SYNTHESIS AND ANALGESIC ACTIVITY OF METHYL-1-ANTIPYRYL-4-AROYL-2,3-DIOXO-2,3,5,10-TETRAHYDROBENZO[B]PYRROLO[2,3-E][1,4]DIAZEPINE-10A(1H) –CARBOXYLATES
Abstract
In order to obtain new biologically active compounds, methyl-1-antipyryl-4-aroyl-2,3-dioxo-2,3,5,10-tetrahydrobenzo[b]pyrrolo[2,3-e][1,4]diazepine was synthesized-10a(1H)-carboxylates by reacting 1-antipyryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones with o-phenylenediamine. The structures of the obtained compounds were confirmed by 1H NMR, IR spectroscopy, X-ray diffraction and elemental analysis. The presence of several electrophilic centers in the structure of antipyryl-substituted 1H-pyrrole-2,3-diones gives them a high reactivity with respect to binucleophilic reagents. Apparently, the described interaction is carried out by the initial nucleophilic attack of one aminogroup of o-phenylenediamine on the C5 carbon atom of the pyrrole-2,3-dione ring, followed by the attack of another aminogroup on the carbonyl carbon atom of the aroyl fragment, closing the diazepine ring. The described reaction is a convenient preparative method for the synthesis of previously undescribed methyl-1-antipyryl-4-aroyl-2,3-dioxo-2,3,5,10-tetrahydrobenzo[b]pyrrolo[2,3-e][1,4]diazepine-10a(1H)-carboxylates, which are of interest as pharmacological substances. The described interaction proceeds quickly and with high yields. The obtained compounds were screened for analgesic activity, as a result of which a more pronounced effect was found in some products compared to the reference drug (diclofenac sodium). A preliminary assessment of acute toxicity was carried out, according to which the derivatives of 2,3,5,10-tetrahydrobenzo[b]pyrrolo[2,3-e][1,4]diazepine proved to be safe for further studies. The survival rate of animals in all groups is 100% after 24 h and 100% after 14 days. Screening of analgesic activity was performed by the hot plate method. Registration of time was carried out from the moment of placement on a hot surface until the appearance of a behavioral response to nociceptive stimulation 60 and 120 min after the administration of substances.
For citation:
Lyadov V.A., Makrushin D.E., Denislamova E.S., Maslivets A.N., Triandafilova G.A., Solodnikov S.I. Synthesis and analgesic activity of methyl-1-antipyryl-4-aroyl-2,3-dioxo-2,3,5,10-tetrahydrobenzo[b]pyrrolo[2,3-e][1,4]diazepine-10a(1H) –carboxylates. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2024. V. 67. N 5. P. 17-23. DOI: 10.6060/ivkkt.20246705.6939.
References
Mashevskaya I.V., Makhmudov R.R., Kotegov V.P., Suchkova N.V., Prikhodko Ya.I., Maslivets A.N. Biological activity of hetareno[e]pyrrole-2,3-diones derivatives. Vestn. PGU. 2016. N 4 (24). P. 30-49 (in Russian). DOI: 10.17072/2223-1838-2016-4-30-49.
Mashevskaya I.V., Makhmudov R.R., Kuslina L.V., Mokrushin I.G., Shurov S.N., Maslivets A.N. Synthesis and analgesic activity of the reaction products of 3-aroylpyrrolo[1,2-a]-quinoxaline-1,2,4(5H)-triones with benzoic acid hydrazides. Khim.-Farm. Zhurn. 2011. V. 45. N 11. P. 12-15 (in Russian). DOI: 10.1007/s11094-012-0697-0.
Suchkova N.V., Mashevskaya I.V., Makhmudov R.R., Balandina S.Yu., Maslivets A.N. Synthesis and biological activity of the reaction products of hetareno[e]pyrroldiones with N-aminoacetophenone. The latest concepts of fundamental and applied scientific research: experience, traditions, innovations, effective development strategy. 2015. P. 106-109 (in Russian).
Khalturina V.V., Shklyaev Y.V., Makhmudov R.R., Maslivets A.N. Synthesis, Analgesic and Anti-inflammatory Activity of (1Z,3Z)-4-Aryl-4-hydroxy-1-(3,3-dialkyl-3,4-dihydroisoquinoline-1(2H)-ylidene)-but-3-en-4-ones. Pharm. Chem. J. 2010. V. 44. N 9. P. 480-482. DOI: 10.1007/ s11094-010-0496-4.
Denislamova E.S., Makhmudov R.R., Maslivets A.N., Shklyaev Y.V. Synthesis and Analgesic Activity of 1-Aryl-3-aroyl-4-hydroxy-5’,5’-dimythyl-8’,9’-diethoxy-5’,6’-dihydro-3’H-spiro{pyrrole-2,2’-pyrrole[2,1-a]isoquinoline}-3’,5(1H)-diones. Pharm. Chem. J. 2012. V. 46. N 9. P. 551-552. DOI: 10.1007/s11094-012-0845-6.
Gein V.L., Bobyleva A.A., Levandovskaya E.B., Ode-gova T.F., Vakhrin M.I. Synthesis and Antimicrobial Activity of 5-Aryl-4-acyl(heteroyl)-3-hydroxy-1-(3-ethoxypropyl)-3-pyrrolin-2-ones. Pharm. Chem. J. 2012. V. 46. N 1. P. 23-25. DOI: 10.1007/s11094-012-0728-x.
Gein V.L., Chirkova M.V., Mikhalev V.A., Voronina E.V., Gein L.F. Synthesis, Properties and Antimircobial Activity of 3-Hydrazones of 1-Aryl-5-methyl-5-ethoxycarbonylpyrrolidine-2,3-diones. Pharm. Chem. J. 2005. V. 39. N 8. P. 413-417. DOI: 10.1007/s11094-005-0170-4.
Mashkovsky M.D. Medicines. M.: Novaya Volna. 2019. P. 165-166 (in Russian).
Krutikov V.I., Erkin A.V., Krutikova V.V., Zakharova E.S. Synthesis of antifungal and antiviral compounds in a series of antipyrine derivatives. Izv. SPbGTI(TU). 2014. N 26 (52). P. 53-57 (in Russian). DOI: 10.15217/issn1998984-9.2014. 26.53.
Papezhuk M.V., Volynkin V.A., Stroganova T.A., Krapivin G.D., Usacheva T.R., Pham T.L. Theoretical and Experimental Study of Inclusion Complex Formation of β-Cyclodextrin with some 1,4-Diazepine Derivatives. Macroheterocyles. 2020. V. 13. N 1. P. 64-73. DOI: 10.6060/ mhc191281v.
Ivanova R.Yu., Kalayanova G.D., Ivanov E.I. Synthesis and properties of some xanthine derivatives. Nauchnyi Vzglyad Budushee. 2020. V. 1. N 16. P. 53-59 (in Russian). DOI: 10.30888/2415-7538.2020-16-01-036.
Litvin A.A., Kolyvanov G.B., Zhedrev V.P., Arzamaststev A.P. Relationship between Physicochemical Characteristics and Pharmacokinetic Parameters of 1,4-Benzodiazepine Derivatives. Pharm. Chem. J. 2004. V. 38. N 11. P. 583-586. DOI: 10.1007/s11094-005-0034-y.
Shilov I.B., Shirokova E.S., Voronchikhin V.D. Preparation and investigation of the product of interaction of o-phenylenediamine with epichlorohydrin as an antioxidant of rubber. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2024. V. 67. N 1. P. 97-103 (in Russian). DOI: 10.6060/ivkkt.20246701.6872.
Smiley R.A. Phenylene- and Toluenediamines. Ullmann's Encyclopedia of Industrial Chemistry. 2000. V. 26. P. 617-622. DOI: 10.1002/14356007.a19_405.
Bozdyreva K.S., Alievb Z.G., Maslivetsa A.N. Recyclization of 3-Pivaloylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones by the Action of o-Phenylenediamine. Crystalline and Molecular Structure of 3-[3,3-Dimethyl-2-oxo-1-(3-oxo3,4-dihydroquinoxalin-2-yl)butyl]-1-phenylquinoxalin-2(1H)-one. Zhurn. Org. Khim. 2008. V. 44. N 4. P. 612–616. DOI: 10.1134/S1070428008040234.
Gein V.L., Kataeva A.V., Gein L.F. Reaction of 1,5-diaryl-3-hydroxy-4-methylsulfonyl-3-pyrrolin-2-ones with urea, hydrazine, ethylenediamine, and o-phenylenediamine. Chem. Heterocyc. Comp. 2007. V. 43. N 11. P. 1385-1389. DOI: 10.1007/s10593-007-0214-7.
Mashevskaya I.V., Duvalov A.V., Kol'tsova S.V., Maslivets A.N. Unusual reaction of condensed 2,3-dihydro-2,3-pyrrolediones with o-phenylenediamin. Chem. Heterocycl. Comp. 2000. V. 36. N 5. P. 617-618. DOI: 10.1007/ BF02290859.
Denislamova E.S., Lyadov V.A., Makrushin D.E., Ryabov V.G., Dmitriev M.V., Maslivets A.N. Synthesis of 1-antipyryl-1H-pyrrol-2-ones by reaction of N-antipyryl-substituted enamines with oxalyl chloride. Zhurn. Org. Khim. 2023. V. 59. N 4. P. 535-540 (in Rus-sian). DOI: 10.11 34/S1070428023040127.
Sheldrick G.M. A short history of SHELX. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008. V. 64. P. 112–122. DOI: 10.1107/S0108767307043930.
Sheldrick G.M. Crystal structure refinement with SHELXL. Acta Crystallogr., Sect. C: Struct. Chem. 2015. V. 71. P. 3–8. DOI: 10.1107/S2053229614024218.
Dolomanov O.V., Bourhis L.J., Gildea R.J, Howard J.A.K., Puschmann H.J. Appl. Cryst. 2009. V. 42. P. 339–341. DOI: 10.1107/S0021889808042726.
