RU2291147C2 - [3h]-fluvastatin highly labeled with tritium - Google Patents
[3h]-fluvastatin highly labeled with tritium Download PDFInfo
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- RU2291147C2 RU2291147C2 RU2004138133/04A RU2004138133A RU2291147C2 RU 2291147 C2 RU2291147 C2 RU 2291147C2 RU 2004138133/04 A RU2004138133/04 A RU 2004138133/04A RU 2004138133 A RU2004138133 A RU 2004138133A RU 2291147 C2 RU2291147 C2 RU 2291147C2
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Изобретение относится к области органической химии и может найти применение в аналитической химии, биоорганической химии, биохимии и прикладной медицине.The invention relates to the field of organic chemistry and can find application in analytical chemistry, bioorganic chemistry, biochemistry and applied medicine.
При изучении физиологически активных соединений необходимы их меченые аналоги.In the study of physiologically active compounds, their labeled analogues are necessary.
Известно, что замена атомов соединений на их меченые аналоги не приводит к изменению каких-либо свойств исходного соединения (Evans Е.А. - Tritium and its compounds London Butterworths, 1974, p.48).It is known that replacing the atoms of compounds with their labeled analogues does not lead to a change in any properties of the starting compound (Evans E.A. - Tritium and its compounds London Butterworths, 1974, p. 48).
Известна [R*,S*-(Е)]-(±)-7-[3-(4-фторофенил)-1-(1-метилэтил)-1Н-индол-2-ил]-3,5-дигидрокси-6-гептеновая кислота формулы:Known [R *, S * - (E)] - (±) -7- [3- (4-fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl] -3,5-dihydroxy -6-heptenoic acid of the formula:
Данное соединение, получившее наименование «флувастатин», является сильным ингибитором редуктаз (E.Leitersdorfet at., Eur.J.Clin.Pharmacol. 1993. Vol.45. 513 [1].This compound, called fluvastatin, is a potent inhibitor of reductases (E. Leitersdorfet at., Eur. J. Clin. Pharmacol. 1993. Vol.45. 513 [1].
Известен меченный тритием аналог флувастатина, содержащий метку в ортоположении относительно атома фтора в фторфенильном заместителе (База данных REGISTRY on STN INTERNATIONAL, №776261-24-6 от 08.11.2004) [2].Known tritium-labeled analogue of fluvastatin containing a label in the orthogonal position relative to the fluorine atom in the fluorophenyl substituent (REGISTRY on STN INTERNATIONAL Database, No. 776261-24-6 of 08.11.2004) [2].
Однако молярная радиоактивность данного известного соединения низкая.However, the molar radioactivity of this known compound is low.
Техническим результатом, достигаемым настоящим изобретением, является расширение ассортимента меченых аналогов физиологически активных соединений, повышение молярной радиоактивности целевого продукта.The technical result achieved by the present invention is to expand the range of labeled analogues of physiologically active compounds, increasing the molar radioactivity of the target product.
Достигается указанный технический результат получением высокомеченного тритием [3Н]-флувастатина формулы:This technical result is achieved by obtaining highly labeled tritium [ 3 H] -fluvastatin of the formula:
с молярной радиоактивностью 40-45 Ки/ммоль.with a molar radioactivity of 40-45 Ci / mmol.
Ниже приведен пример реализации изобретения.The following is an example implementation of the invention.
Пример I.Example I.
Раствор 4 мг флувастатина в 0.1 мл метанола добавляли к 100 мг катализатора Линдлара 6% Pd/BaSO4, Метанол удаляли упариванием на роторном испарителе и лиофилизировали. Катализатор с нанесенным на него веществом переносили в реакционную ампулу. Анализ показал, что на катализаторе адсорбировалось 3.5 мг флувастатина. Затем ампулу вакуумировали до давления 0.1 Па, заполняли газообразным тритием до давления 333 гПа и выдерживали при температуре 180°С 6 мин. Избыток газообразного трития удаляли вакуумированием. Полученный [3Н]-флувастатин экстрагировали с катализатора метанолом (5×2 мл) и отделяли фильтрованием. Лабильный тритий удаляли, несколько раз растворяя вещество в метаноле (5×2 мл) и упаривая последний.A solution of 4 mg of fluvastatin in 0.1 ml of methanol was added to 100 mg of Lindlar catalyst 6% Pd / BaSO 4 , Methanol was removed by evaporation on a rotary evaporator and lyophilized. The catalyst coated with the substance was transferred into a reaction vial. Analysis showed that 3.5 mg of fluvastatin was adsorbed on the catalyst. Then, the ampoule was evacuated to a pressure of 0.1 Pa, filled with gaseous tritium to a pressure of 333 hPa and kept at a temperature of 180 ° С for 6 min. Excess tritium gas was removed by vacuum. The resulting [ 3 H] -fluvastatin was extracted from the catalyst with methanol (5 × 2 ml) and separated by filtration. Labile tritium was removed by dissolving the substance several times in methanol (5 × 2 ml) and evaporating the latter.
Очистку [3H]-флувастатина проводили методом ВЭЖХ на колонке: Kromasil 100С 18, 7 мкм, 8·150, элюент - 75% МеОН+0.1% АсОН, 2 мл/мин время удерживания - 7.83 мин. Выход меченого препарата - 15-20%, молярная радиоактивность - 40-45 Ки/ммоль, радиохимическая чистота - 98-99%.[ 3 H] -fluvastatin was purified by HPLC on a column: Kromasil 100C 18, 7 μm, 8 · 150, eluent - 75% MeOH + 0.1% AcOH, 2 ml / min, retention time - 7.83 min. The yield of labeled preparation is 15–20%, molar radioactivity is 40–45 Ci / mmol, and radiochemical purity is 98–99%.
Полученный [3H]-флувастатин хранили в виде этанольного раствора, для чего водно-метанольную фракцию разбавляли водой в 2 раза, сажали на патрон Sep-Pack C18, промыли водой и смыли искомый продукт этанолом.The obtained [ 3 H] -fluvastatin was stored in the form of an ethanol solution, for which the water-methanol fraction was diluted 2 times with water, put on a Sep-Pack C18 cartridge, washed with water and the desired product was washed off with ethanol.
Таким образом получено новое высокомеченное тритием физиологически активное соединение с высокой молярной радиоактивностью.Thus, a new high-tritium-labeled physiologically active compound with high molar radioactivity was obtained.
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