RU2829961C1 - 1,6-dioxo-1-methoxy-6-phenyl-2-cyano-4-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)hexa-2,4-diene-3-olate of potassium, having anti-inflammatory activity - Google Patents
1,6-dioxo-1-methoxy-6-phenyl-2-cyano-4-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)hexa-2,4-diene-3-olate of potassium, having anti-inflammatory activity Download PDFInfo
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- 230000003110 anti-inflammatory effect Effects 0.000 title claims abstract description 10
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 title claims abstract 3
- 229910052700 potassium Inorganic materials 0.000 title claims abstract 3
- 239000011591 potassium Substances 0.000 title claims abstract 3
- -1 1,6-dioxo-1-methoxy-6-phenyl-2-cyano-4-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)hexa-2,4-diene-3-olate Chemical compound 0.000 title abstract description 4
- IZZOKZMGQDMCAE-XQZFLANJSA-N alpha-L-Rhap-(1->2)-[beta-D-GlcpNAc-(1->3)]-alpha-L-Rhap-(1->3)-alpha-L-Rhap-(1->2)-[beta-D-GlcpNAc-(1->3)]-alpha-L-Rhap Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1[C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](C)O[C@H]2O)O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)NC(C)=O)O[C@@H](C)[C@@H]1O IZZOKZMGQDMCAE-XQZFLANJSA-N 0.000 claims 1
- 231100000053 low toxicity Toxicity 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract 1
- 229940125904 compound 1 Drugs 0.000 description 11
- 239000003814 drug Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 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
- 239000002253 acid Substances 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 238000000034 method Methods 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 150000007513 acids Chemical class 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
- ANGDWNBGPBMQHW-UHFFFAOYSA-N methyl cyanoacetate Chemical compound COC(=O)CC#N ANGDWNBGPBMQHW-UHFFFAOYSA-N 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 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
- XPUNCMMFIVTPKI-UHFFFAOYSA-N 3-thiophen-2-yliminofuran-2-one Chemical class S1C(=CC=C1)N=C1C(OC=C1)=O XPUNCMMFIVTPKI-UHFFFAOYSA-N 0.000 description 1
- IRGZBABDIGANPA-UHFFFAOYSA-N CCOC(=O)C1=C(SC(=C1C)C)NC(=CC(=O)C2=CC=C(C=C2)Br)C(=O)O Chemical compound CCOC(=O)C1=C(SC(=C1C)C)NC(=CC(=O)C2=CC=C(C=C2)Br)C(=O)O IRGZBABDIGANPA-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 239000013543 active substance 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
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000006243 chemical reaction 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
- 230000003993 interaction Effects 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
- 230000003637 steroidlike Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity 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 2-амино-4-диоксобутановых кислот, а именно к 1,6-диоксо-1-метокси-6-фенил-2-циано-4-((3-циано-4,5,6,7-тетрагидробензо[b]тиофен-2-ил)амино)гекса-2,4-диен-3-олату калия формулы:The invention relates to the field of organic chemistry, to new biologically active substances of the class of substituted 2-amino-4-dioxobutanoic acids, namely to potassium 1,6-dioxo-1-methoxy-6-phenyl-2-cyano-4-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)hexa-2,4-diene-3-olate 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 4-(4-бромфенил)-2-[(4,5-диметил-3-(этоксикарбонил)тиофен-2-ил)амино]-4-оксобут-2-еновая кислота 2 [Шипиловских Сергей Александрович, синтез и химические превращения замещенных 3-(тиофен-2-ил)имино-3Н-фуран-2-онов, кандидатская диссертация, http://www.chem.msu.ru/rus/theses/2016/2016-04-02-shipilovskikh/] формулы:A structural analogue of the claimed compound is 4-(4-bromophenyl)-2-[(4,5-dimethyl-3-(ethoxycarbonyl)thiophen-2-yl)amino]-4-oxobut-2-enoic acid 2 [Shipilovskikh Sergey Aleksandrovich, synthesis and chemical transformations of substituted 3-(thiophen-2-yl)imino-3H-furan-2-ones, PhD dissertation, http://www.chem.msu.ru/rus/theses/2016/2016-04-02-shipilovskikh/] 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 производных 2-амино-4-диоксобутановых кислот с выраженным противовоспалительным действием и низкой токсичностью.The objective of the invention is to find substances in the series of substituted derivatives of 2-amino-4-dioxobutanoic acids with a pronounced anti-inflammatory effect and low toxicity.
Поставленная задача достигается получением 1,6-диоксо-1-метокси-6-фенил-2-циано-4-((3-циано-4,5,6,7-тетрагидробензо[b]тиофен-2-ил)амино)гекса-2,4-диен-3-олата калия, который обладает противовоспалительной активностью.The set task is achieved by obtaining 1,6-dioxo-1-methoxy-6-phenyl-2-cyano-4-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)hexa-2,4-dien-3-olate potassium, which has anti-inflammatory activity.
Заявляемое соединение 1 синтезируют взаимодействием нитрила 2-[2-оксо-5-фенилфуран-3(2H)-илиден)амино]-4,5,6,7-тетрагидробензо[b]тиофен-3-карбоновой кислоты с метиловым эфиром циануксусной кислоты и третбутилатом калия в среде абсолютного диоксана при 50°С с последующим выделением целевого продукта известными методами по схеме:The claimed compound 1 is synthesized by the interaction of 2-[2-oxo-5-phenylfuran-3(2H)-ylidene)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid nitrile with methyl cyanoacetate and potassium tert-butoxide in an absolute dioxane medium at 50°C, followed by isolation of the target product by known methods according to the scheme:
Пример 1. Получение соединения 1: раствору 334 мг (0,001 моль) нитрила 2-[2-оксо-5-фенилфуран-3(2H)-илиден)амино]-4,5,6,7-тетрагидробензо[b]тиофен-3-карбоновой кислоты в 25 мл безводного диоксана прибавляли 99 мг (0,001 моль) метилового эфира циануксусной кислоты, к полученной смеси добавили 112 мг (0,001 моль) t-BuOK, полученный раствор нагревали до 50°С и выдерживали в течение 60 мин, выпавший осадок отфильтровывали и перекристаллизовывали из диоксана.Example 1. Preparation of compound 1: 99 mg (0.001 mol) of methyl cyanoacetate were added to a solution of 334 mg (0.001 mol) of 2-[2-oxo-5-phenylfuran-3(2H)-ylidene)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid nitrile in 25 ml of anhydrous dioxane, 112 mg (0.001 mol) of t-BuOK were added to the resulting mixture, the resulting solution was heated to 50°C and held for 60 min, the formed precipitate was filtered off and recrystallized from dioxane.
Выход 316 мг (67%), желтые кристаллы, т.пл. 174-175°С (этанол). Спектр ЯМР 1Н (ДМСО- d6) δ, м.д., J/Гц: 1.77 (м, 4Н, СН2), 2.52 (м, 2Н, СН2), 2.60 (м, 2Н, СН2), 3.43 (с, 3Н, СН3), 5.91 (с, 1H, СН), 7.48 (м, 2Наром), 7.59 (м, 1Наром), 7.93 (м, 2Наром), 14.10 (с, 1H, NH). Спектр ЯМР 13С (ДМСО-d6) δ, м.д.: 22.1, 23.1, 24.1, 24.2, 50.1, 92.8, 105.4, 110.3, 113.3, 116.5, 127.3, 127.5, 129.0, 132.0, 134.1, 136.9, 144.6, 146.3, 167.6, 181.9, 188.6. Найдено, %: С, 58.56; Н, 3.87; N, 8.93; 0,13.55; C23H18KN3O4S. Вычислено, %: С, 58.58; Н, 3.85;N, 8.91; 0,13.57.Yield 316 mg (67%), yellow crystals, mp 174-175°C (ethanol). 1H NMR spectrum (DMSO- d6 ) δ, ppm, J/Hz: 1.77 (m, 4H, CH2 ), 2.52 (m, 2H, CH2 ), 2.60 (m, 2H, CH2 ), 3.43 (s, 3H, CH3 ), 5.91 (s, 1H, CH), 7.48 (m, 2H arom ), 7.59 (m, 1H arom ), 7.93 (m, 2H arom ), 14.10 (s, 1H, NH). 13 C NMR spectrum (DMSO-d 6 ) δ, ppm: 22.1, 23.1, 24.1, 24.2, 50.1, 92.8, 105.4, 110.3, 113.3, 116.5, 127.3, 127.5, 129.0, 132.0, 134.1, 136.9, 144.6, 146.3, 167.6, 181.9, 188.6. Found, %: C, 58.56; N, 3.87; N, 8.93; 0.13.55; C 23 H 18 KN 3 O 4 S. Calculated, %: C, 58.58; H, 3.85;N, 8.91; 0.13.57.
Полученное соединение 1 представляет собой желтое кристаллическое вещество, растворимое в ДМСО, толуоле, ацетоне, воде, не растворимое в гексане.The obtained compound 1 is a yellow crystalline substance, soluble in DMSO, toluene, acetone, water, insoluble in 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 // M., 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 относятся 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 toxicity of drugs, compound 1 belongs to class V of practically non-toxic drugs [Izmerov N.F., Sanotsky I.V., Sidorov K.K. Toxicometry 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 в двадцать раз менее токсично, чем препарат сравнения - ортофен. Следовательно, заявляемое соединение 1 может найти применение в медицинской практике в качестве противовоспалительного лекарственного средства с низкой токсичностью.As can be seen from the table, the claimed compound 1 exhibits pronounced anti-inflammatory activity and is twenty times less toxic than the comparison drug - orthofen. Consequently, the claimed compound 1 can find application in medical practice as an anti-inflammatory drug with low toxicity.
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| CN108558848A (en) * | 2018-04-19 | 2018-09-21 | 华东师范大学 | A kind of cycloalkane thiophthene derivative and preparation method thereof and medical usage |
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| CN108558848A (en) * | 2018-04-19 | 2018-09-21 | 华东师范大学 | A kind of cycloalkane thiophthene derivative and preparation method thereof and medical usage |
| RU2798468C1 (en) * | 2022-07-01 | 2023-06-23 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | 1-amino-1,6-dioxo-6-(4-chlorophenyl)-2-cyano-4-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)hexa -2,4-dien-3-olate potassium with anti-inflammatory activity |
| RU2810078C1 (en) * | 2023-03-31 | 2023-12-21 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | POTASSIUM 2-(4-BROMOPHENYL)-6-OXO-4-(PHENYLIMINO)-1,6-CYANO-1-((4-CYANO-3-TETRAHYDROBENZO[b]THIOPHEN-4,5,6,7-YL)AMINO)-2-ETOXYHEXA-2,4-DIENE-3-OLATE WITH ANALGESIC ACTIVITY |
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| RU2785780C1 (en) | APPLICATION OF 2-[(3-(AMINOCARBONIL)-4,5,6,7-TETRAHYDROBENZO[b]THIOPHEN-2-yl)AMINO]-4-OXO-4-(4-CHLOROPHENYL)BUT-2-ENOIC ACID IN AS AN ANTI-INFLAMMATORY DRUG | |
| RU2831363C1 (en) | 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 | |
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| RU2810072C1 (en) | 4-(4-METHOXYPHENYL)-4-OXO-N-PHENYL-2-((3-CYANO-4,5,6,7-TETRAHYDROBENZO[b]THIOPHEN-2-YL)AMINO)BUT-2-ENAMIDE WITH ANALGESIC ACTIVITY | |
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| RU2834687C1 (en) | 1-AMINO-1,6-DIOXO-6-(4-METHOXYPHENYL)-2-CYANO-4-((3-(ETHOXYCARBONYL)-4,5,6,7-TETRAHYDROBENZO[b]THIOPHEN-2-YL)AMINO)HEXA-2,4-DIENE-3-OLATE OF SODIUM, HAVING ANALGESIC ACTIVITY | |
| RU2829963C1 (en) | 4-bromo-n'-((2-((2-(4-bromobenzoyl)-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino)-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(imino)methyl)benzohydrazide, having analgesic activity | |
| RU2798425C1 (en) | 4-oxo-n-(furan-2-ylmethyl)-4-(4-chlorophenyl)-2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)but-2-enamide with analgesic activity | |
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| RU2810070C1 (en) | Ethyl ether 2-amino-(3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)-5-(2-(4-ethylphenyl)-2-oxoethylidene)-4-oxo- 4,5-dihydro-1h-pyrrol-3-carboxylic acid with analgesic activity |