by thin film chromatography and by quantitative analysis of the iodine bound to the fatty acid esters or on the fatty acids.
NMR1H spectra were performed after 2 months, 3 months and 8 months storage at a temperature of 20-22°C, sheltered from the light. The three spectra are identical to that obtained during production. Thin film chromatography (silica gel plate GF 254 AP/T7 9 8/01180
APO 0 0 8 7 4 moving phase : diethylether/hexane 1 : 20 - examination in ultraviolet light at 254 nm and after atomization of a 10 % m/V solution of phosphomolybdenic acid R in alcohol and heating of the plate to 120°C for 5 min) reveals spots identical both in intensity and position to those found on freshly prepared products or in those stored for 8 months.
Stability of iodinated fatty acid esters of rapeseed oil after therapeutic use in the field : the mixture of iodinated fatty acid esters of rapeseed oil was used for the treatment of people living in a region of endemic goitre in Africa. During these surveys, the iodinated esters were submitted to extreme environmental conditions (transportation, exposure to light for several hours and at temperatures of about 45°C). After two weeks of investigations, the iodinated fatty acid esters were analyzed : the NMR1H spectrum was found .to be identical to that of a freshly synthesized oil and thin layer chromatography yields spots identical to those of freshly synthesized iodinated fatty acid esters and does not reveal degradation products. , c
T
Test of tolerance on rats : Before administering the mixture of iodinated fatty acid * j* esters of rapeseed oil to goitrous subjects, the tolerance of the mixture of iodinated esters was tested on adult male rats weighing about 300 g. Each test group consists of 5 rats c submitted to an oral administration of 0.5 ml of mixture of iodinated fatty acid esters of < rapeseed oil. The rats were kept under observation. After one week, the behaviour and general state of the rats in each test group are normal arid identical to those of the control group. The iodinated products prepared by the above-described method are used as generally administered drugs, for example as anti-goitre drugs in the pure state or in combination with appropriate excipients in the form of a drinkable or ingestable liquid, capsules or ampoules for example. These iodinated products can also be used as generally or topically administered drugs, for example as contrast products or as antiinflammatory agents in rheumatoid therapies. These products can be used as drugs which are administered using general or local intravascular delivery for the treatment of certain cancers by chemiembolisation involving the prescription of an anti-cancer drug emulsified into iodinated fatty acid esters acting as carriers to target tumoral lipophilic cells.
Claims (15)
1. Process for obtaining at least one iodinated fatty acid or at least one iodinated fatty acid ester or iodinated derivatives thereof which have pharmaceutical purity, are stable and free from toxic impurities, characterized in that it involves reacting an alkaline iodide with an alkylsilylated reagent in an organic medium giving rise in situ, in the presence of water, to hydrolodic acid reacting with the fatty acid(s), the fatty acid ester(s) or derivatives thereof in such a way that all the double bonds initially present in the fatty acid(s) or fatty ester(s) or derivatives thereof are saturated in iodine in a proportion of one molecule of hydroiodic acid per double bond.
2. Process according to claim 1, characterized in that the alkaline iodide is sodium iodide.
3. Process according to claim 1, characterized in that the alkylsilylated reagent is an alkylsilylated halide.
o
4. Process according to claim 3, characterized in that the alkylsilylated halide^ is trimethylsiiyl chloride or trimethylchlorosilane.
5. Process according to claim 1, characterized in that the organic medium rcontains acetonitrile. ®
6. Process according to claim 1, characterized in that the fatty acid ester(s) consist(s) of fatty acid triglyceride(s) originating from vegetable oil(s) selected from the^ group formed by rapeseed oil, poppyseed oil, soya oil, safflower oil, groundnut oil,L> grapeseed oil, sunflower oil, linseed oil, com oil, olive oil, sesame oil, wheatgerm oil,££ coconut oil, palm oil and oils of animal origin.
7. Process according to claim 1, characterized in that the fatty acid ester(s) consist(s) of fatty acid methyl ester(s) originating from vegetable oil(s) selected from the group formed by rapeseed oil, poppyseed oil, soya oil, safflower oil, groundnut oil, grapeseed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheatgerm oil, coconut oil, palm oil and oils of animal origin.
8. Process according to claim 7, characterized in that the fatty acid ester(s) consist(s) of fatty acid methyl ester(s) originating from rapeseed oil, used as low cost price biological fuel for car engines.
9. Process according to claim 1, characterized in that the fatty acid ester(s) consist (s) of fatty acid ethyl ester(s) originating from vegetable oil(s) selected from the group formed by rapeseed oil, poppyseed oil, soya oil, safflower oil, groundnut oil, grapeseed oil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil, wheatgerm oil, coconut oil, palm oil and oils of animal origin.
AP o ο υ 8 7 4
10. Process according to claim 1, characterized in that the fatty acid(s) is/are selected from the group formed by oleic acid, linoleic acid, α-Iinolenic acid, erucic acid, arachidonic acid and ricinoleic acid.
1.1. Iodinated fatty acid(s), iodinated fatty acid ester(s) or iodinated derivatives thereof, obtained by the process according to any one of the claims 1 to 10 and not having the double bond, for use as a drug.
12. Use of the iodinated fatty acid(s), iodinated fatty acid ester(s) or iodinated derivatives thereof according to claim 11, characterized in that the drug is intended for the preventive and/or therapeutic treatment of goitre and is used in the pure state or in combination with appropriate excipients in drinkable or ingestable form, in the form of capsules or ampoules, for example.
13. Use of the iodinated fatty acid(s), iodinated fatty acid ester(s) or iodinatedQ derivatives thereof according to claim 11, characterized in that the drug is intended forQQ anti-inflammatory treatment in rheumatoid therapies, administered by general or topical methods. * β
14. Iodinated fatty acid(s), iodinated fatty acid ester(s) or iodinated derivatives thereof, obtained by the process according to any one of the claims 1 to 10 for the use in oc the treatment of certain cancers by chemiemboiization.
15. Iodinated fatty acid(s), iodinated fatty acid ester(s) or iodinated derivatives thereof, obtained by the process according to claim 14 for the use as carrier(s) for anticancer drug emulsified in said iodinated fatty acid(s), iodinated fatty acid ester(s) Or derivatives thereof, for tumoral lipophilic cells.
16. Iodinated fatty acid(s), iodinated fatty acid ester(s) or iodinated derivatives thereof, obtained by the process according to any one of the claims 1 to 10 for the use as a contrast product.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9508582A FR2736549B1 (en) | 1995-07-11 | 1995-07-11 | ESTERS OF IODINE FATTY ACIDS, IODINE FATTY ACIDS AND DERIVATIVES THEREOF, OBTAINED BY IODOHYDRINATION USING ALKYLSILYL DERIVATIVES WITH ALKALINE IODIDES AND THEIR PHARMACOLOGICAL ACTIVITIES |
| PCT/FR1996/001075 WO1997003038A1 (en) | 1995-07-11 | 1996-07-10 | Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkylsilylated derivatives and alkaline iodides, and pharmacological activities thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AP874A true AP874A (en) | 2000-09-13 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1998/001180A AP874A (en) | 1995-07-11 | 1996-07-10 | Iodinated fatty acid esters, iodinated fatty acids and derivatives thereof, produced by iodohydrination using alkysilylated derivatives and alkaline iodides, and pharmacological activities thereof. |
Country Status (21)
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| US (1) | US6124357A (en) |
| EP (1) | EP0840720B1 (en) |
| CN (1) | CN1077880C (en) |
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| FR (1) | FR2736549B1 (en) |
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| TR (1) | TR199800031T1 (en) |
| UA (1) | UA56142C2 (en) |
| WO (1) | WO1997003038A1 (en) |
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| US6426367B1 (en) * | 1999-09-09 | 2002-07-30 | Efa Sciences Llc | Methods for selectively occluding blood supplies to neoplasias |
| FR2891461B1 (en) * | 2005-09-30 | 2010-09-03 | Jacques Theron | INJECTABLE VISCOUS MEDICINAL PREPARATION COMPRISING ETHANOL AND X-RAY OPAQUE LIPOSOLUBLE COMPOUND |
| CN101245007B (en) * | 2008-03-13 | 2011-03-23 | 武汉工程大学 | Process for producing iodination vegetable oil fatty acid ethyl ester |
| FR2976491B1 (en) * | 2011-06-14 | 2015-07-10 | R I P H | IODIZED FATTY ACID ESTERS CONTAINING AT LEAST 50 PER CENT OF MONOIODO STEARIC ACID ESTERS OR DERIVATIVES IN THE FORM OF A SOFT CAPSULE OR GELULE, USEFUL IN A NUCLEAR ACCIDENT. |
| CN107287029B (en) * | 2016-05-30 | 2021-04-06 | 江苏恒瑞医药股份有限公司 | Preparation method of iodized vegetable oil fatty acid ethyl ester |
| CN109251144B (en) * | 2017-07-12 | 2021-06-18 | 财团法人食品工业发展研究所 | The preparation method of iodinated fatty acid ethyl ester |
| CN109251142A (en) * | 2017-07-12 | 2019-01-22 | 财团法人食品工业发展研究所 | Preparation method of iodized fatty acid ethyl ester |
| EA202090139A1 (en) | 2017-08-07 | 2020-08-06 | Юниверсити Оф Женева | CONTRAST AGENT FOR COMPUTER TOMOGRAPHY |
| CN110387286A (en) * | 2018-04-18 | 2019-10-29 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of iodized vegetable oil fatty acid ethyl ester |
| CN109438240B (en) * | 2018-09-10 | 2022-05-03 | 季珉 | Preparation method of stable iodized linoleate |
| AU2020223505B2 (en) | 2019-02-13 | 2024-11-21 | Adiposs SA | CT contrast agent for detection of cachexia |
| CN114606055B (en) * | 2020-12-08 | 2024-02-13 | 成都西岭源药业有限公司 | Method for removing unstable iodine combined in iodized vegetable oil fatty acid ethyl ester |
| JP2024530159A (en) * | 2021-08-02 | 2024-08-16 | マイクロベンション インコーポレイテッド | Iodized fatty acids for medical imaging |
| PL245039B1 (en) * | 2022-02-15 | 2024-04-22 | Centrum Badan I Rozwoju Tech Dla Przemyslu Spolka Akcyjna | Bioactive candle and method of producing bioactive candle |
| WO2025145066A1 (en) * | 2023-12-28 | 2025-07-03 | Navinta, Llc | An improved process for preparation of ethiodized oil |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3513323A1 (en) * | 1985-04-13 | 1986-10-23 | Merck Patent Gmbh, 6100 Darmstadt | STABILIZED IODINE FATS AND METHOD FOR THE PRODUCTION THEREOF |
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| JPS53119817A (en) * | 1977-03-26 | 1978-10-19 | Sinloihi Co Ltd | Glycerilltri*22iodoohexadecanoate* and process for preparing same |
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1995
- 1995-07-11 FR FR9508582A patent/FR2736549B1/en not_active Expired - Fee Related
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1996
- 1996-07-10 RO RO98-00028A patent/RO120337B1/en unknown
- 1996-07-10 AP APAP/P/1998/001180A patent/AP874A/en active
- 1996-07-10 TR TR1998/00031T patent/TR199800031T1/en unknown
- 1996-07-10 WO PCT/FR1996/001075 patent/WO1997003038A1/en active IP Right Grant
- 1996-07-10 AT AT96924964T patent/ATE249414T1/en not_active IP Right Cessation
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- 1996-07-10 US US08/981,931 patent/US6124357A/en not_active Expired - Lifetime
- 1996-07-10 DE DE69629928T patent/DE69629928T2/en not_active Expired - Lifetime
- 1996-07-10 AU AU65234/96A patent/AU6523496A/en not_active Abandoned
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- 1996-07-10 PL PL96324383A patent/PL185807B1/en not_active IP Right Cessation
- 1996-07-10 HU HU9901340A patent/HUP9901340A3/en unknown
- 1996-07-10 BR BR9609610-1A patent/BR9609610A/en active Search and Examination
- 1996-07-11 CN CN96107188A patent/CN1077880C/en not_active Expired - Fee Related
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- 1996-07-11 MA MA24310A patent/MA23935A1/en unknown
- 1996-10-07 UA UA98020668A patent/UA56142C2/en unknown
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3513323A1 (en) * | 1985-04-13 | 1986-10-23 | Merck Patent Gmbh, 6100 Darmstadt | STABILIZED IODINE FATS AND METHOD FOR THE PRODUCTION THEREOF |
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| DE69629928T2 (en) | 2004-07-22 |
| CN1077880C (en) | 2002-01-16 |
| HUP9901340A2 (en) | 1999-09-28 |
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| EA199800120A1 (en) | 1998-10-29 |
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| AU6523496A (en) | 1997-02-10 |
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| FR2736549A1 (en) | 1997-01-17 |
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| EP0840720A1 (en) | 1998-05-13 |
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| IN185195B (en) | 2000-12-02 |
| WO1997003038A1 (en) | 1997-01-30 |
| EP0840720B1 (en) | 2003-09-10 |
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| DE69629928D1 (en) | 2003-10-16 |
| PL185807B1 (en) | 2003-08-29 |
| OA10650A (en) | 2002-09-18 |
| MX9800322A (en) | 1998-09-30 |
| RO120337B1 (en) | 2005-12-30 |
| CN1143067A (en) | 1997-02-19 |
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