RU2422436C1 - 4-(2-aminoethyl)pyrocatechol uniformly labelled with deuterium or tritium using nanodiamond powder - Google Patents
4-(2-aminoethyl)pyrocatechol uniformly labelled with deuterium or tritium using nanodiamond powder Download PDFInfo
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- RU2422436C1 RU2422436C1 RU2010115058/04A RU2010115058A RU2422436C1 RU 2422436 C1 RU2422436 C1 RU 2422436C1 RU 2010115058/04 A RU2010115058/04 A RU 2010115058/04A RU 2010115058 A RU2010115058 A RU 2010115058A RU 2422436 C1 RU2422436 C1 RU 2422436C1
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- aminoethyl
- pyrocatechol
- deuterium
- tritium
- uniformly labelled
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- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229910052722 tritium Inorganic materials 0.000 title claims abstract description 11
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 title claims abstract description 10
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 title claims abstract description 10
- 229910052805 deuterium Inorganic materials 0.000 title claims abstract description 10
- 239000002113 nanodiamond Substances 0.000 title abstract description 3
- 239000000843 powder Substances 0.000 title abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000004431 deuterium atom Chemical group 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 1
- 229910013684 LiClO 4 Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 150000003943 catecholamines Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis 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
- 239000000284 extract Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 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
- 239000011981 lindlar catalyst Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- -1 methanol-water-acetic acid-trifluoroacetic acid Chemical compound 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002086 nanomaterial Substances 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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 меченые аналоги.When studying 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) [I].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 EA - Tritium and its compounds London Butterworths, 1974, p. 48) [I].
Известен 4-(2-аминоэтил)пирокатехол формулы I:Known 4- (2-aminoethyl) pyrocatechol formula I:
Данное соединение является эндогенным катехоламином с α- и β-адренергической активностью (Мерк 3479) (J. F. Dasta, M. G. Kirby // Pharmacotherapy 6, 304 (1986) [2]).This compound is an endogenous catecholamine with α- and β-adrenergic activity (Merck 3479) (J. F. Dasta, M. G. Kirby // Pharmacotherapy 6, 304 (1986) [2]).
Известен способ получения его меченного тритием аналога (C.N.Filer, D.Orphanos, R.J.Seguin "Synthesis of [Ring-3H]dopamine and fluoro analogues at high specific activity" // Synthetic Communications. 2006. Vol. 36. P.975-978 [3]). Полученный препарат содержал метку только в ароматическом кольце (44 Ки/ммоль), при этом содержание изотопа водорода в среднем равнялось около 1.5 атомов на молекулу 4-(2-аминоэтил)пирокатехола.A known method for producing its tritium-labeled analogue (CNFiler, D.Orphanos, RJSeguin "Synthesis of [Ring-3H] dopamine and fluoro analogues at high specific activity" // Synthetic Communications. 2006. Vol. 36. P.975-978 [3]). The resulting preparation contained a label only in the aromatic ring (44 Ci / mmol), while the hydrogen isotope content averaged about 1.5 atoms per 4- (2-aminoethyl) pyrocatechol molecule.
Техническим результатом, достигаемым настоящим изобретением, является получение равномерномеченного дейтерием и тритием 4-(2-аминоэтил)пирокатехола с использованием наноалмазного порошка (НАП), что расширит ассортимент меченых аналогов физиологически активных соединений.The technical result achieved by the present invention is to obtain 4- (2-aminoethyl) pyrocatechol uniformly labeled with deuterium and tritium using nanodiamond powder (NAP), which will expand the range of labeled analogues of physiologically active compounds.
Достигается указанный технический результат получением меченного изотопами водорода 4-(2-аминоэтил)пирокатехола формулы I:This technical result is achieved by obtaining 4- (2-aminoethyl) pyrocatechol of formula I labeled with hydrogen isotopes:
Ниже приведен пример реализации изобретения.The following is an example implementation of the invention.
Пример I.Example I.
20 мг НАП смешивали с раствором 2 мг солянокислого 4-(2-аминоэтил)пирокатехола в 30 мкл метанола, растворитель упарили, а остаток лиофилизировали. Остаток смешали с 60 мг катализатора Линдлара, механически растерли и снова лиофилизировали.20 mg of NAP was mixed with a solution of 2 mg of 4- (2-aminoethyl) pyrocatechol hydrochloride in 30 μl of methanol, the solvent was evaporated, and the residue was lyophilized. The residue was mixed with 60 mg of Lindlar catalyst, mechanically triturated and lyophilized again.
Высушенный остаток помещали в ампулу. Ампулу вакуумировали и заполняли дейтерием или тритием. Реакцию вели при 180°С в течение 15 мин. Ампулу снова вакуумировали, катализатор наносили на фильтр, вещество экстрагировали смесью метанола с уксусной кислотой (5×0.5 мл метанола с 1% уксусной кислотой). Экстракты упаривали, остаток растворяли в метаноле (3×1 мл) и вновь упаривали для удаления лабильного дейтерия или трития.The dried residue was placed in an ampoule. The ampoule was evacuated and filled with deuterium or tritium. The reaction was carried out at 180 ° C for 15 minutes. The ampoule was again evacuated, the catalyst was applied to a filter, the substance was extracted with a mixture of methanol with acetic acid (5 × 0.5 ml of methanol with 1% acetic acid). The extracts were evaporated, the residue was dissolved in methanol (3 × 1 ml) and again evaporated to remove labile deuterium or tritium.
Анализ проводили на Милихроме А-02, колонка ProntoSIL-120-5-C18 AQ DB-2003, 2.0×75 мм, 5 мкм, 0.2 мл/мин, 35°С, детекция - 210 нм, А - 0.2 М LiClO4+0.005М НСlO4 буфер, Б - метанол, градиент Б→(0-100) за 12.5 мин, время удерживания 4-(2-аминоэтил)пирокатехола - 4.27 мин. Время удерживания 4-(2-аминоэтил)пирокатехола при анализе в тех же условиях, но при использовании воды, содержащей 0.1% трифторуксусной кислоты, в качестве системы А равнялось 3.83 мин.The analysis was performed on Milichrome A-02, ProntoSIL-120-5-C 18 AQ DB-2003 column, 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 → (0-100) for 12.5 minutes, retention time of 4- (2-aminoethyl) pyrocatechol - 4.27 minutes. The retention time of 4- (2-aminoethyl) pyrocatechol when analyzed under the same conditions, but when using water containing 0.1% trifluoroacetic acid as system A, was 3.83 min.
Меченый 4-(2-аминоэтил)пирокатехол очищали также методом высокоэффективной жидкостной хроматографии. Хроматографию проводили на колонке Kromasil 100C18, 8×150 мм, 7 мкм, система: метанол-вода-уксусная кислота-трифторуксусная кислота (20:80:0.1:0.01), скорость потока - 2 мл/мин, время удерживания - 11 мин, содержание меченого препарата не менее - 98%, выход - 7-10%.Labeled 4- (2-aminoethyl) pyrocatechol was also purified by high performance liquid chromatography. Chromatography was performed on a Kromasil 100C 18 , 8 × 150 mm, 7 μm column, system: methanol-water-acetic acid-trifluoroacetic acid (20: 80: 0.1: 0.01), flow rate - 2 ml / min, retention time - 11 min , the content of the labeled drug is not less than 98%, the yield is 7-10%.
а) В случае использования дейтерия в молекулу 4-(2-аминоэтил)пирокатехола включалось в среднем 4.8 атома детерия. Причем распределение дейтерия доходило до семи атомов в молекулу допамина (14%), а изотопомер, содержащий 5 атомов дейтерия, образовывался с наибольшим выходом (31%). Таким образом, при использовании наноматериалов распределение метки в полученном соединении и прототипе существенно отличалось, т.е. получено новое меченое соединение с другими характеристиками.a) In the case of using deuterium, an average of 4.8 deuterium atoms were included in the 4- (2-aminoethyl) pyrocatechol molecule. Moreover, the distribution of deuterium reached seven atoms in the dopamine molecule (14%), and the isotopomer containing 5 deuterium atoms formed with the highest yield (31%). Thus, when using nanomaterials, the label distribution in the obtained compound and prototype was significantly different, i.e. received a new labeled compound with other characteristics.
б) В случае использования трития получен меченый 4-(2-аминоэтил)пирокатехол с молярной радиоактивностью до 130-135 Ки/ммоль, что в три раза выше, чем в прототипе.b) In the case of using tritium, labeled 4- (2-aminoethyl) pyrocatechol with a molar radioactivity of up to 130-135 Ci / mmol, which is three times higher than in the prototype, was obtained.
Таким образом получено равномерномеченное изотопами водорода соединение.Thus, a compound uniformly labeled with hydrogen isotopes is obtained.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2538862C2 (en) * | 2013-03-18 | 2015-01-10 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | Tritium-marked nanodiamonds and method of obtaining thereof |
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| RU2218326C2 (en) * | 2001-08-20 | 2003-12-10 | Новосибирский институт органической химии им.Н.Н.Ворожцова СО РАН | Method for preparing 4-(2-aminoethyl)phenol |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2218326C2 (en) * | 2001-08-20 | 2003-12-10 | Новосибирский институт органической химии им.Н.Н.Ворожцова СО РАН | Method for preparing 4-(2-aminoethyl)phenol |
Non-Patent Citations (2)
| Title |
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| FARNUM MARTIN, PALCIC MONICA, KLINMAN JUDITH P.: «pH Dependence of deuterium isotope effects and tritium exchange in the bovine plasma amine oxidase reaction: a role for single-base catalysis in amine oxidation and imine exchange» BIOCHEMISTRY. USA, 1986, vol. 25, no. 8, p. 1898-904. AHN NATALIE, KLINMAN JUDITH P.: «Mechanism of modulation of dopamine p-monooxygenase by pH and fumarate as deduced from initial rate and primary deuterium isotope effect studies» BIOCHEMISTRY. USA, 1986, vol. 22, no.13, p.3096-106. MILLER SUSAN M., KLINMAN JUDITH P.: «Magnitude of intrinsic isotope effects in the dopamine β-monooxygenase reaction» BIOCHEMISTRY. USA, 1986, vol. 22, no. 13, p. 3091-6. C.N.FILER, D.ORPHANOS, R.J.SEGUIN: «Synthesis of [Ring-3H]dopamine and fluoro analogues at high specific activity» SYNTHETIC COMMUNICATIONS. 2006, vol.36, p.975-978. KLINMAN JUDITH P., HUMPHRIES HOPE, VOET JUDITH G.: «Deduction of kinetic mechanism in multisubstrate enzyme reactions from tritium isotope effects * |
| PAJAK, M.; KANSKA, M.: «Enzymatic synthesis of dopamine ring labeled with hydrogen isotopes» JOURNAL OF RADIOANALYTICAL AND NUCLEAR CHEMISTRY. POL., 2009, vol. 279, no. 2, p.455-458. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2538862C2 (en) * | 2013-03-18 | 2015-01-10 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Московский государственный университет имени М.В. Ломоносова" (МГУ) | Tritium-marked nanodiamonds and method of obtaining thereof |
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