RU2831363C1 - 5-amino-3-(morpholine-4-carbonyl)-1-(2-oxo-2-(4-fluorophenyl)ethylidene)-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-a]pyrimidin-2(1h)-one, having anti-inflammatory activity - Google Patents
5-amino-3-(morpholine-4-carbonyl)-1-(2-oxo-2-(4-fluorophenyl)ethylidene)-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-a]pyrimidin-2(1h)-one, having anti-inflammatory activity Download PDFInfo
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- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 11
- -1 5-amino-3-(morpholine-4-carbonyl)-1-(2-oxo-2-(4-fluorophenyl)ethylidene)-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 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 abstract description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 abstract description 5
- 238000000034 method Methods 0.000 abstract description 4
- AUZPMUJGZZSMCP-UHFFFAOYSA-N 3-morpholin-4-yl-3-oxopropanenitrile Chemical compound N#CCC(=O)N1CCOCC1 AUZPMUJGZZSMCP-UHFFFAOYSA-N 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 238000003756 stirring Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 239000013543 active substance Substances 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract 1
- 238000000605 extraction Methods 0.000 abstract 1
- 230000003993 interaction Effects 0.000 abstract 1
- 150000002825 nitriles Chemical class 0.000 abstract 1
- 229940125904 compound 1 Drugs 0.000 description 11
- 239000003814 drug Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229920001525 carrageenan Polymers 0.000 description 2
- 229940113118 carrageenan Drugs 0.000 description 2
- 235000010418 carrageenan Nutrition 0.000 description 2
- 239000000679 carrageenan Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 2
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect 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
- 238000001228 spectrum Methods 0.000 description 1
- 230000003637 steroidlike Effects 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 замещенных тиенопирролопиримидинов, а именно к 5-амино-3-(морфолин-4-карбонил)-1-(2-оксо-2-(4-фторфенил)этилиден)-6,7,8,9-тетрагидробензо[4,5]тиено[3,2-е]пирроло[1,2-а]пиримидин-2(1Н)-ону формулы:The invention relates to the field of organic chemistry, to new biologically active substances of the class of substituted thienopyrrolopyrimidines, namely to 5-amino-3-(morpholine-4-carbonyl)-1-(2-oxo-2-(4-fluorophenyl)ethylidene)-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-a]pyrimidin-2(1H)-one of the formula:
который обладает противовоспалительной активностью, что позволяет предположить его использование в медицине в качестве лекарственного средства с противовоспалительными свойствами и низкой токсичностью.which has anti-inflammatory activity, which suggests its use in medicine as a drug with anti-inflammatory properties and low toxicity.
Аналогом по структуре заявляемому соединению является 2,5-диоксо-1-(2-оксо-2-фенилэтилиден)-1,2,4,5,6,7,8,9-октагидробензо[4,5]тиено[3,2-е]пирроло[1,2-а]пиримидин-3-карбоксамид [Rogova A. et al, European Journal of Medicinal Chemistry, 2023, Vol. 254, pp. 115325] формулы:A structural analogue of the claimed compound is 2,5-dioxo-1-(2-oxo-2-phenylethylidene)-1,2,4,5,6,7,8,9-octahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-a]pyrimidine-3-carboxamide [Rogova A. et al, European Journal of Medicinal Chemistry, 2023, Vol. 254, pp. 115325] of the formula:
Эталоном сравнения был выбран ортофен формулы:The comparison standard chosen was orthofen with the formula:
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 an aliphatic acid and an analogue in action [Mashkovsky M.D. Medicines. - 15th ed., revised, corrected and supplemented. - M .: OOO Novaya Volna, 2005. - p. 170].
Задачей изобретения является поиск веществ в ряду замещенных тиенопирролопиримидинов с выраженным противовоспалительным действием и низкой токсичностью.The objective of the invention is to find substances in the series of substituted thienopyrrolopyrimidines with a pronounced anti-inflammatory effect and low toxicity.
Поставленная задача достигается получением 5-амино-3-(морфолин-4-карбонил)-1-(2-оксо-2-(4-фторфенил)этилиден)-6,7,8,9-тетрагидробензо[4,5]тиено[3,2-е]пирроло[1,2-а]пиримидин-2(1Н)-она, который обладает противовоспалительной активностью.The set task is achieved by obtaining 5-amino-3-(morpholine-4-carbonyl)-1-(2-oxo-2-(4-fluorophenyl)ethylidene)-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-a]pyrimidin-2(1H)-one, which has anti-inflammatory activity.
Заявляемое соединение 1 синтезируют взаимодействием нитрила 2-((2-оксо-5-(4-фторфенил)фуран-3(2Н)-илиден)амино)-4,5,6,7-тетрагидробензо[b]тиофен-3-карбоновой кислоты с 3-морфолино-3-оксопропаннитрилом в присутствии 1 эквивалента диизопропилэтиламина (DIPEA). Реакция протекает в диоксане при перемешивании и температуре 90°С в течение 90 минут с последующим выделением целевого продукта известными методами по схеме:The claimed compound 1 is synthesized by the reaction of 2-((2-oxo-5-(4-fluorophenyl)furan-3(2H)-ylidene)amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid nitrile with 3-morpholino-3-oxopropanenitrile in the presence of 1 equivalent of diisopropylethylamine (DIPEA). The reaction takes place in dioxane with stirring and a temperature of 90°C for 90 minutes, followed by isolation of the target product by known methods according to the scheme:
Пример 1. Получение соединения 1: к раствору 3,52 г (0,01 моль) нитрила 2-((2-оксо-5-(4-фторфенил)фуран-3(2Н)-илиден)амино)-4,5,6,7-тетрагидробензо[b]тиофен-3-карбоновой кислоты в 50 мл безводного диоксана прибавляли 1,54 г (0,01 моль) 3-морфолино-3-оксопропаннитрила и 1,29 г (0,01 моль) диизопропилэтиламина. Полученный раствор выдерживали 90 минут при температуре 90°С при интенсивном перемешивании. Затем смесь охлаждали до 0°С, выпавший осадок отфильтровывали и промывали диоксаном. Выход 4,40 г (87%), желтые кристаллы, т.пл. 236.1-237.9°С (диоксан). ПК спектр, ν, см-1; 1667 (N-C=O), 3330, 3457 (NH2). Спектр ЯМР 1H (CDCl3), δ, м.д.: 1.96 (м, 4H, 2СН2), 2.79 (м, 2Н, СН2), 3.03 (м, 2Н, СН2), 3.60 (м, 4Н, 2СН2), 3.67 (м, 4Н, 2СН2), 6.68 (с, 1H, С=СН), 7.12 (м, 2Н, Наром), 7.69 (уш. с, 1Н, NH2), 8.01 (м, 2Н, Наром), 9.94 (уш. с, 1Н, NH2). Спектр ЯМР 13С (CDCl3), δ, м. д.: 21.9, 22.2, 24.7, 25.9, 66.8, 67.1, 91.5, 100.0, 111.4, 111.5, 115.9, 116.1, 116.5, 129.6, 130.0, 131.5, 132.8, 135.8, 146.0, 156.3, 161.8, 167.6, 173.6, 190.3. Найдено, %: С, 61.70; Н, 4.60; N, 11.00; S, 6.31. C26H23FN4O4S. Вычислено, %: С, 61.65; Н, 4.58; N, 11.06; S,6.33.Example 1. Preparation of compound 1: 1.54 g (0.01 mol) of 3-morpholino-3-oxopropanenitrile and 1.29 g (0.01 mol) of diisopropylethylamine were added to a solution of 3.52 g (0.01 mol) of 2-((2-oxo-5-(4-fluorophenyl)furan-3(2H)-ylidene)amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid nitrile in 50 ml of anhydrous dioxane. The resulting solution was maintained for 90 minutes at 90°C with vigorous stirring. The mixture was then cooled to 0°C, the formed precipitate was filtered off and washed with dioxane. Yield 4.40 g (87%), yellow crystals, mp 188–189°C. 236.1-237.9°C (dioxane). PC spectrum, ν, cm -1 ; 1667 (NC=O), 3330, 3457 (NH 2 ). 1H NMR spectrum ( CDCl3 ), δ, ppm: 1.96 (m, 4H, 2CH2 ), 2.79 (m, 2H, CH2 ), 3.03 (m, 2H, CH2 ), 3.60 (m, 4H, 2CH2 ), 3.67 (m, 4H, 2CH2 ), 6.68 (s, 1H, C=CH), 7.12 (m, 2H, Harom ), 7.69 (br s, 1H, NH2 ), 8.01 (m, 2H, Harom ), 9.94 (br s, 1H, NH2 ). 13C NMR spectrum ( CDCl3 ), δ, ppm: 21.9, 22.2, 24.7, 25.9, 66.8, 67.1, 91.5, 100.0, 111.4, 111.5, 115.9, 116.1, 116.5, 129.6, 130.0, 131.5, 132.8, 135.8, 146.0, 156.3, 161.8, 167.6, 173.6, 190.3. Found, %: C, 61.70; H, 4.60; N, 11.00; S, 6.31. C 26 H 23 FN 4 O 4 S. Calculated, %: C, 61.65; H, 4.58; N, 11.06; S, 6.33.
Полученное соединение 1 представляет собой желтое кристаллическое вещество, растворимое в хлороформе, ДМСО, при нагревании в толуоле, ацетоне, не растворимое в воде и гексане.The obtained compound 1 is a yellow crystalline substance, soluble in chloroform, DMSO, when heated in 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 by the method of G.N. Pershin [Pershin G.N. Methods of experimental chemotherapy // Moscow, pp. 100, 109-117 (1971)]. Compound 1 was administered intraperitoneally to white mice weighing 16-18 g as a suspension in 2% starch mucus and the behavior and mortality of the animals were observed for 10 days. For the studied compound 1, 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. Toximetry parameters of industrial poisons with a single exposure: Handbook. Moscow, 1977. - p. 196].
Пример 3. Противовоспалительная активность соединения 1 изучена в опытах на 30 белых беспородных крысах обоего пола массой 220-260 г. Соединение 1 вводили внутрибрюшинно в дозе 50 мг/кг в виде взвеси в 2% крахмальном растворе за час до моделирования острого каррагенинового воспаления. Каррагениновый отек вызывали субплантарной инъекцией 0,1 мл 1% раствора флогогена в заднюю лапу крысы. О противовоспалительной активности судили по изменению выраженности воспаления в динамике, которое регистрировали онкометрически через 2 и 4 часа после моделирования воспаления [Методические рекомендации по экспериментальному изучению нестероидных противовоспалительных веществ, фармакологический комитет МЗ СССР, протокол №22 от 11 ноября 1982. Москва. 1982]. Контрольным животным вводили эквиобъемное количество 2% крахмального раствора. Препаратом сравнения служил ортофен в дозе 10 мг/кг. Результаты испытаний представлены в таблице:Example 3. The anti-inflammatory activity of compound 1 was studied in experiments on 30 white mongrel rats of both sexes weighing 220-260 g. Compound 1 was administered intraperitoneally at a dose of 50 mg/kg as a suspension in a 2% starch solution one hour before modeling acute carrageenan inflammation. Carrageenan edema was induced by a subplantar injection of 0.1 ml of a 1% phlogogen solution into the hind paw of the rat. The anti-inflammatory activity was judged by changes in the severity of inflammation over time, which were recorded oncometrically 2 and 4 hours after modeling the inflammation [Methodological recommendations for the experimental study of non-steroidal anti-inflammatory substances, Pharmacological Committee of the USSR Ministry of Health, Protocol No. 22 of November 11, 1982. Moscow. 1982]. Control animals were administered an equivolume amount of a 2% starch solution. The comparison drug was orthofen at a dose of 10 mg/kg. The test results are presented in the table:
Как видно из таблицы, заявляемое соединение 1 проявляет выраженную противовоспалительную активность и более чем в 20 раз менее токсично, чем препарат сравнения - ортофен. Следовательно, заявляемое соединение 1 может найти применение в медицинской практике в качестве противовоспалительного лекарственного средства.As can be seen from the table, the claimed compound 1 exhibits pronounced anti-inflammatory activity and is more than 20 times less toxic than the comparison drug - orthofen. Consequently, the claimed compound 1 can find application in medical practice as an anti-inflammatory drug.
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| RU2810252C1 (en) * | 2023-05-25 | 2023-12-25 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | 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 |
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| RU2810252C1 (en) * | 2023-05-25 | 2023-12-25 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | 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 |
| RU2815045C1 (en) * | 2023-07-14 | 2024-03-11 | федеральное государственное автономное образовательное учреждение высшего образования "Санкт-Петербургский политехнический университет Петра Великого" (ФГАОУ ВО "СПбПУ") | (e)-5-amino-2-oxo-1-((e)-2-oxo-4-phenylbut-3-en-1-ylidene)-1,2,6,7,8,9-hexahydrobenzo[4,5]thieno[3,2-e]pyrrolo[1,2-a]pyrimidine-3-carboxamide, having anticancer activity in pulmonary melanoma therapy |
Non-Patent Citations (1)
| Title |
|---|
| Rogova A. et al., Synthesis of thieno[3,2-e]pyrrolo[1,2-a]pyrimidine derivatives and their precursors containing 2-aminothiophenes fragments as anticancer agents for therapy of pulmonary metastatic melanomaEuropean Journal of Medicinal Chemistry, Vol. 254, pp. 115325, 2023. 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, 84, 24, 15788-15796, 2019. * |
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