RU2323224C1 - Tritium uniformly labeled 3h-amphotericin b - Google Patents
Tritium uniformly labeled 3h-amphotericin b Download PDFInfo
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- RU2323224C1 RU2323224C1 RU2006143746/04A RU2006143746A RU2323224C1 RU 2323224 C1 RU2323224 C1 RU 2323224C1 RU 2006143746/04 A RU2006143746/04 A RU 2006143746/04A RU 2006143746 A RU2006143746 A RU 2006143746A RU 2323224 C1 RU2323224 C1 RU 2323224C1
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- amphotericin
- tritium
- uniformly labeled
- labeled
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- 229910052722 tritium Inorganic materials 0.000 title claims abstract description 13
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 title claims abstract description 12
- 229960003942 amphotericin b Drugs 0.000 title claims abstract description 10
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 claims description 7
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 2
- 238000003786 synthesis reaction Methods 0.000 abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000003708 ampul Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- HBEQXAKJSGXAIQ-UHFFFAOYSA-N oxopalladium Chemical compound [Pd]=O HBEQXAKJSGXAIQ-UHFFFAOYSA-N 0.000 description 2
- 229910003445 palladium oxide Inorganic materials 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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Abstract
Description
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 бывают необходимы их меченые аналоги.When studying physiologically active compounds, their labeled analogues are necessary.
Известно, что замена атомов водорода органического соединения на их изотопы не приводит к изменению каких-либо свойств исходного соединения (Evans Е.А. - Tritium and its compounds London Butterworths, 1974, p.48) [1].It is known that replacing the hydrogen atoms of an organic compound with their isotopes does not lead to a change in any properties of the starting compound (Evans EA - Tritium and its compounds London Butterworths, 1974, p. 48) [1].
Известен амфотерицин В формулы:Amphotericin B of the formula is known:
Данное соединение является сильным антибактериальным и фунгицидным препаратом (H.A. Gallis et al. // Rev. Infect. Dis. 1990. Vol. 12. 308-329) [2].This compound is a strong antibacterial and fungicidal drug (H.A. Gallis et al. // Rev. Infect. Dis. 1990. Vol. 12. 308-329) [2].
Однако его меченный тритием аналог не описан.However, its tritium-labeled analog is not described.
Техническим результатом, достигаемым настоящим изобретением, является расширение ассортимента меченых аналогов физиологически активных веществ.The technical result achieved by the present invention is to expand the range of labeled analogues of physiologically active substances.
Достигается указанный технический результат получением нового меченого физиологически активного соединения - равномерномеченного тритием амфотерицина В формулы:This technical result is achieved by obtaining a new labeled physiologically active compound - uniformly labeled with tritium amphotericin B of the formula:
На чертеже изображено распределение радиоактивности и оптического поглощения после обработки амфотерицина В тритиевой водой (анализ методом ВЭЖХ: на колонке Kromasil C18, 4.0×150 мм, 7.0 мкм, скорость элюента - 1,0 мл/мин, в системе метанол: 50 мМ буфер рН 2.8, 75:25, время удерживания - 4.28 мин).The drawing shows the distribution of radioactivity and optical absorption after treatment of amphotericin B with tritium water (HPLC analysis: on a Kromasil C 18 column, 4.0 × 150 mm, 7.0 μm, eluent speed - 1.0 ml / min, methanol in the system: 50 mM buffer pH 2.8, 75:25, retention time - 4.28 min).
Ниже приведен пример реализации изобретения.The following is an example implementation of the invention.
Пример I.Example I.
В первую камеру реакционной двухкамерной ампулы помещали катализатор - 40 мг окиси палладия и 55 мг 5% PdO/BaSO4, в другую - раствор 10 мг амфотерицина В и 20 мкл триэтиламина в 250 мкл диметилсульфоксида. Вторую камеру замораживали жидким азотом, ампулу вакуумировали до давления 0,1 Па и заполняли газообразным тритием до давления 333 гПа, затем первую камеру нагревали до 70°С. Окись палладия восстанавливалась, тритиевая вода перемораживалась во вторую камеру. Реакционную ампулу, не прекращая охлаждение второй камеры жидким азотом, вакуумировали до давления 0,1 Па и заполняли аргоном. Затем содержимое второй камеры переносили в первую камеру, которую затем запаивали.A catalyst — 40 mg of palladium oxide and 55 mg of 5% PdO / BaSO 4 — was placed in the first chamber of the reaction two-chamber ampoule; in another, a solution of 10 mg of amphotericin B and 20 μl of triethylamine in 250 μl of dimethyl sulfoxide. The second chamber was frozen with liquid nitrogen, the ampoule was evacuated to a pressure of 0.1 Pa and filled with gaseous tritium to a pressure of 333 hPa, then the first chamber was heated to 70 ° C. Palladium oxide was reduced, tritium water was frozen in the second chamber. The reaction ampoule, without stopping the cooling of the second chamber with liquid nitrogen, was evacuated to a pressure of 0.1 Pa and filled with argon. Then, the contents of the second chamber were transferred to the first chamber, which was then sealed.
Таким образом, реакционная смесь состояла из палладиевого катализатора, 100% тритиевой воды, триэтиламина и раствора амфотерицина В в диметилсульфоксиде. Содержимое ампулы нагревали в течение 30 мин при 120°С. Затем ампулу вскрывали, реакционную смесь разбавляли 0.5 мл метанола, катализатор отделяли фильтрованием, промывали метанолом (5×1 мл). Тритиевую воду и триэтиламин отгоняли на роторе. Лабильный тритий удаляли, несколько раз растворяя вещество в метаноле (5×2 мл) и упаривая последний. Диметилсульфоксид удаляли твердофазной экстракцией. Анализ методом ВЭЖХ показал, что в амфотерицине В было включено 19,5 мКи (см. чертеж).Thus, the reaction mixture consisted of a palladium catalyst, 100% tritium water, triethylamine and a solution of amphotericin B in dimethyl sulfoxide. The contents of the ampoule were heated for 30 min at 120 ° C. Then the ampoule was opened, the reaction mixture was diluted with 0.5 ml of methanol, the catalyst was separated by filtration, washed with methanol (5 × 1 ml). Tritium water and triethylamine were driven off on a rotor. Labile tritium was removed by dissolving the substance several times in methanol (5 × 2 ml) and evaporating the latter. Dimethyl sulfoxide was removed by solid phase extraction. HPLC analysis showed that 19.5 mCi was included in amphotericin B (see drawing).
Выход меченого препарата после хроматографии составил 36%, молярная радиоактивность 18.2 Ки/ммоль.The yield of the labeled preparation after chromatography was 36%, the molar radioactivity of 18.2 Ci / mmol.
Таким образом, получено новое равномерномеченное тритием физиологически активное соединение.Thus, a new physiologically active compound uniformly labeled with tritium was obtained.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RU2006143746/04A RU2323224C1 (en) | 2006-12-12 | 2006-12-12 | Tritium uniformly labeled 3h-amphotericin b |
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| RU2006143746/04A RU2323224C1 (en) | 2006-12-12 | 2006-12-12 | Tritium uniformly labeled 3h-amphotericin b |
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| RU2323224C1 true RU2323224C1 (en) | 2008-04-27 |
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2006
- 2006-12-12 RU RU2006143746/04A patent/RU2323224C1/en not_active IP Right Cessation
Non-Patent Citations (1)
| Title |
|---|
| NOBUO MONJI, THE JOURNAL OF ANTIBIOTICS, 1976, 438-443. D.PERLMAN ET ALL, BIOTECHNOLOGY AND BIOENGINEERING, 1965, VII, 133-137. LINKE HARALD A.B., THE JOURNAL OF ANTIBIOTICS, 1974, 27 (3), 155-160. * |
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Effective date: 20121213 |