RU2808999C1 - Use of n-[2-(1-oxo-3,5-diphenyl-2-azaspiro[5.5]undec-3-en-2 il)phenyl]-3-bromobenzamide as analgesic - Google Patents
Use of n-[2-(1-oxo-3,5-diphenyl-2-azaspiro[5.5]undec-3-en-2 il)phenyl]-3-bromobenzamide as analgesic Download PDFInfo
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- RU2808999C1 RU2808999C1 RU2023111459A RU2023111459A RU2808999C1 RU 2808999 C1 RU2808999 C1 RU 2808999C1 RU 2023111459 A RU2023111459 A RU 2023111459A RU 2023111459 A RU2023111459 A RU 2023111459A RU 2808999 C1 RU2808999 C1 RU 2808999C1
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- diphenyl
- analgesic
- azaspiro
- phenyl
- bromobenzamide
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- 230000000202 analgesic effect Effects 0.000 title claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title 1
- -1 N-[2-(1-oxo-3,5-diphenyl-2-azaspiro[5.5]undec-3-ene-2- yl)phenyl]-3-bromobenzamide Chemical compound 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 239000000730 antalgic agent Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 229940125904 compound 1 Drugs 0.000 description 6
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- 239000002904 solvent 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
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 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 2
- 238000000034 method Methods 0.000 description 2
- RNWRVPVPLQMTAP-UHFFFAOYSA-N methyl 1-bromocyclohexane-1-carboxylate Chemical compound COC(=O)C1(Br)CCCCC1 RNWRVPVPLQMTAP-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 238000005698 Diels-Alder reaction Methods 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
- 230000004913 activation Effects 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 230000003502 anti-nociceptive effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000284 extract Substances 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
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229960002523 mercuric chloride Drugs 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- 229960000362 metamizole sodium Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 238000006362 organocatalysis Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000008533 pain sensitivity Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 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
- 239000000758 substrate Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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 N-[2-(1-оксо-3,5-дифенил-2-азаспиро[5.5]ундец-3-ен-2-ил)фенил]-3-бромбензамиду формулы 1:The invention relates to the field of organic chemistry, namely to N-[2-(1-oxo-3,5-diphenyl-2-azaspiro[5.5]undec-3-en-2-yl)phenyl]-3-bromobenzamide 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 9-(1-гидроксиаллил)-7-тозил-8-фенил-7-азаспиро[4.5]дец-8-ен-1,6-дион, обладающий биологической активностью [X. Jiang, X. Shi, S. Wang, Т. Sun, Y. Cao, R. Wang / Bifunctional Organocatalytic Strategy for Inverse-Electron-Demand Diels-Alder Reactions: Highly Efficient In Situ Substrate Generation and Activation to Construct Azaspirocyclic Skeletons // Angewandte Chemie. 2012. Vol. 124. No 9. P. 2126-2129. DOI: 10.1002/ange.201107716], формулы:The structural analogue of the claimed compound is 9-(1-hydroxyallyl)-7-tosyl-8-phenyl-7-azaspiro[4.5]dec-8-ene-1,6-dione, which has biological activity [X. Jiang, X. Shi, S. Wang, T. Sun, Y. Cao, R. Wang / Bifunctional Organocatalytic Strategy for Inverse-Electron-Demand Diels-Alder Reactions: Highly Efficient In Situ Substrate Generation and Activation to Construct Azaspirocyclic Skeletons // Angewandte Chemie. 2012. Vol. 124. No. 9. P. 2126-2129. DOI: 10.1002/ange.201107716], formulas:
Задачей изобретения является изыскание в ряду спиро-δ-лактамов новых соединений, обладающих анальгетической активностью и расширение арсенала средств воздействия на живой организм.The objective of the invention is to find new compounds among spiro-δ-lactams that have analgesic activity and expand the arsenal of means of influencing a living organism.
Поставленная задача решается синтезом N-[2-(1-оксо-3,5-дифенил-2-азаспиро[5.5]ундец-3-ен-2-ил)фенил]-3-бромбензамида 1, который обладает выраженной анальгетической активностью.This problem is solved by the synthesis of N-[2-(1-oxo-3,5-diphenyl-2-azaspiro[5.5]undec-3-en-2-yl)phenyl]-3-bromobenzamide 1, which has pronounced analgesic activity.
Синтезируют заявляемое соединение 1 путем взаимодействия 1-(3-бромбензоил)-2,4-дифенил-2,3-дигидро-1H-1,5-бензодиазепина 2 с метил 1-бромциклогексанкарбоксилатом и цинком в среде растворителя с последующим выделением целевых продуктов, по следующей схеме:The claimed compound 1 is synthesized by reacting 1-(3-bromobenzoyl)-2,4-diphenyl-2,3-dihydro-1H-1,5-benzodiazepine 2 with methyl 1-bromocyclohexanecarboxylate and zinc in a solvent, followed by isolation of the target products, according to the following scheme:
Процесс ведут при температуре 140-145°С, а в качестве растворителя используют оксилол.The process is carried out at a temperature of 140-145°C, and oxylene is used as a solvent.
Изобретение иллюстрируется следующими примерами.The invention is illustrated by the following examples.
Пример 1. N-[2-(1-Оксо-3,5-дифенил-2-азаспиро[5.5]ундец-3-ен-2-ил)фенил]-3-бромбензамид (1)Example 1 N-[2-(1-Oxo-3,5-diphenyl-2-azaspiro[5.5]undec-3-en-2-yl)phenyl]-3-bromobenzamide (1)
Смесь 2,8 г (0,007 моль) 1-(3-бромбензоил)-2,4-дифенил-2,3-дигидро-1H-1,5-бензодиазепина 2, 1,83 г (0,028 моль) металлического цинка, 40 мл безводного оксилола, 4 мл ГМФТА, каталитического количество сулемы и 3,09 г (0,014 моль) метилового эфира 1-бромциклогексанкарбоновой кислоты кипятили в течение 6 часов. После охлаждения к реакционной смеси добавляли 5% уксусную кислоту до растворения осадка. Затем водный слой отделяли и трижды экстрагировали этилацетатом. Органические вытяжки объединяли и сушили прокаленным сульфатом натрия. Растворители отгоняли, к остатку добавляли 15 мл этанола и оставляли кристаллизоваться. Продукт перекристаллизовывали из этилацетата. Выход 21%, Т.пл.=187-190°С.A mixture of 2.8 g (0.007 mol) 1-(3-bromobenzoyl)-2,4-diphenyl-2,3-dihydro-1H-1,5-benzodiazepine 2, 1.83 g (0.028 mol) zinc metal, 40 ml of anhydrous oxygen, 4 ml of HMPTA, a catalytic amount of mercuric chloride and 3.09 g (0.014 mol) of 1-bromocyclohexanecarboxylic acid methyl ester were boiled for 6 hours. After cooling, 5% acetic acid was added to the reaction mixture until the precipitate dissolved. The aqueous layer was then separated and extracted with ethyl acetate three times. Organic extracts were combined and dried with calcined sodium sulfate. The solvents were distilled off, 15 ml of ethanol was added to the residue and left to crystallize. The product was recrystallized from ethyl acetate. Yield 21%, mp.=187-190°C.
ПК спектр, ν, см-1: 3356 (NH), 1678, 1658 (СО), 1588 (С=С).PC spectrum, ν, cm -1 : 3356 (NH), 1678, 1658 (CO), 1588 (C=C).
Спектр ЯМР 1Н, δ, м. д. (J, Гц): 1.05-1.99 м (10Н, 5СН2); 3.62 д (0.87Н, С5Н, J 7.6); 3.81 д (0.13Н, С5Н, J 4.8); 5.60 д (0.13Н, С4Н, J 4.8); 5.76 д (0.87Н, С4Н, J 7.2); 6.85-7.65 м (14.26Н, Ar); 7.87 д (1.74Н, Ph, J 8.0); 7.98 с (0.13Н, 3-BrC6H4); 8.05 с (0.87Н, 3-BrC6H4); 8.40 с (0.13Н, NH); 8.52 с (0.87Н, NH). 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. 1H NMR spectrum, δ, ppm (J, Hz): 1.05-1.99 m (10H, 5CH2 ); 3.62 d (0.87H, C 5 H, J 7.6); 3.81 d (0.13H, C 5 H, J 4.8); 5.60 d (0.13H, C 4 H, J 4.8); 5.76 d (0.87H, C 4 H, J 7.2); 6.85-7.65 m (14.26H, Ar); 7.87 d (1.74H, Ph, J 8.0); 7.98 s (0.13Н, 3-BrC 6 H 4 ); 8.05 s (0.87Н, 3-BrC 6 H 4 ); 8.40 s (0.13H, NH); 8.52 s (0.87H, NH). 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 активностиExample 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).Evaluation 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 заявляемых соединений 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 compounds 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.
Claims (3)
Publications (1)
| Publication Number | Publication Date |
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| RU2808999C1 true RU2808999C1 (en) | 2023-12-05 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002085354A1 (en) * | 2001-04-18 | 2002-10-31 | Euro-Celtique S.A. | Spiroindene and spiroindane compounds |
| RU2455284C1 (en) * | 2011-03-15 | 2012-07-10 | Государственное образовательное учреждение высшего профессионального образования "Пермский государственный университет" | Method of producing 5-aryl-2-methyl-1,3-dioxo-2-azaspiro[5,5] undecane-4-carbonitriles and agent exhibiting analgesic activity |
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002085354A1 (en) * | 2001-04-18 | 2002-10-31 | Euro-Celtique S.A. | Spiroindene and spiroindane compounds |
| RU2455284C1 (en) * | 2011-03-15 | 2012-07-10 | Государственное образовательное учреждение высшего профессионального образования "Пермский государственный университет" | Method of producing 5-aryl-2-methyl-1,3-dioxo-2-azaspiro[5,5] undecane-4-carbonitriles and agent exhibiting analgesic activity |
Non-Patent Citations (1)
| Title |
|---|
| Никифорова Е.А. и др. Взаимодействие 1-бензоил-2,4-дифенил-2,3-дигидро-1H-1,5-бензодиазепина с алициклическими реактивами Реформатского. Химия гетероциклических соединений 2021, 57 (1), с.92-94. Зверев Д.П. и др. Синтез и структура N-(2-(3-спиро-2-оксо-4,6-дифенил-3,4-дигидропиридин-1(2N)-ил)фенил)бензамидов. Современные аспекты химии. Материалы VII молодежной школы-конференции, Пермь, 2020, с.193-196. * |
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