RU2802003C1 - 4-(3,4-dibromothiophenecarbonil)-2,6,8,12-tetraacetil-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11,05,9]dodecane derivatives with salicylic acids as analgesics and method for their production - Google Patents
4-(3,4-dibromothiophenecarbonil)-2,6,8,12-tetraacetil-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11,05,9]dodecane derivatives with salicylic acids as analgesics and method for their production Download PDFInfo
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- RU2802003C1 RU2802003C1 RU2022134694A RU2022134694A RU2802003C1 RU 2802003 C1 RU2802003 C1 RU 2802003C1 RU 2022134694 A RU2022134694 A RU 2022134694A RU 2022134694 A RU2022134694 A RU 2022134694A RU 2802003 C1 RU2802003 C1 RU 2802003C1
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- hexaazatetracyclo
- dodecane
- dibromothiophenecarbonyl
- tetraacetyl
- hydroxybenzoyl
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- 238000000034 method Methods 0.000 title claims abstract description 7
- 150000003870 salicylic acids Chemical class 0.000 title claims description 3
- 238000004519 manufacturing process Methods 0.000 title abstract description 4
- 239000000730 antalgic agent Substances 0.000 title description 4
- 229940035676 analgesics Drugs 0.000 title description 2
- SNRUBQQJIBEYMU-NJFSPNSNSA-N dodecane Chemical class CCCCCCCCCCC[14CH3] SNRUBQQJIBEYMU-NJFSPNSNSA-N 0.000 title 1
- 230000000202 analgesic effect Effects 0.000 claims abstract description 9
- DSGKWFGEUBCEIE-UHFFFAOYSA-N (2-carbonochloridoylphenyl) acetate Chemical compound CC(=O)OC1=CC=CC=C1C(Cl)=O DSGKWFGEUBCEIE-UHFFFAOYSA-N 0.000 claims abstract description 3
- DVIHKVWYFXLBEM-UHFFFAOYSA-N 2-hydroxybenzoyl chloride Chemical compound OC1=CC=CC=C1C(Cl)=O DVIHKVWYFXLBEM-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000010933 acylation Effects 0.000 claims abstract 2
- 238000005917 acylation reaction Methods 0.000 claims abstract 2
- -1 4-(3,4-Dibromothiophenecarbonyl)-10-(2-hydroxybenzoyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5.5.0, 03,11,05,9] dodecane Chemical compound 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- MHMCXQJITGOOCM-UHFFFAOYSA-N 1-[6,8,12-triacetyl-10-(3,4-dibromothiophene-2-carbonyl)-2,4,6,8,10,12-hexazatetracyclo[5.5.0.03,11.05,9]dodecan-2-yl]ethanone Chemical compound BrC1=C(SC=C1Br)C(=O)N1C2N(C3N(C2NC2N(C3N(C12)C(C)=O)C(C)=O)C(C)=O)C(C)=O MHMCXQJITGOOCM-UHFFFAOYSA-N 0.000 claims 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 abstract description 53
- 230000000694 effects Effects 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 230000000144 pharmacologic effect Effects 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 239000000048 adrenergic agonist Substances 0.000 description 2
- 230000001773 anti-convulsant effect Effects 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 108010004523 aspulvinone dimethylallyltransferase Proteins 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- NTZHVNFZZRZXPJ-UHFFFAOYSA-N 2,4,6,8,10,12-hexazatetracyclo[5.5.0.03,11.05,9]dodecane Chemical class N1C2NC3NC4C1NC2NC3N4 NTZHVNFZZRZXPJ-UHFFFAOYSA-N 0.000 description 1
- 108091006334 Anaphylatoxin receptors Proteins 0.000 description 1
- 108010000519 Aryl-acylamidase Proteins 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 102000000887 Transcription factor STAT Human genes 0.000 description 1
- 108050007918 Transcription factor STAT Proteins 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 239000000014 opioid analgesic Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000011197 physicochemical method Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Abstract
Description
Изобретение относится к органической и медицинской химии, а именно к способу получения 4-(3,4-дибромтиофенкарбонил)-10-(2-гидроксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекана и 4-(3,4-дибромтиофенкарбонил)-10-(2-ацетилоксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекана. The invention relates to organic and medicinal chemistry, and in particular to a method for producing 4-(3,4-dibromothiophenecarbonyl)-10-(2-hydroxybenzoyl)-2,6,8,12-tetraacetyl-2,4,6,8,10 ,12-hexaazatetracyclo[5.5.0.0 3.11.0 5.9 ] dodecane and 4-(3,4-dibromothiophenecarbonyl)-10-(2-acetyloxybenzoyl)-2,6,8,12-tetraacetyl -2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0 3.11.0 5.9 ] dodecane.
Структурное изображение 4-(3,4-дибромтиофенкарбонил)-10-(2-гидроксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекана и 4-(3,4-дибромтиофенкарбонил)-10-(2-ацетилоксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекана.Structural image of 4-(3,4-dibromothiophenecarbonyl)-10-(2-hydroxybenzoyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0, 0 3.11 .0 5.9 ] dodecane and 4-(3,4-dibromothiophenecarbonyl)-10-(2-acetyloxybenzoyl)-2,6,8,12-tetraacetyl-2,4,6,8,10, 12-hexaazatetracyclo[5.5.0.0 3.11.0 5.9 ] dodecane.
Производные 2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекана - каркасные полициклические амины уникальной структуры, что делает актуальным их исследование в различных областях органической химии. Derivatives of 2,4,6,8,10,12-hexaazatetracyclo[5,5,0,0 3,11,0 5,9 ] dodecane are framework polycyclic amines with a unique structure, which makes their study relevant in various fields of organic chemistry.
Неопиоидный анальгетик, с мультитаргетным воздействием 4-(3,4-дибромтиофенкарбонил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекан [Discovery of a Novel Non-Narcotic Analgesic Derived from the CL-20 Explosive: Synthesis, Pharmacology, and Target Identification of Thiowurtzine, a Potent Inhibitor of the Opioid Receptors and the Ion Channels / S. Aguero, S. Megy, V. Eremina et al. // ACS Omega. - 2021. - № 6. - Vol.23. - P. 15400-15411; Патент РФ № 2565766 РФ. 4-(3,4-дибромтиофенкарбонил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекан в качестве анальгетического средства и способ его получения / С.Г. Крылова, Е.Н. Амосова, Е.П. Зуева, Т.Г. Разина, и др. - № заявки 2014146024; заявлено 17.11.2014; опубликовано 20.10.2015; Патент РФ № 2684107. 4-(3,4-дибромтиофенкарбонил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекан в качестве противосудорожного средства / С.Г. Крылова, Е.Н. Амосова, Е.П. Зуева, Т.Г. Разина, Д.А. Кулагина и др. - № заявки 2018101183; заявлено 12.01.2018; опубликовано 04.04.2019], проявляет противосудорожную активность и не имеет побочных эффектов, характерных для существующих обезболивающих препаратов, включая нестероидные противовоспалительные средства. Производные 4-(3,4-дибромтиофенкарбонил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекана обладают сходной анальгетической активностью.Non - opioid analgesic, with multi-target action .0 5.9 ]dodecane [Discovery of a Novel Non-Narcotic Analgesic Derived from the CL-20 Explosive: Synthesis, Pharmacology, and Target Identification of Thiowurtzine, a Potent Inhibitor of the Opioid Receptors and the Ion Channels / S. Aguero, S. Megy, V. Eremina et al. // ACS Omega. - 2021. - No. 6. - Vol.23. - P. 15400-15411; RF patent No. 2565766 RF. 4-(3,4-dibromothiophenecarbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0 3.11.0 5.9 ] Dodecane as an analgesic agent and method for its production / S.G. Krylova, E.N. Amosova, E.P. Zueva, T.G. Razin, and others - Application No. 2014146024; declared on 11/17/2014; published on 20.10.2015; Patent of the Russian Federation No. 2684107 0 5.9 ]dodecan as an anticonvulsant / S.G. Krylova, E.N. Amosova, E.P. Zueva, T.G. Razina, D.A. Kulagina and others - Application No. 2018101183; declared on 01/12/2018; published on 04/04/2019], exhibits anticonvulsant activity and does not have side effects characteristic of existing painkillers, including non-steroidal anti-inflammatory drugs. Derivatives 4-(3,4-dibromothiophenecarbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0 3.11 .0 5.9 ]dodecane have similar analgesic activity.
Задачей заявляемого изобретения является расширение арсенала анальгетических препаратов. The objective of the claimed invention is to expand the arsenal of analgesic drugs.
Поставленная задача решается предложенным способом получения новых производных 4-(3,4-дибромтиофенкарбонил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекана с салициловыми кислотами. The problem is solved by the proposed method for obtaining new derivatives of 4-(3,4-dibromothiophenecarbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,0 3 ,11 .0 5.9 ]dodecane with salicylic acids.
Предлагаемые 4-(3,4-дибромтиофенкарбонил)-10-(2-гидроксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекан и 4-(3,4-дибромтиофенкарбонил)-10-(2-ацетилоксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекан синтезированы впервые. Структура соединений полностью подтверждена с помощью физико-химических методов анализа (ИК-спектроскопия, элементный анализ, 1H и 13C ЯМР-спектроскопия). Suggested 4-(3,4-dibromothiophenecarbonyl)-10-(2-hydroxybenzoyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0 3.11 .0 5.9 ]dodecane and 4-(3,4-dibromothiophenecarbonyl)-10-(2-acetyloxybenzoyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12 -hexaazatetracyclo[5.5.0.0 3.11.0 5.9 ] dodecane was synthesized for the first time. The structure of the compounds was fully confirmed by physicochemical methods of analysis (IR spectroscopy, elemental analysis, 1 H and 13 C NMR spectroscopy).
4-(3,4-дибромтиофенкарбонил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекан легко подвергается ацилированию. Введение дополнительной функциональной группы в 4-(3,4-дибромтиофенкарбонил)-2,8,10,12-тетраацетил-2,4,6,8,10,12-гексаазаизовюрцитан проходит при умеренных температурах. Однако, выход продуктов не превышает 65 %, что связанно с пространственными затруднениями, вызванными разветвленной структурой вводимых заместителей. 4-(3,4-dibromothiophenecarbonyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0 3.11.0 5.9 ] dodecane is easily acylated. The introduction of an additional functional group into 4-(3,4-dibromothiophenecarbonyl)-2,8,10,12-tetraacetyl-2,4,6,8,10,12-hexaazaisowurtzitane takes place at moderate temperatures. However, the product yield does not exceed 65%, which is associated with steric hindrances caused by the branched structure of the introduced substituents.
Схема получения 4-(3,4-дибромтиофенкарбонил)-10-(2-гидроксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекана и 4-(3,4-дибромтиофенкарбонил)-10-(2-ацетилоксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додеканаScheme for the preparation of 4-(3,4-dibromothiophenecarbonyl)-10-(2-hydroxybenzoyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0, 0 3.11 .0 5.9 ] dodecane and 4-(3,4-dibromothiophenecarbonyl)-10-(2-acetyloxybenzoyl)-2,6,8,12-tetraacetyl-2,4,6,8,10, 12-hexaazatetracyclo[5.5.0.0 3.11.0 5.9 ] dodecane
Возможность осуществления заявляемого изобретения подтверждается примерами конкретного выполнения способа получения заявленных соединений.The possibility of carrying out the claimed invention is confirmed by examples of specific implementation of the method for obtaining the claimed compounds.
Пример 1. Получение 4-(3,4-дибромтиофенкарбонил)-10-(2-гидроксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додеканаExample 1 Preparation of 4-(3,4-dibromothiophenecarbonyl)-10-(2-hydroxybenzoyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5.5, 0.0 3.11 .0 5.9 ]dodecane
К раствору 1,17 г (0,0075 моль) 2-гидроксибензоил хлорида в 40 мл сухого ацетонитрила добавляют 3,02 г (0,005 моль) 4-(3,4-дибромтиофенкарбонил)-2,6,8,12-тетраацетил-2,4,6,8,10,12- гексаазатетрацикло[5,5,0,03,11,05,9]додекана. Суспензию розоватого цвета кипятят с обратным холодильником в течение 18 часов. Полученный осадок отфильтровывают, промывают ацетонитрилом (3 х 10 мл) и сушат на воздухе. Выход продукта с температурой плавления 298-302°С составляет 2,32 г (64 %).To a solution of 1.17 g (0.0075 mol) of 2-hydroxybenzoyl chloride in 40 ml of dry acetonitrile was added 3.02 g (0.005 mol) 2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0 3.11.0 5.9 ] dodecane. The pinkish suspension is refluxed for 18 hours. The resulting precipitate is filtered off, washed with acetonitrile (3 x 10 ml) and air dried. The yield of the product with a melting point of 298-302°C is 2.32 g (64%).
Брутто-формула: C26H24Br2N6O7S Molecular formula: C 26 H 24 Br 2 N 6 O 7 S
Найдено (%): С 42,89; Н 3,38; N 11,57. Found (%): C 42.89; H 3.38; N 11.57.
Вычислено (%): С 43,11; Н 3,34; Br 22,06; N 11,60; О 15,46; S 4,43.Calculated (%): C 43.11; H 3.34; Br 22.06; N 11.60; About 15.46; S 4.43.
ИК-спектр (ν/см-1): 3396, 3134, 3003, 1679, 1523, 1415, 1354, 1332, 1274, 1165, 1037, 987, 879, 753, 705, 611, 569.IR spectrum (v/cm -1 ): 3396, 3134, 3003, 1679, 1523, 1415, 1354, 1332, 1274, 1165, 1037, 987, 879, 753, 705, 611, 569.
1H ЯМР (ДМСО-d6, δ, м.д): 1.93-2.01 (м,12H,CH3), 5.39 (уш.с,H,ОH), 5,96-6.21 (м,2H,CH), 6.64-7.00 (м,4H,CH), 7.39-7.56 (м,4H,ар), 8.12 (д, 1H, СН). 1 H NMR (DMSO-d6, δ, ppm): 1.93-2.01 (m, 12H, CH 3 ), 5.39 (br. s, H, OH), 5.96-6.21 (m, 2H, CH) , 6.64-7.00 (m, 4H, CH), 7.39-7.56 (m, 4H, ar), 8.12 (d, 1H, CH).
13C ЯМР (ДМСО-d6, δ, м.д): 21.17, 21.43, 22.32, 22.67, 64.59, 65.15, 66.96, 67.72, 70.02, 71.52, 112.93, 114.22, 117.88, 118.56, 119.04, 128.01, 132.91, 166.83, 167.27, 167.54, 168.01, 168,34. 13 C NMR (DMSO-d6, δ, ppm): 21.17, 21.43, 22.32, 22.67, 64.59, 65.15, 66.96, 67.72, 70.02, 71.52, 112.93, 114.22, 117.88, 118. 56, 119.04, 128.01, 132.91, 166.83 , 167.27, 167.54, 168.01, 168.34.
Пример 2. Получение 4-(3,4-дибромтиофенкарбонил)-10-(2-ацетилоксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додеканаExample 2 Preparation of 4-(3,4-dibromothiophenecarbonyl)-10-(2-acetyloxybenzoyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5.5, 0.0 3.11 .0 5.9 ]dodecane
К раствору 1,49 г (0,0075 моль) хлорангидрида 2-ацетилоксибензойной кислоты в 40 мл сухого ацетонитрила добавляют 3,02 г (0,005 моль) 4-(3,4-дибромтиофенкарбонил)-2,6,8,12-тетраацетил-2,4,6,8,10,12- гексаазатетрацикло[5,5,0,03,11,05,9]додекана. Полученную суспензию кипятят с обратным холодильником в течение 30 часов. Полученный осадок отфильтровывают, промывают ацетонитрилом (3 х 10 мл) и сушат на воздухе. Выход продукта с температурой плавления 315-319°С составляет 1,42 г (37%).To a solution of 1.49 g (0.0075 mol) of 2-acetyloxybenzoic acid chloride in 40 ml of dry acetonitrile is added 3.02 g (0.005 mol) of 4-(3,4-dibromothiophenecarbonyl)-2,6,8,12-tetraacetyl -2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0 3.11.0 5.9 ] dodecane. The resulting suspension is refluxed for 30 hours. The resulting precipitate is filtered off, washed with acetonitrile (3 x 10 ml) and air dried. The yield of the product with a melting point of 315-319°C is 1.42 g (37%).
Брутто-формула: C28H26Br2N6O8S Molecular formula: C 28 H 26 Br 2 N 6 O 8 S
Найдено (%): С 44,03; Н 3,47; N 15,17. Found (%): C 44.03; H 3.47; N 15.17.
Вычислено (%): С 43,88; Н 3,42; Br 20,85; N 10,97; О 15,46; S 4,43.Calculated (%): C 43.88; H 3.42; Br 20.85; N 10.97; About 15.46; S 4.43.
ИК-спектр (ν/см-1): 3096, 3067, 2994, 1687, 1539, 1462, 1384, 1328, 1256, 1182, 1056, 983, 870, 759, 712, 608.IR spectrum (v/cm -1 ): 3096, 3067, 2994, 1687, 1539, 1462, 1384, 1328, 1256, 1182, 1056, 983, 870, 759, 712, 608.
1H ЯМР (ДМСО-d6 , δ, м.д): 1.87-2.12 (м,15H,CH3), 5,57-5.98 (м,2H,CH), 6.21-6.83(м,4H,CH), 7.58-7.93(м,4H,ар), 8.10-8.15 (м, 1H, СН). 1 H NMR (DMSO-d6 , δ, ppm): 1.87-2.12 (m, 15H, CH 3 ), 5.57-5.98 (m, 2H, CH), 6.21-6.83 (m, 4H, CH) , 7.58-7.93(m, 4H, ar), 8.10-8.15 (m, 1H, CH).
13C ЯМР (ДМСО-d6 , δ, м.д): 21.17, 21.43, 22.32, 22.67, 25.15, 65.31, 65.95, 66.32, 66.59, 68.02, 70.99, 112.93, 114.22, 117.88, 118.56, 119.04, 128.01, 132.91, 166.83, 167.27, 167.54, 168.01, 168,34. 13C NMR (DMSO-d6 , δ, ppm): 21.17, 21.43, 22.32, 22.67, 25.15, 65.31, 65.95, 66.32, 66.59, 68.02, 70.99, 112.93, 114.22, 117. 88, 118.56, 119.04, 128.01, 132.91 , 166.83, 167.27, 167.54, 168.01, 168.34.
Возможность осуществления заявляемого изобретения в части анальгетической активности подтверждается примером конкретного выполнения теоретического исследования фармакологической активности 4-(3,4-дибромтиофенкарбонил)-10-(2-гидроксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекана и 4-(3,4-дибромтиофенкарбонил)-10-(2-ацетилоксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекана. The possibility of implementing the claimed invention in terms of analgesic activity is confirmed by an example of a specific theoretical study of the pharmacological activity of 4-(3,4-dibromothiophenecarbonyl)-10-(2-hydroxybenzoyl)-2,6,8,12-tetraacetyl-2,4,6, 8,10,12-hexaazatetracyclo[5.5.0.0 3.11.0 5.9 ] dodecane and 4-(3,4-dibromothiophenecarbonyl)-10-(2-acetyloxybenzoyl)-2.6.8, 12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0 3.11.0 5.9 ] dodecane.
Пример 3Example 3
Согласно теоретическим расчетам, полученным при использовании отечественного программного обеспечения PASS Refinder [Computer-aided prediction of biological activity spectra for organic compounds: the possibilities and limitations / Poroikov V.V. et al. // Russian Chemical Bulletin. - 2019. - Vol. 68. - № 12. - P. 2143-2154] 4-(3,4-дибромтиофенкарбонил)-10-(2-гидроксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло [5,5,0,03,11,05,9]додекан и 4-(3,4-дибромтиофенкарбонил)-10-(2-ацетилоксибензоил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло [5,5,0,03,11,05,9]додекан обладают существенной анальгетической активностью. Результаты расчета приведены в таблицах 1 и 2.According to theoretical calculations obtained using the domestic software PASS Refinder [Computer-aided prediction of biological activity spectra for organic compounds: the possibilities and limitations / Poroikov VV et al. // Russian Chemical Bulletin. - 2019. - Vol. 68. - No. 12. - P. 2143-2154] 4-(3,4-dibromothiophenecarbonyl)-10-(2-hydroxybenzoyl)-2,6,8,12-tetraacetyl-2,4,6,8,10 ,12-hexaazatetracyclo [5.5.0.0 3.11.0 5.9 ]dodecane and 4-(3,4-dibromothiophenecarbonyl)-10-(2-acetyloxybenzoyl)-2,6,8,12-tetraacetyl -2,4,6,8,10,12-hexaazatetracyclo [5,5,0,0 3,11,0 5,9 ] dodecane have significant analgesic activity. The calculation results are shown in tables 1 and 2.
Claims (2)
Publications (1)
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| RU2802003C1 true RU2802003C1 (en) | 2023-08-22 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7851464B2 (en) * | 2005-11-18 | 2010-12-14 | Merck Sharp & Dohme Corp. | Spirolactam aryl CGRP receptor antagonists |
| RU2786231C1 (en) * | 2021-09-13 | 2022-12-19 | Федеральное государственное бюджетное учреждение науки Институт проблем химико-энергетических технологий Сибирского отделения Российской академии наук (ИПХЭТ СО РАН) | 4-(3,4-dibromothiophene carbonyl)-10-(2-ethoxyacetyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11,05,9]dodecane as an analgesic agent and method for production thereof |
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7851464B2 (en) * | 2005-11-18 | 2010-12-14 | Merck Sharp & Dohme Corp. | Spirolactam aryl CGRP receptor antagonists |
| RU2786231C1 (en) * | 2021-09-13 | 2022-12-19 | Федеральное государственное бюджетное учреждение науки Институт проблем химико-энергетических технологий Сибирского отделения Российской академии наук (ИПХЭТ СО РАН) | 4-(3,4-dibromothiophene carbonyl)-10-(2-ethoxyacetyl)-2,6,8,12-tetraacetyl-2,4,6,8,10,12-hexaazatetracyclo[5,5,0,03,11,05,9]dodecane as an analgesic agent and method for production thereof |
Non-Patent Citations (1)
| Title |
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| Кулагина Д. А. и др., Синтез и анальгетическая активность 4,10-бис((±)-5-бензоил-2,3-дигидро-1H-пирроло[1,2-a]пиррол-1-карбонил)-2,6,8,12-тетраацетил-2,4,6,8,10,12-гексаазатетрацикло[5,5,0,03,11,05,9]додекана. Химико-фармацевтический журнал, 2020, т.54, No.11, с.35-39. Кулагина Д.А., Разработка методов синтеза ацильных производных гексаазаизовюрцитана: дис. канд. х. наук: 02.00.03, 2018, с.126. * |
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