RU2829963C1 - 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 - Google Patents
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 Download PDFInfo
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- 230000000202 analgesic effect Effects 0.000 title claims abstract description 10
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 title description 2
- -1 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 Chemical compound 0.000 claims abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical class OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 231100000053 low toxicity Toxicity 0.000 abstract description 3
- 239000013543 active substance Substances 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 229940125904 compound 1 Drugs 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- UYIMBYKIIMYFPS-UHFFFAOYSA-N 4-bromobenzohydrazide Chemical compound NNC(=O)C1=CC=C(Br)C=C1 UYIMBYKIIMYFPS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- SQTLUXJWUCHKMT-UHFFFAOYSA-N 4-bromo-n,n-diphenylaniline Chemical compound C1=CC(Br)=CC=C1N(C=1C=CC=CC=1)C1=CC=CC=C1 SQTLUXJWUCHKMT-UHFFFAOYSA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 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
- 125000001931 aliphatic group Chemical group 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
- 125000001841 imino group Chemical group [H]N=* 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
- 239000002184 metal Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- VTHCULBLEKIUTL-UHFFFAOYSA-N thiophene-3-carbonitrile Chemical compound N#CC1=[C]SC=C1 VTHCULBLEKIUTL-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
Изобретение относится к области органической химии, к новым биологически активным веществам класса замещенных пиридазин-3(2H)-онов, а именно к 4-бром-N'-((2-((2-(4-бромбензоил)-3-оксо-6-фенил-2,3-дигидропиридазин-4-ил)амино)-4,5,6,7-тетрагидробензо[b]тиофен-3-ил)(имино)метил)бензогидразиду формулы:The invention relates to the field of organic chemistry, to new biologically active substances of the class of substituted pyridazin-3(2H)-ones, namely to 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 of the formula:
который обладает анальгетической активностью, что позволяет предположить его использование в медицине в качестве лекарственного средства с анальгетическими свойствами и низкой токсичностью.which has analgesic activity, which suggests its use in medicine as a drug with analgesic properties and low toxicity.
Аналогом по структуре заявляемому соединению является этиловый эфир 2-[(3-оксо-6-фенил-2-этил-2,3-дигидропиридазин-4-ил)амино]-4,5,6,7-тетрагидробензо[b]тиофен-3-карбоновой кислоты [S. A. Shipilovskikh, А. Е. Rubtsov, Russian Journal of Organic Chemistry, 2014, Vol.50, No. 12, pp.1853-1855, doi: 10.1134/S1070428014120288] формулы:A structural analogue of the claimed compound is ethyl ester of 2-[(3-oxo-6-phenyl-2-ethyl-2,3-dihydropyridazin-4-yl)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid [S. A. Shipilovskikh, A. E. Rubtsov, Russian Journal of Organic Chemistry, 2014, Vol.50, No. 12, pp.1853-1855, doi: 10.1134/S1070428014120288] 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 пиридазин-3(2Н)-онов с выраженным анальгетическим действием и низкой токсичностью.The objective of the invention is to find substances in the series of substituted pyridazin-3(2H)-ones with a pronounced analgesic effect and low toxicity.
Поставленная задача достигается получением 4-бром-N'-((2-((2-(4-бромбензоил)-3-оксо-6-фенил-2,3-дигидропиридазин-4-ил)амино)-4,5,6,7-тетрагидробензо[6]тиофен-3-ил)(имино)метил)бензогидразида, который обладает анальгетической активностью.The stated objective is achieved by obtaining 4-bromo-N'-((2-((2-(4-bromobenzoyl)-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino)-4,5,6,7-tetrahydrobenzo[6]thiophen-3-yl)(imino)methyl)benzohydrazide, which has analgesic activity.
Заявляемое соединение 1 синтезируют взаимодействием (Е)-2-((2-оксо-5-фенилфуран-3(2Н)-илиден)амино)-4,5,6,7-тетрагидробензо[b]тиофен-3-карбонитрила с 4-бромбензогидразидом. Реакция протекает в диоксане при перемешивании и температуре 90°C в течение 1 часа с последующим удалением растворителя и выделением целевого продукта известными методами по схеме:The claimed compound 1 is synthesized by the interaction of (E)-2-((2-oxo-5-phenylfuran-3(2H)-ylidene)amino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile with 4-bromobenzohydrazide. The reaction takes place in dioxane with stirring and a temperature of 90°C for 1 hour, followed by removal of the solvent and isolation of the target product by known methods according to the scheme:
Пример 1. Получение соединения 1: к раствору 334 мг (0,001 моль) (£)-2-((2-оксо-5-фенилфуран-3(2H)-илиден)амино)-4,5,6,7-тетрагидробензо[6]тиофен-3-карбонитрила в 30 мл безводного диоксана прибавляют 642 мг (0,003 моль) 4-бромбензогидразида и выдерживают при температуре 90°С в течение 1 часа. Смесь охлаждают до 0°С, выпавший осадок отфильтровывают и перекристаллизовывают.Example 1. Preparation of compound 1: 642 mg (0.003 mol) of 4-bromobenzohydrazide are 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[6]thiophene-3-carbonitrile in 30 ml of anhydrous dioxane and the mixture is maintained at 90°C for 1 hour. The mixture is cooled to 0°C, the resulting precipitate is filtered off and recrystallized.
Полученное соединение 1 представляет собой оранжевое кристаллическое вещество, растворимое в ДМСО, ацетоне, не растворимое в воде и гексане.The obtained compound 1 is an orange crystalline substance, soluble in DMSO, acetone, insoluble in water and hexane.
Выход: 602 мг (81%), оранжевые кристаллы, т.пл. 108-110°С (этанол). Спектр ЯМР 1Н (ДМСОd6), δ, м. д.: 1.76 м (4Н, 2СН2), 2.51 м (2Н, СН2), 2.61 м (2Н, СН2), 5.99 с (1Н, СН), 6.87 с (1Н, NH), 7.29 м (2Н, Наром), 7.58 м (2Н, Наром), 7.65-7.86 м (9Н, Наром), 9.28 уш. с. (1Н, NH), 9.84 уш. с. (1Н, NH), 10.43 уш. с. (Ш, NH). Найдено, %: С 53.12; Н 3.49; N 11.28; S 4.32. C33H26Br2N6O3S. Вычислено, %: С 53.10; Н 3.51; N11.26; S 4.29.Yield: 602 mg (81%), orange crystals, mp 108-110°C (ethanol). 1H NMR spectrum (DMSO d6 ), δ, ppm: 1.76 m (4H, 2CH 2 ), 2.51 m (2H, CH 2 ), 2.61 m (2H, CH 2 ), 5.99 s (1H, CH), 6.87 s (1H, NH), 7.29 m (2H, Harom ), 7.58 m (2H, Harom ), 7.65-7.86 m (9H, Harom ), 9.28 br s (1H, NH), 9.84 br s (1H, NH), 10.43 br s. (SH, NH). Found, %: From 53.12; H 3.49; N 11.28; S 4.32. C 33 H 26 Br 2 N 6 O 3 S. Calculated, %: C 53.10; H 3.51; N11.26; S 4.29.
Полученное соединение 1 представляет собой оранжевое кристаллическое вещество, растворимое в ДМСО, ацетоне, не растворимое в воде и гексане.The obtained compound 1 is an orange crystalline substance, soluble in DMSO, 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 // 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 death 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. 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. Et ther. 1957. - Vol.11. - No.4 - P. 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 h before placing the animals on a metal plate heated to 53.5°C. The pain sensitivity indicator was the duration of the animal's stay on the hot plate until the moment of licking its hind legs, measured in seconds. The effect was compared with orthofen. 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 comparison drug - orthofen. Consequently, the claimed compound 1 can find application in medical practice as an analgesic drug.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2808995C1 (en) * | 2023-03-31 | 2023-12-05 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | OBTAINING 2-((6-(2-METHOXYPHENYL)-3-OXO-2-ETHYL-2,3-DIHYDROPYRIDAZIN-4-YL)AMINO)-4,5,6,7-TETRAHYDROBENZO[b]THIOPHENE-3-CARBONITRILE WITH ANALGESIC ACTIVITY |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2808995C1 (en) * | 2023-03-31 | 2023-12-05 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | OBTAINING 2-((6-(2-METHOXYPHENYL)-3-OXO-2-ETHYL-2,3-DIHYDROPYRIDAZIN-4-YL)AMINO)-4,5,6,7-TETRAHYDROBENZO[b]THIOPHENE-3-CARBONITRILE WITH ANALGESIC ACTIVITY |
| RU2809054C1 (en) * | 2023-03-31 | 2023-12-06 | Федеральное государственное автономное образовательное учреждение высшего образования "Пермский государственный национальный исследовательский университет" | USE OF AN ANALGETIC DRUG BASED ON 2-((6-(4-METHOXYPHENYL)-2-METHYL-3-OXO-2,3-DIHYDROPYRIDAZINE-4(1H)-YLIDENE)AMINO)-4,5,6,7- AMIDE TETRAHYDROBENZO[b]THIOPHENE-3-CARBOXYLIC ACID |
Non-Patent Citations (2)
| Title |
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| GOKCE M. et al., Synthesis and analgesic and anti-inflammatory activities 6-substituted-3(2H)-pyridazinone-2-acetyl-2-(p-substituted/nonsubstituted benzal)hydrazone derivatives, European Journal of Medicinal Chemistry, 2009, vol.44, no.9, p. 3760-3764. * |
| МАШКОВСКИЙ М.Д., Лекарственные средства, 15-е изд., перераб., испр. и доп., М.: ООО "Новая волна", 2005, 1200 c, стр. 170. SHIPILOVSKIKH S.A. et al., Chemistry of Iminofurans. Recyclization of Ethyl 2-[2-Oxo-5-phenylfuran-3(2H)-ylideneamino]-4,5,6,7-tetrahydro1-benzothiophene-3-carboxylate by the Action of HydrazinesRussian Journal of Organic Chemistry, 2014, v. 50, no. 12, p. 1853-1855. * |
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