RU2398755C1 - 5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol uniformly labelled with tritium - Google Patents
5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol uniformly labelled with tritium Download PDFInfo
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- RU2398755C1 RU2398755C1 RU2009111025/04A RU2009111025A RU2398755C1 RU 2398755 C1 RU2398755 C1 RU 2398755C1 RU 2009111025/04 A RU2009111025/04 A RU 2009111025/04A RU 2009111025 A RU2009111025 A RU 2009111025A RU 2398755 C1 RU2398755 C1 RU 2398755C1
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- tritium
- dimethylheptyl
- hydroxypropyl
- cyclohexyl
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- 229910052722 tritium Inorganic materials 0.000 title claims abstract description 10
- YNZFFALZMRAPHQ-SYYKKAFVSA-N 2-[(1r,2r,5r)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol Chemical compound OC1=CC(C(C)(C)CCCCCC)=CC=C1[C@H]1[C@H](CCCO)CC[C@@H](O)C1 YNZFFALZMRAPHQ-SYYKKAFVSA-N 0.000 title claims abstract description 9
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 9
- 239000000126 substance Substances 0.000 abstract description 3
- 229940121376 cannabinoid receptor agonist Drugs 0.000 abstract description 2
- 239000003537 cannabinoid receptor agonist Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- YNZFFALZMRAPHQ-UHFFFAOYSA-N CCCCCCC(C)(C)c1cc(O)c(C(C2)C(CCCO)CCC2O)cc1 Chemical compound CCCCCCC(C)(C)c1cc(O)c(C(C2)C(CCCO)CCC2O)cc1 YNZFFALZMRAPHQ-UHFFFAOYSA-N 0.000 description 1
- 229910013684 LiClO 4 Inorganic materials 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229930003827 cannabinoid Natural products 0.000 description 1
- 239000003557 cannabinoid Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 210000004044 posterior horn cell Anatomy 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
Description
Изобретение относится к области органической химии и может найти применение в аналитической химии и биологических исследованиях.The invention relates to the field of organic chemistry and may find application in analytical chemistry and biological research.
При изучении физиологически активных соединений необходимы их равномерномеченые аналоги.When studying physiologically active compounds, their uniformly labeled analogues are necessary.
Известно, что замена атомов соединений на их меченые аналоги не приводит к изменению каких-либо свойств исходного соединения (Evans E.A. - Tritium and its compounds London Butterworths, 1974, р.48) [1].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) [1].
Известен 5-(1,1-диметилгептил)-2-[5-гидрокси-2-(3-гидроксипропил)циклогексил]фенол формулы I:Known 5- (1,1-dimethylheptyl) -2- [5-hydroxy-2- (3-hydroxypropyl) cyclohexyl] phenol of the formula I:
Данное соединение является одним из самых интенсивно изучаемых селективных агонистов каннабиноидных рецепторов (L.M.Johanek, D.A.Simone. Cannabinoid Agonist, CP 55,940, Prevents Capsaicin-Induced Sensitization of Spinal Cord Dorsal Horn Neurons. J Neurophysiol 93: 989-997, 2005. [2]).This compound is one of the most intensively studied selective cannabinoid receptor agonists (LMJohanek, DASimone. Cannabinoid Agonist, CP 55,940, Prevents Capsaicin-Induced Sensitization of Spinal Cord Dorsal Horn Neurons. J Neurophysiol 93: 989-997, 2005. [2] )
Однако его равномерномеченный тритием аналог не описан.However, its counterpart uniformly labeled with tritium is not described.
Техническим результатом, достигаемым настоящим изобретением, является расширение ассортимента меченых аналогов физиологически активных соединений.The technical result achieved by the present invention is to expand the range of labeled analogues of physiologically active compounds.
Достигается указанный технический результат получением равномерномеченного тритием 5-(1,1-диметилгептил)-2-[5-гидрокси-2-(3-гидроксипропил)циклогексил]фенола формулы I:This technical result is achieved by obtaining uniformly labeled with tritium 5- (1,1-dimethylheptyl) -2- [5-hydroxy-2- (3-hydroxypropyl) cyclohexyl] phenol of the formula I:
Ниже приведен пример реализации изобретения.The following is an example implementation of the invention.
Пример I.Example I.
Раствор 2 мг 5-(1,1-диметилгептил)-2-[5-гидрокси-2-(3-гидроксипропил)циклогексил]-фенола в 0,2 мл диметилсульфоксида добавляли к 200 мг 5% Pd/BaSO4, диметилсульфоксид удаляли лиофилизацией. Остаток измельчали в ступке и вновь лиофилизировали. Сухую смесь переносили в реакционную ампулу. Затем ампулу вакуумировали до давления 0,1 Па, заполняли газообразным тритием до давления 400 гПа и выдерживали при температуре 180°С 15 мин. Избыток газообразного трития удаляли вакуумированием. Вещество с катализатора отделяли фильтрованием, экстракцию проводили метанолом (5×1 мл). Лабильный тритий удаляли несколько раз, растворяя вещество в метаноле (5×1 мл) и упаривая последний. Радиоактивность выделенной реакционной массы - около 1,4 Ки.A solution of 2 mg of 5- (1,1-dimethylheptyl) -2- [5-hydroxy-2- (3-hydroxypropyl) cyclohexyl] phenol in 0.2 ml of dimethyl sulfoxide was added to 200 mg of 5% Pd / BaSO 4 , dimethyl sulfoxide was removed lyophilization. The residue was ground in a mortar and lyophilized again. The dry mixture was transferred to a reaction vial. Then, the ampoule was evacuated to a pressure of 0.1 Pa, filled with gaseous tritium to a pressure of 400 hPa, and kept at a temperature of 180 ° С for 15 min. Excess tritium gas was removed by vacuum. The substance from the catalyst was separated by filtration, extraction was carried out with methanol (5 × 1 ml). Labile tritium was removed several times, dissolving the substance in methanol (5 × 1 ml) and evaporating the latter. The radioactivity of the isolated reaction mass is about 1.4 Ci.
Анализ меченого препарата проводили на Милихроме А-02 колонка ProntoSIL-120-5-С18 AQ DВ-2003, 2,0×75 мм, 5 мкм, 0,2 мл/мин, 35°С, детекция - 210 нм, А - 0,2 М LiClO4 + 0,005 М HClO4 буфер, Б - метанол, градиент Б→(75-100) за 12,5 мин, время удерживания - 4,33 мин. Для удаления продуктов деградации и полимеризации реакционную массу растворяли в 1 мл 70% метанола и сажали на патрон, упакованный SipC18 (SepPack). Патрон промывали последовательно 3 мл 90% метанола с уксусной кислотой (вымылось 260 мКи, где содержалось основное количество искомого соединения) и 4 мл метанола (вымылось 800 мКи), на патроне осталось около 300 мКи продуктов полимеризации.The analysis of the labeled drug was carried out on a Milichrome A-02 ProntoSIL-120-5-C column 18 AQ DB-2003, 2.0 × 75 mm, 5 μm, 0.2 ml / min, 35 ° C, detection - 210 nm, A 0.2 M LiClO 4 + 0.005 M HClO 4 buffer, B methanol, gradient B → (75-100) for 12.5 minutes, retention time 4.33 minutes. To remove degradation and polymerization products, the reaction mass was dissolved in 1 ml of 70% methanol and put on a cartridge packed with SipC18 (SepPack). The cartridge was washed sequentially with 3 ml of 90% methanol with acetic acid (washed with 260 mCi, which contained the main amount of the desired compound) and 4 ml of methanol (washed with 800 mCi), about 300 mCi of polymerization products remained on the cartridge.
Препаративную хроматографию проводили на колонке Kromasil 100С18, 8×150 мм, 7 мкм, система: 80% метанол-0,1% уксусная кислота, скорость потока - 2 мл/мин, время удерживания 5-(1,1-диметилгептил)-2-[5-гидрокси-2-(3-гидроксипропил)циклогексил]фенола - 8,08 мин (фиг.1).Preparative chromatography was performed on a Kromasil 100C 18 , 8 × 150 mm, 7 μm column, system: 80% methanol-0.1% acetic acid, flow rate 2 ml / min, retention time 5- (1,1-dimethylheptyl) - 2- [5-hydroxy-2- (3-hydroxypropyl) cyclohexyl] phenol - 8.08 min (Fig. 1).
После очистки методом ВЭЖХ радиохимическая чистота равномерномеченого препарата - 98%, выход - 20-25%, молярная радиоактивность - 70 Ки/ммоль. Таким образом, получено новое меченное тритием соединение.After purification by HPLC, the radiochemical purity of the uniformly labeled preparation was 98%, the yield was 20-25%, and the molar radioactivity was 70 Ci / mmol. Thus, a new tritium-labeled compound was obtained.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU98118226A (en) * | 1998-10-15 | 2000-06-27 | Институт молекулярной генетики РАН | METHOD FOR PRODUCING ORGANIC COMPOUNDS EXCELLENT BY TRITIUM AND ORGANIC COMPOUND EXCELLENT BY TRITIUM |
| RU2291147C2 (en) * | 2004-12-27 | 2007-01-10 | Институт Молекулярной Генетики Российской Академии Наук (Имг Ран) | [3h]-fluvastatin highly labeled with tritium |
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| RU2163903C2 (en) * | 1998-10-05 | 2001-03-10 | Институт молекулярной генетики РАН | Method of incorporation of tritium label in organic compounds and highly tritium-labeled methyl-(e)-{2-[6-(2-cyanophenoxy)- -pyrimidine-4-yloxy]phenyl]}-3-methoxyacrylate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU98118226A (en) * | 1998-10-15 | 2000-06-27 | Институт молекулярной генетики РАН | METHOD FOR PRODUCING ORGANIC COMPOUNDS EXCELLENT BY TRITIUM AND ORGANIC COMPOUND EXCELLENT BY TRITIUM |
| RU2291147C2 (en) * | 2004-12-27 | 2007-01-10 | Институт Молекулярной Генетики Российской Академии Наук (Имг Ран) | [3h]-fluvastatin highly labeled with tritium |
Non-Patent Citations (1)
| Title |
|---|
| MARKT Patrick et al. Discovery of Novel CB2 Receptor Ligands by a Pharmacophore-Based Virtual Screening Workflow. Journal of Medicinal Chemistry, 2009, 52(2), 369-378. DEVANE William A. et al. Determination and characterization of a cannabinoid receptor in rat brain. Molecular Pharmacology, 1988, 34(5), 605-613. Lisa M. JOHANEK et al. Cannabinoid Agonist, CP 55,940. Prevents Capsaicin-Induced Sensitization of Spinal Cord Dorsal Horn Neurons. J. Neurophysiol. 2005, т.93, с.989-997. Золотарев Ю.А. и др. Твердофазный изотопный обмен со спилловер-водородом в аминокислотах, пептидах и белках. Биоорганическая химия, 2005, т.31, №1, с.3-21. * |
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