RU2605698C1 - Derivatives of 2-(adamant-2-yl)ethylamine, having potential antiviral activity - Google Patents
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Предлагаемое изобретение относится к новым адамантансодержащим аминам, конкретно к 2-(адамант-2-ил)пентан-1-амину и 2-(адамант-2-ил)фенилэтил-1-амину, которые могут быть использованы в качестве веществ, проявляющих антивирусную активность, а также в качестве полупродуктов для синтеза 2-замещенных производных адмантана, среди которых имеется ряд эффективных противораковых агентов, соединений, проявляющих анальгетическую активность.The present invention relates to new adamantane-containing amines, specifically to 2- (adamant-2-yl) pentan-1-amine and 2- (adamant-2-yl) phenylethyl-1-amine, which can be used as substances exhibiting antiviral activity, as well as intermediates for the synthesis of 2-substituted derivatives of admantanum, among which there are a number of effective anticancer agents, compounds exhibiting analgesic activity.
Известно, что 4-({[2-(адамант-2-ил)этил]амино}метил)бензойная кислота, полученная на основе 2-(адамант-2-ил)этиламина является в три раза более эффективным ингибитором HDAC (по сравнению с 1-замещенным аналогом (panHDAC=0.28 и panHDAC=0.9 соответственно) и проявляет высокую противораковую активность в отношении трех видов раковых клеток человека (НСТ116, NCI-H460 и U251) [Balasubramanian Gopalan Thanasekaran Ponpandian, Virendra Kachhadia, Kuppusamy Bharathimohan, Radhakrishnan Vignesh, Velaiah Sivasudar, Shridhar Narayanan, Bhonde Mandar, Rajendran Praveen, Nithyanandan Saranya, Sriram Rajagopal, Sridharan Rajagopal. Discovery of adamantane based highly potent HDAC inhibitors. Bioorg. Med. Chem. Lett, 2013, 23, №9 pp. 2532-2537].It is known that 4 - ({[2- (adamant-2-yl) ethyl] amino} methyl} benzoic acid derived from 2- (adamant-2-yl) ethylamine is three times more effective HDAC inhibitor (compared with a 1-substituted analogue (panHDAC = 0.28 and panHDAC = 0.9, respectively) and exhibits high anti-cancer activity against three types of human cancer cells (HCT116, NCI-H460 and U251) [Balasubramanian Gopalan Thanasekaran Ponpandian, Virendra Kachhadia, Kuppusamy Bharathimim Bharathimim , Velaiah Sivasudar, Shridhar Narayanan, Bhonde Mandar, Rajendran Praveen, Nithyanandan Saranya, Sriram Rajagopal, Sridharan Rajagopal. Discovery of adamantane based highly potent HDAC inhibitors. Bioorg. Med. Chem. Lett, 2013, 2332, No. 25 pp. ] .
Известно, что 2-адамантилэтиламины проявляют себя как вещества, связывающие рецептор NMDA, а также проявляют себя как анальгетики [Пат. ЕР 1305306 В1. Опубл. 24.11.2004]. Так, при исследовании указанных соединений для связывания рецептора NMDA было показано, что IC50 для синтезированных авторами соединений - 1.09±0.40 и 2.70±0.54, а для мемантана и кетамина - 6.50±0.94 и 6.51±4.54 соответственно. При оценивании анальгетического эффекта синтезированных соединений поведение испытуемых крыс после иньекции изменилось с 0 - нет эффекта, до 3 - максимальный эффект.It is known that 2-adamantylethylamines manifest themselves as substances that bind the NMDA receptor, and also manifest themselves as analgesics [US Pat. EP 1305306 B1. Publ. November 24, 2004]. Thus, in the study of these compounds for NMDA receptor binding, it was shown that the IC 50 for the compounds synthesized by the authors was 1.09 ± 0.40 and 2.70 ± 0.54, and for memantan and ketamine, they were 6.50 ± 0.94 and 6.51 ± 4.54, respectively. When evaluating the analgesic effect of the synthesized compounds, the behavior of the tested rats after injection changed from 0 - no effect, up to 3 - the maximum effect.
Известно, что 2-адамантил-производные демонстрируют высокий уровень ингибирования 11β-HSD1 в печени и умеренный в жировых клетках и клетках мозга после 16 часов связывания [Su X., Vicker N., Trusselle M., Halem H., Culler M.D., Potter B.V.L. Discovery of novel inhibitors of human 11β-hydroxysteroid dehydrogenase type 1. Mol. Cell. Endocrinology, 2009, 301, №1-2, pp. 169-173].2-adamantyl derivatives are known to exhibit a high level of inhibition of 11β-HSD1 in the liver and moderate in fat and brain cells after 16 hours of binding [Su X., Vicker N., Trusselle M., Halem H., Culler MD, Potter Bvl Discovery of novel inhibitors of human 11β-hydroxysteroid dehydrogenase type 1. Mol. Cell. Endocrinology, 2009, 301, No. 1-2, pp. 169-173].
Известно, что спиро[циклопропан-1,2′адамантан]-2-амины проявляют противовирусную активность в микромолярных концентрациях против гриппа A (H2N2) штамма в концентрациях в 125 раз меньших, чем в случае применения амантадина [Kolocouris N., Kolocouris A., Foscolos G.B., Fytas G., Neyts J., Padalko E., Balzarini J., Snoeck R., Andrei G., De Clercq E. Synthesis and Antiviral Activity Evaluation of Some New Aminoadamantane Derivatives. 2. J. Med. Chem. 1996, 39, №17, pp. 3307-3318].It is known that spiro [cyclopropane-1,2′adamantane] -2-amines exhibit antiviral activity in micromolar concentrations against influenza A (H2N2) strain in concentrations 125 times lower than in the case of amantadine [Kolocouris N., Kolocouris A. , Foscolos GB, Fytas G., Neyts J., Padalko E., Balzarini J., Snoeck R., Andrei G., De Clercq E. Synthesis and Antiviral Activity Evaluation of Some New Aminoadamantane Derivatives. 2. J. Med. Chem. 1996, 39, No. 17, pp. 3307-3318].
Задачей предлагаемого изобретения является синтез новых производных 2-(адамант-2-ил)этиламина, обладающих потенциальной противовирусной активностью.The objective of the invention is the synthesis of new derivatives of 2- (adamant-2-yl) ethylamine with potential antiviral activity.
Техническим результатом является расширение арсенала противовирусных средств.The technical result is the expansion of the arsenal of antiviral agents.
Технический результат достигается производными 2-(адамант-2-ил)этиламина общей формулы:The technical result is achieved by derivatives of 2- (adamant-2-yl) ethylamine of the general formula:
где R=С3Н7, С6Н5, обладающие потенциальной противовирусной активностью.where R = C 3 H 7 , C 6 H 5 with potential antiviral activity.
В связи с возможной высокой противовирусной активностью полученных 2-(адамант-2-ил)этиламинов, по программе «PASS» института биомедицинской химии им. В.Н. Ореховича РАМН [система PASS [Электронный ресурс]: прогнозирование биологической активности соединений. - http://www.way2drug.com/PASSOnline/downloads.php; http://www.way2drug.com/PASSOnline/downloads/software/Evaluation.zip] был проведен вычислительный прогноз возможного наличия различных видов биологической активности. Результаты прогноза представлены в таблице.In connection with the possible high antiviral activity of the obtained 2- (adamant-2-yl) ethylamines, according to the PASS program of the Institute of Biomedical Chemistry named after V.N. Orekhovich RAMS [PASS system [Electronic resource]: prediction of the biological activity of compounds. - http://www.way2drug.com/PASSOnline/downloads.php; http://www.way2drug.com/PASSOnline/downloads/software/Evaluation.zip] a computational prediction of the possible presence of various types of biological activity was carried out. The forecast results are presented in the table.
Целевые производные 2-(адамант-2-ил)этиламина получали путем восстановления непредельных адамантансодержащих нитрилов алюмогидридом лития в 2-метилтетрогилрофуране (2-MeTHF). Синтез проводили по схеме:The desired 2- (adamant-2-yl) ethylamine derivatives were prepared by reduction of unsaturated adamantane-containing nitriles with lithium aluminum hydride in 2-methyltetrogylrofuran (2-MeTHF). The synthesis was carried out according to the scheme:
где: R=-С3Н7, -С6Н5.where: R = —C 3 H 7 , —C 6 H 5 .
Структура полученных соединений подтверждена методами хроматомасс-, ИК- и ЯМР-1Н-спектрометрии.The structure of the obtained compounds was confirmed by chromatographic mass, IR and NMR- 1 H-spectrometry.
Из представленных в таблице данных видно, что полученные производные 2-(адамант-2-ил)этиламина обладают потенциальной противовирусной активностью в отношении вирусов гриппа, пикорновирусов, риновирусов, аденовируса человека.From the data presented in the table it is seen that the obtained derivatives of 2- (adamant-2-yl) ethylamine have potential antiviral activity against influenza viruses, picornoviruses, rhinoviruses, and human adenovirus.
Достаточно большое значение Ра - вероятность наличия активности - и низкое значение Pi - вероятность отсутствия активности - дают основания ожидать потенциальную противовирусную активность синтезированных соединений в отношении указанных вирусов.A sufficiently large value of Ra - the probability of the presence of activity - and a low value of Pi - the probability of the absence of activity - give reason to expect the potential antiviral activity of the synthesized compounds against these viruses.
Для сравнения в таблице представлены данные по расчету противовирусной активности, рассчитанные на той же программе для широко применяемого в клинической практике римантадина (4) и прошедшего испытания 2-римантадина (3). Из представленных данных видно, что 2-(адамант-2-ил)пентан-1-амин (1) и 2-(адамант-2-ил)фенилэтил-1-амин (2) могут проявлять противовирусную активность, сравнимую с известными препаратами.For comparison, the table presents data on the calculation of antiviral activity calculated on the same program for rimantadine (4) widely used in clinical practice and 2-rimantadine tested (3). From the presented data it is seen that 2- (adamant-2-yl) pentan-1-amine (1) and 2- (adamant-2-yl) phenylethyl-1-amine (2) can exhibit antiviral activity comparable to known drugs .
Пример 1. 2-(Адамант-2-ил)пентан-1-амин.Example 1. 2- (Adamant-2-yl) pentan-1-amine.
В плоскодонную колбу с магнитной мешалкой загружают 3.4 г (0.088 моль) алюмогидрида лития, 60 мл абсолютного 2-MeTHF и 10.9 г (0.05 моля) 2-(адамант-2-ил)пентаннитрила, растворенного в 200 мл абсолютного 2-MeTHF. Смесь нагревают при перемешивании с обратным холодильником в течение 8 часов. По окончании реакции добавляют 12 мл воды 5 мл 10% NaOH, отфильтровывают осадок, из фильтрата отгоняют 2-MeTHF, остаток перегоняют в вакууме, перекристаллизовывают продукт из EtOH.3.4 g (0.088 mol) of lithium aluminum hydride, 60 ml of absolute 2-MeTHF and 10.9 g (0.05 mol) of 2- (adamant-2-yl) pentannitrile dissolved in 200 ml of absolute 2-MeTHF are loaded into a flat-bottomed flask with a magnetic stirrer. The mixture was heated under stirring under reflux for 8 hours. At the end of the reaction, 12 ml of water, 5 ml of 10% NaOH are added, the precipitate is filtered off, 2-MeTHF is distilled off from the filtrate, the residue is distilled off in vacuo, the product is recrystallized from EtOH.
Получают 8.6 г (0.039 моль, 78%) продукта, Т. кип. 138-141°С (4 мм.рт.ст.).8.6 g (0.039 mol, 78%) of product are obtained, T. bp. 138-141 ° C (4 mm Hg).
Содержание основного вещества по данным хромато-масс-спектрометрии составляет 97.6%.The content of the main substance according to chromatography-mass spectrometry is 97.6%.
ИК спектр, ν, см-1: 669.2, 704.2, 792.7, 806.1, 842.5, 934.8, 1013.6, 1042.4, 1065.1, 1099.3, 1214.8, 1309.5, 1353.5, 1452.2, 1469.4, 1605.4, 1652.9, 2329.5, 2840.8, 2898.9, 2962.1, 3348.2.IR spectrum, ν, cm -1 : 669.2, 704.2, 792.7, 806.1, 842.5, 934.8, 1013.6, 1042.4, 1065.1, 1099.3, 1214.8, 1309.5, 1353.5, 1452.2, 1469.4, 1605.4, 1652.9, 2329.5, 2840.8, 2898.9, 2962.1 , 3348.2.
Спектр ЯМР 1H, δ, м.д. (J, Гц): 0.83-0.87 т (3Н, СН3, J 5.57), 0.99 с (2Н, NH2), 1.06-1.81 м (15Н СНAd, 1Н СН(С3Н7), 4Н СН(СН 2СН 2 СН3)), 2.49-2.70 м (2Н, СН2). 1 H NMR spectrum, δ, ppm (J, Hz): 0.83-0.87 t (3Н, СН 3 , J 5.57), 0.99 s (2Н, NH 2 ), 1.06-1.81 m (15Н СН Ad , 1Н С Н (С 3 Н 7 ), 4Н СН (C H 2 C H 2 CH 3 )), 2.49-2.70 m (2H, CH 2 ).
Масс-спектр, (ЭУ, 70 эВ), m/e (Iотн, %): 222 (100) [М]+1, 204 (39) [М-17]+1, 176 (12), 175 (22), 162 (10), 161 (45), 148 (44), 135 (15).Mass spectrum, (EU, 70 eV), m / e (I Rel ,%): 222 (100) [M] +1 , 204 (39) [M-17] +1 , 176 (12), 175 ( 22), 162 (10), 161 (45), 148 (44), 135 (15).
Пример 2. 2-(Адамант-2-ил)фенилэтил-1-амин.Example 2. 2- (Adamant-2-yl) phenylethyl-1-amine.
Синтез проводят аналогично примеру 1, за исключением 4.75 г (0.125 моль) алюмогидрида лития, 60 мл абсолютного 2-MeTHF и 10.9 г (0.05 моля) фенил(трицикло[3.3.1.13,7]дек-2-илиден) ацетонитрила, растворенного в 200 мл абсолютного 2-MeTHF получают 7.65 г (0,03 моль, 60%) IIв, т. кип. 178-181°С (4 мм рт.ст.).The synthesis is carried out analogously to example 1, except for 4.75 g (0.125 mol) of lithium aluminum hydride, 60 ml of absolute 2-MeTHF and 10.9 g (0.05 mol) of phenyl (tricyclo [3.3.1.1 3,7 ] dec-2-ylidene) acetonitrile, dissolved in 200 ml of absolute 2-MeTHF, 7.65 g (0.03 mol, 60%) of IIb are obtained, i.e. 178-181 ° C (4 mmHg).
Содержание основного вещества по данным хромато-масс-спектрометрии составляет 98.3%.The content of the basic substance according to chromatography-mass spectrometry is 98.3%.
ИК спектр, ν, см-1: 669.3, 698.9, 765.2, 810.5, 935.9, 1009.9, 1030.6, 1067.9, 1098.7, 1216.9, 1353.3, 1449.5, 1469.3, 1492.3, 1599.7, 2847.0, 2901.1, 2962.1, 3348.2.IR spectrum, ν, cm -1 : 669.3, 698.9, 765.2, 810.5, 935.9, 1009.9, 1030.6, 1067.9, 1098.7, 1216.9, 1353.3, 1449.5, 1469.3, 1492.3, 1599.7, 2847.0, 2901.1, 2962.1, 3348.2.
Спектр ЯМР 1Н, δ, м.д. (J, Гц): 0.56 с (2Н, NH2), 1.20-1.98 м (15Н, CHAd), 2.60-2.66 м (1Н, СН(С6Н5)), 2.79-2.93 м (2Н, CH 2NH2), 7.07-7.17 м (5Н, С6Н5). 1 H NMR spectrum, δ, ppm (J, Hz): 0.56 s (2Н, NH 2 ), 1.20-1.98 m (15Н, CH Ad ), 2.60-2.66 m (1Н, С Н (С 6 Н 5 )), 2.79-2.93 m (2Н, C H 2 NH 2 ), 7.07-7.17 m (5H, C 6 H 5 ).
Масс-спектр, (ЭУ, 70 эВ), m/e (Iотн, %): 256 (10) [М]+1, 255 (1) [М]+, 239 (8) [М-17]+1, 238 (34) [М-17]+, 225 (21), 224 (100), 135 (15).Mass spectrum, (EU, 70 eV), m / e (I Rel ,%): 256 (10) [M] +1 , 255 (1) [M] + , 239 (8) [M-17] + 1 , 238 (34) [M-17] + , 225 (21), 224 (100), 135 (15).
Таким образом, 2-(адамант-2-ил)пентан-1-амин и 2-(адамант-2-ил)фенилэтил-1-амин являются новыми производными 2-(адамант-2-ид)этиламина, обладающими потенциальной противовирусной активностью.Thus, 2- (adamant-2-yl) pentan-1-amine and 2- (adamant-2-yl) phenylethyl-1-amine are new derivatives of 2- (adamant-2-yl) ethylamine with potential antiviral activity .
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EP1305306B1 (en) * | 2000-07-25 | 2004-11-24 | Vernalis Research Limited | 2-adamantylethylamines and their use in the treatment of conditions generally associated with abnormalities in glutamatergic transmission |
RU2447060C2 (en) * | 2005-06-17 | 2012-04-10 | Эпоуджи Биотекнолоджи Корпорейшн | Sphyngosine kinase inhibitors |
RU2495020C1 (en) * | 2012-10-22 | 2013-10-10 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Волгоградский государственный технический университет" (ВолгГТУ) | Method of producing 2-(2-amino)alkyladamantanes |
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EP1305306B1 (en) * | 2000-07-25 | 2004-11-24 | Vernalis Research Limited | 2-adamantylethylamines and their use in the treatment of conditions generally associated with abnormalities in glutamatergic transmission |
RU2447060C2 (en) * | 2005-06-17 | 2012-04-10 | Эпоуджи Биотекнолоджи Корпорейшн | Sphyngosine kinase inhibitors |
RU2495020C1 (en) * | 2012-10-22 | 2013-10-10 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования "Волгоградский государственный технический университет" (ВолгГТУ) | Method of producing 2-(2-amino)alkyladamantanes |
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SU.X et al., Discovery of novel inhibitors of Human 11β-hydroxysteroid dehydrogenas type 1, Molecular Cell. Endocrinology, 2009,301, No.,p.169-173. * |
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