RU2809056C1 - Use of 4-phenyl-2,3-diazaspiro[4.4]non-3-en-1-one as an analgetic - Google Patents
Use of 4-phenyl-2,3-diazaspiro[4.4]non-3-en-1-one as an analgetic Download PDFInfo
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- 230000000202 analgesic effect Effects 0.000 title claims abstract description 11
- -1 4-phenyl-2,3-diazaspiro[4.4]non-3-en-1-one Chemical compound 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 239000000730 antalgic agent Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 229940126601 medicinal product Drugs 0.000 abstract 1
- 229940125904 compound 1 Drugs 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 4
- DJGAAPFSPWAYTJ-UHFFFAOYSA-M metamizole sodium Chemical compound [Na+].O=C1C(N(CS([O-])(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 DJGAAPFSPWAYTJ-UHFFFAOYSA-M 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- DCJKUXYSYJBBRD-UHFFFAOYSA-N 2,5-diphenyl-1,3,4-oxadiazole Chemical compound C1=CC=CC=C1C1=NN=C(C=2C=CC=CC=2)O1 DCJKUXYSYJBBRD-UHFFFAOYSA-N 0.000 description 2
- VXMYWVMXSWJFCV-UHFFFAOYSA-N 3-(4-imidazol-1-ylphenyl)-4,5-dihydro-1h-pyridazin-6-one Chemical class N1C(=O)CCC(C=2C=CC(=CC=2)N2C=NC=C2)=N1 VXMYWVMXSWJFCV-UHFFFAOYSA-N 0.000 description 2
- 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
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 230000003502 anti-nociceptive effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960000362 metamizole sodium Drugs 0.000 description 2
- YGWINKVROAENAL-UHFFFAOYSA-N methyl 1-bromocyclopentane-1-carboxylate Chemical compound COC(=O)C1(Br)CCCC1 YGWINKVROAENAL-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ITJITFFIFBRRSI-UHFFFAOYSA-N 1-(4-imidazol-1-ylphenyl)-2,3-diazaspiro[4.4]non-1-en-4-one Chemical compound C1CCCC11C(=O)NN=C1C(C=C1)=CC=C1N1C=CN=C1 ITJITFFIFBRRSI-UHFFFAOYSA-N 0.000 description 1
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000008533 pain sensitivity Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Abstract
Description
Изобретение относится к области органической химии, а именно к 4-фенил-2,3-диазаспиро[4.4]нон-3-ен-1-ону формулы 1:The invention relates to the field of organic chemistry, namely to 4-phenyl-2,3-diazaspiro[4.4]non-3-en-1-one of formula 1:
обладающему антиноцицептивной активностью, который может быть использован в качестве анальгетического средства в фармакологии.possessing antinociceptive activity, which can be used as an analgesic in pharmacology.
Аналогом по структуре заявляемому соединению является 4-(4-(1H-имидазол-1-ил)фенил)-2,3-диазаспиро[4.4]нон-3-ен-1-он, обладающий биологической активностью [I. Sircar, G.C. Morrison, S.E. Burke, R. Skeean, R.E. Weishaar / Cardiotonic agents. 6. Synthesis and inotropic activity of 2,4-dmydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones: ring-contracted analogues of imazodan (CI-914) // Journal of Medicinal Chemistry. 1987. Vol.30. №10. P. 1724-1728. DOI: 10.1021/jm00393a007], формулы:The structural analogue of the claimed compound is 4-(4-(1H-imidazol-1-yl)phenyl)-2,3-diazaspiro[4.4]non-3-en-1-one, which has biological activity [I. Sircar, G.C. Morrison, S.E. Burke, R. Skeean, R.E. Weishaar / Cardiotonic agents. 6. Synthesis and inotropic activity of 2,4-dmydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones: ring-contracted analogues of imazodan (CI-914) / / Journal of Medicinal Chemistry. 1987. Vol.30. No. 10. P. 1724-1728. DOI: 10.1021/jm00393a007], formulas:
В качестве эталона сравнения по фармакологическому действию выбран известный практической медицине анальгетический препарат, метамизол натрия (анальгин).An analgesic drug known to practical medicine, metamizole sodium (analgin), was chosen as a comparison standard for pharmacological action.
Задачей изобретения является изыскание в ряду 4-спиро-5-арил-2,4-дигидро-3H-пиразол-3-онов новых соединений, обладающих анальгетической активностью и расширение арсенала средств воздействия на живой организм.The objective of the invention is to find new compounds among 4-spiro-5-aryl-2,4-dihydro-3H-pyrazol-3-ones that have analgesic activity and expand the arsenal of means of influencing a living organism.
Поставленная задача решается синтезом 4-фенил-2,3-диазаспиро[4.4]нон-3-ен-1-она 1, который обладает выраженной анальгетической активностью.This problem is solved by the synthesis of 4-phenyl-2,3-diazaspiro[4.4]non-3-en-1-one 1, which has pronounced analgesic activity.
Синтезируют заявляемое соединение 1 по известной методике [Е.А. Nikiforova, N.F. Kirillov, D.V. Baibarodskikh, S.N. Shurov, M.V. Dmitriev, D.P. Zverev / Reaction of Reformatsky reagents with 2,5-diphenyl-l,3,4-oxadiazole // Mendeleev Communications. 2021. Vol.31. №2. P. 248-250. DOI: 10.1016/j.mencom.2021.03.035] путем взаимодействия 2,5-дифенил-1,3,4-оксадиазола 2 с метил 1-бромциклопентанкарбоксилатом 3 и цинком в среде растворителя с последующим выделением целевых продуктов известными методами, по следующей схеме:The claimed compound 1 is synthesized according to a known method [E.A. Nikiforova, N.F. Kirillov, D.V. Baibarodskikh, S.N. Shurov, M.V. Dmitriev, D.P. Zverev / Reaction of Reformatsky reagents with 2,5-diphenyl-l,3,4-oxadiazole // Mendeleev Communications. 2021. Vol.31. No. 2. P. 248-250. DOI: 10.1016/j.mencom.2021.03.035] by reacting 2,5-diphenyl-1,3,4-oxadiazole 2 with methyl 1-bromocyclopentanecarboxylate 3 and zinc in a solvent, followed by isolation of the target products using known methods, according to the following scheme :
Процесс ведут при температуре 105-115°С, а в качестве растворителя используют толуол.The process is carried out at a temperature of 105-115°C, and toluene is used as a solvent.
Анальгетическая (антиноцицептивная) активность 4-фенил-2,3-диазаспиро[4.4]нон-3-ен-1-она 1 ранее не была исследована.The analgesic (antinociceptive) activity of 4-phenyl-2,3-diazaspiro[4.4]non-3-en-1-one 1 has not been previously studied.
Изобретение иллюстрируется следующими примерами.The invention is illustrated by the following examples.
Пример 1. 4-Фенил-2,3-диазаспиро[4.4]нон-3-ен-1-он (1).Example 1. 4-Phenyl-2,3-diazaspiro[4.4]non-3-en-1-one (1).
Смесь 2.00 г измельченного в мелкую стружку цинка, каталитического количества сулемы, 30 мл безводного бензола, 1 мл ГМФТА, 22 ммоль (4.55 г) метил 1-бромциклопентанкарбоксилата 3 и 10 ммоль (2.22 г) 2,5-дифенил-1,3,4-оксадиазола 2 кипятили 3 ч, охлаждали, сливали с избытка цинка, гидролизовали 5%-ной уксусной кислотой, органический слой отделяли, из водного слоя продукты реакции дважды экстрагировали толуолом. После высушивания экстракта безводным сульфатом натрия растворители отгоняли и соединение 1 перекристаллизовывали из этанола. Выход 38%, т.пл. 182 -183°С.A mixture of 2.00 g of finely ground zinc, a catalytic amount of sublimate, 30 ml of anhydrous benzene, 1 ml of HMPTA, 22 mmol (4.55 g) methyl 1-bromocyclopentanecarboxylate 3 and 10 mmol (2.22 g) 2,5-diphenyl-1,3, 4-oxadiazole 2 was boiled for 3 hours, cooled, the excess zinc was decanted, hydrolyzed with 5% acetic acid, the organic layer was separated, and the reaction products were extracted twice from the aqueous layer with toluene. After drying the extract with anhydrous sodium sulfate, the solvents were distilled off and compound 1 was recrystallized from ethanol. Yield 38%, mp. 182 -183°С.
ПК спектр, ν, см-1: 3178 (NH), 1697 (С=O). Спектр ЯМР 1Н, δ, м.д.: 1.99-2.44 м [8Н, (СН2)4], 7.37 - 7.44 м (3Наром.), 7.70 - 7.76 м (2Наром.), 8.93 с (1H, NH). Спектр ЯМР 13С, δ, м.д.: 27.51, 35.82, 55.95 (циклопентан), 126.39, 128.92, 130.02, 130.93 (Ph), 162.81 (C=N), 183.46 (С=O). Найдено, %: С 73.02; Н 6.47; N 13.25. C13H14N2O. Вычислено, %: С 72.87; Н 6.59; N 13.07.PC spectrum, ν, cm -1 : 3178 (NH), 1697 (C=O). 1H NMR spectrum, δ, ppm: 1.99-2.44 m [8H, ( CH2 ) 4 ], 7.37 - 7.44 m (3H arom .), 7.70 - 7.76 m (2H arom .), 8.93 s (1H , NH). 13 C NMR spectrum, δ, ppm: 27.51, 35.82, 55.95 (cyclopentane), 126.39, 128.92, 130.02, 130.93 (Ph), 162.81 (C=N), 183.46 (C=O). Found, %: From 73.02; H 6.47; N 13.25. C 13 H 14 N 2 O. Calculated, %: C 72.87; H 6.59; N 13.07.
Соединение 1 представляет собой белое кристаллическое вещество, легкорастворимое в ДМСО, хлороформе, ацетоне, трудно растворимое в спирте и алканах, нерастворимое в воде. Устойчиво при хранении в обычных условиях.Compound 1 is a white crystalline substance, readily soluble in DMSO, chloroform, acetone, sparingly soluble in alcohol and alkanes, insoluble in water. Stable when stored under normal conditions.
Пример 2. Фармакологическое исследование соединения 1 на наличие анальгетической активности.Example 2. Pharmacological study of compound 1 for analgesic activity.
Оценку анальгетических свойств соединения 1 изучали на беспородных мышах массой 18-22 грамм методом термического раздражения «горячая пластинка» по Эдди и Леймбах (Eddy N.B., Leimbarh D.J.- Pharmacol and Exper. Gher., 1953, 385-393). В качестве препарата сравнения использовали анальгин (метамизол натрия) (М.Д. Машковский, «Лекарственные средства», т.1, стр. 184, М., Медицина, 1978).The assessment of the analgesic properties of compound 1 was studied on outbred mice weighing 18-22 grams using the “hot plate” thermal stimulation method according to Eddy and Leimbach (Eddy N.B., Leimbarh D.J. - Pharmacol and Exper. Gher., 1953, 385-393). Analgin (metamizole sodium) was used as a comparison drug (M.D. Mashkovsky, “Medicines”, vol. 1, p. 184, M., Medicine, 1978).
Исследуемое соединение, вводили внутрибрюшинно в виде 2% крахмальной слизи в дозе 50 мг/кг за 2 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.The test compound was administered intraperitoneally in the form of 2% starch mucus at a dose of 50 mg/kg 2 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.
Проведенные исследования показали (см. табл.), что соединение 1 обладают анальгетической активностью. Данные о фармакологической активности заявляемого соединения 1 в доступной литературе отсутствуют.Studies have shown (see table) that compound 1 has analgesic activity. There are no data on the pharmacological activity of the claimed compound 1 in the available literature.
Как видно из таблицы, заявляемое соединение 1 проявляет выраженную анальгетическую активность, превышающую таковую для препарата сравнения - анальгина. 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, exceeding that of the reference drug - analgin. Therefore, the claimed compound 1 can find use in medical practice as an analgesic drug.
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| RU2785784C1 (en) * | 2022-02-24 | 2022-12-13 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | APPLICATION OF 4-(4-METHOXYPHENYL)-4-OXO-2-[(3-(CYANO)-4,5,6,7-TETRAHYDROBENZO[b]THIOPHEN-2-yl)AMINO]BUT-2-ENOIC ACID AS AN ANALGESIC DRUG |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2785784C1 (en) * | 2022-02-24 | 2022-12-13 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | APPLICATION OF 4-(4-METHOXYPHENYL)-4-OXO-2-[(3-(CYANO)-4,5,6,7-TETRAHYDROBENZO[b]THIOPHEN-2-yl)AMINO]BUT-2-ENOIC ACID AS AN ANALGESIC DRUG |
| RU2022104919A (en) * | 2022-02-24 | 2023-08-24 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | APPLICATION OF N-(5-(4-BROMOPHENYL)-2-OXOFURAN-3(2H)-YLYDEN)-4-METHYLBENZOHYDRAZIDE AS AN ANALGESIC DRUG |
Non-Patent Citations (1)
| Title |
|---|
| I. SIRCAR и др., Cardiotonic agents. 6. Synthesis and inotropic activity of 2,4-Dihydro-5-[4-(1H-imidazol-1-yl)phenyl]-3H-pyrazol-3-ones: ring-contracted analogues of imazodan (CI-914). Journal of Medicinal Chemistry. 1987. Vol.30. No 10. P.1724-1728. Е.А. NIKIFOROVA и др., Reaction of Reformatsky reagents with 2,5-diphenyl-l,3,4-oxadiazole. Mendeleev Communications. 2021. Vol.31. No 2. P. 248-250. * |
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