RU2810252C1 - 5-AMINO-1-(2-OXO-2-PHENYLETHYLIDENE)-3-(PYRROLIDINE-1-CARBONYL)-6,7,8,9-TETRAHYDROBENZO[4,5]THIENO[3,2-e]PYRROLO[1,2-a]PYRIMIDIN-2(1H)-ONE, WHICH HAS ANALGESIC ACTIVITY - Google Patents
5-AMINO-1-(2-OXO-2-PHENYLETHYLIDENE)-3-(PYRROLIDINE-1-CARBONYL)-6,7,8,9-TETRAHYDROBENZO[4,5]THIENO[3,2-e]PYRROLO[1,2-a]PYRIMIDIN-2(1H)-ONE, WHICH HAS ANALGESIC ACTIVITY Download PDFInfo
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- 230000000202 analgesic effect Effects 0.000 title claims abstract description 10
- -1 5-AMINO-1-(2-OXO-2-PHENYLETHYLIDENE)-3-(PYRROLIDINE-1-CARBONYL)-6,7,8,9-TETRAHYDROBENZO[4,5]THIENO[3,2-e]PYRROLO[1,2-a]PYRIMIDIN-2(1H)-ONE Chemical compound 0.000 title claims abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 239000013543 active substance Substances 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 229940125904 compound 1 Drugs 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000003814 drug Substances 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- GFNDBKDXYYZDRL-UHFFFAOYSA-N 2-[(2-oxo-5-phenylfuran-3-ylidene)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid Chemical compound O=C1OC(=CC1=NC=1SC2=C(C1C(=O)O)CCCC2)C2=CC=CC=C2 GFNDBKDXYYZDRL-UHFFFAOYSA-N 0.000 description 2
- VEUDVNNBYYRZBV-UHFFFAOYSA-N 3-oxo-3-pyrrolidin-1-ylpropanenitrile Chemical compound N#CCC(=O)N1CCCC1 VEUDVNNBYYRZBV-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000008533 pain sensitivity Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
Изобретение относится к области органической химии, к новым биологически активным веществам класса тиенопирролопимиридинов, а именно к 5-амино-1-(2-оксо-2-фенилэтилиден)-3-(пирролидин-1-карбонил)-6,7,8,9-тетрагидробензо[4,5]тиено[3,2-е]пирроло[1,2-а]пиримидин-2(1Н)-ону 1, формулы:The invention relates to the field of organic chemistry, to new biologically active substances of the thienopyrrolopyridine class, namely 5-amino-1-(2-oxo-2-phenylethylidene)-3-(pyrrolidine-1-carbonyl)-6,7,8, 9-tetrahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-a]pyrimidin-2(1H)-one 1, formula:
который обладает анальгетической активностью, что позволяет предположить его использование в медицине в качестве лекарственного средства с анальгетическими свойствами.which has analgesic activity, which suggests its use in medicine as a drug with analgesic properties.
Аналогом по структуре заявляемому соединению является этиловый эфир 2-амино-4-оксо-5-(2-оксо-2-фенилэтилиден)-1-(3-(этоксикарбонил)-4,5,6,7-тетрагидробензо[b]тиофен-2-ил)-4,5-дигидро-1H-пиррол-3-карбоновой кислоты [Sergei A. Shipilovskikh, Aleksandr Е. Rubtsov, J. Org. Chem. 2019, 84, 24, 15788-15796, doi: 10.1021/acs.joc.9b00711] формулы:The structural analogue of the claimed compound is ethyl ester 2-amino-4-oxo-5-(2-oxo-2-phenylethylidene)-1-(3-(ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophene -2-yl)-4,5-dihydro-1H-pyrrole-3-carboxylic acid [Sergei A. Shipilovskikh, Aleksandr E. Rubtsov, J. Org. Chem. 2019, 84, 24, 15788-15796, doi: 10.1021/acs.joc.9b00711] formulas:
Эталоном сравнения был выбран ортофен формулы:Ortofene of the formula was chosen as the standard of comparison:
который широко применяется в лечебной практике и является аминопроизводным алифатической кислоты и аналогом по действию [Машковский М.Д. Лекарственные средства.- 15-е изд., перераб., испр. и доп. - М.: ООО «Новая волна», 2005. - с. 170].which is widely used in medical practice and is an amino derivative of aliphatic acid and an analogue in action [Mashkovsky M.D. Medicines. - 15th ed., revised, corrected. and additional - M.: New Wave LLC, 2005. - p. 170].
Задачей изобретения является поиск в ряду производных тиенопирролопимиридинов веществ с выраженным анальгетическим действием и низкой токсичностью.The objective of the invention is to search for substances with a pronounced analgesic effect and low toxicity among thienopyrrolopyridine derivatives.
Поставленная задача достигается получением 5-амино-1-(2-оксо-2-фенилэтилиден)-3-(пирролидин-1-карбонил)-6,7,8,9-тетрагидробензо[4,5]тиено[3,2-е]пирроло[1,2-а]пиримидин-2(1Н)-она 1, который обладает анальгетической активностью.This goal is achieved by obtaining 5-amino-1-(2-oxo-2-phenylethylidene)-3-(pyrrolidine-1-carbonyl)-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2- e]pyrrolo[1,2-a]pyrimidin-2(1H)-one 1, which has analgesic activity.
Заявляемое соединение 1 синтезируют взаимодействием нитрила 2-[(2-оксо-5-фенилфуран-3(2Н)-илиден)амино]-4,5,6,7-тетрагидробензо[b]тиофен-3-карбоновой кислоты с 3-оксо-3-(пирролидин-1-ил)пропаннитрилом. Реакция протекает в безводном диоксане и диизопропилэтиламине при перемешивании при нагревании до 90°С в течение 60 минут, с последующим выделением целевых продуктов известными методами по схеме:The claimed compound 1 is synthesized by reacting nitrile 2-[(2-oxo-5-phenylfuran-3(2H)-ylidene)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid with 3-oxo -3-(pyrrolidin-1-yl)propanenitrile. The reaction takes place in anhydrous dioxane and diisopropylethylamine with stirring and heating to 90°C for 60 minutes, followed by isolation of the target products by known methods according to the following scheme:
Пример 1: Получение соединения 1: к раствору 0,34 г (1,0 ммоль) нитрила 2-[(2-оксо-5-фенилфуран-3(2Н)-илиден)амино]-4,5,6,7-тетрагидробензо[b]тиофен-3-карбоновой кислоты в 5 мл безводного диоксана прибавляют 0,14 г (1,0 ммоль) 3-оксо-3-(пирролидин-1-ил)пропаннитрила и 0,13 г (1,0 ммоль) диизопропилэтиламина при нагревании до 90°С. Полученную смесь интенсивно перемешивают в течение 60 минут. Выпавший осадок отфильтровывают и перекристаллизовывают. Выход 0.33 г (70%), оранжевые кристаллы, т. пл. 234-236°С (дихлорметан). Спектр ЯМР 1H (DMSOd6), δ, м. д.: 8.86 с (1H, NH2), 7.86 м (2Н, Наром), 7.57 м (1Н, Наром), 7.45 м (2Н, Наром), 7.32 с (1Н, NH2), 6.67 с (1Н, СН), 3.33 м (2Н, СН2), 3.22 м (2Н,СН2), 2.82 м (2Н, СН2), 2.71 м (2Н, СН2), 1.78 м (4Н, СН2), 1.70 м (4Н, СН2). 13С NMR (DMSOd6) δ 193.16, 173.51, 162.84, 162.48, 157.96, 146.52, 137.24, 136.49, 133.57, 129.40, 128.94, 128.88, 127.42, 115.20, 110.44, 96.51, 66.84, 46.57, 45.58, 25.86, 25.50, 24.56, 22.56, 22.11. Найдено, %: С, 66,09; Н, 5,14; N, 11,84; S, 6,77. C26H24N4O3S. Вычислено, %: С, 66,08; Н, 5,12; N, 11,86; S, 6,78Example 1: Preparation of compound 1: to a solution of 0.34 g (1.0 mmol) nitrile 2-[(2-oxo-5-phenylfuran-3(2H)-ylidene)amino]-4,5,6,7- tetrahydrobenzo[b]thiophen-3-carboxylic acid in 5 ml of anhydrous dioxane add 0.14 g (1.0 mmol) 3-oxo-3-(pyrrolidin-1-yl)propanenitrile and 0.13 g (1.0 mmol ) diisopropylethylamine when heated to 90°C. The resulting mixture is stirred intensively for 60 minutes. The precipitate that forms is filtered off and recrystallized. Yield 0.33 g (70%), orange crystals, mp. 234-236°C (dichloromethane). 1H NMR spectrum (DMSO d6 ), δ, ppm: 8.86 s (1H, NH2 ), 7.86 m (2H, Harom ), 7.57 m (1H, Harom ), 7.45 m (2H, Harom ), 7.32 s (1H, NH 2 ), 6.67 s (1H, CH), 3.33 m (2H, CH 2 ), 3.22 m (2H, CH 2 ), 2.82 m (2H, CH 2 ), 2.71 m (2H , CH 2 ), 1.78 m (4H, CH 2 ), 1.70 m (4H, CH 2 ). 13 C NMR (DMSO d6 ) δ 193.16, 173.51, 162.84, 162.48, 157.96, 146.52, 137.24, 136.49, 133.57, 129.40, 128.94, 128.88, 127.42, 115 .20, 110.44, 96.51, 66.84, 46.57, 45.58, 25.86, 25.50, 24.56, 22.56, 22.11. Found, %: C, 66.09; N, 5.14; N, 11.84; S, 6.77. C 26 H 24 N 4 O 3 S. Calculated, %: C, 66.08; N, 5.12; N, 11.86; S, 6.78
Полученное соединение 1 представляет собой оранжевое кристаллическое вещество, растворимое в ДМСО, толуоле, ацетоне, не растворимое в воде и гексане.The resulting compound 1 is an orange crystalline substance, soluble in DMSO, toluene, acetone, insoluble in water and hexane.
Пример 2. Острую токсичность (ЛД50, мг/мл) соединения 1 определяли по методу Г.Н. Першина [Першин Г.Н. Методы экспериментальной химиотерапии // М., С. 100, 109-117 (1971)]. Соединение 1 вводили внутрибрюшинно белым мышам массой 16-18 г в виде взвеси в 2% крахмальной слизи и наблюдали за поведением и гибелью животных в течение 10 суток. Для исследуемого соединения 1 ЛД50 составляет >1500 мг/кг.Example 2. Acute toxicity (LD 50 , mg/ml) of compound 1 was determined according to the method of G.N. Pershina [Pershin G.N. Methods of experimental chemotherapy // M., S. 100, 109-117 (1971)]. Compound 1 was administered intraperitoneally to white mice weighing 16-18 g in the form of a suspension in 2% starch mucus, and the behavior and death of the animals were observed for 10 days. For test compound 1, the LD 50 is >1500 mg/kg.
Согласно классификации токсичности препаратов соединение 1 относится к V классу практически нетоксичных препаратов [Измеров Н.Ф., Саноцкий И.В., Сидоров К.К. Параметры токсикометрии промышленных ядов при однократном воздействии: Справочник. М., 1977. - с. 196].According to the classification of drug toxicity, compound 1 belongs to class V of practically non-toxic drugs [Izmerov N.F., Sanotsky I.V., Sidorov K.K. Parameters of toxicometry of industrial poisons with a single exposure: Handbook. M., 1977. - p. 196].
Пример 3. Анальгетическую активность соединения 1 изучали на беспородных мышах (самках) массой 18-22 г с помощью теста «горячая пластинка» [Radell Z.O., Selitto J.J. A method for measurement of analgesic activity on inflamed tissue. // Arch. Intermat. Pharmacodun. Et ther. 1957. - Vol. 11. - №4- S. 409 -419].Example 3. The analgesic activity of compound 1 was studied on outbred mice (females) weighing 18-22 g using the “hot plate” test [Radell Z.O., Selitto J.J. A method for measuring analgesic activity on inflamed tissue. //Arch. Intermat. Pharmacodun. Etther. 1957. - Vol. 11. - No. 4 - S. 409 -419].
Исследуемое соединение вводили внутрибрюшинно в виде 2% крахмальной слизи в дозе 50 мг/кг за 0,5 ч до помещения животных на нагретую до 53,5°С металлическую пластинку. Показателем болевой чувствительности служила длительность пребывания животного на горячей пластинке до момента облизывания задних лапок, измеряемая в секундах. Эффект сравнивали с ортофеном. Результаты испытаний представлены в таблице:The test compound was administered intraperitoneally in the form of 2% starch mucus at a dose of 50 mg/kg 0.5 hours before placing the animals on a metal plate heated to 53.5°C. The indicator of pain sensitivity was the duration of the animal's stay on the hot plate until the moment of licking the hind legs, measured in seconds. The effect was compared with ortofen. The test results are presented in the table:
Как видно из таблицы, заявляемое соединение 1 проявляет выраженную анальгетическую активность и в двадцать раз менее токсично, чем препарат сравнения - ортофен. Следовательно, заявляемое соединение 1 может найти применение в медицинской практике в качестве анальгетического лекарственного средства.As can be seen from the table, the claimed compound 1 exhibits pronounced analgesic activity and is twenty times less toxic than the reference drug, ortofen. Therefore, the claimed compound 1 can find use in medical practice as an analgesic drug.
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| RU2810252C1 true RU2810252C1 (en) | 2023-12-25 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2294937C9 (en) * | 2001-07-28 | 2007-07-20 | Астразенека Аб | Thienopyrimidnediones, methods for their preparing (variants) and pharmaceutical composition |
| RU2434871C2 (en) * | 2005-02-03 | 2011-11-27 | Вертекс Фармасьютикалз Инкорпорейтед | Pyrrolopyrimidines used as protein kinase inhibitors |
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2294937C9 (en) * | 2001-07-28 | 2007-07-20 | Астразенека Аб | Thienopyrimidnediones, methods for their preparing (variants) and pharmaceutical composition |
| RU2434871C2 (en) * | 2005-02-03 | 2011-11-27 | Вертекс Фармасьютикалз Инкорпорейтед | Pyrrolopyrimidines used as protein kinase inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| SHIPILOVSKIKH S.A. et al. One-Pot Synthesis of Thieno[3,2-e]pyrrolo[1,2-a]pyrimidine Derivative Scaffold: A Valuable Source of PARP-1 Inhibitors. Journal of Organic Chemistry. 2019, 84, 24, 15788-15796. Е.Г. ПАРОНИКЯН и др. Синтез и противосудорожная активность конденсированных тиено[2,3-e]пирроло[1,2-a]пиримидин-8,12-дионов. Химико-фармацевтический журнал. 2013, т.47, N2, сс.24-27. * |
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